Surface chemistry directs crystal formation in pharmaceutical industry

Different crystal forms (polymorphs) of active pharmaceutical ingredients exhibit different physicochemical properties and can behave very differently once inside the body, so reliable production of the required polymorph is vital.

In 2014, Sendhil Poornachary at the A*STAR Institute of Chemical and Engineering Sciences and colleagues showed that the surface chemistry of modified glass vials influences nucleation and growth of selective crystal polymorphs of the anticonvulsant drug carbamazepine.

While needle-shaped crystals preferentially formed in the cyano-functionalised vials, tetrahedral-shaped crystals formed in those modified with fluoro- and mercapto-groups. A mixture of the two forms was crystallised inside a control (unmodified) glass vial.

Now, the team has extensively studied the temperature ranges and solute concentrations at which the crystallisation of carbamazepine occurs on different chemically-modified surfaces. By observing the crystal polymorph formed in these vials at a given temperature and concentration, the polymorph occurrence regions were plotted on a temperature–concentration phase diagram. "This type of representation is important to the pharmaceutical industry in the context of defining the design space for a robust crystallisation process development," Poornachary says.

The impact of surface chemistry on the crystallisation process was then investigated with the help of molecular models. "The experimental results were correlated with the results from a molecular modeling study, which revealed that specific chemical interactions between the crystal structure and functional groups on the template surface promoted nucleation of a particular polymorph," explains Poornachary.

"We envisage that the insights from this work will help develop in silico models to predict the crystallisation of [any] active pharmaceutical ingredient on a given template surface," he adds. It is also hoped that surfaces that promote selective nucleation of crystal forms may enable greener, aqueous solvents to be used in a wider range of crystallisations.

Next, the team plans to test the use of functionalised templates to direct the crystallisation of carbamazepine on a larger scale. "Potential design approaches for template-induced crystallisation process development could include forced flow through functionalised glass capillaries or using functionalised template particles as seeds, rather than the functionalised vessels we have used for this work."