pH-Dependent Liquid-Liquid Phase Separation of Highly Supersaturated Solutions of Weakly Basic Drugs
pH-Dependent Liquid-Liquid Phase Separation of Highly Supersaturated Solutions of Weakly Basic Drugs
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DOI：
10.1021/acs.molpharmaceut.5b00056
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发表时间：
2015-07-01
影响因子：
4.9
通讯作者：
Taylor, Lynne S.
中科院分区：
文献类型：
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作者：
Indulkar, Anura S.;Box, Karl J.;Taylor, Lynne S.
低水溶性药物的过饱和溶液可以在体内和体外形成。例如，在胃肠道运输过程中pH值的升高会降低弱碱性药物的水溶性，导致过饱和，特别是在离开酸性胃环境时。最近有研究发现，低水溶性药物的高度过饱和溶液在结晶前可进行液-液相分离（LLPS），形成浑浊溶液，使得连续溶液中的药物浓度对应于无定形的溶解度，而胶体相则由无序的富药相组成。虽然已经确定结晶弱碱性药物的平衡溶解度遵循亨德森-哈塞尔巴尔奇关系，但pH对LLPS现象或无定形溶解度的影响尚未探讨。在这项工作中，使用三种不同的方法确定了三种弱碱性化合物——氯霉唑、硝地平和阿扎那韦的LLPS浓度作为pH的函数，并将其与预测的非晶态溶解度进行了比较，预测的非晶态溶解度是通过估算非晶态和晶态之间的自由能差来计算的。观察到，与结晶溶解度类似，在任意pH下的实验非晶态溶解度遵循亨德森-哈塞尔巴尔奇关系，如果已知游离碱的非晶态溶解度，则可以预测其溶解度。观察到LLPS浓度与预测的无定形溶解度之间的良好一致性。非晶态药物的溶解研究表明，在该ph下，溶液浓度可以达到相应的LLPS浓度。沉淀物质的固态分析证实了非晶态性质。这项工作提供了对低水溶性化合物的ph依赖性沉淀行为的见解，并为理解过饱和剂型的性能提供了基础基础。
Supersaturated solutions of poorly aqueous soluble drugs can be formed both in vivo and in vitro. For example, increases in pH during gastrointestinal transit can decrease the aqueous solubility of weakly basic drugs resulting in supersaturation, in particular when exiting the acidic stomach environment. Recently, it has been observed that highly supersaturated solutions of drugs with low aqueous solubility can undergo liquid liquid phase separation (LLPS) prior to crystallization, forming a turbid solution such that the concentration of the drug in the continuous solution phase corresponds to the amorphous solubility while the colloidal phase is composed of a disordered drug-rich phase. Although it is well established that the equilibrium solubility of crystalline weakly basic drugs follows the Henderson-Hasselbalch relationship, the impact of pH on the LLPS phenomenon or the amorphous solubility has not been explored. In this work, the LLPS concentration of three weakly basic compounds-clotrimazole, nicardipine, and atazanavir-was determined as a function of pH using three different methods and was compared to the predicted amorphous solubility, which was calculated from the pH-dependent crystalline solubility and by estimating the free energy difference between the amorphous and crystalline forms. It was observed that, similar to crystalline solubility, the experimental amorphous solubility at any pH follows the Henderson-Hasselbalch relation and can be predicted if the amorphous solubility of the free base is known. Excellent agreement between the LLPS concentration and the predicted amorphous solubility was observed. Dissolution studies of amorphous drugs showed that the solution concentration can reach the corresponding LLPS concentration at that pH. Solid-state analysis of the precipitated material confirmed the amorphous nature. This work provides insight into the pH-dependent precipitation behavior of poorly water-soluble compounds and provides a fundamental basis with which to understand the performance of supersaturating dosage forms.