(M1430-09-56) Application of the Hot Melt Extrusion Risk Assessment Classification System (HCS) to a Poor Glass Forming, High Melting Point Drug

Purpose: Malaria continues to be a major global health concern. The emergence of resistance has driven the search for new antimalarial compounds. Among the promising candidates is decoquinate (DQ) which has been relatively unexploited but presents formulation challenges due to its high melting point and extreme hydrophobicity, making it poorly soluble in aqueous environments. Amorphous solid dispersions (ASDs) by hot melt extrusion (HME) have been explored for improving the solubility of existing antimalarials, such as lumefantrine, but haven’t been investigated for DQ. With no current literature on the amorphization and the degradation of this high melting point and hydrophobic compound, this work aims to investigate the conversion of DQ into ASDs and evaluate the applicability of the Hot Melt Risk Assessment classification system (HCS) to highlight a process design space.

Methods: Typically high melting point drugs are considered unsuitable for HME. DQ’s extrusion risk is ranked as an HCS III due to its high melting point and potential low miscibility with polymers. An API-polymer phase diagram of DQ and Kollidon VA64 (VA64) was developed via experimental and theoretical evaluations. Application of the phase diagram and HCS determined an HME process design space; HME experiments were then run within and outside of the design space at 160 °C, 180 °C, 200°C, and 220 °C at two respective screw speeds of 50RPM and 100RPM. Resultant extrudates were then analyzed by powder X-Ray Diffraction (pXRD), Polarized Light Microscopy (PLM), Differential Scanning Calorimetry (DSC), and High Performance Liquid Chromatography (HPLC) to determine residual crystallinity and extent of degradation.

Results: Extrudates processed at 160 °C and 180 °C showed residual crystallinity in both XRD and DSC traces. As these samples were visually opaque PLM wasn’t feasible. Extrudates produced  at 200 °C  were visually transparent, revealed an pXRD amorphous halo and were absent of crystals under PLM, suggesting greater miscibility than predicted with the phase diagram which may be as a result of no annealing step. DSC traces however showed signs of residual crystallinity which can be explained by the extrudates being  kinetically stable  but thermodynamically unstable which is depicted by cold crystallisation followed by melting in the DSC scan,  when an ASD is exposed to thermal energy or environmental stress nucleation and crystal growth can subsequently be initiated. This agrees with the HCS system as these extrudates were produced outside the identified design space. Using the process design space, 220 °C, extrudates produced should be both kinetically and thermodynamically stable ASDs with no degradation however as with the samples produced at 200°C although extrudates were visually transparent with no traces of crystallinity through PLM and pXRD, DSC traces showed signs of residual crystallinity.  This may be attributed to DQ being a poor glass former thus under ambient storage conditions can exhibit kinetic stability as the polymer acts as a kinetic barrier. However, the input of thermal energy during  heating provides sufficient molecular mobility for the drug to reorganise into its favoured thermodynamic crystalline state. It should be noted that the upper boundary should be  limited by the degradation temperature of the least thermally stable ingredient, in this case both the API and polymer remain thermally stable until 250 °C, therefore the upper boundary was to limited  to this. Through API HPLC analysis of the extrudates the presence of a second ‘degradation’ peak is observed from as low as 180 °C  and increases with temperature which contradicts the HCS, as extrudates cannot be produced in the identified design space without notable degradation. It is apparent that VA64 induced DQ’s degradation as API degradation was observed well  below its intrinsic degradation point.  Accordingly, thermal analysis and HPLC evaluation of physical mixtures should be performed prior to HME, particularly for high-risk HCS III systems, to assess potential drug–polymer incompatibilities.

Conclusion: The present work addresses key knowledge gaps by investigating the conversion of decoquinate (DQ) to its amorphous form and evaluating the HCS as a material-sparing tool to inform process design space. Analysis of the resulting extrudates—focusing on residual crystallinity and thermal degradation—indicates that HCS is not a suitable predictive method for this system. Notably, the findings suggest that VA64 is not a viable carrier for DQ-based ASDs, as degradation of the API was observed at temperatures well below its intrinsic degradation point. DQ demonstrates poor glass-forming ability (GFA), associated with a high tendency to crystallize and thermodynamic instability in the amorphous state. Although VA64 provided kinetic stabilization and prevented recrystallization under ambient conditions, it could not overcome the inherent thermodynamic instability of the system. Furthermore, VA64 appears to induce degradation of DQ when exposed to elevated temperatures. As such, thermal analysis and HPLC of physical mixtures should be performed prior to HME to assess compatibility, particularly for high-risk, poor GFA compounds like DQ.

References: H. Wang, Y. Fan, L. Qin, Z. Cheng, X. Chen, S. Zeng, S. Liang, Y. Tong, Z. Tao, Y. Liu, X. Liu, X. Ning, P. Chen, S. Zhao, X. Chen, Preparation of Decoquinate Solid Dispersion by Hot-Melt Extrusion as an Oral Dosage Form Targeting Liver-Stage Plasmodium Infection, Antimicrob Agents Chemother 66 (2022).
T.N. Hiew, D.Y. Zemlyanov, L.S. Taylor, Balancing Solid-State Stability and Dissolution Performance of Lumefantrine Amorphous Solid Dispersions: The Role of Polymer Choice and Drug–Polymer Interactions, Mol Pharm 19 (2022) 392–413.
S.O. Kyeremateng, K. Voges, S. Dohrn, E. Sobich, U. Lander, S. Weber, D. Gessner, R.C. Evans, M. Degenhardt, A Hot-Melt Extrusion Risk Assessment Classification System for Amorphous Solid Dispersion Formulation Development, Pharmaceutics 14 (2022) 1044.

Acknowledgements: The authors would like to thank BASF Corporation for the financial support .

Figure 1. X-ray Diffractograms of pulverized extrudates at 50RPM

Figure 2. X-ray Diffractograms of pulverized extrudates at 100RPM

Figure 3. decoquinate recovery (%) and degradation extent (%) post extrusion