Using Polymers to Enhance Solubility of Poorly Soluble Drugs - Pharmaceutical Technology

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Using Polymers to Enhance Solubility of Poorly Soluble Drugs
The authors demonstrate how melt-extrusion and spray-drying methods can help to prepare solid dispersions of poorly soluble drugs using Eudragit polymers.

Pharmaceutical Technology

Materials and methods

Materials. Felodipine for spray-drying was purchased at Shiono Chemical Co. (Tokyo) for melt-extrusion trials in Zhejiang Yiyuan, China. Carbamazepine was a gift from Evonik (Dossenheim, Germany). The authors also used Eudragit E and Eudragit NE30D (Evonik Röhm GmbH, Darmstadt, Germany) and ethanol (Wako Pure Chemical Industries, Osaka, Japan).

Spray-drying. Eight-five percent of 5% Eudragit E PO, 5% Eudragit 30D, and 10% felodipine were dissolved in ethanol (95%). The organic solution contained 14% of solid. Ten percent carbamazepine and 90% Eudragit E PO were dissolved in ethanol (95%) with a solid content of 6%. The spray-drying process was conducted with a Mini Spray-Dryer B-290 (Buech, Tokyo). Operational conditions are described in Table I.

XRPD was carried out on a Mini-Flex, DSC was carried out on a Thermo plus 2–DSC 8230 (Rigaku, Tokyo), and the scanning electronic microscope (SEM) used was a JSM–6360LV (Jeol, Tokyo).

Solubility was measured with high-performance liquid chromatography (HPLC). The drug, the physical mixture, or the spray-dried sample was dispersed in 0.1N hydrochlorid acid (pH 1.2); the dispersion was homogenized with ultra sonic vibration for 10 min and filtered. Solutions with felodipine were diluted with the mobile phase acetonitrile/0.01 M phosphate buffer pH 4.5 (70/30). The wavelength was set to 237 nm and the flow rate was 1 mL/min. Dissolution testing was performed with a paddle apparatus (DT610, Jasco, Tokyo), at a rotation speed of 100 rpm. The authors used 900 mL of 0.1N hydrochlorid acid (pH 1.2) and added samples equivalent to 18 mg of felodipine or 360 mg of carbamazepine. The wavelength was set to 237 nm for felodipine and 285 nm for carbamazepine.

Melt extrusion. Solid dispersions containing felodipine (melting point=145 °C), Eudragit E, and Eudragit NE 30D (10%/85%/5%) and solid dispersion with 10% carbamazepine (190 °C) and 90% Eudragit EPO were prepared by melt extrusion on a twin-screw extruder (Micro 18 GL Pharma, Leistritz, Nürnberg, Germany). The temperature profile of the felodipine sample was between 70°C and 160°C, the screw speed was set at 200rpm, the feeding rate of the solids at 0.7 kg/h and Eudragit NE 30D was dosed with a hose pump. For the carbamazepine sample, the temperature was between 70 °C and 200 °C, the screw speed was 150 rpm, and the feeding rate of the solids was set at 0.5 kg/h. The extrudate was pushed through an orifice, collected on a conveying belt, and granulated. The granules were milled to 250 µm.

XRPD was carried out on an X'Pert Pro MPD Diffraktometer (Panalytical, Almelo, The Netherlands), DSC was done with a Pyris 1 DSC (Perkin Elmer, Waltham, MA). Dissolution testing was performed with a paddle apparatus (DT 700, Erweka, Heusenstamm, Germany) at a rotation speed of 100 rpm. The authors used 500 mL of simulated gastric fluid sine pepsin (SGFsp) at a 1.2 pH and added samples equivalent to 10 mg of felodipine or 200 mg of carbamazepine. The concentration of felodipine was measured with HPLC using acetonitile/phosphate buffer pH 3/methanol 40/40/20 % (v/v/v) as a mobile phase. The wavelength was set to 362 nm and the flow rate was 1 mL/min. The concentration of carbamazepine was measured with an ultraviolet spectrometer at a wavelength of 285 nm.

Preparation of physical mixture. Physical mixtures were prepared by blending the substances for 10 min at 40 rpm in a double-cone mixer (Erweka, Heusenstamm, Germany). For the physical mixture containing Eudragit NE 30D, the dispersions were dried to obtain a solid.


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