Murdande Sharad B, Pikal Michael J, Shanker Ravi M, Bogner Robin H
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269; Pfizer Global Research and Development, Groton Labs, Groton, Connecticut 06340.
J Pharm Sci. 2011 Oct;100(10):4349-56. doi: 10.1002/jps.22643. Epub 2011 May 31.
A method is described for screening compounds that inhibit crystallization in solution to enable more accurate measurement of amorphous drug solubility. Three polymers [polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose acetate succinate (HPMCAS)] were screened for their ability to inhibit the crystallization of neat amorphous drugs during measurement of solubility of the amorphous form in water. Among the polymers evaluated, HPMCAS was found to be most promising. The use of HPMCAS provided an "apparent solubility" of amorphous drugs that was closer to the theoretically calculated values. With danazol, agreement was essentially quantitative, and for griseofulvin and iopanoic acid, agreement was within a factor of two; these maximum concentrations were sustained for a period of 40-90 min. Dynamic light scattering of filtered samples (0.22 µ) revealed the presence of colloidal drug-polymer assemblies in solution (100-150 nm). The supernatant resulting from this centrifugation gradually decreased in concentration, but remained supersaturated with respect to crystalline drug for several hours. Thus, HPMCAS has been shown to be a useful additive in dissolution media to allow a more accurate determination of the solubility of fast crystallizing neat amorphous drugs, at least for the drugs studied, and it should also serve to retard crystallization in vivo and therefore, facilitate improved bioavailability.
本文描述了一种筛选能够抑制溶液中结晶的化合物的方法，以实现对无定形药物溶解度更准确的测量。筛选了三种聚合物[聚乙烯吡咯烷酮、羟丙基甲基纤维素和醋酸琥珀酸羟丙基甲基纤维素（HPMCAS）]，评估它们在测量无定形药物在水中的溶解度时抑制纯无定形药物结晶的能力。在所评估的聚合物中，发现HPMCAS最具前景。使用HPMCAS可得到更接近理论计算值的无定形药物“表观溶解度”。对于达那唑，基本达到定量一致；对于灰黄霉素和碘番酸，结果在两倍以内；这些最大浓度持续40 - 90分钟。对过滤后的样品（0.22 µm）进行动态光散射分析，结果显示溶液中存在胶体药物 - 聚合物聚集体（100 - 150 nm）。离心得到的上清液浓度逐渐降低，但相对于结晶药物仍保持数小时的过饱和状态。因此，已证明HPMCAS是溶出介质中一种有用的添加剂，至少对于所研究的药物而言，它能更准确地测定快速结晶的纯无定形药物的溶解度，并且还应有助于延缓体内结晶，从而提高生物利用度。
