Thermal Processing

A selection of articles from European Pharmaceutical Review covering Thermal Processing, Calorimetry and Isothermal Titration Calorimetry:


Isothermal calorimetry in the pharmaceutical sciences

Isothermal calorimetry in the pharmaceutical sciences

13 June 2013  •  Anthony E. Beezer and Simon Gaisford, UCL School of Pharmacy

Fifty years ago, isothermal microcalorimetry (IMC) was a means to determine thermodynamic data (principally values for enthalpies of formation or reaction to assist in the calculation of Gibb’s Free Energy functions and entropies). These data were used in the compilation of tables of thermodynamic values, for use in evaluating, inter alia, reaction feasibilities, reaction extents (effectively equilibrium constants) and, indeed, reaction enthalpies. For these measurements, an experimental timescale of 30 minutes was considered long. The applications of IMC have developed and expanded considerably over the years, to the point where it can be considered a real-time process monitor with application to virtually all areas of pharmaceutical development. Accompanying this evolution has been a significant growth in the availability of commercial instruments (in contrast to the previous practice of individual, laboratory designed and built instruments).

Figure 3: The global TSC spectrum of caffeine Form I

Applications of thermally stimulated current spectroscopy in pharmaceutical research

10 July 2012  •  Milan Antonijević, School of Science, University of Greenwich

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.

Figure 1 Free energy diagram for a single step binding interaction between protein (P) and ligand (L). For a binding reaction of this type increasing affinity is achieved by lowering the free energy of the PL complex. Increasing residence (decreasing koff) time is achieved by lowering the free energy of the PL complex and/or destabilizing the transition state

Thermodynamics and kinetics driving quality in drug discovery

31 August 2011  •  Geoff Holdgate, AstraZeneca

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.

Figure 1 Comparison of ITC and TSA data for lead compound 3b binding to the N-terminal domain of Hsp90 target protein4. Left panels show ITC data, right panels – TSA data. Upper panels (a) and (c) show raw data while lower panels show the dosing curves

Isothermal titration calorimetry and thermal shift assay in drug design

20 June 2011  •  Asta Zubrienė, Egidijus Kazlauskas, Lina Baranauskienė, Vytautas Petrauskas and Daumantas Matulis, Department of Biothermodynamics and Drug Design, Vilnius University Institute of Biotechnology

Isothermal titration calorimetry (ITC) is a method of choice in the pharmaceutical industry for determination of equilibrium binding enthalpy, entropy, and the Gibbs free energy. The method is very powerful for determination of intrinsic binding parameters that could be used in structure-energetics correlations. Here we discuss how to overcome several limitations of ITC. First, it is easy to complement ITC results with thermal shift assay (TSA) in order to avoid the narrow window of ITC Kd measurements. Second, several examples are provided on how to determine intrinsic enthalpy of binding and Kd. Third, ITC and TSA Kds are compared with enzymatic inhibition methods. Isothermal titration calorimetry is a wellestablished method for determining the association constant and other thermodynamic parameters of intermolecular interactions in aqueous solutions. The technique has been widely used to study interactions between very different molecular species such as proteins, DNA, RNA, lipids, drug leads, metal ions and many other chemical substances as previously reviewed1,2.


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