Search

IR and X-ray analysis demonstrate that hydrotalcite forms during the aging of aluminum hydroxycarbonate gel and magnesium hydroxide gel mixtures. The formation of hydrotalcite produces a change in the pH-stat titrigram and a sharp increase in the pH of the mixture. Hydrotalcite was noted earlier in mixtures having a high molar ratio of magnesium to aluminum, a high total gel concentration, a high initial pH, or in mixtures stored at elevated temperatures. The addition of sorbitol to the mixtures substantially delayed the appearance of hydrotalcite. Nonacid-reactive hydrotalcite formed when mixtures of chloride-containing aluminum hydroxide gel and magnesium hydroxide gel were aged.

□ The effect of freeze-thaw cycles on the physical stability of aluminum hydroxycarbonate and magnesium hydroxide gels was studied. Coagulation following a freeze-thaw cycle, leading to the formation of visible aggregates, affected the content uniformity of both gels. The freeze-thaw cycles did not affect the crystal form or surface characteristics of the gels as determined by X-ray powder diffraction and point of zero charge, but caused a slight reduction in the rate of acid neutralization and a large increase in the rate of sedimentation. The greatest effect was observed after the first freeze-thaw cycle. While the duration of freezing was not a factor, the rate of freezing was important and was inversely related to the aggregate size. The aggregates which formed following a freeze-thaw cycle were not redispersed by shaking, but were reversed by ultrasonic treatment or homogenization. The adsorption of polymers or surface-active agents prior to freezing reduced and, in some cases, prevented the formation of aggregates. The physical instability produced by a freeze-thaw cycle was explained by the modified DLVO theory. The force exerted on the particles by the growing ice crystals forced the particles into the primary minimum, producing strong interparticle attraction. On thawing, simple agitation did not provide enough force to overcome the attractive force of the primary minimum. Adsorption of polymers or surface-active agents increased the steric repulsive force and prevented the particles from reaching the primary minimum.

The pH-stat titration of aluminum hydroxide gel was evaluated and was affected by pH, temperature, concentration, and ionic strength. Control of these parameters resulted in a highly sensitive and reproducible in vitroantacid test. The utility of the pH-stat test was illustrated by monitoring the aging of several carbonate-containing aluminum hydroxide gels and by comparing the antacid properties as measured by the pH-stat titration, the acid-consuming capacity, the Rossett-Rice test, and the test proposed by the Food and Drug Administration Drug Evaluation Panel. The pH-stat titration also was useful for relatively nonreactive aluminum hydroxide gels. The use of sodium fluoride as the reaction medium extended the capability of the pH-stat titration to monitor the aging of chloride-containing gels. The pH-stat titrigram was interpreted in terms of a previously published polymer model of the structure of a chloride-containing aluminum hydroxide gel. The acid reactivity of relatively nonreactive gels is believed to be due totally to the chemical neutralization of acid, because the milliequivalents of aluminum ion appearing in solution is the same as the milliequivalents of acid neutralized throughout the pH-stat titration.

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, NaAI(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.

Pepsin adsorbed on gibbsite or boehmite, non-acid-reactive forms of aluminum hydroxide, had a significantly lower activity than pepsin in solution. IR and desorbed pepsin activity studies showed that the reduced activity of adsorbed pepsin was not due to denaturation of pepsin on adsorption. Steric occlusion of the active site, following pepsin adsorption, was responsible for the lower activity of pepsin adsorbed on gibbsite. The porous morphology of boehmite caused diffusional resistance and steric exclusion, contributing to the decreased activity of adsorbed pepsin. The specific inactivation of pepsin by adsorption on aluminum hydroxide may be important in ulcer therapy.

Adsorption of pepsin by gibbsite and boehmite, non-acid-reactive forms of aluminum hydroxide, was observed and related to the surface area of the adsorbent. Adsorption was pH dependent, with maximum adsorption occurring between pH 2.7–3.3 for gibbsite and pH 2.7–4.3 for boehmite. Electrostatic attraction was an important adsorption mechanism at the pH conditions encountered in the GI tract; the isoelectric point of pepsin was ~1, giving it a negative charge, and the point of zero charge for the adsorbents was >9, giving them a positive charge. However, the pH-adsorption profile can not be fully explained by electrostatic considerations. Desorption studies indicate the importance of specific adsorption because pepsin was not desorbed by washing with acidified water, but was partly desorbed by exchange with phosphate. The IR spectrum of adsorbed pepsin also suggested that specific adsorption of pepsin occurred through anionic ligand exchange involving carboxylate groups of pepsin and surface aluminum ions.

The point of zero charge of 36 carbonate‐containing aluminum hydroxide gels decreased with increased carbonate‐to‐aluminum molar ratio. Theoretical analysis supported this observation and showed (a) that the point of zero charge was sensitive to low fractional coverage of surface sites by carbonate and (b) that divalent carbonate is the predominant form of carbonate on the surface. The implications of the pH‐point of zero charge relationship of aluminum hydroxide on the viscosity, adsorptive properties, rate of filtration, and removal of sodium are discussed.

Phosphate is specifically adsorbed by aluminum hydroxycarbonate by anion ligand exchange. IR analysis indicated that phosphate exchanged with specifically adsorbed carbonate. Adsorption is favored by low pH and is inversely related to particle size. Adsorption of phosphate decreases the rate of acid neutralization of aluminum hydroxycarbonate. The results are applied to the treatment of hyperphosphatemia and hypophosphatemia.

IR, X-ray diffraction, and adsorption studies showed that digoxin is adsorbed onto montmorillonite by a reversible adsorption mechanism at pH2 and 6. Degradation studies indicated abnormally high acid hydrolysis rates for digoxin interacted with montmorillonite. Accelerated digoxin degradation is attributed to the ability of the clay surface to concentrate both digoxin and protons. The effective pH at the clay surface appeared to be 1.5pH units lower than the bulk suspension pH. Bisdigoxigenin was the major adsorbed degradation product. A similar catalytic effect also may occur with other neutral drugs that degrade by acid hydrolysis and should be considered in the formulation of clay-containing drug products or their coadministration with other drugs.

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.

Degradation of hydrocortisone in attapulgite suspensions was monitored by high-pressure liquid chromatography and UV spectrophotometry. The rate of oxidative degradation of hydrocortisone was accelerated significantly in the presence of attapulgite. In addition, degradation appeared to be composed of two apparent first-order reactions rather than the single apparent first-order degradation reaction observed for hydrocortisone solutions. However, the same degradation products were obtained in both hydrocortisone solutions and attapulgite suspensions, indicating that interaction with attapulgite did not alter the degradation pathway. Kinetic and adsorption studies suggested that hydrocortisone is adsorbed weakly by attapulgite and undergoes oxidative degradation, which is catalyzed by adsorbed iron oxides or hydroxides as well as by structural ferric iron at the clay surface. Since clay minerals generally contain surface ferric iron, the potential for accelerating the oxidative degradation of drugs should be considered whenever clays and drugs are combined.

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.

Carbonate was completely desorbed from amorphous aluminum hydroxycarbonate gel by purging with nitrogen. The reversibility of carbonate adsorption suggests that aluminum hydroxycarbonate particles are composed of planes of aluminum hydroxide with carbonate adsorbed at edge aluminum sites. A slow-reacting phase which was identified as a precursor of gibbsite, formed when the carbonate/aluminum molar ratio was <0.20.

The rate of acid neutralization of anhydrous suspensions of amorphous aluminum hydroxide in methanol did not change during aging. At low water content, when all of the water was adsorbed, an initial decrease in the rate of acid neutralization was observed but no further change occurred during aging. When enough water was present to exceed the adsorptive capacity and produce water in the bulk methanol, the initial rate of acid neutralization decreased and a decrease in the rate of acid neutralization also occurred during aging. The decrease in rate of acid neutralization during aging is believed to be due to polymorphic transformation of the amorphous aluminum hydroxide and aggregation. The change caused by aggregation could be reversed by dehydration or sonication, but the change due to polymorphic transformation could not be reversed.

The application of shear to carbonate ion containing aluminum hydroxide suspensions caused a change in the apparent viscosity by two possible mechanisms: change in the surface charge because of desorption of specifically adsorbed carbonate ion, and aggregate dispersal and formation of more extensive particle networks. The desorption of specifically adsorbed carbonate ion is related to the expansion of the air-liquid interface during shear. Shear-inducing processing equipment which generates a minimal amount of new air-liquid interface was found to produce the least change in pH and, consequently, in surface charge. However, viscosity increases caused by aggregate dispersal and formation of more extensive particle networks may occur without a shear-induced change in surface charge.

IR and X-ray analyses of the interaction of clindamycin with montmorillonite indicate that clindamycin is adsorbed by a cation-exchange mechanism under pH conditions favoring the cationic form of the drug and by physical adsorption when the unionized drug is present. This physical adsorption is relatively weak since the drug is readily desorbed by alkaline washing. Tetracycline is adsorbed by cation exchange

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.

X-ray diffraction and IR and 27Al-NMR spectroscopy indicate that aluminum chlorohydrate is composed of a central aluminum in a tetrahedral configuration surrounded by 12 aluminum atoms in octahedral configuration. The complex, Al13O4(OH) 24(H2O)127+, is essentially spherical, with the +7 charge equally distributed on the surface. Seven chloride ions are associated with the complex as counterions. This structure is consistent with both the method of synthesis and the proposed mechanisms of antiperspirant activity.

Sepiolite, a member of the fibrous mineral group of clays. is relatively free of surface ferric iron and does not accelerate significantly the oxidative degradation of hydrocortisone. The compatibility of sepiolite with drugs that can undergo oxidative degradation is in sharp contrast to the catalytic effect of attapulgite, another fibrous mineral, which contains a significant amount of surface ferric iron and which therefore accelerates oxidative degradation. Sepiolite adsorbs hydrocortisone by a weak adsorption mechanism, which was shown by IR spectroscopy to be chiefly due to hydrogen bonding. However, accelerated oxidative degradation of the adsorbed hydrocortisone does not occur. Maximum adsorption occurs at pH 7-8.5. Desorption occurs readily by washing with water. Sepiolite has similar rheological properties to attapulgite. The results of this study suggest that sepiolite may be useful as a pharmaceutical excipient for drugs that undergo oxidative degradation.

IR spectroscopy and changes in the rate of acid neutralization were used to study the interaction between various polyols and aluminum hydroxide. Hydrogen bonding is responsible for this interaction, although structural requirements limit the polyols that interact with aluminum hydroxide. Mannitol and sorbitol, both linear polyols, interacted with sulfate-containing aluminum hydroxide gel and aluminum hydroxycarbonate gel, while inositol, a cyclic polyol, did not interact The adsorbed polyol has the favorable effect of inhibiting the polymerization reaction that occurs on aging and the negative effect of reducing the rate of acid neutralization. Thus, the specific polyol and concentration must be carefully selected to maximize the desired effect of stabilizing the gel structure. The presence of mannitol in the reaction medium during precipitation did not significantly enhance gel structure stability, probably because the mannitol was desorbed during the washing process as a consequence of the weak adsorption forces.

Carbonate-containing aluminum hydroxide was precipitated at constant pH at intervals of 0.5pH units from pH 6 to 10 by pumping 0.5M AlCl3into the reaction vessel at a constant rate of 2mL/min and infusing 2M Na2CO3at a rate necessary to maintain the desired pH. The pH of precipitation affected both the particle size and the composition of the precipitate. The particle size of the precipitate decreased as the pH of precipitation was increased from 6 to 10. The precipitates formed between pH 7.5 and 9.5 contained crystalline sodium aluminum hydroxycarbonate (dawsonite) in addition to amorphous carbonate-containing aluminum hydroxide.

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.

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.

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)0.45and 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.

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 acidconsuming 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.

Data are presented which demonstrate that 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.

The effect of oxalic acid, citric acid, and their sodium salts on the structure of aluminum hydroxycarbonate gel was studied to illustrate the various mechanisms by which polybasic acids interact with aluminum hydroxycarbonate gel. Analysis of changes in the pH-stat titrigram, the carbonate to aluminum ratio, the aluminum content of the supernate following centrifugation, and the adsorption of the organic solute indicates that polybasic acids may: (a) partially neutralize the aluminum hydroxycarbonate gel by a general acid effect, (b) modify the aluminum hydroxycarbonate surface by adsorption of the anionic form of the polybasic acid, (c) extract aluminum by the formation of a soluble complex, and (d) lead to the precipitation of a new crystalline phase.

Changes in the partial molar free energy of the ionic species of tetracycline as a result of interaction with sodium-saturated montmorillonite were monitored by UV spectroscopic titrations. The stronger interaction between the clay and the protonated (H3T+) species relative to the zwitterionic (H2T0) species is responsible for the apparent displacement of pK1in clay suspensions. The displacement of the first equilibrium favors the H3T+species due to its stabilization by the negative clay surface. Little effect of the clay was observed on pK2and pK3, because the ionic species of tetracycline associated with these equilibria (H2T0, HT−, and T2-) did not interact strongly with the negative clay surface. Therefore, the ionic species distribution of tetracycline in a sodium montmorillonite suspension is significantly different than that expected based on solution equilibria. The degree of equilibrium displacement depended on the accessibility of the negative charge at the clay surface. Fraction bound curves support the hypothesis that the clay surface causes a change in tetracycline equilibria. The H3T+form of tetracycline was highly bound to the sodium montmorillonite, but little adsorption was observed for the H2T0species.

The adsorption of tetracycline by clays commonly used in pharmacy can be predicted if the identity and character of the commercial 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 commercial 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.

A tension cell was designed to measure the gel structure of aluminum hydroxycarbonate gel. Equilibrium measurements of the total water outflow versus applied tension give insight into the rigidity of the gel structure. Dynamic measurements of the rate of outflow of water at various applied tensions yield the capillary conductivity of the gel, which is related to the apparent surface area, particle size, and porosity. An aluminum hydroxycarbonate gel with a high apparent viscosity exhibited an increase in viscosity upon aging at 25d, which was accompanied by an increase in the equilibrium tension of the water phase, an increase in ΓH2Oand a decrease in capillary conductivity. In contrast, the apparent viscosity of a low viscosity aluminum hydroxycarbonate gel, which was precipitated from the same reagents but with different precipitation temperature, pH, and stirring speed, exhibited a decrease in equilibrium water tension, a decrease in δGH2O, and an increase in capillary conductivity during aging at 25°.

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.