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Insoluble APIs
One of the main challenges in drug delivery is to guarantee the bioavailability of the
active ingredients, especially when they are poorly soluble and/or with a limited
gastrointestinal permeability. To improve
aqueous solubility and thus the
therapeutic effectiveness of such compounds, a number of formulation strategies
have already been largely tested. It is a big challenge to find the right solubilization
tool for these active ingredients.
We will first explain why to choose -Cyclodextrins as a solubilization tool, and all
you need to know to successfully complexate your active ingredient with
-Cyclodextrins. Then using concrete examples will ease the understanding of the
tools used to study inclusion on -CDs: phase solubility, stability constant, and
complexation efficiency, complexation processes in liquid and solid state.
The Biopharmaceutics Classification System (BCS) predicts oral drug absorption
based on the chemicals aqueous solubility and intrinsic permeability through the
gastrointestinal mucosa. Two studies have been realized with highly permeable
drugs with limited water solubility, considered as BCS class II : Zotepine and
Zaleplon. These studies demonstrate why the Roquettes KLEPTOSE range
(chemically modified Beta Cyclodextrin) is the best solution for improving solubility
enhancement.
What do you need to know about your API to successfully complexate it with
cyclodextrins (CDs)?
Small molecules:
how many atoms contains:
how many condensed rings:
water solubility:
melting point temperature:
molecular weight:
electrostatic charge:
log P
pKa
stability issues:
Large molecules:
the side chain in macromolecules may contain suitable groups which can interact with CDs in
aqueous solutions and form a partial complex with CDs.
Source: Lovatt,M., Cooper,A. and Camilleri,P. (1996) Eur. J. Biophys., 24, 354357
In the presence of water, CDs (host molecule) can form inclusion complexes with many drugs
(guest molecule) by taking up the molecule, or more frequently some lipophilic part of the
molecule, into the central cavity by a steric and a thermodynamic interaction. Drug molecules
in the complex are in rapid equilibrium with free molecules in the solution. No covalent bonds
are formed or broken during the complex formation.
Source: Frmming and Szejtli: Cyclodextrins in Pharmacy Kluwer Acad. Press, Dordrecht, 1994.
CASE STUDIES:
Using concrete examples will ease the understanding of the tools used to study inclusion on
-CDs: phase solubility, stability constant, and complexation efficiency, complexation processes
in liquid and solid state:
Fig.1 Vials set up for Phase Solubility evaluation at RT (25C) in deionized water (pH 6.5).
Fig.2. Samples set up for HPLC solubility evaluation, stability evaluation and lyophilization
Fig 3. Phase-solubility profiles of Zotepine in BCD,HPBCD, Crysmeb and SBE at RT (25oC) in deionized water (pH 6.5).
Where m is the slope of Phase Solubility curve as determined by linear regression and S0 is the
drug solubility in DI water or buffer as determined after (1 to 7) days of mixing (depending at what
time point the saturation solubility is reached).
Table 2. Zotepine complexes K 1:1 and CE at RT (25oC) in deionized water (pH 6.5).
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Fig. 9 Phase-solubility profiles of Zaleplon in BCD,HPBCD, and Crysmeb at RT (25oC) in deionized water (pH 6.5).
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The DSC chromatogram shows the peak disappearance and proves the API:BCDs complexation.
Table 4 Zaleplon complexes K 1:1 and CE at RT (25C) in delionized water (pH 6.5)
The complexation efficiency and stability constants are high when complexed with Crysmeb
and HPBCD
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The stability of the complexes after 30 and 60 days at 25C and 40C is ranking as follows:
Crysmeb > HPBCD > BCD SBE
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Zaleplon solid dispersion inclusions prepared by: spray drying (SD), freeze
drying (LYO), physical mixture (PM=kneading)
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CONCLUSION
As demonstrated in the case studies of this document, -Cyclodextrins are fully
adapted tools to increase the aqueous solubility of APIs and their physico-chemical
stability.
They can also be used to reduce toxicity (e.g: local irritation after topical or oral
administration) and to mask material bad taste or odor.
Several pharmaceutical products containing Hydroxypropyl Betacyclodextrin have
already received market approval from several regulatory authorities and have
successfully reached the market.
The patent situation has evolved, in favour of more uses of HPBCD. This new
context makes this excipient an easily accessible formulation aid for the
development scientist.
Roquette provides a range of KLEPTOSE HPBCD derivatives suitable for the
cosmetics and the pharmaceutical industries, including a PYROGEN FREE grade
for parenteral applications. KLEPTOSE Crysmeb is a product under development
showing interesting inclusion properties.
Roquette is in a privileged position to discuss the specific needs of the
pharmaceutical and cosmetics industry for information on scientific assistance,
regulatory and patent issues.
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Pharma.business.unit@roquette.com
www.roquettepharma.com
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