Solubility measurements of metastable polymorphs are often complicated by solvent-mediated transformation toward more stable forms. In this review, we first summarize potential experimental methods to estimate the solubility of metastable polymorphs. Then, we discuss a methodology based on a thermodynamic model, which allows solubility predictions from (i) solubility data of the stable form, and (ii) solid-state properties of the stable and metastable forms.

We show that seeding is not always sufficient to control cystal polymorphism and illustrate how kinetic modeling can help controlling polymorphism.

Mixed-suspension mixed-product removal (MSMPR) crystallizers can potentially allow the production of metastable polymorphs. A necessary (but not sufficient) condition is to select operating conditions such that the steady-state concentration remains above the solubility of the metastable form. In this paper, we provide a framework that helps controlling polymorphism in MSMPR. We consider paracetamol as a model system and target the production of form II, which is metastable and rapidly converts to form I in batch. We combine experimental characterization (inline infrared spectroscopy, Raman spectroscopy, and imaging) with population balance modeling to investigate the possibility to produce the metastable form in a continuous manner. We identify a design space allowing the visualization of the regions where each form is obtained at steady state as a function of the kinetic parameters of both forms. We show that form II cannot be obtained at steady state in pure ethanol. However, the addition of a small amount of metacetamol (1% in mass with respect to paracetamol) in the feed is sufficient to obtain form II at steady state. We interpret the effect of metacetamol in light of a kinetic model and quantify its incorporation in the crystals with high-performance liquid chromatography.