Pharmaceutical Cocrystals: An Overview

Authors

  • Jagdish Kumar Rawal Bhupal Noble’s College of Pharmacy, Bhupal Noble's University, Udaipur
  • Dr. Anshu Sharma Bhupal Noble’s College of Pharmacy, Bhupal Noble's University, Udaipur

DOI:

https://doi.org/10.22270/ajprd.v13i3.1580

Abstract

Poor aqueous solubility and low oral bioavailability of an active pharmaceutical ingredient are the major constraints during the development of new product. Various approaches have been used for enhancement of solubility of poorly aqueous soluble drugs, but success of these approaches depends on physical and chemical nature of molecules being developed. Cocrystallization of drug substances offers a great opportunity for the development of new drug products with superior physicochemical such as melting point, tabletability, solubility, stability, bioavailability and permeability, while preserving the pharmacological properties of the active pharmaceutical ingredient. Cocrystals are multicomponent systems in which two components, an active pharmaceutical ingredient and a coformer were present in stoichiometric ratio and bonded together with non-covalent interactions in the crystal lattice. This review article presents a systematic overview of pharmaceutical cocrystals. Differences between cocrystals with salts, solvates and hydrates are summarized along with the advantages of cocrystals with examples. The theoretical parameters underlying the selection of coformers and screening of cocrystals have been summarized and different methods of cocrystal formation and evaluation have been explained.

 

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Author Biographies

Jagdish Kumar Rawal, Bhupal Noble’s College of Pharmacy, Bhupal Noble's University, Udaipur

Bhupal Nobles College of Pharmacy, Bhupal Noble's University, Udaipur

Dr. Anshu Sharma, Bhupal Noble’s College of Pharmacy, Bhupal Noble's University, Udaipur

Bhupal Nobles College of Pharmacy, Bhupal Noble's University, Udaipur

References

Desiraju GR. Supramolecular synthons in crystal engineering—a new organic synthesis. Angewandte Chemie International Edition in English. 1995 Nov 17;34(21):2311-27.

Desiraju GR. Crystal engineering: a holistic view. Angewandte Chemie International Edition. 2007 Nov 12; 46(44):8342-56.

Desiraju GR. Chemistry beyond the molecule. Nature. 2001 Jul; 412(6845):397-400.

Steed JW, Atwood JL. Supramolecular chemistry. John Wiley & Sons; 2013 May 21.

Gavezzotti A. Crystal packing of hydrocarbons. Effects of molecular size, shape and stoichiometry. Acta Crystallographica Section B: Structural Science. 1990 Apr 1; 46(2):275-83.

Anderson KM, Probert MR, Goeta AE, Steed JW. Size does matter—the contribution of molecular volume, shape and flexibility to the formation of co-crystals and structures with Z′> 1. CrystEngComm. 2011;13(1):83-7.

Dunitz JD, Filippini G, Gavezzotti A. Molecular shape and crystal packing: a study of C12H12 isomers, real and imaginary. Helvetica Chimica Acta. 2000 Sep 6;83(9):2317-35.

Gavezzotti A, Filippini G. Self-organization of small organic molecules in liquids, solutions and crystals: static and dynamic calculations. Chemical Communications. 1998(3):287-94.

Aakeröy CB, Sinha AS, Epa KN, Chopade PD, Smith MM, Desper J. Structural chemistry of oximes. Crystal growth & design. 2013 Jun 5;13(6):2687-95.

Adams CJ, Haddow MF, Lusi M, Orpen AG. Crystal engineering of lattice metrics of perhalometallate salts and MOFs. Proceedings of the National Academy of Sciences. 2010 Sep 14;107(37):16033-8.

Merz K, Vasylyeva V. Development and boundaries in the field of supramolecular synthons. CrystEngComm. 2010;12(12):3989-4002.

Kavuru P, Aboarayes D, Arora KK, Clarke HD, Kennedy A, Marshall L, Ong TT, Perman J, Pujari T, Wojtas Ł, Zaworotko MJ. Hierarchy of supramolecular synthons: persistent hydrogen bonds between carboxylates and weakly acidic hydroxyl moieties in cocrystals of zwitterions. Crystal growth & design. 2010 Aug 4;10(8):3568-84.

Shattock TR, Arora KK, Vishweshwar P, Zaworotko MJ. Hierarchy of supramolecular synthons: persistent carboxylic acid••• pyridine hydrogen bonds in cocrystals that also contain a hydroxyl moiety. Crystal growth and design. 2008 Dec 3;8(12):4533-45.

Khan M, Enkelmann V, Brunklaus G. O− H••• N heterosynthon: a robust supramolecular unit for crystal engineering. Crystal Growth and Design. 2009 May 6;9(5):2354-62.

Takusagawa F, Shimada A. Isonicotinic acid. Acta Crystallographica Section B: Structural Crystallography and Crystal Chemistry. 1976 Jun 15;32(6):1925-7.

Desiraju GR. Crystal and co-crystal. CrystEngComm. 2003 Nov 14;5(82):466-7.

Dunitz JD. Crystal and co-crystal: a second opinion. CrystEngComm. 2003 Dec 9;5(91):506-.

Friščić T, MacGillivray LR. Modularity in organic solid state and supramolecular chemistry. Croatica chemica acta. 2006 Jul 19;79(2):327-33.

Sokolov AN, Friščić T, MacGillivray LR. Enforced face-to-face stacking of organic semiconductor building blocks within hydrogen-bonded molecular cocrystals. Journal of the American Chemical Society. 2006 Mar 8;128(9):2806-7.

Eger C, Norton DA. Androgenic steroid complexes with p-Bromophenol. Nature. 1965 Dec;208(5014):997-9.

Bhatt PM, Desiraju GR. Co-crystal formation and the determination of absolute configuration. CrystEngComm. 2008;10(12):1747-9.

Eccles KS, Deasy RE, Fábián L, Maguire AR, Lawrence SE. The use of co-crystals for the determination of absolute stereochemistry: An alternative to salt formation. The Journal of organic chemistry. 2011 Feb 18;76(4):1159-62.

Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Crystal growth and design. 2009 Jun 3;9(6):2950-67.

Vishweshwar P, McMahon JA, Peterson ML, Hickey MB, Shattock TR, Zaworotko MJ. Crystal engineering of pharmaceutical co-crystals from polymorphic active pharmaceutical ingredients. Chemical communications. 2005(36):4601-3.

Bucar DK, Henry RF, Lou X, Duerst RW, MacGillivray LR, Zhang GG. Cocrystals of caffeine and hydroxybenzoic acids composed of multiple supramolecular heterosynthons: screening via solution-mediated phase transformation and structural characterization. Crystal Growth and Design. 2009 Apr 1;9(4):1932-43.

Blagden N, Berry DJ, Parkin A, Javed H, Ibrahim A, Gavan PT, De Matos LL, Seaton CC. Current directions in co-crystal growth. New Journal of Chemistry. 2008;32(10):1659-72.

Babu NJ, Nangia A. Solubility advantage of amorphous drugs and pharmaceutical cocrystals. Crystal Growth & Design. 2011 Jul 6;11(7):2662-79.

Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Crystal growth and design. 2009 Jun 3;9(6):2950-67.

Trask AV, Jones W. Crystal engineering of organic cocrystals by the solid-state grinding approach. InOrganic solid state reactions 2005 Jan 1 (pp. 41-70). Springer, Berlin, Heidelberg.

Weyna DR, Shattock T, Vishweshwar P, Zaworotko MJ. Synthesis and structural characterization of cocrystals and pharmaceutical cocrystals: mechanochemistry vs slow evaporation from solution. Crystal Growth and Design. 2009 Feb 4;9(2):1106-23.

Chen J, Sarma B, Evans JM, Myerson AS. Pharmaceutical crystallization. Crystal growth & design. 2011 Apr 6;11(4):887-95.

Braga D, Giaffreda SL, Grepioni F, Pettersen A, Maini L, Curzi M, Polito M. Mechanochemical preparation of molecular and supramolecular organometallic materials and coordination networks. Dalton transactions. 2006(10):1249-63.

Jayasankar A, Somwangthanaroj A, Shao ZJ, Rodríguez-Hornedo N. Cocrystal formation during cogrinding and storage is mediated by amorphous phase. Pharmaceutical research. 2006 Oct 1;23(10):2381-92.

Aakery CB, Salmon DJ. Building co-crystals with molecular sense and supramolecular sensibility. CrystEngComm, 2005, 7(72), 439–448

Miroshnyk I, Mirza S, Sandler N. Pharmaceutical co-crystals–an opportunity for drug product enhancement. Expert opinion on drug delivery. 2009 Apr 1;6(4):333-41.

McMohan JA. Crystal engineering of novel pharmaceutical forms. Master of Science thesis, Department of Chemistry, University of South Florida, USA, 2006.

Jones W, Motherwell WS, Trask AV. Pharmaceutical cocrystals: an emerging approach to physical property enhancement. MRS bulletin. 2006 Nov;31(11):875-9.

Bhogala BR, Nangia A. Ternary and quaternary co-crystals of 1, 3-cis, 5-cis-cyclohexanetricarboxylic acid and 4, 4′-bipyridines. New Journal of Chemistry. 2008; 32(5):800-7.

Yao J, Chen JM, Xu YB, Lu TB. Enhancing the solubility of 6-mercaptopurine by formation of ionic cocrystal with zinc trifluoromethanesul fonate: single-crystal-to-single-crystal transformation. Crystal growth & design. 2014 Oct 1; 14(10):5019-25.

Braga D, Grepioni F, Maini L, Prosperi S, Gobetto R, Chierotti MR. From unexpected reactions to a new family of ionic co-crystals: the case of barbituric acid with alkali bromides and caesium iodide. Chemical communications. 2010 Oct 12; 46(41):7715-7.

Published

2025-06-15

How to Cite

Jagdish Kumar Rawal, & Dr. Anshu Sharma. (2025). Pharmaceutical Cocrystals: An Overview. Asian Journal of Pharmaceutical Research and Development, 13(3), 208–217. https://doi.org/10.22270/ajprd.v13i3.1580