Wirth D D, Baertschi S W, Johnson R A, Maple S R, Miller M S, Hallenbeck D K, Gregg S M
Lilly Research Laboratories, Eli Lilly and Company, Lafayette, Indiana 47905, USA.
J Pharm Sci. 1998 Jan;87(1):31-9. doi: 10.1021/js9702067.
Analysis of commercially available generic formulations of fluoxetine HCl revealed the presence of lactose as the most common excipient. We show that such formulations are inherently less stable than formulations with starch as the diluent due to the Maillard reaction between the drug, a secondary amine hydrochloride, and lactose. The Amadori rearrangement product was isolated and characterized; the characterization was aided by reduction with sodium borohydride and subsequent characterization of this reduced adduct. The lactose-fluoxetine HCl reaction was examined in aqueous ethanol and in the solid state, in which factors such as water content, lubricant concentration, and temperature were found to influence the degradation. N-Formylfluoxetine was identified as a major product of this Maillard reaction and it is proposed that N-formyl compounds be used as markers for this drug-excipient interaction since they are easy to prepare synthetically. Many characteristic volatile products of the Maillard reaction have been identified by GC/MS, including furaldehyde, maltol, and 2,3-dihydro-3,5-dihydroxy-6-methyl-4 H-pyran-4-one. Close similarity between the degradation products of simple mixtures and formulated generic products was found; however, at least one product decomposed at a rate nearly 10 times that predicted from the simple models. Maillard products have also been identified in unstressed capsules. The main conclusion is that drugs which are secondary amines (not just primary amines as sometimes reported) undergo the Maillard reaction with lactose under pharmaceutically relevant conditions. This finding should be considered during the selection of excipients and stability protocols for drugs which are secondary amines or their salts, just as it currently is for primary amines.
对市售盐酸氟西汀仿制药制剂的分析表明，乳糖是最常见的辅料。我们发现，由于药物（一种仲胺盐酸盐）与乳糖之间的美拉德反应，此类制剂本质上比以淀粉为稀释剂的制剂稳定性更低。分离并表征了阿马多里重排产物；通过硼氢化钠还原及对该还原加合物的后续表征辅助了表征过程。在乙醇水溶液和固态条件下研究了乳糖 - 盐酸氟西汀反应，发现水分含量、润滑剂浓度和温度等因素会影响降解。N - 甲酰氟西汀被鉴定为该美拉德反应的主要产物，并且由于它们易于合成制备，建议将N - 甲酰化合物用作这种药物 - 辅料相互作用的标志物。通过气相色谱/质谱法鉴定了许多美拉德反应的特征挥发性产物，包括糠醛、麦芽酚和2,3 - 二氢 - 3,5 - 二羟基 - 6 - 甲基 - 4H - 吡喃 - 4 - 酮。发现简单混合物和仿制药制剂的降解产物之间有密切相似性；然而，至少有一种产物的分解速率几乎是简单模型预测值的10倍。在未受胁迫的胶囊中也鉴定出了美拉德产物。主要结论是，仲胺类药物（不仅仅是有时报道的伯胺类药物）在药学相关条件下会与乳糖发生美拉德反应。在为仲胺类药物或其盐类选择辅料和稳定性方案时，应考虑这一发现，就如同目前对伯胺类药物所做的那样。
