Microenvironmental pH modulation based release enhancement of a weakly basic drug from hydrophilic matrices

For weakly basic drugs, pH-dependent solubility characteristics can translate into low and incomplete release of these drugs from sustained release formulations. The objective of this study was to quantitatively analyze the relationship between microenvironmental pH modulation and release enhancement of a weakly basic drug in the free base form. A prototype matrix system primarily consisting of trimethoprim (pK(a) 6.6), hydroxypropyl methylcellulose (HPMC), and a polymeric or nonpolymeric pH modulator was used. Incorporation of the methacrylic acid polymer, Eudragit L100-55 resulted in marginal release enhancement as the pH modulation effected by this polymer was attenuated by the basicity of the drug. Water uptake and scanning electron microscopy (SEM) studies suggested that Eudragit L100-55 incorporation also resulted in reduced water uptake and matrix permeability. The effect of nonpolymeric pH modulators on release enhancement was also studied. The lowering in microenvironmental pH by malic acid was sufficiently high and persistent to result in pH-independent release. A correlation plot between the experimentally determined microenvironmental pH, effected by the polymeric and nonpolymeric pH modulators, and percent drug release, exhibited good linearity with a correlation coefficient of 0.83; thereby, indicating that drug diffusion across the gel barrier is the predominating mechanism of release.     

pH-independent release of a basic drug from pellets coated with the extended release polymer dispersion Kollicoat SR 30 D and the enteric polymer dispersion Kollicoat MAE 30 DP.

The objective of this study was to obtain pH-independent release profiles from coated pellets containing drugs with pH-dependent solubility. pH-independent release of the basic model drug verapamil HCl was achieved by coating with a combination of the neutral polymer dispersions Kollicoat SR 30 D (aqueous dispersion of polyvinyl acetate) and the enteric polymer dispersion Kollicoat MAE 30 DP (aqueous dispersion of methacrylic acid and ethyl acrylate copolymer; methacrylic acid copolymer type C). The two polymers where applied either as separate layers (enteric polymer + extended release polymer or vice versa) or as a polymer blend. A careful balance of the ratios of the polymers allowed the achievement of a pH-independent release. Higher amounts of the enteric polymer in the polymer blend resulted in a reversal of the pH-dependency, e.g. a faster release at pH 6.8 than in 0.1 N HCl.     

Effect of montmorillonite on drug release from polymeric matrices

Drug release from matrices of polyvinyl alcohol was affected by molecular weight and solubility of the drugs (either sodium salicylate or papaverine hydrochloride), and by the matrix loading. - Montmorillonite addition to the matrix formulation modified only the release constant of papaverine hydrochloride owing to drug interaction with the clay by an ionic exchange process. The kinetics exponent was affected a little bit by interaction of the drug with montmorillonite, whereas the influence of the matrix loading was more remarkable.     

Effect of anionic polymers on the release of propranolol hydrochloride from matrix tablets.

Anionic polymers, namely Eudragit S, Eudragit L 100-55, and sodium carboxymethylcellulose, were incorporated into hydroxypropylmethylcellulose (HPMC K100M) to modify the drug release from HPMC matrices. The effects of changing the ratio of HPMC to anionic polymers were examined in water and in media with different pH. The dissolution profiles were compared according to release rates. The interaction between propranolol hydrochloride and anionic polymers was confirmed using the UV difference spectra method. The drug release was controlled with the type of anionic polymer and the interaction between propranolol hydrochloride and anionic polymers. The HPMC-anionic polymer ratio also influenced the drug release. The matrix containing HPMC-Eudragit L 100-55 (1:1 ratio) produced pH-independent extended-release tablets in water, 0.1 N HCl, and pH 6.8 phosphate buffer.     

Dimensional changes, gel layer evolution and drug release studies in hydrophilic matrices loaded with drugs of different solubility

The objective of this investigation was to explore the effects of drug solubility on the evolution of matrix dimensions and gel layer's during drug release and investigate the relationship between these effects and the mechanism and the rate of drug release. Two hydrophilic swellable polymers Polyox (POL) and cross-linked Carbopol (CARB) were employed as carriers. Caffeine (CAF) and theophylline (THE), two drugs having similar chemical structure but different aqueous solubility, were used as model drugs. Both drug and polymer characteristics were found to influence the dimensional changes of matrices and the development of the gel layer formed around the glassy core. The dimensional expansion in CAF matrices was always more pronounced than the THE matrices. Also the CARB matrices demonstrated greater maximum expansion and lower drug release than the POL matrices, due to a smaller degree of erosion of CARB. The dimensions of CARB/CAF matrices, unlike all the other matrices studied, exhibited a biphasic increase at early times, which was attributed to the cross-linked structure of CARB and the high solubility of CAF. With both polymers, a thinner gel layer was developed in the matrices containing the less soluble THE compared to the CAF matrices. The thickness of the gel layer increased continuously with time in the CAF matrices whereas it increased initially and after reaching a maximum started to decrease in THE matrices. All formulations except those of CARB/THE exhibited burst release, which depended on drug and polymer characteristics. The gel layer thickness and erosion rate appeared to determine the rate of drug release from the CARB and POL formulations. The results clearly indicate that for these matrices gel thickness and fluctuation of gel thickness affect the release rate/h of drug proportionally. Analysis of the release kinetics indicated that CAF was released mainly through diffusion whereas, THE was released mainly through matrix erosion.     

Drug release from complexes with a series of poly(carboxyalkyl methacrylates), a new class of weak polyelectrolytes

Carboxyalkyl methacrylates, a new class of non-cross-linked, hydrophobic weak polyelectrolytes, were synthesized, and then bound to cationic drugs (propranolol.HCl, diltiazem.HCl and verapamil.HCl) to form water-insoluble complexes that release the bound drug only in ionic media (pH 7.4). Compressed tablets were prepared from these cation exchange polyelectrolytes. Release profiles followed zero order kinetics (n>0.90; n is the release exponent). As the hydrophobicity of the polyelectrolytes increased, the rate of release decreased and deviated from linearity (n=0.7). Both the ionic strength of the medium as well as the solubility of the drug affected the rate of release. In acidic media (pH 1.2) a burst of drug was released but the release was halted by a layer of non-ionized polymer precipitated on the surface of the tablets. The results indicate that it is possible to "tailor-make" the release kinetics by using a polyelectrolyte from the series with the suitable hydrophobicity.     

Swellable matrices for the controlled-release of diclofenac sodium: formulation and in vitro studies

Oral administration has been the most usual and convenient employed route of drug delivery systems. Particularly, oral sustained-release systems for the delivery of drugs by a process of continuous swelling of the polymeric carrier have been investigated. Thus, the goal of this study was to evaluate the effects of hydroxypropyl methylcellulose (HPMC) and carboxypolymer (Carbopol 934) on the release behavior of diclofenac sodium (DS) from a swellable matrix tablet system. Nine different DS controlled-released tablets were compressed by using the wet-granulation technology. The influence of the polymer content, the polymer ratio, the polymeric swelling behavior, and the pH changes on the release rate of DS was investigated. There was no significant difference in drug release when total polymer concentration was 10%. When the tablets were formulated having 20% or 30% of HPMC/carbomer, it was observed that a more rapid release of DS occurred as the carboxypolymer ratio within the matrices increased. In agreement with previous results, the dissolution studies demonstrated that the combination of these two polymeric matrix formers resulted in near zero-order release rate of DS. The DS release from all these matrix tablets was pH dependent, being markedly reduced at lower pH, and could be attributed to the poor solubility of DS at this pH value. In HCl 0.1 N solution, HPMC controlled drug release because the carbomer has a low solubility at this pH. As the pH increased, the carbomer became ionized, being able to interact with HPMC to control the drug release.     

The effects of drug physico-chemical properties on release from copoly (lactic/glycolic acid) matrix

A study on the effect of physico-chemical properties of drugs on their release behavior from copoly (l-lactic/glycolic acid); (PLGA) matrix was performed. PLGA and drugs of acidic, neutral or basic nature were mixed and molded by heat compression method into a cylindrical matrix. The release rate of drugs from the rod depended on their physico-chemical properties. Basic drugs were found to show high PLGA/aqueous medium partition coefficients (K_app), implying a strong ionic interaction with the polymer. This interaction kept these drugs dissolved in the matrix during the release studies. The interaction shielded the polymer terminal carboxyl residues resulting in the slower matrix erosion, and made the matrix less swellable, thus diminishing drug diffusion through the matrix. Consequently, K_app could be regarded as the determinant parameter to evaluate the release rate of basic drugs. In contrast, acidic and neutral drugs had only weak interaction with PLGA, so that the drugs quickly precipitated out as crystals in the matrix during the release studies. In this case, the drugs did not affect the matrix erosion, and hence the solubility of each drug in the hydrated matrix became the predominant parameter affecting drug diffusion.     

Influence of dissolution media composition on drug release and in-vitro/in-vivo correlation for paracetamol matrix tablets prepared with novel carbomer polymers

The influence of dissolution media composition on drug release kinetics and in-vitro/in-vivo correlation (IVIVC) for hydrophilic matrix tablets based on Carbopol 971P and Carbopol 71G was investigated. A number of buffered and unbuffered media differing with respect to their pH value, ionic strength and ionic species was evaluated. The observed in-vitro drug release profiles were compared with the hypothetical drug release profiles in-vivo calculated by numerical deconvolution from the results of an in-vivo study. The obtained IVIVC plots were examined using linear and non-linear (proportional odds, proportional hazards and proportional reversed hazards) mathematical models. Although the studied sustained release agents were chemically identical, they exhibited pronounced differences in drug product behaviour both in-vitro and in-vivo. The use of non-linear modelling resulted in an improved level of correlation, especially in the case of Carbopol 71G matrices. The obtained results indicated the susceptibility of drug release kinetics and hence IVIVC in the case of anionic polymer matrices to media composition, and emphasized the need for thorough evaluation of applied media during the development of biorelevant dissolution methodology. Although the use of non-linear modelling could be advantageous, the need for a simple and meaningful non-linear relationship is pointed out.     

Swelling, erosion and release behavior of alginate-based matrix tablets.

Hydrophilic matrix tablets based on the alginate system have been used in relation to their possible function in modified drug delivery formulations using metronidazole as a model drug. The matrix tablets were prepared by direct compression using different grades of alginate. The effect of some factors (i.e. particle size of drug, additive used, and pH of medium) on drug release from alginate-based matrix tablets was also investigated. Swelling, erosion, and in vitro release studies of the matrix tablets were carried out in 0.1N HCl or phosphate buffer (pH 6.8). The alginate-based matrix tablets swelled or eroded while in contact with the aqueous medium and formed a continuous gel layer or underwent combination of swelling and erosion. The swelling action of alginate matrices is controlled by the rate of its hydration in the medium. Different grades of alginate insignificantly influenced the matrix swelling in acidic medium but significantly influenced in neutral medium. The presence of ammonium or calcium salts induced tablet disintegration in acidic medium. However, incorporation of calcium acetate and sodium bicarbonate can alter the tablet swelling in acidic medium. Release studies showed that all investigated factors influence the drug release. The extent of matrix swelling, erosion, and diffusion of drug determined the kinetics as well as mechanism of drug release from alginate-based matrix tablets. Most of the release data in acidic medium showed a good fit into Korsmeyer-Peppas equation but fitted well with zero-order release model, in neutral medium.     

Strategies for the design of hydrophilic matrix tablets with controlled microenvironmental pH

Incorporation of weak acids as pH modifiers enhances the release of weakly basic drugs in higher pH environments by reducing the microenvironmental pH (pHM). The objectives of this study were: (a) to investigate the relationship between pHM, drug release, and pH modifier release and (b) to achieve simultaneous release of the drug and the pH modifier over the entire dissolution time (6 h, phosphate buffer, pH 6.8). Using dipyridamole as a model drug, we investigated drug and acid release and determined the average pHM potentiometrically using tablet cryosections. The first approach was based on incorporating different concentrations of pH modifiers in conventional matrix tablets based on hydroxypropylmethylcellulose. Owing to its high acidic strength and low aqueous solubility, fumaric acid resulted in simultaneous release and maintained a constant acidic pHM. Secondly, press-coated matrix tablets, comprising an acidic reservoir, were found to be a valuable approach for retarding the diffusion of more water-soluble acids. Using the power law expression (Mt/Minfinity = ktn) it became evident that the inclusion of acids increased drug release. Higher acid concentrations tended to decrease n standing for the slope, whereas the release constant k increased. Furthermore, the medial check term parameters depended on the type of pH modifier used.     

Microenvironmental pH modulation in solid dosage forms

There are many reports in the literature referring to the effect of microenvironmental pH on solid dosage form performance, particularly stability and dissolution profiles. Several techniques have been proposed for the measurement of the microenvironmental pH. Those techniques use certain assumptions and approximations and many of them employ a solution calibration curve of a probe to predict hydrogen ion activity in a substantially dry solid. Despite the limitation of the methodology, it is clear from the literature that microenvironmental pH has a significant impact on stability of compounds which demonstrate pH dependent stability in solution. Degradation kinetics of such compounds, and in some cases degradation profile as well, are dependent on the microenvironmental pH of the solid. Modulation of the microenvironmental pH through the use of pH modifiers can hence prove to be a very effective tool in maximizing solid dosage form stability. Judicial selection of the appropriate pH modifier, its concentration and the manufacturing process used to incorporate the pH modifier is necessary to enhance stability. Control of microenvironmental pH to maximize stability can be achieved without the use of pH modifier in some cases if an appropriate counter ion is used to provide an inherently optimal pH for the salt. Microenvironmental pH modulation was also shown to control the dissolution profile of both immediate and controlled release dosage forms of compounds with pH dependent solubility. The pH modifiers have been used in conjunction with high energy or salt forms in immediate release formulations to minimize the precipitation of the less soluble free form during initial dissolution. Additionally, pH modifiers were utilized in controlled release dosage forms of weakly basic drugs which exhibit diminished release in dissolution media with high pH. The incorporation of acidic pH modifiers in the controlled release formulation increases the solubility of the basic drug even as the high pH dissolution medium enters into the dosage form hence increasing drug release rate.     

Influence of Carbopol 71G-NF on the release of dextromethorphan hydrobromide from extended-release matrix tablets

The objective of this study was to evaluate the potential of Carbopol^® 71G-NF on the release of dextromethorphan hydrobromide (DM) from matrix tablets in comparison with hydroxypropyl methylcellulose (HPMC^® K15M) and Eudragit^® L100-55 polymers. Controlled release DM matrix tablets were prepared using Carbopol 71G-NF, HPMC K15M, and Eudragit L100-55 at different drug to polymer ratios by direct compression technique. The mechanical properties of the tablets as tested by crushing strength and friability tests were improved as the concentration of Carbopol, HPMC, and Eudragit increased. However, Carbopol-based tablets showed a significantly (P?<?0.05) higher crushing strength and a lower friability than HPMC and Eudragit tablets. No significant differences in weight uniformity and thickness values were observed between the different formulations. It was also found that Carbopol significantly (P?<?0.05) delayed the release of DM in comparison with HPMC K15M and Eudragit L100-55. A combination of HPMC K15M and Eudragit L100-55 in a 1:1 ratio at 20 and 30% significantly (P?<?0.05) delayed the release of DM than Eudragit L100-55 alone. Moreover, blends of Carbopol and HPMC at a 1:1 ratio at the 10, 20, and 30% total polymer concentration were investigated. The blend of Carbopol and HPMC at 10% level significantly (P?<?0.05) slowed the release of DM than Carbopol or HPMC alone, whereas blends at 20 and 30% level significantly (P?<?0.05) delayed the release of DM compared with HPMC or Carbopol alone. The results with these polymer blends showed that it was possible to reduce the total amount of polymers when used as a combination in formulation.     

Design of pH-independent controlled release matrix tablets for acidic drugs

The rate and extent of drug release from most controlled release systems are influenced by the pH of the dissolution medium for drugs with pH-dependent solubility. This dependency of drug release on pH may lead to additional inter- and intra-subject variability in drug absorption. In the present study, a pH-independent controlled release matrix system for acidic drugs was designed by incorporating release-modifiers in the formulation. Controlled release matrix tablets were prepared by compression of divalproex sodium, Methocel K4M and Eudragit E 100 or Fujicalin as the release-modifier. For formulations without any release-modifier, the extent and rate of drug release at pH 6.8 was much higher than that at pH 1.0. Formulations containing Eudragit E 100 provided drug release that was essentially independent of pH. This was achieved because Eudragit E 100 significantly increased the drug release in acidic medium and slightly decreased the release rate at higher pH. The increased release in the acidic medium can be attributed to the elevation of the micro-environmental pH in the swollen polymer gel layer. Formulations containing Fujicalin were less effective than those containing Eudragit E 100. This was attributed to the relative inability to elevate the pH and shorter residence time of Fujicalin in the matrix relative to Eudragit E 100.     

Extruded and spheronized beads containing Carbopol 974P to deliver nonelectrolytes and salts of weakly basic drugs

The purpose of the study was to explore the utilization of Carbopol 974P, NF, resin in a bead dosage form manufactured by extrusion and spheronization. It was possible to prepare beads in this study by using calcium chloride to overcome the tack problem associated with wetted Carbopol 974P. The actives included both salts of weakly basic drugs (chlorpheniramine maleate and diphenhydramine hydrochloride) and nonelectrolytes (caffeine and dyphylline) which have a broad range of solubilities. Nonelectrolytes were released faster than the salts of weakly basic drugs. This is contrary to the behavior typically seen with a matrix system where the more soluble drug is released faster than a poorly soluble one. In the results of the present study, the solubility does not determine the drug release rate. Ionic interactions between the protonated amines of the salts and the carboxylates of the Carbopol resin are suggested to be the reason for the slower release of the salts of weakly basic drugs. Data from tack measurements confirm that this ionic interaction affects the behavior of the wetted Carbopol. In addition to the drug release profiles, bead average diameter, roundness, friability, and density were also determined.     

Propranolol forms affect properties of Carbopol-containing extruded-spheronized beads

Drug release rates from extruded-spheronized beads containing Carbopol have been shown to be dependent on the chemical nature of different types of drugs. To further clarify solubility, salt counterion, pH, and ionic strength effects on Carbopol bead characteristics, including but not limited to the drug release profile, the present study utilizes propranolol in its free base, hydrochloride, and maleate forms. Different forms of propranolol resulted in different bead average diameter, roundness, and smoothness, but the ruggedness was not affected. Release profiles for the two salt forms were nearly superimposable, but the free base form was released more slowly. Mathematical analysis of the release data revealed that Fickian diffusion and polymer relaxation were contributing factors to the release mechanism in each case, although polymer relaxation was more influential with the free base form. In light of these results, the choice of the form of a drug should be considered carefully when preparing Carbopol-containing beads produced by extrusion-spheronization.     

pH-Solubility profile of papaverine hydrochloride and its relationship to the dissolution rate of sustained-release pellets

The pH-solubility profile of papaverine hydrochloride (I) was determined using the phase-solubility technique and equilibrium solubilities in buffers. The release of I from sustained-release pellets consisting of a shellac-based matrix was determined by the USP basket technique and was found to exhibit zero-order kinetics. Release rates at various pH values of the permeating solvent were compared with the pH-solubility profile and were directly proportional to the solubility below, but not above, the apparent pHmax (3.9). This lack of proportionality was also shown by the intrinsic dissolution rates. The effect was attributed to the self-buffering action of I and the metastability of the papaverine salt-base system in the vicinity of pHmax. It is postulated that the outer layer of polymer and filler on the surface of the pellets forms a barrier which determines the rate of release. The inner matrix serves as a drug reservoir in which the internal pH may not be the same as the bulk pH.     

Enteric polymers as acidifiers for the pH-independent sustained delivery of a weakly basic drug salt from coated pellets

Weakly basic drugs and their salts exhibit a decrease in aqueous solubility at higher pH, which can result in pH-dependent or even incomplete release of these drugs from extended release formulations. The objective of this study was to evaluate strategies to set-off the very strong pH-dependent solubility (solubility: 80 mg/ml at pH 2 and 0.02 mg/ml at pH 7.5, factor 4000) of a mesylate salt of weakly basic model drug (pK_a 6.5), in order to obtain pH-independent extended drug release. Three approaches for pH-independent release were investigated: (1) organic acid addition in the core, (2) enteric polymer addition to the extended release coating and (3) an enteric polymer subcoating below the extended release coating. The layering of aspartic acid onto drug cores as well as the coating of drug cores with an ethylcellulose/Eudragit L (enteric polymer) blend were not effective to avoid the formation of the free base at pH 7.5 and thus failed to significantly improve the completeness of the release compared to standard ethylcellulose/hydroxypropyl cellulose (EC/HPC)-coated drug pellets. Interestingly, the incorporation of an enteric polymer layer underneath the EC/HPC coating decreased the free base formation at pH 7.5 and thus resulted in a more complete release of up to 90% of the drug loading over 18 h. The release enhancing effect was attributed to an extended acidification through the enteric polymer layer. Flexible release patterns with approximately pH-independent characteristics were successfully achieved.     

New co-polymer zwitterionic matrices for sustained release of verapamil hydrochloride

Stable co-polymer [vinyl acetate-co-3-dimethyl(methacryloyloxyethyl) ammonium propane sulfonate, p(VA-co-DMAPS)] latex of different compositions has been synthesized for the first time by emulsifier-free emulsion copolymerization. The unusual >overshooting< behavior of the co-polymer tablets has been explained by the formation of specific clusters from the opposite oriented dipoles-zwitterionic species. The change of their concentration with the DMAPS unit fraction (mDMAPS), pH and ionic strength has been considered responsible for the differences observed in the swelling kinetics. The results obtained prove that mDMAPS and ionic strength could be used to control the swelling degree of the p(VA-co-DMAPS) matrices and their sustained drug delivery. In this way, p(VA-co-DMAPS) matrices could be effectively used to control the sustained release of drugs with basic properties like verapamil hydrochloride from model tablets.