Structure and solid-state chemistry of anhydrous and hydrated crystal forms of the trimethoprim-sulfamethoxypyridazine 1 : 1 molecular complex

The crystal structure of the equimolar trimethoprim (TMP) and sulfame-thoxy pyridazine (SMPD) complex in the anhydrous form (TMP.SMPD) and that of the species with 1.5 molecules of water of crystallization (TMP.SMPD.W) are rep orted in this article. X-ray powder diffraction patterns (both computer gen erated and experimental) and thermal analytical data from differential scan ning calorimetry (DSC) and thermogravimetry useful for the characterization of TMP.SMPD and TMP.SMPD.W are provided. The stability of TMP.SIMPD.W, whi ch retains its crystallographic order under 0% relative humidity (RH) condi tions at room temperature (22 degrees C) and 20 mmHg, is accounted for in t erms of crystal structure and hydrogen bonding. Transformation of TMP.SMPD to the hydrate complex by exposure to approximate to 100% RH, suspension in water, and wet granulation, and dehydration of TMP.SNIPD.W by thermal trea tment and by desiccation with methanol were investigated and tentatively in terpreted in terms of crystal properties. Interactions in the physical mixt ure of TMP and SMPD by grinding, compression, heating, and contact with wat er were also studied. Water-mediated formation of TMP.SMPD.W by wetting and metastable eutectic melting-mediated formation of TMP.SMPD by heating was demonstrated. Mechanical activation by milling makes the physical mixture p rone to solid-state transformation into dimorphic anhydrous cocrystals by s upply of thermal energy during a DSC scan. (C) 2000 Wiley-Liss, Inc, and th e American Pharmaceutical Association J Pharm Sci 89: 478-489, 2000.