Isidoro Caraballo

Percolation theory: application to the study of the release behaviour from inert matrix systems

Abstract In the present paper, release profiles obtained from matrix tablets prepared with Eudragit ® RS-KC1 and a usual eccentric machine were studied. The results were in agreement with previously reported release studies for compacts prepared using a hydraulic press. The most outstanding aspect is the study of the influence of the particle size of drug and excipient on the release behaviour of the matrices, and its evaluation on the basis of percolation theory. The influence of soluble drug loading has also been studied. This new theory has been shown to be a useful tool to explain the release profiles from inert matrix compressed tablets.

Factors affecting drug release from hydroxypropyl methylcellulose matrix systems in the light of classical and percolation theories.

Importance of the field: Hydroxypropyl methylcellulose (HPMC) is a versatile polymer widely used in the preparation of pharmaceutical dosage forms. The behavior of this polymer is a key factor in designing a variety of controlled release systems, especially hydrophilic matrices in which HPMC can be the only substance responsible for controlling the release rate of the drug. Areas covered in this review: A new approach, proposed in 2004, based on percolation theory to explain the influence of the main formulation factors on drug release from HPMC matrices has been analyzed, paying attention to the advantages with respect to previous theories. What the reader will gain: The influence of especially important factors such as polymer concentration and particle size is now much better known thanks to these new theories. Take home message: To formulate a HPMC matrix, the system must be above the polymers critical point, that is, allowing HPMC to act as outer phase. In this way, a coherent gel layer will be obtained because the first moment and the drug release will be controlled by this layer. Furthermore, knowing the critical points allows the vicinity of these points to be avoided, which are regions of high variability. In this way, robust dosage forms can be obtained.

Application of percolation theory in the study of an extended release Verapamil hydrochloride formulation

The percolation theory studies the critical points or percolation thresholds of the system, where one component of the system undergoes a geometrical phase transition, starting to connect the whole system. The objective of the present paper was to study the existence of critical points governing the water and drug transport inside hydroxypropylmethylcellulose (HPMC) hydrophilic matrix systems obtained with different polymer viscosity grades. For this purpose, extended release formulations of Verapamil HCl, have been prepared and studied. The percolation theory has been applied for the first time to multi-component hydrophilic matrices. The materials used to prepare the tablets were Verapamil HCl, four different viscosity grades of HPMC, microcrystalline cellulose, lactose, magnesium stearate and colloidal silicon dioxide NF. 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. From the point of view of the percolation theory, the optimum concentration for all the studied polymers, to obtain a hydrophilic matrix system for the controlled release of Verapamil HCl is higher than 20% (v/v) HPMC. Above 20% (v/v) HPMC, an infinite cluster of excipient would be formed, ensuring uniform hydration, maintaining integrity of the system and controlling the drug release.

Statistical optimization of a sustained-release matrix tablet of lobenzarit disodium.

The statistical optimization of sustained-release matrix tablets of lobenzarit disodium salt (LDS) was performed using the central composite experiment design 23 for three independent variables: the amount of polymer (Eudragit® RS-PO) AP, the total volume of granulation solvent VS, and the amount of filler (microcrystalline cellulose) CE. The t90% was selected as the response variable. The response surfaces were performed from a statistical mathematical model. The optimal formulation was obtained for the variables (AP = 15 mg, VS = 60 μl, and CE = 0).

Synthesis and characterization of some new homo- and co-poly(vinylsaccharides). Some preliminary studies as drug delivery

Abstract Homopolymers P1 and P3 were prepared by free radical polymerization reactions of 1,3,4,6-tetra- O -acetyl-2-acrylamido-2-deoxy-α- d -glucopyranose monomer ( M1 ) and 1,2:3,4-di- O -isopropylidene-6- O -acryloyl-α- d -galactopyranose monomer ( M2 ), respectively. Both monomers were also copolymerized at two different ( M1 / M2 ) feed ratios (1:1, and 3:1) to yield P4 and P5 , respectively. The free radical polymerization reactions were carried out in a mixed solvent system under either nitrogen atmosphere or vacuum at 60°C using AIBN as free radical initiator. P1 was deacetylated to P2 , while P4 was first deacetylated to P6 and then deacetonated to hydrophilic P7 . The new poly(vinylsaccharides) were characterized by elemental analysis, DSC, GPC, and FT IR, 1 H- and 13 C-NMR spectroscopies. Inherent viscosities and specific optical rotations were also recorded. Some preliminary rheological studies have demonstrated that the hydrophobic, non-swelling acrylic polymer P4 seems to be a good substrate for employment as matrix-forming material for controlled release tablets as drug delivery systems.

Design of controlled release inert matrices of naltrexone hydrochloride based on percolation concepts.

The percolation theory is a statistical theory able to study chaotic or disordered systems that has been applied in the pharmaceutical field since 1987. Through the application of this theory, the design of controlled release inert matrices has been improved. The aim of the present paper is to estimate the percolation thresholds, the most important concept of the percolation theory, which characterise the release behaviour of controlled release inert matrices of naltrexone hydrochloride. Matrix tablets were prepared using naltrexone hydrochloride as a potent narcotic antagonist and Eudragit(R) RS-PM as matrix forming material in different ratios, keeping constant the drug and excipient particle sizes. In vitro release assays were carried out exposing only one side of the tablets to the dissolution medium. The drug percolation threshold was estimated using different methods. The method of Leuenberger and Bonny gives 31.11+/-7.95% v/v as the critical porosity, which corresponds to a percolation range from 12 to 20% (w/w) of drug content. The release profiles and the release kinetics are in agreement with this result. A change in the exponent k (from 0.29 to 0.57) has been found in this region. Using scanning electron microscopy, the percolation threshold has been observed in a higher concentration range (20-35% w/w). This fact can be attributed to the low accuracy of the visual methods, mainly due to the extrapolation from 2D to 3D systems. If a percolating cluster is observed in two dimensions, the percolation threshold of the 3D system will be already clearly exceeded. The excipient percolation threshold is estimated between 25.4 and 31.1% (v/v) based on the release profiles and the analysis of the release kinetics.

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.

Estimation of the percolation thresholds in dextromethorphan hydrobromide matrices.

Percolation theory is a multidisciplinary theory that studies chaotic systems. It has been applied in the pharmaceutical field since 1987. Knowledge of the percolation threshold -- one of the most important concepts in percolation theory -- results in a clear improvement of the solid dosage form design. The percolation threshold is the concentration showing the maximum probability to obtain, for the first time, a percolating cluster of a substance. In this work, the percolation thresholds of dextromethorphan.HBr/Eudragit RS-PM inert matrices were estimated. The drug percolation threshold was estimated as 0.3691+/-0.0541 (P=0.05) of the total porosity (ranging between 23 and 36% w/w of drug). The SEM micrographs of the matrices are consistent with the estimated percolation range. In agreement with previous reports, different percolation thresholds were found for the matrix forming excipient Eudragit RS-PM. The site percolation threshold (based on the release properties) ranged between 10 and 20% v/v of the excipient, the site-bond percolation threshold (estimated from the mechanical properties) between 29.5 and 34% v/v of the excipient and the swelling percolation threshold between 34.3 and 46.9% v/v of the excipient. These percolation ranges are in agreement with those found previously for Eudragit RS-PM matrices containing naltrexone.HCl and morphine.HCl.

Physical characterization of carteolol: Eudragit® L binding interaction

Eudragit® L 30D was used as a carrier to prepare carteolol polymeric complexes in order to obtain controlled release dosage forms. The polyanionic form of the polymer, neutralized at different degrees, reacts readily with carteolol hydrochloride to give water-insoluble complexes. Carteolol complexes were characterized by differential scanning calorimetry, IR, 1H- and 13C-NMR spectroscopy. In fact, results indicated that there were intermolecular associations between the polymer and the drug consisting in ammonium salt interactions. Maximum carteolol content was found to be 22% in the complexes.

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.