Solifenacin, which is used to treat overactive bladder disease, is known to be decomposed by oxidation to produce related substances. In particular, there is a problem that this is caused by accelerating decomposition by oxidation when in contact with moisture. For this reason, it is difficult to ma...
Solifenacin, which is used to treat overactive bladder disease, is known to be decomposed by oxidation to produce related substances. In particular, there is a problem that this is caused by accelerating decomposition by oxidation when in contact with moisture. For this reason, it is difficult to manage related substances caused by contact with water during the manufacturing process when developing a solifenacin succinate tablet by a wet granulation method, which is a commonly used manufacturing method, including Reference listed drug (RLD). In this study, the manufacturing process of the solifenacin succinate tablet is changed to a direct compression method rather than a wet granulation method to achieve stability and simplification of the process. This is because solifenacin is a drug classified in BCS class 1 and has relatively high solubility and cell membrane permeability. Therefore, granulation of the drug is not essential to improve physical properties such as solubility. In addition, the content of solifenacin in the finished product is 6.67% based on 10 mg of the reference drug VESICARE® tablet, which is a small amount. Accordingly, even though the manufacturing process of the solifenacin succinate tablet is changed to a direct compression method, density and flowability are increased using a functional excipient, thereby preventing productivity from being degraded due to problems in flowability and tabletting properties of the mixture. To this end, functional excipients for direct tableting with very low moisture content and excipients having a size similar to the PSD of API for mixing uniformity were selected instead of excipients with high moisture content used in RLD to ensure product stability and productivity. QTPP was selected to achieve the desired quality in consideration of the safety, stability and efficacy of the developed product, and properties affecting the quality of the final product were classified and managed as CQA. Based on the R&D batch scale, an initial risk assessment of the formulation development and manufacturing process was conducted, and the experiment was designed by setting Microcrystalline cellulose (MCC), Crospovidone (CP) and Polyvinylpyrrolidone (PVP) as major factors that could affect CQA through the QBD approach. The formulation was optimized by evaluating several CQAs, and the risk assessment was updated based on this. The optimized formulation confirmed dissolution equivalence with the reference drug in 0.1N HCl selected as BE Critical media, It was confirmed that the final optimized formulation exhibits a stable related substance profile through the accelerated condition stability test and the harsh stability comparison test with RLD.
Solifenacin, which is used to treat overactive bladder disease, is known to be decomposed by oxidation to produce related substances. In particular, there is a problem that this is caused by accelerating decomposition by oxidation when in contact with moisture. For this reason, it is difficult to manage related substances caused by contact with water during the manufacturing process when developing a solifenacin succinate tablet by a wet granulation method, which is a commonly used manufacturing method, including Reference listed drug (RLD). In this study, the manufacturing process of the solifenacin succinate tablet is changed to a direct compression method rather than a wet granulation method to achieve stability and simplification of the process. This is because solifenacin is a drug classified in BCS class 1 and has relatively high solubility and cell membrane permeability. Therefore, granulation of the drug is not essential to improve physical properties such as solubility. In addition, the content of solifenacin in the finished product is 6.67% based on 10 mg of the reference drug VESICARE® tablet, which is a small amount. Accordingly, even though the manufacturing process of the solifenacin succinate tablet is changed to a direct compression method, density and flowability are increased using a functional excipient, thereby preventing productivity from being degraded due to problems in flowability and tabletting properties of the mixture. To this end, functional excipients for direct tableting with very low moisture content and excipients having a size similar to the PSD of API for mixing uniformity were selected instead of excipients with high moisture content used in RLD to ensure product stability and productivity. QTPP was selected to achieve the desired quality in consideration of the safety, stability and efficacy of the developed product, and properties affecting the quality of the final product were classified and managed as CQA. Based on the R&D batch scale, an initial risk assessment of the formulation development and manufacturing process was conducted, and the experiment was designed by setting Microcrystalline cellulose (MCC), Crospovidone (CP) and Polyvinylpyrrolidone (PVP) as major factors that could affect CQA through the QBD approach. The formulation was optimized by evaluating several CQAs, and the risk assessment was updated based on this. The optimized formulation confirmed dissolution equivalence with the reference drug in 0.1N HCl selected as BE Critical media, It was confirmed that the final optimized formulation exhibits a stable related substance profile through the accelerated condition stability test and the harsh stability comparison test with RLD.
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