Metered dose inhalers III: Metaproterenol sulphate; particle size distribution and dose uniformity.

Three American products and one Canadian product were examined for content uniformity and particle size distribution. The results showed that not all products performed equally well. Some of the products exhibited high sprays early in the canister lifetime and all products demonstrated loss of prime. The particle size distributions were determined using the Andersen cascade impactor (USP Induction Port) and the fine particle fraction was determined using the twin impinger. The results showed that three of the four products had similar particle size distribution profiles. Both the Andersen cascade impactor and the twin impinger yielded the same trends in the amount of drug substance delivered to the fine particle fraction.

Chiral identification and determination of ephedrine, pseudoephedrine, methamphetamine and methcathinone by gas chromatography and nuclear magnetic resonance.

The enantiomers of the related substances methamphetamine, ephedrine, pseudoephedrine and methcathinone were determined by both gas chromatography after derivatization and by nuclear magnetic resonance using a chiral solvating agent. For GC the substances were derivatized with (R)-(+)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic acid (MTPA) to give diasteromeric derivatives. Resolution (baseline) of at least 1.6 was obtained between all derivatives. NMR determination of the enantiomers was conducted in a chiral environment by the addition of the chiral solvating agent, (R)-(+)-1,1'-bi-2-naphthol, to NMR solutions of the substances. Racemization of methcathinone was demonstrated to be facile by exposure to alkaline solutions for varying periods of time. Enantiomeric ratios of some products derived from the oxidation of ephedrine were determined.

Chiral resolution of cationic drugs of forensic interest by capillary electrophoresis with mixtures of neutral and anionic cyclodextrins.

Chiral resolution of a number of cationic drugs of forensic interest (amphetamine, methamphetamine, cathinone, methcathinone, cathine, cocaine, propoxyphene, and various alpha-hydroxyphenethylamines) is achieved via capillary electrophoresis (CE) with added cyclodextrins (CDs), including novel mixtures of neutral and anionic CDs. In the latter studies, resolution and migration speed are readily adjusted by varying the ratio of the two added CDs, as the anionic CD acts as a counter-migrating complexing reagent. The neutral CD, heptakis(2,6-di-O-methyl)-beta-CD, was found suitable for the analysis of illicit cocaine and khat leaves (Catha edulis Forsk), which contain (-)-alpha-aminopropiophenone ((-)-cathinone), (+)-norpseudoephedrine (cathine), (-)-norephedrine, and trace levels of the phenylpentenylamines (+)-merucathinone, (+)-merucathine, and possibly (-)-pseudomerucathine. The use of mixtures of the neutral and the anionic CD (beta-CD sulfobutyl ether IV) was found suitable for the analysis of illicit amphetamine, methamphetamine, methcathinone, and propoxyphene. A model is presented for the impact of mixtures of neutral and anionic CDs on migration behavior and chiral resolution in CE.

Identification of N-formylnorcocaine and N-benzoylnormethylecgonine in illicit cocaine.

Gas chromatographic determination of the acidic and neutral components of illicit cocaine indicated the presence of one or more common components in different samples. Isolation and examination of the spectroscopic properties of the major impurity indicated it to be N-formylnorcocaine. The material was compared with authentic material synthesized from norcocaine. N-Benzoylnormethylecgonine was also found to be present in illicit cocaine.

Stability of methadone in four vehicles for oral administration.

The stability of methadone in vehicles commonly used for oral administration was determined. Solutions of methadone were prepared in (1) orange-flavored Tang, (2) grape-flavored Kool-Aid, (3) apple juice, (4) grape-flavored Crystal Light, and (5) grape-flavored Crystal Light plus 0.1% sodium benzoate. For each of the first four preparations listed, two solutions were formulated at each methadone hydrochloride concentration of 0.2, 0.8, and 1.5 mg/mL; one set of three concentrations of each solution was stored in a refrigerator at 5 degrees C for up to 55 days, and the other set was stored unprotected from light at 20-25 degrees C for up to 17 days. Only three Crystal Light plus sodium benzoate solutions were prepared at the same methadone concentrations and stored at 20-25 degrees C for up to 29 days. Methadone concentrations were measured by high-performance liquid chromatography. Methadone was stable (loss of potency, less than 5%) for up to 17, 11, 9, and 8 days when stored at 20-25 degrees C in Kool-Aid, Tang, apple juice, and Crystal Light, respectively, and for up to 29 days when stored at 20-25 degrees C in Crystal Light plus sodium benzoate. Methadone was stable for up to 55, 49, 47, and 34 days when stored at 5 degrees C in Kool-Aid, Tang, apple juice, and Crystal Light, respectively. All the solutions that did not contain sodium benzoate and were stored at room temperature displayed unacceptable microbial growth after approximately two weeks. No significant loss of methadone potency occurred in any of the vehicles for oral administration during the study.

Identification of an imidazolinium salt, the major product from reaction of benzathine with iodine.

The isolation and identification of an imidazolinium salt are described. Unambiguous determination of structure was accomplished by independent synthesis. The isolated product interferes in the iodometric assay of the benzathine salts of penicillin.

Isolation and identification of a fluorophore from ampicillin degradation.

A fluorescent impurity in ampicillin has been isolated and identified as 2-hydroxy-3-phenylpyrazine. The product is formed under acidic conditions similar to those employed in some fluorometric assay procedures. The mechanism of the reaction is proposed to involve cyclization by condensation of the penilloaldehyde of ampicillin. The structure was confirmed by independent synthesis.