The phenothiazines, a class of drugs widely used as neuroleptics in the therapy of schizophrenia, organic psychoses, the manic phase of manic depressive illness and other acute or chronic idiopathic psychotic illnesses1 although divided into the aliphatic, piperidine and piperazine subclasses, based on similarities in their chemical structure exhibit different pharmacological activity and potency. The piperazine subclass (Figure 1, Table 1) including, prochlorperazine (1), perphenazine (2) trifluoperazine (3) and fluphenazine (4) possess potent antipsychotic activity with more pronounced extrapyramidal but fewer anticholinergic and sedative effects than the other groups.

The phenothiazines known to cause a variety of adverse effects in individuals2 with high doses producing ocular opacity, tremors and deposition of melanin in the skin,3'4 have also been associated with photosenstivity effects in individuals exposed to light. These photosensitising properties have been assessed using two physical models.4'5 Both the phospholipid spherule and the lecithin monolayer model concur with the involvement of the chlorine containing derivatives in photosensitivity reactions and explain a mechanism involving the liberation of HC1 with subsequent formation of the 2-hydroxy derivatives contributing to a decrease in pH which explains the sensitivity, inflammation, or dermatitis that usually precedes the deposition of melanin in the skin of patients treated with large doses of the drug. In contrast to the increased surface activity observed with the chloro derivatives the trifluoromethyl-containing derivatives, trifluoperazine and fluphenazine are essentially non-photosensitising.

Figure 1. General Structure.
Table 1 Propyl piperazine-substituted phenothiazines




Prochlorperazine (1)



Perphenazine (2)



Trifluoperazine (3)



Fluphenazine (4)



The nature of the R2 and Rio substituents affects the neuroleptic activity of the phenothiazine with the presence of the trifluoromethyl and hydroxyethyl groups contributing to enhanced activity as compared to the chloro and methyl groups respectively, while the influence of structure on stability has been noted by Pawelczyk et al.6'7'8 where trifluoperazine is found to be more photostable than prochlorperazine. However, although the effect of the Rio substituent on activity has been reported this is not so in terms of its effect on photostability. Pilpel et al.3 explain the adverse effects associated with the phenothiazines on exposure to light to be due to the formation of the hydroxy derivatives following dechlorination only by the action of UV irradiation, while the sulphoxides which are natural metabolites of the phenothiazines in the body and therefore in low doses are unlikely to be responsible for the adverse effects of these drugs associated with sunlight. The effect of structure on the development of adverse effects must therefore be taken into account in the comparative study on the activity versus the stability of these drug molecules.

2 STRUCTURE-ACTIVITY 2.1 Introduction

The mechanism of action of these phenothiazine drugs involves blockade of the dopamine receptors in the brain by virtue of their ability to mimic the trans alpha conformation of dopamine while the distances of the nitrogen atoms of the piperazine ring from the centres of the aromatic rings are more or less constant and correspond to those occurring at the dopamine receptor as illustrated in the preferred conformation of dopamine and the propyl piperazine derivative, prochlorperazine9 (Figure 2).

In this preferred conformation, the side chain is tilted toward ring A allowing for favourable v.d. Waals interaction of the side chain with the R2 substituent. A CF3/piperazine/ hydroxyethyl group provides a greater number of favourable v.d. Waals contact with the side chain than does a Cl/alkylamino/methyl group.10 This model allows several predictions to be made about the structure of the phenothiazines that might be expected to lead to enhanced interaction with the dopamine receptor.

Figure 2. Conformation of dopamine and prochlorperazine.

2.2 Activity

Structure-activity describing the relationship between molecular structure or physical properties and activity proposes to explain the effect of structure on the interaction of the drug with the relevant receptor. A widely used theoretical method based on the work of Hansch considers relationships between biological activity and common physical properties, namely lipid solubility, degree of ionisation or molecular size. The octanol-water system allows for the measurement of the preference of drugs for the hydrophilic or lipophilic phase.11 This preference is described by Hansch as the partition coefficient P and the parameter for the phase distribution relationship is standardised as log P or n. Thus some optimum value of log P for a particular drug in a given biological system would give rise to a maximum probability of reaching the receptor in a given time. It has been shown that such an optimum value for those drugs active in the CNS such as the phenothiazines is 2. The two benzene rings present in all phenothiazines confer sufficient lipid solubility for penetration of the brain; however, the implication of the R2 substituent in lipophilicity is supported by Hansch where n is a measure of the contribution of the substituent to the lipophilicity of the molecule. K Values for the trifluoromethyl (1.07) and chloro (0.76) groups confirm the greater contribution of the former group to enhanced lipophilicity.11

This contribution of the trifluoromethyl group to the hydrophobicity of the molecule is further confirmed by the surface activity determinations of 0.58 for prochlorperazine and 0.12 for trifluoperazine, where values of less than 1 indicate greater surface activity than chlorpromazine. Nightingale et al.12 have demonstrated a correlation of pharmacological effect with physicochemical properties of the phenothiazines, and the role of the absorptive process in modifying such a response in apparent water/dodecane partition coefficients is effective in predicting phenothiazine absorption efficiency, which suggests a relationship between phenothiazine absorption and hydrophobicity showing the greater contribution of the trifluoromethyl group. The idea of "dissecting" drug activity into physical contributions

(hydrophobic, electronic, steric) is the central theme of the Hansch approach with the enhanced activity of trifluoperazine and fluphenazine as compared with the chloro derivatives being explained in terms of their hydrophobicity.

Thus activity of these propyl piperazine derivatives is determined by the strucural features contributing to lipophilicity and enhanced interaction with the receptor resulting in the reporting of a decreased order of activity being as follows: fluphenazine, trifluoperazine, perphenazine and prochlorperazine.1


As a result of reported phototoxicity of the phenothiazines, their photoreactivity has been extensively investigated.6'7'8

Pawelczyk et al.6'7 report the rate and type of photodegradation of aqueous solutions of various perazine derivatives to be dependent upon the nature of the R2 substituent. The methodology used involves irradiation by UV light of 254nm (low pressure TUV 30 Philips lamp) of an aqueous solution of the salts of perazine derivatives in a phosphate buffer at pH 3 in the presence of air and nitrogen. Results indicate the absence of sulphoxides in the presence of nitrogen and for prochlorperazine and trifluoperazine, the degradation proceeds due to reversible first-order photooxidation. The photochemical degradation of perazine and thioethylperazine is complex consisting of parallel reactions of photolysis and photooxidation, while substituents CI and cf3 prevent photolysis such that the rate of degradation is determined by the rate of the photooxidation process. Based on these findings, this group continued the investigation on some physicochemical parameters in order to explain the chemical reactivity of these compounds. Many observations can be explained in terms of the volume (A) including the fact that the basic properties increase with an increase in the substituent volume. In the Hammett type plot showing the relationship between the basicity of the compound and the rate of degradation prochlorperazine (A = 29) exhibits an increased degradation rate on irradiation as compared with trifluoperazine (A = 88). The double-lined Hammett plot due to different R2 substituents suggests two different mechanisms of reaction confirming degradation by photooxidation for those derivatives with CI and cf3 substituents and photooxidation and photolysis for the H and sc2h5 containing derivatives.

The fact that both Moore et al.13 and Sharpies14 report on the photolabile nature of chlorine in chloro-aromatic compounds can be applied to prochlorperazine and perphenazine which would then be capable of undergoing both Type I (free radical) and Type II (singlet molecular oxygen) reactions. Prochlorperazine yielded chloride and hydrogen ions at half the rate observed for chlorpromazine and thus appears to be an effective photosensitiser of 2,5-dimethylfuran oxidation. In both studies, methanolic solutions of the phenothiazines were irradiated over a period of time under nitrogen or oxygen as desired using in the case of Moore and coworkers13 a medium pressure mercury lamp (Hanovia, 125W), and in the other study an Allen type A 409 fixed wavelength (365nm) UV lamp.14 Sharpies reports that the 2-chlorophenothiazines give rise to a dechlorinated product, a dimer and the corresponding sulphoxide. The free radicals formed are believed to explain the high phototoxicity of the chloro-substituted phenothiazines. These results concur with those reported by Moore et al.,13 who also found that the HC1 yield is independent of the solvent used. When considering the mechanism whereby chloropromazine photoinitiates the polymerisation of acrylamide, it is possible that either the promazine radical arising from the direct homolysis of the triplet chlorpromazine or the chlorpromazine cation radical may be implicated. This cation radical on reaction with oxygen gives rise to the sulphoxide. Irradiation of 2-chlorophenothiazine in methanol gives rise to phenothiazine and 2-methoxy phenothiazine. Photodechlorination of the same compound occurs in acetonitrile-water implicating the iV-alkyl substituent in the acceleration of chlorine removal by an intramolecular electron transfer mechanism.15

The work published by Underberg16 and Abdel-Moety17 et al. represents important findings in respect of the R2 trifluoromethyl-substituted phenothiazines. Consideration of the thermal degradation of selected phenothiazines attempts to ascertain whether there is a relationship between oxidative degradation and the nature of the R2 substituent. In the case of the trifluoromethyl derivatives, it was found that the degradation was pH dependent yielding the sulphoxide at pH 3 while at pH 6.3 an additional product, jV-monomethyl-nortrifluopromazine was isolated. This latter product occurs in the degradation profile due to the cleavage of the side chain of these molecules only if the R2 substituent is electron-withdrawing and if the dimethylamino group is unprotonated.16 Results from the accelerated trifluoperazine photolysis carried out on the aqueous solution of the drug using a 60W UV (254nm) lamp indicate the development of reddish brown solution and a new photoproduct 3-trifluoromethyl(biphenylthiophen)sulphoxide characterised by mass spectrometry. In the UV spectrum of the irradiated aqueous solutions an increase in the light absorption in the visible region at about 523nm caused a red colouration. The observed red colour in the case of trifluoperazine can be attributed to the stable red radical. Because of the distribution of the n electrons in the trifluoperazine molecule, radical forms may develop at the S atom, the N10 and between the S and the N atom on the phenothiazine ring. Owing to the effect of the short-lasting UV irradiation, a radical at the S atom is expected. Decomposition of this sulphoxide dimer results to give the sulphoxide, which is confirmed by the presence of relevant absorption bands in the UV spectrunu

While the metabolism of these four piperazine-substituted derivatives is proposed to occur via //-oxidation, iV-demethylation, sulphoxidation and hydroxylation, the degradation of the piperazine ring is independent of the presence of the methyl or (5-hydroxyethyl substituent and the R2 substituent with no further mention of the role of these substituents in their metabolism. However, there certainly is a relationship between phototoxicity and the R2 substituent where the chloro derivatives are photosensitising with the trifluoromethyl derivatives showing few adverse effects. In the stability studies it is reported that the degradation of those compounds with CI and CF3, R2 substituents occurs via photooxidation. It can thus be seen that these R2 and Rio substituents which contribute to activity also play a role in the metabolism, development of adverse effects and stability of these compounds.

3.2 Photoreactivity - Kinetics

A study of instability problems in pharmaceutical products is important since there are at least six possible results of drug instability i.e. loss of the active drug, vehicle and content uniformity, reduction of bioavailability, impairment of pharmaceutical elegance and production of potentially toxic materials.18 The loss of active drug and formation of degradants on irradiation can be used not only as a means of predicting stability and thus relating structure to photoreactivity but the nature of the degradants serves to evaluate their potential as toxic photoproducts based on previous stability and metabolic studies.

Drug stability is affected by both the intensity and the spectral character of radiation; thus, in order to evaluate the photostability of these related phenothiazines various light sources need to be utilised.19 Photochemical and oxidative decomposition reactions are a stability liability with respect to certain liquid dosage forms, particularly small volume parenterals. Although both of these reactions are free radical mediated, the photochemical reaction can occur in the absence of oxygen, and oxidative reactions can occur in the absence of the catalytic effect of light. In ampoules the large surface area to formulation volume ratio allows maximum impingement on the relatively dilute drug solution and the short path length. In addition, the head space gas to formulation offers a presence of molecular oxygen. Although irradiation stress testing is widely used qualitatively the quantitative estimate of photolytic decomposition based on stress testing has proved to be difficult. From a practical point of view for the pharmaceutical scientist the first 10-20% degradation on irradiation of a commercial dosage is most significant. Although zero-order behaviour has been predicted in many cases for dilute solutions a first-order relationship is apparent.

Although the rate of photodegradation is quantified in forms of a rate constant, the difficulty associated with the comparisons of photochemical as opposed to thermal reactions is due to the dependence of photochemical reactions on the wavelength and intensity of the irradiating source and the shape and distance of the reaction vessel from the source. Thus, although the rate of photodegradation of a dilute solution of a drug may approximate to firstorder kinetics, these mixtures may only be compared if exactly the same irradiation conditions are applied.

Exposure of the four propyl piperazine-substituted derivatives to three different irradiation sources (30W Philips UV lamp, sunlight and a 55 W fluorescent/diffuse light) allow the degradation rates of the different derivatives in the presence of each light source to be compared.

The pseudo first-order rate constants, Kapp, will be complex constants containing contributions from factors other than the chemical reaction itself, i.e.:

Kapp =/(reaction, irradiation conditions, temperature) (1)

The irradiation contribution may be further factored into the contributions from the intensity and the wavelength of the radiation as previously mentioned19 while the reaction contribution will include the influence of the substituents.

Figure 3 represents the logarithm of the residual phenothiazine derivative (D) in solution (KH2P04/Na0H, pH 6.4) irradiated in the presence the three light sources expressed as a percentage of the initial concentration (D0).

10 15 20

Time (days) 30W Philips UV - Glass Ampoule

0 0

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