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pH-dependent solubility of indomethacin-saccharin and carbamazepine-saccharin cocrystals in aqueous media
Luleå University of Technology, Department of Health Sciences, Medical Science.
Department of Pharmaceutical Sciences, University of Michigan.
Department of Pharmaceutical Sciences, University of Michigan.
Luleå University of Technology, Department of Health Sciences, Medical Science.ORCID iD: 0000-0002-0654-5410
2012 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 9, no 9, 2605-2612 p.Article in journal (Refereed) Published
Abstract [en]

Cocrystals constitute an important class of pharmaceutical solids for their remarkable ability to modulate solubility and pH dependence of water insoluble drugs. Here we show how cocrystals of indomethacin-saccharin (IND-SAC) and carbamazepine-saccharin (CBZ-SAC) enhance solubility and impart a pH-sensitivity different from that of the drugs. IND-SAC exhibited solubilities 13 to 65 times higher than IND at pH values of 1 to 3, whereas CBZ-SAC exhibited a 2 to 10 times higher solubility than CBZ dihydrate. Cocrystal solubility dependence on pH predicted from mathematical models using cocrystal K(sp), and cocrystal component K(a) values, was in excellent agreement with experimental measurements. The cocrystal solubility increase relative to drug was predicted to reach a limiting value for a cocrystal with two acidic components. This limiting value is determined by the ionization constants of cocrystal components. Eutectic constants are shown to be meaningful indicators of cocrystal solubility and its pH dependence. The two contributions to solubility, cocrystal lattice and solvation, were evaluated by thermal and solubility determinations. The results show that solvation is the main barrier for the aqueous solubility of these drugs and their cocrystals, which are orders of magnitude higher than their lattice barriers. Cocrystal increase in solubility is thus a result of decreasing the solvation barrier compared to that of the drug. This work demonstrates the favorable properties of cocrystals and strategies that facilitate their meaningful characterization.

Place, publisher, year, edition, pages
2012. Vol. 9, no 9, 2605-2612 p.
National Category
Other Health Sciences
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Health Science
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URN: urn:nbn:se:ltu:diva-11574DOI: 10.1021/mp300189bLocal ID: a94f40e2-ca71-444e-bfa1-0e556fa0ad90OAI: oai:DiVA.org:ltu-11574DiVA: diva2:984524
Note
Validerad; 2012; 20120827 (andbra)Available from: 2016-09-29 Created: 2016-09-29 Last updated: 2017-11-21Bibliographically approved

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