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The study of the high-pressure behavior of molecular crystals helps find limits of their stability, as well as obtain previously unknown new phases. This may result in the creation of new materials and their forms for a variety of applications: pharmaceutics, optoelectronics, etc. Nevertheless, until recently, there was no practical unified scheme for high-pressure studies of organic molecules, paying close attention to various inter- and intramolecular interactions. In this work, we compare different computational methods for the high-pressure research of molecular crystals in terms of the energy of particular interactions. Tolazamide polymorphs are taken as a representative system. It is shown that not only "structure-forming" interactions, e.g. H-bonds and stacking interactions, but also multiple van der Waals interactions should be taken into account. Moreover, we compare two different concepts for studying particular H-bonds in terms of absolute and relative energies, showing their importance in understanding the high-pressure behavior of tolazamide polymorphs. Finally, several important details about the high-pressure research of organic crystals at a molecular level by computational methods are formulated. [ABSTRACT FROM AUTHOR]

Highlights • The binding of tolazamide with albumin was examined using affinity microcolumns. • Normal human serum albumin and glycated forms of this protein were considered. • Frontal analysis was used to examine the overall changes in binding with glycation. • Zonal elution was used to examine binding of this drug at Sudlow sites I and II. • The changes in binding were compared with those seen for other sulfonylurea drugs. Abstract Sulfonylurea drugs are antidiabetic drugs that are utilized in the treatment of type II diabetes and often have significant binding with human serum albumin (HSA). Immobilized samples of normal or glycated HSA in affinity microcolumns were used to investigate interactions of these proteins with the sulfonylurea drug tolazamide. HPLC and frontal analysis were used to first examine the overall binding of this drug with these samples of HSA. It was found that tolazamide had two general classes of binding sites (i.e., high and low affinity) for normal and glycated HSA. The higher affinity sites had binding constants of around 4.3–6.0 × 104 M−1 for these interactions at pH 7.4 and 37 °C, while the lower affinity sites had binding strengths of 4.9–9.1 × 103 M−1. Zonal competition studies between tolazamide and probes for Sudlow sites I and II on HSA were also performed and used to provide site-specific affinities for tolazamide at these sites. A decrease of 22% in affinity was observed for tolazamide at Sudlow site I and an increase up to 58% was seen at Sudlow site II when comparing glycated HSA with normal HSA. These observed changes were compared to those of other first-generation sulfonylurea drugs, providing information on how glycation can alter the total and local binding strength of tolazamide and related compounds with HSA under levels of glycation seen in patients with diabetes. [ABSTRACT FROM AUTHOR]

In this paper, vibrational spectra of tolazamide have been investigated by ab initio techniques in combination with experimental studies. Data on the FT-IR spectra (400–4000 cm −1 ) and Laser-Raman spectra (100–4000 cm −1 ) of tolazamide have been obtained in the solid phase. Assignments corresponding to the vibrational frequencies have been found and interpreted by the contribution of the potential energy distributions. The theoretical results are compared X-ray experimental data for this. Structural parameters such as bond lengths and angles, frequencies and intensities regarding Raman and IR spectra of the compound have been computed by density functional theory and Hartree–Fock methods with 6-311G++( d , p ) and 6-31G( d ) basis sets. They have been observed that the computed vibrational frequencies and optimized structural parameters are consistent with the corresponding experimental results. In addition, the images of frontier molecular orbitals (highest occupied and lowest unoccupied) have been presented and interpreted. [ABSTRACT FROM AUTHOR]

A diblock copolymer, poly(ethylene glycol)-block-poly(lactic acid) ( PEG- b- PLA), modulates the crystal growth of tolazamide ( TLZ), resulting in a crystal morphology change from needles to plates in aqueous media. To understand this crystal surface drug-polymer interaction, we conducted molecular dynamics simulations on crystal surfaces of TLZ in water containing PEG- b- PLA. A 130-ns simulation of the polymer in a large water box was run before initiating 50 ns simulations with each of the crystal surfaces. The simulations demonstrated differentiated drug-polymer interactions that are consistent with experimental studies. Interaction of PEG- b- PLA with the (001) face occurred more rapidly (≤10 ns) and strongly (total interaction energy of −121.1 kJ/mol/monomer) than that with the (010) face (∼35 ns, −85.4 kJ/mol/monomer). There was little interaction with the (100) face. Hydrophobic and van der Waals ( VDW) interactions were the dominant forces, accounting for more than 90% of total interaction energies. It suggests that polymers capable of forming strong hydrophobic and VDW interactions might be more effective in inhibiting crystallization of poorly water-soluble and hydrophobic drugs in aqueous media (such as gastrointestinal fluid) than those with hydrogen-bonding capacities. Such in-depth analysis and understanding facilitate the rational selection of polymers in designing supersaturation-based enabling formulations. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2132-2141, 2015 [ABSTRACT FROM AUTHOR]

Background: Sulfonylurea receptors are classified as either high-affinity type 1 (SUR1) or low-affinity type 2 receptors (SUR2), and the gene expression of SURs has recently been demonstrated in kidney. However, functional data regarding a renal SUR are lacking. We previously demonstrated that mesangial cell (MC) gene and protein expression of extracellular matrix components were up-regulated by the sulfonylurea, tolazamide. After noting this biological response, we next sought to investigate the presence of a sulfonylurea receptor in rat MCs.Methods: Equilibrium binding studies employing [3H]glibenclamide as a ligand were performed on crude MC membrane preparations. Gene expression for SUR was explored by Northern analysis of cultured MCs and whole kidney tissue. The effect of sulfonylurea on intracellular Ca2+ in MCs was assayed by spectrofluorometry, and glibenclamide-induced changes in the contractility of MCs were assessed.Results: MCs bound [3H]glibenclamide with a KD of 2.6 microM and a Bmax of 30.4 pmol/mg protein as determined by Scatchard analysis. Three SUR2 transcripts were detected in MCs. A major transcript was detected at 5.5 kb and minor transcripts at 7.5 and 8.6 kb. Following sulfonylurea treatment of MCs, real-time videomicroscopy revealed intense MC contraction, coinciding with oscillatory increments of intracellular Ca2+ concentration. Further evidence of sulfonylurea-induced MC contraction was demonstrated by glibenclamide-induced deformation of a silicone rubber substrate.Conclusions: These results demonstrate that SUR2 resides on MCs. Functional activation of this receptor by sulfonylurea induces Ca2+ transients that result in MC contraction. [ABSTRACT FROM AUTHOR]