Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.
Faculty of Pharmacy, University of Coimbra, Portugal.
Int J Pharm. 2014 May 15;466(1-2):68-75. doi: 10.1016/j.ijpharm.2014.02.048. Epub 2014 Mar 4.
A thermodynamic based approach is used to investigate diflunisal+nicotinamide binary and solution mixtures. A 2:1 co-crystal could be prepared by liquid assisted ball mill grinding and by solution crystallization from ethanol. The diflunisal+nicotinamide+ethanol ternary phase diagram points out conditions for co-crystal scaling-up. From the diflunisal+nicotinamide binary phase diagram, besides identification of the co-crystal stoichiometry, two additional useful binary compositions, eutectic mixtures, were characterized. From a solution enthalpy based approach, the enthalpic stabilization of the co-crystal relative to the pure solid components is quantified. Intrinsic dissolution rate, IDR, in test conditions consistent with USP requirements, including those referred in the diflunisal tablet monograph, were carried out, indicating that the co-crystal improves diflunisal IDR by about 20%. The systematic study of diflunisal+nicotinamide mixtures presented in this work is of particular interest due to the relevance of diflunisal, both as a non-steroidal anti-inflammatory drug and also due to the potentiality of orally administrated diflunisal in familial amyloid polyneuropathy.
采用热力学方法研究了双氟尼柳+烟酰胺的二元和溶液混合物。通过液辅助球磨和乙醇溶液结晶可以制备 2:1 共晶。双氟尼柳+烟酰胺+乙醇三元相图指出了共晶放大的条件。从双氟尼柳+烟酰胺二元相图中，除了鉴定共晶的化学计量比外，还确定了两个额外的有用二元组成，即共熔混合物。从基于溶液焓的方法出发，定量了共晶相对于纯固体组分的焓稳定性。在与 USP 要求一致的测试条件下进行了固有溶解速率（IDR）的测定，包括双氟尼柳片剂专论中提到的那些条件，结果表明共晶使双氟尼柳的 IDR 提高了约 20%。由于双氟尼柳作为非甾体抗炎药的相关性，以及口服双氟尼柳在家族性淀粉样多发性神经病中的潜在应用，本工作中对双氟尼柳+烟酰胺混合物的系统研究具有特别的意义。
