(M1530-01-03) Drug Nanocrystals Enable Rapid Formulation Transfer from Liquid-Phase Pre-clinical Testing to First-in-Human Solid Dosage Forms

Purpose: Since the vast majority of newly developed drugs suffer from poor aqueous solubility and bioavailability, drug transfer from pre-clinical development to first-in human (FIH) clinical testing often represents a bottle-neck. In vitro bioactivity screening and pre-clinical in vivo tests, employ solubilization strategies based on surfactant micelles or dimethyl sulfoxide solutions, unviable for later application to humans where solid dosage forms (tablets or capsules) are preferred. The development of such formulations is time-consuming and often results in significantly reduced bioavailability, which can ultimately lead to failed clinical trials of pre-clinically viable drugs. It would be therefore massively beneficial to unify the formulation approach at all stages of drug development and use the same form of the API during early-stage bioactivity screening studies as in FIH trials. This paper presents a strategy based on drug nanocrystals. The purpose of research is therefore two-pronged: first, examination of universal paths to drug nanocrystal production at early stage when only a small quantity of API is available, and more importantly, development of a solidification method preserving key nanocrystal characteristics, such as crystal form stability, fast dissolution and redispersibility, which can be rapidly scaled-up when formulation prototypes for FIH trials are required.

Methods: Lab-scale screening of top-down drug nanomilling was done as previously communicated, including subsequent morphological and XRPD analysis [1, 2]. Of the working set of ten poorly water-soluble drugs, two were chosen for subsequent solid form development. Solidification of nanosuspensions was carried out in several 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. Thirdly, wet granulation of polymer-thickened drug nanosuspensions with Prosolv 90 and Avicel PH 101 was performed. Employed dissolution tests have been performed via standardized USP II devices and drug-specific protocols. 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.

Results: Aqueous nanosuspensions (10% w/w) of two drugs (BCS II; drug A – angiotensin II receptor antagonist, drug B – cholesterol synthesis 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. The 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. These achieved complete dissolution within 15 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.

Conclusion: 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), submitted.

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

Graphical summary-flowchart of the presented abstract, with several keynote data points presented and highlights of main techniques used.
Left to right: SEM micrographs of APIs considered for nanonization; summary of main data gathered inthe top-down milling stage; summary of the solid phase formulation development.