(M0930-03-19) The Effect of Controlled After-Melt Cooling Rate on Amorphization Degree of High-Drug Loaded Solid Dispersions of a Poor Glass-Forming Drug

Purpose: Amorphization is an important step in enhancing drug solubility using polymer-based solid dispersions (SDs). Apart from the inherent drug properties (glass-forming ability, drug-polymer miscibility), the amorphicity can be affected by process parameters, such as after-melt cooling rate when obtaining SDs by a melting method.^1,2 With the conversion of poor glass-formers being more difficult, the choice of optimal polymer type and process conditions are critical to generating a high amorphous content and hence maintaining low levels of polymer excipient . Therefore, this study was aimed at examining the potential of increasing the amorphization degree of high drug-loaded SDs of a poor glass-former drug naproxen (NPX) by care consideration of polymer type and cooling rate.

Methods: SDs with NPX (T_m(onset) = 154, T_m(peak) = 158℃) and polymers Eudragit EPO (EPO; T_g = 54℃), Kollidon VA64 (VA64; T_g = 104℃), and Soluplus (SOL; T_g = 72℃) with 90, 80, and 70% (w/w) drug loadings (DLs) were obtained by the 1^st slow heating (20→180°C at 10°/min) of drug-polymer mixtures in DSC 8000 (Perkin Elmer) cell and subsequent cooling (180→20°C) at 15, 80, or 150°/min. The 2^nd heating (20→200°C at 150°/min) run was used to assess an estimate of SD amorphicity according to (1): Amorphicity, % = (ΔH_m(NPX)× DL ‒ ΔH_m(SD) / ΔH_m(NPX)× DL) × 100%. 70% SDs were studied for drug-polymer interactions by FT-IR (Perkin Elmer Spectrum 100 FT-IR). All experiments were done in triplicate and three-way ANOVA (p < 0.05) was applied to reveal significant differences in the effects on SD amorphicity.

Results: According to DSC, NPX miscibility increased in the sequence SOL (41%) < VA64 (62%) < EPO (65%, w/w) (data not shown). Also, FTIR showed that the principal interactions manifesting at 3500-2900 and 1760-1500 cm^-1 were the strongest in the SD_EPO spectrum, whereas SD_SOL was the closest to the pure NPX (the lowest interaction; Fig. 1). Stronger drug-polymer interactions often result in higher miscibility, as well as more delayed drug crystallization.² In the cooling cycle, faster cooling, lowered crystallization enthalpy (ΔH_c), however, the significant of thios effect depended on DL and the polymer type. The less the drug was miscible with the polymer, low DLs displayed a more pronounced difference (Fig. 2A). Most SDs showed cold crystallization in the 2^nd heating cycle (min onset 60 ‒ max offset 130°C temperature range), therefore the total crystallization was assessed as a sum of ΔH_c in the cooling and 2^nd heating cycles (Fig. 2B). Cold crystallization took place mainly after high-speed cooling, so the effect of the cooling rate on the total ΔH_c (Fig. 2B) tended to be less pronounced (Fig. 2A). At a 70% DL using EPO and VA6, cooling rate had no observable effect on total enthalpy. So, for these polymers, 70% DL showed no difference in terms of the cooling rate effect on the cooling ΔH_c and total ΔH_c, whereas at 70% DL, SOL (with the lowest drug-polymer miscibility) enthalpy was dependent on cooling rate (Fig. 2A-B). For all three polymers, SDs with 80% DLs demonstrated the most pronounced amorphicity change as a function of cooling rate, while at 70 and 90% DL cooling rate was less influential (Fig. 2C). The cooling rate main effect was significant but much less pronounced than DL and polymer type. Significant differences were established between cooling rates of 15 and 80°/min as well as 15 and 150°/min, but not between 80 and 150°/min cooling rates.

Conclusion: Faster cooling resulted in lower crystallization enthalpies. The cold crystallization in the 2^nd heating cycle (because of high-speed cooling) reduced the amount of amorphous drug kinetically trapped in the solid dispersion (and possibly unstable upon long-term storage). In terms of amorphicity, for all three polymers, the most influence of the cooling rate was observed on 80% SDs, which might be explained by this drug-polymer ratio appearing to be a discriminating factor for the cooling rate effect manifestation at these experimental conditions. Further work will examine the effect of cooling rate on the physical stability of ASDs during storage.

References: (1) Kumar, N. S. K.; Suryanarayanan, R. Mol. Pharmaceutics 2022, 19 (2), 472-483.
(2) Lalge, R.; Kumar, N. S. K.; Suryanarayanan, R. Mol. Pharmaceutics 2023, 20 (3), 1806-1817.

Acknowledgements: The study was funded by the British Academy in cooperation with CARA under 'Researchers at Risk' Fellowship Programme.

Fig. 1. FTIR spectra of the crystalline naproxen and its 70% SDs with each polymer

Fig. 2. The effect of the cooling rate on the crystallization tendency of NPX SDs in terms of (A) ΔHc in the cooling cycle, (B) total ΔHc in both cooling and 2nd heating cycles, and (C) drug amorphicity percentage based on 2nd heating ΔHm