Analysis And Control Of The Impurity In Spironolactone

Spironolactone is classified as potassium-retain diuretic drug. Aim to improveproduct quality thus to promote the product into regulatory markets of European andAmerica more smoothly, the author of this thesis conducts analysis and research onImpurity profile of spironolactone, furthermore optimization to production process aswell.First of all, define the analytical method of impurity detection of spironolactone,then the accuracy, precision, specificity, limit of detection, limit of qualification,linearity and range, and robustness of the optimized analytical method are validated.By summarizing impurities testing results of10consecutive batches, we identifythat four impurities can be detected in spironolactone, three of which are more than0.10%. To comply with ICH Q3A and customers’ requirements on impurity structureand impurity standards, we perform structure identification of the three impurities.Through separation, impurities are aggregated and purified, by MS and NMR aswell other spectrum analysis we obtain chemical structure of impurities: impurityA:7α-acetylthio-17α,21-hydroxy-3-oxo-pregn-4-ene-21-cardoxylic acid, γ-lactone,impurity B:7α-acetylthio-17β-ethoxy methyl-17α-hydroxy-trione androst, impurity C:7α–acetylthio-17α–hydroxyl–3–oxo-pregn-1,4-diene-21-cardoxylic acid,γ-lactone. After this, we make a conclusion on the generation mechanism of impurities,all of the three impurities are by-products generated in synthesis reaction, in whichimpurity A firstly as a by-product of deesterification process is finally generated bycondensation reaction, impurity B previously as a by-product of lactonization process isfinally generated by condensation reaction with canrenone, impurity C originally as aby-product of dehydrogenation process is finally generated by lactonization,deesterification and condensation process.As a follow-up, we conduct orthogonal selecting experiments to control impurity Aand C. And also make improvement to generation process which generates impurity B,by doing this, not only the quantity of all the intermediates have been improved, also theassay of impurity A, B, C have been decreased0.18%,0.10%,0.08%respectively. Theimpurities of spironolactone are successfully and quantitatively controlled in productionprocess, and finally the aim to control impurities assay is obtained.