Characterization of Chloramphenicol Palmitate Form C and Absorption Assessments of Chloramphenicol Palmitate Polymorphs

抄録

To clarify the thermodynamic stability of chloramphenicol palmitate polymorphic forms (form A, form B, and form C), differential scanning calorimetry and powder X-ray diffractometry at elevated temperatures were performed, and solubilities in 35% t-butanol/water mixture at various temperatures were determined. Furthermore, the effects of polymorphic forms on the plasma levels of chloramphenicol in dogs were evaluated, and the dissolution rate in the presence of sodium cholate and enzymatic hydrolysis rate in the presence of lipase were then determined to confirm the relationship between thermodynamic stability and absorption of chloramphenicol from chloramphenicol palmitate polymorphic forms. The van't Hoff plots of solubility data of the three forms indicated that thermodynamic stability was in the order form A>form B>form C. The order of thermodynamic stability of the polymorphic forms agreed well with the results of thermal analysis and powder X-ray diffraction at elevated temperatures, but was inconsistent with that previously reported by Aguiar and Zelmer. When each form was administered orally as arabic gum suspensions, the areas under the curve (AUCs) of form C and form B were respectively 2.2 times and 1.6 times those of form A. The order of AUCs of the forms corresponded well with the order of thermodynamic stability. The differences in chloramphenicol level in plasma among the polymorphic forms were due to the differences in dissolution rate, which affected the apparent enzymatic hydrolysis rate.