The assessment of drug–polymer equilibrium solubility is of critical importance for predicting suitable loading and physical stability of solid dispersion formulations. However, quantitative measurement of this parameter is nontrivial due to the difficulties associated with ascertaining equilibrium values in systems that are prone to supersaturation and are simultaneously highly viscous, thereby slowing the equilibration process considerably; no standard methodology has yet been agreed for such measurements. In this study, we propose a new approach involving quasi-isothermal modulated temperature DSC (QiMTDSC), whereby unsaturated and supersaturated samples are held at defined temperatures and subject to a sinusoidal heating signal at a zero underpinning heating rate, thereby allowing the heat capacity of the sample to be measured as a function of time and temperature. We are not only able to ascertain whether equilibrium has been reached by monitoring the time-dependent heat capacity signal, but we can also measure solubility as a function of temperature via the absolute heat capacity values of the components. We are also able to measure the kinetics of recrystallization from the supersaturated systems. Dispersions of olanzapine in PLGA at concentrations up to 50% w/w, prepared by spray drying, were prepared and characterized using conventional and QiMTDSC as well as hot stage microscopy. The new QiMTDSC protocol was successfully able to determine olanzapine solubility in PLGA at 90 °C to be 23.1 ± 6.1% w/w, which was comparable to the values calculated using other established methods at this temperature, while a temperature/solubility profile was obtained using the method at a range of temperatures. Drug crystallization kinetics from the solid dispersions could also be modeled directly from the QiMTDSC data using the Avrami approach, thereby allowing the effect of drug loading on the rate of crystallization and the effective completion of crystallization to be investigated. Overall, an alternative protocol for measuring drug–polymer solubility has been developed and validated via comparison to established methods, the approach allowing solubility as a function of temperature, identification of equilibrium following demixing, and kinetic analysis of crystallization to be performed within one set of experiments.

中文翻译：

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用于药物-聚合物混溶性和结晶动力学的准等温量热法的发展：装载奥氮平的PLGA微粒

药物-聚合物平衡溶解度的评估对于预测固体分散体制剂的合适载量和物理稳定性至关重要。但是，由于难以确定容易达到过饱和并且同时具有高粘性的系统中的平衡值，因此很难对该参数进行定量测量；尚无用于此类测量的标准方法。在这项研究中，我们提出了一种涉及准等温调制温度DSC（QiMTDSC）的新方法，通过该方法，将不饱和和过饱和的样品保持在定义的温度下，并且在零支撑加热速率下经受正弦加热信号，从而可以根据时间和温度来测量样品的热容量。我们不仅能够通过监视随时间变化的热容信号来确定是否已经达到平衡，而且还可以通过组件的绝对热容值来测量溶解度随温度的变化。我们还能够测量过饱和系统的重结晶动力学。使用常规和QiMTDSC以及热台显微镜，通过喷雾干燥制备了奥氮平在PLGA中浓度高达50％w / w的分散液，并对其进行了表征。新的QiMTDSC方案成功地确定了奥氮平在90°C下在PLGA中的溶解度为23.1±6.1％w / w，与在该温度下使用其他既定方法计算得出的值相当，而使用该方法在一定温度范围内获得了温度/溶解度曲线。固体分散体的药物结晶动力学也可以使用Avrami方法直接从QiMTDSC数据建模，从而可以研究药物负载量对结晶速率和结晶有效完成的影响。总的来说，已经开发出了另一种测量药物-聚合物溶解度的方案，并通过与既定方法进行比较得到了验证，该方法允许溶解度随温度变化，在混合后鉴定平衡以及在一组结晶中进行结晶动力学分析。实验。固体分散体的药物结晶动力学也可以使用Avrami方法直接从QiMTDSC数据建模，从而可以研究药物负载量对结晶速率和结晶有效完成的影响。总的来说，已经开发出了另一种测量药物-聚合物溶解度的方案，并通过与既定方法进行比较得到了验证，该方法允许溶解度随温度变化，在混合后鉴定平衡以及在一组结晶中进行结晶动力学分析。实验。固体分散体的药物结晶动力学也可以使用Avrami方法直接从QiMTDSC数据建模，从而可以研究药物负载量对结晶速率和结晶有效完成的影响。总的来说，已经开发出了另一种测量药物-聚合物溶解度的方案，并通过与既定方法进行比较得到了验证，该方法允许溶解度随温度变化，在混合后鉴定平衡以及在一组结晶中进行结晶动力学分析。实验。