Pharmaceutical Solid Form

Pharmaceutical Solid Form� Screening, Characterization, and Selection - Yuchuan Gong, Ph.D.- Abbott

1. Pharmaceutical Solid Form
Screening, Characterization,
and Selection
Enhancing Drug Bioavailability and Solubility
Yuchuan Gong, Ph.D.
Boston, MA, Jan. 25, 2012

2. Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
2
Outline
1. Solid Forms
Solid Forms
Solid State Thermodynamics
3. Solid Form Development
Solid Form Screening
Solid State Characterization
Solid Form Selection
2. Impact of Solid Form
Solubility/Dissolution
Stability
Morphology/Processing

3. 3
Outline
1. Solid Forms
Solid Forms
Solid State Thermodynamics
3. Solid Form Development
Solid Form Screening
Solid State Characterization
Solid Form Selection
2. Impact of Solid Form
Solubility/Dissolution
Stability
Morphology/Processing
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

4. 4
Why Solid?
Most drugs are marketed in solid dosage forms
Common Dosage Forms Phase of API in Drug
Tablet solid
Capsule solid, liquid
Powder, granule solid
Ointment, cream, gel solid
Transdermal solid
Suppository solid
Solution liquid
Disperse 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 Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

5. 5
Types of Solid Forms
Solid
Crystalline AmorphousLiquid Crystalline
Polymorphs
Salt Molecular Adducts
Solvate/Hydrate Co-crystal
long range order
short range order
single
component
multiple
components
ionic non-ionic
+
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

6. 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
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

7. 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
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

8. 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
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

9. 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,
dichloromethane
dimethylformamide …
Solvates are not acceptable for API (except ethanol solvate)
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

10. 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
0.51 2 3 4 5 6 7 8 9
Hydration Number
N
u
m
b
e
r

o
f

O
c
c
u
r
e
n
c
e
s
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

11. 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
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

12. 12
1.Interaction between the components
2.Proton transfer
Solid Forms (Salts / Co-crystals)
Crystalline Salts and Co-crystals
contain two or more components in the same lattice
O
O H
R
R
1
N R
2
O
R
O
-
R
1
N
+
R
2H
Salt Co-crystal
Differentiation is debatable:
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

13. 13
Solid Forms (Salts / Co-crystals)
Property modification:
Dissolution rate
Chemical and physical stability
Crystallinity
Hygroscopicity
Bulk properties
Density, particle size, flowability, etc.
Manufacturability
drying, 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 Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

14. 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, 2004
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

15. 15
Types of Solid Forms (Stoichiometry)
Solid
Crystalline AmorphousLiquid Crystalline
Polymorphs
Salt Molecular Adducts
Solvate/Hydrate Co-crystal
long range order
short range order
single
component
multiple
components
stoichiometric non-stoichiometric
ionic non-ionic
+
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

16. 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)
Solid State Thermodynamics
Enthalpy: Internal energy
Free Energy: measure of thermodynamic potential
Entropy: measure of “disorderness”
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

17. 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?
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

18. 18
Only quantity that determines the thermodynamic relationship (relative
stability) between phases
Solid State Thermodynamics (Polymorph)
DG
III
= G
II
– G
I
= DH
III
– TDS
III

G
II
< G
I
Þ DG
III
< 0
Phase II is more stable Þ Phase I  II is a spontaneous process
G
II
> G
I
Þ DG
III
> 0
Phase II is less stable Þ Phase II  I is a spontaneous process
G
II
= G
I
Þ DG
III
= 0
Phase I and II is equally stable Þ Phase I and II are in equilibrium
Free energy:
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

19. 19
Solubility (Activity):
Solid State Thermodynamics (Polymorph)
DG
III
= G
II
– G
I
= RT ln(a
II
/a
I
)
= RT ln(g
II
C
sII
/ g
I
C
sI
) = RT ln(g
II
/g
I
·C
sII
/C
sI
)
» RT ln(C
sII
/C
sI
)*
where C
sI
and C
sII
: solubility of solid form I and II;
g
I
and g
II
: activity coefficients at C
sI
and C
sII
.
* In dilute solutions, g
I
= g
II
G
II
< G
I
Þ DG
III
< 0
Phase II is more stable Þ Phase II has less solubility
G
II
> G
I
Þ DG
III
> 0
Phase II is less stable Þ Phase II has higher solubility
G
II
= G
I
Þ DG
III
= 0
Phase I and II is equally stable Þ Phase I and II are in equilibrium
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

20. 20
T
t
T
m , IIT
m , I
G
l iqu id
G
I I
G
I
Temperature, T
Free Energy, G
T
m , II
T
m , I
G
liqu id
G
I I
G
I
Temperature, T
Free Energy, G
Temperature, T
Solubility
T
t
C
I
C
II
Monotropic
Enantiotropic
Temperature, T
Solubility
C
I
C
II
Solid State Thermodynamics (Polymorph)
DG
III
= DH
III
– TDS
III

G = H – TS
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

21. 21
)(2)(
,
)(2
,
gassolid
HpK
solid
OnHDOnHD
trtd
+¾¾¾¾ ®¬×
D
The equilibrium between the anhydrous and hydrate forms of a drug D
can be represented as
Therefore
,or
(g)2(g)2
t
c
OHOH ppaa >> hydrate is more stable
,or
(g)2(g)2 t
c
OHOH ppaa << anhydrate is more stable
,or
(g)2(g)2 t
c
OHOH ppaa == anhydrate and hydrate are
equally stable
nn
s
tnc
OH
OnHD
nc
OHD
RH
p
p
a
a
aa
][][][
][
]][[
K
(g)2
(s)2
(g)2(s)
d ====
×
Solid State Thermodynamics (Hydrate/Solvate)
* Solvates are treated similarly
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

22. 22
0
100
0 1004.5 30 47
Mono
Tri
Penta
%

W
e
i
g
h
t

W
a
t
e
r
Relative Humidity
Copper Sulfate
0
9H
2
O
0 100
2H
2
O
8H
2
0
O
u
b
a
i
n
.
n
H
2
O
Temperature (
o
C)
Ouabain
Solid State Thermodynamics (Hydrate/Solvate)
Relative stability of hydrates at various RH
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

23. 23
Temperature dependence of hydrate stability
Apply van’t Hoff equation to K
d
)()ln()ln(
12(g)2(g)2
11
12 TTnR
Hc
OH
c
OH
tr
aa --=-
D
1/T (1/K)
L
n
(
C
r
i
t
i
c
a
l
W
a
t
e
r

A
c
t
i
v
i
t
y
)
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 Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

24. 24
Amorphous: “glass”, no long-range order between molecules
Solid State Thermodynamics (Amorphous)
Liquid
Supercooled
Liquid
Glass 1
T
mT
g
T
k
Glass 2
Temperature
Volume, Enthalpy
Crystalline
Re la xa tion
T
m
– melting temperature
T
g
– glass transition temperature
T
k
– Kauzmann temperature
Mobility
Relaxation
Crystallization
Important concepts:
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

25. 25
Outline
1. Solid Forms
Solid Forms
Solid State Thermodynamics
3. Solid Form Development
Solid Form Screening
Solid State Characterization
Solid Form Selection
2. Impact of Solid Form
Solubility/Dissolution
Stability
Morphology/Processing
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

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

27. 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
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

28. 28
21.
S
S
Form II
Form I
=
Impact of Solid Forms (Solubility)
Sulfamerazine
Solubility at 25
o
C
Form I – Metastable
Form II –Most Stable
Gong, et. al, 2008.
Me
SNH
O
O
N
N
H2N
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

29. 29
( )
h
CSD
CC
h
DS
dt
dM
s
s

»-=
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;
C
s
: solubility;
C : concentration
Impact of Solid Forms (Dissolution)
Distance from Solid Surface
Diffusion layer Bulk solution
C
o
n
c
e
n
t
r
a
t
i
o
n
/
s
o
l
u
b
i
l
i
t
y
C
bulk
C
S
Solid State
Driving force
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

30. 30
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 Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

31. 31
Succinyl sulfathiazole, in ~0.001 N H
2
SO
4
solution at 20°C
CO2H
SNH
O
O
N
S
NHCCH2
O
CH2
Shefter & Huguchi , 1963.
Impact of Solid Forms (Dissolution)
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

32. 32
Impact of Solid Forms (Dissolution)
Substantial increase in apparent solubility by salt formation, which will lead to the
enhancement in dissolution rate
pK
a
pH
max
Different salt forms will have different extent of apparent solubility improvement
Salt 1
Salt 2
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

33. 33
Impact of Solid Forms (Dissolution)
Forbes et al, 1995
p-Aminosalicylic acid: antibacterial
CO2H
OH
H
2
N

( )
h
CSD
CC
h
DS
dt
dM
s
s

»-=
Parent
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

34. 34
Distance from Solid Surface
Diffusion layer Bulk solution
C
o
n
c
e
n
t
r
a
t
i
o
n
/
s
o
l
u
b
i
l
i
t
y
pH
max
pH
bulk
C
bulk
C
S
C
FA
C
Salt
Solid State
BH
+
A
-
Solid
A
-
A
-
A
-
A
-
HA
HA
HA
HA
A
-
HA
p
H
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 Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

35. 35
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 Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

36. 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 Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

37. 37
Outline
1. Solid Forms
Solid Forms
Solid State Thermodynamics
3. Solid Form Development
Solid Form Screening
Solid State Characterization
Solid Form Selection
2. Impact of Solid Form
Solubility/Dissolution
Stability
Morphology/Processing
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

38. 38
Solid Form Development Work Flow
Crystallization of ParentCrystallization of Parent
Manual 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
Lead
Scale-Up
Lead Verification
Solid Form Selection
SingleSingle
CrystalCrystal
StructureStructure
Polymorph Screening
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

39. 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 pK
a
differences
•2,6-dihydroxybenzoic acid
(pK
a
: 1.3)
•Caffeine (pK
a
: 0.7)
• DpK
a
=

-0.6
Personal conversation
with Dr. Geoff Zhang
* Salt/cocrystal continuum: DpK
a
1 – 3 could result in salt or cocrystal
Cocrystals: hydrogen bonding potential
Salts: the strength of acids/bases: DpK
a
³ 2*
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

40. 40
Common Crystallization Techniques
•Reactive
•Antisolvent addition
•Solvent evaporation
•Temperature gradient
•Slurry
Salt/Cocrystal Screening (Crystallization)
Generate
Supersaturation
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 Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

41. 41
Solution Crystallization
Crystallization
Nucleation Crystal Growth
Primary
Secondary
(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 Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

42. 42
Crystallization (Solvent Evaporation)
From a single solvent
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10
Time (hr)
V
o
l
u
m
e
(
m
L
)
100
1000
10000
0 2 4 6 8 10
Time (hr)
C
o
n
c
e
n
t
r
a
t
i
o
n
(
m
g
/
m
L
)
Column of solvent decreases
Concentration increases
Solubility remains same
S
Supersaturation
Potential Problem:
Evaporation rate is too high
Solubility is too high
Advantage: Easy
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

43. 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)
V
o
l
u
m
e
(
m
L
)

o
r
%
S
o
l
v
e
n
t
Volume
Solvent A %
Solvent B %
0
50
100
150
200
250
0 1 2 3 4 5
Time (hr)
C
o
n
c
e
n
t
r
a
t
i
o
n

o
r
S
o
l
u
b
i
l
i
t
y

(
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 solubility
Dual effect on supersaturation
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

44. 44
Crystallization (Heat & Cool)
Temperature drops
Solubility of API decreases
Concentration remains same
Heat & Cool
S
T
e
m
p
Time
C
o
n
c
e
n
t
r
a
t
i
o
n
C
0
Supersaturation
High Temp Low Temp
Potential Problem:
Degradation
Advantage:
Moderate solubility
Better yield
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

45. 45
Crystallization (Anti-solvent)
% bad solvent increases
Solubility of API decreases
Concentration of API decreases
Anti-solvent
S
B
a
d

S
o
l
v
e
n
t

%
Time
C
o
n
c
e
n
t
r
a
t
i
o
n
Supersaturation
Good Solvent %
A
B
Potential Problem:
Complex solvent system
Titration rate
Advantage:
More solvent options
High yield
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

46. 46
Crystallization (pH Adjustment)
pK
a
pH
max
At higher pH, apparent solubility of ionic API increases
At pH > pH
max
, concentration of API > Solubility of salt
Driving force of the crystallization of the salt increases
pH Adjustment (Salt formation)
S
salt
Supersaturation
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

47. 47
Crystallization (SMPT)
S
o
lu
t
io
n

C
o
n
c
e
n
t
r
a
t
io
n
S
o
lid

C
o
m
p
o
s
it
io
n
S
Metastable
S
Stable
Time
12 3
100% Metastable Phase
100% Stable Phase
Solution-Mediated
Phase Transformation
G
I
> G
II
Slurry of I
C
I
> C
II
Supersaturation of II
Crystallization of II
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

48. 48
Crystallization (SMPT)
Water Activity (a
w
) or Relative Humidity (RH)
Identity of the Crystal Form
Anhydrate
Hydrate
0 (0%) 1 (100%)
Critical Water
Activity (a
w,c)
Water Activity (a
w
) or Relative Humidity (RH)
Identity of the Crystal Form
Anhydrate
Hydrate
0 (0%) 1 (100%)
Critical Water
Activity (a
w,c)

Co-crystal Former Activity (a
CCF)
Identity of the Crystal Form
Drug
Co-crystal
0 1
Critical Co-crystal
Former Activity (a
CCF,c
)
Co-crystal
stable region
Drug stable
region
Co-crystal Former Activity (a
CCF)
Identity of the Crystal Form
Drug
Co-crystal
0 1
Critical Co-crystal
Former Activity (a
CCF,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 Selection
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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 Selection
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50. 50
Solid Form Development Work Flow
Crystallization of ParentCrystallization of Parent
Manual 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
Lead
Scale-Up
Lead Verification
Solid Form Selection
SingleSingle
CrystalCrystal
StructureStructure
Polymorph Screening
Pharmaceutical Solid Form Screening, Characterization, and Selection
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51. 51
Solid Form Characterization
Characterizations Techniques
Chemical identity NMR, IC
Crystalline solid form identificationMicroscopy, PXRD, Raman, IR, DSC
Melting temperature DSC
Morphology Microscopy
Solvate/hydrate identification DSC, TGA/MS, PXRD
Hygroscopicity Moisture sorption balance
Dissolution rate m-Diss
Crystalline solids
Amorphous solids
Physical stability assessment (Tg, relaxation kinetics, crystallization kinetics)
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

52. 52
Solid Form Characterization (PXRD)
lqnd =sin2
q
dsinq
d
Bragg’s Law
q’
dsinq’
d
’
Each d corresponds to a q
Pharmaceutical Solid Form Screening, Characterization, and Selection
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53. 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 Selection
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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 Selection
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55. 55
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 Selection
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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 Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

57. 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
Pharmaceutical Solid Form Screening, Characterization, and Selection
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58. 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)
Pharmaceutical Solid Form Screening, Characterization, and Selection
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Solid Form Characterization (Thermal-DSC)
Baseline Shift
Glass transition
Endothermic Events Exothermic Events
Solid-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
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DSC
Applications of DSC
 Melting temperature
 Heat of fusion
 Impurity
 Solid state solubility
 Dehydration/desolvation
 Chemical reaction
 Polymorphism
etc.
DSC
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61. 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°C
28.42J/g
-4
-3
-2
-1
0
H
e
a
t

F
lo
w

(
W
/
g
)
145 155 165
Temperature (°C)
Sample: Indium
Size: 3.2640 x 0.0000 mg
Method: Temperature (°C)
Comment: Cell constant calibration
DSC
File: S:\3S\Gong\INDIUM.001
Operator: YG
Run Date: 24-Apr-2008 14:59
Instrument: DSC Q2000 V24.2 Build 107
Exo Up Universal V4.4A TA Instruments
Onset Temp
Peak Temp
T
m
of Indium
DSC is commonly used to measure melting temperature of crystalline
solids
Pharmaceutical Solid Form Screening, Characterization, and Selection
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012

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DSC (Heat of fusion)
158.76°C
158.03°C
28.42J/g
-4
-3
-2
-1
0
H
e
a
t

F
lo
w

(
W
/
g
)
145 155 165
Temperature (°C)
Sample: Indium
Size: 3.2640 x 0.0000 mg
Method: Temperature (°C)
Comment: Cell constant calibration
DSC
File: S:\3S\Gong\INDIUM.001
Operator: YG
Run Date: 24-Apr-2008 14:59
Instrument: DSC Q2000 V24.2 Build 107
Exo Up Universal V4.4A TA Instruments
DH
f
T
m
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 Selection
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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 T
m
Pharmaceutical Solid Form Screening, Characterization, and Selection
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64. 64
DSC (Melting with decomposition)
Decomposition is a kinetic phenomenon,
therefore, melting/decomposition temperature changes with heating rate
Higher heating rate
Higher “T
m
”
Thomas, L. http://www.tainstruments.com/pdf/literature/TA315.pdf
Pharmaceutical Solid Form Screening, Characterization, and Selection
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65. 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
Pharmaceutical Solid Form Screening, Characterization, and Selection
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66. 66
DSC (Polymorphism)
Different polymorphs usually have
different melting temperatures and heat of fusions
higher melting form; lower DH
f
higher melting form; higher DH
f
DH
f, II
T
t
T
m, II
T
m , I
G
liqu id
G
II
G
I
Temperature, T
Energy (G, H)
H
II
H
I
H
L
DH
f, I
Monotropic
T
t
T
m , II
T
m, I
G
liquid
G
II
G
I
Temperature, T
Energy (G, H)
H
II
H
I
DH
f, II
DH
f, I
H
L
Enantiotropic
Heat of Fusion Rule
Pharmaceutical Solid Form Screening, Characterization, and Selection
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67. 67
DH
f, II
T
t
T
m, II
T
m , I
G
liquid
G
II
G
I
Temperature, T
Energy (G, H)
H
II
H
I
H
L
DH
f, I
DSC (Polymorphism)
Phase transitions of
Monotropic Polymorphs
I
IIL
ILII
I
IILIL
LII
II
IIL
III
IIL
I
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68. 68
T
t
T
m, II
T
m, I
G
liquid
G
II
G
I
Temperature, T
Energy (G, H)
H
II
H
I
DH
f, II
DH
f, I
H
L
DSC (Polymorphism)
Phase transitions of
Enantiotropic Polymorphs
II
IL
IILI
IL
IIIII
IL
IIL
LI
II
IL
III III
I
I
IL
Pharmaceutical Solid Form Screening, Characterization, and Selection
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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 Selection
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70. 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
50
o
C/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 Selection
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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
T
end
and Tg as a function of D-mannitol concentration in PVP
T
end
Tg
T
end
Pharmaceutical Solid Form Screening, Characterization, and Selection
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72. 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
Pharmaceutical Solid Form Screening, Characterization, and Selection
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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 Selection
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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
D
e
r
iv
.

W
e
ig
h
t

(
%
/
°
C
)
92
94
96
98
100
W
e
ig
h
t

(
%
)
20 40 60 80 100 120 140 160 180 200
Temperature (°C)
Sample: Erythromycin A dihydrate
Size: 24.3160 mg
Method: to 200 @ 10
Comment: Lot 86-434-CD
TGA
File: P:...\Geoff\Ery\A T06110301 Ery.2H2O
Operator: Geoff
Run Date: 11-Jun-2003 14:45
Instrument: 2950 TGA HR V5.3C
Universal V4.0C TA Instruments
M% weight loss
Drug
Solvent
MW
M
MW
M
X
-
=
100
Pharmaceutical Solid Form Screening, Characterization, and Selection
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75. 75
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 Selection
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76. 76
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 Selection
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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 Selection
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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 Types
A
B
C
Pharmaceutical Solid Form Screening, Characterization, and Selection
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79. 79
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 Selection
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Solid Form Development Work Flow
Crystallization of ParentCrystallization of Parent
Manual 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
Lead
Scale-Up
Lead Verification
Solid Form Selection
SingleSingle
CrystalCrystal
StructureStructure
Polymorph Screening
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81. 81
•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 Selection
PXRD
DSC
Moisture sorption
isotherm
DSC
Polymorph, solvate,
hydrate screening and
characterization
TGA
Stable at ambient
conditions
In vitro: solubility,
dissolution, physical
stability in suspension
In vivo (animal)
Accelerated
stability
Screen solvents for solubility
Evaluate feasibility at smaller scale
Initial assessment of control: induction time,
desupersaturation rate, size and
distribution
Pharmaceutical Solid Form Screening, Characterization, and Selection
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82. 82
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 Selection
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83. 83
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
Pharmaceutical Solid Form Screening, Characterization, and Selection
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84. 84
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, 1994
Serajuddin and Pudipeddi, 2008
Tier 1 Crystallinity
Crystallization from different solvents
Aqueous solubility
Tier 2 Evaluation of crystalline form
Thermal properties
Hygroscopicity
Tier 3 humidity/temperature-dependent
changes in crystal form
Tier 4 bioavailability screening
stress stability
scale-up considerations
Polymorph screening
TieredIntegrated
salt 1salt 2salt 3salt 4
crystallinity
hygroscopicity
melting point
polymorphism
physical stability
solubility/dissolution
chemical stability
manufacturability
The “best” approaches will lay between the two extremes
–Timing, intrinsic properties of the compound, availability of material……
Pharmaceutical Solid Form Screening, Characterization, and Selection
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85. 85
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 Selection
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86. 86
Solid Form Development Work Flow
Crystallization of ParentCrystallization of Parent
Manual 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
Lead
Scale-Up
Lead Verification
Solid Form Selection
SingleSingle
CrystalCrystal
StructureStructure
Polymorph Screening
Pharmaceutical Solid Form Screening, Characterization, and Selection
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87. 87
Polymorph Screening
Pharmaceutical Solid Form Screening, Characterization, and Selection
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88. 88
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 Selection
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89. 89