APPLICATION OF CYCLODEXTRINS IN THE PHARMACEURICAL INDUSTRY FOR
DRUG SOLUBILITY IMPROVEMENT
Mario Grassi1, Lorenzo Magarotto1, Italo Colombo2
1
2
Eurand International S.p.A., Research Department, via del Follatoio 12, Trieste, I – 34148
Eurand International S.p.A, via Martin Luther King 13, Pessano con Bornago (MI), I – 20060
In the last decades, the competition in the pharmaceutical field took place on the production of new
dosage forms containing marketed drugs but having improved physico-chemical properties. This
approach allows an improvement of the in vivo drug performances such as patient compliance,
better therapeutic action and reduction of side effects [1]. Among the many strategies that can be
undertaken at this purpose, cyclodextrins proved to be very interesting both from a theoretical and
industrial point of view. Indeed, these cyclic oligosaccharides, characterised by a torus-like
macroring shape built up from glucopyranose units, usually show a good tendency to interact with
drugs [2]. This, in turn, can provoke the enhancement of drug solubility in a hydrophilic medium, as
proved by the Higuchi-Connors phase diagram [2, 3]. Obviously, the drug solubility increase will
result in a bioavailability improvement on condition that the drug does not show permeability
problems in crossing cellular membranes. In other words, it must belong to the second class (poor
solubility, good permeability) of the Amidon drug classification [4].
A possible way for the realization of drug/cyclodextrin (usually cyclodextrin) interactions is
represented by the use of the mechanical energy supplied by a high energy vibrational mill [5]. The
high number of collisions between the grinding media determine both the drug and the carrier
crystalline structure partial rupture with the formation of drug nanocrystals or drug amorphous
phase (this corresponds to a crystal of zero radius) stabilized by the carrier (cyclodextrin). As it is
well known that crystal size reduction determines both drug solubility increase according to the
Kelvin law [6] and drug melting point decrease [7-9], we can say to have realized an activated
compound. Indeed, the energy required to melt or to solubilize the compound is reduced, this
reflecting in drug dissolution and bioavailability enhancement. This work is aimed to study the
properties of the Nimesulide/cyclodextrin system that underwent a mechanical activation. In
particular, differential scanning calorimeter and RX analyses allow to verify the activated condition
of the co-grounded Nimesulide/cyclodextrin system (lower melting point, no presence of
polymorphic phases) and in vitro release tests allow to see the superiority of the co-grounded
system in comparison with an identical one (from the composition point of view) made up by a
simple physical Nimesulide/cyclodextrin mixture.
References
[1] L. Magarotto, S. Bertini, C. Cosentino, G. Torri. Characterization of nimesulide/-cyclodextrin
composite obtained by solid state activation. J. of Metastable and Nanocrystalline Materials, 10,
643-648, 2001.
[2] Higuchi, T., Connors, K. A. 1965. Phase-solubility techniques. Adv. Anal. Chem. Instrum.
4:117-212
[3] K. H. Frömming, J. Szejtli, Cyclodextrins in Pharmacy, Kluwer Academic Publishers, J. E. D.
Davies, ed., Dordrecht, Boston, London, 1994.
[4] G. L. Amidon, H. Lennernäs, V. P. Shah, J. R. Crison. A theoretical basis for biopharmaceutic
drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability.
Pharm. Res., 12(3), 413–420, 1995.
[5] F Carli, I. Colombo and C. Torricelli. Drug/-cyclodextrin systems by mechano-chemical
activation. Chimicaoggi., may, 61–64, 1987.
[6] A. W. Adamson, A. Gast, Physical Chemistry of surfaces, 6th edition, John Wiley & Sons, Inc.,
New York, chapter X, 1997.
[7] F. Carli, I. Colombo. Physical state of drug loaded into silica gel carriers. Acta Pharm. Jugosl,
38, 361-371, 1988.
[8] M. Brun, A. Lallemand, J. F. Quinson, C. Eyraud. Changement d’etat liquide/solide dans les
milieux poreux. J. De Chimie Physique, 70(6), 979-989, 1973.
[9] I. Colombo, F. Carli, L. Magarotto. Differential scanning calorimetry of drug solid dispersions
in crosslinked polymers. APGI Symposium, Paris 3-5 June 1986.