Compression of Controlled-Release Pellets Produced by a Hot-Melt Extrusion and Spheronization Process

Abstract

The purpose of this study was to investigate the physicomechanical and dissolution properties of tablets containing controlled-release pellets prepared by a hot-melt extrusion and spheronization process. A powder blend of anhydrous theophylline, Eudragit Preparation 4135 F, and functional excipients was melt-extruded, pelletized, and then spheronized. The pellets were compressed into tablets using forces of 5, 10, 15, and 20 kN. Tablet diluents included microcrystalline cellulose, a mixture of spray-dried lactose and microcrystalline cellulose, modified food starch, and soy polysaccharides. The effective porosity of the compressed pellets was measured using mercury porosimetry and helium pycnometry, while the surface area was determined using Brunauer, Emmett, and Teller (BET) analysis. The disintegration time, hardness, and friability of compacts were determined. Drug release studies were performed according to USP 27 Apparatus 3 guidelines in 250 mL of medium (pH 1.0, 3.0, 5.0, 6.8, and 7.4) 37 degrees C and 20 dpm. Samples were analyzed by high pressure-liquid chromatography (HPLC). Effective porosity and surface area determinations of the melt-extruded pellets were not influenced by compression. The percent of theophylline released from rapidly disintegrating tablets was not affected by compression force or excipient selection, but tablets with prolonged disintegration times exhibited delayed drug release in acidic media. However, dissolution profiles of uncompressed pellets and all compacts were identical after transition from 0.1 N HCl to media increasing in pH from 3.0 to 7.4. Furthermore, pellet to filler excipient ratio and filler excipient selection did not influence the rate of drug release from compacts.

The Impact of Hot Melt Extrusion and Spray Drying on Mechanical Properties and Tableting Indices of Materials Used in Pharmaceutical Development

“…Upon milling the extrudate, the hard particles exhibit poor bonding and lower TS, resulting in a CP 61% greater than for “as is” material to achieve a SF of 0.85. This is similar to the finding on the poor compressibility of melt‐extruded particles . Spray‐dried HPMCAS had a higher BI than “as is” material.…”

“…30 Powders processed by HME are subjected not only to elevated processing temperatures but also to high pressure. The reduced free volume further retards molecular mobility and can prevent further densification during tableting, 31,32 which could adversely impact product performance such as drug dissolution. Crowley et al showed that guaifenesin matrix tablets containing binary mixtures of guaifenesin and ethyl cellulose, prepared by HME exhibited considerably slower drug release relative to those prepared by direct compression.…”

Physicochemical properties and mechanisms of drug release from melt-extruded granules consisting of chlorpheniramine maleate and Eudragit FS

“…The porosity of the compressed granules was 50% greater than melt extruded granules. A similar effect of the melt extrusion process on the porosity of melt-extrudate ethyl cellulose matrix has previously been reported 13,16 .…”

“…The granular form of Eudragit Õ FS was used in this study. Eudragit Õ FS as a thermoplastic carrier for melt-extruded sustained-release dosage forms has only been reported by Young et al 16 . In their study, Eudragit Õ FS in combination with PEG 8000 at 7:1 ratio was used as the thermoplastic carrier to prepare sustained-release theophylline pellets, which were further compressed into tablets.…”

Amorphous Solid Dispersions

“…Powders processed by HME are subjected to elevated processing temperatures as well as high pressure. The reduced free volume retards molecular mobility and prevents further densification during tableting (Zhu et al 2002;Young et al 2005), which could adversely impact the product performance Fig. 13.3.…”