RESUMEN
Rivastigmine is a drug against Alzheimer's disease, and is a non-pharmacopoeial compound. During the preparation of rivastigmine in our laboratory, two impurities were detected and identified with a simple and sensitive reversed-phase liquid chromatography coupled with electrospray-mass spectrometry. The same impurities were also observed in commercial batches. These impurities were isolated by preparative HPLC and co-injected with rivastigmine sample to confirm the retention times in HPLC. These impurities were characterized as N,N-dimethyl-3-[1-dimethylaminoethyl]phenylcarboxylate (dimethyl-rivastigmine) and N,N-diethyl-3-[1-dimethylaminoethyl]phenylcarboxamide (diethyl-rivastigmine). Structural elucidation of these impurities by spectral data (1H NMR, 13C NMR and MS) is discussed.
Asunto(s)
Inhibidores de la Colinesterasa/análisis , Contaminación de Medicamentos , Fenilcarbamatos/análisis , Cromatografía Líquida de Alta Presión , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Rivastigmina , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Three process-related impurities were observed in routine monitoring of the samples by HPLC. These impurities were identified by LC-MS. One of the impurities, Imp-3 [rizatriptan-2,5-dimer] was reported in literature. Other two impurities were isolated by preparative HPLC and characterized by NMR, Mass and IR. Pure impurities obtained by isolation were co-injected with Rizatriptan benzoate sample to confirm the retention times in HPLC. Structure elucidation of these impurities by spectral data has been discussed in detail. These impurities were identified as 4-(5-((1H-1,2,4-triazol-1-yl)methyl)-3-(2-(dimethylamino)ethyl)-1H-indol-1-yl)-4-(5-((1H-1,2,4-triazol-1-yl)methyl)-3-(2-(dimethylamino)ethyl)-1H-indol-2-yl)-N,N-dimethylbutan-1-amine [rizatriptan-1,2-dimer] and [4,4-bis-(5-((1H-1,2,4-triazol-1-yl)methyl)-3-(2-(dimethylamino)-ethyl)-1H-indol-2-yl)-N,N-dimethylbutan-1-amine [rizatriptan-2,2-dimer].
Asunto(s)
Contaminación de Medicamentos , Agonistas de Receptores de Serotonina/química , Triazoles/química , Triptaminas/química , Cromatografía Líquida de Alta Presión/métodos , Espectroscopía de Resonancia Magnética/métodos , Espectrometría de Masas/métodos , Estructura Molecular , Reproducibilidad de los Resultados , Agonistas de Receptores de Serotonina/análisis , Agonistas de Receptores de Serotonina/normas , Espectrofotometría Infrarroja/métodos , Triazoles/análisis , Triazoles/normas , Triptaminas/análisis , Triptaminas/normasRESUMEN
Clindamycin palmitate hydrochloride is a water soluble hydrochloride salt of the ester of clindamycin and palmitic acid. It is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin. Total 12 impurities at levels ranging from 0.05% to 0.5% were detected by isocratic reverse-phase high performance liquid chromatography (HPLC) using RI detector. The molecular weights of impurities were determined by LC-MS analysis. Two impurities were starting materials and the remaining impurities were isolated from crude samples/enriched mother liquors using reverse-phase preparative HPLC. Based on the spectral data the structures of these impurities were characterized as, clindamycin palmitate sulphoxides alpha-/beta-isomers (impurity I); clindamycin laurate (impurity II); lincomycin palmitate (impurity III); clindamycin myristate (impurity IV); epiclindamycin palmitate (impurity V); clindamycin palmitate 3-isomer (impurity VI); clindamycin pentadecanoate (impurity VII); clindamycin B-palmitate (impurity VIII); clindamycin heptadecanoate (impurity IX) and clindamycin stearate (impurity X). Structural elucidation of all impurities by spectral data ((1)H NMR, (13)C NMR, MS and IR) and formation of these impurities have been discussed in detail.
Asunto(s)
Antibacterianos/química , Cromatografía Líquida de Alta Presión/métodos , Clindamicina/análogos & derivados , Contaminación de Medicamentos , Clindamicina/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Peso Molecular , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Infrarroja , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Several related substances (RS4-RS10) were detected in lopinavir drug substance at levels ranging from 0.03% to 0.1% by employing gradient RP-HPLC. The related substances were identified by LC-MS analysis. These related substances were isolated and characterized by Mass, (1)H NMR and FT-IR spectral data. The separation was achieved on a YMC Pack ODS-AQ (250 mm x 4.6 mm, 5 microm) column thermostated at 45 degrees C using 0.02 M KH(2)PO(4) (pH 2.5): acetonitrile as a mobile phase in gradient elution mode. A PDA detector set at 210 nm was used for detection. The investigated validation elements showed the method has acceptable specificity, accuracy, linearity, precision, robustness and high sensitivity with detection limits and quantitation limits ranging from 0.028 microg/ml to 0.063 microg/ml and 0.084 microg/ml to 0.192 microg/ml respectively. The method can be used for routine quality control analysis and stability testing of lopinavir drug substance.
Asunto(s)
Contaminación de Medicamentos , Inhibidores de la Proteasa del VIH/química , Preparaciones Farmacéuticas/química , Pirimidinonas/química , Tampones (Química) , Cromatografía Líquida de Alta Presión/instrumentación , Cromatografía Líquida de Alta Presión/métodos , Estabilidad de Medicamentos , Guías como Asunto , Inhibidores de la Proteasa del VIH/análisis , Inhibidores de la Proteasa del VIH/síntesis química , Concentración de Iones de Hidrógeno , Lopinavir , Espectrometría de Masas , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Preparaciones Farmacéuticas/análisis , Fosfatos/química , Compuestos de Potasio/química , Pirimidinonas/análisis , Pirimidinonas/síntesis química , Control de Calidad , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectroscopía Infrarroja por Transformada de Fourier , Temperatura , Factores de Tiempo , Agua/químicaRESUMEN
In the process for the preparation of quetiapine fumarate (1), six unknown impurities and one known impurity (intermediate) were identified ranging from 0.05-0.15% by reverse-phase HPLC. These impurities were isolated from crude samples using reverse-phase preparative HPLC. Based on the spectral data, the impurities were characterized as 2-[4-dibenzo[b,f][1,4]thiazepine-11-yl-1 -piperazinyl]1 -2-ethanol (impurity I, desethanol quetiapine), 11-[(N-formyl)-1-piperazinyl]-dibenzo[b,f][1,4]thiazepine (impurity II, N-formyl piperazinyl thiazepine), 2-(2-hydroxy ethoxy)ethyl-2-[2-[4-dibenzo[b,f][1,4]thiazepine-11- piperazinyl-1-carboxylate (impurity III, quetiapine carboxylate), 11-[4-ethyl-1-piperazinyl]dibenzo [b,f][1,4] thiazepine (impurity IV, ethylpiperazinyl thiazepine), 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]1-ethyl ethanol [impurity V, ethyl quetiapine), 1,4-bis[dibenzo[b,f][1,4]thiazepine-11-yl] piperazine [impurity VI, bis(dibenzo)piperazine]. The known impurity was an intermediate, 11-piperazinyldibenzo [b,f][1,4]thiazepine (piperazinyl thiazepine). The structures were established unambiguously by independent synthesis and co-injection in HPLC to confirm the retention times. To the best of our knowledge, these impurities have not been reported before. Structural elucidation of all impurities by spectral data (1H NMR, 13C NMR, MS and IR), synthesis and formation of these impurities are discussed in detail.
Asunto(s)
Dibenzotiazepinas/química , Cromatografía Líquida de Alta Presión , Contaminación de Medicamentos , Espectroscopía de Resonancia Magnética , Fumarato de Quetiapina , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
One unknown impurity (degradation product) present at a level below 0.1% in the initial samples increased to a level of 0.5% in 6M/40 degrees C/75% RH stability samples of risperidone tablets was detected by gradient reverse-phase high-performance liquid chromatography (HPLC). This impurity was isolated using reverse-phase preparative liquid chromatography. Based on the spectral data the structure of this impurity is characterized as 3-[2-[4-[6-fluoro-1,3-benzoxazol-2-yl]piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidin-4-one. Structural elucidation of this impurity by spectral data ((1)H NMR, (13)C NMR, DEPT, MS and IR), formation and mechanism has been discussed in detail.
Asunto(s)
Contaminación de Medicamentos , Isoxazoles/química , Risperidona/análogos & derivados , Risperidona/química , Antipsicóticos/química , Cromatografía Líquida de Alta Presión/métodos , Estabilidad de Medicamentos , Calor , Isoxazoles/aislamiento & purificación , Luz , Espectroscopía de Resonancia Magnética/métodos , Espectrometría de Masas/métodos , Modelos Químicos , Estructura Molecular , Risperidona/aislamiento & purificación , ComprimidosRESUMEN
Didanosine is an antiviral drug. During the preparation of didanosine in our lab, six process related known impurities and one unknown impurity were detected in HPLC analysis at levels ranging from 0.05 to 0.8%. The same unknown impurity was also observed in commercial batches. This new impurity was isolated by preparative HPLC and co-injected with didanosine sample to confirm the retention times in HPLC. This impurity was characterized as, 9-(2,3,5-trideoxy-beta-D-glycero-pentofuranosyl)-9H-purin-6-one (2',3',5'-trideoxyinosine). Structural elucidation of this impurity by spectral data (1H NMR, 13C NMR, MS and IR) has been discussed.
Asunto(s)
Fármacos Anti-VIH/análisis , Didanosina/análisis , Contaminación de Medicamentos , Inosina/análogos & derivados , Cromatografía Líquida de Alta Presión , Contaminación de Medicamentos/prevención & control , Inosina/análisis , Espectroscopía de Resonancia Magnética , Estructura Molecular , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría de Masas en TándemRESUMEN
Zaleplon is a pyrazolopyrimidine derivative and possesses sedative and hypnotic properties. Seven unknown impurities in zaleplon bulk drug at levels below 0.1% were detected by reverse-phase high performance liquid chromatography (HPLC). The starting material, 3-amino-4-cyanopyrazole and an intermediate, N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]-phenyl]-N-ethylacetamide (DOPEA) were also present in the sample at a level below 0.1%. The molecular weights of impurities were determined by LC-MS analysis. These impurities were isolated from crude samples of zaleplon using reverse-phase preparative HPLC. Based on the spectral data the structures of these impurities were characterized as, N-(3-(3-(4-amino-2H-pyrazolo [3,4-d]pyrimidin-6-yl) pyrazolo[1,5-a] pyrimidin-7-yl)phenyl)-N-ethylacetamide (impurity I); N-[3-(3-carboxamidopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide (impurity II); N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]acetamide (impurity III); N-[3-(3-cyanopyrazolo [1,5-a]pyrimidin-7-yl)phenyl]-N-methylacetamide (impurity IV); N-[3-(3-cyanopyrazolo[1,5-a] pyrimidin-5-yl)phenyl]-N-ethylacetamide (impurity V); N-[3-(3-cyanopyrazolo[1,5-a] pyrimidin-7-yl)phenyl]-N-ethylamine (impurity VI); N-[3-(3-cyano-6-[(E)-3-((N-ethyl-N-acetyl)amino)phenyl-3-oxoprop-1-enyl] pyrazolo[1,5-a]pyrimidin-7-yl) phenyl]-N-ethylacetamide (impurity VII). Structural elucidation of all impurities by spectral data ((1)H NMR, (13)C NMR, MS and IR) and formation of these impurities are discussed in detail.
Asunto(s)
Acetamidas/análisis , Contaminación de Medicamentos , Hipnóticos y Sedantes/análisis , Pirimidinas/análisis , Acetamidas/síntesis química , Acetamidas/química , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Peso Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Espectroscopía Infrarroja por Transformada de Fourier , Temperatura de TransiciónRESUMEN
Ceftizoxime sodium is a parenteral beta-lactamic antibacterial drug. In the synthesis of ceftizoxime sodium, eight process related impurities were detected in HPLC analysis. Pure impurities obtained by both synthesis and preparative HPLC were co-injected with ceftizoxime sample to confirm the retention times in HPLC. The impurities were characterized as, (6R,7R)-7-amino-3-cephem-4-carboxylic acid (impurity I); (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-cephem-1-oxo-4-carboxylic acid (impurity II); (4RS,6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetamido]-3,4-dihydro-3-cephem-4-carboxylic acid (impurity III); (6R,7R)-7-[(E)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylic acid (impurity IV); (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-cephem-N-(3-cephem-4-carboxy-7-yl)-4-carboxamide (impurity V); (6R,7R)-7-[(Z)-2-[[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetylamino]thiazol-4-yl]-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (impurity VI); 2-mercaptobenzothiazole (impurity VII) and 2-mercapto benzothiazolyl [(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino] acetate (impurity VIII). Structural elucidation of all impurities by spectral data ((1)H NMR, (13)C NMR, MS and IR) has been discussed.