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Preformulation in early drug development (small molecules), part 1

Updated: Oct 21, 2021

Welcome to My Blog series in preformulation for drug development


A well executed preformulation study is key to a good formulation design. In this third series of preformulation blog I will talk about solubility aspects for small molecules in early development. The solubilization strategies using formulation excipients will be addressed on future blogs (stay tuned and follow clearviewpharmallc.com blogs). If you wonder why the biologics is not included, is because they are more complex and will follow the small molecule series. Be patient, but feel free the check my company's website for the offered services (clearviewpharmallc.com).


Apparent Solubility and Equilibrium Solubility

Physical state of the solute in equilibrium with the solution is a key factor in determining its solubility. Because the solute may cease to exist in its original physical state once it is equilibrated, it cannot have any effect on its equilibrium solubility. Crystal modifications can produce an increase in dissolution rate and a temporary or apparent increase in solubility (kinetic solubility). The effect of crystal structure on solubility lasts only if the modified solid is in equilibrium with the solution. Given sufficient time it will revert to the most stable crystal form (thermodynamic solubility).


Apparent Solubility and Particle Size

The relationship between the radius r of a spherical particle and its solubility is given by the Kelvin equation RT=lnS/So=2gV/r, where g (gamma) is the surface energy of the solute (g is not constant, increases as the radius decreases), V – molecular volume, So - solubility of an infinite large solute particle. The Kelvin equation predicts that particles grow with time. Ball milling produces an increase in the apparent solubility. Spray drying and freeze drying can be used to produce small particles and increase apparent solubility.

pH-Solubility profile of Weak Acids and Bases

Solubilization of weak acids (AH) are mirror images of weak bases (B) and are the sum of the ionized and unionized species. From the Henderson-Hasselbalch equation, one can derive the solubility equation for a weak acid, S=So[1+10^(pH-pKa)] and a weak base, S=So[1+10^(pKa-pH)], where So is the intrinsic solubility (solubility of the unionized species).

Note: You can determine the solubility of the salts without first creating the salts from pHmax (Mole, J., Box, K., Comer, J. AAPS 2010 www.sirius-analytical.com).


Common Ion Effect

Slightly soluble electrolytes are characterized by their solubility product Ksp, a constant that is unique for a certain salt; units: M^2, M^n (as in the case of any equilibrium expressions, the molar concentration M of each ion is raised to a power equal to the number of ions appearing in the formula). If an ion in common with the weak electrolyte is added to the solution, the equilibrium is altered (momentarily). To reestablish the equilibrium, some of the salt in solution will precipitate. The result of adding common ion is to reduce the solubility of a slightly soluble electrolyte (important for stability of solid suspensions); exception, when the common ion forms a complex with the salt. Salts having no ion in common with the slightly soluble electrolyte produce an effect opposite to that of a common ion: at moderate concentration, they increase rather than decrease the solubility because they lower the activity coefficient (but not dramatically!).


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Pharmaceutical consulting | Clearview Pharma Solutions LLC (clearviewpharmallc.com)

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