Novel Bioequivalent Tablet of Solifenacin Succinate Prepared Using Direct Compression Technique for Improved Chemical Stability

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

Solifenacin succinate (SOL), a competitive muscarinic antagonist with high selectivity for the M3 receptor in the urinary bladder, is prescribed to treat overactive adult bladder symptoms [1,2,3]. After a 12-week phase III study, patients who orally received 5 or 10 mg of SOL showed marked reductions in the number of voids, incontinence episodes, and urgency episodes per 24 h [4]. Although the muscarinic antagonist is lipophilic (logp value of 1.69, at pH 7.0), its succinate salt is sparingly soluble (10 mg/mL, pH 7.2) in aqueous media [5]. The plasma SOL levels peaked 3–8 h after oral administration (5 or 10 mg tablets). The drug has a high bioavailability of over 88% in healthy participants [6,7]. Currently, the drug is commercially formulated as immediate-release (IR) tablets (Vesicare®, Astellas Pharma Europe, B.V., Leiden, The Netherlands). It was fabricated via a wet granulation process employing maize starch and lactose monohydrate as diluents, hypromellose as a binder, magnesium stearate and macrogol as lubricants, and talc and titanium dioxide as anti-caking agents [8]. During wet granulation using organic solvents or distilled water, amorphous active compounds can be produced using pharmaceutical excipients [9,10,11]. The crystalline form of SOL is chemically stable under harsh conditions; however, the amorphous form of SOL is extremely unstable and forms a substantial amount of degradation products under high temperature and high humidity conditions [12]. The amorphous form of SOL is easily oxidized, producing several degradation products via N-oxide at the quinuclidine ring or benzylic radical formation [13]. Therefore, sophisticated formulation studies are essential for improving the chemical stability of muscarinic antagonists.

The direct compression (DC) method is the first choice for preparing tablets [14]. The production process includes blending the active substances with pharmaceutical excipients and lubricants, followed by tabletization, with no additional processing steps. It offers the following several advantages: (i) it is more economical than the wet granulation process because it requires fewer unit operations; (ii) it is a better choice for moisture- and heat-sensitive APIs because the wetting and drying steps are eliminated; and (iii) drug crystalline conversion during the wet granulation and drying processes can be avoided, providing a stable dissolution profile [15,16,17]. However, a crucial selection of pharmaceutical excipients is required compared to those used for granulation to ensure the appropriate flowability and compressibility of drug powders. Moreover, problems may arise when low amounts of active compounds need to be incorporated into tablets, because it is challenging to accurately blend a small amount of active ingredients in a large amount of excipient to achieve the desired uniformity and homogeneity. Despite the advantages of the DC method, to the best of our knowledge, no SOL-loaded tablet dosage forms have been fabricated using this technique.

The principal goal of this study is to design a new tablet dosage form of SOL using the DC technique to simultaneously ensure improved chemical stability and a bioequivalent pharmacokinetic profile compared to those of the commercial product. The tablet composition was established by evaluating the drug content uniformity, mechanical properties, and in vitro dissolution. The chemical stability of the direct compressed tablet (DCT) in terms of drug content and degradation substances was evaluated and compared with that of the tablets prepared via wet granulation using distilled water (DWT) or ethanol (ETT), and with that of the marketed product. Furthermore, the bioequivalence of the DCT with a commercial SOL tablet fabricated using wet granulation was evaluated in healthy adult male participants.

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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