Dasabuvir is a non-nucleoside polymerase inhibitor for the treatment of hepatitis C virus (HCV) infection. It is an extremely weak diacidic drug (pK a = 8.2 and 9.2) and a prolific solvate former. Due to its exceedingly low aqueous solubility (≤0.127 μg/mL at pH 1−6.8, dose number of 1.31 × 10 4 ), crystalline dasabuvir free acid exhibited poor oral bioavailability in initial animal pharmacokinetic (PK) assessment. This necessitated the development of enabling formulation for human clinical studies to achieve the required therapeutic in vivo concentration of dasabuvir. While salt formation has been widely used to enhance the solubility and dissolution rate of solids, this approach has rarely been applied to develop oral solid dosage forms for acidic drugs as weak as dasabuvir due to concerns of rapid disproportionation and crystallization of its free acid. In this contribution, we detail our efforts in identifying dasabuvir monosodium monohydrate as a drug substance that is stable, manufacturable, and, most importantly, significantly enhances the dissolution and oral absorption of this poorly soluble drug. The oral delivery of dasabuvir through the salt approach has enabled the commercialization of the triple-combination direct-acting antiviral HCV regimen, Viekira Pak. The methodologies and solutions identified in targeted studies to overcome technical challenges encountered along the way (i.e., incorporation of polymers to inhibit crystallization and disproportionation and species mapping to enable salt manufacturing process, etc.) can be applied to other insoluble compounds.
Challenges in the synthesis of the cystic fibrosis transmembrane
receptor corrector ABBV-3748 were addressed to enable a multikilogram-scale
GMP sequence. Implementation of an early-stage telescoped titanium-mediated
alkylation and palladium-catalyzed hydrogenation limited the formation
of a dimerization impurity and provided consistent yields across reaction
scales. Development of late-stage enantioselective hydrogenation installed
the stereocenter present in the active pharmaceutical ingredient.
Aspects of reagent and catalyst selection, reaction optimization,
and crystallization in these two key synthetic steps are described
herein.
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