(M1430-03-18) Super Material-Sparing HME Screening: Simultaneous API Loading and Degradation Predictions

Purpose: Hot melt extrusion (HME) offers a high throughput process to manufacture amorphous solid dispersions. A variety of experimental and model-based approaches exist to predict API solubility in polymer melts, but these methods are typically aimed at determining the thermodynamic solubility and do not take into account kinetics of dissolution or the associated degradation of the API during thermal processing, both of which are critical considerations to generating a successful amorphous solid dispersion by HME. Micro compounders are the current industry standard for small-scale HME feasibility screening, yet still require gram-scale quantities of material per run, which can lead to substantial material burden. This work aims to develop a material sparing approach for screening a given pharmaceutical active for hot melt extrusion with physically relevant parameters.

Methods: Piroxicam (PXCM) and ritonavir (RTV) were used as model compounds with PVP VA64 as the dispersion polymer. The maximum processing temperature was first determined by gravimetric and visual analysis of the pure components and their 50/50 physical mixtures. 200mg of physical mixtures were then mixed for three minutes at temperature using a small device made in-house, termed the MiniMixer. Processed samples were analyzed by powder X-ray diffraction (PXRD), and the residual crystalline signal used to quantitate the amount of solubilized active. To test this prediction, 6g mixtures of various API loadings were processed with the ThermoFisher Haake MiniLab 3 micro compounder for 3 minutes at 200rpm followed by PXRD analysis. Degradation profiles of the actives were also compared between samples processed by both techniques at multiple temperature using high performance liquid chromatography.

Results: RTV was shown to be fully soluble at 50wt% active loading at 150°C by both MiniMixer and MiniLab, which is not surprising as the process temperature is well above the compound’s melting point and it is not prone to rapid crystallization. The MiniMixer prediction for PXCM at 150°C was 22wt%, which matched well to the MiniLab processing that showed a fully PXRD amorphous sample at 20% PXCM, but crystals were present in the 25% sample. The MiniMixer samples all show lower degradation compared to the Haake samples, and the offset increases with increasing temperatures. Despite the reduced degradation results of the MiniMixer, the offset is predictive within the processing temperature range, independent of API.

Conclusion: We present screening flowchart and simple device that allows rapid formulation screening using HME-relevant time, temperature, and mixing conditions to predict achievable API loading and expected degradation. This method has good correlation to processing with a micro compounder, an HME screening industry standard, but requires only 100mg of API!

HME screening process and MiniMixer diagram



Diffractograms of the Haake MiniLab processed material showing good correlation to the MiniMixer predicted loading



Comparison of the experimental degradation of the MiniMixer and MiniLab processed samples, and ratio of measured impurities from MiniMixer and Haake processing for all formulations studied at the same 3 minute mixing time.