Jansen P J, Oren P L, Kemp C A, Maple S R, Baertschi S W
Lilly Research Laboratories, Pharmaceutical and Analytical Development Division, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
J Pharm Sci. 1998 Jan;87(1):81-5. doi: 10.1021/js970133r.
Duloxetine hydrochloride ((S)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine hydrochloride) has been found to react with polymer degradation products or residual free acids present in the enteric polymers hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP) in dosage formulations to form succinamide and phthalamide impurities, respectively. The rate of formation of the impurities is accelerated by heat and humidity. The structures were deduced using molecular weights obtained from LC-MS experiments and confirmed by comparison of UV spectra, HPLC retention times, and electrospray mass spectra to independently synthesized material. It is proposed that polymer-bound succinic and phthalic substituents can be cleaved from the polymer, resulting in the formation of either the free acids or the anhydrides. It is postulated that the reaction is enabled by migration of either (1) the free acid or anhydride or (2) the parent drug through the formulation. The formation of these impurities was minimized by increasing the thickness of the physical barrier separating the enteric coating from the drug.
已发现盐酸度洛西汀（(S)-N-甲基-3-(1-萘氧基)-2-噻吩丙胺盐酸盐）与剂型中肠溶聚合物醋酸羟丙甲纤维素琥珀酸酯（HPMCAS）和邻苯二甲酸羟丙甲纤维素（HPMCP）中存在的聚合物降解产物或残留游离酸发生反应，分别形成琥珀酰胺和邻苯二甲酰胺杂质。杂质的形成速率会因热和湿度而加快。通过液相色谱-质谱实验获得的分子量推导结构，并通过将紫外光谱、高效液相色谱保留时间和电喷雾质谱与独立合成的物质进行比较来确认。有人提出，聚合物结合的琥珀酸和邻苯二甲酸取代基可从聚合物上裂解下来, 从而形成游离酸或酸酐。据推测，该反应是通过（1）游离酸或酸酐或（2）母体药物在制剂中的迁移而发生的。通过增加将肠溶包衣与药物隔开的物理屏障的厚度，可将这些杂质的形成降至最低。
