Ask a Formulator: How Do You Solubilize an API That Does Not Want to Dissolve?

April 19, 2022

One of the most common issues faced during topical formulation development is difficulty in dissolving the active pharmaceutical ingredient (API) in water or other water-soluble solvent systems. When this happens, several approaches may be taken when trying to dissolve stubborn APIs.

Click here for a primer to solubility studies.

Adjusting the pH of the solvent system

Being Polar Can Have Advantages

Solubility of an API can be dependent on the pKas of its different functional groups. Protonated functional groups will be more lipid-soluble, while dissociated functional groups will be more water soluble. If the API is in a more acidic environment relative to the pKas of its functional groups, the more likely it will hang on to its protons and remain neutral, making it more lipid soluble. If the API is in a more alkaline environment, the more likely it will donate its protons, thus becoming ionized and more water soluble.1

Dissolving the API in binary and tertiary systems

If the API does not dissolve well in any single-solvent system, one approach is the use of co-solvents to increase solubility. Different functional groups on an API may be more soluble in different types of solvents. For example, any long aliphatic chains of an API may be more soluble in less polar solvents like esters while hydroxyl functional groups may be more soluble in polar solvents like glycols.

Using surfactants to increase solubility

Surfactants may be used to help increase solubility of an API. Similar to the idea of using multiple solvents, the hydrophobic and hydrophilic parts of a surfactant can help solubilize different parts of an API molecule. The advantage of using surfactants to dissolve an API is that fewer excipients may be needed to dissolve the API. Common surfactants used in topical drug products to help solubilize APIs in a formula include polysorbate 20 and PEG-35 castor oil.

Using hydrotropes to increase solubility

Hydrotropes are co-solvents which help to increase the solubility of an API in water. They accomplish this via their hydrophobic and hydrophilic portions. The main difference between a hydrotrope and a surfactant is that hydrotropes don’t have large enough hydrophobic ends which would cause the molecule to spontaneously self-aggregate.2 Some examples of hydrotropes include urea and sodium benzoate.3

Physical Techniques

Should chemical techniques fail to increase the solubility of an API, physical changes can be made to the API material, including particle size reduction and modification of the crystal habitat.4,5 It is possible that a combination of physical changes to the API as well as chemical techniques are necessary to dissolve an API.

And if the API still will not dissolve…

A suspension product may be developed containing the API as a solid dispersion. While a suspended product will require assessment of particle size over time, a suspended product can be as stable and efficacious as dissolved systems.


  1. A. Yartsev. “Factors which determine the lipid solubility of drugs.” October 2020. Deranged Physiology.
  2. A. J. O’Lenick, Jr. “Comparatively Speaking: Hydrotrope vs. Emulsifier.” May 2018. Cosmetic & Toiletries.
  3. S. Abbott. “Other Hydrotropes.” Practical Solubility – Hydrotropes & Solubilizers.
  4. K. T. Savjani, A. K. Gajjar, and J.K. Savjani. “Drug Solubility: Importance and Enhancement Techniques,” ISRN Pharmaceutics., 2021 May; 2012 (195727): 1-10. doi: 10.5402/2012/195727
  5. S. Sareen, G. Matthew, and L. Joseph. “Improvement in solubility of poor water-soluble drugs by solid dispersion,” Int J Pharm Investig. 2012 Jan; 2(1): 12-7. doi: 10.4103/2230-973X.96921.