de Villiers Melgardt M, Mahlatji Mabatane D, van Tonder Elsa C, Malan Sarel F, Lötter Antonie P, Liebenberg Wilna
Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana 71209, USA
Drug Dev Ind Pharm. 2004 Jul;30(6):581-92. doi: 10.1081/ddc-120037489.
In an effort to produce physically stable and pharmaceutically acceptable suspensions of niclosamide, this study reports the differences in physical and chemical stability of aqueous vs. nonaqueous suspensions of a niclosamide anhydrate, two monohydrates HA and HB, a 1:1 niclosamide N,N-dimethylformamide solvate, a 1:1 niclosamide dimethyl sulfoxide solvate, a 1:1 niclosamide methanol solvate, and a 2:1 niclosamide tetraethylene glycol hemisolvate. Evaluation of aqueous and nonaqueous suspensions showed that in aqueous suspensions anhydrous, and solvated niclosamide crystal forms were transformed to a monohydrate, HA, which was reasonably stable but which did eventually transform to the most stable monohydrate HB. The order in which these crystal forms transformed to monohydrate HB were: Anhydrate > N,N-dimethylformamide > dimethyl sulfoxide > methanol > tetraethylene glycol > monohydrate HA. In a nonaqueous propylene glycol vehicle, the transformation to the monohydrous forms was not observed and on desolvation the solvated crystals transformed to the anhydrous form. In all cases, immediately upon desolvation or dehydration, the crystal structures of the desolvated materials were similar to that of the solvated materials. However, the isomorphic structures, formed after desolvation, were unstable and rehydrated or resolvated when exposed to the solvent or converted to the anhydrous form in a dry environment. The crystal forms remained chemically stable in both aqueous and nonaqueous suspensions for the length of the study.
为了制备物理稳定且药学上可接受的氯硝柳胺混悬液，本研究报告了无水氯硝柳胺、两种一水合物HA和HB、1:1氯硝柳胺N,N-二甲基甲酰胺溶剂化物、1:1氯硝柳胺二甲基亚砜溶剂化物、1:1氯硝柳胺甲醇溶剂化物以及2:1氯硝柳胺四甘醇半溶剂化物的水性混悬液与非水性混悬液在物理和化学稳定性方面的差异。对水性和非水性混悬液的评估表明，在水性混悬液中，无水和溶剂化的氯硝柳胺晶型转变为一水合物HA，其稳定性尚可，但最终确实转变为最稳定的一水合物HB。这些晶型转变为一水合物HB的顺序为：无水物＞N,N-二甲基甲酰胺＞二甲基亚砜＞甲醇＞四甘醇＞一水合物HA。在非水性丙二醇载体中，未观察到向一水合物形式的转变，并且在去溶剂化时，溶剂化晶体转变为无水形式。在所有情况下，一旦去溶剂化或脱水，去溶剂化材料的晶体结构与溶剂化材料的晶体结构相似。然而，去溶剂化后形成的同构结构不稳定，在暴露于溶剂时会重新水合或重新溶剂化，或在干燥环境中转变为无水形式。在研究期间，晶型在水性和非水性混悬液中均保持化学稳定。
