CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 10 3483–3485
PerspectiVes On the Solubility of Saccharinate Salts and Cocrystals Claire L. Cooke* and Roger J. Davey The Department of Chemical Engineering and Analytical Science, The UniVersity of Manchester, Manchester, United Kingdom ReceiVed June 13, 2008; ReVised Manuscript ReceiVed July 18, 2008
ABSTRACT: A simple relationship allows pH versus solubility plots for molecular salts to be calculated from known pK’s together with one measurement of solubility and the pH of the corresponding supersaturated solution. Using this methodology the solubility of a series of salts may be properly compared and judged against that of a cocrystal. One advantage of this method is that the equations also allow the calculation of an important thermodynamic parametersthe solubility product. In the manufacture of pharmaceutical products, molecular salts of active ingredients are routinely used to improve certain solid form physical properties for production, processing, and formulation. Salt screening is, therefore, a major commercial research activity.1-5 Salt formation is an acid-base reaction, involving the transfer of protons. The relative strengths (dissociation constants, pKa) of the acid and the base concerned are thus of vital importance and determine whether or not salt formation occurs. This is reflected in the much quoted “rule” stating that the difference in pKa between the acid and the base (∆pKa) must be >2 units for the salt to form.6 pH solubility relationships have been reported previously,7,8 usually determined by titrimetry and spectrophotometric methods. These demonstrate that the pH of the saturated solution is a major factor in salt solubility, a feature of considerable importance in both salt isolation and in determining bioavailability of pharmaceutical products. While solubility data are not always accompanied by measurement of an associated pH,9 Jones et al. 10 have recently shown how the simultaneous determination of the pH and solubility can be used to calculate the thermodynamic solubility product (Ksp). This method, which needs only one solubility value at a known pH together with the pK of each component, is employed in this paper. It offers an alternative to the more frequent11-13 use of direct concentration measurements to calculate Ksp using the equation
Ksp ) [A]x[B]y
(1)
for the dissociation of the salt AxBy according to
AxBy T xAy++ yBx-
(2)
Here we apply this methodology to some recently reported data on saccharinates published by Bhatt et al.14 and Banerjee * To whom correspondence should be addressed. Phone: 0161 3064362. E-mail:
[email protected].
et al.15 Their interest was in comparing the solubility of saccharinate salts with saccharin cocrystals. A selection of pharmaceutical bases was crystallized with saccharin resulting in the isolation of 10 salts and one cocrystal. On the basis of their measured solubility it was concluded that, at least in the case of saccharin, salts are more soluble than cocrystals. This brief reexamination of their data serves two purposes. First, because they reported both the pH and the composition of the saturated solutions, we wish to emphasize how a simple calculation enables such data to be converted into a fundamental thermodynamic parameter, Ksp, the solubility product of the salts. Second, because solubility of salts and cocrystals depend on the ternary composition of the solution, comparison of solubilities can only be made with due attention paid to the pH. In the current examples, the pH of the saturated cocrystal solution was 3.27, much lower than those of the salts, which lay between 5.25 and 6.25. We were interested in the effect this pH difference might have on the relative solubilities. Saccharin, with a pKa of 2.2, acts as a weak acid to form a salt with a sufficiently basic molecule, or as a neutral molecule to form a cocrystal. Using the experimentally determined pH value and aqueous pK values given in these papers14,15 (see Table 1), speciation diagrams were constructed. These showed that, at least in an aqueous environment, a salt could theoretically form for all the basic active pharmaceutical ingredients (APIs) with saccharin, including piroxicam (Figure 1). The latter in fact was isolated as a cocrystal, a consequence presumably of the shift in pK’s in the mix of chloroform and ethanol used for crystallization. An illustrative example of a system that formed a salt, haloperidol saccharinate, is shown in Figure 2. In Figure 2 it is evident that between pHs 3 and 7 both former and active are nearly totally ionized, while this region is much smaller for the cocrystal system in Figure 1. In reality these materials were
10.1021/cg800621q CCC: $40.75 2008 American Chemical Society Published on Web 08/29/2008
3484 Crystal Growth & Design, Vol. 8, No. 10, 2008
Perspectives
Table 1. The Physical Properties of APIs and Their Saccharinate Salts API
API saccharinate a
API
solubility (g/L)
haloperidol mirtazapine piroxicam quinine pseudoephedrine lamivudine risperidone sertraline venlaflaxine zolpidem amlopine
