Chlorpromazine-iodine

Conductimetric Titrations and Spectrophotometric Study of the Chlorpromazine-Iodine Reaction... 

F. Gutmann and H. Keyzer, Study of Phenothiazine and Chlorpromazine-Iodine Complexes, J. Chem. Phys. 46(5), 1968-1974 (1967). 

Chlorpromazine (33) can probably be considered the prototype of the phenothiazine major tranquilizers. The antipsychotic potential of the phenothiazines was in fact discovered in the course of research with this agent. It is of note that, despite the great number of alternate analogs now available to clinicians, the original agent still finds considerable use. The first recorded preparation of this compound relies on the sulfuration reaction. Thus, heating 3-chlorodiphenylamine (30) with sulfur and iodine affords the desired phenothiazine (31) as well as a lesser amount of the isomeric product (32) produced by reaction at the 2 position. The predominance of reaction at 6 is perhaps due to the sterically hindered nature of the 2 position. Alkylation with w-C3-chloropropyl)dimethylamine by means of sodium amide affords chlorpromazine (33). ... 

Chlorpromazine hydrochloride in injectable solutions can be measured spectrophotometrically upon formation of the charge-transfer complex with iodine [84]. The complex is formed in an aqueous medium in the presence of excess I2, and is extracted into chloroform for a spectrophotometric determination at 292 and 362 nm. This method is unaffected by exposure to direct light. 

The strength of the NMR method is made evident, for example, in the study of the behavior of phenothiazine derivatives and their EDA complexes in solution [89]. First, the solution properties of, for example, the tranquilizer chlorpromazine hydrochloride and base in a variety of solvents were established leading to the unambiguous notion of self-association and micellization, with the HC1 form being the more stable. Second, the conformation of these compounds in self-adducts were discovered to be virtually unchanged as a function of temperature in the range 20 to 60°C. Iodine stabilized both molecular forms. Third, the complexation sites in these molecules were clearly established, as well as the stoichiometry of the complexes. The stability of these CTC can be followed with time. 

Clinically important, potentially hazardous interactions with acetazolamide, aminoglycosides, anticholinesterases, bambuterol, calcium channel blockers, chloroquine, chlorpromazine, clindamycin, d-pencillamine, ecothiophate iodine, enflurane, furosemide, halothane, hexomethonium, isoflurane, ketamine, lidocaine, lincomycin, lithium salts, magnesium salts, mannitol, MAO inhibitors, organophosphates, pancuronium, phenytoin, polymyxins, procainamide, quinidine, sevoflurane, spectinomycin, tetracyclines... 

Chlorpromazine plus iodine is not a combination that is likely to occur in a pharmaceutical formulation nor is the interaction of any significance in therapeutics. The study of the reaction is of biological importance, however, because of the information provided with respect to the electronic properties of the phenothiazine derivatives, and these properties in turn are likely to have significance in understanding the underlying mechanisms of the drug. That is, CPZ-I2 is a model system. 

FIGURE 4. Conductimetric titrations at 20°C of chlorpromazine hydrochloride (CPZ HCl) with iodine, both dissolved in acetonitrile. Initial concentrations CPZ HCl and I3, 1.24 x 10 Af. <7 means conductance, REL. signifies relative. 

FIGURE 6. (a) Spectra of chlorpro-mazine hydrochloride and of its iodine complex in the frequency range F = 3500-1200 cm Curve marked A is the spectrum of chlorpromazine hydrochloride in a paraffin mull. Curve marked B refers to the iodine complex of chlorpromazine hydrochloride. (b)Same for Figure 6a but in the range 1300-400 cm T is transmittance in arbitrary units. 

Charge transfer complexes of iodine with chlorpromazine (CPZ), methotrimeprazine (MTZ), trifluoperazine (TFP), trimeprazine (TMZ), prochlorperazine (PCP), thioproperazine (TPP), and promethazine (PMZ) have been studied by conductometric and spectral methods. 

Other drug delivery applications include deliver) of 5-fluorouracil for anticancer therapy (Gebelein, et al, 1990), delivery of neuroactive drugs (Menei, et al, 1994), ketoprofen (Giunchedi, et al, 1994), phenobarbitone (Berrabah, et al, 1994), cyclosporin, (Guzman, etal, 1993), cisplatin (Wada, etal, 1991), carteolol (Marchal-Heussler, et al, 1993), flurbiprofen (Pandey, et al., 1994), chlorpromazine (Chang, et al, 1994), povidone-iodine (Dunn, et al, 1986), and minocycline (Kyun, et al, 1990). 

The attachment of pendant phenothiazine groups onto an ionene type chain has not, at this stage, much improved the resistivity gompgred with other ionenes in general which are in the region of 10 -10 ohm cm (Table III), but has dropped the activation energy markedly. See also Ref 34. Compared to the resistivity of pure phenothiazines or the model compound chlorpromazine hydroc Joj de, however, a dramatic improvement is observed, i.e., a drop from 10 to 10 ohm cm. The iodine complex... 

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