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 submillimeter-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. ■ INTRODUCTIONSolid form selection of active pharmaceutical ingredients (APIs) is an important issue in drug development since the bioactivities of APIs are largely dependent on the crystal polymorph or form, size, and morphology. 1,2 The selection of solid form often determines the fate of commercial viability of pharmaceutical products. 2 The primary mode of crystal screening is conducted via a high-throughput workflow system, which enables automation of the entire crystallization procedure. 3 In order to select the best crystal form with desired physicochemical properties for drug development, a number of crystallization conditions on the basis of solvent, salt and substrate concentrations, pH, and temperature have been investigated. 4 Crystal forms found using a high-throughput workflow system are then re-examined through multistep scaleup experiments in order to evaluate reproducibility and characterize specific physicochemical parameters, such as packing arrangement (e.g., molar volume, hygroscopicity), thermodynamic properties (e.g., melting point, entropy, enthalpy, solubility, vapor pressure, free energy), kinetic attributes (e.g., dissolution rate, reaction rates, stability), surface features (e.g., surface free energy, crystal habit, wettability), and mechanical properties (e.g., hardness, tableting, flow ability). 5,6 Here, it is critical to assess the aforementioned parameters in a timely manner due to the highly competitive intellectual property arena as well as providing quick insight into new opportunities for "life-cycle management of the product". 4 During the analysis of selected crystal forms in scale-up experiments, powder X-ray diffraction (XRD) is general...

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