Electron diffraction and imaging of uncompressed monolayers of amphiphilic molecules on vitreous and hexagonal ice.

A new approach is described for probing domains of ordered self-assemblies of amphiphilic monolayers at the aqueous solution interface. The method has potential importance for the study of membrane structure, Langmuir-Blodgett films, and nucleation processes of two-and three-dimensional crystals. Electron diffraction (ED) patterns indicative of two-dimensional crystalline self-assembly were obtained from samples, which were examined by cryo-electron microscopy, of monolayers of water-insoluble amphiphiles on vitrified aqueour substrates. The apparent hexagonal symmetry of an ED pattern from a C(16)H(33)OH monolayer was interpreted in terms of multiple twinning. Monolayers of the CL(31)H(63)OH and cadmium salt of C(19)H(39)CO(2)H that were studied by dark-field techniques displayed faceted two-dimensional crystallites with a maximal size of 1 to 2 micrometers. Epitaxial nucleation of hexagonal ice by the C(31)H(63)OH monolayer has also been demonstrated by ED.

Crystallinity of the double layer of cadmium arachidate films at the water surface.

A crystalline counterionic layer at the interface between an electrolyte solution and a charged layer of insoluble amphiphilic molecules was observed with grazing incidence synchrotron x-ray diffraction. Uncompressed arachidic films spread over 10(-3) molar cadmium chloride solution (pH 8.8) spontaneously form crystalline clusters with coherence lengths of approximately 1000 angstroms at 9 degrees C. Ten distinct diffraction peaks were observed, seven of which were attributed to scattering only from a crystalline Cd(2+) layer and the other three to scattering primarily from the arachidate layer. The reflections from the Cd(2+) layer were indexed according to a 2 x 3 supercell of the arachidate lattice with three Cd(2+) ions per cadmium unit cell.

When poor solubility becomes an issue: from early stage to proof of concept.

Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. The issue arose especially when drug discovery and medicinal chemistry moved from wet chemistry to combinatorial chemistry and high throughput screening in the mid-1990s. Taking into account the drug product development times of 8-12 years, the apparent R&D productivity gap as determined by the number of products in late stage clinical development today, is the result of the drug discovery and formulation development in the late 1990s, which were the early and enthusiastic times of the combinatorial chemistry and high throughput screening. In parallel to implementation of these new technologies, tremendous knowledge has been accumulated on biological factors like transporters, metabolizing enzymes and efflux systems as well as on the physicochemical characteristics of the drug substances like crystal structures and salt formation impacting oral bioavailability. Research tools and technologies have been, are and will be developed to assess the impact of these factors on drug absorption for the new chemical entities. The conference focused specifically on the impact of compounds with poor solubility on analytical evaluation, prediction of oral absorption, substance selection, material and formulation strategies and development. The existing tools and technologies, their potential utilization throughout the drug development process and the directions for further research to overcome existing gaps and influence these drug characteristics were discussed in detail.

The use of MTDSC to assess the amorphous phase content of a micronized drug substance.

Mechanical treatments such as grinding, milling or micronization applied to crystalline drug substances may induce changes such as the occurrence of crystal defects and/or amorphous regions. These changes are likely to affect the chemical and physical properties of the material as well as the corresponding drug product performances. Various analytical techniques such as standard differential scanning calorimetry, isothermal and solution microcalorimetry as well as dynamic vapour sorption can be used to characterise and possibly quantify the amorphous phase content of these materials. These techniques have been applied for the development of analytical methods based on temperature- or solvent-induced (including water) recrystallization of the amorphous phase in semi-crystalline drug substances and excipients and have sometimes allowed for detecting low amounts of amorphous phase. We have developed an alternative MTDSC method for the quantitation of the amorphous content in samples of a micronized drug substance co-crystal (form A), an antibiotic drug substance which does not recrystallize even when exposed to temperature or solvent vapours. This is performed through measurement of the heat capacity jump associated with the amorphous phase glass transition. The MTDSC parameters and experimental conditions were optimised for this system. The amorphous content calibration curve was established using pure crystalline and amorphous drug substance samples and their known mixtures. Limits of detection and quantification of 0.9 and 3.0% (w/w) respectively were obtained for specimen mass less than 5 mg.