Saquinavir-Piperine Eutectic Mixture: Preparation, Characterization, and Dissolution Profile

Abstract

The dissolution rate of the anti-HIV drug saquinavir base (SQV), a poorly water-soluble and extremely low absolute bioavailability drug, was improved through a eutectic mixture formation approach. A screening based on a liquid-assisted grinding technique was performed using a 1:1 molar ratio of the drug and the coformers sodium saccharinate, theobromine, nicotinic acid, nicotinamide, vanillin, vanillic acid, and piperine (PIP), followed by differential scanning calorimetry (DSC). Given that SQV-PIP was the only resulting eutectic system from the screening, both the binary phase and the Tammann diagrams were adapted to this system using DSC data of mixtures prepared from 0.1 to 1.0 molar ratios in order to determine the exact eutectic composition. The SQV-PIP system formed a eutectic at a composition of 0.6 and 0.40, respectively. Then, a solid-state characterization through DSC, powder X-ray diffraction (PXRD), including small-angle X-ray scattering (SAXS) measurements to explore the small-angle region in detail, Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and a powder dissolution test were performed. The conventional PXRD analyses suggested that the eutectic mixture did not exhibit structural changes; however, the small-angle region explored through the SAXS instrument revealed a change in the crystal structure of one of their components. FT-IR spectra showed no molecular interaction in the solid state. Finally, the dissolution profile of SQV in the eutectic mixture was different from the dissolution of pure SQV. After 45 min, approximately 55% of the drug in the eutectic mixture was dissolved, while, for pure SQV, 42% dissolved within this time. Hence, this study concludes that the dissolution rate of SQV can be effectively improved through the approach of using PIP as a coformer.

Keywords: dissolution enhancement; eutectic mixtures; piperine; powder diffraction; saquinavir; small-angle X-ray scattering; solid-state characterization.

Figure 1

Chemical structures of saquinavir base (SQV) and piperine (PIP).

Figure 2

DSC analysis of the eutectic mixture screening. The DSC curves of SQV, PIP and the eutectic mixture SQV-PIP are presented.

Figure 3

(a) DSC curves used to construct (b) the eutectic phase diagram where the filled triangle represents the variable liquidus line; the filled circles represent the solidus line. (c) The Tammann diagram of SQV-PIP eutectic mixture. Measurements to construct the phase and Tammann diagram were performed in triplicate (n = 3).

Figure 4

PXRD of the pure components as well as the eutectic system SQV-PIP at 0.4:0.6 molar ratio. Experiments were performed in replicate for each sample (n = 2).

Figure 5

2D small-angle PXRD patterns of PIP (a), SQV (b), and SQV-PIP eutectic mixture (c) obtained using a SAXS instrument in an ultra-high resolution configuration. The region observed in these patterns corresponds to 2q angles up to 10°.

Figure 6

Small-angle PXRD data of the SQV and SQV-PIP (eutectic mixture) samples, obtained by azimuthal integration of the corresponding 2D patterns shown in Figure 5.

Figure 7

FT-IR spectra in the range of 600 to 2000 cm⁻¹ of SQV, SQV-PIP eutectic system, and PIP. The dotted lines are used for indicating the bands.

Figure 8

Micrographs of (a) SQV 1500× and (b) SQV 5000×; (c) Piperine (PIP) 1000× and (d) PIP 1500×; and eutectic composition (e) SQV-PIP 2500× and (f) SQV-PIP 5000×.

Figure 9

Comparative dissolution profile of the drug SQV and the eutectic mixture SQV-PIP. The dissolution experiment was performed in triplicate (n = 3).