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Thermal Analysis - Articles and news items
Thermally Stimulated Current Spectroscopy (TSC) is a new tool that can be used to analyse pharmaceutically important molecules. TSC studies are usually conducted to provide additional information about molecular mobility in the solid state, and as a result characterise phase transitions that are related to thermal transitions in the crystalline (polymorphic) and amorphous phases. The ability of TSC to probe molecular mobilities, previously undetected in materials, and link them to the stability of different phases has sparked immense scientific interest in this technique.
In the last 10 years, the pharmaceutical market has seen a significant decrease in approved new drug entities. Although many factors may be responsible for this trend, one of them is insufficient information / characterisation of a lead molecule. Consequently, new techniques are often applied in the pharmaceutical field with the simple goal to aid better selection of the drug candidate and dosage form.
Improving the performance of existing drug products is another goal that often requires comprehensive information about the properties of the drug molecules. In recent years, the physical sciences have made great progress towards understanding the properties of pharmaceutically important amorphous and polymorphic materials. The major focus of this work is to utilise the advantages that they may bring to formulated products (e.g. faster solubility of amorphous drugs compared to crystalline counterparts) and at the same time to overcome stability problems (e.g. tendency to recrystallise on storage) that they may demonstrate.
Recently, there has been renewed interest in using thermodynamic and kinetic data, alongside empirical rules (particularly focused upon cLogP and molecular weight) and guiding metrics such as ligand efficiency and lipophilic ligand efficiency developed for fragments, leads and drugs in order to facilitate the design of compounds with a greater chance of producing successful drugs1. This interest has been assisted both by improvements in instrumentation as well as evidence that thermodynamically and kinetically optimised compounds fare better in the clinic2.
Optimisation of the binding affinity, which may have to be improved by several orders of magnitude from initial hit to drug molecule, can be achieved by modifying the individual thermodynamic and kinetic contributions. However, medicinal chemists have, up to now, been reluctant to consider these measurements during hit selection and lead optimisation, because it has been difficult to understand how the different design strategies affect the individual forces resulting in different thermodynamic and kinetic profiles. By incorporating both retrospective analysis and real time data collection in active projects, the value of using these fundamental contributions to guide the selection of chemical start points and how they can be used to influence optimisation strategies will become clear.
During the optimisation of drug candidates, improvements in affinity and selectivity play a critical role. This task is usually accomplished by establishing accurate correlations between the affinity/selectivity of different chemical scaffolds and through chemical modifications to a selected scaffold.
Differential scanning calorimetry (DSC) is a widely used technique within the pharmaceutical industry because the range of phase transitions it can measure usually allows near complete physical characterisation of a new active principal early during preformulation. In addition, because DSC measures a property change that is ubiquitous† (heat) there are very few samples that cannot be investigated.
Thermal analysis techniques cover all methods in which a physical property is monitored as a function of temperature or time, whilst the sample is being heated or cooled under controlled conditions. Calorimetric methods measure the energy involved in every process. The quicker new developments attain the market, such as the progression of micro or nanotechnologies, combinations of different hyphenated techniques, as well as the development of high automated or high throughput systems, the faster new horizons will open in the industrial environment. In addition, the application of sophisticated kinetic software in DSC, calorimetry and reaction calorimetry gives better safety predictions.
Enthalpic efficiency and the role of thermodynamic data in drug development: possibility or a pipeline dream!
The determination of accurate thermodynamic data for the interactions of biomolecules has been enhanced over the last decade by the use of isothermal titration calorimetric (ITC) instrumentation. These instruments are now standard kits in many biophysical/structural biochemistry laboratories of pharmaceutical companies. Despite this, there is little evidence for the input of thermodynamic data into the drug development process.
Drug development involves the identification and subsequent optimisation of low molecular weight compounds with a desired biological activity. Often, the initial binding affinity of those compounds towards their intended target needs to be improved by five or more orders of magnitude before they become viable drug candidates; a process that would be greatly facilitated if the different forces that contribute to binding were experimentally accessible. Isothermal titration calorimetry (ITC) provides such a tool.
Issue 3 2007 / 23 May 2007 / Simon Gaisford PhD and Rita Ramos PhD, School of Pharmacy, University of London
In the previous article (European Pharmaceutical Review, Issue 2, 2007) an introduction to calorimetry was given and its application to polymorph characterisation, discussed. Another area of application of growing importance is quantification of (usually small) amorphous contents. A requirement to demonstrate the presence or absence of amorphous material is becoming more important in regulatory documentation and calorimetric techniques are emerging as major tools in this arena. This article focuses on the use of various calorimetric techniques for quantifying amorphous content.
Characterising the properties of a material, understanding how these properties change in relation to local environment and quantifying potential interactions with other species are facets central to any drug development programme. Not understanding and, more importantly, not controlling these factors can have serious consequences for a pharmaceutical, from irreproducible processing to poor bioavailability, product instability and, worse, patentability. Properties that may be characterised include solubility, dissolution rate, stability (in combination with other excipients and as a function of relative humidity and temperature) and per cent crystallinity (or amorphous content).
Thermal analysis methods and coupled techniques are well established procedures in material science. Due to the different information delivered, thermal analysis methods are concurrent or complementary to other analytical techniques such as spectroscopy, chromatography, melting point determination, loss on drying, assay, for identification, purity and quantitation. They are basic methods in the field of polymer analysis and in physical and chemical characterisation of pure substances as well as for mixtures. They find best application for pre-formulation, processing and control of the drug product.
Issue 4 2006, Past issues / 20 July 2006 / Prof. P. A. Barnes, School of Applied Sciences, Prof. E. L. Charsley, Head of the Centre for Thermal Studies and Dr G. M. B. Parkes, Senior Lecturer in Analytical Science, University of Huddersfield
The determination of the key physical and chemical properties of a new material is essential. The melting point, glass transition temperature, the number and identification of the different phases it may have, and the temperatures at which they are formed are all of great value, not only in assessing its practical pharmaceutical potential but also as they can form the basis of many routine QC procedures.
Issue 4 2005, Past issues / 11 November 2005 / Dr Paul G. Royall, Lecturer in Pharmaceutics, School of Chemical Sciences & Pharmacy University of East Anglia, See-wah Jai Tang, Pharmaceutical Science Research Division, King’s College London
Thermal analysis equipment can be found in nearly all of the analytical, development, formulation and QA laboratories within the pharmaceutical industry. However, these work horse instruments are learning to run faster and to analyse an ever more varied field of samples.