Characterisation of drug loaded insoluble polymeric matrices prepared by hot melt extrusion technology for drug delivery applications.

Abstract

The main aim of this research was to manufacture and characterise the physiochemical, rheological and drug release properties of drug loaded insoluble matrices prepared by HME technology, to provide a deeper understanding of the mechanisms which affect drug release from hot melt extruded solid dosage forms. Polymethacrylate polymers are frequently used within the pharmaceutical industry as film coating agents many of which offering unique pH-solubility profiles for targetted drug delivery. Eudragit RL PO and RS PO are insoluble polymers which remain intact across the physiological pH range and represent a largely understudied category of materials as polymeric matrices for drug delivery. The physical and chemical characteristics of Eudragit RL PO were investigated showing good thermal stability at processing temperatures below 180°C. Above 180°C, thermal decomposition proceeded by a mechanism which caused cleavage and subsequent loss of ammonio methacrylate functional groups. Eudragit RL PO exhibited hygroscopic properties containing approximately 3% adsorbed residual moisture when stored at ambient temperature at atmospheric conditions. Acceptable processing limits for hot melt extrusion of Eudragit RL PO were defined with an optimal temperature window between 120°C and 170°C and screw speed between 100 and 150rpm. Adsorbed water vapour above 60% relative humidity acted as a plasticizer for Eudragit'4 RL PO which lowered the glass transition to below ambient temperature causing an increase in permeability of the material, prompting recommendations for storage of amorphous drug dispersions with a desiccant to prevent the ingress of moisture and improve solid sate stability. Modelling of the water uptake kinetics of extruded polymer samples showed that the polymer exhibited anomalous non-Fickian transport behaviour where the rate of inward diffusion was approximately equal to the rate of polymer chain relaxation. Water ingress resulted in plasticization of the polymer causing changes in the viscoelastic properties of the material resulting in a reduction of Young’s modulus and tensile strength and an increase in percentage elongation. A model water soluble drug, metformin hydrochloride (MHC1), was formulated within the Eudragit1 RL PO carrier matrix using HME. MHC1 and Eudragit RL PO exhibited a poor interaction during HME with the calculated solubility of MHC1 in the molten polymer matrix low at 2.38 ± 1.9 % w/w. The glass transition temperature of the polymer remained unchanged by the presence of MHC1 at concentrations below 30% w/w showing that MHC1 did not act as a solid state plasticizer. MHC1 caused antiplasticization above concentrations of 30% w/w. PXRD showed that no crystalline to amorphous transition of MHC1 occurred during hot melt extrusion. The drug release properties of MHC1 in Eudragit1 RL PO extrudates were investigated indicating that HME could produce dosage forms with sustained release properties. Drug loading had a significant influence on the drug release profile of MHC1 from the matrix. At high drug loadings (15 and 30% w/w), an extensive pore network caused by leaching of large drug crystals formed a continuous network, which affected the polymer microstructure and resulted in a reduction in tortuosity of the matrix facilitating a faster rate of dissolution. Eudragit® RS PO was added to the hot melt formulation and caused retardation of drug release from the matrix providing a mechanism through which release of MHC1 could be tailored to specification. Hot melt extrudates containing a second model drug, Quinine, were manufactured and the effect of drug form on the physiochemical and drug release properties evaluated. The free base (QB), hydrochloride (QHC1) and sulphate (QSO4) forms were selected and formulated with Eudragit" RL PO. The free base form exhibited the highest saturation solubility within the matrix at 28.48 ± 3.4 % w/w, QS04 19.27 ± 2.34% w/w and the hydrochloride the lowest solubility at 7.96 ± 2.2 % w/w, thus solubility of drug in the molten polymer matrix followed the order QB>QS04>QHC1. A crystalline to amorphous transition occurred during hot melt extrusion for all three quinine forms when formulated at concentrations below the drug saturation solubility. QB, QHC1 and QSO4 acted as solid state plasticizers for Eudragit" RL PO causing a reduction the glass transition temperature at concentrations below saturation solubility. All forms were confirmed to be in a one phase molecular dispersion at concentrations below the saturation solubility indicating complete dissolution in the polymer during extrusion. Above the saturated solubility, the quinine form exerted a significant impact on the plasticization efficiency of the drug. Increasing the concentration of the least miscible drug, QHC1, beyond 10% w/w did not significantly depress the glass transition temperature of the polymer. At high loadings as high as 50% vv/w, the forms with the higher solubility, QB and QSO4 continued to act as solid state plasticizers. Two additional quinine salts were manufactured using acid base reactions forming quinine benzoate and quinine salicylate. Through the use of these additional salt forms, salt counter ion was confirmed to impart a significant influence on the solubility of drug within the polymer matrix, which in turn directly affected the physiochemical properties of hot melt extrudates such as crystallinity and glass transition. It was found that the lower the solubility of drug in the molten matrix, the higher the crystalline component within the hot melt extrudates produced. Single crystal XRD of the newly manufactured salts provided evidence that an interaction between the N atom of the quinine quinuclidine moiety and the carboxcylic acid group -OH of the acid molecules occurred during salt formation. From this it was proposed that polymer drug interactions strongly influenced the drug solubility in the matrix which in turn had a significant impact on the physiochemical properties of the extrudates. Subsequent studies investigated further the drug polymer interactions formed during hot melt extrusion and evaluated the effect of physiochemical properties on drug release properties. The rheological properties of virgin and drug loaded molten Eudragif*' RL PO systems were investigated using capillary rheometry. Capillary rheometry has been used extensively in the engineering sector to characterise polymer melts but has attracted limited interest within the pharmaceutical field in spite of unsurpassable potential to characterise drug polymer melts. Eudragit RL PO exhibited non Newtonian behaviour with viscosity possessing a greater temperature dependence than shear dependence. The Power law was a suitable predictive model and the Power law index for Eudragit: RL PO increased with increasing temperature indicating that the lower the processing temperature, the more shear thinning the melt. The activation energy (Ea) was calculated using the Arrhenius equation, which progressively decreased with increasing the shear rate showing that temperature sensitivity of the polymer melt reduced with increasing shear rate. Results from capillary rheometry highlighted a significant risk of extrusion instability when the polymer was processed at temperatures of 135°C and below and above shear rates of ISOsec'1. Shear rate did not exert a significant influence on the Eudragit' RL PO microstructre post processing and the glass transition temperature and water uptake properties of the polymer remained unchanged when processed at higher shear rates. Elastic recoil properties of the polymer caused significant die swell post processing and it was shown that increasing the length of the extrusion die could increase the retention and relaxation time reducing potential die swell problems that may arise during processing. Addition of QB to the formulation caused an improvement in the thermal processability of the material due to solid state plasticization of the polymer. All drug loaded formulations exhibited significant swell behaviour and increasing the concentration of the drug caused a reduction in the extrudate swell ratio as a result of a reduction in the elastic recoil properties of the material showing that highly drug loaded extrudates therefore pose a lower risk of swell behaviour post processing. Application of a drawing force on the drug release properties from QB loaded Eudragit" RL PO extrudates were evaluated and no significant difference in the dissolution properties were observed at any of the applied drawing forces. Capillary rheometry therefore was shown to be an efficient technique for the characterization of drug loaded polymeric systems and the definition of processing limits for hot melt extrusion in line with current industrial quality by design guidelines. The dissolution properties and drug polymer interactions of hot melt extrudates containing QB, QHC1 and QSO4 were also investigated. Compressed tablets containing 5% w/w QB and Eudragit RL PO showed a significantly slower rate of release than from hot melt extrudates with the same formulation. There was no difference in the release properties of extrudates containing QHC1 or QSO4, but extrudates containing QB were slower with the dissolution rate following the order QHC1=QS04>QB. At 30% w/w loadings however, a significant difference in the rate of dissolution of drug from the extrudates was observed with QHC1>QB>QS04. Water uptake into the hot meltextrudates for the 30% w/w samples was assessed and showed a similar trend with QHC1>QB>QS04. Rapid leaching of the most aqueous soluble form QHC1 resulted in the formation of an extensive pore network throughout the extrudates reducing matrix tortuosity and increasing permeability. Counter intuitively, 30% w/w QB loaded extrudates exhibited a faster rate of dissolution than the more soluble QSO4 due to intense solid state plasticization of the po