Pharmaceutical Solid Form Screening, Characterization and Selection Guide

Pharmaceutical Solid Form
Screening, Characterization,
and Selection

Enhancing Drug Bioavailability and Solubility

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

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

Outline
1. Solid Forms
Solid Forms

Stability


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


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


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

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


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


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


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

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


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


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.


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

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


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”


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

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

∆GIII = GII – GI = ∆HIII – T∆SIII

GII < GI ⇒ ∆GIII < 0
Phase II is more stable ⇒ Phase I  II is a spontaneous process
GII > GI ⇒ ∆GIII > 0
Phase II is less stable ⇒ Phase II  I is a spontaneous process
GII = GI ⇒ ∆GIII = 0
Phase I and II is equally stable ⇒ Phase I and II are in equilibrium


Solubility (Activity):
∆GIII = 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 ⇒ ∆GIII < 0
Phase II is more stable ⇒ Phase II has less solubility
GII > GI ⇒ ∆GIII > 0
Phase II is less stable ⇒ Phase II has higher solubility
GII = GI ⇒ ∆GIII = 0
Phase I and II is equally stable ⇒ Phase I and II are in equilibrium


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
∆GIII = ∆HIII – T∆SIII
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

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

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)


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)

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


Outline
1. Solid Forms
Solid Forms

Stability


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 ….


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


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.


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


Iopanoic acid

Powder dissolution Intrinsic dissolution

Amorphous
Amorphous

Form II
Form II

Form I
Form I

Amorphous: > Form II: > Form I:

Stagner & Guillory, 1963.

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.


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


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


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

Impact of Solid Forms (Chemical Stability)
Compound A

FB:
Photo-sensitive

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

Impact of Solid Forms (Morphology)
Compound B

 Morphology may have great impact on processing of API and formulation


Outline
1. Solid Forms
Solid Forms

Stability


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


Polymorph Screening


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


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


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.

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)


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)

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


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 %

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


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

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)


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”


Hit Identification
Hit Scale-Up
Thermodynamically
Lead
Identification
Crystal
Structure Lead
Scale-Up

Lead Verification


Polymorph Screening


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)


Solid Form Characterization (PXRD)
Bragg’s Law
2d sin θ = nλ Each d corresponds to a θ

θ
d

dsinθ

θ’

d’
dsinθ’


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


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

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


Be very careful with hydrates/solvates
as they may be missed due to quick
dehydration/desolvation

Conversion rate of the solvates:
Methanol > Ethanol > IPA


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


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


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)


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


DSC

Applications of DSC DSC
 Melting temperature
 Heat of fusion
 Impurity
 Solid state solubility
 Dehydration/desolvation
 Chemical reaction
 Polymorphism
etc.


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.)

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


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


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


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.


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

Heat of Fusion Rule
higher melting form; higher ∆Hf higher melting form; lower ∆Hf

DSC (Polymorphism)
II
Phase transitions of
IIL
Monotropic Polymorphs LII
I
IL IIL
HL
∆H f, II I ILII
∆H f, I
HI
G liquid IIL
H II
I III

T m, I IIL
Tt
G
H
E

T m, II
g
e
n
y

G II
)
(
r
,

GI

Temperature, T

DSC (Polymorphism)
II III IL
Phase transitions of
Enantiotropic Polymorphs I
IL
LI
HL II
IL
∆H f, I IIL
∆H f, II HI
G liquid II IILI
IL
H II

I III III

T m, II
G
H
E
g
e
n
y
)
(
r
,

Tt G II IL
T m, I
GI
Temperature, T

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


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


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


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


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


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


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


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)


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


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


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


Hit Identification
Hit Scale-Up
Thermodynamically
Lead
Identification
Crystal
Structure Lead
Scale-Up

Lead Verification


Polymorph Screening


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)


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

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 Guide

Pharmaceutical Solid Form Screening, Characterization and Selection Guide

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