摘要
目的：
通过新药临床前的研究，建立S-西酞普兰草酸盐原料药及片剂的质量标准，进行新药报批与开发。
方法：
采用红外、紫外、核磁、质谱对S-西酞普兰草酸盐的结构进行确证。根据药典方法对S-西酞普兰草酸盐原料药的外观、熔点、溶解度、旋光度、纯度等理化性质进行了考察；S-西酞普兰草酸盐的鉴别方法：红外光谱、紫外光谱、HPLC法及草酸盐的性质实验；在CHIROBIOTIC V柱上对S-西酞普兰草酸盐原料药进行拆分，并建立了R型异构体含量监控的HPLC方法；选用HPLC法测定了S-西酞普兰草酸盐的含量及有关物质；采用GC法对S-西酞普兰草酸盐合成中可能残留的有害溶剂进行了检测。片剂质量研究的重点是溶出度的测定，用浆法，以水为溶剂，确定转速为50转，根据简单易行的原则采用了紫外分光光度法；同时进行了含量均匀度研究；片剂的含量测定则沿用了原料药的HPLC法。
结果：
通过四大光谱的分析，表明S-西酞普兰草酸盐的结构准确无误。S-西酞普兰草酸盐的外观性状为：白色或淡黄色结晶性粉末，无臭，无味；熔点：151～155℃；旋光度≥+12.8°；其溶解性：在甲醇和二甲基亚砜中易溶，在水和乙醇中略溶，在乙酸乙脂中微溶，在庚烷中不溶；本品在高湿环境中吸湿性很小，放置10天吸湿增重仅为1.867％；在排除降解产物及中间体干扰的色谱条件下，测得原料药中有关物质＜1.0％；S型与R
型异构体在手性柱上的分离度大于1.5，且均与峰面积呈良好
的线性关系:S一西酞普兰草酸盐的回归方程为As=
40224.77ses+55.066(rs=0.9991，n=5)，线性范围:0.01一
0.25mg/ml，R一西酞普兰草酸盐的回归方程为AR=
一764.os3eR+0.556，(rR=0.9993，n=5)，可确保R型异构体
含量监控的可靠性，R型异构体<5%。S一西酞普兰草酸盐中有
机溶剂残留检测结果表明:只有<0.05%乙醇残留，其余五种溶剂
均未检出;S一西酞普兰草酸盐三批样品含量为:101.30%、
100.46%和99.60%(RSD<1.30%)，符合含量测定的技术
要求。片剂质量标准的研究中，采用紫外分光光度法测试溶出度，
溶液浓度与吸光度值具良好的线性，在0.002一0.030 mg/ml浓度范
围内，其线性方程为:A科2.598le+0.0234(二0.9995，n=7)，30而n
内产品的溶出率达到80%以上。含量均匀度研究的表明A+1.85
成8，完全符合中国药典的规定(A+1.85成15)。片剂的含量测定
中，辅料对主药测定无干扰，回收率达到99%以上，RSD值为1 .19
%，完全符合要求。
结论:
所建标准可以有效控制和评价S一西酞普兰草酸盐的质量。S一西酞
普兰草酸盐的理化性质、含量、有关物质、溶剂残留、均匀度、
溶出度等指标符合新药审批的技术要求。
To develop the quality standard of the Escitalopram Oxalate and its tablets. Method:
The molecule structure of the Escitalopram Oxalate was validated by analyse of DR., VU, NMR and MS. To describe outward appearance and determine constants of physics and chemistry of Escitalopram Oxalate, according to methods of pharmacopoeia. IR, UV, HPLC and property experiment of Oxalate were used in the identification test. To separate the enantiomers of Citalopram Oxalate and determinate R-citalopram Oxalate was performed by HPLC on a CHIROBIOTIC V column. A rapid high-performance liquid chromatographic method used to determine the contents of Escitalopram Oxalate and its tablets and relevant substance on C18 column was described. A gas chromatography method was established to determine of the residual organic volatile solvents in Escitalopram Oxalate with a HP-INNOWAX column. To Determination of dissolution and uniformity was performed by Ultraviolet spectroscopy. Paddle method was used to determine dissolution. The rotation speed was 50 r min-1 and the dissolution medium was water. Result:
Accuracy of Escitalopram Oxalate construction was proved. Escitalopram Oxalate outward appearance form is: White or light yellow powder, having no smelly, tasteless; the melting range: between 151C and 155 C . Escitalopram Oxalate was dissolved easily in methanol and dimethyl sulfoxide(DMSO), dissolved slightly in water
and ethanol, and dissolved tiny in ethyl acetate. Escitalopram Oxalate increasing weight 1.867%, after it was deposited in condition of high humidity. Relevant substance was controlled not more than 1.0%. The enantiomers of Citalopram Oxalate could be completely separated (R>1.5). The regression equation for Escitalopram Oxalate was As = 40224.778Cs+55.066 ( r = 0.9991, n=5) over the range of: 0.01 ~0.25mg/ml, and the regression equation for R-citalopram Oxalate was Ar = 1764.083CR+0.856, (r=0.9993, n=5 ) . This method allows accurate quantification for S- and R- citalopram Oxalate. R-citalopram Oxalate was requested not more than 5%. Only not more than 0.05% ethanol was found in determination of the residual organic volatile solvents. The other organic volatile solvents were not found in sample. Contents of Escitalopram Oxalate in production was 101.30% 100.46% and 99.60% ( RSD<1.30% ) . It was suitable for quantification criterion. Ultraviolet spectroscopy was validated, and the excipients did not interfer
e with determination of its tablets. The standard curve was linear within the range of 0.002-0.030 mg/ml with the correlation coefficient of 0.9998. The drug dissolution at 30min was above 80%. The results of study on uniformity show that its tablets accord with request of pharmacopoeia (A+1.8S<8) . Contents of the tablets in production was accurate. The average recovery was 99% with a relative standard deviation of 1.19%. Conclusion:
The quality standard can be used to evaluate and control effectively the quality of Escitalopram Oxalate. Escitalopram Oxalate and its tablets conform to the quality requirements under new drug and its tablets of pharmacopoeia of P. R. China (part II, Edi2ooo)
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