(W0930-03-15) Amorphous Aprepitant Prepared by Spray-Freeze-Drying can be Stabilized with Low Viscosity HPC Grades

Purpose: Aprepitant, an antiemetic drug belonging to the class of neurokinin-1 receptor antagonists, is used to treat nausea and vomiting associated with chemotherapy. It is an API with low solubility, like many other newly developed drugs, and is currently marketed in capsules or as a nanosuspension for oral delivery (Hargreaves 2011). To overcome this low solubility and open up new routes of administration (e.g. nasal, inhalative), we investigated the spray-freeze-drying (SFD) process to produce an amorphous lyophilized powder. In addition, a novel low viscosity hydroxypropyl cellulose (HPC) grade (HPC UL) was compared with well-known HPC SSL in its ability to stabilize the formulation and improve dissolution.

Methods: SFD-particles and film casts were produced from pure DMSO solutions. For this purpose, three different aprepitant to HPC ratios (20/80, 40/60 and 100/0) were prepared, all of them in a final solid content of 5% (w/v) in DMSO. During the spray-freeze-drying process, the DMSO solutions were sprayed into a cooling tower in which the small droplets were frozen in free fall at -100 °C, as previously described (Kožák 2022). Frozen droplets were subsequently freeze-dried for 48 hours (0.05 mbar). Casted HPC films were first dried at room temperature under a laboratory hood and residual solvent was then extracted by vacuum drying. Before further testing, film casts were milled to ensure comparability with the particle sizes of SFD-particles. SFD-particles were analyzed for their particle size distribution (Camsizer X2, Germany), specific surface area (Belsorp Mini X, Germany), residual DMSO content (Focus GC, Germany) and morphologically examined under a scanning electron microscope (Hitachi SU3500, Japan). Dissolution tests of the SFD- and film cast-particles were performed in a dissolution apparatus according to USP2 at pH 1.2 (0.1 M HCl). This data was further extended by X-ray powder diffraction (XRPD; X’Pert MRD Pro, Netherlands) of the particles shortly after production and after one year of storage.

Results: SFD-particles were spherical, singular particles with a monomodal particle size distribution. The medians of the powders were between 315 and 397 µm. Specific surface area was not affected by polymer grade or drug ratio, varying around 5 m²/g, while values of pure aprepitant were slightly higher at about 7 m²/g. The residual DMSO content was below one percent (w/w) in all cases. Immediately after production, all SFD-particles exhibited halo patterns in the XRPD, suggesting an amorphous state of the API and polymer. The 20/80 ratio film casts did not show any peaks either, whereas the 40/60 ratio film casts exhibited sharp peaks shortly after their production, which is consistent with crystalline state. Crystallinity could also explain the slower release compared to the SFD-particles and other aprepitant/HPC ratios. Even after one year of storage at 25 °C, only 20/80 ratio SFD-particles remained in an amorphous state. In dissolution unprocessed, crystalline aprepitant did not reach saturation concentration (29.3 ± 0.6 µg/ml) in the respective release medium after 180 min. In contrast, the (100/0) SFD-particles consisting of pure aprepitant were able to induce a 1.5-fold supersaturation (44.3 ± 2.6 µg/ml) after one minute at pH 1.2. However, that is followed by reprecipitation within the first half hour. The HPC-containing SFD-particles achieved supersaturation rapidly. After 5 min at pH 1.2 the saturation solubility was exceeded approximately 4-fold and 2-fold with HPC UL 20/80 and 40/60 respectively (115.3 ± 4.9; 60.8 ± 1.8 µg/ml). A pronounced parachute effect was observed across all HPC-containing formulations. No significant difference was found when comparing the HPC grades at pH 1.2. Only at 20/80 ratio with HPC UL a slightly higher supersaturation and more stable parachute effect was observed. Overall, the SFD-particles exhibited similar or better dissolution behavior, compared to film cast-particles. In formulations with a 40/60 ratio, the release of SFD-particles is considerably higher.

Conclusion: The spray-freeze-drying process enables the production of an amorphous, freeze-dried powder utilizing DMSO as a solvent, which results in rapid dissolution and high supersaturation. HPC UL and HPC SSL are able to stabilize the created ASD (SFD-particles or film casts) especially in higher proportions and also increase the supersaturation of the API.

References: Hargreaves R, Ferreira JC, Hughes D, Brands J, Hale J, Mattson B, Mills S. Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Ann N Y Acad Sci. 2011;1222:40-8. doi: 10.1111/j.1749-6632.2011.05961.x
Kožák J, Chrétien C, Pellequer Y, Lamprecht A. Rivaroxaban lyospheres prepared by a dimethyl sulfoxide-based spray-freeze-drying process. Int J Pharm. 2022;627:122235. doi: 10.1016/j.ijpharm.2022.122235.

Acknowledgements: This work was funded and supported by Nippon Soda CO., Ltd., Tokyo, Japan.


Figure 1: electron microscopy images of SFD-particles from 5% solid content DMSO solutions with either 20/80 (left), 40/60 (middle) or 100/0 (right) aprepitant/HPC UL ratio


Figure 2: dissolution in pH 1.2 medium of pure substance, SFD-particles and film castings


Figure 3: XRPD spectra of SFD-particles and film castings with different aprepitant to HPC ratios