Compatibility of lithium citrate syrup with 10 neuroleptic solutions

The visual compatibility of lithium citrate syrup (1.6 meq Li+/ml) in mixtures with each of 10 neuroleptic drug solutions or concentrates was studied. Lithium citrate syrup (5 or 10 ml) was mixed with four volumes (representing minimal to maximal clinical dosages) of each of 10 liquid neuroleptic drug products--chlorpromazine hydrochloride, haloperidol lactate, thioridazine hydrochloride, trifluoperazine hydrochloride, fluphenazine hydrochloride, loxapine hydrochloride, mesoridazine besylate, molindone hydrochloride, perphenazine, and thiothixene hydrochloride. Samples were prepared in duplicate by both orders of mixing at 25 +/- 2 degrees C and 4 +/- 1 degrees C and observed visually immediately and six hours later. Samples observed to be incompatible were centrifuged, and resulting layers were tested for drug with thin-layer chromatography. At six hours after mixing, pH values of the mixtures were measured. Chlorpromazine, haloperidol, thioridazine, and trifluoperazine products were incompatible with lithium citrate syrup; other products were compatible. Centrifugation of incompatible mixtures yielded two liquid phases--a more voluminous clear supernatant and a viscous, translucent, hydrophobic sediment. Thin-layer chromatography verified the presence of the neuroleptic drug in both phases. The incompatibility is independent of pH and lithium or citrate ions. The four incompatible neuroleptic solutions were each mixed with 1.64 M sodium chloride solution, and the same incompatibility was noted as with 5 ml of lithium citrate syrup. This suggested that the precipitation is caused by excessive ionic strength in the mixtures, resulting in salting out of undissociated, solvated ion pairs of the protonated neuroleptic bases and their respective anions. The incompatible mixtures should be avoided because clinically important underdoses could occur.