Form A - Seventh Street Development Group

Physical Stability: How Do I Know
Which Form is the Most Stable?
Ann Newman
Seventh Street Development Group
PO Box 526, Lafayette, IN 47902
765-650-4462
[email protected]
Webcast April 3, 2013
©2013 Seventh Street Development Group
Background
SUNY
Fredonia
Storrs, CT
New Brunswick, NJ
West Lafayette, IN
• Undergraduate at SUNY Fredonia
– BS Chemistry and Medical Technology
• Graduate at Univ. of Connecticut
– PhD in Inorganic Chemistry
• ER Squibb/Bristol- Myers Squibb
– Materials Science Group in
Pharmaceutical Research Institute
• SSCI/Aptuit
– VP Materials Science
– VP Research and Development
• Seventh Street Development Group
– Pharmaceutical Consultant
What is a Polymorph?
• Different crystalline forms of a compound
– Example: allotropes of elements
• Carbon
Diamond
Graphite
http://phycomp.technion.ac.il/~anastasy/diamgraph1ips.html
What is a Polymorph?
• Organic molecules can also crystallize as
different forms
= organic molecule
Carbamazepine
Form II
Form I
Form II
Form IV
Definitions
• Polymorph
– FDA: crystalline and amorphous forms as well as
solvated and hydrated forms
– Purists: crystalline forms with the same molecular
composition (for example two anhydrous forms can be
polymorphs, or two monohydrates can be polymorphs,
but an anhydrate and a monohydrate can not be
polymorphs)
• How polymorph is used in journal articles and
regulatory documents is important in
understanding what is being said
FDA definition: http://www.fda.gov/CDER/GUIDANCE/7590fnl.htm#_Toc167002781
Multi-Component Crystals
Classes of multi -component molecular crystals
= water/
solvent
= API
= neutral
guest
= counterion
+
Neutral
Polymorphs
Charged
+
+
-
+
+
-
-
+
-
+
-
-
+
5. Salt
-
-
-
+
4. Cocrystal hydrate
+
+
+
+
+
+
-
-
-
-
+
+
-
+
-
-
3. Cocrystal
+
-
-
+
-
2. Hydrate/solvate
+
1. Homomeric
6. Salt hydrate/solvate 7. Salt cocrystal
-
+
-
+
-
+
-
+
+
+
8. Salt hydrate cocrystal
Polymorphs of Salts
Enalapril maleate (Vasotec)
ACE inhibitor to treat high blood pressure
Form I
Form II
C
N
O
monoclinic
orthorhombic
Form I: Precigoux et al. Acta Crystallogr C 1986, 42, 1022-1024
Form II: Kiang etal. J. Pharm. Sci. 2003, 92(9), 1844-1853
Polymorphs of Cocrystals
Carbamazepine: saccharin
treat epilepsy and bipolar disorder
Form I
N
S
O
Form II
Form I: Hickey, et al. Eur. J. Pharm. and Biopharm. 2007, 67, 112-119
Form II: Porter et al. Cryst. Growth Des. 2008, 8, 14-16
Stability
Stability of pharmaceutical compounds
– Includes both chemical and physical stability
• Chemical- degradation
oxidation
cyclization
hydrolysis
• Physical- change in form
Stability
• Conventional stability testing
– Includes heat and humidity
– Used for both chemical and physical testing
ICH Q1A (R2) Stability Testing of New Drug Substances and Products, Nov 2003.
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm128204.pdf
Physical Stability
• Change in form can be due to
•
•
•
•
Conversion from a metastable form to a more stable form
Formation of hydrate/solvate
Salt/cocrystal formation
Etc
cocrystals, salts
dissociation
Morris et al. Adv Drug Delivery Rev. 2001, 48, 91-114
Physical Stability
Raffinose
5.5
pentahydrate
5
moles
water
4.5
tetrahydrate
4
3.5
3
2.5
trihydrate
0
20
40
60
80
100
% relative humidity
Saleki-Gerhardt et al J. Pharm. Sci. 1995, 84, 318
Physical Stability
Similar cocrystals will exhibit different RH stability
theophylline:citric acid
anhydrous cocrystal
caffeine:citric acid
anhydrous cocrystal
theophylline
98% RH, 3 d
caffeine
cocrystal hydrate
98% RH, 7 d
caffeine hydrate
citric acid
98% RH, 7 d
no change
Karki et al. Mol. Pharm. 2007, 4, 347-354
Thermodynamic Stability
• Most stable form
– Determined for polymorphs, such as multiple
unsolvated forms
– Based on thermodynamic definition of stability
• ΔG = ΔH - T ΔS
• Lowest free energy is most thermodynamically stable
– Related to solubility
• most stable form is less soluble than metastable forms
Compound
Aq Solubility Form I
Aq Solubility Form II
Stability
Nimodipine
0.036 mg/100 mL
0.018 mg/100mL
Form II more stable at RT
Grunengberg et al. Int J Pharm. 1995, 118, 11-21
Thermodynamic Stability
• Most stable form can be determined by slurry interconversion
studies
• Interconversion studies are based on solubility
– If seeds of two forms are present in a saturated solution and slurried
over time, the less stable form (more soluble) will dissolve and
recrystallize as the more stable form (less soluble)
– Can be used to determine the most stable form at RT by recovering
and characterizing remaining solid
dissolution of
metastable form
metastable
and stable form
crystal growth
supersaturated solution
with seeds of stable form
stable form
Thermodynamic Stability
• Interconversion studies
– Can be performed at ambient or other temperatures (higher or lower)
– Should be independent of solvent if there are no solvent effects
– Formation of solvates during interconversion makes the experiment unsuitable for
determining the thermodynamically stable form
• Samples for interconversion studies should have the same
composition
– Difficult to use unsolvated and solvated forms in same experiment to determine
thermodynamic stability; experiments with unsolvated and solvated materials will
give information on the least soluble composition in that solvent
• Most stable form
– Least soluble
– Lowest free energy
• Energy temperature diagram
– Schematic to visualize stability ranking of forms
– Qualitative information
– Relates relative stability, free energy, enthalpy, melting points
Energy Temperature (ET) Diagram
•
•
Compounds with same chemical composition are put on one ET
diagram
Gibbs-Helmholtz-Equation
ΔG = ΔH - T ΔS




G - free energy
H - enthalpy
T - temperature
S - entropy
Energy
Liquid
Form II
Form I
• Lower free energy - more stable
• Melting point (mp) is where the
•
free energy line crosses the
liquid line
Free energy lines converge and
will only intersect once
Free Energy (G)
0
GII
GL GI
Temperature [K] mp II mp I
ET Diagram
•
Gibbs-Helmholtz-Equation
ΔG = ΔH - T ΔS




•
•
•
•
G - free energy
H - enthalpy
T - temperature
S - entropy
Enthalpy(H)
ΔHf I
Energy
Larger change in enthalpy- more
stable
Heat of fusion (ΔHf) measured at
melting point (mp)
Heat of transition (ΔHtr) is the
energy difference between forms
Enthalpy lines are parallel and do
not intersect
Liquid
ΔHf II
Form II
ΔHTr
Form I
Ttr, III
0
Temperature [K]
mp II mp I
HL
HII
HI
ET Diagram
Monotropic System
Energy
Most stable form has higher melting point
and higher heat of fusion
HL
ΔHf I endothermic
ΔHf II
Liquid
Form II
H II
HI
ΔHTr II-I
exothermic
Form I
G II
GG I
L
0 Temperature [K]
mp II mp I
Monotropic System
• Ritanovir
– Form II known to be more stable form
– Higher melting form has the higher heat of fusion
– Lower melting form has the lower heat of fusion
Form
I
II
Melting Point (˚C)
122
125
ΔH (J/g)
78.2
87.8
Chemburkar et al, Organic Process Research and Development 2000, 4, 413
Monotropic System
Ritanovir
Energy
mp I 122 C (395 K)
mp II 125 C (398 K)
ΔHf I 78 J/g
ΔHf II 88 J/g
ΔHTr 10 J/g
Liquid
HL
ΔHTr I-II
10 J/g
ΔHf I
78 J/g
ΔHf II
88 J/g
HI
H II
Form I
Form II
0 Temperature [K]
mp I
(395 K)
Data from Chemburkar et al, Organic Process Research and Development 2000, 4, 413
mp II
(398 K)
GI
G G II
L
Monotropic System
• Free energy lines do not cross before the melt
• One form is thermodynamically more stable over
the entire temperature range (subambient to melt)
• Higher melting form has the higher heat of fusion
• The higher melting form is the more stable form
• Exothermic transition (solid to solid conversion)
usually indicates monotropic system
Monotropic vs Enantiotropic
Most Stable Form at RT
•
•
G
Monotropic: most stable form at RT is most stable form at elevated
temperatures
Enantiotropic: the most stable form is dependent on temperature and
a transition temperature is determined to define the stability.
Liquid
0
Monotropic
Liquid
G
Form II
Form II
Form I
Form I
GL
Temperature [K]
Enantiotropic
GII
GI
0
GI
G GII
Temperature [K] Ttr
L
ET Diagram
Enantiotropic System
Energy
Most stable form below transition temperature has
lower melting point and higher heat of fusion
HL
ΔHf II endothermic
Liquid
H II
HI
ΔHf I
endothermic ΔHTr II-I
Form II
Form I


Most stable form below
transition temperature has
lower melting point
0 Temperature [K]

GI
GL
Ttr
mp I mp II
G II
Enantiotropic System
• Nimodipine
– lower melting form has the higher heat of fusion
Form
I
II
Melting Point (˚C)
124
116
ΔH (J/g)
39
46
Grunenberg et al, Int. J. Pharm. 1995, 118, 11-21
Enantiotropic System
Nimodipine
Energy
mp I 124 C
mp II 116 C
ΔHf I 39 kJ/mol
ΔHf II 46 kJ/mol
ΔHTr 7 J/g
Liquid
HL
ΔHTr II-I
7 kJ/mol
ΔHf I
39 kJ/mol
ΔHf II
46 kJ/mol
HI
H II
Form I
Form II



GI
GL
0 Temperature [K]
Ttr
mp II mp I
G II
Enantiotropic System
• Free energy lines cross at the transition
temperature before the melt
• One form is thermodynamically more stable up to
the transition temperature. Above the transition
temperature, that form becomes less
thermodynamically stable.
• Lower melting form has the higher heat of fusion
• The higher melting form is not the more stable
form at ambient (but is more stable above the
transition temperatue)
• Endothermic transition (solid to solid conversion)
usually indicates enantiotropic system
Monotropic vs Enantiotropic
Most Stable Form: Burger and Ramberger’s Rules
– Heat-of-Fusion Rule (HFR)
• if the higher melting form has the lower heat of fusion the
two forms are usually enantiotropic, otherwise they are
monotropic
Monotropic
Enantiotropic
mp 2 > mp 1
mp 2 > mp 1
ΔH f 2 > ΔH f 1
ΔH f 2 < ΔH f 1
Form 2 melt
Form I melt
Burger and Ramberger, Mikrochimica Acta [Wein] 1979, II, 259-271, 273-315.
Monotropic vs Enantiotropic
Most Stable Form: Burger and Ramberger’s Rules
– Heat-of-Transition Rule (HTR)
• if an endothermal transition is observed at some temperature it may
be assumed that there is a transition point below it, i.e. the two
forms are related enantiotropically
Form II to Form I
Melt of Form I
Burger and Ramberger, Mikrochimica Acta [Wein] 1979, II, 259-271, 273-315.
Monotropic vs Enantiotropic
Most Stable Form: Burger and Ramberger’s Rules
– Heat-of-Transition Rule (HTR)
• if an exothermal transition is observed at some temperature it may
be assumed that there is no transition point below it, i.e. the two
forms are either related monotropically or the transition temperature
is higher
Melt of Form I
Form II to Form I
Burger and Ramberger, Mikrochimica Acta [Wein] 1979, II, 259-271, 273-315.
Monotropic vs Enantiotropic
Most Stable Form: Burger and Ramberger’s Rulesa
– Density Rule (DR)
• if one modification of a molecular crystal has a lower density than the
other, it may be assumed to be less stable at absolute zero (valid 8085% of the time)
Compound
Density Form I
Density Form II
Stability
DR
Ritanovirb
1.28 g/cm3
1.25 g/cm3
Form II stable up to melt
DR not valid
Nimodipinec 1.27 g/cm3
1.30 g/cm3
Form I less stable below Ttr
DR valid
– Infrared Rule (IR)
• if the first absorption band in the IR spectrum of a hydrogen bonded
molecular crystal is higher for one modification than for the other, that
form may be assumed to have the larger entropy.
a. Burger and Ramberger, Mikrochimica Acta [Wein] 1979, II, 259-271, 273-315.
b. Bauer et al. Pharm. Res. 2001, 18, 859-866
c. Grunenberg et al, Int. J. Pharm. 1995, 118, 11-21
Transition Temperature (Ttr )
• Defines enantiotropic
system
• Important for processing
and crystallization
– crystallization above Ttr will G Liquid
not give the stable form at
Form II
ambient temperature. Can
commonly result in a mixture
of forms and lack of process
Form I
control.
– Wet granulation and drying
can also be affected.
• Can be estimated or
determined experimentally
0
Enantiotropic
Temperature [K] Ttr
GI
G GII
L
Estimating Ttr
• Ideal solubility equations for each form can be
combined and solved for an expression of the ratio
of their solubilities
Form A: RT ln XA = -ΔHfA(T0A-T)/T0A
Form B: RT ln XB = -ΔHfB(T0B-T)/T0B
RT ln (XA/XB) = [ΔHfB(T0B-T)/T0B] - [ΔHfA(T0A-T)/T0A]
where
X = molal solubility
R = ideal gas constant
ΔHf = heat of fusion
T0 = melting onset
T = any temperature
• At the transition temperature, solubilities are equal
and ratio of solubilities is unity.
Estimating Ttr
• For carbamazepine Forms I and III:
Form
I
III
Melting Point (˚C)
189
173
ΔH (J/g)
26
29
RT ln (XIII/XI) = [ΔHfI(T0I-T)/T0I] - [ΔHfIII(T0III-T)/T0III]
T0 I =
T0III =
189 C
173 C
ΔHfI = 26 kJ/mol
ΔHfIII = 29 kJ/mol
• Transition temperature estimated as 71 °C
– Form III more stable below 71 °C
• Measured transition temperature: 73 ° C
– van’t Hoff plot
Behme et al, J Pharm Sci, 1991, 80, 986-990.
Experimental Ttr
• Interconversion studies at elevated
temperatures (nimodipine)
• Van’t Hoff plot of solubilities at various
temperatures (carbamazepine)
• Eutectic mixtures (ROY)
Experimental Ttr
• Interconversion experiments
– Can narrow down transition temperature by doing variable
temperature interconversion studies
– Solution needs to be saturated with solids present
– Can be performed with pure forms or with seeds
• Seeds can speed up the interconversion
– Times can range from hours to days to weeks
dissolution of
metastable form
metastable
and stable form
crystal growth
supersaturated solution
with seeds of stable form
stable form
Experimental Ttr
Nimodipine
• Pure forms used in interconversion studies
• Below 80 °C Form II is observed, indicating it is the more stable form
• Transition temperature between 80 and 95 °C based on the appearance of
Form I. Average of 88 °C taken as estimated Ttr
• Form II is more stable below ~ 88 ° C and Form I is more stable above~ 88 ° C
Solvent
Temp (°C)
Time (hrs)
Starting Form
Residue
2-propanol
25
22
I
II
25
8
II
II
40
96
I
II
40
96
II
II
80
32
I
I/II
80
32
II
II
95
8
I
I
95
8
II
I/II
1:3 ethanol: water
1:5 ethanol: water
Grunenberg et al, Int. J. Pharm. 1995, 118, 11-21
Experimental Ttr
Nimodipine
Energy
mp I 124 °C
mp II 116 °C
TTr ~88 °C
ΔHf I 39 kJ/mol
ΔHf II 46 kJ/mol
ΔHTr 7 J/g
Liquid
HL
ΔHTr II-I
7 kJ/mol
ΔHf I
39 kJ/mol
ΔHf II
46 kJ/mol
HI
H II
Form I
Form II



GI
GL
0 Temperature [K]
Ttr
mp II mp I
G II
Experimental Ttr
Monotropic
– Plot of log solubility vs 1/T (K)
Solubility
• van’t Hoff Plot
• Slope = -ΔH/R
• Intercept = ΔS/R
• lines will not cross
– Enantiotropic system
1/T
Enantiotropic
Form II
Solubility
– Monotropic system
Form I
Form II
Form I
1/T
• Lines will cross at transition temperature where
solubilities are equal
Experimental Ttr
1.9
Form I
• Carbamazepine
1.7
1.5
log Solubility
– Form III more stable at ambient
– Solubilities determined in 2propanol
– Extrapolated curves give
transition temperature of 73 °C
Form III
1.3
1.1
0.9
0.7
0.5
0.0028
0.0030
0.0032
0.0034
0.0036
1/T (K)
Temp (C)
Solubility I (mg/mL)
Solubility III (mg/mL)
Temp (1/K)
Log Sol I
Log Sol II
2.0
4.42
3.30
0.00360
0.65
0.52
12.0
6.41
4.61
0.00351
0.81
0.66
17.0
7.76
6.40
0.00345
0.89
0.81
26.0
11.16
9.27
0.00334
1.05
0.97
40.0
18.11
15.98
0.00320
1.24
1.20
57.5
34.42
32.6
0.00303
1.54
1.51
Behme et al, J Pharm Sci, 1991, 80, 986-990
Experimental Ttr
Carbamazepine
Energy
mp I 189 °C
mp III 173 °C
TTr ~73 °C
ΔHf I 26 kJ/mol
ΔHf III 29 kJ/mol
ΔHTr 7 J/g
Liquid
HL
ΔHTr II-I
7 kJ/mol
ΔHf I
26 kJ/mol
ΔHf III
29 kJ/mol
HI
H III
Form I
Form III



G III
GL
0 Temperature [K]
Ttr
~73 °C
mp II mp I
173 °C
189 ° C
GI
CH3
Eutectic Mixtures
S
N
NO2
H
C
N
• ROY system has 12 polymorphic forms
• Stability relationships determined
initially for six forms
ROY Polymorphs
– Yellow prisms (Y), yellow needles (YN),
orange plates (OP), orange needles
YN(sol’n)
(ON), orange red plates (ORP), red
prisms (R )
– Monitored solid by XRPD and Raman YN(melt)
– Most conversions take hours/days
– Some take years
• Solution interconversion studies at
different temperatures
– Showed all forms converted to Y
between 20 and 60 °C
– Y most stable form in this temperature
range
Yu, et. al. J. Am. Chem. Soc. 2000, 122, 585-591
Y
R
hours/days
ORP
ON
Y
days
OP
R
years
Y
Eutectic Mixtures
• Eutectic mixtures used
to determine the
transition temperature.
• Find/prepare eutectic
mixtures and measure
the melting points
• Determine temperature
where eutectics of each
form are the same.
Yu, et. al. J. Am. Chem. Soc. 2000, 122, 585-591
Eutectic Mixtures
• Two pairs enantiotropically related
• Two pairs monotropically related
• Thermodyanamic parameters calculated from data
Yu, et. al. J. Am. Chem. Soc. 2000, 122, 585-591
Eutectic Mixtures
Quantitative ET Diagram
Yu, et. al. J. Am. Chem. Soc. 2000, 122, 585-591
1.2
YN
0.8
G-GY (kJ/mol)
• All energies normalized to Y
• G-Gy calculated from melt
and eutectic data
• Y and ON enantiotropic
• Y and OP enantiotropic
• ON and OP enantiotropic
• Y most stable between 20
and 60 °C
• Y less stable than OP and ON
at higher temperatures
• ORP not included due to
scarcity of material
Can also produce quantitative ET
diagram with solubility measurements
L-s c
0.4
R
ON
OP
Y
0
OP
Y
ON
-0.4
L
30
50
70
90
110
130
T(°C)
Stability relationships between polymorphs from
eutectic and melting data. Each line represents the
free energy of the polymorph with respect to form Y.
Transition Temperature
• Transition temperature defines an
enantiotropic system
• Can estimate transition temperature based on
thermal data
• Can measure transition temperature
experimentally
– Slurries at different temperatures
– Solubilities at different temperatures (van’t Hoff
plot)
– Eutectic mixtures
Form Selection
• It is advisable to pick the most stable form
– Usually most chemically stable form
– Will not convert to another polymorph during storage as drug product
– Care must be taken to avoid conversion to a metastable form during
processing
– If it is not the most processable form, excipients and formulation can be used
to improve the properties
• Metastable polymorphs can be developed
– if faster dissolution and increased solubility is needed to achieve rapid
absorption, efficacy, or acceptable systemic exposure
• Risks must be evaluated for metastable forms
– Will change in form have substantive effect on product quality or
bioavailability?
– Will changes occur under normal storage conditions?
– Can analytical methods and sampling be developed that can detect change to
the more stable form?
Singhal and Curatolo. Adv Drug Delivery Rev. 2004, 56, 335-347
Form Selection
• Other considerations
–
–
–
–
–
–
Solubility
Chemical stability
Hygroscopicity
Melting point
Morphology
Etc
• There may not be one form with all the desired
characteristics
– Choose the best form based on the needs of the
project
Case Study
• LY334370 HCl
• Five forms found in polymorph screen
– Three anhydrates (Forms I-III)
• Form I: organic solvents, aqueous organic mixtures, and
pure water with slow cooling
• Form II: heat dihydrate to 150 °C
• Form III: heat dihydrate to 210 °C
– Dihydrate
• Generated from water with rapid cooling
– Acetic acid solvate
• Generated from glacial acetic acid at 30 °C
Reutzel-Edens et al. J. Pharm. Sci. 2003, 92, 1196-1205
Case Study
DSC -LY334370 HCl
– Form I
– mp 274 °C
– Form II
– mp 190 °C
– recrystallization exo 216 °C
– Form III melt 265 °C
– Form III
– mp 265 °C
– Dihydrate
– dehydration endo ~100 °C
– recrystallization exo 216 °C
– Form III melt 265 °C
Form
mp (°C)
ΔHf (kJ/mol)
I
274
57.8
II
190
30.8
III
265
24.8
Reutzel-Edens et al. J. Pharm. Sci. 2003, 92, 1196-1205
Case Study
LY334370 HCl
Energy
Forms I and II monotropic
Forms I and III monotropic
Forms II and III enantiotropic
mp I 274 °C
ΔHf I 58 kJ/mol
mp II 190 °C
ΔHf II 31 kJ/mol
mp III 265 °C
ΔHf III 25 kJ/mol
ΔHf III
25 kJ/mol
HL
ΔHf I
58 kJ/mol
H III
H II
HI
ΔHf III
31 kJ/mol
Liquid
ΔHTr II-III
Form III
Form II

Form I



0 Temperature [K]
Ttr
mp II mp III mp I
190 °C 265 ° C 274 ° C
G II
G
G I III
GL
Case Study
Intrinsic dissolution rate
• LY334370 HCl
– Based on properties, Form I
and dihydrate possible for
development
– Dihydrate found to dissolve
6X faster in water
– Van’t Hoff plot shows
dihydrate more soluble
over temperature range
– Parallel slopes for two lines
2.45 mg/cm2/min
0.40 mg/cm2/min
Reutzel-Edens et al. J. Pharm. Sci. 2003, 92, 1196-1205
Case Study
• Relationship between forms was determined based on the
characterization data
• Form I and dihydrate acceptable for development:
– Easy to prepare
– Highly crystalline
– Physically stable at RT
over wide RH range
– Can be crystallized in
acceptable morphologies
– Stable to compression
• Additional studies resulted in
Form I being chosen for development
– Dihydrate more soluble and dissolved more rapidly
– Form I still had acceptable solubility (5 mg/mL) and dissolution rate
– Choosing Form I, the thermodynamically stable form, avoids potential
conversion to a more stable form
Reutzel-Edens et al. J. Pharm. Sci. 2003, 92, 1196-1205
What Have We Learned
• Most stable form is least soluble
– with seeds and sufficient solubility, most stable form will result
from interconversion study (if there are no solvent effects)
• Monotropic system
– same form is the most stable over entire temperature range
• Enantiotropic system
– stability of forms is defined by the transition temperature
• Transition temperature can be determined by solubility,
interconversion, eutectic experiments
• Choosing the best form for development is dependent on
the data obtained and the development plan for the
compound
Why Do We Care
• Knowing the stable form will help in
– Choosing the best form for development
– Developing a crystallization process to produce the
desired form consistently
– Producing a dosage form with the desired form
• Choosing the best form early will help
– Prevent redevelopment of a crystallization step later
in development to produce the new form
– Prevent bridging bioavailability studies later in
development to compare new and old forms
– Prevent additional formulation development if a new
form is found
Resources
•A. Burger and R. Ramberger “On the Polymorphism of Pharmaceuticals and Other
Molecular Crystals. I” Mikrochimica Acta [Wien] 1979, II, 259-271.
•A. Burger and R. Ramberger “On the Polymorphism of Pharmaceuticals and Other
Molecular Crystals. II” Mikrochimica Acta [Wien] 1979, II, 273-316.
•A. Grunenberg et. al. “Theoretical Derivation and Practical Application of
Energy/Temperature Diagrams as an Instrument in Preformulation Studies of Polymorphic
Drug Substances” Int. J. Pharm. 1996, 129, 147-158.
•R. J. Behme, et. al. “Characterization of Polymorphism of Gepirone Hydrochloride” J. Pharm
Sci. 1985, 74(10), 1041-1046.
•R. J. Behme, et. al. “Heat of Fusion Measurement of Low Melting Polymorph of
Carbamazepine That Undergoes Multiple-Phase Changes During Differential Scanning
Calorimetry Analysis” J. Pharm. Sci. 1991, 80(10), 986-990.
•L. Yu, et. al. “Thermochemistry and Conformational Polymorphism of a Hexamorphic
Crystal System” J. Am. Chem. Soc. 2000, 122, 585-591.
•L. Yu, “Inferring Thermodynamic Stability Relationship of Polymorphs from Melting Data” J.
Pharm. Sci 1995, 84(8), 966-974.
•A. Burger et al. “Energy/Temperature Diagram and Compression Behavior of the
Polymorphs of D-Mannitol” J. Pharm. Sci. 2000, 89(4), 457-468.
Ann Newman, Seventh Street Development Group, 765-650-4462, [email protected]
www.seventhstreetdev.com