Table Of ContentProceedings of the Ninth International
Symposium on Cyclodextrins
Santiago de Compostela, Spain, May 31-June 3, 1998
Edited by
JJ. Torres Labandeira
and
J.L. Vila-Jato
Department of Pharmacy and Pharmaceutical Technology,
University of Santiago de Compostela,
Spain
KLUWER ACADEMIC PUBLISHERS
DORDRECHT / BOSTON / LONDON
A CLP. Catalogue record for this book is available from the Library of Congress.
ISBN 0-7923-5721-3
Published by Kluwer Academic Publishers,
P.O. Box 17, 3300 AA Dordrecht, The Netherlands.
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by Kluwer Academic Publishers,
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In all other countries, sold and distributed
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Printed on acid-free paper
The cover illustration displays the solid-state conformation of a-cycloaltrin (a-CA) in different
forms: the molecule adopts a conformation of 3-fold rotational symmetry with a unique alternating
sequence Of4C and 1C altropyranose chair geometries (upper left model, space group P6), resul-
1 4 3
ting in banana-shaped disaccharide units, of which one is represented as a space-filling CPK-type
model (lower left entry). In the crystal lattice the compact molecules are stacked in transposed lay-
ers (upper right, water molecules left off for clarity). Each a-CA molecule is embedded into a
matrix of 21 water molecules (lower right, view along the hexagonal c-axis). The space filling
models reveal a-CA to be devoid of a central 'through-going' cavity. The graphics were generated
using Brickmann's MOLCAD molecular modeling program; for further information see the web-
pages at 'http://caramel.oc.chemie.tudarmstadt.de/immel/molcad/Gallery.htmror 'S. Immel, G.E.
Schmitt, and RW. Lichtenthaler: a-Cycloaltrin: Conformation and Properties in the Solid-State and
Aqueous Solution.', pp. 41-48 of this volume.
All Rights Reserved
© 1999 Kluwer Academic Publishers
No part of the material protected by this copyright notice may be reproduced or
utilized in any form or by any means, electronic or mechanical,
including photocopying, recording or by any information storage and
retrieval system, without written permission from the copyright owner.
Printed in the Netherlands.
Dedicated to
Dr. Tsuneji Nagai and Dr. Josef Szejtli
on their 65th Birthday
Dear Colleagues and Friends,
Welcome to this small and wonderful town in the Westcorner of Spain. After the
discovery of the tomb of the Apostle St. James, the city has become the goal of
thousands of pilgrims who came from all over Europe to venerate the Apostle and
looking for a renew of their soul and life. This has not changed nowadays, but
Santiago has become a place for cultural and scientific pilgrimage. It's University
celebrated its 500th anniversary in 1995, and Santiago became a scientific mee-
tingpoint for the thousands of researchers that participated in the Conferences and
Meetings.
This is the 9th International Symposium on Cyclodextrins. Previous Cyclodextrin
Meetings were very successful and we wish you all the best for this one.
Cyclodextrin technology has grown up a lot since the discovery of these substances
at the beginning of the Century. Many people from all over the world have contri-
buted to this development, looking for its characterization and for new applications.
This is not the end of the way and our participation in this Symposium proves it.
We have here the opportunity to continue the trail, renew our knowledge and share
with our friends the scientific uneasiness.
Have a nice stage in Santiago de Compostela and we look forward to being able to
welcome you again some other time in future!
A C K N O W L E D G E M E N TS
The generous financial support of the following sponsors
made it possible to organize this Symposium:
UNIVERSITY OF SANTIAGO DE COMPOSTELA. (Spain)
Secretarfa de Estado de Universidades e Investigation (Spain)
XUNTA DE GALICIA. Direction Xeral de Investigation (Spain)
The Nagai Foundation (Japan)
CYCLOLAB Ltd. (Hungary)
Cyclodextrin Technology Development Inc. CTD Inc. (USA)
CyDex, L.C. (USA)
Wacker-Chemie GmbH (Germany)
Asahi Foods Corporation (Japan)
Nihon Shokuhin Kako Co., Ltd (Japan)
Mercian Corporation (Japan)
Ensuiko (Bio Research Corp. of Yokohama. Japan)
Cyclodextrin Society of Japan
GlaxoWellcome, S.A.(Spain)
Chiesi Farmaceutici S.p.A. (Italy)
Kluwer Academic Publishers (The Netherlands)
Special thanks to Mr. Carlos M. Varela LJlIa, your help made it possible.
Contents
Preface: Welcome to Santiago de Compostela ....................................... xvii
Acknowledgements and Sponsors .......................................................... xviii
1. Separation and Characterization
Development of a Fluorimetric-FIA Method to Monitor Cyclodextrin
Production from Starch and the Formation of Inclusion Complexes ......... 3
Development of Enzyme Immunoassays Specific for Natural β- and γ-
Cyclodextrins and Synthetic Derivatives. Pharmacokinetic Analysis
of Cyclodextrins in Rat ................................................................................ 7
The Role of Host Guest Interaction in Thickening and Phase
Separation of β-Cyclodextrin Polymer and Polymers Bearing Cyclic
Hydrophobic Side Groups .......................................................................... 11
Specific Binding and Precipitation of γ-Cyclodextrin with
Monosaccharide in an Aqueous Solution ................................................... 15
Analysis of Hydroxypropyl Cyclodextrins by Liquid Chromatography
and Evaporative Light Scattering Detection ............................................... 19
LC-ELSD or (and) LC-MS: a Well Suited Technique for
Characterization of the Differences in the Commercially Available
DM-β-CDS .................................................................................................. 23
Thermal Degradation of Cyclodextrins ............................................................. 27
2. Cyclodextrin Derivatives
Selective Modifications of Cyclodextrins .......................................................... 33
Cyclodextrin Derivatives with Enhanced Solubilizing Power and Lower
Toxicity ........................................................................................................ 37
α-Cycloaltrin: Conformation and Properties in the Solid State and
Aqueous Solution ........................................................................................ 41
Symmetrical and Non-Symmetrical Urea Derivatives of β-Cyclodextrin
and Piperazine: Application in Capillary Electrophoresis ........................... 49
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viii Contents
Sulfated Cyclodextrin Derivatives ..................................................................... 53
The Molecular Geometries of Cyclofructins ..................................................... 57
Molecular Geometries of Furanoid β(1→3) and β(1→6)-Linked
Cyclogalactins ............................................................................................. 63
Synthesis and Characterization of Peptido-Cyclodextrins Dedicated to
Drug Targeting ............................................................................................ 69
Mono-6-Tosyl-β-Cyclodextrin: Preparation, Hydrolysis and Self-
Inclusion Studies in Aqueous Solution ....................................................... 73
Thiourea-Bridged β-Cyclodextrin Conjugates .................................................. 77
Associations of Amphiphilic Degradable Polymers with β-Cyclodextrin
Polymers: pH – Dependant Network .......................................................... 81
Original Associating System between Hydrophobically Modified N, N-
Dimethylacrylamide Hydroxyethyl Methacrylate Copolymers and
Water Soluble β-Cyclodextrins Polymers ................................................... 85
Production of Cyclomaltonaose (δ-Cyclodextrin) by Various
Cyclodextrin Glycosyltransferases ............................................................. 89
Capillary Electrophoretic Investigation of the Inclusion Complex
Forming Properties of Large Cyclodextrins ................................................ 93
New Sorbents Containing β-Cyclodextrin: Synthesis, Characterization
and Sorption Properties .............................................................................. 97
Preparation and Characterization of Sorbents Containing βCD
Derivatives Coated or Grafted Onto Silica Gel .......................................... 101
Comparative Cation Chelating Properties of Per (3,6 Anhydro), -and
Per (3,6 Anhydro-2-OMe) α-Cyclodextrins ................................................ 105
Synthesis of Cyclodextrin Glycerol Ethers and Investigation of Their
Binding Properties ...................................................................................... 109
Conformational Equilibria of α-Cycloaltrin in Solutions .................................... 113
The Synthesis of Oligosaccharide-Branched Cyclodextrins ............................ 117
Crystallization of Partially O-Alkylated β-Cyclodextrins by Including
Polymers ..................................................................................................... 121
Synthesis of Per (2,3-di-o-Hexanoyl)-β-Cyclodextrin and
Characterization of Amphiphilic β-Cyclodextrin Nanoparticles .................. 125
Thiamine-Appended Cyclodextrin Dimer as a Ligase Model ........................... 129
Substituted Cyclodextrins with Amino Acids as Hydrolysis Enzyme
Models ......................................................................................................... 133
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Contents ix
Synthesis and Molecular Recognition Abilities of Modified γ-
Cyclodextrins Bearing Two Pyrene Moieties ............................................. 137
Molecular "Lego" Composed of Monosubstituted Cyclodextrins ..................... 141
Structural Analyses of Sugar Branched Cyclodextrin Derivatives by the
Post-Source Decay Fragment Method in MALDI-TOF Mass
Spectrometry ............................................................................................... 145
Three Dimensional Structure of Branched α-Cyclodextrins in Solution .......... 149
Synthesis and Enhanced Chemiluminescence of New
Monocyclomaltooligosaccharide-Bound
6-Phenylimidazo[1,2-α]Pyrazin-3(7H)-Ones .............................................. 153
Thermal Behaviour and Phase Transitions of
Cyclomaltononaose(δ-Cyclodextrin) .......................................................... 157
Textile Finishing with MCT-β-Cyclodextrin ....................................................... 161
Isolation, Purification, and Characterization of Cyclomaltooctadecaose
(ν-CD) and Cyclomaltononadecaose (ξ-CD) ............................................. 167
Supramolecular Assembly of Polycharged β-Cyclodextrin Derivatives:
Formation of Heterodimers between a Polyamino- and a
Polysulfonato-β-Cyclodextrin ...................................................................... 171
Insoluble Polymers with High Amounts of β CD: Characterization and
Adsorption Capacity .................................................................................... 175
Influence of pH on the Stability of the Inclusion Complex of Methyl
Orange and β-Cyclodextrin ......................................................................... 179
An Improved Synthesis of Per(6-Deoxyhalo) Cyclodextrins Using
TV-Halo Succinimides-Triphenylphosphine in Dimethylformamide .......... 183
3. Cyclodextrins in Pharmacy and Biotechnology
Anti-Asthmatic-Cyclodextrin Inclusion Complex for Pulmonary Delivery ........ 189
Cyclodextrin-Containing Membranes. Synthesis and Separation
Properties in Pertraction ............................................................................. 193
Efficacy and Safety of Cyclodextrins in Nasal Drug Delivery ........................... 197
A Preliminary Study of a β-Cyclodextrin/Salbutamol Complex for
Possible Use Is a Dry Powder Inhaler ........................................................ 203
Solubility of a Isoxazolyl-Naphtoquinone by Complexation with
Hydropxypropyl-β-Cyclodextrin .................................................................. 207
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A Comparative Study of the Dissolution Properties of Piroxicam-β-
Cyclodextrin Inclusion Complexes Prepared by Different Methods .......... 211
A Comparative Pharmacokinetic Study of Intravenous Solutions of
Miconazole with or Without Cyclodextrins ................................................. 215
Development of a Sustained Release Dosage Form Containing a
Diclofenac-Cyclodextrin Inclusion Complex ............................................... 219
Influence of Cyclodextrins on the Solubility and the Pharmacokinetics of
Albendazole ................................................................................................ 223
Evaluation of Spironolactone Bioavailability from Solutions of β-
Cyclodextrin Derivatives in Rats ................................................................. 227
Chemosensors of Modified Cyclodextrins for Detecting Molecules ................ 231
Molecularly Imprinted Cyclodextrin Polymers as Artificial
Receptors – the Requisites for Remarkable Imprinting ............................. 235
New Developments in Improvement of Drug Solubility and Availability
by Cyclodextrins ......................................................................................... 239
Design and Evaluation of Colon-Specific Drug Delivery System Based
on Cyclodextrin Conjugates ....................................................................... 247
The Effect of 2-Hydroxypropyl-β-Cyclodextrin on the Solubility, Stability
and Brain Targeting of Chemical Delivery Systems for
Neuropeptides ............................................................................................ 251
Enhanced Complexation Efficacy of Cyclodextrins .......................................... 257
Coadministration of a Water-Soluble Polymer Increases the Usefulness
of Cyclodextrins in Solid Oral Dosage Forms ............................................ 261
Evaluation of Degradation Studies Performed in Aqueous Cyclodextrin
Solutions ..................................................................................................... 265
The Effect of Cellulose Ethers on Indomethacin/Cyclodextrin
Complexation .............................................................................................. 269
Physicochemical Characterization and Pharmacological Properties of
Different Cyclodextrin Complexes of a Platelet Activating Factor
Receptor Antagonist: SR 27417A .............................................................. 273
Mutual Solubility Enhancement by Binary and Multicomponent
Complexation of Clomiphene and Tamoxifen ............................................ 277
Preparation and Characterization of Piroxicam Alkali-Salt-γ-
Cyclodextrin Complexes ............................................................................. 281
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Contents xi
Design and Evaluation of a Porosity-Controlled Osmotic Pump Tablet
for Chlorpromazine Using (SBE) -β-CD ................................................... 285
7m
Comparison of the Solubilizing Effect of Ethyl Carbonate of
γ-Cyclodextrin to Other Cyclodextrin Derivatives ....................................... 289
Improved Solubility and Oral Bioavailability of Cyclosporin a by
Hydrophilic Cyclodextrin Complexation ...................................................... 293
Effect of Amorphous β-Cyclodextrins on Crystallization and
Polymorphic Transition of Tolbutamide in Solid State ............................... 297
A New Method for Determination of Stability Constant of Cyclodextrin
Complexes by Membrane Permeation Technique .................................... 301
Effects of Hydrophilic Cyclodextrins in Aggregation of Recombinant
Human Growth Hormone ........................................................................... 305
Preparation and Pharmaceutical Evaluation of Heptakis
(2,6-di-O-Methyl-3-O-acetyl)-β-Cyclodextrin .............................................. 309
Characterization of Itraconazole/2-Hydroxypropyl-β-Cyclodextrin
Inclusion Complex in Aqueous Solution ..................................................... 313
Sustained Release and Intestinal Absorption of Drug from the
Hydrophobic α-, β- and γ-Cyclodextrin Complexes ................................... 317
Hydroxypropyl Gamma-Cyclodextrin as a Solubiliser and Dissolution
Enhancing Agent: the Case of Tolbutamide-a Poorly Water-Soluble
Drug ............................................................................................................ 321
Interactions of Surfactants with Tolbutamide-β-Cyclodextrin Inclusion
Compound: the Consequence in Drug Dissolution .................................... 325
Differential Scanning Calorimetry as an Analytical Tool in Determining
the Interaction between Drug and Cyclodextrin ......................................... 329
Solubility Enhancer Decreases the Dissolution of Complexed Drugs:
Effect of Sodium-Lauryl-Sulfate on Dissolution Profile of Complexed
Drugs ........................................................................................................... 333
Interaction between Ranitidine Hydrochloride and β-Cyclodextrin .................. 337
Physical and Chemical Changes in the Properties of β-Cyclodextrin on
Inclusion Complex Formation ..................................................................... 341
A New Nonlinear Method on Determination of the Stability Constant for
the Steroid-Cyclodextrin Complex .............................................................. 343
2,4-Dichlorophenoxyacetic Acid α- and β CD Inclusion Complexes. A
1H-Nuclear Magnetic Resonance Study ..................................................... 347
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