University of Michigan, College of Pharmacy, Ann Arbor, Michigan 48109-1065.
University of Michigan, College of Pharmacy, Ann Arbor, Michigan 48109-1065.
J Pharm Sci. 2018 Jan;107(1):380-389. doi: 10.1016/j.xphs.2017.09.014. Epub 2017 Oct 6.
Current interest in cocrystal development resides in the advantages that the cocrystal may have in solubility and dissolution compared with the parent drug. This work provides a mechanistic analysis and comparison of the dissolution behavior of carbamazepine (CBZ) and its 2 cocrystals, carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) under the influence of pH and micellar solubilization. A simple mathematical equation is derived based on the mass transport analyses to describe the dissolution advantage of cocrystals. The dissolution advantage is the ratio of the cocrystal flux to drug flux and is defined as the solubility advantage (cocrystal to drug solubility ratio) times the diffusivity advantage (cocrystal to drug diffusivity ratio). In this work, the effective diffusivity of CBZ in the presence of surfactant was determined to be different and less than those of the cocrystals. The higher effective diffusivity of drug from the dissolved cocrystals, the diffusivity advantage, can impart a dissolution advantage to cocrystals with lower solubility than the parent drug while still maintaining thermodynamic stability. Dissolution conditions where cocrystals can display both thermodynamic stability and a dissolution advantage can be obtained from the mass transport models, and this information is useful for both cocrystal selection and formulation development.
目前，人们对共晶开发的兴趣在于与母体药物相比，共晶在溶解度和溶解性能方面可能具有优势。本工作提供了在 pH 值和胶束增溶作用影响下，卡马西平（CBZ）及其 2 种共晶（CBZ-糖精（CBZ-SAC）和 CBZ-水杨酸（CBZ-SLC））的溶解行为的机理分析和比较。基于传质分析，推导出了一个简单的数学方程，用于描述共晶的溶解优势。溶解优势是共晶通量与药物通量的比值，定义为溶解度优势（共晶与药物溶解度比）乘以扩散优势（共晶与药物扩散比）。在这项工作中，确定了存在表面活性剂时 CBZ 的有效扩散系数是不同的，并且小于共晶的有效扩散系数。从溶解共晶中药物的较高有效扩散系数，即扩散优势，可以赋予溶解度低于母体药物的共晶溶解优势，同时仍保持热力学稳定性。可以从传质模型中获得共晶可以显示热力学稳定性和溶解优势的溶解条件，这对于共晶选择和制剂开发都非常有用。
