Carbon-13 magnetic resonance spectroscopy of drugs. Sulfonamides.

The natural abundance 13C magnetic resonance spectra of a series of sulfonamide drugs(sulfanilamide, sulfaguanidine,sulfathiazole, sulfasuxidine, sulfadiazine, sulfamerazine, sulfamethiazine, and sulfapyridine) have been determined at 25.15 MHz employing the pulse Fourier transform technique. The chemical shefts have been assigned with the aid of off-resonance and selective proton decoupling techniques, as well as by long-range carbon-13 proton coupling patterns.

Drug physical state and drug-polymer interaction on drug release from chitosan matrix films.

Four different grades of chitosan varying in molecular weight and degree of deacetylation were used to prepare chitosan films. Salicylic acid and theophylline were incorporated into cast chitosan films as model acidic and basic drugs, respectively. Crystalline characteristics, thermal behavior, drug-polymer interaction and drug release behaviors of the films were studied. The results of Fourier transform infrared and solid-state 13C NMR spectroscopy demonstrated the drug-polymer interaction between salicylic acid and chitosan, resulting in salicylate formation, whereas no drug-polymer interaction was observed in theophylline-loaded chitosan films. Most chitosan films loaded with either salicylic acid or theophylline exhibited a fast release pattern, whereas the high viscosity chitosan films incorporated with salicylic acid showed sustained release patterns in distilled water. The sustained release action of salicylic acid from the high viscosity chitosan films was due to the drug-polymer interaction. The mechanism of release was Fickian diffusion control with subsequent zero order release. It was suggested that the swelling property, dissolution characteristics of the polymer films, pK(a) of drugs and especially drug-polymer interaction were important factors governing drug release patterns from chitosan films.

Continuous-flow system for determination of diffusion coefficients: use of a natural membrane.

A natural membrane was employed in an automated diffusion system. A mature male Mongolian gerbil sebaceous gland pad was excised and mounted into a suitable retainer so that the external surface was oriented toward the concentrated aqueous drug solution. Aqueous solutions of benzoic acid and the three commonly used parabens were studied. The gerbil sebaceous pad effectively prevented any diffusion of these drug solutions within 15 hr. Water by itself, however, was transported through the skin even against a pressure gradient. Although no apparent diffusion of these compounds occurred, a significant amount of drug was retained by the sebaceous pad. An expression for membrane-water partition coefficients could be calculated. Based upon thicknesses of natural and synthetic membranes, theoretical approximations of diffusion rates were found using lag time calculations.

Carbon-13 magnetic resonance spectroscopy of drugs II: antihistamines.

The natural abundance carbon-13 magnetic resonance spectra of a series of antihistamines (pheniramine, chlorpheniramine, methapyrilene, tripelennamine, pyrilamine, and thonzylamine) were detemined using the pulse Fourier transform technique. The chemical shifts were assigned with the aid of long-range carbon-13-hydrogen coupling constants.

In vitro adsorption-desorption of fluphenazine dihydrochloride and promethazine hydrochloride by microcrystalline cellulose.

Fluphenazine dihydrochloride and promethazine hydrochloride were adsorbed in vitro from suspensions of the tableting excipient, microcrystalline cellulose. Studies were undertaken to determine how this adsorption phenomenon was affected by the type of phenothiazine derivative, the type of microcrystalline cellulose, and pH and ionic strength adjustment. The smaller the microcrystalline cellulose particle size, the more drug was adsorbed. Changes in the pH, the ionic strength, and the valency of the cation used to adjust the ionic strength all had a major effect on the extent of adsorption. The adsorption process was rapidly and completely reversed in vitro at gastric pH and ionic strength values.

Determination of porosity and pore-size distribution of aspirin tablets relevant to drug stability.

Total porosity and pore-size distribution of aspirin tablets prepared from aspirin, starch USP, and precipitated colloidal silicon dioxide were determined using mercury porosimetry. The model represented a hydrolyzable drug substance in combination with simple excipients. The role of starch and silicon dioxide on the microstructure of the tablets was investigated, as was the chemical stability of various systems. In general, the porosity of tablets containing a constant quantity of starch increased linearly with silicon dioxide concentration. Examination of the pore-size distribution, however, revealed that a low concentrations silicon dioxide functioned primarily to reduce the size and volume of coarse pores representing the spaces between the agglomerates of starch and aspirin particles. This effect was optimum at 3%. A further increase in silicon dioxide concentration produced tablets with relatively larger pore sizes. Studies of changes in the porosity characteristics of tablets as influenced by water vapor over time showed distinct differences in this complex parameter. A unique trend in the change of the pore-size distribution was noted with tablets containing 3% silicon dioxide. These observations are discussed relative to the stability of aspirin tablets in which this concentration of silicon dioxide produced a maximum stabilizing effect.

Nonisothermal aqueous calorimetry: computation of process-dependent temperature change and aspects of calorimeter design.

A general method for determining the process-dependent (intrinsic) temperature change in a nonisothermal calorimeter is presented. The nonisothermal approach to calorimetric investigations requires an estimate of the magnitude of the process independent (extrinsic) temperature change during the reaction period. The proposed method can be applied to any calorimeter whose output is a discrete or continuous temperature--time profile. It is based on a first-derivative transformation of the temperature--time profile and the partitioning of the observed temperature variation into two components: pure extrinsic variation, which occurs outside the reaction period, and the combined extrinsic and intrinsic effects during the reaction period. Close examination of the pure extrinsic variation was considered essential, since it provided the basis for identifying the form of a descriptive mathematical function consistent with the observed extrinsic behavior. Once a suitable function was selected, parameters for the equation were determined through a linear regression procedure. The resulting equation was used to predict the extrinsic variation within the reaction period. Subtraction of predicted extrinsic variation from the observed total variation and integration over the time course of the experiment provide an estimate of the process-dependent temperature change. The differential approach was examined for processes performed in a calorimeter of simple design. Aspects of calorimeter design and advantages of the proposed method of data analysis are discussed.

Application of immersional calorimetry to investigation of solid-liquid interactions: microcrystalline cellulose-water system.

A comprehensive characterization of the specific solid-liquid interaction for microcrystalline cellulose and water is presented. The procedure consisted of a conjoint vapor adsorption and immersional wetting experiment. The following information was obtained with respect to the solid. Estimates of the total surface are (138 m2/g) and the external surface (9.2 m2/g) were calculated from the adsorption and immersion data, respectively. Existence of an energetically homogeneous surface was verified by a linear decrease in the heat of immersion of samples containing adsorbed moisture approximately up to monolayer capacity. Integral and differential free energy, enthalpy, and entropy changes accompanying the adsorption process were calculated, and a lack of swelling was substantiated by comparison with a similar study of cellulose fibers. Immersional hysteresis was observed, and its magnitude suggested that sorption hysteresis was of enthalpic as well as entropic origin. The experimental method is potentially valuable for routine characterization of hydrophilic powders.

Recording pH method of characterizing composition and monitoring dissolution profile of an anhydride-acid copolymer and its salt derivatives.

A sensitive potentiometric monitoring method was developed that permits the continuous measurement of the disolution profiles of methyl vinyl ether-maleic anhydride-acid copolymers and salt derivatives. Three distinct rate periods were observed in the dissolution rate of the anhydride copolymer, expressed as percent anhydride dissolved, was independent of sample weight over the weight range studied. The acid form of the copolymer showed only one dissolution rate period, with dissolution being very rapid. The rapid initial pH decrease observed during the first stage of dissolution for a series of anhydride-acid copolymer powder samples correlated closely with the anhydride-acid ratio, permitting chemical characterization of the copolymer functionality simultaneously with the analysis of dissolution profiles. Similarly, the extent of copolymer alkaline salt conversion was inversely proportional to the initial maximum pH increase observed during the first stage of dissolution of these salts. Mechanisms of dissolution of copolymer powder materials are discussed and compared to the dissolution of compressed disks and films reported previously.

Bactericidal properties of quaternary ammonium compounds in dispersed systems.

Alkyltrimethylammonium bromides of selected chain length were synthesized and characterized with respect to their bactericidal properties. A partitioning method was developed, and the aqueous phases of the partitioned systems were evaluated for their antibacterial activity against Staphylococcus aureus. The relationships between the quaternary ammonium compound chain length and the aliphatic alcohol chain length were determined. The effect of selected hydrocarbons on the bactericidal effectiveness of the systems was studied. Cream systems corresponding to the partitioned systems were prepared and evaluated against S. aureus. The relationship between the aqueous phase concentration of the bactericidal agent was studied, and a correlation was shown between the bactericidal activity of the partitioned systems and cream systems.

Quantitative evaluation of pharmaceutical effervescent systems I: Design of testing apparatus.

Two new devices were developed to monitor the reactivity of pharmaceutical effervescent systems. The first method monitored carbon dioxide pressure generation during the effervescent reaction in a plastic pressure vessel fitted with a pressure gauge. The second method monitored weight loss, attributed to carbon dioxide loss to the atmosphere, by means of a double cantilever beam and an electromagnetic proximity transducer. In the pressure device, the quantification of an effervescent reaction was accomplished by measuring the dissolution time of the effervescent system and the pressure generated. Quantification of an effervescent reaction using the beam device utilized the total carbon dioxide weight loss, the rate of weight loss, and the effervescent reaction lag time.

Quantitative evaluation of pharmaceutical effervescent systems II: Stability monitoring by reactivity and porosity measurements.

The stability of selected effervescent tablet systems was monitored by means of mercury intrusion porosimetry and by a cantilever beam/proximity transducer balance. The porosity measurements proved to be useful in elucidating tablet pore structure changes over time. The measured parameter, percent pores greater than the experimental range, was a useful measure of porosity for statistical evaluations. The study showed that compression pressure and manufacturing conditions are not significant factors in the stability of an effervescent tablet system when nonhygroscopic materials are used.

Mechanism of freeze-thaw instability of aluminum hydroxycarbonate and magnesium hydroxide gels.

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.

Role of water in the aging of aluminum hydroxide suspensions.

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.

Use of microcapsules as timed-release parenteral dosage form: application as radiopharmaceutical imaging agent.

The development of a new type of parenteral dosage form is described. A system of microencapsulation was formulated which produced microcapsules containing a water-soluble core material. The basic microencapsulation system could be altered to produce microcapsules with varied timed-release characteristics. Tracer methodology was employed as a sensitive and versatile analytical tool for the development and evaluation of the microencapsulation system. The core material was labeled by neutron activation after microcapsule formulation, which eliminated the radiation hazard and contamination problems that could occur during formulation with a labeled core material. Both in vitro and in vivo testing showed that the release patterns of labeled core material could be altered and detected. The microcapsules developed have potential as a timed-release parenteral dosage form and as an organ-imaging radiopharmaceutical.

Cost evaluation of alternative pharmaceutical tableting processes by simulation.

A simulation model and a subsequent computer program were developed as experimentation methods for evaluating tableting processes with respect to cost. These methods also allow estimation of the various times involved in a tableting operation (e.g., the processing time). The model was programmed in FORTRAN using the GASP IV simulation language. After verification of the program, experiments were run that involved comparing different levels of specific input variables to determine which variable had an effect on the cost-time relationships of a particular processing method. Among the possible input variables chosen for evaluation were the drying method, the type of tableting machine, the batch size, the labor rate, and the operation of the equipment in the process. An analysis of variance was made, and three separate regression equations were developed that described the relationship between the input variables and the dependent variables of processing cost and time. Graphs were developed from the regression equations by manipulating them through series of different independent variables. These graphs then were used in determining minimum costs and times, breakeven points, and rates of change, as well as in simple evaluation of processes through graphic representation. By using the simulation program to run experiments and then by analyzing them, results can be obtained to help in making intelligent decisions about the cost-time relationships of a particular tableting procedure before it is implemented.

Oxidative degradation of hydrocortisone in presence of attapulgite.

Degradation of hydrocortisone in attapulgite suspensions was monitored by high-pressure liquid chromatography and UV spectrophotometry. The rate of oxidative degration 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 potentiala for accelerating the oxidative degradation of drugs should be considered whenever clays and drugs are combined.

Effect of shear on the apparent viscosity of amorphous carbonate ion containing aluminum hydroxide suspensions.

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.

The effect of moisture content on the compression properties of maltodextrins.

The effect of moisture content on the compression properties of maltodextrin powders obtained by different degrees of hydrolysis (depolymerization) of corn starch has been studied using the yield pressure determined from the Heckel plot and the compact tensile strength measured by the diametrical compression method. An increase in the moisture content of the powder reduced the yield pressure and improved the densification for all five maltodextrins evaluated. At the same moisture level, the extent of densification which occurred during compaction was greater for maltodextrins with a lower degree of polymerization. Compacts produced by maltodextrins with a lower degree of polymerization also exhibited a greater tensile strength for a given pressure at a moisture content below 8.0%. However, further increase in moisture content resulted in a decrease in compact tensile strength for maltodextrins having a lower degree of polymerization. Despite the significant difference in compression behaviour, the five maltodextrins did not show noticeable differences in crystallinity as revealed by their x-ray powder diffraction pattern.

Evaluation of the sorbent suspension reciprocating dialyser in the treatment of overdose of paracetamol and phenobarbitone.

Poisoning with paracetamol (acetaminophen) and phenobarbitone is a common occurrence in the United States and Europe. The removal efficiency of these drugs by a sorbent suspension reciprocating dialyser (SSRD) has been investigated. The SSRD is a parallel plate dialyser with a reciprocating blood flow and free mobile sorbent suspension composed of charcoal and zeolites. This arrangement provided a system with minimal sorbent saturation. High performance liquid chromatography was used for the quantification of the drugs in aqueous and serum fluids. The in-vitro removal efficiency of the dialyser was studied by dialysing a large volume of the drug in solution for 12 to 16 h. The removal efficiency remained relatively constant up to 10 h of dialysis. The in-vivo dialysis studies were performed using normal dogs. Large doses of the drugs were administered orally or intravenously to achieve high blood levels. The clearance values obtained from these studies were comparable with, or in excess of, the values reported in the literature for conventional dialysers. The major advantage of the SSRD is the ability of the unit to be used for prolonged dialysis and to provide a system with minimal sorbent saturation due to mixing and interchange of sorbent granules next to the membrane surface.