Mechanical properties and drug release of venlafaxine HCl solid mini matrices prepared by hot-melt extrusion and hot or ambient compression.

Objective/significance: To elucidate the role of plasticizers in different mini matrices and correlate mechanical properties with drug release. METHODS: Cylindrical pellets were prepared by hot-melt extrusion (HME) and mini tablets by hot (HC) and ambient compression (AC). Venlafaxine HCl was the model drug, Eudragit® RSPO the matrix former and citric acid or Lutrol® F127 the plasticizers. The matrices were characterized for morphology, crystallinity, and mechanical properties. The influence of plasticizer's type and content on the extrusion pressure (Pe) during HME and ejection during tableting was examined and the mechanical properties were correlated with drug release parameters. RESULTS: Resistance to extrusion and tablet ejection force were reduced by Lutrol® F127 which also produced softer and weaker pellets with faster release, but harder and stronger HC tablets with slower release. HME pellets showed greater tensile strength (T) and 100 times slower release than tablets. Pe correlated with T and resistance to deformation of the corresponding pellets (r2 = 0.963 and 0.945). For both HME and HC matrices the decrease of drug release with T followed a single straight line (r2 = 0.990) and for HME the diffusion coefficient (De) and retreat rate constant (kb) decreased linearly with T (r2 = 0.934 and 0.972). CONCLUSIONS: Lutrol® F127 and citric acid are efficient plasticizers and Lutrol® F127 is a thermal binder/lubricant in HC compression. The different bonding mechanisms of the matrices were reflected in the mechanical strength and drug release. Relationships established between T and drug release parameters for HME and HC matrices may be useful during formulation work.

Relationships between the properties of self-emulsifying pellets and of the emulsions used as massing liquids for their preparation.

Self-emulsifying pellets were prepared using microcrystalline cellulose, emulsions of caprylic/capric triglyceride, and three Cremophors (ELP, RH40, and RH60) at 1.5 and 2.3 weight ratios, and two drugs (furosemide and propranolol) of different lipophilicity. Droplet size, zeta potential (ζ) and viscosity of emulsions, and pellet size, shape, friability, tensile strength, disintegration, and drug migration in pellets were determined. Evaluation of reconstituted emulsions was based on droplet size and ζ. Factorial design and 3-way ANOVA was applied to estimate the significance of the effects of the drug, surfactant and oil/surfactant ratio. It was found that droplet size, viscosity and ζ of emulsions, and size, shape, and friability of pellets were affected by the studied factors and were significant interactions between their effects on pellet size and friability. Migration of drug towards the pellet surface was higher for the less lipophilic furosemide and higher oil content. Linear relationships were found between the emulsion viscosity and the shape parameters of the pellets (for the aspect ratio R (2) = 0.796 for furosemide and R (2) = 0.885 for propranolol and for the shape factor, e R R (2) = 0.740 and R (2) = 0.960, respectively). For all the formulations examined, an exponential relationship was found between migration (M%) and the product of viscosity (η) and solubility of drug in oil/surfactant mixture (S) (M% = 98.1e-0.016 [η•S], R (2) = 0.856), which may be useful in formulation work.

Effect of plasticiser type on the hot melt extrusion of venlafaxine hydrochloride.

OBJECTIVES: During hot melt extrusion (HME), phase changes and interactions due to thermo-mechanical stresses affect the drug incorporation into polymeric matrices. Two HME compositions of venlafaxine HCl with Eudragit RSPO (Evonic, Darmstadt, Germany) as the matrix polymer and either citric acid monohydrate (CAMH) or Lutrol F127 (BASF, Ludwigshafen, Germany) as plasticisers were compared. METHODS: Miscibility and extrusion temperatures were elucidated based on solubility parameters and differential scanning calorimetry. Thermal changes in the extruded melts and their respective physical mixtures were compared. Powder X-ray diffraction was applied to detect changes in crystallinity and fourier transform infrared (FT-IR) spectroscopy for chemical interactions. KEY FINDINGS: Both plasticisers (15%) enabled extrusion easily. With Lutrol, the drug remained crystalline, whereas with CAMH a single-phase amorphous transparent extrudate was obtained. Differences between the thermographs of extruded and physical mixtures indicated the importance of mechanical stresses in the single-screw extruder. In the FT-IR spectrum of Eudragit/CAMH/drug extrudate, the abscence of the peak due to venlafaxine OH and the merging of the two peaks due to CAMH carbonyl, into one, indicated esterification. CONCLUSIONS: CAMH and Lutrol have different reactivities towards venlafaxine HCl and also different plasticising mechanisms for Eudragit RSPO because of hydrogen bonding and because of similar overall molecular attractive forces, respectively.