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.
Economics of General-Purpose Assembly Robots
Summary A study of the comparative economics of various automatic assembly systems using general-purpose assembly robots is described. In the study, use is made of a “typical” candidate assembly whose profile is obtained from statistical analysis of actual products submitted by interested companies. It is shown that the choice of assembly system and the various parts presentation methods depends on three main factors, namely: the annual production volume per shift, the number of parts in the product and the equipment payback period.