Studies On The Quality Control For M-Nisoldipine

Dihydropyridine calcium antagonists (DHP) are widelyused in clinic to treat ischermic cardio-cerebral vasculardiseases, hypertension, etc. with significant effect. But thephotostability of this kind of drugs is very weak, which cause alot of inconvenience to the process of producing, storing andtransporting. m-Nisoldipine is a new kind of DHPs which wasdeveloped by School of Pharmacy of Hebei Medical University.Some tests showed that pharmacological effect and toxity ofm-nisoldipine were similar to that of nisoldipine. And thephotostability of m-nisoldipine was superior to the same kindof drugs. But m-nisoldipine is a first developed drug, which hasno reasonable or efficient standard to control its quality. Ourresearch aims to study the quality of m-nisoldipine in order toestablish a base of drawing a quality standard.Objective: To study physical and chemical properties ofm-nisoldipine which relate to its quality in order to draw aquality standard.Methods: (1) Physical and chemical properties:â‘ Solubility: According to ChP (2000), the solublity ofm-nisoldipine was investigated in ordinary solvent. â‘¡Meltingpoint: The melting point was determinined of m-nisoldipine byusing the method from ChP (2000). â‘¢The standard absorptioncoefficient[E_1cm^1%]: According to The direction of chemicalmedicine and biological product for treating, the standardabsorption coefficient of m-nisoldipine was determined with 5different type of instrument. (2)Identification: â‘ Chemicalmethod: Take some m-nisoldipine and valilla aldehyde, mixwith sulfuric acid, and then heat it in water. Keep it to be cold,add some ethanol, and observe the phenomenon. â‘¡UV: Takethe sample and reference substance of m-nisoldipine, anddissolve it with ethanol absolute to a concentration of 15μg/ml.Scan the solutions from 200nm to 400nm wavelength. â‘¢IR:Take the sample of m-nisoldipine and press it into tablet withKBr, then record the spectrum and compare with that of thereference. â‘£HPLC: Take some m-nisoldipine and make asolution having a known concentration of 0.05mg/ml withmethanol. The mobile phase was a mixture containing 70volume of methanol and 30 volume of water. The detectionwavelength was set at 237nm. Record the chromatograph andcompare it with that of the reference. (3)Test: â‘ Ordernaryimpurity: According to the appendix of the ChP (2000), thechloride and sulphate, loss on drying, residue on ignition,heavy metal and arsenic was checked. â‘¡Related substances:Two methods including TLC and HPLC were adopted to testthe related substances in m-nisoldipine. (4)Assay: Ceriumsulphate method, UV and HPLC were used to determinem-nisoldipine, and the results of three methods were compared.Results: (1)The physical and chemical properties:â‘ Solubility: m-Nisoldipine can be easily dissolved inchloroform or acetone, slightly dissolved in methanol orethanol, and can not be dissolved in water. â‘¡Melting point:m-Nisoldipine's melting point was the range from 134℃to137 ℃. â‘¢The standard absorption coefficient[E_1cm^1%]: Thestandard absorption coefficients of m-nisoldipine at 237nm and353nm wavelength are 721.9 and 174.3. (2)Identification:â‘ Chemical method: The sample showed brown color whenheated in water, and showed purple after added ethanol. â‘¡UV:The sample had maximum absorption at 237nm and 353nm,being the same as the reference. â‘¢IR: The infrared absorptionspectrogram of the sample was accorded to that of thereference. â‘£HPLC: Retention time of m-nisoldipine inchromatogram of sample was the same as the reference. (3)Test:â‘ ordernary impurity: After the test, the content of cholride inm-nisoldipine was not more than 0.01%, and the content ofsulphate was not more than 0.1%. Loss on drying:m-Nisoldipine was dried to constant weight at 105℃. The losswas not more than 0.5%. Residue on ignition: After be ignitedat 500⁶00℃, the residue of m-nisoldipine was not more than0.1%. Heavy metal: According to the ChP (2000), the residueon ignition was used to be tested, and the assay of heavy metalwas not more than 10ppm. Arsenic: Comparing the color of thearsenic spot of the sample with the standard, the spot from thesample must be not more intense than that from the standard.The limit of the arsenic was 2ppm. â‘¡The related substances:Two developing solution were used for TLC, which were amixture of chloroform-toluene-methanol (3:4:1) or a mixture ofcyclohexane-ethyl acetate-ethanol (6:2:1). The sample showedclear without other second spot. The LOD was 0.76μg.Chromatogram condition of HPLC was determined: the systemwas carried out using ODS column and the mobile phase ofmethanol-water (70:30) with flow rate of 1.0ml/min and thedetection wavelength was at 237nm. The LOD was 0.30ng.With qualitative, quantitative and sensitive character,RP-HPLC was used to determine the related substances inm-nisoldipine. The limit of impurity was 2.0%. (4)Assay: Incerium sulphate method, the precise was very well with RSDof the reproducibility of 0.13%. The results which we gotfrom three methods were consistent. The assay of the samplewas not less than 98.5%. At last, cerium sulphate method wasascertained as the method of assay.Conclusion: The methods of identification, test and assayfor m-nisoldipine were established, which provided a guidelinewith quality control.The preparation of m-nisoldipine has been manufactured.In order to ensure the quality of the preparation, we studied itscharacter and established efficient and simple methods todetect.Objective: To study the method of identification, test andassay for m-nisoldipine tablets in order to establish a base ofdrawing a quality standard.Methods: (1) Identification: â‘ Chemical method: Takesome powder of m-nisoldipine tablets and valilla aldehyde, mixwith sulfuric acid,and then heat it in water. Keep it to be cold,add some ethanol, and observe the phenomenon. â‘¡UV: Takethe sample of m-nisoldipine tablets and dissolve it with ethanolwithout water to a concentration of 15μg/ml. Scan the solutionfrom 200nm to 400nm wavelength. â‘¢HPLC: Take somepowder of m-nisoldipine tablets and make a solution having aconcentration of about 0.05mg/ml with methanol. The mobilephase was a mixture containing 70 volume of methanol and 30volume of water. The detection wavelength was set at 237nm.Record the chromatograph and compare it with that of thereference. (2)Test: â‘ The related substances: HPLC was usedfor checking the related substances of m-nisoldipine tablets.â‘¡Dissolution: 0.2% of SDS was added to the solvent of0.1mol/L hydrochloric acid. According to the related method inChP (2000), the rotate speed was set at 100r/min. At 45min,solution was taken out to determine by HPLC. â‘¢Uniformity ofdosage units: The specification of the preparation is 10mg pertablet, so the uniformity of dosage units should be tested toensure the quality. (3)Assay: UV and HPLC were used todetermine the content of m-nisoldipine tablets. The results oftwo methods were compared.Results: (1) Identification: â‘ Chemical method: Thesample showed brown color when heated in water, and showedpurple after added ethanol. â‘¡UV: The sample had themaximum ultraviolet absorption at 237nm and 353nm.â‘¢HPLC: Retention time of m-nisoldipine in chromatogram ofsample was the same as the reference. (2)Test: â‘ The relatedsubstances: The limit of impurity was 3.0%, and the LOD was0.10ng. The method was sensitive. â‘¡Dissolution: The linearityrange was 2.01μg/ml～18.09μg/ml with egression equation ofY=65475X+273584(r=0.9997). The RSD values of precisionand reproducibility were 0.10% and 0.89%. The averagerecovery was 99.53% with RSD of 0.86%. At 45min, thedissolution rate was mot less than 75%. â‘¢Uniformity ofdosage units: UV was used to test because this method wassimple and accurate. (3)Assay: â‘ UV: The linearity range was...