Ozonation of ranitidine: Effect of experimental parameters and identification of transformation products.

This study focuses on the effect of experimental parameters on the removal of ranitidine (RAN) during ozonation and the identification of the formed transformation products (TPs). The influence of pH value, the initial concentrations, the inorganic and the organic matter on RAN's removal were evaluated. Results indicated high reactivity of RAN with molecular aqueous ozone. Initial ozone concentration and pH were proven the major process parameters. Alkaline pH values promoted degradation and overall mineralization. Dissolved organic matter reacts competitively to RAN with the oxidants (ozone and/or radicals), influencing the target compound's removal. The presence of inorganic ions in the matrix did not seem to affect RAN ozonation. A total of eleven TPs were identified and structurally elucidated, with the complementary use of both Reversed Phase (RP) and Hydrophilic Interaction Liquid Chromatography (HILIC) quadrupole time of flight tandem mass spectrometry (Q-ToF-MS/MS). Most of the TPs (TP-304, TP-315b, TP-299b, TP-333, TP-283) were generated by the attack of ozone at the double bond or the adjacent secondary amine, with the abstraction of NO2 moiety, forming TPs with an aldehyde group and an imine bond. Oxidized derivatives with a carboxylic group (TP-315a, TP-331a, TP-331b, TP-299a) were also formed. RAN S-oxide was identified as an ozonation TP (TP-330) and its structure was confirmed through the analysis of a reference standard. TP-214 was also produced during ozonation, through the CN bond rupture adjacent to the NO2 moiety. HILIC was used complementary to RP, either for the separation and identification of TPs with isomeric structures that may have been co-eluted in RPLC or for the detection of new TPs that were not eluted in the RP chromatographic system. Retention time prediction was used as a supporting tool for the identification of TPs and results were in accordance with the experimental ones in both RP and HILIC.

Effect of Pithecellobium dulce (Roxb.) Benth. fruit extract on cysteamine induced duodenal ulcer in rats.

The edible fruits of Pithecellobium dulce (Roxb.) Benth. are traditionally used for various gastric complications in India. Here, we investigated the antiulcer activity of hydroalcoholic fruit extract of P. dulce (HAEPD) by applying cysteamine induced duodenal ulcer model in rats. Duodenal ulcer was induced in male albino Wistar rats by oral administration of cysteamine @ 420 mg/kg body wt. as a single dose. The rats were pre-administered orally with HAEPD @ 200 mg/kg body wt. for 30 days prior to ulcer induction. Rats pre-administered with ranitidine @ 30 mg/kg body wt. served as reference drug control. Ulcer score, thiobarbituric acid reactive substances (TBARS), glycoproteins, superoxide dismutase, catalase and glutathione peroxidase and reduced glutathione levels were measured in the duodenum. Rats pre-administered with the HAEPD showed significantly reduced ulcer score comparable to that of ranitidine pretreated rats. The co-administration of HAEPD lowered the TBARS level and also restored the levels of glycoproteins, enzymatic and non-enzymatic antioxidants. Histopathological observations confirmed the presence of inflammation, necrosis and hemorrhagic spots in the duodenum of ulcer control rats which were significantly reduced due to HAEPD treatment. No abnormal alterations were observed in normal rats treated with HAEPD at the dosage studied. The results demonstrated antioxidant and cytoprotective nature of P. dulce, and thereby its significant anti ulcer property.

Statistical optimization of ranitidine HCl floating pulsatile delivery system for chronotherapy of nocturnal acid breakthrough.

Present work conceptualizes a specific technology, based on combining floating and pulsatile principles to develop drug delivery system, intended for chronotherapy in nocturnal acid breakthrough. This approach will be achieved by using a programmed delivery of ranitidine hydrochloride from a floating tablet with time-lagged coating. In this study, investigation of the functionality of the outer polymer coating to predict lag time and drug release was statistically analyzed using the response surface methodology (RSM). RSM was employed for designing of the experiment, generation of mathematical models and optimization study. The chosen independent variables, i.e. percentage weight ratios of ethyl cellulose to hydroxypropyl methyl cellulose in the coating formulation and coating level (% weight gain) were optimized with a 3(2) full factorial design. Lag time prior to drug release and cumulative percentage drug release in 7h were selected as responses. Results revealed that both, the coating composition and coating level, are significant factors affecting drug release profile. A second-order polynomial equation fitted to the data was used to predict the responses in the optimal region. The optimized formulation prepared according to computer-determined levels provided a release profile, which was close to the predicted values. The proposed mathematical model is found to be robust and accurate for optimization of time-lagged coating formulations for programmable pulsatile release of ranitidine hydrochloride, consistent with the demands of nocturnal acid breakthrough.

ZantacÒ 150 y ranitidina de producción nacional: liberación in vitro / ZantacÒ150 and ranitidine of national production: in vitro release

Dentro del proceso global de la liberación de un fármaco, la disolución constituye el paso más importante pues se encuentra íntimamente relacionada con los procesos de absorción, determinantes en la biodisponibilidad de un medicamento administrado por vía oral. En el presente trabajo se realizaron los perfiles de disolución de 3 lotes de ZantacÒ (GlaxoWellcome), medicamento líder del principio activo ranitidina (DCI) y de 3 lotes de ranitidina 150 mg de producción nacional. Para el estudio de disolución se utilizó el método descrito en la USP 23. Los datos de porcentaje de principio activo liberado contra tiempo fueron sometidos a un estudio de ajuste a 4 modelos comunes a perfiles de disolución mediante el programa CurveExpert. Todos los lotes estudiados cumplen con los criterios de la Food and Drug Administration (FDA) para los estudios de bioequivalencia in vitro(AU)

Quantitative analysis of polymorphic mixtures of ranitidine hydrochloride by Raman spectroscopy and principal components analysis.

Ranitidine hydrochloride exists as two polymorphs, forms I and II, both of which are used to manufacture commercial tablets. Raman spectroscopy can be used to differentiate the two forms but univariate methods of quantitative analysis of one polymorph as an impurity in the other lack sensitivity. We have applied principal components analysis (PCA) of Raman spectra to binary mixtures of the two polymorphs and to binary mixtures prepared by adding one polymorph to powdered tablets of the other. Based on absorption measurements of seven spectral regions, it was found that >97% of the spectral variation was accounted for by three principal components. Quantitative calibration models generated by multiple linear regression predicted a detection limit and quantitation limit for either forms I or II in mixtures of the two of 0.6 and 1.8%, respectively. This study demonstrates that PCA of Raman spectroscopic data provides a sensitive method for the quantitative analysis of polymorphic impurities of drugs in commercial tablets with a quantitation limit of less than 2%.