Development of stability-enhanced ternary solid dispersions via combinations of HPMCP and Soluplus® processed by hot melt extrusion

Abstract

The aim of this study was to evaluate a novel combination of hydroxypropyl methylcellulose phthalate (HPMCP-HP-50) and Soluplus polymers for enhanced physicochemical stability and solubility of the produced amorphous solid dispersions (ASDs). This was achieved using hot melt extrusion (HME) to convert the crystalline active pharmaceutical ingredient (API) into a more soluble amorphous form within the ternary systems. Itraconazole (ITZ), a Biopharmaceutics Classification System class II (BCS II) API, was selected as the model drug. The ASDs were characterized by Powder X-Ray diffraction (PXRD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Fourier Transform Infrared (FTIR) spectroscopy, Solid State Nuclear Magnetic Resonance (ssNMR) and dissolution studies. The data showed that the ASDs were physically and chemically stable at 20°C and 50% RH over 12 months. PXRD results indicated that the ITZ in the ASDs was in the amorphous state and no recrystallization occurred. DSC scans confirmed that each formulation exhibited a single intermediate glass transition (T), around 96.4°C, indicating that ITZ was completely miscible in the polymeric blends of HPMCP and Soluplus at up to 30% (w/w) drug loading and that the two polymers were miscible with each other in the presence of ITZ. The FTIR analysis indicated the formation of strong hydrogen bonding between ITZ, HPMCP and Soluplus. The dissolution end-point of the ASDs was determined to be approximately 10 times greater than that of the crystalline ITZ.

Evaluation of Dissolution Enhancement of Aprepitant Drug in Ternary Pharmaceutical Solid Dispersions with Soluplus® and Poloxamer 188 Prepared by Melt Mixing

“…In binary SDs an API matrix system is usually developed by dispersing the API on a single thermoplastic matrix forming carrier, which, in most cases, is a polymer or a copolymer. On the contrary, in a more realistic product development scenario ternary (or higher) SDs having instead of the two said components (i.e., an API and a polymer) a third component with multi-functionality (such as matrix forming, plasticizing, crystallization inhibiting and dissolution rate enhancing abilities) are usually needed [40][41][42][43][44][45][46][47][48][49][50]. When designing such multi-component SDs the complexity of formulation development increases by much, since several factors, including the selection of appropriate polymer/additive composition and the synergistic/antagonistic effects of all components, are introduced into the system.…”

Evaluation of Dissolution Enhancement of Aprepitant Drug in Ternary Pharmaceutical Solid Dispersions with Soluplus® and Poloxamer 188 Prepared by Melt Mixing

“…In all cases, one of the most significant reasons for these observed limitations is the fact that the majority of the published and ongoing research is still handling preliminary proof of concept trials based on binary SD systems In binary SDs an API matrix system is usually developed by dispersing the API on a single thermoplastic matrix forming carrier, which, in most cases, is a polymer or a copolymer. On the contrary, in a more realistic product development scenario ternary (or higher) SDs having instead of the two said components (i.e., an API and a polymer) a third component with multi-functionality (such as matrix forming, plasticizing, crystallization inhibiting and dissolution rate enhancing abilities) are usually needed [40][41][42][43][44][45][46][47][48][49][50]. When designing such multi-component SDs the complexity of formulation development increases by much, since several factors, including the selection of appropriate polymer/additive composition and the synergistic/antagonistic effects of all components, are introduced into the system.…”

A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier

“…Amorphous solid dispersions present a promising strategy for improving the bioavailability of poorly soluble drugs [ 30 , 31 , 32 ]. Solid dispersions can be prepared by thermal methods (e.g., melting and hot-melt extrusion (HME)) [ 33 , 34 , 35 ], solvent evaporation [ 36 , 37 ], and supercritical fluid technology [ 38 , 39 , 40 ]. Binary solid dispersions of highly lipophilic drugs such as atovaquone and polymeric carriers are limited in their drug loading capacity and therefore their feasibility due to dissolution rate limitations [ 41 ].…”