Nondestructive viscoelastic analysis of anisotropy in compressed tablets.

A nondestructive procedure for determining anisotropy levels in compressed tablets was developed based on dynamic stress/strain measurements of viscoelasticity in the axial and radial directions. An instrument was designed and built capable of 10 nm resolution of strain and operating over the frequency range 1-64 Hz. Tablets of 11 pharmaceutical excipients and drugs, representing both plastic and brittle materials, were found to behave as three-parameter viscoelastic solids in both the axial and radial directions. Elastic and viscous parameters were computed, based on frequency dependence over the range studied, and were found to differ greatly in the axial and radial directions. Degrees of anisotropy, defined as the ratio of the uncoupled spring parameters in the radial vs the axial direction, were found to range from 2- to 12-fold over the materials studied. These levels of anisotropy are thought to be typical of tablets manufactured in a rotary press under normal conditions. Measurements of this type can be easily made routinely as a further means of quality control and reflect an important feature of the internal structure of compressed tablets.

Determination of intraparticulate mass transfer coefficients via permeation measurements: theory and experimental validation.

A mathematical model of mass transfer through a heterogeneous, multiphase barrier has been developed where the dispersed phase is capable of uptake of the diffusant according to a linear relationship. The model was used to describe the penetration of drugs through dispersions of permeable globules in media of known diffusional properties. Water-in-oil-in-water (W/O/W) multiple emulsions have been studied by this method. When used to analyze data obtained with a simple diffusion cell, the model allows the calculation of the mass transfer coefficient which characterizes the diffusional mass transfer across oil-water interfaces within the emulsions. The mass transfer coefficient is directly related to the drug release rate from the internal phases of multiple emulsions. Those cases where instantaneous equilibria are established or where impermeable globules are present can be treated as special limiting cases. Differential equations which express diffusant concentrations as functions of time, space, and dispersion system parameters have been solved by Laplace transformation without recourse to numerical methods. The values of the mass transfer coefficient are shown to reflect the physical characteristics of multiple emulsion systems.

Thermodynamic analysis of energy dissipation by pharmaceutical tablets during stress unloading.

A thermodynamic analysis of the energy transformations occurring within pharmaceutical tablets during the unloading phase of compaction was performed on Avicel, calcium phosphate, acetaminophen, and calcium oxalate. This analysis was based on viscoelastic stress data collected using an instrumented rotary press and was conducted for the purpose of determining the extent and nature of energy release, beyond that of force displacement, during this phase of compaction. The four materials investigated were selected to reflect a range of compaction properties, and the viscous vs force-displacement energy distributions were seen to be consistent with their brittle vs plastic character. Magnesium stearate, added in various concentrations up to 4% w/w, was found to act both as an internal lubricant for particle-particle slipping and as a moderator of interparticulate bonding.

Structure evolution of tablets during compression unloading.

The evolution of internal structure within compacts composed of selected drugs and direct compression excipients, occurring during the unloading phase of compaction, was studied in an instrumented rotary tablet press. Utilizing three-dimensional viscoelastic analysis applied to successive, sequential segments of the unloading phase, elastic and viscous parameters were obtained that provide quantitative, incremental measures of the changing behavior of the compact during this period. It is apparent from these studies that the principal feature of this phase of compaction is the generation and propagation of internal fractures as a result of the release of internal stresses through expansion. The progression of elastic parameters from positive initial values to negative terminal values during unloading, coupled with the strong relationships they display to corresponding viscous parameters, supports this conclusion. These results follow well-established Dugdale fracture dynamics in which rate-dependent flow, occurring in the immediate surroundings of crack tips, accompanies crack formation and propagation. The extent of viscous flow depends both on the brittle versus plastic nature of the substance and on the extent of crack growth.

Timing relationships among maxima of punch and die-wall stress and punch displacement during compaction of viscoelastic solids.

The times of occurrence of maxima in punch stress, die-wall stress, and punch displacement in instrumented rotary tablet machines are shown to be noncoincidental for compacts exhibiting viscoelastic behavior. Equations are presented which characterize materials behaving as Kelvin solids in either or both distortion and dilation. These equations explicitly relate the timing of stress maxima to punch strain and strain rate. Typical effects are illustrated by data obtained for Avicel PH 101, Klucel, and mannitol. Punch stress maxima are shown to significantly precede the time of maximum punch insertion into the die for viscoelastic materials compacted at rates typical of production. Die-wall stress maxima occur after punch stress maxima due to internal rate-limited processes.

Unloading and postcompression viscoelastic stress versus strain behavior of pharmaceutical solids.

The viscoelastic properties of several compacts composed of drugs and direct compression excipients have been measured during the stress unloading and postcompression phases of the tablet compression process. Measurements of applied strains and the resultant stresses, generated in the tablet structure under compaction, were made using a rotary press. The press was instrumented to measure punch and die wall stresses at normal operating speeds. The three-dimensional viscoelastic theory, used in data analysis, provides for the separate characterization of tablet behavior into its dilation and distortion components. The tablets investigated were found to behave elastically in dilation, but to have both viscous and elastic contributions to their stress/strain relaxation in distortion. This latter behavior could be modeled well as a Kelvin solid. Data derived from an elastic-in-dilation, Kelvin-in-distortion analysis of tablets, compressed at similar machine speeds but at various peak pressures, were found to vary widely depending on tablet composition. Dependence of the viscous and elastic parameters on compression conditions was found to be predictive of conditions under which capping or lamination of the compact would occur.

Viscoelastic stress/strain behavior of pharmaceutical tablets: analysis during unloading and postcompression periods.

The processes of nonequilibrium generation and decay of axial and radial stresses within tablet compacts were analyzed in terms of three-dimensional linear viscoelastic theory. A rotary tablet press was instrumented to measure punch and die wall stresses during the compression and postcompression periods. Following compression, tablets were permitted to remain at the compression site within the die, and the die wall stress was followed. Microcrystalline cellulose, spray-processed lactose, and sulfacetamide are known to have different compression characteristics and were found to differ significantly in their viscoelastic parameters. Compacts assumed their final viscoelastic state prior to the time of punch separation. Theory permits separation of material behavior into dilation and distortion components. Dilation, thought to be dependent on voids, was elastic in all cases. Distortion effects could be described well by a Kelvin solid model. Results indicate that viscoelastic properties are functions of compression conditions and may be useful in adjusting compression conditions to avoid problems such as capping.

Electronic monitoring of events within dynamic particulate beds: conductance and capacitance measurements.

Methods for monitoring mechanical events occurring within particulate solids systems in a dynamic state are described. The electrical conductance and capacitance characteristics of such systems, as they relate to the degree of bed dilation or expansion, extent of interparticulate contact, and intensity of particle motion, were studied and are discussed. To establish the potential of this approach, harmonically vibrated beds of monodispersed conducting spheres were used. A technique, based on the frequency modulation of standard FM broadcast frequency carrier signals, was developed to measure low and high frequency fluctuations in bed capacitance. The electrical conductance of these systems also was determined by both voltage drop and current flow methods. The experimental techniques developed are broadly applicable to various materials and modes of agitation or flow. They permit the evaluation of the time courses of both bed dilation and particle motion which, in turn, are known to determine of modify critically powder flow and mixing behavior.

Micellar distribution equilibria: ultracentrifugal study of apparent partition coefficients.

Ultracentrifugation was used for the partial isolation of polysorbate 80 micelles in aqueous media to determine the apparent partition coefficients of various drug species between water and the micellar pseudophase. The ratio of solute concentration in the micelles to that in water was measured for procaine, salicylic acid, sulfapyridine, sulfisoxazole, and sodium 2-naphthalensulfonate over ranges of pH, surfactant concentration, drug concentration, and micelle sedimentation. Apparent partition coefficients for the systems investigated were independent of both drug concentration and surfactant concentration, indicating that the mode(s) of surfactant-drug interaction are essentially invariant over the ranges of systematic variables studied. The method provides a relatively simple and rapid means of quantitatively evaluating drug-surfactant interactions above the CMC, when surfactant and solute can be assayed in mixtures without interference.

Polydisperse particulate solids mixing and segregation: nonstationary Markov chains.

The feasibility of analyzing interparticulate translocations within agitated beds of polydisperse particulate solids in terms of Markov chains was investigated. A binary mixture of spherical particles subjected to vertical sine wave vibration is shown to behave in accordance with a nonstationary. Markov chain having singly stochastic transition matrixes. The transition probability elements of such matrixes, calculated from a knowledge of the initial and final occupancy vectors, agree with those estimated using tracer particles. With appropriate restrictions, the former method, based on the solution of simultaneous equations, permits a quantitative evaluation of particle mobilities throughout the bed.

Microenvironmental kinetic effects within a lyotropic smectic biophase model: conformational restrictions in Fischer indole cyclization.

The microenvironmental orientation effects, arising from an orderer solvent structure, were studied in a model liquid crystalline biophase for the cyclization of a series of 2-substituted cyclohexanone phenylhydrazones. The magnitude of such solvent-induced intramolecular conformational constraints were determined from a comparison of the kinetics of the Fischer indole rearrangement in a lyotropic smectic liquid crystal versus those in an isotropic liquid of similar chemical composition but lacking the structured nature of the mesophase. Solutions consisting of 50% (w/w) polyoxyethylene 6 tridecyl ether or 44% (w/v) polyethylene glycol in aqueous buffers comprised the smectic or isotropic media, respectively. The apparent dissociation constants of the conjugate acids of the phenylhydrazones were determined kinetically, as were their partition coefficients between lipid and polar isotropic phases approximating the compositions of the smectic lamellae. Intrinsic first-order rate constants, corrected for partitioning within the lamellar mesophase, were used to compute the enthalpies and entropies of activation. The somewhat slower intrinsic rates of cyclization and the accompanying less negative entropies of activation generally observed in the liquid crystalline medium, as opposed to the isotropic system, are attributed to the orienting effects of the lamellar lyotropic mesophase.