Packing Interactions in Hydrated and Anhydrous Forms of the Antibiotic Ciprofloxacin: a Solid-State NMR, X-ray Diffraction, and Computer Simulation Study (original) (raw)
Related papers
Crystal Structures of Norfloxacin Hydrates
Crystal Growth & Design, 2008
Two novel hydrate forms of norfloxacin (NF) were serendipitously obtained during cocrystallization with eugenol. NF 1.25 hydrate and 1.125 hydrate are isomorphous crystal structures in the P2 1 /c space group, each with two symmetry-independent drug molecules, two full water molecules, and a third water of 0.5 and 0.25 partial occupancy, respectively. Water promoted proton transfer results in a shift from neutral to ionic hydrogen bonding between norfloxacin molecules in hydrate structures. The presence of eugenol additive gave novel NF hydrates of lower water stoichiometry, whereas crystallization in its absence gave the known NF dihydrate.
Physical Chemistry Chemical Physics, 2005
The 1H, 13C and 19F magic-angle spinning NMR spectra have been recorded for Form 1 of flurbiprofen. In the case of 19F, spinning sideband analysis has produced data for the components of the shielding tensor. The chemical shift of the hydrogen-bonded proton was found to be 14.0 ppm. Shielding parameters for all three nuclei have been calculated using Density Functional Theory (DFT) together with the Gauge Including Projector Augmented Wave (GIPAW) method which takes full allowance for the repetition inherent in crystalline structures. Such computations were made for the reported geometry, for a structure with all the atomic positions relaxed using DFT, and with only the hydrogen positions relaxed. The relationships of the computed shifts to those observed are discussed. In general, the correlations are good.
2017_Intech_FTIR for hydrated macromolecules.pdf
The interaction between biological macromolecules (proteins, nucleic acids, lipids and other biomolecules in the cell) and environmental water is an important determining factor in their conformational properties, stability and function. The hydration processes of biopolymers have been extensively studied in the past 20 years with reference to a considerable variety of models and concepts. In all recent works, a distinction is made between intracellular water that maintains the ordinary liquid state (bulk water) and water ordered in extended hydrogen‐bonded lattices at the surface and structured in the internal grooves of macromolecules (hydration water) in dependence on the chemical properties of the macromolecule surface. FTIR spectroscopy has been implemented in this field both for the sensitivity in the conformational analysis of biological macromol‐ ecules and the reliability in the investigation of the water network. A perturbation tech‐ nique such as dehydration‐rehydration treatment modifies the macromolecule structure and water distribution. It was applied to two structurally different proteins: lysozyme, a globular (α + β) protein and collagen, a fibrous protein characterized by the triple helix structure. Submitted to the treatment both of them display irreversible conformational changes.
Hydration study of homopolypeptides by2H NMR
Biopolymers, 2007
Deuteron T 1 and T 2 was studied as a function of hydration in homopolyglycine (PG) and homopolyproline (PP). Water deuteron relaxation rates in PG conform to a hydration model involving two types of primary hydration sites where water is directly bonded to the polymer. Once these sites are filled, additional water only bonds to water molecules at the primary sites and in so doing affect their dynamics. PP exhibits an anomalous T 1 and T 2 hydration dependence which has been interpreted in terms of a cooperative water molecule-PP molecule helical conformational rearrangement which occurs once a certain hydration level is reached. The proposal of a water-PP structure is tested using molecular dynamics simulations. #
Journal of Chemical Information and Modeling, 1989
In an earlier article' the need was demonstrated for atomic physicochemical properties for three dimensional structure directed quantitative structure-activity relationships, and it was shown how atomic parameters can be developed for successfully evaluating the molecular octanol-water partition coefficient, which is a measure of hydrophobicity. In this work we report more refined atomic values of octanol-water partition coefficients derived from nearly twice the number of compounds. Carbon, hydrogen, oxygen, nitrogen, sulfur and halogens are divided into 110 atom types of which 94 atomic values are evaluated from 830 molecules by least squares. These values gave a standard deviation of 0.470 and a correlation coefficient of 0.931. These parameters predicted the octanol-water partition coefficient of 125 compounds with a standard deviation of 0.520 and a correlation coefficient of 0.870. There is only a correlation coefficient of 0.432 between the atomic octanol-water partition coefficients and the atomic contributions to molar refractivity over the 93 atom types used for both the properties. This suggests that both parameters can be used simultaneously to model intermolecular interactions. We evaluated the CND0/2 gross atomic charge distribution over several molecules to check the validity of our classification. We found that the charge density on the heteroatoms in conjugated systems is strongly affected by the presence of similar atoms in the conjugation which suggests it should be incorporated as a separate parameter in evaluating the partition coefficient.
International Journal of Pharmacy and Pharmaceutical Sciences, 2017
Molecular simulation is increasingly used by medicinal chemists in the process and product development. Reliable computational predictions are of great value not only for the design of an active pharmaceutical ingredient with novel properties but also for the avoidance of an undesirable change of form in the late stages of development of an industrially important molecule. In the pharmaceutical industry, drug polymorphism can be a critical problem and is the subject of various regulatory considerations. This contribution tried to review the fuzzy frontiers between the chemical structure of the molecule and its crystal energy landscape with a particular focus on the crystal structure prediction (CSP) methodology to complement polymorph screening. A detailed application of CSP in the pharmaceutical industry is illustrated on ciprofloxacin; describing its putative polymorphs. This approach successfully identifies the known crystal form within this class, as well as a large number of other low-energy structures. The performance of the approach is discussed in terms of both the quality of the results and computational aspects. CSP methods are now being used as part of the interdisciplinary range of studies to establish the range of solid forms of a molecule. Moreover, further methodological improvements aimed at increasing the accuracy of the predictions and at broadening the range of molecules i.e. co-crystals, salts and solvates.
Biochemistry, 1988
The solution conformation of the antibacterial polypeptide cecropin A from the Cecropia moth is investigated by nuclear magnetic resonance (NMR) spectroscopy under conditions where it adopts a fully ordered structure, as judged by previous circular dichroism studies [Steiner, H. (1 982) FEBS Lett. 137, 283-2871, namely, 15% (v/v) hexafluoroisopropyl alcohol. By use of a combination of two-dimensional N M R techniques the 'H N M R spectrum of cecropin A is completely assigned. A set of 243 approximate interproton distance restraints is derived from nuclear Overhauser enhancement (NOE) measurements. These, together with 32 distance restraints for the 16 intrahelical hydrogen bonds identified on the basis of the pattern of short-range NOEs, form the basis of a three-dimensional structure determination by dynamical simulated annealing [Nilges, M., Clore, G. M., & Gronenborn, A. M. (1988) FEBS Lett. 229, 3 17-3241.
Crystals
One problem that often arises during the formulation of a dosage form is the solubility and dissolution of the active ingredients. This problem arises in ciprofloxacin, which is a BCS class IV fluoroquinolone antibiotic. A pseudopolymorph is a kind of polymorph in which the number of hydrates is different. In this study, a new pseudopolymorph comprised of ciprofloxacin and salicylic acid was found, namely the salt ciprofloxacin salicylate 1.75 hydrate form. This new solid phase was analyzed by Fourier-transform infrared spectroscope (FTIR), Raman spectroscopy, and thermal analysis and proven by Powder X-ray Diffractometry (PXRD) analysis. The crystal structure was successfully determined by Single Crystal X-ray Diffractometry (SCXRD) analysis. It was found that the piperazinyl group of ciprofloxacin is protonated by H+ from the carboxylic group of salicylic acid. In the unit cell, two ciprofloxacin and two salicylic acid molecules were independent with four water molecules, in which...
Journal of Pharmaceutical Sciences, 2012
The dehydration/desolvation of two hydrate solvates of the pharmaceutically important compound finasteride (namely, bisfinasteride monohydrate monotetrahydrofuran and bisfinasteride monohydrate mono-1,4-dioxane) has been studied by solid-state nuclear magnetic resonance, powder X-ray diffraction, thermogravimetric analysis (including coupling with mass spectrometry) and dynamic vapour sorption. The structure is unusual in that water holds the host finasteride molecules together by hydrogen bonding to form channels in which the solvent is sited. Whilst the solvent guest molecules are not strongly bound to the host, their presence is essential for structural stability. Desolvation is not found to occur at a well-defined temperature or even to consistently produce the same anhydrous form (form I vs. form II), but is instead highly dependent on the physical environment and, therefore, on the technique used. This behaviour complicates investigations, but the combination of complementary methods does allow the desolvation to be understood. Water and solvent are shown to be lost simultaneously, with no evidence of an intermediate form or increased mobility of the hydrogen-bonded water molecules. The results are consistent with a model in which structural collapse and rearrangement follows the loss of a small fraction of the solvent molecules from the channel structure, with the final form produced being very sensitive to the presence of water vapour during desolvation.