Category: Formulation and Quality
Purpose: Tablet formulations for polymer based amorphous solid dispersions (ASDs) are commonly developed on a case-by-case basis depending on the drug-polymer combination  as there are only few systematic investigations conducted in literature with limited model compounds . The aim of this work is to investigate the impact of different drugs and their drug loads on material properties of the obtained ASD prepared by hot-melt extrusion to facilitate excipient selection for direct compression of ASDs. Additionally, the impact of water content on material properties of ASDs was investigated.
Methods: Poly(vinylpyrrolidone-co-vinyl acetate) 60:40 (copovidone) was used as the model polymer and ketoconazole (KTZ) griseofulvin (GSF) and M3814 (Merck Healthcare KGaA, Darmstadt, Germany) as model drugs. The impact of the drug on the glass transition temperature (Tg) was investigated using differential scanning calorimetry (DSC). ASDs containing up to 40 % of the model drugs in copovidone were extruded using a Leistritz ZSE 18 extruder and subsequently milled using a hammer mill. Different water contents of copovidone extrudates were achieved after open storage at controlled conditions for different durations. Afterwards, the extrudate powders were directly compressed into tablets using a compaction simulator without any additives and the obtained tablets were analyzed regarding their hardness, dimensions and disintegration.
Results: Regarding the glass transition temperature (Tg), water was found to be the strongest plasticizer in copovidone due to its very low Tg (≈ -137 °C), followed by KTZ and GSF (Fig. 1). Addition of M3814 did not impact the Tg of the mixture as the Tg of the neat drug is close to the Tg of copovidone (≈ 108 °C), indicating no plasticizing properties.
Hot-melt extrusion of the drug/polymer mixtures yielded fully amorphous extrudates (checked by X-ray diffraction, DSC and microscopy), which were subsequently milled to similar particle sizes. Water content was controlled in all cases to ensure comparability. Tablet compression was possible for all milled extrudates without any additives and acceptable ejection forces were reached (< 1000 N). All model compounds (including water) were found to increase the tablet hardness with increasing drug loads at the same compression pressure (Fig. 2). Except for M3814, this finding is explainable by the plasticizing effect of these drugs observed as a decrease in the glass transition temperature using DSC. However, M3814 clearly shows, that no changes in the glass transition temperature do not inevitably correlate with no plasticizing properties regarding mechanical properties, indicating that DSC measurements are not a suitable predictor for evaluating compression behavior.
Disintegration of the extrudate tablets revealed a strong increase in disintegration time with increasing drug loads of GSF and M3814, whereas increasing drug loads of KTZ and water showed a minor impact on the disintegration time (Fig. 3). Furthermore, the disintegration time did not change with the tablet hardness in all cases. This finding can be explained by the observation of gel formation of copovidone during testing, resulting in slow surface erosion instead of an actual disintegration, rendering the tablet hardness and particle size less relevant for this process.
Conclusion: The results of this study show a disconnect between the plasticizing ability of a drug regarding the glass transition temperature and mechanical properties relevant for tablet compression. These observations clearly highlight the importance of characterizing hot-melt extrudates regarding their mechanical properties to better evaluate required excipients. Additionally, the disintegration time of the extrudates is highly dependent of the incorporated drug, which is not fully explainable by physicochemical properties like solubility or logP values, indicating the necessity of further investigations. These experiments are an important step towards rational formulation development of hot-melt extrudates based on systematic investigations rather than experience.