Improvement of physico-chemical properties of drugs and their analytical
separation using cyclodextrins
T. Sohajda (1), I. Puskás (1), Sz. Béni (2), B. Noszál (2), L. Szente (1)
(1) Cyclolab R&D Ltd, Budapest, H-1097 Illatos út 7, Hungary
(2) Semmelweis University, Department of Pharmaceutical Chemistry, Budapest, H-1092 Hőgyes Endre u. 9, Hungary
e-mail: [email protected]
Introduction
Cyclodextrins in drug formulations
Disadvantageous physico-chemical properties of drugs and drug candidates
represent a constant challenge in pharmaceutical industry in the technological
processes. It is known that numerous biologically active analytes have low aqueous
solubility, low stability against direct light or humidity, unfavourable aggregation
properties, etc.
The ever-growing family of cyclodextrin (CD) derivatives holds the possibility to
overcome the formulation difficulties owing to their encapsulating properties. The
hydrophobic inner cavity of these substances enables them to form complexes with a
great variety of guest molecules thereby modifying the electrochemical, spectral and
physicochemical properties of the guest. As a result of the complexation, enhanced
stability (against oxidation or photochemical degradation) and aqueous solubility can
be achieved moreover the possible side-effects of the drugs may also be reduced. In
addition, since a wide variety of cyclodextrins are available, a highly specific
derivative can be selected for the individual guests [1].
Advantages achieved by
complexation
Sublingual
tablet
Prostaglandin E1
-CD
Injection/
Infusion
Piroxicam
-CD
Tablet
Anti-inflammatory effect increases
Limaprost
-CD
Tablet
Solubility and chemical stability increases
Benexate
-CD
Capsule
Masking of bitter taste, solubility increases
Iodine
-CD
Solution
Disinfecting effect increases, mucous
membrane and skin irritation decreases
Dexamethasone
-CD
Paste
Solubility increases, therapeutic effect lasts
longer
Nitroglycerin
-CD
Sublingual
tablet
Unpleasant taste is masked, chemical
stability increases, controlled release
Cefotiam-hexetil
-CD
Tablet
Solubility increases, reduced precipitation
3600-fold
Cephalosporin
-CD
Tablet
Bioavailability increases
Diphenhydramine
-CD
Chewing
tablet
Susceptibility to hydrolysis decreases,
solubility increases
Itraconazole
Hydroxypropyl-β-CD
Solution
Solubility increases, possibility to formulate
into injectable form
Chloramphenicol
Methyl--CD
Solution
Solubility and stability increases
Nimesulide
-CD
Powder
Solubility and tolerability increases
Nicotine
-CD
Sublingual
and chewing
tablet
Adstringent taste, irritation decreases,
bioavailability increases (independently of
oral pH), susceptibility to oxidation decreases
Voriconazole
sulfobutyl ether β-CD
Injection
Solubility increases
Mitomycin
Hydroxypropyl-β-CD
Infusion
Irritation and side effects reduce
Solubility
Cyclodextrin
enhancement
Drug
AL
Cyclodextrin
Dosage
form
-CD
Cyclodextrins possess a concentration dependent influence on the analyte
aqueous solubility. According to the self-solubility of the guest and host, an
enhancement or decrease in solubility may be observed via different mechanisms.
AP
Drug
substance
Prostaglandin E2
Enhancement of aqueous solubility
St
Drug substances are also approved in cyclodextrin inclusion complex form in
several marketized products. The variety of products covers all the application
forms and a wide therapeutic range of pharmaceuticals.
Solubility increases,
sensitivity to oxidation reduces
AN
Progesterone Hydroxypropyl-γ-CD
Dissolved
guest
BS
SO
BI
SC
Cyclodextrin concentration
Disoxaril
Methyl-β-CD
3800-fold
Acitretin
Methyl-β-CD
> 1000-fold
Imatinib
Methyl-β-CD
10-fold
Theoretical Phase Solubility Diagram
Enantioseparation
Enantiomeric purity is also a key parameter of chiral drugs in terms of quality
control and biological activity. Among the various chiral selectors, cyclodextrins
represent the major class to optimize the separation of enantiomers via complexation
[3]. Capillary electrophoresis (CE) is suitable for the investigation of both complex
stability constants and enantioseparating properties of CDs with various guest
molecules. Performing the chiral separation in an optimized system, minor
enantiomeric impurities even to the level of 0.1 % are detectable.
+
R
+
+
S
-
Diclofenac-Na
Hydroxypropyl--CD
Eye drop
Solubility increases, incompatibility with
benzalkonium chloride decreases, chemical
stability increases, adsorption rate
increases through cornea
Indomethacin
Hydroxypropyl-β-CD
Eye drop
Bioavailability and anti-inflammatory effect
increases
Omeprazole
-CD
Tablet
Storage stability, solubility, bioavailability
increases
17-estradiol
Methyl--CD
Nasal spray
Solubility and adsorption rate increases
through mucous membrane
Cetirizine
-CD
Chewing
tablet
Bitter taste is masked
ENANTIOSEPARATION OF SITAGLIPTIN ENANTIOMERS
(S)
(R)
RS=7.01
9
9,5
10
10,5
11 t (min)
Performing
an
optimized
chiral
separation, minor enantiomeric impurities
even to the level of 0.1 % are detectable.
Unlike in other separation techniques,
migration order of the enantiomers in CE
can be reversed not only by using a
cyclodextrin of adverse selectivity but also
performing reverse mode electrophoresis or
changing the pH.
ENANTIOSEPARATION OF PREGABALIN ENANTIOMERS
S
pH = 9.2
Rs = 1.11
Rs = 0.57
pH = 4.7
3,3
Rs < 0.1
3,8
4,3
R
4,8
5,3
t (min)
8,1
acid,
hydrocortisone,
ziprasidone
mesylate,
dextro-
As a result of cyclodextrin complexation several physico-chemical properties
can be improved:
• Increase in aqueous solubility
• Increased bioavailability
• Stability enhancement
• Improved pharmacokinetics
• Reduction of side-effects or irritation
Rs = 3.75
8,3
28
Summary
S
pH = 2.5
7,9
tiaprofenic
R
(S)
7,7
flunarizine, betahistidine, meloxicam, aripiprazole, maropitant (VET),
methorphan, minoxidil, etc.
pH = 7.2
7,5
chlordiazepoxide, cisapride, Tc-99 teboroxime, alprostadil, rofecoxib,
EOF
DETERMINATION OF CHIRAL IMPURITY
(R) – 0.1 %
Other drugs also available as cyclodextrin complexes in the market:
30
32
34
36
t (min)
References
1. J. Szejtli: Cyclodextrins and their inclusion complexes. 1982, Akadémiai Kiadó, Budapest.
2. B. Chankvetadze: Enantioseparations by using capillary electrophoretic techniques.
The story of 20 and a few more years J. Chromatogr. A, 2007, 1168, 45-70.
3. Z. Juvancz, R. Bodáné Kendrovics, R. Iványi, L. Szente:
The role of cyclodextrins in chiral capillary electrophoresis Electrophoresis 2008, 29, 1701-1712.
A practical analytical advantage of cyclodextrin usage is that as being a chiral
selector enantioseparations can be carried out, enantioselective drug
preparations can be monitored and enantiomeric impurities can be detected and
determined in minute concentrations.
Formulations containing cyclodextrins have the advantage for being patentable
on their own, thus the life-cycle of a drug may be extended.
In addition, due to the improved bioavailability using cyclodextrins so called
super-generics can be developed.
PhysChem Forum 12, Budapest, 2012. April 19.