Download Understanding the pH-Solubility of Salt Forms by Predicting pHmax

Understanding the pH-Solubility of Salt Forms by Predicting pHmax
P. K. Kondamudi, R. P. Gangwal, L. Yadav, S. Ramakrishnan
Dr. Reddy's Laboratories Ltd.
Purpose
Solubility plays an important role in dissolution and thereby in vivo absorption of drugs. So, understanding drug solubility during the
early phase of drug discovery is important. pHmax plays a critical role in understanding the salt solubility at different pH. The objective
of the current study is to understand the pH solubility profile of salt form by predicting pHmax.
Methods
Solubility of drugs (salt forms) [Cinacalcet hydrochloride (A), Pioglitazone hydrochloride and Drotaverine hydrochloride (C)] was
determined by saturation solubility method. About 5 to 10 g of drugs, separately were added to 100mL of respective media (pH
ranging from 1.2-8) and kept on a shaker water bath for 24 hours at 37°C. Solubility was estimated by stability indicating assay. For
finding the observed pHmax, solubility data was divided into two parts. The intersection of two lines was taken as pHmax.
pH-solubility profile for weak acids and weak bases can be explained by Henderson-Hasselbalch (HH) equation (1) and (2),
respectively.
LogS = LogS0 [1+10 (pH-pKa)]…………………………………(1)
LogS = LogS0 [1+10 (pKa-pH)]…………………………………(2)
Where, S0: intrinsic solubility of free base or free acid ; pKa: ionization constant.
Solubility of salt forms of weak bases can be given by using the modified HH equation
LogST = LogS0 [1+10 (2pH-pKa1-pKa2)] …………………………………(3)
Where, ST: intrinsic solubility of drug ; pKa1:Ionization constant of free base and pKa2: Ionization constant of salt co-former.
At pHmax, the salt and the free acid or free base are present in equi-molar concentrations in solid state, and is unique to the transition
point in pH-solubility profile.
Usually for weak acids and weak bases, pHmax is usually provided by the equations (4) and (5), respectively.
pHmax = pKa+log [√(Ksp )/S0]…………………………………(4)
pHmax = pKa+log [S0/√(Ksp)]…………………………………(5)
Where, Ksp: solubility product of salt form.
If, we assume that log ratio of drug solubility and the intrinsic solubility is not more than 1, then pHmax will be dependent on acidity or
basicity of drug and co-former. So, we equalize the right hand side of both the equations (2) and (3) (salt form and weak base) and the
predicted pHmax equation is as follows
pHmax = (2pKa1+pKa2)/3 …………………………………(6)
Where, pKa1: pKa of free acid or base; pKa2: pKa of salt co-former (Ex: Hydrochloric acid, Tartaric acid).
Results
pHmax defines the limiting pH above which (for a weak acid) and below which (for a weak base) the solid phase constitutes the salt
rather than the free acid or base. Figure 1 shows the pHmax understanding of weak base salt.
The predicted and observed pHmax of drugs (A, B& C) are found to be 1.39, 1.31 and 2.93; 1.38, 1.3 & 3 respectively. Predicted pHmax
was in good agreement with the experimental pHmax value
For weak base, if pKa1+pKa2 >0, then there will be a decrease in the solubility below the pHmax value. If pKa1+pKa2<0, then the
solubility below pHmax will be constant.
Conclusion
The pHmax equation can be utilized in understanding the solubility of salt form. Below pHmax, solubility behaviour of drugs was also
evaluated based on co-former concentration and ionization constant of free base, where the predicted solubility behaviour was in good
agreement with the observed.