Overview of experimental and computational methods for the determination of the pKa values of 5-fluorouracil, cyclophosphamide, ifosfamide, imatinib and methotrexate

We present a review of the available literature concerning pKa values and methods for the determination of selected anticancer drugs as well as the most up-to-date knowledge on their different ionic forms depending on solution pH. Additionally, to clarify the existing state of knowledge we have presented an overview on the obtained pKa values with the use of experimental and computational methods. As a result, we have demonstrated and proposed acid-base equilibria of cyclophosphamide (CF), ifosfamide (IF), 5-fluorouracil (5-FU), methotrexate (MTX), and imatinib (IMT) in an aqueous solution, and their species distribution curves as a function of pH calculated on the basis of the acid dissociation constants, which are as follows: