Surface adsorbed templates for directing the crystal growth of entacapone as monitored using process analytical techniques

Crystallization of entacapone (E-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5- nitrophenyl) propenamide) in acetone solution at the 500 mL scale using a self-assembled layer of the host material on Au(111) as a seeding template was studied and monitored using attenuated total reflectance (ATR)-UV-vis spectroscopy and focused beam reflectance measurement (FBRM). The data reveal that the template promotes crystal growth at lower supersaturations and at an increased rate when compared to experiments carried out without the template. Crystals prepared using the template are also found to have superior properties compared to crystals produced without the template. Notably, use of the template produces crystals with a much narrower size distribution, greatly increased perfection and a more equant crystal morphology. These observations are consistent with the template providing a sympathetic surface for the promotion of crystallization through an analogous mechanism to that associated with conventional seeding, but with the added advantage of conferring a well-ordered, easily reproducible and more robust process

Child violence experiences in institutionalised/orphanage care

Institutions are not necessarily good environments for children. In the face of challenges such as HIV, Ebola, poverty, conflict and disaster the numbers have grown rather than reduced. Some countries have closed institutions down –driven by findings that cognitive developmental delay is associated with institutional care. Yet insight into abuse and violence within institutionalised settings is neglected. Maltreatment -violence and abuse -may be an issue. This systematic review series addresses violence and abuse experiences in institutionalised care, exploring firstly the frequency of abuse/violence in institutions, secondly any interventions to reduce such violence or abuse and thirdly the perpetrators of such violence or abuse. The final systematic review updates the findings on cognitive delay associated with institutionalised care. With a violence lens, cognitive delay may well be considered under the umbrella of neglect. Maltreatment and abuse may be a driver of cognitive delay. The keyword search covered several electronic databases and studies were included for data abstraction if they met adequacy criteria. Eight studies were identified on the prevalence of abuse in institutions and a further three studies reported on interventions. Only one study was identified documenting peer on peer violence in institutions. Sixty-six studies were identified examining cognitive development for institutionalised children. All but two of these record cognitive deficits associated with institutionalisation. Only two asked about violence or abuse which was found to be higher in institutionalised children. Overall the abuse experiences of children in institutions are poorly recorded, and in one study violence was associated with high suicidal attempts. The major intervention pathway for ameliorating cognitive challenge seems to be placement out of the institutions which shows benefits and redresses some cognitive outcomes – yet not a total panacea. The single study providing training and monitoring of harsh punishment and maltreatment showed immediate and decided reductions. This data suggest, despite the paucity of studies, violence and abuse, by commission or omission is prevalent in institutions, has an effect on child well-being and is amenable to intervention. Simple training or more complex structures to place children within conducive alternative environments (or to avoid institutionalised placements in the first place) seem to be the main pathway of intervention

Examination of inequivalent wetting on the crystal habit surfaces of RS-ibuprofen using grid-based molecular modelling

Synthonic engineering tools, including grid-based searching molecular modelling, are applied to investigate the wetting interactions of the solute and four crystallisation solvents (ethanol, ethyl acetate, acetonitrile and toluene) with the {100}, {001} and {011} forms of RS-ibuprofen. The grid-based methods, in particular the construction of a crystal slab parallel to a given plane in a coordinate system with one axis perpendicular to the surface, are defined in detail. The interaction strengths and nature (dispersive, hydrogen bonding (H-bonding) or coulombic forces) are related to the crystal growth rates and morphologies. The solute is found to interact strongest with the capping {011}, then the side {001} and weakest with the top {100} habit surfaces. The solute interactions with the {100} and {001} surfaces are found to be almost solely dominated by dispersive force contributions, whilst the same with the {011} surfaces are found to have a greater contribution from H-bonding and coulombic forces. The increased surface rugosity, at the molecular level of the {011} surfaces, results in a favourable docking site in a surface 'valley', not present in the {100} and {001} surfaces. The H-bonding solvents ethanol, acetonitrile and ethyl acetate are found to strongly interact with the {011} surfaces and weakly with the {001} surfaces, with the {011} interactions having a much greater contribution from H-bonding and coulombic forces. The interaction energies of the apolar and aprotic solvent toluene, with the {011} and {001} surfaces, are found to be very close. Toluene is found having slightly stronger interactions with the {001} than the {011} surfaces, which are all dominated by dispersive interactions. The ratio of the average energy of the top 100 solvent interactions with the {001} surface divided by the average energy of the top 100 interactions with the {011} surface is compared to the ratio of the experimentally measured growth rates of the same forms. In general, the interaction energy ratio is found to have an inverse ratio with the growth rates, implying that the solvents which are calculated to interact strongly with a particular surface are impeding the growth of that surface and reducing the growth rate, in turn impacting upon the final morphology of the material

Understanding Mental Health in the Context of Adolescent Pregnancy and HIV in Sub-Saharan Africa: A Systematic Review Identifying a Critical Evidence Gap

Adolescent (10–19 years) mental health remains an overlooked global health issue. Rates of adolescent pregnancy within sub-Saharan Africa are some of the highest in the world and occur at the epicentre of the global HIV epidemic. Both experiencing adolescent pregnancy and living with HIV have been found to be associated with adverse mental health outcomes, when investigated separately. Poor mental health may have implications for both parent and child. The literature regarding mental health within groups experiencing both HIV and adolescent pregnancy is yet to be summarised. This systematic review sought to identify (1) the prevalence/occurrence of common mental disorder amongst adolescents who are living with HIV and have experienced pregnancy, (inclusive of adolescent fathers) in sub-Saharan Africa (2) risk and protective factors for common mental disorder among this group, and (3) interventions (prevention/treatment) for common mental disorder among this group. A systematic search of electronic databases using pre-defned search terms, supplemented by hand-searching, was undertaken in September 2020. One author and an independent researcher completed a title and abstract screening of results from the search. A full-text search of all seemingly relevant manuscripts (both quantitative and qualitative) was undertaken and data extracted using pre-determined criteria. A narrative synthesis of included studies is provided. Quality and risk of bias within included studies was assessed using the Newcastle-Ottawa scale. A systematic keyword search of databases and follow-up hand searching identifed 2287 unique records. Of these, thirty-eight full-text quantitative records and seven fulltext qualitative records were assessed for eligibility. No qualitative records met the eligibility criteria for inclusion within the review. One quantitative record was identifed for inclusion. This study reported on depressive symptomology amongst 14 pregnant adolescents living with HIV in Kenya, identifying a prevalence of 92.9%. This included study did not meet the high methodological quality of this review. No studies were identifed reporting on risk and protective factors for common mental disorder, and no studies were found identifying any specifc interventions for common mental disorder for this group, either for prevention or for treatment. The limited data identifed within this review provides no good quality evidence relating to the prevalence of common mental disorder among adolescents living with HIV who have experienced pregnancy in sub-Saharan Africa. No data was available relating to risk and protective factors or interventions for psychological distress amongst this group. This systematic review identifes a need for rigorous evidence regarding the mental health of pregnant and parenting adolescents living with HIV, and calls for granular interrogation of existing data to further our understanding of the needs of this group. The absence of research on this topic (both quantitative and qualitative) is a critical evidence gap, limiting evidence-based policy and programming responses, as well as regional development opportunities

Adolescent mothers affected by HIV and their children: A scoping review of evidence and experiences from sub-Saharan Africa

While adolescents have received increasing attention in the global HIV response and international strategies and commitments, adolescent mothers and their children remain largely overlooked in research, funding and, programming for health-related outcomes. We conducted an extensive scoping review of current evidence on the experiences of adolescent mothers affected by HIV and their children in this region. We included published literature and conference abstracts, complemented by consultations with key stakeholders, and a review of documents through grey literature searching. First, we summarise the experiences of adolescent mothers and their children related to HIV and key health and development indicators. The syndemic of early motherhood and HIV in sub-Saharan Africa increases the vulnerability of adolescent mothers and their children. We then highlight lessons from a series of promising programmes focused on supporting adolescent mothers through novel approaches. In sub-Saharan Africa, supporting adolescent mothers living in high HIV-risk communities is critical not only to eliminate HIV/AIDS, but also to attain the Sustainable Development Goals. While research on and programming for adolescent mothers and their children is growing, the complex needs for this vulnerable group remain unmet. We conclude with evidence gaps and programming priorities for adolescent mothers affected by HIV and their children

Combining Morphological Population Balances with Face-Specific Growth Kinetics Data to Model and Predict the Crystallization Processes for Ibuprofen

A route map for modeling pharmaceutical manufacturing processes utilizing morphological population balance (MPB) is presented in terms of understanding and controlling particle shape and size for optimizing the efficiency of both the manufacturing process and final properties of the formulated drugs. This is applied to batch cooling crystallization of the pharmaceutical compound ibuprofen from supersaturated ethanolic solutions in which the MPB is combined with the known crystal morphology and associated face-specific growth kinetics (Nguyen et al. CrystEngComm 2014, 16, 4568-4586) to predict the temporal evolution of the shape and size distributions of all crystals. The MPB simulations capture the temporal evolution of the size and shape of ibuprofen crystals and their distributions at each time instance during the crystallization processes. The volume equivalent spherical diameter and crystal size distribution converted from MPB simulation are validated against the experimental studies on the 1 L scale size (Rashid et al. Chem. Eng. Res. Des. 2012, 90, 158-161), confirming the promise of this approach as a powerful simulation, optimization, and control tool for the digital design of precision pharmaceutical processes and products with the desirable properties, with potential applications in crystallization design for personalized medicines

Morphology and Growth of Methyl Stearate as a Function of Crystallization Environment

In situ studies of methyl stearate growing from supersaturated n-dodecane, kerosene, and toluene solutions reveal strong evidence that solvent choice influences the crystal morphology and crystal growth kinetics. Crystals with similar habit are observed in all solvents, with the exception of lower supersaturations in kerosene, where a less symmetric morphology was observed. BFDH analysis based on the monoclinic C2 crystal structure of methyl stearate yielded the morphological indexation to be (110), (1–10), (−110), and (−1–10) for the dominant observed habit and (110) (1–10) (−1–10) (−240) (−3–10) for the less symmetric habit observed in kerosene solvent. Measurements of the growth rate for the (110) and (1–10) faces are similar for all solutions ranging from 0.02 to 1.13 μm/s, for significantly lower values of supersaturation in the case of toluene. The tendency of the growth rate dependence on σ was consistent with the Burton-Cabrera-Frank (BCF) growth mechanism in n-dodecane, the Birth and Spread (B&S) mechanism in kerosene and diffusion controlled in toluene solvent

Crystallographic Structure, Intermolecular Packing Energetics, Crystal Morphology and Surface Chemistry of Salmeterol Xinafoate (Form I).

Single crystals of salmeterol xinafoate (form I), prepared from slow cooled supersaturated propan-2-ol solutions, crystallise in a triclinic P‾1 symmetry with two closely related independent salt pairs within the asymmetric unit, with an approximately double unit cell volume compared to the previously published crystal structure(1). Synthonic analysis of the bulk intermolecular packing confirms the similarity in packing energetics between the two salt pairs. The strongest synthons, as expected, are dominated by coulombic interactions. Morphological prediction reveals a plate-like morphology, dominated by the {001}, {010} and {100} surfaces, consistent with experimentally grown crystals. Though surface chemistry of the slow growing {001} face comprises of large sterically hindering phenyl groups, weaker coulombic interactions still prevail from the alcohol group present on the phenyl and hydroxymethyl groups. The surface chemistry of the faster growing {010} and {100} faces are dominated by the significantly stronger cation/anion interactions occurring between the carboxylate and protonated secondary ammonium ion groups. The importance of understanding the cohesive/adhesive nature of the crystal surfaces of an API, with respect to their interaction with other API crystals and excipients and how that may impact formulation design is highlighted

The integrated DL_POLY/DL_FIELD/DL_ANALYSER software platform for molecular dynamics simulations for exploration of the synthonic interactions in saturated benzoic acid/hexane solutions

Three separately developed software Molecular Dynamics packages at Daresbury Laboratory, namely DL_FIELD (DL_F), DL_POLY and DL_ANALYSER, have been integrated to form an efficient computational infrastructure to investigate the detailed solution chemistry of saturated benzoic acid in hexane solutions. These software capabilities are demonstrated, in combination with the Synthonic Engineering tools and density functional theory (DFT) calculations, to assess the extent that the solute-solute intermolecular synthonic interactions in solution mirrors the synthons in the crystal structure. The results show that the majority of the COOH groups are forming OH … O H-bonds, which are a combination of classic OH … O homo-dimers and three membered H-bonding clusters. The formation of pi-pi stacking interactions is observed, but in far fewer numbers than observed for the OH … O interactions. The DFT simulations of the IR spectra of the multiple benzoic acid aggregates extracted from the MD trajectories provides further in-depth analysis of previously published IR data, by matching simulated peaks to the experimental peaks, hence identifying the exact bonding modes that are responsible for such peaks. This study demonstrates the value of a multi-scale and multi-technique approach to exploring the molecular transition pathway from solution to crystal structure

Multiple markers of cortical morphology reveal evidence of supragranular thinning in schizophrenia.

In vivo structural neuroimaging can reliably identify changes to cortical morphology and its regional variation but cannot yet relate these changes to specific cortical layers. We propose, however, that by synthesizing principles of cortical organization, including relative contributions of different layers to sulcal and gyral thickness, regional patterns of variation in thickness of different layers across the cortical sheet and profiles of layer variation across functional hierarchies, it is possible to develop indirect morphological measures as markers of more specific cytoarchitectural changes. We developed four indirect measures sensitive to changes specifically occurring in supragranular cortical layers, and applied these to test the hypothesis that supragranular layers are disproportionately affected in schizophrenia. Our findings from the four different measures converge to indicate a predominance of supragranular thinning in schizophrenia, independent of medication and illness duration. We propose that these indirect measures offer novel ways of identifying layer-specific cortical changes, offering complementary in vivo observations to existing post-mortem studies.KW is supported by the University of Cambridge MB/PhD Programme and, together with KJW, by the Wellcome Trust. IMG by a Wellcome Trust Strategic Award (RNAG/260), and LR and PCF by the Bernard Wolfe Health Neuroscience Fund and Wellcome Trust