A new insight for quantitative determination of the complex interaction of kinetics of reactive crystallization is gained by a study of the acidification of monosodium glutamate with hydrochloric acid in a semibatch reactor. The dynamic equilibrium of the L-glutamic acid ions, their simultaneous presence in the solution, and the effect on the crystal size and size distribution are simulated using a mathematical model based on integration of the population balance equation with the crystallization kinetics and thermodynamics of the process. The model includes equations of chemical reactions, pH, nucleation, size-independent growth, and population balance. This allows a precise determination of the driving force for the reactive crystallization and the parameters of the nucleation and crystal growth rate expressions. The model considers the effect of the controlling parameters such as the rate of addition of the acid and the initial concentrations of ionic species and can be used to predict the concentrations in the solution, the pH, and the crystal mass. The effect of process conditions on the crystal size, crystal size distribution, and morphology is studied.

A measurement-based closed-loop control system using in-process ATR-FTIR spectroscopy coupled with a multivariate chemometric PLS calibration model is developed, validated, and applied to the monitoring and control of supersaturation in a 250- L industrial pilot-plant crystalliser. Supersaturation control experiments are carried out on seeded batch cooling crystallisation of β-l-glutamic acid from aqueous solutions using two methods of seeding involving addition of seeds to the solution and generation of seeds within the solution. The generic applicability of the approach is demonstrated through this challenging system reflecting this molecule’s weak chromophore for infrared and relatively low solubility compared with previous solute−solvent systems. Based on the laboratory experiments, the system was fully tested and optimised prior to a series of trials carried out in an industrial pilot plant at Syngenta, Münchwillen, Switzerland. Good control of the supersaturation is achieved at three levels, 1.1, 1.2, and 1.3, within a prescribed range of ±0.025. The average product crystal size is found to decrease with increasing supersaturation. Comparison between product crystals produced at the 20- and 250-L scales indicates that secondary nucleation is more prevalent at the smaller-scale size. For the same level of supersaturation, the rate of depletion of solute is faster at the 20-L scale size than at 250-L scale, and hence a higher cooling rate is required to maintain the desired supersaturation. However, for a given crystalliser scale size, as expected, the mean cooling rate required to maintain a constant supersaturation is found to increase with increasing supersaturation level.

A recent evaluation of a new in situ particle viewer (ISPV) system for the examination of particle shape and its subsequent development during crystal growth is presented. Precharacterization studies using conventional and hot-stage microscopy reveal that the ISPV probe system together with a commercial image analysis software is capable of generating representative high-quality images which can be processed and analysed. ISPV studies of the batch crystallization of L-glutamic acid in a 20-L reactor are shown to be able to characterise effectively crystallization and polymorphic phase transformation processes, revealing potential applications in both small-and large-scale reactor systems. Some improvements to the probe, such as increasing the resolution and reducing the encrustation using thermal coating, are suggested.

Particle–particle interactions impact the processability and performance of drug products. Faceted particulates exhibit distinct surface chemistries that affect their adhesion, causing downstream processing challenges such as poor flow, punch sticking, and compaction. Currently, there is a lack of tools to assist formulators in predicting these challenges based on particle properties. Here, we present a methodology for navigating the energy landscape of interparticle interactions. We used molecular mechanics to calculate the interactions between slabs of molecules representing distinct facets. The workflow enables a rapid assessment of the total energy landscape between interacting particles, providing insight into the effects of different surface chemistries and molecular topologies. Previously, the strongest interaction (lowest energy) was used to calculate the propensity to adhere, but we demonstrate that this does not always predict an accurate description of the likely surface interactions. We chose paracetamol to demonstrate the application of this methodology. The most cohesive facets were (101) and (10-1). Comparing surface interactions between particles allows a ranking of the most energetically compatible surfaces. The significance of this ranking and understanding how surface chemistry can impact interparticle interactions is a step toward assisting formulation decisions and improvements in product performance.

PF-610355 is a novel inhaled β-2 adrenoreceptor agonist. Process development of the final intermediate and the API are discussed with emphasis on the control of physical properties and subsequent isolations. This includes development of a constant volume distillation and evaluation of Nutsche filtration, agitated filter drying, and centrifugation to prevent particle attrition. The optimized process employed to manufacture 100 kg of the API is described.