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Abstract：
Semisolids constitute a significant proportion of topical pharmaceutical dosage forms available on the market, with creams being considered profitable systems for releasing active substances into the skin. This work aimed at the development of a generic Clotrimazole topical cream, based on the assumptions that assist the development of such formulations. First, the critical parameters to obtain a final formulation as similar as possible to the reference product were defined. Then, the percentages of cetyl palmitate and octyldodecanol were identified as critical variables and chosen for optimization in further studies. A \"quality by design\" approach was then used to identify the effect of process variability on the structural and functional similarity (Q3) of the generic product qualitatively (Q1) and quantitatively (Q2). A two-factor central composite orthogonal design was applied and eleven different formulations were developed and subjected to physicochemical characterization and product performance studies. The results were used to estimate the influence of the two variables in the variation of the responses, and to determine the optimum point of the tested factors, using a design space approach. Finally, an optimized formulation was obtained and analysed in parallel with the reference. The obtained results agreed with the prediction of the chemometric analysis, validating the reliability of the developed multivariate models. The in vitro release and permeation results were similar for the reference and the generic formulations, supporting the importance of interplaying microstructure properties with product performance and stability. Lastly, based on quality targets and response constraints, optimal working conditions were successfully achieved.
摘要：
半固体在市场上可获得的局部药物剂型中占很大比例，面霜被认为是释放活性物质进入皮肤的有利可图的系统。这项工作旨在开发一种通用的克霉唑外用乳膏，基于有助于开发此类配方的假设。首先,定义了获得与参比产品尽可能相似的最终制剂的关键参数。然后，棕榈酸十六烷基酯和辛基十二烷醇的百分比被确定为关键变量，并在进一步的研究中选择进行优化。然后使用“设计质量”方法从定性（Q1）和定量（Q2）上确定过程可变性对通用产品的结构和功能相似性（Q3）的影响。应用了双因素中心复合正交设计，开发了11种不同的配方，并进行了物理化学表征和产品性能研究。结果用于估计两个变量在响应变化中的影响，并确定测试因素的最佳点，使用设计空间的方法。最后,获得了优化的配方，并与参考平行进行了分析。获得的结果与化学计量学分析的预测一致，验证开发的多变量模型的可靠性。参考和通用制剂的体外释放和渗透结果相似，支持将微观结构性能与产品性能和稳定性相互作用的重要性。最后,基于质量目标和响应约束，成功实现了最佳工作条件。
