From structure to crystallisation and pharmaceutical manufacturing: the CSD in CMAC Workflows

Two Workflows are presented that are relevant to the design and construction of end-to-end pharmaceutiucal manufacturing processes. The Workflows target the very early stage crystallisation aspect of these processes – production of the primary crystalline solid form – and relate to establishing decision-driven approaches for the screening for multi-component forms, specifically co-crystals, and to the use of additives to control crystal and primary particle form, notably morphology. These Workflows are shown to benefit from the use of the Million-plus structures in the Cambridge Structural Database and the associated structural informatics and analysis tools and are placed into the context of the work of the CMAC Future Manufacturing Hub

Comparative Study on the Therapeutic Potential of Neurally Differentiated Stem Cells in a Mouse Model of Multiple Sclerosis

Background: Transplantation of neural stem cells (NSCs) is a promising novel approach to the treatment of neuroinflammatory diseases such as multiple sclerosis (MS). NSCs can be derived from primary central nervous system (CNS) tissue or obtained by neural differentiation of embryonic stem (ES) cells, the latter having the advantage of readily providing an unlimited number of cells for therapeutic purposes. Using a mouse model of MS, we evaluated the therapeutic potential of NSCs derived from ES cells by two different neural differentiation protocols that utilized adherent culture conditions and compared their effect to primary NSCs derived from the subventricular zone (SVZ). Methodology/Principal Findings: The proliferation and secretion of pro-inflammatory cytokines by antigen-stimulated splenocytes was reduced in the presence of SVZ-NSCs, while ES cell-derived NSCs exerted differential immunosuppressive effects. Surprisingly, intravenously injected NSCs displayed no significant therapeutic impact on clinical and pathological disease outcomes in mice with experimental autoimmune encephalomyelitis (EAE) induced by recombinant myelin oligodendrocyte glycoprotein, independent of the cell source. Studies tracking the biodistribution of transplanted ES cellderived NSCs revealed that these cells were unable to traffic to the CNS or peripheral lymphoid tissues, consistent with the lack of cell surface homing molecules. Attenuation of peripheral immune responses could only be achieved through multiple high doses of NSCs administered intraperitoneally, which led to some neuroprotective effects within the CNS

Global Citizenship and Cross-Cultural Competency: Student and Expert Understandings of Internationalization Terminology

Internationalization of the curriculum is of increasing interest in many universities; yet, the terminology used to describe it is highly varied and it is not clear that students understand its core concepts. This study explores students\u27 understandings of the terms global citizenship and cross-cultural competency, and compares them with use in the literature and by experts. A large-scale questionnaire of students from a range of disciplines is supplemented with qualitative data from pedagogic and internationalization experts. Findings indicate that student understandings of both terms were mixed, and frequently differed from the way the terms are used by experts and in the literature. The concept of cross-cultural competency was more likely to invoke a sense of agency among students than was global citizenship, contrary to how they are depicted in the literature. This suggests that there may be some pedagogic benefits to be gained from using the former term

Tuning morphology in active pharmaceutical ingredients: controlling the crystal habit of lovastatin through solvent choice and non-size-matched polymer additives

Additive crystallization routes to control the crystal habit of the active pharmaceutical ingredient (API) lovastatin are presented, at small scale up to 25 mL. Lovastatin is an archetypical example of an API that forms needle-like crystals via solution-based recrystallization, causing issues for downstream pharmaceutical processing stages. In this work, the size and shape of lovastatin needles are shown to be subtly influenced by the crystallization solvent, concentration, and crystallization procedure, with moderately hygroscopic ethyl acetate solvent producing needles with improved aspect ratios in comparison to the acetone/water mixtures primarily used for industrial recrystallization. Further, the inclusion of soluble, non-size-matched polymer additives, at very low concentrations (0.5 wt %/wt), into the solution has a pronounced impact on the crystal habit. While the inclusion of the hydrophilic polymer poly(ethylene glycol) promotes the formation of even longer, thinner needles than those formed by nonadditive routes, the use of hydrophobic poly(propylene glycol) improves the habit from needles toward plate-like crystals. The product materials are analyzed by a combination of microscopy, thermal analysis, and diffraction-based techniques, with the latter enabling rationalization of the habit control via identification of the prominent crystal faces and growth directions with respect to the underlying crystal structure

Tuning morphology in active pharmaceutical ingredients: controlling the crystal habit of lovastatin through solvent choice and non-size-matched polymer additives

Additive crystallization routes to control the crystal habit of the active pharmaceutical ingredient (API) lovastatin are presented, at small scale up to 25 mL. Lovastatin is an archetypical example of an API that forms needle-like crystals via solution-based recrystallization, causing issues for downstream pharmaceutical processing stages. In this work, the size and shape of lovastatin needles are shown to be subtly influenced by the crystallization solvent, concentration, and crystallization procedure, with moderately hygroscopic ethyl acetate solvent producing needles with improved aspect ratios in comparison to the acetone/water mixtures primarily used for industrial recrystallization. Further, the inclusion of soluble, non-size-matched polymer additives, at very low concentrations (0.5 wt %/wt), into the solution has a pronounced impact on the crystal habit. While the inclusion of the hydrophilic polymer poly(ethylene glycol) promotes the formation of even longer, thinner needles than those formed by nonadditive routes, the use of hydrophobic poly(propylene glycol) improves the habit from needles toward plate-like crystals. The product materials are analyzed by a combination of microscopy, thermal analysis, and diffraction-based techniques, with the latter enabling rationalization of the habit control via identification of the prominent crystal faces and growth directions with respect to the underlying crystal structure

Tuning Morphology in Active Pharmaceutical Ingredients: Controlling the Crystal Habit of Lovastatin through Solvent Choice and Non-Size-Matched Polymer Additives

Additive crystallization routes to control the crystal habit of the active pharmaceutical ingredient (API) lovastatin are presented, at small scale up to 25 mL. Lovastatin is an archetypical example of an API that forms needle-like crystals via solution-based recrystallization, causing issues for downstream pharmaceutical processing stages. In this work, the size and shape of lovastatin needles are shown to be subtly influenced by the crystallization solvent, concentration, and crystallization procedure, with moderately hygroscopic ethyl acetate solvent producing needles with improved aspect ratios in comparison to the acetone/water mixtures primarily used for industrial recrystallization. Further, the inclusion of soluble, non-size-matched polymer additives, at very low concentrations (0.5 wt %/wt), into the solution has a pronounced impact on the crystal habit. While the inclusion of the hydrophilic polymer poly(ethylene glycol) promotes the formation of even longer, thinner needles than those formed by nonadditive routes, the use of hydrophobic poly(propylene glycol) improves the habit from needles toward plate-like crystals. The product materials are analyzed by a combination of microscopy, thermal analysis, and diffraction-based techniques, with the latter enabling rationalization of the habit control via identification of the prominent crystal faces and growth directions with respect to the underlying crystal structure

Characterization of 46C-NS cells.

<p>(A–C) Immunofluorescence staining showed 46C-NS cells expressed nestin, red (A) and 3CB2, red (B) but not GFAP, green (A) or MAP2, green (B). (<b>D–E</b>) Following neuronal or astrocytic differentiation, 46C-NS cells expressed βIII-Tubulin, red and MAP2, green (C) or GFAP (D), respectively.</p

Differentiation potential of GS-N cells.

<p>(A–C) Immunofluorescence staining showed GS-N cells expressed nestin, red (A), A2B5, red (B) and βIII-Tubulin, red and MAP2, green (C). (D–E) Following neuronal or astrocytic differentiation, GS-N cells expressed MAP2, green and NeuN, red (D) or GFAP (E), respectively. (F–K) Electrophysiological assessment of GS-N cell-derived neurons. Neurons in high density (F) fired spontaneous action potentials (APs), which were blocked by tetrodotoxin (TTX) (G). The depolarization giving rise to the APs (H) was underpinned by an inward current (I). Sparsely growing neurons (J) did not display spontaneous activity but APs could be evoked by depolarising current steps (K).</p