466 research outputs found
Microfactory – Blend – Compression - Performance test
Aims and objectives - API’s with acicular habits are commonplace and present processing and handling challenges due to poor flow. This is traditionally addressed by wet granulation processes during formulation. Currently continuous direct compression (CDC) is gaining favour as a simplified formulation and dose formation process. However, poor flow properties limit CDC. This work aims to enable CDC by spherical agglomeration in the primary process and develop underpinning modelling approaches to allow formulations to be explored in-silico (i.e. digital twin) - Here at CMAC an integrated crystalisation-spherical agglomeration-drying-blending-compression process is being developed (microfactory) to be used to parameterise and develop modelling tools on the g-formulate package - This work presents some of the activities on the compression component to parameterise and develop a suitable model to enable the process to be explored (i.e. digital twin
Vehicle/engine integration
VEHICLE/ENGINE Integration Issues are explored for orbit transfer vehicles (OTV's). The impact of space basing and aeroassist on VEHICLE/ENGINE integration is discussed. The AOTV structure and thermal protection subsystem weights were scaled as the vehicle length and surface was changed. It is concluded that for increased allowable payload lengths in a ground-based system, lower length-to-diameter (L/D) is as important as higher mixture ration (MR) in the range of mid L/D ATOV's. Scenario validity, geometry constraints, throttle levels, reliability, and servicing are discussed in the context of engine design and engine/vehicle integration
Oscillatory flow reactors (OFRs) for continuous manufacturing and crystallization
Continuous crystallization is an attractive approach for the delivery of consistent particles with specified critical quality attributes (CQAs), which are attracting increased interest for the manufacture of high value materials, including fine chemicals and pharmaceuticals. Oscillatory flow reactors (OFRs) offer a suitable platform to deliver consistent operating conditions under plug-flow operation while maintaining a controlled steady state. This review provides a brief overview of OFR technology before outlining the operating principles and summarizing applications, emphasizing the use for controlled continuous crystallization. While significant progress has been made to date, areas for further development are highlighted that will enhance the range of applications and ease of implementation of OFR technology. These depend on specific applications but include scale down, materials of construction suitable for chemical compatibility, encrustation mitigation, the enhancement of robust operation via automation, process analytical technology (PAT), and real-time feedback control
Spray drying as a reliable route to produce metastable carbamazepine form IV
Carbamazepine is an active pharmaceutical ingredient used in the treatment of epilepsy that can form at least five polymorphic forms. Metastable form IV was originally discovered from crystallisation with polymer additives however has not been observed from subsequent solvent only crystallisation efforts. This work reports the reproducible formation of phase pure crystalline form IV by spray drying of methanolic carbamazepine solution. Characterisation of the material was carried out using diffraction, SEM and DSC. In situ Raman spectroscopy was used to monitor the spray dried product during the spray drying process. This work demonstrates spray drying provides a robust method for the production of form IV carbamazepine and the combination of high supersaturation and rapid solid isolation from solution overcomes the apparent limitation of more traditional solution crystallisation approaches to produce metastable crystalline forms
Correction: Population Genomics of the Immune Evasion (var) Genes of Plasmodium falciparum
Var genes encode the major surface antigen (PfEMP1) of the blood stages of the human malaria parasite Plasmodium falciparum. Differential expression of up to 60 diverse var genes in each parasite genome underlies immune evasion. We compared the diversity of the DBLalpha domain of var genes sampled from 30 parasite isolates from a malaria endemic area of Papua New Guinea (PNG) and 59 from widespread geographic origins (global). Overall, we obtained over 8,000 quality-controlled DBLalpha sequences. Within our sampling frame, the global population had a total of 895 distinct DBLalpha "types" and negligible overlap among repertoires. This indicated that var gene diversity on a global scale is so immense that many genomes would need to be sequenced to capture its true extent. In contrast, we found a much lower diversity in PNG of 185 DBLalpha types, with an average of approximately 7% overlap among repertoires. While we identify marked geographic structuring, nearly 40% of types identified in PNG were also found in samples from different countries showing a cosmopolitan distribution for much of the diversity. We also present evidence to suggest that recombination plays a key role in maintaining the unprecedented levels of polymorphism found in these immune evasion genes. This population genomic framework provides a cost effective molecular epidemiological tool to rapidly explore the geographic diversity of var genes
Affinity proteomics reveals elevated muscle proteins in plasma of children with cerebral malaria
Systemic inflammation and sequestration of parasitized erythrocytes are central processes in the pathophysiology of severe Plasmodium falciparum childhood malaria. However, it is still not understood why some children are more at risks to develop malaria complications than others. To identify human proteins in plasma related to childhood malaria syndromes, multiplex antibody suspension bead arrays were employed. Out of the 1,015 proteins analyzed in plasma from more than 700 children, 41 differed between malaria infected children and community controls, whereas 13 discriminated uncomplicated malaria from severe malaria syndromes. Markers of oxidative stress were found related to severe malaria anemia while markers of endothelial activation, platelet adhesion and muscular damage were identified in relation to children with cerebral malaria. These findings suggest the presence of generalized vascular inflammation, vascular wall modulations, activation of endothelium and unbalanced glucose metabolism in severe malaria. The increased levels of specific muscle proteins in plasma implicate potential muscle damage and microvasculature lesions during the course of cerebral malaria
Quality by design approach for early understanding of active pharmaceutical ingredient recovery process through dead-end filtration
This study applied some concepts of quality-by-design (QbD) approach for an early understanding of crystal recovery through filtration. A bespoke laboratory scale dead-end filtration platform (modified Biotage vacuum master (BVM) ≈ 50 mL working volume) was used to investigate the recovery of an active pharmaceutical ingredient (API) of different size distributions using acetaminophen crystals (micronised, medium-sized Bioxtra and coarse) as a case study. The method involved: (1) identification of critical process parameters (CPPs) with significant impact on process stability (a process risk evaluation step based on one factor at a time); (2) design of experiment to screen the influence of design factors (such as filter pore size, pressure difference, crystal loading and particle size distribution (PSD)) contributing to process instability based on process responses (volumetric flux and specific cake resistance); and (3) investigate the optimal process window for reduced probability of failure and process predictability. The filtration process responses were characterised by assessing the filtrate flow rate by the application of Darcy’s law. Initial assessments of process steadiness for acetaminophen crystals recovery shows that the filter pore size and API crystal sizes are critical. A non-linear process dependency was observed between the applied pressure difference, pore size, and crystal size. Screening crystal recovery conditions based on the design of experiment (DoE) approach indicated a steady filtration process for all crystal sizes tested except for coarse crystals which shows non-valid (negative) specific cake resistance at conditions of 5 µm pore size filter and 100 mbar pressure difference. However, pressure difference and pore size had a notable impact on the process responses. As a result, 10 µm pore size filter was used for investigating the optimal process window. Process predictability was demonstrated by data clustering and refinement based on partial least square model. The results showed good predictability with >98% regression between the predicted and experimental data. Verification of optimal operating window with less than 5% probability failure resulted in conditions of 300 – 450 mbar pressure difference and PSD of 45 – 110 µm. The approach studied using the small-scale BVM provided an early data gathering and systematic approach to understanding process interactions affecting crystal recovery through dead-end filtration
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