The aim of this study is the identification, structural characterization, and qualification of a degradation impurity of bisoprolol labeled as Impurity RRT 0.95. This degradation product is considered as a principal thermal degradation impurity identified in bisoprolol film-coated tablets. The impurity has been observed in the stress thermal degradation study of the drug product. Using HPLC/DAD/ESI-MS method, a tentative structure was assigned and afterwards confirmed by detailed structural characterization using NMR spectroscopy. The structure of the target Impurity RRT 0.95 was elucidated as phosphomonoester of bisoprolol, having relative molecular mass of 406 (positive ionization mode). The structural characterization was followed by qualification of Impurity RRT 0.95 using several different in silico methodologies. From the results obtained, it can be concluded that no new structural alerts have been generated for Impurity RRT 0.95 relative to the parent compound bisoprolol. The current study presents an in-depth analysis of the full characterization and qualification of an unidentified impurity in a drug product with the purpose of properly defining the quality specification of the product.
The purpose of this study was to develop and validate a discriminative dissolution method for the metformin film-coated tablet with immediate release of the active substance that belongs to class III of the Biopharmaceutical Classification System (BCS). Different conditions such as type of dissolution medium, volume of dissolution medium, rotation speed, apparatus, and filter suitability were evaluated. The most discriminative release profile for the metformin film-coated tablet was accomplished by using Apparatus II (paddle) and 1000 mL of phosphate buffer pH 6.8 as the dissolution medium and maintained on 37 ± 0.5°C with a rotation speed of 75 rpm. The quantification of the released active substance was performed by UV/Vis spectrophotometry, at 232 nm. Acceptance criteria for not less than 75% (Q) of the labeled content for 45 minutes were set. The dissolution method was validated according to the current international guidelines using the following parameters: specificity, accuracy, precision, linearity, robustness, and stability of the solutions, found to be meeting the predetermined acceptance criteria. A developed dissolution method has discriminatory power to reflect the characteristics of the medicinal product and is able to distinguish any changes related to quantitative formulation and can be also applied for routine batch testing.
This research highlights the specificity of the new stability-indicating method developed to evaluate the impurity profile of Atorvastatin film-coated tablets. The proposed method has the ability to capture any possible changes that may occur during the stability studies over time and under different stress factors, and is selective enough to enable quality control of finished product from different suppliers of active pharmaceutical ingredient (API)/excipients.
Satisfactory critical peak resolution between specified and unspecified impurities was achieved using the fused-core shell technology and extensively endcapped diisopropyl-cyanopropylsilane stationary phase (Halo ES-CN 150 mm × 4.6 mm, 2.7 µm), with a 10 mM ammonium formate buffer pH 3.5 and acetonitrile as mobile phase. A potential worse case impurity profile was assumed by using retained samples combined with the data obtained for samples manufactured with APIs from different suppliers exposed to the forced degradation study. The mass balance for stressed samples demonstrated the stability-indicating capability of the proposed method.
This study presents optimization of a statistically based approach for setting up the dissolution test conditions for bisoprolol film-coated tablets using multivariate release models as predictive in vivo assessment tools for formulation behaviour. Additionally, the dissolution profiles of three different strengths of bisoprolol film-coated tablets were evaluated. According to the biopharmaceutics classification system, the tested medicinal product belongs to BCS Class I (high solubility, high permeability).
Three dissolution media, including the dissolution medium of choice (pH 1.2) according to the USP monograph for bisoprolol tablets and two apparatus, paddle and basket were applied. The optimal conditions for performing the dissolution test were following: 900 mL of pH 1.2 as dissolution medium, apparatus 2 (paddle) with 75 r/min stirring speed. The quantity of the released active substance was determined using HPLC method.
For a reliable statistical analysis, multivariate methods such as model-dependent approach coupled to multivariate statistics (Weibull), multivariate model-independent approach based on generalized statistical distance (Mahalanobis distance) have been applied for evaluation of dissolution profiles. All applied statistical approaches unequivocally support the underlying similarity of the pairs in different media between different strengths. Moreover, the optimized dissolution method has a discriminatory power to reflect the characteristics of the medicinal product in order to distinguish any changes related to quantitative composition of the formulation.
Keywords: bisoprolol film-coated tablet, dissolution profiles, model-independent multivariate statistical distance, model-dependent multivariate statistical distance
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