Carbamazepine Co-crystal Screening with Dicarboxylic Acids Co-Crystal Formers

Authors: Syarifah Abd Rahim, Fatinah Ab Rahman, Engku N. E. M. Nasir, Noor A. Ramle

Abstract:

Co-crystal is believed to improve the solubility and dissolution rates and thus, enhanced the bioavailability of poor water soluble drugs particularly during the oral route of administration. With the existing of poorly soluble drugs in pharmaceutical industry, the screening of co-crystal formation using carbamazepine (CBZ) as a model drug compound with dicarboxylic acids co-crystal formers (CCF) namely fumaric (FA) and succinic (SA) acids in ethanol has been studied. The co-crystal formations were studied by varying the mol ratio values of CCF to CBZ to access the effect of CCF concentration on the formation of the co-crystal. Solvent evaporation, slurry and cooling crystallization which representing the solution based method co-crystal screening were used. Based on the differential scanning calorimetry (DSC) analysis, the melting point of CBZ-SA in different ratio was in the range between 188oC-189oC. For CBZ-FA form A and CBZ-FA form B the melting point in different ratio were in the range of 174oC-175oC and 185oC-186oC respectively. The product crystal from the screening was also characterized using X-ray powder diffraction (XRPD). The XRPD pattern profile analysis has shown that the CBZ co-crystals with FA and SA were successfully formed for all ratios studied. The findings revealed that CBZ-FA co-crystal were formed in two different polymorphs. It was found that CBZ-FA form A and form B were formed from evaporation and slurry crystallization methods respectively. On the other hand, in cooling crystallization method, CBZ-FA form A was formed at lower mol ratio of CCF to CBZ and vice versa. This study disclosed that different methods and mol ratios during the co-crystal screening can affect the outcome of co-crystal produced such as polymorphic forms of co-crystal and thereof. Thus, it was suggested that careful attentions is needed during the screening since the co-crystal formation is currently one of the promising approach to be considered in research and development for pharmaceutical industry to improve the poorly soluble drugs.

Keywords: Carbamazepine, co-crystal, co-crystal former, dicarboxylic acid.

Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1100525

References:

[1] N. Blagden, M. de Matas, P. T. Gavan, P. York, “Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates,” Adv. Drug Deliv. Rev., vol. 59, 2007, pp. 617–630.
[2] C. B. Aakeroy, S. Forbes, J. Desper, “Using cocrystals to systematically modulate aqueous solubility and melting behavior of an anticancer drug,” J. Am. Chem. Soc, vol. 131, 2009, pp. 17048-17049.
[3] R. Thakuriaa, A.Deloria, W. Jonesa, P. Maya, L. Royb, N. Hornedo, “Pharmaceutical cocrystals and poorly soluble drugs,” vol. 453, 2013, pp. 101– 125.
[4] N. Qiao, M. Li, W. Schlindwein, N. Malek, A. Davies, T. Gary, “Pharmaceutical cocrystals: An overview,” vol 419, 2011, pp. 1-11.4
[5] N. A. Zakiriah, “Solid phase transformation and stability of carbamazepine-saccharin co-crystal,” 2012.
[6] Z. Rahman, C. Agarabi, A. S. Zidan, S. R. Khan, M. A. Khan, “Physicomechanical and stability evaluation of carbamazepine cocrystal with nicotinamide”, AAPS PharmSciTech, vol. 12(2), 2011, pp. 693–704.
[7] L. Padrela, M. A. Rodrigues, S. P. Velaga, A. C. Fernandes, H. A. Matos, E. G. de Azevedo, “Screening for pharmaceutical cocrystals using the supercritical fluid enhanced atomization process”, J Supercrit Fluids, vol. 53(1–3), 2010, pp. 156–64.
[8] J. Wouters, L. Quere, D. E. Thurston, “Pharmaceutical salts and cocrystal. Royal Society of Chemistry”, 2011, pp. 346.
[9] M. T. Ansari, H. Pervez, M. T. Shehzad, S. S. U. Hassan, Z. Mehmood, N. H. S. Syed, M. T. Razi., G. Murtaz, “Improved Physicochemical Characteristics of Artemisinin using Succinic Acid,” Acta Poloniae Pharmaceutica ñ Drug Research, vol. 71, 2014, pp. 451-462.
[10] S. L. Childs, N. Rodríguez-Hornedo, L. S. Reddy, A. Jayasankar, C. Maheshwari, L. McCausland, R. Shipplett, B. C. Stahly, “Screening Strategies based on solubility and solution composition generate pharmaceutically acceptable cocrystals of carbamazepine,” Crystal Engineering Communication, vol. 10, 2008, pp. 856–864.
[11] J. A. McMahon, “Crystal engineering of novel pharmaceutical forms”, 2006, Graduate Theses and Dissertations.
[12] A. L. Grzesiak, M. Lang, K. Kim, A. J. Matzger, “Comparison of the Four Anhydrous Polymorphs of Carbamazepine and the Crystal Structure of Form I,” Journal of Pharmaceutical Sciences, vol. 92, 2003, pp. 2260-2271.
[13] A. V. Trask, D. A. Haynes, W. D. S. Motherwell, W. Jones, “Screening for crystalline salts via mechanochemistry,” Chem. Commun., 2005, pp. 51-53.
[14] K. Sypek, I. S. Burns, A. J. Florence, J. Sefcik, “In Situ Monitoring of Stirring Effects on Polymorphic Transformations during Cooling Crystallization of Carbamazepine,” Cryst Growth Des, vol 12, 2012, pp. 4821-4828.
[15] S. Abd Rahim, R. B. Hammond, A. Y. Sheikh, K. J. Robert, “A comparative assessment of the influence of different crystallization screening methodologies on the solid forms of carbamazepine cocrystals,” CrystEngComm, vol. 15, 2013, pp. 3862-3873.