Papers by Isidoro Caraballo
European Journal of Pharmaceutical Sciences Official Journal of the European Federation For Pharmaceutical Sciences, Sep 1, 2009
The aim of this work is to estimate the excipient percolation threshold for a new combined matrix... 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.
Acta Farmaceutica Bonaerense, 2000
International Journal of Pharmaceutics, 2015
There are many factors influencing the drug release behaviour from a pharmaceutical formulation a... 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.
The main objective of this work is to study the influence of the drug particle size on the pharma... more The main objective of this work is to study the influence of the drug particle size on the pharmaceutical availability of ultrasound compacted tablets. Inert matrix systems containing different drug particle sizes were prepared using both, an ultrasound-assisted press and a traditional eccentric machine. Potassium chloride was used as drug model and Eudragit ® RS-PM as matrix forming excipient. The excipient particle size was kept constant. The cross-sectional microphotographs of ultrasound tablets show the existence of a quasi-continuum medium. Keeping constant the drug load, US-tablets showed very similar release rates, whereas for traditional tablets, an increase in the particle size resulted in a clear decrease in the release rate. In these tablets, the excipient forms an almost continuum medium. In an infinite theoretical system of these characteristics, the size of the drug particles will not modify the percolation threshold. The percolation of the excipient in this system can be assimilated to a continuum percolation model. In accordance with the proposed model, a lower influence of the drug particle size on the drug release rate was obtained for the US-tablets in comparison with traditional tablets. This fact can be indicative of the similarity of the drug percolation thresholds in these systems.
The knowledge of the percolation thresholds of a system results in a clear improvement of the des... more 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. Despite hydrophilic matrices are one of the most used controlled delivery systems in the world, but actuality, the mechanisms of drug release from these systems continue to be a matter of debate nowadays. The objective of the present paper is to apply the percolation theory to study the release and hydration rate of hydrophilic matrices. Matrix tablets have been prepared using KCl as a drug model and HPMC K4M as matrixforming material, employing five different excipient/drug particle size ratios (ranging from 0.42 to 2.33). The formulations studied containing a drug loading in the range of 20-90% (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. The percolation theory has been applied for the first time to the study of matrix type controlled delivery systems. The application of this theory allowed to explain changes in the release and hydration kinetics of these matrices. The critical points observed in dissolution and water uptake studies can be attributed to the excipient percolation threshold, being this threshold one of the main factors governing the gel layer formation and consequently, the drug release control from hydrophilic matrices.
ABSTRACT A specific HPLC method was applied to study the evolution of the concentrations of thime... 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.
ABSTRACT In the present paper, release profiles obtained from matrix tablets prepared with Eudrag... 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.
ABSTRACT In the present paper, percolation theory has been applied to the study of the release me... 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.
... A linear relationship between the relative drug/excipient particle size ratio and the drug pe... 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. ...
International Journal of Pharmaceutics, 1995
... 118 (1995) 151-160 intemational journal of pharmaceutics Research Papers Influence of diluent... 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. ...
International Journal of Pharmaceutics, 1996
ABSTRACT The efficiency of a new controlled release oral system containing morphine hydrochloride... 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.
International Journal of Pharmaceutics, 1997
Polymeric complexes based on the interaction between Eudragit * L and naltrexone hydrochloride we... more Polymeric complexes based on the interaction between Eudragit * L and naltrexone hydrochloride were elaborated. A preformulation study of the drug was designed to address the following points: (a) the development of two alternative methods (high performance liquid chromatography (HPLC) and UV spectrophotometry) for the analysis and quantifying of naltrexone; (b) the determination of the aqueous solubility of naltrexone hydrochloride; and (c) the characterization of naltrexone hydrochloride from the following points of view: morphological (scanning electronic microscopy, SEM), thermal (differential scanning calorimetry, DSC and hot stage-microscopy, HSM) and spectroscopical (~H-and ~3C-nuclear magnetic resonance, NMR). Furthemore, some of these thechniques were used for the physical and chemical characterization of naltrexone polymeric complexes. An interaction by means of hydrogen bonds between the polymer and naltrexone was demonstrated using NMR spectroscopic techniques. The in vitro release of naltrexone-Eudragit ® L complex using a pH gradient technique was studied. A significant reduction in the release rate of drug from the complex used as naltrexone controlled release system as well as a very high efficiency in the dissolution process have been found. © 1997 Elsevier Science B.V.
International Journal of Pharmaceutics, 1999
The percolation theory is a statistical theory able to study chaotic or disordered systems that h... 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.
International Journal of Pharmaceutics, 1995
ELSEVIER International Journal of Pharmaceutics 114 (1995) 1321 intemational journal of pharmaceu... 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 ...
International Journal of Pharmaceutics, 2015
The main aim of this paper is the synthesis and characterization of a new linear functional biode... 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.
The Scientific World Journal, 2012
Percolation theory has been applied in order to study the existence of critical points as well as... more Percolation theory has been applied in order to study the existence of critical points as well as the possibility to find a "combined percolation threshold" for ternary hydrophilic matrices prepared with HPMC, NaCMC, and theophylline. For this purpose, different batches of ternary as well as binary hydrophilic matrices have been prepared. Critical points have been found for binary hydrophilic matrices between 21.5 and 31.3% (v/v) of HPMC and between 39 and 54% (v/v) of NaCMC, respectively. In a previous work carried out with the same polymers but a much more soluble drug (KCl), it was demonstrated the existence of a partial collaboration between the polymers in order to establish the gel layer. In this work, it has been observed for the first time the need of a minimum concentration of one of the matrix-forming polymer (between 10 and 20% v/v, approximately) for establishing an effective collaboration.
International Journal of Pharmaceutics, 2008
The percolation theory studies the critical points or percolation thresholds of the system, where... more 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.
International journal of pharmaceutics, Jan 14, 2011
The release behaviour of clozapine matrix pellets was studied in order to investigate if it is po... 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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Papers by Isidoro Caraballo