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

  • Mohammad Afzal

Student thesis: Doctoral Thesis


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.
Date of Award2023
Original languageEnglish
SupervisorEnes Supuk (Co-Supervisor) & Barbara Conway (Co-Supervisor)

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