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Mixtures containing aminophylline and ephedrine hydrochloride were found to be discolored13 due to an exchange reaction between the two drugs. The ethylenediamine in aminophylline is presumed to liberate ephedrine base which decomposes rapidly. The color change was accelerated by temperature and humidity.
Numerous reports are found in the literature on the stability of aminophylline in suppository bases, especially those containing fatty acids. Dissolution of suppositories made with cocoa butter base was markedly lower than those ma e with macrogol base after storage at 22" for up to a yearaP5 Other physical properties of cocoa butter suppositories such as melting point Tm and melting time have been known to increase within weeks of storage at 22" 10 KAILAS D.
Decomposition of aminophylline suppositories is presumed to be due to the formation of insoluble amides ethylenediamine and fatty acids of the suppository b base. Methods of Analysis 5. The melting point of theophylline liberated from aminophylline is the basis of one of the compendia1 identification tests. Ethylenediamine must be released from aminophylline and converted to acetate or hydrochloride.
Primary aliphatic and aromatic amines interfere with the test. Color de elopment is rapid. This reaction is the basis of on of the compendia1 identification tests for aminophylline. Titrations with alkali have be59 carried out t o Jgsay aminophylline using a potentiometric or colorimetric end-point thymolphthalein as indicator in mixtures of pha rmaceutica1s. GRADY 12 5. Basej6gtlthis property, several assay methods have been develop including the compendia1 assay for aminophylline.
Some presence of amm nia is necessary when precipitating silver theophyllate. A differential titrimetric method for aminophylline was dexgloped using acetous perchloric acid as the titrant. The method of Schack and Waxler was used most extensively for analysis of aminophylline in early pharmacokinetics research.
Since theophylline was reversibly adsorbed on charcoal, elution with organic solvent was followed by measurement of W absorbance. Determination of aminophylline in the blood of patients was carried out after gfidation with potassium dichromate in an acidic medium, separation of the oxidation product by steam distillation and measurement of W absorbance at nm. Therefore assays of theophylline in biological fluids are also included here due to their obvious applicability.
Table contd. GRADY 16 analysis of aminophylline and its dosage forms. Table Zorka et alS8 separated and identified several pharmaceuticals in a mixture including aminophylline using silica gel G plates and neutral, acidic, and alkaline mobile phases. Detection was done by UV. Riechert5' developed a "micro"-TLC method for analysis of theophylline in biological fluids. None of the dietary xanthines or other commonly coadministered drugs appear to interfere. Several xanthines were separated. Among these, theophylline and aminophylline were best chromatographed in Britton-Robinson buffer at pH Table IV No.
Reverse-phase C ion-pair acetonitri1e:water containing 10 mM tet rabutylammonium chloride 2.
Reverse-phase C ethano1:water 4. Reverse-phase C p-Bondapak C acetonitrile:O. Ol M - sodium acetate pH 4. Assay of theophylline 6 3 in plasma; separation of theophylline from sulfisoxazole and ampic i11in. Molecular ultrafiltration to remove plasma proteins Direct injection. Stationary phase 5. Reverse-phase C p-Bondapak C acetonitri1e:acetate buffer pH 4.
Table IV contd. Stationary phase Mobile Phase Pre-treatment of sample Comments 9.
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Reverse-phase methano1:sodium acetate Deproteinization of serum samples with two volumes of methanol B-Hydroxyethyltheophylline used as internal standard; no interference from antibiotics or metabolites. Reverse-phase methano1:amonium phosphate Extraction with organic solvent before analysis u1 of serum sample can be analyzed; theophylline can be analyzed in presence of anticonvulsants. R verse-phase C acet nitrile : acetate buffer pH 4. NO Table IV contd.
NO Reverse-phase C acetonitrile: acetate buffer pH 4. Reverse-phase C methanol Reverse-phase Separation of xanthines; sensitivity of detection 0. Stationary phase Mobile Phase Pre-treatment of sample Comments Developed on Technicon "Fast-LC" p 1 sample required.
No interference was observed. Reverse-phase RP-8 Reverse-phase C Ref. Reverse-phase C Whatman Partisi1 ODS acetonitrile: 10 mM phosphate buffer Protein denaturation by acetonitrile No pre-column necessary; no interference observed.
Volume 44. Profiles of Drug Substances, Excipients, and Related Methodology
Reverse-phase C p-Bondapak methano1:pH 2. Reverse-phase C 5 p Solvent A: water containing. Stationary phase Reverse phase p-Bondapak C Mobile Phase Pre-treatment of sample Comments Proteins precipitated by perchloric acid, supernatant neutralized and injected 50 of serum are Ref. Normal phase column silica ch1orform:dioxane: formic acid Cation-exchange 0.https://itlauto.com/wp-includes/top/2056-comment-espionner-le.php
Series: Profiles of Drug Substances, Excipients and Related Methodology
NO Mass spectrometry used for identification. NO Sample filtered to remove particulate matter General method for W-absorbing compounds in urine; 1 30 compounds tested.
GRADY 26 5. Table V lists some of the more recent methods. Theophylline or a derivative is also linked to an enzyme, in this case, glucosephosphate dehydrogenase. When a patient's serum containing free theophylline is mixed with a solution of antibodies and enzyme-labelled theophylline, the free drug and the enzymelabelled drug compete for the binding sites on antibodies.
The reduction in enzyme activity when bound to antibodies can be monitored by using the proper substrate; in this case NADH. This assa s rapid, specific, and requires small s easily adaptable to ommercial sample size. Vinet et all2' developed another enzyme immunoassay. Inhibition of beef liver phosphatase by theophylline is determined at 25" C, using p-nitrophenyl acetate as the substrate in a pH 9.
In another application nephelometric, competitive immunoassay was developed. Stationary phase 1. Stationary phase Conditions 4.
It is then transferred into cyclohexane: pentane mixture S , the solvent evaporated, and it is redissolved in methanol. Stationary phase Conditions 7.
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Table V contd. Stationary phase Conditions Pre-treatment of sample Comments Ref. Ra ioimmunoassays f r th ophylline have been developed using 'H-theophylline. There is no interference from endogenous purines or known metabolites of theophylline at the concentrations studied.
Metabolism UsinglJZ4C] aminophylline injection, Caldwell, Monks and Smith determined that the metabolites of aminophylline are the same as those of theophylline. However, the rate and extent of conversion to 1,3-dimethyluric acid and 3-methylxanthine were higher or aminophylline than for theophylline.
The formation of 3-methylxanthine follows saturation kinetics; therefore, the presence of circulating methylxan ines from The foods affects the elimination of aminophylline. Jenne et all2' determined that 1-demethylation of theophylline to 3-methylxanthine is the dominant reaction determining theophylline concentration in serum. Presence of ethylenediaminelyyst affect this conversion, but how it does is not known. Biopharmaceutics and Pharmacokinetics Pharmacokinetics of aminophylline has been studied extensively. Since aminophylline and theophylline are indistinguishable in biological fluids, pharmacokineticists d o not differentiate between the two.
Aminophyl line is administered orally as a ,, Or as a singlesustained-re1 dose capsulg- ordosage tablet, fo 15', intravenously or by infusion ntramuscularly, or rectally as suppositories or enema. GRADY forms, rect 1 positories give the widest variation. In some case intra-patient variation in doselblood levels is observedfh6 during milk levels continuous long-term therapy.