I dissolved a poorly soluble drug molecule into a solution of 0.1N HCl and β-cyclodextrin, but when I increased the pH by adding NaOH, the solute returned from the solution and turned the solution into a milky dispersion. What is the reason behind this return? How can I overcome it?
The most likely explanation is that you are changing the ionization state of groups on the drug, which can affect solubility. I have no experience with cyclodextrin, but you may wish to look at the two components separately to try to understand which is responsible for the milky appearance. (Of course it may require the combination of the two to see the effect).
As for fixing the issue you will just need to try different formulations. Other possibilities would be to use pure DMSO and make a concentrated drug stock. Sometimes PEG solutions are used, or mixtures of PEG and ethanol. Of course you may be limited in what you can try because of the intended use of the drug.
Finally, the addition of NaOH to a solution of drug in HCl is not the easiest way to control the pH, as you have no buffering power. Unless you are astonishing lucky, your pH will be either very low or very high, with nothing in between. So, adding a buffer may allow you to explore values in the range 5-9, which may afford better solubility.
The drug could form a hydrochloride salt in your 0.1N HCl solution helping it to dissolve in water, when you are adding NaOH, you are neutralizing the HCl and the drug molecule is no longer in salt form and precipitates out. As Prof. Nick Gee suggested, you will need to use an appropriate buffer to get your drug dissolved in the desired pH range.
The role of β-cyclodextrin is to draw the hydrophobic moiety of the molecule inside its cavity. It does not work for hydrophilic compounds. More likely you have a compound that ionizes in basic conditions and is expelled from β-cyclodextrin and precipitates.
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