The effect of moisture during thermal treatment of directly compressed Eudragit ®RLPO matrices

Matrix systems;Moisture;Eudragit;Methacrylates;Sustained release tablets;Coalescence;Humidity

Pirayavaraporn, Chompak ; Tucker, Ian ; Rades, Thomas

University of Otago

关键词: Matrix systems;    Moisture;    Eudragit;    Methacrylates;    Sustained release tablets;    Coalescence;    Humidity;   

Others  :  https://ourarchive.otago.ac.nz/bitstream/10523/2512/1/PirayavarapornChompak2012PhD.pdf

美国|英语

来源: Otago University Research Archive

【 摘 要 】

Purpose: This thesis investigated of the effect of moisture on a polymeric matrix system. The effect of moisture on compaction and coalescence behaviours, which are major influences on drug release regulation, is of particular interest. Much emphasis has been placed on water as a plasticizer, but it may also act by other mechanisms to cause changes in mechanical properties thereby affecting drug release. Previous research mainly focused on thermal treatment of matrix tablets, and has not investigated the influence of water on coalescence to a great extent; therefore, a study on the role of water was required. Prior to studying the influence of moisture on coalescence, it was necessary to quantify moisture levels and to determine the types of water present in a model polymer under various storage humidities.Methods: Eudragit® RLPO powder was stored at various relative humidities (RH) of 33, 56, 75, 94%. Four water determination methods, [weight loss on drying (LOD), thermo gravimetric analysis (TGA), differential scanning calorimetry (DSC), and Karl Fischer titration (KFT)] were utilized to determine moisture content. DSC was used to study the thermal behaviour and identify the glass transition temperature (Tg) of moist and dry samples. The Gordon-Taylor Equation was used to calculate the amount of plasticizing water. Scanning electron microscopy was employed to examine the morphology of the polymer particles after thermal analyses. Fourier Transform Infrared spectroscopy (FTIR)-DRIFTS was used to investigate molecular interactions between water and polymer, and water loss over time. Using a curve fitting procedure, the water region (3100-3700 cm-1) of the spectrum was analysed and used to identify water present, and to determine the water loss kinetics upon purging the sample with dry compressed air. Pure polymer tablets and binary mixture tablets containing a model drug (indomethacin) were compressed at 3 tonnes, with 2 minutes dwell time. After compression, the tablets were cured at 40, 55 or 70 C, at ambient RH or at the previous storage RH of the polymer for 24 hours. The diameter and thickness of the tablets were measured using digital Vernier callipers. The mechanical properties were investigated using a texture analyser equipped with a 250 kg load cell. A USP dissolution apparatus (I) was used to investigate drug release for each formulation (20-60% polymer) using 900 ml, 0.2 M phosphate buffer pH 7.2, at 37 °C. A UV/VIS spectrophotometer was used to quantify the amount of drug released at 318 nm (USP method). A first order model for percentage mass release versus time was fitted to estimate the rate constant, using PRISMTM (Graph pad ver5.0). The stability of indomethacin was studied using an HPLC (stability indicating assay). SPSS version 17.0 was used for statistical analysis, at the five percent level of significance. Scanning electron microscopy (SEM) was used to examine the coalescence behaviour of polymer particles and the appearance of the tablets after an 8 hour dissolution study. X-ray micro tomography (μ-CT) was used to inspect the effect of moisture on the pore structure and porosity of the pure polymer tablets.Results: By storing Eudragit RLPO powder at various RHs, the moisture content increased with time and reached equilibrium at different levels. The KFT was found to be an accurate measurement of total water content as all of the polymer powder was completely dissolved and subjected to the analysis. The thermal methods (LOD, TGA, and DSC) underestimated total moisture content, which could be due to the coalesced non-porous film covering the sample surface and, subsequently, inhibiting water evaporation (as seen in SEM images). DSC thermograms showed that there was no bulk water, and yet the Tg values of the moist samples were about the same (~55°C) for all RHs. In other words, not all moisture was plasticizing moisture. According to Gordon-Taylor prediction, for polymers containing 10% moisture, approximately 25% of the water is plasticizing water, reducing the Tg by 25°C. The FTIR analysis showed that there were four water bindings present in this polymer. The most tightly bound water (directly binding to the carbonyl groups) is believed to act as plasticizing water (~25%), consequently lowering the Tg, while the remaining water (~75%) is non-plasticizing water and may influence the matrix formation in other ways. The moisture sorption upon curing was found to support polymer compaction, i.e., strengthening of the tablets, in both pure polymer and binary mixture tablets. However, the stress-strain profile of the binary mixture tablets was slightly different from that of the pure polymer tablets, indicating that indomethacin influences bond formation. An increase in the tensile strength and work of failure were found in high moisture tablets, and these effects were enhanced when treating the tablets at or above the Tg. This was comparable with the dissolution study, for which a lower drug release was predicted from the moist tablets cured at 55 and 70°C, compared to 40°C treated tablets. A greater coalescence of moist polymer particles was apparent in the SEM images when the tablets were cured at the Tg or above. This could inhibit further drug release from the inside of tablets resulting in a lower drug release. These results present an enhanced effect of moisture upon curing around the Tg or above, at which the polymer chains are more mobile and could interact more with water, especially with the previously non-plasticizing portion. It may now plasticize the polymer during the long curing period. The newly arisen plasticizing water could further reduce the Tg, i.e. lower than 55°C, thus intensifying the interaction. In addition, the reduction of viscosity above the Tg results in a higher viscous flow, thereby increasing particle contact area and facilitating the inter-particle diffusion of polymer segments. Moisture enhancing coalescence led to a marked reduction in the porosity of tablets (particularly when moisture content exceeded 5%), as demonstrated using an X-ray method. It also showed that the pore structure was remarkably altered at high moisture content, resulting in fewer but larger pores.Conclusion: Although the total water content of the polymer increased as storage humidity increased, the Tg was reduced from about 80 °C to 55 °C at all storage humidities. Thus it is concluded that different types of water (plasticizing/non-plasticizing) are present in the polymer. Approximately one quarter (25 %) of the water in a sample of Eudragit RLPO, which is 10% water, was found to be ;;plasticising’ water. The remaining water is probably dispersed in nano-domains which do not freeze on cooling to sub-zero temperatures. However, both plasticising and non-plasticizing water affect coalescence upon thermal treatment; so it is not sufficient to understand coalescence as being affected only by the nature (rubber-glass) of the polymer, and hence a function of Tg. There are a number of potential mechanisms by which the non-plasticizing water could lead to the coalescence of polymer particles. These include 1) softening of polymer particles and creating more contact areas; 2) capillary force and liquid bridges pulling the particles closer together and into contact; and 3) the constrained water residing in the nano-domains of the polymer (mostly non-plasticizing water) could be released when the polymer chains become more mobile at the Tg, interacting more with the polymer and resulting in a multiplied effect of both water and temperature.