The preparation of an amorphous solid dispersion (ASD) by dissolving a poorly water-soluble active pharmaceutical ingredient (API) in a polymer matrix can improve the bioavailability by orders of magnitude. Crystallization of the API in the ASD, though, is an inherent threat for bioavailability. Commonly, the impact of crystalline API on the drug release of the dosage form is studied with samples containing spiked crystallinity. These spiked samples possess implicit differences compared to native crystalline samples, regarding size and spatial distribution of the crystals as well as their molecular environment. In this study, we demonstrate that it is possible to grow defined amounts of crystalline API in solid dosage forms, which enables us to study the biopharmaceutical impact of actual crystallization. For this purpose, we studied the crystal growth in fenofibrate tablets over time under an elevated moisture using transmission Raman spectroscopy (TRS). As a nondestructive method to assess API crystallinity in ASD formulations, TRS enables the monitoring of crystal growth in individual dosage forms. Once the kinetic trace of the crystal growth for a certain environmental condition is determined, this method can be used to produce samples with defined amounts of crystallized API. To investigate the biopharmaceutical impact of crystallized API, non-QC dissolution methods were used, designed to identify differences between the various amounts of crystalline materials present. The drug release in the samples manufactured in this fashion was compared to that of samples with spiked crystallinity. In this study, we present for the first time a method for targeted crystallization of amorphous tablets to simulate crystallized ASDs. This methodology is a valuable tool to generate model systems for biopharmaceutical studies on the impact of crystallinity on the bioavailability.

中文翻译：

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使用量身定制的结晶API生产无定形固体分散体，用于生物制药测试

通过将水溶性差的活性药物成分（API）溶解在聚合物基质中来制备无定形固体分散体（ASD），可以将生物利用度提高几个数量级。但是，ASD中API的结晶是对生物利用度的固有威胁。通常，使用含有尖峰结晶度的样品研究结晶API对剂型药物释放的影响。与天然晶体样品相比，这些加标样品在晶体的尺寸和空间分布及其分子环境方面具有明显的差异。在这项研究中，我们证明有可能在固体剂型中生长一定量的结晶API，这使我们能够研究实际结晶的生物制药影响。以此目的，我们使用透射拉曼光谱（TRS）研究了非诺贝特片在高湿度下随时间变化的晶体生长。作为评估ASD制剂中API结晶度的一种非破坏性方法，TRS能够监控单个剂型中的晶体生长。一旦确定了在特定环境条件下晶体生长的动力学轨迹，就可以使用该方法生产具有确定量的结晶API的样品。为了研究结晶API的生物制药影响，使用了非QC溶解方法，旨在识别存在的各种结晶物质之间的差异。将以此方式制造的样品中的药物释放与具有尖峰结晶度的样品中的药物释放进行了比较。在这项研究中，我们首次提出了无定形片剂的靶向结晶方法，以模拟结晶的ASD。该方法学是生成用于结晶度对生物利用度影响的生物药物研究模型系统的有价值的工具。