pH-Dependent Solubility of Indomethacin鈥揝accharin and Carbamazepine鈥揝accharin Cocrystals in Aqueous Media

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• 作者：Amjad Alhalaweh ; Lilly Roy ; Na铆r Rodr铆guez-Hornedo ; Sitaram P. Velaga
• 刊名：Molecular Pharmaceutics
• 出版年：2012
• 出版时间：September 4, 2012
• 年：2012
• 卷：9
• 期：9
• 页码：2605-2612
• 全文大小：343K
• 年卷期：v.9,no.9(September 4, 2012)
• ISSN：1543-8392

文摘

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鈥搒accharin (IND鈥揝AC) and carbamazepine鈥搒accharin (CBZ鈥揝AC) enhance solubility and impart a pH-sensitivity different from that of the drugs. IND鈥揝AC exhibited solubilities 13 to 65 times higher than IND at pH values of 1 to 3, whereas CBZ鈥揝AC 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.

Keywords:

p://pubs.acs.org/action/doSearch?action=search&searchText=cocrystal&qsSearchArea=searchText">cocrystal; p://pubs.acs.org/action/doSearch?action=search&searchText=solubility&qsSearchArea=searchText">solubility; p://pubs.acs.org/action/doSearch?action=search&searchText=indomethacin&qsSearchArea=searchText">indomethacin; p://pubs.acs.org/action/doSearch?action=search&searchText=carbamazepine&qsSearchArea=searchText">carbamazepine; p://pubs.acs.org/action/doSearch?action=search&searchText=saccharin&qsSearchArea=searchText">saccharin; p://pubs.acs.org/action/doSearch?action=search&searchText=pH&qsSearchArea=searchText">pH; p://pubs.acs.org/action/doSearch?action=search&searchText=solubility&qsSearchArea=searchText">solubility; p://pubs.acs.org/action/doSearch?action=search&searchText=eutectic+point&qsSearchArea=searchText">eutectic point