Photochemistry and Photostability

Edited by A. Albini and E. Fasani

Drugs: Photochemistry and Photostability


Photochemistry and Photostability

Edited by A. Albini

Dell' Universita Di Pavia, Italy £. Fasani

Dell' Università Di Pavia, Italy te.- THE ROYAL SOCIETY OF CHEMISTRY

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Based on the proceedings of the 2nd International Meeting on Photostability of Drugs held in Pavia, Italy on 4-17 September 1997.

Special Publication No. 225 ISBN 0-85404-743-3

A catalogue record for this book is available from the British Library © The Royal Society of Chemistry 1998 All rights reserved.

Apart from any fair dealing for the purpose of research or private study, or criticism or review as permitted under the terms of the UK Copyright, Designs and Patents Act, 1988, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry, or in the case of reprographic reproduction only in accordance with the terms of the licences issued by the Copyright Licensing Agency in the UK, 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 Chemistry at 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.


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 18461 and industry-sponsored studies on the photochemistry of drugs were already systematically carried out in the twenties.2 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.

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 (T0nnesen), 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 Pavia, March 1998


Photochemistry of Drags: An Overview and Practical Problems 1

A. Albini and E. Fasani

Medicinal Photochemistry (An Introduction with Attention to Kinetic Aspects) 74

G.M.J. Beijersbergen van Henegouwen

Photoreactivity of Selected Antimalarial Compounds in Solution and in the 87

Solid State

H.H. T0nnesen, S. Kristensen and K. Nord

Photochemistry of Diuretic Drugs in Solution 100

D.E. Moore

New Results in the Photoinstability of Antimycotics 116

K. Thoma and N. Kubier

Photoreactivity versus Activity of a Selected Class of Phenothiazines: 134

A Comparative Study

Photoprocesses in Photosensitising Drugs Containing a Benzophenone-like 150


S. Monti, S. Sortino, S. Encinas, G. Marconi, G. De Guidi and M.A. Miranda

Photostability of Coumarin 162

Photostabiiities of Several Chemical Compounds used as Active Ingredients 171

in Sunscreens

An Analytical and Structural Study of the Photostability of some Leukotriene B4 182 Antagonists

C. Orford, M.L. Webb, K.H. Cattanach, F.H. Cottee, R.E. Escott,

I.D. Pitfield and J.J. Richards

Molecular Mechanisms of Photosensitization Induced by Drugs on Biological 194

Systems and Design of Photoprotective Systems

G. De Guidi, G. Condorelli, L.L. Costanzo, S. Giuffrida, S. Monti and S. Sortino

A Comparison between the Photochemical and Photosensitising Properties of 211

Different Drugs

M. Tronchin, F. Callegarin, F. Elisei, U. Mazzucato, E. Reddi and

G. Jori

Photostability of Drug Substances and Drug Products: A Validated Reference 227

Method for Implementing the ICH Photostability Study Guidelines

The Elaboration and Application of the ICH Guideline on Photostability: A 243

European View P. Helboe

Selecting the Right Source for Pharmaceutical Photostability Testing 247

J.T. Piechocki

Design and Validation Characteristics of Environmental Chambers for 272

Photostability Testing

J. Boxhammer and C. Willwoldt

Design Limits and Qualification Issues for Room-size Solar Simulators in a GLP 288 Environment

P.D. Forbes

Actinometry: Concepts and Experiements 295

G. Favaro inms-2-Nitrocinnamaldehyde as Chemical Actinometer for the UV-A Range in 305 Photostability Testing of Pharmaceuticals

E. Bovina, P. De Filippis, V. Cavrini and R. Ballardini

Subject Index

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