Inert gas sparge leads to alternate reaction pathway.

The effect of sparging with an inert gas (argon) was evaluated during the investigation of the solution kinetics of an oxidation-prone amphiphilic drug containing a sulphide moiety. Samples stored with an air headspace in pH7 and 8 phosphate buffers at elevated temperatures and in the absence of light degraded to two main products, a sulphoxide and a cinnamic acid analogue. Initially, this appeared to be a sequential mechanism which could be blocked by removing oxygen. Instead, argon-sparge forced the direct degradation to the cinnamate, which was evidenced by the formation of a strong odour of sulphide. In addition, argon-sparged samples remained colourless, while those sparged with oxygen or stored with an air headspace turned yellow and had negligible odour. The half-lives for samples stored in pH 8 buffers at 93 degrees C at an initial drug concentration of 25 mg mL(-1) were 128 days (argon sparged), 86 days (air headspace), and 65 days (oxygen sparged). The results indicated that for the drug under study, sparging with an inert gas affected the mechanism as well as the rate of the reaction at elevated temperatures.

Change in order of reaction above and below the critical micelle concentration of an amphiphilic sulfide drug.

This paper reports a change in order of reaction for the degradation of the disodium salt form of a synthetic leukotriene antagonist as a function of drug concentration. Buffered solutions, with and without ethylenediaminetetraacetic acid (EDTA).2Na, were prepared at initial drug concentrations above and below the critical micelle concentration (cmc) of the drug, and sparged with argon, oxygen, or left with an air headspace. Samples were stored at elevated temperatures and analyzed by HPLC over a period of 6 months. Above the cmc, a zero-order reaction was observed, and below the cmc, a non-zero-order (approximately first-order) reaction was observed. The suspension-type (zero-order) kinetics observed at drug concentrations above the cmc suggest that the drug in micellar form is stable, providing a sink from which the decomposing submicellar species is replenished. Use of reduced-time plots to normalize the data allowed the order of the reaction to be confirmed across all treatments for a given drug concentration (above or below the cmc). A slight difference in energy of activation (Ea), attributed to the heat of micellization, was observed above and below the cmc for samples stored with an air headspace.

Particle size distributions in mesh cuts and microscopically estimated volumetric shape factors.

When particle size distribution parameters are calculated from sieve analysis, it is generally assumed that the distribution within the particle cut is either linear, producing a mean particle size equal to the average of the mesh openings (1-3), or that a more proper number is the geometric mean of these two apertures. It is shown here that particles within a mesh cut are not linearly distributed, but rather may be normally, long-normally, or biphasic combinations of the two. Three compounds were examined in this fashion, and results are reported here.

Determination of mass transfer dissolution rate constants from critical time of dissolution of a powder sample.

This article presents a method for obtaining mass transfer dissolution rate constants of polydisperse, particulate solids under given hydrodynamic conditions. Oxalic acid, salicylic acid, and phthalimide were recrystallized and classified into various mesh cuts, which were then subjected to dissolution in a USP dissolution apparatus II. Expressions were derived for the anticipated dissolution profiles, and it is shown that cube root plots should show a nick at the point were the smallest particle dissolves. Time and microscopic dimensions then allow calculation of the mass transfer dissolution rate constant.

Particle size distributions from multiparticulate dissolution.

It has been demonstrated theoretically that the particle size distribution of particles in a given sieve fraction of a powder may be assessed by means of short-term dissolution data. Theoretical considerations in this article show that by accounting for polydispersity in a powder sample, the cubic expression in time for amount undissolved and fraction undissolved gives rise to integrals that are essentially moments of the distribution function of one of the defining dimensions of the particle. The first and the second moments can be used to calculate the distribution parameters, (mean and standard deviation) of such a dimension of a crystalline powder. The theory is based on a model geometry, a parallelepiped, for the description of particles such as needles, plates, and prisms. The theory is substantiated by experimental data. A method for obtaining the particle size distribution parameters from the results of dissolution of three sieve fractions of oxalic acid dihydrate, and the general application of this to particle size determination is discussed. To validate the method, the distribution of lengths and breadths of oxalic acid dihydrate particles was obtained from microscopy. From actual powder dissolution data, an estimate of the mean height-to-breadth ratio of these particles belonging to a certain sieve fraction was obtained. With the knowledge of the dissolution rate constant, K, for oxalic acid dihydrate under specified hydrodynamic conditions, it was possible to evaluate the moments of the distribution function. The distribution parameters so obtained were in good agreement with the results obtained from microscopy.

Dissolution testing of soft shell capsules-acetaminophen and nifedipine.

The problem of pelliculation of soft gelatin capsules on aging has been studied. Pelliculation frequently differs in soft shell capsules from hard shell capsules because of the larger mass of gelatin in the softshell dosage form. Two batches of nifedipine soft shell capsules are described. One batch failed in vivo testing and the other batch did not, after storage at 25 degrees C, yet both batches failed dissolution testing by the USP apparatus II method. The USP dissolution apparatus III-method, however, distinguished correctly between the batches. The study reported here was carried out with acetaminophen and was set up to establish whether the USP apparatus III testing method would be more suitable, and if so, what the most desirable dissolution medium should be. To create controlled pelliculation, samples were made with 0, 20, and 80 ppm of formaldehyde. The resulting capsules were subjected to ambient and accelerated storage and dissolution testing was carried out. It was found that the USP apparatus III method best reflected distinction between acceptable and substandard capsules.

Quantitative characterization of adsorption isotherms using isothermal microcalorimetry.

The integral heat of adsorption of water vapor on sodium benzoate samples was determined at various partial vapor pressures using a heat conduction microcalorimeter. An equation is presented to describe the calorimetric integral heat response (mJ/g of solid) as a function of relative humidity. This equation, although similar in principle to the well-known BET equation, relates the heat evolved (rather than volume or mass of gas adsorbed) upon adsorption to the partial pressure of the gas. It qualitatively describes the shape of the calorimetric isotherm and quantitatively allows the calculation of "monolayer capacity" or the apparent surface area with water as the adsorbate. The modified BET equation was applied to the calorimetric adsorption data available in the literature. The surface area or the monolayer coverage values of the solid samples used in these studies were calculated from data-fitted parameter estimates. Good agreement was found between Vm or surface area values obtained by the application of the model to the calorimetric data and those reported by the authors using conventional gravimetric or volumetric measurement of adsorption. The model satisfactorily described the experimental calorimetric data of water vapor adsorption on sodium benzoate. The model equation and the use of isothermal microcalorimetry provide a means to obtain the water adsorption surface area of solid materials. The method may also be useful in comparing the surface properties of drugs and excipients obtained by different methods or from different sources. The microcalorimetric method to characterize adsorption is more sensitive and convenient in comparison with some of the conventional techniques.

Confirmation of the Mukerjee term in an extended Corrin-Harkins relation using an anionic amphiphilic drug.

The amphiphilic behavior of the S-enantiomer of 3(S)-[(2-carboxyethyl)sulfanyl]-3-[2-(8-phenyloctyl)phenyl] propionic acid disodium salt (C26H32O4S.2Na) has been investigated as a function of the ionic strength, mu (buffer and simple electrolyte). The linearity predicted by the Corrin-Harkins relation (J. Am. Chem. Soc. 1947, 69, 683-688) is observed at low buffer concentrations, and it is verified that the nature of the buffer is of less importance than the concentration of the counterion. At high counterion concentrations, the salting-out effect predicted by Mukerjee in 1965 (J. Phys. Chem. 1965, 69, 4038-4040) and 1967 (Adv. Coll. Interf. Sci. 1967, 1, 241-275) manifests itself, and a more complete equation resulting from attaching a salting-out term to the Corrin-Harkins relation, as used recently by Mukerjee and Chan (ACS Abstracts of Papers 1993, 206, COLL 164; Ph.D. Thesis, University of Wisconsin, 1993), gives a better representation of the experimental data. It is shown that the parameter values obtained from this equation are reasonable and predict self-association in the form of micelles rather than as small aggregates.

Effect of change in shape factor of a single crystal on its dissolution behavior.

PURPOSE: To study the effect of change in the shape factor of real crystals on their dissolution behavior using a potassium dichromate crystal as a model for particulates in general. METHODS: A model geometry (parallelepiped) has been suggested for a dissolving particle. Single crystals of potassium dichromate which are monoclinic prisms were grown individually from supersaturated solutions at 40 degrees C. Dissolution studies were carried out on five such crystals in 0.1N H2SO4 at 25 degrees C and a stirrer speed of 50 +/- 1 rpm. The five crystals had different degrees of non-isometricity. Initial dimensions of the crystals were measured using image analysis techniques. The shape factor of the dissolving crystal as a function of time was obtained indirectly from the dissolution data. RESULTS: The shape factor of a single crystal changed significantly after about 50% dissolution. The nature of this change depended on the degree of non-isometricity of the crystal. The change in shape factor of the dissolving crystal was accounted for in the Hixson-Crowell cube root law, and a modified form of the cube root equation was developed. This equation for dissolution explained the observed upward curvature in the cube root law plot. CONCLUSIONS: The shape factor for any non-isometric particle cannot be considered to be constant over the dissolution event, as is commonly assumed. This change has an appreciable effect on the dissolution behavior of crystals. This study is particularly of significance for elongated shapes like needles and platelets. By the methodology described here, it was possible to determine the initial shape factor of the crystal and the intrinsic dissolution rate constant.

Calorimetric determination of the heat of precipitation of pseudoephedrine racemic compound--its agreement with the heat of solution.

The heat of precipitation of dl-pseudoephedrine was determined by direct calorimetry using a Tronac isoperibolic calorimeter. The precipitation of dl-pseudoephedrine was induced by mixing aqueous solutions of the two enantiomers, namely, d- and l-pseudoephedrine, directly in the calorimeter. The molar heat of precipitation of dl-pseudoephedrine was -2.7 and -3.0 kcal/mol at 25 and 30 degrees C, respectively. The aqueous solubility of dl-pseudoephedrine was determined over a temperature range of 20-40 degrees C. The van't Hoff solubility plot was nonlinear. The apparent heat of solution at saturation was obtained from the solubility data using a nonlinear regression model. A good agreement between the magnitude of the apparent heat of solution at saturation and the heat of precipitation was noticed at both 25 and 30 degrees C.

Mechanism and kinetics of metal ion-mediated degradation of fosinopril sodium.

Fosinopril sodium (I), a new angiotensin converting enzyme inhibitor, is a diester prodrug of the active moiety II. We report here a novel transformation of fosinopril into beta-ketoamide, III, and a phosphonic acid, IV, mediated through metal ion participation. The interaction of fosinopril with magnesium ions was studied in a solution model system in which methanol was used as the solvent and magnesium acetate as the source of metal ions. Kinetic analysis indicated the degradation to be a bimolecular process, with the rate being first order in both metal ion and fosinopril concentration. The degradation products II, III, and IV effectively retarded the magnesium ion mediated reaction of fosinopril. Based on the results of 31P-NMR, 1H-NMR, Mn(II)-EPR spectroscopy experiments and mass spectrometry, a mechanism is postulated for this transformation. A key reactive intermediate has been characterized that supports the proposed mechanism. The results can account for the observed degradation profile of the fosinopril sodium in a prototype tablet formulation.

Statistical approaches to stability protocol design.

In stability protocols, data are usually visualized as being generated, and stability evaluation is accomplished at a point in time when sufficient data have been accumulated. Often, data are simply treated by the "statistically best fit" and, as a consequence, statements describing some batches as being first order and some being zero order are frequently used. From a scientific point of view, it is more advantageous at the preformulation stage to ascertain what the stability profile should be (i.e., what the mechanism is) and then apply the statistics to this format. Examples are given of pH profiles, Arrhenius plotting, and dissolution data. In the first case, the use of fractional factorials (a matrix approach) is suggested.

Methods for the assessment of the stability of tablet disintegrants.

To allow assessment of the long-term stability of tablet disintegrants, two mechanisms for their functionality (i.e., water uptake and swelling force generation) were monitored. Three disintegrants, alginic acid, sodium starch glycolate, and crospovidone, were used to establish the methodology. The water uptake and swelling force methodologies developed were reproducible, thus allowing for the evaluation of the effect of time, temperature, and humidity on these properties of disintegrants. The data obtained suggest that the process of water uptake and swelling force generation was essentially a two-step process. Initially, water entered the pore space in the powder bed; there was a definitive lag time before a swelling force was generated. In the stability evaluation of alginic acid and sodium starch glycolate, samples were stored for 1-year. Above 30 degrees C and 75% relative humidity, the swelling force performance of alginic acid was markedly affected. Changes seen with sodium starch glycolate were much less marked.

Amorphous-to-crystalline transformation of sucrose.

The transformation of amorphous sugar in the form of lyophilized spheres into crystalline sucrose was studied. The lyophilisate, when exposed to moist atmospheres, picks up moisture to a constant weight. The amount of moisture addition is a function of relative humidity of the atmosphere and temperature. The loose "lyophilisate structure" collapses to form a denser amorphous phase ("hydrated amorphate"). After a lag time which varies with relative humidity of the atmosphere and temperature, the hydrated amorphate loses moisture (weight) and, in the process, forms crystalline sucrose. The phase nature of the hydrated amorphate is equivalent to an aqueous solution that is supersaturated with respect to crystalline sucrose. A model was developed for the lag time which accounts for the experimental results.