Abstract
Among the great number of poorly soluble drugs in pharmaceutical development, most of them are weak bases. Typically, they readily dissolve in an acidic environment but are prone to precipitation at elevated pH. This was aimed to be counteracted by the preparation of amorphous solid dispersions (ASDs) using the pH-dependent soluble polymers methacrylic acid ethylacrylate copolymer (Eudragit L100–55) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) via hot-melt extrusion. The hot-melt extruded ASDs were of amorphous nature and single phased with the presence of specific interactions between drug and polymer as revealed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FT-IR). The ASDs were milled and classified into six particle size fractions. We investigated the influence of particle size, drug load, and polymer type on the dissolution performance. The best dissolution performance was achieved for the ASD made from Eudragit L100–55 at a drug load of 10%, whereby the dissolution rate was inversely proportional to the particle size. Within a pH-shift dissolution experiment (from pH 1 to pH 6.8), amorphous-amorphous phase separation occurred as a result of exposure to acidic medium which caused markedly reduced dissolution rates at subsequent higher pH values. Phase separation could be prevented by using enteric capsules (Vcaps Enteric®), which provided optimal dissolution profiles for the Eudragit L100–55 ASD at a drug load of 10%.
Highlights
A fundamental problem in pharmaceutical development is the poor aqueous solubility of most of the new chemical entities
We successfully prepared amorphous solid dispersions (ASDs) at two drug loads (10% and 25%) using Eudragit L100–55 and hydroxypropylmethylcellulose acetate succinate (HPMCAS) LG as pH-dependent soluble polymers and KTZ as weakly basic model drug by hot-melt extrusion
The dissolution performance was studied at a static pH of 6.8, which revealed the most promising results for the L100–55 ASD at a drug load of 10% as a complete dissolution and a stable supersaturation without precipitation could be obtained
Summary
A fundamental problem in pharmaceutical development is the poor aqueous solubility of most of the new chemical entities. The poor solubility entails a low oral bioavailability [1,2,3,4]. There is a need for formulation strategies which are capable to overcome this limitation. Several approaches have been tested to address this by increasing the solubility or the dissolution rate of these compounds [5]. Among these formulation approaches, amorphous solid dispersions (ASDs) were successfully applied.
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