Machado Tatiane Cogo, Kuminek Gislaine, Cardoso Simone Gonçalves, Rodríguez-Hornedo Naír
Programa de Pós-Graduação em Farmácia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina 88040-900, Brazil.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065, United States.
Eur J Pharm Sci. 2020 Sep 1;152:105422. doi: 10.1016/j.ejps.2020.105422. Epub 2020 Jun 10.
Cocrystals that are more soluble than the constituent drug, generate supersaturation levels during dissolution and are predisposed to conversion to the less soluble drug. Drug release studies during cocrystal dissolution generally compare several cocrystals and their crystal structures. However, the influence of drug dose and solubility in different dissolution media has been scarcely reported. The present study aims to investigate how drug dose/solubility ratio (Do=C/S), cocrystal solubility advantage over drug (SA=S/S), and dissolution media affect cocrystal dissolution-drug supersaturation and precipitation (DSP) behavior. SA and K values of 1:1 cocrystals of meloxicam-salicylic acid (MLX-SLC) and meloxicam-maleic acid (MLX-MLE) were determined at cocrystal/drug eutectic points. Results demonstrate that both cocrystals enhance SA by orders of magnitude (20 to 100 times for the SLC and over 300 times for the MLE cocrystal) in the pH range of 1.6 to 6.5. It is shown that during dissolution, cocrystals regulate the interfacial pH (pH) to 1.6 for MLX-MLE and 4.5 for MLX-SLC, therefore diminishing the cocrystal dissolution rate dependence on bulk pH. Do values ranged from 2 (pH 6.5) to 410 (pH 1.6) and were mostly determined by the drug solubility dependence on pH. Drug release profiles show that maximum supersaturation (σ=C/Sand AUC increased with increasing Do as pH decreased. When Do>>SA, the cocrystal solubility is not sufficient to dissolve the dose so that a dissolution-precipitation quasi-equilibrium state is able to sustain supersaturation for the extent of the experiment (24 h). When Do<<SA, cocrystal solubility is more than adequate to dissolve the dose. Low σ values (1.7 and 1.5) near the value of Do (2.3 and 2.4) were observed, where a large fraction of the cocrystal added is dissolved to reach σ. Two different cocrystal to drug conversion pathways were observed: (1) surface nucleation of the metastable MLX polymorph IV on the dissolving cocrystal preceeded formation of the stable MLX polymorph I in bulk solution (in all conditions without FeSSIF), and (2) bulk nucleation of the stable MLX polymorph (in FeSSIF). The interplay between cocrystal SA, Do and drug precipitation pathways provide a framework to interpret and understand the DSP behavior of cocrystals.
共晶体比其组成药物更易溶，在溶解过程中产生过饱和水平，并易于转化为溶解度较低的药物。共晶体溶解过程中的药物释放研究通常会比较几种共晶体及其晶体结构。然而，药物剂量和在不同溶解介质中的溶解度的影响鲜有报道。本研究旨在探究药物剂量/溶解度比（Do = C/S）、共晶体相对于药物的溶解度优势（SA = S/S）以及溶解介质如何影响共晶体溶解 - 药物过饱和与沉淀（DSP）行为。在共晶体/药物低共熔点处测定了美洛昔康 - 水杨酸（MLX - SLC）和美洛昔康 - 马来酸（MLX - MLE）1:1共晶体的SA和K值。结果表明，在1.6至6.5的pH范围内，两种共晶体均将SA提高了几个数量级（SLC共晶体提高20至100倍，MLE共晶体提高超过300倍）。结果表明，在溶解过程中，共晶体将界面pH（pH）调节为MLX - MLE的1.6和MLX - SLC的4.5，因此降低了共晶体溶解速率对本体pH的依赖性。Do值范围为2（pH 6.5）至410（pH 1.6），主要由药物溶解度对pH的依赖性决定。药物释放曲线表明，随着pH降低，最大过饱和度（σ = C/S）和AUC随Do增加而增加。当Do >> SA时，共晶体溶解度不足以溶解剂量，从而在实验过程（24小时）中溶解 - 沉淀准平衡状态能够维持过饱和。当Do << SA时，共晶体溶解度足以溶解剂量。在接近Do值（2.3和2.4）处观察到低σ值（1.7和1.5），此时添加的大部分共晶体溶解以达到σ。观察到两种不同的共晶体向药物的转化途径：（1）在所有无FeSSIF的条件下，在溶解的共晶体上亚稳的MLX多晶型IV的表面成核先于本体溶液中稳定的MLX多晶型I的形成，以及（2）稳定的MLX多晶型的本体成核（在FeSSIF中）。共晶体SA、Do和药物沉淀途径之间的相互作用提供了一个框架来解释和理解共晶体的DSP行为。
