Badawy Sherif I Farag, Hussain Munir A
Bristol-Myers Squibb Pharmaceutical Research Institute, New Brunswick, New Jersey, USA.
J Pharm Sci. 2007 May;96(5):948-59. doi: 10.1002/jps.20932.
There are many reports in the literature referring to the effect of microenvironmental pH on solid dosage form performance, particularly stability and dissolution profiles. Several techniques have been proposed for the measurement of the microenvironmental pH. Those techniques use certain assumptions and approximations and many of them employ a solution calibration curve of a probe to predict hydrogen ion activity in a substantially dry solid. Despite the limitation of the methodology, it is clear from the literature that microenvironmental pH has a significant impact on stability of compounds which demonstrate pH dependent stability in solution. Degradation kinetics of such compounds, and in some cases degradation profile as well, are dependent on the microenvironmental pH of the solid. Modulation of the microenvironmental pH through the use of pH modifiers can hence prove to be a very effective tool in maximizing solid dosage form stability. Judicial selection of the appropriate pH modifier, its concentration and the manufacturing process used to incorporate the pH modifier is necessary to enhance stability. Control of microenvironmental pH to maximize stability can be achieved without the use of pH modifier in some cases if an appropriate counter ion is used to provide an inherently optimal pH for the salt. Microenvironmental pH modulation was also shown to control the dissolution profile of both immediate and controlled release dosage forms of compounds with pH dependent solubility. The pH modifiers have been used in conjunction with high energy or salt forms in immediate release formulations to minimize the precipitation of the less soluble free form during initial dissolution. Additionally, pH modifiers were utilized in controlled release dosage forms of weakly basic drugs which exhibit diminished release in dissolution media with high pH. The incorporation of acidic pH modifiers in the controlled release formulation increases the solubility of the basic drug even as the high pH dissolution medium enters into the dosage form hence increasing drug release rate.
文献中有许多报道提及微环境pH对固体剂型性能的影响，特别是稳定性和溶出曲线。已经提出了几种测量微环境pH的技术。这些技术使用了某些假设和近似值，其中许多技术采用探针的溶液校准曲线来预测基本上干燥的固体中的氢离子活性。尽管该方法存在局限性，但从文献中可以清楚地看出，微环境pH对在溶液中表现出pH依赖性稳定性的化合物的稳定性有重大影响。此类化合物的降解动力学，以及在某些情况下的降解曲线，均取决于固体的微环境pH。因此，通过使用pH调节剂来调节微环境pH可以证明是最大化固体剂型稳定性的非常有效的工具。为了提高稳定性，必须谨慎选择合适的pH调节剂、其浓度以及用于加入pH调节剂的制造工艺。在某些情况下，如果使用适当的抗衡离子为盐提供固有的最佳pH，则无需使用pH调节剂即可实现对微环境pH的控制以最大化稳定性。微环境pH调节还被证明可以控制具有pH依赖性溶解度的化合物的速释和控释剂型的溶出曲线。在速释制剂中，pH调节剂已与高能或盐形式结合使用，以尽量减少初始溶解过程中较难溶解的游离形式的沉淀。此外, pH调节剂被用于弱碱性药物的控释剂型中，这些药物在高pH值的溶出介质中释放减少。在控释制剂中加入酸性pH调节剂可增加碱性药物的溶解度，即使高pH值的溶出介质进入剂型，从而提高药物释放速率。
