DR C R PULHAM
The phenomenon of polymorphism in the crystallisation of compounds is not only of fundamental interest to experimental and theoretical structural chemists, but is also of crucial importance to the pharmaceutical industry. Two polymorphs of the same drug molecule may have different physical properties, e.g. solubilities, melting points, colour, and may have dramatically different properties that affect processibility. The conditions under which polymorphs interconvert is also of crucial importance, particularly when drugs may be distributed throughout many countries of the world where environmental conditions such as temperature and humidity may vary substantially. The drug regulatory authorities are increasingly demanding more and more information about drug products before granting licenses for distribution. Intellectual property can also become an issue for the pharmaceutical companies who develop and market new drug products, where challenges to patents have been made on the basis of the discovery of a new polymorph. Similar remarks apply to solvates of drug molecules. Pharmaceutical companies therefore deploy substantial effort and resource for the identification and characterisation of drug polymorphs and solvates. These techniques are often laborious and involve recrystallisations from a wide range of solvents under a variety of conditions, e.g. temperature, humidity, ionic strength, etc. Even after these exhaustive tests, a new polymorph may remain undetected for many years or a sample of a new polymorph may be obtained once but never again – the phenomenon of so-called " disappearing polymorphs ". The development of a more systematic method that would allow for more rapid identification and characterisation of polymorphs and solvates would be of great benefit to the pharmaceutical industry and would enhance our understanding of the factors that are responsible for the packing arrangements of drug molecules in the solid state. This is the aim of our research programme. A very powerful method of tuning the intermolecular interactions responsible for the packing arrangements of molecules in the solid state is the application of pressures in the range 1000-150,000 atmospheres. These pressures are attained very easily by squeezing compounds between two small diamond anvils. The compressed sample is then studied by Raman and infrared spectroscopy, X-ray and neutron powder diffraction, single crystal X-ray diffraction, and computational methods. The effect of pressure can be very striking, resulting in the production of new phases in which not only the packing of the molecules change, but sometimes the coordination number, e.g. PbCl 4 changes from discrete tetrahedral molecules to a structure …
1H-detected double-J-modulated INEPT-INADEQUATE for simultaneous determination of one-bond and long-range carbon-carbon connectivities and the measurement of all carbon-carbon coupling constants.
We describe a new NMR experiment, (1)H-detected double-J-modulated (DJM)-INEPT-INADEQUATE, for tracing out the carbon skeleton of molecules. This experiment allows simultaneous correlation of directly bonded carbon atoms and those separated by multiple bonds, while at the same time also providing the values of all J(CC) coupling constants. This is achieved by replacing both fixed carbon-carbon coupling evolution intervals of the INEPT-INADEQUATE experiment by variable time intervals, which are incremented in concert with the DQ evolution period (t(1)). We show that the analysis of the fine structure of cross-peaks in DJM-INEPT-INADEQUATE spectra leads to accurate values of coupling constants and give guidelines for the proper usage of the method. The proposed experiment is two times less sensitive that the original INEPT-INADEQUATE experiment. We show that, using a 600-MHz cryoprobe and 20 mg of a monosaccharide, spectra that are suitable for the analysis of coupling constants as small as 2 Hz can be obtained within 24 h. Instead of performing multiple experiments, a single DJM-INEPT-INADEQUATE experiment can thus provide a wealth of information for the structural analysis of small molecules.
Three-Bond C−O−C−C Spin-Coupling Constants in Carbohydrates: Development of a Karplus Relationship
A range of 13C-labeled carbohydrates containing C−O−C−C coupling pathways having different structures and dihedral angles has been prepared and used to identify structural factors affecting 3JCOCC,...