Dipharma (Italy)

This chapter examines the state-of-the-art approaches used in the solid-state characterization of pharmaceutical systems using a combination of NMR, X-ray diffraction and computer modelling. Solid-state NMR spectroscopy is highly sensitive to strong and weak crystal packing interactions and is a powerful partner of X-ray diffraction in crystal structure validation/determination; ab initio calculations are very often required to support NMR studies in complex structures, therefore this chapter also highlights the main computational approaches used to extract structural information. The outline of the chapter is as follows. The chapter starts with a high-level introduction into the fields of solid-state NMR, powder and single-crystal X-ray diffraction (Section 6.2), providing a general overview of the main methods and latest developments of each technique in the field of pharmaceutical solid-state chemistry. A vast selection of key application case studies is presented in Section 6.3, ranging from the study of polymorphism (Section 6.3.1), amorphous systems (Section 6.3.2), drug delivery systems (Section 6.3.3), formulated drugs (Section 6.3.4), crystal packing interactions and structure determination (Section 6.3.5). A comprehensive literature selection is provided in each section, highlighting the contributions of each technique (solid-state NMR, X-ray diffraction), their individual drawbacks and the complementarity of their combined use for the characterization and structural elucidation of various pharmaceutical systems.

Abstract The synthesis of silodosin, an antidysuria drug, has been accomplished starting from commercially available indoline. The synthetic strategy is based on CuI‐catalysed C–C arylation, regioselective cyanation, and diastereoselective reductive amination. The enantiopure compound was obtained by selective crystallisation of a diasteroisomeric mixture.

High-density SNP arrays for genome-wide assessment of allelic variation have made high resolution genetic characterization of crop germplasm feasible. A medium density array for apple, the IRSC 8K SNP array, has been successfully developed and used for screens of bi-parental populations. However, the number of robust and well-distributed markers contained on this array was not sufficient to perform genome-wide association analyses in wider germplasm sets, or Pedigree-Based Analysis at high precision, because of rapid decay of linkage disequilibrium. We describe the development of an Illumina Infinium array targeting 20K SNPs. The SNPs were predicted from re-sequencing data derived from the genomes of 13 Malus × domestica apple cultivars and one accession belonging to a crab apple species (M. micromalus). A pipeline for SNP selection was devised that avoided the pitfalls associated with the inclusion of paralogous sequence variants, supported the construction of robust multi-allelic SNP haploblocks and selected up to 11 entries within narrow genomic regions of ±5 kb, termed focal points (FPs). Broad genome coverage was attained by placing FPs at 1 cM intervals on a consensus genetic map, complementing them with FPs to enrich the ends of each of the chromosomes, and by bridging physical intervals greater than 400 Kbps. The selection also included ∼3.7K validated SNPs from the IRSC 8K array. The array has already been used in other studies where ∼15.8K SNP markers were mapped with an average of ∼6.8K SNPs per full-sib family. The newly developed array with its high density of polymorphic validated SNPs is expected to be of great utility for Pedigree-Based Analysis and Genomic Selection. It will also be a valuable tool to help dissect the genetic mechanisms controlling important fruit quality traits, and to aid the identification of marker-trait associations suitable for the application of Marker Assisted Selection in apple breeding programs.

We sought to evaluate the association between constipation severity, productivity losses and healthcare utilization in a national sample of Italian patients with chronic non-organic constipation (CC). We enrolled 878 outpatients with CC. Clinical and demographic data were collected by physicians during clinical examinations. Patients completed a self-administered questionnaire (Patient Assessment of Constipation-Symptoms, PAC-SYM; Work Productivity and Activity Impairment; healthcare utilization, and Symptoms Checklist 90 Revised - Somatization Scale, SCL-90 R). Mean PAC-SYM score was 1.62 ± 0.69. Mean weekly sick time due to constipation was 2.7 ± 8.6 h and productivity losses due to presenteeism was 19.7% ± 22.3%. Adjusted productivity losses in patients with severe CC (PAC-SYM score 2.3-4.0) compared to patients with mild symptoms (PAC-SYM score 0.0-1.0) was Italian Purchase Power Parity US$ 6160. Constipation severity (PAC-SYM quintiles) was associated with higher healthcare utilization (RRPAC-SYM 4/01.84; p-value for linear trend <0.01). After adjustment for somatization scores, the association of constipation severity with productivity losses and healthcare utilization rates was attenuated yet statistically significant. We observed a graded increase in productivity losses and healthcare utilization with increasing constipation severity. Further studies should evaluate whether significant savings might be achieved with regimens aimed at reducing the constipation severity.