(M1430-04-22) Determining Critical Parameters that Predict Physical Stability of Amorphous Solid Dispersions

Purpose: Amorphous Solid Dispersions (ASD) have been studied extensively to improve the solubility and bioavailability of poorly water-soluble drugs. To date, numerous ASD-based drug products have been approved and released into the market. Despite their prevalence, their dynamic behavior is not yet fully understood (e.g., re-crystallization, supersaturation). In particular, predicting their physical stability can be challenging when considering the drug’s physicochemical properties, drug loading, and manufacturing process. As a result, the development of ASDs remains a trial and error process despite numerous studies that attempt to design ASDs effectively and rationally. While characteristics that predict the stability of pure amorphous compounds (neat drug molecules) have been evaluated, there has been limited success in finding these “critical parameters” for ASDs containing polymeric carriers. Therefore, our research focuses on determining critical parameters that can be used to predict physical stability of ASDs.

Methods: A total of 48 ASD formulations were manufactured (comprising different combinations of four poorly water-soluble drugs (Felodipine, Indomethacin, Itraconazole, Ritonavir), three polymers (Kollidon VA64, HPMCAS, Soluplus), two drug:polymer ratios (drug/polymer = 40/60, 60/40), and two manufacturing methods (spray drying (SD) and hot-melt extrusion (HME)). Regarding manufacturing conditions, the processing temperature for HME was set to 5-10°C higher than the melting temperature (Tm) of the respective drug to ensure complete melting. For SD, solvent systems were chosen that could completely dissolve drug-polymer combinations. To evaluate and classify the storage stability of these formulations, accelerated stability studies at 50°C were conducted. Differential Scanning Calorimetry (DSC), Wide Angle X-ray Diffraction (WAXS), and Polarized Light Microscopy (PLM) were used to confirm whether a formulation contained traces of crystalline drug. Principal component analysis was used to identify a critical parameter(s) that predicts the physical stability of ASDs.

Results: Immediately after manufacturing, some ASD compositions showed traces of crystallinity. Interestingly, the identity of these crystalline formulations differed between SD and HME. Although each formulation was not manufactured using an optimized manufacturing method in this research, it was hypothesized that the poor stability of these formulations caused the rapid formation of crystalline drug. Of the four drugs tested, only ritonavir formulations (i.e., total of 12 formulations) exhibited no crystallinity in any formulation at the initial time point. While glass transition temperature (Tg) is frequently considered a good predictor of the physical stability of amorphous drug alone (neat molecule), ritonavir and its formulations had similar Tg values as compared to the other drug molecules and formulations. In contrast, for the drug-specific parameters, ritonavir had the highest molecular weight (Mw), the greatest reduced glass transition temperature (Trg) (i.e., Trg = Tg/Tm) and configurational entropy of the four drugs, which suggested that these may be critical parameters to determine ASD stability. Configurational entropy is a measure of the difference in the number of configurations between the amorphous and crystalline phases. The stability study at 50 °C for HME and SD formulations showed that almost half of the formulations had crystallinity at the one-month time point. In terms of storage stability, HME formulations tended to have equal or increased stability compared to their SD-manufactured counterparts. Differences in particle size can explain this; that is, SD ASD with smaller particle size and larger surface area showed reduced storage stability because of the higher mobility of surface molecules due to a decreased number of immediately adjacent neighbor molecules*¹. Based on the one-month stability data, no ASD parameters (e.g., Tg) correlate well with storage stability, and polymer preference appeared to be dependent on the identity of the drug. In contrast, no ritonavir formulations exhibited crystallinity under the conditions tested, suggesting that drug related parameter are dominant for ASD stability, and especially the drug parameters described above are critical for ASD stability.

Conclusion: Based on the stability study results, particle size impacted the stability of ASDs. Additionally, drug related parameters were dominant for ASD stability, where Mw, Trg and configuration entropy of the drug were correlated with ASD stability. These drug related parameters are readily calculated from its chemical structure and evaluated by DSC, and particle size can be controlled by manufacturing method/process. By using and controlling these parameters, ASD formulations may be designed more efficiently and rationally.

References: *1 Kohsaku Kawakami, Pharmaceutics, 2019, 11(5), 202