Determination of residence time distribution and axial dispersion coefficient in a meso-scale oscillatory baffled crystallizer using a computational fluid dynamics approach [Abstract]

Determination of residence time distribution and axial dispersion coefficient in a meso-scale oscillatory baffled crystallizer using a computational fluid dynamics approach [Abstract

Characterisation of axial dispersion in a meso-scale oscillatory baffled crystalliser using a numerical approach. [Abstract]

Characterisation of axial dispersion in a meso-scale oscillatory baffled crystalliser using a numerical approach. [Abstract

Developing process understanding for continuous manufacturing of Lamivudine (Epivir®) Stable Form I

Why the considerations for Lamivudine? * Increasing numbers of HIV/AIDS infections on yearly basis (2.1 million new cases in 2015, UNAIDS) * Hepatitis B infections (257 million cases globally, WHO) * Currently FDA-approved antiretroviral therapy for the prevention and treatment of both viral infections (FDA). Key research considerations and interests To the best of our knowledge, no publication yet exists on continuous manufacturing of stable Lamivudine form 1. The key research question here is: * Translate current batch crystallisation into a continuous process? * Improve the downstream process-ability by modifying the particle properties? * Develop miniaturise platforms for accelerated process development

The role of residence time distribution in the continuous steady-state mixed suspension mixed product removal crystallization of glycine

In this work, a vacuum-driven intermittent transfer technique has been implemented to solve transfer line blockage issues and facilitate steady-state cooling crystallization studies of α-glycine in a single- and two-stage mixed suspension mixed product removal (MSMPR) crystallizer. Experimental residence time distribution (RTD) analysis of the stirred tank MSMPR cascade is performed using an imperfect pulse method of the axial dispersion model to benchmark the mixing performance against that of tubular crystallizers and determine the influence of RTD on steady-state size distribution of α-glycine product. Process analytical technology (PAT) is used to monitor and understand crystallization process dynamics, and the effect of MSMPR operating temperature, mean residence time, and number of MSMPR stages on mean particle size, crystal size distribution, and yield is studied. Results show the significance of nucleation and growth mechanisms alongside RTD in determining steady-state size distribution, and the need for optimum control of supersaturation to benefit from improved RTDs provided by multistage MSMPR crystallizers

High spatial resolution ToF-SIMS imaging and image analysis strategies to monitor and quantify early phase separation in amorphous solid dispersions

Amorphous solid dispersions (ASDs) are formulations with enhanced drug solubility and dissolution rate compared to their crystalline counterparts, however, they can be inherently thermodynamically unstable. This can lead to amorphous phase separation and drug re-crystallisation, phenomena that are typically faster and more dominant at the product’s surfaces. This study investigates the use of high-resolution time of flight-secondary ion mass spectrometry (ToF-SIMS) imaging as a surface analysis technique combined with image-analysis for the early detection, monitoring and quantification of surface amorphous phase separation in ASDs. Its capabilities are demonstrated for two pharmaceutically relevant ASD systems with distinct re-crystallisation behaviours, prepared using hot melt extrusion (HME) followed by pelletisation or grinding: (1) paracetamol-hydroxypropyl methylcellulose (PCM-HPMC) pellets with drug loadings of 10–50% w/w and (2) indomethacin-polyvinylpyrrolidone (IND-PVP) ground material with drug loadings of 20–85% w/w. PCM-HPMC pellets showed intense phase separation, reaching 100% surface coverage within 1-5 months. In direct comparison, IND-PVP HME ground material was more stable with only a moderate formation of isolated IND-rich clusters. Image analysis allowed the reliable detection and quantification of local drug-rich clusters. An Avrami model was applied to determine and compare phase separation kinetics. The combination of chemical sensitivity and high spatial resolution afforded by SIMS was crucial to enable the study of early phase separation and re-crystallisation at the surface. Compared with traditional methods used to detect crystalline material, such as XRPD, we show that ToF-SIMS enabled detection of surface physical instability already at early stages of drug cluster formation in the first days of storage

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Solid-liquid axial dispersion performance of a mesoscale continuous oscillatory flow crystalliser with smooth periodic constrictions using a non-invasive dual backlit imaging technique

A dual backlit imaging technique has been developed for liquid and solid phase residence time distribution (RTD) measurements in a mesoscale (millilitre) continuous oscillatory flow crystalliser with smooth periodic constrictions (herein known as the SPC mesoscale crystalliser). The pixel-based technique enables reliable determination and direct comparison of experimentally determined hydrodynamic parameters for the liquid and solid phase without concern for errors that may be introduced by utilising different measurement techniques for each phase. Additionally, the non-invasive technique offers benefits over traditional intrusive methods as demonstrated herein. Results of solid-liquid RTD experiments reveal that for a set of oscillatory flow conditions, particles do not experience the same degree of axial dispersion and mean residence time as the continuous liquid phase. The SPC mesoscale crystalliser, however, provides solid-liquid plug flow at low net flow rates. Findings in this work emphasise the importance of characterising solid phase axial dispersion for active pharmaceutical ingredient (API) systems during continuous crystallisation development to identify minimum dispersion operating conditions essential for solid-liquid plug flow crystallisation

Supplementary files for 'Solid-liquid axial dispersion performance of a mesoscale continuous oscillatory flow crystalliser with smooth periodic constrictions using a non-invasive dual backlit imaging technique'

Supporting data for a publication in Chemical Engineering Journal (2019)Solid-liquid axial dispersion performance of a mesoscale continuous oscillatory flow crystalliser with smooth periodic constrictions using a non-invasive dual backlit imaging technique Iyke. I. Onyemelukwe, Zoltan K. Nagya, Chris. D. RiellyMATLAB® script for image analysisData tables for axial dispersion coefficients</div