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Characterization and adsorptive properties of pharmaceutical grade clays.

The adsorption of tetracycline by clays commonly used in pharmacy can be predicted if the identity and character of the commerical clay sample are established. X-ray diffraction. IR spectroscopy, and chemical analysis were used to identify the clay component and any nonclay diluents present in a series of commerical pharmaceutical grade clays. The major clay components were montmorillonite, hectorite, attapulgite, saponite, and kaolinite. The clay structure, the nature of the exchangeable cation, and the presence of nonclay components are important factors affecting the tetracycline-clay interaction. In general, clay structures with a high surface charge lead to a greater interaction with the protonated form of tetracycline, while interaction with the zwitterionic form of tetracycline occurs in clay structures with minimal surface charge. The presence of multivalent, exchangeable cations on the clay surface diminishes interaction with the protonated form of tetracycline. Nonclay components such as calcite and dolomite increase the interactions of the zwitterionic and anionic forms of tetracycline with the clay.

Adsorption↗

Isolation and identification of piperacillin amide as an impurity in piperacillin.

Piperacillin amide (IV) was successfully identified as the predominant impurity in commercial lots of piperacillin monohydrate (III). The impurity was isolated via a preparative liquid chromatographic scheme utilizing Florisil as the adsorbent and a mobile phase of water-acetonitrile (4:96, v/v). The isolated component had nearly the same reverse-phase HPLC properties as piperacillin and was chemically and thermally unstable. This labile impurity was spectroscopically identified by field desorption (FD), fast atom bombardment (FAB) with collision activation decomposition (CAD), and desorption chemical ionization (DCI) mass spectrometries , and NMR and IR spectrometries . Identity was confirmed on comparison of the chromatographic and spectrometric data of the impurity with an independently synthesized sample of piperacillin amide.

Chemical Phenomena↗

Physicochemical and analytical characteristics of amiodarone.

Data are reported on the analytical and physicochemical characteristics of amiodarone, for use in identifying and/or assaying this antiarrhythmic agent. The drug is highly soluble in chloroform and poorly soluble in water. Its acid-base constant (pKa) is 6.56, and its maximal lipid solubility range is from pH 3.5 to 5.5.

Amiodarone↗

Determination of the chemical constituents and spectral properties of commercial and NF reference standard potassium guaiacolsulfonate: implications of the findings on compendial analytical methodology.

HPLC analysis confirmed a difference in the chemical composition of commercial versus NF reference standard potassium guaiacolsulfonate. After separation by fractional crystallization, the two constituents comprising the former sample were identified by 1H-NMR as potassium guaiacol-4- and -5-sulfonate, respectively. The former isomer predominated. The reference standard material was identified as the 4-sulfonate salt by HPLC, NMR, IR, and UV. This difference raises questions concerning the validity of the compendial identification tests and assay procedure for the drug, which are based on methods requiring direct comparison between it and the reference standard. In fact, the IR test has now been shown to be unreliable as a rigorous criterion for identification, in light of significant differences found in the fingerprint regions of the spectra of the two isomers. However, because the two isomers exhibit identical UV absorption characteristics in solutions of pH less than or equal to 7 (but not in alkaline solution), the compendial UV identification test and assay procedure appear to be valid under the conditions specified. The pKa values of the isolated isomers were estimated by a spectrophotometric method to be 8.74 and 9.16 for the phenolic group of potassium guaiacol-4- and -5-sulfonate, respectively.

Acetylation↗

Dissolution of theophylline monohydrate and anhydrous theophylline in buffer solutions.

The dissolution kinetics of theophylline monohydrate and anhydrous theophylline were investigated with a rotating-disk apparatus in buffer solutions at 298 K under sink conditions. The observed dissolution rate of theophylline monohydrate under various conditions agreed well with predictions based on the Extended Simultaneous Chemical Reaction and Dissolution concept. Below 337 K, anhydrous theophylline is converted to theophylline monohydrate in contact with water. The dissolution profile of anhydrous theophylline can be divided into three phases: a pre-transformation phase: anhydrous theophylline dissolves; the transformation phase, during which its dissolution rate drops to the level of the theophylline monohydrate dissolution rate; and steady state, at which the dissolution rate of anhydrous theophylline equals the dissolution rate of theophylline monohydrate. The presence of theophylline monohydrate crystals at the dissolving surface was confirmed by IR spectroscopy and microscopic observation. The length of the transformation phase, depending on the characteristics of the diffusion boundary layer, varied with the experimental conditions (e.g., pH and rotation speed). It was concluded that during the dissolution process the disk is covered with theophylline monohydrate crystals that precipitate from the supersaturated medium adjacent to the disk surface, and that crystallization of theophylline monohydrate is a precipitation process controlled by hydrodynamic and diffusion parameters.

Buffers↗

Chromogenic reactions of tertiary amines with polycarboxylic acids and acetic anhydride: carbon suboxide as the reactive species in the malonic acid reagent.

Analytical methods based on the title reactions are reviewed, and the malonic acid-acetic anhydride system was selected for detailed study. It is postulated that carbon suboxide, O = C = C = C = O, formed by the action of acetic anhydride on malonic acid, is the effective reactive species in this system. Carbon suboxide was prepared and identified, and spectrophotometric observations of its reactions with tertiary amines are described. Aliphatic and aromatic tertiary amines generate colored products upon reaction with carbon suboxide in the presence of acetic anhydride. It was found that aliphatic tertiary amines form colors upon reaction with carbon suboxide in the absence of acetic anhydride, whereas aromatic tertiary amines require the presence of acetic anhydride.

Acetates↗

Spectrophotometric determination of cycloserine with 9-methoxyacridine.

Spectrophotometric assay for cycloserine based on the interaction of the drug with 9-methoxyacridine as a chromogenic agent is described. The highly colored substituted acridine product was identified as 9-(d-4-imino-3-isoxazolidinone)acridine. Color development was affected by time and temperature of heating and by the quantity of 9-methoxyacridine reagent utilized. The absorbance at 438 nm is linearly proportional to concentrations of cycloserine with a detection limit of 0.3 microgram/mL. The optimum range for the assay of cycloserine was from 5.0 X 10(-6) to 3.0 X 10(-4) M (correlation coefficient = 0.9999, n = 6). When applied to cycloserine capsules labeled to contain 250 mg, the proposed method gave mean recoveries of 101.84 +/- 0.48%. The procedure is sufficiently sensitive, precise, and accurate for the determination of cycloserine in its dosage form.

Acridines↗

High-performance liquid chromatographic methods for the determination of ranitidine and related substances in raw materials and tablets.

High-performance liquid chromatographic methods have been developed for the determination of ranitidine and related compounds in drug raw material and tablets. The method has been shown to resolve at least nine related compounds from the drug. The sensitivity of the method to related compounds is better than 0.01%. Eight raw material samples and 11 tablet samples were examined for related compounds. Total impurities found ranged from 0.31 to 0.79% in raw materials and from 0.40 to 1.75% in tablets. Drug raw materials and tablets were assayed by HPLC; results for raw materials were between 98.2 and 101.1%, and those for tablets were between 96.1 and 102.2%, with a relative standard deviation for the assay of less than 1%. Raw material assay results were confirmed by nonaqueous titration.

Chemical Phenomena↗

Respirable form of crystals of cromoglycic acid.

Respirable crystals of cromoglycic acid (CA) were prepared by precipitation of CA with hydrochloric acid from aqueous solutions of cromolyn sodium and subsequent recrystallization from hot water or mixtures of dimethyl sulphoxide and water. The properties of the materials were established by melting point measurements, UV, IR, and NMR spectroscopy, and X-ray diffraction. Aerosols of CA were generated by nebulization of dilute CA suspensions and drying. The aerodynamic size distribution of CA in the dried aerosols was found by cascade impaction, and could be characterized by a logarithmic normal function with a mass median aerodynamic diameter (MMAD) of 0.7 micron and geometric standard deviation (sigma g) of 1.9. The likely advantages and problems of CA aerosols in the prevention of asthma are discussed.

Aerosols↗

A chromatographic and spectroscopic study of photodegraded metronidazole in aqueous solution.

Preparative reversed-phase HPLC has been used to isolate a yellow photodegradation (2) product from aqueous metronidazole (1) solutions buffered with citrate:phosphate. Compound 2 can be further degraded into colorless materials by light, heat, or the addition of the nonaqueous solvents. These products have been characterized by UV, IR, proton NMR, mass spectroscopy, and melting point determination. It is proposed that the initial yellow degradation product (2) is an "excimer ion-pair" formed by the stabilization of 1 in its first electronic excited state by the citrate molecule.

Chromatography, High Pressure Liquid↗

Spectrophotometric determination of hydralazine with 2-hydroxy-1-naphthaldehyde in pharmaceuticals.

A new extraction-spectrophotometric method for the determination of hydralazine, based on its reaction with 2-hydroxy-1-naphthaldehyde at 25 degrees C, is described. The calibration curve was linear between 0.4 and 6 mg/mL of hydralazine. The molar absorbtivity of the product at 408 nm is 40,900 L.mol-1.cm-1. The method described was applied to the analysis of hydralazine in pharmaceutical preparations containing reserpine, hydrochlorothiazide, bendrofluorthiazine, propranolol, and other substances. The agreement with the U.S.P. XXI method was satisfactory for tablets and injections, but not for pellets.

Hydralazine↗

Physical characterization and dissolution properties of ibuprofen: Eudragit coprecipitates.

Ibuprofen:Eudragit coprecipitates were prepared in 10:3 ratios and their physical properties and related dissolution characteristics were determined. The Eudragit polymers used for the studies were three anionics (Eudragit L100, Eudragit L100-55, and Eudragit S-100), one anionic:cationic mixture used in a 1:1 ratio (Eudragit S100 + E100), and four zwitterionics (Eudragits RL 100, RS 100, RSPM, and RLPM). Physical characterizations were made using qualitative and quantitative X-ray diffractometry, IR spectrophotometry, and differential scanning calorimetry (DSC). Except for Eudragit S100 + E100 coprecipitates, no sizeable interaction at a molecular level was detected between the drug and the polymer. The crystalline structure of the drug was slightly modified in the coprecipitates. Regardless of the lack of interaction, dissolution of ibuprofen was retarded from all the coprecipitates studied (except Eudragit L100), especially in the pH 6.8 to 7.5 media in which the drug is freely soluble. The dissolution rate constants of the coprecipitates, calculated using Higuchi equation, demonstrated that dissolution decreased in the order of anionics greater than zwitterionic greater than anionic + cationic mixtures. The data obtained suggest that the release mechanisms involved are the swelling and slower dissolution of the polymer matrix relative to precipitated ibuprofen. The coprecipitates possess improved flow properties compared with ibuprofen with the exception of Eudragit RLPM and Eudragit RSPM. Eudragit coprecipitates can be useful tools in preparing ibuprofen sustained-release tablets. The coprecipitation technique used is simple and minimizes the use of organic solvents.

Acrylic Resins↗

High-performance liquid chromatographic determination of the pi values of azol-N-yl substituents.

The pi (hydrophobic constant) values for 16 parent azoles (pyrrole, imidazole, pyrazole, four triazoles, two tetrazoles, indole, benzimidazole, 1H- and 2H-indazoles, 1H- and 2H-benzotriazoles, and carbazole) were calculated from the logarithms of the capacity factors (log k') determined by HPLC. The values thus obtained are discussed according to an additive model in which the number and position of pyridinelike nitrogen atoms and the annelation effect are considered.

Azoles↗

Structure--anticancer and structure--genetic activity relationships of homo-aza-steroidal esters of N,N-bis(2-chloroethyl)aminocinnamic acid isomers.

Four steroidal lactams of the A- and D-rings were used for the esterification in the C-3 or C-17 positions, respectively, of their nuclei with the N,N-bis(2-chloroethyl)aminocinnamic acid isomers. The condensation reaction of the hydroxylic group of the steroidal lactams with each mustard was effected in dichloromethane in the presence of the catalyst p-dimethylaminopyridine and dicyclohexylcarbodiimide as dehydrating agent. The esters were obtained in pure form after column chromatography, and their structures were verified and confirmed by analytical methods (IR and UV spectra). The 12 esters were tested in vivo against P388, L1210 leukemias, Ehrlich ascites tumor, and melanoma B16. The esters 3 alpha-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17- oic-13,17-lactam-o,m,p-N,N-bis(2-chloroethyl)aminocinnamates, in which the alkylating agents are linked to the modified steroid in the axial position, are inactive in the above experimental animal tumor systems. The effect of the homo-aza-steroidal esters of N,N-bis(2-chloroethyl)aminocinnamic acid isomers on the incorporation of radioactive precursors into DNA, RNA, and proteins of L1210, P388 leukemias, Ehrlich ascites tumor, and baby hamster kidney cells was investigated. Higher inhibitory effects on the incorporation of the radioactive precursors was obtained with the ortho-derivatives, yielding > 40% inhibition of thymidine incorporation in all tumor lines tested. The effect of four esters in which the m- N,N-bis(2-chloroethyl)aminocinnamic acid is linked to the modified steroids on sister chromatid exchanges in human lymphocyte culture was investigated.

Alkylating Agents↗

Formation of a perbenzoic acid derivative in the photodegradation of fenofibrate: phototoxicity studies on erythrocytes.

The phototoxic antihyperlipoproteinemic drug fenofibrate (1) is photolabile under aerobic conditions. Irradiation of a methanol solution of 1 produces, under oxygen, photoproducts 2, 3, and 4. A peroxidic photoproduct 2 was isolated and identified. The biologically active antioxidants glutathione and cysteine efficiently reduce 2 to its acid. This photoproduct was also capable of efficiently oxidizing tetramethyl phenylendiamine (TMP) through an electron transfer mechanism, detecting a TMP+ species by UV-visible spectrometry. Fenofibrate was screened in vitro at different concentrations for UV-visible-induced phototoxic effects in a photohemolysis test, under oxygen as well as argon. The photohemolysis rate was low under anaerobic conditions. No hemolysis occurred without irradiation. The isolated photoproduct 2 induced hemolysis without irradiation.

Chlorobenzoates↗

Isolation and structure elucidation of a novel product of the acidic degradation of cefaclor.

The acidic aqueous degradation of cefaclor, an orally administered cephalosporin antibiotic, has been investigated. The most prominent peak in the high-performance liquid chromatography profile of a degraded solution of cefaclor was isolated by preparative high-performance liquid chromatography. Mechanistically, the formation of this degradent from cefaclor involves a condensation of two cefaclor degradation products in which both products have undergone contraction from a six-membered cephem ring to a five-membered thiazole ring, presumably via a common episulfonium ion intermediate.

Cefaclor↗