无定形药物制剂物理稳定性的热力学机制,Industrial & Engineering Chemistry Research

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无定形药物制剂物理稳定性的热力学机制
Industrial & Engineering Chemistry Research ( IF 3.8 ) Pub Date : 2023-01-11 , DOI: 10.1021/acs.iecr.2c02953
Qiao Chen ₁ , Yuanhui Ji ₁

Affiliation

吸湿性是影响无定形固体分散体（ASDs）在长期储存过程中物理稳定性的重要因素。在这项工作中，系统地研究了温度、相对湿度 (RH) 和聚合物赋形剂对无定形厄贝沙坦 (IRB) 和奥沙普秦 (OXA) 相行为的影响。ASDs 是通过溶剂蒸发法制备的。在 25 °C、60% RH、25 °C、90% RH 和 40 °C、75% RH 的条件下测量制剂中的吸水性。结果表明，含有聚乙烯吡咯烷酮（PVP）的配方的吸湿性强于含有聚（乙烯吡咯烷酮）的配方。-醋酸乙烯酯）（PVPVA 46），吸湿性随着温度和 RH 的升高而增加。随着活性药物成分（API）含量的增加，在相同的RH下重结晶现象显着。PVP 比 PVPVA 46 能更好地抑制 IRB 再结晶。相比之下，PVPVA 46 比 PVP 能更好地保持 OXA 的无定形形式。使用扰动链统计相关流体理论 (PC-SAFT) 和 Gordon-Taylor 方程预测了 60% RH 和无水条件下无定形 API/聚合物配方的热力学相图。此外，利用密度泛函理论（DFT）计算了 API 和聚合物之间的静电势（ESP）和结合能，这解释了 ASD 的分子相互作用机制。

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Thermodynamic Mechanism of Physical Stability of Amorphous Pharmaceutical Formulations

Hygroscopicity is an important factor affecting the physical stability of amorphous solid dispersions (ASDs) during long-term storage. In this work, the effects of temperature, relative humidity (RH), and polymeric excipients on the phase behavior of amorphous irbesartan (IRB) and oxaprozin (OXA) were systematically investigated. The ASDs were prepared by the solvent evaporation method. The water sorption in formulations was measured under the conditions of 25 °C, 60% RH, 25 °C, 90% RH, and 40 °C, 75% RH. The results showed that the hygroscopicity of formulations containing polyvinylpyrrolidone (PVP) was stronger than that containing poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA 46) and the hygroscopicity increased with increasing temperature and RH. With increasing content of active pharmaceutical ingredients (APIs), the recrystallization phenomenon is significant at the same RH. PVP can better inhibit IRB recrystallization than PVPVA 46. In contrast, PVPVA 46 can better maintain the amorphous form of OXA than PVP. The thermodynamic phase diagrams of amorphous API/polymer formulations at 60% RH and anhydrous conditions were predicted using perturbed chain statistical associated fluid theory (PC-SAFT) and the Gordon–Taylor equation. Furthermore, the electrostatic potential (ESP) and binding energies between APIs and polymers were calculated with density functional theory (DFT), which explained the molecular interaction mechanism of ASDs. This work is expected to guide the screening of excipients and API loadings for designing ASDs and the selection of storage conditions.

更新日期：2023-01-11

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