Resolution of the enantiomers of ibuprofen; comparison study of diastereomeric method and chiral stationary phase method.

In this study, an indirect diastereomeric method and a direct method utilizing a chiral stationary phase (CSP) were investigated for the resolution of ibuprofen enantiomers. In the indirect method, ethylchloroformate (ECF) and 2-ethoxy-1-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) were utilized as first-step derivatizing reagents in acetonitrile or toluene. In the direct CSP method, ibuprofen enantiomers were derivatized to p-nitrobenzyl ureides and then resolved on an (R)-(-)-(1-naphthyl)ethylurea CSP column. The derivatization procedure took place in 10 min with an overall inversion efficiency of 90.3%. Racemization was not observed under the derivatization conditions used. The HPLC-CSP method was utilized to study the pharmacokinetics of ibuprofen enantiomers in dog plasma after a single oral administration of 200 mg of ibuprofen racemate.

Enantiomeric analysis of phenylpropanolamine in plasma via resolution of dinitrophenylurea derivatives on a high performance liquid chromatographic chiral stationary phase.

Racemic phenylpropanolamine was resolved on a high performance liquid chromatographic (HPLC) chiral stationary phase (CSP) as the 3,5-dinitrophenyl ureide derivative. The CSP was prepared by a simple in situ procedure in which (R)-(1-naphthyl)ethyl isocyanate was bound to aminopropyl silanized silica through a urea linkage. The enantiomeric ureides were prepared by a room-temperature, 60-second procedure, accomplishing simultaneous extraction and derivatization and utilizing achiral 3,5-dinitrophenyl isocyanate as reagent. Baseline resolution was readily achieved under normal phase conditions, with a separation factor (alpha) of 1.16 and a resolution factor (RS) of 2.2. Elution was complete within 10 min. A limit of detection, by UV at 235 nm, of 250 pg per isomer was established. Feasibility of the procedure for plasma determinations was demonstrated by assay of samples from a canine subject.

Chiral recognition model for the resolution of ephedrine and related alpha,beta-aminoalcohols as enantiomeric oxazolidine derivatives.

The mechanism of chiral recognition has been investigated for a series of enantiomeric cis-oxazolidines on a commercially available high-performance liquid chromatographic chiral stationary phase (HPLC-CSP). The oxazolidine molecules were synthesized through the condensation of ephedrine and ephedrine-related molecules with aromatic aldehydes. The resulting molecules are rigid five-membered rings whose configuration has been determined by proton magnetic resonance and single-crystal X-ray diffraction. The oxazolidines derived from the condensation of ephedrine and aldehydes containing a pi-basic moiety such as naphthaldehyde were resolved on the HPLC-CSP as were those oxazolidines synthesized by using a pi-acidic aldehyde such as p-nitrobenzaldehyde. However, there was a reversal in the elution order for the two types of oxazolidines. Oxazolidines resulting from the condensation of ephedrine and a pi-neutral aldehyde such as benzaldehyde were not resolved. The results of this study suggest a chiral recognition model based on the formation of diastereomeric solute-CSP complexes through a single attractive interaction and chiral discrimination resulting from the difference in steric fit.

Liquid chromatographic chiral stationary phases in pharmaceutical analysis: determination of trace amounts of the (-)-enantiomer in (+)-amphetamine.

A rapid and accurate method was developed for the determination of the enantiomeric composition of amphetamine preparations. Amide derivatives of the amphetamine enantiomers are first formed by using achiral 2-naphthoyl chloride. The resulting enantiomeric amides are then chromatographed on a commercially available chiral stationary phase. The capacity factors (k') of (-)- and (+)-2-naphthoylamphetamine are 20 and 22, respectively, and the separation factor (alpha) for the two enantiomers is 1.08. The method allows detection of as little as 0.5% of the (-)-enantiomer in (+)-amphetamine and is applicable to both bulk drug and single-tablet analyses.

Column chromatographic analysis of barbiturates in their dosage forms. IV. Combinations with parabens.

The nature of the alkaline hydrolysis of some barbiturates in combinations with parabens (p-hydroxybenzoates) was studied with controlled variables, including temperature, viscosity, and concentrations of sodium hydroxide, barbiturate, and parabens. The kinetic studies showed that parabens could be completely hydrolyzed in strong base at 40 degrees C in 1 hr, while the barbiturate remained intact and was readily isolated by partition chromatography, Based on the theoretical results, a partition chromatographic procedure for butabarbital with parabens was devised. Standard recoveries averaged 100.7% with a standard deviation of 0.89. Kinetic data indicate that the hydrolysis of parabens could also be applied to analyze combinations with amo-, seco-, and pentobarbitals. Phenobarbital and parabens are readily separated by partition chromatographic methods without prior hydrolysis of the parabens. The low extraction constant for phenobarbital allowed its retention on a column against relatively strong solvents while the intact parabens are eluted. A slightly modified method was applied to the separation of phenobarbital from parabens. Standard recoveries average 99.9% with a standard deviation of 0.69.

Extraction and partition chromatography of tolbutamide as ion-pairs with quaternary ammonium cations.

The partition of tolbutamide (1-butyl-3-(p-tolylsulfonyl) urea) as ion-pairs with homologous tetraalkyl ammonium cations was studied. The determination of experimental extraction constants permitted quantitative calculation of distribution ratios, in agreement with theoretical relationships, over a continuous range of about one billion. The nature and the concentration of the counter-ion and solvent composition were the variables studied. Based on the theoretical results, a rapid partition chromatographic procedure was devised. A solution of tolbutamide sample in 10% aqueous tetraethyl ammonium hydroxide is incorporated in the system as the immobile phase in the partition column. A 1+1 mixture of chloroform and isooctane removes extraneous materials; then chloroform elutes the tolbutamide-tetraethyl ammonium ion-pair, which is converted to the free acid by passing the eluate through a phosphoric acid segment, and tolbutamide is determined spectrophotometrically without further treatment. Standard recoveries averaged 100.5+/-0.70%; commercial tablets assayed 100.5+/-0.85%.

Configuration of dienestrol.

Uncertainty concerning the configuration of dienestrol was resolved by a detailed spectrochemical investigation, including single-crystal X-ray diffraction, of the active drug and its stereoisomers. A symmetric structure in which the phenyl and methyl groups are cis about each double bond is unambiguously assigned.

Determination of potassium guaiacolsulfonate by ion-pairing partition chromatography.

Potassium guaiacolsulfonate, a highly polar, acidic substance, is readily eluted by chloroform from a pH 4.5 Celite column in the form of its ion-pair with trihexylamine, thereby effecting facile separation from other pharmaceuticals. The sulfonic acid is then back-extracted into aqueous alkali and determined spectrophotometrically. Assay of standard solutions by this procedre averaged 100.44 plus or minus 0.81%. The method was applied successfully to 4 commercial cough preparations containing a variety of other drugs.

Determination of procaine and related local anesthetics. II. Collaborative study.

The ion-pairing chromatographic method reported previously for the isolation and spectrophotometric determination of the local anesthetics, alone and in combination, was studied collaboratively. Three solutions were assayed. One containing procaine as the single active component gave an average recovery of 99.8 plus or minus 1.7%. A mixture of procaine and tetracaine gave results of 99.3 plus or minus 1.6 and 98.9 plus or minus 8.82%, respectively. A third solution containing procaine and propoxycaine assayed 100.0 plus or minus 1.5 and 99.1 plus or minus 1.9%, respectively. It was shown that low results for tetracaine were due to loss during the final evaporative step. The method for samples containing tetracaine should be studied further. The other methods have been adopted as official first action.

Determination of procaine and related local anesthetics. I. Partition chromatographic separation and assay of mixtures of procaine with tetracaine and with propoxycaine.

Determination of ionization and extraction constants for procaine, tetracaine, and propoxycaine led to selection of a simple partition chromatographic system for separation and assay of mixtures of these anesthetics. A 65% solution of chloroform in isooctane elutes tetracaine or propoxycaine from a pH 4:sodium bromide column; procaine is retained and subsequently eluted by chloroform as the bromide ion-pair. The anesthetics are then determined spectrophotometrically. Results of assay of standard and commercial formulations are presented.