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Strategy for the Prediction and Selection of Drug Substance Salt Forms
Through consideration of the ionic equilibria of acids and bases, one may readily calculate the formation constant of a salt species solely on the basis of knowledge of the pKA value of the acid and the pKB value of the base.
Utility of salt-form ionic equilibria in the design of salt-selection studies
Table I: Predicted degree of salt formation for a strong base* with acids of differing pKA values.
The ability to calculate log(KS) values can be very helpful when designing the scope of a salt-selection study because it can be used to determine the acidity
or basicity range of potential salt-forming species. For example, consider a drug substance containing a basic functionality
characterized by a pKA value of 10.60 so that pKB would equal 3.40. One can then calculate the log(KS) values for a series of acids of varying pKA values, obtaining the results shown in Table I. If an acceptable salt is defined as one whose degree of formation would exceed
99%, then it would follow that any acid characterized by a pKA value that was less than 6.0 would form a product that would
be worth isolating. The value of this rather strict definition is that any salt whose degree of formation exceeded 99% would
also be predicted to undergo less than 1% disproportionation when dissolved in water.
Table II: Predicted degree of salt formation for a moderate base* with acids of differing pKA values.
Continuing the analysis, now consider a drug substance containing a basic functionality characterized by a pKA value of 8.55, so that pKB would equal 5.45. Again calculating the log(KS) values for a series of acids of varying pKA values yields the results shown in Table II.
Using the definition of an acceptable salt as one whose degree of formation would exceed 99%, then it follows that only acids
characterized by pKA values less than 4.0 would form acceptable salts that would not be susceptible to disproportionation.
Table III: Predicted degree of salt formation for a weak base* with acids of differing pKA values.
Finally, consider a weakly basic drug substance containing a functionality characterized by a pKA value of 7.25. Since its pKB would equal 6.75, the log(KS) values shown in Table III were calculated for the series of acids of varying pKA values.
To form an acceptable salt whose degree of formation exceeded 99%, then only acids characterized by pKA values less than 3.0 would form acceptable salts that would not be susceptible to disproportionation.
In the illustrated case of a basic drug substance, once the range of acceptable acidic salt-formers has been determined, one
only needs to consult the various compilations of pharmaceutically acceptable acids (1–3, 6) to specify the list of salts
that would be actually prepared in the laboratory.
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
Articles by Harry G. Brittain, PhD
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