Useful Terms and Expressions in the Photoreactivity Testing of Drugs

Actinometer A chemical system or physical device which determines the number of photons in a beam integrally or per unit time. This name is commonly applied to devices used in the ultraviolet and visible wavelength ranges. Solutions of iron(III) oxalate can be used as a chemical actinometer while thermopiles are examples of physical devices giving a reading that can be correlated to the number of photons detected. Action spectrum A plot of the reciprocal of the number of incident photons...

Info

Figure 2.3 Spectral power distribution of daylight and white fluorescent light sources. (Redrawn from Thorington, L., Ann. N. Y. Acad. Sci., 453 28-54,1985.) particular combination of photon source and absorbing substance. A familiar example of this definition of an action spectrum is the sunburn or erythemal effectiveness spectrum, which is the overlap of the sunlight UV spectrum and the absorption spectra of proteins and nucleic acids as shown in Figure 2.4 (Parrish et al., 1978). The sunburn...

Spectral Characteristics Of Sunlight And Artificial Light Sources

In the course of manufacture and storage through ultimate use by the consumer, pharmaceuticals may be exposed to light from a number of sources, ranging from direct sunlight through filtered sunlight to a variety of artificial light conditions. In 300 400 500 600 700 800 900 1000 1100 WAVELENGTH (nm) Figure 2.2 Spectral power distribution of sunlight compared with an incandescent lamp (the 300 400 500 600 700 800 900 1000 1100 WAVELENGTH (nm) Figure 2.2 Spectral power distribution of sunlight...

References

Aloisi, G.G., Elisei, F., Moro, S., Miolo, G., and Dall'Acqua, F. (2000) Photophysical properties of the lowest excited singlet and triplet states of thio- and seleno-psoralens, Photochem. Photobiol., 71, 506-513. Amouyal, E., Bensasson, R.V., and Land, E.J. (1974) Triplet states of ubiquinone analogs studied by ultra violet and electron nanosecond irradiation, Photochem. Photobiol., 20, 415-422. Andrisano,V., Gotti, R., Leoni, A., and Cavrini, V. (1999) Photodegradation studies on atenolol by...

A

Figure 3.13 Zero order (linear) plot for the photodegradation of ketrolac tromethamine (initial concentration 100 mg mL) in ethanol solution under argon and air atmospheres. (Replotted data from Gu et al., 1988.) Figure 3.13 Zero order (linear) plot for the photodegradation of ketrolac tromethamine (initial concentration 100 mg mL) in ethanol solution under argon and air atmospheres. (Replotted data from Gu et al., 1988.) This type of kinetic order variation is referred to as saturation...

Absorption Of Radiation In Materials

Based on the incident spectral irradiance of radiation, e.g., sunlight, only the radiation absorbed by a material according to its spectral absorption characteristics, e(l), may produce an effect in the material. A very small part of the absorbed radiation will result in primary photochemical processes. The UV range and, partially, the visible wavelength range, of solar radiation have a major influence. Determination of the spectral sensitivity (Trubiroha, 1987) and the activation spectrum...

Acknowledgments

Vicki S. Krage for her patience and assistance in the preparation of this chapter, which was presented in part in the following three articles Photolytic degradation of drugs, Am. J. Hosp. Pharm., 49, 2704-2705, 1992 Photochemical considerations of light-sensitive cold kits and radiopharmaceuticals, J. Nucl. Med. Technol., 21, 90-91, 1993 The packaging of light-sensitive cold kits, J. Nucl. Med. Technol., 23, 45-46, 1995 and Light-sensitive cold kits and the...

Action Mechanisms Of Pdt On The Cellular Level

Depending on the conditions, PDT destroys tumors by a direct effect on tumor cells or by an effect on cells of the vascular system (Moan and Berg, 1992 Dougherty et al., 1998 Morton et al., 2002). The endothelial cells lining the vascular walls seem to take up large concentrations of photosensitizers after intravenous, as well as intraperitoneal, administration. Cells exposed to light in the presence of photosensitizers can be destroyed through a number of mechanisms. Large light exposures of...

Active Forms Of Oxygen And Oxidant Species

As noted previously, formation of free radicals or singlet oxygen is very often accompanied by the generation of various other short-lived species (such as hydroxyl radicals, superoxide radicals, and peroxyl radicals) that, together with singlet oxygen, are termed reactive oxygen species (Pryor, 1986). For example, superoxide radicals can be generated following photoionization (Equation 2.4) from singlet oxygen by electron transfer between O2 and the ground state sensitizer (Equation 2.18) or...

Addressing the Problem of Light Instability during Formulation Development

Clapham, and F. D. Sanderson CONTENTS 13.2 Photoinstability of the Drug 13.3 Photoinstability of 13.3.1 Intravenous 13.3.1.1 Light Degradation of the Drug Substance as a Powdered 13.3.1.2 Light Degradation of the Drug Substance in Solution 290 13.3.2 Topical 13.3.3 Solid Oral Dosage

Alternatives to Quinine

Because quinine does not meet the generally accepted requirements of a chemical actinometer (Bunce, 1989), possible alternatives have been investigated. Recent work (Allen et al., 2000) has confirmed that 2-nitro benzaldehyde (2NB) is converted to 2-nitroso benzoic acid on irradiation, following the original work (Pitts, 1966), and that the amount of acid formed can be readily estimated by titration. Alternatively, the amount of base corresponding to the acid liberated after the required...

And Method Validation

The ICH Guideline states that the purpose of forced degradation studies is to evaluate the overall photosensitivity of the material for method development purposes and or degradation pathway elucidation. No specific testing conditions are recommended. Clearly, in order to develop valid methods for determining the photostability of drug substances and products, a forced photodegradation study on the drug substance should be performed. It is easier to develop and largely validate methods for the...

Approaches To Stabilization Of Formulations Against Photodegradation

In principle, formulations containing drugs susceptible to photoreactions should be clearly marked and stored appropriately. However, in some situations the ideals are not maintained, and it is worth considering whether special procedures or additives should be included. Using an inert atmosphere in the container is an important first approach that, clearly, will limit reactions involving oxygen. However, many examples have been found in which oxygen does not take part, e.g., sulfamethoxazole....

Aromatics And Heteroaromatics

Aromatic and heteroaromatic rings are often a feature of drug molecules and lead to a strong absorption in the UV. With carbocyclic aromatics, the reactions observed involve a substituent, not the ring, and are classified accordingly. Heterocycles give the same types of reactions and, furthermore, undergo ring cleavage and fragmentation. Ring halogenated aromatics and heterocycles often undergo substitution of the halogen or reduction upon irradiation (Scheme 4.11). Perhaps unexpectedly, in...

Basics of Photochemistry

In order to understand the basis of test design and the limitations of particular tests, it is important to understand the basic principles of photochemistry. Concepts such as the relationship between the photon flux of a source and its irradiance quantum yield and only absorbed photons causing photochemical reactions (Moore, 1987, 1996a) are fundamental. The spectral power distribution (SPD) of a source (i.e., the energy emitted as a function of wavelength and the absorption spectrum of the...

Biological Effects

Figure 1.1 Possible consequences of drug photoinstability. in all cases. Derivatives of the drug nifedipine have a photochemical half-life of only a few minutes, while other drugs may decompose only a few percent after several weeks' exposure (Squella et al., 1990). All are sensitive to light, but the same precautions are not required in handling these compounds. Knowledge about the photostability of drug substances and drug products is important in order to evaluate Handling, packaging, and...

Carboncarbon Double Bonds

Simple alkenes do not absorb ambient light, but may react upon photosensitization by an added sensitizer (which may be an impurity or a component of the drug formulation). As an example, photosensitized oxidation may be quite efficient. Conjugated alkenes and polyenes absorb strongly in the UV (in some cases also in the visible) and photoreact. 4.2.1 Isomerization and Rearrangement Conjugated olefins undergo E Z isomerization (Scheme 4.1a), as shown in the case of vitamin A, retinal, and its...

Carbonheteroatom Double Bond

Aldehydes and ketones are probably the most investigated class of compounds in photochemistry. Even nonconjugated derivatives absorb in the UV-B region, and conjugated compouds absorb well into UV-A. The reactive excited state is often an np* state of radical character, the singlet, or more frequently, the triplet. Compounds containing a carbon-nitrogen (or sulfur) double bond often react similarly. 4.4.1 Fragmentation a to a C O Double Bond A typical reaction of ketones is a-cleavage (Norrish...

Ch3ch

Narcotic analgesic drug methadone (90, Scheme 4.48) (Reisch et al., 1972 Denson et al., 1991) or for metyrapone (91, Scheme 4.49), where the radical pair that were formed recombine, giving in part an unsaturated compound that rapidly polymerizes (Fasani et al., 1997b). Alpha-cleavage further occurs in cyclic (particularly five-membered) ketones, e.g., androstan-17-one derivatives, which undergo epimerization at ring D (Scheme 4.50) via homolytic C-C bond cleavage and radical recombination

Chemical Actinometry

Although physical instrumentation is more convenient, lack of an integrated output and the need for regular calibration are hindrances to its widespread application to measurement of the number of photons absorbed by a sample. The alternative is to use a chemical actinometer system in which a photochemical reaction of known characteristics is monitored when subjected to the same irradiation conditions as the test sample. When used in the fashion described next, the chemical actinometer measures...

Ci

Figure 11.5 The structures of flourescein and Rose Bengal. They have hetercyclic ring systems. such as chlorpromazine (max 310 nm), tetracycline (max, 365 nm), and the porphyrins (392 nm 500 to 650 nm) (Roberts, 1984). In the older human, drugs dietary supplements, dyes (i.e., hypericin) and diagnostic dyes (photodynamic therapy porphyrins) that absorb in the 400- to 600-nm region could produce phototoxic damage to the lens (Schey et al., 2000) and the retina. In very young humans, all drugs...

Co

Methyl Nitrosopropane Epr

Figure 2.10 Transient absorption spectra obtained on laser flash photolysis at 266 nm of naproxen (0.1 mM pH 7.0). The spectra were recorded 0.02 ( ), 0.26 (o), and 1.29 msec ( ) after the flash. (From Moore, D.E. and Chappuis, PP., Photochem. Photobiol., 47 173-181, 1988.) Figure 2.10 Transient absorption spectra obtained on laser flash photolysis at 266 nm of naproxen (0.1 mM pH 7.0). The spectra were recorded 0.02 ( ), 0.26 (o), and 1.29 msec ( ) after the flash. (From Moore, D.E. and...

Conclusion

Photostability testing of the drug substance is undertaken to evaluate the overall photosensitivity of the material for development and validation purposes and to provide information necessary for handling, packaging, and labeling. A photostabil-ity assay for pharmaceutical products should provide information related to the practical use of the product, i.e., light-exposure conditions that the product will experience under its normal applications. Well-designed photostability studies ensure the...

Conclusions

In order to provide a sound basis for making decisions with regard to labeling and the use of protective packs, pharmaceutical laboratories should determine the susceptibility of their products to simulated glass-filtered daylight, which can be optionally supplemented with visible light. The ICH Guideline on Photostability represents a realistic test, with an acceptable level of reproducibility to the regulatory agencies, and is reasonably straightforward to conduct in pharmaceutical R& D...

Consequences Of Excited State Processes To Drug Stability In Vitro

The photodecomposition reactions of a large number of drug substances were reviewed by Greenhill and McLelland (1990) and Albini and Fasani (1998). A catalogue of the most common reaction types shows that, following light absorption, a drug might experience (see also Chapter 4) It is also possible that a drug sensitizes its own degradation. Elucidating the mechanism for some photodegradation reactions is very difficult because several pathways are reported for many drugs. Additionally, the...

Contributors

Department of Organic Chemistry University of Pavia Pavia, Italy Research Alnwick Research Centre Alnwick, Northumberland, U.K. Eli Lilly and Company Lilly Corporate Center Indianapolis, IN Atlas Material Testing Technology GmbH Sanofi-Synthelabo Research Alnwick Research Centre Alnwick, Northumberland, U.K. Pharmaceutical Technologies GlaxoSmithKline Pharmaceuticals Harlow, Essex, U.K. Pharmaceutical Technologies GlaxoSmithKline Pharmaceuticals Harlow, Essex, U.K. Department of Organic...

Direct Reactions From Excited States Of The Drug

The excited molecule has a different electronic character compared to the ground state and is often able to form a complex (called an exciplex) with another species (designated as Q), i.e., the complex is D*Q. The symbol Q is used because, in effect, the interacting molecule is a quencher of the native fluorescence of D. Sometimes, at a high concentration of the absorbing molecule, this occurs with the ground state (in which case the D*D species formed is called an excimer). The formation of...

En Iso 2001

Note ISO International Organization for Standardization TC technical committee DIS draft international standard. - Ultraviolet radiation of wavelengths shorter than those occurring in natural exposure - Spectral distribution that differs widely from that of daylight - High specimen temperatures, particularly with materials that readily undergo changes from thermal effects alone Statement that all testing conditions need to be ensured on specimen area where the materials are really exposed...

Esr

Radical and oxyradical intermediates Cell culture whole tissue. The first reported assay for phototoxicity in human ocular cells (Roberts, l981) measured changes in macromolecular synthesis in the presence and absence of a light-activated drug. Other studies have assessed damage to corneal and uveal melanocytes, lenticular and retinal cells by measuring pump function and enzyme activities in vitro and in situ (Hu et al., 2002 Andley et al., 2004 Roberts et al., l994 Organisiak and Winkler, 1994...

Evaluation of Results

Confirmatory studies should identify precautionary measures needed in manufacturing or in formulation of the drug product, and if light resistant packaging is needed. When evaluating the results of confirmatory studies to determine whether change due to exposure to light is acceptable, it is important to consider the results from the other formal stability studies in order to assure that the drug will be within justified limits at the time of use (see the relevant ICH Stability and Impurity...

Filter Effect and Homogeneity of Samples

Liquid samples may have a high optical density, thus leading to a severe filter effect, i.e., only a thin surface layer can absorb the radiation, thereby protecting the inner part of the preparation from exposure. The filter effect should be avoided in kinetic and mechanistic studies (Chapter 3). This can be obtained by diluting and stirring the samples the stirring must be standardized to obtain reproducible results. The purpose of photostability testing according to the ICH guideline is to...

Formulation Approaches for Improving Solubility and Its Impact on Drug Photostability

16.1.1 Why the Formulation Process Can Influence Drug 16.2 Solid 16.2.1 Photochemical Reactions in the Solid 16.2.2 Dispersion of Drugs in 16.2.2.1 Solid 16.2.2.3 Polymeric 16.2.4 Reduction in Particle 16.3 Arranged Liquid 16.3.1 Complex Formation with 16.3.2 Micellar 16.4 Photostabilization of Drugs in Dosage

H

Decomposition of trace amounts of peroxide or hydroperoxide impurities. Indeed, the development of biodegradable packaging is an application of this principle. Figure 2.8 shows an example of the chain reaction process leading to the breakdown of a hydrocarbon polymer backbone. In biological systems, free radicals can react with cellular macromolecules in a variety of ways, the most important of which is hydrogen abstraction from DNA leading to chain scission or cross-linking. In proteins,...

Mbf

Figure 15.4 Examples of caged compounds and other photoactivatable drugs. (a) and (b) on photolysis the o-nitrobenzyl protecting group detaches and releases ATP and cAMP, respectively (c) photosensitive chelator. The cis form of the molecule binds Zn2+ but the trans form does not (d) frequently used photosensitive calcium chelators. Nitr-2 (R CH3), Nitr-5 (R h) (e) ICYP-diazirine, a photoaffinity reagent that becomes covalently attached to b-adrenergic receptors upon photolysis. inactive to an...

Ho

An example of the complexity of path followed is shown for the case of 1-dehydrotestosterone acetate (97, Scheme 4.57) (Frei et al., 1966). Many further steroidal dienones have been found to undergo similar photoreac-tions (Arakawa et al., 1985 Hidaka et al., 1980), including prednisone (Williams et al., 1979) prednisolone (Williams et al., 1980) dexamethasone (Reisch et al., 1986b) betamethasone and some of its acetates (Thoma et al., 1987) and methyl prednisolone suleptanate (98,...

Hold

Laser pulse and closes after the event under examination is completed, and appropriate filters are placed between the analyzing lamp and the sample in order to minimize the photolysis of the sample by the monitoring light. The monitoring light is then dispersed in wavelength by a monochromator and then on to a photodetector. The transmittance of light at this wavelength is detected by this photodetector before, during and after the laser pulse. The detector is also connected to an automatic...

How to Determine Exposure Time

The ICH guideline does not specify an irradiance level, only the overall illumination (i.e., end criterion). The irradiance level can therefore be adjusted according to individual requirements. Test conditions corresponding to the maximum output of the lamp will often be the first choice because the exposure time can thus be reduced. It is, however, important to realize that a high irradiance level can change the mechanisms of the degradation process even when the spectral distribution of the...

How To Obtain Information On Drug Photoreactivity

The ICH Harmonized Tripartite Guideline on Stability Testing of New Drug Substances and Products (ICH Q1B) was implemented in Europe in 1996 and in the U.S. and Japan in 1997. Since January 1, 1998 it has been obligatory to provide photostability data for all new drug license applications to the markets in the U.S., the European Union, Japan, and Canada. Photostability testing of drugs may be considered as consisting of two parts. Stress testing is undertaken to evaluate the overall...

How to Obtain the Correct Overall Illumination

For confirmatory studies, the ICH guideline recommends a total exposure of not less than 200 Wh m-2 in the UV range (320 to 400 nm) and 1.2 million lx h in the visible range (400 to 800 nm). Inside a room, the UV level decreases rapidly outside the region of direct sunlight (i.e., farther away from any windows). The minimum visible exposure levels proposed in the ICH guideline represent approximately 3 months of continuous exposure to artificial (visible) light in the pharmacy, warehouse, or...

I

4.3.6 Ring Rearrangement and Ring Cleavage in Heterocycles The azetidinone ring is cleaved in penem (62) to give thiazole (63) and 3-hydroxy-butyric acid in methanolic solution in the crystals, intramolecular hydrogen abstraction occurs and the biradical is trapped by oxygen to yield hydroperoxide (64) (see

1

Figure 6.8 Artificial daylight fluorescent tube. Figure 6.8 Artificial daylight fluorescent tube. irradiance in the 380- to 400-nm region is relatively low (2.5 ) compared to a glass-filtered xenon source (approximately 4 ), and the total UV is also slightly lower (8 compared with 9.5 for glass-filtered xenon). However, this and similar full spectrum or artificial daylight tubes do provide an acceptable UV spectral distribution for photostability testing. For tests simulating indoor light, for...

Ues

Lateral diffusion of degradation products Interliposome exchange Liposomal aggregation Membrane fusion Macroscopic aggregation Precitpitation of multilamellar lipid Figure 15.3 Postulated multistep release process by photo-oxidation of semisynthetic plas-menylcholine liposomes. Liposomal aggregation Membrane fusion Deactivation of an excited state molecule may follow a nonradiative pathway. If the absorbed energy is released as heat, a local temperature increase may induce chemical changes to...

In Vitro Photosensitization Studies

The components of the in vitro assay discussed thus far are important for a better understanding of the overall photoreactivity of a drug substance or preparation. To assess the potential of a compound or preparation to provoke adverse effects, a number of other aspects must be taken into account. An extended in vitro screening will also in most cases be needed. The photosensitization studies should be planned according to the knowledge obtained so far from the in vitro assay and from the...

In Vitro Screening of the Photoreactivity of Antimalarials A Test Case

Hanne Hjorth T0nnesen and Solveig Kristensen CONTENTS 10.2 Photoreactivity 10.2.1 Absorption 10.2.2 Reaction Medium and Photon 10.2.3 Photolysis and Identification of Degradation Products 221 10.2.4 Degradation 10.2.5 Changes in Physicochemical 10.2.6 Fluorescence and 10.2.7 Quantum 10.2.8 Action 10.2.9 Identification of 10.3 In Vitro Photosensitization 10.3.1 Examples of Test 10.3.2 Aspects of Main 10.3.2.1 Pharmacokinetic 10.3.2.2 Normalization of 10.3.2.3 Influence of Degradation

In Vivo Testing

The use of the short or more detailed (Table 11.1 and Table 11.2) screens for ocular phototoxicity will not totally eliminate the need for accurate in vivo experiments. The function of these studies is to limit the need for in vivo testing for ocular phototoxicity of large numbers of drugs. Those drugs found in screening to be highly likely to produce phototoxic side effects in the eye should be tested further with animal studies to determine the exact site and extent of damage to be expected...

Inconsistencies and Deficiencies in Current Official Regulations Concerning Photolytic Degradation of Drugs

8.2 Standard Light Stability 8.3 Official Regulations for Light-Sensitive 8.3.1 Deficiencies and Inconsistencies in USP 27-NF 22 176 8.3.2 USP 27-NF 22 vs. Package 8.3.3 Deficiencies of Package 8.4 Labeling and Packaging of Light-Sensitive Cold 8.4.1 Labeling Light-Sensitive Cold 8.4.2 Packaging Light-Sensitive Cold 8.5 Recommendations for Official Regulations for Light-Sensitive Drugs 184

Increase in Temperature

The temperature inside a petri dish or other suitable containers can easily exceed 40 to 50 C during exposure. This could lead to unwanted thermal reactions from the ground state or excited state of the drug molecule or its photoproducts sublimation melting or evaporation. The heating effect can be reduced by a reduction in the lamp intensity (reduced irradiance). When possible, small holes can be made in the container (e.g., plastic film covering the petri dish). It is difficult to determine...

Influence Of Excipients On Drug Stability

The compatibility of the drug with the excipients in a given formulation must be established early in the development program. For solutions and suspensions, this is usually a matter of choice of buffer and pH, determined from solution kinetic studies. For parenterals, compatibility with packaging components (plugs, plastics), as well as the possibility of metal ion contamination, is also investigated. For solid products, the investigation is more complex because of the greater range of...

Influence Of The Container

A container for pharmaceutical use is the article that contains and is in direct contact with the product, including the closure. The container is considered part of the formulation (European Pharmacopoeia, 2002), provides protection and delivery of the product, and should not interact physically or chemically with the contents. Glass and plastic are the most commonly used materials and closures are made by elastomers such as rubber or silicone (European Pharmacopoeia, 2002). Parenteral...

Influence Of The Vehicle

The composition of the formulation (the vehicle) can have a vital influence on the photochemical reactivity of the drug substance. The pharmacologically active compound can be photochemically stable in one environment and highly reactive in another. Composition of the formulation will influence the absorption properties of the drug and the mechanisms by which energy is dissipated from the excited molecule. Excipients that are demonstrated to stabilize one drug substance can have the opposite...

Introduction

Some families of drugs, such as glucocorticosteroids and vitamin D derivatives, were the subject of detailed studies in the 1960s and 1970s indeed, they have been important issues in the development of modern organic photochemistry. For drugs in general, the interest has been only occasional until recently. In the last decade, work in this field has expanded for reasons discussed elsewhere in this book, and the basic photoreaction paths have been recognized for most classes. In the first...

Introduction Photostability Testing of Drugs and Drug Formulations Why and

1.1 Rationale for Evaluation of Drug 1.1.1 Handling, Packaging, and 1.1.2 Adverse 1.1.3 Therapeutic Aspects and New Drug Delivery Systems 4 1.2 What Can Be Achieved by Evaluation of Drug 1.3 How to Obtain Information on Drug It is well known that light can change the properties of different materials and products. This is often observed as bleaching of colored compounds like paint and textiles or as a discoloration of colorless products. Photostability has for many years been a main concern...

Irradiance Radiant Exposure

The available technical data for various artificial radiation sources in use for photo-stability testing show some confusion concerning the use of photometric and radiometric units. Both have their proper place in science and engineering however, it is necessary to be aware of the differences in terminologies and uses and determine which is most appropriate for each type of study. Based on a given relative spectral distribution of light sources, radiometric units for a specific wavelength...

Kinetic Treatment Of Photochemical Reactions

Testing the photostability of a drug substance at the preformulation stage invariably involves a study of the drug's rate of degradation in solution when exposed for a period of time to a source of irradiation. The experimenter wishes to know the kinetics of the process however, he will find that the value of the rate constant depends very much on the design of the experiment, for the same reasons as those outlined earlier. The factors that determine the rate of a photochemical reaction are...

Lamp Pulsing Unit

Figure 12.3 Block diagram of the laser flash photolysis system used in our laboratory. series) capable of delivering up to 1 J of energy at 1064 nm in pulses of 12-ns duration as the excitation source. The fundamental beam can be frequency doubled, tripled, and quadrupled to deliver light of 532, 355, and 266 nm, respectively. The harmonics are separated using a prism and or beam splitter. The sample under investigation is contained in a quartz cell and changed after each laser pulse, using a...

Level Of Exposure And Light Sources 661 Exposure

During the course of ICH discussions on product testing, it was agreed that 1.2 million lx h, which represents 2 to 3 days' exposure close to a south-facing sunny window in the summer, is a suitable visible light exposure. A near-UV exposure of 200 Wh m-2 between 320 and 400 nm is recommended, corresponding to about 1 to 2 days close to a sunny window. This exposure recommendation is based on the assumption that products will be exposed to a mixture of glass-filtered natural light and indoor...

Material Surface Temperature

Because it is not practical to monitor the surface temperature of individual exposed samples, a specified black-coated flat plate sensor so-called black panel thermometer (BPT) has been used for decades to measure and control temperature on the sample surface in material testing. Currently, a so-called black standard thermometer (BST sometimes called insulated black panel thermometer in the Figure 5.15 Calibration scheme calibration standard lamp. Figure 5.15 Calibration scheme calibration...

N

Promethazine (108, Scheme 4.66) (Hashiba et al., 1979) and vitamin riboflavin (Cairns and Metzler, 1971 Ahmad and Rapson, 1990 Moore et al., 1994). Thiols are often oxidized to disulfides via a photoinitiated radical path, as with thiorfan (111, Scheme 4.67) (Gimenez et al., 1988), or up to sulfinate and sulfonate as with the antineoplastic 6-mercaptopurine (Hemmens and Moore, 1984). Both alkyl and aryl sulfides are photooxidized to sulfoxides, as in the formation of S-oxides (110) from...

Need For Uniformity In Photodegradation Studies

Thermal stability studies on pharmaceutical formulations have been formalized for many years. Specific protocols have been developed to provide data from which a shelf-life determination can be made (Carstensen, 1995). Thus, procedures followed in one laboratory are readily reproduced in another, and shelf-life is a consistent estimation for the product, independent of the laboratory in which the data were gathered. In thermal stability studies, the principal consideration is how long the drug...

Number of Batches

The test should be carried out on one batch unless the results are equivocal. In practice, this means that if a repeating experiment is likely to give a different outcome (i.e., pass or fail), two additional batches could be tested before the final conclusion on acceptable or unacceptable change is made. Lag time between exposure and quantitative analysis may influence the results and should be standardized for maximum reproducibility. Dark reactions initiated by a photochemical process can...

O

As in the hydration taking place by irradiation of the vasoconstrictor ergotamine in water to yield an alcohol (Karliceck and Klimesova, 1977). Irradiation of alkenes in the presence of oxygen often leads to oxidation reactions (Scheme 4.8), such as the oxidative cleavage of the double bond in A 9(11)-dehydro-estrone methyl ether (9, Scheme 4.9) (Lupon et al., 1984) or ene addition as with

Oh

A CO group in the antibacterial trimethoprim (45, Scheme 4.31) (Dedola et al., 1999). Oxidation and fragmentation occur also with the antineoplastic agent methotrexate, a diaminopteridine derivative (Chatterji and Gallelli, 1978). Benzylic C-C fragmentation typically occurs with arylacetic acids and with some phenethylamines. Arylacetic and b-arylpropionic acids are a large family of anti-inflammatory and analgesic drugs and easily decarboxylate. The benzyl radicals formed are reduced or...

Oo

Figure 2.9 Chemical quenching of singlet oxygen. (a) The ene reaction addition of singlet oxygen to an olefin with allylic hydrogen (b) the ene reaction of cholesterol (c) endoperoxide formation by singlet oxygen to imidazole residue as in histidine. There are several methods for the detection of 1O2 generated in an irradiated solution. A characteristic luminescence at 1270 nm, corresponding to the return of singlet oxygen to the ground state, can be detected with the appropriate equipment...

Other Approaches To Photoinduced Drug Delivery

The application of photodynamic therapy (PDT) in treatment of bacterial infections will definitely continue to attract the attention of scientists. It is considered unlikely that bacteria develop resistance against singlet oxygen therefore, PDT may become a useful weapon to battle infections. For treatment of infections in the oral cavity, a smart toothpaste containing a photosensitizer that is selectively absorbed by bacteria is under development. This can be used in combination with a laser...

Other Photoreactive Moieties

The inducement of a photoreaction by the amino group, e.g., benzylic cleavage, has been mentioned earlier. Some reactions more directly concerning the amino function are discussed next, along with those (in part analogous) of sulfides and thioethers. A few relevant photoreactions of inorganic complexes are added. Amino groups often undergo photochemical oxidation at the nitrogen or a-carbon or cleavage of the C-N bond. Thus, chlorpromazine and thioridazine give the N-oxides (22, see Scheme...

Penetration Of Uv

The extent to which UV radiation (UVR) is able to provoke reactions is obviously dependent on its penetration of the system. For pharmaceutical formulations, this will depend on the degree of transparency of the packaging material. The most frequently used materials for which this is an issue are glass and plastic, but a variation in light transmission characteristics is caused by different compositions. The transmission cutoff can only be clearly delineated in terms of a filter of defined...

Performance Testing Of Drugs

From the discussion of the previously specified technical requirements for photo-stability tests on materials other than pharmaceuticals and by comparison with the specified performance tests of drugs, it can be concluded that it is necessary to define more precisely the important factors determining correlation and variability of test results. The first step involves defining spectral energy distribution of radiation during real-time exposure as a real basis for simulation. Assuming that the...

Photoactivated Drugs and Drug Formulations

Jan Karlsen and Hanne Hjorth T0nnesen CONTENTS 15.2 Photoactivated Dosage 15.2.1 Photosensitive 15.2.2 Photosensitive 15.2.3 Photosensitive 15.2.3.1 Direct Activation 15.2.3.2 Mediated Activation 15.2.3.2.2 Photoinduced 15.2.3.2.3 Photothermal 15.3 Photoactivated Drug 15.3.1 Caged 15.3.2 Photodynamic 15.3.2.1 Role of Delivery 15.4 Other Approaches to Photoinduced Drug

Photochemical and Photophysical Methods Used in Study of Drug Photoreactivity

12.1.3 Internal 12.1.4 Intersystem 12.2 Photochemical 12.2.1 Steady-State 12.2.1.1 Optical Absorption 12.2.1.2 Optical Emission 12.2.1.3 Separation 12.2.1.4 Electron Spin Resonance 12.2.1.5 Singlet Oxygen (1O2*) 12.2.2 Time-Resolved 12.2.2.1 Laser Flash 12.2.2.1.1 Triplet-Triplet Absorption Spectrum 265 12.2.2.1.2 Determination of Molar Absorption 12.2.2.1.3 Determination of Quantum Yields 268 12.2.2.1.4 Characterization of 12.2.2.1.5 Monophotonic or 12.2.2.2 Time-Resolved Raman Resonance...

Photochemical Reactions

The preceding deactivation processes are generally considered to be photophysical processes. In addition to these, deactivation can take place via photochemical processes such as photoionization, decarboxylation, dechlorination, and permanent product formation. All these processes can be studied under steady-state or time-resolved domains. The simple steady-state photolysis apparatus shown in Figure 12.2 consists of a light source such as a high- or medium-pressure mercury vapor lamp,...

Photodegradation Of Dyes During

Most photosensitizers are degraded during light exposure (Moan, 1986 Bonnett and Martinez, 2001). The photolabilities of dyes differ widely (Figure 9.2). Under anoxic conditions, the quantum yield of degradation is usually smaller than in the presence of oxygen, and other products are formed. From porphyrins, for instance, chlorine-type photoproducts are formed under reducing conditions (Harel et al., 1976 Moan, 1986 Rotomskis et al., 1997 Bonnett and Martinez, 2001).

Photoinstability Of Formulations

The approach to dealing with a drug's instability will clearly depend on the nature of the presentation and its mode of use (T0nnesen and Moore, 1993). Four case histories are presented here that exemplify an approach to identifying, quantifying, and resolving the issues raised by a photolabile drug substance or formulation. An intravenous infusion presentation offers considerable challenge to the formulation group because the problems associated with light instability will most closely...

Photon Sources For Photodegradation Studies

The first question to be answered relates to the nature of the irradiation source to which the drug should be exposed. Some may argue that, when handled and stored correctly, a pharmaceutical should never be exposed to direct sunlight, and therefore sunlight should not be contemplated as an irradiation source. Although that may be possible in the best of practices, it is an erroneous view studies have shown that numerous situations occur when various formulations are exposed to direct or...

Photophysical and Photochemical Aspects of Drug Stability

2.1 Absorption Spectra of 2.2 Spectral Characteristics of Sunlight and Artificial Light Sources 11 2.3 Action Spectrum and Overlap 2.4 Penetration of 2.5 Excited States, Radiative, and Nonradiative 2.6 Direct Reactions from Excited States of the 2.6.1 Photodehalogenation 2.7 Photosensitized 2.7.1 Type I Photosensitization of Chain 2.7.2 Electron Transfer-Sensitized 2.7.3 Detection of Free 2.7.4 Polymerization as Detector of Free 2.8 Singlet Oxygen and Its 2.8.1 Quenchers of Singlet 2.8.2...

Photosensitized Reactions

Any photochemical process in which there is a transfer of reactivity to a species other than that absorbing the radiation initially is called a photosensitization reaction. As a result of the long lifetime and the biradical nature with unpaired electron spins, the excited triplet states can mediate photosensitized reactions, the most common of which are photosensitized oxidations. Due to the triplet spin nature of its ground state, oxygen is spin matched with the drug triplet state and also is...

Photosensitizing And Photolabile Dyes In Medicine

In 1900 Oscar Raab reported in Zeitschrift f r Biologie that paramecia were killed by exposure to acridine and light (Spikes, 1997 Calzavara-Pinton et al., 2001). Neither acridine alone or light alone had any harmful effect on the organisms. A few years later von Tappeiner and Jodlbauer (1904) demonstrated that oxygen was required for the biological response to acridine and light, terming the process photo-dynamic action (von Tappeiner and Jodlbauer, 1904). These are the first scientific...

Photostability of Parenteral Products

14.2 Influence of the 14.2.1 Drug 14.2.3 Buffers and 14.2.4 Oxygen 14.2.6 Metal Ions and Chelating 14.2.7 Tonicity Adjusters, Preservatives, Bulking Agents, Protectants 318 14.2.8 Disperse 14.2.9 Drug 14.3 Influence of the Container 322 14.4 Ex Tempore Preparations of Parenteral 14.5 Storage and Administration of Parenteral

Photostability Testing Design and Interpretation of Tests on New Drug Substances and Dosage Forms

Byard CONTENTS 6.1.1 Basics of 6.2 Objectives of Testing Photostability under Practical Usage 6.3 Forced Photodegradation of Drug Substance and Method Validation 140 6.4 Confirmatory Testing (Formal Test) for Drug 6.4.1 Sample 6.4.2 Light 6.4.4 Sample 6.4.5 Evaluation of 6.5 Testing Pharmaceutical 6.5.1 Sequential Product 6.5.2 Sample 6.5.3 Sample 6.5.4 Evaluation of 6.5.5 Determination of Acceptable 6.6 Level of Exposure and Light 6.7 Measurement of Visible Light...

Practical Usage Conditions

It is extremely difficult to establish the actual exposure of pharmaceutical products during practical usage. During discussions of the international harmonization of photostability testing of pharmaceutical products in which one of the authors (Anderson) participated, it was apparent that there were differences among Europe, the U.S., and Japan. In the U.S. and Japan, product exposure to glass-filtered daylight was believed to occur rarely, if at all, in hospitals or pharmacies (Riehl et al.,...

Predicting Ocular Phototoxicity

Based on the theoretical considerations stated previously, it is relatively easy to predict that a drug cannot cause ocular damage through a photoinduced event. The short screen given in Table 11.1 will dramatically reduce the number of potential substances that need to be considered for ocular phototoxicity. 11.2.1 Short Screen for Potential Ocular Phototoxicity 11.2.1.1 Measure the Absorbance Spectrum In order for a chemical compound (diagnostic dye, drug, endogenous sensitizer) to induce a...

Preface

This is the second edition of Photostability of Drugs and Drug Formulations the first was published in 1996. The philosophy of this new edition remains unchanged, i.e., to provide the background and overview necessary for planning standardized photochemical stability studies evaluating drug photoreactivity as a part of drug development and formulation work and safely handling photolabile drug products. Thus, the book covers in vitro and in vivo aspects of drug photoreactivity. It should thereby...

Protection

Even if a drug has the potential to produce phototoxic side effects in the eye, no damage will be done if the specific wavelengths of optical radiation absorbed by the drug are blocked from transmittance to the eye. This can be easily done with wrap-around eyeglasses (Gallas and Eisner, 2001 Sliney, 1999 Merriam, 1996) that incorporate specific filters. Furthermore, nontoxic quenchers and scavengers could be given in conjunction with the phototoxic drug to negate its ocular side effects while...

Protection of Samples

Many commercial test chambers are equipped with a strong fan for temperature control. This can blow the drug substance or dosage form throughout the chamber unless a protecting material is used to cover the sample. The drug substance or product should be placed in a suitable container (e.g., a petri dish) of known transmittance for direct exposure. A transmission spectrum can be obtained by scanning (part of) the container in a UV VIS spectrophotometer. Hygroscopic substances and low-melting or...

Qu

Figure 10.1 Chemical structures of the antimalarials investigated. Accumulation in skin, eye, and hair. Several of the antimalarial compounds possess a large distribution volume, an extremely long half-life, and strong interaction with melanin in vitro. These drugs are known to accumulate in melanin-rich areas of the body (eye, skin, hair) (Tanenbaum and Tuffanelli, 1980). Due to low turnover of melanin in the eye, a long-term retention, even for years, may be observed for drugs with high...

Questions Related To Radiation Source

The term light source is used throughout the guideline. Light refers, however, to the photopic response, i.e., radiant energy acting on the retina. Visual perception is normally taken to cover a range of 400 to 800 nm with a maximum in response sensitivity around 550 nm. Although the term light often is recognized as having a broader meaning, the scientifically correct terms in this context are radiation, photon, or photolysis source. These will cover the UV regions and the visible light.

Quinine Actinometry

The principles of actinometry are well established, but there is no well-established actinometric system sensitive only to UV radiation (Kuhn et al., 1989 Piechocki and Wolters, 1993). Quinine was originally proposed by the Japanese National Institute of Health Sciences and the Japanese Pharmaceutical Manufacturer's Association (Yoshioka et al., 1994). The results of the work of the FDA and U.S. laboratories have confirmed its suitability (Drew et al., 1998). At the recommended concentration (2...

R

Is believed to require several exposures and an induction period before the response is observed, and it has a histology different from that of phototoxicity. The incidence of drug-induced cutaneous photosensitivity and the mechanisms involved are given in a recent review (Moore, 2002). It is believed that phototoxicity causes cellular damage by direct modification of certain target molecules, such as DNA, lipids, and or amino acids and proteins. In principle, this can occur by the...

Radiometry

The UV filter radiometer comprises a detector with a UV wide-band filter, which allows UV irradiation of defined wavelengths to reach the sensor (see Figure 6.12). Unfortunately, no international standards have been established for filters, so the relative weighting given to the different UV wavelengths depends on the filters, i.e., meters from different manufacturers do not measure the same fraction of irradiance from a given source. Meters should be fitted with a cosine corrector to allow...

Rationale For Evaluation Of Drug Photostability

The most obvious result of drug photodecomposition is a loss of potency of the product. In the final consequence, this can result in a therapeutically inactive drug product. Although this is not often the case, even less severe degradation can lead to problems. Adverse effects due to the formation of minor degradation products during storage and administration have been reported (de Vries et al., 1984). The drug substance can also cause light-induced side effects after administration to the...

Rationalizing the Photochemistry of Drugs

Angelo Albini and Elisa Fasani CONTENTS 4.2 Carbon-Carbon Double 4.2.1 Isomerization and 4.2.2 Addition 4.2.3 Reactions with 4.3 Aromatics and 4.3.2 Detachment of Other 4.3.3 Reactions of 4.3.4 Reactions of Phenols and 4.3.5 Side-Chain Fragmentation and 4.3.6 Ring Rearrangement and Ring Cleavage in Heterocycles 85 4.3.7 Reactions of Heterocycles 4.4 Carbon-Heteroatom Double 4.4.1 Fragmentation a to a C O Double 4.4.2 Hydrogen Abstraction by 4.4.3 Rearrangement of Conjugated 4.4.4 Reactions of...

Recommendations For Official Regulations For Lightsensitive Drugs

The ICH FDA guideline on photostability testing (Guideline for the Photostability Testing of New Drug Substances and Products, 1997) provides an in-depth and standardized basic testing of the intrinsic photostability characteristics of new drug substances and products. However, there are three major shortcomings in the aforementioned guideline that needed to be rectified 1. Inclusion of two options for scientifically different irradiation sources, but no guidance is given as to the selection...

Rooc

30 R Et, R' CH2-2-tetrahydrofuryl intramolecular hydrogen abstraction, in particular with 4-nitrophenyl-1,4-dihydro-pyridines used as vasodilators. In solution (Pietta et al., 1981 Al-Turk et al., 1988 Sadana and Goghare, 1991) and in the solid state (Marciniec and Rychcik, 1994 Thoma and Kerker, 1992 Teraoka et al., 1999 Hayase et al., 1994), 4-(2-nitrophenyl) derivatives, e.g., nifedipine (29), react efficiently to yield the corresponding 2-nitrosophenylpyridine (Scheme 4.24). The nitroso...

S

The presence of well-known scavengers. Davies et al. (1976) irradiated an oxygen-free isopropanol solution of chlorpromazine (ClP), a major tranquilizer, and found that within 15 min the absorption spectrum changed to that of promazine. However, no spectral changes were observed in an oxygenated solution even after 2 h of irradiation, from which they concluded that the dechlorination of ClP occurs from its excited triplet state. However, in many cases the spectra of the drug and its...

Sample Analysis

At the end of the exposure period, the samples should be examined for any changes in physical properties (e.g., appearance, clarity, or color of solution) and for degradation by a validated method. Because any photodegradation is limited to the sample surface, it is important to ensure that a representative portion of solid drug substance is used in individual tests. Similar sampling considerations, such as homogenization of the entire sample, apply to other materials that may not be...

Sample Presentation

The ICH Guideline gives useful practical advice on sample presentation, noting that the conditions should not alter the physical state of the drug substance and containers should allow full exposure of the sample. Thus, a thin layer of drug substance, typically 1 to 3 mm but not more than 3 mm, should be spread in a shallow dish and protected with a transparent cover such as a cling film or a thin film of polyethylene. The transmittance properties of the cover material may be determined by...

Screening Dyes Drugs and Dietary Supplements for Ocular Phototoxicity

11.1.1 Structure of the 11.1.2 Light Absorption by the Human 11.1.3 Direct Light Damage in the 11.1.4 Drug-Induced Ocular 11.2 Predicting Ocular 11.2.1 Short Screen for Potential Ocular 11.2.1.1 Measure the Absorbance 11.2.1.2 Examine the Chemical 11.2.1.3 Test Solubility 11.2.1.4 Measure Binding of the Drug to Ocular Tissues 242 11.2.1.5 Note Reports of Skin 11.2.2 Detailed Screen for Predicting Ocular 11.2.2.1 Determine Potential Sites for Ocular Damage 243 11.2.2.2 Determine Location Uptake...

Spectral Distributions Of Artificial Light Sources Proposed For Drug Photostability Tests Compared With Global

The only (rather general) description of lamps in the ICH guideline for lamp options allows for using lamps with quite different spectral distributions especially in the UV range of radiation. Some examples used for photostability tests on drugs in the past and those recommended in the ICH guideline are shown in Figure 5.17 and Figure 5.18 and compared with global solar radiation behind window glass. The graphs are normalized to 100 in the 300 to 800-nm (Figure 5.17) and 300- to 400-nm (Figure...

Spectral Energy Distribution Of Solar Radiation

Most drug compounds and drug formulations will be subjected to light during production, storage, distribution, and use by the patient. It is obvious that various kinds of artificial light sources as well as sunlight present in rooms behind window glass may be major stress factors and therefore may initiate the degradation processes. Real room conditions will include large variances sunlight through the window may represent the worst case of stress on drugs. Generally, as a basis for...

Standardization of Kinetic Studies of Photodegradation Reactions

3.1 Need for Uniformity in Photodegradation 3.2 Photon Sources for Photodegradation 3.2.1 Arc 3.2.2 Fluorescent 3.3 Measurement of Irradiation 3.3.1 Photon Intensity Irradiance, Fluence, and 3.3.2 Physical Instrumentation for Intensity 3.4 Chemical 3.4.1 Quantum Yield of a Photochemical 3.4.2 Actinometer Experimental 3.4.3 Ferrioxalate 3.4.4 Other Actinometer 3.5 Kinetic Treatment of Photochemical 3.5.1 Deviations from First-Order 3.5.2 Systems with More Than One Absorbing 3.5.3 Application of...

Table of Contents

Chapter 1 Introduction Photostability Testing of Drugs and Drug Formulations Why and Chapter 2 Photophysical and Photochemical Aspects of Drug Stability 9 Chapter 3 Standardization of Kinetic Studies of Photodegradation Chapter 4 Rationalizing the Photochemistry of Chapter 5 Technical Requirements and Equipment for Photostability J rg Boxhammer and Artur Sch nlein Chapter 6 Photostability Testing Design and Interpretation of Tests on New Drug Substances and Dosage Chapter 7 The Questions Most...