Department of Science and Environment, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark.
Department of Science and Environment, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark; Drug Product Development, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium.
Int J Pharm. 2019 Apr 5;560:357-364. doi: 10.1016/j.ijpharm.2019.02.019. Epub 2019 Feb 22.
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.
溶液 pH 值是药物配方和处理过程中的一个重要因素。pH 值的变化带来了挑战。pH 值的调节通常通过缓冲体系来实现，缓冲体系必须具有合适的 pK 值。缓冲剂的 pK 值取决于温度、压力和离子强度。此外，pK 值还可能受到溶剂极性的影响，例如通过添加共溶剂。理论考虑和可获得的实验数据用于了解药用相关缓冲剂的 pK 值如何取决于这些因素。温度的变化也会影响缓冲剂的 pK 值。羧酸部分受温度变化的影响最小。含氨基的缓冲剂受温度变化的影响最大，随着温度的升高，pK 值降低。根据离解反应的焓变和热容的变化，能够准确预测缓冲剂 pK 值随温度的变化。对于 <100 MPa 的压力，压力变化对缓冲剂 pK 值的影响有限。在更高的压力下，缓冲剂 pK 值的变化可达 0.5 pH 单位。改变溶剂的离子强度或极性会对缓冲剂 pK 值产生轻微影响。然而，在药物配方和处理过程中，可以保持溶剂的离子强度和极性不变。
