Abstract：
Since 3D printing technology is an emerging field in pharmaceutical technology, the present study aimed at the development of a mixed-mode liquid chromatographic method for the separation and determination of hydrochlorothiazide, diltiazem, and propranolol to investigate their in-vitro release performance from 3D printed tablets. Due to the unique properties of the mixed-mode stationary phase, the three drugs were separated in less than 8 min under isocratic elution. Method development was accomplished following the Analytical Quality by Design principles and was evaluated using risk assessment and multivariate analysis. The influences of critical method parameters on critical method attributes (were screened using a 2-level fractional factorial design and subsequently optimized through a central composite design. The method operable design region was approved by the establishment of a robust zone using Monte Carlo simulation and capability analysis. The validation of the HPLC method was performed based on the total error concept. The relative bias was varied between ─ 11.6 % and 10.5 % and the RSD values for repeatability and intermediate precision were below 4.4 % in all cases. The limits of detection (LOD) ranged between 0.17 - 0.90 μg/mL and were adequate for the specific application. The developed method was successfully applied to the analysis of the studied drugs in in-vitro drug release samples obtained from 3D-printed tablets combining the above-mentioned active pharmaceutical ingredients (APIs).
摘要：
由于3D打印技术是制药技术中的新兴领域，本研究旨在开发用于分离和测定氢氯噻嗪的混合模式液相色谱方法，地尔硫卓,和普萘洛尔，以研究其在3D打印片剂中的体外释放性能。由于混合模式固定相的独特性质，在等度洗脱下，三种药物在不到8分钟的时间内分离。方法开发是根据设计原则的分析质量完成的，并使用风险评估和多变量分析进行评估。关键方法参数对关键方法属性的影响（使用2级分数阶乘设计进行筛选，然后通过中央复合设计进行优化。通过使用蒙特卡洛模拟和能力分析建立稳健区域，批准了该方法的可操作设计区域。基于总误差概念进行HPLC方法的验证。相对偏差在11.6％和10.5％之间变化，重复性和中间精度的RSD值在所有情况下均低于4.4％。检测限（LOD）在0.17-0.90μg/mL之间，足以满足特定应用。所开发的方法已成功应用于分析从结合上述活性药物成分（API）的3D打印片剂获得的体外药物释放样品中的研究药物。
