Uday Khandavilli,PhD student,School of Chemistry,University College Cork, Cork

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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 groupsThey 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

Introduction to Solid State Chemistry of Drugs

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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)

A. Nangia, Acc. Chem. Res., 2008, 41, 595

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

Conformational Polymorphs

Synthon Polymorphs

Packing polymorphs

Conformational Isomorphs,

Polymorph iPolymorph ii

Polymorph iii

Polymorph iv

v

Polymorph vi Polymorph vii

cisoid

transoid

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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, 50134

New Polymorphs of Curcumin

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.

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

Art New materials - properties New/ alternate solid forms of drugs Intellectual Property

O

N H

N

O

H

O

O H

N

O

H

O

O H N

H

O

O H

O

O

H

33% 35%Homosynthon

47%

Heterosynthon

90%

acid dimer synthon amide dimer synthon

acid-pyridine synthon acid-amide synthon

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Spring and Parachute model

Why cocrystals show higher solubility than API?

The spring and parachute concept to achieve high apparent solubility for insoluble drugs

Possible fate of pharmaceutical cocrystals in dissolution medium

N. J. Babu and A. Nangia, Cryst. Growth Des., 2011, 11, 2662;D. J. Good and N. Rodríguez-Hornedo, Cryst. Growth Des., 2009, 9, 2252

Generally high soluble coformer facilitates high solubility/fast dissolution in a cocrystal and vice-versa as per the well known as ‘coformer solubility rule’.

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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

Fast Dissolving Curcumin Cocrystals

Color changes from yellow in Curcumin to dark red or brown in cocrystals are due to more effective conjugation and planarity.

Since there is only moderate improvement in solubility through polymorphs, cocrystals were attempted with high water soluble phenol coformers to improve solubility and therefore bioavailability.

P. Sanphui, N. R. Goud, U. B. R. Khandavilli and A. Nangia, Cryst. Growth Des., 2011, 11, 4135 8

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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

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