Investigation of moricizine hydrochloride polymorphs.

The antiarrhythmic agent moricizine hydrochloride exhibits a single melting-decomposition endotherm peak at temperatures ranging from 209 to 214.5 degrees C (Form I) when recrystallized from polar solvents, as determined by differential scanning calorimetric analysis. However, a different polymorphic form (Form II), with a differential scanning calorimetric melting-decomposition peak temperature of 190 degrees C, was generated by recrystallizing moricizine hydrochloride from nonpolar solvents. These two polymorphic forms can be reversibly converted to one another by selecting recrystallization solvents. The existence of these polymorphs was confirmed by Fourier transform IR microscopy, X-ray powder diffractometry, and solution calorimetry. Polymorphic Form I exhibited a slightly slower initial dissolution rate than Form II, which correlated well with heats of solution data (less heat needed to dissolve Form II). A simulated wet granulation process did not change the polymorphic form, suggesting that wet granulation is feasible for tablet preparation.

Crystallinity, hygroscopicity and dissolution of moricizine hydrochloride hemihydrate.

A typical anhydrous moricizine hydrochloride, an antiarrhythmic agent, is a non-hygroscopic crystalline material. Three lots of moricizine hydrochloride were found to deliquesce within a day at 85% relative humidity, exhibit different X-ray powder diffraction (XRPD) patterns and have more rapid dissolution rate than that of typical anhydrous material. No change in XRPD pattern was observed when the solvent (ethanol) was removed from these lots by heating to 80 degrees C. A two-step water release was observed by thermogravimetric analysis (TGA): a surface water release and a water of hydration release, for these heated samples. The stoichiometry of the water of hydration suggests that it is a hemihydrate. The dissolution rate of the hemihydrate was faster than that of typical anhydrous material. This hemihydrate could be converted to a typical anhydrous material by heating to 90 degrees C. The granules obtained by a simulated wet granulation process on typical lots and typical lots containing up to 20% of hemihydrate exhibited similar physical behaviour to that of typical anhydrous material.

Complexation of moricizine with nicotinamide and evaluation of the complexation constants by various methods.

The solubility of the antiarrhythmic drug moricizine at physiologic pH is very low. Precipitation after rapid intravenous injection of the hydrochloride salt of moricizine could be a concern. The enhancement of solubility of moricizine near physiologic pH via complexation with nicotinamide was examined as a potential solubilization technique. The studies were performed in pH 6 and pH 7 phosphate buffers at 25 degrees C by the phase solubility method. Moricizine formed 1:1 and 1:2 complexes with nicotinamide at pHs of 6 and 7. The complexation constants K1:1 and K1:2 were estimated by a previously described scheme and equation and compared with those obtained by fitting a line and a parabola to the equations derived from the scheme for both the approximate and exact solutions. The data were best represented by a parabolic regression analysis of the exact solution of the derived equation with values for K1:1 and K1:2 at pH 6 of 16.60 and 0.93 M-1, respectively, and at pH 7 of 7.70 and 5.41 M-1, respectively.

Degradation kinetics and mechanisms of moricizine hydrochloride in acidic medium.

The degradation kinetics of moricizine hydrochloride (1) were examined over a pH range of 0.6 to 6.0 at an ionic strength of 0.3 and 60 degrees C. The disappearance of intact 1 was followed by a stability-indicating HPLC assay. The degradation products, which had approximate solubilities of less than 100 micrograms/mL, precipitated in aqueous solution. The precipitate was collected for HPLC analysis and identification of degradation products. Degradation of 1 was catalyzed by acetate and phosphate buffers and was pH dependent, with the pH of the minimum rate constant located between 2.8 and 3.2. At pH 0.6-2.0, 1 degraded via amide hydrolysis to yield first ethyl (10H-phenothiazin-2-yl) carbamate (2), an amide hydrolysis product, which further oxidized in parallel to give ethyl (3-oxo-3H-phenothiazin-2-yl) carbamate (3), ethyl (10H-phenothiazin-2-yl) carbamate S-oxide (4), and diethyl (3,10'-bi-10H-phenothiazine-2,2'-diyl)bis(carbamate) (5), the dimer of the amide hydrolysis product. At pH 2.2-6.0, 1 degraded via a reverse Mannich reaction, to form the reverse Mannich product ethyl [10-(1-oxo-2-propenyl)-10H-phenothiazin-2-yl] carbamate (6), and by parallel reaction via the described amide hydrolysis pathway. The dimer of the amide hydrolysis product was not detectable at pH greater than 2.8. At pH greater than 4.0, the reverse Mannich product was the predominant degradation product. Degradation of 1 was subject to positive and negative kinetic salt effects at pH 1.0 and 4.0, respectively. Arrhenius plots determined at pH 1.0 and 6.0 were linear between 37 and 70 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacology and clinical use of a new group of antiarrhythmic drugs: derivatives of tricyclic nitrogen-containing systems.

This paper is concerned with a new group of antiarrhythmic drugs: derivatives of phenothiazine and dibenzazepine which belong to tricyclic nitrogen-containing systems. It has been discovered that the transition from omega-aminoalkyl to omega-aminoacyl phenothiazine derivatives results in a decrease in psychotropic activity and an increase in cardiovascular, particularly antiarrhythmic, action. Based on structural and antiarrhythmic activity studies, the new and effective drugs ethmozine, ethacizine and bonnecor have been selected and extensively studied. Data on spectra and mechanisms of their action, obtained in different arrhythmia models, have been confirmed by clinical studies. Correlation between pharmacological properties and electrophysiological mechanisms, and differences in action of the drugs studied on brain and heart plasma membrane receptors may serve as a starting point for the further directed search for new antiarrhythmic drugs among tricyclic nitrogen-containing structures.

Moricizine: a new class I antiarrhythmic.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of the Class I antiarrhythmic agent moricizine hydrochloride are reviewed. Moricizine is chemically similar to the phenothiazines but does not appear to block dopaminergic receptors. Its major electrophysiologic actions are a concentration-dependent decrease in maximum rate of phase 0 depolarization; increased rates of phase 2 and 3 repolarization, decreased action potential duration, and decreased effective refractory period. Moricizine causes a dose-related prolongation of the PR interval and of AV nodal, infranodal, and intraventricular conduction times but has little effect on ventricular repolarization. The antiarrhythmic and electrophysiologic effects are not correlated with plasma concentrations of the drug or its metabolites. Moricizine reduces the occurrence of ventricular premature contractions (VPCs), couplets, and nonsustained ventricular tachycardia. It appears to suppress symptomatic nonsustained ventricular tachycardia, sustained ventricular tachycardia, and ventricular fibrillation or flutter. Moricizine appears to be as effective as quinidine and more effective than disopyramide, propranolol, and imipramine but less effective than flecainide and encainide at reducing VPCs. Moricizine continues to be evaluated in the Cardiac Arrhythmia Suppression Trial, which was designed to assess the long-term benefit of arrhythmia suppression in patients with left ventricular dysfunction after myocardial infarction. Moricizine seems to be better tolerated than quinidine, disopyramide, and imipramine and to have less proarrhythmic potential than flecainide or encainide. Noncardiac adverse effects include dizziness, nausea, and headache. Cimetidine appears to decrease moricizine clearance, and decreased theophylline clearance has been reported in subjects given moricizine. The usual adult dosage of moricizine hydrochloride is 600-900 mg/day given in three divided doses; an every-12-hour regimen may be used in some patients. Because of the risk of proarrhythmic effects, indications are limited to treatment of documented life-threatening arrhythmias. Moricizine will compete with other agents as first-line therapy for life-threatening arrhythmias.