TWO-DIMENSIONAL X-RAY DIFFRACTOMETRY IN

PHARMACEUTICAL PRODUCT AND PROCESS DEVELOPMENT

Naveen K ThakralPPXRD-14

June 8, 2016

1

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Acknowledgements

2

• Prof. Raj Suryanarayanan (Univ. of Minnesota)• Dr. Gregory Stephenson (Eli Lilly & Co.)• Dr. Hiroyuki Yamada (Mitsubishi Pharma, Japan)• Dr. Bob He (Bruker)• Dr. Karl Jacob (Dow Chemical Co.)• Characterization Facility (UMN)• Argonne National Laboratory (Synchrotron)• Eli Lily and Company• Lilly Innovation Fellowship Award

In situ Phase Transformation

In situ phase transformation

Change in physical

form

Drug chemically

stable

3

Market Recall

• 2012: Market recall of nimodipine due tocrystallization of nimodipine in soft gelcapsules, that could adversely affect theproduct's bioavailabilty *

• April 2013, Apotex Corp. recall of 15 lots ofPipercillin and Tazobactum for injection (USP):showing crystallization/precipitation in I.V.bags*

• Dr. Reddy lab (June 2014) and Wockhardt(Sept 2014): Metoprolol succinate prolongedrelease tablet, dissolution failure after 18 and

9 months of storage, respectively* * USFDA

4

Physical Stability

Final product performancein solid dosage forms

API

(Physical form)

Polymorphism

Solvationstate

Degree of crystallinity

5

Mitigation Strategy

6

To obtain

mechanistic

insight into

phase

transformation

in tablet

Simultaneous quantification of reactants

and products

Provide the above

information with spatial resolution

7

Compression induced phase transformation in amorphous

API: A case study

8

Compression of amorphous APIPlan

• Introduction

• Analytical method development

• Proof of concept using amorphous trehalose tablets

• Case study: Compression of amorphous indomethacin

• Conclusion

• Other projects

9

Plan

• Introduction

• Analytical method development

• Proof of concept using amorphous trehalose tablets

• Case study: Compression of amorphous indomethacin

• Conclusion

• Other projects

10

Effect of Compression on Amorphous Indomethacin

11

QTPPDescription : Round flat tablet.Size : Diameter 8 mm.Identity : Positive for active ingredient.Assay : ± 5% weight.Physical form : Amorphous.In vivo availability: Immediate release determined

by in vitro dissolution test.Dose Uniformity : Meet pharmacopoeial standard.Packaging : Unit dose, moisture protection.

Plan

12

• Introduction

• Analytical method development

• Proof of concept using amorphous trehalose tablets

• Case study: Compression of amorphous indomethacin

• Conclusion

• Other projects

Analytical Methods

13

Average phase

information

Powder X-Ray diffractometry

Spectroscopic techniques (IR, RAMAN, Solid

state NMR)

Calorimetry

(DSC, TGA)

X-ray Diffraction

14

B He. 2009

XRD in Space (NASA)

NASA July 2015 15

XRD in Lab.

16

Conventional Vs 2-Dimensional XRD

17

ObjectPoint

detector

2D detector Object

Averaging Integration Algorithm

18

2-D and Texture (Preferred-Orientation)

19

Conventional XRD 2D XRD B He.2009

20

21

• Introduction

• Analytical method development

• Proof of concept using amorphous trehalose tablets

• Case study: Compression of amorphous indomethacin

• Conclusion

• Other projects

22

Glancing angle XRDvs

2D-XRD

Glancing angle XRD – Depth of penetration: Amorphous

trehalose

23

)])2sin(

1

sin

1([

)I

I1(e

I

Ie

lnd lower

coreD

bilayerD)

)2sin(

1

sin

1(f

coreD

bilayerD)

)2sin(

1

sin

1(f

upper

upper

IDbilayer

Trehalose dihydrate

+Brilliant blue (2% w/w)

Amorphous

trehalose

IDcore

Thakral et al 2015

Depth of penetration as a function of incident angle

24

265 µmS

A

Ω = 6°

Depth of penetration as a function of incident angle

25

B

S

Ω = 9°

452 µm

Depth of penetration as a function of incident angle

26

662 µm

C

S

Ω = 12°

Integration of different layers

27

}

])2sin(

1

sin

1[

]1e[{KIdxe

S

BKII

))2sin(

1

sin

1(B

0

))-sin(2

1

sin

1(x

0SB

}

])2sin(

1

sin

1[

]1e[{KIdxe

S

AKII

))2sin(

1

sin

1(A

0

))-sin(2

1

sin

1(x

0SA

}

])2sin(

1

sin

1[

]ee[{KIdxe

A

BKII

))2sin(

1

sin

1(A)

)2sin(

1

sin

1(B

0

))-sin(2

1

sin

1(x

0AB

Thakral et al 2015

Integration of different layers

28

265 µm

187 µm

210 µm 3500 µm

S

Thakral et al 2015

Crystallization– Amorphous trehalose tablets

29

65%RH

Amorphous trehalose tablet

Sample holder

Ammonium nitrate

(saturated solution; 65%RH)

Glancing angle XRD

30

0

20

40

60

80

100

120

0 5 10 15

Time (days)

Cry

sta

llin

ity (

%)

=6º

=9º

=12º

SA (265 m)

S

B (452 m)

S

C (662 m)

2DXRD of split tablets

31

Specimen setup

32

Mapping

Top

Bottom

Core

33

Mapping

Core

34

Surface vs Core: Split tablets

35

Time, days

0 5 10 15 20 25 30 35

Cry

sta

llin

e f

ractio

n,

% w

/w

0

20

40

60

80

100

120

Surface

Core

Conclusion

36

XRD-2D

Critical Spatial Information(Not possible by

conventional XRD or Glancing angle XRD)

Mechanistic insight of phase transformation

• Introduction

• Analytical method development

• Proof of concept using amorphous trehalose tablets

• Case study: Compression of amorphous indomethacin

• Conclusion

• Other projects

37

Effect of Compression on Amorphous Indomethacin

38

QTPPDescription : Round flat tablet.Size : Diameter 8 mm.Identity : Positive for active ingredient.Assay : ± 5% weight.Physical form : Amorphous.In vivo availability: Immediate release determined

by in vitro dissolution test.Dose Uniformity : Meet pharmacopoeial standard.Packaging : Unit dose, moisture protection.

Product and Process Outline

39

Indomethacin (amorphous): particle size180 µm (# 80).

-Tablets (8 mm diameter); 200mg

-Compressed on Universal Material Testing Machine (Zwick GmbH & Co.)

- Compression pressure: 10, 25, 50, 100 MPa

-Compressed tablets stored in sealed Mylar pouch at 35 °C.

Prior Knowledge

40

Thermodynamically Pressure is “intensive variable”

Amorphous compounds lower density than their crystalline counterparts.

Compression densify amorphous materials promote intermolecular interactions and increase the probability of nucleation.

“Amorphous material has an upper density limit, beyondwhich the external pressure induces strain and causes thematerials to crystallize.”

Wu C T 1975

Product CQA

41

Risk:

Amorphous crystalline (stable;low energy state) dissolution failure affect bioavailability

CQA “Stable” amorphous state throughout the shelf life of the product.

Experiment

42

Mylar Pouch fitted with temperature and humidity sensor

Sealed

Stored at ~35°C in Oven

2D XRD

Different TimeIntervals

Analytical techniques

43

• Synchrotron XRD

(First evidence of crystallization)

• 2D-XRD

(Depth profiling)

Synchrotron XRD (Argonne National Laboratory)

Beam-line 17 BM-B

44

Source Bending Magnet

MonochromatorType

Si(111)

Energy Range 15-18 keV

Resolution (ΔE/E) 1.5 x 10 -4

Flux (photons/sec) 8 x 1011 @15 keV

Beam Size (HxV)

Focused

Wavelength

250µm x 160µm

0.72808 Å

Compressed Tablets (100 MPa)Time ‘0’ (SXRD)

45

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

0 5 10 15 20 25 30 35 40

Inte

nsi

ty (

cou

nts

)

2θ, degrees

2D-XRD Depth ProfilingDirections of Mapping

46

Depth Profiling (Radial) – 24 hours

47

10 MPa

100 MPa

0

10

20

30

40

50

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 Co

mp

ress

ion

pre

ssu

re

Cry

stal

line

fra

ctio

n, %

w/w

Distance, mm

10 MPa 100 MPa

Unlubricated radial surface vs Core

48

10 MPa 25 MPa 50 MPa 100 MPa

Cry

sta

lline fra

ction, %

w/w

0

10

20

30

40

50

60

Unlubricated radial surface

Unlubricated core

Unlubricated radial surface vs Core

49

Compression with no wall friction

50

Compression vs hydrostatic

51

0

5

10

15

20

25

30

35

0 20 40 60 80 100 120

Cry

stal

line

fra

ctio

n, %

w/w

Pressure, MPa

Compression Core Hydrostatic

Lubrication (Magnesium stearate)

52

Internal lubricationMagnesium stearate (1% w/w)

was addedto amorphous indomethacin,

before compression

External lubrication

External lubrication

53Magnesium stearate applied to die wall

Internal vs External lubrication

54

External Lubricant

Internal Lubricant

0

10

20

30

40

50

10 Mpa 25MPa 50 Mpa 100 Mpa

Cry

stal

line

fra

ctio

n, %

w/w

Radial Surface (24 hours)

External Lubricant

Internal Lubricant

0

10

20

30

40

50

10 Mpa 25 Mpa 50 Mpa 100 Mpa

Cry

stal

line

fra

ctio

n, %

w/w

Core (24 hours)

Inductively Coupled Plasma Mass Spectrometry (ICP-MS)

55

Conclusion

56

• Compression induces crystallization.

• Shear stress due to die wall additional

crystallization.

• External lubrication arrest additional crystallization.

• As pressure is inherent to compression, crystallization could not be stopped.

Unlubricated radial surface vs Core

57

Wall friction

I.C Sinka 2003

59

For liquids in a tank

60

𝝈z = ρgz

𝝈z (Vertical stress)

z

Z height from top surface

Fluid vs Bulk solids

61

Stress 𝝈z

Z h

eig

ht

Fluid Bulk Solid

Janssen H A 1895

Surface

Bottom

For bulk solids

Janssen’s analysis (stresses in a cylindrical silo)

σz=ρgD

4µK[1 − 𝑒

4µ𝐾

𝐷𝑧]

D Diameter

µ wall friction (µ =𝜏𝑤

σw)

K Stress ration (σw

σ𝑧)

62

𝜏𝑤σw

Janssen H A 1895

𝝈z

Ongoing research

63

Reducing the compression pressure without compromising the tensile strength, by using plastic excipient like microcrystalline cellulose.

0

2

4

6

8

10

12

0 50 100 150 200 250 300 350

Ten

sile

str

en

gth

, MP

a

Compression pressure, MPa

PVP K30 MCC Starch HPMC

64

THANK YOU

QUESTIONS?