Figure 1: Degree of salt formation calculated for the reaction of ibuprofen with basic substances of varying pK values, where
it may be noted that the 99% formation criterion interacts with the curve at a pK
A
value of 8.41.
|
To further illustrate the strategy that would be used to select the range of salt-forming species for a particular drug substance,
consider a hypothetical selection process for ibuprofen. The pK
A
of this acidic compound is 4.41 (16), and equations 25 and 26 can be used to calculate the degree of salt formation as a
function of the pK
A
value of potential basic salt-formers. These results are plotted in Figure 1, and if one accepts the definition of an appropriate
salt as one whose degree of formation equals 99% or higher, then one would only form ibuprofen salts with bases whose pK
A
values exceed 8.41. The formation of sodium or potassium salts (for which pK
A
is approximately 14) is obvious, as would be the formation of salts with arginine (pK
A
= 9.59), lysine (pK
A
= 9.48), ethanolamine (pK
A
= 9.16), diethanolamine (pK
A
= 8.71), and erbumine (pK
A
= 10.68).
The preparation of these salts could be affected by the simple mixing of equimolar amounts of ibuprofen and the pharmaceutically
acceptable bases deduced to have appropriate pK
A
values. These salts would be evaluated on the basis of the degree of acceptability associated with their solubility, hygroscopicity,
or other physical properties. For example, the tiered acceptability criteria outlined in Morris et al. could be used to design the program of salt form evaluation (8).
Conclusions
The identification of a salt form of an active pharmaceutical ingredient becomes essential if the characteristics of the free
acid or free base are not found to be acceptable. Selection of an appropriate salt form of a chemical entity provides one
with the possibility to selectively modify the aqueous solubility, dissolution rate, solution pH, crystal form, hygroscopicity,
chemical stability, melting point, or mechanical properties of a drug substance. The identification of suitable counterions
to be used in the formation of acceptable salt forms does not have to be conducted following trial-and-error methodologies,
but instead appropriate salt-forming candidates can be readily identified through knowledge of the magnitude of the ionization
constants of the acids and bases involved.
An equation has been developed based on the ionic equilibria of acids and bases that permits one to calculate the formation
constant of a salt species solely on the basis of knowledge of the pK
A
value of the acid and the pK
B
value of the base. The initial stages of a salt-selection process for a particular drug substance would begin with knowledge
of its ionization constants and culminate with the calculation of the range of ionization constants of salt-forming agents
that would ensure the formation of salts in high degrees of efficiency. The salt forms identified in this manner would be
predicted to be stable with respect to disproportionation.
Harry G. Brittain, PhD, is the director of the Center for Pharmaceutical Physics and a member of Pharmaceutical Technology's editorial advisory board, 10 Charles Rd., Milford, NJ 08848, tel. 908.996.3509, fax 908.996.3560, hbrittain@centerpharmphysics.com
References
1. S.M. Berge, L.D. Bighley, and D.C. Monkhouse, "Pharmaceutical Salts," J. Pharm. Sci.
66 (1), 1–19 (1977).
|
