Abu T. M. Serajuddin, Ph.D.Abu T. M. Serajuddin, Ph.D.St. John’s University, Queens, New York

E-mail: serajuda@stjohns.edu; Phone: 718-990-7822

Formulation of Poorly Water-Soluble Drugs:Formulation of Poorly Water-Soluble Drugs:

Drug Delivery StrategiesDrug Delivery Strategies

Formulation of Poorly Water-Soluble Drugs:Formulation of Poorly Water-Soluble Drugs:

Drug Delivery StrategiesDrug Delivery Strategies

Research Achievement Winner LectureResearch Achievement Winner Lecture

AAPS Annual Meeting 2010AAPS Annual Meeting 2010

Research Achievement Winner LectureResearch Achievement Winner Lecture

AAPS Annual Meeting 2010AAPS Annual Meeting 2010

2

Recent Trends in New Molecule Solubility

0

10

20

30

40

50

Solubility

Pe

rce

nt

<10<10µg/mLµg/mL 10-10010-100µg/mLµg/mL >100>100µg/mLµg/mL

Two-thirds (?): Two-thirds (?): Insoluble or Insoluble or Practically Practically InsolubleInsoluble

Source: Personal experience, literature data and anecdotal information

Very slightly Very slightly soluble or soluble or solublesoluble

Solubility Solubility < 1 μg/mL (0.001 mg/mL)< 1 μg/mL (0.001 mg/mL) is common is common

NewNewGenerationGeneration

3

A few common strategies to overcome A few common strategies to overcome impacts of low solubility on product impacts of low solubility on product development:development:

– Particle size reductionParticle size reduction• MillingMilling• NanosizingNanosizing

– Salt formationSalt formation– SolubilizationSolubilization– Solid dispersionSolid dispersion– Lipid-based drug deliveryLipid-based drug delivery

To save time and resources in product To save time and resources in product development, relatively simpler development, relatively simpler approaches should be tried first.approaches should be tried first.

Dosage Form Development StrategiesDosage Form Development Strategies

Salt FormationSalt FormationSalt FormationSalt Formation

5

How Does Salt Formation Increase Dissolution Rate?How Does Salt Formation Increase Dissolution Rate?

Diffusion Layer Model

StagnantDiffusion

Layer

Cs, h=0 >>

h

Bulk LiquidPhase

(Dissolution Medium)

C

Solid(salt)

Cs, bulk medium

…. by changing microenvironmentalpH and solubility

•Saturate •Supersaturate,and/or•Fine precipitate

dMdMdtdt

DADAhh((CCss - C - C ))J =J = ==

6

Effect of Salt Formation on Drug SolubilityEffect of Salt Formation on Drug Solubility

pH-Solubility Profile of Haloperidol Mesylate, Hydrochloride and Phosphate

0.1

10

1000

100000

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

pH

Lo

g S

olu

bili

ty (

µg

/mL

)

Mesylate

HCl

Phosphate

Mesylate > HCl > Phosphate

Line: fitted by equation

Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin. Investigation of Solubility and Dissolution of a Free Base and Two Different Salt Forms as a Function of pH. Pharm. Res. 22:628-635 (2005)

2.5 µg/mL2.5 µg/mL

30 mg/mL30 mg/mL

7

Dissolution Profiles of a Free BaseDissolution Profiles of a Free Base

Intrinsic dissolution of haloperidol base

0

5

10

15

20

25

30

35

0 15 30 45 60 75 90 105 120Time (min)

Cu

mu

lativ

e a

mo

un

t rel

ea

sed

(m

g)pH 2.05

pH 5.0

pH 3.08

pH 1.1

Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin. Investigation of Solubility and Dissolution of a Free Base and Two Different Salt Forms as a Function of pH. Pharm. Res. 22:628-635 (2005)

Solubility is practically zero under intestinal pH conditions (5 and higher)

8

Dissolution Rates of Salt Forms of a Basic CompoundDissolution Rates of Salt Forms of a Basic Compound

Intrinsic dissolution of haloperidol mesylate

0

50

100

150

200

250

300

0 15 30 45 60 75 90 105 120

Time (min)

Cum

ulat

ive

amou

nt r

elea

sed

(mg)

pH 3.05

pH 5.01

pH 2.08

pH 1.65pH 1.08

pH 7.0

Intrinsic dissolution of haloperidol hydrochloride

0

5

10

15

20

25

30

35

40

0 15 30 45 60 75 90 105 120

Time (min)

Cum

ulat

ive

amou

nt r

elea

sed

(mg)

pH 3.08

pH 2.02

pH 1.1

pH 5.02

pH 7.0

Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin. Investigation of Solubility and Dissolution of a Free Base and Two Different Salt Forms as a Function of pH. Pharm. Res. 22:628-635 (2005)

Limitation ofLimitation of

Salt FormationSalt Formation

Limitation ofLimitation of

Salt FormationSalt Formation

10

Diffusion Layer Model

StagnantDiffusion

Layer

Cs, h=0 >>

h

Bulk LiquidPhase

(Dissolution Medium)

C

Solid(salt)

Cs, bulk medium

Pre

cip

itat

ed F

ree

Bas

e XXXX

XXXX

Limitation of Salt Formation for the New Generation of Poorly Water-soluble DrugsLimitation of Salt Formation for the New Generation of Poorly Water-soluble Drugs

When the intrinsic When the intrinsic solubility is very low, the solubility is very low, the precipitated free base precipitated free base coats the dissolving coats the dissolving surfacesurface, preventing , preventing further dissolution of salt.further dissolution of salt.

Please note: Please note: Precipitation Precipitation at the surface, not in the at the surface, not in the bulk medium. No increase bulk medium. No increase in surface area.in surface area.

11

High-energy SolidHigh-energy SolidHigh-energy SolidHigh-energy Solid

12TemperatureTemperature

Hea

t co

nte

nt

Hea

t co

nte

nt

(en

thal

py,

H)

(en

thal

py,

H)

Super

-coo

led liq

uid

Glass

StructureStructure of High-energy Solids of High-energy SolidsStructureStructure of High-energy Solids of High-energy Solids

Crystal

liquidHigh-energy amorphous

solid

Low-energycrystalline solid

13

Solid DispersionSolid DispersionSolid DispersionSolid Dispersion

14

Sto

rage

tem

pera

ture

Tg (mixture)

Drug - polymermiscible blend

TemperatureTemperature

Hea

t co

nte

nt

Hea

t co

nte

nt

(en

thal

py,

H)

(en

thal

py,

H)

Tg (drug)

Sup

er-c

oole

d liq

uid

Glassy state

Drug only

Advantage of Solid Dispersion:Advantage of Solid Dispersion: Better Better Stability than Purely Amorphous SystemStability than Purely Amorphous SystemAdvantage of Solid Dispersion:Advantage of Solid Dispersion: Better Better Stability than Purely Amorphous SystemStability than Purely Amorphous System

Elevated Tg

What is Solid Dispersion ? What is Solid Dispersion ? What is Solid Dispersion ? What is Solid Dispersion ?

Complete miscibilityNo miscibility

Carrier

(amorphous)

Partial miscibility

Drug

(crystalline) +

“the dispersion of one or more active ingredients in an inert carrier or matrix,

where the active ingredients could exist in finely crystalline, solubilized or

amorphous state” - Chiou and Riegelman, J Pharm Sci 1971, 60, 1281-1302

16

Dosage Form

Drug in G.I.Tract

Poorly Water-Soluble DrugPoorly Water-Soluble Drug

AbsorptionAbsorptioninto Body Systemsinto Body Systems

Higher DissolutionHigher DissolutionRateRate

Colloidal Drug Colloidal Drug Particles/GlobulesParticles/Globules

Solid DispersionSolid Dispersion

Matrix DissolvesMatrix Dissolves

Tablet/CapsuleTablet/Capsule

Large Solid ParticlesLarge Solid Particles(Usually 5-100 microns)(Usually 5-100 microns)

DisintegrationDisintegration

Lower DissolutionLower DissolutionRateRate

Ref: Serajuddin, J. Pharm. Sci. 1999, 88, 1058

Advantage of Solid Dispersion:Advantage of Solid Dispersion:Higher Dissolution RateHigher Dissolution RateAdvantage of Solid Dispersion:Advantage of Solid Dispersion:Higher Dissolution RateHigher Dissolution Rate

Surfactant-basedSurfactant-based

Solid DispersionsSolid Dispersions

Surfactant-basedSurfactant-based

Solid DispersionsSolid Dispersions

18

Solid dispersion

Solid Plugwith Layer

Solid Plug

Disintegration ofcapsule shell

Non-Surface active vehicle

• Forms drug-rich surface layer

• Retards/prevents dissolutionof drug

Surface active vehicle

• Disperses/emulsifies drug

• Rapid dissolution rate

Solid Dispersion by Melt-Filling: Advantage of SurfactantSolid Dispersion by Melt-Filling: Advantage of Surfactant

Aqueous Dispersion of Solid Plug

19

Composition of Solid Dispersion Composition of Solid Dispersion

PreparedPrepared

Compound A (LAB687)Compound A (LAB687) 20 mg20 mg

Polysorbate 80Polysorbate 80 0-120 mg 0-120 mg

PEG 3350PEG 3350 360-0 mg 360-0 mg

Total WeightTotal Weight 500 mg500 mg

Capsule size # 0Capsule size # 0

Development of Solid Dispersion:Compound A

Ref: Dannenfelser et al., J. Pharm. Sci. 93:1165-1175 (2004)

20

Composition of Solid DispersionComposition of Solid Dispersion

Compound ACompound A 20 mg20 mg

Polysorbate 80Polysorbate 80 120 mg 120 mg

PEG 3350PEG 3350 360 mg 360 mg

Capsule size # 0Capsule size # 0

Solid Dispersion Selected for Clinical Study: Compound A

Ref: Dannenfelser et al., J. Pharm. Sci. 93:1165-1175 (2004)

21

Formulation AUC (0-48h) RelativeFormulation AUC (0-48h) Relative

(ng.h/mL) Bioavailability(ng.h/mL) Bioavailability

Solid dispersion 6960 100Solid dispersion 6960 100

Solubilized system 6900 100Solubilized system 6900 100

Capsule (mic. Powder) 681 10Capsule (mic. Powder) 681 10

Bioavailability in Dogs from Solid Bioavailability in Dogs from Solid Dispersion: Compound ADispersion: Compound ABioavailability in Dogs from Solid Bioavailability in Dogs from Solid Dispersion: Compound ADispersion: Compound A

Ref: Dannenfelser et al., J. Pharm. Sci. 93:1165-1175 (2004)

22

Solid Dispersion bySolid Dispersion by

Melt ExtrusionMelt Extrusion

Solid Dispersion bySolid Dispersion by

Melt ExtrusionMelt Extrusion

23

Melt extrusion is a single-step process ideally suitable Melt extrusion is a single-step process ideally suitable to manufacture solid dispersionto manufacture solid dispersion

Homogeneous mixture of active, polymerHomogeneous mixture of active, polymerplasticizer, surfactantplasticizer, surfactant

Solid Dispersion by Melt Extrusion Solid Dispersion by Melt Extrusion TechnologyTechnology

Ref: Adapted from J. Kowalski (Novartis) presentation

24

Crystalline drug subs.

Polymer

+Hightemperaturemelt extrusion

Drugdegradation

Am

orp

h. e

xtru

dat

e

Amorphous drug subs.

+Polymer

Lower temperaturemelt extrusion

Stable product

Lower Temperature Melt Extrusion – A Novel StrategyLower Temperature Melt Extrusion – A Novel Strategy

Ref: Lakshman et al., Molecular Pharmaceutics, 5:994-1002, 2008

25

MicroemulsionMicroemulsionMicroemulsionMicroemulsion

26

Dilution with

water

Without dilution

Sandimmune® Neoral® Cyclosporin A 20 – 150 nm( < 200 nm)

Microemulsion(o/w)

What is Microemulsion? -‘Cyclosporine A’ What is Microemulsion? -‘Cyclosporine A’ ExampleExampleWhat is Microemulsion? -‘Cyclosporine A’ What is Microemulsion? -‘Cyclosporine A’ ExampleExample

Ref:A. Meinzer et al,BT Gattefosse 88 :21-26, 1995

Systematic Screening of Lipids forSystematic Screening of Lipids for

Microemulsion FormationMicroemulsion Formation

Systematic Screening of Lipids forSystematic Screening of Lipids for

Microemulsion FormationMicroemulsion Formation

Structures of LipidsStructures of LipidsCC88 Chain fatty acid Chain fatty acid  

Glyceryl Caprylate/CaprateGlyceryl Caprylate/Caprate

(Capmul MCM; ABITEC Co.)(Capmul MCM; ABITEC Co.)

Glyceryl Dicaprylate Glyceryl Dicaprylate

(ABITEC Co.)(ABITEC Co.)

  

  

  

Glyceryl Tricaprylate Glyceryl Tricaprylate

  (Captex 8000; ABITEC Co.)(Captex 8000; ABITEC Co.)

Ternary System for Monoglyceride (Glyceryl Caprylate/Caprate), Cremophor EL and WaterTernary System for Monoglyceride (Glyceryl Caprylate/Caprate), Cremophor EL and Water

Gel

%

Water

Oil : Surfactant

9:1 7:3 5:5 3:7 2:8 1:9

70 4815 7865 1215 2481 28 15

80 7126 3859 1532 1265 18 12

90 1609 3242 743 473 15 12

99 2978 1173 578 430 15 14

Particle Size, nm

Ternary System for Diglyceride( Glyceryl Dicaprylate), Cremophor EL and WaterTernary System for Diglyceride( Glyceryl Dicaprylate), Cremophor EL and Water

%

Water

Oil : Surfactant

9:1 7:3 5:5 3:7 2:8 1:9

70 2788 492 90 17 80 32

80 2007 286 55 20 77 14

90 1844 222 35 18 19 14

99 1903 153 35 20 19 16

Particle Size, nm

Ternary System for Triglyceride (Caprylate/ Caprate Triglyceride), Cremophor EL and WaterTernary System for Triglyceride (Caprylate/ Caprate Triglyceride), Cremophor EL and Water

%

Water

Oil : Surfactant

9:1 7:3 5:5 3:7 2:8 1:9

70 1580 619 1296 533 867 116

80 1794 463 634 390 685 39

90 2136 380 383 334 402 22

99 3851 291 218 172 154 20

Particle Size, nm

%

Wate

r

Oil : Surfactant

9:1 7:3 6:4 5:5 4:6 3:7 2:8 1:9

70 3353 1105 115 43 22 20 18 24

80 5303 395 153 21 17 15 14 33

90 875 546 44 21 17 16 14 16

99 338 41 30 25 20 18 16 16

Pseudo-Ternary System using 1:1-Tri- + Mono-Glycerides, Cremophor EL and WaterPseudo-Ternary System using 1:1-Tri- + Mono-Glycerides, Cremophor EL and Water

Particle Size, nm

%

Water

Oil : Surfactant

7:3 5:5 3:7 2:8 1:9

70 1029 1079 150 82 80

80 1063 442 22 18 17

90 870 252 18 16 17

99 50 78 20 16 16

Particle Size, nm

Pseudo-Ternary System using 1:1-Di- + Mono-Glycerides, Cremophor EL and WaterPseudo-Ternary System using 1:1-Di- + Mono-Glycerides, Cremophor EL and Water

34

Solid Microemulsion PreconcentrateSolid Microemulsion Preconcentrate

- A Novel Solid Dispersion- A Novel Solid Dispersion

Solid Microemulsion PreconcentrateSolid Microemulsion Preconcentrate

- A Novel Solid Dispersion- A Novel Solid Dispersion

35

Solid dispersion Solid

preconcenrate

Liquid

preconcentrate

Solid Microemulsion PreconcentrateSolid Microemulsion Preconcentrate

NH

O

OCH3

CH3

CF3

NH

O

Component Solid Microemulsion Preconcentrate

Compound A (%w/w) 4 8

Capmul PG8 (%w/w) 28.8 27.6

Cremophor EL (%w/w)

28.8 27.6

PEG 3350 (%) 38.4 36.8

Compound A

Ref: Li et al., J. Pharm. Sci., 98:1750-1763, 2009

36

Formulation of Poorly Water-Soluble Formulation of Poorly Water-Soluble DrugsDrugsFormulation of Poorly Water-Soluble Formulation of Poorly Water-Soluble DrugsDrugs

Concluding RemarksConcluding Remarks Almost one-third of compounds synthesized Almost one-third of compounds synthesized

by discovery scientists is extremely water-by discovery scientists is extremely water-insoluble (solubility in water: <10 insoluble (solubility in water: <10 µg/mL)µg/mL)

Conventional formulation techniques may no Conventional formulation techniques may no longer be applicable to most, if not all, of longer be applicable to most, if not all, of them.them.

Special formulation approaches are Special formulation approaches are necessary to enable development of such necessary to enable development of such compounds.compounds.

Formulation strategies must be selected Formulation strategies must be selected based on dose, solubility and other based on dose, solubility and other physicochemical properties of NCEs.physicochemical properties of NCEs.