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 pKa. The pKa of buffers depends on temperature, pressure and ionic strength. In addition, the pKa 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 pKa values of pharmaceutically relevant buffers depend on these factors. Changes in temperature also affect the buffer pKa. Carboxylic acid moieties were least affected by changes in temperature. Buffers containing amino groups were most affected by changes in temperature, and the pKa decreased as temperature was increased. It was possible to predict accurately how buffer pKa varies with temperature, based on changes in enthalpy and heat capacity for the ionization reactions. Changes in pressure had a limited effect on buffer pKa for pressures <100 MPa. At higher pressures, buffer pKa varied by up to 0.5 pH units. Altering the ionic strength or polarity of the solvent influenced buffer pKa slightly. However, it is possible to keep both the ionic strength and the polarity of the solvent constant during drug formulation and processing.