(T0930-05-28) Nanoscale Catch-and-Release - Development of Redispersing Solid Nanocrystalline Drug Forms

Purpose: While drug nanocrystals have long been a documented route for improving properties of poorly soluble drugs, their contribution to the drug market has lagged behind other approaches, such as production of amorphous solid dispersions or lipid formulations. This poster contribution builds on our earlier findings concerning stable top-down nanocrystal productions. Our main objective is to determine the viability of solid nanocrystal-containing forms of varied drug loading, using both different nanocrystal stabilizers and different fillers of the solid matrix. We consider this formulation step to be a significant step toward improved patient adherence due to the possibility of creating highly efficacious drug carriers which preserve the simplicity and ease of use of classic dosage forms such as tablets and capsules.

Methods: Lab-scale screening of top-down drug nanomilling was done as previously communicated, including subsequent morphological and XRPD analysis [1, 2]. Three model drugs were chosen from the previously used set as model drugs for further tests of solidification approaches. Solidification of nanosuspensions was carried out in two main ways. First, hundreds-of-milligrams-scale tray lyophilization of shock-frozen nanosuspensions was performed, with admixed cryoprotectants and fillers (lactose, trehalose, HPMC E5, Tween 80). Secondly, spray drying of nanosuspension-lactose systems was done on an in-house device SPREJOBOT [3] used for fast solid form screening. Lyophilized and spray-dried solid forms have undergone a unified redispersibility test in deionized water, 0.01M hydrochloric acid simulating gastric conditions and phosphate buffer saline of pH 7.4. In all cases, particle size distributions (PSDs) of prepared nanosuspensions and obtained powders was determined by dynamic and static light scattering respectively. XRPD analysis and SEM imaging of solid forms were carried out as well. Subsequent dissolution tests have been performed under standardized USP II conditions.

Results: Aqueous nanosuspensions (10% w/w) of three drugs (A – angiotensin II receptor antagonist, B – cholesterol synthesis inhibitor, C – tyrosine kinase inhibitor) stabilized by HPMC E5 and SLS (0.83%; 0.33% w/w), were prepared in laboratory scale, achieving mean volume sizes from 100 to 250 nm based on milling time from 24 hours to 14 days. All suspensions remained stable after 12 months of storage. Lyophilized and spray-dried nanosuspensions were prepared, yielding homogeneous, non-hydrophobic powders, drug content ranging from 9 to 90 percent in mass. Large aggregated clusters formed throughout lyophilization, while spherical particles (10-40 μm) were formed during spray drying. While the redispersibility of solids depended on medium (best in deionized water), multiple systems of high lactose content showed immediate redispersibility to PSDs of originating nanosuspensions, irrespective of API or stabilizers used. Standardized dissolution tests indicated improved dissolution properties of spray-dried powders. Two major reasons have been observed: first, the use of a strongly soluble filler (lactose) and the relatively low viscosity of nanocrystal stabilizer used. These achieved complete dissolution within 10 minutes, contrasting the incomplete dissolution of marketed product containing drug A after 60 minutes. The dissolutions were incomplete for lyophilized powders and granulates, due to overcompaction and use of polymer binders respectively, though similar trends have been observed even in their case. Regardless, comparison with existing results indicates a possible 2- to 3-fold possible improvement in bioavailability. Successful preparation of well-described solid form nanocrystals of multiple drugs was achieved and described, while preserving their original crystal form. Excipients leading to best colloidal stability before workup while also achieving fast redispersibility were identified. Moreover, viability of multiple paths of solidification was proven by redispersibility and standardized dissolution tests, often achieving large improvements in dissolution rate in comparison to existing formulations. The authors see future prospects of this work in upcoming attempts to establish solid-form nanocrystals as a platform technology in drug development and preformulation

References: 1. Hládek, F., Chvíla, S., et al., Systematic Investigation of Wet-Milling Kinetics and Colloidal Stability of Pharmaceutical Nanocrystals, Crystal Growth & Design (2022), 22(12), 6928-6940.
2. Lizoňová, D. et al., Surface stabilization determines macrophage uptake, cytotoxicity, and bioactivity of curcumin nanocrystals, International Journal of Pharmaceutics (2022), 626, 122133.
3. Klimša, V. et al., Spray drying robot for high-throughput combinatorial fabrication of multicomponent solid dispersions, Powder Technology (2023), 428, 118872.

Acknowledgements: The authors thank The Parc (Pharmaceutical Applied Research Center) for providing drugs and excipients. Moreover, we acknowledge the support of the Czech Science Foundation (GAČR project no. 19-26127X).


Graphic 1. Schematic depiction of workflow: production of drug nanocrystals, solid form manufacturing and redispersibility and dissolution analysis.