Iglesias
SCHEME 1. Possible Acid-Base Equilibrium of Novocaine in Aqueous Solutions
including poor bioavailability, associated to a poorly soluble
drug: limited shelf life, due to the sensitivity of the drug to
destructing factors, and restricted utility, when the drug is
irritating to skin, membranes, tissues, and so on.11-15
In a strong acid medium (pH < 2), the majority of species is
the diprotonated molecule, NoH2+2, and conversely, in an
alkaline medium (pH > 10), the neutral form (No) predominates;
between these two extremes (2 < pH < 10), the tertiary amine
group is protonated (NoH+). With regard to the host molecule,
â-CD ionizes at pH > 11, and the pKa of a secondary OH group
is 12.3;22 consequently, in an alkaline medium, the â-CD
molecules bear a negative charge (CD-).
â-Cyclodextrin and its derivates are the most interesting for
drug complexation in both the solution and solid states, in which
case each guest, or some part of it (commonly the less-polar
part), is sequestered inside the hydrophobic CD cavity, whereas
the most polar and often charged group of the guest is exposed
to the bulk solvent just outside the wider opening of the cavity.
A good understanding of the encapsulation equilibrium, making
reference to structural information, stability, and/or reactivity
of the included drug, is necessary to draw a complete picture
of the CD/drug interaction.16-19
With the previous considerations in mind, the present
investigation was planned by defining the following possible
different situations.
1. Strong acid medium (pH < 2). Aqueous solutions of
+2
hydrochloric acid were used. The guest is a dication, NoH2
,
and the host is a neutral molecule (eq 1). Changes in the spectra
The main objective of this investigation is the analysis of
the complexation by â-CD of the local anesthetic novocaine
(nov) in an aqueous medium under various experimental
conditions, with the aim to obtain a wide range of information
about the molecular interactions that drive the complexation
process. To perform the study, different methodologies have
been applied, which make use of changes in spectroscopic
properties of novocaine, of electrical conductance of the charged
drug, and of common reactions of novocaine occurring in either
aqueous acid or an alkaline medium, such as the nitrosation of
the primary amine group in an acid medium or the hydrolysis
of the ester in an alkaline medium. The kinetic characteristics
of the two reactions in an aqueous medium have been
investigated in detail.20
of UV-vis absorption of fluorescence emission were used to
study the complexation process. Chloride ions form inclusion
complexes with â-CD; nevertheless, the stability constant is very
small (Kc ) 2.56 mol-1 dm3)23 and allows us to avoid its
consideration at low chloride ion concentrations.24
2. Mild acid medium (pH > 4). In aqueous buffered solutions
of acetic acid-acetate, the guest is a cation, NoH+, and the
host is neutral (eq 2). To study the complex formation, we
Novocaine is a tertiary amine that also contains a primary
amine group bonded to a phenyl ring (Scheme 1). The pKa
values of these two basic centers are largely different (primary
amine, pKa1 ) 2.31;20 tertiary amine, pKa2 ) 9.306,21) because
no interaction effects are expected between both centers.
Therefore, depending on the acidity of the solution, novocaine
carried out the kinetic study of the nitrosation reaction of the
primary amine group to give diazonium ions, the electrical
conductivity of the guest, and changes on the fluorescence
emission spectrum of the guest. The nitrosation reaction of
novocaine has been studied in water in the absence of cyclo-
dextrin.20 Acetic acid molecules and acetate ions are also
competitors for the â-CD cavity; however, as for chloride ions,
the small stability constant (Kc < 7 mol-1 dm3)24 makes it
possible for us to avoid its consideration under low buffer
concentrations.
may exist as a neutral molecule, No, as a monocation, NoH+,
+2
or as a dication, NoH2
.
(11) Nadai, T.; Ueda, H. In ComprehensiVe Supramolecular Chemistry;
Szejtli, J., Osa, T., Eds.; Pergamon: New York, 1996; Vol. 3, Chapter 14.
(12) Hedges, A. R. Chem. ReV. 1998, 98, 2035.
(13) Konno, A.; Misaki, M.; Toda, J.; Wada, T.; Yasumatsu, K. Agric.
Biol. Chem. 1986, 46, 2203.
(14) Nakanishi, K.; Masukawa, T.; Nadai, T.; Yoshii, K.; Okada, S.;
Miyajima, K. Biol. Pharm. Bull. 1997, 20, 68.
3. Mild basic medium (pH ∼ 10). Both the guest and the
host are neutral molecules (eq 3). The basic medium was
(15) Brown, N. O.; Butler, D. L.; Chiang, P. K. J. Pharm. Pharmacol.
1993, 45, 666.
(16) Tabushi, I. Acc. Chem. Res. 1982, 15, 66.
(17) Liu, Y.; Zhang, Y.-M.; Qi, A.-D.; Chen, R.-T.; Yamamoto, K.;
Wada, T.; Ionue, Y. J. Org. Chem. 1997, 62, 1830.
(18) Iglesias, E. J. Am. Chem. Soc. 1998, 120, 13057. Iglesias, E.; Casado,
J. Int. ReV. Phys. Chem. 2002, 21, 37.
obtained from aqueous solutions of carbonate-bicarbonte buffer
of pH 10.4. The complexation process was investigated from
(19) Csernak, O.; Buvari-Barcza, A.; Samu, J.; Barcza, L. Inclusion
Phenom. Macr. Chem. 2005, 51, 59.
(22) Geld, R. I.; Schwarts, L. M.; Laufer, D. A. Bioorg. Chem. 1982,
11, 274.
(23) Rohrbach, R. P.; Rodr´ıguez, L. J.; Eyring, E. M.; Wojclk, J. F. J.
Phys. Chem. 1977, 81, 944.
(20) Iglesias, E.; Brandariz, I.; Penedo, F. Chem. Res. Toxicol. 2006,
19, 594.
(21) Kamaya, H.; Hayes, J. J.; Ueda, I. Anesth. Analg. (Baltimore) 1983,
62, 1025. See also: CAS Database, registry number 59-46-1.
(24) Iglesias, E. J. Org. Chem. 2000, 65, 6583.
4384 J. Org. Chem., Vol. 71, No. 12, 2006