Functional Performance of Chitosan/Carbopol 974P NF Matrices in Captopril Tablets.

Chitosan and Carbopol have been used to form a complex through an electrostatic interaction between the protonated amine (NH3+) group of chitosan and the carboxylate (COO-) group of Carbopol. In situ polyelectrolyte complexes formations based on the physical mixture of chitosan and sodium alginate were found and could be used as an oral controlled release matrix. The aim of this work is the assessment of a possible interaction between the particles of chitosan and Carbopol 974P NF that could modify their technological performance in captopril tablets. The drug and excipients were evaluated as mixtures of powders and tablets. The mixtures with captopril contained Carbopol 974P NF, chitosan, or a 1 : 1 mixture thereof with polymer proportions of 10%, 20%, and 30%. The evaluated parameters were the powder flow rate, the powder compressibility index, and the compactibility and release behavior of the tablets. The observed technological behavior points out to a greater interaction between the particles of polymers with different charge than between particles of the individual polymers. This produces more coherent matrices restricting more efficiently the drug dissolution, more coherent tablets with higher compactibility, and less flowing powder mixtures. All this, however, requires additional investigation to confirm the current results.

Effect of antioxidants on captopril floating matrices.

Stability of captopril in a controlled release formulation has been a challenge for some time. The sustained release of captopril from floating matrices has been studied varying the antioxidant load, the sodium bicarbonate proportion and the compaction pressure. Although in many cases the effect of compaction pressure remains hidden, actual results show that matrices compacted at 55 MPa have smaller density and float in the dissolution medium while those compacted at 165 MPa float only adding sodium bicarbonate. The increase of compaction pressure reduces the hydration volume and increases the time necessary to attain its maximum. These changes are attributed to lower matrix porosity and to the consequent diminution of water and drug transport. Increasing ascorbic acid proportions increase the matrix hydration volume and the drug released. The use of sodium ascorbate and the substitution of 15% polymer with sodium bicarbonate reduce the matrix hydration volume, shorten the matrix hydration process and increase the drug released. This is attributed to carbon dioxide bubbles that decrease the matrix coherence and expand the matrix volume, facilitating drug dissolution and only a limited further matrix expansion. The antioxidant protection provided by sodium ascorbate was lesser of that of ascorbic acid because of greater molecular mass and lesser release rate.

Effect of stearic acid on the properties of metronidazole/methocel K4M floating matrices / Efeito do ácido esteárico nas propriedades de metronidazol / Methocel K4M matrizes flutuante

The properties of metronidazole/Methocel K4M sustained release floating tablets have been studied varying the proportion of the lubricant, stearic acid, on formulations with and without sodium bicarbonate. The variables studied include technological properties of the tablets such as tablet hardness and ejection pressure, the drug release profile, the hydration kinetics and the floating behaviour. The presence of stearic acid and sodium bicarbonate improves the floating behaviour for more than 8 hours. The hydration volume, the tablet hardness and the ejection pressure decrease as the stearic acid content increases and the polymer content decreases. Drug dissolution increases with increasing proportions of stearic acid and decreasing proportions of the polymer in the tablets. The presence of sodium bicarbonate extends the differences in dissolution produced by stearic acid. These results are attributed to decreasing matrices coherence with an increasing quantity of stearic acid and a reducing polymer proportion. The carbon dioxide bubbles produced by sodium bicarbonate expand the matrices facilitating the dissolution, although their presence obstructs also the diffusion path through the hydrated gel layer.

Estudaram-se as propriedades de comprimidos flutuantes de metronidazol/Methocel K4M de liberação controlada, variando-se a proporção do lubrificante, ácido esteárico, nas formulações com e sem bicarbonato de sódio. As variáveis estudadas incluem propriedades tecnológicas dos comprimidos, tais como dureza, pressão de ejeção, perfil de liberação do fármaco, cinética de hidratação e comportamento de flutuação. A presença de ácido esteárico e do bicarbonato de sódio melhora o comportamento de flutuação para mais de 8 horas. O volume de hidratação, a dureza e a pressão de ejeção do comprimido decrescem à medida que o conteúdo de ácido esteárico e de polímero diminui. A dissolução do fármaco aumenta com o aumento das proporções de ácido esteárico e a diminuição das proporções de polímero nos comprimidos. A presença de bicarbonato de sódio amplia as diferenças na dissolução produzidas pelo ácido esteárico. Estes resultados são atribuídos à coesão decrescente das matrizes, com o aumento da quantidade de ácido esteárico e a redução da proporção de polímero. Bolhas de dióxido de carbono produzidas pelo bicarbonato de sódio expandem as matrizes, facilitando a dissolução, embora a presença delas obstrua, também, a difusão através da camada de gel hidratado.

Effect of antioxidants on captopril floating matrices.

Stability of captopril in a controlled release formulation has been a challenge for some time. The sustained release of captopril from floating matrices has been studied varying the antioxidant load, the sodium bicarbonate proportion and the compaction pressure. Although in many cases the effect of compaction pressure remains hidden, actual results show that matrices compacted at 55 MPa have smaller density and float in the dissolution medium while those compacted at 165 MPa float only adding sodium bicarbonate. The increase of compaction pressure reduces the hydration volume and increases the time necessary to attain its maximum. These changes are attributed to lower matrix porosity and to the consequent diminution of water and drug transport. Increasing ascorbic acid proportions increase the matrix hydration volume and the drug released. The use of sodium ascorbate and the substitution of 15% polymer with sodium bicarbonate reduce the matrix hydration volume, shorten the matrix hydration process and increase the drug released. This is attributed to carbon dioxide bubbles that decrease the matrix coherence and expand the matrix volume, facilitating drug dissolution and only a limited further matrix expansion. The antioxidant protection provided by sodium ascorbate was lesser of that of ascorbic acid because of greater molecular mass and lesser release rate.

Sustained delivery of captopril from floating matrix tablets.

The development of a controlled release formulation of captopril has been a challenge for some time. In this work, the in vitro sustained release of captopril from Metolose SH 4000 SR/sodium bicarbonate floating tablets has been studied, varying the proportions of Metolose and bicarbonate. This was studied at two different compaction pressures. Other studied variables include the kinetics of the hydration volume, the matrices floating time and the matrix density. The results show that matrices compacted at 55 MPa float in the dissolution medium for more than 8h while those compacted at 165 MPa float only when sodium bicarbonate is included in the formulation. The increase of the matrix polymer proportion increases the maximal hydration volume as well as the time to attain this maximum. The matrices hydration volume increases with the inclusion of sodium bicarbonate in the formulation. The matrix density is lower when compacted at 55 MPa. The drug release constant (k) decreases and the exponent indicative of the release mechanism (n) increases with increasing polymer contents. The drug released with time is lesser when sodium bicarbonate is included in the formulation. Carbon dioxide bubbles obstruct the diffusion path and decrease the matrix coherence. The effect of compaction pressure to reduce the drug release rate has to be made clear in further studies.

Effect of sodium bicarbonate on the properties of metronidazole floating matrix tablets.

The effect of sodium bicarbonate (SB) on the swelling behavior and the sustained release of floating systems was studied with varied proportions of this excipient and metronidazole. Two polymers with different hydration characteristics, Methocel K4M and Carbopol 971P NF, were used to formulate the matrices. Under in vitro dissolution conditions, the addition of SB to metronidazole sustained-release tablets modifies the matrix hydration volume, increasing at the beginning, reaching a maximum, and then declining. Pure Carbopol matrices show a rapid hydration with a limited further effect of the SB and metronidazole loads. Methocel show a significant increase of the apparent hydration volume due to SB addition with no further notable change due to metronidazole load. Increasing the metronidazole load reduces the floating time of Carbopol matrices while no effect on Methocel matrices could be observed within 8 hours dissolution. Matrices show increasing release constant values (k) as the metronidazole load increases. Methocel matrices release the drug 10% to 15% faster than Carbopol matrices. SB increases the cumulative amount of drug released from Methocel but not that releasing from Carbopol. These results are attributed to the intrinsic polymer properties, the barrier effect of CO(2) bubbles, and the matrix volume expansion produced after addition of SB.

Effect of formulation and process variables on the release behavior of amoxicillin matrix tablets.

The sustained release of amoxicillin is desired to be confined to the upper gastrointestinal tract to treat certain kind of infections. In vitro dissolution, at pH 1.2, of amoxicillin sustained release tablets has been studied varying the proportion of Carbopol 971P NF and sodium alginate as well as the ethanol/water proportion in the granulation fluid. M(t), the amount of drug released at time (t) and defined in terms of the total drug released over a long time period (M(inf), was described by M(t)/M(inf) = kt(n). Matrices with increasing proportions of sodium alginate showed increasing values of the exponent indicative of the release mechanism (n) and increasing release constant values (k). This is attributed to a drop in the coherence of the polymeric matrix with increasing alginate proportions that produces an increasing polymer relaxation and erosion. Decreasing Carbopol 971P NF proportions reduce the amount of dissolved polymer during granulation, producing a lesser obstruction of amoxicillin dissolution. Alginate proportions of 80% produce near zero order release profiles. Granules obtained with increasing ethanol proportions showed increasing release constant values and a minor change in the exponent (n) values. This is considered a result of lower polymer dissolution during granulation that allows a lesser matrix coherence and a greater amoxicillin dissolution. Alginate matrices granulated with different ethanol/water proportions showed no significant changes in the amoxicillin release profile. There is a trend toward increasing floating times with increasing Carbopol 971P NF proportions.

Influence of enteric-coated lactose on the release profile of 4-aminopyridine from HPMC matrix tablets.

A weakly basic experimental drug, 4-aminopyridine, was taken as a model to study the influence of enteric-coated lactose (EL) on the release profile from hydroxypropyl methylcellulose matrices. Powder mixtures were wet-granulated with water. The dried granulation was compressed with a hydraulic press at 85 MPa. Dissolution studies were made using HCl 0.1 N and then phosphate buffer pH 7.4. Dissolution curves were described by M(t)/M(inf) = k*t(N). A trend toward increasing exponent (n) and decreasing release constant (k) values is observed with increasing EL concentrations up to 9%; this is attributed to an increasing obstruction of the diffusion path by isolated EL particles that are insoluble in HCl and are surrounded by a water-filled space. After a critical EL concentration, the water-filled spaces surrounding EL particles percolate, producing the opposite effect, increasing the release constant and decreasing the exponent (n) values as the EL proportion increases from 10% to 50%. EL particles (2% to 9%) decrease the drug and water transport in matrices dissolving in HCl. Thereafter, at pH 7.4, the pores formed by dissolution of EL particles produce the opposite. Both processes contribute to flattening the release profile. Release profiles with decreasing release constant values show a logarithmic trend toward increasing values of the exponent (n), changing from diffusion toward relaxation-erosion-controlled processes.

Assay of amoxicillin sustained release from matrix tablets containing different proportions of Carbopol 971P NF.

The sustained release of amoxicillin is desired because of its short biological half-life. Particularly to treat Helicobacter pylori infections, the sustained release is desired to be confined to the upper gastrointestinal tract. In vitro dissolution of amoxicillin has been evaluated utilizing a direct UV-absorption method. However, UV-absorption has been reported as not useful to determine amoxicillin in acidic dissolution test medium. To clarify the suitability of the assay method, the stability and dissolution behavior of amoxicillin sustained release tablets was determined by HPLC, iodometric titration and UV-absorption. Stability of amoxicillin studied under dissolution test conditions of pH 1.2, 37 degrees C and 50 rpm and determined by HPLC and titration showed considerable degradation of amoxicillin. On the other hand, the UV-absorption increased progressively as amoxicillin degradation proceeded. Amoxicillin release curves determined by different analytical methods show different release profiles, which can be corrected for amoxicillin degradation and change in the UV-absorption to produce similar dissolution results. Release curves determined by UV-absorption and obtained from tablets containing 1017 mg amoxicillin trihydrate and Carbopol 971P NF in a range from 180 to 680 mg showed increasing values of the exponent indicative of the release mechanism (n) and decreasing release constant values (k) as the matrix polymer content increased. The release constant (k) and the exponent (n) were found to be logarithmically related.

Compactibility of agglomerated mixtures of calcium carbonate and microcrystalline cellulose.

The tablet tensile strength (T) of agglomerated mixtures of microcrystalline cellulose-Avicel PH 102 (MC), calcium carbonate (CC) and polyvinylpyrrolidone (Povidone, PVP), lubricated with magnesium stearate (MS), and formed under a compaction pressure (P(c)) ranging up to 618MPa has been determined. The compactibility was defined through: ln(-ln(1-T/T(max)))=Slope x lnP(c)+Intercept. MC/CC mixtures added of an agglutinant, before and after lubrication, show an important positive effect on their tablet tensile strength compared to a lineal relationship. This positive effect becomes smaller with decreasing compaction pressures. By different mixing methods, the higher the mixing efficiency the higher the compactibility, following the order: spray-dried>wet massing>tumble mixing. The compactibility of MC/CC/PVP spray-dried mixtures with calcium carbonate content from 20 to 60% was equal to or greater than that of pure microcrystalline cellulose. After lubrication with 2% MS the compactibility decreased, only the mixture with the maximal tablet tensile strength attained the tensile strength of pure microcrystalline cellulose. The presence of the binder, the lubricant and higher compaction pressures allow the accommodation of higher calcium carbonate proportions in the mixtures, at the maximal tablet tensile strength of the series. The lubricant decreases in a greater extent the compactibility of mixtures with a continuous phase of MC/PVP than that of CC/PVP. This is attributed to the plastic behavior of the MC/PVP continuous phase compared to a calcium carbonate continuous phase able to disrupt the Povidone and the possible lubricant coatings allowing a stronger interparticle interaction.

Effect of varying the restriction degree of 4-aminopyridine release from HPMC matrices on the mechanism controlling the process.

Among different technological variables that influence drug release from hydrophilic matrices, different proportions of the polymer and a water-soluble excipient have been used to control the drug release properties. These variables were used to modify the drug release rate and to examine its effect on the mechanism controlling the process. Tablets of the model drug 4-aminopyridine (4-AP) were prepared varying the matrix proportion of hydroxypropyl methylcellulose (HPMC) and citric acid (CA). The matrices release behavior (USP apparatus 2, paddle, at 50 rpm) was examined using 0.1N HCl and 0.2M phosphate buffer as dissolution media. Dissolution curves were described by M(t)/M(inf)=kt(n), applied separately for each dissolution medium. The increase of the HPMC matrix content reduced the release rate of the drug. The release mechanism showed a linear trend toward higher n values with a continuous reduction of drug release. The addition of increasing proportions of CA produced the opposite. An increasing drug release rate produced logarithmic decreasing n values. The results demonstrate, as a general rule, that every restriction of the drug release rate is associated with increasing values of the mechanism-indicating exponent n. This relationship means a logarithmic movement away from a release mechanism controlled by diffusion toward a mechanism controlled by relaxation, erosion and dissolution of the polymeric matrix as the drug release rate is restricted. These results are attributed to an increasing hydration and dissolution of the polymeric matrix, as the drug release is subject to limitation.

Influence of enteric citric acid on the release profile of 4-aminopyridine from HPMC matrix tablets.

A weakly basic experimental drug, 4-aminopyridine (4-AP), was taken as a model to study the influence of enteric citric acid (ECA) on the release profile from hydroxypropyl methylcellulose (HPMC) matrices, to set up a system bringing about gradual release of the drug. For this purpose, powder mixtures were wet granulated with water and compressed with a hydraulic press at 55 MPa. Dissolution studies were made using first 900 ml HCl 0.1 N, and then phosphate buffer pH 7.4. Dissolution curves were described by M(t)/M(inf)=kt(n). As physically expected, increasing proportions (2-9%) of the in acid insoluble ECA decreased the release rate. In an acid medium, ECA acts as a physical barrier obstructing the diffusion path, dissolving after the pH change to 7.4. Both circumstances flattening the release profile. Apparent zero order release was observed at ECA concentrations of about 10%. The presence of ECA compensates the effect of decreased solubility of 4-AP at pH 7.4. Unexpectedly, higher ECA proportions (10-50%) act increasing the dissolution rate. This is attributed to a void space formation around the insoluble ECA, after HPMC hydration, which percolates after a critical ECA proportion of approximately 10%. Moreover, decreasing release constant values (k) show a logarithmic relationship with increasing values of the exponent (n). This indicates that an apparent zero-order release can be obtained at a given release constant.