RESUMEN
Cevimeline is muscarinic receptor agonist which increases secretion of exocrine glands. Cevimeline base is a liquid (m.p. 20-25 °C) at ambient conditions, therefore its pharmaceutical formulation as a solid hydrochloride hemihydrate has been developed. The synthesis of cevimeline yields its cis- and trans-isomers and only the cis-isomer is recognized as the API and used in the finished formulation. In this study structural and physicochemical investigations of hydrochloride hemihydrates of cis- and trans-cevimelines have been performed. Single crystal X-ray analyses of both cis- and trans-isomers of cevimeline are reported here for the first time. It was found that the cis-isomer, the API, has less dense crystal packing, lower melting point and higher solubility in comparison to the trans-isomer.
Asunto(s)
Contaminación de Medicamentos , Quinuclidinas/análisis , Quinuclidinas/química , Tiofenos/análisis , Tiofenos/química , Difracción de Rayos X/métodos , Cristalografía por Rayos X/métodos , Agonistas Muscarínicos/análisis , Agonistas Muscarínicos/química , EstereoisomerismoRESUMEN
A selective and simple reversed phase HPLC method using naphthalethyl stationary phase was developed and validated for the quantitative determination of palonosetron hydrochloride (PALO), its related compounds and degradation products. Chromatographic separation (R(s)>2) was achieved with linear gradient mode of elution at a flow rate of 1 mL/min and with UV detection at 210 nm. The intra and inter-day coefficients of variation were less than 1.0% (RSD). Consistent recoveries were obtained for PALO (99.2-100.5%) and its impurities (90.0-104.8%). All the analytes exhibited excellent linearity with R² value greater than 0.998. Limit of detection (LOD) and limit of quantification (LOQ) were determined to be in the range 0.011-0.013 µg/mL and 0.035-0.046 µg/mL respectively. The test solution was found to be stable up to 5 days. Induced degradation methods were applied to study the degradation behavior of the drug. LC-MS was used to analyze the degraded samples and possible structural identifications were assigned based upon known reactivity of the drug and molecular weights. The m/z values matched with the hydroxylated, keto and N-oxide metabolites of PALO. The stress samples were assayed against a qualified reference standard and the mass balance was found close to 99.9%.
Asunto(s)
Cromatografía Líquida de Alta Presión , Cromatografía de Fase Inversa , Isoquinolinas/análisis , Naftalenos/química , Quinuclidinas/análisis , Antagonistas de la Serotonina/análisis , Tecnología Farmacéutica/métodos , Cromatografía Líquida de Alta Presión/normas , Cromatografía de Fase Inversa/normas , Estabilidad de Medicamentos , Concentración de Iones de Hidrógeno , Isoquinolinas/efectos de la radiación , Estructura Molecular , Palonosetrón , Fotólisis , Quinuclidinas/efectos de la radiación , Estándares de Referencia , Reproducibilidad de los Resultados , Antagonistas de la Serotonina/efectos de la radiación , Espectrofotometría Ultravioleta , Tecnología Farmacéutica/normas , TemperaturaRESUMEN
After the dosing of an extended-release (ER) formulation, compounds may exist in solutions at various concentrations in the colon because the drugs are released at various speeds from the ER dosage form. The aim of this study was to investigate the relationship between the drug concentration profiles in plasma and the drug doses in the colon. Several drug solutions of different concentrations were directly administered into the ascending colon of dogs using a lubricated endoscope, and the effects of the drug dose on colonic absorption were estimated. As a result, dose-dependency of colonic absorption varied from compound to compound. Although the relative bioavailability of colonic administration of diclofenac, metformin and cevimeline compared to oral administration was similar regardless of the drug doses in the colon, colonic absorption of diltiazem varied according to the doses. From the results of the co-administration of verapamil and fexofenadine, it was clear that diltiazem underwent extensive hepatic and gastrointestinal first-pass metabolism, resulting in a low area under the curves (AUC) at a low drug dose. During the design of oral ER delivery systems, a colonic absorption study of candidate compounds should be carried out at several solutions of different drug concentrations and assessed carefully.
Asunto(s)
Colon/metabolismo , Preparaciones de Acción Retardada/farmacocinética , Administración Oral , Animales , Antialérgicos/metabolismo , Antiarrítmicos/metabolismo , Antiinflamatorios no Esteroideos/análisis , Antiinflamatorios no Esteroideos/sangre , Antiinflamatorios no Esteroideos/farmacocinética , Antihipertensivos/análisis , Antihipertensivos/sangre , Antihipertensivos/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Preparaciones de Acción Retardada/análisis , Diclofenaco/análisis , Diclofenaco/sangre , Diclofenaco/farmacocinética , Diltiazem/análisis , Diltiazem/sangre , Diltiazem/farmacocinética , Perros , Relación Dosis-Respuesta a Droga , Hipoglucemiantes/análisis , Hipoglucemiantes/sangre , Hipoglucemiantes/farmacocinética , Metformina/análisis , Metformina/sangre , Metformina/farmacocinética , Agonistas Muscarínicos/análisis , Agonistas Muscarínicos/sangre , Agonistas Muscarínicos/farmacocinética , Quinuclidinas/análisis , Quinuclidinas/sangre , Quinuclidinas/farmacocinética , Terfenadina/análogos & derivados , Terfenadina/metabolismo , Tiofenos/análisis , Tiofenos/sangre , Tiofenos/farmacocinética , Verapamilo/metabolismoRESUMEN
AIMS: Solifenacin succinate is used for the treatment of overactive bladder (OAB). The potential for pharmacokinetic and/or pharmacodynamic interactions between solifenacin and warfarin or digoxin was investigated. METHODS: The solifenacin-warfarin study was a two-period crossover trial conducted in healthy males. Subjects received warfarin on the 10th day of 16 days of dosing with either solifenacin or placebo. The solifenacin-digoxin study was an one-sequence crossover trial conducted in healthy males and females. Following a phase-in period for digoxin, solifenacin was administered concomitantly with the drug on days 9-18. RESULTS: The AUC(PT; 0-168 h) following a single dose of warfarin was unchanged in the presence of solifenacin [point estimate = 1.005; 90% confidence interval (CI) 0.98, 1.02)]. The AUC(0-infinity) values for both warfarin enantiomers were also unchanged. A small increase in the C(max) of digoxin was observed during treatment with solifenacin, but for AUC(ss,tau) and C(max) the 90% CI fell within the prespecified interval of 0.80-1.25. Combined administration of solifenacin and warfarin or digoxin was well tolerated. CONCLUSIONS: Since the pharmacokinetics and pharmacodynamics of a single dose of warfarin and the steady-state pharmacokinetics of digoxin were not affected by coadministration of solifenacin in healthy subjects, the need for dosing adjustments for digoxin and/or warfarin does not seem warranted.
Asunto(s)
Anticoagulantes/farmacocinética , Cardiotónicos/farmacocinética , Digoxina/farmacocinética , Antagonistas Muscarínicos/administración & dosificación , Quinuclidinas/administración & dosificación , Tetrahidroisoquinolinas/administración & dosificación , Warfarina/farmacocinética , Administración Oral , Adulto , Anticoagulantes/administración & dosificación , Anticoagulantes/análisis , Área Bajo la Curva , Cardiotónicos/administración & dosificación , Cardiotónicos/análisis , Digoxina/administración & dosificación , Digoxina/análisis , Método Doble Ciego , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/efectos adversos , Antagonistas Muscarínicos/análisis , Quinuclidinas/efectos adversos , Quinuclidinas/análisis , Succinato de Solifenacina , Tetrahidroisoquinolinas/efectos adversos , Tetrahidroisoquinolinas/análisis , Warfarina/administración & dosificación , Warfarina/análisisRESUMEN
The 1H and 13C NMR spectra of six 5-substituted 2-azabicyclo[2.2.2]octane derivatives were fully assigned by COSY and HSQC experiments.
Asunto(s)
Espectroscopía de Resonancia Magnética/métodos , Quinuclidinas/análisis , Quinuclidinas/química , Isótopos de Carbono , Espectroscopía de Resonancia Magnética/normas , Protones , Valores de ReferenciaRESUMEN
A method based on the coupling of capillary electrophoresis with mass spectrometry (CE/MS) was developed for the monitoring of 3-quinuclidinol and its four N-alkyl derivatives (methyl, ethyl, propyl and isopropyl derivatives). A fragmentation study (collision-induced dissociation of ions in an ion trap) and optimization of the ion optics set-up for CE/MS experiments using direct infusion of a methanolic solution of the standards into the mass spectrometer were carried out in advance. Molecular ions of all quaternary compounds and the quasi-molecular ion [M + H]+ of free 3-quinuclidinol prevail in the mass spectra. In the MS/MS of propyl and isopropyl derivatives, the elimination of the alkyl chain dominates, leading to the ion at m/z 128. The fragmentation of the other compounds is more complex. Previous CE separation of the mixture of isobaric propyl and isopropyl derivatives is necessary for their unambiguous identification. A 10 mM ammonium acetate buffer (pH 4.0) is the optimum running electrolyte, allowing the CE separation of methyl, ethyl, propyl and isopropyl derivatives. A 0.5% (v/v) solution of acetic acid in methanol provides sufficient detection sensitivity when used as the sheath liquid. Limits of detection of 0.1 ppm for 3-quinuclidinol and 0.05 ppm for quaternary derivatives were achieved under the optimum conditions. The optimized method was applied to the determination of 3-quinuclidinol and related quaternary derivatives spiked into a sample of pond water. The experimental set-up for CE/MS/MS was investigated, which strongly increases the identification capability of the technique.
Asunto(s)
Electroforesis Capilar/métodos , Espectrometría de Masas/métodos , Quinuclidinas/análisis , Quinuclidinas/química , Contaminantes del Agua/análisis , Agua Dulce/química , Alucinógenos/análisis , Alucinógenos/química , Estructura Molecular , Quinuclidinil Bencilato/análogos & derivados , Quinuclidinil Bencilato/química , Sensibilidad y EspecificidadRESUMEN
A capillary electrophoresis (CE) method utilizing indirect ultraviolet (UV) detection was developed for the determination of a non-UV absorbing degradation product, Ro 5-5172, in clidinium bromide drug substance. The electrophoresis buffer consisted of sodium phosphate and benzyltrimethylammonium bromide. Rinsing the capillary with sodium hydroxide followed by water then fresh capillary electrophoresis buffer was found to significantly improve the reproducibility of the migration times of the analytes. To further improve run-to-run reproducibility, an internal marker was used to account for differences in injection volumes and migration times between runs. The precision of the method was found to be less than 1% relative standard deviation for the migration time ratio and peak area ratio of Ro 5-5172 to the internal standard. The method was found to be linear for 0.05-1% Ro 5-5172 with respect to a 10 mg ml-1 sample preparation. The limit of detection was found to be less than 0.01% Ro 5-5172. Results obtained for the analysis of a clidinium bromide drug substance lot using this CE method and a thin layer chromatography method were compared and found to be in agreement.
Asunto(s)
Parasimpatolíticos/análisis , Quinuclidinas/análisis , Quinuclidinil Bencilato/análogos & derivados , Estabilidad de Medicamentos , Electroforesis Capilar , Parasimpatolíticos/química , Quinuclidinil Bencilato/análisis , Quinuclidinil Bencilato/química , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrofotometría UltravioletaRESUMEN
By using optically pure 3S-quinuclidinol, two diastereoisomers (3S-1) and (3S-2) of 3-(substituted) alkoxy-quinuclidine were synthesized. 1H and 13C NMR spectra of (3S-1) and (3S-2) have been completely analyzed utilizing double-quantum filtered COSY, 13C-1H COSY and NOE difference experiment. The NOE difference experiment was used to determine the absolute configuration at C-11 of the diastereomers. According to the results of NOE difference and variable concentration NMR experiments, the configuration about C-11 of (3S-1) is designated as R (1A), whereas the configuration about C-11 of (3S-2) is designated as S (1B). The result was confirmed by X-ray diffraction analysis.
Asunto(s)
Parasimpatolíticos/análisis , Quinuclidinas/análisis , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The location of muscarinic receptors in the rat pituitary gland was examined with an autoradiographic technique. Slides containing 10 or 20 micron horizontal sections of tissue were incubated in a solution of 1 n M[3H]quinuclidinyl benzilate (QNB) in phosphate-buffered saline to label muscarinic receptors. Autoradiograms were produced by placing the slides into X-ray cassettes with tritium-sensitive film and processing the film 8-10 weeks later. Minimal binding occurred when sections were incubated in 1 nM[3H]QNB plus 1 microM atropine. Highest specific binding of QNB was found in the anterior and intermediate lobes along their border with the pituitary cleft. Patches of high binding were also seen penetrating the intermediate lobe and at the border between the intermediate and neural lobes. The remainder of the intermediate lobe had background density of autoradiographic grains. Moderate density of specific binding was found throughout the anterior lobe. Low specific binding occurred in the neural lobe.
Asunto(s)
Hipófisis/análisis , Quinuclidinas/análisis , Quinuclidinil Bencilato/análisis , Receptores Muscarínicos/análisis , Animales , Autorradiografía , Sitios de Unión , Masculino , Ratas , Ratas EndogámicasRESUMEN
Parameters associated with the separation of antianxiety-antispasmodic agents were investigated using high-pressure liquid chromatography. Eight widely prescribed drugs were studied. The compounds were chromatographed on reversed-phase octadecyltrichlorosilane (C18) or diphenyldichlorosilane (phenyl) columns, using mixtures of absolute methanol and distilled water buffered with ammonium dihydrogen phosphate, ammonium acid phosphate, or ammonium carbonate. A mixture of phenobarbital-propantheline bromide was selected to demonstrate the utility of the separation and quantification method. The mixture was chromatographed on a phenyl column, using absolute methanol-aqueous 1 percent ammonium dihydrogen phosphate (60:40) (pH 5.85) at a flow rate of 1.4 ml/min. Each determination can be achieved in approximately 15 min with an accuracy of 1-2 percent.