The complexation can influence the solubilities of all components. Many small organic compounds increase CD solubility. A good example is the p-toluenesulfonic acid that increases the bCD aqueous solubility of bCD dramatically (>30%).

Additionally, the 30 mM is still low (~3.4%) solubility despite the almost doubled bCD concentration.

The real question is, if you isolate the complex in solid form, what is its maximal aqueous solubility.

The complexation can influence the solubilities of all components. Many small organic compounds increase CD solubility. A good example is the p-toluenesulfonic acid that increases the bCD aqueous solubility of bCD dramatically (>30%).

Additionally, the 30 mM is still low (~3.4%) solubility despite the almost doubled bCD concentration.

The real question is, if you isolate the complex in solid form, what is its maximal aqueous solubility.

Laszlo Jicsinszky

The drug I used here is a tosylate form

so, according to you is @the tolsylate disassociated from salt form of drug is helping in increasing the solubility of cyclodextrind?

why 30mM is low?

Above 16mM concentration betacyclodextrin precipitates out but still the solubility of drug is increasing, why?

Kindly check https://www.intechopen.com/books/colloid-science-in-pharmaceutical-nanotechnology/effect-of-cyclodextrin-derivatization-on-solubility-and-efficacy-of-drugs

Also check https://www.mdpi.com/2218-0532/87/4/33/pdf

>why 30mM is low?

Because for a chemist, the near 3% solubility is low. I know for pharmaceutical components are high. Additionally, I could prepare ~40 % bCD solution using sodium tosylate (as far as I remember, it was > 30 years ago, so I am not sure that it was TsONa or TsOH., I just wanted to point, in chemically terms, the solubility is not exceptionally high.

>Above 16mM concentration betacyclodextrin precipitates out but still the solubility of drug is increasing, why?

It is new information. You wrote that the bCD solubility was 30 mM.

About the CD solubilities:

There are many factors that influence CD solubility. E.g. 'hydrotope' materials (it is chemically a terrible word) like urea, hydrazine, etc. increases the aq. solubility. The CDs, particularly the bCD which is more rigid as compared to gCD, can form various associates, like head-to-head, head-to-tail, tail-to-tail, which is connected with hydrogen bonds and the associates precipitating.

The derivatizations (not all) also break or prevent the formation of the H-bond system which results in higher solubility. The methyl substitution introduces a lipophilic moiety but the solubility of CDs increases.

Besides that, in the most useful CD derivatives, the substituents are randomly allocated which also prevents the formation of the stable association and so the complexes of the randomly substituted derivatives are more soluble than the symmetrical ones.

The 6-O-monotosyl-bCD or 2/3/6-mono(2-hydroxy)propyl-bCD is considerably less soluble (0.2-0.5%) in water.

The symmetry origin solubilities can be well studied with the heptakis(2,6-di-O-methyl)-bCD (DIMEB). This compound is less soluble in hot water than in cold. But! The commercially available DIME, in the best case, contains only ~40 % real heptakis derivative, and some over/undermethylated and isomeric (=not 2,6 but 2,3- or 3/6-methylated glucopyranoside residues). This so-called DIMEB is practically freely soluble in water at r.t. (~30-35%). As you are purifying, the r.t dissolution is more difficult by the increasing real DIMEB content. Although decreasing the temperature the dissolution becomes complete and warming up to r.t. the solution remains stable, the increasing symmetry reduces the solubility. The same can be observed when the commercially DIMEB is dissolved in hot acetone but upon cooling the precipitates is containing more symmetrically methylated bCD than before the dissolution. After the filtration, you cannot dissolve the solid in acetone anymore.

> so, according to you is @the tolsylate disassociated from salt form of drug is helping in increasing the solubility of cyclodextrind?

It is rare if a strong acid anion (like pTsO-) can completely be separated from the cation without an external electric field. I rather assume that the salt is complexed.

You wrote that the guest solubility is increasing after the bCD is precipitating. There are a few questions to be clarified.

1. Are you sure about this? How do you know that the bCD is precipitating and not your guest? With the lack of knowledge about your guest, it is difficult to think out the possibilities.

2. Is your guest monobasic or dibasic but only a half salt? Because the pTsOH is a strong acid if there is a second (weakly) basic group, that can be ionized also.

3. Have you checked that your guest does not transform into a more soluble compound (TLC/HPLC)? Sometimes the complexation accelerates the decomposition (oxidation/photodecomposition) of the guest.

4. Did you use water or buffer?

5. Did you check the pH of the solution?

etc.

As Laszlo Jicsinszky wrote, the total solubility of CD can be increased by complexation. The total concentration of CD is the sum of uncomplexed CD and complexed CD.

While the solubility of uncomplexed betaCD is only 16 mM you can get more CD into solution by formation of soluble inclusion complexes. If you have 30 mM of betaCD in solution, 15 mM may be in the form of complexed CD while another 15 mM may be in the form of free CD. Since the concentration of free betaCD is below the solubility of betaCD, no CD will precipitate.

For more information on phase-solubility diagrams (especially Bs-type) I recommend my own article in Int J Pharm. :) Post-print is freely available here:

https://rucforsk.ruc.dk/ws/portalfiles/portal/59786918/Post_print.pdf

Hi Christian,

> If you have 30 mM of betaCD in solution, 15 mM may be in the form of complexed CD while another 15 mM may be in the form of free CD.

I do not entirely agree with you. The complex solubility and the components' solubilities are somehow independent.

If the complex is well soluble, and the complex stability constant is high, the CD concentration can much higher than the pure CD while practically no "free" bCD is in the solution. It is clear and OK.

But please keep in mind that the solubility of contaminated materials (a mixture of compounds/isomers, crude product, etc.) is generally higher than that of pure compounds.

I can give you two CD examples, too. In some cases, the preparation of symmetrically/regioselectively substituted CDs involves a recrystallization step from an organic solvent and, after removal of the impurities (isomers and/or incompletely substituted compounds, etc.), the more pure product is not or barely soluble in the same solvent.

Although the DIMEB is not a perfect example, it is fine for demonstration purposes in the CD world. The commercially available (2,6-di-O-Me)-bCD ( 98% heptakis version dissolves around 20-25% (at r.t.) only. It is a common phenomenon, and there are many examples, not only in organic chemical systems.

Laszlo