Buffer solutions in drug formulation and processing: How pK values depend on temperature, pressure and ionic strength.

Solution pH is an important factor during drug formulation and processing. Changes in pH present challenges. Regulation of pH is typically managed by using a buffer system, which must have a suitable pK. The pK of buffers depends on temperature, pressure and ionic strength. In addition, the pK can also be affected by the polarity of the solvent, e.g., by the addition of a co-solvent. Theoretical considerations and accessible experimental data were used to understand how the pK values of pharmaceutically relevant buffers depend on these factors. Changes in temperature also affect the buffer pK. Carboxylic acid moieties were least affected by changes in temperature. Buffers containing amino groups were most affected by changes in temperature, and the pK decreased as temperature was increased. It was possible to predict accurately how buffer pK varies with temperature, based on changes in enthalpy and heat capacity for the ionization reactions. Changes in pressure had a limited effect on buffer pK for pressures <100 MPa. At higher pressures, buffer pK varied by up to 0.5 pH units. Altering the ionic strength or polarity of the solvent influenced buffer pK slightly. However, it is possible to keep both the ionic strength and the polarity of the solvent constant during drug formulation and processing.