Novel approach to evaluating granulation and segregation level considering the contribution of hydroxypropyl cellulose to the surface property change of granules.

The granulation process is critical to the uniformity of not only the active ingredient (API) but also other excipients in granules. Insufficient granulation results in unexpected product quality, e.g. delayed dissolution and lack of uniformity of API. Therefore, evaluating the granulation and segregation level of granules helps secure the uniformity of drug product quality. Here, we found that the polar surface free energy (SFE) of studied granules increased as granulation by a high shear granulator proceeded. Among the excipients formulated in the studied granules, only hydroxypropyl cellulose (HPC) showed a higher specific free energy of adsorption (ΔGsp) of chloroform, which is a parameter used to calculate polar SFE. This indicates that the ΔGsp of chloroform in granules helps detect the level of contribution of HPC to the granulation progress by inverse gas chromatography (IGC). We concluded that the ΔGsp of chloroform in a granulated sample is a novel critical material attribute (CMA) in relation to granulation level. In addition, we propose a novel approach to evaluating the quantitative granulation and segregation level based on the ΔGsp of chloroform in a granulated sample by focusing on the distribution of HPC in the granulated sample.

Development of extended-release solid dispersion granules of tacrolimus: evaluation of release mechanism and human oral bioavailability.

OBJECTIVES: We aimed to prepare a once-daily modified-release oral formulation of tacrolimus by utilizing an extended-release granules (ERG). METHODS: Extended-release granules were prepared using ethylcellulose (EC), hydroxypropylmethylcellulose (HPMC) and lactose via a solvent evaporation method with ethanol. Physicochemical and biopharmaceutical studies were performed to determine the formulation with optimum release profile of tacrolimus from ERG. KEY FINDINGS: Tacrolimus existed in an amorphous state in ERG. Tacrolimus release from ERG was attenuated by EC and facilitated by lactose, suggesting that drug release kinetics could adequately be regulated by these components. Those release profiles were consistent with Higuchi's equation, suggesting a diffusion-type release mechanism. Smooth surface of ERG changed to the structure with pores after the release test, likely derived from the dissolution of HPMC and lactose. But ERG structure formed by EC was still maintained after the release test, leading to the longer maintenance of diffusion-type release. Two ERG formulations selected by blood concentration simulation successfully provided long-term retention of tacrolimus in blood in a human absorption study. CONCLUSIONS: We successfully developed the formulation exhibiting a significant reduction in Cmax , the longer mean residence time and AUC close to that of an immediate-release tacrolimus formulation, being preferred from the viewpoint of safe and effective immunosuppressant pharmacotherapy.