Solution Thermodynamics

What thermodynamics does is that a few very general experimental observation data is expressed in mathematical form, and then the logical relationships between these macroscopic observation data such as temperature, pressure, and volume are established. These relationships have great practical value. Pharmaceutical thermodynamics is the chemical thermodynamic study on drug action. Almost every aspect of how a drug behaves in solution and within the body (more importantly) is governed by the simple principles of thermodynamics. The drugs solubility, partitioning between immiscible solvents, drug-excipient interactions, and drug-receptor binding can all be treated in thermodynamic terms.

The optimization of molecular interactions between a drug candidate and its binding target are key parts of drug design and development. Thermodynamic characterization can provide some valuable information, which may help understand interconnecting relations between molecular properties and also control them. Moreover, it can be used to design interactions rationally and pave the way for new drugs or biological materials. Thermodynamic characterization is essential for understanding and optimizing molecular interactions. In drug design process, the information derived from thermodynamics is increasingly becoming an indispensable evidence. It has been found that thermodynamic is widely adopted at different stages of the drug design and development process. The crucial thermodynamic parameter describing the interaction of binding partners is the Gibbs free energy (ΔG). Generally, ΔG is defined by the enthalpy (?H) and entropy (?S) changes:

ΔG = ΔH-TΔS

Enthalpic changes primarily reflect the strength of the interactions (hydrogen bonds, van der Waals interactions). For a full thermodynamic characterization, both the enthalpic and entropic contributions to the Gibbs free energy need to be determined. However, it is difficult to quantify the entropy change and measurement of the dissociation constant Kd (which describes the affinity of a binding interaction) and the enthalpy change is required. Measurements of the thermodynamics may be performed in both direct and indirect ways. However, it is the direct measurements that have the highest quality, which is attractive to drug discovery. Calorimetric methods, as the direct measurements methods, are widely applied. Modern calorimetry methods, mainly including isothermal scanning calorimetry (ITC) and differential scanning calorimetry (DSC), provides extremely accurate measurements of the enthalpy and entropy contributions, dominate in biophysics and biochemistry.

Isothermal Titration Calorimetry (ITC)

Isothermal titration calorimetry (ITC) is considered as the gold standard to obtain thermodynamic parameters. ITC allows the measurement of the enthalpy ?H and affinity Kd of a binding reaction with high sensitivity. Through an ITC experiment at a fixed experimental temperature, Kd and ?H can be obtained directly, and then ?S can consequently be calculated. A full thermodynamic characterisation is available using the relationship in the following equation. Direct determination of binding energetics using ITC is an extremely powerful and useful approach, and the highly accurate determination of thermodynamic parameters can be completed without requirement for chemical modification, labelling or immobilization. ITC is usually favored in drug development.

ΔG = ΔH-TΔS = RTlnKd

Where T is the temperature (in Kelvin) and R is the gas constant.

Differential Scanning Calorimetry (DSC)

Along with ITC, differential scanning calorimetry (DSC) is a powerful method for the direct measurement of thermodynamic parameters. DSC is applied for understanding biomolecular interactions and it is an interesting technique in the process of drug design. DSC measures the excess heat capacity of a solution (Cp) of the molecule as a function of temperature. Kd and ΔG are temperature dependent through the heat capacity change (ΔCp). ΔH and ΔCp can be measured directly through DSC. DSC is available for investigating the thermodynamic properties of various pharmaceutical products, such as biopolymers, proteins, peptides and lipid carriers.

Alfa Chemistry has deep professional knowledge in thermodynamics. With the rich experience in solution thermodynamics and through these analysis methods, we can offer you accurate and comprehensive thermodynamic information on rational design to make more benign solvent choices and optimize separation for the pharmaceutical synthesis. Our extensive thermodynamic knowledge base can also be helpful for multiple phase solvent extractions and final washes and workups.

We offer specific services focused on the thermodynamics measurement. Please contact us to learn more detailed information.

References

• Holdgate GA. (2007) "Thermodynamics of binding interactions in the rational drug design process." Expert Opin Drug Discov., 2(8), 1103-1114.

• Chiu MH, Prenner EJ. (2011) "Differential scanning calorimetry: an invaluable tool for a detailed thermodynamic characterization of macromolecules and their interaction." Journal of Pharmacy and Bioallied Sciences, 3(1), 39-59.