Diltiazem cream, which is used in chronic anal fissure (CAF) treatment, is known to be susceptible to hydrolysis and degradation in aqueous solutions. The major pathway of degradation is o-deacetylation which leads to formation of 'desacetyl diltiazem' and this study focuses on this degradation mechanism. In this study, degradation of diltiazem incorporated into an oil-in-water cream base was investigated. It was especially aimed to show the effect of the formulation preparation procedure on impurity formation during the diltiazem cream formulation. In this regard, preliminary studies were performed to optimize the formulation parameters for stability. The outcome of these studies was applied to the preparation procedure; the compositions of excipients were kept constant while the order of addition of excipients to the aqueous phase and the mixing time were varied. To our knowledge, there is no study published regarding the relation between this degradation and the formulation process. Formulations were characterized in terms of formation of the desacetyl diltiazem impurity with a validated stability indicating HPLC method. The cream formulation with the highest stability was obtained through mixing propylene glycol and water first and adding diltiazem active substance in the final step of formation of aqueous phase with a shortened stirring time. This preparation procedure exhibited reduced desacetyl diltiazem impurity formation.
The goal of the current study was to develop a precise, sensitive and validated reverse phase HPLC method for determination of fesoterodine fumarate (FST). The current investigation was performed for a stability indicating method in order to obtain both assay and impurity profiles of FST. All the experiment was done on HPLC Shimadzu Prominence 20A having stainless steel ACE5 C18 column with a particle size of 5µm and a dimension of 4.6 mm X 150 mm. The mobile phase was in gradient mode with mobile phase A (0.03M ammonium acetate buffer : acetonitrile : methanol (55:30:15 v/v) pH 3.8) and mobile phase B (water) . The flow rate was 1.2 mL/min and the wavelength 208 nm was selected for detection. This method was validated for linearity and range, accuracy, precision and robustness in accordance with ICH requirements. The retention time of fesoterodine was found as 11.0 min. The main degradation product 5-hydroxymethyltolterodine (5-HMT; active metabolite of FST) and the other process impurities; aldehyde, benzylated hydroxy, tolterodine ester, diester impurities were detected easily at the retention times 3.8, 13.5, 16.7, 21.5, 37.1 minutes, respectively. It was observed that the retention times of the main peak and its impurities were not affected and the selectivity of the method was proved under the applied stress conditions. With this developed method, FST and its impurities can easily be detected. It is also stable, simple, accurate, and completely validated RP-HPLC technique for the analysis of FST and related impurities that meets with ICH standards.
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