Solubility enhancement, formulation development, characterization and IVIVC of sustained release tablet of ketoprofen

Ketoprofen granules were prepared by a relatively newer method, namely surfactant-assisted wet granulation (SAWG) approach using different concentrations (1-5%) of Soluplus®, polyethylene glycol (PEG) 6000, PEG 4000, poloxamers L6200 and L3100. The developed granule formulations were characterized for physicochemical and dissolution characteristics. FTIR examined for any drug-excipients interactions. Granule size, percent yield, bulk and tap density, Hausner’s ratio, and angle of repose of granules were found to be 571 ± 0.81 μm, 93.1 ± 0.84 %, 0.223 ± 0.01g/ml, 0.231 ± 0.002 g/ml, 1.098 ± 0.005, 33.81 ± 0.23º, respectively. Granules with 1% Soluplus® revealed highest solubility (3.09 mg/ml), but with 58.3% ketoprofen release until 12 h. Granules containing 5% PEG-6K demonstrated improved solubility of ketoprofen as compared to pure drug, i.e. 2.81 mg/ml vs 0.010 mg/ml.

This increase in solubility was observed to be due to micellar solubilization, complex formation, or hydrogen bonding, which was supported by FTIR. All the formulations exhibited release comparable to that of USP-stipulated sustained release pattern following Weibull model (β=1.08) and showing erosion-controlled release. FTIR indicated no chemical interaction between ketoprofen and excipient in granule formulation. The SAWG successfully ameliorated ketoprofen solubility and sustained its release as well. To develop the single unit dose to achieve the better bioavailability of sustained release ketoprofen granules, matrix tablets were prepared using the defined concentration, i.e., 1%, 3% and 5% of Soluplus®, PEG-6K, PEG-4K, L6200 and L3100. The prepared ketoprofen tablets were characterized for physicochemical, in vitro dissolution, FTIR and in-vivo (human pharmacokinetic study) parameters. FTIR studies were carried out to ensure any possible interactions among active and other excipients. Friability, thickness, hardness, weight variation, drug content and swelling index were found to be 0.14%, 4.77mm, 7.5 kgcm-1, 401mg, 99.95% and 29.38% respectively. In-vitro dissolution revealed 60-102% release till 8h. MT2, MT13 depicted the ideal sustained release pattern till 8h, i.e., > 80% which was fitted to Weibull release model with ß value 2.57 and 1.06 respectively, indicating the complex release mechanism. FTIR evident the compatibilities of drug-excipient during compression.

A tablet formulation with similar profile to that of the sustained release, MT2 was selected for pharmacokinetic study. MT16 was also selected as a control for PK parameters evaluation. MT16 promptly attained the plasma peak within 1h after administration and followed a rapid exponential decrease till 12h. MT2 as a sustained release tablet showed delayed peak plasma concentration which was maintained above 0.7-1.0 μg.ml-1 till 24h with a gradual decline. The maximum plasma concentration (Cmax) resulting from administration of 200 mg of MT2 was statistically lower than that of the MT16 (5.19 ± 0.66 vs 9.62±0.76 μg.ml-1, P<0.05). The time to reach Cmax (Tmax) from MT2 was delayed to 5.56±0.30 h as compared to 1.15±0.11 h of MT16. The AUC0-∞, 78.65±7.64 μg.h.ml-1, of MT2 was higher than 34.39±3.06 μg.h.ml-1 of MT16. Considering MT2 as Test and MT16 as Reference formulation, the relative bioavailability was found to be 228.89±12.578%. Clearance of drug was observed to be declined for MT2 compared to MT16 (5.855±0.539 to 2.561±0.235 L/h), a reason for sustaining drug concentration in blood beyond 24 h instead of 12 h for MT16. The delayed Tmax, decreased Cmax, increased AUC and decreased ClT, MT2 exhibited an in-vivo behavior corresponding to the sustained drug delivery system. MT2 sustained release matrix tablets depicted the therapeutic ketoprofen plasma level effectively even beyond 24h.

Thus, there is a likelihood of administration of once-a-day single dose without plasma fluctuations which were expected from the administration of two doses in a day of MT16. The in-vitro characteristics, i.e., the dissolution of MT2 were predictive of the in-vivo profile of the drug. The IVIVC evaluation indicated a good correlation for the drug releases in-vitro and absorbed in-vivo at predicated time intervals. The SAWG successfully helped developing the swellable-erodible sustained release matrix tablet formulation of ketoprofen with desired in-vitro, biopharmaceutical and pharmacokinetics properties without incorporation of any special ingredients or major manipulation of the formulation ingredients. The desired features in the present dosage form were accomplished just by surfactant-assisted granulation, thus SAWG was regarded as the simpler approach.