the role of molecular mobility and hydrogen bonding

The Role of Molecular Mobility and Hydrogen Bonding Interactions on

the Physical Stability of Amorphous Pharmaceuticals

A DISSERTATION

SUBMITTED TO THE FACULTY OF

UNIVERSITY OF MINNESOTA

BY

Khushboo Kothari

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS

FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

Dr. Raj Suryanarayanan, Adviser

September 2014

i

Acknowledgements

I would like to take this opportunity to extend my deepest appreciation to my adviser, Dr.

Raj Suryanarayanan, for his immense contributions to both my professional and personal

growth. His guidance, support and encouragement have made the completion of this

thesis possible. His passion for science, dedication and sincerity have set an example, I

someday hope to match.

I am very grateful to my committee members, Dr. Ronald Siegel, Dr. Timothy Wiedman

and Dr. Alon McCormick for serving on my committee and critically reviewing my

thesis. I want to thank Dr. Calvin Sun for serving on my oral examination committee

and for his valuable feedback and suggestions throughout my graduate studies.

I am very thankful to Dr. Vishard Ragoonanan for all the helpful suggestions, discussions

and valuable inputs into my thesis. He has been a wonderful friend and a great

collaborator. I am very grateful to Dr. Bakul Bhatnagar for mentoring me during the

initial years of my graduate studies. His splendid work ethics and sincerity have been a

constant source of inspiration. I also want to take this opportunity to show my gratitude to

my industrial mentors, Dr. Evgenyi Shalaev, Dr. Ravi Shanker, Dr. Chandan Bhugra and

Dr. Adnan Salameh for valuable inputs and suggestions.

I also want to thank all members of Dr. Sury’s research group, Dr. Kapil Arora, Dr. Nitin

Tayade, Dr. Aditya Kaushal, Dr. Sarat Mohapatra, Dr. Naveen Thakral, Dr. Seema

Thakral, Dr. Paroma Chakravarty, Dr. Prakash Sundaramurthi, Dr. Sunny Bhardwaj,

Michael Burcusa, Mehak Mehta, Pinal Mistry, Michelle Fung and Sampada Koranne for

their scientific suggestions, help with my experiments and especially maintaining a

friendly environment in the lab. My gratitude also extends to all the faculty, staff and

fellow graduate students in the Department of Pharmaceutics for their friendship and

camaraderie. I sincerely thank Ms. Linda Sauer and Dr. Michael Manno for their help,

ii

instrument training and assistance with my X-ray experiments at the Characterization

Facility. I also want to thank Dr. Gregory Halder at the Argonne National Labs in IL for

help with my synchrotron XRD experiments.

Last but not the least I want to express my heartfelt gratitude towards my family and

friends for their unconditional love and support. This accomplishment would not have

been possible without the innumerous sacrifices and unconditional love of my parents. I

want to thank my sister, Neha, for being a constant source of support. And, finally I want

to thank my husband, Amit for his love and unwavering support.

iii

To Mummy and Pappa

iv

Abstract

The physical instability of amorphous pharmaceuticals and our inability to reliably

predict their crystallization propensity is a major impediment to their use in solid oral

dosage forms. The central goal of this thesis work is to gain a fundamental insight into

the roles of (i) specific molecular mobility (global or local) on the observed physical

instability (crystallization) in the supercooled as well as glassy states of amorphous

pharmaceuticals and (ii) the influence of hydrogen bonding on molecular mobility and

thereby the physical stability. Our ultimate objective is to be able to use molecular

mobility as a predictor of drug crystallization from complex multi-component solid

dispersions. The different modes of molecular motions were comprehensively

characterized using broadband dielectric spectroscopy (BDS). Since, BDS is traditionally

conducted with film samples, we first validated the use of powder samples for measuring

molecular mobility. Crystallization kinetics was monitored by powder X-ray

diffractometry using either a laboratory or a synchrotron X-ray source. Physical

instability, both above and below Tg in our model systems (griseofulvin, nifedipine and

nifedipine-PVP dispersion), increased with a decrease in structural relaxation time. Next,

a causal relationship between hydrogen bonding interactions and molecular mobility was

established. The higher physical stability in felodipine as compared to nifedipine was

attributed to the reduced molecular mobility brought about by the stronger and more

extensive hydrogen bonding interactions in the former. In solid dispersions of nifedipine

with each PVP, HPMCAS and PAA, the drug-polymer interactions, by modulating

molecular mobility, influenced the drug crystallization kinetics. The strength of drug-

polymer hydrogen bonding, the structural relaxation time and the crystallization kinetics

were rank ordered as: PVP > HPMCAS > PAA. Finally a model derived from the

relationship between diffusion and relaxation time was used to predict drug

crystallization from solid dispersions. Molecular mobility proved to be an effective

predictor of drug crystallization in nifedipine solid dispersions.

v

Table of Contents

List of Tables .....................................................................................................................xi

List of Figures ...................................................................................................................xii

Chapter 1: Introduction …...............................................................................................1

1.1 Introduction ……………………………………………………………………….2

1.2 Literature Review ………………………………………………………...……….4

1.2.1 Amorphous State ……………………………………………………...…….4

1.2.2 Solid Dispersions ………………………………...…………………………7

1.2.3 Molecular Mobility ………………………………...……………………….9

1.2.4 Hydrogen Bonding Interactions ………………………………..………….15

1.3 Motivation and Thesis Overview………………………………………………...…..16

1.3.1 Chapter 2……………………..…………………………………………….16

1.3.2 Chapter 3…………………………………………………………….……..17

1.3.3 Chapter 4…………………………………………………………………...18

1.3.4 Chapter 5……………………………………………….…………………..19

1.3.5 Chapter 6…………………………………………….……………………..20

1.4 References ……………………………………………………………………….28

vi

Chapter 2: Dielectric spectroscopy of small molecule pharmaceuticals - Effect of

sample configuration……………………………………….…………………….…….43

2.1 Synopsis..…………………………………………………………………..……44

2.2 Introduction…………………………………………….………………….……..44

2.3 Experimental Section…………………………………...………………………..46

2.3.1 Preparation of Amorphous Phases…………………….…………………46

2.3.2 Baseline Characterization……………..…………………………………46

2.3.3 Powder X-ray Diffractometry (XRD) ……………………..…………….47

4.3.4 Broadband Dielectric Spectrometry (BDS)……………………..……….47

2.4 Results……………………………………………………………………………48

2.4.1 Dielectric Constant and Dielectric Loss………………………...……….48

2.4.2 α - Relaxation time and shape parameters………………………….…....51

2.4.3 β - Relaxation………………………………………………….…………53

2.5 Conclusion……………………………………..………………………….……54

2.6 References …………………………………………………………………...…65

Chapter 3: Influence of Hydrogen Bonding Interactions on Molecular Mobility and

Physical Stability in Felodipine and Nifedipine……………………...……………….69

3.1 Synopsis..…………………………………………………………………..……70

vii

3.2 Introduction……………………………………………………….……….……..70

3.3 Experimental Section…………………………………………...………….…….72

3.3.1 Materials and Methods…………………………....……………….……..72

3.3.2 Thermal Analysis …………………………………………………..……72

3.3.3 Dielectric Spectroscopy (BDS)…………………………………….…….72

3.3.4 FTIR Spectroscopy…………………………………………...………….73

3.4 Results and Discussion…………………………………..………………………74

3.4.1 Influence of Structure on α-relaxation Time……………………….…….74

3.4.2 Influence of Structure Hydrogen Bonding Interactions………………….75

3.4.3 Role of Hydrogen Bonding Interactions on Molecular Mobility………...76

3.5 Conclusion…………….…………….………………………….….…………….79

3.6 References ……………………………………………………………………….86

Chapter 4: Influence of Molecular Mobility on the Physical Stability of Amorphous

Pharmaceuticals in the Supercooled and Glassy States……………..……………….89

4.1 Synopsis..…………………………………………………………..……………90

4.2 Introduction……………………………………………………..………………..91

4.3 Experimental Section……………………………...……………………………..94

4.3.1 Materials and Methods…………………………………..………………94

viii

4.3.2 Preparation of amorphous materials……………………………..………94

4.3.3 Karl Fischer Titrimetry……………………………….………………….95

4.3.4 Thermal analysis………………………………………...……………….95

4.3.5 Powder X-ray diffractometry (XRD) …………………………...……….95

4.3.6 Synchrotron XRD (SXRD)……………………………………...……….96

4.3.7 Quantification of XRD data…………………………….……….……….96

4.3.8 Dielectric Spectroscopy (BDS)………………………..…………………97

4.4 Results……………………………………………………...…………………….98

4.4.1 Characterization………………..………………………………..……….98

4.4.2 Analysis of Dielectric Spectra…………………………………..……….98

4.4.3 Relaxation behavior in the supercooled state…………………………….98

4.4.4 Relaxation behavior in the glassy state………………………….……….99

4.4.5 Crystallization – above and below Tg………..…………………...…….100

4.4.6 Correlation of crystallization with molecular mobility………...……….101

4.5 Conclusion…………….…………….…………….………………...………….104

4.6 References ……………………………………………………………………...120

Chapter 5: The Role of Drug-Polymer Hydrogen Bonding Interactions on the

Molecular Mobility and Physical Stability of Nifedipine Solid Dispersions

………….……………………………………………………………...………….…….126

ix

5.1 Synopsis..………………………………………………………………………127

5.2 Introduction……………………………………………………………………..127

5.3 Experimental Section…………………………………………….……………..130

5.3.1 Materials and Methods………………………...………………..………130

5.3.2 Preparation of amorphous materials……………………………………130

5.3.3 Karl Fischer Titrimetry…………………………………...…………….131

5.3.4 Thermal analysis……………………………………………….……….131

5.3.5 Dielectric Spectroscopy (BDS) ………………………….……………..131

5.3.6 FT-IR Spectroscopy……………………………………………..……...132

5.3.7 Powder X-ray diffractometry (XRD) …………………………………..133

5.4 Results…………………………………………………………………………..133

5.4.1 Baseline Characterization………………………………………………133

5.4.2 Influence of Polymer Type on Molecular Mobility…………………….134

5.4.3 Influence of Polymer Type on Drug-Polymer Interactions…………….136

5.4.4 Influence of Polymer Type on Physical Stability………………………137

5.5 Discussion………………………………………………………………………138

5.6 Conclusion……………………………………………………………………...139

5.7 References ……………………………………………………………………...153

x

Chapter 6: Molecular Mobility as an Effective Predictor of Physical Stability in

Nifedipine Solid Dispersions…………………………..………………..…………….160

6.1 Synopsis..………………………………………………………………………161

6.2 Introduction……………………………………………….…………….………161

6.3 Material and Methods…………………………..………………………………163

6.3.1 General Methods………………………………..………………………163

6.3.2 Preparation of amorphous systems………………………….……….…163

6.3.3 Karl Fischer Titrimetry…………………………………...…………….164

4.3.4 Thermal analysis………………………………….…………………….164

6.3.5 Powder X-ray diffractometry (XRD) …………………….…………….164

6.3.6 Synchrotron XRD (SXRD)…………………………………….……….165

6.3.7 Quantification of XRD data……………………………....…………….165

6.3.8 Dielectric Spectroscopy (BDS)…………………………………………165

6.4 Results…………………………………………………………….…………….166

6.4.1 Baseline Characterization………………………………………...…….166

6.4.2 Influence of Polymer Concentration on Molecular Mobility…………..167

6.4.3 Influence of Polymer Concentration on Physical Stability……………..169

6.4.4 Molecular Mobility as a Predictor of Physical Stability ……………………….169

6.5 Conclusion…………….…………….……………………….….……………...173

xi

6.6 Significance……………………………………………………………………..173

6.7 References…………………………..…………………………………………..187

Chapter 7: Summary ………………………..…………………………………………193

Chapter 8: Future Work ……………………….………………………………………197

Bibiliography ………………………………………………………………………….201

xii

List of Tables

1.1 Biopharmaceutics Classification System of drugs in the market and in the pipeline

……………………………………………………………………………......…..21

1.2 Current drug products marketed as solid dispersions…………………...……….22

2.1 Relaxation times and the SD (standard deviation) from the HN fit for nifedipine

and indomethacin film and powder samples at 60 °C………………...…………55

4.1 VTFH parameter values obtained from model fitting of the relaxation time

data…………………………………………………....………………….……..105

5.1 Summary of the DSC results of the model systems…………………………….140

6.1 Comparison of the values of M and A in Equation 8 obtained using our

experimental data (“experimental”) and the “assumed” values………….……..175

xiii

List of Figures

Chapter 2

2.1 Dielectric constant of nifedipine, indomethacin, itraconazole, and griseofulvin as

a function of frequency…………………………..………………………………56

2.2 Dielectric constant of nifedipine, indomethacin and itraconazole film and powder

samples………………………………………………………………………..….57

2.3 Dielectric loss of nifedipine, indomethacin and itraconazole film and powder

samples……………………………………………………………………..…….58

2.4 The temperature dependence of α-relaxation time in nifedipine, indomethacin,

itraconazole and griseofulvin film and powder samples…………………………59

2.5 Plot of α-relaxation shape parameters as a function of temperature in nifedipine

films and powders………………………………………………………………..60

2.6 Cole-Cole plots obtained from dielectric data using nifedipine indomethacin

griseofulvin and itraconazole films and powders………………………..………61

2.7 The temperature dependence of β-relaxation time in itraconazole film and powder

samples………………………………………………………………..………….62

2.8 Dielectric loss of griseofulvin film and powder at 95 °C………………..………63

2.9 Griseofulvin powder at 95 °C fitted simultaneously to two HN functions,

revealing two relaxations………………………………………….……………..64

Chapter 3

3.1 Structures of FEL and NIF……………………………………….………………80

xiv

3.2 Dielectric permittivity and dielectric loss at 60 °C for melt quenched samples of

FEL and NIF………………………………………………….………………….81

3.3 α-relaxation time in NIF and FEL from 50 – 75 °C……………………………..82

3.4 Deconvolution of the IR spectrum of NIF and FEL in the NH stretching region.83

3.5 A plot of the temperature dependence of the hydrogen bonded and free NH

populations in felodipine……………………………………………………..…..84

3.6 Plot of logarithm of relaxation time of FEL and NIF as a function of inverse

temperature............................................................................................................85

Chapter 4

4.1 A representative plot of the total integrated intensity (crystalline + amorphous)

during the isothermal crystallization studies of amorphous nifedipine at

60°C…………………………………………………………………………….106

4.2 DSC heating curves (10 °C/min) of nifedipine-PVP, nifedipine and

griseofulvin……………………………………………………………………..107

4.3 Dielectric loss behavior of griseofulvin in the temperature range of 97 to 115°C

and nifedipine (50 to 70°C)……………………………………………...……..108

4.4 Dielectric loss behavior of nifedipine-PVP dispersion in the temperature range of

50°C to 70°C……………………………………………………………………109

4.5 Temperature dependence of α- and β-relaxation times in griseofulvin and

nifedipine………………………………………………………….……………110

4.6 Representative plot from fitting the VTF model to the relaxation time………..111

4.7 Dielectric loss behavior of β-relaxation in griseofulvin……………………..…112

xv

4.8 XRD patterns revealing progressive drug crystallization from nifedipine solid

dispersion at 60°C from 0 min to 10 mins and % crystallinity in nifedipine as a

function of time……………………………………………………….…..…….113

4.9 Plot of α (fraction crystallized) versus time following storage of amorphous

griseofulvin at several temperatures above Tg, and the resultant Johnson-Mehl-

Avrami (JMA) plots for griseofulvin crystallization………………………..….114

4.10 SXRD patterns of amorphous griseofulvin (25°C) as a function of time revealing

very early crystallization and the corresponding one dimensional XRD patterns

revealing characteristic diffraction peaks……………………………………....115

4.11 SXRD patterns in amorphous nifedipine at 40°C as a function of time revealing

progressive crystallization from the sample and % crystallinity in nifedipine as a

function of time……………………………………………………...………….116

4.12 Plot of diffusion coefficient versus α-relaxation time in nifedipine and plot of

crystallization time versus the translational diffusion coefficient……….....…..117

4.13 Correlation between molecular mobility and physical stability in (a) griseofulvin,

(b) nifedipine and (c) nifedipine –PVP dispersions in the supercooled state…..118

4.14 Correlation between molecular mobility and physical stability in (a) griseofulvin,

(b) nifedipine and (c) nifedipine –PVP dispersions in the glassy state………....119

Chapter 5

5.1 A representative plot of the total integrated intensity (crystalline + amorphous)

during the isothermal crystallization studies of amorphous NIF-PVP……...….141

5.2 Representative DSC heating curves of NIF and NIF solid dispersions with each

PVP, HPMCAS and PAA………………………………………………………142

xvi

5.3 Dielectric loss behavior of solid dispersions (10% w/w polymer) as a function of

temperature……………………………………………………………………..143

5.4 Dielectric loss behavior of NIF and NIF solid dispersions with PVP, HPMCAS

and PAA at 60 °C with (a) 10% and (b) 20% w/w polymer concentration…….144

5.5 Relaxation time of NIF solid dispersions (10% w/w polymer concentration) as a

function of temperature…………………………………………………………145

5.6 Structures of nifedipine, PVP, PAA and HPMCAS……………………………146

5.7 FTIR spectra of NIF as a function of temperature and the wavenumber of the NH

peak as a function of temperature……………………………………………....147

5.8 A plot of wavenumber (NH peak of NIF; FTIR spectra) as a function of

temperature for the three solid dispersions…………………………………..…148

5.9 Overlaid FTIR spectra of NIF and NIF-PVP dispersion and use of a pattern

subtraction technique to identify the drug-polymer hydrogen bonding interactions

in solid dispersions…………………………………………………………...…149

5.10 A plot of absorption coefficient versus frequency of NH stretching

vibration………………………………………………………………………...150

5.11 X-ray powder diffraction patterns of the SDs held at 70 °C for 400 minutes and

crystallization kinetics of the solid dispersions (70 °C)………………………..151

5.12 Effect of polymer concentration on the hydrogen bonding behavior and molecular

mobility……………………………………………………………...………….152

Chapter 6

6.1 Representative DSC heating curves of NIF and NIF solid dispersions with each 5

and 10 % w/w PVP…………………………………………………………..…176

xvii

6.2 Dielectric loss behavior of NIF solid dispersions with 2.5, 5 and 10 % w/w PVP

as a function of temperature…………………………………………………….177

6.3 Dielectric loss behavior of NIF and NIF solid dispersions with 10 and 20% w/w

PVP at 70°C…………………………………………………………………….178

6.4 Relaxation time of NIF and NIF solid dispersions with 10 and 20 % w/w PVP as a

function of temperature…………………………………………………………179

6.5 Cole-Cole plots obtained from dielectric data of NIF and NIF solid dispersions

with 10 and 20% w/w PVP at 70 °C……………………………………………180

6.6 X-ray powder diffraction patterns of NIF and NIF solid dispersions with 2.5, 10

and 20% w/w PVP at 70 °C…………………………………………………….181

6.7 Effect of polymer concentration on time taken for 10% of the incorporated NIF to

crystallize from the solid dispersions at 70 °C…………………………………182

6.8 Synchrotron XRD patterns of NIF and NIF solid dispersions with 2.5, 5 and 10 %

w/w PVP at 25 °C………………………………………………………………183

6.9 Plot of diffusion coefficient versus α-relaxation time in nifedipine……………184

6.10 A plot of relaxation time as a function of polymer concentration at a series of

temperatures between 55 and 75 °C……………………………………………185

6.11 A plot of crystallization time versus relaxation time for NIF solid

dispersions……………………………………………........................................186

1

Chapter 1

Introduction

2

1.1.Introduction

New drug discovery methods such as high-throughput screening and combinatorial

chemistry have led to the identification of a large number of highly target-selective and

potent new drug candidates.1-2

Although, these techniques enable rapid identification of

new lead molecules, a majority of these compounds (80-90%) are practically insoluble in

water.3 According to the USP, a compound is considered insoluble if 1 part of solute

dissolves in 10,000 or more parts of solvent.4 This poses a major challenge in the

effective oral delivery of these compounds. For a drug to be systemically effective

following oral administration, drug absorption into the systemic circulation is a

prerequisite.5-6

There are two main barriers to oral drug absorption - dissolution in the

gastrointestinal (GI) fluid followed by permeation across the GI membrane.7-9

These two

barriers, solubility and permeability, form the basis of the Biopharmaceutical

Classification System (BCS).7 Table 1 summarizes the distribution, of both the drugs in

the market and the new chemical entities in the pipeline, based on the BCS.3

Drugs belonging to BCS class II are characterized by poor aqueous solubility – believed

to be the major oral absorption barrier. Recently, according to the developability

classification system (DCS), the BCS class II drugs were further subdivided into IIa and

IIb based on whether the drugs show dissolution rate limited or solubility limited

absorption respectively.10

Drugs are classified under IIa, if the dissolution rate is slower

than the transit time of the drug through the absorption site. In class IIb drugs, there is

insufficient GI fluid to dissolve the administered dose.

Current efforts to enhance the drug dissolution rate focus on approaches to increase both

the surface area and the solubility.11-13

Particle size reduction, leading to an increase in

the surface area, is potentially a simple approach. Various size reduction techniques,

including milling, have resulted in enhancement in the in vitro dissolution rate and

consequently the oral bioavailability. 14-16

While there are several examples of

enhancement in oral bioavailability brought about by particle size reduction, the effect

can be modest to pronounced (typically 2-20 fold).17-23

While particles size reduction

3

techniques may work well for dissolution rate limited drugs belonging to class IIa of the

DCS, for practically insoluble drugs belonging to class IIb, this approach may not

provide the required bioavailability enhancement. For these compounds, effective oral

delivery may necessitate increased aqueous solubility.10

In addition, there are numerous

practical problems with milled particles. Alteration in particle size and surface

characteristics brought about by milling can adversely affect both the blending and flow

properties.24

These issues warrant particular consideration in large scale manufacturing.

Milling can also lead to disorder of the crystal lattice, and in extreme cases, cause

amorphization.25-27

While this can enhance the dissolution rate, accidental and

uncontrolled lattice disruption can potentially lead to erratic dissolution behavior.

Several other approaches such as the use of metastable polymorphs, salts and co-crystals

have also been utilized to improve the solubility and consequently the dissolution rate of

poorly soluble drugs.3, 28-30

The use of a metastable polymorph, much like particle size

reduction, usually provides a limited enhancement in dissolution rate and

bioavailability.31-32

Pudipeddi and Serajuddin compiled the solubility ratios of 65

pharmaceutical polymorphs.33

They reported a typical solubility enhancement of only ~

four-fold which is unlikely to translate to significant increase in bioavailability. Weak

acids and bases can be converted to the corresponding salts resulting in enhanced

solubility and bioavailability.29, 34

However, this approach has several limitations. Neutral

molecules without ionizable functional groups are not amenable to salt formation.

Secondly, compounds with very poor intrinsic solubility may not be able to provide the

required dissolution advantage. There is also the potential for the salt to convert back to

the free acid (or base), thereby negating the solubility advantage – a problem encountered

with salts of weak acids in the acidic stomach pH.35

Finally, the mechanical properties

and the hygroscopic nature of some salts may pose processing problems.36-38

Cocrystal

formation of the API with a second pharmaceutically acceptable component is another

potential avenue to overcome the problem of poor aqueous solubility.30, 39

This approach

has resulted in bioavailability enhancement, sometimes substantial, for several drugs.40-45

However, it is usually limited to APIs which can hydrogen bond with the coformer, the

most common interaction for cocrystal formation.

4

Amorphization is increasingly emerging as an effective approach to increase the

solubility of drugs. The higher free energy associated with the amorphous form lends it a

higher apparent solubility than its crystalline counterpart.46-49

Gupta et al documented the

solubility difference between amorphous (estimated as peak solubility) and crystalline

celecoxib at several temperatures (Figure 1.1). The authors determined that the favorable

entropy and free energy of solution was responsible for the enhanced solubility of the

amorphous form.50

The enhancement in apparent solubility has been noted for many drug

compounds and in several cases has resulted in an enhanced dissolution rate.3, 51

For

example, Six et al showed about an order of magnitude increase in the dissolution rate of

amorphous itraconazole as compared to its crystalline form.52

While it is well known that amorphization can be utilized as a strategy to improve the

solubility and consequently the dissolution rate of poorly soluble drug candidates, the

physical instability associated with the amorphous form is a major challenge. For

example, drug crystallization from a solid dispersion has resulted in the recall of a drug

product (Norvir®) used in the treatment of AIDS.

53 The central goal of my thesis work is

to gain a fundamental insight into the possible mechanisms governing physical instability

of drugs in dispersions, thus providing a scientific basis for the formulation of stable solid

dispersions.

1.2. Literature Review

1.2.1. Amorphous State

An amorphous compound, unlike its crystalline counterpart, lacks a three dimensional

long range lattice periodicity. Figure 1.2 is a plot of enthalpy/entropy for a crystalline and

amorphous material as a function of temperature.47, 54-56

A crystalline material on heating

past its melting point will turn into a liquid. Upon cooling the liquid, if crystallization is

avoided the material will enter the supercooled liquid regime. On further cooling, the

supercooled liquid is unable to keep up with the change in the temperature and will fall

out of “equilibrium”. This temperature is known as the glass transition temperature (Tg),

and is characteristic of amorphous materials. Below Tg, the material enters into a “glassy”

5

state and is characterized by a lower free volume, enthalpy and entropy than the

supercooled liquid.

Amorphous materials are characterized by rotational and translational motions which

impart a higher heat capacity (Cp) compared to their crystalline counterparts. The excess

Cp also known as the configurational heat capacity, , is given by Equation 1.

57

=

( ) - ( ) … Equation 1

where, ( ) and

( ) are the heat capacity of the amorphous and the crystalline forms

respectively at temperature T. Similarly, the configurational entropy (Sc), enthalpy (Hc)

and free energy (Gc) can be calculated equations (2) to (4).

= ( ) - ( ) = ΔSm + ∫

… Equation 2

= ( ) - ( ) = ΔHm + ∫

… Equation 3

( ) = ( ) ( ) … Equation 4

The higher free energy associated with the amorphous form makes it thermodynamically

unstable leading to a tendency to crystallize into the stable form. The first step of the

crystallization process is aggregation of a critical number of molecules to form stable

nuclei. The rate of homogenous nucleation, I, is given by the classical nucleation theory

58-59

I =

… Equation 5

where, ΔG*, the thermodynamic component of nucleation is the Gibbs free energy change

associated with the formation of nuclei of critical size, K, a pre-exponential factor is the

6

kinetic component and is proportional to the rate of transport of molecules from the

amorphous phase to the nuclei, kB is the Boltzman constant and T is the temperature. The

critical Gibbs free energy, ΔG* is given by,

ΔG* =

π r

3 ΔGv + ΔGcr … Equation 6

where, ΔGv is the thermodynamic driving force for crystallization given by the degree of

undercooling and ΔGcr is the free energy change necessary to form a stable nucleus of

radius r. As the degree of undercooling increases, the driving force for crystallization

increases. However as the temperature of the system is lowered, the viscosity of the

system increases thereby reducing the molecular mobility and increasing the kinetic

barrier for crystallization. Molecular mobility in amorphous systems is discussed in detail

in section 1.2.3. Due to the different temperature dependencies of the thermodynamic

and kinetic driving forces for crystallization, the actual rate of nucleation and or

crystallization is a balance between the two factors. Nucleation of the system is followed

by crystal growth. Growth of the crystals is usually described by the continuous growth

model. The growth rate of crystals (U) is described as follows,60-61

U =

[1 – exp (-

)] … Equation 7

In the above equation, η is the viscosity and the other parameters have been discussed

above. Nucleation and crystal growth have different temperature dependencies. The most

widely used model for studying crystallization kinetics is the Kolmogorov – Johnson –

Mehl – Avrami (KJMA) theory,62-63

α(t) = 1 – exp [-k(t – t0)n] … Equation 8

where, α is the fraction crystallized, k is the crystallization rate constant, t0 is the

induction time and n describes the morphology of crystal growth.

7

1.2.2. Solid Dispersions

Solid dispersions are a promising strategy to overcome the physical instability associated

with amorphous compounds. They were first defined by Chiou and Riegelman as the “…

dispersion of one or more active ingredients in an inert carrier…” 64-68

Polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) and polyethylene

glycol (PEG), are some of the commonly used polymeric carriers.69

Using this approach,

dissolution enhancement and a consequent improvement in bioavailability has been

realized in numerous compounds.66-73

For example, when crystalline vemurafenib was

formulated as a solid dispersion, a thirty-fold increase in apparent solubility was

observed. This translated into a ~ five-fold enhancement in human bioavailability.72

Several marketed drugs, encompassing numerous therapeutic classes (antifungals,

antivirals, anti-inflammatory etc.) are currently formulated as solid dispersions (Table

2).67, 69

If a drug in a solid dispersion is present at a concentration below its “solubility” limit in

the polymer, the system will be thermodynamically stable without any risk of

crystallization.74-75

Here we are referring to the solubility of the most stable crystalline

form of a drug in a polymer. However, in many systems of practical interest, the drug

concentration in the dispersion will be much higher than its solubility. Since the drug is

supersaturated in the polymeric matrix, there will always be a thermodynamic driving

force for the drug to crystallize out of the dispersion. However, if the drug is in the

amorphous state, the concept of drug – polymer miscibility becomes relevant.74

The drug

and the polymer are considered miscible if the change in the free energy of mixing

(ΔGmix) is negative.

ΔGmix = ΔHmix - TΔSmix ... Equation 9

In Equation 9, ΔHmix is the enthalpy of mixing and ΔSmix is the entropy of mixing. The

Flory Huggins lattice theory, which is an extension of the regular solution theory, is used

to estimate the enthalpic as well as entropic contributions to the ΔGmix.76

The entropy

8

term contribution towards the ΔGmix is always favorable to mixing and is calculated using

Equation 10.

ΔSmix = - kB (n1lnϕ1 + n2lnϕ2) … Equation 10

In the above equation, kB is the Boltzmann constant, n1 and n2 are the number of moles

and ϕ1 and ϕ2 are the volume fractions of the drug and the polymer respectively. The

ΔHmix component is calculated using Equation 11.

ΔHmix = kBTχn1ϕ2 … Equation 11

In the above equation, χ is the interaction parameter. When considering the ideal mixing

of two small molecules, the adhesive and cohesive forces between the molecules are

assumed to be equal in strength (i.e. χ = 0) and thus the enthalpic contribution to ΔGm is

zero. However, in the case of solid dispersions, the specific interactions between the drug

and the polymer can have a significant contribution to the enthalpic component and

consequently dictate the drug – polymer miscibility.77

A negative χ value reflects strong

adhesive interactions between the drug and the polymer favoring miscibility, whereas a

positive χ value indicates that the cohesive interactions predominate with a potential for

phase separation. Substituting Equations 10 and 11 in Equation 9, ΔGmix (a predictor of

drug–polymer miscibility) is given by,

ΔGmix = kT(n1lnϕ1 + n2lnϕ2 + χn1ϕ2) … Equation 12

In the above equation, the value of the χ parameter will dictate the sign of the free energy

of mixing. The value of χ has been shown to be temperature as well as composition

dependent and its experimental determination is not trivial. A few studies in the literature

have attempted to predict as well as experimentally measure the value of χ.77-78

A better

understanding of the factors influencing the χ value will significantly improve our ability

to formulate miscible dispersions.

9

When compared to a pure amorphous drug, the lower chemical potential of the drug in a

miscible drug-polymer dispersion will reduce its thermodynamic driving force for

crystallization. A miscible solid dispersion, though metastable, can resist phase

separation. This kinetic stabilization is an avenue for increasing resistance to drug

crystallization. A decrease in molecular mobility is postulated to be an effective

stabilization mechanism. A decrease in molecular mobility can be brought about by: (a)

increasing Tg of the system by using a high Tg polymer (anti–plasticization), (b) specific

drug-polymer interactions such as hydrogen bonding and ionic interactions, and (c)

removing sorbed water. Several excellent review articles on solid dispersions discuss

these mechanisms in detail.67-69

For the purpose of this thesis we will focus on the role of

molecular mobility and, specifically, the role of drug-polymer hydrogen bonding

interactions on the physical stability of drugs in solid dispersions.

1.2.3 Molecular Mobility

Amorphous materials move towards thermodynamic equilibrium by a process known as

structural relaxation. These molecular motions are often defined in terms of the time

taken by the material to respond to an applied stress (mechanical, thermal, electrical,

etc.). The molecular relaxation processes in amorphous systems are believed to be

responsible for the observed physical and chemical instability. Two types of molecular

motions are observed in amorphous materials – (i) global (α-relaxation) and (ii) local (β-

relaxations).

Global Mobility and Role in Physical Stability

If a melt resists crystallization when cooled below its freezing point, it enters the

supercooled regime wherein molecules exhibit rotational and translational motions. From

Tm to Tg, molecules are typically characterized by a structural relaxation time < 100 s and

viscosity < 102

Pa.s.55-56

The temperature dependence of the molecular motions can be

described by the Vogel-Fulcher-Tamman-Hesse model (Equation 13).55

10

( ) (

) … Equation 13

In the above equation, τ is the average relaxation time at temperature T, D is the strength

parameter, a measure of the fragility of the material, T0 represents the zero mobility

temperature (theoretical Kauzmann temperature) and τ0 is quasi lattice vibration period,

assumed to be 10-14

s. The temperature dependence of the relaxation time (or viscosity) of

a supercooled material forms the basis of classification of glass forming liquids. Very

strong glass formers (D 100), often characterized by a three dimensional network of

strong covalent bonds (Eg. SiO2), show Arrhenius temperature dependence of the

relaxation time. Small organic molecules such as aromatic hydrocarbons are typically

fragile glass formers (D < 10) and show a pronounced deviation from Arrhenius

behavior. Crowley and Zografi have shown that several pharmaceutical glass formers

have D values in the range of 7-15 indicating their fragile nature.79

A characteristic feature of supercooled liquids is their non-exponential relaxation

behavior. The dynamic heterogeneity in amorphous systems is described by the empirical

Kohlrausch-Williams-Watts (KWW) relationship.80

( ) [ (

)

] … Equation 14

where (t) is the extent of relaxation at any time t, τ is the mean relaxation time and

is the relaxation time distribution parameter ( can take values between 0 and 1

with 1 reflecting exponential behavior). For many materials, the value of the exponent

has also been correlated with the fragility of the system with values < 0.5 for fragile

systems. The heterogeneity observed in supercooled liquids has been explained by

(Figure 1.3.):81

(i) A heterogeneous response reflecting a spatial distribution of exponentially

relaxing groups, each at a different rate.

11

(ii) A homogeneous response reflecting a uniform non-exponential relaxation.

Recently, molecular dynamic simulations of supercooled liquids revealed spatially

heterogeneous relaxation behavior in the supercooled state. The heterogeneous sets of

relaxing environments are comprised of domains with different mobilities. These

domains are believed to be roughly 3 nm in size. The molecular dynamics between the

slowest and fastest moving domains typically differ by 1-5 orders of magnitude.82

Another important feature of the molecular motions in supercooled liquids is the

observed decoupling between the translational motions and viscosity.55-56, 83-84

As a liquid

is cooled, between 1.2Tg and Tg, a pronounced difference in the temperature dependence

of translational motions and viscosity has been reported for several small molecules.

Translational diffusion coefficient (Dtrans) has significantly weaker temperature

dependence than η.54, 82-88

This has been attributed to the breakdown of the Stokes-

Einstein relationship (Equation 15).83

…

Equation 15

Here, kB is the Boltzmann constant and r is the radius of the diffusing species. In this

temperature range, Dtrans has significantly weaker temperature dependence than η. The

decoupling factor, between Dtrans and η is expressed as,

Dtrans … Equation 16

Throughout the supercooled regime, viscosity and rotational motions have similar

temperature dependence. Equation 15 can therefore also be expressed as,


Several studies in the literature have attempted to experimentally measure the value of .

In o-terphenyl temperature dependence of translation and rotational motions was

12

determined using tracer diffusion experiments and a of 0.75 was obtained (Figure

1.4).84-85, 89-90

Similar values were obtained for other small molecules including

trinapthylbenzene.85

As we decrease the temperature of the supercooled liquid towards Tg, there is a marked

decrease in the free volume of the system. Tg marks the lower limit of the free volume of

the system, and below Tg much more cooperation is required for molecular movement.91-

92 Due to the extremely high viscosity, structural relaxation in the glassy phase is very

slow. According to the Adam – Gibbs theory, molecular relaxation requires cooperative

rearrangement of a group of molecules (z).93

With a decrease in temperature and increase

in viscosity, the movement of one molecule will disturb an increasingly large number of

its neighboring molecules. The barrier for rearrangement of molecules is proportional to

the size of rearranging unit. The relaxation time τ in the system, can then be expressed

as,

τ = exp (

) … Equation 18

In the above equation, is the potential energy barrier per molecule and is the

configurational entropy of the smallest rearranging unit.

The configuration entropy in supercooled liquids can be expressed using a hyperbolic

relationship with temperature i.e., = K/T, where K is a proportionality constant.

In the glassy state, the Kauzmann temperature (approximated as T0) marks the lower limit

of the excess entropy in the amorphous state. In the glassy state, the concept of ftictive

temperature (Tf) was introduced by Tool94

and Narayanswamy.95

It is the temperature at

which the thermodynamic properties of the glassy state will be the same as that of the

extrapolated supercooled liquid (Figure 1.5). Using the fictive temperature concept, the

configurational entropy can then be calculated,

( ) +∫

= ∫

dT = K (

) … Equation 19

13

In the above equation, Cpl – Cp

g is the heat capacity difference between the

supercooled liquids and the glassy state at T0. Sc(T0) is assumed to be 0, the zero point

entropy of the glass at T0. By substituting Equation 19 into the Adam-Gibbs model

(Equation 18), we obtain,

( ) (

(

)

) … Equation 20

The above equation, known as the Adam-Gibbs-Vogel model or the Hodge equation has

been used to calculate the relaxation time in the glassy state.96-97

In the “equilibrium”

supercooled state, when T = Tf, the AGV equation will reduce to the VTF equation.

Given that global mobility brings about the glass transition, several studies have

attempted to correlate physical instability with global mobility. Initially Tg was

considered to be a marker of global mobility and many reports in the literature have tried

to correlate physical stability with Tg. However, compounds like nifedipine and

felodipine which have nearly the same glass transition temperature but drastically

different crystallization behavior indicate that Tg might not be a true predictor of global

mobility and physical stability. Recent studies from our laboratory have shown an

excellent correlation between global mobility and physical stability in amorphous

trehalose and itraconazole.98-99

Similar observations have also been made for several

other small molecules including celecoxib.100-101

Bhugra et al attempted to predict the

crystallization of a number of pharmaceuticals (sucrose, ketoconazole, indomethacin,

flopropione, nifedipine, and phenobarbital) below the glass transition temperature using

global mobility measurements above Tg.102-104

The prediction was successful at T > Tg

and unreliable at temperatures below Tg. Other factors such as local mobility and drug

polymer interaction were believed to be dominant below Tg. One of the goals of my

14

thesis work is to be able to measure or calculate molecular motions in the glassy state so

as to identify the specific mobility responsible for physical instability below Tg.

Local Mobility and Role in Physical Stability

Local mobility also known as secondary or β-relaxations, are non-cooperative motions

evolving from individual molecules or a part of a molecule.105-107

The temperature

dependence of local motions is described by Arrhenius kinetics. As compared to α-

relaxations, local motions are characterized by shorter relaxation times and lower

activation energies. Unlike a single structural relaxation, a given molecule can possess

many local motions, the most important being the Johari–Goldstein (JG) relaxation. The

JG relaxation is the slowest of all local motions and is believed to be universally present

in all organic small molecules. The JG relaxation is thought to herald the global mobility

and is therefore thought to be closely coupled to crystallization. The extended coupling

model of Ngai, relates the JG relaxations to the global relaxations by a crossover time τc

which is independent of the temperature.108

=

x

… Equation 21

where, τ0 is the relaxation time of the JG relaxation, τα is the average α-relaxation time,

βkww is a measure of the system heterogeneity as measured by the Kohlraush–William–

Watts equation and τc is the crossover time, measured to be 2 picoseconds by quasi

electron neutron scattering.

There is increasing evidence of the role of local motions in the observed instability in

amorphous compounds.109

Crystallization of triphenylethylene below its glass transition

temperature was attributed to β-relaxations. The calculated crystal growth using β-

relaxation times correlated well with experimental crystallization times suggesting the

possible role of local mobility in the crystallization of triphenylethylene.110

Crystallization or evidence of nucleation has been reported in amorphous

pharmaceuticals (indomethacin and fulvene) at temperatures much below the Tg.111-113

15

Crystallization at sub-Tg temperatures could not be explained by global mobility and was

attributed to local mobility. Local mobility was also found to be responsible for the

chemical and physical instability of macromolecules including insulin and β-

galactosidase.114-115

There are only a few studies in the literature documenting a direct

correlation between secondary relaxations and crystallization. Alie et al. demonstrated,

although indirectly, a relationship between the crystallization kinetics and secondary

relaxations indicating the importance of local mobility on the physical stability of

amorphous compounds.116

A careful and comprehensive investigation of the role of local

mobility on physical stability is therefore warranted.

1.2.4 Hydrogen Bonding

Hydrogen bonding and its role in the stabilization of amorphous phases has been the

subject of numerous investigations.117-121

Polymers are used to inhibit crystallization and

to stabilize amorphous materials via specific drug-polymer interactions such as ionic and

hydrogen bonding. Matsumato et al. studied the effect of polymer type and concentration

on the isothermal crystallization of indomethacin.122

The authors concluded that at lower

polymer concentrations, where the polymer did not significantly raise the Tg of the

system, stabilization was attributed to the polymer-drug hydrogen bonding. In a similar

study, Miyazaki et al. also attributed the inhibition of acetaminophen crystallization to the

drug-polymer hydrogen bonding and postulated that the degree of inhibition depended on

the strength of the hydrogen bonding, with the stronger hydrogen bonded system showing

greater resistance to crystallization.123

The structural relaxation in acetaminophen was

believed to be influenced by the strength and extent of hydrogen bonds, since molecular

rearrangement in hydrogen bonded systems will require the breaking and reforming of

hydrogen bonds. In glassy acetaminophen, it was speculated that hydrogen bonding

contributed to a decrease in the enthalpy and the entropy of the system.124

However,

there are also studies suggesting that hydrogen bonding may not be influential in

inhibiting drug crystallization from dispersions.125-126

At this stage, it is not possible to

reconcile these differences since a fundamental mechanistic understanding of the

influence of specific interactions on the physical stability of amorphous systems is

16

unknown. Our goal is to establish the influence of hydrogen bonding interactions

(strength and extent) on molecular mobility and consequently on physical stability.

1.3.Motivation and Thesis Overview

As mentioned earlier, in metastable amorphous dispersions, the challenge is to reliably

predict their kinetic stability. There is evidence of correlation between molecular mobility

and physical instability. The objective of my thesis work is to gain a fundamental insight

into the roles of (i) specific molecular mobility on the observed physical instability

(crystallization) in the supercooled as well as glassy states of amorphous pharmaceuticals

and (ii) the influence of specific interactions (hydrogen bonding) on molecular mobility

and consequently on the physical stability.

1.3.1. Chapter 2

Molecular mobility has conventionally been studied by calorimetric techniques

[differential scanning calorimetry (DSC), thermal activity monitor (TAM)] and by

nuclear magnetic resonance spectroscopy (NMR).109

Even though these techniques

provide valuable information, there are several limitations. Calorimetric techniques

provide an indirect measure of mobility (based on enthalpic recovery) and cannot

distinguish between local and global mobility. NMR, although an excellent tool to

measure mobility, requires expensive instrumentation and long data collection times.

Dielectric relaxation spectroscopy (DES) on the other hand is ideally suited to measure

molecular mobility. The analysis of both small and large molecules, over a wide range of

temperature and frequencies is possible. It enables us to directly monitor both global and

local motions. The short data collection times and relatively straightforward data

interpretation make it a very attractive tool for studying molecular mobility.

Traditionally, in DES, samples are analyzed as films, prepared either by melt quenching

the material or by solvent evaporation. This method of sample preparation is often

unsuitable for pharmaceutical materials since the very act of powder processing for

preparing films may result in the loss of valuable information. Pharmaceuticals are

usually encountered as powders and there is significant advantage in studying the powder

17

samples in their native form. Such an approach will enable the characterization of the

drug either alone or in a complex, multicomponent system. To be able to analyze

molecular mobility directly in powder samples, it is necessary to validate dielectric

spectroscopy measurements of powder samples. In Chapter 2, we have compared the

dielectric properties (permittivity, dielectric loss, relaxation time and shape parameters)

of four model compounds (nifedipine, indomethacin, itraconazole and griseofulvin) in

film and powder configurations.

Our working hypothesis was:

The relaxation time measured using film and powder samples are identical.

The relaxation time, a property of immense importance to the pharmaceutical

community, was not influenced by the sample configuration. The magnitudes of the

intrinsic dielectric properties were affected by the sample configuration with the powder

samples consistently yielding lower values. The use of effective medium theories enabled

us to account for the effect of air in the powder samples.

1.3.2. Chapter 3

There have been numerous investigations on the role of specific interactions, especially

hydrogen bonding, on the physical stability of amorphous materials.117-121

However, the

mechanisms by which such interactions influence the crystallization behavior is not

known. As a first step, in chapter 3, we have investigated in detail the differences in the

hydrogen bonding interactions (strength and extent) in two model compounds, nifedipine

and felodipine, which have drastically different crystallization tendencies despite

virtually identical Tg values.

Our working hypothesis was:

18

When compared to nifedipine, the stronger and more extensive hydrogen bonding

interactions in felodipine, by reducing molecular mobility, will impart a higher

physical stability.

Dielectric spectroscopy revealed slower mobility i.e. longer relaxation times and FTIR

revealed a stronger and greater extent of hydrogen bonding interaction in amorphous

felodipine when compared to nifedipine. Thus a causal link between molecular mobility

and hydrogen bonding interactions in single component systems was established.

1.3.3. Chapter 4

In several compounds, an excellent correlation has been established between molecular

mobility and crystallization (onset and kinetics) in the supercooled state.98-104

Previous

work from our laboratory has established the role of global mobility in the crystallization

of supercooled trehalose and itraconazole.98-99

However, since pharmaceuticals are stored

below the glass transition temperature, identifying the role of the specific molecular

mobility involved in the physical stability of glassy pharmaceuticals is crucial.

Traditionally DSC has been used to measure molecular mobility in pharmaceuticals.109

However, DSC is unable to distinguish between the various modes of relaxation.

Measuring structural relaxation in the glassy state is not trivial due to the extremely long

timescales of molecular motions. We therefore were interested in obtaining a reliable

measure of structural relaxation and local motions in the glassy state to identify the role

of the specific mobility involved in the physical stability of glassy pharmaceuticals. In

chapter 4, we investigated the correlation between molecular mobility and physical

stability in three model systems, including griseofulvin, nifedipine, and nifedipine – PVP

dispersion, and we identified the specific mobility mode responsible for instability.

The hypothesis tested was:

1. Structural relaxation in the glassy state is responsible for the observed physical

instability below Tg.

19

A strong correlation was observed between the α-relaxations and physical instability

(crystallization) in the glassy state. On the other hand, β-relaxation did not seem to

influence the crystallization behavior of glassy pharmaceuticals. The results suggested

that structural relaxation is a major contributor to physical instability both above and

below Tg in these model systems.

1.3.4. Chapter 5

Solid dispersion technology is widely employed to enhance the physical stability of

amorphous drugs.68

A fundamental understanding of the factors governing the physical

stability of drugs in dispersions is lacking. Stabilization of itraconazole in solid

dispersions was thought to be brought about by the reduction in molecular mobility due

to polymer addition. Currently a large number of polymers are available for solid

dispersion development and rational polymer selection is a challenge. Studies have

reported the stabilizing influence of specific interactions between the drug and the

polymer.118-123

As a next step, in order to rationalize the selection of polymers, we

investigated the influence of drug-polymer hydrogen bonding interactions on molecular

mobility and consequently the physical stability in three model dispersions of nifedipine

with each polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMCAS) and

polyacrylic acid (PAA).

The hypothesis tested was:

Drug-polymer hydrogen bonding interactions, by decreasing the molecular mobility,

will enhance the physical stability of nifedipine in solid dispersions.

The rank ordering of the relaxation time and the strength of hydrogen bonding was PVP

> HPMCAS > PAA. When compared to the other two polymers, the stronger NIF-PVP

interactions caused a much higher fraction of the drug molecules to be involved in

hydrogen bonding. Consequently, the PVP dispersions were much more stable. The

20

results from these studies highlight for the first time, that drug-polymer interactions, by

modulating the molecular mobility, influence drug crystallization.

1.5.5. Chapter 6

Once the ‘ideal’ polymer is selected, the next challenge is to determine the minimum

effective polymer concentration which can provide physical stabilization for the desired

time period. If the polymer is effective at a low concentration, it can afford the formulator

great flexibility in terms of dosage form design and processing. In chapter 6, we have

investigated the role of polymer concentration on the molecular mobility and physical

stability of nifedipine – PVP dispersions.

The hypothesis tested was

PVP, in a concentration dependent manner, will reduce the molecular mobility of the

system and thereby enhance the physical stability of nifedipine in solid dispersions.

With an increase in polymer concentration, the α-relaxation times measured by

broadband dielectric spectroscopy were longer reflecting a decrease in molecular

mobility. The increase in polymer concentration also led to enhanced physical stability of

nifedipine in the dispersion. The ultimate goal while formulating an amorphous

dispersion is to be able to reliably predict drug crystallization propensity during the shelf

life of the formulation. To achieve this goal, we used molecular mobility to predict

crystallization from solid dispersions. The predictions were in excellent agreement with

the experimental data.

21

Table 1: Biopharmaceutics Classification System of drugs in the market and in the

pipeline (as of 2011).3

BCS Class Solubility Permeability % Marketed

Drugs

% NCEs

(pipeline)

I High High 35 5 -10

II Low High 30 60 – 70

III High Low 25 5 – 10

IV Low Low 10 10 – 20

22

Table 2: Current drug products marketed as solid dispersions. 68-69

Brand Name Drug Major

Excipient

Manufacturer

Certican Everolimus HPMC Novartis

Cesamet Nabilone PVP Valeant

Isoptin SR-E Verapamil HPC/HPMC Abbott

Intelence Etravirin HPMC Tibotec

Kaletra Lopinavir, ritonavir PVPVA Abbott

Gris-PEG Griseofulvin PEG6000 Pedinol Pharmacal Inc.

Sporanox Itraconazole HPMC Janssen Pharmaceutica

Nivadil Nivaldipine HPMC Fujisawa Pharmaceutical Co., Ltd

Prograf Tacrolimus HPMC Fujisawa Pharmaceutical Co., Ltd

Rezulin

Troglitazone PVP Developed by Sankyo, manufactured

by Parke-Davis division of

Warner-Lambert

Zelboraf Vemurafenib HPMCAS Roche

Incivek Telaprevir HPMCAS-M Vertex Pharmaceuticals

23

Figure 1.1. van’t Hoff type plots revealing the higher solubility of amorphous celecoxib

(■) over the crystalline form (♦), in the temperature range studied.50

24

Figure 1.2 Schematic depicting the change in enthalpy and volume as a function of

temperature.47

25

Figure 1.3 Explanation for non-exponential molecular dynamics observed in supercooled

liquids. Left panel: heterogeneous domains and right panel: single homogenous domain.81

26

Figure 1.4 The decoupling between rotational and translational motions observed

between Tg and 1.2Tg in o-terphenyl.90

27

Figure 1.5 Schematic representation of the configurational enthalpy and entropy as

function of temperature. The green line shows the fictive temperature (Tf) of a fresh glass

at temperature T1.

28

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43

Chapter 2

Dielectric Spectroscopy of Small Molecule Pharmaceuticals –

Effect of Sample Configuration

44

2.1. Synopsis

In dielectric spectroscopy, a technique traditionally used to characterize molecular

mobility in polymers, the sample is usually analyzed as a thin film. In recent years, the

technique has been extended to characterize both drug substances and drug products.

However, the usefulness and versatility of the technique would be greatly enhanced if

powder samples could be analyzed. Therefore the dielectric behavior of several

compounds of pharmaceutical interest – nifedipine, indomethacin, itraconazole and

griseofulvin as powder and film samples were compared. The magnitudes of the intrinsic

dielectric properties were affected by the sample configuration with the powder samples

consistently yielding lower values. Use of effective medium theories enabled us to

account for effect of air in the powder samples. The relaxation time, a property of

immense importance to the pharmaceutical community, was not influenced by the sample

configuration.

2.2. Introduction

The pharmaceutical community is increasingly relying on amorphization as an approach

to improve the oral bioavailability of poorly water soluble new drug candidates.1-2

However, the use of amorphous pharmaceuticals is limited by their physical instability,

i.e. crystallization propensity. The current efforts of the pharmaceutical community are

focused on predicting the stability of amorphous pharmaceuticals.3

Recent studies suggest a strong correlation between the molecular motions in amorphous

materials and their stability, both physical and chemical.4-5

Bhardwaj et al. have shown an

excellent correlation between α-relaxation time (a measure of slow cooperative molecular

motions; also referred to as global mobility) and crystallization onset time in amorphous

trehalose and itraconazole.6-7

A similar correlation was also observed in sucrose and

celecoxib.8-9

In select pharmaceuticals, local mobility (i.e. β-relaxation), fast non-

cooperative motions arising from the orientation of individual molecules or their parts,

45

has been implicated for the observed physical instability.10-11

Hence, a reliable prediction

of the physical stability may be enabled by a comprehensive understanding of the

molecular motions in amorphous materials. Broadband dielectric spectroscopy (BDS)

provides a direct measure of the different molecular motions of amorphous materials.

This information coupled with crystallization studies provide a powerful means of

correlating the specific mobility responsible for instability.

In BDS, a technique extensively used to characterize molecular mobility in polymers, the

sample is analyzed as a thin film obtained either by melt-quenching or solvent casting.

Many pharmaceuticals are thermolabile rendering the melt-quenching approach

unsuitable. Moreover, many small molecule pharmaceuticals are not amenable to solvent

casting. Though not widely used, it is also possible to analyze a sample as a compact.12

Unfortunately, amorphous compounds may crystallize upon compression, limiting this

approach.13

The problems detailed above can be overcome by using amorphous powder

samples. Since pharmaceuticals, particularly for the manufacture of solid dosage forms,

are prepared and processed as powders, there is significant value in analyzing the powder

samples directly. This will provide information about the analyte in the “native” state,

and avoid any effect of processing. A recent publication revealed the unique capability of

BDS in the characterization of a widely used pharmaceutical, amorphous trehalose. The

method of preparation (spray or freeze drying, melt quenching, milling) influenced the

physical stability of amorphous trehalose, an effect attributed to molecular mobility.7

Moreover, such an approach will enable the characterization of the drug either alone or in

a complex, multicomponent system. Since drug products often contain multiple

components, we can obtain direct insight into the behavior of these complex systems,

including the influence of water.

However, there is potential for error with the use of powder samples, with entrapped air

being a major source of concern. In light of the unique advantages offered by the use of

powder samples particularly in the characterization of pharmaceuticals, a careful and

systematic comparison of the powder and film sample forms (the terms sample form and

configuration have been used interchangeably) is warranted. This communication aims at

46

comparing the dielectric measurements: (i) dielectric constant, (ii) dielectric loss, (iii)

relaxation times and (iv) relaxation peak shape obtained using powder and film samples.

Several compounds of pharmaceutical interest – nifedipine, indomethacin, itraconazole

and griseofulvin were used for this purpose.

2.3. Experimental Section

2.3.1. Preparation of Amorphous Phases

Amorphous powders (nifedipine, indomethacin, itraconazole, and griseofulvin) were

prepared by melting the drug in aluminum plans and then quenching on aluminum blocks

precooled to -20 °C. The melt-quenched material was lightly crushed using a mortar and

pestle in a glove box at room temperature (Relative Humidity < 5 %). Films were

prepared by melting the analyte between the two electrodes followed by quenching

between two aluminum blocks precooled at -20 °C.

2.3.2. Baseline Characterization

The model amorphous compounds were observed to be X-ray amorphous. The glass

transition temperatures, determined by differential scanning calorimetry, were in

excellent agreement with the literature values.14-15

Thermogravimetric analysis and Karl

Fischer titrimetry revealed a water content < 0.5 % w/w. Powder porosity (p) was

calculated from the bulk density (ρbulk; obtained from the sample mass and volume of the

sample cell) and true density (ρtrue).16-18

… Equation 1

47

2.3.3. Powder X-ray Diffractometry

A powder X-ray diffractometer (D8 ADVANCE; Bruker AXS, Madison, WI) equipped

with a Si strip one-dimensional detector (LynxEyeTM

; Bruker AXS) was used. Samples

were exposed to Cu K radiation (40 kV x 40 mA) over an angular range of 5 – 40° 2θ

with a step size of 0.05° and a dwell time of 1 s.

2.3.4. Broadband dielectric spectrometry

A broadband dielectric spectrometer (Novocontrol Alpha-A high performance frequency

analyzer, Novocontrol Technologies, Germany), was used for the isothermal dielectric

analysis at several temperatures (between 0 and 130 °C) in the frequency range of 10−2

to

107

Hz. The powder was filled between two gold plated copper electrodes (20 mm

diameter) using a PTFE ring (thickness: 1 mm; area: 59.69 mm2; capacitance: 1.036 pF)

as a spacer. The spacer confined the sample between the electrodes. For the film samples

PTFE fibers (thickness: 50 μm) were used to maintain a constant spacing between the

two electrodes. Measurements were corrected for stray capacitance, spacer capacitance

and edge compensation. The control software WinDETA®

was used to subtract out the

effects of spacer and edge capacitance. The cell stray capacitance was calculated using

Equation 2.

C = εA/d … Equation 2

Here, C is the capacitance between the two electrodes, d is the thickness of the sample, 1

mm and A is the area of electrode (314.16 mm2) – area of spacer (59.69 mm

2). The

dielectric constant for an empty cell was found to be 2.45. The empty cell capacitance

was found to be 623.1 mm. Using ε = 1 for air, the cell stray capacitance was found to be

3.26 pF

The Havriliak-Negami (Equation 3) or the Cole-Davidson (Equation 4) model was used

to fit the dielectric data to obtain the relaxation time (τHN or τCD) and shape parameters

(αHN and βHN or βCD).19-21

48

( )

[ ( ) ] … Equation 3

( )

[ ( )] … Equation 4

Relaxation times and their standard deviations at select temperatures in select systems are

given in Table 2.1. In the above equations, ε*(ω) is the complex dielectric permittivity,

consisting of real (ε’) and imaginary (ε”) components, ω represents the angular

frequency, which is equal to 2πf with f being the frequency in Hz and dielectric strength

∆ε = εs-ε∞, where εs gives the low frequency limit (ω→0) of ε’(ω) and ε∞ is the high

frequency limit (ω→∞) of ε’(ω).

2.4. Results and Discussion

2.4.1. Dielectric Constant and Dielectric Loss

For all the model compounds in the α-relaxation temperature range, at high frequencies,

the dielectric constant (ε’) is low. At these high frequencies, only the atomic and

electronic polarizations contribute to the dielectric constant. The rapidly oscillating

electric field does not allow the alignment of dipoles. However, at lower frequencies, the

dielectric constant increases due to the reorientation of the molecular dipoles. In all the

model compounds, both the film and powder samples, exhibited similar dielectric

behavior as a function of frequency. At lower frequencies, effective dipole reorientation

resulted in a pronounced increase in the dielectric constant. The dielectric constant

spectra of all the model compounds presented in Figure 2.1. However, the magnitude of

dielectric constant was influenced by the sample form, with the powders yielding

substantially lower values (Figure 2.2). In powder samples, both the analyte and the

entrapped air contribute to the measured dielectric constant. The magnitude of the

measured dielectric constant will be influenced by the sample porosity, the distribution of

49

the entrapped air and its effect on the polarization of the neighboring particles. In each

powder sample, we have assumed uniform porosity throughout.

The influence of sample porosity, p, on the observed dielectric constant, εr, has been

addressed in the Maxwell-Garnett (MG) effective medium theory (Equation 5).22

( )

… Equation 5

Using the film permittivity values and the experimentally measured porosity, the powder

permittivity was calculated using Equation 5 and plotted as a function of frequency

(Figure 2.2, solid line). An increase in porosity (i.e. reduced density) will lead to a

decrease in the observed dielectric constant. This approach yielded lower dielectric

constant values in the powder sample. As expected, the dielectric constant values

calculated using the MG theory were lower than the observed values. This effect was

more pronounced at lower frequencies. This equation, based on the Clausius-Mossotti

relation, assumes spherical shape of molecules/particles. It does not take into account

effects due to the polarization of the environment or dipole interactions. It also does not

take into account the effect of multipoles, the proximity effects of nearby particles, which

can enhance the permittivity at higher volume fractions. For heterogeneous samples, the

electric field experienced by each particle depends on its microenvironment and is a

combination of the external electric field and the induced electric field of the surrounding

particles. This issue is addressed in the effective medium theory of Kamiyoshi.23

Rayleigh had derived the equation to calculate the effective dielectric constant of spheres

distributed at cubic lattice points while Kamiyoshi’s modification accounted for random

arrangement encountered in powders. The Kamiyoshi modified Rayleigh equation is

given by,

50

… Equation 6

where,

(

⁄) … Equation 6a

and

(

⁄) … Equation 6b

The fill fraction, f, in Equations 6a and 6b is given by 1-p. In Kamiyoshi’s equation, the

assumption is made that both the voids and the particles are equally distributed and that

the particles are non-porous. The Kamiyoshi equation reduces to Equation 5 at low fill

fraction or at low dielectric strength due to the reduction in particle-particle (electric

field) interaction.23

Substituting values obtained from Equation 6a and 6b in Equation 6, the dielectric

constant was calculated (Figure 2.2, dash line). The Kamiyoshi approach, which takes

into account the effect of induced multipoles, showed very good agreement with the

measured values. These results strongly suggest that the reduction in the observed

dielectric constant values can be solely attributed to air and not due to any other

experimental artifacts. At higher frequencies, both the Maxwell-Garnett and Kamiyoshi

equations were in close agreement due to low dielectric strength. At a characteristic

frequency, the dielectric loss, (ε”), exhibits a maximum (Figure 2.3), the magnitude of

which is proportional to the dielectric relaxation strength, ∆ε. The measured value of ∆ε

will also be dependent on sample density. As is evident from Figure 2.3, the dielectric

strength obtained with the film was higher than with the powder sample. For the film

51

sample, the measured signal can be attributed almost exclusively to model compound.

This is not the case with the powder samples. As before, the Kamiyoishi prediction was

in good agreement with the experimental data (Figure 2.3). In itraconazole, the poor

agreement between the calculated and experimental data at lower frequencies is attributed

to a liquid crystalline phase transition occurring at a slightly lower temperature in

powders.24

Consistent with literature, the models predicted a shift in the relaxation peak

to slightly higher frequencies.25

Comparison of the data for griseofulvin powders and

films using effective medium theories was not performed due to rapid sample

crystallization in powders.

2.4.2. α-Relaxation Time and Shape Parameters

Our next interest was to compare the α-relaxation times obtained using powder and film

samples. In addition, the shape parameters, a measure of the relaxation heterogeneity,

were also compared. The Havriliak−Negami (HN) model (Equation 3) was used to fit the

dielectric loss data and obtain the average relaxation time (τHN) and shape parameters

(αHN and βHN). The sample form (powder vs. film), had little bearing on the average

relaxation time for all the four model systems (Figure 2.4). Thus, we had evidence that

the powder samples provided a reliable measure of the structural relaxation time. It was

also observed in powder samples that the magnitude of the dielectric strength obtained

using the HN equation was approximately equal to the step change in the dielectric

constant spectra.

It should be emphasized that the above results are likely to be system specific. In non-

homogeneous systems, the Maxwell-Sillars-Wagner polarization due to the blocking of

charges at the boundaries of inhomogeneity can be erroneously attributed to a relaxation

phenomenon.26

The contribution due to charge blocking at the powder particle interfaces

is expected to be small because of the contact between the particles in the BDS holder.

Furthermore, the Maxwell-Sillars-Wagner polarization becomes a serious issue in highly

conductive (high loss) materials, a problem not routinely encountered with organic

52

pharmaceuticals. In light of the good agreement between the relaxation times of films and

powders, we believe that the results were not influenced by the Maxwell-Sillars-Wagner

polarization.

The parameters, α and β, in the HN equation relate to symmetric and asymmetric peak

broadening respectively. Since the α value for the film samples in nifedipine was ~ 1, the

HN model (Equation 3) simplifies to the Cole-Davidson (CD) model (Equation 4).

However, this was not the case for the powder samples. Additionally, due to the

difference in the peak shape, the β parameter values obtained from the HN model for the

film and the powder samples were also not in good agreement (Figure 2.5). The

difference in peak shape between films and powders, can be readily visualized from the

Cole-Cole plot (Figure 2.6). For nifedipine, indomethacin and griseofulvin deviations

from the CD relaxation for powders are revealed. This deviation is due to the additional

symmetric peak broadening in powders. The differences can be explained by the spatial

inhomogeneity intrinsic in powder samples. Effective medium analysis postulates a

decrease in the β-parameter due to preferred orientation of the powder particles packed

between the electrodes - particles which are oriented perpendicular to the electric field

should contribute to the high frequency flank of the relaxation peak.25

Despite the

disparity in the shape parameters, the relaxation time of the film and the powder samples

obtained using the HN model were not significantly affected. In itraconazole films, the

additional relaxation observed due to the liquid crystalline phase (referred to as α’

relaxation) may explain the deviation from the Cole-Davidson relaxation.24

Interestingly,

the powder and film samples exhibit very similar shape parameters as can be visualized

form the Cole-Cole plots. In the supercooled state, the viscous flow confers “film like”

character (visually observed) to the original powder sample.

The change in shape parameters with sample form can have important consequences

when characterizing the mobility of a material. The shape parameters from the HN model

have been used to calculate the stretch exponential, βKWW, in the Kohlrausch-Williams-

Watts model (Equation 7).27

53

= αHNβHN … Equation 7

The βKWW is a measure of the distribution of relaxation times which can be important in

estimating other properties, e.g. the mobility at the surface of the glass.28

The difference

in shape parameter values, between films and powders, will have a bearing on the

calculated βKWW values. For example, in nifedipine powder, the βKWW was 0.36 while for

films it was 0.46.

2.4.3. β-Relaxation

β-relaxation in itraconazole film and powder samples revealed similar relaxation times

(Figure 2.7). The energy of activation (Eaβ) calculated for the film (89.5 kJ/mol) and the

powder (88.4 kJ/mol) samples were in excellent agreement with the literature value

reported for film.24

In both nifedipine and indomethacin film and powder samples, a

weak β-relaxation could also be discerned. Since this relaxation was observed only as an

“excess wing”, further analysis was not carried out. The β-relaxation signal was also very

weak in griseofulvin films. However, in powder samples, the signal was sufficiently

pronounced to determine its temperature dependence. The Eaβ was calculated to be 58.2

kJ/mol. This enabled the calculation of Eaβ/RTg to be 19.4 strongly suggesting that this

was the Johari-Goldstein (JG) relaxation. A value close to 24 has been observed for the

JG relaxation of several glass formers.29

As with α-relaxation, the magnitude of dielectric

loss was influenced by the sample form, with the powders yielding lower values. The

magnitude of this effect for the JG β-relaxation was not as pronounced as for α-

relaxation. As a result, the JG relaxation became slightly more “apparent” in the powder

(Figure 2.8 and 2.9). The JG relaxation has been attributed to highly mobile low density

regions termed “islands of mobility”, predominantly identified in glassy systems.30

It is

expected that the surrounding medium will not influence the two types of relaxations in a

similar manner. This is due to the spatial difference in the origin of the two types of

relaxations. A similar observation has been made though to a much greater extent where

54

the peak height of the β-relaxation becomes approximately equal to the height of the α-

relaxation peak in nano-confined materials.31

One possible explanation is that the

surrounding medium will not influence the two types of relaxations in a similar manner.

This is due to the spatial difference in the origin of the two types of relaxations with the

Johari-Goldstein relaxation attributed to highly mobile low density regions.32

2.5. Conclusions

The results of this study reveal the potential of dielectric spectroscopy to provide unique

and fundamental information in pharmaceutical systems. While the current investigation

deals with a drug substance, the ultimate objective is to extend the utility of this

technique to study drug formulations which are often complex, multicomponent systems.

The information obtained can be used to understand the crystallization behavior in these

systems and help design robust dosage forms. By being able to analyze powder samples,

we have the added advantage of monitoring the influence of (i) processing conditions, (ii)

sample history and (iii) water content. The structural relaxation times, determined using

films and powders, were in excellent agreement, revealing that the sample form did not

influence these results. Hence powder configuration provides a reliable measure of the

molecular mobility. The small enhancement in the β-relaxation signal using powder

samples may be a potential advantage. However, using powders, some intrinsic properties

including dielectric strength and constant could not be reliably obtained. This is a

potentially serious limitation of powder samples. The appearance of spurious relaxation

processes is another likely source of error and has been reported: (i) at the conductivity

relaxation frequency of the material,33

(ii) due to microcrystals on the surface of

amorphous particles 34

and (ii) due to adsorbed water.35

Therefore, a good practice will be

to obtain the dielectric spectra of film samples if at all possible, and use this as a

“reference” before proceeding to perform more detailed experiments with the powder

samples.

55

Table 2.1: Relaxation times and the SD (standard deviation) from the HN fit for

nifedipine and indomethacin film and powder samples at 60 °C.

Sample Relaxation time SD for relaxation time

Nifedipine films (60°C) 1.7630e-02 ± 3.7e-04

Nifedipine powders (60°C) 1.4730e-02 ± 5.1e-04

Indomethacin films (60°C) 1.8300e-02 ± 8.3e-04

Indomethacin powders (60°C) 1.9420e-02 ± 9.1e-03

56

Figure 2.1: Dielectric constant of (A) nifedipine, (B) indomethacin, (C) itraconazole, and

(D) griseofulvin as a function of frequency.

Frequency (Hz)

1e-1 1e+0 1e+1 1e+2 1e+3 1e+4 1e+5 1e+6 1e+7

1

10

100

90 C

95 C

100 C

105 C

110 C

Die

lectr

ic c

on

sta

nt,

'

Frequency (Hz)

1e-1 1e+0 1e+1 1e+2 1e+3 1e+4 1e+5 1e+6 1e+7

1

10

50 C

55 C

60 C

65 C

70 C

Die

lectr

ic c

onsta

nt,

'

Frequency (Hz)

1e-1 1e+0 1e+1 1e+2 1e+3 1e+4 1e+5 1e+6 1e+7

1

10

50 C

55 C

60 C

65 C

70 C

Die

lectr

ic c

onsta

nt,

'

Frequency (Hz)

1e-1 1e+0 1e+1 1e+2 1e+3 1e+4 1e+5 1e+6 1e+7

1

10

100

50 C

55 C

60 C

65 C

70 C

Die

lectr

ic c

onsta

nt,

'

(A)

(D)

(B)

(C)

57

Figure 2.2: Dielectric constant of (A) nifedipine, (B) indomethacin and (C) itraconazole

film (●) and powder (■) samples. For the powders, the calculated dielectric constants

using the Maxwell-Garnett (MG) and Kamiyoshi models are shown by the solid and

broken lines respectively.

58

Figure 2.3: Dielectric loss of (A) nifedipine, (B) indomethacin and (C) itraconazole film

(●) and powder (■) samples. For the powders, the calculated dielectric loss using the

Maxwell-Garnett (MG) and Kamiyoshi models are shown by the dotted and broken lines

respectively.

59

Figure 2.4: The temperature dependence of α-relaxation time in (A) nifedipine, (B)

indomethacin, (C) itraconazole and (D) griseofulvin film (●) and powder (■) samples

(mean ± SD; n = 3).

60

Figure 2.5: Plot of α-relaxation shape parameters* as a function of temperature in

nifedipine films (●,▲) and powders (■,▼) (mean ± SD; n=3).

* The shape parameters are: αHN representing symmetric broadening and βHN representing

asymmetric broadening. Equation 3 describes the HN model.

61

Figure 2.6: Cole-Cole plots obtained from dielectric data using (A) nifedipine (B)

indomethacin (C) griseofulvin and (D) itraconazole films (●) and powders (■). While

only an asymmetric peak broadening was observed for all the films (CD relaxation

behavior), both symmetric and asymmetric broadening was observed in powders (HN

relaxation behavior) except itraconazole, where film as well as powder samples showed

HN type relaxation behavior. Each data set was normalized with respect to its maximum

loss value. The semi-circle (dashed line) represents a Debye relaxation (α = β = 1). For a

CD relaxation the data follows half of the semi-circle.

62

Figure 2.7: The temperature dependence of β-relaxation time in itraconazole film (●) and

powder (■) samples.

63

Figure 2.8: Dielectric loss of griseofulvin film (●) and powder (■) at 95 °C respectively.

Griseofulvin powder sample has been fitted with 2HN functions whereas the film is fitted

with only 1HN function.

64

Figure 2.9: Griseofulvin powder at 95 °C fitted simultaneously to two HN functions,

revealing two relaxations. The red line reveals a combined fit for both the relaxations.

The black line is for the α-relaxation appearing at a lower frequency and the blue line

reveals the fit for the faster β-relaxation.

65

2.6 References


Biopharmaceutic Drug Classification: The Correlation of in vitro Drug Product

Dissolution and in vivo Bioavailability. Pharm Resarch 1995, 12 (3), 413-420.








5. Yoshioka, S.; Aso, Y., Correlations between Molecular Mobility and Chemical

Stability During Storage of Amorphous Pharmaceuticals. Journal of Pharmaceutical

Sciences 2007, 96 (5), 960-981.






2012, 9 (11), 3209-3217.










66


Sciences 2004, 93 (1), 218-233.



12. Martin Steve, W.; Yao, W.; Berg, K., Space Charge Polarization Measurements as

a Method to Determine the Temperature Dependence of the Number Density of Mobile

Cations in Ion Conducting Glasses. In Zeitschrift für Physikalische Chemie International

journal of research in physical chemistry and chemical physics, 2009; Vol. 223, p 1379.

13. Joshi, A. B.; Patel, S.; Kaushal, A. M.; Bansal, A. K., Compaction Studies of

Alternate Solid Forms of Celecoxib. Advanced Powder Technology 2010, 21 (4), 452-

460.





Physical Stability and Improved Dissolution Properties of Itraconazole, a Class II Drug,

by Solid Dispersions That Combine Fast‐and Slow‐Dissolving Polymers. Journal of


16. Marsac, P.; Li, T.; Taylor, L., Estimation of Drug–Polymer Miscibility and



17. Overhoff, K. A.; Moreno, A.; Miller, D. A.; Johnston, K. P.; Williams III, R. O.,

Solid Dispersions of Itraconazole and Enteric Polymers Made by Ultra-Rapid Freezing.

International journal of pharmaceutics 2007, 336 (1), 122-132.

18. Wu, T.; Sun, Y.; Li, N.; de Villiers, M. M.; Yu, L., Inhibiting Surface

Crystallization of Amorphous Indomethacin by Nanocoating. Langmuir 2007, 23 (9),

5148-5153.

19. Davidson, D.; Cole, R., Dielectric Relaxation in Glycerine. The Journal of


67

20. Davidson, D. W.; Cole, R. H., Dielectric Relaxation in Glycerol, Propylene

Glycol, and n-Propanol. The Journal of Chemical Physics 1951, 19 (12), 1484-1490.

21. Havriliak, S.; Negami, S., A Complex Plane Analysis of α-Dispersions in Some

Polymer Systems. Journal of Polymer Science Part C: Polymer Symposia 1966, 14 (1),

99-117.

22. Garnett, J. M., Colours in Metal Glasses, in Metallic Films, and in Metallic

Solutions. II. Philosophical Transactions of the Royal Society of London. Series A,

Containing Papers of a Mathematical or Physical Character 1906, 237-288.

23. Kamiyoshi, K., A New Deduction Formula for Determining the Dielectric

Constant of Powder Dielectric. Part II. Science reports of the Research Institutes, Tohoku

University. Ser. A, Physics, chemistry and metallurgy 1950, 2, 180-192.

24. Tarnacka, M.; Adrjanowicz, K.; Kaminska, E.; Kaminski, K.; Grzybowska, K.;

Kolodziejczyk, K., . . . Kocot, A., Molecular Dynamics of Itraconazole at Ambient and

High Pressure. Physical Chemistry Chemical Physics 2013, 15 (47), 20742-20752.

25. Pelster, R., Dielectric Spectroscopy of Confinement Effects in Polar Materials.

Physical Review B 1999, 59 (14), 9214-9228.

26. Steeman, P. A. M.; van Turnhout, J., Dielectric Properties of Inhomogeneous

Media. In Broadband Dielectric Spectroscopy, Kremer, F.; Schönhals, A., Eds. Springer

Berlin Heidelberg: 2003; pp 495-522.

27. Alvarez, F.; Alegra, A.; Colmenero, J., Relationship between the Time-Domain

Kohlrausch-Williams-Watts and Frequency-Domain Havriliak-Negami Relaxation

Functions. Physical Review B 1991, 44 (14), 7306-7312.

28. Capaccioli, S.; Ngai, K. L.; Paluch, M.; Prevosto, D., Mechanism of Fast Surface

Self-Diffusion of an Organic Glass. Physical Review E 2012, 86 (5), 051503.

29. Ngai, K. L.; Capaccioli, S., Relation between the Activation Energy of the Johari-

Goldstein β-relaxation and Tg of Glass Formers. Physical Review E 2004, 69 (3), 031501.


Physics 1973, 58 (4), 1766-1770.

68

31. Bergman, R.; Mattsson, J.; Svanberg, C.; Schwartz, G. A.; Swenson, J.,

Confinement Effects on the Excess Wing in the Dielectric Loss of Glass-Formers. EPL

(Europhysics Letters) 2003, 64 (5), 675.

32. Johari, G. P., Localized Molecular Motions of β-relaxation and Its Energy


33. Richert, R.; Agapov, A.; Sokolov, A. P., Appearance of a Debye Process at the

Conductivity Relaxation Frequency of a Viscous Liquid. The Journal of Chemical

Physics 2011, 134 (10).

34. Ermolina, I.; Polygalov, E.; Bland, C.; Smith, G., Dielectric Spectroscopy of

Low-Loss Sugar Lyophiles: II. Relaxation Mechanisms in Freeze-Dried Lactose and

Lactose Monohydrate. Journal of Non-Crystalline Solids 2007, 353 (47–51), 4485-4491.

35. Steeman, P. A. M.; Maurer, F. H. J., An Interlayer Model for the Complex

Dielectric Constant of Composites. Colloid & Polymer Sci 1990, 268 (4), 315-325.

69

Chapter 3

The Role of Hydrogen Bonding Interactions on the Molecular Mobility

and Physical Stability of Nifedipine and Felodipine

70

3.1. Synopsis

Amorphization is increasingly emerging as an effective approach to increase the

solubility of drugs. Due to its high free energy state, the thermodynamic instability

associated with the amorphous state can lead to a conversion back to the stable crystalline

form and loss of the solubility and any potential bioavailability advantage Our objective

is to gain physical insights into the role of hydrogen bonding on molecular mobility, and

consequently, physical stability. To establish the causal link between hydrogen bonding

and molecular mobility, nifedipine (NIF) and felodipine (FEL), a pair of structurally

similar compounds were selected as the model system. Despite their near identical glass

transition temperatures (Tg), NIF exhibited a much higher crystallization propensity than

felodipine. Dielectric spectroscopy revealed longer relaxation times for felodipine as

compared to nifedipine. FTIR analysis of the hydrogen bonding patterns revealed

stronger and extensive interactions for FEL as compared to NIF. Our results reveal a

direct link between intramolecular hydrogen bonding interactions and molecular mobility

(measured as structural relaxation time) in amorphous organic compounds. This study

provides physical insights into why structurally similar compounds, due to differences in

their hydrogen bonding interactions, can exhibit pronounced differences in molecular

mobility.

3.2. Introduction

Amorphous materials are of interest in several disciplines including physics, geology,

food and pharmaceutical sciences.1 In drugs with very low aqueous solubility, the

amorphous state has been exploited for effective oral delivery.2 However, if the

amorphous form crystallizes, the solubility advantage will be lost.3 While the

thermodynamic factors governing the amorphous crystalline transition are well

understood, the kinetics of this transition remains unpredictable.4 Recently, in several

organic compounds, molecular mobility measured as structural relaxation time (by

71

dielectric spectroscopy), showed an excellent correlation with physical stability. Though

preliminary, these studies strongly suggest that the α-relaxation time can be used to

predict both crystallization onset and kinetics.5-9

An added consideration in organic

compounds is their potential to exhibit inter or intramolecular hydrogen bonding

interactions. The molecular relaxation processes in these systems often involve the

rearrangement of hydrogen bonds.10

For example, the hydrogen bonding in glassy

acetaminophen was speculated to influence the structural relaxation time.11

Our objective is to gain physical insights into the role of hydrogen bonding on molecular

mobility, and consequently, physical stability. To establish the causal link between

hydrogen bonding and molecular mobility, nifedipine (NIF) and felodipine (FEL), a pair

of structurally similar compounds were selected as the model system (Figure 3.1).

Despite their near identical glass transition temperatures (Tg), NIF exhibited a much

higher crystallization propensity than feldipine.12

At 25 °C, the free energy difference

between the amorphous and crystalline forms of NIF was greater than that between the

corresponding FEL forms, reflecting a higher thermodynamic driving force for

crystallization in the former. The enthalpic component was the major contributor to the

free energy difference in NIF. On the other hand, in several compounds including

ritonavir, crystallization studies under non-isothermal conditions revealed that

compounds with the highest entropic barriers and lowest mobilities were most resistant to

crystallization.13

In these compounds, the free energy difference between the amorphous

and crystalline forms was not a predictor of physical stability. Interestingly, for our

model system, enthalpic relaxation measurements, an indirect measure of the molecular

mobility, did not reveal any significant differences between the two systems.12

Marsac et al also investigated the influence of hydrogen bonding interactions on the

physical stability of amorphous FEL and NIF. The NH peak position, a measure of the

strength of hydrogen bonding interactions, was identical for the two compounds in the

amorphous state. However, the increased peak width in NIF suggested a broader

“distribution” of hydrogen-bonded populations. The effect of this difference on the

overall strength of hydrogen bonding is not known.

72

In an attempt to understand the differences in the crystallization behavior of these two

compounds, we characterized in detail, the molecular mobility using dielectric

spectroscopy and the hydrogen bonding interactions by FT-IR spectroscopy. We

hypothesize that hydrogen bonding interactions, by influencing the molecular mobility,

will have a dramatic influence on the physical stability. Our results suggest that the

differences in the extent of hydrogen bonding coupled with the effective strength of

hydrogen bonding between molecules influences the global mobility of the system. This

can explain the lower molecular mobility in FEL when compared with NIF. In light of the

established relationship between mobility and stability, the longer relaxation time of FEL

can explain its greater resistance to crystallization as compared to NIF.


3.3.1. Methods and Materials

NIF (C17H18N2O6) and FEL (C18H19Cl2NO4) were purchased from Laborate

Pharmaceutical Ltd. and Sigma Aldrich respectively and used without further

purification.

3.3.2. Thermal Analysis

A Differential Scanning Calorimeter (DSC) (Q2000, TA instruments, New Castle, DE)

equipped with a refrigerated cooling accessory was used. All the measurements were

done under dry nitrogen purge (50 mL/min) at a heating rate of 10 °C/min.

3.3.3. Dielectric Spectroscopy (BDS)

Using a broadband dielectric spectrometer (Novocontrol Alpha-AK high performance

frequency analyzer, Novocontrol Technologies, Germany), isothermal dielectric

measurements were conducted over the frequency range of 10-2

to 107 Hz and between -

100 °C and 150 °C. The Havriliak-Negami (HN) model (Equation 1) was used to fit the

73

dielectric data so as to obtain the average relaxation time (HN) and shape parameters (αHN

and βHN).

sHN

ii HNHN

))(1()(*

… Equation 1

In the above equation, is the angular frequency, *() is the complex dielectric

permittivity consisting of real (’) and imaginary (”) components, and dielectric

strength, = s – , where s gives the low frequency limit (0) of ’() and is

the high frequency limit () of ’(). The shape parameters account for the

symmetric (αHN) and asymmetric (βHN) peak broadening with 0 < α (or β) < 1. The

crystalline powder sample was melt quenched between two gold plated copper electrodes

(20 mm diameter) using teflon spacers (thickness: 0.05 mm). Measurements were

corrected for stray capacitance and edge compensation.

3.3.4. FTIR Spectroscopy

Crystalline powders were melt-quenched between two CaF2 windows (16 mm diameter;

0.5 mm thickness). Spectra were collected, as a function of temperature, using an IR

microscope (Thermo-Nicolet Continuum FTIR Spectrometer with a mercury cadmium

telluride detector; Thermo Electron, Waltham, MA) equipped with an FDCS 196 freeze-

drying cryostage (Linkam Scientific Instruments, U.K.). The FTIR scan resolution was 4

cm−1

, and 128 IR scans were averaged to obtain each spectrum in the 4000−900

cm−1

wavenumber range. The stage was initially set at -20 °C and then heated to 110 °C

at 2 °C/min. The IR spectra were analyzed using OMNIC (Thermo-Nicolet) and Peakfit4

software (Systat Software, San Jose, CA).

74


3.4.1. Influence of Structure on α-relaxation Time

Dielectric spectroscopy yielded a direct measure of the rotational relaxation times in

supercooled (T > Tg) NIF and FEL. Both the compounds exhibited well resolved α-

relaxation peaks which shifted to lower frequencies with an increase in temperature,

indicating faster mobility and shorter relaxation times (Figure 3.2). The dielectric

strength (∆ε = εs - ε) of NIF (∆ε = ~ 21) was higher than that of FEL (∆ε = ~ 13).

Dielectric strength can be expressed using the Kirkwood-Fröhlich-Onsager equation

(Equation 2) 14

… Equation 2

where µ is the dipole moment, N is the number of dipoles and V is the volume of sample.

Based on Equation 2 the higher ∆ε value for NIF could be attributed to the density

differences or a difference in the dipole moment. The true density for NIF and FEL are

1.2 g/cm3 and 1.28 g/cm

3. The molecular weight of NIF and FEL are 346 g/mol and 384

g/mol. The marginally larger number of NIF molecules (~ 4% more) cannot explain the

large differences in the dielectric strength of the two compounds. NIF may have a higher

dipole moment due to the polarization of the molecule caused by the higher electron

withdrawing capacity of the nitro (NO2) group as compared to the chloride (Cl) in FEL.

A greater degree of association between FEL molecules may also lower the overall dipole

moment.15

Interestingly, as is evident from Figure 3.2, FEL exhibited a longer relaxation time (~2.5

times) than NIF. The temperature dependence of the relaxation times in the model

compounds is provided in the Figure 3.3. Given the already established relationship

75

between mobility and physical stability, these results strongly suggest that the faster

mobility in NIF can explain its higher propensity to crystallize. Fitting the VTFH

equation to the dielectric data revealed slight differences in the fragility (measured by the

D value, the strength parameter) of the two compounds. The D value of NIF was ~ 8

whereas it was 9 for FEL. The slightly higher D value suggests stronger intermolecular

interactions in FEL.

3.4.2. Influence of Structure Hydrogen Bonding Interactions

The next objective was to identify the possible reasons for the observed difference in the

molecular mobility of the two compounds. Detailed analyses of the NH stretching

vibration provided a measure of the difference in hydrogen bonding interaction (strength

and extent) between the two compounds. A comparison of the wavenumber temperature

coefficients (WTC) of the NH stretching vibration peak, suggests a possible relationship

between hydrogen bonding and molecular mobility. As reported previously, the WTC for

FEL (0.110 cm-1

/°C) was smaller than that of NIF (0.145 cm-1

/°C).16

Thus, the

supercooled FEL structure is less sensitive to changes in temperature, an interpretation

also borne out by its slightly higher D value.

To quantify the strength and extent of intermolecular hydrogen bond interactions in FEL,

the NH peak was deconvolved, using Voigt functions, into two populations. Based on

literature, the peak at 3342 cm-1

was assigned to the non-hydrogen bonded NH and the

neighboring peak (on the lower wavenumber side) to the hydrogen bonded population

(Figure 3.4 (a)).17

The peak at ~ 3250 cm-1

can be attributed to a two phonon vibration

involving the carbonyl vibration in Fermi resonance with the fundamental NH stretching

vibration.18

The strength and extent of hydrogen bonding were determined using a

method developed by Wang et al. which accounts for the wavenumber dependence of the

IR absorption coefficient of the NH bond.19

A plot of the fractions of hydrogen bonded

and free drug as a function of temperature is provided in the Figure 3.5. At the glass

transition temperature, ~50 % of molecules were hydrogen bonded and this fraction

76

decreased linearly with increasing temperature. Using a two state dissociation model

(Equation 3),

(

) … Equation 3

The hydrogen bonded and free fractions can be related to the change in the Gibbs free

energy ( ), and therefore the enthalpy (

) and entropy ( ) of hydrogen bond

dissociation. For FEL, the enthalpy and entropy of hydrogen bonding was 12 kJ/mol and

29 J/mol·K, respectively. A similar analysis in amorphous polyurethane revealed an

enthalpy of 9.6 kJ/mol for the NH…CO hydrogen bond.

3.4.3. Role of Hydrogen Bonding Interactions on Molecular Mobility

Similarly, the NH peak of NIF was also deconvolved into two populations: (i) NH…CO

hydrogen bond at ~3342 cm-1

and (ii) free NH at ~3416 cm-1

(Figure 3.4 (b)). However, a

comparison of the fitted profile with the experimental data, suggested a third

“population” with a peak at ~3390 cm-1

(based on the residuals). This population could

be attributed to the interaction of the NH group with either the NO2 group or the -ring in

NIF. Hydrogen bonding motifs not observed in the crystalline form may occur in the

amorphous state because of the increased conformational diversity in this state as seen in

indomethacin.20

Hydrogen bonding between the NH and NO2 groups has been reported in

other compounds, including N,N’-diethyl-4-nitrobenzene-1,3-diamine.21

Hydrogen

bonding between NH and -rings was observed in amorphous polyeurethane at a similar

wavenumber (~3400 cm-1

). In either case this can be classified as a “weak” hydrogen

bond since there is a small peak shift (~26 cm-1

) relative to the free NH. Due to the

presence of a third population, the two state model could not be used and the the

hydrogen bond strength (∆H) was estimated using the empirical relationship (Equation

4).17

77

( ) … Equation 4

which relates the change in the stretching vibration (∆) of the H-bond donor group to

the H-bonding enthalpy. Using this relationship, the enthalpy of the “unknown NH”

hydrogen bonded population was ~ 6.6 kJ/ mol and the NH…CO hydrogen bond

enthalpy was ~ 11 kJ/ mol. Therefore the unknown NH population is more weakly

hydrogen bonded than the NH…CO hydrogen bond. The similar NH…CO hydrogen

bond enthalpies in NIF (11 kJ/mol) and FEL (12 kJ/mol) can be explained by their

similar intermolecular hydrogen-bonding motif.

The “unknown” NH population at ~3390 cm-1

was very weakly hydrogen bonded and

was therefore assumed to exist in a relatively “free” and consequently mobile state. To

considerably simplify the NIF FTIR analysis and use the two state model, we assumed

that, the “free” NH is a combination of the free and very weakly hydrogen bonded

(“unknown” NH population) molecules (Figure 3.4 (c)). Using the approach described

earlier for FEL, we found the enthalpy and entropy of “hydrogen bonding” for NIF to be

~ 7 kJ/mol and 23 J/mol·K, respectively. The enthalpy value obtained for NIF does not

agree with FEL. This is due to the fact that fitted enthalpy and entropy values for NIF are

associated with the conversion of the strongly hydrogen bonded population to the mobile

(combined; free + weakly hydrogen bonded) population. In this analysis we assumed that

only the mobile population would participate in the viscous flow.

Our ultimate goal was to relate the hydrogen bond interaction (strength and extent) to the

molecular mobility in the two model compounds. This relationship was expected based

on the argument that viscous flow is derived from broken bonds.10

The temperature

dependence of viscosity in the supercooled state can then be expressed by 10,22

( ) (

) [ (

)] … Equation 5

78

where C and D are the entropy and enthalpy of bond dissociation, respectively. Based on

the Maxwell model, the viscosity, η, is directly proportional to the relaxation time, τ.

Therefore, we can use Equation 5 to also model the relaxation time data. Since we are

only interested in the effect of hydrogen bonding on mobility, A and B can be treated as

fitting parameters, and therefore combined into a single term given by ( )

(

). The relaxation time can then be described by the Equation 6.

( ) [ (

)] … Equation 6

The estimates of the entropy (C) and enthalpy (D) of hydrogen bond formation obtained

from the FTIR data were used to fit the equation to relaxation time data of FEL. Clearly,

a good fit could be obtained (Figure 3.6).

Our final objective was to predict the relaxation times of NIF based on the hydrogen

bonding analyses of its FTIR data. To accomplish this, we again use Equation 6. Given

the structural similarity between FEL and NIF, the f(T) (obtained from fitting the

relaxation time data of FEL to Equation 5) values for the two compounds were assumed

to be identical. The predicted and the observed relaxation times were in good agreement,

especially at lower temperatures. The above analysis suggests that the differences in

hydrogen bonding between NIF and FEL molecules lead to the observed differences in

molecular mobility and perhaps crystallization.

79

3.5. Conclusions

Our results reveal a direct link between intramolecular hydrogen bonding interactions and

molecular mobility (measured as structural relaxation time) in amorphous organic

compounds. This study provides physical insights into why structurally similar

compounds, due to differences in their hydrogen bonding interactions, can exhibit

pronounced differences in molecular mobility. These results are critical in light of the

role of molecular mobility on the physical stability (crystallization propensity and

kinetics) of amorphous compounds. A potential practical application of this work is in the

field of pharmaceutical solid dispersion development. Drug-polymer hydrogen bonding

can be a tool to modulate the physical stability of the drug, both during preparation of the

dispersion but also during its storage.

80

Figure 3.1: Structures of (a) FEL and (b) NIF. The differences in their structures have

been highlighted. The hydrogen bond donor (NH group) in both the model compounds is

marked with an *.

81

Figure 3.2: Dielectric permittivity (left y-axis) and dielectric loss (right y-axis) at 60 °C

for melt quenched samples of (a) FEL and (b) NIF.

82

Figure 3.3: α-relaxation time in NIF and FEL from 50 – 75 °C

1000* T-1

(K-1

)

2.85 2.90 2.95 3.00 3.05 3.10

Rela

xation tim

e (

s)

1e-5

1e-4

1e-3

1e-2

1e-1

1e+0

1e+1

FEL

NIF

83

Figure 3.4. (a) Deconvolution of the IR spectrum of FEL in the NH stretching region. (b)

Deconvolution of the IR spectrum of NIF in the NH stretching region using (a) “fixed”

parameters for the free NH population (obtained from fitting FEL), and (b) no fixed

parameters. Only the free and H-bonded NH populations are shown. The residuals for the

overall fit are shown. The residuals in (3b) are not randomly distributed and suggest the

presence of a third population.

Abso

rban

ce

0.1

0.3

0.5

0.7

0.9

1.1

1.3FEL

Overall Fit

H- Bonded

Free

Wavenumber (cm-1)

3150 3200 3250 3300 3350 3400 3450 3500 3550

-0.03

0.00

0.03

Abso

rban

ce

0.1

0.3

0.5

0.7

0.9

1.1

1.3

1.5

1.7

NIF

Overall Fit

H- Bonded

Free

Wavenumber (cm-1)

3150 3200 3250 3300 3350 3400 3450 3500 3550

-0.18

0.00

0.18

Abso

rban

ce

0.1

0.3

0.5

0.7

0.9

1.1

1.3

1.5

1.7

NIF

Overall Fit

H- Bonded

Free

Wavenumber (cm-1)

3150 3200 3250 3300 3350 3400 3450 3500 3550

-0.18

0.00

0.18

(a) (b)

(c)

84

Figure 3.5: A plot of the temperature dependence of the hydrogen bonded and free NH

populations in felodipine.

Temperature ( C)

40 50 60 70 80 90 100 110Fra

ctio

n (

fre

e a

nd H

-bon

de

d p

opu

latio

ns)

0.2

0.3

0.4

0.5

0.6

0.7

0.8

H-bonded

Free

85

Figure 3.6: Plot of logarithm of relaxation time of FEL and NIF as a function of inverse

temperature. Equation 6 has been fitted to the FEL data. The line for NIF is predicted

using Equation 5.

86

3.6 References





(1), 47-60.










2012, 9 (11), 3209-3217.





2012, 9 (6), 1748-1763.

8. Dantuluri, A. K. R.; Amin, A.; Puri, V.; Bansal, A. K., Role of Α-Relaxation on



87

9. Kothari, K.; Ragoonanan, V.; Suryanarayanan, R., Influence of Molecular

Mobility on the Physical Stability of Amorphous Pharmaceuticals in the Supercooled and

Glassy States. Molecular Pharmaceutics 2014.

10. Doremus, R. H., Viscosity of Silica. Journal of Applied Physics 2002, 92 (12),

7619-7629.


Glass. Pharm Res 2006, 23 (5), 967-979.

12. Marsac, P.; Konno, H.; Taylor, L., A Comparison of the Physical Stability of

Amorphous Felodipine and Nifedipine Systems. Pharm Res 2006, 23 (10), 2306-2316.

13. Zhou, D.; Zhang, G. G. Z.; Law, D.; Grant, D. J. W.; Schmitt, E. A., Physical

Stability of Amorphous Pharmaceuticals: Importance of Configurational Thermodynamic

Quantities and Molecular Mobility. Journal of Pharmaceutical Sciences 2002, 91 (8),

1863-1872.

14. Schönhals, A.; Kremer, F., Theory of Dielectric Relaxation. In Broadband

Dielectric Spectroscopy, Kremer, F.; Schönhals, A., Eds. Springer Berlin Heidelberg:

2003; pp 1-33.

15. Morgan, S. O.; Yager, W. A., Dielectric Properties of Organic Components

Relation to Chemical Composition and Physical Structure. Industrial & Engineering

Chemistry 1940, 32 (11), 1519-1528.

16. Tang, X.; Pikal, M.; Taylor, L., The Effect of Temperature on Hydrogen Bonding

in Crystalline and Amorphous Phases in Dihydropyrine Calcium Channel Blockers.

Pharm Res 2002, 19 (4), 484-490.

17. Tang, X.; Pikal, M.; Taylor, L., A Spectroscopic Investigation of Hydrogen Bond

Patterns in Crystalline and Amorphous Phases in Dihydropyridine Calcium Channel

Blockers. Pharm Res 2002, 19 (4), 477-483.

88

18. Coleman, M. M.; Lee, K. H.; Skrovanek, D. J.; Painter, P. C., Hydrogen Bonding

in Polymers. 4. Infrared Temperature Studies of a Simple Polyurethane. Macromolecules

1986, 19 (8), 2149-2157.

19. Wang, F. C.; Feve, M.; Lam, T. M.; Pascault, J.-P., Ftir Analysis of Hydrogen

Bonding in Amorphous Linear Aromatic Polyurethanes. I. Influence of Temperature.

Journal of Polymer Science Part B: Polymer Physics 1994, 32 (8), 1305-1313.

20. Xiang, T.-X.; Anderson, B. D., Molecular Dynamics Simulation of Amorphous

Indomethacin. Molecular Pharmaceutics 2012, 10 (1), 102-114.

21. Payne, T. J.; Thurman, C. R.; Yu, H.; Sun, Q.; Mohanty, D. K.; Squattrito, P. J., . .

. Kirschbaum, K., N,N'-Diethyl-4-Nitrobenzene-1,3-Diamine, 2,6-Bis(Ethylamino)-3-

Nitrobenzonitrile and Bis(4-Ethylamino-3-Nitrophenyl) Sulfone. Acta Crystallographica

Section C 2010, 66 (7), o369-o373.

22. Ojovan, M. I.; Travis, K. P.; Hand, R. J., Thermodynamic Parameters of Bonds in

Glassy Materials from Viscosity–Temperature Relationships. Journal of Physics:

Condensed Matter 2007, 19 (41), 415107.

89

Chapter 4

Influence of Molecular Mobility on the Physical Stability of

Amorphous Pharmaceuticals in the Supercooled and Glassy

States

90

4.1. Synopsis

We investigated the correlation between molecular mobility and physical stability in

three model systems – griseofulvin, nifedipine and nifedipine-PVP dispersion and

identified the specific mobility mode responsible for instability. The molecular mobility

in the glassy as well as the supercooled liquid states of the model systems were

comprehensively characterized using dynamic dielectric spectroscopy. Crystallization

kinetics was monitored by powder X-ray diffractometry using either a laboratory (in the

supercooled state) or a synchrotron (glassy) X-ray source. Structural (α-) relaxation

appeared to be the mobility responsible for the observed physical instability at

temperatures above Tg. While the direct measurement of the structural relaxation times

below Tg were not experimentally feasible, dielectric measurements in the supercooled

state were used to provide an estimate of the α-relaxation times as a function of

temperature in glassy pharmaceuticals. Again, there was a strong correlation between the

α-relaxations and physical instability (crystallization) in the glassy state but not with any

secondary relaxations. These results suggest that structural relaxation is a major

contributor to physical instability both above and below Tg in these model systems.

4.2. Introduction

For drugs with poor aqueous solubility, formulation in the amorphous state offers a

potential for enhanced oral bioavailability.1 However, the excess free energy and the

associated thermodynamic instability can cause crystallization and may negate the

bioavailability advantage brought about through the enhanced solubility.2-3

It is therefore

critical to ensure that the drug is retained in the amorphous state during processing and

storage. Extensive efforts have been directed towards understanding the causes of

physical instability (i.e. crystallization tendency) in amorphous pharmaceuticals.4-5

In

particular, several studies have investigated the possible correlation between molecular

mobility and physical instability.4-8

Recently, Bhardwaj et al established a correlation

91

between the global mobility (structural or α-relaxation) and the physical stability of

amorphous itraconazole and trehalose.9-10

Such a link has also been established for

several other pharmaceuticals (indomethacin, felodipine, flopropione and celecoxib) in

the supercooled state (T > Tg).11-12

However, amorphous pharmaceuticals are usually

stored in the glassy state (T < Tg). Hence, from a practical standpoint, it is of importance

to understand the role of structural mobility on the physical stability of glassy

pharmaceuticals. In addition to the α-relaxation, it is recognized that local mobility (β-

relaxations; fast non-cooperative motions of individual molecules or parts of molecules),

which is significant below the glass transition temperature, could also be influencing

stability.4 This necessitates, ideally the measurement, or at the very least the calculation

of the relaxation times of the different modes of mobility below Tg.

The viscosity of a supercooled liquid and the time scale for molecular motions increase

dramatically (typically 10-12 orders of magnitude between melting temperature and Tg)

as the temperature is lowered towards Tg.13

Below Tg, the molecules are essentially

‘frozen in’ due to the extremely high viscosity of the glassy phase and the reorientation

motion of the molecules cannot keep up with the decrease in temperature resulting in an

observed deviation of the measured timescales of molecular motions from the

‘equlibrium supercooled liquid’. The α-relaxation times for supercooled liquids are

usually in the nanosecond range, whereas, below Tg, relaxation times are extremely long

(> 100 s) and often longer than the time scale of experimental observation.13-14

In

supercooled liquids, the temperature dependence of the α-relaxation time can be

described by the Vogel-Tamman-Fulcher-Hesse (VTFH) model (Equation 1), whereas in

the glassy state the relaxation behavior has been often described by the Adam-Gibbs-

Vogel (AGV) model (Equation 2).15-21

(

( )) … Equation 1

92

(

( ( )) … Equation 2

In the above equations, τ is the relaxation time, D is a measure of fragility of the system,

τ0 is the pre-exponential relaxation factor, T0 is the zero mobility temperature and Tf is the

fictive temperature at which the glassy state will have the same macroscopic properties as

the ‘equilibrium supercooled liquid’. The concept of Tf was introduced by Tool to explain

the departure of the structural relaxation time from the equilibrium values below Tg.22-23

In contrast, β-relaxations generally obey an Arrhenius temperature dependence (Equation

3).4, 24

(

( )) … Equation 3

where, R is the gas constant and Eaβ the activation energy for β-relaxations, which

usually has a much smaller value than for α-relaxations.

Molecular mobility measurement in the glassy state can be challenging. Bhattacharya and

Suryanarayanan have listed the techniques available to measure molecular mobility in the

glassy state and their advantages and limitations.4 Calorimetric techniques, in light of the

ease of data collection and analyses, are very popular. Using isothermal microcalorimetry

and differential scanning calorimetry (based on enthalpic recovery measurement), Bhugra

et al successfully predicted the crystallization time of several glassy pharmaceuticals near

Tg, but not at temperatures significantly below Tg.11, 25

Calorimetric techniques provide

an “average” measure of relaxation time and are unable to distinguish between the

different modes of molecular motions. Since the physical stability may be correlated to a

specific molecular mobility, this approach may not provide nuanced information. On the

93

other hand, broadband dynamic dielectric spectroscopy (BDS, the terms dielectric

spectroscopy and BDS have been used interchangeably throughout the manuscript),

probes the reorientation of dipoles under an electric field applied at specific frequencies

allowing a direct measure of the relaxation time. The wide frequency and temperature

range enables a systematic analysis of the different mobility modes (primary and

secondary motions) both above and below Tg. In the glassy regime, BDS has been

extensively used to study local motions. Based on investigation of over 100 protein

systems, Cicerone et al demonstrated that the local dynamics were correlated with storage

stability.26

Crystallization in amorphous fulvene and indomethacin at T < Tg was also

circumstantially attributed to β-relaxation.27-28

On the other hand, in several glasses of pharmaceutical interest, including nifedipine,

celecoxib and several macrolide antibiotics, structural relaxation times below Tg were

closely coupled to crystallization.29-31

However, due to the extremely long time scales of

these molecular motions, in none of these investigations, the α-relaxation times were

directly measured. Therefore different approaches have been attempted to estimate the

structural relaxation time.29-32

For example, in nifedipine and griseofulvin, the structural

relaxation time below Tg was calculated using the AGV model and the heating rate

dependence of Tg characterized by calorimetry.30,32

Using dielectric spectroscopy,

coupled with time temperature superposition, the structural relaxation time was

determined in celecoxib, azithromycin, clarithromycin and roxythromycin. 29,31

While,

both α and β-relaxations can influence the physical stability in the glassy state, very few

studies have systematically and comprehensively characterized all the mobility modes

which may influence crystallization in the temperature range of interest. The first

objective of our work was to characterize, using dielectric spectroscopy, both global and

local motions in two model glasses (nifedipine and griseofulvin). Since the structural

relaxation times in the glassy state could not be experimentally measured, they were

calculated using Equation 2. The second objective was to determine the potential

correlation between each of these mobility modes and the crystallization kinetics in these

systems. The use of highly sensitive synchrotron X-ray diffractometry enabled these

94

quantitative studies. Finally, our investigations were extended to nifedipine–

polyvinylpyrrolidone (PVP) solid dispersion. These studies enabled the development of

correlation models which permit prediction of crystallization kinetics in glasses of

interest. The ultimate goal of our investigation is to enable the development of

stabilization approaches based on modulating the specific mobility responsible for

physical instability.


4.3.1. Materials and Methods

Griseofulvin (C17H17ClO6; Glaxo Laboratories, Canada; Purity > 98 %) and nifedipine

(C17H18N2O6; Laborate Pharmaceutical Ltd, India; purity > 98 %) were used without

further purification. Polyvinylpyrrolidone (PVP) (K12 grade) was supplied by BASF

Corporation.

4.3.2. Preparation of Amorphous Materials

Amorphous drugs (nifedipine and griseofulvin) were prepared by melting in aluminum

pans (~5 °C above the melting point of the drug; 180 °C for nifedipine and 225 °C for

griseofulvin) and then quenching on aluminum blocks precooled to -20 °C. The

nifedipine-PVP solid dispersion was prepared by a solvent evaporation technique

followed by melt quenching. Physical mixtures of nifedipine (97.5 % w/w) and PVP (2.5

% w/w) were dissolved in acetone, and the solvent evaporated at 40 °C under reduced

pressure (IKA-HB10 digital system, Werke GmbH and Co. Staufen, Germany). The

mixture was further dried under vacuum at room temperature for 24 h and then the melt

was quenched from ~5 °C above the melting point of the drug to obtain the solid

dispersions. The melt-quenched materials were lightly crushed using a mortar and pestle

in a glove box at room temperature (RH < 5 %). The amorphous materials were stored at

-20 °C in desiccators containing anhydrous calcium sulfate until further use.

95

4.3.3.Karl Fischer Titrimetry

The water content in the amorphous materials was determined coulometrically using a

Karl Fischer titrimeter (Model DL 36 KF Coulometer, Metler Toledo, Columbus, OH).

Accurately weighed samples were directly added to the Karl Fischer cell and the water

content was determined.



equipped with a refrigerated cooling accessory was used. The instrument was calibrated

with tin and indium. In a glove box, the powder was accurately weighed and sealed

hermetically in aluminum pans. All the measurements were done under dry nitrogen

purge (50 mL/min) at a heating rate of 10 °C/min.

4.3.5. Powder X-ray Diffractometry (XRD)


with a variable temperature stage (TTK 450; Anton Paar, Graz-Straßgang, Austria) and Si

strip one-dimensional detector (LynxEyeTM

; Bruker AXS) was used. These isothermal

crystallization studies were conducted in the nifedipine systems at four temperatures, all

above Tg (55 to 70 °C). Samples were periodically exposed to Cu K radiation (40 kV x

40 mA) over an angular range of 6 – 27° 2θ with a step size of 0.04° and a dwell time of

0.5 s.

96

4.3.6. Synchrotron XRD (SXRD)

Isothermal crystallization studies below Tg were conducted in all the model systems at 4

temperatures (25 to 45 °C). The samples were stored at the desired temperature and then

exposed to synchrotron radiation (17-BM-Sector; 0.72910 Å; Argonne National

Laboratory, IL) in hermetically sealed DSC pans (in a glove box maintained at RH< 5

%). The sample to detector distance was set at 900 mm. The calibration was performed

using Al2O3 (NIST; SRM-647a) standard. The two-dimensional (2D) data were

integrated to yield one-dimensional (1D) d spacing (Å) or 2θ (°) scans using the FIT2D

software developed by A. P. Hammersley of the European Synchrotron Radiation

Facility.

4.3.7. Quantification of XRD Data

At each storage time point the crystallinity index was calculated using Equation 4. The

crystallinity index can be equivalent to the % crystallinity in the sample, if the total

integrated intensity (crystalline + amorphous) remains constant throughout the isothermal

crystallization experiment.33

(Figure 4.1)

… Equation 4

A custom built program (using Fortran 77®; Tuscan, AZ) was used to quantify

crystallinity. In this program, the amorphous intensity contribution was based on the

experimental XRD pattern of the amorphous “reference” material (preparation method is

provided above). The subtraction of the amorphous intensity from the total pattern

yielded the intensity contribution from the crystalline peaks. The percent crystallinity was

97

plotted as function of time, and a characteristic crystallization time (tc) was obtained for a

desired level of crystallization (either 0.5 or 10 %).








and βHN).

HNHN

HNi

))(1()(*

… Equation 5





symmetric (αHN) and asymmetric (βHN) peak broadening with 0 < αHN (or βHN) < 1. At

higher temperatures, the contribution of conductivity was observed on the low frequency

side of the dielectric spectra. This was taken into consideration by adding the

conductivity component, σ0/iεsω to the HN equation where, σ0 is the dc conductivity.

The powder was filled between two gold plated copper electrodes (20 mm diameter)

using a PTFE ring (thickness: 1 mm; area: 59.69 mm2; capacitance: 1.036 pF) as a spacer.

The spacer confined the sample between the electrodes Measurements were corrected for

stray capacitance, spacer capacitance and edge compensation.

98


4.4.1. Characterization:

The model amorphous materials were observed to be X-ray amorphous. The glass

transition temperatures, determined by DSC (Griseofulvin – 90.2 Nifedipine –

46.2 ; Nifedipine-PVPK12 – 46.6 ; determined using a 10 °C/min

heating rate) were in excellent agreement with the literature values.30, 34

The DSC heating

curves are included in Figure 4.2. Karl Fischer titrimetry revealed a water content < 0.5%

w/w.

4.4.2. Analysis of Dielectric Spectra

For the dielectric spectroscopy experiments, isothermal frequency sweeps were

conducted at several temperatures ranging from (Tg – 50 °C) to (Tg + 50 °C). At each

temperature, the frequency range traversed was 10−2

to 107 Hz and the measurement time

ranged from 6 to 15 min.

4.4.3. Relaxation Behavior in the Supercooled State

We investigated two model drugs, griseofulvin and nifedipine and nifedipine-PVP solid

dispersion. The dielectric spectra of amorphous griseofulvin revealed a well resolved α-

relaxation peak in the temperature range of 95 to 118°C (Figure 4.3 (a)). At temperatures

higher than 118°C, due to crystallization of the amorphous griseofulvin during the DES

run, the temperature dependence of the α-relaxation could not be monitored. For

nifedipine (Figure 4.3 (b)) as well as nifedipine–PVP solid dispersions (Figure 4.4), the

α-relaxation was observed in the temperature range of 45 to 75 °C. In all the three model

systems, with an increase in temperature, the α-relaxation peak moved towards higher

frequencies indicating an increase in the overall mobility i.e. shorter relaxation time. The

99

decrease in the magnitude of the dielectric loss peak with an increase in temperature is

indicative of the progressive sample crystallization. The average α-relaxation time for all

the model compounds was determined using the HN model (Equation 5) at several

temperatures above Tg and its temperature dependence could be described by the VTFH

model (Equation 1). Figures 4.5 (a) and 4.5 (b) reveal the temperature dependence of α-

relaxation time in griseofulvin and nifedipine respectively. The VTFH parameter values

obtained from model fitting of the relaxation time data (representative example given in

the Figure 4.6) are provided in Table 4.1 (Sigmaplot®; Systat Software; San Jose, CA).

The values in the first two columns were obtained by fixing the pre-exponent (τ0) value to

10-14

s, the quasi lattice vibration period.13

The strength parameter (D) for nifedipine

(drug as well as dispersion) was ~ 7.8 and for griseofulvin ~6.5, reflecting that these were

fragile glass formers. These results were not in good agreement with the parameter values

obtained using differential scanning calorimetry.30, 32, 35

Using a τ0 value of 10-17

s, Goresy

and Böhmer calculated the D and T0 to be 12.9 and 242 K respectively for nifedipine.36

Using this value for τ0, our results (Table 4.1; columns 3 and 4) were in excellent

agreement with the literature values. Using the VTFH parameters (Table 4.1; Column 1

and 2) and τ = 100s at Tg, the dielectric Tg of the model systems were calculated

(Griseofulvin – 89 °C Nifedipine – 43°C; Nifedipine-PVPK12 – 42.5 °C). These values

were in good agreement with the calorimetric Tg values.

4.4.4. Relaxation Behavior in the Glassy State

The structural relaxation times of all the model glasses were extremely long and outside

the frequency range of the dielectric spectrometer. Since a direct experimental

measurement was not possible, we calculated the relaxation time using the AGV model

(Equation 2) and the parameters obtained from the VTFH equation (Table 4.1; Columns 1

and 2). In other studies of these model systems, Tf was assumed to be same as the Tg

(calorimetric).30, 32

The basis of this approximation is that the configurational entropy

does not change significantly with temperature for most freshly prepared and rapidly

100

quenched fragile glasses.37

In the sub-Tg range, for griseofulvin, a weaker relaxation peak

was observed, attributed to β- or local relaxation (Figure 4.7). The β-relaxation followed

an Arrhenius temperature dependence and the activation energy was 58.2 kJ/mol (Figure

4.5a). The calculated value of Eaβ/RTg was 19.4, close to the value of 24 observed for the

Johari-Goldstein (JG) relaxation of several glass formers.38

In both nifedipine and

nifedipine-PVP systems, an excess wing was observed, attributable to β-relaxation. Due

to the weak nature of the signal, its temperature dependence could not be ascertained.

Goresy and Böhmer also observed an excess wing in amorphous nifedipine and

acetaminophen alloys.36

In addition, at very low temperatures, a local relaxation

exhibiting Arrhenius temperature dependence was detected in nifedipine (literature data

in Figure 4.5b).36, 39

4.4.5. Crystallization – Above and Below Tg

As expected, above Tg the crystallization was rapid and was monitored continuously in

the XRD. Progressive drug crystallization from the nifedipine solid dispersions was

evident from the increase in intensity of the XRD peaks of the dispersion held

isothermally at 60 °C (Figure 4.8 (a)). The time taken for 10 % of the drug to crystallize,

tc, was calculated (Figure 4.8 (b)). By carrying out the experiments at several

temperatures, the temperature dependence of tc was obtained. Similar experiments were

carried out for nifedipine to obtain tc. In case of griseofulvin, the crystallization kinetics

data from the literature were used to obtain τcry from the crystallization rate constant using

the Johnson-Mehl-Avrami equation (Figure 4.9).32

In the glassy systems, our intent was to measure the crystallization onset down to 40 °C

below Tg. The enhanced sensitivity of the synchrotron source at the Argonne National

Laboratories enabled us to measure low levels of crystallization (0.5 %) in glassy

griseofulvin (representative data Figure 4.10). In case of nifedipine systems, the drug

crystallization was very rapid even at (Tg – 15 °C). Therefore, the time taken for 10 %

101

crystallization was determined. Figure 4.11 (a) contains representative SXRD patterns

revealing the progressive crystallization of amorphous nifedipine at 40 °C. The patterns

were integrated to obtain the 1D-XRD patterns, and the time taken for 10% drug

crystallization was calculated (Figure 4.11 (b)).

4.4.6. Correlation of Crystallization with Molecular Mobility

Equation 6 enabled us to examine the coupling between the crystallization time (τcry/tc)

and the average relaxation time (τ) in the supercooled as well as the glassy states.9-10

( ) ( ) … Equation 6

where A is a constant and M is the coupling coefficient. A coupling coefficient value

close to unity, suggests that the two processes are strongly coupled. This equation is

based on the relationship between any diffusion limited process and viscosity.5

In the supercooled state, for all the model systems studied, the coupling coefficient value

was ~0.64 (Griseofulvin – 0.65 Nifedipine –0.62 ; Nifedipine-PVPK12 –

0.67 ) indicating substantial but not very strong coupling between crystallization

and the mobility measured by BDS (Figure 4.13). Dielectric spectroscopy can measure

only rotational mobility (i.e. reorientation of dipoles) in amorphous solids. Two modes of

molecular motions – rotational (τr) and translational (τt) have been observed in

supercooled liquids which are related to the viscosity (η) by the Debye (Equation 7) and

the Stokes-Einstein (Equation 8) equations respectively.32, 40

102

… Equation 7

… Equation 8

In the above equation, Dtrans and Drot are the translational and rotational diffusivities

respectively, r is the radius of the molecule, kB is the Boltzmann constant, and T is

absolute temperature. In the supercooled temperature regime, rotational motions and

viscosity exhibit the same temperature dependence.13-14, 16

A similar relationship exists

between translational motions and viscosity at temperatures > 1.2Tg. However, between

Tg and 1.2Tg, the temperature range for the crystallization studies, the two motions were

observed to decouple in several fragile liquids.40-44

In this temperature range only the

rotational motions and viscosity remain coupled. The Dtrans were observed to be an order

of magnitude higher than that predicted by the Stokes-Einstein equation.13

While the

diffusion coefficient of nifedipine is not reported, it has been suggested that it would be

close to that of indomethacin since the relaxation times of the two compounds are very

close over a wide temperature range.45

Based on the bulk diffusivity of indomethacin, the

coupling coefficient between translational diffusion and rotational motions in nifedipine

was found to be 0.77 (Figure 4.12). This indicates that there exists a decoupling between

these two kinds of motions between Tg and 1.2Tg.The coupling coefficient between

crystallization and diffusion was found to be 0.82 (Figure 4.12). These results reveal that

the physical stability of fragile liquids, in the temperature range of Tg to 1.2Tg, may be

better coupled to translational rather than to rotational motions.

Finally, we wanted to identify the specific mobility mode responsible for instability

(crystallization) in the glassy state. This was accomplished in griseofulvin, where we

determined the influence of the structural as well as the JG relaxation on the observed

instability. The JG relaxation times could not be experimentally obtained in the

103

temperature range (25 – 45 °C) where the physical stability was monitored. However,

since the JG is known to exhibit Arrhenius temperature dependence, the relaxation times

could be obtained by extrapolation (Figure 4.5b). Using Equation 6, we found an

excellent coupling between the structural relaxation time and the crystallization kinetics

in glassy griseofulvin; (Figure 4.14 (a)). Such a correlation did not exist with

the JG relaxation (coupling coefficient – 2.6 ). However, since the JG relaxation is

an intermolecular relaxation involving motions of all the molecules in the system, it is

believed to be a precursor to α-relaxation and may indirectly influence the physical

stability.46-48

The indirect influence of the JG relaxation on the physical stability of

amorphous celecoxib has also been recently highlighted.31

In nifedipine systems as well,

the structural relaxation time was a very good predictor of physical instability with

coupling coefficient values of 0.9 for nifedipine and 1.2 for the dispersion

(Figure 4.14 (b) and 4.14 (c)). While coupling coefficients can take values from 0 - 1, the

observed higher value may be attributed to experimental errors. As mentioned earlier, the

temperature dependence of JG relaxation could not be ascertained. However, at

temperatures << Tg, secondary relaxations in amorphous nifedipine have been identified.

Using the reported temperature dependence, we calculated the relaxation times at

temperatures of interest to us.36,39

However, the coupling model revealed that the

crystallization kinetics in the glassy state was not linked to these faster secondary

motions observed in glassy nifedipine (coupling coefficient – 1.8 ). In summary,

our results reveal the strong influence of the cooperative α-relaxations on the physical

stability of glassy nifedipine and griseofulvin systems.

It has recently been established that surface crystallization is also an important driver of

instability in both nifedipine and griseofulvin.34,45

This rapid surface crystallization may

in turn then induce crystallization in the bulk. However, since our measurements, in both

BDS and XRD are carried out on bulk samples and it is therefore difficult to tease out the

contribution of surface mobility.

104

4.5. Conclusion

In light of the challenges with the direct measurement of the structural relaxation times

below Tg, dielectric measurements in the supercooled state provided a quick estimate of

the α-relaxation times as a function of temperature in glassy pharmaceuticals.

Crystallization kinetics in the supercooled state was investigated using a laboratory

powder X-ray diffractometer while synchrotron radiation enabled similar studies in the

glassy state. There was a strong correlation between the cooperative α-relaxations and

physical instability (crystallization) in both glassy and supercooled griseofulvin,

nifedipine and in nifedipine-PVP dispersion.

105

Table 4.1: VTFH (Equation 1) parameter values obtained from model fitting of the

relaxation time data (standard error of fitting in parenthesis). The pre-exponent (τ0) value

was assumed to be either 10-14

s (first two columns) or 10-17

s (last two columns). The

results of Goresy and Böhmer are marked with an *36

Sample DT0 T0 (K) DT0 T0 (K)

τ0 = 10-14

s τ0 = 10-17

s

Nifedipine 1994 (37) 262 (1.2) 3066 (34)

3129*

245 (0.9)

242*

Nifedipine – PVP 2008 (63) 261 (3.6)

Griseofulvin 1996 (54) 308 (1.9)

106

Figure 4.1: A representative plot of the total integrated intensity (crystalline +

amorphous) during the isothermal crystallization studies of amorphous nifedipine at 60

°C.

107

Figure 4.2: DSC heating curves (10 °C/min) of nifedipine-PVP, nifedipine and

griseofulvin.

108

Figure 4.3: (a) Dielectric loss behavior of griseofulvin in the temperature range of 97 to

115°C and (b) nifedipine (50 to 70 °C). For the sake of clarity, the dielectric loss

behavior at only select temperatures is shown.

109

Figure 4.4: Dielectric loss behavior of nifedipine-PVP dispersion in the temperature

range of 50 °C to 70 °C. For the sake of clarity, the data at only select temperatures are

shown.

10-2 10-1 100 101 102 103 104 105 106

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

''

f/Hz

50 C

55 C

60 C

65 C

70 C

110

Figure 4.5: Temperature dependence of α- and β-relaxation times in (a) griseofulvin and

(b) nifedipine. Black circles represent the α-relaxation time at temperatures above Tg and

the blue dashed line is the calculated α-relaxation time in the glassy state. The β-

relaxation times (red circles) in griseofulvin were also obtained experimentally. Mean ±

Relative Error; n = 3. In case of nifedipine, the β-relaxation times were obtained from the

literature (36, 39). The red dashed line is an extrapolation of the β-relaxation time.

111

Figure 4.6: Representative plot from fitting the VTF model to the relaxation time data. F

= 3447; p < 0.001.

T/K

320 330 340 350

Log

s

-5

-4

-3

-2

-1

0

1

2

Nifedipine

95% Confidence Band

95% Prediction Band

112

Figure 4.7: Dielectric loss behavior of β-relaxation in griseofulvin (50 to 85 °C).

113

Figure 4.8: (a) XRD patterns revealing progressive drug crystallization from nifedipine

solid dispersion at 60 °C from 0 min to 60 min. (b) % Crystallinity in nifedipine as a

function of time.

114

Figure 4.9: (a) Plot of α (fraction crystallized) versus time following storage of

amorphous griseofulvin at several temperatures above Tg (digitized from Reference 29),

and the resultant (b) Johnson-Mehl-Avrami (JMA) plots for griseofulvin crystallization

(n=2).

We used the crystallization profiles for griseofulvin (Fig 5a in Reference 29) in order to

determine a characteristic relaxation time, τcry (inverse of the crystallization rate constant,

k). The data was analyzed using the JMA equation,

α =1- exp [-(k(t- t0))n], where α is the fraction crystallized at time t, t0 is the induction

time, and n is the reaction order (n=2; Zhou et al). Fig 4.9b shows the JMA plots for

isothermal crystallization in the conversion range 0.2 < α < 0.8.

Time/min

0 200 400 600 800 1000

0.0

0.2

0.4

0.6

0.8

1.0

115°C

120°C

123°C

125°C

130°C

134°C

139°C

Time/min

0 100 200 300 400 500 600 700

[-ln

(1-

)]1

/n

0.4

0.6

0.8

1.0

1.2

1.4

115°C

120°C

123°C

125°C

130°C

134°C

139°C

115

Figure 4.10: (a) SXRD patterns of amorphous griseofulvin (25 °C) as a function of time

revealing very early crystallization. The dotted lines indicate the position of the

characteristic diffraction rings of crystalline griseofulvin. (b) Corresponding one

dimensional XRD patterns revealing some characteristic diffraction peaks. Peaks marked

with ‘*’ are attributed to the sample holder.

116

Figure 4.11: (a) SXRD patterns in amorphous nifedipine at 40 °C as a function of time

revealing progressive crystallization from the sample. (b) % Crystallinity in nifedipine as

a function of time. Mean ± SD; n = 3.

117

Figure 4.12: (a) Plot of diffusion coefficient versus α-relaxation time in nifedipine. (b)

Plot of crystallization time versus the translational diffusion coefficient. The diffusion

data were obtained from Reference 42.

Log s

-4.0 -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5

Log D

/ m

2/s

-18.0

-17.5

-17.0

-16.5

-16.0

-15.5

log (D) = -0.77 log (τα) – 18.4

55 C

60 C

65 C

70 C

Log D/ m2/s

-18.0 -17.5 -17.0 -16.5 -16.0 -15.5

Log t

c/

s

2.2

2.4

2.6

2.8

3.0

3.2

3.4

3.6

3.8

4.0

4.2

log (tc) = -0.82 log (D) – 10.5

55 C

60 C

65 C

70 C

118

Figure 4.13: (a) Plot of characteristic crystallization time (τcry, inverse of the

crystallization rate constant) versus α-relaxation time in griseofulvin. The crystallization

data was obtained from Reference 29. Plots of crystallization time (tc, time taken for 10

% crystallization) versus α-relaxation time in (b) nifedipine and (c) nifedipine-PVP

dispersion. Mean ± Relative Error; n = 3.

Log /s

-6.0 -5.5 -5.0 -4.5 -4.0 -3.5

Log

cry

/s

2.5

3.0

3.5

4.0

4.5

log (τcry) = 0.65 log (τα) + 6.5

115 C

120 C

123 C

125 C

130 C

134 C

139 C

Log s

-4.0 -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5

Log

tc/s

2.0

2.5

3.0

3.5

4.0

4.5

log (tc) = 0.62 log (τα) + 4.5

70 C

65 C

60 C

55 C

Log /s

-3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5

Log t

c/s

2.0

2.5

3.0

3.5

4.0

4.5

5.0

log (tc) = 0.67 log (τα) + 4.8

70 C

65 C

60 C

55 C

119

Figure 4.14: Plots of crystallization time [tc, time taken for 0.5 % crystallization in (a)

and 10 % (b) and (c)] versus α-relaxation time in (a) griseofulvin, (b) nifedipine, and (c)

nifedipine-PVP dispersion. Mean ± Relative Error; n = 3.

120

4.6 References



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Tarnacka, M.; Paluch, M.; Cal, K., Molecular Dynamics in Supercooled Liquid and

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(2), 384-391.

31. Grzybowska, K.; Paluch, M.; Grzybowski, A.; Wojnarowska, Z.; Hawelek, L.;

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35. Zhou, D.; Grant, D. J. W.; Zhang, G. G. Z.; Law, D.; Schmitt, E. A., A

Calorimetric Investigation of Thermodynamic and Molecular Mobility Contributions to

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the Physical Stability of Two Pharmaceutical Glasses. Journal of Pharmaceutical

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36. Goresy, T. E.; Böhmer, R., Dielectric Relaxation Processes in Solid and

Supercooled Liquid Solutions of Acetaminophen and Nifedipine. Journal of Physics and





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Rademann, K.; Emmerling, F., Crystal Growth Rates and Molecular Dynamics of

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126

Chapter 5

The Role of Drug-Polymer Hydrogen Bonding Interactions on the Molecular

Mobility and Physical Stability of Nifedipine Solid Dispersions

127

5.1. Synopsis

We investigated the influence of drug-polymer hydrogen bonding interactions on

molecular mobility and the physical stability in solid dispersions of nifedipine with each

polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMCAS) and polyacrylic

acid (PAA). The drug-polymer interactions were monitored by FTIR spectroscopy, the

molecular mobility characterized using broadband dielectric spectroscopy and the

crystallization kinetics evaluated by powder X-ray diffractometry. The strength of drug-

polymer hydrogen bonding, the structural relaxation time and the crystallization kinetics

were rank ordered as: PVP > HPMCAS > PAA. The strength influenced the extent of

interaction and, at a fixed polymer concentration, the fraction of the drug bonded to the

polymer was the highest with PVP. Addition of 20 % w/w polymer resulted in ~65-fold

increase in the relaxation time in the PVP dispersion and only ~5-fold increase in

HPMCAS dispersion. In the PAA dispersions, there was no evidence of drug-polymer

interactions and the polymer addition did not influence the relaxation time. Thus, the

strongest drug-polymer hydrogen bonding interactions in PVP solid dispersions

translated to the longest structural relaxation times and the highest resistance to drug

crystallization. Thus drug-polymer interactions, by modulating the molecular mobility,

influenced the drug crystallization kinetics.

5.2. Introduction

A large number of new drug candidates in the pipeline suffer from the problem of

extremely low aqueous solubility.1-2

Several approaches including particle size reduction,

physical (amorphous and other metastable forms) and chemical modifications (salt and

cocrystal) have been employed to improve their oral bioavailability.3-6

In compounds

with extremely low aqueous solubility (according to USP, a compound is considered

insoluble if 1 part of solute dissolves in 10,000 or more parts of solvent), particle size

reduction will often result only in modest bioavailability enhancement (~2-20 fold).3, 7-8

128

Salt formation approach cannot be utilized for neutral molecules without ionizable

functional groups.9 Cocrystal formation is usually limited to active pharmaceutical

ingredients which can hydrogen bond with the coformer, the most common interaction

for cocrystal formation.10

Amorphization is a very promising route to improve the

solubility and consequently the oral bioavailability of these new drug candidates. The

higher free energy of the amorphous form compared to its crystalline counterpart, while

enhancing solubility also confers thermodynamic instability, with the potential for

transition back to the stable crystalline form.11-13

Hence when formulating amorphous

materials, the challenge is to design a robust dosage form which can resist crystallization

during processing, storage as well as dissolution. Solid dispersions (SD), homogenous

drug-polymer mixtures, are known to physically stabilize amorphous drugs.14

Several

mechanisms have been postulated for the physical stabilization brought about by the

polymer.15-17

In order to formulate a robust SD, it is crucial to develop a thorough

understanding of the mechanisms governing physical instability. Currently a large

number of polymers are available for SD development and rational polymer selection is a

challenge.15,18-24

Several polymer screening methodologies have been developed based on

potential stabilization mechanisms. We will investigate the influence of drug-polymer

interactions, specifically hydrogen bonding and molecular mobility, on the physical

stability of drugs in SD.

The role of specific drug-polymer interactions as a mechanism of physical stabilization of

drugs has formed the basis of several successful polymer screening studies.18-20

Matsumoto and Zografi attributed the superior physical stability of indomethacin SD with

each polyvinylpyrrolidone (PVP) and PVP-co-vinylacetate (PVAC) to the hydrogen

bonding interactions between the drug and the polymer.25

Kestur et al. evaluated the

stabilizing effect of several polymers and concluded that the polymers which formed

stronger and extensive hydrogen bonds with felodipine were more effective inhibitors of

drug crystallization.26

Drug-polymer ionic interactions which are generally stronger than

hydrogen bonding, translated to better physical stabilization of amorphous resveratrol in

SD.27

Eerdenbrugh and Taylor demonstrated the ability of seven chemically diverse

129

polymers to inhibit the crystallization of several small molecule pharmaceuticals. Acidic

polymers while very effective in stabilizing basic drugs with amide functional groups,

were ineffective with acidic drugs.19

Another approach utilized crystal engineering

methodologies to identify polymers which could disrupt drug-drug interactions in favor

of drug-polymer interactions. The predictions agreed well with the experimental results.20

Gunawan et al. speculated that the hydrogen bonding in glassy acetaminophen

contributed to the decrease in the enthalpy and the entropy of the system. The structural

relaxation in acetaminophen was believed to be influenced by the strength of hydrogen

bonds, since molecular rearrangement in hydrogen bonded systems will require the

breaking and reforming of hydrogen bonds.28

In another investigation, enthalpic recovery

as an indirect estimate of the molecular mobility was measured by differential scanning

calorimetry in acetaminophen SD with each polyacrylic acid (PAA) and PVP dispersions.

The stronger hydrogen bonding interactions between the drug and the polymer in the

former were believed to be responsible for the reduced molecular mobility and the

increased physical stability. However, the authors provided no direct experimental

evidence of the drug-polymer hydrogen bonding interactions.29

Although these studies

have implied a relationship between mobility and physical stability, the role of the

specific molecular mobility involved in physical stabilization was not systematically

investigated. Few studies in the literature have investigated the role of the specific

molecular mobility on the physical stability of amorphous pharmaceuticals.30

Recently,

Bhardwaj et al. established an excellent correlation between global mobility (structural or

α-relaxation time) and the physical stability of itraconazole in the supercooled state.31

A

similar correlation, sometimes indirect, between global mobility and physical stability has

also been established for other pharmaceuticals including trehalose, indomethacin,

felodipine, flopropione and celecoxib.32-36

Similar investigations to identify the role of

specific molecular mobility involved in physical stability have been extended to SD.37

Although these studies establish a relationship between the type of molecular mobility

and physical instability, the combined effect of the mobility mode involved in the

instability and the influence of hydrogen bonding has not been investigated.

130

We hypothesize that hydrogen bonding interactions between the drug and the polymer,

by reducing the molecular mobility of the system, will enhance the physical stability. To

test this hypothesis, we have chosen nifedipine (NIF) as our model drug and prepared SD

with each PVP, PAA and hydroxypropylmethyl cellulose acetate succinate (HPMCAS).

The SD, in the supercooled state, were characterized by several techniques – molecular

mobility by dielectric spectroscopy, the strength and extent of drug-polymer hydrogen

bonding interaction by FTIR spectroscopy, and the physical stability by powder X-ray

diffractometry. The results reveal, for the first time, a systematic influence of the nature

of hydrogen bonding on the molecular mobility and consequently the physical stability

(crystallization) of NIF in SD.



NIF (C19H16ClNO4) was purchased from Laborate Pharmaceuticals, India (purity > 98%)

and used without further purification. PVP (Mw ~ 2000-3000 gmol-1

) and HPMCAS–HF

(Mw ~ 18,000 gmol-1

) polymers were supplied by BASF Corp. and Shin Etsu Chemicals,

respectively. PAA (Mw ~ 1800 gmol-1

) was purchased from Sigma Aldrich, USA.

5.3.2. Preparation of Amorphous Materials

Amorphous NIF was prepared by melting crystalline NIF (to ~5 °C above its melting

temperature of 175 °C) in aluminum plans and then quenched on aluminum blocks

precooled to -20 °C. The NIF-polymer SD were prepared by a solvent evaporation

technique followed by melt quenching. Physical mixtures of NIF (90 - 80% w/w) and the

polymer (10 - 20% w/w) were dissolved in the appropriate solvent (acetone, methanol or

dichloromethane). The solvent was then evaporated at 40 °C under reduced pressure

(IKA-HB10, Werke GmbH and Co., Germany) and the drying was continued at room

131

temperature for 24 h. Finally, the powder samples were melt quenched and the SD were

lightly crushed using a mortar and pestle in a glovebox at room temperature (RH < 5%).

The powders were stored at -20 °C in desiccators containing anhydrous calcium sulfate.

5.3.3. Karl Fischer Titrimetry

The water content in the amorphous materials was determined coulometrically using a

Karl Fischer titrimeter (Model DL 36 KF Coulometer, Metler Toledo, Columbus, OH).

Accurately weighed samples were directly added to the Karl Fischer cell and the water

content was determined.




with tin and indium. The powder was accurately weighed in a glove box and sealed










and βHN).

sHN ii HNHN

))(1()(* … Equation 1

132





symmetric (αHN) and asymmetric (βHN) peak broadening with 0 < α (or β) < 1. At higher

temperatures, the contribution of conductivity was observed on the low frequency side of

the dielectric spectra. This was taken into consideration by adding the conductivity

component, σ0/iεsω to the HN equation where, σ0 is the dc conductivity. The powder was

filled between two gold plated copper electrodes (20 mm diameter) using a PTFE ring

(thickness: 1 mm; area: 59.69 mm2; capacitance: 1.036 pF) as a spacer. The spacer

confined the sample between the electrodes. Measurements were corrected for stray

capacitance, spacer capacitance and edge compensation. The validity of the relaxation

time measurements obtained using powder samples, have been the subject of a previous

manuscript.38

5.3.6. FT-IR Spectroscopy

Following the solvent evaporation step (details given in ‘Preparation of amorphous

materials’), the powder was melt-quenched between two CaF2 windows (16 mm

diameter; 0.5 mm thickness). The FT-IR spectra were collected, as a function of

temperature, using an IR microscope (Thermo-Nicolet Continuum FT-IR Spectrometer

with a mercury cadmium telluride detector; Thermo Electron, Waltham, MA) equipped

with an FDCS 196 freeze-drying cryostage (Linkam Scientific Instruments, U.K.). The

FT-IR scan resolution was 4 cm−1

, and 128 IR scans were averaged to obtain each

spectrum in the 4000−900 cm−1

wavenumber range. The stage was initially set at -20 °C

and then heated to 110 °C at 2 °C/min. The IR spectra were analyzed using OMNIC

(Thermo-Nicolet, Madison, WI) and Peakfit4 software (Systat Software, San Jose, CA).

133

5.3.7. Powder X-ray diffractometry (XRD)



strip one dimensional detector (LynxEye; Bruker AXS, Madison WI) was used.

Isothermal crystallization studies were conducted at 70 °C. Samples were periodically

exposed to Cu Kα radiation (40 kV x 40 mA) over an angular range of 6 – 27° 2θ with a

step size of 0.04° and a dwell time of 0.5 s. At each time point, the crystallinity index was

calculated using Equation 2. The crystallinity index can be equivalent to the %

crystallinity in the sample, if the total integrated intensity (crystalline + amorphous)

remains constant throughout the isothermal crystallization experiment (Figure 5.1).39

… Equation 2

A custom built program (using Fortran 77; Tucson, AZ) was used to quantify

crystallinity. The amorphous intensity contribution was based on the experimental XRD

pattern of the amorphous “reference” material (preparation method is provided above).

The amorphous intensity was subtracted from the total pattern to yield the intensity

contribution from the crystalline peaks.

5.4. Results

5.4.1. Baseline Characterization

The samples prepared, both the drug substance and the dispersions, were observed to be

X-ray amorphous. Figure 5.2 contains representative DSC heating curves of NIF-SD with

134

each PVP, HPMCAS and PAA and the relevant results are summarized in Table 5.1. The

calorimetric Tg values of the three dispersions (at 10 % w/w polymer) were virtually

identical. At higher concentration, the strong specific interactions between the drug and

the polymer (discussed later) can explain the much higher Tg of the PVP dispersions as

was observed in thiazide diuretics.40

Karl Fischer titrimetry revealed a water content <

0.5 % w/w.

5.4.2. Influence of Polymer Type on Molecular Mobility

Dielectric spectroscopy was used to characterize the molecular mobility in NIF and NIF

solid dispersions in the supercooled as well as the glassy states. Isothermal frequency

experiments were conducted at several temperatures ranging from (Tg - 50 °C) up to (Tg

+ 75 °C). In the supercooled state, all the systems revealed well resolved α-relaxation

peaks (Figure 5.3). In PAA SD, α-relaxation was observed in the temperature range of 45

to 75 °C. At higher temperatures (>75 °C), rapid drug crystallization precluded data

collection. The SD with PVP and HPMCAS on the other hand, were much more resistant

to crystallization and α-relaxation could be monitored at temperatures > 75 °C. With an

increase in temperature, the α-relaxation peak shifted to higher frequencies indicating an

increase in the global mobility of the system i.e. shorter relaxation times. However, there

was a decrease in the magnitude of the dielectric loss peak, attributable to progressive

sample crystallization.

At any given temperature and polymer concentration, the unique effect exerted by each

polymer on the molecular mobility was evident from the peak frequency of the dielectric

loss (Figure 5.4). The dielectric loss peak in the PVP dispersions appeared at a much

lower frequency, indicating a more pronounced lowering in molecular mobility, than in

the corresponding HPMCAS and PAA dispersions. The loss curves of the PAA

135

dispersion could be virtually superimposed on that of NIF revealing the “ineffectiveness”

of this polymer.

The average α-relaxation time, determined using Equation 1 (Figure 5.5), over the entire

temperature range could be rank ordered as: PVP > HPMCAS > PAA. The presence of

PAA, irrespective of its concentration, did not reveal any significant influence on

relaxation time. Addition of 10 % w/w polymer resulted in an 8- and 3-fold increase in

relaxation time with PVP and HPMCAS respectively. An increase in polymer

concentration to 20 %, caused a disproportionate 65-fold increase in the relaxation time

of the PVP system, whereas the HPMCAS system showed only a 5-fold increase. The

temperature dependence of the relaxation time could be described by the VTFH model

(Equation 3; model fitting using Sigmaplot®; Systat Software; San Jose, CA).

42-45

(

( )) … Equation 3

In the above equation, τ is the average α-relaxation time, D is the strength parameter, a

measure of the system fragility, τ0 is the relaxation time of the unrestricted material (10-14

s, the quasi lattice vibration period) and T0 is the zero mobility temperature.46-47

At higher

temperatures, the influence of the polymer becomes less pronounced and at temperatures

~25 °C > Tg, the relaxation times appear to be independent of the polymer (Figure 5.5).

Thus “accelerated” studies, at temperatures >> Tg, can be misleading. On the other hand,

near Tg (~Tg + 5 °C), the differences in the polymer effectiveness were amplified. The D

value for NIF, and all the dispersions was ~7.8 reflecting the fragile nature of these

systems. The T0 value was ~ 262 K and independent of polymer type and concentration.

We also attempted to characterize the molecular mobility of these systems in the glassy

state. In NIF and NIF-SD, an excess wing was observed, attributable to β-relaxation. Due

to the weak nature of the signal, its temperature dependence could not be ascertained.

136

5.4.3. Influence of Polymer Type on Drug-Polymer Interactions

FT-IR spectroscopy was used to characterize the dug-polymer hydrogen bonding

interactions in the SD, both in the supercooled and glassy states. The interactions were

investigated as a function of temperature from -20 °C to 120 °C. The dihydropyridine NH

group of amorphous NIF, at 3342 cm-1

, acts as a hydrogen bond donor and interacts with

the acceptor groups in the polymers (Figure 5.6). With an increase in temperature, the

NH peak shifts to higher wavenumbers, indicating a decrease in the hydrogen bond

strength (Figure 5.7 (a)). As we transition from the glassy to the supercooled state, the

change in the strength of intermolecular interactions are reflected by an abrupt increase in

the thermal expansion coefficient. This can be observed from the change in the

temperature dependence of the NH stretching vibration frequency around Tg (Figure 5.7

(b)). The SD exhibited a similar behavior (Figure 5.8). At any given temperature and

polymer concentration, the difference in the hydrogen bonding interactions between the

drug and the polymer are evident from the shape and the position of the NH peak. In the

PVP dispersion, a shoulder developed on the lower wavenumber side of the NH peak

(Figure 5.9 (a)), whereas, in HMPCAS dispersion this occurred at higher wavenumbers.

These “shoulder peaks” could be readily discerned by subtracting the NIF spectrum from

that of the dispersions (Figure 5.9 (b)). The subtraction clearly shows new populations in

both PVP (3290 cm-1

) and HPMCAS dispersions (3363 cm-1

). A lower wavenumber

indicates that the hydrogen bonding between the drug and the polymer is stronger than

the intermolecular hydrogen bonding between the drug molecules. Similar observations

have been made in SD of felodipine, a structural analog of NIF.48

The subtracted

spectrum of PAA SD strongly suggests no hydrogen bonding interaction between the

drug and polymer. The rank ordering of the strength of hydrogen bonding is the same as

the relaxation time: PVP > HPMCAS > PAA. The extent of drug-polymer hydrogen

bonding was estimated from the ratio of the height of the peak attributed to drug-polymer

interaction to the height of the peak attributed to the amount of drug in the dispersion

(1530 cm-1

; N–O symmetric stretch peak). Only NIF absorbs at 1530 cm

-1 with no

interference from the three polymers. The peak intensity ratio was then adjusted for the

variation in the absorption coefficient of the NH peak with wavenumber (Figure 5.10).49

137

Due to the stronger interaction between NIF and PVP, at any given polymer

concentration, the PVP dispersion, always had a higher fraction of the drug molecules

bonded to the polymer.

5.4.4. Influence of Polymer Type on Physical Stability

The polymer type had a dramatic influence on the physical stability of NIF in the SD.

This was first evident in the non-isothermal DSC experiments which showed a

progressive delay in NIF crystallization in the order: PVP > HPMCAS > PAA NIF

(Figure 5.2). This superior inhibitory effect of PVP was observed at both 10 and 20%

polymer concentration (Table 5.1). This trend was also apparent from the BDS and FT-IR

results. A reduction in the magnitude of the dielectric loss peak is indicative of sample

crystallization. For example, at 80 °C, the decrease in the magnitude of the dielectric loss

peak was more pronounced for HPMCAS than the PVP dispersion (Figures 5.3 (a) and

5.3 (b)). In the PAA SD, at 80 °C, due to extensive sample crystallization, it was not

possible to measure the magnitude of the dielectric loss peak (Figure 5.3 (c)). Finally, in

the FT-IR spectra, NIF crystallization is evident from the shift in the stretching frequency

of the NH group involved in hydrogen bonding to a lower wavenumber (from 3351 to

3322 cm-1

). For the PVP and HPMCAS SD, no amorphous to crystalline transition was

observed whereas in PAA dispersions it occurred at temperatures of 100 °C. In an

attempt to understand the influence of polymer type on NIF stabilization in the SD, drug

crystallization was monitored at 70 °C by XRD. PVP SD showed the strongest resistance

to drug crystallization followed by HPMCAS and PAA, in excellent agreement with the

observations under non-isothermal conditions. The XRD experiments provided a measure

of both the rate and extent of crystallization (Figure 5.11).

138

5.5. Discussion

In the solid dispersions prepared with the three polymers (10 % w/w polymer), the most

pronounced drug crystallization inhibition (physical stabilization) was observed with

PVP. These dispersions also exhibited the longest relaxation time (slowest molecular

mobility). This enhanced physical stability can be attributed to the higher strength and

consequently greater extent of drug-polymer interactions in the PVP dispersions leading

to the observed reduction in mobility. There are literature reports of depression in

molecular motions in associated liquids brought about by the formation of hydrogen bond

chains or networks.50-51

While n-hexane and n-heptanol are structurally similar, the

significantly longer relaxation times in the latter are attributed to the hydrogen bonding

network.51

Moving to two component systems, in mixtures of ethanol and n-hexanol, the

intermolecular hydrogen-bonding interactions between the aliphatic groups were believed

to play a significant role in the dynamics of molecular reorientation.52

Silica when

blended with polymethylmethacrylate reduced the molecular mobility of the system. This

concentration dependent effect was attributed to the formation of strong intermolecular

hydrogen bonds between the two components.53

Similarly, in our model systems, an

increase in polymer concentration caused an increase in relaxation time. However, the

magnitude of this effect was polymer specific. As the polymer concentration was doubled

(10 to 20 % w/w), due to the strong nature of NIF-PVP interactions, a higher fraction of

the drug molecules were involved in the hydrogen bonding interactions with the polymer.

The strong hydrogen bonding interactions between NIF and PVP caused a

disproportionate lowering in mobility (~ 11 fold increase in the relaxation time) than in

the HPMCAS (~ 1.6 fold increase in the relaxation time) dispersions.

The strength and extent of interaction between drug and polymer will be one of the

determinants of the molecular mobility of the system. The addition of the polymer is

believed to increase the “friction” experienced by the drug molecules resulting in reduced

molecular mobility as was observed in polychlorinated biphenyl (Aroclor 1248) solutions

containing either polystyrene or polybutadiene.54

Polystyrene, in a concentration

dependent manner, disrupted the solvent clusters, through hydrogen bonding interactions

139

with the solvent and reduced the mobility by increasing the effective friction coefficient

(ζ). A measure of ζ is τ/τNIF, where τ is the relaxation time of the dispersion and τNIF is the

relaxation time of the pure solvent (NIF in our case). Similarly for the PVP and

HPMCAS dispersions, with an increase in polymer concentration, we observe both an

increase in the value of ζ and the extent of drug-polymer interactions (Figure 5.12).

While the extent of drug-polymer interactions are polymer specific (PVP > HPMCAS),

the differences are not very pronounced. On the other hand, there is a disproportionate

influence of the strength of drug-polymer interactions in reducing the overall mobility of

the system. The stronger interaction of PVP with NIF translated to a much higher friction

coefficient and this effect was amplified when the polymer concentration was increased

(Figure 5.12). These observations establish the causal link between hydrogen bonding,

specifically the strength of hydrogen bonding, and molecular mobility. The results from

these studies highlight for the first time that drug-polymer interactions, by modulating the

molecular mobility, influenced the drug crystallization kinetics.

5.6. Conclusion

With the availability of a wide variety of polymers, a major challenge in solid dispersion

design is polymer selection. This will be greatly facilitated by understanding the

mechanisms governing the physical stability of a drug in a SD. An ideal polymer should,

at a low concentration, effectively prevent drug crystallization throughout the shelf-life of

the dispersion. This will enable high drug loading and will also afford flexibility to the

formulator in terms of dosage form design, processing and manufacturing. We have

observed that specific drug – polymer hydrogen bonding interactions provide physical

stabilization by reducing the molecular mobility of the system.

140

System Tg (°C) Crystallization

exotherm (°C)

Tg (°C) Crystallization

exotherm (°C)

Nifedipine 46.2 (0.3)* 86.3 (0.6)

Polymer Concentration

(10% w/w) (20% w/w)

Nifedipine – PVP 48.0 (0.04) 140.38 (0.7) 52.9 (0.6) No

crystallization

Nifedipine – HPMCAS 47.9 (0.5) 128.7 (0.8) 49.3 (0.6) 86.3 (0.6)

Nifedipine – PAA 47.7 (0.5) 111.7 (0.8) 46.2 (0.3) -**

Table 5.1: Summary of the DSC results of the model systems. Figure 5.2 contains the

DSC curves. *mean ± SD; n = 3,

** In light of potential phase separation, the data was

deemed unreliable.

141

Figure 5.1: A representative plot of the total integrated intensity (crystalline +

amorphous) during the isothermal crystallization studies of amorphous NIF-PVP (10 %

w/w) at 70 °C.

0 100 200 300 400

0

5e+4

1e+5

2e+5

2e+5

Inte

nsity (

co

unts

)

Time (min)

142

Figure 5.2: Representative DSC heating curves of NIF and NIF solid dispersions with

each PVP, HPMCAS and PAA. The polymer concentration was 10 % w/w. The

endotherms observed at temperatures > 150 °C are attributed to the melting of different

physical forms of NIF.41

These events were outside the scope of our interest in this

manuscript.

143

Figure 5.3: Dielectric loss behavior of NIF solid dispersions (10 % w/w polymer). The

polymers used were (a) PVP, (b) HPMCAS and (c) PAA. The progressive shift in the

dielectric loss peak (as the temperature is increased) is indicated by the arrows.

144

Figure 5.4: Dielectric loss behavior of NIF (●) and NIF solid dispersions with PVP (●),

HPMCAS (▼) and PAA (■) at 60 °C with (a) 10 % and (b) 20 % w/w polymer

concentration. The loss curves have been normalized with respect to the maximum loss

value.

145

Figure 5.5: Relaxation time of NIF solid dispersions (10 % w/w polymer concentration)

as a function of temperature.

146

Figure 5.6: Structures of (a) nifedipine, (b) PVP, (c) PAA and (d) HPMCAS. The

hydrogen bond donor group in nifedipine and the hydrogen bond acceptor group in PVP

and PAA are pointed out. In HPMCAS, there are multiple hydrogen bonding sites.48

147

Figure 5.7: (a) FTIR spectra of NIF as a function of temperature (-20 to 95 °C

temperature range). The wavenumber range is restricted to the NH peak involved in the

intermolecular hydrogen bonding. The spectra in the supercooled liquid temperature

range (light blue) are clearly separated from each other, while those in the glassy region

(dark blue spectra) are clustered (more details in the text). (b) The wavenumber of the

NH peak as a function of temperature. The change in the temperature dependence around

Tg is evident. For the sake of clarity, only select data points are shown.

148

Figure 5.8: A plot of wavenumber (NH peak of NIF; FTIR spectra) as a function of

temperature for the three solid dispersions. For the sake of clarity, only select data points

are shown in the figure.

149

Figure 5.9: (a) Overlaid FTIR spectra of NIF and NIF-PVP dispersion. The shoulder

attributed to the drug-polymer hydrogen bonding interaction is pointed out. (b) Use of a

pattern subtraction technique to identify the drug-polymer hydrogen bonding interactions

in solid dispersions. The peaks observed in the subtracted spectra are attributed to

hydrogen bonding interactions between NIF and each polymer. The NH peak in pure NIF

was observed at 3342 cm-1

(indicated by the vertical line). The peak position, relative to

the NH peak in pure NIF, reveals the strength of hydrogen bonding interactions in the

dispersions.

150

Figure 5.10: A plot of absorption coefficient versus frequency of NH stretching vibration.

The absorption coefficient of the NH stretch vibration is known to be highly wavenumber

dependent. From Beer-Lambert’s law, the size of any population is proportional to the

quotient of peak absorbance and the absorption coefficient.49

Therefore, to estimate the

relative extent of hydrogen bonding the height of drug-polymer peaks, from the

subtracted spectra, were divided by the wavenumber specific absorption coefficient.

151

Figure 5.11: (a) X-ray powder diffraction patterns of the SDs held at 70 °C for 400

minutes. (b) Crystallization (expressed as % crystallinity) kinetics of the solid dispersions

(70 °C).

152

Figure 5.12: Effect of polymer concentration on the hydrogen bonding behavior and

molecular mobility in (a) PVP solid dispersions and (b) HPMCAS solid dispersions.

Left y-axis. Normalized* peak intensity ratio (3290 cm

-1 (PVP) and 3363 cm

-1

(HPMCAS) peak to that of 1530 cm-1

) as an estimate of the hydrogen bonded population

of the drug in the SD. *The intensity ratio for the NIF-PVP dispersion (20% w/w

polymer) was arbitrarily set at 1.0.

Right y-axis. τ/τNIF, a measure of the friction coefficient (ζ), of the solid dispersions.

153

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159

52. Petong, P.; Pottel, R.; Kaatze, U., Dielectric Relaxation of H-Bonded Liquids.

Mixtures of Ethanol and n-Hexanol at Different Compositions and Temperatures. Jounral

of Physical Chemistry A 1999, 103 (31), 6114-6121.

53. Li, C.; Wu, J.; Zhao, J.; Zhao, D.; Fan, Q., Effect of Inorganic Phase on Polymeric

Relaxation Dynamics in PMMA/Silica Hybrids Studied by Dielectric Analysis. European

Polymer Jounral 2004, 40 (8), 1807-1814.

54. Morris, R. L.; Amelar, S.; Lodge, T. P., Solvent Friction in Polymer Solutions and

Its Relation to the High Frequency Limiting Viscosity. Jounral of Chemical Physics

1988, 89 (10), 6523-6537.

160

Chapter 6

Molecular Mobility as an Effective Predictor of Physical Stability in Nifedipine

Solid Dispersions

161

6.1. Synopsis

We investigated the influence of polymer concentration (2.5 – 20 % w/w) on the

molecular mobility and the physical stability in solid dispersions of nifedipine (NIF) with

polyvinylpyrrolidone (PVP). With an increase in polymer concentration, the α-relaxation

times measured by broadband dielectric spectroscopy were longer reflecting a decrease in

molecular mobility. The temperature dependence of the relaxation time indicated similar

fragilities for all the dispersions. Under isothermal conditions, a linear relationship was

observed between the polymer concentration (2.5 – 20 % w/w) and relaxation time. The

results suggested that in the concentration range investigated, the mechanism by which

the polymer influences the relaxation time remains unaltered. In the supercooled state, the

time for NIF crystallization increased as a function of polymer concentration. Using

molecular mobility as a predictor, a model was built to predict NIF crystallization from

the dispersions in the supercooled state. The predictions were in excellent agreement with

the experimental data, thus establishing the validity of the prediction model.

6.2. Introduction

By formulating as amorphous solid dispersions, there is a potential to enhance the

solubility and the oral bioavailability of poorly water soluble compounds.1-2

A wide

variety of polymers are available to formulate amorphous drugs into solid dispersions.3

However, when the drug loading is high, it can be a challenge to develop robust solid

dispersions which can resist crystallization.4-5

However, in practice, only a few polymers

have been used as is evident from the commercial solid dispersions in the market.6

Polymer selection can be rationalized by developing a comprehensive understanding of

the mechanisms governing drug stabilization by the polymer. The ideal polymer should

be effective enough at a low concentration to physically stabilize the drug during

manufacture as well as the shelf life of the dispersion. Several studies have investigated

the role of thermodynamic and kinetic factors to help provide a scientific rationale for the

selection of an appropriate polymer.4 In particular, the role of molecular mobility as a

162

predictor of physical stability of amorphous pharmaceuticals has received a lot of

attention.7-16

The correlation between global mobility (α-relaxation) and the

crystallization propensity has recently been established in nifedipine (NIF) - PVP solid

dispersions in the supercooled as well as the glassy states.17

Apart from molecular mobility, the influence of drug-polymer interactions (hydrogen

bonding and ionic) on physical stability of drugs in solid dispersions has been the topic of

numerous investigations.18-23

We recently investigated the possible role of drug-polymer

interactions and molecular mobility on the physical stability of NIF dispersions with each

PVP, HPMCAS and PAA. The strength of drug-polymer hydrogen bonding, the

structural relaxation time and the resistance to crystallization were rank ordered as: PVP

> HPMCAS > PAA. Thus, PVP was much more effective than HPMCAS and PAA in

stabilizing NIF in the dispersion and its effectiveness could be attributed to the decrease

in molecular mobility brought about by the hydrogen bonding of the drug with the

polymer.

Having established the effectiveness of PVP in stabilizing NIF dispersions, as a next step,

we have investigated the influence of PVP concentration on the molecular mobility and

physical stability. The polymer concentration needed to stabilize the drug in a dispersion

is of immense practical importance. In pharmaceutical dosage forms, the goal is to

physically stabilize the drug (i.e. prevent drug crystallization) during processing and

storage (shelf-life) of the dosage form. It is also instructive to recognize that high dose

drugs can be formulated as solid dispersions only if the polymer is effective at a low

concentration.

We hypothesize that PVP, in a concentration dependent manner, will reduce the

molecular mobility of the system and thereby enhance the physical stability of NIF in the

dispersion. In a previous investigation, we had established a relationship between

molecular mobility and physical stability (measured as crystallization time) in amorphous

trehalose. Unfortunately, those studies could not be completed because of drug

decomposition during storage. However, in this chapter, we have extended the coupling

163

model to successfully predict, for the first time, NIF crystallization in solid dispersions.

More importantly, using the crystallization data obtained at elevated temperatures in

dispersions with low polymer concentrations (conditions of rapid crystallization), we

have successfully predicted the crystallization behavior in systems exhibiting much

slower crystallization kinetics (higher polymer concentrations and lower temperatures). If

our approach is successful, it can be used to predict crystallization during the shelf life of

the dosage form and significantly reduce the time for solid dispersion development.



NIF (C17H18N2O6; purity > 98%) was purchased from Laborate Pharmaceutical Ltd, India

and was used without further purification. Polyvinylpyrrolidone (PVP) (K12 grade) was

supplied by BASF Corporation.

6.3.2. Preparation of Amorphous Systems

Amorphous NIF was prepared by melting in aluminum pans and then quenching on

aluminum blocks precooled to -20 °C. The NIF-PVP solid dispersion was prepared by a

solvent evaporation technique followed by melt quenching. Physical mixtures of NIF and

PVP (concentration ranged between 2.5 and 20 % w/w) were dissolved in either acetone

or acetone and methanol mixtures (50:50 v/v), and the solvent evaporated at 40 °C under

reduced pressure (IKA-HB10 digital system, Werke GmbH and Co. Staufen, Germany).

The mixture was further dried under reduced pressure at room temperature for 24 h. It

was then heated to 5 °C above the melting point of NIF and quenched to -20 °C. The

melt-quenched materials were lightly crushed using a mortar and pestle in a glove box at

room temperature (RH < 5 %). The amorphous materials were stored at -20 °C in

desiccators containing anhydrous calcium sulfate.

164

6.3.3. Karl Fischer Titrimetry

The water content in the amorphous model systems was determined coulometrically

using a Karl Fischer titrimeter (Model DL 36 KF Coulometer, Metler Toledo, Columbus,

OH). Accurately weighed samples were directly added to the Karl Fischer cell and the

water content was determined.

6.3.4. Thermal analysis

A differential scanning calorimeter (DSC) (Q2000, TA instruments, New Castle, DE)


with tin and indium. In a glove box, the powder was accurately weighed and sealed



6.3.5. Powder X-ray Diffractometry (XRD)



strip one-dimensional detector (LynxEyeTM

; Bruker AXS) was used. These isothermal

crystallization studies were conducted in the NIF systems at four temperatures above Tg

(55 to 70 °C). Samples were periodically exposed to Cu K radiation (40 kV x 40 mA)

over an angular range of 6 – 27° 2θ with a step size of 0.04° and a dwell time of 0.5 s.

6.3.6. Synchrotron XRD (SXRD)

165

Isothermal crystallization studies in the glassy state were conducted in select systems.

The samples were stored at the desired temperature in hermetically sealed DSC pans and

then exposed to synchrotron radiation (17-BM-Sector; 0.72910 Å; Argonne National

Laboratory, IL). The synchrotron experiments were conducted at room temperature. The

sample to detector distance was set at 900 mm. The calibration was performed using

Al2O3 (NIST; SRM-647a) standard. The two-dimensional (2D) data were integrated to

yield one-dimensional (1D) d spacing (Å) or 2θ (°) scans using the FIT2D software

developed by A. P. Hammersley of the European Synchrotron Radiation Facility.

6.3.7. Quantification of XRD Data

At each storage time point, the crystallinity index (intensity of crystalline peaks/total

diffracted intensity) was calculated. The crystallinity index can be equivalent to the %

crystallinity, if the total integrated intensity (crystalline + amorphous) remains constant

throughout the isothermal crystallization experiment.17, 24

A custom built software

(Fortran 77®; Tucson, AZ) was used to quantify crystallinity, wherein, the amorphous

intensity contribution was based on the experimental XRD pattern of the amorphous

“reference” material (preparation method is provided above). The subtraction of the

amorphous intensity from the total pattern yielded the intensity contribution from the

crystalline peaks. The percent crystallinity was plotted as function of time, and a

characteristic crystallization time (tc) was obtained for 10 % crystallization.







166


and βHN).25

HNHN

HNi

))(1()(*

… Equation 1





symmetric (αHN) and asymmetric (βHN) peak broadening with 0 < αHN (or βHN) < 1. At

higher temperatures, the contribution of conductivity was taken into consideration by

adding the conductivity component, σ0/iεsω to the HN equation where, σ0 is the dc

conductivity. The powder was filled between two gold plated copper electrodes (20 mm

diameter) using a PTFE ring (thickness: 1 mm; area: 59.69 mm2; capacitance: 1.036 pF)

as a spacer. The spacer confined the sample between the electrodes. Measurements were

corrected for stray capacitance, spacer capacitance and the edge compensation.


6.4.1. Baseline characterization

The model amorphous systems were observed to be X-ray amorphous. The glass

transition temperatures were determined by DSC at a 10 °C/min heating rate. The DSC

heating curves for select systems are included in the Figure 6.1. Karl Fischer titrimetry

revealed a water content < 0.5 % w/w.

167

6.4.2. Influence of Polymer Concentration on Molecular Mobility

Dielectric spectroscopy of the solid dispersions in the supercooled state revealed well

resolved α-relaxation peaks. With an increase in temperature, the α-relaxation peak

shifted to higher frequencies indicating an increase in the global mobility of the system

i.e. shorter relaxation times. The temperature dependence of the dielectric loss peak for

select solid dispersions is provided in the Figure 6.2. At high temperatures, due to sample

crystallization, there was a decrease in the magnitude of the dielectric constant. The

influence of PVP concentration on the molecular mobility is evident from Figure 6.3.

With an increase in polymer concentration, the α-relaxation peak progressively shifted to

lower frequencies reflecting decreased mobility of the system. The relaxation time at

each temperature was determined using the HN Model (Equation 1). At polymer

concentrations > 10 % w/w, the pronounced contribution of dc conductivity increased the

values of ε” (Figure 6.3; indicated by arrow). Shinyashaki et al. reported significant dc

conductivity contribution to the dielectric loss spectra of PVP – chloroform mixtures.26

To account for the conductivity contribution, the relaxation times were calculated using

an additional conductivity term in the HN model (details in Materials and Methods

section).

The temperature dependence of the relaxation time (for select systems) is shown in

Figure 6.4. As indicated earlier, with an increase in polymer concentration, there was a

progressive increase in the α-relaxation time and this effect became more pronounced at

higher polymer concentrations. At 70 °C, a change in polymer concentration from 5 to 10

% w/w resulted in a ~3 fold increase in the relaxation time (data not shown). When the

polymer concentration was raised to 20 % w/w, the relaxation time increased

dramatically (~ 15 fold). An increase in polymer concentration, by making the matrix

more viscous, will “immobilize” the drug molecules. This will restrict the cooperative

motions of the molecules, and decrease the global mobility of the system. At higher

polymer concentrations, due to the strong intermolecular interactions between NIF and

PVP, a large fraction of the drug molecules are hydrogen bonded to the polymer. The

degree of reduction in the molecular mobility is modulated by the strength and extent of

168

drug-polymer interactions. The temperature dependence of the relaxation time was

described by the VTFH model (Equation 2).

(

( )) … Equation 2

In the above equation, τ is the average α-relaxation time, D the strength parameter is a

measure of the system fragility, τ0 is the pre-exponential relaxation factor (10-14

s, the

quasi lattice vibration period)27

and T0 is the zero mobility temperature. The fitting of the

relaxation time data to the VTFH model (for amorphous NIF) was discussed in detail in

our earlier work.17

The D value for NIF (drug as well as dispersions) was ~8 reflecting

the fragile nature of these glass formers. The T0 value was also unaffected by the polymer

concentration.

As is evident from the Cole-Cole plots, with an increase in the polymer concentration,

there was spectral broadening (Figure 6.5).28-29

In polymer systems, this broadening has

been explained by the concentration fluctuation model.30-32

It assumes a local Gaussian

concentration distribution in the blend, relatively fast dipole relaxation and a uniform

glass transition temperature in the microscopic sub-volumes within the blend. The

observed α-relaxation is the sum of the individual sub-volume α-relaxations within the

blend.

In glassy NIF and the solid dispersions, an “excess wing” was observed, attributable to β-

relaxation. Since the signal was weak, its temperature dependence could not be

ascertained. Goresy and Böhmer also observed an excess wing in amorphous NIF and

acetaminophen alloys, attributable to the Johari-Goldstein relaxation.33

6.4.3. Influence of Polymer Concentration on Physical Stability

169

Our next objective was to use XRD to study the influence of polymer concentration on

the physical stability of NIF in dispersions. With an increase in polymer concentration,

there was a dramatic decrease in the rate and the extent of drug crystallization (Figure

6.6). The time taken for 10 % w/w of the drug to crystallize, tc, was calculated (Figure

6.7). For the drug alone, at 70 °C, the tc was ~5 min. Addition of PVP (2.5 % w/w)

caused an ~ 1.8-fold increase in the tc (~9 min). At very low polymer concentrations, a

similar dramatic increase in physical stability has been reported, both in NIF and other

drugs in solid dispersions.11, 34-35

With further increase in polymer concentration,

crystallization took progressively longer (Figure 6.7). Thus, the influence of polymer

concentration had similar effects on the α-relaxation (Figure 6.4) and crystallization times

(Figure 6.7). To study the influence of polymer concentration on physical stability in the

glassy state, the dispersions were held isothermally at 25 °C and crystallization was

monitored using synchrotron radiation. The high sensitivity afforded by this source

enabled us to detect crystallization even at a polymer concentration of 10 % w/w (Figure

6.8). When the polymer concentration was increased to 20 %, drug crystallization was not

observed even after 60 days of storage.

6.4.4. Molecular Mobility as a Predictor of Physical Stability

The crystallization rate, G(T), at the melt-crystal interface is given by Equation 3,36

G(T) = D(T) . f(T) … Equation 3

where D(T) is the temperature dependence of molecular diffusion and f (T) is the free

energy term (nucleation/crystal growth). In light of the challenges with the measurement

of translational diffusion, the above equation is often approximated by Equation 4:

G(T) = ( )

( ) … Equation 4

170

where, η(T) is the temperature dependence of viscosity. Our interest is in the supercooled

state close to Tg. In the range between Tg and 1.2Tg, the temperature dependence of

molecular and viscous transport exhibit a pronounced difference. Translational diffusion

coefficient (Dtrans) has significantly weaker temperature dependence than η. A

pronounced enhancement of Dtrans over η is observed at temperatures close to Tg (~ 2

orders of magnitude).36-41

This has been attributed to the breakdown of the Stokes-

Einstein relationship (Equation 5).39

… Equation 5

Here, kB is the Boltzmann constant and r is the radius of the diffusing species. In this

temperature range, Dtrans has significantly weaker temperature dependence than η. A

pronounced enhancement of Dtrans over η is observed at temperatures close to Tg (~ 2

orders of magnitude). The decoupling factor, between Dtrans and η is expressed as,


In light of the similar temperature dependence exhibited by viscosity and rotational

motions, Equation 6 can be expressed as:


171

Based on experimental determinations of Dtrans and the rotational diffusion coefficient

(Drot), was found to be 0.75 for OTP.42-43

Similarly, in NIF, we had reported to be

0.77, reflecting decoupling between rotational and translational motions (Figure 6.9).

Equation 3 provided the relationship between the temperature dependence of molecular

diffusion and crystallization rate while Equation 7 related the Dtrans to the rotational

relaxation times. Our objective was to determine the role of molecular mobility on

physical stability over a narrow (20 °C) temperature range. We therefore used the

coupling model based on the established relationship between crystallization time and

relaxation time.

log (tc) = M log (τα) + log A … Equation 8

In the above equation, tc is the time for 10 % crystallization, tα is the α-relaxation time, M

is the coupling coefficient and A is a constant. An M value of 1 will indicate “perfect”

coupling between the two processes. Since we are using τα, a measure of the rotational

relaxation time, we expect a coupling coefficient of ~ 0.75, given the decoupling between

translational and rotational motions within the temperature range of Tg and 1.2Tg. In NIF

– PVP (2.5 % w/w) solid dispersion in the supercooled state, the coupling coefficient was

0.67, reasonably close to the decoupling factor of 0.77 obtained for NIF alone.17

Therefore the relationship between α-relaxation and crystallization times could be

expressed as:

log (tc) = 0.67 log (τα) + 4.8 … Equation 9

At this low polymer concentration of 2.5 % w/w, crystallization was fairly rapid, and tc

was experimentally determined over a temperature range of 55 to 70 °C. As the polymer

concentration is increased, in light of the slower crystallization, studying crystallization

kinetics in practical timescales can be challenging. We therefore attempted to use

Equation 9 to predict crystallization in dispersions with 5 and 10 % w/w PVP

concentration. We believe that the value of the coupling coefficient (M=0.67) obtained at

a polymer concentration of 2.5 % w/w, is valid at the higher polymer concentrations. This

172

assumption is based on three observations (Figure 6.10): (i) Linear relationship between

relaxation time and polymer concentration (2.5 to 20 % w/w; 5 polymer concentrations)

under isothermal conditions. These experiments were conducted at 5 temperatures

between 55 and 75 °C (Figure 6.10). (ii) Similar polymer concentration dependence of

the relaxation times over this temperature range. (ii) Similar temperature dependence of

the relaxation times in dispersions. While these investigations were also carried out in

solid dispersions with different polymer concentrations, for the sake of clarity only a few

are shown in Figure 6.4. These results suggest that in the polymer concentration range of

2.5 – 20 % w/w, the mechanism by which the polymer influences the relaxation time is

unaltered. However, this assumption may not hold true at concentrations higher than (i.e.

> 20 % w/w), possibly due to the saturation of the hydrogen bonding sites available for

the drug. Thus, our assumption is likely to be valid only over a defined range of polymer

concentrations and temperatures.

At higher polymer concentrations of 5 and 10 % w/w, tc was experimentally determined

at 70 °C. This enabled us to calculate the value of the constant ‘A’ in Equation 9. This

constant is a measure of the thermodynamic “barrier” to crystallization. With an increase

in polymer concentration, there was increased resistance to crystallization. Thus the

relationship between tc and τα for dispersions with 5 and 10 % w/w polymer

concentration can be expressed by Equations 10 and 11 respectively,

log (tc) = 0.67 log (tα) + 5.4 … Equation 10

log (tc) = 0.67 log (tα) + 6.6 … Equation 11

These equations enable the prediction of the crystallization time, as long as the α-

relaxation time can be experimentally obtained. We predicted tc at 55, 60 and 65 °C. In

an effort to check the reliability of the prediction, tc was also experimentally determined

by XRD. Figure 6.11 shows an excellent agreement between the predicted and the

experimental crystallization times.

173

As mentioned earlier, the value of constant A in Equation 10 and 11 were based on the

experimentally observed crystallization and relaxation times at 70 °C and assuming a

value of 0.67 for M. The experimental data (crystallization and relaxation times between

55 and 70 °C) provided the values of M and A for the two systems. As is evident from

Table 6.1, there is a good agreement between the two. We believe that this is a

confirmation of the validity of the model.

6.5. Conclusion

An increase in polymer concentration led to an increase in the relaxation time as well as

the crystallization time in NIF solid dispersions. The previously established relationship

between crystallization and α-relaxation time in NIF-PVP (2.5 % w/w) solid dispersions

was used to predict crystallization in dispersions at higher polymer concentrations of 5

and 10 % PVP. The predictions matched very well with the experimental data which

validated the reliability of the model.

6.6. Significance

Amorphous solid dispersions will find widespread use if the potential for drug

crystallization can be reliably predicted. Such a prediction will be possible by

understanding the mechanisms governing instability. Crystallization is recognized as a

complex process involving nucleation and crystal growth. Assuming that molecular

mobility can be an effective predictor of drug crystallization, we identified the specific

mobility responsible for instability in a drug (itraconazole) and an excipient (trehalose).13-

14 We extended this approach and developed a model relating nifedipine crystallization

from solid dispersions with molecular mobility. In this system, since the polymer (PVP)

concentration was very low (2.5 % w/w), crystallization occurred rapidly in both the

supercooled and glassy states.17

However, commercial solid dispersions are unlikely to

174

exhibit rapid drug crystallization. This is practically accomplished by raising the polymer

concentration and storage under appropriate conditions – typically in the glassy state. In

such systems, the challenge will be to predict drug crystallization during the shelf life

(typically two years) of the dosage form. As a first step, we monitored physical instability

under conditions of rapid crystallization (low polymer concentration of 2.5 % PVP;

elevated temperatures) and used this information to successfully predict crystallization in

dispersions with higher polymer concentrations. The concept applied for the current

model dispersions can next be extended to systems of practical interest (higher polymer

concentrations) stored under pharmaceutically relevant conditions (ambient or sub-

ambient temperatures).

175

M Log A

Assumed* Experimental Assumed

** Experimental

NIF – PVP (5% w/w) 0.67 0.73 (0.02) 5.4 5.6 (0.05)

NIF – PVP (10% w/w) 0.67 0.72 (0.1) 6.6 6.7 (0.1)

Table 6.1: Comparison of the values of M and A in Equation 8 obtained using our

experimental data (“experimental”) and the “assumed” values. The assumed* value of M

was obtained from Equation 9. The assumption of the value of A** was based on

crystallization studies conducted in solid dispersions with 2.5 % PVP at 70 °C.

176

Figure 6.1: Representative DSC heating curves of NIF and NIF solid dispersions with

each 5 and 10 % w/w PVP.

Temperature ( C)

0 50 100 150 200

Hea

t flo

w (

arb

itra

ry u

nits)

NIF

NIF-PVP (5% w/w)

NIF- PVP (10% w/w)

177

Figure 6.2: Dielectric loss behavior of NIF solid dispersions with (a) 2.5 (b) 5 and (c) 10

% w/w PVP as a function of temperature.

1e-2 1e-1 1e+0 1e+1 1e+2 1e+3 1e+4 1e+5

0.0

0.4

0.8

1.2

1.6

Die

lectr

ic lo

ss,

''

Frequency (Hz)

50 C

55 C

60 C

65 C

70 C

Frequency (Hz)

1e-2 1e-1 1e+0 1e+1 1e+2 1e+3 1e+4 1e+5 1e+6

Die

lectr

ic loss,

"

0.2

0.4

0.6

0.8

50 C

55 C

60 C

65 C

70 C

75 C

80 C

Frequency (Hz)

1e-1 1e+0 1e+1 1e+2 1e+3 1e+4 1e+5

Die

lectr

i lo

ss

"

0.5

1.0

1.5

2.0

2.5

50 C

55 C

60 C

65 C

70 C

75 C

80 C

a b c

178

Figure 6.3: Dielectric loss behavior of (■) NIF and NIF solid dispersions with (▼) 10 and

(●) 20 % w/w PVP at 70 °C. The loss curves have been normalized with respect to the

maximum loss value. The arrow points out the contribution of conductivity to the

dielectric loss.

Frequency (Hz)

1e-1 1e+0 1e+1 1e+2 1e+3 1e+4 1e+5 1e+6

Die

lectr

ic loss,

"

0.2

0.4

0.6

0.8

1.0

1.2

1.4

NIF - PVP (20% w/w)

NIF - PVP (10% w/w)

NIF

179

Figure 6.4: Relaxation time of (■) NIF and NIF solid dispersions with (▼) 10 and (●) 20

% w/w PVP as a function of temperature.

1000* T-1

(K-1

)

2.8 2.9 3.0 3.1

Rela

xation tim

e

s)

1e-6

1e-5

1e-4

1e-3

1e-2

1e-1

1e+0

1e+1

1e+2

NIF - PVP (20 % w/w)


NIF

180

Figure 6.5: Cole-Cole plots obtained from dielectric data of (■) NIF and NIF solid

dispersions with (▼) 10 and (●) 20 % w/w PVP at 70 °C. Both symmetric and

asymmetric broadening were observed. Each data set was normalized with respect to its

maximum loss value.

Permittivity, '

0.0 0.5 1.0 1.5 2.0

Die

lectr

ic lo

ss,

''

0.0

0.4

0.8

1.2



NIF

181

Figure 6.6: X-ray powder diffraction patterns of (a) NIF and NIF solid dispersions with

(b) 2.5, (c) 10 and (d) 20 % w/w PVP at 70 °C.

182

Figure 6.7: Effect of polymer concentration on time taken for 10 % of the incorporated

NIF to crystallize from the solid dispersions at 70 °C.

Polymer Concentration (% w/w)

0 2 4 6 8 10 12

t c (

min

)

1e+0

1e+1

1e+2

1e+3

1e+4

NIF

NIF - PVP (2.5% w/w)

NIF - PVP (5% w/w)

NIF - PVP (10% w/w)

183

Figure 6.8: Synchrotron XRD patterns of (a) NIF and NIF solid dispersions with (b) 2.5,

(c) 5 and (d) 10 % w/w PVP at 25 °C.

184

Figure 6.9: Plot of diffusion coefficient* versus α-relaxation time in nifedipine.

17

Log (s)

-4.0 -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5

Log D

(m

2/s

)

-18.0

-17.5

-17.0

-16.5

-16.0

-15.5

log (D) = -0.77 log (τα) – 18.4

70 C

65 C

55 C

50 C

185

Figure 6.10: A plot of relaxation time as a function of polymer concentration at a series

of temperatures between 55 and 75 °C

Polymer concentration (% w/w)

0 5 10 15 20 25

Rela

xation tim

e (

s)

1e-4

1e-3

1e-2

1e-1

1e+0

1e+1

1e+2 55 C

60 C

65 C

70 C

75 C

186

Figure 6.11: A plot of crystallization time versus relaxation time for NIF solid

dispersions. The data for the dispersions with 2.5 % polymer concentration (●) were

reported earlier.17

The solid black line represents linear regression line (Eq. 9). At

polymer concentrations of 5 (---) and 10% (---), the lines are the predicted crystallization

times as a function of the experimentally determined relaxation times (Eq. 10 and 11).

The data points (5 % (●) and 10 % (●)) are the experimentally obtained crystallization

times.

Log t (s)

-3 -2 -1 0

Log tc (

s)

2

3

4

5

6

7

8

9NIF - PVP(2.5% w/w)

NIF - PVP(5% w/w)

NIF - PVP(10 % w/w)

Predicted NIF - PVP (5% w/w)

Predicted NIF- PVP (10% w/w)

187

6.7 References

1. Serajuddin, A., Solid Dispersion of Poorly Water‐Soluble Drugs: Early Promises,

Subsequent Problems, and Recent Breakthroughs. Journal of pharmaceutical sciences

1999, 88 (10), 1058-1066.



12 (23), 1068-1075.

3. Warren, D. B.; Benameur, H.; Porter, C. J. H.; Pouton, C. W., Using Polymeric

Precipitation Inhibitors to Improve the Absorption of Poorly Water-Soluble Drugs: A

Mechanistic Basis for Utility. Journal of Drug Targeting 2010, 18 (10), 704-731.


in Crystallization from the Amorphous State. Journal of pharmaceutical sciences 2008,

97 (4), 1329-1349.



6. Huang, Y.; Dai, W.-G., Fundamental Aspects of Solid Dispersion Technology for

Poorly Soluble Drugs. Acta Pharmaceutica Sinica B 2014, 4 (1), 18-25.

7. Aso, Y.; Yoshioka, S.; Kojima, S., Molecular Mobility‐Based Estimation of the

Crystallization Rates of Amorphous Nifedipine and Phenobarbital in Poly

(Vinylpyrrolidone) Solid Dispersions. Journal of pharmaceutical sciences 2004, 93 (2),

384-391.



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188


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192







193

Chapter 7

Summary

194

In light of the correlation between molecular mobility and physical stability, a

comprehensive understanding of the different motions in amorphous systems is crucial.

Dielectric spectroscopy is traditionally used to monitor molecular mobility in polymers.

The sample is usually analyzed as a thin film prepared either by melt quenching or

solvent evaporation. However, pharmaceutical materials are not amenable to these

sample preparation techniques. Moreover, the very act of sample preparation can lead to

loss of valuable information. Therefore, analyzing the “as is” powder samples has

significant advantages and will also enable analyses of complex multicomponent

systems. This work in Chapter 2 was aimed at comparing the dielectric behavior in

several model compounds in film and powder configurations. When compared with

films, a decrease in the magnitude of dielectric loss and permittivity was observed in

powders. Effective medium theory of Kamiyoshi enabled us to predict the loss in the

magnitude of the dielectric properties due to the presence of air in the powder samples.

The dielectric relaxation times, both α- and β-, were unaffected by the sample

configuration. Cole-Cole plots revealed the differences in the shape parameters of the

film and powder samples. Interestingly, a slight enhancement in the β-relaxation was

observed with powder samples. A similar observation, although to a much greater extent

has been observed for nano-confined materials. In light of the challenges associated with

the measurement of β- relaxation, the enhancement observed in powder samples can be

used to our advantage.

In chapter 3, we investigated the cause of the drastically different crystallization behavior

in nifedipine and felodipine, despite their structural similarity and virtually identical Tg.

Dielectric spectroscopy revealed, longer relaxation times i.e. slower mobility in

felodipine. In light of the established relationship between mobility and stability, the

longer relaxation time of felodipine can explain its greater resistance to crystallization. A

detailed FTIR analysis, using the two state model, enabled us to calculate the enthalpy

and the entropy of the hydrogen bond dissociation in both nifedipine and felodipine The

results revealed stronger and more hydrogen bonding interactions in felodipine. The

objective of the work was to relate the difference in the hydrogen bonding behavior in the

195

two model compounds to the molecular mobility. This relationship is expected based on

the argument that viscous flow is derived from broken bonds. The model enabled

prediction of relaxation time based on the hydrogen bonding data. A good agreement was

observed between the experimental and predicted relaxation times.

The role of molecular mobility on the physical stability of supercooled liquids has been

established for several small molecules. Since pharmaceuticals are stored at temperatures

below Tg, it is of much greater practical use to identify the role of the specific mobility

involved in the physical stability of amorphous pharmaceuticals. In Chapter 4, we

comprehensively characterized the molecular mobility (both global and local) in the

model systems (griseofulvin, nifedipine and nifedipine-PVP dispersion) using dielectric

spectroscopy. Due to the extremely long time scales of structural relaxation in the glassy

state we were not able to experimentally measure them. We therefore used the Adam

Gibbs Vogel model and the dielectric relaxation data in the supercooled state to calculate

the α-relaxation in the glassy state. In the supercooled state, a coupling coefficient of

~0.65 was observed in all the model systems. For nifedipine, using diffusion data

available in the literature, we were able to establish a coupling coefficient of 0.82. The

better coupling observed with the diffusion data as compared to the rotational relaxation

time data was attributed to the observed decoupling between diffusional and rotational

motions in the temperature range between Tg and 1.2Tg. The crystallization kinetics in the

glassy state was measured using synchrotron radiation. A strong correlation (coupling

coefficient of ~1) between the α-relaxations and physical instability (crystallization) in

the glassy state was observed. On the other hand no correlation was observed between

secondary relaxations and physical stability in the glassy state.

Currently a large number of polymers are available for solid dispersion development and

rational polymer selection is a challenge. In Chapter 5 in solid dispersions of nifedipine

with each PVP, HPMCAS and PAA, the influence of drug-polymer interactions on the

molecular mobility, and consequently on the physical stability of the drug was analyzed.

The strength of drug-polymer hydrogen bonding as well the structural relaxation time

were rank ordered as: PVP > HPMCAS > PAA. The stronger interactions between

196

nifedipine and PVP also resulted in a greater extent of the drug being hydrogen bonded to

the polymer. The results from this study reveal for the first time a direct influence of the

role of hydrogen bonding interactions (strength as well as extent) on the molecular

mobility of nifedipine solid dispersions. The crystallization studies in the supercooled

state revealed that the PVP dispersion with the slowest mobility and strongest interaction

also showed the greatest resistance to crystallization. Thus drug-polymer interactions, by

modulating the molecular mobility, influenced the drug crystallization kinetics.

Once the ‘ideal’ polymer is selected, the next challenge is to determine the minimum

effective polymer concentration which can provide physical stabilization for the desired

time period. If the polymer is effective at a low concentration, it can afford the formulator

great flexibility in terms of dosage form design and processing. In chapter 6, we have

investigated the role of polymer concentration on the molecular mobility and physical

stability of nifedipine – PVP dispersions. With an increase in polymer concentration, the

α-relaxation times measured by broadband dielectric spectroscopy were longer reflecting

a decrease in molecular mobility. The increase in polymer concentration also led to

enhanced physical stability of nifedipine in the dispersion. The ultimate goal while

formulating an amorphous dispersion is to be able to reliably predict drug crystallization

propensity during the shelf life of the formulation. To achieve this goal, we used

molecular mobility to predict crystallization from solid dispersions. The predictions were

in excellent agreement with the experimental data.

197

Chapter 8

Future Work

198

In chapter 2, we compared the dielectric behavior in several model compounds in film

and powder configurations. The dielectric relaxation times, both α- and β-, were

unaffected by the sample configuration. Cole-Cole plots revealed the differences in the

shape parameters of the film and powder samples. This was attributed to the packing of

the powder in the DES holder. Shape parameters provide valuable information regarding

the heterogeneity of the system. A detailed investigation on the validity of the shape

parameters obtained using powder samples will increase the applicability of powder

samples in dielectric spectroscopy. Interestingly, a slight enhancement in the β-relaxation

was observed with powder samples. A similar observation, although to a much greater

extent has been observed for nano-confined materials. In light of the challenges

associated with the measurement of β- relaxation, the enhancement observed in powder

samples can be used to our advantage. β-relaxation often occurs as an excess wing or a

weak signal in the dielectric spectra and thus ascertaining its temperature dependence is

very challenging. In light of the potential role of β-relaxation in the physical stability of

small molecules, this unique advantage offered by the powder samples should be

investigated in detail.

In Chapter 4, we comprehensively characterized the molecular mobility (both global and

local) in the model systems (griseofulvin, nifedipine and nifedipine-PVP dispersion)

using dielectric spectroscopy. Due to the extremely long time scales of structural

relaxation in the glassy state we were not able to experimentally measure them. We

therefore used the Adam Gibbs Vogel model and the dielectric relaxation data in the

supercooled state to calculate the α-relaxation in the glassy state. While the use of model

enabled the calculation of relaxation time in the glassy state, the lack of experimental

data in support of the models makes us weary of using them to develop predictive models

for crystallization. As a next step, it will interesting to experimentally measure the

structural relaxation time in the glassy state using time domain dielectric spectroscopy.

Once the validity of the Adam Gibbs Vogel equation can be established using

experimentally obtained data, we can build robust models to predict drug crystallization

from the glassy state.

199

In chapter 3, we investigated the cause of the drastically different crystallization behavior

in nifedipine and felodipine, despite their structural similarity and virtually identical Tg.

In Chapter 5 in solid dispersions of nifedipine with each PVP, HPMCAS and PAA, the

influence of drug-polymer interactions on the molecular mobility, and consequently on

the physical stability of the drug was analyzed. The strength of drug-polymer hydrogen

bonding as well the structural relaxation time were rank ordered as: PVP > HPMCAS >

PAA. The stronger interactions between nifedipine and PVP also resulted in a greater

extent of the drug being hydrogen bonded to the polymer. The results from these studies

reveal for the first time a direct influence of the role of hydrogen bonding interactions

(strength as well as extent) on the molecular mobility of nifedipine solid dispersions.

Apart from hydrogen bonding interactions, recently a lot of attention has been given to

ionic interactions between the drug and the polymer in dispersions. The stronger nature of

ionic interactions as compared to hydrogen bonding interactions is believed to enhance

the physical stability of the drug in the dispersions. However, the mechanism by which

ionic interaction enhances the physical stability of amorphous form is not well

understood. It will be interesting to study the influence of the strength of interactions on

the molecular mobility of solid dispersions. Such studies will enable us to develop a

mechanistic understanding of the stabilization brought about by the polymer and help

rationalize the selection of polymer for formulating amorphous dispersions.

In chapter 6 the role of polymer concentration on the molecular mobility of nifedipine

solid dispersions was investigated. With an increase in polymer concentration, a decrease

in the molecular mobility of the system was observed. Using the coupling model drug

crystallization was predicted from dispersions with 5 and 10 % w/w PVP. The predictions

were in excellent agreement with the experimental data. The model used the experimental

mobility data obtained using dielectric spectroscopy. The thermodynamic component in

the model was calculated using limited experimental data. Since, both the thermodynamic

and the kinetic component contribute to the crystallization process, it will be very

valuable to tease out the different contributions of these factors. To enhance the practical

relevance of the model, experiments with dispersions at higher polymer concentrations

200

will be interesting. Since pharmaceuticals are stored in the glassy state extending the

model in below Tg will increase the practical utility of the model.

201

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