Review Article Photostability and Photostabilization of...

Review ArticlePhotostability and Photostabilization ofDrugs and Drug Products

Iqbal Ahmad1 Sofia Ahmed1 Zubair Anwar1 Muhammad Ali Sheraz1 and Marek Sikorski2

1Baqai Institute of Pharmaceutical Sciences Baqai Medical University Toll Plaza Super Highway Gadap RoadKarachi 74600 Pakistan2Faculty of Chemistry Adam Mickiewicz University in Poznan Umultowska 89b 61ndash64 Poznan Poland

Correspondence should be addressed to Iqbal Ahmad iqbalahmedbaqaiedupkand Muhammad Ali Sheraz ali sheraz80hotmailcom

Received 27 October 2015 Accepted 29 February 2016

Academic Editor Adel A Ismail

Copyright copy 2016 Iqbal Ahmad et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Photostability studies of drugs and drug products are an integral part of the product development process in the pharmaceuticalindustry These studies are carried out to ensure quality efficacy and safety of the formulated products during manufacturestorage and use This review deals with the concept of photostability and related aspects and the literature available in thefield It highlights the role of the photochemistry in the photostability studies describes the functional groups important for thephotoreactivity of drugs explains photophysical processes and deals with the kinetics of photochemical reactions The variousmodes of photodegradation of drugs with examples of selected compounds are presentedThe biological consequences of the effectof light on the drug degradation are described The photostability testing of drugs and drug products and the requirements underICHguideline are discussed Some information on the packaging requirements for the formulated products is providedThe variousmethods used for the photostabilization of solid and liquid dosage forms are also discussed

1 Introduction

A large number of drugs are sensitive to light [1 2] andtherefore their formulated products may degrade duringmanufacturing storage and administration This may resultin potency loss altered efficacy and adverse biological effectsThe European Pharmacopoeia [3] prescribes light protectionfor more than 250 drugs and adjuvants Knowledge of thephotochemical behavior of drugs can provide guidance forhandling packaging and labeling of drug products The useof the appropriate containers and packaging material canprotect the products from the deleterious effects of lightThe sensitivity of a drug to a particular spectral region oflight may vary with its chemical structure photoreactivityand nature of the dosage form The rate of a photochemicalreaction may be influenced by the intensitywavelengths ofthe radiation source and the transmission characteristics ofthe container The study of the photochemical reactions may

provide information on themode of stabilization of the activeingredients in a product These reactions are often complexand involve free radical species that form photoproducts [4ndash6] Photosensitized reactions may also lead to the degra-dation of the drug substances [6] The photoproducts of adrug may be harmful and cause phototoxic photoallergicor photosensitization reactions upon administration [7ndash9]These reactions may also be initiated by the interaction of adrug with endogenous substances in the body in the presenceof light The evaluation of the photochemical stability ofdrugs and drug products is an essential component ofthe formulation development process in the pharmaceuticalindustry Several monographs [10ndash12] details [13ndash23] andreviews [24ndash29] have been published on the photochemistryphotostability and related aspects of the drugs and drugproducts Information on the photosensitivity photostabilityand storage of pharmaceuticals is also provided in thepharmacopoeias [1ndash3] and other literature [14 30 31]

Hindawi Publishing CorporationInternational Journal of PhotoenergyVolume 2016 Article ID 8135608 19 pageshttpdxdoiorg10115520168135608

2 International Journal of Photoenergy

2 Photostability

The photostability of a drug substance may be defined as theresponse of the drug or drug product to the exposure to solarUV and visible light in the solid semisolid or liquid state thatleads to a physical or chemical change

The response of the drug to light absorption and excita-tion can be considered in terms of photodegradation (pho-tolysis) reactions through the formation of free radicals orphotosensitization reactions by intermolecular energy trans-fer These reactions involve primary (photochemical) andsecondary (chemical) reactions that give the final products

21 Objectives of the Photostability Studies In view of thephotosensitivity and photoinstability of drugs and adjuvantsknowledge of the photostability of these substances and theirformulated products is necessary to evaluate the following

(i) The intrinsic photostability characteristics(ii) Thephysical and chemical changes upon the exposure

to light(iii) The photodegradation pathways and mechanisms(iv) The shelf life of the products(v) The efficacy of the stabilizing agents in photostabiliza-

tion(vi) The need for modification of the formulation param-

eters(vii) The need for the measures to overcome the effects of

the light exposure during manufacturing packaginglabeling transportation and storage

(viii) The light-induced biological effects(ix) The primary and secondary package design

22 Requirements for the Photostability Studies Consider thefollowing

(i) The solubility of the drug and choice of reactionmedium

(ii) The spectral characteristics of the drug molecule(iii) The sensitivity of the drug molecule to the solar UV

and visible light(iv) The reaction vessel and the radiation source appro-

priate for the spectral characteristics of the drugmolecule

(v) The knowledge of the photodegradation mode andthe nature of the photoproducts from the preliminarystudies

(vi) A validated stability-indicating assay method todetermine the intact drug and the photoproducts inthe degraded material

3 Photochemical Reactions

The photochemistry of the organic compounds has beenstudied for a long time [32ndash36] and an advanced treatment

of this subject is available [6 37] The study of the pho-tochemistry provides a basis for the understanding of thephotochemical reactions of the drug substances that affecttheir stability and efficacy

Photochemical reactions may lead to the degradationof the drug substances by one or more pathways to formdifferent products The elucidation of the mechanisms ofthese pathways requires a thorough understanding of thenature and type of the photochemical reactions involvedThese would largely depend on the presence of certain func-tional groups physical characteristics (light absorption p119870assolubility etc) and the degradation mode of the compoundThe assessment of the photostability of the drug substances isbased on the study of all those factors that determine the ratesand mechanisms of the underlying photochemical reactions

31 Spectral Regions of the UV Visible and Solar RadiationThespectral regions of theUV visible and solar light involvedin the photochemical reactions are as follows

UVA 320ndash400 nmUVB 290ndash320 nmUVC 200ndash290 nmVisible 400ndash700 nmSolar including UVA UVB and visible ranges

The majority of the photochemical reactions occur with thehelp of the UVA UVB or visible light

32 Chemical Groups Important for the Photoreactivity ofthe Drug Molecules The presence of the following chemicalfunctional groups in the drug molecules [10] is usuallynecessary for the occurrence of photochemical reactions

(i) Double bond C=C (oxidationisomerization)(ii) Carbonyl group C=O group

(reductionfragmentation)(iii) Aryl chloride C

6H4Cl2

(homolyticheterolyticdechlorination)

(iv) Nitroaromatic group ndashC6H4NO2(hydrogen abstrac-

tionnitrite ester rearrangement)(v) A weak CndashH bond (photoinduced fragmentation via

hydrogen atom transfer or electron-proton transfer)(vi) Sulfides alkenes polyenes and phenols (highly reac-

tive with singlet oxygen photochemically formedfrom the ground-state triplet oxygen)

33 Photophysical Processes It is necessary to understand thevarious photophysical processes involved in the absorptionand dissipation of the light energy (see (1)ndash(7)) that have beendescribed byMoore [38]Thesemay be followed by additionalreactions forming free radicals and subsequently the finalproducts (see (8)ndash(11)) as a result of the photodegradationof the drug substances

(i) Absorption

Aoℎ]997888997888rarr1A (singlet excited state) (1)

International Journal of Photoenergy 3

(ii) Internal conversion1A 997888rarr Ao (singlet ground state) (2)

(iii) Fluorescence1A 997888rarr Ao + ℎ] (3)

(iv) Photoionization1A 997888rarr A∙+ + eminus (4)

(v) Intersystem crossing

1A 997888rarr 3A (triplet excited state) (5)

(vi) Internal conversion3A 997888rarr Ao (singlet ground state) (6)

(vii) Phosphorescence3A 997888rarr Ao + ℎ] (7)

(viii) Radical formation3A + Ao 997888rarr A∙+ + A∙minus (ionic radicals) (8)

A∙+ minusH997888997888rarr A∙ (oxidized radical) (9)

A∙minus +H997888997888rarr AH∙ (reduced radical) (10)

(ix) Final products

2AH∙ 997888rarr AH2+ Ao (11)

Upon the absorption of a photon at a specific wavelengthin the UV or visible range a molecule in the ground state(Ao) is promoted to the singlet excited state (1A) with theelectron spins remaining antiparallel (see (1)) The moleculein the singlet excited state may dissipate its energy withinnanoseconds by different physical process and thus getdeactivated This may happen by internal conversion (IC)(see (2)) a nonradiative transition to the ground state orphoton emission (fluorescence) leading back to the groundstate (see (3)) The excess energy in the excited state may alsobe dissipated as heat on collision with neighboring moleculesby vibrational relaxation (VR) Since the ionization potentialof the molecule is lower in the singlet excited state it iseasier to remove an electron from an excited rather thanfrom the ground state This occurs in the presence of anelectron acceptor as a result of photoionization (see (4))particularly in molecules having an anionic state Anotherprocess that can occur from the singlet excited state is theintersystem crossing (ISC) to ametastable triplet excited state(3A) with parallel electron spins (see (5)) The ISC is highlyefficient for the photochemically active moleculesThe tripletexcited state with its lifetime in the microsecond to secondrange has a greater probability for the reaction with othermolecules Alternatively it can return back to the ground stateby another ISC (see (6)) or by phosphorescence emission (see

(7)) Further photochemical processes involving the tripletexcited statemay lead to the formation of cationic and anionicradicals (see (8)) and neutral (oxidized) (see (9)) and reducedfree radicals (see (10)) The reduced free radicals may reactto form the final products (see (11)) The triplet excited stateis a more powerful electron donor or acceptor than theground state of a molecule All these processes occur mostlywithin nanosecond to seconds after the excitation andmay bestudied by laser flash photolysis time-resolved spectroscopyand other techniques [39]

34 Kinetics of the Photochemical Reactions The preformu-lation studies in the drug development also include thephotostability testing of the drug substancesThis is necessaryto evaluate their overall photosensitivity and to ascertainthe rate at which they degrade under specific experimentalconditions These aspects involve the study of the kinetics ofthe photodegradation reactions The rate of a photochemicalreaction depends on the number119873 of photons absorbed persecond and the quantum yield of the reaction Φ Moore [40]has presented the following kinetic treatment for the photo-chemical reactions that can be applied to the degradation ofthe drug molecules

The rate of a photochemical reaction may be expressed as

Rate

= number of molecules transformed per second

= 119873Φ

(12)

The value of119873 at a particular wavelength 120582 is given by

119873120582= 119868120582minus 119868119905= 119868120582(1 minus 10

minus119860) (13)

where 119868120582and 119868119905are the incident and the transmitted light

intensities respectively and119860 is the absorbance of the sampleat the irradiation wavelength119873 is directly proportional to the concentration at low

absorbance values (119860 lt 002) provided that the substancefollows Beerrsquos law relation between the absorbance and theconcentration

119873120582= 2303119868

120582119860 = 2303119868

120582L120582119887119862 (14)

where L120582is the molar absorptivity at the wavelength 120582 119862 is

the molar concentration of the absorbing species and 119887 isthe optical path length of the reaction vessel Since 119868

120582and

L120582vary with the wavelength (14) integrated over the relevant

wavelength range gives

119873

= 2303119887119862int (119868120582L120582) d120582 integrated from 120582

1and 120582

2

Rate = 2303119887119862Φint (119868120582L120582) d120582

(15)

Theoverlap integralint 119868120582L120582d120582 is a constant for a particular

combination of the photon source and the absorbing sub-stance 119887 is obtained from the reaction vessel used and Φ is


the reaction property On combining the constant terms intoan overall constant 119896

1 the expression may be stated in the

form of a first-order equation

Rate = minus119889 [Drug]119889119905= 1198961119862

or [Drug]119905= [Drug]

0eminus1198961119905

or ln [Drug]119905= ln [Drug]

0minus 1198961119905

(16)

The compliance of the analytical data to the first-orderkinetics may be confirmed by the linearity of the plot of log119862 versus 119905 with the slope equal to minus119896

1

The factors that influence the rate of a photochemicalreaction include the concentration of the drug the volumeof sample the quantum yield of the photochemical reactionand the intensity and spectral distribution of the light sourceThese have been discussed in detail by Beijersbergen vanHanegowen [41]

4 Photodegradation Reactions

Many drug substances of diverse molecular structure havebeen found to be photoreactive They undergo degradationreactions in aqueous and organic solvents by various path-ways upon exposure to light These reactions may proceedthrough free radical intermediates involving several steps toform the final productsThemajor modes of the photodegra-dation of drugs are as follows

(i) Photoaddition (eg riboflavin)(ii) Photoaquation (eg cyanocobalamin)(iii) Photocyclization (eg meclofenamic acid)(iv) Photodealkylation (eg chloroquine)(v) Photodecarboxylation (eg amino acids)(vi) Photodehalogenation (eg norfloxacin)(vii) Photodehydrogenation (eg nifedipine)(viii) Photodimerization (eg primaquine)(ix) Photoelimination (eg mefloquine)(x) Photoinduced hydrolysis (eg sulfacetamide)(xi) Photoisomerization (eg aztreonam)(xii) Photooxidation (eg benzaldehyde)(xiii) Photoinduced rearrangement (eg benzydamine)(xiv) Photoreduction (eg riboflavin)(xv) Photoinduced ring cleavage (eg norfloxacin)

In some of the photodegradation reactions more thanone pathway may be involved for example the hydrolysisof sulfacetamide is followed by oxidation the reductionof riboflavin is followed by oxidation the oxidation offurosemide is followed by reduction and the ring cleavage offluoroquinolones is followed by oxidation The photodegra-dation of the drug substances may occur by zero-order first-order and second-order reactions or by simultaneous (paral-lel) reactions to give two or three products and by consecutive

reactions involving intermediate species to give the finalproduct Several examples of the photodegradation reactionsof the drug substances involving different mechanisms havebeen reported [10ndash12 16 18ndash21 27] Some examples of thephotodegradation reactions are presented in this section

41 Photoaddition Reactions Riboflavin Riboflavin (RF) (1)undergoes photodegradation by the photoaddition pathwayin the presence of divalent ions such as HPO

4

2minus and SO4

2minus

to form cyclodehydroriboflavin [CDRF] at pH values gt 60[42] The intramolecular photoaddition of the Cndash21015840 hydroxylgroup occurs at periposition C(9) in the benzene ring Thereaction occurs via a RFndashHPO

4

2minus complex (2) which createssterically favorable condition for C(9)O(21015840120572)-interaction[42] The involvement of the singlet excited state of RF[1RFox] in this reaction has been suggested based on thequenching experiments The RFndashHPO

4

2minus complex leads tothe formation of a dihydroflavin intermediate (3) which uponautooxidation gives rise to CDRF (4) The presence of theHPO4

2minus ions may facilitate the reorientation of the Cndash21015840hydroxyl group to affect the photoaddition [Figure 1] Thekinetics of the photoaddition reactions of RF has been studied[43]

42 Photoaquation Reactions Cyanocobalamin Cyanocobal-amin (vitamin B

12) is sensitive to light and its photochemical

conversion to hydroxocobalamin (vitamin B12b) takes place

in aqueous solutions [14 44 45] The sequence of the pho-todegradation reactions of B

12[46] is presented as follows

Singlet excited stateB12

[Co3+ CN] 1[Co3+ CN]h

(17)

Singlet excited state Triplet excited state

ISC1[Co3+ CN] 3

[Co3+ CN] (18)

B12b

3[Co3+ CN] [Co3+ OH] + CNminusH2O

(19)

H+H+

OHminus pKa = 78[Co3+ OH] [Co3+ OH2]

+ (20)

Corrin ring cleavage productsB12b

O2[Co3+ OH] (21)

According to this scheme B12

is excited to the singletstate (17) followed by its transformation to the triplet excitedstate by ISC (18) The 3[Co3+ CN] may react with a moleculeof H2O and undergoes photoaquation to form B

12b (19)which exists in equilibrium with aquocobalamin (p119870a 78) inaqueous solutions (20) In the photoaquation reaction the


Dihydroflavin

Intermediate

Autooxidation

(1) (2)(3)

(4)

N

N

NH

N

O

O

CH

CH

CH

HO

HO

HO

CH2OH

CH2

H3C

H3C

N

N

NH

N

O

O

O

H

H

OH

OH

OH

H

H

H3C

H3C

Na2HPO4

1RF HPO42minush

Figure 1 Photoaddition reactions of riboflavin

CNminus group is removed with its full complement of electronsand is replaced by a water molecule without any change inthe oxidation state of cobalt This reaction takes place by theabsorption of light to cause a 120587-120587lowast transition in the corrinring The [Co3+ OH] molecule may be oxidized to corrinring cleavage products (21) The photodegradation reactionof B12

is pH dependent as B12

is a polyacidic base with sixweakly basic amide groups and has p119870a of 33 [47] In theacidic pH range the molecule exists as a cation [B

12H+] due

to the ionization of the 56-dimethylbenzimidazole moietyThe rates of the photodegradation reactions depend on theionization state of the molecule in the pH 1ndash12 range [45]

43 Photocyclization Reactions Meclofenamic Acid Expo-sure of aqueous solutions of meclofenamic acid (5) (N-(26-dichloro-m-tolyl)anthranilic acid) to UV or visiblelight results in the dehydrohalogenation and cyclization

to form approximately equimolar amounts of 8-chloro-5-methylcarbazole-1-carboxylic acid (6) and 8-chloro-7-methylcarbazole-1-carboxylic acid (7) [48] [Figure 2]

44 Photodealkylation Reaction Chloroquine Chloroquine(8) undergoes photochemical degradation in aqueous solu-tions (pH 74) on irradiation with 240ndash600 nm light Themajor reaction leads to N-dealkylation to give several prod-ucts including (9)ndash(11) which have been identified byMS andNMR spectrometry [49] Some of the dealkylation reactionsare shown in Figure 3

45 Photodecarboxylation Reactions Amino Acids Aliphaticamino acids undergo decarboxylation to produce carbondioxide and an aldehyde by riboflavin (RF) sensitized pho-tooxidation [50]

RF ISC1RF 3RFh (22)


(5) (6) (7)

Cl

HN

ClCOOH

CH3

HN

ClCOOH

CH3

HN

ClCOOH

CH3

h +

Figure 2 Photocyclization reactions of meclofenamic acid

NCl

NH N

NCl

NH N

H

(8) (9)

(10)(11)

CH3 CH3

NCl

NH

OH

CH3

hh

h

CH2CH3

CH2CH3 CH2CH3

NCl

NH2

Figure 3 Photodealkylation reactions of chloroquine

COOHH

R

3RF + NH2 CO2 + RCHO + NH3 (23)

RF on light absorption is excited to the singlet state [1RF]which may be converted to the triplet excited state [3RF]by intersystem crossing (ISC) [3RF] reacts with the aminoacids and causes their oxidation according to the reactionsexpressed by (22) and (23)

46 Photodehalogenation Reactions Norfloxacin Fluoro-quinolones contain at least one fluorine atom and undergodefluorination in neutral solutions [51] Norfloxacin (12) onirradiation in aqueous solutions (pH 72) is degraded slowlyby defluorination (120593 = 006) The process involves solvolysisat position 6 (13) [52] [Figure 4]

47 Photodehydrogenation Reactions Nifedipine Visible irra-diation of nifedipine (14) in 95 ethanol results in thedehydrogenation of the molecule The degradation is fastestin aqueous solutions at pH 20 [53]The degradation productshave been identified by 1Hndash and 13Cndash NMR studies as 4-(2-nitrosophenyl)pyridine (15) and its oxidation product 4-(2-nitrophenyl)pyridine (16) derivatives [54] [Figure 5]

48 Photodimerization Reactions Primaquine The photo-chemical stability of primaquine (17) has been studied byirradiating the aqueous solutions of primaquine diphosphate(pH 74) with a 120W high-pressure mercury lamp (emissionat 320ndash600 nm) It gives numerous products including thedimer (18) that has been identified by GCMS and NMRspectrometry [55] The dimerization reaction is shown inFigure 6

49 Photoelimination Reactions Mefloquine Mefloquine(19) in aqueous solutions undergoes photoelimination to


(12) (13)

NN

O

F

+H2N

COOminus

minusFminus

NN

O

+H2N

COOminus

+

Figure 4 Photodehalogenation reaction of norfloxacin

(14) (16)(15)

N

H

N

NO

N

H3COOCH3COOCH3COOC

H3C H3C H3CCH3 CH3 CH3

COOCH3 COOCH3 COOCH3

NO2 NO2

O2h

Figure 5 Photodehydrogenation reactions of nifedipine

form 28-bis(trifluoromethyl)-4-hydroxyquinoline (20) [56][Figure 7]

410 Photoinduced Hydrolysis Reactions Sulfacetamide Sul-facetamide (21) on UV irradiation in aqueous solutions ishydrolyzed to sulfanilamide (22) [57] [Figure 8]

411 Photoisomerization Reactions Aztreonam Aqueoussolutions (pH 50) of aztreonam (23) (a third-generationcephalosporin) undergo syn-anti-isomerization (24) on UVirradiation involving the alkoxyimino group in the side chain[58] [Figure 9]

412 Photooxidation Reactions

4121 Photooxidation of Benzaldehyde The photooxidationof drugs by UV radiations usually involves a free radicalmechanism as reported for benzaldehyde [59] In the freeradical chain process a sensitizer abstracts a hydrogen atomfrom the drugmolecule (see (24))The free radical of the drugnext reacts with molecular oxygen to form a hydroperoxideradical (see (25))The chain reaction is propagated by remov-ing hydrogen atom from another molecule of the oxidant(see (26)) The hydroperoxide radicals then react further toform inert products (see (27)) The following equations showinitiation propagation and termination steps in the chainreaction involved in the photooxidation of benzaldehyde

CHO

Initiation+

k1

CO∙

h (24)

Propagation+k2

CO∙ CO3∙

O2

(25)

CHO

Propagation ++k3

CO∙CO3∙ CO3H

(26)


N

NH N

H

N

(17) (18)

CH3

CH3

H3CO

H3CO

N

NH

CH3

H3CO

NH2

h

Figure 6 Photodimerization reaction of primaquine

(19) (20)

N

H

HON

HH

CF3

CF3

N

OH

CF3

CF3

h

Figure 7 Photoelimination reaction of mefloquine

Termination Inert productsk4

2CO3∙

(27)

4122 Photooxidation of Menadione Menadione (vitaminK3) (25) is oxidized in aqueous solutions (pH 6ndash12) on UV

irradiation to give 2-methyl-23-epoxy-14-naphthoquinone(26) [60] [Figure 10]

413 Photoinduced Rearrangement Reactions BenzydamineBenzydamine (27) on UV irradiation in aqueous solu-tions undergoes rearrangement to give product (28) [61][Figure 11]

414 Photoreduction Reactions Riboflavin A detailed studyof the photoreduction reaction of riboflavin (RF) (1) inaqueous and organic solvents has been made [62ndash74]

A reaction scheme for the photodegradation of RF bythe photoreduction pathway is shown in Figure 12 RF onlight absorption is promoted to the singlet excited state [1RF]which may be converted to the triplet excited state [3RF](29) The [3RF] abstracts a hydrogen atom by intramoleculartransfer from the C-21015840 atom of the ribityl side chain toN-1 of the isoalloxazine ring leading to the formation ofthe biradical (30) earlier suggested by Brdicka [75] in

the photolysis of RF through polarographic studies Thebiradical is oxidized to form formylmethylflavin [FMF] (31)an intermediate product isolated by Smith and Metzler [76]FMF is hydrolyzed to lumichrome [LC] (32) in acid solutionsand LC and lumiflavin [LF] (33) in alkaline solutions [77ndash79] It is also oxidized to carboxymethylflavin [CMF] (34)in aqueous solutions [79 80] The rate-pH profile indicatesa greater susceptibility of RF to photodegradation in thealkaline solutions as a result of the sensitivity of [3RF] toalkaline hydrolysis [81]

415 Photoinduced Ring Cleavage Reactions NorfloxacinNorfloxacin (12) on UV irradiation in aqueous solutionsundergoes piperazine ring cleavage to give product (35) [51][Figure 13]

5 Biological Effects of the Photoinstability

The biological consequences of the action of light on drugsundergoing photodegradation are important These includeseveral adverse biological reactions involving phototoxicityphotoallergy photosensitization and others [7ndash9 82ndash87]UV radiation present in the sunlight is usually classifiedinto different spectral ranges including UVA (320ndash400 nm)UVB (290ndash320 nm) andUVC (270ndash290 nm) UVC radiationis absorbed by ozone and is thus absent at the sea levelUVA radiations involve longer wavelengths than those ofUVB and are less harmful UVB radiations may affect humanskin and can produce erythema edema and pigmentation


(21) (22)

hSO H

N

O O

H2N

OHminus+S

OO

H2NNH2

CH3COOH

Figure 8 Photoinduced hydrolysis reaction of sulfacetamide

(23) (24)

h

O

HN

O

N

O

HOOC

S

N

CH3

CH3

CH3

+H3N

SO3minusO

HN

O

N

O

COOH

S

N CH3

CH3

+H3N

SO3minus

H3C

Figure 9 Photoisomerization reaction of aztreonam

[88] UVB may also cause photoaging immunosuppressionand photocarcinogenesis [85 89] The use of dermatologicalpreparations or other drugs in the treatment of these disor-ders by application as a thin film on the skin can lead to rapidphotodegradation on exposure to light This may make themineffective or form toxic photodegradation products affectingthe skin The list of some drugs causing adverse biologicalreactions [8 84] is given in Table 1

Kullavanijaya and Lim [9] have suggested the use ofthe sunscreen agents containing UV light filters for thephotoprotection of the human skin An ideal sunscreenagent should be photochemically stable and dissolve in asuitable vehicle The photostability of the product dependson the nature of the UV filter One of the first widely usedsunscreen filters is para-aminobenzoic acid (PABA) (120582max =283 nm) It is soluble in water and is very effective againstUVB radiations at 5 concentration in 50ndash60 alcoholbase [90] However PABA causes photoallergy and is apotent carcinogen therefore its use in sunscreen productsis limited [91] The commonly used UV filters nowadaysinclude avobenzone octinoxate and octyl dimethyl PABAThese compounds are photolabile being rapidly destroyed onexposure to UV light [92ndash94] Some of the photostable filtersinclude terephthalylidene dicamphor sulfonic acid (MexorylSX) drometrizole trisiloxane (Mexoryl XL) methylene-bis-benzotriazolyl tetramethylbutylphenol (Tinosorb M) andbis-ethylhexyloxyphenol methoxyphenol triazine (TinosorbS) [92] ZnO TiO

2 octocrylene salicylates and methylben-

zylidene camphor have been found to increase the photosta-bility of the sunscreen products [9] The organic sunscreenagents may interact with the skin on exposure to light andinduce adverse biological reactions resulting in photoallergyphototoxicity and photosensitivity [95ndash101] Therefore careshould be exercised in the selection of the sunscreen agentsby consultation with a dermatologist The Food and Drug

Administration USA has provided a list of 16 agents for useas sunscreens including UVA and UVB filters [101] A list ofcommonUVfilters approved inAustralia Europe Japan andthe United States is also available [102]

6 Packaging Requirements

The light sensitivity of the drug substances requires theuse of an effective packaging system to protect them fromphotochemical damage The pharmacopoeias [1ndash3] prescribeconditions for containers (eg light-resistant) and storage(eg protected from light) for the light-sensitive drugsand formulated products The requirements for a packagingsystem for pharmaceuticals differ from product to productthat is solid or liquid dosage form There is a greater chanceof interaction between a liquid dosage form and the containerthan that of the solid dosage formThe efficacy of a packagingsystem for a particular drug or product may be evaluatedby performing photostability studies Protection of a productfrom light can be achieved by the use of an opaque or amber-colored container Amber glass is suitable for drugs absorbingin the UV region as it transmits light above about 470 nm Anopaque secondary packagemay also be used for this purpose

Light transmission tests may be applied to evaluate thelight transmission characteristics of containers to be used forphotosensitive drugs [2] Templeton et al [28] have discussedthe implications of photostability on the manufacturingpackaging and storage of formulated products emphasizingthe need for appropriate measures to protect photosensitiveproducts during these processes

7 Photostability Testing

Photostability testing of drug substances and formulatedproducts is an integral part of the development process


(25) (26)

h

O

O

O

CH3

O

O

CH3

pH 6ndash12

Figure 10 Photooxidation of menadione

(27) (28)

h

NN

O NCH3

CH3

CH2Ph

N

O

N NCH3

CH3

CH2Ph

Figure 11 Photoinduced rearrangement reaction of benzydamine

in industry to ensure their quality during the shelf lifeperiod It is carried out under standardized conditions todetermine the extent to which the drug or the productundergoes an undesirable chemical change Photostabilitytesting is undertaken to evaluate the overall photosensitivityof the pharmaceuticals for the development and validationpurposes and to provide information necessary for handlingpackaging and labeling [11] ldquoICH Harmonized TripartiteGuideline for Photostability Testing of New Drug Substancesand Productsrdquo [103] has stated the importance of lighttesting as an integral part of stress testing It is necessary todetermine the intrinsic photostability characteristics of thenew drug substances and products during the developmentprocess and to demonstrate that light exposure does notresult in an unacceptable change Another objective of thisstudy is to demonstrate whether precautionary measures inmanufacturing packaging and labeling of the products areneeded to overcome changes due to light exposure [104]

Photostability testing of drug substances and products isconducted according to ICH Q1B guideline [103] with thechoice of an appropriate light source being an importantconsideration for the uniformity of the results The pho-todegradation of a drug in a product is a function of thespectral distribution and the intensity of the light sourceTherefore the use of specific light sources is necessary toachieve harmony in the evaluation of photostability ICHguideline specifies the use of an artificial daylight fluorescentlamp a xenon lamp or a metal halide lamp emitting inthe UV and visible region with an output similar to thatof the standard daylight lamp D65ID65 Any radiationemitted below 320 nm should be eliminated by the use ofan appropriate filter Alternatively a cool white fluorescentlamp (emission sim320ndash800 nm) or a near UV lamp (emission320ndash400 nm) with the maximum emission between 350 and370 nm should be used The details of the photostability

testing procedures for the drug substances and drug productsare stated in the ICH guideline [103]

Several publications have dealt with the light sourcestheir spectral distribution and use [20 40 105ndash111] photosta-bility chambers [104 112 113] and experimental conditions[28 108 114ndash117] for the photostability testing

Various aspects of the photostability testing in relation tothe application of the ICH guidelines have been discussed [1720 25 118ndash123] and there is a need to improve the guideline inthe light of these studiesThe application of the photostabilitytesting in the pharmaceutical industry is necessary to ensurethe potency the efficacy and the safety of the manufacturedproducts in their clinical use

8 Photostabilization

The photosensitivity of the drug substances and the solid andliquid dosage forms makes it necessary to adopt appropri-ate measures for their stabilization during manufacturingcompounding and storage The common approach to affordphotostabilization of pharmaceuticals is to protect them fromlight by using suitable primary and secondary packagingThevarious methods of photostabilization [12 27 124 125] andphotoprotection [9 20] have already been reviewed and arebriefly presented in the following sections

81 Spectral Overlay The photosensitive drugs or productscan be protected by reducing the amount of the undesirablelight impinging on the material This can be achieved bythe application of the principle of the spectral overlay to thepharmaceutical formulations [126] It is based on the use ofexcipients that exhibit the absorption spectra similar to thatof the drugThis results in the absorption of light by the excip-ients at the expense of the drug and thus protecting it fromphotodegradation Molsidomine tablets have been stabilized


(1) (29)

(31)

(30)

(32) (33) (34)

N

N

NH

N O

O

OH

R

H3C

H3C

N

N

NH

HN O

O

CR

OH

H3C

H3C

N

N

NH

N O

O

H

O

H3C

H3C

N

N

NH

HN O

O

H3C

H3C N

N

NH

N O

O

O

OH

H3C

H3C

N

N

NH

N O

O

OH

R

H3C

H3C

h

N

N

NH

N O

O

H3C

H3C

CH3

O2

O2

OHminus

H+ OHminus

R = (CHOH)3H

Figure 12 Photoreduction reactions of riboflavin

by adding the UV absorber Eusolex 9020 [4-(t-butyl-41015840-methoxydibenzoyl)-methane] [127] These tablets have alsobeen stabilized by the addition of riboflavin absorbing lightin the UV and visible region [128] The photostabilizationof diclofenac gel has been achieved by the use of a UVabsorber 3-(4-methylbenzylidene)-camphor (Eusolex 6300)[129] Food colorants have been employed as photostabilizingagents for the oral dosage forms for the UV and visible ranges[130]Ubidecarenone has been stabilized by120572-(o-tolylazo)-120573-naphthylamine in a dry emulsion [131]

82 Use of Opacifying and Coating Agents Thoma [124]and Thoma and Spilgies [127] have discussed the use ofopacifying and coating agents in the photostabilization ofdrugs in various dosage formsThe yellow red and black iron

oxides have been employed as opacifiers for the protectionof sorivudine molsidomine and nifedipine tablets [132] Thephotoprotective effect of these pigments depends on theirparticle size which influences the light absorption and scat-tering capacity These are most effective on even distributionover the surface of the drug particles in the tabletmatrix [127]The photoprotection of the solid dosage forms may also beachieved by the use of opaque blisters and capsules [133ndash136]The opaqueness of the material can be produced by the use ofa suitable dye with an absorption spectrum similar to that ofthe drug or by the use of a reflecting pigment such as titaniumdioxide The addition of UV and visible absorbing opacifiersis also useful in the case of creams ointments and liquidformulations [20]


(35) (35)

Piperazinering cleavage

h

NN

O

FOH

O

+H2N

NHN

O

FOH

O

+H3N

Figure 13 Photoinduced ring cleavage reaction of norfloxacin

Table 1 Drugs causing adverse biological reactions

Phototoxicity Photoallergy PhotosensitivityAcridine Aminobenzoic acid derivatives 2-Benzyl-46-dichlorophenolAminobenzoic acid derivatives Bithionol ChlorophenolsAnthraquinone dyes Chlorpromazine EthanolAnthracene Chlorpropamide HexachlorobenzeneChlorpromazine Fentichlor OestrogensNalidixic acid 6-MethylcoumarinPhenothiazine PromethazineProtriptyline SalicylanilidesPsoralens SulfanilamidePyrene ThiazidesSulfanilamideTetracycline

Another method of photostabilization of the tablet for-mulations involves film coating with agents possessing lightabsorption or reflection properties The protective effectof the film coating depends on its absorption which isrelated to the film thickness and concentration of the absorb-ingreflecting excipient [127] Film coatings have been usedfor the photoprotection of sulfisomidine [137] nifedipine[135 138] and other drugs [139]

83 Complex Formation Complex formation between pho-tosensitive drugs and complexing agents is among the earliermethods for the stabilization of drugs Caffeine has beenemployed as a complexing agent for the photostabilizationof riboflavin a highly photosensitive drug It is most stablein the complex form in aqueous solution being suitable forpharmaceutical formulations [140] Caffeine complexationhas been reported by several workers and occurs by theformation of stacking complexes [141ndash144] Riboflavin alsoforms a complex between the ribityl side chain and boric acidresulting in the photostabilization of the vitamin [145 146]

84 Cyclodextrin Complexation The photostabilization ofdrugs by the cyclodextrin inclusion complexation has beendiscussed by Thoma [124] Yoshioka and Stella [18] andSheraz et al [29] Cyclodextrins are nonreducing cyclicoligosaccharides that consist of six (120572-CD) seven (120573-CD) or eight (120574-CD) dextrose units Internally these

molecules are relatively hydrophobic while externally rela-tively hydrophilicThis structure imparts to them the capabil-ity of forming inclusion complexes with the drug moleculesand thus provides photoprotection for the latter [18]

Numerous examples of the photostabilization of drugsby cyclodextrin complexation have been reported Theseinclude the complexation of clofibrate with 120573- and 120574-CD inthe solid state [147] nifedipine pyridoxine HCl and retinolacetate with 120573-CD in aqueous solutions and in the solid state[148] doxorubicin with 120574-CD in aqueous solutions [149]daunorubicin with octakis (26-di-o-methyl)-120574-CD in acidicsolutions [150] mitomycin Cwith 120574-CD in aqueous solutions[151] riboflavin with 120572- 120573- and 120574-CD in aqueous solutions[152ndash158] diphenylhydramine with 120573-CD in aqueous solu-tions [159] isradipine with methyl 120573-CD [160] triprolidineHCl with 120573-CD [161] and other photosensitive drugs withdifferent CDs [162]

85 Liposome Formation Liposomes are microscopic andsubmicroscopic phospholipid vesicles with a bilayered mem-brane structure Photostabilization of the drug substances byentrapment into liposomes is an effective method to improvetheir photostability Examples of stabilization of the photo-sensitive drugs in liposomal formulations include riboflavin[163ndash167] doxorubicin [168] vitamin A palmitate [169]fluoroquinolones [170 171] rose Bengal [172] amlodipine[173] tretinoin [174] 27-dichlorodihydrofluorescein [175] o-palmitoyl amylopectin [176] and zinc phthalocyanine and


chloroaluminium phthalocyanine [177]The entrapment effi-ciency of the liposomes facilitates the enhancement of thephotostability of the drugs [164 165 174 178] Barnidipinein cyclodextrin-in-liposomes matrices has shown increasedphotostability with a value close to that of the solid formula-tions [174]The photostability of drugs in liposomal formula-tionsmay be affected by the composition of the liposomes theentrapment efficiency and the drug-phospholipid interaction[179]

86 Use of Stabilizers A careful consideration of the factorsthat promote the photodegradation of drugs and their controlmay improve photostability Some factors that adverselyaffect the photostability of drugs include oxygen oxidizingagents and metal ions Photooxidation of drugs is amongthe most commonly occurring modes of their degrada-tion Oxygen present in a formulation may be removedby purging with nitrogen or by the addition of a suitableantioxidant depending on the susceptibility of the drug tophotooxidation The selection of an antioxidant may bemade on the basis of the difference in the redox potentialbetween the drug and the oxidant The effectiveness of anantioxidant is determined by studying the pharmaceuticalsystem under standard oxidation conditions and assaying thedrug content periodically [180]Thedrug substances thatmaybe significantly affected by the oxidation-reduction reactionsleading to photodegradation include ascorbic acid riboflavincyanocobalamin menadione 120572-tocopherol and chlorpro-mazine [14] Some of the commonly used antioxidantsare ascorbic acid 120572-tocopherol butylated hydroxyanisole(BHA) butylated hydroxytoluene (BHT) L-histidine propylgallate and sulfur compounds Ascorbic acid 120572-tocopherol120573-carotene andBHT act as free radical scavengers and singletoxygen quenchers and thus inhibit the photosensitizationreactions If a drug substance acts as a photosensitizer andinitiates a chain reaction in the drug product some of theexcipients may be oxidized while the drug may be protectedfrom photodegradation [38]

Examples of the photostabilization of drugs by the useof an antioxidant and other agents include ascorbic acidstabilized by 120572-tocopherol [181] doxorubicin HCl by sodiumthiosulphate [182] mitomycin and porfiromycin [183] sul-facetamide and sulphanilamide by sulfur compounds [184]vitamin A by propyl gallate citric acid and BHT [185]cholecalciferol by 120572-tocopherol and ascorbic acid [186] cian-idanol by an oxygen adsorbent [187] and riboflavin by EDTAthiourea DL-methionine and sodium thiosulfate [188]

87 Choice of Solvent Solvents can exert considerable influ-ence on the stability of the photosensitive drugs in thepharmaceutical formulations The photodegradation ratesmay be affected by the polarity and viscosity of the mediumThe choice of an appropriate solvent or a solvent combina-tion may improve the photostability of a particular drugIn particular the effect of the dielectric constant on thekinetics of the photodegradation of 10-methylisoalloxazine[62] formylmethylflavin [65] riboflavin [72 189ndash193] mox-ifloxacin [194] and norfloxacin [195 196] in aqueous and

organic solvents has been studied The reaction rates of thesecompounds are a linear function of the solvent dielectric con-stantThismay imply the involvement of a polar intermediatein the reaction pathway [62]

The photodegradation rate of a drug may also be influ-enced by the solvent viscosity In the case of the above-mentioned flavins [62 65 192] and fluoroquinolones [193ndash195] the reaction rates are a reciprocal function of the solventviscosity Thus an increase in the medium viscosity leads toa decrease in the reaction rate This could result from theinhibition of the solute diffusion into the solvent [6] Forexample the photodegradation of cyanocobalamin (vitaminB12) in aqueous solutions is suppressed by the addition

of glycerol due to an increase in the medium viscosity[197] These studies indicate that the solvent characteristicssuch as dielectric constant and viscosity should be givendue consideration in the formulation of drugs to achievephotostabilization

88 Choice of pH The pH of a solution is an importantfactor in the stabilization of the drug substances A drug maybe more stable in its ionized or nonionized form and mayundergo specific acid-base catalysis in aqueous solutionsHowever it would depend on the reactivity of the excited stateof the molecule in the particular pH range The oxidation ofmany drugs is affected by pH for example ascorbic acid (p119870a= 417) undergoes rapid photooxidation in the neutral andalkaline pH range and is stable in the acid pH range [197]Several studies have been conducted to evaluate the effectof pH on the stability of the drug substances [14 198] andto assess the optimum pH from the rate-pH relationships toachieve stabilization [14 45 194 195 199] The buffer speciespresent in a solutionmay be involved in the general acid-basecatalysis [18] and should be carefully selected to avoid thiseffect

9 Conclusions

The photostability evaluation and the photostability testingof the drugs and drug products are an important part of theformulation studies providing information on their intrinsicphotostability characteristics and enabling the developmentof stable safe and effective products The knowledge ofthe photostability of drugs and their mode of degradationhelps to guide the formulator in the assessment of theproduct and thus make modifications necessary to prolongits shelf life under the proposed storage conditions The useof various photostabilization techniquesmay further enhancethe stability of the products The objective of these studiesis to ensure product quality along with all of the necessaryattributes during their storage and use

Competing Interests

The authors declare that they have no competing interests


Acknowledgments

Theauthors are very grateful to Professor Dr S Fazal Hussainof the Baqai Institute of Pharmaceutical Sciences for his kindhelp in the preparation of this paper The study was partlysupported by the research Grant DECndash201205BST401207toMarek Sikorski from theNational ScienceCentre of Poland(NCN)

References

[1] Her Majestyrsquos Stationery Office British Pharmacopoeia HerMajestyrsquos Stationery Office London UK 2013

[2] United States Pharmacopeial Convention United StatesPharmacopeia 29 United States Pharmacopeial ConventionRockville Md USA 2012

[3] EDQM European Pharmacopoeia European PharmacopoeialConvention and the European Union Strasbourg France 8thedition 2015

[4] W H Horspool and D Armesto Organic Photochemistry aComprehensive Treatment Ellis Horwood New York NY USA1992

[5] W H Horspool and F Lensi Eds Handbook of OrganicPhotochemistry and Photobiology CRC Press Boca Raton FlaUSA 2nd edition 2004

[6] N J Turro V Ramamurthy and V Scaiano Modern Molecu-lar Photochemistry of Organic Compounds University SciencePress Sausalito Calif USA 2010

[7] G M J Beijersbergen van Henegouwen ldquoMedicinal photo-chemistry phototoxic and phototherapeutic aspects of drugsrdquoAdvances in Drug Research vol 29 pp 79ndash170 1997

[8] J Moan ldquoBenefits and adverse effects from the combinationof drugs and lightrdquo in Photostability of Drugs and Drug For-mulations H H Tonnesen Ed pp 173ndash188 Taylor amp FrancisLondon UK 1996

[9] P Kullavanijaya and H W Lim ldquoPhotoprotectionrdquo Journal ofthe American Academy of Dermatology vol 52 no 6 pp 937ndash958 2005

[10] A Albini and E Fasani Drugs Photochemistry and Photostabil-ity Royal Society of Chemistry Cambridge UK 1998

[11] H H Tonnesen Photostability of Drugs and Drug FormulationsCRC Press Boca Raton Fla USA 2nd edition 2004

[12] J T Piechocki and KThoma Eds Pharmaceutical Photostabil-ity and Stabilization Technology InformaHealthcare NewYorkNY USA 2007

[13] G M J Beijersbergen van Henegouwen ldquoPhotochemistry ofdrugs in vitro and in vivordquo in Topics in Pharmaceutical SciencesD D Breimer and D Speiser Eds Elsevier Amsterdam TheNetherlands 1981

[14] K A Connors G L Amidon and V J Stella Chemical Stabilityof Pharmaceuticals John Wiley amp Sons New York NY USA3rd edition 1986

[15] J V Greenhill and M A McLelland ldquoPhotodecomposition ofdrugsrdquo in Progress in Medicinal Chemistry G P Ellis and G BWest Eds pp 51ndash121 Elsevier Amsterdam The Netherlands1990

[16] J T Carstensen ldquoCatalysis complexation and photolysisrdquo inDrug Stability J T Carstensen and C T Rhodes Eds pp 133ndash144 Marcel Dekker New York NY USA 3rd edition 2000

[17] B R Mathews ldquoRegulatory aspects of stability testing inEuroperdquo in Drug Stability J T Carstensen and C T Rhodes

Eds pp 579ndash618 Marcel Dekker New York NY USA 3rdedition 2000

[18] S Yoshioka and V J Stella Stability of Drugs and Dosage FormsKluwer Academic New York NY USA 2000

[19] H H Tonnesen ldquoPhotodecomposition of drugsrdquo in Encyclope-dia of Pharmaceutical Technology J Swarbrick and J C BoylanEds vol 3 pp 2197ndash2203 Marcel Dekker New York NY USA2nd edition 2002

[20] E Fasani and A Albini ldquoPhotostability stress testingrdquo inPharmaceutical Stress Testing Predicting Drug Degradation SW Baertschi Ed pp 293ndash325 Taylor amp Francis New York NYUSA 2005

[21] I Ahmad and F H M Vaid ldquoPhotochemistry of flavins inaqueous and organic solventsrdquo in Flavin Photochemistry andPhotobiology E Silva and A M Edwards Eds pp 12ndash40 TheRoyal Society of Chemistry Cambridge UK 2006

[22] E Silva andM Edwards Flavins Photochemistry and Photobiol-ogy The Royal Society of Chemistry Cambridge UK 2006

[23] T Loftsson Drug Stability for Pharmaceutical Scientists Aca-demic Press New York NY USA 2014

[24] J K Sugden ldquoPhotostability of cosmeticmaterialrdquo InternationalJournal of Cosmetic Science vol 7 no 4 pp 165ndash173 1985

[25] H H Toslashnnesen ldquoFormulation and stability testing of photola-bile drugsrdquo International Journal of Pharmaceutics vol 225 no1-2 pp 1ndash14 2001

[26] S Singh and M Bakshi ldquoGuidance on conduct of stresstests to determine inherent stability of drugsrdquo PharmaceuticalTechnology vol 3 pp 1ndash14 2000

[27] N R Bhalekar D Harinarayana A R Madgulkar S J PandyaandD K Jain ldquoImprovement of photostability in formulation areviewrdquoAsian Journal of Chemistry vol 20 no 7 pp 5095ndash51082008

[28] A C Templeton H Xu J Placek and R A Reed ldquoImplicationsof photostability on the manufacturing packaging storage andtesting of formulated pharmaceutical productsrdquoPharmaceuticalTechnology vol 3 pp 68ndash86 2005

[29] M A Sheraz S H Kazi S Ahmed Z Anwar and I AhmadldquoPhoto thermal and chemical degradation of riboflavinrdquo Beil-stein Journal of Organic Chemistry vol 10 pp 1999ndash2012 2014

[30] C J Lintner ldquoPharmaceutical product stabilityrdquo in QualityControl in the Pharmaceutical Industry M S Cooper Ed vol2 pp 141ndash238 Academic Press New York NY USA 1973

[31] C Dollery EdTherapeutics Drugs Churchill Livingston Lon-don UK 2nd edition 1999

[32] A Benrath ldquoOn pure and combined photochemical reactionsrdquoZeitchrift Physikalische Chemie vol 74 pp 115ndash124 1910

[33] A Albini and M Fagnoni ldquoGreen chemistry and photochem-istry were born at the same timerdquoGreen Chemistry vol 6 no 1pp 1ndash4 2004

[34] D Ravelli S Protti and A Albini ldquoEnergy and moleculesfrom photochemicalphotocatalytic reactions An overviewrdquoMolecules vol 20 no 1 pp 1527ndash1542 2015

[35] J G Calvert and N J Pitts Jr Photochemistry John Wiley ampSons New York NY USA 1966

[36] A Gilbert and J Baggott Essentials of Molecular Photochem-istry Blackwell Scientific Publishers London UK 1991

[37] M Klessinger and J Michl Excited States and Photochemistry ofOrganic Molecules Wiley-VCH New York NY USA 2006

[38] D EMoore ldquoPhotophysical and photochemical aspects of drugstabilityrdquo in Photostability of Drugs and Drug Formulations H


H Tonnesen Ed pp 17ndash19 CRC Press Boca Raton Fla USA2nd edition 2004

[39] S Navaratnum ldquoPhotochemical and photophysical methodsused in the study of drug photoreactivityrdquo inThe Photostabilityof Drugs and Drug Formulations H H Tonnesen Ed pp 255ndash284 Taylor amp Francis London UK 2nd edition 2004

[40] D E Moore ldquoStandardization of kinetic studies of photodegra-dation reactionsrdquo in Photostability of Drugs and Drug Formula-tions H H Tonnesen Ed pp 53ndash55 CRC Press Boca RatonFla USA 2nd edition 2004

[41] GM J Beijersbergen vanHanegowen ldquoMedicinal photochem-istry (an introduction with attention to kinetic aspects)rdquo inDrug Photochemistry and Photobiology A Albini and E FasaniEds pp 74ndash86 The Royal Society of Chemistry CambridgeUK 1998

[42] M Schuman Jorns G Schoellnhammer and P HemmerichldquoIntramolecular addition of the riboflavin side chain Anioncatalyzed neutral photochemistryrdquo European Journal of Bio-chemistry vol 57 no 1 pp 35ndash48 1975

[43] I Ahmad Q Fasihullah and F H M Vaid ldquoA study of simul-taneous photolysis and photoaddition reactions of riboflavin inaqueous solutionrdquo Journal of Photochemistry and PhotobiologyB Biology vol 75 no 1-2 pp 13ndash20 2004

[44] J M Pratt ldquoThe chemistry of vitamin B12 Part II Photochem-

ical reactionsrdquo Journal of the Chemical Society pp 5154ndash51601964

[45] I Ahmad W Hussain and A A Fareedi ldquoPhotolysis of cyan-ocobalamin in aqueous solutionrdquo Journal of Pharmaceutical andBiomedical Analysis vol 10 no 1 pp 9ndash15 1992

[46] I A Ansari Photolysis and interactions of cyanocobalamin withsome B-vitamins and ascorbic acid in parenteral solutions [PhDthesis] University of Karachi Karachi Pakistan 2001

[47] J A Hill J M Pratt and R J P Williams ldquoThe corphyrinsrdquoJournal of Theoretical Biology vol 3 no 3 pp 423ndash445 1962

[48] J Philip and D H Szulczewski ldquoPhotolytic decompositionof N-(26-dichloro-m-tolyl) anthranilic acid (meclofenamicacid)rdquo Journal of Pharmaceutical Sciences vol 8 no 9 pp 1479ndash1482 1973

[49] K Nord J Karlsen and H H Toslashnnesen ldquoPhotochemicalstability of biologically active compounds IV Photochemicaldegradation of chloroquinerdquo International Journal of Pharma-ceutics vol 72 no 1 pp 11ndash18 1991

[50] E Choe R Huang and D B Min ldquoChemical reactions andstability of riboflavin in foodsrdquo Journal of Food Science vol 70no 1 pp R28ndashR36 2005

[51] A Albini and S Monti ldquoPhotophysics and photochemistry offluoroquinolonesrdquo Chemical Society Reviews vol 32 no 4 pp238ndash250 2003

[52] E Fasani F F Barberis Negra M Mella S Monti and AAlbini ldquoPhotoinduced C-F bond cleavage in some fluorinated7-amino-4-quinolone- 3-carboxylic acidsrdquo Journal of OrganicChemistry vol 64 no 15 pp 5388ndash5395 1999

[53] I AMajeedW J Murray DW Newton S Othman andW AAl-turk ldquoSpectrophotometric study of the photodecompositionkinetics of nifedipinerdquo Journal of Pharmacy and Pharmacologyvol 39 no 12 pp 1044ndash1046 1987

[54] G S Sadana and A B Ghogare ldquoMechanistic studies on pho-tolytic degradation of nifedipine by use of 1HndashNMR and 13CndashNMRspectroscopyrdquo International Journal of Pharmaceutics vol70 no 1-2 pp 195ndash199 1991

[55] S Kristensen A-L Grislingaas J V Greenhill T SkjetneJ Karlsen and H H Toslashnnesen ldquoPhotochemical stability ofbiologically active compounds V Photochemical degradationof primaquine in an aqueous mediumrdquo International Journal ofPharmaceutics vol 100 no 1ndash3 pp 15ndash23 1993

[56] H H Tnnesen and D E Moore ldquoPhotochemical stability ofbiologically active compounds III Mefloquine as a photosen-sitizerrdquo International Journal of Pharmaceutics vol 70 no 1-2pp 95ndash101 1991

[57] T Ahmad and I Ahmed ldquoDegradation studies on sulphac-etamide eye-drops Part 1rdquo Die Pharmazie vol 36 no 9 pp619ndash621 1981

[58] H Fabre H Ibork and D A Lerner ldquoPhotodegradationkinetics under UV light of aztreonam solutionsrdquo Journal ofPharmaceutical and Biomedical Analysis vol 10 no 9 pp 645ndash650 1992

[59] D E Moore ldquoAntioxidant efficiency of polyhydric phenols inphotooxidation of benzaldehyderdquo Journal of PharmaceuticalSciences vol 65 no 10 pp 1447ndash1451 1976

[60] J C Vire G J Patriarche andGD Christian ldquoElectrochemicalstudy of the degradation of vitamins of theK grouprdquo Pharmazievol 35 pp 209ndash212 1980

[61] F Vargas C Rivas RMachado and Z Sarabia ldquoPhotodegrada-tion of benzydamine phototoxicity of an isolated photoproducton erythrocytesrdquo Journal of Pharmaceutical Sciences vol 82 no4 pp 371ndash372 1993

[62] I Ahmad and G Tollin ldquoSolvent effect on flavin electrontransfer reactionsrdquo Biochemistry vol 20 no 20 pp 5925ndash59281981

[63] I Ahmad and H D C Rapson ldquoMulticomponent spectropho-tometric assay of riboflavine and photoproductsrdquo Journal ofPharmaceutical and Biomedical Analysis vol 8 no 3 pp 217ndash223 1990

[64] P F Heelis G O Phillips I Ahmad et al ldquoThe photodegra-dation of formylmethylflavin a steady state and laser flashphotolysis studyrdquo Photobiochemistry and Photobiophysics vol 1no 2 pp 125ndash130 1980

[65] W E Kurtin M A Latino and P S Song ldquoA study ofphotochemistry of flavins in pyridine and with a donorrdquoPhotochemistry and Photobiology vol 6 no 4 pp 247ndash259 1967

[66] W M Moore J T Spence F A Raymond and S D ColsonldquoPhotochemistry of riboflavin IThe hydrogen transfer processin the anaerobic photobleaching of flavinsrdquo Journal of theAmerican Chemical Society vol 85 no 21 pp 3367ndash3372 1963

[67] M Green and G Tollin ldquoFlash photolysis of flavins I Photore-duction in non-aqueous solventsrdquo Photochemistry and Photobi-ology vol 7 no 2 pp 129ndash143 1968

[68] G R Penzer and G K Radda ldquoPhotochemistry of flavinsrdquoMethods in Enzymology B vol 18 pp 479ndash495 1971

[69] W L Cairns and D E Metzler ldquoPhotochemical degradationof flavins VI A new photoproduct and its use in studyingthe photolytic mechanismrdquo Journal of the American ChemicalSociety vol 93 no 11 pp 2772ndash2777 1971

[70] P F Heelis ldquoThe photophysical and photochemical propertiesof flavins (isoalloxazines)rdquoChemical Society Reviews vol 11 no1 pp 15ndash39 1982

[71] P F Heelis ldquoThe photochemistry of flavinsrdquo in Chemistry andBiochemistry of Flavoenzymes F Muller Ed pp 171ndash193 CRCPress Boca Raton Fla USA 1991

[72] WHolzer J Shirdel P Zirak et al ldquoPhoto-induced degradationof some flavins in aqueous solutionrdquo Chemical Physics vol 308no 1-2 pp 69ndash78 2005


[73] M Insinska-Rak AGolczak andM Sikorski ldquoPhotochemistryof riboflavin derivatives in methanolic solutionsrdquoThe Journal ofPhysical Chemistry A vol 116 no 4 pp 1199ndash1207 2012

[74] M Insinska-Rak and M Sikorski ldquoRiboflavin interactions withoxygen-survey from the photochemical perspectiverdquo Chem-istry vol 20 no 47 pp 15280ndash15291 2014

[75] R Brdicka ldquoDecomposition of lactoflavin by lightrdquo Collectionof Czechoslovak Chemical Communications vol 14 pp 130ndash1441949

[76] E C Smith and D E Metzler ldquoThe photochemical degradationof riboflavinrdquo Journal of the American Chemical Society vol 85no 20 pp 3285ndash3288 1963

[77] P S Song E C Smith andD EMetzler ldquoPhotochemical degra-dation of flavins IIThemechanismof alkaline hydrolysis of 67-dimethyl-9-formyl-methylisoalloxazinerdquo Journal of AmericanChemical Society vol 87 no 18 pp 4181ndash4184 1965

[78] I AhmadHDC Rapson P PHeelis andGO Phillips ldquoAlka-line hydrolysis of 78-dimethyl-10-(formylmethyl)isoalloxazineA kinetic studyrdquo Journal of Organic Chemistry vol 45 no 4 pp731ndash733 1980

[79] I Ahmad T Mirza K Iqbal S Ahmed M A Sheraz and F HM Vaid ldquoEffect of pH buffer and viscosity on the photolysisof formylmethylflavin a kinetic studyrdquo Australian Journal ofChemistry vol 66 no 5 pp 579ndash585 2013

[80] C Fukumachi and Y Sakurai ldquoVitamin B2photolysis V

The photolytic formation of 67-dimethyl-9-acetic ester fromriboflavinrdquo Vitamin (Kyoto) vol 7 pp 939ndash943 1954

[81] I Ahmad Q Fasihullah A Noor I A Ansari andQ NM AlildquoPhotolysis of riboflavin in aqueous solution a kinetic studyrdquoInternational Journal of Pharmaceutics vol 280 no 1-2 pp 199ndash208 2004

[82] F Urbach Ed The Biological Effects of Ultraviolet RadiationsPergamon Oxford UK 1969

[83] J H Epstein and B U Wintroub ldquoPhotosensitivity due todrugsrdquo Drugs vol 30 no 1 pp 42ndash57 1985

[84] L C Harber I E Kochevar and A R Shalita ldquoMechanismof photosensitization to drugs in humansrdquo in Science of Pho-tomedicine J D Regan and J A Parrish Eds pp 323ndash347Plenum Press New York NY USA 1982

[85] D Moyal and A Fourtanier ldquoAcute and chronic effects of UVon skinrdquo in Photoaging D S Rigel R A Weiss H W Lim andJ S Dover Eds pp 15ndash32 Marcel Dekker New York NY USA2004

[86] J E Roberts ldquoScreening dyes drugs and dietary supplementsfor ocular phototoxicityrdquo in Photostability of Drugs and DrugFormulations H H Tonnesen Ed pp 235ndash254 CRC PressBoca Raton Fla USA 2nd edition 2004

[87] H V DeBuys S B Levy J C Murray D L Madey and SR Pinnell ldquoModern approaches to photoprotectionrdquo Dermato-logic Clinics vol 18 no 4 pp 577ndash590 2000

[88] R C Romanhole J A Ataide P Moriel and P G MazzolaldquoUpdate on ultraviolet A and B radiation generated by the sunand artificial lamps and their effects on skinrdquo InternationalJournal of Cosmetic Science vol 37 no 4 pp 366ndash370 2015

[89] E M Gil and T H Kim ldquoUV-induced immune suppressionand sunscreenrdquo Photodermatology Photoimmunology and Pho-tomedicine vol 16 no 3 pp 101ndash110 2000

[90] R Roelandts ldquoShedding light on sunscreensrdquo Clinical andExperimental Dermatology vol 23 no 4 pp 147ndash157 1998

[91] F P Gasparro M Mitchnick and J F Nash ldquoA review ofsunscreen safety and efficacyrdquo Photochemistry and Photobiologyvol 68 no 3 pp 243ndash256 1998

[92] E Chatelain and B Gabard ldquoPhotostabilization of butylmethoxydibenzoylmethane (Avobenzone) and ethylhexylmethoxycinnamate by bis-ethylhexyloxyphenol methoxy-phenyl triazine (Tinosorb S) a new UV broadband filterrdquoPhotochemistry and Photobiology vol 74 no 3 pp 401ndash4062001

[93] H Maier G Schauberger K Brunnhofer and H HonigsmannldquoChange of ultraviolet absorbance of sunscreens by exposure tosolar-simulated radiationrdquo The Journal of Investigative Derma-tology vol 117 no 2 pp 256ndash262 2001

[94] D A Buckley D OrsquoSullivan and G M Murphy ldquoContact andphotocontact allergy to dibenzoylmethanes and contact allergytomethylbenzylidene camphorrdquoContact Dermatitis vol 29 no1 p 47 1993

[95] M F Naylor and K C Farmer ldquoThe case for sunscreens areview of their use in preventing actinic damage and neoplasiardquoArchives of Dermatology vol 133 no 9 pp 1146ndash1154 1997

[96] S Schauder and H Ippen ldquoPhotoallergic and allergic contactdermatitis from dibenzoylmethanesrdquo Photodermatology vol 3no 3 pp 140ndash147 1986

[97] S Schauder and H Ippen ldquoContact and photocontact sensi-tivity to sunscreens Review of a 15-year experience and of theliteraturerdquo Contact Dermatitis vol 37 no 5 pp 221ndash232 1997

[98] R J Motley and A J Reynolds ldquoPhotocontact dermatitis due toisopropyl and butyl methoxy dibenzoylmethanes (Eusolex 8020and Parsol 1789)rdquo Contact Dermatitis vol 21 no 2 pp 109ndash1101989

[99] E J Parry D Bilsland andW N Morley ldquoPhotocontact allergyto 4-tert-butyl-41015840-methoxy-dibenzoylmethane (Parsol 1789)rdquoContact Dermatitis vol 32 no 4 pp 251ndash252 1995

[100] T Schmidt J Ring and D Abeck ldquoPhotoallergic con-tact dermatitis due to combined UVB (4-methylbenzylidenecamphoroctyl methoxycinnamate) and UVA (benzophenone-3butyl methoxydibenzoylmethane) absorber sensitizationrdquoDermatology vol 196 no 3 pp 354ndash357 1998

[101] Food and Drug Administration USA ldquoRules and regulationsrdquoFederal Register vol 64 no 98 p 27687 1999

[102] R Jansen U Osterwalder S Q Wang M Burnett and HW Lim ldquoPhotoprotection part II Sunscreen developmentefficacy and controversiesrdquo Journal of the American Academyof Dermatology vol 69 no 6 pp 867e1ndash867e14 2013

[103] ICH ldquoHarmonized tripartite guideline photostability testingof new drug substances and products ICH-Q113 Nov 1996rdquoFederal Register vol 62 pp 27115ndash27122 1996

[104] S C Valvani ldquoIndustrial stability testing in the United Statesand computerization of stability datardquo in Drug Stability Prin-ciples and Practices J T Carstensen and C T Rhodes Eds pp515ndash552Marcel Dekker NewYork NY USA 3rd edition 2000

[105] N H Anderson D JohnstonM AMcLelland and PMundenldquoPhotostability testing of drug substances and drug products inUKpharmaceutical laboratoriesrdquo Journal of Pharmaceutical andBiomedical Analysis vol 9 no 6 pp 443ndash449 1991

[106] J P Riehl C L Maupin and T P Layloff ldquoOn the choice of alight source for the photostability testing of pharmaceuticalsrdquoPharmacopoeial Forum vol 21 no 6 pp 1654ndash1663 1995

[107] M Matsuo Y Machida H Furuichi K Nakamura and YTakeda ldquoSuitability of photon sources for photostability testingof pharmaceutical productsrdquoDrug Stability vol 1 no 3 pp 179ndash187 1996

[108] H H Tonnesen and J Karlsen ldquoPhotochemical degradation ofcomponents in drug formulations A discussion of experimen-tal conditionsrdquo PharmaEuropa vol 7 pp 137ndash141 1995


[109] J J Piechocki ldquoSelecting the right source for photostabilitytestingrdquo in Drugs Photochemistry and Photostability A AlbiniandE Fasani Eds pp 247ndash271TheRoyal Society ofChemistryCambridge UK 1998

[110] H H Anderson and S J Byard ldquoPhotostability testing designand interpretation of tests on new drug substance and dosageformsrdquo in Photostability of Drugs and Drug Formulations H HTonnesen Ed pp 137ndash160 CRC Press Boca Raton Fla USA2nd edition 2004

[111] J Boxhammer and A Schonlein ldquoTechnical requirements andequipment for photostability testingrdquo in Photostability of Drugsand Drug Formulations H H Tonnesen Ed pp 111ndash136 CRCPress Boca Raton Fla USA 2nd edition 2004

[112] J Boxhammer andCWillwoldt ldquoDesign and validation charac-teristics of environmental chambers for photostability testingrdquoin Drugs Photochemistry and Photostability A Albini and EFasani Eds pp 272ndash287 The Royal Society of ChemistryCambridge UK 1998

[113] J B Davis ldquoQualification calibration and maintenance ofstability chambersrdquo in Handbook of Stability-Testing in Phar-maceutical Development Regulations Methodologies and BestPractices K Huynh-Ba Ed pp 285ndash302 Springer New YorkNY USA 2009

[114] D EMoore ldquoPrinciples and practice of drug photodegradationstudiesrdquo Journal of Pharmaceutical and Biomedical Analysis vol5 no 5 pp 441ndash453 1987

[115] H D Drew ldquoPhotostability of drug substances and drugproducts a validated reference method for implementing ICHphotostability study guidelinesrdquo in Drugs Photochemistry andPhotostability A Albini and E Fasani Eds pp 227ndash242 TheRoyal Society of Chemistry Cambridge UK 1998

[116] W Grimm ldquoA rational approach to stability testing and analyti-cal development for NCE drug substance and stability testingrdquoin Drug Stability Principles and Practices J T Carstensen andC T Rhodes Eds pp 415ndash482 Marcel Dekker New York NYUSA 3rd edition 2000

[117] W Grimm G Harnischfeger and M Tegtmeier Stabilitatspru-fung in der PharmazieThieme Stuttgart Germany 3rd edition2011

[118] S Nema R J Washkuhn and D R Beussink ldquoPhotostabilitytesting an overviewrdquo Pharmaceutical Technology vol 19 pp170ndash185 1995

[119] P Halboe ldquoThe elaboration and application of the ICH guide-line on photostability a European viewrdquo in Drugs Photochem-istry and Photobiology A Albini and E Fasani Eds pp 243ndash246 The Royal Society of Chemistry Cambridge UK 1998

[120] T G Beaumont ldquoPhotostability testingrdquo in International Stabil-ity Testing D JMazzo Ed pp 59ndash72 InterpharmPress BuffaloGrove Ill USA 1999

[121] F Sequeira and C Vozone ldquoPhotostability studies of drugsubstances and products practical implications of the ICHguidelinerdquo Pharmaceutical Technology vol 24 no 8 pp 30ndash352000

[122] S RThatcher R KMausfield R BMiller et al ldquoPharmaceuti-cal photostability a technical guide and practical interpretationof the ICH guideline and its application to pharmaceuticalstability Irdquo Pharmaceutical Technology vol 25 no 3 pp 50ndash522001

[123] S R Thatcher R K Mansfield R B Miller C W Davisand SW Baertschi ldquoPharmaceutical photostability a technicalguide and practical interpretation of the ICH guideline and

its application to pharmaceutical stability IIrdquo PharmaceuticalTechnology vol 25 no 4 pp 50ndash62 2001

[124] K Thoma ldquoPhotodecomposition and stabilization of com-pounds in dosage formsrdquo in The Photostability of Drugs andDrug Formulations H H Tonnesen Ed pp 111ndash140 Taylor ampFrancis London UK 1996

[125] K A Connors G L Amidon andV J Stella ldquoSolid-state chem-ical decompositionrdquo in Chemical Stability of PharmaceuticalsK A Connors G L Amidon and V J Stella Eds pp 115ndash132John Wiley amp Sons New York NY USA 3rd edition 1986

[126] K Thoma and R Klimek ldquoPhotostabilization of drugs indosage forms without protection from packaging materialsrdquoInternational Journal of Pharmaceutics vol 67 no 2 pp 169ndash175 1991

[127] K Thoma and H Spilgies ldquoPhotostabilization of solid andsemisolid dosage formsrdquo in Pharmaceutical Photostability andStabilization J T Piechocka and K Thoma Eds pp 323ndash334Informa Healthcare New York NY USA 2007

[128] K Thoma and N Kubler ldquoEinflub vis hilfostffen aus diephotozersetzing von arzeistoffenrdquoDie Pharmazie vol 52 no 2pp 122ndash129 1997

[129] K Thoma ldquoProtection of drugs against light achieved protec-tion and possibilities of stabilizationrdquo in Proceedings of the 3rdInternational Meeting on Photostability of Drugs (Photostabilityrsquo99) Washington DC USA July 1999

[130] E E Kaminsk R M Cohn J L McGure and J T CarstensenldquoLight stability of norethindrone and ethinyl estradiol formu-lated with FDampC colorantsrdquo Journal of Pharmaceutical Sciencesvol 68 no 3 pp 368ndash370 1979

[131] H Takeuchi H Sasaki T Niwa et al ldquoImprovement ofphotostability of ubidecarenone in the formulation of a novelpowdered dosage form termed redispersible dry emulsionrdquoInternational Journal of Pharmaceutics vol 86 no 1 pp 25ndash331992

[132] D S Desai M A Abdelnasser B A Rubitski and S AVaria ldquoPhotostabilization of uncoated tablets of sorivudineand nifedipine by incorporation of synthetic iron oxidesrdquoInternational Journal of Pharmaceutics vol 103 no 1 pp 69ndash76 1994

[133] Y Matsuda T Itooka and Y Mitsuhashi ldquoPhotostability ofindomethacin in model gelatin capsules effects of film thick-ness and concentration of titanium dioxide on the colorationand photolytic degradationrdquo Chemical and PharmaceuticalBulletin vol 28 no 9 pp 2665ndash2671 1980

[134] R Teraoka Y Matsuda and I Sugimoto ldquoQuantitative designfor photostabilization of nifedipine by using titanium dioxideandor tartrazine as colourants in model film coating systemsrdquoThe Journal of Pharmacy and Pharmacology vol 41 no 5 pp293ndash297 1989

[135] S R Bechard O Quraishi and E Kwong ldquoFilm coatingeffect of titanium dioxide concentration and film thicknesson the photostability of nife dipinerdquo International Journal ofPharmaceutics vol 87 no 1ndash3 pp 133ndash139 1992

[136] K Thoma and R Kerker ldquoPhotounstabilitat von arzneimitteln3Mitteilung photoinstabilitat und stabilisierung von nifedipinein arzneiforminrdquo Pharmazeutische Industrie vol 54 no 4 pp359ndash365 1992

[137] Y Matsuda H Inouye and R Nakanishi ldquoStabilization ofsulfisomidine tablets by use of film coating containing UVabsorber protection of coloration and photolytic degradationfrom exaggerated lightrdquo Journal of Pharmaceutical Sciences vol67 no 2 pp 196ndash201 1978


[138] A Mukharya P U Patel and S Chaudhary ldquoEffect assessmentof lsquofilm coating and packagingrsquo on the photo-stability of highlyphoto-labile antihypertensive productsrdquo International Journalof Pharmaceutical Investigation vol 3 no 2 pp 77ndash87 2013

[139] H Nyqvist M Nicklasson and P Lundgren ldquoStudies on thephysical properties of tablets and tablet excipients V Filmcoating for protection of a light-sensitive tablet-formulationrdquoActa Pharmaceutica Suecica vol 19 no 3 pp 223ndash228 1982

[140] I Ahmad S Ahmed M A Sheraz M Aminuddin and F HM Vaid ldquoEffect of caffeine complexation on the photolysis ofriboflavin in aqueous solution a kinetic studyrdquo Chemical andPharmaceutical Bulletin vol 57 no 12 pp 1363ndash1370 2009

[141] G R Penzer and G K Radda ldquoThe chemistry and biologicalfunction of isoalloxazines (flavines)rdquoQuarterly Reviews Chem-ical Society vol 21 no 1 pp 43ndash65 1967

[142] E DeRitter ldquoVitamins in pharmaceutical formulationsrdquo Journalof Pharmaceutical Sciences vol 71 no 10 pp 1073ndash1096 1982

[143] M P Evstigneev A O Rozvadovskaya A A H Santiagoet al ldquoA 1H NMR study of the association of caffeine withflavinmononucleotide in aqueous solutionsrdquo Russian Journal ofPhysical Chemistry A vol 79 no 4 pp 573ndash578 2005

[144] R S Rivlin ldquoRiboflavin (vitamin B2)rdquo inHandbook of Vitamins

J Zempleni R B Rucker D B McCormick and J W SuttieEds p 240 CRC Press New York NY USA 4th edition 2007

[145] D AWadke andD E Guttman ldquoComplex formation influenceon reaction rate II Hydrolytic behavior of riboflavin in boratebufferrdquo Journal of Pharmaceutical Sciences vol 53 pp 1073ndash1076 1964

[146] I Ahmad S Ahmed M A Sheraz and F H M VaidldquoEffect of borate buffer on the photolysis of riboflavin inaqueous solutionrdquo Journal of Photochemistry and PhotobiologyB Biology vol 93 no 2 pp 82ndash87 2008

[147] K Uekama K Oh M Otagiri et al ldquoImprovement of somepharmaceutical properties of colfibrate by cyclodextrin com-plexationrdquo Pharmaceutica Acta Helvetica vol 58 no 12 pp338ndash342 1983

[148] K Tomono H Gotoh M Okamura et al ldquoEffect of 120573-cyclodextrin and its derivatives on the photostability of photo-sensitive drugsrdquo Yakuzaigaku vol 48 no 4 pp 322ndash325 1988

[149] M E Brewster T Loftsson K S Estes J-L Lin HFridriksdottir and N Bodor ldquoEffect of various cyclodex-trins on solution stability and dissolution rate of doxorubicinhydrochloriderdquo International Journal of Pharmaceutics vol 79no 1ndash3 pp 289ndash299 1992

[150] A Suenaga O Bekers J H Beijnen et al ldquoStabilization ofdaunorubicin and 4-demethoxydaunorubicin on complexationwith octakis(26-di-O-methyl)-120574-cyclodextrin in acidic aque-ous solutionrdquo International Journal of Pharmaceutics vol 82 no1-2 pp 29ndash37 1992

[151] OAG J van derHouwen J TeeuwsenO Bekers JH BeijnenA Bult and W J M Underberg ldquoDegradation kinetics of 7-N-(p-hydroxyphenyl)mitomycin C (M-83) in aqueous solutionin the presence of 120574-cyclodextrinrdquo International Journal ofPharmaceutics vol 105 no 3 pp 249ndash254 1994

[152] Y L Loukas ldquoA Plackett-Burnam screening design directsthe efficient formulation of multicomponent DRV liposomesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 26 no2 pp 255ndash263 2001

[153] Y L Loukas V Vraka and G Gregoriadis ldquoFluorimetricstudies of the formation of riboflavin-120573-cyclodextrin inclusioncomplex determination of the stability constant by use of

a non-linear least-squares modelrdquo Journal of Pharmacy andPharmacology vol 49 no 2 pp 127ndash130 1997

[154] X-M Wang and H-Y Chen ldquoA spectroelectrochemical studyof the interaction of riboflavin with 120573-cyclodextrinrdquo Spec-trochimica Acta-Part AMolecular Spectroscopy vol 52 no 5 pp599ndash605 1996

[155] X-M Wang M-D Yan J-J Zhu and H-Y Chen ldquoThesurface-enhanced Raman spectroelectrochemical study on theinteraction between 120573-cyclodextrin and the electrochemicallygenerated radical intermediate of flavinrdquo Journal of Electroana-lytical Chemistry vol 451 no 1-2 pp 187ndash192 1998

[156] I V Terekhova M Kozbiał R S Kumeev and G A AlperldquoInclusion complex formation between modified cyclodextrinsand riboflvin and alloxazine in aqueous solutionrdquo Journal ofSolution Chemistry vol 40 no 8 pp 1435ndash1446 2011

[157] I V Terekhova M N Tikhova T V Volkova R S Kumeevand G L Perlovich ldquoInclusion complex formation of 120572- and 120573-cyclodextrins with riboflavin and alloxazine in aqueous solu-tion thermodynamic studyrdquo Journal of Inclusion Phenomenaand Macrocyclic Chemistry vol 69 no 1-2 pp 167ndash172 2011

[158] I V Terekhova ldquoComplexation of cyclodextrins with flavines inaqueous solutionsrdquoRussian Journal of Physical Chemistry A vol88 no 1 pp 65ndash72 2014

[159] B D Glass M E Brown S Daya et al ldquoInfluence of cyclodex-trins on the photostability of selected drugmolecules in solutionand the solid-staterdquo International Journal of Photoenergy vol 3no 4 pp 205ndash211 2001

[160] J Mielcarek and E Daczkowska ldquoPhotodegradation of inclu-sion complexes of isradipine with methylndash120573ndashcyclodextrinrdquoJournal of Pharmaceutical and Biomedical Analysis vol 21 no2 pp 393ndash398 1999

[161] R Pomponio R Gotti J Fiori et al ldquoPhotostability studies onnicardipine-cyclodextrin complexes by capillary electrophore-sisrdquo Journal of Pharmaceutical and Biomedical Analysis vol 35no 2 pp 267ndash275 2004

[162] R Challa A Ahuja J Ali and R K Khar ldquoCyclodextrins indrug delivery an updated reviewrdquo AAPS PharmSciTech vol 6no 2 pp E329ndashE357 2005

[163] M J Habib and A F Asker ldquoPhotostabilization of riboflavin byincorporation into liposomesrdquo Journal of Parenteral Science andTechnology vol 15 no 3 pp 124ndash127 1991

[164] Y L Loukas P Jayasekera and G Gregoriadis ldquoCharacteriza-tion and photoprotection studies of a model 120574ndashcyclodextrin-included photolabile drug entrapped in liposomes incorporat-ing light absorbersrdquo Journal of Physical Chemistry vol 99 no27 pp 11035ndash11040 1995

[165] Y L Loukas P Jayasekera and G Gregoriadis ldquoNovelliposome-based multicomponent systems for the protection ofphotolabile agentsrdquo International Journal of Pharmaceutics vol117 no 1 pp 85ndash94 1995

[166] B B Bhowmik and A Sil ldquoPhotoinduced interaction ofriboflavin dye with different reducing agents in aqueous andliposome mediardquo Chemistry and Physics of Lipids vol 127 no2 pp 189ndash197 2004

[167] I Ahmad A Arsalan S A Ali et al ldquoFormulation andstabilization of riboflavin in liposomal preparationsrdquo Journal ofPhotochemistry and Photobiology B Biology vol 153 pp 358ndash366 2015

[168] S Bandak A Ramu Y Barenholz and A Gabizon ldquoReducedUV-induced degradation of doxorubicin encapsulatedin polyethyleneglycol-coated liposomesrdquo PharmaceuticalResearch vol 16 no 6 pp 841ndash846 1999


[169] M E Carlotti V Rossatto M Gallarate M Trotta and FDebernardi ldquoVitamin A palmitate photostability and stabilityover timerdquo Journal of Cosmetic Science vol 55 no 3 pp 233ndash252 2004

[170] J L Vazquez M Berlanga S Merino et al ldquoDetermina-tion by fluorimetric titration of the ionization constants ofciprofloxacin in solution and in the presence of liposomesrdquoPhotochemistry and Photobiology vol 73 no 1 pp 14ndash19 2001

[171] M Budai P Grof A Zimmer K Papai I Klebovich andK Ludanyi ldquoUV light induced photodegradation of liposomeencapsulated fluoroquinolones an MS studyrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 198 no 2-3 pp268ndash273 2008

[172] M Fadel and K Kassab ldquoEvaluation of the photostability andphotodynamic efficacy of Rose Bengal loaded in multivesicularliposomesrdquo Tropical Journal of Pharmaceutical Research vol 10no 3 pp 289ndash297 2011

[173] G Ragno E Cione A Garofalo et al ldquoDesign and monitoringof photostability systems for amlodipine dosage formsrdquo Inter-national Journal of Pharmaceutics vol 265 no 1-2 pp 125ndash1322003

[174] G Ioele E Cione A Risoli G Genchi and G RagnoldquoAccelerated photostability study of tretinoin and isotretinoin inliposome formulationsrdquo International Journal of Pharmaceuticsvol 293 no 1-2 pp 251ndash260 2005

[175] Y Sadzuka K Nakagawa H Yoshioka and T Sonobe ldquoAliposomal formulation study of 27-dichlorodihydrofluoresceinfor detection of reactive oxygen speciesrdquo International Journalof Pharmaceutics vol 356 no 1-2 pp 300ndash305 2008

[176] J Cheng J-B Zhu N Wen and F Xiong ldquoStability andpharmacokinetic studies of O-palmitoyl amylopectin anchoreddipyridamole liposomesrdquo International Journal of Pharmaceu-tics vol 313 no 1-2 pp 136ndash143 2006

[177] S M T Nunes F S Sguilla and A C Tedesco ldquoPhoto-physical studies of zinc phthalocyanine and chloroaluminumphthalocyanine incorporated into liposomes in the presence ofadditivesrdquo Brazilian Journal of Medical and Biological Researchvol 37 no 2 pp 273ndash284 2004

[178] M J Habib and J A Rogers ldquoStabilization of local anestheticsin liposomesrdquoDrug Development and Industrial Pharmacy vol13 no 9ndash11 pp 1947ndash1971 1987

[179] M Michaelis A Zimmer N Handjou J Cinatl and J CinatlJr ldquoIncreased systemic efficacy of aphidicolin encapsulated inliposomesrdquo Oncology Reports vol 13 no 1 pp 157ndash160 2005

[180] L Lachman P DeLuca and M J Akers ldquoKinetics principlesand stability testingrdquo in The Theory and Practice of IndustrialPharmacy L Lachman H A Lieberman and J L Kanig Edspp 760ndash803 Lea amp Febiger Philadelphia Pa USA 3rd edition1986

[181] I Ahmad M A Sheraz S Ahmed R Bano and F H M VaidldquoPhotochemical interaction of ascorbic acid with riboflavinnicotinamide and 120572-tocopherol in cream formulationsrdquo Inter-national Journal of Cosmetic Science vol 34 no 2 pp 123ndash1312012

[182] M J Habib and A F Asker ldquoPhotostabilization of doxorubicinhydrochloride with radioprotective and photoprotective agentspotential mechanism for enhancing chemotherapy duringradiotherapyrdquo Journal of Parenteral Science and Technology vol43 no 6 pp 259ndash261 1989

[183] W J M Underberg and H Lingeman ldquoAspects of the chemicalstability of mitomycin and porfiromycin in acidic solutionrdquo

Journal of Pharmaceutical Sciences vol 72 no 5 pp 549ndash5531978

[184] T Ahmad and I Ahmad ldquoThe effect of antioxidants onthe photolysis of aqueous sulphacetamide and sulfanilamidesolutionsrdquo Polish Journal of Pharmacology and Pharmacy vol35 no 1 pp 69ndash75 1983

[185] M J OrsquoNeil Ed The Merck Index Merck amp Co Rahway NJUSA 13th edition 2001

[186] J Sawicka ldquoThe influence of excipients and technological pro-cess on cholecalciferol stability and its liberation from tabletsrdquoDie Pharmazie vol 46 no 7 pp 519ndash521 1991

[187] K Akimoto H Nakagawa and I Sugimoto ldquoPhoto-stabilityof cianidanol in aqueous solution and in the solid staterdquo DrugDevelopment and Industrial Pharmacy vol 11 no 4 pp 865ndash889 1985

[188] A F Asker and M J Habib ldquoEffect of certain stabilizers onphotobleacing of riboflavin solutionsrdquo Drug Development andIndustrial Pharmacy vol 16 no 1 pp 149ndash156 1990

[189] J Koziol ldquoStudies on flavins in organic solventsmdashII Pho-todecomposition of riboflavin in the presence of oxygenrdquoPhotochemistry and Photobiology vol 5 no 1 pp 55ndash62 1966

[190] W C Schmidt ldquoLight-induced redox cycles of flavins in variousalcoholacetic acidmixturesrdquo Photochemistry and Photobiologyvol 36 no 6 pp 699ndash703 1982

[191] W W Moore and R C Ireton ldquoThe photochemistry ofriboflavin V The photodegradation of isoalloxazines in alco-holic solventsrdquo Photochemistry and Photobiology vol 25 no 4pp 347ndash356 1977

[192] I Ahmad Z Anwar S Ahmed M A Sheraz R Bano and AHafeez ldquoSolvent effect on the photolysis of riboflavinrdquo AAPSPharmSciTech vol 16 no 5 pp 1122ndash1128 2015

[193] G R Brunk K A Martin and A M Nishimura ldquoA study ofsolvent effects on the phosphorescence properties of flavinsrdquoBiophysical Journal vol 16 no 2 pp 1373ndash1384 1976

[194] I Ahmad R Bano S G Musharraf et al ldquoPhotodegradation ofmoxifloxacin in aqueous and organic solvents a kinetic studyrdquoAAPS PharmSciTech vol 15 no 6 pp 1588ndash1597 2014

[195] P Bilski L J Martinez E B Koker and C F Chignell ldquoInflu-ence of solvent polarity and proticity on the photochemicalproperties of norfloxacinrdquo Photochemistry and Photobiologyvol 68 no 1 pp 20ndash24 1998

[196] M M Haque and M Muneer ldquoPhotodegradation of nor-floxacin in aqueous suspensions of titanium dioxiderdquo Journalof Hazardous Materials vol 145 no 1-2 pp 51ndash57 2007

[197] C B Grissom A M Chagovetz and Z Wang ldquoUse ofviscosigens to stabilize vitaminB

12solutions against photolysisrdquo


[198] S M Blaug and B Hajratwala ldquoKinetics of aerobic oxidation ofascorbic acidrdquo Journal of Pharmaceutical Sciences vol 61 no 4pp 556ndash562 1972

[199] A F Asker D Canady and C Cobb ldquoInfluence of DL-methionine on the photostability of ascorbic acid solutionsrdquoDrug Development and Industrial Pharmacy vol 11 no 12 pp2109ndash2125 1985

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


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Advances in

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Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

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Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


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Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


2 Photostability

The photostability of a drug substance may be defined as theresponse of the drug or drug product to the exposure to solarUV and visible light in the solid semisolid or liquid state thatleads to a physical or chemical change

The response of the drug to light absorption and excita-tion can be considered in terms of photodegradation (pho-tolysis) reactions through the formation of free radicals orphotosensitization reactions by intermolecular energy trans-fer These reactions involve primary (photochemical) andsecondary (chemical) reactions that give the final products

21 Objectives of the Photostability Studies In view of thephotosensitivity and photoinstability of drugs and adjuvantsknowledge of the photostability of these substances and theirformulated products is necessary to evaluate the following

(i) The intrinsic photostability characteristics(ii) Thephysical and chemical changes upon the exposure

to light(iii) The photodegradation pathways and mechanisms(iv) The shelf life of the products(v) The efficacy of the stabilizing agents in photostabiliza-

tion(vi) The need for modification of the formulation param-

eters(vii) The need for the measures to overcome the effects of

the light exposure during manufacturing packaginglabeling transportation and storage

(viii) The light-induced biological effects(ix) The primary and secondary package design

22 Requirements for the Photostability Studies Consider thefollowing

(i) The solubility of the drug and choice of reactionmedium

(ii) The spectral characteristics of the drug molecule(iii) The sensitivity of the drug molecule to the solar UV

and visible light(iv) The reaction vessel and the radiation source appro-

priate for the spectral characteristics of the drugmolecule

(v) The knowledge of the photodegradation mode andthe nature of the photoproducts from the preliminarystudies

(vi) A validated stability-indicating assay method todetermine the intact drug and the photoproducts inthe degraded material

3 Photochemical Reactions

The photochemistry of the organic compounds has beenstudied for a long time [32ndash36] and an advanced treatment

of this subject is available [6 37] The study of the pho-tochemistry provides a basis for the understanding of thephotochemical reactions of the drug substances that affecttheir stability and efficacy

Photochemical reactions may lead to the degradationof the drug substances by one or more pathways to formdifferent products The elucidation of the mechanisms ofthese pathways requires a thorough understanding of thenature and type of the photochemical reactions involvedThese would largely depend on the presence of certain func-tional groups physical characteristics (light absorption p119870assolubility etc) and the degradation mode of the compoundThe assessment of the photostability of the drug substances isbased on the study of all those factors that determine the ratesand mechanisms of the underlying photochemical reactions

31 Spectral Regions of the UV Visible and Solar RadiationThespectral regions of theUV visible and solar light involvedin the photochemical reactions are as follows

UVA 320ndash400 nmUVB 290ndash320 nmUVC 200ndash290 nmVisible 400ndash700 nmSolar including UVA UVB and visible ranges

The majority of the photochemical reactions occur with thehelp of the UVA UVB or visible light

32 Chemical Groups Important for the Photoreactivity ofthe Drug Molecules The presence of the following chemicalfunctional groups in the drug molecules [10] is usuallynecessary for the occurrence of photochemical reactions

(i) Double bond C=C (oxidationisomerization)(ii) Carbonyl group C=O group

(reductionfragmentation)(iii) Aryl chloride C

6H4Cl2

(homolyticheterolyticdechlorination)

(iv) Nitroaromatic group ndashC6H4NO2(hydrogen abstrac-

tionnitrite ester rearrangement)(v) A weak CndashH bond (photoinduced fragmentation via

hydrogen atom transfer or electron-proton transfer)(vi) Sulfides alkenes polyenes and phenols (highly reac-

tive with singlet oxygen photochemically formedfrom the ground-state triplet oxygen)

33 Photophysical Processes It is necessary to understand thevarious photophysical processes involved in the absorptionand dissipation of the light energy (see (1)ndash(7)) that have beendescribed byMoore [38]Thesemay be followed by additionalreactions forming free radicals and subsequently the finalproducts (see (8)ndash(11)) as a result of the photodegradationof the drug substances

(i) Absorption

Aoℎ]997888997888rarr1A (singlet excited state) (1)












(ix) Final products

2AH∙ 997888rarr AH2+ Ao (11)





Rate


= 119873Φ

(12)


119873120582= 119868120582minus 119868119905= 119868120582(1 minus 10

minus119860) (13)




119873120582= 2303119868

120582119860 = 2303119868

120582L120582119887119862 (14)



120582and



119873


1and 120582

2

Rate = 2303119887119862Φint (119868120582L120582) d120582

(15)







Rate = minus119889 [Drug]119889119905= 1198961119862


0eminus1198961119905


0minus 1198961119905

(16)


1








4

2minus and SO4

2minus


4


4










(17)


ISC1[Co3+ CN] 3

[Co3+ CN] (18)

B12b


(19)

H+H+


+ (20)


O2[Co3+ OH] (21)





Dihydroflavin

Intermediate

Autooxidation

(1) (2)(3)

(4)

N

N

NH

N

O

O

CH

CH

CH

HO

HO

HO

CH2OH

CH2

H3C

H3C

N

N

NH

N

O

O

O

H

H

OH

OH

OH

H

H

H3C

H3C

Na2HPO4

1RF HPO42minush





12H+] due






RF ISC1RF 3RFh (22)


(5) (6) (7)

Cl

HN

ClCOOH

CH3

HN

ClCOOH

CH3

HN

ClCOOH

CH3

h +


NCl

NH N

NCl

NH N

H

(8) (9)

(10)(11)

CH3 CH3

NCl

NH

OH

CH3

hh

h

CH2CH3

CH2CH3 CH2CH3

NCl

NH2


COOHH

R

3RF + NH2 CO2 + RCHO + NH3 (23)







(12) (13)

NN

O

F

+H2N

COOminus

minusFminus

NN

O

+H2N

COOminus

+


(14) (16)(15)

N

H

N

NO

N

H3COOCH3COOCH3COOC



NO2 NO2

O2h







CHO

Initiation+

k1

CO∙

h (24)

Propagation+k2

CO∙ CO3∙

O2

(25)

CHO

Propagation ++k3

CO∙CO3∙ CO3H

(26)


N

NH N

H

N

(17) (18)

CH3

CH3

H3CO

H3CO

N

NH

CH3

H3CO

NH2

h


(19) (20)

N

H

HON

HH

CF3

CF3

N

OH

CF3

CF3

h



2CO3∙

(27)











(21) (22)

hSO H

N

O O

H2N

OHminus+S

OO

H2NNH2

CH3COOH


(23) (24)

h

O

HN

O

N

O

HOOC

S

N

CH3

CH3

CH3

+H3N

SO3minusO

HN

O

N

O

COOH

S

N CH3

CH3

+H3N

SO3minus

H3C













(25) (26)

h

O

O

O

CH3

O

O

CH3

pH 6ndash12


(27) (28)

h

NN

O NCH3

CH3

CH2Ph

N

O

N NCH3

CH3

CH2Ph











(1) (29)

(31)

(30)

(32) (33) (34)

N

N

NH

N O

O

OH

R

H3C

H3C

N

N

NH

HN O

O

CR

OH

H3C

H3C

N

N

NH

N O

O

H

O

H3C

H3C

N

N

NH

HN O

O

H3C

H3C N

N

NH

N O

O

O

OH

H3C

H3C

N

N

NH

N O

O

OH

R

H3C

H3C

h

N

N

NH

N O

O

H3C

H3C

CH3

O2

O2

OHminus

H+ OHminus

R = (CHOH)3H






(35) (35)


h

NN

O

FOH

O

+H2N

NHN

O

FOH

O

+H3N



















9 Conclusions


Competing Interests



Acknowledgments


References
































































































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of












(ix) Final products

2AH∙ 997888rarr AH2+ Ao (11)





Rate


= 119873Φ

(12)


119873120582= 119868120582minus 119868119905= 119868120582(1 minus 10

minus119860) (13)




119873120582= 2303119868

120582119860 = 2303119868

120582L120582119887119862 (14)



120582and



119873


1and 120582

2

Rate = 2303119887119862Φint (119868120582L120582) d120582

(15)







Rate = minus119889 [Drug]119889119905= 1198961119862


0eminus1198961119905


0minus 1198961119905

(16)


1








4

2minus and SO4

2minus


4


4










(17)


ISC1[Co3+ CN] 3

[Co3+ CN] (18)

B12b


(19)

H+H+


+ (20)


O2[Co3+ OH] (21)





Dihydroflavin

Intermediate

Autooxidation

(1) (2)(3)

(4)

N

N

NH

N

O

O

CH

CH

CH

HO

HO

HO

CH2OH

CH2

H3C

H3C

N

N

NH

N

O

O

O

H

H

OH

OH

OH

H

H

H3C

H3C

Na2HPO4

1RF HPO42minush





12H+] due






RF ISC1RF 3RFh (22)


(5) (6) (7)

Cl

HN

ClCOOH

CH3

HN

ClCOOH

CH3

HN

ClCOOH

CH3

h +


NCl

NH N

NCl

NH N

H

(8) (9)

(10)(11)

CH3 CH3

NCl

NH

OH

CH3

hh

h

CH2CH3

CH2CH3 CH2CH3

NCl

NH2


COOHH

R

3RF + NH2 CO2 + RCHO + NH3 (23)







(12) (13)

NN

O

F

+H2N

COOminus

minusFminus

NN

O

+H2N

COOminus

+


(14) (16)(15)

N

H

N

NO

N

H3COOCH3COOCH3COOC



NO2 NO2

O2h







CHO

Initiation+

k1

CO∙

h (24)

Propagation+k2

CO∙ CO3∙

O2

(25)

CHO

Propagation ++k3

CO∙CO3∙ CO3H

(26)


N

NH N

H

N

(17) (18)

CH3

CH3

H3CO

H3CO

N

NH

CH3

H3CO

NH2

h


(19) (20)

N

H

HON

HH

CF3

CF3

N

OH

CF3

CF3

h



2CO3∙

(27)











(21) (22)

hSO H

N

O O

H2N

OHminus+S

OO

H2NNH2

CH3COOH


(23) (24)

h

O

HN

O

N

O

HOOC

S

N

CH3

CH3

CH3

+H3N

SO3minusO

HN

O

N

O

COOH

S

N CH3

CH3

+H3N

SO3minus

H3C













(25) (26)

h

O

O

O

CH3

O

O

CH3

pH 6ndash12


(27) (28)

h

NN

O NCH3

CH3

CH2Ph

N

O

N NCH3

CH3

CH2Ph











(1) (29)

(31)

(30)

(32) (33) (34)

N

N

NH

N O

O

OH

R

H3C

H3C

N

N

NH

HN O

O

CR

OH

H3C

H3C

N

N

NH

N O

O

H

O

H3C

H3C

N

N

NH

HN O

O

H3C

H3C N

N

NH

N O

O

O

OH

H3C

H3C

N

N

NH

N O

O

OH

R

H3C

H3C

h

N

N

NH

N O

O

H3C

H3C

CH3

O2

O2

OHminus

H+ OHminus

R = (CHOH)3H






(35) (35)


h

NN

O

FOH

O

+H2N

NHN

O

FOH

O

+H3N



















9 Conclusions


Competing Interests



Acknowledgments


References
































































































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





Rate = minus119889 [Drug]119889119905= 1198961119862


0eminus1198961119905


0minus 1198961119905

(16)


1








4

2minus and SO4

2minus


4


4










(17)


ISC1[Co3+ CN] 3

[Co3+ CN] (18)

B12b


(19)

H+H+


+ (20)


O2[Co3+ OH] (21)





Dihydroflavin

Intermediate

Autooxidation

(1) (2)(3)

(4)

N

N

NH

N

O

O

CH

CH

CH

HO

HO

HO

CH2OH

CH2

H3C

H3C

N

N

NH

N

O

O

O

H

H

OH

OH

OH

H

H

H3C

H3C

Na2HPO4

1RF HPO42minush





12H+] due






RF ISC1RF 3RFh (22)


(5) (6) (7)

Cl

HN

ClCOOH

CH3

HN

ClCOOH

CH3

HN

ClCOOH

CH3

h +


NCl

NH N

NCl

NH N

H

(8) (9)

(10)(11)

CH3 CH3

NCl

NH

OH

CH3

hh

h

CH2CH3

CH2CH3 CH2CH3

NCl

NH2


COOHH

R

3RF + NH2 CO2 + RCHO + NH3 (23)







(12) (13)

NN

O

F

+H2N

COOminus

minusFminus

NN

O

+H2N

COOminus

+


(14) (16)(15)

N

H

N

NO

N

H3COOCH3COOCH3COOC



NO2 NO2

O2h







CHO

Initiation+

k1

CO∙

h (24)

Propagation+k2

CO∙ CO3∙

O2

(25)

CHO

Propagation ++k3

CO∙CO3∙ CO3H

(26)


N

NH N

H

N

(17) (18)

CH3

CH3

H3CO

H3CO

N

NH

CH3

H3CO

NH2

h


(19) (20)

N

H

HON

HH

CF3

CF3

N

OH

CF3

CF3

h



2CO3∙

(27)











(21) (22)

hSO H

N

O O

H2N

OHminus+S

OO

H2NNH2

CH3COOH


(23) (24)

h

O

HN

O

N

O

HOOC

S

N

CH3

CH3

CH3

+H3N

SO3minusO

HN

O

N

O

COOH

S

N CH3

CH3

+H3N

SO3minus

H3C













(25) (26)

h

O

O

O

CH3

O

O

CH3

pH 6ndash12


(27) (28)

h

NN

O NCH3

CH3

CH2Ph

N

O

N NCH3

CH3

CH2Ph











(1) (29)

(31)

(30)

(32) (33) (34)

N

N

NH

N O

O

OH

R

H3C

H3C

N

N

NH

HN O

O

CR

OH

H3C

H3C

N

N

NH

N O

O

H

O

H3C

H3C

N

N

NH

HN O

O

H3C

H3C N

N

NH

N O

O

O

OH

H3C

H3C

N

N

NH

N O

O

OH

R

H3C

H3C

h

N

N

NH

N O

O

H3C

H3C

CH3

O2

O2

OHminus

H+ OHminus

R = (CHOH)3H






(35) (35)


h

NN

O

FOH

O

+H2N

NHN

O

FOH

O

+H3N



















9 Conclusions


Competing Interests



Acknowledgments


References
































































































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Dihydroflavin

Intermediate

Autooxidation

(1) (2)(3)

(4)

N

N

NH

N

O

O

CH

CH

CH

HO

HO

HO

CH2OH

CH2

H3C

H3C

N

N

NH

N

O

O

O

H

H

OH

OH

OH

H

H

H3C

H3C

Na2HPO4

1RF HPO42minush





12H+] due






RF ISC1RF 3RFh (22)


(5) (6) (7)

Cl

HN

ClCOOH

CH3

HN

ClCOOH

CH3

HN

ClCOOH

CH3

h +


NCl

NH N

NCl

NH N

H

(8) (9)

(10)(11)

CH3 CH3

NCl

NH

OH

CH3

hh

h

CH2CH3

CH2CH3 CH2CH3

NCl

NH2


COOHH

R

3RF + NH2 CO2 + RCHO + NH3 (23)







(12) (13)

NN

O

F

+H2N

COOminus

minusFminus

NN

O

+H2N

COOminus

+


(14) (16)(15)

N

H

N

NO

N

H3COOCH3COOCH3COOC



NO2 NO2

O2h







CHO

Initiation+

k1

CO∙

h (24)

Propagation+k2

CO∙ CO3∙

O2

(25)

CHO

Propagation ++k3

CO∙CO3∙ CO3H

(26)


N

NH N

H

N

(17) (18)

CH3

CH3

H3CO

H3CO

N

NH

CH3

H3CO

NH2

h


(19) (20)

N

H

HON

HH

CF3

CF3

N

OH

CF3

CF3

h



2CO3∙

(27)











(21) (22)

hSO H

N

O O

H2N

OHminus+S

OO

H2NNH2

CH3COOH


(23) (24)

h

O

HN

O

N

O

HOOC

S

N

CH3

CH3

CH3

+H3N

SO3minusO

HN

O

N

O

COOH

S

N CH3

CH3

+H3N

SO3minus

H3C













(25) (26)

h

O

O

O

CH3

O

O

CH3

pH 6ndash12


(27) (28)

h

NN

O NCH3

CH3

CH2Ph

N

O

N NCH3

CH3

CH2Ph











(1) (29)

(31)

(30)

(32) (33) (34)

N

N

NH

N O

O

OH

R

H3C

H3C

N

N

NH

HN O

O

CR

OH

H3C

H3C

N

N

NH

N O

O

H

O

H3C

H3C

N

N

NH

HN O

O

H3C

H3C N

N

NH

N O

O

O

OH

H3C

H3C

N

N

NH

N O

O

OH

R

H3C

H3C

h

N

N

NH

N O

O

H3C

H3C

CH3

O2

O2

OHminus

H+ OHminus

R = (CHOH)3H






(35) (35)


h

NN

O

FOH

O

+H2N

NHN

O

FOH

O

+H3N



















9 Conclusions


Competing Interests



Acknowledgments


References
































































































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


(5) (6) (7)

Cl

HN

ClCOOH

CH3

HN

ClCOOH

CH3

HN

ClCOOH

CH3

h +


NCl

NH N

NCl

NH N

H

(8) (9)

(10)(11)

CH3 CH3

NCl

NH

OH

CH3

hh

h

CH2CH3

CH2CH3 CH2CH3

NCl

NH2


COOHH

R

3RF + NH2 CO2 + RCHO + NH3 (23)







(12) (13)

NN

O

F

+H2N

COOminus

minusFminus

NN

O

+H2N

COOminus

+


(14) (16)(15)

N

H

N

NO

N

H3COOCH3COOCH3COOC



NO2 NO2

O2h







CHO

Initiation+

k1

CO∙

h (24)

Propagation+k2

CO∙ CO3∙

O2

(25)

CHO

Propagation ++k3

CO∙CO3∙ CO3H

(26)


N

NH N

H

N

(17) (18)

CH3

CH3

H3CO

H3CO

N

NH

CH3

H3CO

NH2

h


(19) (20)

N

H

HON

HH

CF3

CF3

N

OH

CF3

CF3

h



2CO3∙

(27)











(21) (22)

hSO H

N

O O

H2N

OHminus+S

OO

H2NNH2

CH3COOH


(23) (24)

h

O

HN

O

N

O

HOOC

S

N

CH3

CH3

CH3

+H3N

SO3minusO

HN

O

N

O

COOH

S

N CH3

CH3

+H3N

SO3minus

H3C













(25) (26)

h

O

O

O

CH3

O

O

CH3

pH 6ndash12


(27) (28)

h

NN

O NCH3

CH3

CH2Ph

N

O

N NCH3

CH3

CH2Ph











(1) (29)

(31)

(30)

(32) (33) (34)

N

N

NH

N O

O

OH

R

H3C

H3C

N

N

NH

HN O

O

CR

OH

H3C

H3C

N

N

NH

N O

O

H

O

H3C

H3C

N

N

NH

HN O

O

H3C

H3C N

N

NH

N O

O

O

OH

H3C

H3C

N

N

NH

N O

O

OH

R

H3C

H3C

h

N

N

NH

N O

O

H3C

H3C

CH3

O2

O2

OHminus

H+ OHminus

R = (CHOH)3H






(35) (35)


h

NN

O

FOH

O

+H2N

NHN

O

FOH

O

+H3N



















9 Conclusions


Competing Interests



Acknowledgments


References
































































































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


(12) (13)

NN

O

F

+H2N

COOminus

minusFminus

NN

O

+H2N

COOminus

+


(14) (16)(15)

N

H

N

NO

N

H3COOCH3COOCH3COOC



NO2 NO2

O2h







CHO

Initiation+

k1

CO∙

h (24)

Propagation+k2

CO∙ CO3∙

O2

(25)

CHO

Propagation ++k3

CO∙CO3∙ CO3H

(26)


N

NH N

H

N

(17) (18)

CH3

CH3

H3CO

H3CO

N

NH

CH3

H3CO

NH2

h


(19) (20)

N

H

HON

HH

CF3

CF3

N

OH

CF3

CF3

h



2CO3∙

(27)











(21) (22)

hSO H

N

O O

H2N

OHminus+S

OO

H2NNH2

CH3COOH


(23) (24)

h

O

HN

O

N

O

HOOC

S

N

CH3

CH3

CH3

+H3N

SO3minusO

HN

O

N

O

COOH

S

N CH3

CH3

+H3N

SO3minus

H3C













(25) (26)

h

O

O

O

CH3

O

O

CH3

pH 6ndash12


(27) (28)

h

NN

O NCH3

CH3

CH2Ph

N

O

N NCH3

CH3

CH2Ph











(1) (29)

(31)

(30)

(32) (33) (34)

N

N

NH

N O

O

OH

R

H3C

H3C

N

N

NH

HN O

O

CR

OH

H3C

H3C

N

N

NH

N O

O

H

O

H3C

H3C

N

N

NH

HN O

O

H3C

H3C N

N

NH

N O

O

O

OH

H3C

H3C

N

N

NH

N O

O

OH

R

H3C

H3C

h

N

N

NH

N O

O

H3C

H3C

CH3

O2

O2

OHminus

H+ OHminus

R = (CHOH)3H






(35) (35)


h

NN

O

FOH

O

+H2N

NHN

O

FOH

O

+H3N



















9 Conclusions


Competing Interests



Acknowledgments


References
































































































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

NH N

H

N

(17) (18)

CH3

CH3

H3CO

H3CO

N

NH

CH3

H3CO

NH2

h


(19) (20)

N

H

HON

HH

CF3

CF3

N

OH

CF3

CF3

h



2CO3∙

(27)











(21) (22)

hSO H

N

O O

H2N

OHminus+S

OO

H2NNH2

CH3COOH


(23) (24)

h

O

HN

O

N

O

HOOC

S

N

CH3

CH3

CH3

+H3N

SO3minusO

HN

O

N

O

COOH

S

N CH3

CH3

+H3N

SO3minus

H3C













(25) (26)

h

O

O

O

CH3

O

O

CH3

pH 6ndash12


(27) (28)

h

NN

O NCH3

CH3

CH2Ph

N

O

N NCH3

CH3

CH2Ph











(1) (29)

(31)

(30)

(32) (33) (34)

N

N

NH

N O

O

OH

R

H3C

H3C

N

N

NH

HN O

O

CR

OH

H3C

H3C

N

N

NH

N O

O

H

O

H3C

H3C

N

N

NH

HN O

O

H3C

H3C N

N

NH

N O

O

O

OH

H3C

H3C

N

N

NH

N O

O

OH

R

H3C

H3C

h

N

N

NH

N O

O

H3C

H3C

CH3

O2

O2

OHminus

H+ OHminus

R = (CHOH)3H






(35) (35)


h

NN

O

FOH

O

+H2N

NHN

O

FOH

O

+H3N



















9 Conclusions


Competing Interests



Acknowledgments


References
































































































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


(21) (22)

hSO H

N

O O

H2N

OHminus+S

OO

H2NNH2

CH3COOH


(23) (24)

h

O

HN

O

N

O

HOOC

S

N

CH3

CH3

CH3

+H3N

SO3minusO

HN

O

N

O

COOH

S

N CH3

CH3

+H3N

SO3minus

H3C













(25) (26)

h

O

O

O

CH3

O

O

CH3

pH 6ndash12


(27) (28)

h

NN

O NCH3

CH3

CH2Ph

N

O

N NCH3

CH3

CH2Ph











(1) (29)

(31)

(30)

(32) (33) (34)

N

N

NH

N O

O

OH

R

H3C

H3C

N

N

NH

HN O

O

CR

OH

H3C

H3C

N

N

NH

N O

O

H

O

H3C

H3C

N

N

NH

HN O

O

H3C

H3C N

N

NH

N O

O

O

OH

H3C

H3C

N

N

NH

N O

O

OH

R

H3C

H3C

h

N

N

NH

N O

O

H3C

H3C

CH3

O2

O2

OHminus

H+ OHminus

R = (CHOH)3H






(35) (35)


h

NN

O

FOH

O

+H2N

NHN

O

FOH

O

+H3N



















9 Conclusions


Competing Interests



Acknowledgments


References
































































































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


(25) (26)

h

O

O

O

CH3

O

O

CH3

pH 6ndash12


(27) (28)

h

NN

O NCH3

CH3

CH2Ph

N

O

N NCH3

CH3

CH2Ph











(1) (29)

(31)

(30)

(32) (33) (34)

N

N

NH

N O

O

OH

R

H3C

H3C

N

N

NH

HN O

O

CR

OH

H3C

H3C

N

N

NH

N O

O

H

O

H3C

H3C

N

N

NH

HN O

O

H3C

H3C N

N

NH

N O

O

O

OH

H3C

H3C

N

N

NH

N O

O

OH

R

H3C

H3C

h

N

N

NH

N O

O

H3C

H3C

CH3

O2

O2

OHminus

H+ OHminus

R = (CHOH)3H






(35) (35)


h

NN

O

FOH

O

+H2N

NHN

O

FOH

O

+H3N



















9 Conclusions


Competing Interests



Acknowledgments


References
































































































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


(1) (29)

(31)

(30)

(32) (33) (34)

N

N

NH

N O

O

OH

R

H3C

H3C

N

N

NH

HN O

O

CR

OH

H3C

H3C

N

N

NH

N O

O

H

O

H3C

H3C

N

N

NH

HN O

O

H3C

H3C N

N

NH

N O

O

O

OH

H3C

H3C

N

N

NH

N O

O

OH

R

H3C

H3C

h

N

N

NH

N O

O

H3C

H3C

CH3

O2

O2

OHminus

H+ OHminus

R = (CHOH)3H






(35) (35)


h

NN

O

FOH

O

+H2N

NHN

O

FOH

O

+H3N



















9 Conclusions


Competing Interests



Acknowledgments


References
































































































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


(35) (35)


h

NN

O

FOH

O

+H2N

NHN

O

FOH

O

+H3N



















9 Conclusions


Competing Interests



Acknowledgments


References
































































































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










9 Conclusions


Competing Interests



Acknowledgments


References
































































































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Acknowledgments


References
































































































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

























































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Review Article Photostability and Photostabilization of...

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