Abstract
The preparation of amorphous solid dispersions (ASDs) is a suitable approach to overcome solubility-limited absorption of poorly soluble drugs. In particular, pH-dependent soluble polymers have proven to be an excellently suitable carrier material for ASDs. Polyvinyl acetate phthalate (PVAP) is a polymer with a pH-dependent solubility, which is as yet not thoroughly characterized regarding its suitability for a hot-melt extrusion process. The objective of this study was to assess the processability of PVAP within a hot-melt extrusion process with the aim of preparing an ASD. Therefore, the influence of different process parameters (temperature, feed-rate) on the degree of degradation, solid-state and dissolution time of the neat polymer was studied. Subsequently, drug-containing ASDs with indomethacin (IND) and dipyridamole (DPD) were prepared, respectively, and analyzed regarding drug content, solid-state, non-sink dissolution performance and storage stability. PVAP was extrudable in combination with 10% (w/w) PEG 3000 as plasticizer. The dissolution time of PVAP was only slightly influenced by different process parameters. For IND no degradation occurred in combination with PVAP and single phased ASDs could be generated. The dissolution performance of the IND-PVAP ASD at pH 5.5 was superior and at pH 6.8 equivalent compared to commonly used polymers hydroxypropylmethylcellulose acetate succinate (HPMCAS) and Eudragit L100-55.
Highlights
An emerging number of new chemical entities (NCE) are poorly soluble compounds, associated with a limited oral bioavailability [1,2]
The glass transition temperature of neat Polyvinyl acetate phthalate (PVAP) was determined via Differential Scanning Calorimetry (DSC) by applying a heat-cool-heat cycle to remove the thermal history of the raw material and it was found to be at 115 ◦C (please see supplementary data (Figure S1))
PVAP turned out to be processable by hot-melt extrusion (HME) if a sufficient plasticizer (PEG 3000) was added in a reasonable amount (10%)
Summary
An emerging number of new chemical entities (NCE) are poorly soluble compounds, associated with a limited oral bioavailability [1,2]. Amorphous solid dispersions (ASDs) have been proven to be able to increase oral bioavailability [3,4,5,6]. Thereby, the drug can be in a thermodynamically stable state when its saturation solubility within the polymer is not exceeded at room temperature, or kinetically stabilized by means of reduced molecular mobility and increased glass transition temperature [9,10,11]. A further decisive feature of an ASD is the generation of a supersaturated solution, facilitated by an increased wettability and presence of the drug in the amorphous state [12]. The supersaturated state may be maintained by the precipitation inhibitory properties of the polymer [13]
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