Mónica Millán

Relationship Between Drug Percolation Threshold and Particle Size in Matrix Tablets

AbstractPurpose. Since a previous qualitative study carried out by us showed the existence of an important influence of the particle size on the percolation thresholds and taking into account that the existing theoretical models can only provide qualitative explanation to this influence, the purpose of this work is to carry out the first quantitative study of the influence of the particle size over the drug percolation thresholds. Methods. Matrix tablets have been elaborated using potassium chloride as drug model and Eudragit RS-PM as matrix forming material. Five different KC1 particle size fractions have been employed whereas the Eudragit® RS-PM particle size was kept constant. In-vitro release assays were carried out for all the elaborated lots. The drug percolation thresholds were estimated following the method proposed by Bonny and Leuenberger. Results. A linear relationship has been found between the drug particle size and the corresponding drug percolation threshold. Conclusions. This finding confirms the results previously obtained in our qualitative study and has important repercussions in the design of pharmaceutical solid dosage forms. If this linear behaviour is general, the percolation threshold can soon become a useful preformulation parameter.

The role of the drug/excipient particle size ratio in the percolation model for tablets.

AbstractPurpose. In previous papers, a linear relationship between drug particle size and drug percolation threshold was found in inert matrix tablets. The main objectives of the present work are: to study the influence of the excipient particle size on the drug percolation threshold and to investigate if the change in the drug percolation threshold is due either to the absolute or to the relative drug particle size. Methods. Matrix tablets have been prepared using KC1 (7 different particle size fractions) as a drug model and Eudragit® RS-PM (4 granulommetric fractions) as matrix forming material. In vitro release assays were carried out on the 66 lots of tablets. The drug percolation thresholds were estimated following the method of Bonny and Leuenberger. Results. The particle size of the excipient has shown an opposite effect to the drug size on the drug percolation threshold. Nevertheless, the influence of drug and excipient sizes on the drug percolation threshold are of the same magnitude. Conclusions. The drug percolation threshold depends linearly on the relative drug particle size. This finding is in agreement with percolation theory and can facilitate the use of the percolation threshold as a preformulation parameter to improve the pharmaceutical dosage forms design.

Percolation thresholds in ultrasound compacted tablets

Twenty matrix systems with different KCl content (as drug model, from 10 to 90% w/w) and Eudragit RS-PM (as inert excipient) were prepared using an ultrasound-assisted press and a traditional eccentric machine. The release behavior from both types of matrices was examined; the kinetic parameters for the release (intrinsic dissolution) and the technological properties of the final tablets (total porosity) were used to estimate the percolation threshold for the drug model and the excipient in both systems. For the systems compacted by ultrasound (US) the estimated value for the excipient percolation threshold ranges from 13.4 to 20.2% v/v (lower than that found for traditional tablets), that agrees with a continuum percolation model suggesting the presence of a continuum phase inside the tablet. This depends on a thermoplastic deformation of Eudragit RS-PM under ultrasound, that destroyed the particulate system of the excipient and transform it into a continuum medium. The percolation threshold for KCl ranged from 58.6 to 61.0% v/v for US and from 26.7 to 42.2% v/v for the traditional tablets. The higher value for ultrasound compacted tablets can be explained by the difficulty of KCl to outcome from a matrix containing insoluble phase that surrounds KCl crystals.

Study of critical points of drugs with different solubilities in hydrophilic matrices

Hydrophilic matrices are one of the most popular controlled release systems in the world. It is well known that drug solubility increases the osmotic stress in hydrophilic matrices, resulting in higher swelling through the creation of microcavities and influencing the release rate. Drug solubility also affects the drug release mechanism, favouring the diffusion against the erosion mechanism. Nevertheless it has not been studied whether this can modify the critical points of the hydrophilic matrices. The objective of the present work is to estimate the excipient percolation threshold in HPMC K4M hydrophilic matrices containing acetaminophen, theophiline and ranitidine.HCl, and to study the influence of the drug solubility on the excipient percolation threshold. Dissolution assays were performed using the paddle method. Water uptake was examined using the modified Enslin apparatus. In order to estimate the excipient percolation threshold, the behaviour of the kinetic parameters versus the excipient volume fraction plus initial porosity, was studied. The excipient percolation thresholds were situated between 24.8-25.8, 14.7-18.4 and around 31.2% (v/v) HPMC in theophiline, ranitidine.HCl and acetaminophen matrices, respectively. On the other hand, using these and some previously reported values no relation has been found between drug solubility and excipient percolation threshold in hydrophilic matrices.

Study of the critical points in lobenzarit disodium hydrophilic matrices for controlled drug delivery.

Percolation theory is a multidisciplinary theory that studies chaotic systems. It has been applied in the pharmaceutical field since 1987. The application of this theory to study the release and hydration rate of hydrophilic matrices allowed for first time to explain the changes in release and hydration kinetic of swellable matrices type controlled delivery systems. The objective of the present paper is to estimate the percolation threshold of HPMC K4M in matrices of lobenzarit disodium and to apply the obtained result to the design of hydrophilic matrices for the controlled delivery of this drug. The materials used to prepare the tablets were Lobenzarit disodium (LBD) and HPMC of viscosity grade K4M. The drug mean particle size was 42+/-0.61 mum and the polymer was sieved and 150-200 microm granulometric fraction was selected. The formulations studied were prepared with different excipient contents in the range of 10-80% w/w. Dissolution studies were carried out using the paddle method and the water uptake measurements were performed using a modified Enslin apparatus. In order to estimate the percolation threshold, the behaviour of the kinetic parameters with respect to the volumetric fraction of each component at time zero, was studied. According to percolation theory, the critical points observed in dissolution and water uptake studies are attributed to the existence of an excipient percolation threshold. This threshold was situated between (18.58 to 24.33% v/v of HPMC). Therefore, the LBD-HPMC K4M matrices with a relative HPMC particle size of should be formulated with an excipient content above 24.33% v/v of HPMC, to obtain a control of the drug release from these systems.

Study of morphine hydrochloride percolation threshold in Eudragit® RS-PM matrices

Abstract Percolation theory has been applied in the pharmaceutical field since 1987. The knowledge of the percolation thresholds of a system results in a clear improvement of the design of controlled release dosage forms such as inert matrices. In the present paper, the percolation thresholds of morphine hydrochloride inert matrices have been estimated and the obtained results have been applied to the design of controlled release inert matrices of this drug. The tablets were prepared by compression of binary mixtures of morphine hydrochloride, as a drug of clinical interest to cancer patients, and Eudragit® RS–PM, a hydrophobic acrylic polymer as matrix forming material. Drug loadings between 10% and 90% (w/w) were prepared, keeping constant the drug and excipient particle sizes. The dissolution assay was carried out exposing only one side of the tablets to the dissolution medium. The drug percolation threshold was estimated following the method of Leuenberger and Bonny as 0.506±0.014 of total porosity, corresponding to ca. 40% (w/w) drug content. The scanning electron microscopy (SEM) micrographs corresponding to the tablet side facing the lower punch and to the cross-section of these matrices are in agreement with the estimated percolation range.On the other hand, according to the SEM study and to the tablet integrity after the release assays, the excipient percolation threshold is expected to range from 65 to 80% (w/w) of drug, i.e. from 29.5 to 17% (v/v) of excipient. The release profiles of the matrices situated above the percolation threshold of the swelling substances (more than 41% v/v of excipient) have shown practically linear release profiles, which appear to not be sensitive to the drug load.

Study of percolation thresholds in ternary tablets

Abstract One of the handicaps for the application of the principles of percolation theory in pharmaceutical systems is the fact that this theory has been developed for binary systems. The aim of this work is to study for the first time the existence and behaviour of the percolation thresholds in ternary pharmaceutical tablets. For this purpose, mixtures containing three substances with very different hydrophilicity and water-solubility—KCl, polyvinylpyrrolidone cross-linked (PVP-CL) and Eudragit® RS-PM—were prepared and compressed. The bulk and tapped densities of the mixtures as well as the hardness and in-vitro release behaviour of the tablets have been studied. The KCl percolation threshold has been estimated in the range 0.26–0.31 of total porosity. A range where PVP-CL percolates can be defined between 10 and 30% v/v. This influences the hardness of the tablet. On the other hand, the existence of a ‘combined percolation threshold’ of the sum of all the hydrophilic substances, i.e. KCl and PVP-CL, has been found at 35% v/v approximately. This fact is in agreement with previous results.

Zero-order release periods in inert matrices. Influence of the distance to the percolation threshold

Abstract The zero-order release periods obtained from KCl/Eudragit ® RS-PM matrices have been investigated in this paper. Three drug loadings and five different drug particle sizes were employed. The influence of the particle size and drug loading governing the time-period for a constant release has been investigated. Furthermore, the relationship between this time and the distance to the percolation threshold has been studied for the first time. The time of onset of the zero-order periods increased as the distance to the respective percolation threshold decreased. This result is in agreement with the concepts of percolation theory. As a rough model the studied time of onset of the constant release periods was considered as a lag time due to the existence of a region of higher density close to the tablet surface. An acceptable agreement with the proposed equations has been found.

Influence of two different types of excipient on drug percolation threshold

Abstract The application of the principles of percolation theory is providing a more rational pharmaceutical dosage form design. The drug percolation threshold is the parameter that provides a better description of the system according to this theory. In order to check the possibility of use the drug percolation threshold as a preformulation parameter, the influence of the main formulation factors is being studied. The aim of this work is to study the influence of the type of excipient on the drug percolation threshold. For this purpose, two excipients exhibiting very different mechanical behaviour have been selected. Inert matrices were prepared using Ethocel® 100 and Eudragit® RS-PM as excipients and KCl as a model drug. Release assays were performed using the rotating disk method. The drug percolation threshold was estimated employing the method of Leuenberger and Bonny. The following confidence intervals (95%) were obtained: ϵ c =0.3644±0.0641 and ϵ c =0.3407±0.0345 of total porosity for matrices containing Eudragit® RS-PM and Ethocel® 100, respectively. On the light of the obtained results, no significant differences were found on the drug percolation thresholds for two excipients having very different mechanical behaviour.

Stability Study of Flutamide in Solid State and in Aqueous Solution

ABSTRACT A high-performance liquid chromatography (HPLC) assay has been developed for the determination of flutamide and its degradation products. Using this method, the influence of important formulation factors on the stability of flutamide has been estimated. The stability studies have been carried out in solid state as well as in aqueous solution. The results obtained have shown a good stability for flutamide in solid state. This drug remained practically unchanged after a four-month assay in adverse temperature and humidity conditions. On the other hand, the results obtained from the stability study in solution during 12 days have shown that flutamide in aqueous solution underwent a clear degradation at mean or high temperature (22°C, 37°C) and acidic pH conditions (1.1). With respect to the influence of ionic strength, it has been found that the presence of sodium chloride prevents the degradation of flutamide in aqueous solution. The second-order kinetics model provides the best fit for highly degraded solutions.