This one hour webcast covers special techniques used in polymorph screens, including stable forms, hydrates, processing stresses, ionic liquids, and highly solvating compounds. Access a free copy of our paper on specialized screening published in Organic Process Research and Development.

1. Specialized Screening: How Do I
Deal with Difficult Compounds?
Ann Newman
Seventh Street Development Group
PO Box 526, Lafayette, IN 47902
765-650-4462
ann.newman@seventhstreetdev.com
www.seventhstreetdev.com
Webcast February 28, 2013 ©2013 Seventh Street Development Group
Newman. Org Proc Res and Dev, 2013, early view, DOI 10.1021/op300241f

2. Background
• 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
New Brunswick, NJ
West Lafayette, IN
Storrs, CT
SUNY
Fredonia
2

3. What is a Polymorph
What are polymorphs?
• Polymorphs are different forms
of a compound
– Elements (allotropes), inorganic
(minerals), organic compounds
– Lattice used to define forms
• FDA definition includes all solid
forms
– Anhydrates, hydrates, solvates,
amorphous
• Different solid forms are also
possible for salts and cocrystals
• Different forms can have
different properties
– Solubility, dissolution, melting
point, stability, etc
coformer
+
API
cocrystal
+
water/
solvent
cocrystal hydrate/solvate
coformer
+
API
cocrystal
+
water/
solvent
water/
solvent
cocrystal hydrate/solvate
acid
API/base
+
salt hydrate/solvate
water/
solvent
salt
-
+
+
+
+
+
+
-
-
-
-
-
proton
transfer
-
-
-
-
-
-
-
-
+
+
+
+
+
+
+
+
acid
API/base
+
salt hydrate/solvate
salt
-
+
+
+
+
+
+
-
-
-
-
-
proton
transfer
acid
API/base
+
salt hydrate/solvate
water/
solvent
water/
solvent
water/
solvent
salt
-
+
+
+
+
+
+
-
-
-
-
-
salt
salt
-
+
+
+
+
+
+
-
-
-
-
-
proton
transfer
-
-
-
-
-
-
-
-
+
+
+
+
+
+
+
+
+
-
water/
solvent
water/
solvent
water/
solvent
API
solvate or hydrate
3

4. Why We Screen
25
220
Single Form
Multiple Forms
89% of compounds screened exhibited
multiple forms (based on 245 screens)
 includes 10 steroids, 7 peptide-based
structures, 5 cephalosporins, 4
organometallics, 2 macrolide
antibiotics
1 has 28
1 has 34
1 has 87
Stahly. Cryst. Growth Des, 2007, 7, 1007-1026

5. 5
Interconversion of Forms
Succinylsulfathiazole (anhydrous)
Ethanol
(anhydrous
)
Acetonitrile Acetone
Water
Stirring
in water
Stirring
in water
Stirring
in water
100 °C 100% RH
20 min stirring
in water
100 °C
100% RH
130 °C
Stirring in ethyl acetate
160 °C
Stirring in organic
solvent (anhydrous)
Crystallization in:
HI HII
HII
I
SA
II I
V
VI
IV
III
A. Burger and U. J. Griesser. Eur. J. Pharm. Biopharm. 1991, 37(2), 118-124.
MILLING

6. What is a Polymorph Screen
• Set of experiments to find the possible forms of a
compound
– Small scale (2 to 50 mg)
– Forms include anhydrates, hydrates, solvates, and amorphous
– What are the issues with the original solid form that you want
to change (example- crystallinity, hygroscopicity, melting point,
solubility…)
– What is needed for development
• Want to cover a wide area of crystallization space to
find a variety of forms
– The same form can be produced under a variety of conditions,
but some conditions may provide easier initial crystallization
than others
– Solvent and nonsolvent approaches should be included
6

7. What is a Polymorph Screen
• Search for seeds, not a search for a process
– Do not limit to Class III solvents
– Can gain information on crystallization process
(example- solvate formation, slurry expts)
– Can always use the initial crystals as seeds for a
crystallization process
• Need to determine which forms are relevant to
development
– Anhydrates vs hydrates vs solvates
– Initial goal is to find the most thermodynamically
stable form
• No screen can guarantee to find all forms 7

8. Polymorph Screen vs Selection
• Polymorph screen
– Find possible forms under various conditions
• Polymorph selection
– Determine which form has the best properties for
development
• Polymorph screen and selection are sometimes
considered the same function
– Not all forms found in a screen will be relevant when
choosing a lead candidate (example- solvates)
– However, knowing the possible forms will help in
developing robust processes (API and drug product)
8

9. Screen/Selection
XRPD, DSC, TG, etc
Solvent and nonsolvent conditions
Usually one technique used (XRPD, Raman)
Group data to determine possible forms
Collect specific data (solvent content, etc)
Scale-up of select materials may be needed
XRPD, DSC, TG, moisture uptake, solubility, etc
Material with best properties
Characterize starting material
Generate samples
Analyze samples
Data analysis
Characterize materials
Select form
Scale-up
Screening
Selection
Preliminary characterization
9

10. Sample Generation
Solvent methods
– Temperature
• Low temperatures to induce crystallization
– Refrigerator, freezer, salt baths; check freezing point of solvent
• Elevated temperatures to increase solubility
– Hot plate, heating mantle, sand or oil bath; check boiling point of solvent
– Rate of evaporation
– Vials
• Glass, silanized glass, acid or base washed, or polymer vials can be
used
• Check stability of plastic vials with various solvents
– Different salt/cocrystal formation conditions can result in
various forms
– Always look for single crystals for single crystal structure
determination
10

11. Sample Generation
• Solvent based methods can be employed based on
solubility in various solvents
– High solubility systems
• High concentrations can result in gels/oils
• Antisolvent additions, cooling experiments below
supersaturation
– Low solubility systems
• Want to increase solubility or allow time for conversion
• Slurry experiments, cooling crystallization from elevated
temperature
• Start with amorphous material to increase solubility
• Can tailor crystallization experiments to increase
success 11

12. Sample Generation
Polla et al., Int. J. Pharm. 2005, 301, 33-40;
Reutzel-Edens et al. J. Pharm. Sci. 2003, 92, 1196-1205
olanzapine
• Nonsolvent methods can be
tailored based on other
properties/data
– Heating/desolvation
temperature based on TG loss
– Heating/melting temperature
based on DSC, hot stage data
– Exposure to RH conditions
based on water uptake data
LY334370 HCl
12

13. Sample Generation
13
Adapted from Anderton. Amer. Pharm. Rev. 2007, 10, 34-40

14. Specialized Screens
• Stable Form
• Hydrate
• Processing Stresses
• Polymers
• Highly Solvating Compounds
• Ionic Liquids
• Gels
• Conformations in Solution
14

15. Stable Form Screen
Stable Form Screen
– Targeted for early
development to find the most
stable form
– Small amount of compound
needed (100-250 mg)
– Slurry experiments used
(solvent mediated
polymorphic transformation)
– Material suspended in diverse
group of solvents for two
weeks
– Solubility estimated using
gravimetric method Miller et al. Pharm. Dev. Technol. 2005, 10, 291-297
Metastable
Form
dissolution Stable
Form
Supersaturated
Solution
nucleation
crystal
growth
15

16. Stable Form Screen
Pfizer Compound A
• Form I was initial form
• Transformation to more stable Form II observed
– 6 out of 18 solvents in 2 days and 8 out 18 solvents in 2 weeks produced Form II
– Dioxane solvate also found
Fastest tranfsormation
at highest solubilities
decomposition
Miller et al. Pharm. Dev. Technol. 2005, 10, 291-297 16

17. Stable Form Form
• Information used to guide scale-
up efforts of stable form
• Ethyl acetate used (3.42 mg/mL)
– Fast conversion (36 hrs)
– Relatively low solubility gave
higher yield
• In-situ data collected using
Raman spectroscopy
• Screen used for 43 compounds
– 26% converted to more
stable form
– No other more stable forms
observed later in
development for the 43
compounds
Miller et al. Pharm. Dev. Technol. 2005, 10, 291-297 17

18. Hydrate Screen
• Methods
– Exposure to RH
• Dynamic vapor isotherm (DVI)
• High humidity (HH) chambers
– Slurry in water
• Suspension
• Water soluble compounds may dissolve and recrystallize
– Temperature cycling of aqueous suspension (TC)
• Suspension
• Water soluble compounds may dissolve and recrystallize
– Mixed solvent systems (MSS)
• Good for water-insoluble compounds
• Samples dissolved
• Dependent on water activity
– Vapor diffusion (VD)
• Water activity will change over time
• Need to consider solubility and hygroscopicity of compounds
• Ten hydrate forming compounds and 6 conditions were tested
18
Cui et al. J Pharm Sci, 2007, 97, 2730-2744

19. Hydrate Screen
Naproxen sodium
• Multiple hydrated
forms reported
• High solubility in water
– 200 mg/mL
• Five conditions resulted
in hydrates
– Different conditions
resulted in different
hydrated forms
– Vapor diffusion did not
result in sufficient solid
19
naproxen sodium
anhydrate
high humidity
mixed solvent
slurry
temp cycling
Cui et al. J Pharm Sci, 2007, 97, 2730-2744

20. Hydrate Screen
• Combination of slurry or temperature cycling (TC) with the
mixed solvent systems (MSS) could provide a screening
strategy with reasonable reliability
20
Cui et al. J Pharm Sci, 2007, 97, 2730-2744
Low water
activity

21. Hydrate Screen
• Medium throughput hydrate screen using crystallizer
• Need to determine cycling sequence to find best parameters
– Preferred cycle of 25 °C → °40 °C → 5 °C → 25 °C over 6 hrs
– Preferred solvent system of acetonitrile-water
– Method needs approximately 15-20 mg
21
Sistla et al. Pharm Dev Technol. 2011, 16, 102-109

22. Hydrate Screen
• Conditions investigated with 9 compounds
– Hydrates found in 7 cases
– Chlorthiazide and indomethacin have no known hydrates
22
Sistla et al. Pharm Dev Technol. 2011, 16, 102-109

23. Processing Stresses
Automated screen to mimic processing stresses
– Wet massing (100 mg), compaction, milling (30 mg) (200
mg), drying (50 mg)
– Crystallization (2.5 mL)
23
Alleso et al. J Pharm Sci. 2010, 99, 3711-3718

24. Processing Stresses
• Theophylline anhydrate
used for wet massing
experiments (2 min)
– Monohydrate formed
• Theophylline
monohydrate produced
in wet massing step
used for drying studies
(60 °C/50 min)
– Anhydrate formed upon
drying
• No metastable
anhydrate observed 24
Alleso et al. J Pharm Sci. 2010, 99, 3711-3718

25. Processing Stresses
• Amorphous nifedipine used
for milling and compaction
studies
• Milling initially converted
amorphous to crsytalline β
form within 4 min
– Further milling resulted in a
mixture of β and α forms
• Compaction resulted in and
α form
• Can also be performed with
mixtures of API and
excipients
25
Alleso et al. J Pharm Sci. 2010, 99, 3711-3718

26. Polymers
• Use polymers as heteronucleation sites
• Plate screens performed with insoluble
polymers in wells
– API solutions added to wells for crystallization
26
Price et al. JACS, 2005, 127, 5512-5517; Grezesiak and Matzgar. J Pharm Sci. 2008, 96, 2978-2986
Monomers used in combinatorial cross-linked polymer libraries

27. Polymers
Flurbiprofen (FBP)
• Three known forms
– Form I: unsolvated, stable at
ambient, crystal structure known
– Form II: unsolvated, stable at
ambient
– Form III: only stable when
crystallized between cover slip
and glass slide
• Polymer screen resulted in
– New hydrate: 3:2 FBP:water
– Crystal structure of new hydrate
– Bulk quantities of Form III
– Crystal structure of Form III
27
Grezesiak and Matzgar. J Pharm Sci. 2008, 96, 2978-2986
Form III
Hydrate

28. axitinib
Highly Solvating API
Axitinib
• Oncology candidate under
development
• Targets the vascular growth
factor (VEGF) to prevent
growth and proliferation of
cancer cells
• Screening studies were
performed to find the
optimal form
28
Chekal et al. Org Proc Res Dev. 2009, 13, 1327-1337; Campeta et al. J Pharm Sci. 2010, 99, 3874-3886

29. Screen 1 resulted in mostly solvated forms
-Forms I to VIII
-Form IV found as most stable form during screen and used in early clinical studies
Two additional screens (Screens 2 and 3) conducted with Form IV material
-Forms IX-XXIV found
Screen 4 conducted using Form IX (hydrate) as starting material
-Mostly slurries
-No new patterns found
Form XXV produced during process development studies;determined to be more stable than Form IV
Screen 5 performed with Form XXV material to confirm stability
-Forms I to VIII
-Form IV found as most stable form during screen and used in early clinical studies
During large scale manufacturing campaign Form XLI is produced
-Found to be most stable form, total of 5 anhydrous forms and 66 solvated forms identified to date
-Most stable form was not found during any screen
Devised new approaches targeting high temperature desolvation to ensure Form XLI was most stable form
-Vacuum drying at 100 °C
15% of solvates did not desolvate
57% desolvated to Form IV
5% produced form XLI
-Solvent based desolvation at high temperatures
Slurry in ethanol at 90 °C: 97% produced Form XLI
Higher solubility allows transformation to more stable form
Slurry in heptane at 105 °C: 33% produced Form XLI, 45 desolvated to Form IV
Slurry in p-cymene at 150 °C: 83% produced Form XLI

30. Highly Solvating API
30

31. Highly Solvating API
Methods used
• Vacuum drying at 100 °C
• 15% of solvates did not desolvate
with this method
• 57% desolvated to Form IV
• 5% produced Form XLI
• Solvent based desolvations at high
temperatures
– Slurry in ethanol at 90 °C
• 97% produced form XLI
• Higher solubility allows
transformation to more stable form
– Slurry in heptane at 105 °C
• 33% produced Form XLI
• 45% desolvated to Form IV
– Slurry in p-cymene at 150 °C
• 83% produced Form XLI
31
Campeta et al. J Pharm Sci. 2010, 99, 3874-3886
100 mg scale
120 experiments

32. Ionic Liquids
• Purely ionic, salt-like materials that are liquid at low
temperatures
– Room temperature ionic liquids (RTIL): Salts with melting points
below room temperature
• Commercially available
• Be used as-is or as mixtures with water or organic solvents
32
Kohno ad Ohno. Chem. Commun. 2012, 48, 7119-7130.

33. Ionic Liquids
Adefovir dipivoxil
• Enzyme inhibitor of HIV
• Six polymorphs identified using organic and
water solvents
• Screen performed with ionic liquid AEImBF4
using “drowning-out crystallization”
33
An et al. Cryst Growth Des. 2010, 10, 3044-3050
AEImBF4
Adefovir dipivoxil

34. Ionic Liquid
• Solubility of AD in AEImBF4
- in
water
– AD highly soluble in pure
AEImBF4
- (64 mg/mL)
– Solubility reduced with
increasing water fraction
– Solubility slightly dependent on
temperature with 50:50 vol %
water: AEImBF4
-
• increased only 2 mg/mL from 25-
90 °C
An et al. Cryst Growth Des. 2010, 10, 3044-3050

35. Ionic Liquids
• Drug was dissolved in an ionic liquid at a
concentration of 64 mg/mL
• Heated to crystallization temperature
– Range of 25-90 °C
– Fixed composition of 50:50 ionic liquid: water used for
temperature studies
• Water added to ionic liquid and vial capped
– Volume of water fraction varied from 0.2 to 0.8
• After 24 hr of crystallization, the crystals were
isolated and characterized
35
An et al. Cryst Growth Des. 2010, 10, 3044-3050

36. Ionic Liquids
• Known Form II produced below 70 °C
• New form N-1 found at 80 °C
• New form N-II found at 90 °C
36
An et al. Cryst Growth Des. 2010, 10, 3044-3050
Form II
N-I
N-II

37. Ionic Liquids
Second study performed using a variety of ionic
liquids and crystallization conditions
37
antisolvent
An et al. Cryst. Growth Des.
2013, 13, 31-39.
solvent

38. Ionic Liquids
• Antisolvent crystallization
produced a new polymorph (NF)
• Produced by unique
intermolecular interactions of the
drug molecule induced by the
ionic liquids (AEImBF4/AAImBF4)
• Known forms also produced from
mixed ionic liquids
– Controlled by temperature
38
An et al. Cryst. Growth Des. 2013, 13, 31-39.

39. Ionic Liquids
• Ionic liquids can be used with organic solvents or as mixtures of ionic
liquids to expand the crystallization space during the screen
• Unique interactions with drug can produce new forms
• Ionic liquids were found to chemically stabilize the adefovir dipivoxil at
elevated temperatures (100 °C) compared to conventional organic
solvents which resulted in a wider temperature range with the ionic
liquids
39
Form NF anhydrate (C20H32N5O8P) drowning out AEImBF4/BDMImBF4 This Work

40. Gels
• Gels used as matrix for crystal growth
• Gel network strong enough to sustain
and protect crystals but so rigid as to
prevent their growth
• Mass transfer of crystallizing molecules
proceeds steadily by diffusion
• Secondary nucleation is strongly reduced
so crystals exhibit low aggregation,
narrow particle size distribution, high
homogeneity in shape
• Crystal recovery is an issue
– Manual removal of crystals
– Use pH to obtain sol-gel transition in a
reversible gel
• Addition of API can change gel
properties
40
Foster et al. Nature Chem 2010, 2, 1037-1043
Gel prepared with 1:9 CHCl3: toluene
Acetate ion added to top of gel to dissolve
Crystal recovered by filtration or manual
extraction
Gelator
Recovery of single crystal of carbamazepime
Form III by acetate anion gel dissolution

41. Gels
• Polymorph screen performed on
carbamazepime
• Three different gels and a variety of solvents
used
• In some cases, no gel was produced or no
crystals were produced
• Different forms found in different gels with
the same solvent
– Form I usually produced from melt at
170 °C or by dehydrating dihydrate at low
RH conditions
• Transformation in gel observed
• Acetate ion added to liquefy gel and
isolate crystals
41
Foster et al. Nature Chem 2010,
2, 1037-1043

42. Gels
• Other systems investigated
• Attempts to recover NPU with acetate
ion resulted in dissolution of both gel
and API in some solvents (MeCN,
EtOAc, CHCl3), but not others
(MeOH:H2O)
– Specific anion-NPU interaction
confirmed by solution NMR
• Anion recovery method limited to
– Compounds that do not compete with
gel for anion binding
– Compounds that are chemically stable
at the pH produced
42
Foster et al. Nature Chem 2010, 2, 1037-1043

43. Thermogel
• Use heat to make a reversible gel system for
crystallization around 20 °C
– Poloxamer 407 used
– Water solutions with different percentages of poloxamer
407, α-lactose monohydrate, and ethanol prepared
– Characterized to understand how different components
alter the gelling temperature
• Allows easy removal of crystals
– Reduce temperature to convert gel to liquid at gel point
• Lactose used as model compound
43
Cespi et al. Pharm Res. 2012, 29, 818-826

44. Thermogel
Three phases
• Initial characterization of
water/poloxamer/lactose system
– Understand how components
influence gel point
• Optimization to select best
conditions for lactose
crystallization
• Harvested crystals characterized
and compared to starting and
control samples
44
Cespi et al. Pharm Res. 2012, 29, 818-826
Effect of poloxamer and lactose concentration
on gel point
•Low gel points at high lactose concentration
-Useful to obtain system that can gel
around 16-20 C
•Lactose concentration higher than 18%
results in partial or no gel formation
- Lactose-poloxamer interactions block the
aggregation of the poloxamer and inhbitis
gel formation

45. Thermogel
• Rheological analysis showed that
lactose markedly influenced to
properties of the gel
– Possible to prepare a crystallization
system that gelled at room
temperature and liquefied below
18 °C by adjusting
poloxamer/lactose ratio
• Small amounts of ethanol did not
alter the gelling properties by
changed the solubility
– Made it possible to prepare
systems with different levels of
supersaturation
45
Cespi et al. Pharm Res. 2012, 29, 818-826

46. Thermogel
Lactose monohydrate crystallized from gels
• Some samples contained some amorphous material
46
Dehydration Melting
Lactose Monohydrate
Crystallization of amorphous
Cespi et al. Pharm Res. 2012, 29, 818-826

47. Gels
• Another option for single crystal growth and
polymorph screening
• Provides a different environment for crystal
growth with slow diffusion
• Need to assess the affect of API on gel
formation
• Need to investigate isolation methods (pH,
thermogel) for each gel and solid
47

48. Conformations in Solution
• Crystallization is a multi-step
process
– Molecules associate into
prenucleation aggregates
– Aggregates assemble into
crystal nuclei
– Leads to crystal growth
48
• Conformer produced in solution can determine form
• Primary factor for conformational polymorph formation
is stabilization of the conformer in the crystalline
environment relative to that in saturated solution
• Type of solvent is one major factor in polymorph
selectivity
Reutzel-Edens. Current Opinion Drug Disc Dev 2006, 9, 806-815
Abromov et al. Chapter 26 in Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing, D.
am Ende, Ed., John Wiley and Sons, 2010.

49. Conformers in Solution
• Solvent selection is usually
based on solubility
• A higher conformer
population in solution should
contribute to increased
nucleation of the
corresponding polymorph
with that conformer
49
Can we predict conformational population in different
solvents to explore different conformational populations
in solution?
Abromov et al. Chapter 26 in Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing, D.
am Ende, Ed., John Wiley and Sons, 2010.
Crystal A Crystal B

50. 50
Famotidine polymorph A
(refcode FOGVIG04)
Famotidine polymorph B
(refcode FOGVIG05)
Conformers in Solution
• Famotidine polymorphs A and B
– Monotropically related with Form A being more
stable
– Form A is crystallized from MeOH and ACN
– Form B is crystallized from water at high drug
concentration
• Conformational populations were predicted at
a crystallization temperature of 50 °C in three
solvents
– Conformations from single crystal were used
due to the high flexibility
• Conformer A displays highest population in
MeOH and ACN
• Conformer B increases in water solutions
• Agrees with experimental data reported in
literautre
A
A
A
B
B
B
B A
Abromov et al. Chapter 26 in Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing, D.
am Ende, Ed., John Wiley and Sons, 2010.

51. Conformers in Solution
• Use in virtual polymorph screening
• Diverse set of solvents used to determine whether
solvent induces conformational switch
– Presence of intramolecular H-bonding
– Noticeable variation of molecular hydrophobic and
hydrophilic surfaces
– Suggest polar protic: water (both donor and acceptor)
and diethyl amine (donor)
– Polar aprotic: acetone (acceptor)
– Non-polar: hexane
– Self media: mimic solid amorphous
51

52. Conformers in Solution
52
Form I
Refcode YIGPIO
Form II
Refcode YIGPIO01
Solvent Solid Form (2d)a Solid Form (2w)a Conformer I
Population (%)
Conformer II
Population (%)
Water I II 21 79
Hexane I I,II mixture 85 15
MTBE I I 39 61
1,2-Xylene I I 70 30
Toluene I I 68 32
Nitromethane II II 31 69
Ethyl acetate II II 35 65
Acetonitrile II II 26 74
2-Propanol II II 32 68
2-Butanone II II 34 66
Acetone II II 27 73
1,2-Dimethoxyethane II II 28 72
Ethanol II II 30 70
Ritanovir
• Compared experimental polymorph screen results
with predicted conformer populations at RT
• Good agreement with experimental and predicted
a. Result of polymorph screen reported by Miller et al. Pharm Dev Technol. 2005, 10: 291-297

53. What Have We Learned
• Polymorph screens
– Are a search for seeds and should cover a wide crystallization
space including solvent and nonsolvent methods
– Can be tailored to the information needed for compound
development
• Polymorph screening is different from selection
• One screen will likely not give you all the form information on a
compound
• Specialized screening methods may be helpful for difficult
compounds or special situations
– Stable form, hydrate, processing, highly solvating, ionic liquids,
gels, computational
53

54. Why Do We Care
Knowing the possible forms will help to
– Choose the best form for development
– Determine the most stable form
– Develop a robust crystallization process
– Develop a suitable formulation process
– Avoid processing conditions that could produce another
form
– Prevent latent polymorphs from appearing late in
development or in marketed products
– Prepare an acceptable regulatory package
– Expand intellectual property for the compound
– Assess lifecycle management
54

55. Resources
• Solid-State Chemistry of Drugs, 2nd edition, S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell,
SSCI, Inc, West Lafayette, IN 1999.
• Polymorphism in Molecular Crystals, J. Bernstein, Oxford University Press, NY 2002.
• Aaltonen et al. Eur J Pharm Biopharm. 2009, 71, 23-37.
• Guillory. Chapter 5 in Polymorphism in Pharmaceutical Solids, H. G. Brittain, Ed., Marcel
Dekkar, New York 1997.
• Hilfiker et al. Chapter 11 in Polymorphism in the Pharmaceutical Industry, R. Hilfiker,
Ed., Wiley-VCH, Weinheim 2006.
• Maiwald. Amer Pharm Rev. 2006, May/June, 95-99.
• O’Neill. Pharm. Technol. 2003, 44—56. Polymorphism in Pharmaceutical Solids, H. G.
Brittain, Ed., Marcel Dekker, NY 1999.
• Yamasaki et al. Cryst. Growth Des. 2006, 9, 2007-2010.
Ann Newman
Seventh Street Development Group
765-650-4462
ann.newman@seventhstreetdev.com
www.seventhstreetdev.com
55