Several drug substances or excipients are hygroscopic. The uptake or loss of water of such substances is generally difficult
to control during processing or storage of drug products. DSC instruments with sub-ambient temperature equipment allow the
determination of the amount of freezable water by measuring the corresponding melting enthalpy.
The determination of freezable water adds valuable information complementary to TG analysis for understanding the processing
and storage of raw materials and drug products. Several substances were tested as is, without treatment, after storage at
92% r.h. and after equilibration with water. The results of these experiments showed that it was possible to demonstrate defined
hydrate formation, to determine the upper level of binding of water in amorphous substances and to confirm reversible hydrate
formations demonstrated by temperature resolved X-ray diffraction.
Authors:D. Giron, Ch. Goldbronn, M. Mutz, S. Pfeffer, Ph. Piechon, and Ph. Schwab
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.
Several hydrates and even polymorphic forms thereof can be encountered. Upon dehydration crystal hydrates may retain more
or less their original crystal structure, they can lose crystallinity and give anamorphous phase, they can transform to crystalline
less hydrated forms or to crystalline anhydrous forms.
The proper understanding of the complex polyphasic systemhydrates–polymorphs–amorphous state needs several analytical methods.
The use of techniques such as DSC-TG, TG-MS, sorption-desorption isotherms, sub-ambient experiments, X-ray diffraction combined
with temperature or moisture changes as well as crystal structure and crystal modelling in addition to solubilities and dissolution
experiments make interpretation and quantitation easier as demonstrated with some typical examples.
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.