(M0930-05-31) Assessment of Stability and Erosion Behavior of ASDs by Using VCM Technique

Purpose: Pre-formulation studies to select suitable polymer and required concentration for hot melt extrusion to develop amorphous solid dispersions (ASD) is still challenging. This is mainly due to low availability of API at the development stage. However vacuum compression molding (VCM) technique, extensive pre-formulation studies using small amount of API can be carried out efficiently. A VCM machine was used to produce ASD-discs to carry out pre-formulation studies of model API and carrier polymers. One of these studies included microscopic erosion time tests (METT) to investigate the drug-load-limit (DLL) of a polymer in ASDs.

Methods: For preparing the ASD-discs, cryo-milled physical mixtures of Itraconazole (ITZ) and Fenofibrate (FF) each mixed with different polymers (AQOAT AS-MF (AS-MF), PVPVA64 and PVP K30) in various ratios (1:1, 1:2 and 1:4) were melted and shaped via a VCM tool (MeltPrep GmbH, Graz, Austria). Approximately 30 mg of the cryo-milled API/polymer blends were used to prepare 8 mm-discs for the METT experiments. The method was based on the paper by Bochmann et. al.⁽¹⁾ The test was performed with a stereo-microscope from Zeiss (Stemi 2000C). A heating plate was installed on the microscope table and pre-heated to 37°C. The ASD-disc was placed in a one depression concave object slide on top of the heating plate, covered with 0.3 ml pre-heated degassed phosphate buffer (pH 6.8) and a cover slip which was sealed with nail polish to prevent water evaporation. The erosion of the ASD-discs were monitored over 60 min by taking pictures every 10 min.

Results: To identify the drug-load-dependent threshold between eroding and non-eroding ASDs for the APIs used in this study, all ASD-discs were produced with various API concentrations. Each polymer used in this study has a specific DLL. When the maximum API dose is reached, the ASD-disc will form an impenetrable gel layer. This gel layer is soon be reached by using ITZ in the VA64 and K30 matrix (Fig.1). By comparing the erosion of the discs with FF and ITZ, the DLL of the polymers is much higher for FF (Fig.2). The discs with VA 64 shows a complete erosion after 20 min for a concentration up to 33% of FF whereby K30 reached a DDL already with a concentration of 33% FF (Fig.2). With an API concentration of 50% the DLL for VA64 and K30 was observed due to undissolved gel-like pieces floating in the buffer solution (Fig.2). In contrast, the erosion of AS-MF is much slower for each API and each concentration, a real DLL was not observed, because the disc still erodes after 60 min. For FF, the erosion of the disc is much faster for the high drug load of 50% than for the lower concentration of 33% and 20% and could be explained by the less hydrophilic character of HPMCAS which results in a slower erosion rate.⁽²⁾ Another reason why the erosion is slower could on the one hand be a decrease in porosity of the ASD-disc, the higher the drug load the more porous is the surface and thus the water can better infiltrate the disc, the dissolution is more API-driven⁽³⁾ and on the other hand an insufficient amount of buffer solution to dissolve the polymer.

Conclusion: METT is a simple method to observe the DLL of a polymer in ASDs. The DLL of VA64 and K30 is much higher for FF compared to ITZ. By comparing the polymers, HPMCAS shows no real DLL because of the still ongoing erosion of the ASD-discs after 60 min for each API/AS-MF combination. The erosion-speed of the discs is dependent from the hydrophilic character of the polymers, whereby VA64 > K30 > AS-MF. As the DLL is reached, a gel layer around the ASD-disc is formed which is not visible for AS-MF. The observed slower erosion of the ASD-discs prepared with AS-MF might be related as well to a more polymer driven erosion/dissolution and an insufficient amount of buffer to dissolve the ASD-discs. This leads to the assumption that the DLL could be higher than the DLL of the other polymers. The reason behind the slower erosion of HPMCAS needed to be more investigated.

References: 1. Bochmann E.S., Steidel A., Rosenblatt K.M., Gessner D., Liepold B.; Assessment of the amorphous solid dispersion erosion behavior following a novel small-scale predictive approach; E. J. of Pharm. Sciences 158, (2021)
2. Jørgensen J.R., Mohr W., Rischer M., Sauer A., Mistry S., Müllertz A., Rades T.; Stability and intrinsic dissolution of vacuum compressed molded amorphous solid dispersions of efavirenz; Int. J. of Pharm. 632, (2023)
3. Indulkar A.S., Lou X., Zhang G.G.Z., Taylor L.S.; Insights into the dissolution mechanism of ritonavir-Copovidone amorphous solid dispersions: Importance of congruent release for enhanced performance; Mol. Pharm. 16, 1327-1339

Figure 1. METT images of ITZ ASD-disc with different polymers and drug loads in 0.3 ml phosphate buffer (pH 6.8).

Figure 2. METT images of FF ASD-disc with different polymers and drug loads in 0.3 ml phosphate buffer (pH 6.8).