Roxadustat (RXD) is an approved drug substances for the treatment of renal anemia. It has poor aqueous solubility and photochemical stability. This study employs a comprehensive approach to enhance the stability and physicochemical properties RXD through coformer selection and characterization. The investigation integrates delta pKa analysis, molecular complementary assessment, molecular electrostatic potential surface analysis, and machine learning techniques to predict potential co-crystal formation and binding interactions between drug molecules and coformers. The co-crystal screening which lead to in a novel RXD-nicotinamide co-crystal (RXD-NA). Experimental characterization underscores the physical and chemical stability of the co-crystals. To elucidate the supramolecular synthons and understand the intermolecular interactions in the RXD-NA co-crystal, Hirshfeld surfaces analysis, quantum theory of atoms in molecules (QTAIM) analysis and non-covalent interaction (NCI) analysis were performed. Computational analysis of photo-isomer formation aligns with experimental observations, further enhancing our understanding of RXD-coformer interactions. RXD-NA co-crystal was found photo-chemically stable as compared to free base API drug substance. This integrated methodology provides a systematic framework for informed co-crystal design, holding promise for optimizing RXD formulations based on molecular interactions and stability considerations. Consequently, this study contributes valuable insights to the field of rational drug design and formulation optimization.
- MeSH
- glycin * MeSH
- rozpustnost MeSH
- Publikační typ
- časopisecké články MeSH
Beauverolides (beauveriolides) are abundant, biologically active cyclodepsipeptides produced by many entomopathogenic fungi, including those that are used as biopesticides. Beauverolides act as cholesterol acyltransferase inhibitors in humans; thus, their mode of action has been the subject of pharmacological and clinical research. The cost-effective analytical methods are needed for fast, routine laboratory analysis of beauverolides. We isolated beauverolides from the fungal strain Isaria fumosorosea PFR 97-Apopka and opened the rings of the isolated beauverolides using a pyridine alkaline medium. We separated fractions of cyclic and linearized beauverolides by thin-layer chromatography, and found the chloroform-acetate (9:1, v/v) and chloroform-acetonitrile-acetate (8:1:1, v/v/v) mobile phases, respectively, to be the most efficient. We examined all the fractions by liquid chromatography-mass spectrometry using ion trap and Orbitrap high resolution mass spectrometry. For rapid screening of the contents of cyclic, and, particularly, linearized beauverolides, we developed a novel analytical method that consisted of using capillary electrophoresis coupled with contactless conductivity detection. Furthermore, we improved the separation of the peptides by applying capillary micellar electrokinetic chromatography with the N-cyclohexyl-2-aminoethanesulfonic acid:SDS:NaOH buffer, pH 9.8 as the background electrolyte. The described novel methods allow fast and cost-effective separation of chemically related groups of beauverolides.
Twenty juvenile individuals of brown bullhead (Ameiurus nebulosus), average weight 77 g, were fed by abiraterone acetate prodrug dissolved in olive oil via gastric probe. Dose applied was 3 mg/10 g fish weight. After feeding, they were let out into aquarium and kept there for 3 days. Aquarium water containing excreted metabolites was extracted, and sample was purified and finally analyzed by means of HPLC/MS. Expected both primary (products of hydroxylation) and secondary (products of glucuronidation and sulfatation) metabolites of abiraterone acetate were identified. The NMR measurement of one of the prevailing metabolites presumed to be one of possible hydroxy-abiraterones discovered that it is not hydroxy-abiraterone but abiraterone 16,17-epoxide. Closer analysis of MS2 and MS3 spectra revealed that one of presumed hydroxy-abiraterone acetates and also some secondary metabolites are probably 16,17-epoxides.
An aminoborane side product from the nicergoline manufacture process was identified by single-crystal X-ray diffraction. As boranes of pharmaceutical molecules are quite rare, the binding potential of the BH3 group was investigated and compared with similar compounds using Cambridge Structural Database (CSD). Surprisingly, the packing was stabilized by a dihydrogen bond, which triggered a false alert for too-short contact of hydrogen atoms in IUCR checkCIF. As the dihydrogen bond concept is not widely known, such an alert might mislead crystallographers to force -CH3 optimal geometry to -BH3 groups. The B-H distances equal to or less than 1.0 Å (17% of the CSD structures) are substantially biased when analyzing the structures of aminoborane complexes in CSD. To conduct proper searching, B-H bond length normalization should be applied in the CSD search.
Analysis of brown bullhead (Ameiurus nebulosus) bile by ultra performance liquid chromatography high-resolution mass spectrometry (UPLC/HRMS) revealed a series of bile acids similar to those found in humans. Accordingly, we chose this fish as a model organism to examine the metabolism of obeticholic acid, a bile acid used to treat a number of human liver diseases and the one that has the potential to occur as an environmental contaminant. The taurine and glycine conjugates of obeticholic acid and keto-obeticholic acid were identified, as well as the D-cysteinolic acid conjugate of obeticholic acid, likely a metabolite specific to fish. In addition, metabolites of obeticholic acid (sulphate and glucuronide) and several hydroxy-obeticholic acid derivatives were found, representing typical pathways of primary and secondary steroid metabolism. Brown bullhead exposed to obeticholic acid at a dose of 100 mg/kg gave no overt signs of distress or toxicity.
- MeSH
- chemické látky znečišťující vodu farmakokinetika toxicita MeSH
- ekotoxikologie metody MeSH
- glycin metabolismus MeSH
- hmotnostní spektrometrie MeSH
- Ictaluridae metabolismus MeSH
- kyselina chenodeoxycholová analogy a deriváty analýza farmakokinetika toxicita MeSH
- taurin metabolismus MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- žluč chemie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
X-ray structure analysis results have been widely used in the pharmaceutical research, development and control, especially for mapping polymorphism, to determine the chirality of active substances, in the pharmaceutical documentation and patent policy for many years. The greatest progress in X-ray diffraction techniques has been made in improving the quality of the poor material for successful data collection (magnetically oriented microcrystal arrays, serial snapshot crystallography). Prospects of the pharmaceutical application of X-ray crystallography lie in the acceleration of data collection, time-resolved structural studies obtained from the material of pharmaceutical batches without modification, and, in addition to that, in solving structures of semi-solid and amorphous phases and monitoring structural changes in drug formulations.
- MeSH
- difrakce rentgenového záření MeSH
- duševní vlastnictví MeSH
- farmaceutická technologie MeSH
- krystalografie rentgenová * metody přístrojové vybavení využití MeSH
- léčivé přípravky * analýza MeSH
- spektrální analýza metody přístrojové vybavení využití MeSH
- stereoizomerie MeSH
- Publikační typ
- práce podpořená grantem MeSH
Vyd. 1. 768 s. : il. ; 27 cm
- MeSH
- houby klasifikace MeSH
- komplementární terapie MeSH
- léčivé rostliny MeSH
- rostlinné extrakty farmakologie chemie MeSH
- Publikační typ
- encyklopedie MeSH
- Konspekt
- Botanika
- NLK Obory
- botanika
- alternativní lékařství
- chemie, klinická chemie
- Klíčová slova
- lékařský znak,
- MeSH
- dějiny lékařství MeSH
- lidé MeSH
- znaky a insignie * dějiny klasifikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- historické články MeSH
Powdery pharmaceuticals are prone to electrostatic charging due to collisions of particles and friction with device walls. The generated electrostatic charge is influenced by particle properties, processing and conditions. The charge of active particles and excipients is often inconvenient being able to cause problems in the production of solid dosage forms. The electrostatic charge of powdery particles affects properties of the materials and all procedures as the charge affects the behaviour and purity of the final dosage form. The problem of electrostatic charging of powders is more complicated when two or more compounds with different physical, chemical and dielectric properties are combined. To better understand the mechanism of electrostatic charging it is necessary to explain all the effects that contribute to charging solid active ingredients and excipients.
- MeSH
- farmaceutická technologie * MeSH
- lékové formy * MeSH
- lidé MeSH
- pevné částice * MeSH
- skladování léků MeSH
- stabilita léku MeSH
- statická elektřina MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Two procedures have been developed for the synthesis of sorafenib tosylate. The aim of the development was to minimize production of symmetric ureas in the course of synthesis, which create the major impurities of the preceeding processes and are difficult to remove. The major achievements were the purity of sorafenib thus obtained (> 99.8 %, HPLC) and possibility to scale up the syntheses.
