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E activity CS8013

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University College Cork
University College Cork

Uday is a PhD student studying solid state chemistry in Dr. Simon Lawrence's research group. Solid state chemistry involves studying the synthesis, structure, and properties of materials in solid form. Over 80% of drugs are available as tablets or capsules, but 40% have issues with solubility and stability. Polymorphism, where compounds can exist in multiple solid forms, can impact properties and is important to drug development. Uday's current research focuses on using cocrystal technology to improve enantiopurity of organic compounds.

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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
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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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E activity CS8013

  • 1. Uday, PhD student, Dr. Simon E. Lawrence research group, School of Chemistry, University College Cork, Cork 1
  • 2. 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
  • 3. 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
  • 4. 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
  • 5. 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.
  • 6. 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
  • 7. 7
  • 8. 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. 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.
  • 10. Thank you very much for your kind attention 10