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Pharmaceutical Solid FormScreening, Characterization, and Selection

Enhancing Drug Bioavailability and Solubility

Yuchuan Gong, Ph.D.Boston, MA, Jan. 25, 2012

Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

2

Outline

1. Solid FormsSolid Forms

Solid State Thermodynamics

3. Solid Form DevelopmentSolid Form Screening

Solid State Characterization

Solid Form Selection

2. Impact of Solid FormSolubility/Dissolution

Stability

Morphology/Processing

3

Outline






2. Impact of Solid Form

Solubility/Dissolution

Stability



4

Why Solid?

Most drugs are marketed in solid dosage forms

Common Dosage Forms Phase of API in DrugTablet solid

Capsule solid, liquidPowder, granule solid

Ointment, cream, gel solidTransdermal solidSuppository solid

Solution liquidDisperse solid, liquid

Solid is more stable than its liquid counterpart

API’s are usually manufactured, transported, and stored as solid


5

Types of Solid Forms

Solid

Crystalline AmorphousLiquid Crystalline

PolymorphsSalt Molecular Adducts

Solvate/Hydrate Co-crystal

long range order short range order

singlecomponent

multiplecomponents

ionic non-ionic

+


6

Solid Forms (Polymorphs)

Polymorphs:crystalline forms with the same chemical composition but

different internal structures (packing, conformation, etc.)

More than 80% of the pharmaceutical solids exhibit polymorphs

Conformational:

Tautomeric:

Packing:

NH

O OH

N

H-Bonding


7

The thermodynamically most stable form of a pharmaceutical solid is normally preferred on account of its greatest stability

A metastable polymorph is sometimes developed, when it can provide an acceptable balance between processability and stability

The thermodynamically most stable form of a pharmaceutical solid is less soluble, but more stable

A metastable polymorph is more soluble, but less stable

metastable

stable

Solid Forms (Polymorphs)

Ritonavir


8

Solid Forms (Solvates/Hydrates)

Solvates / Hydrates

Molecular adducts that incorporate solvent molecules in their crystal lattices;

Solvent is water Hydrates

Solvent is other solvents Solvates

SolvateNon-solvated


9

Solid Forms (Solvates)

Solvate is the most stable form in the particular solvent

Knowing if a solvate can form in a particular solvent is essential to processing.

Solvate formation can be used for purification

Solvate may be used to prepare a desolvated solid form

Common organic solvents in solvates

Methanol, ethanol, 1-propanol, IPA, 1-butanol, acetone, MEK, acetonitrile, diethyl ether, THF, dioxane, acetic acid

hexane, cyclohexane,benzene, toluene,ethyl acetate,dichloromethanedimethylformamide …

Solvates are not acceptable for API (except ethanol solvate)


10

Solid Forms (Hydrates)

Organic compounds frequently form hydrates in presence of water due to

Small molecular size of water

The multidirectional hydrogen bonding capability of water

Distribution of stoichiometry of hydrates among 6000 non-organometallic compounds (3.8% of all) in Cambridge Crystallographic Database

0

500

1000

1500

2000

2500

3000

0.5 1 2 3 4 5 6 7 8 9

Hydration Number

Num

ber

of O

ccure

nce

s


11

Solid Forms (Hydrates)

Hydrate is the most stable solid form in water,

least soluble form in GI environment

However,

Stable hydrates with acceptable bioavailability can be developed:

may have better physicochemical properties

may be the only crystalline form of a API

Non-hydrous solid form is usually favored over hydrates


12

1. Interaction between the components

2. Proton transfer

Solid Forms (Salts / Co-crystals)

Crystalline Salts and Co-crystalscontain two or more components in the same lattice

O

O H

R R1

N R2

O

R

O-

R1

N+ R2H

Salt Co-crystal

Differentiation is debatable:


13

Solid Forms (Salts / Co-crystals)

Property modification:Dissolution rateChemical and physical stabilityCrystallinityHygroscopicityBulk properties

Density, particle size, flowability, etc.

Manufacturabilitydrying, filtrability

Salt / co-crystal formation of API are investigated in

great frequency because

Crystallization tool:Purification

Powder dissolution

Childs et al., J Am Chem Soc 126:13335-13342, 2004.


14

Solid Forms (Amorphous)

Amorphous solid

solid in which there is no long-range order of the positions of molecules/atoms.

Amorphous solid has higher free energy than its corresponding crystalline solids, therefore, higher apparent solubility and dissolution rate

Amorphous

Crystalline

Law et al., J. Pharm. Sci. 93:563, 2004Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

15

Types of Solid Forms (Stoichiometry)

Solid

Crystalline AmorphousLiquid Crystalline

PolymorphsSalt Molecular Adducts

Solvate/Hydrate Co-crystal

long range order short range order

singlecomponent

multiplecomponents

stoichiometric non-stoichiometric

ionic non-ionic

+


16

Gibbs free energy:

G = H – TS

where: G : Gibbs free energy (KJ/mol)

H : enthalpy (KJ/mol)T : temperature (K)S : entropy (J/mol·K)


Enthalpy: Internal energy

Free Energy: measure of thermodynamic potential

Entropy: measure of “disorderness”


17

G = H – TS

Solid State Thermodynamics (Polymorph)

Enthalpy is the heat needed to create something from “nothingness”

Therefore, different solid forms have different enthalpy due to different bonding/interactions between molecules in the solid forms

Entropy is a measure of “disorderness”

Therefore, solid forms have different entropy due to internal arrangement

The higher the disorder, the higher the entropy

Any system tends to change towards the direction of lower disorder

Why does the same chemical identity of different solid forms have different G?


18

Only quantity that determines the thermodynamic relationship (relative stability) between phases


GIII = GII – GI = HIII – TSIII

GII < GI GIII < 0Phase II is more stable Phase I II is a spontaneous process

GII > GI GIII > 0 Phase II is less stable Phase II I is a spontaneous process

GII = GI GIII = 0Phase I and II is equally stable Phase I and II are in equilibrium

Free energy:


19

Solubility (Activity):


GIII = GII – GI = RT ln(aII/aI)

= RT ln(IICsII/ ICsI) = RT ln(II/I·CsII/CsI)

RT ln(CsII/CsI)*

where CsI and CsII : solubility of solid form I and II;

I and II : activity coefficients at CsI and CsII.

* In dilute solutions, I = II

GII < GI GIII < 0Phase II is more stable Phase II has less solubility

GII > GI GIII > 0 Phase II is less stable Phase II has higher solubility

GII = GI GIII = 0Phase I and II is equally stable Phase I and II are in equilibrium


20

T t Tm, II Tm, I

G liquid

G II

G I

Temperature, T

Fre

e E

ne

rgy,

G

Tm, IITm, I

G liquid

G II

G I

Temperature, T

Fre

e E

ne

rgy,

G

Temperature, T

So

lub

ility

T t

CI

CII

Monotropic

Enantiotropic

Temperature, T

So

lub

ility

CI

CII


GIII = HIII – TSIII

G = H – TS


21

)(2)( ,

)(2,

gassolidHpK

solid OnHDOnHD trtd

The equilibrium between the anhydrous and hydrate forms of a drug D can be represented as

Therefore

,or (g)2(g)2 t

cOHOH ppaa hydrate is more stable

,or (g)2(g)2 t

cOHOH ppaa anhydrate is more stable

,or (g)2(g)2 t

cOHOH ppaa anhydrate and hydrate are

equally stable

nn

s

tncOH

OnHD

ncOHD

RHpp

aaaa

][][][][]][[

K(g)2

(s)2

(g)2(s)

d

Solid State Thermodynamics (Hydrate/Solvate)

* Solvates are treated similarly


22

0

100

0 1004.5 30 47

Mono

Tri

Penta

% W

eig

ht

Wate

r

Relative Humidity

Copper Sulfate

0

9H2O

0 100

2H2O

8H20

Ou

bai

n.n

H2O

Temperature (oC)

Ouabain


Relative stability of hydrates at various RH


23

Temperature dependence of hydrate stability

Apply van’t Hoff equation to Kd

)()ln()ln(12(g)2(g)2

1112 TTnR

HcOH

cOH

traa

1/T (1/K)

Ln(

Cri

tica

l Wat

er A

ctiv

ity)

Higher T

Lower T

Critical water activity increase with temperature

Hydrate is less stable at higher temperatures

Hydrate is more stable at lower temperatures

Keep the hydrate under cool and humid conditions!



24

Amorphous: “glass”, no long-range order between molecules

Solid State Thermodynamics (Amorphous)

Liquid

Supercooled

Liquid

Glass 1

TmTgTk

Glass 2

Temperature

Vo

lum

e,

En

tha

lpy

Crystalline

Relaxation

Tm – melting temperature

Tg – glass transition temperature

Tk – Kauzmann temperature

Mobility

Relaxation

Crystallization

Important concepts:


25

Outline








Stability



26

Impact of Solid Forms

Different solid forms show different physical, chemical, and mechanical properties

Melting point

Spectral properties

Solubility

Density

Hardness

Crystal shape

Stability (physical & chemical)

Dissolution rate

Bioavailability

Hygroscopicity

Bulk properties

Manufacturability ….

“Druggability”


27

Hydrates

Impact of Solid Forms (Solubility / Dissolution)

• Lower solubility in water

• Higher “solubility” in other solvents

Amorphous

• Always has higher “solubility” than its crystalline counterparts

Consideration:

Thermodynamic Solubility v.s. Apparent Solubility

Salts

• Modify “solubility” by adjusting pH


28

21.S

S

Form II

Form I

Impact of Solid Forms (Solubility)

Sulfamerazine

Solubility at 25oC

Form I – Metastable

Form II –Most Stable

Gong, et. al, 2008.

MeS NH

O

O

N

N

H2 N


29

h

CSDCC

h

DS

dt

dM ss

Whitney-Noyes equation:

Where dM/dt : dissolution rate; M : mass of solute dissolved;D : diffusion coefficient;S : surface area of the exposed solid;h : thickness of the diffusion layer;Cs : solubility;C : concentration

Impact of Solid Forms (Dissolution)

Distance from Solid Surface

Diffusion layer Bulk solution

Co

nce

ntr

atio

n/s

olu

bili

ty

Cbulk

CSSolid State

Driving force


30

Iopanoic acid

Stagner & Guillory, 1963.

Amorphous: Form I: Form II:


Powder dissolution Intrinsic dissolution

Amorphous

Form II

Form I

Amorphous

Form II

Form I

> >


31

Succinyl sulfathiazole, in ~0.001 N H2SO4 solution at 20°C

CO 2 H

SNH

O

O

N

SNH C CH 2

O

CH 2

Shefter & Huguchi , 1963.



32


Substantial increase in apparent solubility by salt formation, which will lead to the enhancement in dissolution rate

pKapHmax

Different salt forms will have different extent of apparent solubility improvement

Salt 1

Salt 2


33


Forbes et al, 1995

p-Aminosalicylic acid: antibacterialCO 2 H

OH

H2 N

h

CSDCC

h

DS

dt

dM ss

Parent


34

Distance from Solid Surface

Diffusion layer Bulk solution

Co

nc

en

tra

tio

n/s

olu

bil

ity

pHmax

pHbulk

Cbulk

CS

CFA

CSalt

Solid State

BH+A-

Solid

A-

A-

A-

A-

HA

HA

HA

HA

A-

HA

pH

Impact of Solid Forms (Dissolution)Dissolution enhancement of salt may be jeopardized by the precipitation of the parent API


35

Impact of Solid Forms (Chemical Stability)

Compound A

FB:

Photo-sensitive

Forming crystalline salts can improve photo-stability of API at ambient temperatures


36

Impact of Solid Forms (Morphology)

Compound B

Morphology may have great impact on processing of API and formulation


37

Outline








Stability



38

Solid Form Development Work Flow

Crystallization of ParentCrystallization of ParentManual salt/co-crystal screeningManual salt/co-crystal screening

Thermodynamically Thermodynamically most stable form of hitsmost stable form of hits

Detailed SS characterizationDetailed SS characterization

Hit Identification

Lead Identification

Hit Scale-Up

Pharmaceutical EvaluationPharmaceutical Evaluation Manufacturability EvaluationManufacturability Evaluation

LeadScale-Up

Lead Verification


SingleSingleCrystalCrystal

StructureStructure

Polymorph Screening


39

Safety is the overriding consideration

Salt/Cocrystal Screening (Guest Selection)

The property of the solid is more important than the differentiation of salt vs. cocrystal no need to worry about the pKa differences

• 2,6-dihydroxybenzoic acid(pKa: 1.3)

• Caffeine (pKa: 0.7)

• pKa = -0.6 Personal conversation with Dr. Geoff Zhang

* Salt/cocrystal continuum: pKa 1 – 3 could result in salt or cocrystal

Cocrystals: hydrogen bonding potential

Salts: the strength of acids/bases: pKa 2*


40

Common Crystallization Techniques • Reactive

• Antisolvent addition

• Solvent evaporation

• Temperature gradient

• Slurry

Salt/Cocrystal Screening (Crystallization)

GenerateSupersaturation

Should we consider the ability to scale up?

• At early stage, scale up is less of a concern

• As the candidate moves to later stages, the ability to perform crystallization at larger scale becomes increasingly important

• Preferred industrial crystallization usually involves reactive, antisolvent, and temperature gradient


41

Solution Crystallization

Crystallization

Nucleation Crystal Growth

PrimarySecondary(induced by crystals)

Homogeneous(spontaneous)

Heterogeneous(induced by foreign surfaces)

Mullin, 1992.

• Can be controlled by either nucleation or crystal growth

• Usually nucleation the slowest, rate-limiting step


42

Crystallization (Solvent Evaporation)

From a single solvent

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10Time (hr)

Vol

ume

(mL

)

100

1000

10000

0 2 4 6 8 10

Time (hr)

Con

cent

rati

on (

mg/

mL

)

Column of solvent decreases

Concentration increases

Solubility remains same

SSupersaturation

Potential Problem:Evaporation rate is too highSolubility is too high

Advantage: Easy


43

Crystallization (Solvent Evaporation)

Volume of solvent decreases

Concentration of API increases

Solubility of API decreases

0

20

40

60

80

100

0 1 2 3 4 5

Time (hr)

Vol

ume

(mL

) or

% S

olve

nt

Volume

Solvent A %

Solvent B %

0

50

100

150

200

250

0 1 2 3 4 5

Time (hr)

Con

cent

rati

on o

r So

lubi

lity

(m

g/m

L)

Concentration

Solubility

From a solvent mixture

S

Bad Solvent (A)

Good Solvent (B)Supersaturation

Potential Problem:Complex solvent system

Advantage: Adjustable solubilityDual effect on supersaturation


44

Crystallization (Heat & Cool)

Temperature drops


Concentration remains same

Heat & Cool

S

Te

mp

Time

Co

nc

en

tra

tio

n

C0

Supersaturation

High Temp Low Temp

Potential Problem:Degradation

Advantage: Moderate solubilityBetter yield


45

Crystallization (Anti-solvent)

% bad solvent increases


Concentration of API decreases

Anti-solvent

S

Ba

d S

olv

en

t %

Time

Co

nc

en

tra

tio

nSupersaturation

Good Solvent %

AB

Potential Problem:Complex solvent systemTitration rate

Advantage: More solvent optionsHigh yield


46

Crystallization (pH Adjustment)

pKapHmax

At higher pH, apparent solubility of ionic API increases

At pH > pHmax, concentration of API > Solubility of salt

Driving force of the crystallization of the salt increases

pH Adjustment (Salt formation)

Ssalt

Supersaturation


47

Crystallization (SMPT)

Sol

utio

n C

once

ntra

tion

Sol

id C

ompo

sitio

n

SMetastable

SStable

Time

1 2 3100% Metastable Phase

100% Stable Phase

Solution-Mediated Phase Transformation

GI > GII

Slurry of I

CI > CII

Supersaturation of II

Crystallization of II


48

Crystallization (SMPT)

Water Activity (aw) or Relative Humidity (RH)

Identity of the Crystal Form

Anhydrate

Hydrate

0 (0%) 1 (100%)

Critical Water Activity (aw,c)

Water Activity (aw) or Relative Humidity (RH)


Anhydrate

Hydrate

0 (0%) 1 (100%)

Critical Water Activity (aw,c)

Co-crystal Former Activity (aCCF)


Drug

Co-crystal

0 1

Critical Co-crystal Former Activity (aCCF,c)

Co-crystal stable region

Drug stable region

Co-crystal Former Activity (aCCF)


Drug

Co-crystal

0 1

Critical Co-crystal Former Activity (aCCF,c)

Co-crystal stable region

Drug stable region

Hydrate: various water activity

Co-crystal: maximum co-crystal former activity

Crystallization of


49


Factors may impact Additives (impurity, other additives) Solvent (solubility, viscosity, solute-solvent interaction etc.) Rate of reaching supersaturation

(evaporation rate, cooling rate, anti-solvent addition rate) Temperature Mechanical impact (agitation, sonication) Solid/solvent ratio (SMPT) Particle size/surface area (SMPT) etc.

Only trick to success is “keep trying”


50





Hit Identification

Lead Identification

Hit Scale-Up


LeadScale-Up

Lead Verification



StructureStructure

Polymorph Screening


51

Solid Form Characterization

Characterizations Techniques

Chemical identity NMR, IC

Crystalline solid form identification Microscopy, PXRD, Raman, IR, DSC

Melting temperature DSC

Morphology Microscopy

Solvate/hydrate identification DSC, TGA/MS, PXRD

Hygroscopicity Moisture sorption balance

Dissolution rate -Diss

Crystalline solids

Amorphous solids

Physical stability assessment (Tg, relaxation kinetics, crystallization kinetics)


52

Solid Form Characterization (PXRD)

nd sin2

dsin

d

Bragg’s Law

’

dsin’ d’

Each d corresponds to a


53


PXRD is the most commonly used technique to identify solid form

Different solid forms generally have different PXRD patterns

PXRD can not be used to distinguish the chemical identity of the solids, unless

the solid forms of each compound are known

Single crystal structure is the most direct way to determine the nature of a

crystalline solid.

Single crystal X-ray data can be used to calculate the PXRD pattern


54


Be very careful with two solids having “same” PXRD patterns

Are they really “same” or “very similar”?


55


Be very careful with hydrates/solvates

as they may be missed due to quick

dehydration/desolvation

Conversion rate of the solvates:

Methanol > Ethanol > IPA


56

Solid Form Characterization (NMR / IC)

Solution NMR

Determine the chemical identity / purity

Determine the stoichiometry of solvates/co-crystals

Determine the stoichiometry of salts with organic counter ions

Ion Chromatography

Determine the stoichiometry of salts with inorganic counter ions


5757

Solid Form Characterization (Spectroscopy)

Raman and IR Spectroscopy

Most commonly used in characterizing pharmaceutical solids

Small sample requirement

Simple sample preparation /Can be used in-situ

Not everything is Raman or IR active

(Raman) may be not representative / Fluorescence / Burning

(IR) low spatial resolution (XY&Z) / less information at low wavelength

Metastable

Stable

Flufenamic Acid


58

Solid Form Characterization (Thermal)

Advantages:

• Small sample size

• Information on melting point and phase transition (DSC)

• Information on enthalpy difference

• Stoichiometry for solvates and hydrates (TGA)

Disadvantages:

• Destructive Method

• Thermal manipulation

• Interference (other components, thermal products, etc.)

• “Black box” (total heat exchange)


59

Solid Form Characterization (Thermal-DSC)

Baseline ShiftGlass transition

Endothermic Events Exothermic EventsSolid-solid transitions

Degradation

Melting, boiling, sublimation, vaporization

Desolvation

Solid-solid transitions

Degradation

Crystallization

DSC is used to monitor heat exchange when the sample is heated/cooled or maintained isothermally


60

DSC

Applications of DSC

Melting temperature Heat of fusion Impurity Solid state solubility Dehydration/desolvation Chemical reaction Polymorphismetc.

DSC


61

DSC (Melting)

Melting Point:

– Sharpness reflects the chemical purity

– Defined by extrapolated onset temperature (pure)

– Reported using peak temperature (with impurity)

– May overlap with other physical processes (recrystallization, solid-solid transition, etc.) and chemical processes (decomposition etc.)

158.76°C

158.03°C28.42J/g

-4

-3

-2

-1

0

Hea

t Flo

w (

W/g

)

145 155 165

Temperature (°C)

Sample: IndiumSize: 3.2640 x 0.0000 mgMethod: Temperature (°C)Comment: Cell constant calibration

DSCFile: S:\3S\Gong\INDIUM.001Operator: YGRun Date: 24-Apr-2008 14:59Instrument: DSC Q2000 V24.2 Build 107

Exo Up Universal V4.4A TA Instruments

Onset Temp

Peak Temp

Tm of Indium

DSC is commonly used to measure melting temperature of crystalline solids


62

DSC (Heat of fusion)

158.76°C

158.03°C28.42J/g

-4

-3

-2

-1

0

Hea

t Flo

w (

W/g

)

145 155 165

Temperature (°C)

Sample: IndiumSize: 3.2640 x 0.0000 mgMethod: Temperature (°C)Comment: Cell constant calibration

DSCFile: S:\3S\Gong\INDIUM.001Operator: YGRun Date: 24-Apr-2008 14:59Instrument: DSC Q2000 V24.2 Build 107

Exo Up Universal V4.4A TA Instruments

Hf

Tm of Indium

DSC is commonly used to measure the heat of fusion of a crystalline solid

Heat of Fusion:

– Integrated area under melting curve

– May overlap with recrystallization

– May overlap with decomposition and sublimation


63

DSC (Melting without decomposition)

Melting is a thermodynamic phenomenon,

therefore, melting point does not change much with heating rate

Thomas, L. http://www.tainstruments.com/pdf/literature/TA315.pdf

Higher heating rate

Same Tm


64

DSC (Melting with decomposition)

Decomposition is a kinetic phenomenon, therefore, melting/decomposition temperature changes with heating rate

Higher heating rate

Higher “Tm”

Thomas, L. http://www.tainstruments.com/pdf/literature/TA315.pdf


65

DSC (Dehydration/desolvation)

- Usually at lower temperatures

- Large enthalpy because of the evaporation of released water/solvent

- May result in lower hydrates, anhydrous phases, or amorphous phase

Carbamazepine dihydrate

Li Y. et al., Pharm. Dev. Tech., 2000. 5, 257.

DSC is used to determine dehydration/desolvation


66

DSC (Polymorphism)Different polymorphs usually have

different melting temperatures and heat of fusions

higher melting form; lower Hf

higher melting form; higher Hf

H f, II

T tTm, II

Tm, I

G liquid

G II

G I

Temperature, T

En

erg

y (G

, H)

HII

HI

HL

H f, I

Monotropic

T t

Tm, II

Tm, I

G liquid

G II

G I

Temperature, TE

ne

rgy

(G, H

)

HII

HIH f, II

H f, I

HL

Enantiotropic

Heat of Fusion Rule


67

H f, II

T tTm, II

Tm, I

G liquid

G II

G I

Temperature, T

En

erg

y (G

, H)

HII

HI

HL

H f, I

DSC (Polymorphism)

Phase transitions of

Monotropic Polymorphs

I

IIL

ILII

I

IILIL

LII

II

IIL

III

IIL

I


68

T t

Tm, II

Tm, I

G liquid

G II

G I

Temperature, T

En

erg

y (G

, H)

HII

HIH f, II

H f, I

HL

DSC (Polymorphism)

Phase transitions of

Enantiotropic Polymorphs

IIIL

IILI

ILIIIII

ILIIL

LIII

IL

III IIII

I

IL


69

MDSC (Theory)

MDSC separates the total heat flow response into the reversing and non-reversing components

Modulated DSC (MDSC) applies a sinusoidal heating program on top of a linear heating rate in order to measure the heat flow that responds to the changing heating rate

Paul G. et. al. Pharm. Res., 1998, 15(7), 1117

Mudunuri P. Ph.D. Thesis., 2007


70

MDSC (Glass transition, Phase separation)

Vasanthavada M. et. al. Pharm. Res., 2004, 21(9), 1598 Mudunuri P. Ph.D. Thesis., 2007

MDSC reversing heat flow scans of trehalose-dextran mixture (40/60) stored 50oC/75%RH

0 day

2 days

4 days

13 days

23 days

34 days

Measured Tg can be used to determine phase homogeneity

Single Tg: Single phase

Multiple Tg’s: phase separation


71

DSC/MDSC (Solid-State Solubility)

DSC is used to determine solubility of crystalline small molecule in polymer

Jing T. et al. Pharm. Res. 2009, 26(4) 855

Tend and Tg as a function of D-mannitol concentration in PVP

Tend

Tg

Tend


72

Solid Form Characterization (TAM)

Pros• Excellent isothermal condition

• High sensitivity

Applications

• Recrystallization

(heat and/or moisture induced)

• Excipient compatibility

• Slow reactions

Bystrom. Thermometric Application Note 22004, 1990

Cons• Disturbance when the experiment starts

• Limited temperature range


73

Solid Form Characterization (Thermal-TGA)

Thermogravimetric Analysis:

- provides information on volatile content

- type of purge gas and purge rate can affect curve

Ref Pan

Sample Pan

Furnace

Purge Gas

Measures the thermally induced weight change of a material as a function of temperature


74

TGA (Dehydration / Desolvation)

TGA is often used to measure the weight loss upon heating, from which stoichiometry of hydrate and solvate can be determined

4.660% (1.133mg)

Ramp 10.00 °C/min to 200.00 °C

0.0

0.1

0.2

0.3

0.4

Der

iv. W

eigh

t (%

/°C

)

92

94

96

98

100

Wei

ght (

%)

20 40 60 80 100 120 140 160 180 200

Temperature (°C)

Sample: Erythromycin A dihydrateSize: 24.3160 mgMethod: to 200 @ 10Comment: Lot 86-434-CD

TGAFile: P:...\Geoff\Ery\A T06110301 Ery.2H2OOperator: GeoffRun Date: 11-Jun-2003 14:45Instrument: 2950 TGA HR V5.3C

Universal V4.0C TA Instruments

M% weight loss

Drug

Solvent

MWM

MWM

X

100


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TGA (Degradation)

TGA is often used to determine the thermal stability of sample

Thermal profiles of polymers (PVC, PMMA, HDPE, PTFE, and PI)

http://www.tainstruments.com/pdf/brochure/TGA_IR_Brochure.pdf


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Advantages:

• Small sample size

• Information on melting point and phase transition (DSC)

• Information on enthalpy difference

• Stoichiometry for solvates and hydrates (TGA)

Disadvantages:

• Destructive Method

• Thermal manipulation

• Interference (other components, thermal products, etc.)

• “Black box” (total heat exchange)


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Other techniques, e.g. microscopy, diffraction, and spectroscopy, are combined with thermal analysis methods to characterization solid phase changes

Common Hyphenated Thermal Techniques:

DSC/TGA

Hot-stage Microscopy

VT-PXRD

TGA-MS, TGA-FTIR

etc.

Giron D. J of Therm Anal Calori, 2002. 68, 335

Hyphenated Thermal Techniques:


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Solid Form Characterization (Moisture Sorption)

A: monolayer adsorption

B: multi-layer adsorption

C: deliquescence

Determine moisture uptake at various water activity / Relative humidity

Sorption Isotherm TypesA

B

C


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Solid Form Characterization (Moisture Sorption)

Sorption:

<10%RH : monohydrate

10% - 90%RH: Trihydrate

>90%RH: Heptahemi-hydrate

Desorption:

>10%RH: Heptahemi-hydrate

<10%RH: monohydrate

Monitor formation of hydrates(Nedocromil Sodium)


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Hit Identification

Lead Identification

Hit Scale-Up


LeadScale-Up

Lead Verification



StructureStructure

Polymorph Screening


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• Solid state– is highly crystalline

– is not hygroscopic (<2% weight across 0-80% RH)

– has a melting point > 150 °C

– does not exhibit complex polymorphic behavior or solvate formation

– does not have a labile hydrate

– is physically stable

• Pharmaceutical – is bioavailable (sufficient dissolution rate/solubility)

– is chemically stable

• Manufacturing– Can be prepared in large scale with robust stoichiometric control and acceptable yield,

volume, and purity (chemical and physical)

– does not exhibit a strongly anisotropic morphology (needle/flask)

Solid State SelectionPXRDDSC

Moisture sorption isotherm

DSC

Polymorph, solvate, hydrate screening and

characterization

TGA

Stable at ambient conditions

In vitro: solubility, dissolution, physical stability in suspensionIn vivo (animal)

Accelerated stability

Screen solvents for solubilityEvaluate feasibility at smaller scaleInitial assessment of control: induction time, desupersaturation rate, size and distribution


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Cross-functional Decision

Decision Making (Solid From Selection)Stability

Apparent Solubility

Hygroscopicity Crystallinity

Dissolution Rate

Certain properties have higher priority• Chemical stability v.s. Polymorphism

Candidates with good properties all-around is a “no-brainer”. But, Balancing/compromising is often required• “Must have” vs. “nice to have”• Formulation/delivery: parent vs. salt

Some key properties are inter-related

• Crystallinity & Hygroscopcity

Project/Compound specific properties• Dissolution enhancement (insoluble API)• Chemical stability (strong amines)


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Approaches: Early vs. Late

How early is early?

• Before the nomination of the development candidate

Pros and Cons

• Pros (Early)

– less likely to switch salt during later development

– better definition of formulation approach at candidate nomination

– likely to enable fast formulation development

• Cons (Early)

– Resources could be “wasted”

– Less flexibility in formulation design and process selection


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Pros and Cons

• Pros (Integrated)– Polymorphism considered early

– Fair comparison among the candidates

• Cons (Integrated)– Resource-intensive, time-consuming, and material consumption

Approaches: Integrated v.s. Tiered

Morris et al, 1994Serajuddin and Pudipeddi, 2008

Tier 1 CrystallinityCrystallization from different solventsAqueous solubility

Tier 2 Evaluation of crystalline formThermal propertiesHygroscopicity

Tier 3 humidity/temperature-dependentchanges in crystal form

Tier 4 bioavailability screeningstress stabilityscale-up considerations

Polymorph screening

TieredIntegrated

salt 1 salt 2 salt 3 salt 4crystallinity

hygroscopicitymelting pointpolymorphism

physical stabilitysolubility/dissolution

chemical stabilitymanufacturability

The “best” approaches will lay between the two extremes

– Timing, intrinsic properties of the compound, availability of material……


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Pros and Cons

• Pros (Robotic)

– Hundreds of salts/cocrystals crystallization simultaneously

– Less labor

• Cons (Robotic)

– Many unsuccessful crystallization

– Less characterization, especially the confirmation of the chemical make-up

– Requires more material for typical compounds

Approaches: Robotic vs. Manual

Based on material availability

Develop new robotic methods


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Hit Identification

Lead Identification

Hit Scale-Up


LeadScale-Up

Lead Verification



StructureStructure

Polymorph Screening


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Polymorph Screening

Polymorph Screening


Thermodynamic Polymorph Screening(Suspension/Slurry)

Anti-solvent

Heat/Cool

Evaporation


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Summary

Screening, characterizing, and selecting a solid form is an essential/critical task in drug product development

Logical screening and selection processes will result in good solid forms with less material, time, and labor; ultimately efficiency in solid form selection and formulation development

Solid form selection has strong impact on the product development due to various pharmaceutically relevant properties of solid forms

– Solid state, pharmaceutical, manufacturing properties

Communication

– Multi-functional team, requires constant dialogue/discussion/negotiation within the team

The future of solid form selection: Incorporate formulation/processing (i.e. Materials Science) considerations


Download - Solubility boston-2012-published

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