A one hour webcast on solid-state polymorphs and how they impact on drug development

1. What Are Polymorphs and
Why Do We Care?
Ann Newman
Seventh Street Development Group
PO Box 526, Lafayette, IN 47902
765-650-4462
ann.newman@seventhstreetdev.com
www.seventhstreetdev.com
November 15-16, 2010 ©2010 Seventh Street Development Group

2. 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
2

3. What is a Polymorph?
• Organic molecules can also crystallize as
different forms
= organic molecule
Form I Form II
3

4. Organic Polymorphs
• How do the molecules fit into a box called the
lattice?
• Lattice is defined by lattice parameters that
define the box
– a, b, c = the lengths of the three sides
– α, β, γ = the angles of the lattice
cubic: a = b = c,
α = β = γ = 90º
triclinic: a  b  c,
α  β  γ
4

5. Lattices
Seven crystal systems describe the crystalline lattice
High symmetry
Low symmetry
http://www.seas.upenn.edu/~chem101/sschem/solidstatechem.html 5

6. Organic Polymorphs
Drugs: carbamazepine
treat epilepsy and bipolar disorder
Gresiak et al. J. Pharm. Sci. 2003, 92, 2260-2271
Form I Form II
Form III Form IV
6

7. Organic Polymorphs
Excipients/Dyes: Maize 1
Price et al. Crystal Growth & Design, 2003, 3, 1021–1025
Form I (triclinic) Form II (triclinic) Form III (triclinic)
7

8. Organic Polymorphs
• Also applies to salts and cocrystals
= counterion
= API = neutral guest
polymorphs salt cocrystal
Scultheiss and Newman. Crystal Growth & Design, 2009, 9, 2950-2967
API-Active pharmaceutical ingredient
8

9. Polymorphs of Salts
Enalapril maleate (Vasotec)
ACE inhibitor to treat high blood pressure
Form I: Precigoux et al. Acta Crystallogr C 1986, 42, 1022-1024. Form II: Kiang etal. J. Pharm.
Sci. 2003, 92, 1844-1853
C
N
O
Form I Form II
orthorhombic
monoclinic
9

10. Polymorphs of Cocrystals
Carbamazepine: saccharin
Form I Form II
Form I: Hickey, et al. Eur. J. Pharm. and Biopharm. 2007, 67, 112-119
Form II: Porter et al. Crystal Growth & Design. 2008, 8, 14-16
N
S
O
10

11. Solvates/Hydrates
• Solvates: crystal
forms containing
either stoichiometric
or nonstoichiometric
amounts of a
solvent.
• If the incorporated
solvent is water, the
solvate is commonly
known as a hydrate.
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
-
-
-
-
-
-
-
-
+
+
+
+
+
+
+
+
+
-
Figures: Scultheiss and Newman. Crystal Growth & Design, 2009, 9, 2950-2967
water/
solvent
water/
solvent
water/
solvent
API
hydrate or solvate
11

12. Solvates/Hydrates
Olanzapine (Zyprexa): multiple hydrated forms
treat schizophrenia and bipolar disorder
Reutzel-Edens et al. Crystal Growth &
Design, 2003, 3, 897-907
12

13. Solvates/Hydrates
Theophylline:citric acid cocrystal monohydrate
Karki et al. Mol. Pharm. 2007, 4, 347-354
13

14. Other Solid Forms
Harmon et al. AAPS Newsmagazine,
2009, Sept, 14-20.
• Amorphous
– No long range order
– Silicon dioxide in glass windows
is amorphous
– Amorphous materials can also
be powders
– Less physically and chemically
stable than crystalline
materials
– Higher dissolution than
crystalline materials
• Amorphous solid dispersions
– Amorphous drug with polymer
– Polymer stabilizes amorphous
drug
– Results in better stability and
higher dissolution 14

15. Definitions
• Polymorph
– FDA: crystalline and amorphous forms as well as
solvate and hydrate 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 15

16. Do Pharmaceutical Compounds
Exist in Multiple Solid Forms?
25
220
Single Form
Multiple Forms
89% of compounds screened resulted in
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. Crystal Growth & Design. 2007, 7, 1007-1026

17. Solid Forms
• Propensity to produce different
forms not significantly different
for salts and non-salts
• Need more data on cocrystals?
Stahly. Crystal Growth & Design.
2007, 7, 1007-1026
17

18. Why do we care?
18

19. Properties Affected by Solid Form
Yield
Drying
Solubility
Hygroscopicity
Dissolution rate
Physical stability
Chemical stability
Compressibility
Chargeability
Filterability
Flow
Millability
Melting point
Color
Morphology
Density
Toxicology
etc…
Levels of gastric irritation
Bioavailability
Taste
Excipient compatibility
Clinical results
Hue
Color
Strength
Stability
Rheology
Dispersibility
Opacity
19

20. Physical Stability
• Theophylline monohydrate compacts
– Produced at compression pressures of 50, 70, 100, 150 MPa
– Stored at 22% RH for 1, 24, or 168 hr
• Monohydrate showed tendency to form Anhydrous II
Suihko et al. Int J Pharm. 2001, 217, 225-236
20

21. Dissolution Rate and Solubility
Milosovich. J Pharm Sci.
1964, 53, 484-487.
Sulfathiazole
• Sulfa antibiotic
• Anhydrous forms I and II
0
5
10
15
20
25
30
35
40
45
15 25 35 45 55 65
Solubility
(g/1000
g)
Temperature (C)
Sulfathiazole Solubility
Form I
Form II
Dissolution Rate Solubility
Temperature
(°C)
Form I
(mg cm–2 s ec–1)
Form II
(mg cm–2 s ec–1)
Form I
(g / 1 0 0 0 g m)
Form II
(g / 1 0 0 0 g m)
59.1 0.185 0.239 31.5 40.7
48.8 0.102 0.145 19.8 28.1
39.4 0.0598 0.0913 14.0 21.4
29.6 0.0355 0.0597 9.93 16.7
24.1 0.0237 0.0413 8.15 14.2
20.4 0.0201 0.0371 7.10 13.1
(95% alcohol)

22. Dissolution Rate
Ampicillin
– Anhydrate and trihydrate
Wadke and Reier. J Pharm Sci. 1972 , 61(6), 868-71. 22

23. Solubility
Norfloxacin
– Broad spectrum antibiotic
Compound Type Crystallization
Solvent
Apparent Aqueous
Solubility (mg/mL)
norfloxacin free base ----- 0.21
isonicotinamide solvate cocrystal chloroform 0.59
malonate dihydrate salt water 3.9
hemisuccinate monohydrate salt water 6.6
maleate monohydrate salt water 9.8
Bassavoju et al. Cryst. Growth Des. 2006, 6, 2699-2708
23

24. Bioavailability
Chloramphenicol palmitate
– Broad spectrum antibiotic
– Anhydrous forms A and B
Original data: Aguir et al. J Pharm Sci. 1967, 56, 847-853. Figure: Florence and Attwood, Physicochemical Principles of
Pharmacy – Fourth edition , 2005.
Need to consider form
changes over time in solutions
and suspensions
24

25. Bioavailability
Ampicillin
– Anhydrate and trihydrate
Time
Wadke and Reier. J Pharm Sci. 1972 , 61(6), 868-71
25

26. Bioavailability
AMG-517:Sorbic acid cocrystals
500 mg/kg free base
30 mg/kg cocrystal
Bak et. J Pharm Sci. 2008, 97, 3942-3956
500 mg/kg cocrystal
26

27. Bioavailability
Amorphous solid dispersion
– Improved dissolution and bioavailability compared
to crystalline material
Harmon et al. AAPS Newsmagazine, 2009, Sept, 14-20.
In vitro dissolution data using fasted
simulated intestinal fluid (Fassif)
27

28. 28
Processing
A. Burger and U. J. Griesser. Eur. J. Pharm. Biopharm. 1991, 37(2), 118-124.
MILLING

29. Form Crystallization Conditions
Polymorph I Chloroform at 5 °C
Polymorph II Methanol or ethanol at 5 °C
Polymorph III Chloroform at -20 °C
Acetone solvate Acetone at 5 °C
Chloroform solvate Chloroform at 25 °C
Benzene solvate Benzene at 25 °C
Crystallization
F
CO2H
S
H3C
CH3
O
Tros de Ilarduya et al. J. Pharm. Sci. 1997, 86, 248
Sulindac
▪ anti-inflammatory
29

30. Drying
Olanzapine (Zyprexa)
higher hydrate
dihydrate E
Reutzel-Edens et al. Crystal Growth & Design, 2003,
3(6), 897-907 30

31. Drying
Trehalose
– Three known forms: dihydrate, anhydrate, amorphous
– Form obtained upon drying dihydrate depends on particle
size, rate, drying conditions
Taylor and York. J Pharm Sci, 1998, 87, 347-355
XRPD patterns of dihydrate dried under
(a) slow conditions (1 K/min) to form
anhydrate
(b) fast conditions (>50 K/min) to form
amorphous
Willart et al. J Phys Chem B. 2002, 106, 3365-3370
Trehalose Dihydrate
Small particles
(<425 µm)
Large particles
(>425 µm)
dehydration
amorphous
dehydration
anhydrate
31

32. Water Sorption
Saleki-Gerhardt et al J. Pharm. Sci. 1995, 84, 318
2.5
3
3.5
4
4.5
5
5.5
0 20 40 60 80 100
trihydrate
pentahydrate
tetrahydrate
% relative humidity
moles
water
Raffinose
32

33. Wet Granulation
Theophylline
<60 °C, low RH
>60 °C or RH
Morris et al. Adv. Drug Delivery Rev. 2001, 48, 91-114
Possible mixtures
Fast drying
Slow drying
33

34. Liquid Dosage Forms
• Suspension
– Drug is suspended in formulation vehicle
– Even with low solubility formulations, drug can dissolve and
recrystallize over time
– Most stable form usually used to prevent recrystallization
• Solution
– Drug is dissolved in formulation
vehicle
– Concentration should be below
equilibrium solubility of form in
vehicle to prevent crystallization
• Excipients added such as thickeners, preservatives,
buffer agents, sweeteners, etc
34

35. Solution Dosage Forms
• AMG-517 formulated as a
suspension in 10% (w/v) Pluronic
F108® in OraPlus®
• OraPlus® contains 0.1% sorbic
acid as a preservative
• New form precipitated in
formulation as 1:1
AMG517:sorbic acid cocrystal;
affected animal studies at high
doses due to solubility limited
absorption
• Found 12 additional cocrystals in
subsequent studies
• Know what is in your solutions
– can also happen with buffers Bak et al. J Pharm Sci. 2008, 97, 3942-3956.
35

36. Drug Substance
Regulatory
FDA decision tree on polymorphs part of Code
of Federal Regulations (CFR)
ICH Q6A, Federal Register, 2000,
65(251), 83041-83063.
36

37. Regulatory
ICH Q6A, Federal Register, 2000,
65(251), 83041-83063
Drug Substance
37

38. Regulatory
ICH Q6A, Federal Register, 2000,
65(251), 83041-83063.
Drug Product
38

39. Intellectual Property
• New solid forms are patentable
– Polymorphs, hydrates, solvates, salts, cocrystals,
amorphous, amorphous dispersions
– Salts and cocrystals can have different forms
(polymorphs, hydrates, solvates, amorphous)
– Can help lifecycle management
• Patents are listed in the FDA Orange Book and
play an important role in generic approval
Orange book: http://www.fda.gov/cder/ob
US Patent and Trademark Office (USPTO): http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm
39

40. Case Study
Ritanovir
– Novel protease inhibitor used to treat AIDS
– Discovered in 1992
– Marketed in 1996 as Norvir
• oral liquid and Norivir semi-solid capsules
– Ritanovir is not bioavailable from the solid state, so
both formulations contained ritanovir in ethanol/water
based solutions
– Only one crystal form was identified during
development
– 240 lots of Norivir capsules were produced without
stability problems
Bauer et al. Pharm. Res. 2001, 18, 859-866 40

41. Case Study
Ritanovir
– 1998 Norvir capsules failed dissolution
– A new polymorph Form II was identified in the
capsules
Form I Form II
Bauer et al. Pharm. Res.
2001, 18, 859-866 41

42. Case Study
Chemburkar et al, Organic Process Research and Development 2000, 4, 413
Ritanovir
– Form II was found to be
significantly less soluble
than Form I
– Ethanol/water solutions
for the capsules were not
saturated with respect to
Form I, but were 400 %
supersaturated with Form
II
– Oral solutions could no
longer be stored at 2-8 °C
without risk of
crystallization
0
50
100
150
200
250
300
350
0 5 10 15 20 25
Solubility
(mg/mL)
Percent Water in Ethanol
Ritanovir Solubility
Form II
Form I
42

43. Case Study
Form II
orthorhombic
Bauer et al. Pharm. Res. 2001, 18, 859-866
Form I
monoclinic
Ritanovir
– Form II more stable, but hard to crystallize due to an unusual conformation
– Possible heterogeneous nucleation of Form II with a related compound
formed by the base catalyzed reaction of ritanovir
43

44. Case Study
Ritanovir
– Presence of Form II made the original formulation
unmanufacturable
– Crystallization of Form II resulted in limited inventory and
seriously threatened the supply of this lifesaving drug
– Product had to be removed from the market
– New formulation developed using Form II
– Estimated losses:
• Hundreds of millions spent trying to recover Form I
• $250 million in lost sales
Bauer et al. Pharm. Res. 2001, 18, 859-866; Goho. Science News, 2004, 166, 122
Chemburkar et al, Organic Process Research and Development 2000, 4, 413
44

45. Case Study
Ritanovir
– Solid dispersion with PEG
Law et al. J. Pharm. Sci. 2004, 93(3), 563-570
10% ritanovir:90% PEG
20% ritanovir:80% PEG
30% ritanovir:70% PEG
crystalline
45

46. Case Study
Kaletra
– Ritanovir and liponavir combination
product
– Oral tablet and oral solution
– US approval 2000
– Improved tablet formulation 2005
• amorphous dispersion produced
• based on melt extrusion technology
• patients take fewer tablets (from 6 to 4)
• needs no refrigeration
• no food effect
http://www.thebody.com/confs/ias2005/pdfs/WeOa0206.pdf
46

47. What Have We Learned
• Polymorphs are different forms of a compound
– Elements (allotropes), inorganic (minerals), organic
compounds
– Lattice and how the molecules pack define the forms
• FDA definition includes all solid forms
– Anhydrates, hydrates, solvates, amorphous
• Different solid forms are also possible for salts and
cocrystals
• Estimated that close to 90% of organic
pharmaceuticals will have more than one solid form
47

48. Why Do We Care
• Numerous properties can be affected
• Stability, water uptake, solubility, dissolution,
bioavailability, etc
• Processing can change the solid form and alter
desired properties
–Crystallization, drying, manufacturing,
storage, handling, etc
• Understanding solid state forms can help
prevent problems during development of
pharmaceuticals and other organic systems
48

49. 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.
• Polymorphism in the Pharmaceutical Industry, R. Hilfiker, Ed.,
Wiley-VCH, Weinheim 2006.
• Polymorphism in Pharmaceutical Solids, H. G. Brittain, Ed., Marcel
Dekker, NY 1999.
• Physical Characterization of Pharmaceutical Solids, H. G. Brittain,
Ed., Marcel Dekker, NY 1995.
Ann Newman
Seventh Street Development Group
ann.newman@seventhstreetdev.com
www.seventhstreetdev.com 49