Crystal Growth of Aspirin Using a Temperature-Controlled Microfluidic Device

Abstract

Identifying the most appropriate polymorph of active pharmaceutical ingredients is one of the important steps in drug development, since their bioactivities are largely dependent on their solid forms. However, the sample preparation for the characterization of crystal forms is time-consuming and requires large quantities of sample. Here, we introduce a microfluidic device-based method to prepare a sub-millimeter-sized single aspirin crystal from a small quantity of material. For the crystal preparation, a device equipped with a solution flow system and temperature controller was placed under the microscope. To use the device, concentration–temperature phase diagrams were generated, and regions where dominant nucleation or crystal growth with specific directions were clearly determined. By observing time-dependent changes of crystal number and size with solution temperature, a pathway to grow a single crystal of aspirin was determined and applied to prepare a sub-millimeter-sized crystal from 250 μg of aspirin. The obtained crystal was sufficiently large for single-crystal X-ray diffraction analysis, which usually requires 10 mg to 1 g of material per crystallization experiment. Thus, this method can be adapted as an efficient approach to uncovering the crystallization process to obtain required crystal forms with minimal sample consumption.