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 …
Determination of sugar structures in solution from residual dipolar coupling constants: methodology and application to methyl beta-D-xylopyranoside.
We have developed methodology for the determination of solution structures of small molecules from residual dipolar coupling constants measured in dilute liquid crystals. The power of the new technique is demonstrated by the determination of the structure of methyl beta-d-xylopyranoside (I) in solution. An oriented sample of I was prepared using a mixture of C(12)E(5) and hexanol in D(2)O. Thirty residual dipolar coupling constants, ranging from -6.44 to 4.99 Hz, were measured using intensity-based J-modulated NMR techniques. These include 15 D(HH), 4 (1)D(CH), and 11 (n)D(CH) coupling constants. The accuracy of the dipolar coupling constants is estimated to be < +/- 0.02 Hz. New constant-time HMBC NMR experiments were developed for the measurement of (n)D(CH) coupling constants, the use of which was crucial for the successful structure determination of I, as they allowed us to increase the number of fitted parameters. The structure of I was refined using a model in which the directly bonded interatom distances were fixed at their ab initio values, while 16 geometrical and 5 order parameters were optimized. These included 2 CCC and 6 CCH angles, and 2 CCCC and 6 CCCH dihedral angles. Vibrationally averaged dipolar coupling constants were used during the refinement. The refined solution structure of I is very similar to that obtained by ab initio calculations, with 11 bond and dihedral angles differing by 0.8 degrees or less and the remaining 5 parameters differing by up to 3.3 degrees . Comparison with the neutron diffraction structure showed larger differences attributable to crystal packing effects. Reducing the degree of order by using dilute liquid crystalline media in combination with precise measurement of small residual dipolar coupling constants, as shown here, is a way of overcoming the limitation of strongly orienting liquid crystals associated with the complexity of (1)H NMR spectra for molecules with more than 12 protons.
Thermal incompatibility analysis of metal-ceramic systems based on flexural displacement data.
The feasibility of simple tests or analytical methods for prediction of residual stress states in metal-ceramic (MC) prostheses has not been demonstrated. Biomaterial metal-ceramic strips have been proposed to provide sensitive measures of transient and residual stress states through the measurement of midpoint deflection after cooling from the ceramic sintering temperature. The objective of this study was to apply the elastic-viscoelastic analogy to calculate transient and residual midpoint deflections in MC biomaterial strips and to compare these values with deflections measured with a beam-bending viscometer (BBV). Calculations and measurements were made for five MC systems that were found from a clinical study to be "thermally compatible" systems. Metal strips, 64 mm in length, 3 mm wide, and either 0.5 mm, 1.0 mm, or 2.0 mm in thickness, were veneered with four 0.25-mm thick layers of opaque porcelain. Midpoint deflection of the MC strips (ceramic oriented in the posterior position) was measured during cooling from an initial temperature of 700 degrees C. In general, the directions of the measured residual deflections did not agree with the "textbook" convention that negative deflections are associated with positive thermal contraction mismatch (alpha(M) - alpha(c) > 0) regardless of metal thickness. For a metal thickness of 0.5 mm, the residual midpoint deflection for all thermal contraction mismatch cases, except one, was positive (upward deflection) whereas the residual midpoint deflections were all negative when the metal thickness was increased to 1 or 2 mm, independent of the thermal contraction mismatch. The best agreement between calculated and measured values of residual midpoint deflection (+16 microns vs. +14 +/- 2.3 microns, respectively was obtained for MC biomaterial strips with a Ni-Cr alloy (0.5 mm thick) while the largest difference (+346 microns vs. +61 +/- 43.8 microns) was obtained for MC bimaterial strips with a Au-Pd allow (0.5 mm thick). In all but one case, changes in deflection direction as a function of metal thickness were correctly predicted by the viscoelastic analysis. The results of this study indicate that a viscoelastic model is useful for estimating thermal compatibility conditions of MC systems.