Estimating Interaction Energy of Organic Solvents in Water to Predict the Polymorphic Outcome of Curcumin during Liquid Antisolvent Precipitation

Polymorphism remains an important area of research in the pharmaceutical industry. This polymorphism results in different physio-chemical properties in drugs such as solubility, melting point, and most importantly, their thermodynamic stability. The metastable forms, being unstable, possess higher Gibb's Free energy than the stable form. Thus, it exhibits higher solubility and greater bioavailability. Therefore, formulation development should have a metastable form in the formulation than a stable form. However, the metastable form can transform into a stable form without any prior indication during processing or storage or under an external stimulus's influence. Therefore, understanding the polymorphic landscape becomes the first step towards gaining control over the polymorphic outcome.

In this work, curcumin, found in the popular Indian spice turmeric, a poorly water-soluble active pharmaceutical ingredient (API), is used as the model drug. Curcumin exists in three different forms, out of which two forms (Form 2 and Form 3) exist in an orthorhombic crystal structure, whereas Form 1 exists in a monoclinic crystal structure.

In Liquid Antisolvent (LAS) precipitation, the addition of Antisolvent (Water) to the solution of solute (Curcumin) in solvent creates supersaturation resulting in precipitation of solute. Here, the nucleation rate depends on the nucleation barrier. Moreover, it depends on the interaction between antisolvent-solvent molecules, solute-antisolvent molecules, and solute-solute molecules. The precipitated particle's characterization revealed that Form 1 (stable) curcumin was precipitated when the solvent was acetonitrile, acetone, and tetrahydrofuran. In contrast, Form 3 (metastable) was precipitated when the solvent was dimethyl sulphoxide, ethanol, and methanol at ambient conditions.

We estimated the enthalpy of solution (∆H_SOLUTION ) for water and organic solvents by varying the amount of solvent and fixed water amount using Parr-6755 Solution Calorimeter. Solvation of hydrophobic curcumin in solvent was modeled as cavity formation in solvent and interaction accompanied by the cavity's expansion.

The enthalpy of cavity formation(∆H_CAVITY ) was computed using Scaled Particle Theory. The estimation of the enthalpy of interaction (∆H_INTERACTION ) was done using the values of using the calculated values of ∆H_SOLUTION and ∆H_CAVITY . The results obtained in this work suggest that curcumin and solvent's interaction contributes to a relatively lesser extent for the polymorphic outcome. Therefore, if the solvent-antisolvent solution enthalpies are higher than a critical value, faster nucleation would have led to precipitation of the unstable Form 3. On the other hand, if these values are relatively lower, slower nucleation would lead to precipitation of the stable Form 1.