Try to add nonionic surfactants. You can also use DMSO and after adding cyclodextrin, wash it away.

Stir the HPCD solution with your guest vigorously (e.g., ultra-turrax) or sonicate for some time, filter the insoluble, and freeze-dry the solution. You can record a solubility isotherm by this method using various HPßCD concentrations. Eventually, you can try more than one HPßCDs (different DS, Degree of Substitution, number of HP groups/macrocycle). It might be that higher DS (e.g., DS~6.3, which is a USA version of HPßCD) works better.

In the case of low DS (3.5-4.5), the amount of mono(2-hydroxy)propyl-ßCDs is noticeable, and they can form even less soluble complexes than the guest alone.

Please remember that in the case of very insoluble guests, the dilution of the complex solution with water may lead to hazy solutions or sometimes precipitation.

DMSO forms complexes with various CDs, and, additionally, it is practically impossible to remove from the complex.

Laszlo Jicsinszky thank you for your suggestion. I tried to check the solubility of my guest compound at different concentrations(0.2 mg/ml , 0.4 mg/ml, 0.5 mg/ml, 0.8 mg/ml and 1 mg/ml ) in ethanol and sonicated for some time.

0.2 and 0.4 mg/ml concentration resulted into clear solution while rest of the concentrations showed undissolved guest compound. Can I go ahead and prepare the inclusion complex with the 0.2 or 0.4 mg/ml concentration considering (1:1) molar ratio of HP-Beta-CD and guest molecule ?

I would have used distilled water only, as I mentioned in my first message. I am not sure about the water solubility of a complex prepared in EtOH.

Do the same solubility isotherm in water, then filter off the insoluble. If you cannot record the host calibration (UV) in water (due to solubility problems), use a water-EtOH system. And, please remember that you need to add EtOH to your filtered solution to reach the approximately identical water-EtOH composition. Otherwise, the calculation may contain errors.

From the solubility isotherm (mol/mol figure, not mol/wt% or wt%/wt%), you can see whether the 1:1 complex is possible at all. I mean that your sample contains the 1:1 complex only, and the HPßCD is not in excess, i.e., the complex can be 1:1, but to get it dissolved, HPßCD should be in excess. You can also see if the complex composition differs from the 1:1 composition (the curve is bending at higher CD concentrations. A common mistake is to assume that if the components are put together in a 1:1 molar ratio, the solid or solution will contain only the 1:1 complex.

As far as I see that your HPßCD is soluble in EtOH, so I suppose you have HPßCD of DS >4.3-4.5

The good news is that the HPßCD is soluble either at 30-40% in water.

Keep in touch,

Laszlo

It's so simple. just try to follow Higuchi and Connors. make high HP-beta- CD in the highest molarity (according to the solubility) in MQ (in a 50 mL tube) and add your guest molecule as a solid (no need to use organic solvent) to the prepared solution (you can see two phases now a suspension). put the suspension in a shaker (it should be shaken like a circle rotation) for 48 hours. Eventually, centrifuge the suspension at 5000 rpm for 15 min and keep the supernatant. the supernatant is the HOST/GUEST inclusion complex with the highest efficiency. just freeze-dry now.