School of Pharmacy and Pharmaceutical Sciences, University of Dublin, Trinity College, Dublin 2, Ireland.
Mol Pharm. 2011 Apr 4;8(2):532-42. doi: 10.1021/mp1003674. Epub 2011 Mar 3.
Formulations containing amorphous active pharmaceutical ingredients (APIs) present great potential to overcome problems of limited bioavailability of poorly soluble APIs. In this paper, we directly compare for the first time spray drying and milling as methods to produce amorphous dispersions for two binary systems (poorly soluble API)/excipient: sulfathiazole (STZ)/polyvinylpyrrolidone (PVP) and sulfadimidine (SDM)/PVP. The coprocessed mixtures were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and intrinsic dissolution tests. PXRD and DSC confirmed that homogeneous glassy solutions (mixture with a single glass transition) of STZ/PVP were obtained for 0.05 ≤ X(PVP) (PVP weight fraction) < 1 by spray drying and for 0.6 ≤ X(PVP) < 1 by milling (at 400 rpm), and homogeneous glassy solutions of SDM/PVP were obtained for 0 < X(PVP) < 1 by spray drying and for 0.7 ≤ X(PVP) < 1 by milling. For these amorphous composites, the value of T(g) for a particular API/PVP ratio did not depend on the processing technique used. Variation of T(g) versus concentration of PVP was monotonic for all the systems and matched values predicted by the Gordon-Taylor equation indicating that there are no strong interactions between the drugs and PVP. The fact that amorphous SDM can be obtained on spray drying but not amorphous STZ could not be anticipated from the thermodynamic driving force of crystallization, but may be due to the lower molecular mobility of amorphous SDM compared to amorphous STZ. The solubility of the crystalline APIs in PVP was determined and the activities of the two APIs were fitted to the Flory-Huggins model. Comparable values of the Flory-Huggins interaction parameter (χ) were determined for the two systems (χ = -1.8 for SDM, χ = -1.5 for STZ) indicating that the two APIs have similar miscibility with PVP. Zones of stability and instability of the amorphous dispersions as a function of composition and temperature were obtained from the Flory-Huggins theory and the Gordon-Taylor equation and were found to be comparable for the two APIs. Intrinsic dissolution studies in aqueous media revealed that dissolution rates increased in the following order: physical mix of unprocessed materials < physical mix of processed material < coprocessed materials. This last result showed that production of amorphous dispersions by co-milling can significantly enhance the dissolution of poorly soluble drugs to a similar magnitude as co-spray dried systems.
含有无定形活性药物成分（APIs）的配方具有很大的潜力，可以克服生物利用度有限的难溶性 APIs 问题。本文首次直接比较了喷雾干燥和研磨作为制备两种二元体系（难溶性 API/赋形剂）无定形分散体的方法：磺胺噻唑（STZ）/聚乙烯吡咯烷酮（PVP）和磺胺嘧啶（SDM）/PVP。共处理混合物通过粉末 X 射线衍射（PXRD）、差示扫描量热法（DSC）、傅里叶变换红外光谱（FTIR）和固有溶解试验进行了表征。PXRD 和 DSC 证实，通过喷雾干燥，当 0.05≤X（PVP）（PVP 重量分数）<1 时，STZ/PVP 获得了均匀的玻璃态溶液（具有单一玻璃转变的混合物），当 0.6≤X（PVP）<1 时，通过研磨（在 400rpm 下）获得了均匀的玻璃态溶液，通过喷雾干燥，当 0<X（PVP）<1 时，SDM/PVP 获得了均匀的玻璃态溶液，当 0.7≤X（PVP）<1 时，通过研磨获得了均匀的玻璃态溶液。对于这些无定形复合材料，特定 API/PVP 比的 T（g）值不取决于所使用的加工技术。对于所有系统，T（g）随 PVP 浓度的变化均呈单调变化，与 Gordon-Taylor 方程预测的值相匹配，表明药物与 PVP 之间没有强烈的相互作用。无定形 SDM 可以通过喷雾干燥获得，而无定形 STZ 则不能，这一事实不能仅从结晶的热力学驱动力来预测，但可能是由于与无定形 STZ 相比，无定形 SDM 的分子迁移率较低。确定了结晶 API 在 PVP 中的溶解度，并将两种 API 的活性拟合到 Flory-Huggins 模型中。对于两个系统，确定了相似的 Flory-Huggins 相互作用参数（χ）值（SDM 的 χ=-1.8，STZ 的 χ=-1.5），表明这两种 API 与 PVP 具有相似的混溶性。从 Flory-Huggins 理论和 Gordon-Taylor 方程获得了无定形分散体作为组成和温度函数的稳定性和不稳定性区域，并且对于两种 API 而言，这些区域是可比的。在水介质中的固有溶解研究表明，溶解速率的增加顺序为：未加工材料的物理混合物<加工材料的物理混合物<coprocessed 材料。最后一个结果表明，通过共研磨生产无定形分散体可以显著提高难溶性药物的溶解度，其效果与共喷雾干燥系统相似。
