Amorphous Solid Dispersions: Application Of Spray Drying Formulations For Dis...
Pharmaceutical Solid Form
1. Pharmaceutical Solid Form
Screening, Characterization,
and Selection
Enhancing Drug Bioavailability and Solubility
Yuchuan Gong, Ph.D.
Boston, MA, Jan. 25, 2012
2. Outline
1. Solid Forms
Solid Forms
Solid State Thermodynamics
2. Impact of Solid Form
Solubility/Dissolution
Stability
Morphology/Processing
3. Solid Form Development
Solid Form Screening
Solid State Characterization
Solid Form Selection
Pharmaceutical Solid Form Screening, Characterization, and Selection 2
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
3. Outline
1. Solid Forms
Solid Forms
Solid State Thermodynamics
2. Impact of Solid Form
Solubility/Dissolution
Stability
Morphology/Processing
3. Solid Form Development
Solid Form Screening
Solid State Characterization
Solid Form Selection
Pharmaceutical Solid Form Screening, Characterization, and Selection 3
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
4. Why Solid?
Solid is more stable than its liquid counterpart
API’s are usually manufactured, transported, and stored as 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
Pharmaceutical Solid Form Screening, Characterization, and Selection 4
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
5. Types of Solid Forms
Solid
long range order short range order
Crystalline Liquid Crystalline Amorphous
single multiple
component components
ionic non-ionic
Polymorphs
Salt + Molecular Adducts
Solvate/Hydrate Co-crystal
Pharmaceutical Solid Form Screening, Characterization, and Selection 5
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
6. Solid Forms (Polymorphs)
Polymorphs:
crystalline forms with the same chemical composition but
different internal structures (packing, conformation, etc.)
Packing:
Conformational:
H-Bonding
O OH
Tautomeric:
NH N
More than 80% of the pharmaceutical solids exhibit polymorphs
Pharmaceutical Solid Form Screening, Characterization, and Selection 6
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
7. Solid Forms (Polymorphs)
metastable
The thermodynamically most stable form of a
pharmaceutical solid is less soluble, but more stable
A metastable polymorph is more soluble, but less stable
stable
Ritonavir
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
Pharmaceutical Solid Form Screening, Characterization, and Selection 7
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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
Non-solvated Solvate
Pharmaceutical Solid Form Screening, Characterization, and Selection 8
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
9. Solid Forms (Solvates)
Common organic solvents in solvates
Methanol, ethanol, 1-propanol, IPA, 1-butanol, hexane, cyclohexane,
acetone, MEK, benzene, toluene,
acetonitrile, ethyl acetate,
diethyl ether, THF, dioxane, dichloromethane
acetic acid dimethylformamide …
Solvates are not acceptable for API (except ethanol solvate)
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
Pharmaceutical Solid Form Screening, Characterization, and Selection 9
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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
3000
Number of Occurences
2500
2000
1500
1000
500
0
0.5 1 2 3 4 5 6 7 8 9
Hydration Number
Pharmaceutical Solid Form Screening, Characterization, and Selection 10
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
11. Solid Forms (Hydrates)
Hydrate is the most stable solid form in water,
least soluble form in GI environment
Non-hydrous solid form is usually favored over hydrates
However,
Stable hydrates with acceptable bioavailability can be developed:
may have better physicochemical properties
may be the only crystalline form of a API
Pharmaceutical Solid Form Screening, Characterization, and Selection 11
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
12. Solid Forms (Salts / Co-crystals)
Crystalline Salts and Co-crystals
contain two or more components in the same lattice
O O
R R1 R R1
O- H N+ R2 O H N R2
Salt Co-crystal
Differentiation is debatable:
1. Interaction between the components
2. Proton transfer
Pharmaceutical Solid Form Screening, Characterization, and Selection 12
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
13. Solid Forms (Salts / Co-crystals)
Salt / co-crystal formation of API are investigated in
great frequency because
Powder dissolution
Crystallization tool:
Purification
Property modification:
Dissolution rate
Chemical and physical stability
Crystallinity
Hygroscopicity
Bulk properties
Density, particle size, flowability, etc.
Manufacturability
drying, filtrability
Childs et al., J Am Chem Soc 126:13335-13342, 2004.
Pharmaceutical Solid Form Screening, Characterization, and Selection 13
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
14. Solid Forms (Amorphous)
Amorphous solid
solid in which there is no long-range order of the positions of molecules/atoms.
Amorphous
Crystalline
Amorphous solid has higher free energy
than its corresponding crystalline solids,
therefore, higher apparent solubility and
dissolution rate
Law et al., J. Pharm. Sci. 93:563, 2004
Pharmaceutical Solid Form Screening, Characterization, and Selection 14
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
15. Types of Solid Forms (Stoichiometry)
Solid
long range order short range order
Crystalline Liquid Crystalline Amorphous
single multiple
component components
ionic non-ionic
Polymorphs
Salt + Molecular Adducts
Solvate/Hydrate Co-crystal
stoichiometric non-stoichiometric
Pharmaceutical Solid Form Screening, Characterization, and Selection 15
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
16. Solid State Thermodynamics
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)
Free Energy: measure of thermodynamic potential
Enthalpy: Internal energy
Entropy: measure of “disorderness”
Pharmaceutical Solid Form Screening, Characterization, and Selection 16
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
17. Solid State Thermodynamics (Polymorph)
Why does the same chemical identity of different solid forms have different G?
G = H – TS
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
Pharmaceutical Solid Form Screening, Characterization, and Selection 17
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
18. Solid State Thermodynamics (Polymorph)
Free energy:
Only quantity that determines the thermodynamic relationship (relative
stability) between phases
∆GIII = GII – GI = ∆HIII – T∆SIII
GII < GI ⇒ ∆GIII < 0
Phase 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 = 0
Phase I and II is equally stable ⇒ Phase I and II are in equilibrium
Pharmaceutical Solid Form Screening, Characterization, and Selection 18
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
19. Solid State Thermodynamics (Polymorph)
Solubility (Activity):
∆GIII = GII – GI = RT ln(aII/aI)
= RT ln(γIICsII/ γICsI) = RT ln(γII/γI·CsII/CsI)
* In dilute solutions, γI = γII
≈ RT ln(CsII/CsI)*
where CsI and CsII : solubility of solid form I and II;
γI and γII : activity coefficients at CsI and CsII.
GII < GI ⇒ ∆GIII < 0
Phase 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 = 0
Phase I and II is equally stable ⇒ Phase I and II are in equilibrium
Pharmaceutical Solid Form Screening, Characterization, and Selection 19
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
20. Solid State Thermodynamics (Polymorph)
G liqu id CI
Monotropic C II
GI
S
b
u
o
y
t
i
l
G
E
F
G II
g
n
e
y
r
,
G = H – TS T m, I T m, II
Temperature, T Temperature, T
∆GIII = ∆HIII – T∆SIII
C II
G liquid
CI
Enantiotropic
S
b
u
o
y
t
i
l
G II
G
E
F
g
n
e
y
r
,
GI
Tt T m, II T m, I Tt
Temperature, T Temperature, T
Pharmaceutical Solid Form Screening, Characterization, and Selection 20
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
21. Solid State Thermodynamics (Hydrate/Solvate)
The equilibrium between the anhydrous and hydrate forms of a drug D
can be represented as
K , p ∆H
D ⋅ nH 2O( solid ) ← → D( solid ) + nH 2O( gas )
d t,
tr
[aD(s) ][aH 2O(g) ]n
c
p
Therefore Kd = = [aH 2O(g) ]n = [ pt ]n = [ RH ]n
c
[aD⋅nH 2O(s) ] s
aH 2O(g) > aH 2O(g) or p > pt , hydrate is more stable
c
aH 2O(g) < aH 2O(g) or p < pt , anhydrate is more stable
c
aH 2O(g) = aH 2O(g) or p = pt , anhydrate and hydrate are
c
equally stable
* Solvates are treated similarly
Pharmaceutical Solid Form Screening, Characterization, and Selection 21
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
22. Solid State Thermodynamics (Hydrate/Solvate)
Relative stability of hydrates at various RH
9H2O Ouabain
100
Copper Sulfate 8H20
Penta
% Weight Water
Oubain.nH2O
Tri
2H2O
Mono
0 0
04.5 30 47 100 0 100
Relative Humidity Temperature (oC)
Pharmaceutical Solid Form Screening, Characterization, and Selection 22
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
23. Solid State Thermodynamics (Hydrate/Solvate)
Temperature dependence of hydrate stability
Apply van’t Hoff equation to Kd
∆H tr
ln(a c
H 2O(g) 2 ) − ln( a c
) =−
H 2O(g) 1 nR ( T12 − T1 )
1
Critical water activity increase with Higher T
temperature
Ln(Critical Water Activity)
Hydrate is less stable at higher
temperatures
Hydrate is more stable at lower
temperatures
Keep the hydrate under cool and humid
conditions! Lower T
1/T (1/K)
Pharmaceutical Solid Form Screening, Characterization, and Selection 23
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
24. Solid State Thermodynamics (Amorphous)
Amorphous: “glass”, no long-range order between molecules
Important concepts:
uid
Liq Tm – melting temperature
Tg – glass transition temperature
led
oo
erc
up id
S u Tk – Kauzmann temperature
Liq
G la ss 1
Re la xa tion 2
Gla ss
Mobility
m
E
V
p
a
h
n
e
u
o
y
t
,
l
C ryst a llin e Relaxation
Crystallization
Tk Tg Tm
Temperature
Pharmaceutical Solid Form Screening, Characterization, and Selection 24
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
25. Outline
1. Solid Forms
Solid Forms
Solid State Thermodynamics
2. Impact of Solid Form
Solubility/Dissolution
Stability
Morphology/Processing
3. Solid Form Development
Solid Form Screening
Solid State Characterization
Solid Form Selection
Pharmaceutical Solid Form Screening, Characterization, and Selection 25
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
26. Impact of Solid Forms
Different solid forms show different physical, chemical, and mechanical
properties
Melting point Stability (physical & chemical)
Spectral properties Dissolution rate
Solubility Bioavailability “Druggability”
Density Hygroscopicity
Hardness Bulk properties
Crystal shape Manufacturability ….
Pharmaceutical Solid Form Screening, Characterization, and Selection 26
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
27. Impact of Solid Forms (Solubility / Dissolution)
Hydrates
• Lower solubility in water
• Higher “solubility” in other solvents
Amorphous
• Always has higher “solubility” than its crystalline counterparts
Salts
• Modify “solubility” by adjusting pH
Consideration:
Thermodynamic Solubility v.s. Apparent Solubility
Pharmaceutical Solid Form Screening, Characterization, and Selection 27
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
28. Impact of Solid Forms (Solubility)
Sulfamerazine H2 N
O
N Me
S NH
O N
Form I – Metastable
Form II –Most Stable
S Form I
= 1.2
S Form II
Solubility at 25oC
Gong, et. al, 2008.
Pharmaceutical Solid Form Screening, Characterization, and Selection 28
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
29. Impact of Solid Forms (Dissolution)
Whitney-Noyes equation: Driving force
dM DS D S Cs
= ( Cs − C ) ≈
dt h h
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
Diffusion layer Bulk solution
Concentration/solubility
Solid State CS
Cbulk
Distance from Solid Surface
Pharmaceutical Solid Form Screening, Characterization, and Selection 29
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
30. Impact of Solid Forms (Dissolution)
Iopanoic acid
Powder dissolution Intrinsic dissolution
Amorphous
Amorphous
Form II
Form II
Form I
Form I
Amorphous: > Form II: > Form I:
Stagner & Guillory, 1963.
Pharmaceutical Solid Form Screening, Characterization, and Selection 30
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
31. Impact of Solid Forms (Dissolution)
Succinyl sulfathiazole, in ~0.001 N H2SO4 solution at 20°C
O
N
NH S O
S
O NH C CH 2 CH 2 CO 2 H
Shefter & Huguchi , 1963.
Pharmaceutical Solid Form Screening, Characterization, and Selection 31
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
32. Impact of Solid Forms (Dissolution)
Salt 2
Salt 1
pKa
pHmax
Substantial increase in apparent solubility by salt formation, which will lead to the
enhancement in dissolution rate
Different salt forms will have different extent of apparent solubility improvement
Pharmaceutical Solid Form Screening, Characterization, and Selection 32
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
33. dM DS
= ( Cs − C ) ≈ D S C s
Impact of Solid Forms (Dissolution) dt h h
H2 N
p-Aminosalicylic acid: antibacterial
CO 2 H
OH
Parent
Forbes et al, 1995
Pharmaceutical Solid Form Screening, Characterization, and Selection 33
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
34. Impact of Solid Forms (Dissolution)
Dissolution enhancement of salt may be jeopardized by the precipitation of
the parent API
Solid State Diffusion layer Bulk solution
pHmax
HA
A-
A-
HA
BH+A-
pH
Solid A- HA
HA
A-
pHbulk
CS CSalt
Concentration/solubility
A-
HA
Cbulk CFA
Distance from Solid Surface
Pharmaceutical Solid Form Screening, Characterization, and Selection 34
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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 35
Enhancing 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 Selection 36
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
37. Outline
1. Solid Forms
Solid Forms
Solid State Thermodynamics
2. Impact of Solid Form
Solubility/Dissolution
Stability
Morphology/Processing
3. Solid Form Development
Solid Form Screening
Solid State Characterization
Solid Form Selection
Pharmaceutical Solid Form Screening, Characterization, and Selection 37
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
38. Solid Form Development Work Flow
Hit Identification
Crystallization of Parent
Manual salt/co-crystal screening
Hit Scale-Up
Thermodynamically
most stable form of hits
Lead
Identification
Single Detailed SS characterization
Crystal
Structure Lead
Scale-Up
Lead Verification
Pharmaceutical Evaluation Manufacturability Evaluation
Solid Form Selection
Polymorph Screening
Pharmaceutical Solid Form Screening, Characterization, and Selection 38
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
39. Salt/Cocrystal Screening (Guest Selection)
Safety is the overriding consideration
Cocrystals: hydrogen bonding potential
Salts: the strength of acids/bases: ∆pKa ≥ 2*
* Salt/cocrystal continuum: ∆pKa 1 – 3 could result in salt or cocrystal
• 2,6-dihydroxybenzoic acid
(pKa: 1.3)
• Caffeine (pKa: 0.7)
• ∆pKa = -0.6 Personal conversation
with Dr. Geoff Zhang
The property of the solid is more important than the differentiation of salt
vs. cocrystal no need to worry about the pKa differences
Pharmaceutical Solid Form Screening, Characterization, and Selection 39
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
40. Salt/Cocrystal Screening (Crystallization)
Common Crystallization Techniques
• Reactive
• Antisolvent addition Generate
• Solvent evaporation
Supersaturation
• Temperature gradient
• Slurry
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 40
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
41. Solution Crystallization
Crystallization
Nucleation Crystal Growth
Secondary Primary
(induced by crystals)
Heterogeneous Homogeneous
(induced by foreign surfaces) (spontaneous)
• Can be controlled by either nucleation or crystal growth
• Usually nucleation the slowest, rate-limiting step
Mullin, 1992.
Pharmaceutical Solid Form Screening, Characterization, and Selection 41
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
42. Crystallization (Solvent Evaporation)
From a single solvent Advantage: Easy
Column of solvent decreases
Potential Problem:
Concentration increases Evaporation rate is too high
Solubility remains same Solubility is too high
100 10000
90
80
70
Concentration (mg/mL)
Volume (mL)
60
50 1000
40
30
20
10 Supersaturation
0 100 S
0 2 4 6 8 10 0 2 4 6 8 10
Time (hr) Time (hr)
Pharmaceutical Solid Form Screening, Characterization, and Selection 42
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
43. Crystallization (Solvent Evaporation)
From a solvent mixture Advantage:
Volume of solvent decreases Adjustable solubility
Dual effect on supersaturation
Concentration of API increases
Potential Problem:
Solubility of API decreases
Complex solvent system
100 250
Concentration
Solubility
80
Concentration or Solubility (mg/mL)
200
Volume (mL) or % Solvent
Bad Solvent (A)
60 150
40 100
Good Solvent (B)
Supersaturation
20 Volume 50
Solvent A %
Solvent B %
0
S
0
0 1 2 3 4 5 0 1 2 3 4 5
Time (hr) Time (hr)
Pharmaceutical Solid Form Screening, Characterization, and Selection 43
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
44. Crystallization (Heat & Cool)
Heat & Cool Advantage:
Temperature drops Moderate solubility
Better yield
Solubility of API decreases
Potential Problem:
Concentration remains same
Degradation
Concentration
C0
Temp
Supersaturation
S
Time High Temp Low Temp
Pharmaceutical Solid Form Screening, Characterization, and Selection 44
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
45. Crystallization (Anti-solvent)
Anti-solvent Advantage:
More solvent options
% bad solvent increases
High yield
Solubility of API decreases Potential Problem:
Concentration of API decreases Complex solvent system
Titration rate
S
Concentration
A
Bad Solvent %
B
Supersaturation
Time Good Solvent %
Pharmaceutical Solid Form Screening, Characterization, and Selection 45
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
46. Crystallization (pH Adjustment)
pH Adjustment (Salt formation)
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
Supersaturation
Ssalt
pKa
pHmax
Pharmaceutical Solid Form Screening, Characterization, and Selection 46
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
47. Crystallization (SMPT)
Solution-Mediated
Solution Concentration
SMetastable
Phase Transformation
SStable
GI > GII CI > CII
Slurry of I
1 2 3
100% Metastable Phase
Solid Composition
Supersaturation of II
Crystallization of II 100% Stable Phase
Time
Pharmaceutical Solid Form Screening, Characterization, and Selection 47
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
48. Crystallization (SMPT)
Crystallization of
Hydrate: various water activity
Co-crystal: maximum co-crystal former activity
Identity of the Crystal Form
Identity of the Crystal Form
Drug stable Co-crystal
Hydrate region stable region
Co-crystal
Critical Water Critical Co-crystal
Activity (aw,c) Former Activity (aCCF,c)
Anhydrate Drug
0 (0%) 1 (100%) 0 1
Water Activity (aw) or Relative Humidity (RH) Co-crystal Former Activity (aCCF)
Pharmaceutical Solid Form Screening, Characterization, and Selection 48
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
49. 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 49
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
50. Solid Form Development Work Flow
Hit Identification
Crystallization of Parent
Manual salt/co-crystal screening
Hit Scale-Up
Thermodynamically
most stable form of hits
Lead
Identification
Single Detailed SS characterization
Crystal
Structure Lead
Scale-Up
Lead Verification
Pharmaceutical Evaluation Manufacturability Evaluation
Solid Form Selection
Polymorph Screening
Pharmaceutical Solid Form Screening, Characterization, and Selection 50
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
51. Solid Form Characterization
Crystalline solids
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 µ-Diss
Amorphous solids
Physical stability assessment (Tg, relaxation kinetics, crystallization kinetics)
Pharmaceutical Solid Form Screening, Characterization, and Selection 51
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
52. Solid Form Characterization (PXRD)
Bragg’s Law
2d sin θ = nλ Each d corresponds to a θ
θ
d
dsinθ
θ’
d’
dsinθ’
Pharmaceutical Solid Form Screening, Characterization, and Selection 52
Enhancing 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 Selection 53
Enhancing 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 Selection 54
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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 55
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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
Pharmaceutical Solid Form Screening, Characterization, and Selection 56
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57. 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
Flufenamic Acid
Metastable
Stable
Pharmaceutical Solid Form Screening, Characterization, and Selection 57
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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 58
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
59. Solid Form Characterization (Thermal-DSC)
DSC is used to monitor heat exchange when the sample is
heated/cooled or maintained isothermally
Endothermic Events Exothermic Events
Solid-solid transitions Solid-solid transitions
Degradation Degradation
Melting, boiling, sublimation, vaporization Crystallization
Desolvation
Baseline Shift
Glass transition
Pharmaceutical Solid Form Screening, Characterization, and Selection 59
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
60. DSC
Applications of DSC DSC
Melting temperature
Heat of fusion
Impurity
Solid state solubility
Dehydration/desolvation
Chemical reaction
Polymorphism
etc.
Pharmaceutical Solid Form Screening, Characterization, and Selection 60
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
61. DSC (Melting)
DSC is commonly used to measure melting temperature of crystalline
solids
Sample: Indium File: S:3SGongINDIUM.001
Size: 3.2640 x 0.0000 mg DSC Operator: YG
Method: Temperature (°C) Run Date: 24-Apr-2008 14:59
Melting Point: Comment: Cell constant calibration Tm of Indium Instrument: DSC Q2000 V24.2 Build 107
– Sharpness reflects the 0 158.03°C
28.42J/g
chemical purity
Onset Temp
– Defined by extrapolated -1
onset temperature (pure)
Heat Flow (W/g)
– Reported using peak -2
temperature (with impurity)
– May overlap with other
-3
physical processes Peak Temp
(recrystallization, solid-solid 158.76°C
transition, etc.) and -4
145 155 165
chemical processes Exo Up Temperature (°C) Universal V4.4A TA Instru
(decomposition etc.)
Pharmaceutical Solid Form Screening, Characterization, and Selection 61
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
62. DSC (Heat of fusion)
DSC is commonly used to measure the heat of fusion of a crystalline
solid Sample: Indium File: S:3SGongINDIUM.001
Size: 3.2640 x 0.0000 mg DSC Operator: YG
Method: Temperature (°C) Run Date: 24-Apr-2008 14:59
Comment: Cell constant calibration Tm of Indium Instrument: DSC Q2000 V24.2 Build 107
0 158.03°C
28.42J/g
Heat of Fusion:
– Integrated area under -1 ∆Hf
melting curve
Heat Flow (W/g)
– May overlap with -2
recrystallization
– May overlap with -3
decomposition and 158.76°C
sublimation
-4
145 155 165
Exo Up Temperature (°C) Universal V4.4A TA Instruments
Pharmaceutical Solid Form Screening, Characterization, and Selection 62
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
63. DSC (Melting without decomposition)
Melting is a thermodynamic phenomenon,
therefore, melting point does not change much with heating rate
Higher heating rate
Same Tm
Thomas, L. http://www.tainstruments.com/pdf/literature/TA315.pdf
Pharmaceutical Solid Form Screening, Characterization, and Selection 63
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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
Pharmaceutical Solid Form Screening, Characterization, and Selection 64
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
65. DSC (Dehydration/desolvation)
DSC is used to determine dehydration/desolvation
Carbamazepine dihydrate
- Usually at lower temperatures
- Large enthalpy because of the
evaporation of released
water/solvent
- May result in lower hydrates,
anhydrous phases, or
amorphous phase
Li Y. et al., Pharm. Dev. Tech., 2000. 5, 257.
Pharmaceutical Solid Form Screening, Characterization, and Selection 65
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66. DSC (Polymorphism)
Different polymorphs usually have
different melting temperatures and heat of fusions
Monotropic Enantiotropic
HL
HL
∆H f, II ∆H f, I
∆H f, I ∆H f, II HI
HI
G liquid G liquid
H II H II
T m, I
T m, II
G
H
E
g
e
n
y
Tt
)
(
r
,
Tt
G
H
E
T m, II
g
e
n
G II
y
G II
)
(
r
,
GI T m, I
GI
Temperature, T Temperature, T
Heat of Fusion Rule
higher melting form; higher ∆Hf higher melting form; lower ∆Hf
Pharmaceutical Solid Form Screening, Characterization, and Selection 66
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
67. DSC (Polymorphism)
II
Phase transitions of
IIL
Monotropic Polymorphs LII
I
IL IIL
HL
∆H f, II I ILII
∆H f, I
HI
G liquid IIL
H II
I III
T m, I IIL
Tt
G
H
E
T m, II
g
e
n
y
G II
)
(
r
,
GI
Temperature, T
Pharmaceutical Solid Form Screening, Characterization, and Selection 67
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
68. DSC (Polymorphism)
II III IL
Phase transitions of
Enantiotropic Polymorphs I
IL
LI
HL II
IL
∆H f, I IIL
∆H f, II HI
G liquid II IILI
IL
H II
I III III
T m, II
G
H
E
g
e
n
y
)
(
r
,
Tt G II IL
T m, I
GI
Temperature, T
Pharmaceutical Solid Form Screening, Characterization, and Selection 68
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
69. MDSC (Theory)
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
MDSC separates the total heat flow response into the reversing and non-
reversing components Mudunuri P. Ph.D. Thesis., 2007
Paul G. et. al. Pharm. Res., 1998, 15(7), 1117
Pharmaceutical Solid Form Screening, Characterization, and Selection 69
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70. MDSC (Glass transition, Phase separation)
MDSC reversing heat flow scans of
trehalose-dextran mixture (40/60) stored
50oC/75%RH
34 days
23 days
13 days
4 days
2 days
Measured Tg can be used to determine
0 day
phase homogeneity
Single Tg: Single phase
Multiple Tg’s: phase separation Mudunuri P. Ph.D. Thesis., 2007
Vasanthavada M. et. al. Pharm. Res., 2004, 21(9), 1598
Pharmaceutical Solid Form Screening, Characterization, and Selection 70
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71. DSC/MDSC (Solid-State Solubility)
DSC is used to determine solubility of crystalline small molecule
in polymer
Tend
Tend
Tg
Tend and Tg as a function of D-mannitol concentration in PVP
Jing T. et al. Pharm. Res. 2009, 26(4) 855
Pharmaceutical Solid Form Screening, Characterization, and Selection 71
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72. Solid Form Characterization (TAM)
Pros
• Excellent isothermal condition
• High sensitivity
Cons
• Disturbance when the experiment starts
• Limited temperature range
Applications
• Recrystallization
(heat and/or moisture induced)
• Excipient compatibility
• Slow reactions
Bystrom. Thermometric Application Note 22004, 1990
Pharmaceutical Solid Form Screening, Characterization, and Selection 72
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73. Solid Form Characterization (Thermal-TGA)
Thermogravimetric Analysis:
Measures the thermally induced weight change of a material as a
function of temperature
Ref Pan
Sample Pan
- provides information on volatile content
- type of purge gas and purge rate can affect curve
Furnace
Purge Gas
Pharmaceutical Solid Form Screening, Characterization, and Selection 73
Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
74. TGA (Dehydration / Desolvation)
TGA is often used to measure the weight loss upon heating, from
which stoichiometry of hydrate and solvate TGA be determined
can Sample: Erythromycin A dihydrate
Size: 24.3160 mg
Method: to 200 @ 10
File: P:...GeoffEryA T06110301 Ery.2H2O
Operator: Geoff
Run Date: 11-Jun-2003 14:45
Comment: Lot 86-434-CD Instrument: 2950 TGA HR V5.3C
100 0.4
M% weight loss 0.3
98
4.660%
(1.133mg)
Deriv. Weight (%/°C)
M
Weight (%)
MWSolvent
X =
96 0.2
100− M
MWDrug
94 0.1
Ramp 10.00 °C/min to 200.00 °C
92 0.0
20 40 60 80 100 120 140 160 180 200
Temperature (°C) Universal V4.0C TA Instruments
Pharmaceutical Solid Form Screening, Characterization, and Selection 74
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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 75
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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 76
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77. Solid Form Characterization (Thermal)
Hyphenated Thermal Techniques:
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
Pharmaceutical Solid Form Screening, Characterization, and Selection 77
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78. Solid Form Characterization (Moisture Sorption)
Determine moisture uptake at various water activity / Relative humidity
Sorption Isotherm Types
A
A: monolayer adsorption
B: multi-layer adsorption
B
C: deliquescence
C
Pharmaceutical Solid Form Screening, Characterization, and Selection 78
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79. Solid Form Characterization (Moisture Sorption)
Monitor formation of hydrates
(Nedocromil Sodium)
Sorption:
<10%RH : monohydrate
10% - 90%RH: Trihydrate
>90%RH: Heptahemi-hydrate
Desorption:
>10%RH: Heptahemi-hydrate
<10%RH: monohydrate
Pharmaceutical Solid Form Screening, Characterization, and Selection 79
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80. Solid Form Development Work Flow
Hit Identification
Crystallization of Parent
Manual salt/co-crystal screening
Hit Scale-Up
Thermodynamically
most stable form of hits
Lead
Identification
Single Detailed SS characterization
Crystal
Structure Lead
Scale-Up
Lead Verification
Pharmaceutical Evaluation Manufacturability Evaluation
Solid Form Selection
Polymorph Screening
Pharmaceutical Solid Form Screening, Characterization, and Selection 80
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81. Solid State Selection
• Solid state PXRD Moisture sorption
DSC isotherm
– is highly crystalline Polymorph, solvate,
– is not hygroscopic (<2% weight across 0-80% RH) hydrate screening and
characterization
– has a melting point > 150 °C DSC
– does not exhibit complex polymorphic behavior or solvate formation
– does not have a labile hydrate TGA
– is physically stable In vitro: solubility,
Stable at ambient dissolution, physical
conditions stability in suspension
• Pharmaceutical In vivo (animal)
– is bioavailable (sufficient dissolution rate/solubility)
– is chemically stable Screen solvents for solubility
Accelerated Evaluate feasibility at smaller scale
stability Initial assessment of control: induction time,
• Manufacturing desupersaturation rate, size and
distribution
– 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)
Pharmaceutical Solid Form Screening, Characterization, and Selection 81
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82. Decision Making (Solid From Selection)
Stability
Cross-functional Decision
Some key properties are inter-related Hygroscopicity Crystallinity
• Crystallinity & Hygroscopcity
Certain properties have higher priority Apparent Solubility
• Chemical stability v.s. Polymorphism
Dissolution Rate
Project/Compound specific properties
• Dissolution enhancement (insoluble API)
• Chemical stability (strong amines)
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
Pharmaceutical Solid Form Screening, Characterization, and Selection 82
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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 83
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