Identification, synthesis, isolation and characterization of new impurity in metoprolol tartrate tablets.

A new unknown impurity was observed in accelerated stability studies of Metoprolol tartrate tablets. This impurity has been identified, synthesized and characterized through different spectral studies and confirmed as an adduct of lactose and Metoprolol formed by Maillard reaction.

Development of a modified-release pellets formulation--with metoprolol tartrat and kinetic aspects of in vitro release.

AIM: The development of a new pellets formulation which is able to modulate the release of metoprolol tartrate, an active pharmaceutical ingredient very soluble in water and therefore very difficult to process. MATERIALS AND METHODS: Two types of different viscosity grade hydroxypropyl methylcellulose (Methocel K100; HPMC 15.000) and Eudragit NE30D are used as prolonged drug release agents, thus resulting in three formulations which have been prepared in form of pellets, in a conventional coating pan. The obtained pellets are characterized and compared in terms of: particles size distribution, drug loading efficiency, drug content and kinetic of in vitro drug release. RESULTS: Lower amounts of Eudragit NE30D (7.5%) determine more uniform size distributions of particles. Drug content and charging efficiency is higher in case of fractions ranging in size from 0.80 to 1.25 mm. The combination of HPMC 15000 with 10% Eudragit NE30D leads to a prolongation for a period of 11.5 hours of metoprolol tartrate release. Release kinetics analysis was performed by fitting the in vitro release profile with different kinetic models. CONCLUSIONS: It was developed a pellets formulation that release in vitro the metoprolol tartrate in an extended mode, with Korsmeyer-Peppas kinetic-type.

Zinc tetrafluoroborate hydrate as a mild catalyst for epoxide ring opening with amines: scope and limitations of metal tetrafluoroborates and applications in the synthesis of antihypertensive drugs (RS)/(R)/(S)-metoprolols.

The scope and limitations of metal tetrafluoroborates have been studied for epoxide ring-opening reaction with amines, and Zn(BF(4))(2)·xH(2)O has been found to be a mild and efficient catalyst affording high yields under solvent-free conditions at rt with excellent chemo-, regio-, and stereoselectivities. The catalytic efficiency followed the order Zn(BF(4))(2)·xH(2)O ≫ Cu(BF(4))(2)·xH(2)O > Co(BF(4))(2)·6H(2)O ≫ Fe(BF(4))(2)·6H(2)O > LiBF(4) for reactions with cyclohexene oxide and Zn(BF(4))(2)·xH(2)O ≫ Co(BF(4))(2)·6H(2)O ≫ Fe(BF(4))(2)·6H(2)O > Cu(BF(4))(2)·xH(2)O for stilbene oxide, but AgBF(4) was ineffective. For reaction of styrene oxide with aniline, the metal tetrafluoroborates exhibited comparable regioselectivity (1:99-7:93) with preferential reaction at the benzylic carbon of the epoxide ring. A reversal of regioselectivity (91:1-69:31) in favor of the reaction at the terminal carbon of the epoxide ring was observed for reaction with morpholine. The regioselectivity was dependent on the electronic and steric factors of the epoxide and the pK(a) of the amine and independent of amine nucleophilicity. The role of the metal tetrafluoroborates is envisaged as "electrophile nucleophile dual activation" through cooperativity of coordination, charge-charge interaction, and hydrogen-bond formation that rationalizes the catalytic efficiency, substrate reactivity, and regioselectivity. The methodology was used for synthesis of cardiovascular drug metoprolol as racemic and enriched enantiomeric forms.

A design and evaluation of layered matrix tablet formulations of metoprolol tartrate.

The aim of this paper was to evaluate the performance of different swellable polymers in the form of layered matrix tablets to provide controlled therapeutic effect of metoprolol tartrate for twice daily administration. Seven different swellable polymers (carrageenan, hydroxypropylmethyl cellulose, pectin, guar gum, xanthan gum, chitosan, and ethyl cellulose) were evaluated alone or in combination as release-retardant layer. Tablets were tested for weight variation, hardness, diameter/thickness ratio, friability, and drug content uniformity and subjected to in vitro drug-release studies. In addition, the target-release profile of metoprolol tartrate was plotted using its clinical pharmacokinetic data, and the release profiles of the tablets were evaluated in relation to the plotted target release profile. Carrageenan was determined as the best polymer in two-layered matrix tablet formulations due to its better accordance to the target release profile and was selected for preparing three-layered matrix tablets. Carrageenan formulations exhibited super case II release mechanism. Accelerated stability testing was performed on two- and three-layered matrix tablet formulations of carrageenan. The tablets were stored at 25 degrees C/60% relative humidity and 40 degrees C/75% relative humidity for 6 months and examined for physical appearance, drug content, and release characteristics. At the end of the storage time, formulations showed no change either in physical appearance, drug content, or drug-release profile. These results demonstrated the suitability of three-layered tablet formulation of carrageenan to provide controlled release and improved linearity for metoprolol tartrate in comparison to two-layered tablet formulation.

Efficient exploration of large combinatorial chemistry spaces by monomer-based similarity searching.

In modern drug discovery, 2-D similarity searching is widely employed as a cost-effective way to screen large compound collections and select subsets of molecules that may have interesting biological activity prior to experimental screening. Nowadays, there is a growing interest in applying the existing 2-D similarity searching methods to combinatorial chemistry libraries to search for novel hits or to evolve lead series. A dilemma thus arises when many identical substructures recur in library products and they have to be considered repeatedly in descriptor calculations. The dilemma is exacerbated by the astronomical number of combinatorial products. This problem imposes a major barrier to similarity searching of large combinatorial chemistry spaces. An efficient approach, termed Monomer-based Similarity Searching (MoBSS), is proposed to remedy the problem. MoBSS calculates atom pair (AP) descriptors based on interatomic topological distances, which lend themselves to pair additivity. A fast algorithm is employed in MoBSS to rapidly compute product atom pairs from those of the constituent fragments. The details of the algorithm are presented along with a series of proof-of-concept studies, which demonstrate the speed, accuracy, and utility of the MoBSS approach.

Application of kinetic resolution using HCS as chiral auxiliary: novel synthesis of beta-blockers (S)-betaxolol and (S)-metoprolol.

Optically pure (S)-betaxolol and (S)-metoprolol were prepared with an extremely facile and practical method using kinetic resolution of beta-amino alcohols employing HCS as chiral auxiliary. High enantiomeric purity (ee > 99%) was achieved and the synthetic strategy is amenable to industrial scale-up.

Synthesis and cardiovascular activity of metoprolol analogues.

The synthesis of four novel analogues of metoprolol, a well-known beta1-blocker used to reduce arterial blood pressure, is described. The preparation of (2S,2'S)-7, (2R,2'S)-7, (2R,2'R)-8, and (2S,2'R)-8 was based on the reaction of racemic 2-[4-(2'-methoxyethyl)-phenoxymethyl]-oxirane (4) with (R)- or (S)-2-amino-1-butanol. Salient characteristics of analogues 7 and 8 relative to metoprolol are the incorporation of an additional stereogenic center, as well as a methyl group and a hydroxyl function on the nitrogen-containing chain. These novel derivatives present significant hypotensive and bradycardiac activity, although no blocking action toward beta1 and beta2 adrenergic receptor.

The synthesis of metoprolol monitored using Raman spectroscopy and chemometrics.

The synthesis of Metoprolol base was studied using Raman spectroscopy with a 785-nm laser, optical fibres, a holographic transmission grating, confocal optics and a charge-coupled device (CCD) detector. The reaction mixture was heated according to a temperature gradient and spectra of the reaction mixture were obtained by focusing the laser beam through ordinary reaction flasks. Because of overlapping bands, multivariate techniques such as principal components analysis (PCA) and partial least-squares projections to latent structures (PLS) were used in the evaluation of the obtained spectra. The use of PCA or PLS against time does not require any calibration samples and a quantitative calibration is not necessary in order to monitor the reaction. A method for reaction endpoint determination, based on euclidean distances in the score space, is presented. The use of multivariate batch control charts have been demonstrated and a number of problems and solutions regarding the sample presentation have been discussed. The effect of spectral pretreatment on the multivariate results is shown and discussed. The monitoring results show that the time to produce Metoprolol base could be reduced.

Enantioselective preparation of metoprolol and its major metabolites.

To obtain the standard compounds of metoprolol for a pharmacokinetic study, a convenient synthetic procedure to prepare enantiomers of metoprolol (3a) and its major metabolites, 2-4-(2-hydroxy-3-isopropylamino)propoxyphenylethanol (3b) and 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetic acid (4), was developed from their respective starting materials, 4-(2-methoxyethyl)phenol (1a), 4-(2-hydroxyethyl)phenol (1b) and methyl 4-hydroxyphenylacetate (1c). These phenolic compounds (1a, b, c) were converted in situ to their corresponding phenoxides with sodium hydroxide treatment followed by (R)- or (S)-epichlorohydrin treatment. The resulting epoxides 2 were transformed to 3 through reaction with isopropylamine. Ester 3c was hydrolyzed to the metabolite 4. Measured using the HPLC method on chiral column without any derivatization, the optical purity of enantiomers of metoprolol and o-demethylated metabolite 3b ranged between 96-99% ee and that of enantiomers of carboxylic acid metabolite 4 ranged 91% ee.

Synthesis and evaluation of 1'-[18F]fluorometoprolol as a potential tracer for the visualization of beta-adrenoceptors with PET.

(+/-)-1'-[18F]Fluorometoprol 4 was prepared from desisopropylmetoprolol and [18F]fluoroisopropyl tosylate 2 with a radiochemical yield of 2% [corrected for decay to end of bombardment (EOB), synthesis time 90 min]. Synthon 2 was prepared from (S)-1,2-propanediol di(p-toluenesulfonate) in 45% radiochemical yield (EOB, 40 min). Compound 4 shows in two in vitro assays a similar affinity at beta-adrenoceptors (about 0.3 microM) as metoprolol 5, but with a slightly higher beta 1/beta 2-adrenoceptor selectivity ratio (48.6 vs 30.7). In vivo experiments with 4 showed almost no receptor-mediated uptake in the heart, probably because the affinity of (fluoro)metoprolol for the beta 1-adrenoceptors is too low for successful imaging. However, the in vitro experiments suggest that the fluoroisopropyl group is suitable for the synthesis of [18F]fluorinated beta 1-adrenergic receptor binding ligands.

Soft drugs. 7. Soft beta-blockers for systemic and ophthalmic use.

The "inactive metabolite approach" was used to design a series of "soft" drugs derived from the acidic metabolite of metoprolol. Pharmacokinetic and pharmacodynamic properties of these novel "soft" beta-adrenoceptor antagonists were determined: half-lives in human blood ranged from 5 to 754 min. The rates of in vivo disappearance of representative slow, medium, and fast hydrolyzing esters were determined in rats. In each case rapid and quantitative conversion to the corresponding free acid was observed. This suggests a facile, one-step degradation to the predicted major metabolite. The compounds were tested for their ability to decrease intraocular pressure in a rabbit model. Five of the new compounds exerted an ocular hypotensive action comparable to or greater than that of the reference compound, timolol maleate, and with a prolonged duration of action in some cases. In contrast the new compounds showed reduced and shorter duration systemic activity. The adamantylethyl ester emerges as a potentially effective antiglaucoma agent with significantly improved site-specific activity.

Chemical aspects of metoprolol metabolism. Asymmetric synthesis and absolute configuration of the 3-[4-(1-hydroxy-2-methoxyethyl)phenoxy]-1-(isopropylamino)-2-propanols , the diastereomeric benzylic hydroxylation metabolites.

Asymmetric synthesis of 3-[4-(1-hydroxy-2-methoxyethyl)phenoxy]-1-(isopropylamino)-2-propanol (2), the benzylic hydroxylation metabolite of metoprolol (1), is described, and the absolute configurations of the diastereoisomers were assigned. Ketone 3, prepared in a multistep synthesis, was reduced with a complex of (2S)-(-)-2-amino-3-methyl-1,1-diphenylbutan-1-ol (9) and borane, yielding 2, with a ratio of 82:18 for the diastereomers. The absolute configurations 1'S,2S and 1'S,2R were assigned for the diastereomers formed in excess on the basis of reductions on closely related alkyl phenyl ketones and the circular dichroism spectrum. Derivatization of the 1'-hydroxyl group of oxazolidinone 10 with a chiral Mosher acid chloride and the use of an HPLC procedure to resolve the resulting esters enabled us to determine the metabolic product stereoselectivity for 2. In the presence of the rat liver microsomal fraction, the benzylic hydroxylation of 1 was highly product stereoselective favoring 1'R stereochemistry at the new asymmetric center in racemic 1 and in both enantiomers of 1. Determination of the stereochemistry of 2 will facilitate study of this polymorphically controlled metabolic process.