Pharmaceutical and Molecular Biotechnology Research Centre, South East Technological University, Waterford, Ireland; SSPC, The Research Ireland Centre for Pharmaceuticals, South East Technological University, Waterford, Ireland.
Pharmaceutical and Molecular Biotechnology Research Centre, South East Technological University, Waterford, Ireland.
Int J Pharm. 2024 Dec 25;667(Pt A):124913. doi: 10.1016/j.ijpharm.2024.124913. Epub 2024 Nov 6.
Co-amorphous systems (CAMs) have shown promise in addressing the challenges associated with poorly water-soluble drugs. However, the limited selection of co-formers and the use of lab-scale techniques for their preparation present challenges in fully utilizing the advantages of CAMs. In this study, we used aspartame (a methyl ester of the aspartic acid/phenylalanine) as a model dipeptide with the BCS class II drug dipyridamole, to prepare co-amorphous systems using spray drying. The feed solutions were prepared by dissolving the drug and co-former into methanol-water mixtures. The spray drying process was evaluated and solid-state properties were compared with those of the individual amino acids, amino acid mixtures and aspartame as co-formers. Co-amorphous systems prepared with aspartame (AspPhe) exhibited better solid-state properties, including a higher glass transition temperature (T), compared to the individual amino acids and the mixture of amino acids. Additionally, this formulation showed improved physical stability when stored at 25 °C/60 % RH conditions. Hirshfeld Surface (HS) analysis was employed to visualize and analyse the molecular interaction sites within the crystal structures of dipyridamole and aspartame. The observed interactions were then correlated with the molecular interactions identified through FT-IR spectroscopic analysis within the CAMs. The spectroscopic analysis revealed molecular interactions between the sites found at the shortest distances in the HS analysis. The dominant hydrogen bond interactions identified in the co-amorphous DPM-AspPhe system was found to contribute significantly to its improve stability. X-ray powder diffraction in non-ambient mode reveals that both temperature and humidity play a role in the crystallization of the co-amorphous DPM-AspPhe. Crystallization rates increased notably at high temperature and humidity. To predict stability under accelerated conditions, the crystallization rates from DPM-AspPhe were fitted to a modified Arrhenius equation. However, the predictive accuracy of the resulting model was limited to a specific range of conditions.
共无定形系统 (CAMs) 在解决水溶性差的药物所面临的挑战方面显示出了潜力。然而，共晶形成剂的选择有限，以及用于制备它们的实验室规模技术，对充分利用 CAMs 的优势提出了挑战。在这项研究中，我们使用阿斯巴甜（天冬氨酸/苯丙氨酸的甲酯）作为模型二肽，与 BCS 类 II 药物双嘧达莫一起，通过喷雾干燥制备共无定形系统。将药物和共晶形成剂溶解在甲醇-水混合物中制备进料溶液。评估了喷雾干燥过程，并将固态特性与单个氨基酸、氨基酸混合物和阿斯巴甜作为共晶形成剂进行了比较。与单个氨基酸和氨基酸混合物相比，用阿斯巴甜（AspPhe）制备的共无定形系统表现出更好的固态特性，包括更高的玻璃化转变温度 (T)。此外，这种制剂在 25°C/60%RH 条件下储存时表现出更好的物理稳定性。Hirshfeld 表面 (HS) 分析用于可视化和分析双嘧达莫和阿斯巴甜晶体结构中的分子相互作用位点。然后将观察到的相互作用与通过 FT-IR 光谱分析在 CAMs 中识别的分子相互作用相关联。光谱分析揭示了在 HS 分析中最短距离处发现的相互作用位点之间的分子相互作用。在共无定形 DPM-AspPhe 系统中确定的主要氢键相互作用被发现对其稳定性的提高有重要贡献。非环境模式下的 X 射线粉末衍射表明，温度和湿度在共无定形 DPM-AspPhe 的结晶过程中都起着重要作用。在高温和高湿度下，结晶速率显著增加。为了在加速条件下预测稳定性，将 DPM-AspPhe 的结晶速率拟合到修正的 Arrhenius 方程中。然而，所得模型的预测准确性仅限于特定条件范围。
