吡罗昔康片杂质研究

目的：研究吡罗昔康片中的杂质。方法：建立HPLC方法对吡罗昔康片的杂质进行考察：采用Capell-MG Ⅱ C₁₈（4.6 mm×250 mm，5 μm）色谱柱，以0.05 mol·L^-1磷酸二氢钾溶液（用磷酸调节pH至3.0）-乙腈为流动相，梯度洗脱，流速1.0 mL·min^-1，检测波长230 nm；采用HPLC-Q-TOF/MS技术对主要杂质结构进行了初步鉴定：色谱柱为XDB-C₁₈（4.6 mm×100 mm，5 μm），流动相为0.1%甲酸溶液-乙腈，梯度洗脱，流速0.4 mL·min^-1，质谱离子源为ESI离子源，扫描模式为正离子扫描。结果：138批国产吡罗昔康片共检出14个杂质，其中杂质8、10、12、14是主要杂质，96%样品中最大杂质为杂质12，平均含量为0.35%；杂质总量平均为0.57%。杂质主要来源于原料。国外产品与国产产品杂质谱不同，杂质数量及含量远低于国内产品。鉴定了其中8种杂质的结构，其中杂质1、8、14分别对应BP的特定杂质A（2-氨基吡啶）、C（2-甲基-4-羟基-2H-1，2-苯并噻嗪-3-甲酰胺-1，1-二氧化物）和K（2-甲基-4-羟基-2H-1，2-苯并噻嗪-3-甲酸乙酯-1，1-二氧化物），杂质4（1，1-二氧-2-乙基亚胺基-1，2-苯并异噻唑-3-酮）、7（2-甲基-4-羟基-N-（1-氧代-2-吡啶基）-2H-1，2-苯并噻嗪-3-甲酰胺-1，1-二氧化物）、9（N，N'-双（2-吡啶基）草酰胺）、10（2-甲基-4-羟基-N-甲基-2H-1，2-苯并噻嗪-3-甲酰胺-1，1-二氧化物）、12（2，2-二甲基-4-羟基-N-（2-吡啶基）-2H-1，2-苯并噻嗪-3-甲酰胺-1，1-二氧化物）为吡罗昔康片中首次报道。结论：建立的HPLC方法可有效分离主成分吡罗昔康与杂质。国产吡罗昔康片中杂质数量较多，含量较高，应优化生产工艺，控制其质量。

Objective: To study the impurities in piroxicam tablets. Methods: An HPLC method was established to study the impurities in piroxicam tablets:Capell-MG Ⅱ C₁₈ column(4.6 mm×250 mm, 5 μm)was used with gradient elution of a mobile phase consisting of 0.05 mol·L^-1 potassium dihydrogen phosphate solution, which was adjusted to pH 3.0 with phosphoric acid and acetonitrile. The flow rate was 1.0 mL·min^-1, and the UV detection wavelength was 285 nm. HPLC-Q-TOF/MS technique was used to identify the structure of the impurities:XDB-C₁₈ column (4.6 mm×100 mm, 5 μm)was used with gradient elution of a mobile phase consisting of 0.1% formic acid solution and acetonitrile. The flow rate was 0.4 mL·min^-1, and data were collected in positive ion modes with ESI as the ion resource. Results: The study showed that there were fourteen impurities in domestic piroxicam tablets, among which impurities 8, 10, 12, 14 were the main impurities, the dominant impurity in 96% samples was impurity 12 with average content of 0.35%; the average amount of impurities was 0.57%. Impurities were mainly derived from drug substance. The impurity profile of the foreign product was different from that of the domestic product, and the quantity and content of impurities were much lower than those in the domestic product. Eight impurities were identified. Impurities 1, 8, 14 were impurity A (2-pyridylamine), C (4-hydroxy-2-methyl-2H-1, 2-benzothiazine-3-carboxamide1, 1-dioxide), K (ethyl 4-hydroxy-2-methyl-2H-1, 2-benzothiazine-3-carboxylate 1, 1-dioxide)of BP; impurity 4(2-acetaldimine-1, 1-dioxo-1, 2-benzothiazol-3-one), impurity 7 (4-hydroxy-2-methyl-1, 1-dioxo-N-(1-oxido-2-pyridyl)-1, 2-benzothiazine-3-carboxamide), impurity 9 (N, N'-di-(2-pyridinyl)oxamide), impurity 10 (4-hydroxy-2-methyl-1, 1-dioxo-N-methyl-1, 2-benzothiazine-3-carboxamide), impurity 12(4-hydroxy-2, 2-dimethyl-1, 1-dioxo-N-(2-pyridyl)-1, 2-benzothiazine-3-carboxamide) were reported for the first time in piroxicam tablets. Conclusion: The established method can effectively separate the principal components and the impurities in piroxicam tablets, the quantity and content of impurities in domestic products are high, which should be controlled by improvement of manufacturing technique.