Background: Metastable zone width (MSZW) and solubility are crucial for developing crystallization procedures in the purification of active pharmaceutical ingredients (APIs). Traditionally, determining these properties involves labor-intensive methods that can take weeks or even months. With advancements in process analytical technologies (PAT) and the increasing focus on quality by design (QbD) in pharmaceutical manufacturing, more efficient and reliable protocols are needed. In this study, we employ in situ Fourier Transform Infrared (FTIR) spectroscopy and Focused Beam Reflectance Measurement (FBRM) to establish protocols for measuring solubility at different temperatures and MSZW at varying cooling rates. Methods: We experimentally determined MSZW and solubility using FTIR spectroscopy and FBRM. IR spectra were analyzed to obtain solubility concentrations, while FBRM counts were used to extract MSZW and supersolubility concentrations. The collected data were assessed using four theoretical models, including a newly developed model based on classical nucleation theory. By fitting experimental MSZW data to these models, we determined nucleation kinetics and thermodynamic parameters. Results: Our novel model exhibited excellent agreement with experimental MSZW data across different cooling rates, demonstrating its robustness. The nucleation rate constant and nucleation rate ranged between 10²¹ and 10²² molecules/m³·s. The Gibbs free energy of nucleation was calculated as 3.6 kJ/mol, with surface energy values between 2.6 and 8.8 mJ/m². The estimated critical nucleus radius was in the order of 10⁻³ m. Conclusions: The protocols we developed for predicting MSZW and solubility of paracetamol using PAT can serve as a guideline for other APIs. Our theoretical model enhances the predictive accuracy of nucleation kinetics and thermodynamics, contributing to optimized crystallization processes.

Crystals growing via nonclassical crystallisation pathways often lose the shape factor and the mechanisms involved are often anomalous. This makes it difficult to predict the crystal growth kinetics using the conventional crystal growth kinetic models. A new pseudo second order growth kinetic expression to predict the anomalous growth behaviour of curcumin crystals is introduced. This model also allows several important parameters relevant to the kinetics of the crystal growth, such as mass crystallised with respect to time, overall crystal growth kinetic constant, the maximum number of active sites involved in the crystal growth process and the initial crystal growth rate, to be obtained. According to the pseudo second order kinetics, the activation energy for the nonclassical crystal growth of curcumin was found to be ∼69 kJ mol⁻¹, which seems to agree with the activation energy for the classical crystal growth of organic compounds reported in the literature. The total number of active sites involved in the crystal growth process was found to be ∼10²² per gram of the seeds.

Cooling crystallization experiments of curcumin in isopropanol confirmed that curcumin can crystallize via classical or nonclassical pathways, depending on the levels of supersaturation and supercooling. Light microscopy analysis revealed that classical crystallization produces needle-shaped single crystals with an equilibrium habit, while nonclassical crystallization results in spherulitic mesocrystals. Through a series of experiments under various conditions, we developed a crystal habit phase diagram for curcumin in pure isopropanol. Presented here for the first time, this diagram illustrates the relationship between supersaturation, supercooling, and crystal habit, offering a valuable guide for controlling curcumin crystallization pathways.

Developing theory-informed standard operating procedures (SOPs) for the continuous crystallisation of pharmaceuticals still remains a bottleneck. For the continuous manufacturing of pharmaceuticals, the current methods rely on the laborious trial-and-error approach to identify process conditions such as the dilution rate (flow per unit volume of reactor) and initial supersaturation, where the productivity will be at maximum at steady-state conditions. This approach, while proven and considered to be useful, lacks or ignores the information obtained from batch kinetics. Herein for the first time, we propose a theoretical method to develop batch kinetics-informed theoretical procedures for the continuous manufacturing of a model compound curcumin in isopropanol. The theoretical approach uses batch kinetic constants to theoretically identify the optimum dilution rate and the corresponding mass of the model compound curcumin when crystallised, as well as its productivity at steady-state conditions as a function of initial supersaturation. The theory-informed procedures will serve as a valuable guideline to develop operating procedures for the continuous production of the target compound and thus eliminate the trial-and-error approach used to develop the protocols for the continuous manufacturing of pharmaceuticals. We also showed that our methods allow for the estimation of the dilution rate that corresponds to washout conditions (i.e., where all the crystals in the crystalliser will be washed out due to the high flow rate of the input stream) during the continuous manufacturing of crystals.