Application of Hildebrand Solubility Parameter to Identify Ethanol-Free Co-Solvent for Pediatric Formulation

Abstract

Formulation of active pharmaceutical ingredients into liquid dosage form is frequently limited by solubility issues. Ethanol is commonly used as a cosolvent to improve the solubility of drugs. Due to the incomplete expression of ethanol metabolizing enzyme in children under 6 years, several drug authorities such as WHO, EMA, and FDA recommend avoiding the use of ethanol in pediatric formulation whenever possible. In addition to that Muslim consumers are regulated by the halal practice where excessive use of ethanol in pharmaceutical products should be avoided. Thus, it is necessary to explore an alternative co-solvent to reduce the use of ethanol in the pediatric formulation. This study is aimed to identify an alternative co-solvent to ethanol that is safe for the pediatric using Hildebrand Solubility Parameter approach.
 In this study, the solubility parameter of the model drug, MH2011, was determined using Hildebrand Solubility Parameter (HSP). The solubility parameter (δ) of MH2011 was determined using two approaches. The first method is by measuring the maximum solubility of the model drugs in the binary mixture of water and 1,4 dioxane. The second approach is by calculating solubility parameters based on Fedor’s group substitution method.
 Using binary solvent blend, the MH2011 solubility parameter was identified to be approximately 14.0 (cal/cm3 )½. This value is in agreement with the result of the second approach using Fedor’s Group substitution method which is 14. 4 (cal/cm3) ½. With this data, an alternate co-solvent to substitute ethanol was explored. The studies also suggested that propylene glycol 7% v/v may give solubility power as those of ethanol 7% (v/v). This study suggested that Hildebrand’s Solubility Parameter can be applied to identify an alternate co-solvent to ethanol. This cosolvent is important for the research area where the alcohol-free formulation is preferred such as in halal pharmaceuticals and pediatric liquid formulation.