New form discovery for the analgesics flurbiprofen and sulindac facilitated by polymer-induced heteronucleation

The selection and discovery of new crystalline forms is a longstanding issue in solid-state chemistry of critical importance because of the effect molecular packing arrangement exerts on materials properties. Polymer-induced heteronucleation has recently been developed as a powerful approach to discover and control the production of crystal modifications based on the insoluble polymer heteronucleant added to the crystallization solution. The selective nucleation and discovery of new crystal forms of the well-studied pharmaceuticals flurbiprofen (FBP) and sulindac (SUL) has been achieved utilizing this approach. For the first time, FBP form III was produced in bulk quantities and its crystal structure was also determined. Furthermore, a novel 3:2 FBP:H 2 O phase was discovered that nucleates selectively from only a few polymers. Crystallization of SUL in the presence of insoluble polymers facilitated the growth of form I single crystals suitable for structure determination. Additionally, a new SUL polymorph (form IV) was discovered by this method. The crystal forms of FBP and SUL are characterized by Raman and FTIR spectroscopies, X-ray diffraction, and differential scanning calorimetry. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2978–2986, 2007Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57336/1/20954_ftp.pd

Discovery and selection of crystal forms facilitated by polymer -induced heteronucleation.

Polymorphism, the existence of a substance as two or more crystalline phases that differ solely in arrangements and/or conformations of the molecules in the crystal lattice, exerts a profound effect on the properties of materials. Despite the importance of controlling the crystalline form of compounds, no general method exists for producing all of the energetically reasonable polymorphs of a given compound. With the aim of controlling form production by heterogeneous nucleation, chemically diverse surfaces composed of polymers, either commercially available or synthesized utilizing combinatorial methods, were employed as heteronuclei during crystallization. The polymer-induced heteronucleation approach facilitated the discovery of new crystal forms of the pharmaceuticals sulindac and flurbiprofen and the platinum complex Pt(phen)Cl2, all of which were inaccessible by other techniques. Moreover, selective production of known forms was also achieved and this facilitated determination of the thermodynamic relationship among polymorphs in each system. This approach resulted in the discovery of novel extended networks, each derived from a different linking unit, utilizing conditions optimized for the production of a different and previously reported network. This approach was also successful at the selective nucleation of multiple crystal forms of the protein hen egg white lysozyme from a single condition by changing the polymer heteronucleus, which was only previously achieved by changing the concentration, buffer, precipitant, pH, and/or temperature. Therefore, this method could be employed to grow single crystals of multiple forms of macromolecules to better explore the effect packing has on observed protein structure. In all cases, selectivity for a given crystal form could be achieved by optimizing conditions identified during screening experiments, which were generally highly dependent on the chemistry of the polymer heteronucleus. An additional feature of this approach was the production of single crystals suitable for structure determination of both known and previously unknown crystal forms, which enabled accurate phase identification and also offered a glimpse into the relationship between solid-state structure and stability. Thus, the polymer-induced heteronucleation approach represents an additional diversity element during crystallization with the ability to screen by standard high throughput techniques.Ph.D.Pharmacy sciencesPolymer chemistryPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/126701/2/3276169.pd

Comparison of the four anhydrous polymorphs of carbamazepine and the crystal structure of form I Supplementary material: X-ray crystallographic information file (CIF) of triclinic CBZ (form I) is available.

For decades, carbamazepine (CBZ) has served as a model compound for groups engaged in the study of crystal polymorphism. Despite considerable effort, crystal structures for only three of its four anhydrous forms have previously been determined. Herein, we report the first single crystal X-ray structure of the high temperature modification of CBZ (form I). Form I crystallizes in a triclinic cell ( P -1) having four inequivalent molecules with the following lattice parameters: a  = 5.1705(6), b  = 20.574(2), c  = 22.245(2) Å, Α  = 84.12(4), Β  = 88.01(4), and Γ  = 85.19(4)°. Furthermore, we compare the physical properties of the four anhydrous polymorphs of CBZ, including the first comprehensive characterization of form IV. Substantial differences are seen among these forms by powder X-ray diffraction, infrared spectroscopy, thermomicroscopy, and differential scanning calorimetry. These data are correlated to their respective crystal structures for the first time. We have found that all polymorphs possess identical strong hydrogen bonding patterns, similar molecular conformations, and stabilities that are within 0.7 kcal/mol of each other. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2260–2271, 2003Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34508/1/10455_ftp.pd

Controlled Release of Antimicrobial ClO₂ Gas from a Two-Layer Polymeric Film System

We report a two-component label system comprising a chlorite-containing polymer film and an acid-containing polymer film that can release antimicrobial ClO₂ gas upon adhering the two films together to enable a reaction of the chlorite and acid under moisture exposure. The chlorite-containing film comprises a commercial acrylate-based pressure-sensitive adhesive polymer impregnated with sodium chlorite. The acid-containing film comprises a commercial poly­(vinyl alcohol) polymer loaded with tartaric acid. Both of the films were prepared on low ClO₂-absorbing substrate films from stable aqueous systems of the polymers with high reagent loading. Rapid and sustained releases of significant amounts of ClO₂ gas from the label system were observed in an in situ quantification system using UV–vis spectroscopy. It was found that the ClO₂ release is slower at a lower temperature and can be accelerated by moisture in the atmosphere and the films. Controlled release of ClO₂ gas from the label system was demonstrated by tailoring film composition and thickness. A model was developed to extract release kinetics and revealed good conversions of the label system. This two-component system can potentially be applied as a two-part label without premature release for applications in food packaging

Relationship Between Anti-DFS70 Autoantibodies and Oxidative Stress

Background: The anti-DFS70 autoantibodies are one of the most commonly and widely described agent of unknown clinical significance, frequently detected in healthy individuals. It is not known whether the DFS70 autoantibodies are protective or pathogenic. One of the factors suspected of inducing the formation of anti-DFS70 antibodies is increased oxidative stress. We evaluated the coexistence of anti-DFS70 antibodies with selected markers of oxidative stress and investigated whether these antibodies could be considered as indirect markers of oxidative stress. Methods: The intensity of oxidative stress was measured in all samples via indices of free-radical damage to lipids and proteins such as total oxidant status (TOS), concentrations of lipid hydroperoxides (LPH), lipofuscin (LPS), and malondialdehyde (MDA). The parameters of the non-enzymatic antioxidant system, such as total antioxidant status (TAS) and uric acid concentration (UA), were also measured, as well as the activity of superoxide dismutase (SOD). Based on TOS and TAS values, the oxidative stress index (OSI) was calculated. All samples were also tested with indirect immunofluorescence assay (IFA) and 357 samples were selected for direct monospecific anti DFS70 enzyme-linked immunosorbent assay (ELISA) testing. Results:: The anti-DFS70 antibodies were confirmed by ELISA test in 21.29% of samples. Compared with anti-DFS70 negative samples we observed 23% lower concentration of LPH (P = .038) and 11% lower concentration of UA (P = .005). TOS was 20% lower (P = .014). The activity of SOD was up to 5% higher (P = .037). The Pearson correlation showed weak negative correlation for LPH, UA, and TOS and a weak positive correlation for SOD activity. Conclusion: In samples positive for the anti-DFS70 antibody a decreased level of oxidative stress was observed, especially in the case of samples with a high antibody titer. Anti-DFS70 antibodies can be considered as an indirect marker of reduced oxidative stress or a marker indicating the recent intensification of antioxidant processes

Metabolic syndrome is associated with similar long-term prognosis in non-obese and obese patients. An analysis of 45 615 patients from the nationwide LIPIDOGRAM 2004-2015 cohort studies

Aims We aimed to evaluate the association between metabolic syndrome (MetS) and long-term all-cause mortality. Methods The LIPIDOGRAM studies were carried out in the primary care in Poland in 2004, 2006 and 2015. MetS was diagnosed based on the National Cholesterol Education Program, Adult Treatment Panel III (NCEP/ATP III) and Joint Interim Statement (JIS) criteria. The cohort was divided into four groups: non-obese patients without MetS, obese patients without MetS, non-obese patients with MetS and obese patients with MetS. Differences in all-cause mortality was analyzed using Kaplan-Meier and Cox regression analyses. Results 45,615 participants were enrolled (mean age 56.3, standard deviation: 11.8 years; 61.7% female). MetS was diagnosed in 14,202 (31%) by NCEP/ATP III criteria, and 17,216 (37.7%) by JIS criteria. Follow-up was available for 44,620 (97.8%, median duration 15.3 years) patients. MetS was associated with increased mortality risk among the obese (hazard ratio, HR: 1.88 [95% CI, 1.79-1.99] and HR: 1.93 [95% CI 1.82-2.04], according to NCEP/ATP III and JIS criteria, respectively) and non-obese individuals (HR: 2.11 [95% CI 1.85-2.40] and 1.7 [95% CI, 1.56-1.85] according to NCEP/ATP III and JIS criteria respectively). Obese patients without MetS had a higher mortality risk than non-obese patients without MetS (HR: 1.16 [95% CI 1.10-1.23] and HR: 1.22 [95%CI 1.15-1.30], respectively in subgroups with NCEP/ATP III and JIS criteria applied). Conclusions MetS is associated with increased all-cause mortality risk in non-obese and obese patients. In patients without MetS obesity remains significantly associated with mortality. The concept of metabolically healthy obesity should be revised