Combined imaging and chromatic confocal microscopy technique to characterize size and shape of ensembles of cuboidal particles

The presence of needle- and plate-like particles has detrimental consequences on their downstream processing in the fine chemicals sector. Therefore, the ability to accurately characterize the particle size and shape is essential to quantify and predict their impact on the product processability. Nonetheless, tools to characterize both the size and shape of ensembles of cuboidal particles are seldom available. The overarching goal of this work is to provide a fast and accurate offline size and shape characterization tool. To this aim, we have designed and experimentally validated a combined imaging and chromatic confocal microscopy technique. We propose two modes of operation: one that facilitates the accurate 3D reconstruction of particles; and the other that facilitates their rapid characterization. We validate the performance of our technique using a commercial technique. We show that our technique can accurately characterize thousands of particles, making it a valuable addition to existing process analytical technology

Selective manipulation of crystal shape by combined crystallization, milling, and dissolution stages - An approach for robust process design

Solid formulations are nowadays extremely important in everyday life, especially concerning food and pharmaceutical products. Particularly in the latter case, the size and shape of the active pharmaceutical ingredients play a major role in determining their properties, both in terms of processability and bioavailability. For this reason, the interest in the crystallization community is driven nowadays more and more towards the identification of solutions to control the morphology of the particles during crystallization processes. Currently, the use of additives and antisolvents, as well as milling the particles after crystallization, are techniques commonly applied in industry. In order to avoid chemical impurities and fines in the final products, processes involving temperature cycles, eventually combined with a feedback controller, have also proved to be an interesting alternative. In this work, a new technique based on the combination of crystallization, milling and dissolution is proposed to control the shape of crystals. The crystallization stage is used to recover the solute from solution, while milling is used to break particles lengthwise, therefore reducing their length and leading to more equant shaped crystals. The fines formed during rupture are subsequently removed by dissolving them and the three stages are repeated for the desired number of cycles. The approach used for a successful process design is thoroughly explained. First of all, it is necessary to develop devices to reliably and accurately measure multidimensional particle size and shape distributions. This is fundamental for a precise characterization of the basic phenomena occurring during the different stages. To this aim, the flow-through cell, an in-house built device, is used to monitor and measure populations of crystals and characterize them in terms of length and width; on top of that, a hot-stage microscope is used to investigate phenomena at the single particle scale. The experimental observation is used to develop a mathematical model, based on population balance equations. This model allows to describe phenomena typically occurring during crystallization processes, such as breakage and nucleation, hence allowing for an accurate prediction of experimental outcomes. The mathematical model developed proves to be a reliable tool for the investigation of the feasibility of the proposed process. After the identification of process variables, particular focus is placed on the effect of the amount of mass dissolved, the milling intensity and the number of cycles performed, by considering and comparing both average properties and the whole particle size and shape distributions. A parametric analysis is used to identify general process trends and possible tradeoffs, as well as close-to-optimality conditions. To conclude, a comparison with a single crystallization stage and cooling crystallization followed by milling is carried out, highlighting benefits and limitations of the new process on the alternatives proposed

Solubility of Organic Salts in Solvent–Antisolvent Mixtures: A Combined Experimental and Molecular Dynamics Simulations Approach

We combine molecular dynamics simulations with experiments to estimate solubilities of an organic salt in complex growth environments. We predict the solubility by simulations of the growth and dissolution of ions at the crystal surface kink sites at different solution concentrations. Thereby, the solubility is identified as the solution's salt concentration, where the energy of the ion pair dissolved in solution equals the energy of the ion pair crystallized at the kink sites. The simulation methodology is demonstrated for the case of anhydrous sodium acetate crystallized from various solvent-antisolvent mixtures. To validate the predicted solubilities, we have measured the solubilities of sodium acetate in-house, using an experimental setup and measurement protocol that guarantees moisture-free conditions, which is key for a hygroscopic compound like sodium acetate. We observe excellent agreement between the experimental and the computationally evaluated solubilities for sodium acetate in different solvent-antisolvent mixtures. Given the agreement and the rich data the simulations produce, we can use them to complement experimental tasks, which in turn will reduce time and capital in the design of complicated industrial crystallization processes of organic salts

Crystal size, shape, and conformational changes drive both the disappearance and reappearance of ritonavir polymorphs in the mill.

Organic compounds can crystallize in different forms known as polymorphs. Discovery and control of polymorphism is crucial to the pharmaceutical industry since different polymorphs can have significantly different physical properties which impacts their utilization in drug delivery. Certain polymorphs have been reported to 'disappear' from the physical world, irreversibly converting to new ones. These unwanted polymorph conversions, initially prevented by slow nucleation kinetics, are eventually observed driven by significant gains in thermodynamic stabilities. The most infamous of these cases is that of the HIV drug ritonavir (RVR): Once its reluctant form was unwillingly nucleated for the first time, its desired form could no longer be produced with the same manufacturing process. Here we show that RVR's extraordinary disappearing polymorph as well as its reluctant form can be consistently produced by ball-milling under different environmental conditions. We demonstrate that the significant difference in stability between its polymorphs can be changed and reversed in the mill-a process we show is driven by crystal size as well as crystal shape and conformational effects. We also show that those effects can be controlled through careful design of milling conditions since they dictate the kinetics of crystal breakage, dissolution, and growth processes that eventually lead to steady-state crystal sizes and shapes in the mill. This work highlights the huge potential of mechanochemistry in polymorph discovery of forms initially difficult to nucleate, recovery of disappearing polymorphs, and polymorph control of complex flexible drug compounds such as RVR

A Dual Projection Imaging System to Characterize Crystallization Processes: Design and Applications

Crystallization is a separation process that has been practised and applied widely in fine chemical and pharmaceutical industries. In the majority of applications, it is used to obtain a high purity solid form, which often exhibits a distribution of sizes and shapes. Crystallization involves a number of fundamental phenomena -- often poorly understood -- like nucleation, growth, dissolution, agglomeration, to name a few. The lack of reliable monitoring tools and techniques inhibits attaining deeper insights into the mechanisms involved, which naturally affects the robust and optimal operation of these crystallization processes. Poor understanding coupled with stringent targets on the product quality for drugs in terms of purity, stability, and bioavailability, has attracted significant attention from both the academia and the industry. The work presented in this thesis led to improvements in the state-of-the-art imaging techniques for size and shape characterization of the solid phase in batch solution crystallization processes. Based on these improvements, studies making use of the shape information obtained from the imaging device were undertaken for several interesting and previously unexplored applications. The former point led to providing better characterization and understanding of the process from a macroscopic scale. While the latter point with the aid of the former led to several automated and controlled approaches to manipulate the size and shape of undesirable needle-like crystals to equant crystals. The key accomplishments of this thesis were • enhancements to the hardware of a stereoscopic imaging device and to the imaging analysis routines to classify crystals observed by the imaging device into five different shape classes and to obtain a three-dimensional reconstruction of these crystals. • assessing the reliability of commercial spectroscopic techniques to estimate solute concentration in batch crystallization processes and proposing a new approach based on volumetric reconstruction of crystals observed by the stereoscopic imaging device, to estimate the solute concentration. • transformation of needle-like crystals to more equant crystals in a multistage cyclic process consisting of wet milling, dissolution, and growth stages, exploiting the online monitoring capabilities of the imaging device and simple feedback control laws for the individual stages. To summarize, the results obtained certainly reinforce the potential and the competence of imaging tools to tackle a wide array of challenges faced by the crystallization community. Irrespective of the promising outcome, their potential pitfalls are definitely not overlooked and plausible proposals to overcome these are discussed diligently to assist future research on monitoring, on modeling and on control of crystallization processes

Material Screening for Gas Sensing using an Electronic Nose: Gas Sorption Thermodynamic and Kinetic Considerations

To detect multiple gases in a mixture, one must employ an electronic nose or sensor array, composed of several materials as a single material cannot resolve all the gases in a mixture accurately. Given the many candidate materials, choosing the right combination of materials to be used in an array is a challenging task. In a sensor whose sensing mechanism depends on a change in mass upon gas adsorption, both the equilibrium and kinetic characteristics of the gas-material system dictate the performance of the array. The overarching goal of this work is two-fold. First, we aim to highlight the impact of thermodynamic characteristics of gas-material combination on array performance and to develop a graphical approach to rapidly screen materials. Second, we aim to highlight the need to incorporate the gas sorption kinetic characteristics to provide an accurate picture of the performance of a sensor array. To address these goals, we have developed a computational test bench that incorporates a sensor model and a gas composition estimator. To provide a generic study, we have chosen, as candidate materials, hypothetical materials that exhibit equilibrium characteristics similar to metal organic frameworks (MOFs). Our computational studies led to key learnings, namely: (1) exploit the shape of the sensor response as a function of gas composition for material screening purposes for gravimetric arrays; (2) incorporate both equilibrium and kinetics for gas composition estimation in a dynamic system; and (3) engineer the array by accounting for the kinetics of the materials, the feed gas flow rate, and the size of the device

Do adsorbent screening metrics predict process performance? A process optimisation based study for post-combustion capture of CO2

Recent interest in carbon dioxide capture has led to development of hundreds of adsorbents. The selection of the adsorbents and analyzing their performance for a given process is a challenging task. Usually, the expected performances of these adsorbents are evaluated by inspecting the isotherms and using simple adsorbent screening metrics (selectivities, working capacities, figures of merit, etc.). In this work, a process-optimization based approach to screen adsorbents for post-combustion CO2 capture for vacuum swing adsorption (VSA) is presented. Four different adsorbents (Mg-MOF-74, UTSA-16, Zeolite 13X and activated carbon) were chosen as test materials and were subjected to process-optimization studies on a 4-step PSA cycle with light product pressurization (LPP). Two kinds of process optimization studies were performed. The first to maximize purity and recovery and the second to minimize energy consumption and maximize productivity subject to purity/recovery constraints. This study highlights that most commonly used adsorbent metrics do not necessarily rank the performance of the materials at a process scale. It is also shown that the process performance was more sensitive to the affinity of N2 than that of CO2.Fil: Rajagopalan, Ashwin Kumar. University of Alberta; CanadáFil: Avila, Adolfo María. University of Alberta; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rajendran, Arvind. University of Alberta; Canad