Methodology for Replacing Dipolar Aprotic Solvents Used in API Processing with Safe Hydrogen-Bond Donor and Acceptor Solvent-Pair Mixtures

A methodology is presented that allows
hazardous dipolar aprotic
solvents used in the pharmaceutical processing industries to be replaced
with solvent-pair mixtures that consist of a hydrogen-bond donor (HBD)
solvent and a hydrogen-bond acceptor (HBA) solvent. The methodology
uses the solubility of the active pharmaceutical ingredient (API)
in hazardous solvents to estimate the range of required solubility
parameters and Kamlet–Taft parameters for the API and then
intersects these ranges with the solubility parameters and Kamlet–Taft
parameters of the solvent-pair mixtures to identify favorable solvent
pairs and possible working compositions. Solvent pairs are ranked
according to GSK safety and health scores. The methodology was applied
to 13 APIs, where it was found that nonaqueous mixtures (ethanol–isopropyl
acetate, ethanol–ethyl acetate, and ethanol–butyl acetate)
and aqueous mixtures (water−γ-valerolactone and water–dimethyl
sulfoxide) are highly ranked and applicable to many APIs. Solvent
pairs were eliminated from consideration due to their inability to
simultaneously satisfy Kamlet–Taft acidity, basicity, and polarity
parameter constraints. The proposed methodology makes it simple to
identify and rank HBD–HBA solvent-pair mixtures for replacement
of dipolar aprotic solvents used in the pharmaceutical processing
industries.