Novel Bioequivalent Tablet of Solifenacin Succinate Prepared Using Direct Compression Technique for Improved Chemical Stability
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Abstract
We designed a bioequivalent tablet form of solifenacin succinate (SOL) with an improved storage stability using a direct compression (DC) technique. An optimal direct compressed tablet (DCT) containing an active substance (10 mg), lactose monohydrate, and silicified microcrystalline cellulose as diluents, crospovidone as a disintegrant, and hydrophilic fumed silica as an anti-coning agent was constructed by evaluating the drug content uniformity, mechanical properties, and in vitro dissolution. The physicochemical and mechanical properties of the DCT were as follows: drug content 100.1 ± 0.7%, disintegration time of 6.7 min, over 95% release within 30 min in dissolution media (pH 1.2, 4.0, 6.8, and distilled water), hardness > 107.8 N, and friability ~0.11%. The SOL-loaded tablet fabricated via DC showed an improved stability at 40 °C and RH 75%, exhibiting markedly reduced degradation products compared to those fabricated using ethanol or water-based wet granulation or a marketed product (Vesicare®, Astellas Pharma). Moreover, in a bioequivalence study in healthy subjects (n = 24), the optimized DCT offered a pharmacokinetic profile comparable to that of the marketed product, with no statistical differences in the pharmacokinetic parameters. The 90% CIs for the geometric mean ratios of the test to the reference formulation for the area under the curve and the maximum drug concentration in plasma were 0.98–1.05 and 0.98–1.07, respectively, and satisfied the FDA regulatory criteria for bioequivalence. Thus, we conclude that DCT is a beneficial oral dosage form of SOL with an improved chemical stability.
Introduction
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Materials
Powdered SOL was purchased from MSN Laboratories Ltd. (Hyderabad, India). The median diameter (D50) of the drug powder was approximately 80 μm, with D10 (10% of the smaller particles contained) and D90 (90% of the total smaller particles in the sample) values of 30 and 150 μm, respectively. Lactose monohydrate 200 mesh, Supertab 30GR (agglomerated lactose monohydrate), and Flowlac100 (spherical lactose monohydrate) were obtained from DFE Pharma (Veghel, The Netherlands), DFE Pharma (Norten Hardenberg, Germany), and Molkerei Meggle Wasserburg (Wasserburg, Germany), respectively. Several grades of microcrystalline celluloses (MCCs) such as Prosolv SMCC50 and 90 (silicified MCCs), Vivapur pH102, and Vivapur-12 were obtained from JRS Pharma (Weissenborn, Germany). Crospovidone (Kollidon CL) and vinylpyrrolidone–vinyl acetate copolymer (Kollidon VA64) were obtained from BASF (Ludvigshafen, Germany). Magnesium stearate and sodium stearyl fumarate were obtained from Faci (Jurong Island, Singapore) and JRS Pharma (Polanco, Spain). Hydrophilic fumed silicone dioxide (Aerosil 200) and pink film-coating material (Opadry® 03B640016, mainly composed of hypromellose 2901, titanium dioxide, and iron oxide) were provided by Evonik (Rheinfelden, Germany) and Colorcon (Shanghai, China), respectively. Hypromellose 2910 (6 cps), cornstarch, croscarmellose sodium, and sodium starch glycolate were provided by Lotte Fine Chemicals (Incheon, Republic of Korea), Duksan Pure Chemicals (Ansan-si, Republic of Korea), JRS Pharma (Pirna, Germany), and Yung Zip Chemicals (Talchung, Taiwan). Pharmaceutical standards for the potent degradation products of SOL, such as solifenacin N-oxide (purity ≥ 98%), YM217880 ((+)-(R)-quinuclidin-3-yl [2-(2-benzoylphenyl)ethyl]carbamate) (≥98%), isoquinoline ((1S-1-Phenyl-1,2,3,4-tetrahydro-2-isoquinoline) (≥98%), and isoquinoline ester ((1S-ethyl-1-Phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate) (≥98%) were obtained from MSN Laboratories, Ltd. (Hyderabad, India). All organic solvents, including acetonitrile (ACN), methanol, and methyl tert-butyl ether, were of high-pressure liquid chromatography (HPLC) grade and were used without further purification.
Kim, D.H.; Ho, M.J.; Jeong, C.K.; Kang, M.J. Novel Bioequivalent Tablet of Solifenacin Succinate Prepared Using Direct Compression Technique for Improved Chemical Stability. Pharmaceutics 2023, 15, 1723. https://doi.org/10.3390/pharmaceutics15061723
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