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The aim of this work is to estimate the excipient percolation threshold for a new combined matrix native dextran (DT), series B110-1-2 (Mw 2 x 10(6)): HPMC K4M CR: lobenzarit disodium (LBD) system and demonstrate the advantages of this... more
The aim of this work is to estimate the excipient percolation threshold for a new combined matrix native dextran (DT), series B110-1-2 (Mw 2 x 10(6)): HPMC K4M CR: lobenzarit disodium (LBD) system and demonstrate the advantages of this ternary system with respect to previously reported binary dextran:LBD and HPMC:LBD tablets. The formulations studied were prepared with different amounts of excipient (DT:HPMC, 4:1 (wt/wt) for all tablets and relative polymer/drug particle size of 4.17) in the range of 10-70% (wt/wt). Dissolution studies were carried out using the paddle method (100 rpm) and one face water uptake measurements were performed using a modified Enslin apparatus. The Higuchi's models as well as the non-linear regression were employed as empiric methods to study the released data. Values of diffusion exponent 0.588<n<0.784 (Korsmeyer equation) for dissolution profile and water uptake mechanism 0.715<n<0.960 (Davidson and Peppas equation) suggests anomalous or complex mechanisms in all cases. The critical points in ternary tablets were reduced from 44.75% (v/v) of excipient (correspond to purely native dextran) to 22.34% (v/v) (corresponding to mixture native dextran:HPMC, 4:1, wt/wt). The initial porosity (IP) of hydrophilic matrices above the values of 20% has an important influence on the percolation threshold as well as on establishment of the gel barrier responsible for the controlled release from the DT:HPMC:LBD tablets.
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There are many factors influencing the drug release behaviour from a pharmaceutical formulation as the particle size of the drug and excipient, porosity of the system or geometrical phase transitions of the components. Therefore, the... more
There are many factors influencing the drug release behaviour from a pharmaceutical formulation as the particle size of the drug and excipient, porosity of the system or geometrical phase transitions of the components. Therefore, the choice of the adequate excipient to achieve a specific drug release profile is mainly based on the experience and the trial and error method. Taking into account the directives towards the application of the "Quality by Design" approach, in this study the Excipient Efficiency (EE), a parameter able to quantify the capability of an excipient to control the drug release, has been developed. EE was initially calculated dividing the total porosity of the system by its diffusional release rate constant. The influence of several factors on this parameter has been evaluated. As a result, the final parameter has been corrected based on the drug solubility and the excipient particle size. EE provides a rational basis for identifying the most adequate excipients for a concrete formulation.
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ABSTRACT A specific HPLC method was applied to study the evolution of the concentrations of thimerosal (thiomersal), thiosalicylic acid and 2,2'-di(thiosalicylic) acid over a period of 3 months. The mechanism of degradation of... more
ABSTRACT A specific HPLC method was applied to study the evolution of the concentrations of thimerosal (thiomersal), thiosalicylic acid and 2,2'-di(thiosalicylic) acid over a period of 3 months. The mechanism of degradation of thimerosal in pharmaceutical formulations has been proposed. The protective effect of tromethamine has been also evaluated. It has been found that tromethamine does not exert its effect on the initial reaction of thimerosal decomposition but on the degradation of its initial decomposition products.
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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... more
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.
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ABSTRACT In the present paper, percolation theory has been applied to the study of the release mechanism obtained from controlled release tablets of carteolol hydrochloride. These dosage systems had already been studied on the basis of... more
ABSTRACT In the present paper, percolation theory has been applied to the study of the release mechanism obtained from controlled release tablets of carteolol hydrochloride. These dosage systems had already been studied on the basis of ‘classical’ theories. The new approach to this study has allowed us to obtain more complete information about the release behaviour of these inert matrix systems. The results obtained in this study demonstrate that percolation theory can provide useful parameters that can be considered as important tools for the proper design of these controlled release dosage forms.
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ABSTRACT
... A linear relationship between the relative drug/excipient particle size ratio and the drug percolation threshold has ... The drug percolation threshold (p c1 ) was calculated for the matrices containing either ... Potassium chloride... more
... A linear relationship between the relative drug/excipient particle size ratio and the drug percolation threshold has ... The drug percolation threshold (p c1 ) was calculated for the matrices containing either ... Potassium chloride (Acofarma) was used as a model water-soluble drug. ...
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... 118 (1995) 151-160 intemational journal of pharmaceutics Research Papers Influence of diluents and manufacturing method on the in vitro dissolution of carteolol hydrochloride matrix tablets MA Holgado *, I. Caraballo, J.... more
... 118 (1995) 151-160 intemational journal of pharmaceutics Research Papers Influence of diluents and manufacturing method on the in vitro dissolution of carteolol hydrochloride matrix tablets MA Holgado *, I. Caraballo, J. Alvarez-Fuentes, MJ Fernfindez ... Muhammad et al. ...
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ABSTRACT The efficiency of a new controlled release oral system containing morphine hydrochloride elaborated by introducing the drug into the polymeric structure of Eudragit® L30D is evaluated. Its in vitro dissolution behaviour and its... more
ABSTRACT The efficiency of a new controlled release oral system containing morphine hydrochloride elaborated by introducing the drug into the polymeric structure of Eudragit® L30D is evaluated. Its in vitro dissolution behaviour and its effectiveness using the tail flick test model of pain in rats are investigated. A significant reduction in the drug release rate from the morphine-Eudragit® L30D complex as well as a very high efficiency in the dissolution process have been found. The tested morphine complex has an analgesic effect in rats. This effect is very clear from 30 min to 8 h. At 12 h the effect remains clear but with a lower level of statistical significance. Furthermore, there are no significative differences between the different doses tested.
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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... more
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.
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ELSEVIER International Journal of Pharmaceutics 114 (1995) 1321 intemational journal of pharmaceutics Physical characterization of carteolol: Eudragit L binding interaction Maria Angeles Holgado a,,, Mercedes FernandezArevalo a, Josefa... more
ELSEVIER International Journal of Pharmaceutics 114 (1995) 1321 intemational journal of pharmaceutics Physical characterization of carteolol: Eudragit L binding interaction Maria Angeles Holgado a,,, Mercedes FernandezArevalo a, Josefa AlvarezFuentes a, Isidoro Caraballo a, Jose ...
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The main aim of this paper is the synthesis and characterization of a new linear functional biodegradable polythiourethane-d,l-1,4-dithiothreitol-hexamethylene diisocyanate [PTU(DTT-HMDI)]. The SeDeM diagram has been obtained to... more
The main aim of this paper is the synthesis and characterization of a new linear functional biodegradable polythiourethane-d,l-1,4-dithiothreitol-hexamethylene diisocyanate [PTU(DTT-HMDI)]. The SeDeM diagram has been obtained to investigate its suitability to be processed through a direct compression process. Furthermore, the ability of this polymer to act as controlled release matrix forming excipient has been studied. Four batches of matrices containing 10-40% of polymer and theophylline anhydrous as model drug have been manufactured. Release studies have been carried out using the paddle method and the polymer percolation threshold has been estimated. The principal parameters of the SeDeM Expert system, such as the parametric profile (mean radius) and the good compression index (IGC=4.59) for the polymer are very close to the values considered as adequate for direct compression even with no addition of flow agents. Furthermore, the results of the drug release studies show a high ability of the polymer to control the drug release. The excipient percolation threshold has been estimated between 20% and 30% w/w of polymer.
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The release behaviour of clozapine matrix pellets was studied in order to investigate if it is possible to explain it applying the concepts of percolation theory, previously used in the understanding of the release process of inert and... more
The release behaviour of clozapine matrix pellets was studied in order to investigate if it is possible to explain it applying the concepts of percolation theory, previously used in the understanding of the release process of inert and hydrophilic matrix tablets. Thirteen batches of pellets with different proportions of clozapine/microcrystalline cellulose (MCC)/hydroxypropylmethyl cellulose (HPMC) and different clozapine particle size fractions were prepared by extrusion-spheronisation and the release profiles were studied. It has been observed that the distance to the excipient (HPMC) percolation threshold is important to control the release rate. Furthermore, the drug percolation threshold has a big influence in these systems. Batches very close to the drug percolation threshold, show a clear effect of the drug particle size in the release rate. However, this effect is much less evident when there is a bigger distance to the drug percolation threshold, so the release behaviour of...
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... A binder is often added to the granulation liquid during wet granulation to improve ... commonly accepted that binders added in dissolved form, during a granulation process, are ... Manufacturing (Direct Compression) All components... more
... A binder is often added to the granulation liquid during wet granulation to improve ... commonly accepted that binders added in dissolved form, during a granulation process, are ... Manufacturing (Direct Compression) All components were mixed, passed through a 0.8-mm sieve, and ...
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ABSTRACT In the present paper we combine functionalization and biodegradation in the rational design of polymers that can be used as carrier systems for drug delivery in the colon. Functionalization of new polyurethanes (PUs) was achieved... more
ABSTRACT In the present paper we combine functionalization and biodegradation in the rational design of polymers that can be used as carrier systems for drug delivery in the colon. Functionalization of new polyurethanes (PUs) was achieved by thiol–ene coupling reactions, a simple and straightforward procedure included among the so-called click reactions, which are currently accepted as one of the most powerful tools in organic chemistry. Enhancement of the degradability of the new materials by the introduction of disulfide linkages into the polymer backbone has led to a new group of stimulus-responsive sugar-based polyurethanes able to be degraded by tripeptide glutathione under physiological conditions. Atomic Force Microscopy (AFM) on solid-supported multilayered dry polymer films—prepared by spin-coating from dimethylsulfoxide solutions—was used to study the morphology of the polymers and the degradation process in reductive environments. Matrix systems containing polymers selected according to their rheological properties were also investigated as modulated methotrexate-release systems.
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The main objectives of this work are to study the behavior of fluid imbibition into a consolidated matrix through a wet invasive conductivimetric technique, to investigate if the changes in the behavior observed can be related to the drug... more
The main objectives of this work are to study the behavior of fluid imbibition into a consolidated matrix through a wet invasive conductivimetric technique, to investigate if the changes in the behavior observed can be related to the drug percolation threshold, and to use this technique for its estimation. Matrix tablets were prepared using five sieving fractions of KCl and Eudragit RS-PM. In vitro release assays were carried out on 45 batches. The drug percolation thresholds were estimated following the method of Leuenberger and Bonny, and the results were compared to the obtained employing the conductivimetric technique described in this paper. The wet conductivimetric technique and the standard method provided similar results for the estimation of the percolation threshold. The presented technique also provides quantitative information about the consolidated matrix. A new apparatus has been developed for the study of the conductivimetric behavior of matrix tablets during water uptake. This technique provides measurable parameters of fluid penetration and can be used to estimate the drug percolation threshold, providing similar results to the Leuenberger and Bonny method and being clearly faster.
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This study implements the design of an innovative dosage form using ultrasound-assisted compression of thermoplastic polymers and the development of controlled release tablets for the oral administration of deferiprone in two doses per... more
This study implements the design of an innovative dosage form using ultrasound-assisted compression of thermoplastic polymers and the development of controlled release tablets for the oral administration of deferiprone in two doses per day. Binary matrix tablets containing deferiprone and thermoplastic polymers have been prepared using an ultrasound-assisted tableting machine. Scanning electron microscopy has been employed to determine a sintering phenomenon of the excipients. Water uptake and drug release studies have been carried out to evaluate the ability of the polymers to control the drug release. SEM micrographs showed that some polymers underwent the sintering process and the in vitro dissolution test showed good fit of the release data from these tablets to the zero-order kinetic model. Carbopol 974P and 971P have been selected as matrix forming polymers for the final formulation. The polymer percolation threshold has been exceeded with 15% w/w of polymer. Therefore, sustained release tablets have been developed with only 15% of excipient. This implies that matrix tablets containing 750 mg of API, intended for two administrations a day, can be obtained with a similar weight to those existing in the market containing 500 mg of API for three administrations a day.
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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... more
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...
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Research Interests: Kinetics, Pharmaceutical Technology, Pharmaceutical Chemistry, Linear models, Porosity, and 11 morePharmaceutical Sciences, Pharmaceutical, Solubility, Percolation threshold, Particle Size, Tablets, Reproducibility of Results, Excipients, Drug Compounding, Delayed-Action Preparations, and Potassium Chloride
A rapid, sensitive, and accurate reversed-phase HPLC method has been developed for the analysis and quantification of pharmaceutical formulations containing tyrothricin (1), an antibiotic used in antiseptic buccal compressed tablets for... more
A rapid, sensitive, and accurate reversed-phase HPLC method has been developed for the analysis and quantification of pharmaceutical formulations containing tyrothricin (1), an antibiotic used in antiseptic buccal compressed tablets for local application. The assay has been carried out under isocratic conditions, using a stationary phase of alumina particles coated with polybutadiene and an alkaline mobile phase (pH = 8.2). No HPLC method was reported for the analysis of 1. So, this new technique is an alternative to the slow and tedious microbiological methods. On the other hand, it allows the simultaneous quantification of 1, benzocaine (2), and menthol (3), an aromatic compound not currently analyzed by liquid chromatography.
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Research Interests: Water, Kinetics, Nonlinear dynamics, Pharmaceutical Chemistry, Controlled release, and 14 morePorosity, Chaotic System, Solubility, European, Percolation threshold, Delivery System, Tablets, Critical Point, Excipients, Delayed-Action Preparations, Kinetic Parameter, Percolation Theory, Antiviral Agents, and Acyclovir
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... more
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.
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The aim of this work is to estimate the excipient percolation threshold for a new combined matrix native dextran (DT), series B110-1-2 (Mw 2 x 10(6)): HPMC K4M CR: lobenzarit disodium (LBD) system and demonstrate the advantages of this... more
The aim of this work is to estimate the excipient percolation threshold for a new combined matrix native dextran (DT), series B110-1-2 (Mw 2 x 10(6)): HPMC K4M CR: lobenzarit disodium (LBD) system and demonstrate the advantages of this ternary system with respect to previously reported binary dextran:LBD and HPMC:LBD tablets. The formulations studied were prepared with different amounts of excipient (DT:HPMC, 4:1 (wt/wt) for all tablets and relative polymer/drug particle size of 4.17) in the range of 10-70% (wt/wt). Dissolution studies were carried out using the paddle method (100 rpm) and one face water uptake measurements were performed using a modified Enslin apparatus. The Higuchi's models as well as the non-linear regression were employed as empiric methods to study the released data. Values of diffusion exponent 0.588<n<0.784 (Korsmeyer equation) for dissolution profile and water uptake mechanism 0.715<n<0.960 (Davidson and Peppas equation) suggests anomalous or complex mechanisms in all cases. The critical points in ternary tablets were reduced from 44.75% (v/v) of excipient (correspond to purely native dextran) to 22.34% (v/v) (corresponding to mixture native dextran:HPMC, 4:1, wt/wt). The initial porosity (IP) of hydrophilic matrices above the values of 20% has an important influence on the percolation threshold as well as on establishment of the gel barrier responsible for the controlled release from the DT:HPMC:LBD tablets.
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ABSTRACT The paper reports a study of the capability of the percolation theory to explain the influence of several formulation factors over the release behavior of carteolot hydrochloride inert matrix systems. For this purpose, previously... more
ABSTRACT The paper reports a study of the capability of the percolation theory to explain the influence of several formulation factors over the release behavior of carteolot hydrochloride inert matrix systems. For this purpose, previously prepared matrix systems have been employed. The characterization of these matrices by means of “classical theories” has been reported in previous papers. Similar percolation thresholds have been found (52.7%, 56.2% v/v for the insoluble phase and 48.2% to 51.2% v/v for the soluble phase), even with changing formulation factors such as nature and percentage of polymer, type of wetting liquid and nature, and percentage of filler. This fact suggests an advantage for the application of percolation theory to the rationalization of pharmaceutical dosage form design. From the obtained results, the characterization of a multicomponent system on the basis of percolation theory seems to be rather general. On the other hand, the relatively high percolation thresholh obtained can be attributed to the different particle sizes of the components according to correlated percolation models
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ABSTRACT Abstract In the present paper, a simple, direct, accurate and sensitive HPLC method applied over combinations of dextromethorphan, diphenhydramine, phenylephrine, phenylpropanolamine and pseudoephedrine is presented. The use of... more
ABSTRACT Abstract In the present paper, a simple, direct, accurate and sensitive HPLC method applied over combinations of dextromethorphan, diphenhydramine, phenylephrine, phenylpropanolamine and pseudoephedrine is presented. The use of alumina particles bonded with polybutadiene as stationary phase allows the use of an alkaline mobile phase which provides an important improvement of the assay.
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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... more
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 degrees C, 37 degrees 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.
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ABSTRACT Abstract The release process from a controlled-release oral system of morphine, prepared using Eudragit® L30D as a carrier, is considered as the result of the combination of two different processes, the final release mechanism... more
ABSTRACT Abstract The release process from a controlled-release oral system of morphine, prepared using Eudragit® L30D as a carrier, is considered as the result of the combination of two different processes, the final release mechanism being a pH-dependent process. The release mechanism and the influence of the pH value on the dissolution behavior of this morphine complex were studied. An immediate morphine release, without any lag time, is produced in the three dissolution media employed. Considering an initial step of 120 min, the maximum release rate is reached in the assay carried out at pH = 1; above 120 min, the maximum amount of drug released was reached at pH = 7.02.
One of the practical handicaps for the application of the percolation theory to estimate the percolation threshold of drugs in controlled release systems is the fact that the dissolution studies must be carried out so that only one... more
One of the practical handicaps for the application of the percolation theory to estimate the percolation threshold of drugs in controlled release systems is the fact that the dissolution studies must be carried out so that only one surface of the tablet is exposed to the dissolution medium. The aim of this work is to estimate the percolation threshold of the antiarthritic drug lobenzarit dissodium (LBD) in inert matrices prepared with the excipients Ethocel((R)) 100 and Eudragit((R)) RS-PO (10-75% w/w). Release assays were performed using the paddle method. The whole surface of the tablets was exposed to the dissolution medium. For the first time, a new mathematical method is developed to transform the amount of drug released in amount released per surface area in order to calculate the percolation thershold of LBD. The mathematical method proposed allows to calculate, using a new equation, the evolution of the mean surface area (O((t))). The new method was validated and three novel results were achieved: A constant value of (O((t))) at critical time (theta) in the matrices (O((theta))=1.272 cm(2)); a linear relationship between initial surface area (O((0))) and critical time; and a linear relationship between O((t)) and time. Employing the values of O((t)), it was possible to calculate for the first time, the percolation threshold (p(c1)) for LBD in Ethocel((R)) 100 (p(c1)=0.280+/-0.102) and Eudragit((R)) RS-PO (p(c1)=0.344+/-0.07) matrices.
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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... more
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.
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The principles of the percolation theory were applied to further understand and design hydroxypropyl methylcellulose (HPMC) extended release matrix tablets containing carbamazepine and verapamil HCl. This statistical theory studies... more
The principles of the percolation theory were applied to further understand and design hydroxypropyl methylcellulose (HPMC) extended release matrix tablets containing carbamazepine and verapamil HCl. This statistical theory studies disordered or chaotic systems where the components are randomly distributed in a lattice. The application of this theory to study the hydration and drug release of hydrophilic matrices allows describing the changes in hydration and drug release kinetics of swellable matrices. The aim of this work was to study and develop extended release matrix formulations for carbamazepine and verapamil HCl, containing hypromellose (HPMC, METHOCEL Premium K100M CR) as rate controlling polymer using the concepts of percolation theory. The knowledge of the percolation threshold of the components of the matrix formulations contributes to improve their design. First, reducing the time to market and second, avoiding to formulate in the nearby of the percolation threshold, which will result in a lower variability. Therefore these formulations will be more robust when they are prepared at industrial scale. The HPMC percolation threshold for drugs with very different water solubilities was determined and it was shown that there was no significant influence of drug solubility on the HPMC critical concentration threshold (excipient percolation threshold). This may be related to the versatility and broad functionality of the swelling hydrophilic matrices.
Research Interests: Kinetics, Polymers, Computer Simulation, Diffusion, Drug Design, and 12 moreChaotic System, Hydroxypropyl Methylcellulose, Carbamazepine, Percolation threshold, AAPS PharmSciTech, Water soluble polymers, Lactose, Delayed-Action Preparations, Drug Release, Percolation Theory, Extended release, and Verapamil
Research Interests: Research Design, Water, Kinetics, Pharmaceutical Technology, Drug delivery, and 17 morePharmaceutical Chemistry, Percolation, Porosity, Diffusion, Nonlinear Regression, Solubility, Percolation threshold, Particle Size, Tablets, AAPS PharmSciTech, Molecular weight, Empirical Method, Critical Point, Excipients, Drug Compounding, Delayed-Action Preparations, and Kinetic Parameter
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The purpose of this work is to study the ability of a new biodegradable polyurethane PU(TEG-HMDI) obtained by reaction of triethylene glycol (TEG) with 1,6-hexamethylene diisocyanate (HMDI) to act as matrix forming polymer for controlled... more
The purpose of this work is to study the ability of a new biodegradable polyurethane PU(TEG-HMDI) obtained by reaction of triethylene glycol (TEG) with 1,6-hexamethylene diisocyanate (HMDI) to act as matrix forming polymer for controlled release tablets and to estimate its percolation threshold in a matrix system. Matrix tablets weighing 250 mg were prepared by direct compression with 10-30% wt/wt of PU(TEG-HMDI) and anhydrous theophylline as model drug. Release studies were carried out using the paddle method. The results were analyzed using the kinetics models of Higuchi, Korsmeyer-Peppas, and Peppas and Sahlin. These studies confirm the existence of an excipient percolation threshold between 10 and 20 % wt/wt of PU(TEG-HMDI) for the different batches prepared. It has been observed that the new biodegradable polyurethane PU(TEG-HMDI) shows adequate compatibility as well as a high ability to control the drug release.
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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... more
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. 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. The influence of especially important factors such as polymer concentration and particle size is now much better known thanks to these new theories. To formulate a HPMC matrix, the system must be above the polymer's 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.