Weakly acid polymers
with pH-responsive solubility are
being used
with increasing frequency in amorphous solid dispersion (ASD) formulations
of drugs with low aqueous solubility. However, drug release and crystallization
in a pH environment where the polymer is insoluble are not well understood.
The aim of the current study was to develop ASD formulations optimized
for release and supersaturation longevity of a rapidly crystallizing
drug, pretomanid (PTM), and to evaluate a subset of these formulations
in vivo. Following screening of several polymers for their ability
to inhibit crystallization, hypromellose acetate succinate HF grade
(HPMCAS-HF; HF) was selected to prepare PTM ASDs. In vitro release
studies were conducted in simulated fasted- and fed-state media. Drug
crystallization in ASDs following exposure to dissolution media was
evaluated by powder X-ray diffraction, scanning electron microscopy,
and polarized light microscopy. In vivo oral pharmacokinetic evaluation
was conducted in male cynomolgus monkeys (n= 4)
given 30 mg PTM under both fasted and fed conditions in a crossover
design. Three HPMCAS-based ASDs of PTM were selected for fasted-state
animal studies based on their in vitro release performance. Enhanced
bioavailability was observed for each of these formulations relative
to the reference product that contained crystalline drug. The 20%
drug loading PTM-HF ASD gave the best performance in the fasted state,
with subsequent dosing in the fed state. Interestingly, while food
improved drug absorption of the crystalline reference product, the
exposure of the ASD formulation was negatively impacted. The failure
of the HPMCAS-HF ASD to enhance absorption in the fed state was hypothesized
to result from poor release in the reduced pH intestinal environment
resulting from the fed state. In vitro experiments confirmed a reduced
release rate under lower pH conditions, which was attributed to reduced
polymer solubility and an enhanced crystallization tendency of the
drug. These findings emphasize the limitations of in vitro assessment
of ASD performance using standardized media conditions. Future studies
are needed for improved understanding of food effects on ASD release
and how this variability can be captured by in vitro testing methodologies
for better prediction of in vivo outcomes, in particular for ASDs
formulated with enteric polymers.