Douglas Pharma US Inc, 1035 Louis Drive, Warminster, PA, 18974, USA.
Department of Chemistry, GITAM School of Science, GITAM Deemed to be University, Hyderabad, Telangana, 502329, India.
Sci Rep. 2022 Nov 9;12(1):19138. doi: 10.1038/s41598-022-22998-0.
We report an ideal method for quantifying impurities in mycophenolate mofetil drug substances and their oral suspension preparations. We developed a systematic and eco-friendly analytical approach utilizing quality by design (QbD) and green chemistry principles. Initially, the critical method parameters (CMPs) were screened using a D-optimal design. The robust final method conditions were optimized using a systematic central composite design (CCD). Through graphical and numerical optimization, the protocol conditions were augmented. The pH of mobile phase buffer (25 mM KHPO) (MP-A), initial gradient composition (% MP-A), flow rate (mL min), and column oven temperatures (°C) are 4.05, 87, 0.4, and 30, respectively. The best possible separation between the critical pairs was achieved while using the Waters Acquity UPLC BEH C (100 × 2.1) mm, 1.7 µm analytical column. A mixture of water and acetonitrile in the ratio of 30:70 (v/v) was used as mobile phase-B for the gradient elution. The analytical method was validated in agreement with ICH and USP guidelines. The specificity results revealed that no peaks interfered with the impurities and MPM. The mean recovery of the impurities ranged between 96.2 and 102.7%, and the linearity results r > 0.999 across the range of LOQ - 150%. The precision results (%RSD) ranged between 0.8 and 4.5%. The degradation products formed during the base-induced degradation were identified as isomers of mycophenolic acid and sorbitol esters using Q-ToF LC-MS and their molecular and fragment ion peaks. The developed method eco-friendliness and greenness were assessed using analytical greenness (AGREE), green analytical procedure index (GAPI), and analytical eco score, and found it is green.
我们报告了一种用于定量测定霉酚酸酯药物及其口服混悬制剂中杂质的理想方法。我们利用质量源于设计（QbD）和绿色化学原理开发了一种系统的、环保的分析方法。首先，使用 D 最优设计筛选关键方法参数（CMP）。通过系统的中心复合设计（CCD）优化稳健的最终方法条件。通过图形和数值优化，优化了方案条件。流动相缓冲液（25 mM KHPO）（MP-A）的 pH 值、初始梯度组成（%MP-A）、流速（mL min）和柱箱温度（°C）分别为 4.05、87、0.4 和 30。使用 Waters Acquity UPLC BEH C（100×2.1）mm、1.7μm 分析柱，可实现临界对之间的最佳分离。梯度洗脱中，水和乙腈的比例为 30:70（v/v）。作为流动相-B，使用水和乙腈的混合物。分析方法符合 ICH 和 USP 指南的要求进行了验证。专属性结果表明，没有峰与杂质和 MPM 发生干扰。杂质的平均回收率在 96.2%至 102.7%之间，线性结果 r>0.999，LOQ-150%范围内。精密度结果（%RSD）在 0.8%至 4.5%之间。使用 Q-ToF LC-MS 鉴定了在碱诱导降解过程中形成的降解产物，它们是麦考酚酸的异构体和山梨糖醇酯，以及它们的分子和碎片离子峰。使用分析绿色度（AGREE）、绿色分析程序指数（GAPI）和分析生态评分评估开发方法的生态友好性和绿色性，结果发现该方法是绿色的。
