A rapid GC-FID method was developed to simultaneously determine residual levels of triethylamine(TEA), 1,1,3,3-tetramethylguanidine(TMG), and diisopropylamine(DIPA) in the synthetic route of an active pharmaceutical i...A rapid GC-FID method was developed to simultaneously determine residual levels of triethylamine(TEA), 1,1,3,3-tetramethylguanidine(TMG), and diisopropylamine(DIPA) in the synthetic route of an active pharmaceutical ingredient(API). Due to the severe absorption of amines on GC stationary phases,GC columns with various stationary phases were evaluated for optimal peak shape and reproducibility.The final conditions used the Agilent CP-Volamine column to resolve the three amines in 12 min. Various inlet liners were also screened to further improve the sensitivity of the analysis. The Restek Siltek~? liner was selected to achieve the desired detectability for the method. The quantitation limits were 4, 3, and 4 mg/mL for TEA, DIPA, and TMG in the presence of API, respectively. All three amines showed good linearity(r > 0.999) and recoveries(> 90%) over the concentration range of 3 to 16 mg/mL. The testing of residual amines was initially performed at the penultimate stage of the synthesis. However, this work demonstrates that TMG can act as a proton sponge to react with salicylic acid, the counter ion of the penultimate, to form a volatile component that elutes at a different retention time. Consequently, in the final method, these three amines were monitored in the final API to circumvent the matrix interference.Key parameters of the method were qualified per method validation requirements in ICH guidelines. The method was successfully applied for batch testing during development and implemented as an inprocess control procedure at manufacturing sites.展开更多
A rapid, simple and single stereo selective high-performance liquid chromatographic (HPLC) method was developed and validated for enantiomers of palonosetron hydrochloride (PALO) and its process related chiral impurit...A rapid, simple and single stereo selective high-performance liquid chromatographic (HPLC) method was developed and validated for enantiomers of palonosetron hydrochloride (PALO) and its process related chiral impurities. A computer simulating software was used for the development of chiral method. The developed method was able to separate not only the enantiomers of palonosetron hydrochloride but also its process related chiral impurities within 12 min. The chromatographic separation was carried out by normal phase chromatography using a 3 μm column of cellulose based chiral stationary phase (Chiralcel-OD 250mm × 4.6mm) with a mobile phase comprised of n-hexane: ethanol: methanol: heptafluoro butyric acid: diethyl amine (70:15:15:0.05:0.1, v/v) at a flow rate of 1.0 mL/min. The effects of additive concentration as well as nature of polar organic modifier, flow rate, and temperature on enantioselectivity were investigated. The limit of detection (LOD) and limit of quantification (LOQ) of the palonosetron isomers and its related chiral impurities were found to be in the range 0.06-0.10 μg/mL and 0.14 - 0.24 μg/mL respectively. The method showed excellent linearity (R2 > 0.998) over a range of 0.14 to 1.125 μg/mL. The percentage recovery of the isomers in bulk drug samples ranged from 87.0 to 116.0.展开更多
The present study deals with the forced degradation behavior of dexlansoprazole under International Conference on Harmonisation(ICH)prescribed stress conditions. The drug was found to be more labile under acid,base,ne...The present study deals with the forced degradation behavior of dexlansoprazole under International Conference on Harmonisation(ICH)prescribed stress conditions. The drug was found to be more labile under acid,base,neutral,oxidative hydrolysis and thermal stress,while it was moderately stable under photolytic conditions. The known and unknown degradation products were separated on a C-18 column using a stabilityindicating method. Liquid chromatography-mass spectrometry(LC-MS)analysis was performed for all the degradation studies. Isolation and structure characterization of oxidation degradation products were executed using sophisticated tools,viz. preparative high performance liquid chromatography(HPLC),liquid chromatographymass spectrometry / time of flight(LC-MS / TOF),liquid chromatography-tandem mass spectrometry(LC-MS /MS),and nuclear magnetic resonance(NMR). This study demonstrates an ample methodology of degradation studies and structure elucidation of unknown degradation products of dexlansoprazole,which helps in the development and stability study of active pharmaceutical ingredients and formulated products.展开更多
A sensitive,stability-indicating gradient reverse phase ultra performance liquid chromatographic method has been developed for the quantitative estimation of nebivolol impurities in active pharmaceutical ingredient(AP...A sensitive,stability-indicating gradient reverse phase ultra performance liquid chromatographic method has been developed for the quantitative estimation of nebivolol impurities in active pharmaceutical ingredient(API)and pharmaceutical formulation.Efficient chromatographic separation was achieved on an Acquity BEH C18 column(100 mm×2.1 mm,1.7μm)with mobile phase of a gradient mixture.The flow rate of the mobile phase was 0.18 mL/min with column temperature of 30℃and detection wavelength of 281 nm.The relative response factor values of(R*)-2-(benzylamino)-1-((S*)-6-fluorochroman-2-yl)ethanol((R*S*)NBV-1),(R)-1-((R)-6-fluorochroman-2-yl)-2-((S)-2-((S)-6-fluoro-chroman-2-yl)-2-hydroxyethylamino)ethanol((RRSS)NBV-3),1-(chroman-2-yl)-2-(2-(6-fluorochroman-2-yl)-2-hydroxy ethyl amino)ethanol(monodesfluoro impurity),(S)-1-((R)-6-fluorochroman-2-yl)-2-((R)-2((S)-6-fluoro-chroman-2-yl)-2-hydroxyethylamino)ethanol hydrochloride((RSRS)NBV-3)and(R*)-1-((S*)-6-fluorochroman-2-yl)-2-((S*)-2-((S*)-6-fluoro-chroman-2-yl)-2-hydroxyethylamino)ethanol((R*S*S*S*)NBV-2)were 0.65,0.91,0.68,0.92 and 0.91 respectively.Nebivolol formulation sample was subjected to the stress conditions of acid,base,oxidative,hydrolytic,thermal,humidity and photolytic degradation.Nebivolol was found to degrade significantly under peroxide stress condition.The degradation products were well resolved from nebivolol and its impurities.The peak purity test results confirmed that the nebivolol peak was homogenous and pure in all stress samples and the mass balance was found to be more than 98%,thus proving the stability-indicating power of the method.The developed method was validated according to International Conference on Hormonization(ICH)guidelines with respect to specificity,linearity,limits of detection and quantification,accuracy,precision and robustness.展开更多
Online monitoring of chemical reactions by using analytical chemistry tools is a powerful way to maximize control over these processes.In this paper,we demonstrate the use of molecular rotational resonance,an emerging...Online monitoring of chemical reactions by using analytical chemistry tools is a powerful way to maximize control over these processes.In this paper,we demonstrate the use of molecular rotational resonance,an emerging and extraordinarily selective spectroscopic technique,to perform automated reaction monitoring measurements.An interface using a six-port valve with a calibrated sample loop,coupled to a temperature controlled inlet for analyte volatilization,was developed and tested.Two reactions were chosen for initial characterization:an amine-aldehyde condensation reaction to form an imine product and an isotopic exchange reaction of aβ-ketoester with keto-enol tautomerization.The spectrometer was able to provide kinetic information about the reaction and determine reaction completion.In the future,this system can be extended to detect and quantify impurities and characterize reaction selectivity,in addition to the reaction progress.展开更多
文摘A rapid GC-FID method was developed to simultaneously determine residual levels of triethylamine(TEA), 1,1,3,3-tetramethylguanidine(TMG), and diisopropylamine(DIPA) in the synthetic route of an active pharmaceutical ingredient(API). Due to the severe absorption of amines on GC stationary phases,GC columns with various stationary phases were evaluated for optimal peak shape and reproducibility.The final conditions used the Agilent CP-Volamine column to resolve the three amines in 12 min. Various inlet liners were also screened to further improve the sensitivity of the analysis. The Restek Siltek~? liner was selected to achieve the desired detectability for the method. The quantitation limits were 4, 3, and 4 mg/mL for TEA, DIPA, and TMG in the presence of API, respectively. All three amines showed good linearity(r > 0.999) and recoveries(> 90%) over the concentration range of 3 to 16 mg/mL. The testing of residual amines was initially performed at the penultimate stage of the synthesis. However, this work demonstrates that TMG can act as a proton sponge to react with salicylic acid, the counter ion of the penultimate, to form a volatile component that elutes at a different retention time. Consequently, in the final method, these three amines were monitored in the final API to circumvent the matrix interference.Key parameters of the method were qualified per method validation requirements in ICH guidelines. The method was successfully applied for batch testing during development and implemented as an inprocess control procedure at manufacturing sites.
文摘A rapid, simple and single stereo selective high-performance liquid chromatographic (HPLC) method was developed and validated for enantiomers of palonosetron hydrochloride (PALO) and its process related chiral impurities. A computer simulating software was used for the development of chiral method. The developed method was able to separate not only the enantiomers of palonosetron hydrochloride but also its process related chiral impurities within 12 min. The chromatographic separation was carried out by normal phase chromatography using a 3 μm column of cellulose based chiral stationary phase (Chiralcel-OD 250mm × 4.6mm) with a mobile phase comprised of n-hexane: ethanol: methanol: heptafluoro butyric acid: diethyl amine (70:15:15:0.05:0.1, v/v) at a flow rate of 1.0 mL/min. The effects of additive concentration as well as nature of polar organic modifier, flow rate, and temperature on enantioselectivity were investigated. The limit of detection (LOD) and limit of quantification (LOQ) of the palonosetron isomers and its related chiral impurities were found to be in the range 0.06-0.10 μg/mL and 0.14 - 0.24 μg/mL respectively. The method showed excellent linearity (R2 > 0.998) over a range of 0.14 to 1.125 μg/mL. The percentage recovery of the isomers in bulk drug samples ranged from 87.0 to 116.0.
基金the management of Dr. Reddy’s Laboratories Ltd. for supporting this work
文摘The present study deals with the forced degradation behavior of dexlansoprazole under International Conference on Harmonisation(ICH)prescribed stress conditions. The drug was found to be more labile under acid,base,neutral,oxidative hydrolysis and thermal stress,while it was moderately stable under photolytic conditions. The known and unknown degradation products were separated on a C-18 column using a stabilityindicating method. Liquid chromatography-mass spectrometry(LC-MS)analysis was performed for all the degradation studies. Isolation and structure characterization of oxidation degradation products were executed using sophisticated tools,viz. preparative high performance liquid chromatography(HPLC),liquid chromatographymass spectrometry / time of flight(LC-MS / TOF),liquid chromatography-tandem mass spectrometry(LC-MS /MS),and nuclear magnetic resonance(NMR). This study demonstrates an ample methodology of degradation studies and structure elucidation of unknown degradation products of dexlansoprazole,which helps in the development and stability study of active pharmaceutical ingredients and formulated products.
文摘A sensitive,stability-indicating gradient reverse phase ultra performance liquid chromatographic method has been developed for the quantitative estimation of nebivolol impurities in active pharmaceutical ingredient(API)and pharmaceutical formulation.Efficient chromatographic separation was achieved on an Acquity BEH C18 column(100 mm×2.1 mm,1.7μm)with mobile phase of a gradient mixture.The flow rate of the mobile phase was 0.18 mL/min with column temperature of 30℃and detection wavelength of 281 nm.The relative response factor values of(R*)-2-(benzylamino)-1-((S*)-6-fluorochroman-2-yl)ethanol((R*S*)NBV-1),(R)-1-((R)-6-fluorochroman-2-yl)-2-((S)-2-((S)-6-fluoro-chroman-2-yl)-2-hydroxyethylamino)ethanol((RRSS)NBV-3),1-(chroman-2-yl)-2-(2-(6-fluorochroman-2-yl)-2-hydroxy ethyl amino)ethanol(monodesfluoro impurity),(S)-1-((R)-6-fluorochroman-2-yl)-2-((R)-2((S)-6-fluoro-chroman-2-yl)-2-hydroxyethylamino)ethanol hydrochloride((RSRS)NBV-3)and(R*)-1-((S*)-6-fluorochroman-2-yl)-2-((S*)-2-((S*)-6-fluoro-chroman-2-yl)-2-hydroxyethylamino)ethanol((R*S*S*S*)NBV-2)were 0.65,0.91,0.68,0.92 and 0.91 respectively.Nebivolol formulation sample was subjected to the stress conditions of acid,base,oxidative,hydrolytic,thermal,humidity and photolytic degradation.Nebivolol was found to degrade significantly under peroxide stress condition.The degradation products were well resolved from nebivolol and its impurities.The peak purity test results confirmed that the nebivolol peak was homogenous and pure in all stress samples and the mass balance was found to be more than 98%,thus proving the stability-indicating power of the method.The developed method was validated according to International Conference on Hormonization(ICH)guidelines with respect to specificity,linearity,limits of detection and quantification,accuracy,precision and robustness.
文摘Online monitoring of chemical reactions by using analytical chemistry tools is a powerful way to maximize control over these processes.In this paper,we demonstrate the use of molecular rotational resonance,an emerging and extraordinarily selective spectroscopic technique,to perform automated reaction monitoring measurements.An interface using a six-port valve with a calibrated sample loop,coupled to a temperature controlled inlet for analyte volatilization,was developed and tested.Two reactions were chosen for initial characterization:an amine-aldehyde condensation reaction to form an imine product and an isotopic exchange reaction of aβ-ketoester with keto-enol tautomerization.The spectrometer was able to provide kinetic information about the reaction and determine reaction completion.In the future,this system can be extended to detect and quantify impurities and characterize reaction selectivity,in addition to the reaction progress.
