AbstractThe 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 polymer which lowered the polymeric glass transition to temperatures similar to the dissolution media temperature which caused an increase in molecular mobility of polymeric chains resulting in rapid diffusion of drug from the polymer matrix.
QB exhibited multiple sites of interaction with the polymer functional groups. Protonation of the C-N quinuclidine moiety of the quinine molecule occurred within QHC1 and QSO4 during salt formation. An interaction between QB and Eudragit RL PO occurred at the C-N quinuclidine moiety confirming this to be a key site involved in the interaction between drug and polymer during hot melt extrusion. No interaction at this site was observed within QHC1 and QSO4 providing evidence that protonation during salt formation resulted in the occupation of a key site which is involved in the formation of drug polymer interactions during hot melt extrusion, rendering this site less available for interaction with the polymer and thus reducing drug solubility. QB caused interruption of polymeric intramolecular hydrogen bonding at the C-0 and C=0 polymeric ester and carbonyl sites and exhibited a strong interaction with the ionic ammonio methacrylate polymeric functional groups evidenced by the reduction in solubility in the RS PO polymer. QHC1 and QSO4 also had a lower solubility in the RS PO polymer exhibiting an interaction at these sites was lower than QB given by the smaller reduction in solubility in RS PO than RL PO. Stability of hot melt extrudates containing QB, QHC1 and QSO4 following storage at accelerated conditions (40°C/ 75% RH) were assessed showing differences in the rate of recrystallisation. Evidence of surface crystallisation after 3 weeks was observed for QHC1 and QSO4 while QB extrudates remained smooth and surface recrystallisation was not observed until 6 weeks. RL PO acted as a more efficient recrystallisation inhibitor for the free base than for QHC1 and QSO4. Following storage of QB loaded extrudates after 3 weeks, dissolution was faster from the matrix proposed to be attributed to an increased molecular mobility of the polymer due to plasticization by water upon storage. The dissolution profile of QHC1 and QSO4 remained unaffected by surface recrystallisation, however the dissolution of QB was progressively slower with increasing surface recrystallisation due to the poor solubility of the free base.A better understanding of hot melt extruded dosage forms, and in particular insoluble systems has been achieved through these studies. In summary, a key element of this work has shown that altering the physiochemical properties of hot melt extrudates can exert a propitious effect on dissolution performance highlighting a novel and rationalised approach to the dosage form design of such systems. What is clear, is that the causative factors and hence underlying mechanisms which lead to alterations in extrudate physiochemical properties are complex but may be better understood by the development of an appreciation of the chemistry of the interaction which occur between drug and polymer during hot melt processing. From this therefore, it is highly recommended that as a basic pre-requisite for the formulation of hot met extruded dosage forms, an understanding of drug polymer miscibility and solubility should be sought. We have shown that formation of a salt form of an active ingredient significantly impacts upon the physiochemical properties of the dosage form which can be translated to altered dissolution performance hence understanding how a salt form may alter the interaction between drug and polymer during hot melt processing enables manipulation of dissolution performance to create novel dosage forms with better controlled release capabilities. These studies also showed that the salt counter ion is exceptionally important and clearly affects drug polymer interactions which occur during processing. In order to assess more generalised relationships and to understand the counter ion effect more comprehensively, further work would be required using a range of polymer matrices and model drugs and their salt forms. This approach would enable the creation of predictive models such that formulators may have a sound basis for theoretical prediction of how a drug or drugs and their respective forms will behave during hot melt extrusion prior to experimentation. In a second key element of this work, it has been shown that molten materials may be comprehensively characterised in a manor more representative to large scale processing operations. A key element of the utility of this technique is the ability to optimise the manufacturing process by gaining vital information on how the critical process attributes and formulation may impact the final dosage form. Further experimentation would allow the development of a scale up model which allows translation of process optimisation parameters from the lab scale to large scale real time processing.
|Date of Award||Jul 2012|
|Supervisor||Gavin Andrews (Supervisor) & David Jones (Supervisor)|