Cyclodextrin Phosphates

In order to develop cyclodextrin derivatives having improved aqueous solubility, high solubilizing power, and low accumulation upon longer administration charged cyclodextrin derivatives are recommended. In addition to the sulfoalkylated and sulfated cyclodextrins the phosphated ones are also worth considering. In this editorial we summarize the literature on phosphate esters of CD monomers and polymers.

Phosphates of alpha-, beta- and gamma-cyclodextrin

The preparation is quite simple: by reacting a CD with a phosphorylating reagent such as phosphorus pentoxide or phosphorus oxychloride in the presence of an amide-based solvent or an ether-based solvent randomly phosphated CDs are obtained. [1] Using the reaction with phosphorous oxychloride the ratio of mono and diphosphate esters increased when the reaction temperature was raised from 25 to 60°C. [2] The monoesterified phosphate groups were mainly located at C6 of the anhydroglucose units when the reaction pH was 11 or 12. Reactions at pH 10, however, led to a higher degree of substitution at C2 than at C6. [2]

The synthesis of the selectively phosphorylated CD derivatives is more complicated:

• Alpha- and beta-CDs bearing one or two phosphate moieties on the primary rim were prepared by selective O-debenzylation of fully protected derivatives, followed by phosphorylation and deprotection. [3]
• Dialkyl chlorophosphates were used as phosphorylating agents for the synthesis of BCD derivatives bearing only one phosphate group on the primary rim. [4] These monosubstituted compounds were prepared in good to excellent yields in the presence of 4-dimethyl amino pyridine catalyst and dimethylformamide as solvent. The methodology described is highly selective and the purification is simple, because difficulties due to mixture of phosphate regioisomers in the randomly phosphated CDs are avoided.

Random phosphorylation results in enhanced solubility of CDs, especially of BCD, both in water and in ethanol:water (1:3) mixture. [2] The improved solubility is accompanied by enhanced solubilizing effect. As it was expected the solubilizing effect depends not only on the cavity size of the CD phosphate but also on the chemical structure of the guest molecule. The solubilizing capacity of both phosphate esters surpasses that of HPBCD in the case of furosemide, while they underperform compared to HPBCD for hydrocortisone. The GCD phosphate was the best solubilizer among these 3 CD derivatives for the large molecules of amphotericine B, while the BCD phosphate was the best for the smaller ibuprofen.

Even better results can be obtained for the basic drugs. For instance, 7.8 mg/mL concentration of the practically water-insoluble (< 0.1 mg/mL) mebendazole can be achieved in 10% BCD phosphate solution. [1] Cyclodextrins bearing pendant cationic or anionic moieties have been shown to form highly stable inclusion complexes with oppositely charged organic molecules. [5]

The inclusion complexes of anionic CDs, such as CD phosphates with cationic guest molecules, such as vatalanib succinate, and the nanoparticles comprising these inclusion complexes are disclosed in a patent of Schering published in 2007. [6]

 

CD phosphates can be used on various fields, including pharmaceutical industry, analytical applications and other industrial procedures.

Concerning the pharmaceutical applications, CD phosphates are not only good solubilizers, but they have a therapeutic effect: similarly to CD sulfates, they have anti-retroviral activity. [8] CD phosphates showed anti-HIV activity as high as that of CD sulfates, but their anti-coagulant activity was even lower than that of CD sulfates. [9]

Lisozyme refolding with CDs was found to depend on the ability of CD to suppress aggregation of the protein. [10] The presence of anionic substituents like phosphate groups promoted aggregate formation, and this way reduced the refolding ability compared to neutral CD. The presence of both anionic and cationic substituents on the same CD molecule was found to partially restore its renaturation ability.

CD phosphates, similarly to other charged CDs are useful as chiral selectors for enantioseparation of hydrophobic drugs, including corticosteroids, such as triamcinolone acetate by capillary electrophoresis. [11] Metropolol enantiomers were successfully separated (Rs 2.7) by using alpha-CD phosphate in the background electrolyte. [12] Phosphated‐gamma-CD provided lower detection limits, better repeatability of peak areas and migration times than sulfated alpha- and beta-CD for separation of R,S‐tolterodine and R,S‐methoxytolterodine enantiomers. [13] Phosphated‐gamma-CD was the most appropriate for the simultaneous chiral determination of venlafaxine, an antidepressant drug and its main active metabolite, O-desmethyl venlafaxine in clinical samples. [14] Mono(6-O-diphenoxyphosphoryl)-beta-cyclodextrin (I) and mono(6-O- ethoxyhydroxyphosphoryl)-.beta.-cyclodextrin are chiral selctors in amino acid analysis [15].In another study, CD phosphates showed lower affinity for the analytes compared to CD sulfates in enantioseparation of some chiral drugs. [16] Anyhow, CD phosphates increase the choice of the CD derivatives useful as chiral selectors.

A few industrial applications of CD phosphates were also described:

• Cu salt of BCD polyphosphate was used as catalyst in vinyl polymerization with increasing catalytic activity as the number of phosphate groups on the CD increased. [17] The catalytic effect of the methylated CD/Cu complexes was also improved by introducing a phosphate group into the methylated CD. [18]
• CD phosphate was suitable as template for the preparation of organogels with a large variety of planar guests, like polyaromatic hydrocarbons, such as chrysene, using DMF, pyridine, or other polar solvents. [19]
• Similarly to other CDs, phosphated beta-CDs are degraded on heating in inert atmosphere in one major step (252-400°C) leaving a residue (char) which is thermally quite stable. [20] On heating in air, however, unlikely to other CDs where the char is oxidized to volatile products below 600°C, the phosphate substituted cyclodextrins give a ceramic-like residue stable to above 800°C. Cyclodextrin phosphates as flame retardants were described by Wada et al. [21]

 

References

1. Mikuni, K., Nakanishi, K., Hashimoto, H., Jicsinszky, L., Fenyvesi, E., Szejtli, J., Szente, L. Polyphosphorylated cyclodextrin, its production and use. JP 2000191704, 2000
2. Lee, S.-A., Lim, S.-T. Preparation and solubility of phosphorylated b-cyclodextrins. Cereal Chemistry, 1998, 75(5), 690–694
3. Lopez, O., Bols, M. Effective synthesis of negatively charged cyclodextrins. Selective access to phosphate cyclodextrins. Tetrahedron, 2008, 64(32), 7587–7593
4. Simelane, S., Mamba, B.B., Mbianda, X.Y. A convenient procedure for the synthesis of 6-O-mono-phosphate beta-cyclodextrins. Phosphorus Sulfur and Silicon and the Related Elements, 2013, 188, 1675–1679, DOI: http://dx.doi.org/10.1080/10426507.
5. Kraus, T. Modified cyclodextrins with pendant cationic and anionic moieties as hosts for highly stable inclusion complexes and molecular recognition. Current Organic Chemistry, 2011, 15(6), 802-814
6. Fischer, K.C., General, S., Roessling, G. Nanoparticulate inclusion and charge complex for pharmaceutical formulations. WO 2007025767, 2007
7. unpublished results of CycloLab
8. Matsumoto, K., Moriya, T., Otake, T., Ueha, N., Mori, H., Kanai, M., Miyano, K. Anti-retrovirus agent. JPH02304025, 1990
9. Otake, T., Schols, D., Witvrouw, M., Naesens, L., Nakashima, H., Moriya, T., Kurita, H., Matsumoto, K. , Ueba, N., De Clercq, E. Modified cyclodextrin sulfates (mCDS11) have potent inhibitory activity against HIV and high oral bioavailability. Antiviral Chemistry and Chemotherapy, 1994, 5(3), 155–1561
10. Desai, A., Lee, C., Sharma, L., Sharma, A. Lysozyme refolding with cyclodextrins: structure-activity relationship. Biochimie, 2006, 88(10), 1435–1445
11. Izumoto, S., Nishi, H. Capillary electrophoresis of enantiomers and hydrophobic drugs using charged cyclodextrin derivatives. Bunseki Kagaku 1998, 47(10), 739–746. (Chem. Abstr. 130:32624)
12. Juvancz, Z., Markides, K.E., Jicsinszky, L. Perspectives of chiral capillary electrophoresis using phosphated cyclodextrins as additives. Proc. Int. Symp. Cyclodextrins, 8th (1996), 649-652. Editor(s): Szejtli, J.; Szente, L. Publisher: Kluwer, Dordrecht, Neth.
13. Lehnert, P., Přibylka, A., Maier, V., Znaleziona, J., Ševčík, J., Douša, M. Enantiomeric separation of R,S-tolterodine and R,S-methoxytolterodine with negatively charged cyclodextrins by capillary electrophoresis. Journal of Separation Science, 2013, 36(9–10), 1561–1567
14. Rudaz, S., Stella, C., Balant-Gorgia, A.E., Fanali, S., Veuthey, J.-L. Simultaneous stereoselective analysis of venlafaxine and O-desmethylvenlafaxine enantiomers in clinical samples by capillary electrophoresis using charged cyclodextrins. Journal of Pharmaceutical and Biomedical Analysis, 2000, 23(1), 107–115
15. Liu, Y.; Li, B.; Han, B.H.; Li, Y.M.; Chen, R.T. Molecular recognition study on a supramolecular system. 12. Enantioselective recognition of amino acids by b-cyclodextrin 6-O-monophosphates. J. Chem. Soc., Perkin Trans. 2, 1997, (7), 1275-1278
16. Yanes, E.G., Gratz, S.R., Sutton, R.M.C., Stalcup, A.M. A comparison of phosphated and sulfated b-cyclodextrins as chiral selectors for capillary electrophoresis. Fresenius’ Journal of Analytical Chemistry, 2001, 369(5), 412–417
17. Taguchi, H., Kunieda, N., Kinoshita, M. Vinyl polymerization initiated by cycloheptaamylose polyphosphate ammonium salt/metal ion system in water. Mem. Fac. Eng., Osaka City Univ., 1981, 22, 151–156. (Chem. Abstr.: 98:89983)
18. Taguchi, H., Shiode, S., Kunieda, N., Kinoshita, M. Vinyl polymerization initiated by the methylated cyclodextrin / metal ion system in water. Journal of Macromolecular Science, Chemistry, 1983, A20(4), 421–432
19. Rizkov, D., Mizrahi, S., Gun, J., Hoffman, R., Melman, A., Lev, O. Non-stoichiometric gelation of cyclodextrins and included planar guests. Langmuir, 2008, 24(20), 11902-11910
20. Trotta, F., Zanetti, M., Camino, G. Thermal degradation of cyclodextrins. Polymer Degradation and Stability, 2000, 69(3), 373–379
21. Wada, M., Fujishige, S., Uchino, S., Oguri, N. Pyrolysis of flame retardant cellulose fibers using a curie-point pyrolyzer. Sen’i Gakkaishi 1996, 52(10), 558–561 (Chem. Abstr.: 125:331368)

 

This paper was originally published in the Cyclodextrin News, 2018, June.