Teodoro S. Kaufman

Chemometric determination of amiloride hydrochloride, atenolol, hydrochlorothiazide and timolol maleate in synthetic mixtures and pharmaceutical formulations

Different chemometric methods such as classical least squares (CLS), principal components regression (PCR) and partial least squares with one dependent variable (PLS-1) applied on UV spectral data (0 D) and on their first derivatives (1 D) were evaluated for the simultaneous quantification of samples containing mixtures of amiloride hydrochloride, atenolol, hydrochlorothiazide and timolol maleate. Their performances were compared by means of ANOVA tests, which evidenced that 0 D-PCR, 0D-PLS-1, 1D-PCR, 1D-PLS-1, were reproducible and gave statistically similar results, while 0 D-CLS and 1D-CLS displayed higher variances than the former and failed to comply with the Levenes variance homogeneity test at different stages of the method comparison and validation process. The four statistically equivalent procedures were successfully applied to the analysis of synthetic samples with two to four analytes and to commercial tablet preparations containing amiloride hydrochloride and hydrochlorothiazide alone or in association with atenolol or timolol maleate.

A spectrophotometric-partial least squares (PLS-1) method for the simultaneous determination of furosemide and amiloride hydrochloride in pharmaceutical formulations.

A numerical method, based on the use of spectrophotometric data coupled to PLS-1 multivariate calibration, is reported for the simultaneous determination of furosemide and amiloride hydrochloride in synthetic samples and commercial tablets. The method was applied in the concentration ranges of 8.0-13.0 mg l(-1) for furosemide and 1.0-1.6 mg l(-1) for amiloride hydrochloride. Its accuracy and precision were determined, and it was validated by the analysis of synthetic mixtures of both drugs. The method was successfully applied to the quantitation of furosemide and amiloride hydrochloride in three different pharmaceutical formulations, providing results in agreement with those obtained by HPLC. It allowed the rapid, accurate and precise simultaneous estimation of the concentration of both analytes of interest in spite of their important spectral overlap, high concentration relationship and the presence of small amounts of different, unmodelled, absorbing excipients.

Pharmaceutical impurities and degradation products: Uses and applications of NMR techniques

Current standards and regulations demand the pharmaceutical industry not only to produce highly pure drug substances, but to achieve a thorough understanding of the impurities accompanying their manufactured drug substances and products. These challenges have become important goals of process chemistry and have steadily stimulated the search of impurities after accelerated or forced degradation procedures. As a result, impurity profiling is one of the most attractive, active and relevant fields of modern pharmaceutical analysis. This activity includes the identification, structural elucidation and quantitative determination of impurities and degradation products in bulk drugs and their pharmaceutical formulations. Nuclear magnetic resonance (NMR) spectroscopy has evolved into an irreplaceable approach for pharmaceutical quality assessment, currently playing a critical role in unequivocal structure identification as well as structural confirmation (qualitative detection), enabling the understanding of the underlying mechanisms of the formation of process and/or degradation impurities. NMR is able to provide qualitative information without the need of standards of the unknown compounds and multiple components can be quantified in a complex sample without previous separation. When coupled to separative techniques, the resulting hyphenated methodologies enhance the analytical power of this spectroscopy to previously unknown levels. As a result, and by enabling the implementation of rational decisions regarding the identity and level of impurities, NMR contributes to the goal of making better and safer medicines. Herein are discussed the applications of NMR spectroscopy and its hyphenated derivate techniques to the study of a wide range pharmaceutical impurities. Details on the advantages and disadvantages of the methodology and well as specific challenges with regards to the different analytical problems are also presented.

Simultaneous determination of amiloride hydrochloride and hydrochlorothiazide in synthetic samples and pharmaceutical formulations by multivariate analysis of spectrophotometric data

The use of multivariate spectrophotometric calibration for the simultaneous analysis of synthetic samples and commercial tablet preparations containing hydrochlorothiazide (HCT) and amiloride hydrochloride (AMH) is reported. Partial least squares (PLS-1) analysis of electronic absorption spectral data allowed the rapid and accurate resolution of mixtures in which the analyte ratios were approximately 10:1, without the need of a previous separation step and without interference from other sample constituents. The method, validated by the analysis of synthetic mixtures of both drugs, where accuracy over the linear working range as well as inter- and intra-assay precision were determined, was used in the concentration ranges of 21.7-30.4 mg l(-1) for HCT and 1.8-3.0 mg l(-1) for AMH. The proposed method was successfully applied to the evaluation of the stability of the stock solutions of the analytes in MeOH-H(2)O and to the elaboration of drug dissolution profiles of commercial tablets, results being concordant with those furnished by the USP technique. The method was also employed for the determination of drug content in two different pharmaceutical formulations, providing results that were in excellent agreement with those obtained by HPLC.

Development and validation of an HPLC method for the determination of process-related impurities in pridinol mesylate, employing experimental designs.

A simple high performance liquid chromatographic method for the determination of process-related impurities in bulk drug of the central anticholinergic compound pridinol mesylate, has been developed and validated. Spectroscopically characterized synthetic impurities were used as standards. The chromatographic separation was optimized employing an experimental design strategy, and was achieved on a C(18) column with a mobile phase containing 50mM potassium phosphate buffer (pH 6.4), MeOH and 2-propanol (20:69:11, v/v/v), delivered at a flow rate of 1.0mLmin(-1). UV detection was performed at 245nm. The optimized method was thoroughly validated, demonstrating to be selective, when the chromatogram was recorded with a diode-array detector and peak purities were evaluated (>0.9995). The method is robust and linear (r(2)>0.99) over the range 0.05-2.5% (5-250% with regards to the 1% specification limit for both process-related impurities); it is also precise, regarding repeatability (RSD</=1.5% for all of the analytes) and intermediate precision aspects and LOQ values for the impurities are below 0.01%. Method accuracy, evidenced by low bias of the results and analyte recoveries in the range of 99.1-102.7%, was assessed at five analyte concentration levels. The usefulness of the determination was also demonstrated through the analysis of different lots of pridinol mesylate bulk substance. The results indicate that the method is suitable for the quality control of the bulk manufacturing of pridinol mesylate drug substance.

The first chiral version of Jackson N-benzyl-N-tosylaminoacetal cyclization. A new enantioselective total synthesis of 1-s-(-)-salsoiidine

Abstract The first chual verson of Jackson N-benzyl-N-losylamnnoacetal cyclization, enabling a new and efficient enantioselective total synthesis of I-S-(-)-salsolidine, is reported. Chirality was introduced by oxazaborolidine-catalyzed reduction of an aralkyl ketone. coupled with a Mitsunobu-type amination of the resulting benzylic alcohol, resulting in complete configurational inversion of the latter.

The Mitsunobu reaction of ortho-ethers of secondary benzylic alcohols. Concise enantioselective synthesis of a key intermediate of the novel β-adrenergic receptor antagonist MY336-a

Abstract Chiral secondary benzylic alcohols bearing an ortho-alkoxy substituent suffer ring-assisted racemization during the Mitsunobu reaction; however, their congeners bearing also a 3-substituent undergo virtually complete Mitsunobu inversion. A concise enantioselective synthesis of a key intermediate of the β-adrenergic receptor antagonist MY336-a was achieved exploiting this observation.

Pictet-Spengler condensation of N-sulfonyl-β-phenethylamines with α-chloro-α-phenylselenoesters. New synthesis of 1,2,3,4-tetrahydroisoquinoline-1-carboxylates

The reaction of N-sulfonyl-β-phenethylamines with α-chloro-α-phenylseleno acetate/propionate esters under Lewis acid promotion gives moderate to good yields of the corresponding 1,2,3,4-tetrahydroisoquinoline-1-carboxylates. Varying degrees of diastereoselection were obtained using chiral sulfonamides and/or esters. Employing this strategy, the achievement of a new total synthesis of Calycotomine is reported.

CeIII-promoted oxidation. Efficient aerobic one-pot eco-friendly synthesis of oxidized bis(indol-3-yl)methanes and cyclic tetra(indolyl)dimethanes

Indoles and benzaldehyde derivatives undergo an efficient one-pot smooth condensation and a further atmospheric-pressure aerobic dehydrogenation with CeCl3 in i-PrOH, to afford the corresponding oxidized bis(indol-3-yl)methanes. Use of 2,2′-bisindole as the heterocyclic precursor provides cyclic tetra(indolyl)dimethane derivatives, which further undergo partial oxidation to the related calix-shaped macrocycles, carrying an all cis 1,3,7-cyclodecatriene core and supporting a 2,2′-biindolylidene moiety. The syntheses of these high value-added compounds is operationally simple and can be performed at room temperature under mild, neutral and environmentally friendly conditions.

Thioorthoesters in the activated Pictet–Spengler cyclization. Synthesis of 1-thiosubstituted tetrahydroisoquinolines and carboncarbon bond formation via sulfonyl iminium ions generated from N,S-sulfonyl acetals

Abstract The elaboration of 1-alkylthio- and 1-arylthio-tetrahydroisoquinolines by means of the activated Pictet–Spengler reaction of N -sulfonyl-β-phenethylamines with thioorthoesters as electrophiles, and their use as sulfonyl iminium ion precursors for carboncarbon bond formation, leading to 1-substituted tetrahydroisoquinoline derivatives, is reported.