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Comparative Study
. 2019 Jan 10:554:302-311.
doi: 10.1016/j.ijpharm.2018.11.005. Epub 2018 Nov 3.

Formulation of aripiprazole-loaded pH-modulated solid dispersions via hot-melt extrusion technology: In vitro and in vivo studies

Haley McFall  1 , Sandeep Sarabu  1 , Vijaykumar Shankar  1 , Suresh Bandari  1 , S Narasimha Murthy  1 , Karl Kolter  2 , Nigel Langley  3 , Dong Wuk Kim  4 , Michael A Repka  5
Affiliations
Comparative Study

Formulation of aripiprazole-loaded pH-modulated solid dispersions via hot-melt extrusion technology: In vitro and in vivo studies

Haley McFall et al. Int J Pharm. .

Abstract

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 (Cmax and AUC0-12) 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.

Keywords: Acidifier; Aripiprazole; Hot-melt extrusion; Oral bioavailability; Pharmacokinetics; Solid dispersion.

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Conflict of interest statement

Disclosure

The authors report no conflicts of interest in this work.

Figures

Figure 1.
Figure 1.
Solubility of ARI in various (A) acidifiers and (B) polymers
Figure 2.
Figure 2.
DSC (A) and TGA (B) curves for ARI, PVP, SA, and PM
Figure 3.
Figure 3.
Solubility (A) and drug release profile (B) of ARI and formulation tablets
Figure 4.
Figure 4.
Response surfaces from the DoE: (A) Dissolution at 30 minutes (B) Dissolution at 60 minutes (C) Solubility (D) Sweet spot conditions
Figure 5.
Figure 5.
DSC (A) and XRD (B) curves for ARI, SA, PVP, and N6
Figure 6.
Figure 6.
Drug release profiles of ARI, N6, and N6 tablet blend in water (A) and SGF without enzymes (B)
Figure 7.
Figure 7.
Mean plasma concentrations of ARI in of N6, N6 tablet blend, and pure ARI (n=6)
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