315
Labeling experiments with
13
C,
15
N,
2
H, and
19
F enables scientists
to obtain valuable structural information.
Magic-angle spinning (MAS), oriented-sample NMR (OS
NMR), and cross polarization (CP) methods have been applied in
many studies [24–28].
Structural information via
2
H NMR spectroscopy can be
obtained from membrane lipids with
2
H-labeled acyl chains or
polar groups [29]. This idea is applicable also in order to study
drug:CD complexes inside liposomes. The results can be studied
combinatorially with electron crystallography and X-ray experiments [29].
2D ssNMR experiments offer information for comprehending
details related to structural and dynamic characteristics. Vogt and
Strohmeier (2012) applied many 2D ssNMR for analysis of inclusion in drug:cyclodextrin complexes [30]. For example, 2D
1
H −
19
F CP-HETCOR experiment can be employed in order to
investigate close association between β-CD and the drug diflunisal
which has fluorine in its structure [30]. 2D
1
H −
13
C CP-HETCOR
is a similar experiment, but the heteronucleus is carbon and this
fact reduces the sensitivity and consequently longer acquisition
times are necessary [30]. The case of
31
P nucleus is analogous to
19
F, as it offers enhanced NMR sensitivity [30].
Cyclodextrins (CDs) are a family of cyclic oligosaccharides,
and consist of five or more α-1,4-linked glycosidic bonds. Examples
of such molecules are α-CD (six α-1,4-linked glycosidic bonds),
β-CD (seven α-1,4-linked glycosidic bonds), and γ-CD (eight
α-1,4-linked glycosidic bonds). Their shape is toroidal (or cone
shaped), due to the absence of free rotation of the bonds linking
the glucose units. Each glucose unit has three hydroxyl groups,
two secondary connected at carbons 2 and 3 of the glucose unit
and one primary connected at carbon 6 (Fig. 1). Thus, a total
number of 21 hydroxyl groups are present in β-CD and their presence is mainly responsible for CD water solubility. The primary
hydroxyl groups are located in the narrow rim of the cone, while
secondary hydroxyl groups are located in the wide rim. On the
other hand, the interior of cyclodextrins is relatively hydrophobic
due to the presence of ether oxygens at the C-4 and hydrogens
attached at carbons C-3 and C-5, thus creating a cavity for the
entrapment of hydrophobic molecules. α-Cyclodextrin may typically complex low-molecular-weight molecules or compounds with
aliphatic side chains. β-Cyclodextrin can complex aromatic and
heterocyclic molecules.
CDs are used extensively for drug delivery since they can
entrap pharmaceutical molecules and protect them. For example, it
is well known that peptides suffer from several disadvantages like
chemical and enzymatic instability, poor absorption through biological membranes, rapid plasma clearance, and peculiar doseresponse curves. Cyclodextrins are used to eliminate the
NMR Techniques Applied to Drug: Cyclodextrin Complexation
Labeling experiments with
13
C,
15
N,
2
H, and
19
F enables scientists
to obtain valuable structural information.
Magic-angle spinning (MAS), oriented-sample NMR (OS
NMR), and cross polarization (CP) methods have been applied in
many studies [24–28].
Structural information via
2
H NMR spectroscopy can be
obtained from membrane lipids with
2
H-labeled acyl chains or
polar groups [29]. This idea is applicable also in order to study
drug:CD complexes inside liposomes. The results can be studied
combinatorially with electron crystallography and X-ray experiments [29].
2D ssNMR experiments offer information for comprehending
details related to structural and dynamic characteristics. Vogt and
Strohmeier (2012) applied many 2D ssNMR for analysis of inclusion in drug:cyclodextrin complexes [30]. For example, 2D
1
H −
19
F CP-HETCOR experiment can be employed in order to
investigate close association between β-CD and the drug diflunisal
which has fluorine in its structure [30]. 2D
1
H −
13
C CP-HETCOR
is a similar experiment, but the heteronucleus is carbon and this
fact reduces the sensitivity and consequently longer acquisition
times are necessary [30]. The case of
31
P nucleus is analogous to
19
F, as it offers enhanced NMR sensitivity [30].
Cyclodextrins (CDs) are a family of cyclic oligosaccharides,
and consist of five or more α-1,4-linked glycosidic bonds. Examples
of such molecules are α-CD (six α-1,4-linked glycosidic bonds),
β-CD (seven α-1,4-linked glycosidic bonds), and γ-CD (eight
α-1,4-linked glycosidic bonds). Their shape is toroidal (or cone
shaped), due to the absence of free rotation of the bonds linking
the glucose units. Each glucose unit has three hydroxyl groups,
two secondary connected at carbons 2 and 3 of the glucose unit
and one primary connected at carbon 6 (Fig. 1). Thus, a total
number of 21 hydroxyl groups are present in β-CD and their presence is mainly responsible for CD water solubility. The primary
hydroxyl groups are located in the narrow rim of the cone, while
secondary hydroxyl groups are located in the wide rim. On the
other hand, the interior of cyclodextrins is relatively hydrophobic
due to the presence of ether oxygens at the C-4 and hydrogens
attached at carbons C-3 and C-5, thus creating a cavity for the
entrapment of hydrophobic molecules. α-Cyclodextrin may typically complex low-molecular-weight molecules or compounds with
aliphatic side chains. β-Cyclodextrin can complex aromatic and
heterocyclic molecules.
CDs are used extensively for drug delivery since they can
entrap pharmaceutical molecules and protect them. For example, it
is well known that peptides suffer from several disadvantages like
chemical and enzymatic instability, poor absorption through biological membranes, rapid plasma clearance, and peculiar doseresponse curves. Cyclodextrins are used to eliminate the
NMR Techniques Applied to Drug: Cyclodextrin Complexation