M. Donbrow

Zero order drug delivery from double-layered porous films: release rate profiles from ethyl cellulose, hydroxypropyl cellulose and polyethylene glycol mixtures

Laminated double‐layered films comprising a drug‐containing and drug‐free layer were prepared using tripelennamine, barbitone, salicylic acid and caffeine dispersed in hydroxypropylcellulose (HPC) attached to ethyl cellulose (EC) films containing various proportions of polyethylene glycol (PEG) or HPC to enhance permeability. Drug release in vitro followed zero‐order kinetics, rate constants being dependent on the thickness of the drug‐free membrane, which was rate‐controlling. Thickness‐corrected zero order constants were independent of drug‐loading, which did, however, control the duration of release. Permeability coefficient measurements on the same rate‐controlling films used as single barrier membranes enabled the effective drug concentration (Co) at the interface between the laminated membranes to be estimated; Co was independent of drug loading and was of the order expected from the aqueous solubilities of the drugs. Release rates were enhanced by addition of hydrophilic polymer to the rate‐controlling membranes, either linearly with fraction of additive for PEG to 0·6 or HPC to 0·4, or logarithmically for HPC from 0·4 to 0·8. Enhancement coefficients, which were different for each system, reflected the different mechanisms of hydrophilic polymer action. PEG was leached out rapidly, pores being formed in the matrix. In contrast, HPC was largely retained, so that the enhancement was less. The logarithmic enhancement stemmed from formation of swollen hydrated channels, which, unlike the low HPC fractions or the PEG systems, allowed entry of buffer ions, so that only in these channel systems were the release rates altered by change of the external pH.

Enhancement of permeability of ethyl cellulose films for drug penetration.

Permeability constants of salicylic acid, caffeine and benzoic acid have been measured at 37° for heterogeneous films of ethyl cellulose containing up to 50% PEG 4000, the latter component undergoing leaching out. For the first two compounds, steady state constants were independent of film thickness and solute concentration but increased linearly and sharply with PEG content and were reproducible. The films were impermeable to NaOH and permeation rates were independent of receiver compartment pH. Solubility coefficients and diffusion coefficients of the substances in the films were measured using sorption and/or time lag methods and were low as compared with polyethylene films. High solubility seemed to be associated with the presence of a free activated hydrogen, shown by sorption studies on other substances. From the evidence, it appeared that mass transfer was controlled by the solubility diffusion process in the ethyl cellulose of the membranes with all three substances. Enhancement of permeability by PEG thus seemed due to increased porosity, equivalent to reduction in the effective thickness of the matrix, which nevertheless retained its barrier properties. Enhancement coefficients calculated from the slopes of PEG concentration plots may be useful for predicting the increased mass transfer of drugs through such membranes and could enable the porosity and thickness factors to be balanced against each other for formulation of coated products.

Release kinetics of sparingly soluble drugs from ethyl cellulose-walled microcapsules: theophylline microcapsules

Release rates of theophylline from ethyl cellulose‐coated microcapsules were measured as a function of wall thickness and core particle size. The kinetic data conformed with first order release and also the Higuchi matrix model. However, application of the differential rate treatment, hitherto applied only to drug matrix dispersions, showed that release from the microcapsules definitely followed the first order equation. For the purpose of confirming that the release process was membrane‐controlled, the experimental rate constants were transformed into effective permeability constants (P1) with the aid of the microcapsule dimensional parameters needed in the relevant equations and compared with the permeability constant (P) of theophylline measured experimentally using planar ethyl cellulose membranes. P1 values decreased linearly to a moderate extent with wall thickness, probably due to decrease in porosity during wall‐formation. P1 values of the thicker‐walled microcapsules were found to be of the same order as the membrane P value, supporting a release mechanism of membrane control under non‐steady state conditions.

Fundamentals of release mechanism interpretation in multiparticulate systems: determination of substrate release from single microcapsules and relation between individual and ensemble release kinetics

Abstract For assessing theories underlying release kinetics of contents from ensembles of microparticles in multiparticle dispersions, population release studies are incapable of revealing the operative physicochemical mechanism, in spite of attempts by many authors to interpret such cumulative data. The present study pioneers techniques for determining release kinetics from single microparticles, using microcapsules as model systems with microconductimetric or spectrophotometric measurement of contents released into the external medium. In four systems giving overall first-order release from populations, the individuals all released their contents at constant rates almost to total payload. A statistical model relating the sum of individual release to cumulative release was applied to the data. It was based on the distribution of two fundamental parameters of the individuals, m ∞ the payload and t ∞ the time to complete release. Statistical analysis of the experimental data validated the proposed relation in the four systems. The conditions required to obtain first-order cumulative kinetics from summated single constant rate data are either: (1) gamma-distribution with shape parameter = 2 of t ∞ and independence of m ∞ and t ∞ ; or (2) exponential distribution of t ∞ and correlation betw m ∞ and t ∞ . Cumulative kinetics and rate constants based on an approximation to a standard release equation are useful for characterization of batch release properties (e.g. in checking repeatability, effects of production variables, sustained release character under controlled conditions) but do not reveal the underlying release mechanism or the actual distribution of parameters, which require studies on individuals. Cumulative kinetics may in fact be altered if the distribution profile of the population undergoes accidental or pre-determined change.

Fundamentals of release mechanism interpretation in multiparticulate systems: the prediction of the commonly observed release equations from statistical population models for particle ensembles

Abstract The kinetics of release from a population of microparticles is determined by the distribution of a small number of parameters governing the release function in a heterogeneous population. A general model for treatment of the distribution is developed for any release pattern common to a whole population, which is shown to lead to a variety of different cumulative release equations, including those hitherto considered to govern the release mechanism from microcapsules. Thus, the main case, that of constant release rate from individuals differing in rate constant, is shown to yield, according to the statistical distribution of the parameters, ensemble kinetics following first-order, square-root of time (Higuchis equation), cube-root law (Hixson-Crowell) or a combination of initial zero-order followed by square-root of time relationships, all of which have been used to describe experimental systems studied. It is demonstrated that the cumulative release kinetics observed in a multiparticle system, being a function of the statistical distribution of parameters, does not characterize the basic release mechanism, which can only be determined directly from studies on individuals. The treatment also shows that in the case of first-order release by individuals, the ensembles cannot also observe first-order kinetics, except in the rare case of homogeneity of the determining parameters in the population.

Microencapsulation of paracetamol using polyacrylate resins (Eudragit Retard), kinetics of drug release and evaluation of kinetic model

Methacrylate copolymers were used for microencapsulation of paracetamol by phase separation from chloroform with polyisobutylene 6% in cyclohexane. With polyisobutylene as an anti‐aggregating agent, high quality microcapsules were obtained. Drug release appeared to fit both first order and Higuchi matrix model kinetics. However, on application of the differential rate treatment, the evidence supported the first order description, which was further supported by computed simulations of the models. Variation of production conditions showed that increasing the proportion of core material raised the microcapsule drug content and the release rate. Reduction of core particle size correlated with reduced coating thickness and faster release rate. The rate constants correlated with the estimated surface areas and wall thicknesses of the various batches. The data were used to estimate an apparent permeability constant for paracetamol in Eudragit RS microcapsules, which was constant and comparable with values found single core, non‐aggregated microcapsules containing other similar drugs and different wall materials.

Dissolution rate control of the release kinetics of water-soluble compounds from ethyl cellulose film-type microcapsules

Abstract Microcapsules of sodium salicylate and potassium dichromate were prepared by the temperature reduction ethyl cellulose coacervation method using polyisobutylene as a protective colloid. Film-coated microcapsules were obtained. Minute empty wall polymer spheres were also formed in amounts increasing with protective colloid concentration or core particle size and decreasing with ethylcellulose concentration, in conformity with the mechanism previously proposed. Neither matrix diffusion nor first-order kinetics was observed by sodium salicylate experimental release data. Since small pores not initially present were formed, a dissolution model was applied; release conformed with the Hixson-Crowell cube-root law and was influenced by agitation rate in the sink solution. The effective diffusion coefficients from dissolution rate constants were near to the theoretical water value but several orders higher than the measured permeability constant through ethylcellulose cast films. In support of a hypothesis that pore-formation was caused by the high “internal osmotic pressure developed by water-soluble core material”, the release rate fell on increasing external osmotic pressure, which ultimately prevented pore-formation at 7M LiCl. This is the first case in which a dissolution model has been shown applicable to film-coated core materials.

Drug release from non-disintegrating hydrophilic matrices: sodium salicylate as a model drug

Tablets containing different concentrations of sodium salicylate in a (hydroxyethyl)methylcellulose matrix swelled without disintegration or attrition. The release rate of the drug from the whole tablet was shown to conform with a model diffusional equation for two-sided release from a slab maintaining a constant surface-volume ratio on swelling, and the rate constant was linearly dependent on the drug dosage, as predicted by this equation, when the polymer concentration was kept constant. With varying polymer concentration, correction of the rate constants for their dependence on drug content of the matrix yielded constants dependent on the polymer concentration only. Such rate constants observed a semi-logarithmic relation to polymer content and extrapolated to give reasonable diffusion coefficient values for hypothetical low and high polymer content matrices. The temperature coefficient yielded a high value (9.15 kcal . mol−1) for the activation energy of the diffusion process, consistent with the energy barrie in a polymer matrix. Such treatment of rate constants and component concentration variables offers a valuable method of correlating formulation and release parameters in non-disintegrating hydrophilic matrices.

Solubilization of phenolic compounds in nonionic surface-active agents. II. Cloud point and phase changes in solubilization of phenol, cresols, xylenols, and benzoic acid

The cloud point of aqueous polyoxyethylene (24) hexadecanol (cetomacrogol) was depressed by benzoic acid to 44° and by phenol, o-, m-, and p-cresols, and the six xylenols to room temperature. The temperature-additive concentration relation was nonlinear and benzoic acid was exceptional in showing two branches. Salt enhanced the depression without changing the form. Concentrations reducing the cloud point to 25° are inversely related to hydrophobicity of the phenols. Free and micelle-bound concentrations of the cloud points have been measured in the phenol series and utilized to throw light on the mechanism of clouding.

Surface tension and cloud point changes of polyoxyethylenic non-ionic surfactants during autoxidation.

Changes in the surface tension‐concentration curves of the non‐ionic surfactant cetomacrogol, a polyoxyethylenic (POE) hexadecyl ether containing about 24 ethylene oxide (EO) groups, have been examined during autoxidation of aqueous solutions. The curves exhibit decreases in cmc values and changes in the slopes below and above the cmc which lead to the loss of the sharp break characteristic of micelle‐formation. There is also a progressive decrease in the cloud point during autoxidation. Surface tensions and cloud points of a series of known POE hexadecyl ethers containing from 10 to 60 EO units have been measured and related to the number of EO units present. From these data, it is apparent that autoxidation of cetomacrogol is accompanied by degradation of the POE chain rather than the hydrocarbon chain, the number of EO units lost up to the time at which the solution becomes turbid being about 14. The significance of such measurements is discussed in relation to the detection of decomposition and pending rapid decomposition in synthesized and commercial surfactants.