Solubility Behavior and Solution Chemistry of Indomethacin Cocrystals in Organic Solvents

被引：72
作者：
Alhalaweh, Amjad [1 ]
Sokolowski, Anders [2 ]
Rodriguez-Hornedo, Nair [3 ]
Velaga, Sitaram P. [1 ]
机构：
[1] Lulea Univ Technol, Dept Hlth Sci, S-97187 Lulea, Sweden
[2] Uppsala Univ, Dept Pharmaceut Chem, Uppsala, Sweden
[3] Univ Michigan, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA
来源：
CRYSTAL GROWTH & DESIGN | 2011年 / 11卷 / 09期
基金：
瑞典研究理事会;
关键词：
CO-CRYSTALS;
D O I：
10.1021/cg200517r
中图分类号：
O6 [化学];
学科分类号：
0703 ;
摘要：
The main objective of this study was to investigate the solubility behavior and solution chemistry of indomethacin-saccharin (IND-SAC) cocrystals in organic media. We also evaluated previously proposed models of cocrystal solubility in organic solvents. In addition, the solubility behavior of IND-SAC cocrystals was compared with that of indomethacin-nicotinamide (IND-NIC) cocrystals using the eutectic constant approach. Phase solubility diagrams of IND-SAC cocrystals in various solvents were generated and the transition concentrations, at which drug and cocrystals are in equilibrium with the solvents, were determined. The solubility of IND-SAC cocrystals was explained by the solubility product and solution complexation. The tested models were found to fit the experimental data and to adequately explain the solubility behavior of the cocrystals. The solution complexation of IND and SAC is negligible in ethyl acetate and low in methanol and ethanol. The IND-NIC cocrystals were more soluble than the IND-SAC cocrystals in all the solvents studied. The eutectic constants predicted both the solubility and the stability of the cocrystals. Understanding the solubility behavior and solution chemistry of cocrystals has important implications for the screening, scale-up, and formulation development of this solid form. Further, the determination of eutectic constants is a simple and resource sparing means of obtaining key information on cocrystal stability and solution behavior.
引用
收藏
页码：3923 / 3929
页数：7
相关论文
共 28 条
[1]   Building co-crystals with molecular sense and supramolecular sensibility [J].
Aakeröy, CB ;
Salmon, DJ .
CRYSTENGCOMM, 2005, 7 :439-448
[2]   1:1 and 2:1 Urea-Succinic Acid Cocrystals: Structural Diversity, Solution Chemistry, and Thermodynamic Stability [J].
Alhalaweh, Amjad ;
George, Sumod ;
Bostrom, Dan ;
Velaga, Sitaram P. .
CRYSTAL GROWTH & DESIGN, 2010, 10 (11) :4847-4855
[3]   Formation of Cocrystals from Stoichiometric Solutions of Incongruently Saturating Systems by Spray Drying [J].
Alhalaweh, Amjad ;
Velaga, Sitaram P. .
CRYSTAL GROWTH & DESIGN, 2010, 10 (08) :3302-3305
[4]   Crystal engineering of the composition of pharmaceutical phases.: Do pharmaceutical co-crystals represent a new path to improved medicines? [J].
Almarsson, Ö ;
Zaworotko, MJ .
CHEMICAL COMMUNICATIONS, 2004, (17) :1889-1896
[5]   Indomethacin-saccharin cocrystal:: Design, synthesis and preliminary pharmaceutical characterization [J].
Basavoju, Srinivas ;
Bostrom, Dan ;
Velaga, Sitaram P. .
PHARMACEUTICAL RESEARCH, 2008, 25 (03) :530-541
[6]  
Bethune S. J., 2009, THESIS U MICHIGAN AN
[7]   Making co-crystals - The utility of ternary phase diagrams [J].
Chiarella, Renato A. ;
Davey, Roger J. ;
Peterson, Matthew L. .
CRYSTAL GROWTH & DESIGN, 2007, 7 (07) :1223-1226
[8]   Screening strategies based on solubility and solution composition generate pharmaceutically acceptable cocrystals of carbamazepine [J].
Childs, Scott L. ;
Rodriguez-Hornedo, Nair ;
Reddy, L. Sreenivas ;
Jayasankar, Adivaraha ;
Maheshwari, Chinmay ;
McCausland, Linda ;
Shipplett, Rex ;
Stahly, Barbara C. .
CRYSTENGCOMM, 2008, 10 (07) :856-864
[9]   Formation of co-crystals: Kinetic and thermodynamic aspects [J].
Gagniere, E. ;
Mangin, D. ;
Puel, F. ;
Rivoire, A. ;
Monnier, O. ;
Garcia, E. ;
Klein, J. R. .
JOURNAL OF CRYSTAL GROWTH, 2009, 311 (09) :2689-2695
[10]   Cocrystal Eutectic Constants and Prediction of Solubility Behavior [J].
Good, David J. ;
Rodriguez-Hornedo, Nair .
CRYSTAL GROWTH & DESIGN, 2010, 10 (03) :1028-1032
123