Convenient method of simultaneously analyzing aluminum and magnesium in pharmaceutical dosage forms using californium-252 thermal neutron activation.

A commercial antacid suspension containing aluminum hydroxide and magnesium hydroxide products was used as a model sample to study the use of a californium-252 thermal neutron activation as a method for quantifying aluminum content as well as for the simultaneous assay of aluminum and magnesium. A 3.5-micrograms californium-252 source was used for the activation, and the induced aluminum-28 and magnesium-27 activity was simultaneously measured by sodium iodide crystal gamma-ray spectrometry using dual single-channel analyzers and scalers. The antacid suspension was contained in a chamber designed with the unique capability of serving as the container for counting the induced radioactivity in addition to being the irradiation chamber itself. Ten replicate irradiations were performed, and the precision was compared with 10 replicate analyses of the antacid suspension using the official ethylenediaminetetraacetic acid titration method. For aluminum the precision was 1.4 versus 0.62% for the titration method. For the magnesium the precision was 5.3 versus 0.79% for the titration method. This pilot study demonstrated that use of more intense californium-252 sources, which are commonly available, would provide a method that is competitive with the ethylenediaminetetraacetic acid titration method in precision and in other aspects as well.

Carbon-13 magnetic resonance spectroscopy of drugs III: penicillins.

The natural abundance 13C-NMR spectra of a series of penicillins (penicillin V methyl ester, penicillin V, penicillin G, methicillin, oxacillin, cloxacillin, and dicloxacillin) were studied. The chemical shifts were assigned using the pulse Fourier transform technique with the aid of long-range carbon-13 hydrogen coupling. The previous assignments of pencillin V methyl ester were revised.

Demonstration of penicillamine as a product in benzylpenicillenic acid degradation in neutral media using differential pulse polarography.

During the study of the temporal changes of benzylpenicillenic acid in aqueous buffers using differential pulse polarography, penicillamine was found to be a degradation product at neutral pH. Since this result was not previously reported, the effects of pH and buffer concentration on penicillamine formation were investigated. The amount of penicillamine produced was greatest under conditions producing maximum benzylpenicillenic acid stability. Penicillamine was not obtained from benzylpenicilloic acid, the reported degradation product of benzylpenicillenic acid at neutral pH. Penicillamine also was detected in penicillin G solutions of neutral pH. Therefore, it is suggested that penicillamine found in penicillin G solutions arises from benzylpenicillenic acid degradation which, in turn, is produced from penicillin G isomerization. A pathway is proposed to show that penicillamine originates from the UV-absorbing isomer of benzylpenicillenic acid.

Epimerization of benzylpenicilloic acid in alkaline media.

5R,6R-Benzylpenicilloic acid was found to epimerize slowly in alkaline media to 5S,6R-benzylpenicilloic acid until equilibrium was established. Epimerization proceeded via the imine tautomer of penamaldic acid rather than the enamine form and was found to favor the 5S,6R-epimer at equilibrium. The conversion process was monitored using both reverse-phase high-performance liquid chromatography and NMR spectroscopy.

Differential thermal analysis of aluminum hydroxide gel.

The development of order during the aging of aluminum hydroxide gel prepared by the reaction of aluminum chloride and ammonium hydroxide to a final pH of 7.0 can be monitored by differential thermal analysis. The loss of acid reactivity upon aging is accompanied by an increase in the temperature and intensity of the dehydroxylation endotherm and an accompanying decrease in the intensity of the water of hydration endotherm. With continued aging, the thermogram develops the characteristics of a crystalline aluminum hydroxide.

Structure of aluminum hydroxide gel I: initial precipitate.

The initial aluminum hydroxide gel precipitate resulting from the reaction of aluminum chloride or aluminum sulfate with ammonium hydroxide is shown by potentiometric titration, chemical analysis, and the ratio of bound hydroxide to aluminum to fit a polymer model described previously. The formation of polynuclear hydroxyaluminum particles is treated as a stepwise process involving a deprotonation-dehydration mechanism, which results in the formation of six-membered rings; these rings may further coalesce by the same mechanism. The aluminum hydroxide gel precipitated from aluminum chloride can be represented by the formula Al(OH)2.55(Cl)0.45 and probably exists as a polymer of 10 fused six-membered rings. The aluminum hydroxide gel precipitated from aluminum sulfate can be represented by the formula Al(OH)2.30(SO4)0.35. This species probably exists as a polymer of three fused six-membered rings.

Structure of aluminum hydroxide gel II: aging mechanism.

The aging of aluminum hydroxide gel prepared by the reaction of aluminum chloride and ammonium hydroxide was studied by measurement of pH, acid-consuming capacity, hydroxide to aluminum ratio, chloride activity, and X-ray line broadening. The results were consistent with a polymer model involving particle growth by a deprotonation-dehydration mechanism. Anions inhibit this reaction by binding to the positively charged edges of the hydroxyaluminum polymers.

Structure of aluminum hydroxide gel III: mechanism of stabilization by sorbitol.

The effect of sorbitol on the aging of aluminum hydroxide gel, prepared by the reaction of aluminum chloride solution with strong ammonia solution to a final pH of 7.0, was studied by potentiometric titration, acid-consuming capacity, pH, hydroxide to aluminum ratio, chloride activity, X-ray diffraction, and IR spectroscopy. Gels containing sorbitol lost less than 10% of their acid-consuming capacity during a 6-month aging period compared with a loss of more than 60% for an identical gel without sorbitol. The mechanism by which sorbitol stabilizes the gel appears to be inhibition of the secondary polymerization reaction which takes place upon aging. Another polyhydroxy compound, quercetin, also stabilizes aluminum hydroxide gel.

Kinetics of acid neutralization by aluminum hydroxide gel.

The rate of acid neutralization by an aluminum hydroxide gel prepared by the reaction of aluminum chloride solution and strong ammonia solution was studied. The decrease in acid-consuming capacity during aging as measured by the USP test is due to a decrease in the rate of reaction rather than to a decrease in equilibrium reactivity. The reactivity profile has three phases, which are shown to be related to the structure of the gel. The rate of loss of reactivity is directly related to the extent of washing.

Comparison of IR spectroscopic analysis and X-ray diffraction of aluminum hydroxide gel.

Data are presented which demonstrate the IR spectrophotometry is more sensitive than X-ray diffraction to structural changes occurring in aluminum hydroxide gel during aging. By examining changes in peak shape and position in the IR spectrum, evidence is seen for an increasing degree of order as the gel ages. The increased order may be responsible for the loss of acid reactivity observed during aging. IR analysis is also recommended for routine monitoring of aluminum hydroxide gels.

High-pressure liquid chromatographic analysis of penicillin G potassium and its degradation products.

An anion-exchange high-pressure liquid chromatographic system capable of separating penicillin G potassium from five of its degradation products was developed. The retention times were: penicillin G potassium, 17.5 min; DL-penicillamine, 4.5 min; benzylpenilloic acid, 7.0 and 8.0 min; benzylpenamaldic acid, 13.0 min; benzylpenicilloic acid, 19.5 min; and benzylpenillic acid, 22.0 min. In addition, the system permits quantification using linear calibration curves.

Effect of dilution on reactivity and structure of aluminum hydroxide gel.

Aluminum hydroxide gel loses reactivity upon aging. However, a sharp decrease in reactivity occurs when the gel is diluted with double-distilled water. The loss of reactivity is directly related to the degree of dilution, but dilution with dioxane or the mother liquor has no effect on reactivity. It is hypothesized that dilution with water causes a change in the equilibrium between stabilizing ions incorporated in the gel structure and ions in solution. As the stabilizing ions leave the gel structure to reestablish the equilibrium, a loss of reactivity is observed until a new equilibrium is established.

Effect of interaction of aluminum hydroxycarbonate gel and magnesium hydroxide gel on acid neutralization.

Acid neutralization by mixtures of aluminum hydroxycarbonate gel and magnesium hydroxide gel differs from the sum of the acid neutralization of each gel. Acid neutralization by magnesium hydroxide gel in the mixture is not observed until after a substantial portion of the aluminum hydroxycarbonate gel has reacted with acid, even though magnesium hydroxide gel is the faster reacting of the two gels. It is hypothesized that amorphous aluminum hydroxycarbonate forms a coating on the crystalline magnesium hydroxide particles due to electrostatic attraction. This coating prevents protons from reaching the highly reactive magnesium hydroxide until the coating is dissolved by the acid neutralization of aluminum hydroxycarbonate.

Factors affecting homogeneous precipitation of aluminum hydroxide gel.

The variables affecting homogeneous precipitation in the hydrolysis of aluminum nitrate by sodium carbonate were studied. Increased temperature, decreased concentration of reactants, and decreased rate of addition of titrant favor conditions that achieve homogeneous precipitation. During acid hydrolysis, the nitrate anion was the major anion associated with the gel and only small amounts of carbonate were observed. It is recommended that homogeneous conditions be achieved during the precipitation of aluminum hydroxide gel to improve reporducibility.

Structural survey of carbonate-containing antacids.

A series of carbonate-containing antacids was examined by IR and X-ray analysis to establish the role of carbonate and to compare the structure of the antacids to naturally occurring carbonate minerals. Based on IR analysis, the relative degree of perturbation of carbonate increases in the order calcium carbonate, carbonate-containing aluminum hydroxide gel, and dihydroxyaluminum sodium carbonate. The crystalline carbonate-containing antacids were poorly organized forms of the minerals calcite, CaCO3; dawsonite, NaAl(OH)2CO3; and hydrotalcite, Mg6Al2CO3(OH)16-4H2O. Amorphous carbonate-containing aluminum hydroxide gel can be classified mineralogically as amorphous aluminum hydroxycarbonate. IR and X-ray evidence indicates that magaldrate has a hydrotalcite-like structure with sulfate as the major interlayer anion and carbonate also present in the interlayer space.

IR studies of development of order in aluminum hydroxide gels.

The usefulness of deuteration in detecting the development of order in aluminum hydroxide gel by IR spectra is demonstrated. By treatment of gel samples with deuterium oxide vapor at room temperature, the relative ease with which deuteroxyl-hydroxyl exchange takes place is determined as a function of the age of the gel. The use of scale expansion in conjunction with deuteration allows detection of IR absorbance characteristic of gibbsitic material long before such detection is possible by conventional IR analysis or X-ray diffraction.

Role of carbonate in acid neutralization of aluminum hydroxide gel.

The role of carbonate in the acid neutralization of a carbonate-containing aluminum hydroxide gel was studied. The pH-stat neutralization reaction was comprised of three phases: an initial, immediately reacting phase; a slow, zero-order phase; and a terminal, fast zero-order phase. The evolution of carbon dioxide and the appearance of aluminum ions were monitored during neutralization. Acid neutralization is believed to occur predominantly at the aluminum-carbonate bond during the slow phase of neutralization. The reaction of structural carbonate disrupts the gel structure and increases the porosity and surface area of the gel. The diffusion of acid into the gel structure is facilitated and accelerates the neutralization rate, as seen in the final phase of the pH-stat titrigrams. The behavior of carbonate is probably responsible for the rapid and complete neutralization of acid generally observed with carbonate-containing aluminum hydroxide gel.

Nature of amorphous aluminum hydroxycarbonate.

The titration of sodium carbonate with aluminum nitrate is shown to produce amorphous aluminum hydroxycarbonate. This compound is not stoichiometric, although the maximum carbonate to aluminum ratio appears to be 0.5. The pH conditions for achieving the maximum carbonate content are concentration dependent. A model for the particle surface at the solution interface is proposed. This model accounts for the presence of carbonate directly coordinated to the aluminum and carbonate adsorbed by electrostatic forces. Sodium is present in the diffuse layer and is, therefore, not an integral part of the structure.

Separation of penicillin and its major degradation products by ion-pair reversed-phase high-pressure liquid chromatography.

An ion-pair reversed-phase high-pressure liquid chromatographic technique capable of separating penicillin and its major degradation products within 8 min was developed. The influence of pH, counterion concentration, buffer concentration, and organic modifier content was studied and the observed behavior of the compounds during the chromatographic process was discussed.

Effect of surface charge and particle size on gel structure of aluminum hydroxycarbonate gel.

The effect of surface charge and particle size on the gel structure of aluminum hydroxycarbonate gel was studied through the use of a specially designed tension cell. Surface charge has a major effect on the coefficient of bulk compressibility. The charged state is more compressible at lower tensions while the neutral gel is more compressible at higher tensions. In addition, physical properties of gels having a small particle size are more profoundly influenced by interparticle forces than are gels consisting of larger particles. The effect of surface charge and particle size on gel structure is applied to physical properties such as viscosity and dewatering.