pH-Dependent Solubility of Indomethacin–Saccharin and Carbamazepine–Saccharin Cocrystals in Aqueous Media

Abstract

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.

Solubility Enhancement of Lornoxicam by Crystal Engineering

“…The maximum aqueous solubility was obtained with lornoxicamsaccharin sodium cocrystals (F18), which might have resulted from changes in the molecular attributes due to non-covalent interaction in cocrystals. Saccharin has been reported as typical coformer in the literature for improving solubility of the parent API and also to make sweet cocrystal owing its sweetening property [32,33] . The more hydrophilic nature of coformer as compared to the constituent drugs, and therefore such selective drug solubilisation is generally observed with solubilizing agents (coformer) in aqueous media [34] .…”

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

“…Several excellent books and reviews serve as background material for the commentary covering the solubility of druglike molecules: general coverage of solubility [7][8][9][10]; salt formation/selection [11][12][13][14][15][16]; polymorphism [17][18][19][20]; analysis of saturated solution speciation [21][22][23][24][25][26][27]; dissolution/solubility of cocrystals [28][29][30][31][32][33][34][35][36][37]; anhydrous forms versus hydrates [16,38,39].…”

Cocristais: uma estratégia promissora na área farmacêutica

“…9 Neste caso, a adição de agentes solubilizantes do fármaco, para diminuir a vantagem da solubilidade, bem como de inibidores de cristalização, podem ser introduzidos ao meio ou à formulação a fim de evitar ou reduzir as conversões. 8 Outro fator interessante é que a solubilidade dos cocristais pode ser modulada de modo que fique dentro ou fora da região de estabilidade dos cocristais, dependendo da composição do meio como pH, [10][11][12][13] presença de aditivos, [14][15][16][17] concentração de coformador, 18 entre outras.…”

“…Estudos com diversos cocristais que demonstram este comportamento encontram-se reportados na literatura. [10][11][12]101 Para um cocristal com componentes ionizáveis, a solubilidade é governada pelo produto de solubilidade (K sp ), constantes de ionização (K a ), e o pH da solução. 9,100 Na maioria dos casos, os valores de K a são conhecidos e o K sp pode ser calculado a partir da solubilidade do cocristal experimentalmente medida em um determinado pH.…”

“…[14][15][16]27,106,107 Um exemplo interessante é o cocristal de indometacina-sacarina (IND-SAC), cuja vantagem da solubilidade, 26 vezes maior do que a indometacina em pH 2, 11 é eliminada na presença de lauril sulfato de sódio, Brij 99 ou Tween 80, onde o cocristal apresenta menor solubilidade. 11,107 Os agentes solubilizantes podem, de fato, aumentar a solubilidade de ambos, cocristal e fármaco, porém a razão da solubilização (S cocristal /S fármaco ) é variável, dependendo da natureza e da concentração destes agentes.…”