Área de Análisis de Medicamentos, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario and Instituto de Química Rosario (IQUIR, CONICET-UNR), Suipacha 531, Rosario S2002LRK, Argentina.
Laboratorio Industrial Farmacéutico S.E. French 4950, S3006ETP, Santa Fe, Argentina.
J Pharm Sci. 2024 Apr;113(4):930-936. doi: 10.1016/j.xphs.2023.09.023. Epub 2023 Sep 30.
First-line tuberculostatic agents, Rifampicin (RIF), Isoniazid (ISH), Ethambutol (ETB), and Pyrazinamide (PZA) are generally administered as a fixed-dose combination (FDC) for improving patient adherence. The major quality challenge of these FDC products is their variable bioavailability, where RIF and its solid state are key factors. In this work, the analysis of the impact of the polymorphism in the performance of RIF in RIF-ISH and PZA-RIF-ISH combined products was carried out by an overall approach that included the development and validation of two methodologies combining near-infrared (NIR) spectroscopy and partial least squares (PLS) to the further evaluation of commercial products. For NIR-PLS methods, training and validation sets were prepared with mixtures of Form I/Form II of RIF, and the appropriate amount of ISH (for double associations) or ISH-PZA (for triple associations). The corresponding matrix of the excipients was added to the mixture of APIs to simulate the environment of each FDC product. Four PLS factors, reduced spectral range, and the combination of standard normal variate and Savitzky-Golay 1 derivative (SNV-D') were selected as optimum data pre-treatment for both methods, yielding satisfactory recoveries during the analysis of validation sets (98.5±2.0%, and 98.7±1.8% for double- and triple-FDC products, respectively). The NIR-PLS model for RIF-ISH successfully estimated the polymorphic purity of Form II in double-FDC capsules (1.02 ± 0.02w/w). On the other hand, the NIR-PLS model for RIF-ISH-PZA detected a low purity of Form II in triple FDC tablets (0.800 ± 0.021w/w), these results were confirmed by X-ray powder diffraction. Nevertheless, the triple-FDC tablets showed good performance in the dissolution test (Q=99-102%), implying a Form II purity about of 80% is not low enough to affect the safety and efficacy of the product.
一线抗结核药物利福平（RIF）、异烟肼（ISH）、乙胺丁醇（ETB）和吡嗪酰胺（PZA）通常以固定剂量组合（FDC）给药，以提高患者的依从性。这些 FDC 产品的主要质量挑战是其生物利用度的可变性，其中 RIF 和其固体状态是关键因素。在这项工作中，通过包括开发和验证两种结合近红外（NIR）光谱和偏最小二乘（PLS）的方法的整体方法，分析了 RIF 在 RIF-ISH 和 PZA-RIF-ISH 联合产品中的性能的多态性对进一步评估商业产品的影响。对于 NIR-PLS 方法，用 RIF 的 I 型/II 型的混合物以及适量的 ISH（用于双关联）或 ISH-PZA（用于三关联）制备了培训和验证集。将赋形剂的相应矩阵添加到 API 的混合物中，以模拟每个 FDC 产品的环境。选择四个 PLS 因子、减少的光谱范围以及标准正态变量和 Savitzky-Golay 1 导数（SNV-D'）的组合作为两种方法的最佳数据预处理，在验证集分析中得到了令人满意的回收率（双和三 FDC 产品分别为 98.5±2.0%和 98.7±1.8%）。RIF-ISH 的 NIR-PLS 模型成功估计了双 FDC 胶囊中二型的多晶纯度（1.02±0.02w/w）。另一方面，RIF-ISH-PZA 的 NIR-PLS 模型检测到三 FDC 片剂中二型的低纯度（0.800±0.021w/w），这些结果通过 X 射线粉末衍射得到证实。然而，三 FDC 片剂在溶出度试验中表现良好（Q=99-102%），这意味着 II 型的纯度约为 80%不足以影响产品的安全性和疗效。
