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In principle, IR spectroscopy can be used to measure the populations of diastereomeric conformers that are in rapid equilibrium. However, the use of IR spectroscopy suffers from the necessity to obtain independent measures of the extinction coefficients for pertinent bands in a given conformer. Common assumptions are that extinction coefficients are equal for different conformers and independent of temperature. We have examined the NMR spectra of four halocyclohexanes over a temperature range where the axial-to-equatorial equilibration is slow on the NMR chemical exchange time scale. Using complete line-shape analysis, we carefully determined the variation of the equilibrium constant with temperature (allowing calculation of thermodynamic parameters). Measurements of the IR spectra over the same temperature range enabled the calculation of the relative IR extinction coefficients for the C-X bond stretch in the axial and equatorial conformers. The vibrational extinction coefficients ratios are indeed not unity and exhibit a slight temperature dependence. Based on the IR data and on our measurements of the one-bond scalar coupling of the methine carbon to the proton, there are indications that axial carbon-halogen and carbon-hydrogen bonds are weaker than the equatorial counterparts.

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The theory of solid-state nuclear magnetic resonance (NMR) spectroscopy is reviewed, with specific discussions of magnetic interactions in the solid state. Each magnetic interaction (Zeeman, dipole-dipole, chemical-shift, spin-spin, and quadrupolar) is addressed and manifestations of these interactions in the solid state NMR spectrum are explained. The techniques of high-power decoupling, magic-angle spinning, and cross-polarization, used to acquire highly resolved solid-state NMR spectra, are also illustrated. Application of solid-state NMR to pharmaceutical problem solving and methods development is then briefly reviewed.

A general review of the methods available for the physical characterization of pharmaceutical solids is presented. The techniques are classified as being on the molecular level (properties capable of being detected in an ensemble of individual molecules), the particulate level (properties which can be detected through the analysis of an ensemble of particles), and the bulk level (properties which can be measured only using a relatively large amount of material). The molecular-level properties discussed are infrared spectroscopy and nuclear magnetic resonance spectrometry, the particulate-level properties discussed are particle morphology, particle size distribution, powder X-ray diffraction, and thermal methods of analysis, and the bulk-level properties discussed are surface area, porosity and pore size distribution, and powder flow characteristics. Full physical characterization of three modifications of lactose (hydrous, anhydrous, and Fast-Flo) is presented to illustrate the type of information which can be obtained using each of the techniques discussed.