Measuring multidimensional particle size distributions during crystallization

Abstract

A protocol for measuring multidimensional particle size distributions during crystallization is presented. The instrument consists of a flow through cell where it is possible to take images of particles in suspension from two perpendicular directions. The flow through cell is connected to a batch crystallizer through a sampling loop and a dilution system that allow tuning the suspension density in the cell for the sake of image quality. The images thus obtained are analyzed with a fast image analysis algorithm and characteristic lengths of particles are calculated. Generic geometric shapes representing different types of crystals are defined as particle classes. We present a method to classify particles into these classes, which enables for instance to differentiate between different polymorphs of a substance when their shape is different. The capabilities of the measurement device and of the algorithm are illustrated by comparing their performance to standard measurement tools like a Coulter Multisizer. The comparison shows that the two instruments give the same result. The effectiveness and accuracy of the protocol proposed is assessed by monitoring size and shape of crystals of acetylsalicylic acid and of paracetamol during seeded cooling crystallization.