The objective of this study was to formulate aripiprazole (ARI)-loaded pH-modulated solid dispersions (SD) to enhance solubility, dissolution, and bioavailability via hot-melt extrusion (HME) technology. Kollidon ® 12 PF (PVP) and succinic acid (SA) were selected after solubility screenings of various polymers and acidifiers. Several formulations, varying in screw speed and drug/polymer/acidifier ratios, were extruded using an 11 mm twin-screw extruder and were investigated for the effect of these variables. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were used to perform solid-state characterizations of the pure drug and extrudates. The aqueous solubility and dissolution were evaluated for the pure drug and milled extrudates. Among the prepared formulations, N6 was chosen for in vivo absorption studies. Solid-state characterization demonstrated the transformation of the crystalline ARI to an amorphous state in the formulations. Each formulation showed increased solubility and dissolution compared to the drug powder. The oral bioavailability (C max and AUC 0-12 ) of N6 was significantly improved when compared to the pure ARI. This novel study not only discusses the incorporation of acidifiers in SDs but also the preparation of SDs using HME technology as effective techniques to improve drug release and bioavailability.
This work developed a chronotherapeutic drug delivery system (CTDDS) utilizing a potential continuous hot-melt extrusion (HME) technique. Ketoprofen (KTP) and ibuprofen (IBU) were used as two separate model drugs. Eudragit S100 (ES100) was the matrix-forming agent, and ethyl cellulose (EC) (2.5 and 5%) was the release-retarding agent. A 16-mm extruder was used to develop the CTDDS to pilot scale. The obtained extrudate strands were transparent, indicating that the drugs were homogeneously dispersed in the matrix in an amorphous form, confirmed by both differential scanning calorimetry and powder X-ray diffraction. The strands were pelletized into 1, 2, and 3 mm size pellets. A 100% drug release from 1, 2, and 3 mm pellets with 2.5% EC was observed at 12, 14, and 16 h, whereas the drug release was sustained for 14, 16, and 22 h from 5% EC pellets, respectively, for KTP. The release characteristics of IBU were similar to those of KTP with modest variations in release at lag time. The in vitro drug release study conducted in three-stage dissolution media showed a desired lag time of 6 h. The percent drug release from 1, 2, and 3 mm pellets with 40% drug load showed < 20% release from all formulations at 6 h. The amount of ethyl cellulose and pellet size significantly affected drug release. Formulations of both KTP and IBU were stable for 4 months at accelerated stability conditions of 40°C/75% RH. In summary, HME is a novel technique for developing CTDDS.
Introduction: Interest in hot melt extrusion (HME) technology for novel applications is growing day by day, which is evident from several hundred publications within the last five years. HME is a cost-effective, solvent free, "green" technology utilized for various formulations with low investment costs compared to conventional technologies. HME has also earned the attention of the pharmaceutical industry by the transformation of this technology for application in continuous manufacturing.Areas covered: Part II of the review focuses on various novel opportunities or innovations of HME such as multiple component systems (co-crystals, co-amorphous systems and salts), twinscrew granulation, semi-solids, co-extrusion, abuse deterrent formulations, solid self-emulsifying drug delivery systems, chronotherapeutic drug delivery systems and miscellaneous applications.Expert opinion: HME is being investigated as an alternative technology for preparation of multi-component systems such as co-crystals and co-amorphous techniques. Twin-screw granulation has gained increased interest in preparation of granules via twin-screw melt granulation or twin-screw dry granulation. This novel application of the HME process provides a promising alternate approach in the formulation of granules and solid dosage forms. However, this technology may need to be further investigated for scalability aspects of these novel applications for industrial production.
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