Figure 1 Profanation of chloroquine at physiological pH.

Figure 1 Profanation of chloroquine at physiological pH.

The photolysis quantum yield increases with an increase in pH indicating that the drug is most stabile as a dication.20 The degradation process is also strongly dependent on the oxygen level of the sample. There is an increase in degradation rate with a decrease in oxygen concentration leading to the conclusion that the excited triplet of CQ is likely to play an important role in the degradation process. This is further emphasized by the observation that cobaltous ion, a triplet state quencher, has an inhibitory effect on the degradation of CQ. The degradation process seems to be initiated by alpha-C-H cleavage in the side chain.20 The monocation of CQ is demonstrated to be a source of superoxide and hydroxyl radicals, but is a weak source of singlet oxygen and an inefficient quencher of this species.20' 21 The monocation is strongly fluorescent with a fluorescence quantum yield of 0.14, while the dication is strongly phosphorescent with a triplet lifetime of approximately 1 second.22 Chloroquine is a weak inducer of photohaemolysis of red blood cells (RBC), it induces photopolymerization of calf lens proteins and it binds strongly to melanin.23"25

2.1.2 Phototoxic Potential of Chloroquine. Based on the above results CQ should have the potential to induce phototoxic reactions in vivo. Chloroquine has a large distribution volume (200 1/kg) and a long elimination half-life (25-60 days). This indicates that the compound is widely distributed to- and accumulated in various tissues. Chloroquine medication can continue for years, both with respect to malaria prophylaxis and in the treatment of other diseases. The accumulative dose can be high, i.e. more than 200 grams. The absorption spectrum of CQ has a cut-off at 365nm, i.e. chloroquine will absorb radiation that penetrates skin, cornea and lens, but not retina. CQ is known to be retained in the eye for a long time.26 The retinopathy observed after medication with this drug is,however, not likely to be caused by a reaction sensitized by chloroquine due to the fact that CQ does not absorb the wavelengths reaching this tissue. CQ is deposited in the cornea and has also been detected in the tear film, thus corneal adverse effects and lens cataracts resulting from CQ therapy27 can be ascribed to photosensitized reactions. The drug accumulates in the epidermis of the skin, and the observed change in pigmentation14 is also a possible phototoxic reaction. The monocationic form of CQ can penetrate lipid bilayers, e.g. of erythrocytes.28 The RBC membrane is demonstrated to haemolyse after intravascular peroxidation reactions, thus haematologic photosensitization induced by CQ is a possibility.29

2.1.3 Chloroquine in the Solid State. The commercially available quality of chloroquine diphosphate is a hydrate (modification I) which can recrystallize to an anhydrous form on heating.30'31 The ratio of CQ/water in modification I is calculated to 3:1. The bulk substance (modification I) can take up water in humid air at room temperature forming a new hydrate (modification II) with a CQ/water ration of 2:1. Compression and grinding of modifiaction I will lead to the formation of two new forms, modification III and IV respectively. These four crystal modifications of CQ show different sensitivity to irradiation. The formation of modification II from the bulk substance seems to be catalyzed by irradiation. No significant changes seem to occur in the thermogram of modification II during exposure while the thermograms of modifications III and IV show great changes under the same conditions.32 Formation of the degradation products 4-aminoquinoline and desethylchloroquine from the different modifications further emphasize that there is a difference in photostability between these forms in the order modification II > I > III > IV, the first being the most stable. This seems to correspond with a change in colour of the substance. After 50 hours exposure at 80W/m2 in a sun simulating unit the colour of the powders changed from white to yellow described by an increase in Hunter b*-coordinate (measures yellowness) and a simultaneous decrease in the L*-coordinate (measures whiteness). Modifications I and II show less change in the Hunter b* and L* coordinates than modification III and IV.32

2.2 Primaquine Diphosphate

2.2.1 Primaquine in Solution. The pK* values for primaquine (PQ) are reported to be 3.2 and 10.4 for the heterocyclic nitrogen atom and aliphatic nitrogen atom, respectively.

Figure 2 Profanation ofprimaquine at physiological pH.

PQ exists as a monocation at physiological pH (Figure 2). Primaquine is photoreactive as a monocation and forms several degradation products in aqueous solution at physiological pH 33, 34 xhe influence of pH on the degradation process is not investigated at present. The photolysis is, however, strongly dependent on the oxygen content of the medium but in the opposite way compared to chloroquine, e.g. the degradation rate is increased by an increase in oxygen concentration.33 The degradation process is postulated to be initiated by electron transfer between excited PQ and molecular oxygen, leading to the formation of superoxide and the cation radical of PQ.33 In addition to superoxide, primaquine is a source of hydroxyl radicals but the formation of singlet oxygen is not detected.21 On the other hand, primaquine is a very efficient quencher of singlet oxygen with a quenching rate constant of 2.6 x 108 M"1 s1 21 pq has weak fluorescence with a quantum yield of 0.00005 and a short-lived triplet state (lifetime approximately 4.8 (isec). It is a slightly more efficient inducer of phothaemolysis than chloroquine but the two compounds have about the same capacity to induce lens polymerization.23'24 Primaquine also binds to melanin.25

2.2.2 Phototoxic Potential of Primaquine. Like chloroquine, primaquine should also be regarded as a potentially phototoxic compound. PQ has, however, a low distribution volume (3-4 1/kg) and a short elimination half-life (7 hours) compared to chloroquine. It is also usually administered for a shorter period of time and at a lower accumulative dose. The absorption cut-off is 430nm which means that PQ absorbs visible light, i.e. light that reaches the retina, but the pharmacokinetic parameters indicate that primaquine is probably not distributed to the eye. Ocular phototoxicity is therefore quite unlikely. PQ will mainly be located in the blood where it is extensively bound to plasma proteins. Primaquine also penetrates cell membranes and concentrates in the erythrocytes.35 Blood cells are therefore the targets which are most likely to be damaged by photochemical reactions induced by PQ, effectuated by light penetration through the outermost capillaries. This is consistent with the haematologic side effects observed after medication of this drug.

2.2.3 Primaquine in the Solid State. Commercially available primaquine exists only as one crystal modification. Elevated humidity and temperature, irradiation, high pressure or grinding do not lead to the formation of other crystal forms. Exposure of the samples in a sun-simulating unit does, however, lead to a change in colour measured by a change in the Hunter a*, b* - and L* - coordinates. In some cases a bleaching was observed while in some cases the samples became more yellow as a result of exposure. A change in colour was apparently not related to degradation of the drug substance as no decomposition was observed in any of the samples (to be published).

2.3 Mefloquine Hydrochloride

2.3.1 Mefloquine in Solution. Mefloquine consists of a mixture of the monocation (94%) and the neutral form (6%) at physiological pH (Figure 3). The pKa value for the quinoline N in MQ is in the range 4-5.5 while the corresponding value for the amine N is about 8.6.36 Mefloquine in solution is sensitive to irradiation and several photodecomposition products are isolated and identified.37 The photolysis shows the same dependency on pH and oxygen level of the medium as chloroquine, i.e. an increase in degradation rate by an increase in pH and by a decrease in oxygen concentration is observed (to be published). At physiological pH mefloquine is demonstrated to be an efficient source of singlet oxygen with a quantum yield of 0.38.21 The substance is further known to induce the formation of superoxide. The ability to act as a source of reactive oxygen species is dependent on the pH of the medium, i. e. the state of protonation of MQ. This is also the case for the fluorescence quantum yield of this compound.36 The phosphorescence lifetime of the monocation is quite short, about 3.5 milliseconds.36 Mefloquine is a potent inducer of (photo)toxic reactions in the applied test systems. Incubation of RBC with mefloquine did result in a 100% dark haemolysis.23 MQ is further a clearly more powerful inducer of lens polymerization than both chloroquine and primaquine 24 The compound binds to melanin in vitro.25

2.3.2 Phototoxic potential of mefloquine. From the in vitro results mefloquine is a highly phototoxic drug compared to CQ and PQ. The compound has a fairly large distribution volume (13-29 1/kg) and a long elimination half-life (19.5 days). Since the substance is widely distributed to the tissues and slowly eliminated from the body it should also have the possibility of reaching the eye and accumulate in the retina. MQ does, however, not absorb irradiation above 330nm and is therefore not likely to act as a sensitizer in this part of the eye. Photosensitized reactions in the lens and cornea can occur assuming that the drug is distributed to this part of the eye. Mefloquine can accumulate in the melanocytes of the skin, and skin rashes reported to occur after medication with this compound can be due to photosensitized reactions. Unwanted effects are also possible in the blood as MQ is distributed to the erythrocytes and clearly affects the membrane. The phototoxic potential of mefloquine compared to CQ and PQ will be dependent on the applied dosage regime, e.g. single dose or one year prophylaxis, as discussed above.

Figure 3 Protonation of mefloquine at physiological pH.

Figure 3 Protonation of mefloquine at physiological pH.

2.3.3 Mefloquine in the solid state. At least 8 different crystal modificaitons of MQ are described in the littérature.38' 39 In the present work mefloquine bulk substance from two different suppliers has been investigated. The two qualities of MQ represent two crystal modifications. The two modifications respond differently to irradiation. One of the modifications decomposes without any decolouration while the other modification becomes yellow but is not decomposed as a result of exposure in a sun simulating unit. The crystal modifications and/or photostability are changed when the bulk substances are incorporated in a tablet formulation.40

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