Advanced Methodologies for Pharmaceutical Salt Synthesis

Abstract

The version in the Kent Academic Repository may differ from the final published version. Users are advised to check http://kar.kent.ac.uk for the status of the paper. Users should always cite the published version of record.

Heterosynthons, Solid Form Design and Enhanced Drug Bioavailability

“…Various studies have shown that if the pK a difference between base and acid is greater than say 3–4 [Δ pK a =p K a (protonated base)−p K a (acid)], salt formation is expected. When it is less than 0∼−1, cocrystal formation generally ensues [24–26] . In the intermediate region of around 1 to 3, prediction is difficult because the O−H⋅⋅⋅N hydrogen bond will have a mixed character (we are discussing the acid–pyridine synthon here and, in general, pyridine/amine bases).…”

“…When it is less than 0 ~À 1, cocrystal formation generally ensues. [24][25][26] In the intermediate region of around 1 to 3, prediction is difficult because the OÀ H•••N hydrogen bond will have a mixed character (we are discussing the acid-pyridine synthon here and, in general, pyridine/amine bases). In this intermediate region there is a possibility of the existence of a salt-cocrystal continuum where the probability of proton transfer increases with increasing ΔpK a .…”

Absolute configuration determination of pharmaceutical crystalline powders by MicroED via chiral salt formation

“… 26 To introduce an internal chiral standard into a crystalline form, a mini-salt screening was performed using four enantiomerically pure counterions: l / d -tartaric acids and l / d -malic acids. These salt forming counterions were chosen based on their pK a values (a pK a difference of greater than 3 between the API and the counterion is recommended 27 ) and procurement considerations. Crystallization was carried out by precipitation of a stoichiometric mixture of API 1 and each counterion in organic solvents.…”

Co-Former Screening Method for Multicomponent Crystals Based on Partial Least Squares Regression: A Case Study of Ciprofloxacin

“…salts and co-crystals), and coamorphous are common and effective strategies. 3 To date, many cases of multicomponent crystals have been reported, and some have been approved for marketing. 4 When designing drug multicomponent crystals, screening the co-formers that form multicomponent crystals with APIs is considered to be the most critical step.…”