Development and Registration Department, Bosnalijek d.d., Sarajevo, Bosnia and Herzegovina.
Quality Assurance and Quality Control Department, Bosnalijek d.d., Sarajevo, Bosnia and Herzegovina.
PLoS One. 2022 Apr 4;17(4):e0266237. doi: 10.1371/journal.pone.0266237. eCollection 2022.
Formulation of solid dispersions (SDs), in which the drug substance is dissolved or dispersed inside a polymer matrix, is one of the modern approaches to increase the solubility and dissolution rate of poorly soluble active pharmaceutical ingredients (APIs), such as clopidogrel. In the form of a free base, clopidogrel is unstable under increased both high moisture and temperature, so it is most often used as its salt form, clopidogrel hydrogen sulfate (CHS).The aim of this study was the formulation, characterization, and long-term stability investigation of CHS solid dispersions, prepared with four different hydrophilic polymers (poloxamer 407, macrogol 6000, povidone, copovidone) in five API/polymer ratios (1:1, 1:2, 1:3, 1:5, 1:9). SDs were prepared by the solvent evaporation method, employing ethanol (96% v/v) as a solvent. Initial results of the in vitro dissolution test showed an increase in the amount of dissolved CHS from all prepared SD samples compared to pure CHS, corresponding physical mixtures (PMs), and commercial tablets. SDs, prepared with poloxamer 407, macrogol 6000, and copovidone, at CHS/polymer ratios 1:5 and 1:9, notably increased the amount of dissolved CHS (> 80%, after 60 min), thus they were selected for further characterization. To assess the SDs long-term stability, in vitro dissolution studies, clopidogrel content determination, differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR) were performed initially and after 12 months of long-term stability studies under controlled conditions (25°C, 60% RH) meeting the ICH guideline Q1A (R2) requirements. The clopidogrel content in the selected samples was very similar at the beginning (96.13% to 99.93%) and at the end (95.98% to 99.86%) of the conducted test. DSC curves and FT-IR spectra of all SD samples after 12 months of stability study, showed the absence of CHS crystallization, which is an indication of good stability. However, the in vitro dissolution test showed a considerable reduction in CHS released from SDs with macrogol 6000. The amount of dissolved CHS from SDs with macrogol 6000 was initially 94.02% and 92.01%, and after 12 months of stability study, only 65.13% and 49.62%. In contrast, the amount of dissolved CHS from SDs prepared with poloxamer 407 and copovidone was very similar after 12 months of the stability study compared to the initial values. Results obtained indicated the great importance of the in vitro dissolution test in determining the long-term stability and quality of SDs.
固体分散体（SDs）的配方是提高难溶性活性药物成分（API）溶解度和溶解速率的现代方法之一，例如氯吡格雷。氯吡格雷游离碱在高湿度和温度下不稳定，因此最常以其盐的形式使用，即氯吡格雷硫酸氢盐（CHS）。本研究的目的是制备 CHS 固体分散体，并对其进行表征和长期稳定性研究，使用了四种不同的亲水性聚合物（泊洛沙姆 407、聚乙二醇 6000、聚维酮、共聚维酮），API/聚合物比例为 5 种（1:1、1:2、1:3、1:5、1:9）。SDs 通过溶剂蒸发法制备，使用 96%（v/v）乙醇作为溶剂。体外溶解试验的初步结果表明，与纯 CHS、相应的物理混合物（PM）和商业片剂相比，所有制备的 SD 样品中溶解的 CHS 量都有所增加。在 CHS/聚合物比例为 1:5 和 1:9 时，用泊洛沙姆 407、聚乙二醇 6000 和共聚维酮制备的 SD 显著增加了溶解的 CHS 量（>80%，60 分钟后），因此选择它们进行进一步的表征。为了评估 SDs 的长期稳定性，进行了体外溶解研究、氯吡格雷含量测定、差示扫描量热法（DSC）和傅里叶变换红外光谱（FT-IR），最初在受控条件下（25°C、60% RH）进行了 12 个月的长期稳定性研究，符合 ICH 指南 Q1A（R2）的要求。在测试的开始和结束时，选定样品中的氯吡格雷含量非常相似（96.13%至 99.93%）和（95.98%至 99.86%）。经过 12 个月的稳定性研究，所有 SD 样品的 DSC 曲线和 FT-IR 图谱均显示 CHS 无结晶，表明稳定性良好。然而，体外溶解试验表明，具有聚乙二醇 6000 的 SD 中 CHS 的释放量显著减少。具有聚乙二醇 6000 的 SD 中溶解的 CHS 最初为 94.02%和 92.01%，而在 12 个月的稳定性研究后，仅为 65.13%和 49.62%。相比之下，用泊洛沙姆 407 和共聚维酮制备的 SD 在 12 个月的稳定性研究后与初始值相比，溶解的 CHS 量非常相似。研究结果表明，体外溶解试验在确定 SD 的长期稳定性和质量方面非常重要。
