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.

Keywords: bioequivalence; direct compression; pharmacokinetics; solid dosage form; solifenacin succinate; storage stability.

Figure 1

Comparison of the drug content, total impurities, and individual degradation products of the tablets prepared using different fabrication processes. Changes in (A) drug content, (B) total impurities, individual impurity (%) at (C) RRT 0.34 and (D) RRT 0.40 in SOL-loaded tablets prepared via wet granulation or DC technique, under accelerated storage condition (40 °C, RH75%). Notes: SOL-loaded tablets (DWT, ETT, and DCT1) were filled into polyethylene (PE) bottle with silica gels and stored in a stability chamber (40 °C, RH75%) for 4 weeks. To determine the drug content (%) and level of degradation products (%) in the tablets, 10 tablets were pretreated and analyzed once. Impurities at RRT 0.34 and 0.40 were identified in solifenacin N-oxide and YM217880, respectively. N.D. = not detected.

Figure 2

In vitro dissolution profiles of different SOL-loaded DCTs under (A) distilled water, (B) simulated gastric fluid (pH 1.2), (C) citrate buffer solution (pH 4.0), and (D) simulated intestinal fluid (pH 6.8). Note: data are represented as mean ± SD (n = 4).

Figure 3

LC–MS/MS chromatograms of (A) blank plasma, and blank plasma spiked with (B) SOL and (C) IS, respectively.

Figure 4

Comparison of chemical stabilities of SOL in the marketed product (Vesicare^®) and the optimized DCT (DCT11) under accelerated storage condition (40 °C, RH75%). Changes in (A) drug content, (B) total impurities, individual impurity % at (C) RRT 0.34 and (D) RRT 0.40 in SOL-loaded tablets. Note: SOL-loaded tablets were packaged using alu-alu blister and stored in a stability chamber (40 °C, RH75%) for 4 or 8 weeks. To determine the drug content (%) and (B)-related substances (%) in the tablets, 10 tablets were pretreated simultaneously and analyzed. Impurities RRT 0.34 and 0.40 corresponded to solifenacin N-oxide and YM217880, respectively. N.D. = not detected.

Figure 5

Plasma drug concentration–time profiles of SOL following oral administration (10 mg of SOL) of the marketed product (Vesicare^®, ■) or DCT11 (▲) in healthy male participants. Data are represented as mean ± SD (n = 32).