Most marketed pharmaceuticals consist of molecular crystals. The arrangement of the molecules in a crystal determines its physical properties and, in certain cases, its chemical properties, and so greatly influences the processing and formulation of solid pharmaceuticals, as well as key drug properties such as dissolution rate and stability. A thorough understanding of the relationships between physical structures and the properties of pharmaceutical solids is therefore important in selecting the most suitable form of an active pharmaceutical ingredient for development into a drug product. In this article, we review the different crystal forms of pharmaceuticals, the challenges that they present and recent advances in crystal structure determination. We then discuss computational approaches for predicting crystal properties. Finally, we review the analysis of crystal structures in furthering crystal engineering to design novel pharmaceutical compounds with desired physical and mechanical properties.

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Crystal structures of drugs: advances in determination, prediction and engineering

General principles of pharmaceutical solid polymorphism: a supramolecular perspective.

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

Modulators of atp-binding cassette transporters

Using Terahertz Pulsed Spectroscopy to Quantify Pharmaceutical Polymorphism and Crystallinity

Solid form screening--a review.

Thermal analysis methods are well-established techniques in research laboratories of pharmaceutical industry. The robustness and sensitivity of instrumentation, the introduction of automation and of reliable software according to the industrial needs widened considerably the areas of applications inthe last decade. Calibration of instruments and validation of results follow the state of the art of cGMP as for other analytical techniques. Thermal analysis techniques are especially useful for the study of the behavior of the poly-phasic systems drug substances and excipients and find a unique place for new delivery systems. Since change of temperature and moisture occur by processing and storage, changes of the solid state may have a considerable effect on activity, toxicity and stability of compounds. Current requirements of the International Conference of Harmonisation for the characterization and the quantitation of polymorphism in new entities re-enforce the position of thermal analysis techniques. This challenging task needs the use of complementary methods. Combined techniques and microcalorimetry demonstrate their advantages. This article reviews the current use of thermal analysis and combined techniques in research and development and in production. The advantage of commercially coupled techniques to thermogravimetry is emphasized with some examples.

Applications of thermal analysis and coupled techniques in pharmaceutical industry

This article summarizes the main features in the investigation of polymorphic behaviour of pharmaceuticals and emphasizes the role of combined thermoanalytical techniques for proper interpretation of complex problems. The examples illustrate the quality of information gained in relation to thermodynamic and kinetic factors.

Investigations of Polymorphism and Pseudo-polymorphism in Pharmaceuticals by Combined Thermoanalytical Techniques

Manufacturing processes may involve the presence of water in the crystallization of the drug substance or in manufacturing or in the composition of the drug product through excipients. Dehydration steps may occur in drying, milling, mixing and tabletting processes. Furthermore, drug substances and drug products are submitted to different temperatures and relative humidities, due to various climatic conditions giving rise to unexpected hydration or dehydration aging phenomena. Therefore the manufacture and the characterization of hydrates is part of the study of the physical properties of drug substances.

Solid State Characterizations of Pharmaceutical Hydrates

This article summarizes the different steps needed for a proper design and monitoring of the solid-state in pharmaceutical industry in order to fulfill the requirements of the guideline dealing with polymorphism of the International Conference of Harmonization.

Solid-state of pharmaceutical compounds

Modern thermal analysis, microcalorimetry and new emerging combined techniques which deliver calorimetric, microscopic and spectroscopic data offer a powerful analytical battery for the study of pharmaceuticals. These techniques are very useful in all steps of development of new drug products as well as methods for quality control in production. The characterization of raw materials enables to understand the relationships between polymorphs, solvates and hydrates and to choose the proper development of new drug products with very small amount of material in a very short time. Information on stability, purity is valuable for new entities as well as for marketed drug substances from different suppliers. Excipients which vary from single organic or inorganic entity to complexes matrixes or polymers need to be characterized and properly controlled. The thermodynamic phase-diagrams are the basis of the studies of drug-excipients interactions. They are very useful for the development of new delivery systems. A great number of new formulations need proper knowledge of the behaviour of the glass transition temperature of the components. Semi-liquid systems, interactions in aqueous media are also successfully studied by these techniques.

D. Giron

Papers

Applications of thermal analysis and coupled techniques in pharmaceutical industry

Investigations of Polymorphism and Pseudo-polymorphism in Pharmaceuticals by Combined Thermoanalytical Techniques

Solid State Characterizations of Pharmaceutical Hydrates

Solid-state of pharmaceutical compounds

Thermal Analysis, Microcalorimetry and Combined Techniques for the Study of Pharmaceuticals