Solvates, salts, and cocrystals : a proposal for a feasible classification system

The design of pharmaceutical cocrystals has initiated widespread debate on the classification of cocrystals. Current attempts to classify multicomponent crystals suffer from ambiguity, which has led to inconsistent definitions for cocrystals and for multicomponent crystals in general. Inspired by the work of Aitipamula et al. (Cryst. Growth Des. 2012, 12, 2147-2152), we present a feasible classification system for all multicomponent crystals. The present classification enables us to analyze and classify multicomponent crystal structures present in the Cambridge Structural Database (CSD). This reveals that all seven classes proposed are relevant in terms of frequency of occurrence. Lists of CSD refcodes for all classes are provided. We identified over 5000 cocrystals in the CSD, as well as over 12 000 crystals with more than two components. This illustrates that the possibilities for alternative drug formulations can be increased significantly by considering more than two components in drug design

Induction of annexin-1 at transcriptional and post-transcriptional level in rat brain by methylprednisolone and the 21-aminosteroid U74389F

Brain tissue of rats pretreated with methylprednisolone or with the 21-aminosteroid U74389F, and that of untreated control rats, was assessed for the expression of annexin-1 (Anx-1) and the transcription of its mRNA. For this purpose Anx-1 cDNA was amplified and simultaneously a T7-RNA-polymerase promoter was incorporated into the cDNA using a polymerase chain reaction (PCR). Then digoxigenin-11-UTP was incorporated into the transcribed cRNA with T7-RNA-polymerase. With this probe in situ hybridization was carried out on sections of the brain. The probe was visualized by an immunoassay using an antidigoxigenin antibody conjugate. Anx-1 protein was assessed by means of immunohistochemistry using a polyclonal antibody. The various brain areas of the control animals showed an appreciable amount of Anx-1 at mRNA or protein level; on the other hand, the animals which had been pretreated with either steroid, showed a more intense Anx-1 mRNA signal than the controls in many areas. In the pretreated animals Anx-1 immunostaining was unchanged in cortex, basal ganglia, amygdala and septum, but more intense in hippocampus, hypothalamus and thalamus. In ependyma, choroid plexus, meninges, and vascular walls there was no Anx-1 mRNA transcription detectable. An opposite profile was shown by the Anx-1 immunoreactivity, the protein was present in control animals as well as the steroid-pretreated animals, suggesting that here the protein was either from systemic origin, or has diffused from adjacent structures. The results indicated that Anx-1 mRNA transcription is upregulated by either steroid, and that in the untreated animals there is a resting level of Anx-1 mRNA transcription, presumably reflecting physiological influences on Anx-1 expression

A structured approach to cope with impurities during industrial crystallization development

The perfect separation with optimal productivity, yield, and purity is very difficult to achieve. Despite its high selectivity, in crystallization unwanted impurities routinely contaminate a crystallization product. Awareness of the mechanism by which the impurity incorporates is key to understanding how to achieve crystals of higher purity. Here, we present a general workflow which can rapidly identify the mechanism of impurity incorporation responsible for poor impurity rejection during a crystallization. A series of four general experiments using standard laboratory instrumentation is required for successful discrimination between incorporation mechanisms. The workflow is demonstrated using four examples of active pharmaceutical ingredients contaminated with structurally related organic impurities. Application of this workflow allows a targeted problem-solving approach to the management of impurities during industrial crystallization development, while also decreasing resources expended on process development

Impact of impurities on crystallization and product quality : a case study with paracetamol

A thorough, systematic study into the effect that structurally related impurities have on both the process and product quality during the crystallization of an active pharmaceutical ingredient is presented. The presence of acetanilide and metacetamol influences the crystallization and product quality of paracetamol. Where high concentrations of either impurity were present in the crystallization feed, product recovery decreased by up to 15%. Acetanilide is included in the final product through adsorption onto the particle surface in concentrations up to 0.79 mol%, which can be reduced to acceptable levels through product reslurrying. The presence of metacetamol results in much higher concentrations—up to 6.78 mol% in the final product, of which approximately 1 mol% is incorporated into the crystal lattice, resulting in the perturbation of the unit-cell dimensions. The incidental crystallization and subsequent isolation of metastable Form II paracetamol increased product purity in the presence of a low metacetamol concentration. This metastable product converts to stable paracetamol Form I through reslurrying, offering an efficient metacetamol impurity rejection route. The morphology of the product is modified consistently by both impurities. An elongation of the normal prismatic shape is observed, which in the extreme case of high metacetamol contamination results in the isolation of fine, fragile needles. This problematic morphology is also improved by a reslurrying of the crystallization product to give a more equilateral shape. This systematic study of the influence of acetanilide and metacetamol on the crystallization of paracetamol builds a well-rounded picture of the concomitant impact of impurities on the principal quality attributes of a crystallization product

Cost-effectiveness of hepatitis C virus screening, and subsequent monitoring or treatment among pregnant women in the Netherlands

Background The prevalence of diagnosed chronic hepatitis C virus (HCV) infection among pregnant women in the Netherlands is 0.26%, yet many cases remain undiagnosed. HCV screening and treatment of pregnant HCV carriers could reduce the burden of disease and limit vertical transmission from mother to child. We assessed the impact of HCV screening and subsequent treatment with new direct-acting antivirals (DAAs) among pregnant women in the Netherlands. Methods An HCV natural history Markov transition state model was developed, to evaluate the public-health and economic impact of HCV screening and treatment. Besides all 179,000 pregnant women in the Netherlands (cohort 1), we modelled 3 further cohorts: all 79,000 first-time pregnant women (cohort 2), 33,000 pregnant migrant women (cohort 3) and 16,000 first-time pregnant migrant women (cohort 4). Each cohort was analyzed in various scenarios:i no intervention, i.e., the current practice,ii screen-and-treat, i.e., the most extensive approach involving treatment of all individuals found HCV-positive, andiii screen-and-treat/monitor, i.e., a strategy involving treatment of symptomatic (F1-F4) patients and follow-up of asymptomatic (F0) HCV carriers with subsequent treatment only at progression. Results For all cohorts, comparison betweenscenarios(ii) and (i) resulted in ICERs between euro9,306 and euro10,173 per QALY gained and 5 year budget impacts varying between euro6,283,830 and euro19,220,405. For all cohorts, comparison betweenscenarios(iii) and (i) resulted in ICERs between euro1,739 and euro2,749 per QALY gained and budget impacts varying between euro1,468,670 and euro5,607,556. For all cohorts, the ICERs (scenario iiiversusii) involved in delayed treatment of asymptomatic (F0) HCV carriers varied between euro56,607 and euro56,892, well above the willingness-to-pay (WTP) threshold of euro20,000 per QALY gained and even above a threshold of euro50,000 per QALY gained. Conclusion Universal screening for HCV among all pregnant women in the Netherlands is cost-effective. However, it would be reasonable to consider smaller risk groups in view of the budget impact of the intervention

On the aggregation and nucleation mechanism of the monoclonal antibody anti-CD20 near liquid-liquid phase separation (LLPS)

The crystallization of Anti-CD20, a full-length monoclonal antibody, has been studied in the PEG400/Na2SO4/Water system near Liquid-Liquid Phase Separation (LLPS) conditions by both sitting-drop vapour diffusion and batch methods. In order to understand the Anti-CD20 crystallization propensity in the solvent system of different compositions, we investigated some measurable parameters, normally used to assess protein conformational and colloidal stability in solution, with the aim to understand the aggregation mechanism of this complex biomacromolecule. We propose that under crystallization conditions a minor population of specifically aggregated protein molecules are present. While this minor species hardly contributes to the measured average solution behaviour, it induces and promotes crystal formation. The existence of this minor species is the result of the LLPS occurring concomitantly under crystallization conditions