盐酸洛美沙星滴耳液辅料、包材及成盐对光稳定性影响的研究

Study on the effects of excipients, packaging materials, and salt formation on the photostability of Lomefloxacin hydrochloride ear drops

关键词:  盐酸洛美沙星滴耳液  辅料  包材  成盐  光稳定性

Key words:  lomefloxacin hydrochloride ear drops  excipients  packaging materials  salt formation  photostability

摘要:

目的 通过分析盐酸洛美沙星滴耳液不同辅料、包材以及洛美沙星、洛美沙星与盐酸、门冬氨酸成盐光照后的杂质含量变化,进行辅料、包材以及成盐对光稳定性影响的研究。方法 采用Kromasil 100-5 C18柱(4.6 mm×250 mm,5μm),流动相A为戊烷磺酸钠溶液(取戊烷磺酸钠1.5g,磷酸二氢铵3.5g,加水950ml使溶解,用磷酸调节pH值至3.0,用水稀释至1000ml),流动相B为甲醇,梯度洗脱,测定盐酸洛美沙星滴耳液中光降解杂质含量,根据影响因素试验和加速试验,进行辅料及药包材的相容性研究。采用 GL science inertsil ODS-3V色谱柱(4.6 mm×250 mm,5μm),流动相A为10mmoL/L甲酸铵水溶液(用甲酸调节pH至3.0),流动相B为乙腈,梯度洗脱,进行洛美沙星、洛美沙星与盐酸、门冬氨酸成盐光照后的光降解杂质研究。结果 处方中的有机物(甘油、乙醇和丙二醇含量)与光降解杂质含量呈显著负相关,处方中添加适量的有机物可提高盐酸洛美沙星滴耳液的光稳定性,降低光降解反应的发生；盐酸洛美沙星滴耳液包装材料的透光率和光降解杂质含量呈显著正相关,采用遮光包装可降低盐酸洛美沙星光降解反应的发生；洛美沙星成盐有助于提高光稳定性。盐酸洛美沙星产生的光降解杂质以氯代杂质为主,洛美沙星及门冬氨酸洛美沙星光破坏溶液中氯代杂质含量分别为盐酸洛美沙星的1/10、1/4。结论 盐酸洛美沙星滴耳液的生产过程中应采用遮光率高的内包装材料,并在处方中适量添加有机物提高盐酸洛美沙星滴耳液的光稳定性。为提高洛美沙星制剂的光稳定性可选择合适的酸根使洛美沙星成盐。

Abstract:

OBJECTIVE To study the effects of different excipients, packaging materials, and salt formation on the photostability of lomefloxacin hydrochloride ear drops by analyzing the different excipients and packaging materials, as well as the changes in impurity content of lomefloxacin, lomefloxacin and its salt formation with hydrochloric acid and aspartic acid under light irradiation. METHODS Kromasil 100-5 C18 column (4.6 mm×250 mm, 5 μm) was used, and the mobile phase A was sodium pentanesulfonate solution (1.5 g of sodium pentanesulfonate, 3.5 g of ammonium dihydrogen phosphate, dissolved in 950ml of water, adjust the pH value to 3.0 with phosphoric acid, and dilute with water to 1000ml), while methanol was mobile phase B, gradient elution was used to determine the content of photodegradable impurities in lomefloxacin hydrochloride ear drops. The compatibility of excipients and packaging materials was studied based on influencing factor tests and accelerated tests. GL science inertsil ODS-3V column (4.6 mm×250 mm, 5 μm) was used, the mobile phase A was 10 mmol/L ammonium formate aqueous solution (adjusted to pH 3.0 with formic acid), and the mobile phase B was acetonitrile, gradient elution was performed to investigate the photodegradation impurities of lomefloxacin, lomefloxacin with hydrochloric acid and aspartic acid salt under light irradiation. RESULTS The organic matter (glycerol, ethanol, and propylene glycol content) in the formulation was significantly negatively correlated with the content of photodegradable impurities, adding an appropriate amount of organic matter to the formulation could improve the photostability of lomefloxacin hydrochloride ear drops and reduce the occurrence of photodegradation reactions. The transparency of packaging materials for lomefloxacin hydrochloride ear drops was significantly positively correlated with the content of photodegradable impurities, and the use of shading packaging could reduce the occurrence of lomefloxacin hydrochloride photodegradation reaction. The salt formation of lomefloxacin helped to improve the photostability. The photodegradation impurities generated by lomefloxacin hydrochloride were mainly chlorinated impurities, and the chlorinated impurity content in lomefloxacin and lomefloxacin aspartate photodegradation solutions was 1/10 and 1/4 of lomefloxacin hydrochloride, respectively. CONCLUSION High light shielding inner packaging materials should be used in the production process of lomefloxacin hydrochloride ear drops, and an appropriate amount of organic matter should be added to the formulation to improve the photostability of lomefloxacin hydrochloride ear drops. To improve the photostability of lomefloxacin formulations, appropriate acid groups can be selected to salt lomefloxacin.