PAT-based design of agrochemical co-crystallization processes : a case-study for the selective crystallization of 1:1 and 3:2 co-crystals of p-toluenesulfonamide/triphenylphosphine oxide

In this study, the selective crystallization and characterization of the stoichiometric forms of the p-toluenesulfonamide/triphenylphosphine oxide (p-TSA-TPPO) co-crystal system in acetonitrile (MeCN) is demonstrated using batch and semi-batch crystallizers. In the batch study, both 1:1 and 3:2 p-TSA-TPPO were successfully isolated as pure forms. However, process variability was observed in a few experimental runs. To address the batch process variability issue, a control strategy was implemented using temperature cycling, aided by in situ process analytical technologies (PAT) to convert from 3:2 to 1:1 p-TSA-TPPO. In the semi-batch co-crystallization studies, the two molecular co-formers, p-TSA and TPPO, were dissolved in MeCN and pumped separately to the crystallizer. Changing the flow rates of the respective active ingredients allowed control over the co-crystallization outcome, and presents as a promising opportunity for development of a continuous co-crystallization process

Periodic steady-state flow crystallization of a pharmaceutical drug using MSMPR operation

AbstractIn this paper, a novel concept of periodic mixed suspension mixed product removal (PMSMPR) crystallization process is demonstrated. An integrated array of process analytical technologies (PATs), based on attenuated total reflectance ultra violet/visible spectroscopy, focused beam reflectance measurement, particle vision microscopy and Raman spectroscopy, and in-house developed crystallization process informatics system software (CryPRINS) were used to monitor the periodic steady-state flow crystallization of paracetamol. Periodic steady-state is a new concept defined as a state of a system that maintains itself despite transitory effects caused by periodic, but controlled disruptions (state of controlled operation). This work also illustrates the concept of “state of controlled operation” instead of “steady-state operation” as a state that can characterize continuous (periodic) operation. The PMSMPR was configured as either a single- or two-stage unit and operated for up to 11 residence times without blockage or encrustation problems. The number of PMSMPR stages, seed characteristics (size, shape and distribution), and use of recycle stream were the main variables that influenced the periodic operation, significantly affecting the extent of secondary nucleation and growth. The results further illustrate the use of PAT and information system tools together to determine when the periodic operation reaches a state of controlled operation (periodic steady-state). These tools provided a better understanding of the variables and operating procedures influencing the periodic operation

Particle design via spherical agglomeration: A critical review of controlling parameters, rate processes and modelling

Particle design via spherical agglomeration is a size enlargement technique used in various bulk and fine chemical industries, with recent interest extending into pharmaceuticals, in which an immiscible bridging liquid is added to agglomerate crystals prior to deliquoring. Spherical agglomeration has the potential to dramatically simplify downstream processing, and improves the handling of difficult, needle-shaped crystals. This review consolidates the understanding of the controlling process parameters, identifies the rate processes that control agglomerate attributes, and examines the modelling approaches taken in the literature to optimise the design of such systems. The most important controlling parameters are solvent system composition (requiring knowledge of the ternary phase diagram) and bridging liquid to solid ratio (BSR). Agglomerate size is a highly non-linear function of BSR with many literature systems showing qualitatively similar behaviour. However, there is no method to predict the optimum BSR. Other important process parameters are temperature, constituent particle properties, agitation rate and batch/residence time. Each parameter can have significant effects on the final agglomerate properties including agglomerate size, porosity, strength and dissolution profile. The rate processes in spherical agglomeration are analogous to those in wet granulation. A general classification of rate processes is proposed in this review including nucleation by distribution or immersion, consolidation, coalescence, layered growth and breakage. While many papers give proof of concept examples of spherical agglomeration for specific systems, only a few have focused explicitly on mechanistic understanding. There is significant scope for further work to quantify the effect of both process parameters and formulation properties on these rate processes. Recent developments in on-line monitoring using process analytical technologies (PAT) should enable these studies. Using the mechanistic understanding, population balance models can be developed to include kernels for each of the relevant rate processes. Such models should be powerful tools of process optimisation and model driven design with reduced experiments at all scales

Systematic model identification and optimization-based active polymorphic control of crystallization processes

Polymorphism is an important issue in industrial crystallization, since polymorphs of the same compound can present very different properties, such as solubility, melting point or density, influencing considerably the manufacturability and bioavailability of the final product. This work proposes a model-based active polymorphic control strategy that allows obtaining large crystals of the stable polymorph at the end of a batch crystallization process, even in the case of erroneous seeding or in situ nucleation of a mixture of both the stable and metastable forms. A novel systematic experimental design was applied to estimate the kinetic parameters of dissolution, growth and secondary nucleation of the stable and metastable polymorphs of the model compound (ortho-aminobenzoic acid, OABA). Such experimental approach allows the determination of the studied kinetics without any correlation between parameters during the estimation, and without the need of off-line measurements of the crystal size distribution during the experiments. The estimated kinetic parameters were used to build a population balance model for the calculation of the optimal temperature profile needed, during a batch cooling crystallization process, for the (i) elimination of the metastable form crystals nucleated in situ or erroneously seeded and the (ii) maximisation of the size of the crystals of the stable polymorph obtained at the end of the batch process

Efficient Nonlinear Programming Algorithms for Chemical Process Control and Operations

Nonlinear programming (NLP) has been a key enabling tool for model-based decision-making in the chemical industry for over 50 years. Opti-mization is frequently applied in numerous ar-eas of chemical engineering including the de-velopment of process models from experimen-tal data, design of process flowsheets and equip-ment, planning and scheduling of chemical pro-cess operations, and the analysis of chemical pro-cesses under uncertainty and adverse conditions. These off-line tasks frequently require the solu-tion of NLPs formulated with detailed, lareg-scale process models. More recently, these tasks are complemented by time-critical, on-line optimization problem

Measurement of the VH,H → ττ process with the ATLAS detector at 13 TeV

A measurement of the Standard Model Higgs boson produced in association with a W or Z boson and decaying into a pair of τ-leptons is presented. This search is based on proton-proton collision data collected at √s = 13 TeV by the ATLAS experiment at the LHC corresponding to an integrated luminosity of 140 fb−1. For the Higgs boson candidate, only final states with at least one τ-lepton decaying hadronically (τ →hadrons + vτ ) are considered. For the vector bosons, only leptonic decay channels are considered: Z → ℓℓ and W → ℓvℓ, with ℓ = e, μ. An excess of events over the expected background is found with an observed (expected) significance of 4.2 (3.6) standard deviations, providing evidence of the Higgs boson produced in association with a vector boson and decaying into a pair of τ-leptons. The ratio of the measured cross-section to the Standard Model prediction is μττ VH = 1.28 +0.30 −0.29 (stat.) +0.25 −0.21 (syst.). This result represents the most accurate measurement of the VH(ττ) process achieved to date