Difference in physico-pharmaceutical properties between crystalline and noncrystalline 9,3"-diacetylmidecamycin.

Abstract

The noncrystalline solid form 9, 3"-diacetylmidecamycin (MOM), a new macrolide antibiotic obtained by chemical modification of midecamycin, was prepared by spraydrying and the difference in physico-chemical properties between the crystalline and noncrystalline forms was investigated. In differential scanning calorimetry (DSC) measurements, the noncrystalline solid always showed two DSC peaks in the curves ; one exothermic and the other endothermic. These are attributable to crystallization and melting, respectively. The apparent solubility of the noncrystalline solid could be determined in 0.2% hydroxypropylmethylcellulose solution but not in water and was much greater than that of the crystalline solid. When the residue during solubility measurements in water was monitored periodically by X-ray diffractometry, the noncrystalline solid was found to convert gradually to the less soluble crystalline form ; that is, the former was metastable in aqueous suspension. The conversion rate was distinctly temperature-dependent and the higher the temperature, the faster the crystallization occurred. Also, it was confirmed that the solubility of both the crystalline and the noncrystalline solid increased as the temperature was decreased. From the slopes of the van't Hoff plots, the heat of solution was estimated to be -10.9 kcal/mol for the crystalline solid and -7.3 kcal/mol for the noncrystalline solid. In addition, the appearance and the surface area of the noncrystalline solid obtained by spray-drying were examined by electron microscopy and by BET gas adsorption analysis. The spray-drying procedure increased the specific surface area to about four times that of the original crystals. It is considered that the noncrystalline MOM should have a better bioavailability than the crystalline form in vivo.