Basic concepts, mysteries and case studies

1. Presented By:
Madhulika Harde

3. Basic Concept

4. Crystallisation
Crystallization is a process for the formation
of solid crystals from a uniform solution.

5. Concentration of solute during crystallisation
As the boundary of supersolubility (SS) is crossed, nucleation
rate increases rapidly. Increase in metastable zone width during
crystallisation can lead to a higher supersaturation of metastable
phase allowing its arrest; S=solubility.

6. New trends in crystallisation
Capillary Crystallisation
Laser Induced Crystallisation
Sonocrystallisation
Target the nucleation stage

7. Laser Induced Crystallisation
Fig: Course Of Crystallisation And Its Rate Limiting Step

8. Polymorphism
Many chemical substances can crystallise in
different crystal forms, a phenomenon known as
polymorphism.
Polymorphs are defined as crystalline phases that
have different arrangements and / or
confirmations of molecules in a crystal.

9. Polymorphism is a natural property.
Polymorphs are not “created” or
“invented”, they are discovered normally as
a part of routine experimentation related to
drug formulation.

10. Physical and chemical properties that may vary
among polymorphs (partial list)
-Melting point
-Vapor pressure
-Hardness
-Optical, electrical,
magnetic properties
-Color
-IR spectra
-NMR spectra
-Molecular
conformation
-Photochemical
reactivity
-Thermal stability
-Filtration and drying
characteristics
-Dissolution rate
-Bioavailability

11. Irbesartan, C25 H28 N6 O
Tautometry
Desmotropy
Metastable Phase A Stable Phase B
Acicular Crystals Tabular Crystals

12. Characterisation Of Polymorphs
Polarizing Optical Microscopy
Thermomicroscopy
Differential Scanning Calorimetry (DSC)
Thermogravimetric Analysis (TGA)
Nuclear Magnetic Resonance (NMR)
Infrared Spectroscopy (IR)
Raman Spectroscopy
X – Ray Diffraction

13. Polymorphs are most often
recognized because of the difference
in properties…
…but these properties can also be
quite similar.

14. MELTING POINT
Benzocaine D-mannitol
130 -132 C Form I 165.5 C
162 – 163 C Form II 166 C

15. Similar IR Spectra
Two Polymorphs Of Caffeine

16. Crystallisation in the pharmaceutical arena is
a means of ‘giving birth’ to new polymorphs.
Although they have the same elemental
composition, polymorphs exhibit different
physico-chemical and physico-technical
properties.
Due to varied functional behaviours,
polymorphs can also be termed ‘crystal mutants’.

17. Objectives of Polymorph & Crystallisation
Screening
High throughput screening for drug crystalline forms
Identify the most stable and suitable polymorph for
development
Find new polymorphs with minimal sample quantity
in the shortest time-frame
Establish the enantiotropic relationships between
polymorphs
Secure intellectual property for polymorphic forms

18. Contribution
In
Drug
Development

19. Crystallization process is an essential step in
drug development.
A crystallization process is also the most
frequently used technique for purifying solid
drug substances. Irrespective of whether the
chemical or chiral purity needs to be enhanced,
a specially designed crystallization process is
the best choice for processing.

20. Disappearing polymorphs
When a compound exhibits polymorphism-the
existence of more than one crystal structure-it may be
important to obtain a particular polymorph under
controlled and reproducible conditions. However, this is
not always easy to achieve.
Indeed, there are cases where it was difficult to obtain
a given polymorphic form even though this had
previously been obtained routinely over long time
periods.

21. When Drugs Go Bad !
"The worst that can happen for a
pharmaceutical company is if a new
polymorph suddenly appears in the
temperature and humidity conditions
of a blister pack when a compound is
actually on the market."

22. Case
Studies

23. The Ritonavir Story
Ritonavir, or Norvir, was patented in 1993 and
marketed in 1996 by Abbott Laboratories.
The drug was on the market for 18 months
before a serious problem emerged: the drug began
precipitating out of formulation in large quantities.

25. The new form was dubbed Form 2, and was
found to be less soluble, greatly reducing
bioavailability.
Abbott was forced to remove Ritonavir from the
market until they solved the problem, resulting in
extreme losses:
$250 million in sales.
Estimated hundreds of millions of dollars in
R&D trying to recover the original Form I.

26. Ritonavir : The Solution Proposed

27. Abbott Laboratories Receives U.S. FDA
Approval for Reformulated Norvir
(ritonavir) Capsule
New Soft-Gelatin Capsules Offer Non-Refrigerated,
Twice-Daily Treatment Option
ABBOTT PARK, Ill., June 30, 1999 - Abbott Laboratories announced today it has
received U.S. Food and Drug Administration (FDA) approval for Norvir
(ritonavir) soft-gelatin capsules…Norvir soft-gelatin capsules require
refrigerated storage between 36-degrees F to 46-degrees F until dispensed to
patients…
The approval of Norvir soft-gelatin capsules follows intense reformulation work
at Abbott after an announcement in July 1998 that a new crystalline structure of
ritonavir, which affected how the semi-solid capsule dissolved, would interrupt
the production of Norvir semi-solid capsules.
Ritonavir – The Solution Approved

28. Patents And The Polymorphs
Economic Importance
Revenue loss to innovator firms:
$51,508,000,000
Revenue gain to generic firms:
$19,117,000,000
(Figures are for upcoming ten years, discounted at 7%)

29. Developed in 1970’s by Allen & Hanburys Ltd. June
‘77 D. Collin first prepares ranitidine hydrochloride
(RHCl)
US patent 4,128,658 patent (‘658 patent) is granted in
1978.
Ranitidine HCl
15.4.80 Glaxo (serendipitously) discovers new
polymorph, designated Form 2
(US) Patent applied for 10.81; granted 6.85 as patent
4,521,431 (‘431 patent)
Advantage is ‘favourable filtration and drying
characteristics…’

30. Each solid form of a pharmaceutical
can be patented. It is, then, critically
important that the company developing
the drug know all of the forms.

31. “There are many mysteries of nature
that we have not solved. Hurricanes, for
example, continue to occur and often
cause massive devastation. We know
that it will probably happen. But not
why or when. Unfortunately, there is
nothing that we can do today to
prevent a hurricane from striking any
community or polymorphism from
striking any drug.”

32. REFERENCES
1. D. Mangin, F. Puel, S. Veesler, Org Process Res. Dev. 13 (2009)
1241-1253.
2. M. Kitamura, J. Crystal Growth 237–239 (2002) 2205–2214.
3. J. D. Dunitz, J. Bernstein, Acc. Chem. Res. 28 (1995) 193-200.
4. Y. Diao, K. E. Whaley, M. E. Helgeson, M. A. Woldeyes, P. S.
Doyle, A. S. Myerson, T. A. Hatton, B. L. Trout J. Am. Chem. Soc.
134 (2012) 673−684.
5. M. Klimakow, K. Rademann, F. Emmerling, Cryst. Growth Des.
10 (2006) 2693-2698.

33. 6. J.Lu, X. J.Wang, X. Yang, C. B. Ching, Cryst. Growth Des. 7
(2007) 1590-1598.
7. M. Kitamura, T. Ishizu, J. Crystal Growth 192 (1998) 225.
8. M. Kitamura, T. Ishizu, J. Crystal Growth 209 (2000) 138.
9. T. Threlfall, Org. Process Res. Dev. 4 (2000) 384.
10. C. Desgranges, J. Delhommelle, J. Am. Chem. Soc. 128
(2006) 15104−15105.
11. J. Bernstein, Cryst. Growth Des. 11 (2011) 632−650.
12. A. Singh, I. S. Lee, A. S. Myerson, Cryst. Growth Des. 9 (2009)
1182−1185.