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Drugs: Photochemistry and Photostability Drugs Photochemistry and Photostability Edited by A. Albini Dell’ Universita Di Pavia, Italy E. Fasani Dell’ Universita Di Pavia, Italy THE ROYAL Services Based on the proceedingsof the 2nd International Meeting on Photostability of Drugs held in Pavia, Italy on 6 1 7 September 1997. Special Publication No. 225 ISBN 0-85404-743-3 A catalogue record for this book is available from the British Library 0 The Royal Society of Chemistry 1998 All rights reserved. Apartfrom any fair dealing for the purpose of research or private study, or criticism or review as permitted under the terms of the VK Copyright, Designs and Patents Act, 1988, this publication may not be reproduced, stored or transmitted, in anyform or by any means, without the prior permission in writing of The Royal Societyof Chemistry,or in the case of reprographic reproduction only in accordance with the terms of the licences issued by the Copyright LicensingAgency in the VK,or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK.Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistryat the address printed on this page. Published by The Royal Society of Chemistry, Thomas Graham House, Science Park,Milton Road, Cambridge CB4 4WF, UK For further information see our web site at www.rsc.org Printed and bound by MPG Books Ltd, Bodmin, Cornwall, UK. Preface That many drugs, just as non-pharmaceutically active compounds, are photoreactive has been long known. As an example, Pasteur noticed the photolability of quinine in 1846' and industry-sponsored studies on the photochemistry of drugs were already systematically carried out in the twenties.' However, until recently the matter has received only limited attention, mainly on the assumption that by using the appropriate opaque container no significant decomposition could have taken place. As a result, the available knowledge is quite sparse. All Pharmacopoeias mention that some drugs have to be protected from light, but one cannot rely upon such qualitative (and incomplete) information. The number of reports in specialised journals is growing, but remains low. The situation has changed recently, however, and this is due to several causes. First, more sensitive analytical methods are now available and the standard of purity required has become more and more stringent. Thus, even traces of (photochemically formed) impurities must be revealed. This has led to the formulation by ICH of internationally accepted Guidelines for Drug Photostability (see p. 66), which have been implemented since January 1998. Second, there have been cases of promising drugs which have been discarded late in the development process due to a too high photolability. The development of a new drug is very expensive and this calls for more attention to the photochemical properties of a molecule early in the development, or for a way to predict the photostability of a new molecule. Third, significant phototoxic effects have been ascertained for several drugs in common clinically, and in general there is now more attention to the phototoxic effects of drugs (as well as of cosmetic products and sunscreens). Here again, control of the photobiological effects demands that the photohemistry of the active molecule is known. The awareness of this situation has led to the organisation of two international meetings, the first one in Oslo in June 1995, the latter in Pavia in September 1997. Both have been attended by scientists of different affiliations (industries, regulatory agencies, universities) and of different specialisations (pharmaceutical techniques, pharmaceutical chemistry, photochemistry, photophysics, biology, toxicology). The need for a close collaboration between such different areas has been recognised. vi Drugs:Photochemistry and Photostability This book is based on the communications presented at the Pavia meeting, and is organised as follows. 1. Introductory part. This includes an overview on the photochemistry of drugs and on some related problems (dependence on conditions, protection of photolabile drugs) by the editors, the text of the ICH Guidelines on Photostability, and an introduction to medicinal chemistry with attention to the kinetics of photochemical processes by Beijerbergen van Henegouwen. 2. Photochemistry of drugs. Photochemistry of drug families, viz. antimalarials (TQnnesen),diuretic drugs (Moore), antimycotics (Thoma), phenothiazines (Glass), antiinflammatory drugs (Monti), coumarins (Zobel), sunscreens (Allen), Leukotriene B4 antagonists (Webb). The photosensitising properties by some drugs are treated by De Guidi and Tronchin. 3. Photostability of drugs. Methods for implementing the ICH guidelines (Drew) and a discussion of their application (Helboe); the choice of lamps (Piechocki) and in general of the appropriate conditions for carrying out photostability studies (Boxhammer and Forbes); the choice of the actinometer (Favaro and Bovina). It is hoped that these contributions may help to determine on a sound basis the significance of drug photostability for the pharmaceutical industry and also help to serve as support for phototoxicity studies. Thanks are due to Mr F. Barberis and Misses M. Di Muri, M. Parente and F. Stomeo for their help in preparing the manuscripts. A. Albini and E. Fasani 1. L. Pasteur, Comp. Rend., 1853,37, 110. 2. J. Piechocki, p. 247. Pavia, March 1998 Contents Photochemistry of Drugs: An Overview and Practical Problems A. Albini and E. Fasani 1 Medicinal Photochemistry (An Introduction with Attention to Kinetic Aspects) G.M.J. Beijersbergen van Henegouwen 74 Photoreactivity of Selected Antimalarial Compounds in Solution and in the Solid State H.H. T$nnesen, S. Kristensen and K. Nord 87 Photochemistry of Diuretic Drugs in Solution D. E. Moore 100 New Results in the Photoinstability of Antimycotics K. Thoma and N.Kiibler 116 Photoreactivity versus Activity of a Selected Class of Phenothiazines: A Comparative Study B.D. Glass, M.E. Brown and P.M. Drummond 134 Photoprocesses in Photosensitising Drugs Containing a Benzophenone-like Chromophore S. Monti, S. Sortino, S. Encinas, G. Marconi, G. De Guidi and M.A. Miranda 150 Photostability of Coumarin J.M. Lynch and A.M. Zobel 162 Photostabilities of Several Chemical Compounds used as Active Ingredients in Sunscreens J.M. Allen, S.K.Allen and B. Lingg 171 An Analytical and Structural Study of the Photostability of some Leukotriene B4 Antagonists C.O@ord, M.L. Webb, K.H. Cattanach, F.H. Cottee, R.E. Escott, I.D. Pitfield and J.J. Richards 182 ... Vlll Drugs: Photochemistry and Photostability Molecular Mechanisms of Photosensitization Induced by Drugs on Biological Systems and Design of Photoprotective Systems G. De Guidi, G. Condorelli, L.L. Costanzo, S. GiufSrida, S. Monti and S. Sortino 194 A Comparison between the Photochemical and Photosensitising Properties of Different Drugs M. Tronchin, F. Callegarin, F. Elisei, U.Mazzucato, E. Reddi and G. Jori 21 1 Photostability of Drug Substances and Drug Products: A Validated Reference Method for Implementing the ICH Photostability Study Guidelines H.D. Drew 227 The Elaboration and Application of the ICH Guideline on Photostability: A European View P. Helboe 243 Selecting the Right Source for Pharmaceutical Photostability Testing J.T. Piechocki 247 Design and Validation Characteristics of Environmental Chambers for Photostability Testing J. Boxhammer and C. Willwoldt 272 Design Limits and Qualification Issues for Room-size Solar Simulators in a GLP Environment P.D. Forbes 288 Actinometry: Concepts and Experiements G. Favaro 295 trans-2-Nitrocinnamaldehyde as Chemical Actinometer for the UV-A Range in Photostability Testing of Pharmaceuticals E. Bovina, P. De Filippis, V . Cavrini and R. Ballardini 305 Subject Index 3 17