Analysis of the causes for abnormal dissolution of lansoprazole enteric-coated tablets by multiple techniques and different dimensions
-
摘要:
利用激光红外成像技术和轨道阱高分辨质谱技术分析兰索拉唑肠溶制剂抽检中样品溶出度异常的原因并提出改进建议。按照法定标准对抽检制剂进行检验，一批样品的溶出度低于限度，其他项目均符合规定。考虑到本品对酸、碱不稳定，结合对生产企业飞行检查的结论，从不同维度设计实验考察该批次样品溶出度异常的原因，包括高温高湿的贮存环境对样品关键质量属性的影响、2 h抗酸实验对溶出度的影响、片芯成像及包衣层厚度测定、有关物质色谱条件优化、杂质谱分析等。研究发现，流通环节贮存不当和样品包衣工艺差是引起该批次样品溶出度低的原因。流通环节可能出现的高温高湿贮存环境引起样品中崩解剂功效下降，主药难以完全释放；包衣液不能均匀包裹于片芯，引起隔离层薄且厚度不一，继而影响其保护主药防止酸降解的效果。两者共同造成该批次样品溶出度偏低。兰索拉唑肠溶制剂总体质量较好，但部分企业处方和工艺需要优化；流通环节需要严格按照规定控制温湿度。
Abstract:This study aims to find out the causes for the dissolution of unqualified samples found during evaluation sampling of lansoprazole enteric-coated preparations by the laser infrared imaging system and orbitrap high resolution mass spectrometry, with suggestions for improvement. Lansoprazole enteric-coated preparations were tested by current standard, the dissolution of a batch of samples was below the limit and other items were in line with the standard. Considering that this product is unstable to acid and alkali, the following exploratory experiments were designed from different dimensions, based on the conclusion of the unannounced inspection of the company, to explore the reasons for the unqualified batch, including the influence of high-temperature and high-humidity storage environment on the key quality properties of the sample, the influence of 2-hour acid resistance test on dissolution result, the imaging of the core and the measure of coating layer thickness, the optimization of chromatographic conditions of related substances, and the analysis of the source of impurities. It was found that improper storage in circulation and poor coating process caused the low dissolution of this batch: the high-temperature and high-humidity storage environment possible in the circulation process led to the decreasing efficacy of disintegrating agent in the samples and thus the difficulty to release the active pharmaceutical ingredient fully; the coating solution could not be uniformly sprayed on the core, resulting in thin isolation layer and different thickness, which then affected the protection of the main drug against acid degradation. The above two reasons together resulted in unqualified dissolution of this batch. The overall quality of lansoprazole enteric-soluble preparation is good, but the formulation and process in some companies need to be optimized; and the temperature and humidity in the circulation process need to be controlled in strict accordance with the regulations.
-
-
![]()
Figure 3. Chromatogram of forced degradation of lansoprazole
A:Acid degradated; B:Alkai degradated; C:Heat degradated; D:Oxidative degradated; E:UV degradated; F:Not degradated
Table 1 Dissolution test data of recalled lansoprazole enteric-coated tablets
Batch No. Recall place Dissolution quantity/% Average/% 190301 Inner Mongolia 86.6 87.0 83.2 86.2 85.5 87.5 86 190301 Guangdong 79.5 84.7 83.5 85.8 84.3 86.6 84 190301 Heilongjiang 82.7 84.1 84.7 82.6 83.3 84.2 84 190301 Henan 83.8 86.7 84.2 84.0 84.4 84.6 85 190301 Szechuan 84.4 85.9 85.7 85.6 86.1 87.0 86 190301 Other places in H province 84.3 83.9 85.1 84.7 84.7 84.2 84 190301 S enterprise 69.1 72.0 71.3 72.3 74.6 73.9 72 
下载: 导出CSV
Table 2 Comparison of coating thickness of 19 batches of samples from H enterprise（n=3）
Batch No. Mean value of isolation
layer/μmMean value of enteric
layer/μm191001 31.20 91.84 190802 30.80 83.08 191003 38.96 90.12 190502 40.40 94.12 190105 30.88 82.84 190803 31.60 84.48 191003 36.16 103.56 190801 34.80 104.08 191201 37.28 90.84 191201 41.84 103.16 191202 36.72 105.56 190801 37.80 110.00 190801 33.12 108.44 190301 24.92 88.96 200203 38.84 106.44 191202 34.80 95.36 200201 37.56 86.64 191003 34.44 101.00 190801 37.04 109.52
下载: 导出CSV
-
[1] Zong SY, Wang JK, Xiao Y, et al. Solubility and dissolution thermodynamic properties of lansoprazole in pure solvents[J]. J Mol Liq, 2017, 241: 399-406. doi: 10.1016/j.molliq.2017.06.037
[2] Li MH, Feng Q, Li XY, et al. Research progress of clinical applications and adverse reactions of lansoprazole[J]. Chin J Pharmacov (中国药物警戒), 2014, 11(12): 729-731. [3] Satoh H. Discovery of lansoprazole and its unique pharmacological properties independent from anti-secretory activity[J]. CurrPharm Des, 2013, 19(1): 67-75.
[4] Chinese Pharmacopoeia Commission. Chinese Pharmacopoeia: part 2 (中华人民共和国药典: 二部) [S]. Beijing: China Medical Science Press, 2015: 234-235. [5] Li Y, Jia HH, Huang Q, et al. Impurity spectra of lansoprazole enteric-coated preparations by high performance liquid chromatography-high resolution orbital trap mass spectrometry[J]. J China Pharm Univ(中国药科大学学报), 2023, 54(5): 577-585. [6] DellaGreca M, Iesce MR, Previtera L, et al. Degradation of lansoprazole and omeprazole in the aquatic environment[J]. Chemosphere, 2006, 63(7): 1087-1093. doi: 10.1016/j.chemosphere.2005.09.003
[7] Battu S, Pottabathini V. Hydrolytic degradation study of lansoprazole, identification, isolation and characterisation of base degradation product[J]. Am J Anal Chem, 2015(6): 145-155.
计量
- 文章访问数: 99
- HTML全文浏览量: 29
- PDF下载量: 23
