The Influence of Salt Formation on Physicochemical and Electrostatic Properties of Carboxylic Acid Drugs

Salification of an active pharmaceutical ingredient (API) is an approach effectively utilised to
modify physicochemical properties of acidic and basic drugs, including solubility, dissolution
rate, stability and hygroscopicity. It is commonly reported that approximately 50% of drugs
are administered in the salt form, and this continued frequency of salt formation supports
the need for sustained research to discover entities with the greatest physicochemical and
material handling properties to help reduce the cost of manufacturing. However, little work
has been carried out to determine the effects of salt formation upon the tribo-electrification
propensity of the resulting material. Tribo-electrification can influence material handling
properties, whereby powder handling operations can induce a charge upon the particles,
resulting in an increase in tendency of particles to adhere to themselves and the walls of the
processing equipment, leading to blockages in pipes. In industries such as pharmaceutical this
can extend to segregation of material, resulting in poorer content uniformity.

The aim of this study was to investigate the influences of solvent selection and ratio of
counterion to active pharmaceutical ingredient were investigated to determine the effects
upon the final form in terms of crystal habit and tribo-electrification propensity as a result of
solvent selection, the experimental results show the magnitude of ratio selection and solvent
selection upon the crystal habit, and the solvent selection upon the tribo-electrification
propensity. The discovery of the 2:1 flurbiprofen: cyclopropylamine salt cocrystal was utilised
to scrutinise the mechanical, physicochemical and tribo-electrification properties in
comparison to the salt form, to determine any increased benefits over the salt form. The
experimental data showed that both strategies had their merits. Previous research has shown
the influences of counterion selection upon tribo-electrification propensity. For the purpose
of this study three different carboxylic acid drugs were used, flurbiprofen, felbinac and
biphenyl-4-carboxylic acid, due to their similar structures. Also three counterions;
cyclopropylamine cyclobutylamine and cyclopentylamine were selected. This allowed for a
comparison of the influences of counterion selection as well as active pharmaceutical
ingredient to be made. From the results it is evident that significant differences were
observed in physicochemical properties such as a reduction in solubility as the carbon chain
length of the counterion increased, as well as the extremely low charging propensity of biphenyl-4-carboxylic acid, potentially improving powder handling properties. As well as this,
the current trends in salt formation between the Orange book database to reflect north
American activity and the British National Formulary (BNF) were established; to reflect
European territories, in order to ascertain the popularity of counterion selection during a the
latest 12 year period. Salt formation is still a very popular method for forming dosage forms,
Sodium and Chloride were found to be the most popular choice in counterion selection.

This work clearly demonstrates the potential of investigating the drug salt physicochemicaltribo-
electrification property relationship in pharmaceutical materials.