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

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 (Tg), 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.

Albadarin AB ，Potter CB ，Davis MT ，Iqbal J ，Korde S ，Pagire S ，Paradkar A ，Walker G ... -  《-》

Stability-enhanced hot-melt extruded amorphous solid dispersions via combinations of Soluplus® and HPMCAS-HF.

Alshahrani SM ，Lu W ，Park JB ，Morott JT ，Alsulays BB ，Majumdar S ，Langley N ，Kolter K ，Gryczke A ，Repka MA ... -  《AAPS PHARMSCITECH》

Design of spray dried ternary solid dispersions comprising itraconazole, soluplus and HPMCP: Effect of constituent compositions.

A range of 17 ternary formulations of itraconazole (ITZ), HPMCP and Soluplus have been manufactured using spray drying. These amorphous solid dispersions (ASDs) were very stable against crystallisation and ITZ was found to be amorphous in all formulations after one year at 40°C/75% RH. A number of solid state analytical techniques including PXRD, DSC, small angle X-ray scattering, FTIR and solid state NMR were used to characterise the physicochemical properties of the ASDs following processing and storage and to assess any interactions between components. Microtrac laser scattering analysis revealed a relationship between polymer levels and particle size distribution (PSD). Dissolution studies indicated that higher Soluplus content in the formulation resulted in higher concentrations of ITZ in acidic media.

Davis MT ，Potter CB ，Mohammadpour M ，Albadarin AB ，Walker GM ... -  《-》

Application of film-casting technique to investigate drug-polymer miscibility in solid dispersion and hot-melt extrudate.

Determination of drug-polymer miscibility is critical for successful development of solid dispersions. This report details a practical method to predict miscibility and physical stability of drug with various polymers in solid dispersion and, especially, in melt extrudates by applying a film-casting technique. Mixtures of itraconazole (ITZ) with hydroxypropylmethylcellulose phthalate (HPMCP), Kollidon(®) VA 64, Eudragit(®) E PO, and Soluplus(®) were film-casted, exposed to 40°C/75% RH for 1 month and then analyzed using differential scanning calorimetry (DSC), powder X-ray diffractometry, and polarized light microscopy (PLM). ITZ had the highest miscibility with HPMCP, being miscible at drug to polymer ratio of 6:4 (w/w). There was a downward trend of lower miscibility with Soluplus(®) (miscible at 3:7, w/w, and a few microcrystals present at 4:6, w/w), Kollidon(®) VA 64 (2:8, w/w) and Eudragit(®) E PO (<1:9, w/w). PLM was found more sensitive to detect drug crystallization than DSC and powder X-ray diffractometry. There was general correlation between results of film casting and hot-melt extrusion (HME) using a twin screw extruder. For ITZ-Soluplus(®) mixtures, HME at 4:6 (w/w) resulted in a single phase, whereas drug crystallization was observed at higher drug load. HME of ITZ-Kollidon(®) VA 64 mixtures also correlated well with the miscibility predicted by film casting.

Parikh T ，Gupta SS ，Meena AK ，Vitez I ，Mahajan N ，Serajuddin AT ... -  《-》

Increased dissolution and oral absorption of itraconazole/Soluplus extrudate compared with itraconazole nanosuspension.

The purpose of this article was to compare the in vitro and in vivo profiles of itraconazole (ITZ) extrudates and nanosuspension separately prepared by two different methods. And it was proved truly to form nanocrystalline and amorphous ITZ characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) analysis, Fourier transform infrared spectrum (FTIR), transmission electron microscope (TEM), and scanning electron microscope (SEM). The release of ITZ/Soluplus solid dispersions with amorphous ITZ was almost complete while only 40% release was obtained with ITZ nanocrystals. The amorphous state need not to cross over the crystal lattice energy upon dissolution while the crystalline need to overcome it. In the in vivo assay, the AUC(0-t) and C(max) of ITZ/Soluplus were 6.9- and 11.6-time higher than those of pure ITZ. The formulation of the extrudate had an AUC(0-t) and C(max) similar to those of ITZ and also OH-ITZ compared with the commercial capsule (Sporanox®). The relative bioavailability values with their 95% confidence limit were calculated to be 98.3% (92.5-104.1%) and 101.3% (97.9-104.1%), respectively. The results of this study showed increased dissolution and bioavailability of the solid dispersion of Soluplus-based carrier loading ITZ prepared by HME compared with the ITZ nanosuspension prepared by wet milling.

Zhang K ，Yu H ，Luo Q ，Yang S ，Lin X ，Zhang Y ，Tian B ，Tang X ... -  《-》