Use of highly compressible Ceolus™ microcrystalline cellulose for improved dosage form properties containing a hydrophilic solid dispersion.

The development of amorphous solid dispersions containing poorly soluble drug substances has been well-documented; however, little attention has been given to the development of the finished dosage form. The objective of this study was to investigate the use of Ceolus(™) microcrystalline cellulose, a highly compressible excipient, for the production of rapidly disintegrating tablets containing a hydrophilic solid dispersion of a poorly soluble drug, indomethacin. Solid dispersions of indomethacin and Kollidon(®) VA64 were prepared by hot melt extrusion and characterized for amorphous nature. Milled dispersion particles at 500 mg/g drug loading were shown to be amorphous by differential scanning calorimetry and provided rapid dissolution in sink conditions. Physical characterization of the milled extrudate showed that the particle size of the intermediate was comparable with Ceolus(™) PH-102 and larger than the high compressibility grades of microcrystalline cellulose selected for the trial (Ceolus(™) KG-802, Ceolus(™) UF-711). Preliminary tableting trials showed that dissolution performance was significantly reduced for formulations at dispersion loadings in excess of 50%. Using a mixture design of experiments (DOE), the levels of PH-102, KG-802, UF-711, and PH-301 were optimized. Trials revealed a synergistic relationship between conventional grades (PH-102 and PH-301) and highly compressible grades (KG-802 and UF-711) leading to improved compression characteristics and more rapid dissolution rates. The formulation and resulting compressibility were also shown to have an impact on in vitro supersaturation indicating tablet formulation could impact oral bioavailability. Through the use of highly compressible microcrystalline cellulose grades such as Ceolus(™) KG-802 and UF-711, it may be possible to maximize the bioavailability benefit of amorphous solid dispersions administered as tablet dosage forms.

Novel application of hot-melt extrusion for the preparation of monolithic matrices containing enteric-coated particles.

The objective was to investigate a novel application of hot-melt extrusion for the preparation of multiparticulate matrices comprising delayed-release particles. Multiparticulates of different mechanical strengths (theophylline granules, wet-mass extruded/spheronized pellets and drug-layered microcrystalline cellulose spheres) were coated with Eudragit(®) L30D-55 and characterized regarding potency, moisture content, dissolution properties and tensile strength. The coated particles were incorporated into a water-soluble matrix using hot-melt extrusion. Six hydrophilic polymers including polyethylene glycols, poloxamers and polyethylene oxides were studied as the carrier material for the extrusion. Dissolution testing showed that the maintenance of the delayed-release properties of the incorporated particles was independent of the particle tensile strength, but influenced by the nature of the carrier polymer. High miscibility between the carrier and the coating polymer correlated with increased film permeability and higher drug release in acidic media. Of the materials tested, poloxamer 407 exhibited lower miscibility with the Eudragit(®) L polymer and matrices containing up to 40% enteric pellets were compliant with the USP dissolution requirements for delayed-release dosage forms. The potential advantages of hot-melt extrusion over direct compression for the processing of soft drug granules coated with Eudragit(®) L polymer were demonstrated.

Influence of plasticizer type and level on the properties of Eudragit S100 matrix pellets prepared by hot-melt extrusion.

Matrix-type pellets with controlled-release properties may be prepared by hot-melt extrusion applying a single-step, continuous process. However, the manufacture of gastric-resistant pellets is challenging due to the high glass transition temperature of most enteric polymers and an unacceptably high, diffusion-controlled drug release from the matrix during the acidic phase. The objective was to investigate the influence of three plasticizers (triethyl citrate, methylparaben and polyethylene glycol 8000) at two levels (10% or 20%) on the properties of hot-melt extruded Eudragit S100 matrix pellets. Extrusion experiments showed that all plasticizers produced similar reductions in polymer melt viscosity. Differential scanning calorimetry and powder X-ray diffraction demonstrated that the solid state plasticizers were present in the amorphous state. The drug release in acidic medium was influenced by the aqueous solubility of the plasticizer. Less than 10% drug was released after 2 h at pH 1.2 when triethyl citrate or methylparaben was used, independent of the plasticizer level. Drug release at pH 7.4 resulted from polymer dissolution and was not influenced by low levels of plasticizer, but increased significantly at the 20% level. Mechanical testing by diametral compression demonstrated the high tensile strength of the hot-melt extruded pellets that decreased when plasticizers were present.

Properties of melt extruded enteric matrix pellets.

The objective of this study was to investigate the properties of enteric matrix pellets that were prepared by hot-melt extrusion in a one-step, continuous process. Five polymers (Eudragit) L100-55, L100 and S100, Aqoat grades LF and HF) were investigated as possible matrix formers, and pellets prepared with Eudragit S100 demonstrated superior gastric protection and acceptable processibility. Extruded pellets containing Eudragit S100 and up to 40% theophylline released less than 10% drug over 2h in acid, however, the processibility and yields were compromised by the high amounts of the non-melting drug material in the formulation. Efficient plasticization of Eudragit S100 was necessary to reduce the polymer's glass transition temperature and melt viscosity. Five compounds including triethyl citrate, methylparaben, polyethylene glycol 8000, citric acid monohydrate and acetyltributyl citrate were investigated in terms of plasticization efficiency and preservation of the delayed drug release properties. The aqueous solubility of the plasticizer and its plasticization efficiency impacted the drug release rate from the matrix pellets. The use of water-soluble plasticizers resulted in a loss of gastric protection, whereas low drug release rates in acid were found for pellets containing insoluble plasticizers or no plasticizer, independent of the extent of Eudragit S100 plasticization. The release rate of theophylline in buffer pH 7.4 was faster for pellets that were prepared with efficient plasticizers. The microstructure and solid-state properties of plasticized pellets were further investigated by scanning electron microscopy and powder X-ray diffraction. Pellets prepared with efficient plasticizers (TEC, methylparaben, PEG 8000) exhibited matrices of low porosity, and the drug was homogeneously dispersed in its original polymorphic form. Pellets containing ATBC or citric acid monohydrate had to be extruded at elevated temperature and showed physical instabilities in the form of recrystallization at room temperature. Enteric matrix pellets with a diameter below 1mm and containing 30% theophylline could be successfully prepared by hot-melt extrusion when Eudragit S100 plasticized with either TEC or methylparaben was employed as the matrix material.

Citric acid monohydrate as a release-modifying agent in melt extruded matrix tablets.

Incomplete drug release and particle size-dependent dissolution performance can compromise the quality of controlled release matrix systems. The objective of the current study was to investigate the ability of citric acid monohydrate (CA MH) to enhance the release of diltiazem hydrochloride from melt extruded Eudragit RS PO tablets and to eliminate drug particle size effects. Preformulation studies demonstrated the thermal stability of all components, drug insolubility in the polymer but miscibility with the CA MH. Tablets with either constant polymer levels or constant drug-to-polymer ratios and containing different drug particle size fractions and increasing amounts of CA MH were manufactured by melt extrusion and characterized by dissolution testing, powder X-ray diffraction and scanning electron microscopy. The addition of CA MH to the formulation promoted the thermal processibility and matrix integrity by plasticization of the polymer. The drug release from systems with constant drug-to-polymer ratio was significantly increased when CA MH was added as a result of enhanced pore formation. Particle size effects were eliminated when large amounts of CA MH were used due to the loss of drug crystallinity. Matrix tablets with CA MH furthermore showed a faster and more complete drug release compared to systems with drug only or alternative pore formers (sucrose, NaCl, or PEG 3350). The enhanced drug release was attributed to the amorphous character of the soluble components, improved drug dispersion in the plasticized polymer along with increased polymer permeability. In summary, CA MH promoted the miscibility between the drug and Eudragit RS PO during hot-melt extrusion, resulting in the extrusion of an amorphous system with improved dissolution characteristics.

Citric acid as a solid-state plasticizer for Eudragit RS PO.

The use of solid-state plasticizers for the hot-melt extrusion of pharmaceutical dosage forms has been shown to be beneficial compared with liquid plasticizers. The purpose of this study was to determine the suitability of citric acid (CA) as a solid plasticizer for the preparation of Eudragit RS PO extended-release matrix systems by a melt extrusion technique. The influence of increasing levels of CA monohydrate (CA MH) or anhydrous CA in the powder blend on the extrusion process parameters (screw speed and motor load) was determined as a function of temperature. The solubility of CA MH in extruded tablets was studied by means of modulated differential scanning calorimetry (MDSC) and powder X-ray diffraction (PXRD). Films were cast from organic solutions to demonstrate the plasticizing effect of CA MH as a change in physico-mechanical properties (tensile strength, elastic modulus and elongation). The CA release from extruded tablets was studied over 12 h. The monohydrate form was found to distinctly facilitate the extrusion of Eudragit RS PO, whereas the addition of anhydrous CA to the polymer powder was less effective. This divergent behaviour in plasticization of Eudragit RS PO was attributed to the higher solubility of the monohydrate in the acrylic polymer. The plasticizing effect of the CA MH reached a plateau at 25% during hot-melt extrusion, which coincided with the solubility limit of the organic acid in the polymer as shown by MDSC and PXRD results. The CA MH increased the flexibility of Eudragit RS PO films, as demonstrated by a decrease in tensile strength and elastic modulus and an increase in elongation as a function of CA MH concentration. The dissolution of CA from the matrix tablets followed an extended-release profile, with CA MH exhibiting a faster dissolution rate than the anhydrous form. In conclusion, CA MH was found to be an effective plasticizer for Eudragit RS PO that facilitates the production of controlled-release matrix systems by hot-melt extrusion.