Establishing a New Method to Evaluate the Recrystallization of Nanogram Quantities of Paracetamol Printed as a Microarray Using Inkjet Printing

In pharmaceutical preformulation it is important to be able to screen a drug compound for possible solid forms (amorphous, crystal, polymorphs, salts, etc.) prior to scale-up of manufacture for formulation, and as this screening is undertaken prior to scale-up, there is often only a small amount of drug material available. Minimizing the amount of sample required for these solid form investigations is therefore of paramount importance. Typical industrial work-flows require hundreds of milligrams of compound, while a small number of research papers have suggested that new approaches based on conventional inkjet printing may allow only a few milligrams to be used, but even these small quantities of the sample may not be available in early stage drug development. Herein we report an approach based on picoliter inkjet printing. Employing paracetamol as a model compound, we illustrate how a basic solid-form screen may be run using only nanograms of material (around 6 orders of magnitude less material than used in previously reported approaches). For the first time, we were able to monitor the recrystallization of nanogram amorphous paracetamol to metastable crystalline forms II and III. Cross-polarized microscopy and Raman spectroscopy were employed to monitor the recrystallization of the paracetamol microarray. We suggest that further development of this concept may allow preformulation to occur far earlier in drug development than is currently the case, and also a more extensive parameter space to be explored using this new approach in a microarray format.