solubility boston-2012-published
DESCRIPTION
Pharmaceutical Solid Form Screening, Characterization, and Selection - Yuchuan GongTRANSCRIPT
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
1. Solid FormsSolid Forms
Solid State Thermodynamics
3. Solid Form DevelopmentSolid Form Screening
Solid State Characterization
Solid Form Selection
2. Impact of Solid Form
Solubility/Dissolution
Stability
Morphology/Processing
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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
+
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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)
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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:
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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.
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
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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
+
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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)
Solid State Thermodynamics
Enthalpy: Internal energy
Free Energy: measure of thermodynamic potential
Entropy: measure of “disorderness”
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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?
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Only quantity that determines the thermodynamic relationship (relative stability) between phases
Solid State Thermodynamics (Polymorph)
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:
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Solubility (Activity):
Solid State Thermodynamics (Polymorph)
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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Solid State Thermodynamics (Polymorph)
GIII = HIII – TSIII
G = H – TS
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Solid State Thermodynamics (Hydrate/Solvate)
Relative stability of hydrates at various RH
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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!
Solid State Thermodynamics (Hydrate/Solvate)
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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:
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Outline
1. Solid FormsSolid Forms
Solid State Thermodynamics
3. Solid Form DevelopmentSolid Form Screening
Solid State Characterization
Solid Form Selection
2. Impact of Solid Form
Solubility/Dissolution
Stability
Morphology/Processing
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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”
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Iopanoic acid
Stagner & Guillory, 1963.
Amorphous: Form I: Form II:
Impact of Solid Forms (Dissolution)
Powder dissolution Intrinsic dissolution
Amorphous
Form II
Form I
Amorphous
Form II
Form I
> >
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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.
Impact of Solid Forms (Dissolution)
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Impact of Solid Forms (Dissolution)
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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Impact of Solid Forms (Dissolution)
Forbes et al, 1995
p-Aminosalicylic acid: antibacterialCO 2 H
OH
H2 N
h
CSDCC
h
DS
dt
dM ss
Parent
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Impact of Solid Forms (Chemical Stability)
Compound A
FB:
Photo-sensitive
Forming crystalline salts can improve photo-stability of API at ambient temperatures
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
36
Impact of Solid Forms (Morphology)
Compound B
Morphology may have great impact on processing of API and formulation
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Outline
1. Solid FormsSolid Forms
Solid State Thermodynamics
3. Solid Form DevelopmentSolid Form Screening
Solid State Characterization
Solid Form Selection
2. Impact of Solid Form
Solubility/Dissolution
Stability
Morphology/Processing
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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
Solid Form Selection
SingleSingleCrystalCrystal
StructureStructure
Polymorph Screening
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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*
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Crystallization (Heat & Cool)
Temperature drops
Solubility of API decreases
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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Crystallization (Anti-solvent)
% bad solvent increases
Solubility of API decreases
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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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)
Identity of the Crystal Form
Anhydrate
Hydrate
0 (0%) 1 (100%)
Critical Water Activity (aw,c)
Co-crystal Former Activity (aCCF)
Identity of the Crystal Form
Drug
Co-crystal
0 1
Critical Co-crystal Former Activity (aCCF,c)
Co-crystal stable region
Drug stable region
Co-crystal Former Activity (aCCF)
Identity of the Crystal Form
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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Solution Crystallization
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”
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
50
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
Solid Form Selection
SingleSingleCrystalCrystal
StructureStructure
Polymorph Screening
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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)
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
52
Solid Form Characterization (PXRD)
nd sin2
dsin
d
Bragg’s Law
’
dsin’ d’
Each d corresponds to a
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
53
Solid Form Characterization (PXRD)
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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
54
Solid Form Characterization (PXRD)
Be very careful with two solids having “same” PXRD patterns
Are they really “same” or “very similar”?
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Solid Form Characterization (PXRD)
Be very careful with hydrates/solvates
as they may be missed due to quick
dehydration/desolvation
Conversion rate of the solvates:
Methanol > Ethanol > IPA
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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)
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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DSC
Applications of DSC
Melting temperature Heat of fusion Impurity Solid state solubility Dehydration/desolvation Chemical reaction Polymorphismetc.
DSC
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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)
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Solid Form Characterization (Thermal)
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:
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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)
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Solid Form Selection
SingleSingleCrystalCrystal
StructureStructure
Polymorph Screening
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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)
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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……
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Solid Form Selection
SingleSingleCrystalCrystal
StructureStructure
Polymorph Screening
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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Polymorph Screening
Polymorph Screening
Solution Crystallization
Thermodynamic Polymorph Screening(Suspension/Slurry)
Anti-solvent
Heat/Cool
Evaporation
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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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
Pharmaceutical Solid Form Screening, Characterization, and SelectionEnhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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