Determining the Solubility of Aspirin Using Sodium Hydroxide

The determination of solubility of a chemical compound is an essential step for

pharmaceutical applications, and for such industry uses it is important to conduct the

measurement in the most economically feasible way while not compromising accuracy.

The solubility of molecules ranges for more than 15 orders of magnitude, but the range for

medical drugs usually varies between 1 and >100 micrograms per milliliter, and molecules on

the lower range of the solubility spectrum require special development consideration to

remain effective for medical use. Unfortunately, solubility issues are often not recognized

until the oral, solid dosage form is developed at which stage it is impractical to chemically

change the active compound. (1) One equation for solubility, known as the Yalkowsky

equation is shown below, where logP is the water partition coefficient, S is solubility, and mp

is the melting point.

log 𝑆 = 0.8 − log 𝑃 − 0.01(𝑚𝑝 − 25) (1)

Source: Glomme et al. (2005)

Changing the titration solvent from water to aqueous sodium hydroxide improves the

solubility of the solute and also improves the accuracy of the titration curve, making the

determination of a reliable equivalent volume of solution easier and improving on standard

deviation. However, impurities in the aspirin can behave as acids and thus interfere with the

legitimacy of the titration analysis. (2) Poor aqueous solubility is mainly caused by two

factors: strong intermolecular interactions and lipophilicity, the ability to dissolve in non-

polar solvents. Poor aqueous solubility can be overcome with formulation work, but that is

expensive and simply altering the molecule is a preferable alternative. (3)

Measurements of drug solubility in water do not always accurately correspond to their

solubility in the gastrointestinal tract, thus not allowing for an accurate prediction of oral drug

absorption. In order to improve such accuracy, biorelevant media is used, which is composed

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to simulate the fluids present in the human gastrointestinal tract. (4) Some recent research

suggests improving the accuracy and precision of acid-base titration with substances such as

aspirin through the use of micellar systems and a microcomputer-controlled titrator, allowing

for less tedious analysis. (5)

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 References

1. Glomme A, März J, & Dressman JB (2005) Comparison of a Miniaturized Shake-

Flask Solubility Method with Automated Potentiometric Acid/Base Titrations and

Calculated Solubilities. Journal of Pharmaceutical Sciences 94(1):1-16.

2. Nobuyasu Hanari TY, Nobuyasu Itoh, Naomi Fujiki, Yoshie Aoyagi, & Numata

ATaM (2014) Evaluation of perfluorooctanoic acid purity based

on potentiometric titration. Analytical Methods, Royal Society of Chemistry 6:3177-3182.

3. Faller B & Ertl P (2007) Computational approaches to determine drug solubility.

Advanced Drug Delivery Reviews 59(7):533-545.

4. Dressman JB, Vertzoni M, Goumas K, & Reppas C (2007) Estimating drug solubility

in the gastrointestinal tract. Advanced Drug Delivery Reviews 59(7):591-602.

5. Gerakis AM, Koupparis MA, & Efstathiou CE (1993) Micellar acid—base

potentiometric titrations of weak acidic and/or insoluble drugs. Journal of

Pharmaceutical and Biomedical Analysis 11(1):33-41.