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.
The properties of the solid-state of drug substances are critical factors that determine the choice of an appropriate salt
form for the development of the pharmaceutical formulation. The most relevant properties may affect the therapeutic efficacy,
toxicity, bioavailability, pharmaceutical processing and stability. The salt form must fulfil the needs of the targeted formulation,
be suitable for full-scale production and its solid-state properties maintained batchwise as well as over time. Comparison
of the solid-state properties of different salt candidates may be quite complicated if each salt candidate exist as different
solid phases: polymorphs, solvates or amorphous forms. Thermal analysis, microcalorimetry and combined techniques, X-ray diffraction,
solubility, intrinsic dissolution, sorption-desorption and stability studies are basic techniques for the characterisation
of the salt candidates. Some examples show the role of the salt form as well as the polymorphic form in the characteristics
of the solid-state. Thermal analysis and combined techniques are efficient for the detection of unexpected phase transitions
and for the comparison of the suitability of the salt candidates prepared for salt selection.
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 in the 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.
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.
DSC purity analysis is based on thermodynamic phase diagrams for substances (purity ≥98%) which undergo a melting point. Impurities
which have eutectic behaviour with the analyte are determined together.
DSC purity analysis obtained from a single melting event of a 1–2 mg sample is, therefore, extremely attractive for the global
assessment of eutectic impurities. The main advantages in early development lie in the very small amount of material necessary
and the very fast analysis time.
However, the DSC purity analysis cannot replace chromatographic methods which deliver specific individual levels of impurities.
Furthermore, a complete validation of a DSC purity method is difficult and time consuming. Despite these limitations, DSC
is the best support for the development of chromatographic methods, for purity profile and stability assessment during pharmaceutical
Parameters of purity determination and validation aspects are discussed. Examples of use in pharmaceutical development are
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
Authors:D. Giron, P. Piechon, C. Goldbronn, and S. Pfeffer
The polymorphic behaviour of the purine derivative MKS 492 was studied with investigations of suspensions of selected samples in different solvents and of samples obtained by crystallizations. The samples were analyzed by DSC, TG and X-ray diffraction. Six different crystalline modifications called A, B, B, C, D and E and an amorphous form were identified. Four pure crystalline modifications, A, B, C and D have been manufactured and characterized by DSC, X-ray, IR, solubilities, densities, hygroscopicity and dissolution measurements. The four forms A, C, D and E are monotrop to the form B. The form B is enantiotrop to the form B, which revealed the highest melting point of all known polymorphs. This form B is only stable at high temperature. Temperature resolved X-ray diffraction was very helpful for proper interpretation of the thermal events. The melting peaks of the forms A and C and the endothermic peak corresponding to the enantiotropic transition B into B occur in a narrow range of temperature. The form B which is the most stable one at room temperature has been chosen for further development. Quantitative methods to determine the content of the forms A, C and D in samples of form B or to determine the content of form A, B and D in form C have been developed by using X-ray diffraction. Limits of detection are 1 or 2%. For the quantitative determination of the amorphous fraction, X-ray diffraction and microcalorimetry are compared. For high amounts of the amorphous fraction, the X-ray diffraction method is preferred because it is faster. Microcalorimetry is very attractive for levels below 10% amorphous content. The lowest limit of detection is obtained by microcalorimetry, about 1%.