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Uday,
PhD student,
Dr. Simon E. Lawrence research group,
School of Chemistry,
University College Cork, Cork
1

Solid State Chemistry
 Study of the synthesis, structure, and properties of solid phase materials and their
characterization.
 Different solid state forms have diverse physicochemical properties e.g. solubility, stability,
melting point, compressibility etc.
J. Lu and S. Rohani, Curr. Med. Chem., 2009, 16, 884
2

Introduction to Solid State Chemistry of Drugs
 80% of the drugs are available in market in the form of tablets and capsules
 Out of this 40% drugs having solubility and stability problems
 80% of drugs which are in the pipeline (New Chemical Entities) also have solubility problems.
 Conventional methods for improving solubility and stability are polymorphs, amorphous forms
and salts.
 Salts confer dual advantages of solubility and stability (generally have high melting points).
 Drawbacks of salt formulation are:
Not all APIs can be made salts – lack of ionizable or weakly ionizable functional groups
They tend to be hygroscopic
N. J. Babu and A. Nangia, Cryst. Growth Des., 2011, 11, 2662;
P. H. Stahl and C. G. Wermuth, Eds., Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley-VCH, 2002
3

Polymorphism
 “Polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least
two different arrangements of the molecules of that compound in the solid state”. (McCrone , JPS, 1965)
Types of Polymorphism
(a) Conformational polymorphism
(b) Synthon polymorphism and
(c) Packing polymorphism
Importance of Polymorphism
 Alter various physicochemical properties.
 Polymorphs are patentable.
Conformational Polymorphs
Packing polymorphs
cisoid
transoid
Packing Polymorphs
Conformational Isomorphs,
A. Nangia, Acc. Chem. Res., 2008, 41, 595
Conformational Polymorphs
Synthon Polymorphs
Polymorph i
Polymorph ii
Polymorph iii
Polymorph iv
v
Polymorph vi Polymorph vii
4

New Polymorphs of Curcumin
Two new crystalline forms 2 and 3 and an
amorphous of Curcumin were discovered.
1. But aqueous solubility (8.7
mg/L) is less, hence
bioavailability.
2. It is low soluble in acidic
medium and decomposes in
alkaline medium.
3. New polymorphs were
attempted to improve solubility.
P. Sanphui, N. R. Goud, U. B. R. Khandavilli, S. Bhanoth and A. Nangia, Chem. Commun., 2011, 47, 5013 5
Ruby et al. Cancer Lett. 1995, 94, 79, Anand et al. Mol. Pharmaceutics. 2007, 4, 807.

Cocrystal Technology
 A recent approach for modulating the physicochemical properties of drugs is through ‘cocrystals’.
A Cocrystal is a multi-component solid-state assembly of two or more compounds held together by
intermolecular interactions, particularly hydrogen bonds.
A Pharmaceutical Cocrystal is a multi-component solid involving an API (Active Pharmaceutical
Ingredient) and a GRAS (Generally Regarded As Safe) substance.
Carbamazepine, an anti-epileptic drug, is a non-ionizable drug and has low stability and dissolution rate.
Carbamazepine-Saccharin cocrystal has improved properties in terms of stability and dissolution rate.
 Art
 New materials - properties
 New/ alternate solid forms of drugs
 Intellectual Property
N H
O
O
N
H
acid dimer synthon amide dimer synthon
33% 35%
O H
O
O
N
H
O H
O
O
O
O
H
H
O H N
Homosynthon
acid-pyridine synthon acid-amide synthon
47%
Heterosynthon
90%
Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950;
M. B. Hickey et al. Eur. J. Pharm. Biopharm. 2007, 67, 112 ;
N. J. Babu, L. S. Reddy, S. Aitipamula and A. Nangia, Chem. Asian. J., 2008, 3, 1122
6

8
Temozolomide hydrocloride dihydrate
 Temolomide is a prodrug and used as an anti cancer drug and is reported to have
storage related stability problems.
We successfully stabilized the drug by making its hydrochloride dihydrate salt.
 In the crystal structure of the salt, there are two Temozolomide molecules of which
one is protonated at the imidazole N2, four water molecules of which one is a
hydronium ion (O8 water), and two chloride ions in the asymmetric unit.
Babu, N. J.; Sanphui. P.; Nangia, A. Chem.–Asian J., 2012, 7, 2274;
Babu, N. J.; Sanphui, P.; Nath, N. K.; Khandavilli, U. B. R.; Nangia, A. CrystEngComm, 2013, 15, 666

9
Overall conclusions
 Solubility, stability and bioavailability are important for pharmacological
action of a drug molecule.
 Polymorphs can show significant variations in physicochemical properties of
molecules and optimization of a polymorph is a challenge.
 Amorphous forms can show good solubility and bioavailability. But, they are
metastable and can convert to crystalline phases with time.
 Salts confer dual advantage of solubility and stability but all the molecules
cannot able made salts. Further, they tend to be hygroscopic.
 Co-crystal technology is a recent approach to improve the various properties
of a molecule devoid of ionizable functional groups.
 My current research concentrates on the enantiopurity of various organic
compounds through cocrystal technology.

Thank you very
much for your kind
attention
10

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