Benidipine hydrochloride, used as an antihypertensive agent and long-acting calcium antagonist, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studi...Benidipine hydrochloride, used as an antihypertensive agent and long-acting calcium antagonist, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studies of benidipine, process related impurities were detected. These impurities were identified, synthesized and characterized and mechanisms of their formation were discussed in detail. After all standardization procedures, they were used as reference standards for analytical studies. In addition, a separate HPLC method was developed and validated for detection of residual 1-benzylpi- peridin-3-ol （Ben-2）, which is used during benidipine synthesis and controlled as a potential process related impurity. As complementary of this work, stress-testing studies of benidipine were carried out under specified conditions and a stability-indicating UPLC assay method was developed, validated and used during stability studies of benidipine.展开更多
A stability-indicating reverse phase–high performance liquid chromatography（RP–HPLC） method was developed and validated for the determination of atazanavir sulfate in tablet dosage forms using C_（18） column Phen...A stability-indicating reverse phase–high performance liquid chromatography（RP–HPLC） method was developed and validated for the determination of atazanavir sulfate in tablet dosage forms using C_（18） column Phenomenix（250 mm×4.6 mm, 5 μm） with a mobile phase consisting of 900 mL of HPLC grade methanol and100 mL of water of HPLC grade. The pH was adjusted to 3.55 with acetic acid. The mobile phase was sonicated for 10 min and filtered through a 0.45 μm membrane filter at a flow rate of 0.5 mL/min. The detection was carried out at 249 nm and retention time of atazanavir sulfate was found to be 8.323 min. Linearity was observed from 10 to 90 μg/mL（coefficient of determination R^2 was 0.999） with equation, y=23.427x＋37.732.Atazanavir sulfate was subjected to stress conditions including acidic, alkaline, oxidation, photolysis and thermal degradation, and the results showed that it was more sensitive towards acidic degradation. The method was validated as per ICH guidelines.展开更多
Classification systems such as Slope Mass Rating(SMR) are currently being used to undertake slope stability analysis. In SMR classification system, data is allocated to certain classes based on linguistic and experien...Classification systems such as Slope Mass Rating(SMR) are currently being used to undertake slope stability analysis. In SMR classification system, data is allocated to certain classes based on linguistic and experience-based criteria. In order to eliminate linguistic criteria resulted from experience-based judgments and account for uncertainties in determining class boundaries developed by SMR system,the system classification results were corrected using two clustering algorithms, namely K-means and fuzzy c-means(FCM), for the ratings obtained via continuous and discrete functions. By applying clustering algorithms in SMR classification system, no in-advance experience-based judgment was made on the number of extracted classes in this system, and it was only after all steps of the clustering algorithms were accomplished that new classification scheme was proposed for SMR system under different failure modes based on the ratings obtained via continuous and discrete functions. The results of this study showed that, engineers can achieve more reliable and objective evaluations over slope stability by using SMR system based on the ratings calculated via continuous and discrete functions.展开更多
Spectrofluorimetric and spectrophotometric stability-indicating methods were developed and validated for analysis of veralipride （Ver） in presence of its hydrolytic and oxidative degradants. The spectrofluorimetric ...Spectrofluorimetric and spectrophotometric stability-indicating methods were developed and validated for analysis of veralipride （Ver） in presence of its hydrolytic and oxidative degradants. The spectrofluorimetric method was based on direct measurement of the intrinsic fluorescence of Ver at 366 nm after excitation at 299 nm using sodium lauryl sulfate （SLS） as micelle enhancer. The fluorescence intensity plot was linear over the concentration range 1.0-10.0 pg.mL-1. The high sensitivity of the method allowed its successful application to the analysis of Ver in spiked human plasma. Two other methods were developed. They are based on the oxidative coupling reac- tion of Vet with 3-methyl benzothiazolin-2-one hydrazone （MBTH） hydrochloride in presence of ceric ammonium sulphate in an acidic medium. The first method depends on spectrophotometric measurement of the stable green colored oxidative coupling product at 660 nm. The different experimental parameters affecting the reaction were optimized. Linearity range is 10.0--100.0 ~tgomL-1. The second method depends on a fluorescence quenching effect of Vet on the fluorescence of Ce3＋. The difference in fluorescence intensity was measured at 380 nm after excitation at 300 nm. This method is applicable over the concentration ranges 0.25-2.50 pg-mL-1. The methods were validated according to the ICH guidelines. They were successfully applied for the analysis of Ver in drug substance, drug product and in laboratory prepared mixtures containing different percentages of hydrolytic and oxidative degradants.展开更多
基金the management of Deva Holding A.S., Istanbul, Turkey, for supporting this workthe Scientific and Technological Research Council of Turkey (TUBITAK-TEYDEB Project no: 3110426) for the financial support
文摘Benidipine hydrochloride, used as an antihypertensive agent and long-acting calcium antagonist, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studies of benidipine, process related impurities were detected. These impurities were identified, synthesized and characterized and mechanisms of their formation were discussed in detail. After all standardization procedures, they were used as reference standards for analytical studies. In addition, a separate HPLC method was developed and validated for detection of residual 1-benzylpi- peridin-3-ol （Ben-2）, which is used during benidipine synthesis and controlled as a potential process related impurity. As complementary of this work, stress-testing studies of benidipine were carried out under specified conditions and a stability-indicating UPLC assay method was developed, validated and used during stability studies of benidipine.
文摘A stability-indicating reverse phase–high performance liquid chromatography（RP–HPLC） method was developed and validated for the determination of atazanavir sulfate in tablet dosage forms using C_（18） column Phenomenix（250 mm×4.6 mm, 5 μm） with a mobile phase consisting of 900 mL of HPLC grade methanol and100 mL of water of HPLC grade. The pH was adjusted to 3.55 with acetic acid. The mobile phase was sonicated for 10 min and filtered through a 0.45 μm membrane filter at a flow rate of 0.5 mL/min. The detection was carried out at 249 nm and retention time of atazanavir sulfate was found to be 8.323 min. Linearity was observed from 10 to 90 μg/mL（coefficient of determination R^2 was 0.999） with equation, y=23.427x＋37.732.Atazanavir sulfate was subjected to stress conditions including acidic, alkaline, oxidation, photolysis and thermal degradation, and the results showed that it was more sensitive towards acidic degradation. The method was validated as per ICH guidelines.
文摘Classification systems such as Slope Mass Rating(SMR) are currently being used to undertake slope stability analysis. In SMR classification system, data is allocated to certain classes based on linguistic and experience-based criteria. In order to eliminate linguistic criteria resulted from experience-based judgments and account for uncertainties in determining class boundaries developed by SMR system,the system classification results were corrected using two clustering algorithms, namely K-means and fuzzy c-means(FCM), for the ratings obtained via continuous and discrete functions. By applying clustering algorithms in SMR classification system, no in-advance experience-based judgment was made on the number of extracted classes in this system, and it was only after all steps of the clustering algorithms were accomplished that new classification scheme was proposed for SMR system under different failure modes based on the ratings obtained via continuous and discrete functions. The results of this study showed that, engineers can achieve more reliable and objective evaluations over slope stability by using SMR system based on the ratings calculated via continuous and discrete functions.
文摘Spectrofluorimetric and spectrophotometric stability-indicating methods were developed and validated for analysis of veralipride （Ver） in presence of its hydrolytic and oxidative degradants. The spectrofluorimetric method was based on direct measurement of the intrinsic fluorescence of Ver at 366 nm after excitation at 299 nm using sodium lauryl sulfate （SLS） as micelle enhancer. The fluorescence intensity plot was linear over the concentration range 1.0-10.0 pg.mL-1. The high sensitivity of the method allowed its successful application to the analysis of Ver in spiked human plasma. Two other methods were developed. They are based on the oxidative coupling reac- tion of Vet with 3-methyl benzothiazolin-2-one hydrazone （MBTH） hydrochloride in presence of ceric ammonium sulphate in an acidic medium. The first method depends on spectrophotometric measurement of the stable green colored oxidative coupling product at 660 nm. The different experimental parameters affecting the reaction were optimized. Linearity range is 10.0--100.0 ~tgomL-1. The second method depends on a fluorescence quenching effect of Vet on the fluorescence of Ce3＋. The difference in fluorescence intensity was measured at 380 nm after excitation at 300 nm. This method is applicable over the concentration ranges 0.25-2.50 pg-mL-1. The methods were validated according to the ICH guidelines. They were successfully applied for the analysis of Ver in drug substance, drug product and in laboratory prepared mixtures containing different percentages of hydrolytic and oxidative degradants.
