(473c) Toward a Stable Single-Dose Oral Malaria Cure: Enhancing Dissolution Kinetics Using Continuous Nanoparticle Fabrication

Ristroph, K. D., Princeton University
Feng, J., University of Illinois, Urbana-Champaign
McManus, S. A., Princeton University
Zhang, Y., Princeton University
Gong, K., Princeton University
Ramachandruni, H., Medicines for Malaria Venture (MMV)
White, C., Princeton University
Prud'homme, R. K., Princeton University

AIChE 2019 annual conference


“Toward a stable single-dose oral
malaria cure: enhancing dissolution kinetics using continuous nanoparticle

Kurt Ristroph, Jie Feng, Simon A.
McManus, Yingyue Zhang, Kai Gong, Hanu Ramachandruni, Claire E. White, and
Robert K. Prud’homme

OZ439 is a new chemical entity
which is active against drug-resistant malaria and shows potential as a
single-dose cure. However, development of an oral formulation with good
bioavailability has proved problematic, as OZ439 is a poorly soluble (BCS Class
II) drug. In order to be feasible for low and middle income countries, any
process to formulate such a therapeutic must be inexpensive at scale, and the
resulting formulation must survive without refrigeration even in hot, humid
climates. We here demonstrate the scalability and stability of a nanoparticle
formulation of OZ439. We apply a combination of hydrophobic ion pairing and
Flash NanoPrecipitation (FNP) to formulate OZ439 NPs 150 nm in diameter using
the inexpensive stabilizer hydroxypropyl methylcellulose acetate succinate
(HPMCAS). The nanoparticles are then processed into a dry powder by spray
drying. Both FNP and spray drying are continuous unit operations that can be
run continuously and inexpensively at scale.

The spray dried NP powders achieve
over 20-fold higher OZ439 solubilization than unprocessed drug in vitro in
simulated intestinal fluid. The powders are then subjected to a series of
accelerated aging stability trials at high temperature and humidity conditions.
The dissolution kinetics of OZ439 in the NP powders remain constant across 1
month in uncapped vials in an oven at 50°C and 75% RH, and for 6 months in
capped vials at 40°C and 75% RH. X-ray powder diffraction and differential
scanning calorimetry profiles similarly remain constant over these periods.

The combined nanofabrication and
drying process described herein is an important step toward an
industrially-relevant method of formulating the antimalarial OZ439 into a fast-dissolving
single-dose oral form with good stability against humidity and temperature.

Schematic of Flash
NanoPrecipitation (FNP) used to ionically complex the poorly-soluble
antimalarial OZ439 and encapsulate it into a nanoparticle. This schematic
depicts an intermediate-scale multi-inlet vortex mixer that is operated at

Left: Dissolution kinetics of
spray dried NPs, lyophilized NPs, and bulk drug in vitro in fasted-state
intestinal fluid. The spray dried powders exhibit the fastest OZ439
dissolution, over 20x higher than unprocessed drug. Both the spray dried and
lyophilized NP powders achieve OZ439 supersaturation during this test.

Right: Dissolution kinetics of
spray dried NPs across 6 months in storage in an oven at 40 ºC and 75% relative
humidity. Dissolution kinetics, along with DSC and XRD profiles, remain
constant, indicating that in NPs, drug remains stable in its fast-dissolving
amorphous form despite the harsh conditions.