Comments on drugs difficult to compound and the quality of chemicals to be used in compounding.

These comments are minor modifications to the material submitted by the author to the docket for the FDA Pharmacy Compounding Committee that met on October 15 and 16, 1998.

A quantitative circular dichroic investigation of the binding of the enantiomers of ibuprofen and naproxen to human serum albumin.

The binding constants for racemic, R and S naproxen and ibuprofen to human serum albumin have been determined by a circular dichroic technique. The ibuprofens and naproxens show no measurable extrinsic optical activity on interaction with the protein, and so the extrinsic Cotton effect shown following the diazepam-albumin interaction is used as a probe. The presence of the drugs reduce the amount of diazepam bound as shown by the interaction is used as a probe. The presence of the drugs reduce the amount of diazepam bound as shown by the reduced size of the induced ellipticity. The calculated primary binding constants show that the S form of both drugs bind to the albumin more tightly than the R form and that the racemic forms bind less tightly than either enantiomer.

Postcolumn chemiluminescence as a detection technique in the liquid chromatographic analysis of beta-lactam ring containing compounds.

A broad range of compounds containing the beta-lactam ring were screened for enhancement of luminol chemiluminescence. A selection of these compounds were found to enhance the chemiluminescence of luminol. A high-performance liquid chromatographic method for the analysis of some beta-lactams employing postcolumn chemiluminescence was developed via flow injection analysis studies.

The effect of octanoic acid on the binding of the enantiomers of ibuprofen and naproxen to human serum albumin: a chromatographic implication.

PURPOSE: The heats of reaction between the enantiomers and racemates of ibuprofen and naproxen and human serum albumin (HSA) are to be measured with and without the addition of octanoic acid. The effects of octanoic acid on the free energies of interaction between the drugs and HSA is to be determined and compared to that estimated from theoretical equations. METHODS: The heats of reaction have been measured directly by flow microcalorimetry. RESULTS: The data showed that octanoic acid lowered the 1:1 binding constants for all the drug-HSA interactions investigated. The effect of octanoic acid was greater on the R than on the S forms of the drugs as shown by the differences in free energies of interaction in the presence and absence of octanoic acid. CONCLUSIONS: The increased free energy differences for the binding of the enantiomers of both drugs to HSA in the presence of octanoic acid is closer to the value deemed to be necessary for the separation of enantiomers by Davenkov, and shows the importance of the addition of octanoic acid to the mobile phase in the separation of these enantiomers on immobilized albumin columns.

Effects of drug-binding on the thermal denaturation of human serum albumin.

Asymmetric thermograms of defatted albumin, alone and in the presence of two model drugs, have been obtained in phosphate buffers at three pH values. The albumin is less thermally stable in the N form, but is protected by both drugs. The nonsteroidal antiinflammatory benoxaprofen offers more protection than warfarin against thermal denaturation.

Pharmacokinetic evaluation of two ibuprofen-codeine combinations.

The pharmacokinetics of ibuprofen and codeine were compared when given alone or in combination. Six treatments (ibuprofen 400 mg, codeine 60 mg, ibuprofen 400 mg and codeine 30 mg in two separate tablets, ibuprofen 400 mg and codeine 30 mg in one combination tablet, ibuprofen 400 mg and codeine 60 mg in two separate tablets, and ibuprofen 400 mg and codeine 60 mg in one combination tablet) were evaluated. Twenty-four healthy subjects were enrolled in the randomized block design study. Ibuprofen and codeine plasma concentrations were measured by reversed-phase liquid chromatography with UV and fluorescence detection. Pharmacokinetic parameters were estimated by non-compartmental data analysis techniques. Ibuprofen and codeine pharmacokinetic parameters obtained in this study were in agreement with previously published values. In addition, no pharmacokinetic interaction could be detected between codeine and ibuprofen when given alone or in combination. Furthermore, the similar half-life of both drugs (2-2.5 h) is advantageous for a fixed drug combination. The results suggest that ibuprofen and codeine can be given safely in a single oral dosage form.

Penicillin-enhanced chemiluminescence of the luminol-H2O2-Co2+ system.

The luminol-H2O2-Co2+ system has been widely used in chemical and biological analysis. We report here an investigation of the observation that penicillins have the ability to prolong and enhance the intensity of chemiluminescence from luminol. The basis of this phenomenon appears, as revealed by difference spectroscopy, to be the formation of a complex between the beta-lactam and the superoxide ion. The latter is the oxidizing species responsible for the oxidation of luminol in alkaline solution and has a mean lifetime, in solution, of milliseconds. The stabilization of the superoxide ion by penicillin complexation extends the effective lifetime of the superoxide ion by a few orders of magnitude and thereby allows for more efficient oxidation of the beta-lactam. Several penicillins were determined by their enhancement of luminol chemiluminescence. A detection limit of 100 ng mL was obtained for penicillin G with a less-than-ideal detection system.

Effects of tricyclic drug on induced circular dichroism spectra of dicumarol bound to alpha 1-acid glycoprotein.

Effects of both tricyclic and non-tricyclic drugs on the extrinsic Cotton effects of dicumarol bound to human alpha 1-acid glycoprotein (AGP) have been investigated. Basic tricyclic drugs caused the reversal of the signs of the induced Cotton effects of the circular dichroism (CD) spectra of the dicumarol-AGP system while the basic drugs not possessing tricyclic rings and acidic drugs decreased the observed ellipticities without changing the signs of its CD spectra. There was no reversal of the CD signs of the drugs not containing two hydroxycoumarin rings bound to AGP by basic tricyclic drugs. Raising of pH and temperature, and the addition of guanidine hydrochloride decreased the observed ellipticities of the CD spectra of the dicumarol-AGP system without showing any change in the signs of the Cotton effects. The mutual displacement data showed that protriptyline increased its own binding and that of dicumarol with AGP. The results of CD titration and equilibrium dialysis experiments suggest that dicumarol-AGP and dicumarol-AGP-protriptyline form a 1:1 binary complex and a 1:1:1 ternary complex, respectively.

Effect of pH and small inorganic ions on binding of sulfadimethoxine and sulfaphenazole to human serum albumin measured by circular dichroism.

The binding of sulfadimethoxine and sulfaphenazole to human serum albumin (HSA) has been shown by circular dichroism measurements to be dependent on the N-B transition. The secondary drug binding sites were found to be optically active in the B conformation form in HSA but optically inactive in the N form. Moreover, the drug-HSA interaction in Tris-HCl buffer seems to be more sensitive to the conformational change in HSA, compared with that in the phosphate buffer.

Diode array spectroscopy in pharmaceutical analysis: determination of acetaminophen/codeine phosphate tablets.

The use of diode array spectrophotometry for the analysis of tablets containing acetaminophen and codeine has been investigated. The technique was found to be applicable to the analysis of tablets which nominally contain 300 mg acetaminophen and 15, 30 or 60 mg codeine phosphate (Tylenol Nos 2-4, respectively). The concentration of codeine in extracts of Tylenol No. 1, which contains 7.5 mg codeine phosphate, was found to be too low for precise determination. First-derivative spectroscopy is required for the analysis of Tylenol Nos 2 and 3. Tylenol No. 4 can be determined using either the zero or the first-derivative spectra; however, the former was found to give consistently lower values for each component. The influence of derivative order and analytical wavelength range on the precision was investigated. The accuracy of the procedure was assessed by comparing the results from spectroscopy with those from liquid chromatography. Finally, some general conclusions on the applicability of diode array spectroscopy for the multicomponent analysis of pharmaceuticals are presented.

The interaction of dopexamine with various drugs and excipients in parenteral solutions.

The interaction of dopexamine hydrochloride with various excipients and other drugs in parenteral solutions has been investigated by microcalorimetry. The interaction with heparin sodium, in particular, is significant. The interaction is strongest in parenterals containing glucose and is eliminated in normal saline. Divalent cations are more effective than monovalent ones in eliminating the reaction, which is apparently ionic in nature.

Interaction of heparin sodium and dopamine hydrochloride in admixtures studied by microcalorimetry.

Microcalorimetry was used to investigate the interaction between dopamine hydrochloride and heparin sodium in 5% dextrose injection and in 0.9% sodium chloride injection. Heat of reaction (in microjoules) was measured by flow calorimetry for the following combinations of solutions: dopamine hydrochloride solution and heparin sodium solution prepared from powdered forms of the drugs in water; solutions of the powdered drugs in 5% dextrose injection; solutions of the powdered drugs in 0.9% sodium chloride injection; solutions prepared in 5% dextrose injection from commercial dopamine hydrochloride injection and commercial heparin sodium injection; and solutions prepared in 0.9% sodium chloride injection from the commercial drug injections. Mixing the solutions of the powdered drugs in water caused heat to be evolved, as did mixing the solutions of the powdered drugs diluted with 5% dextrose injection and the commercial injections diluted with 5% dextrose injection. The interactions of the two drugs were believed to be ionic, based on the exothermic nature of the reaction. No heat of reaction was measurable when sodium chloride was used as the diluent. Based on this preliminary investigation, admixtures containing heparin sodium and dopamine hydrochloride should be mixed in 0.9% sodium chloride injection to minimize the risk of interaction between the two drugs.