Rheology of Microcrystalline Cellulose and Sodiumcarboxymethyl Cellulose hydrogels using a controlled stress rheometer: part II

Rheological properties of two different commercial grades of Microcrystalline Cellulose/Sodiumcarboxymethyl Cellulose (MCC/NaCMC) hydrogels were investigated. Viscoelastic characterization of the hydrogels using a controlled stress rheometer revealed that structure formation in the gels could be detected at a concentration as low as 1.0% w/w MCC/NaCMC in purified water. The elastic modulus (G') and the linear viscoelastic region (LVR) increased with increase in hydrogel concentration. The frequency sweep study of the hydrogels exhibited a flat G', indicating a stable structure at 1.5% w/w and 2.0% w/w concentrations. The oscillation time sweep study indicated that the rate of structure build up was dependent on the concentration of hydrogel. Structure buildup at various temperatures indicated that structure formation was rapid at higher temperature (40 degrees C), and the gel point was reached fairly quickly. Phase volume of the hydrogel significantly influenced structural recovery at different temperatures.     

The rheological properties of modified microcrystalline cellulose containing high levels of model drugs

The rheological properties of different types of microcrystalline cellulose (MCC) mixed with model drugs and water have been evaluated to identify the influence of sodium carboxymethylcellulose (SCMC) added to the cellulose during preparation. A ram extruder was used as a capillary rheometer. The mixtures consisted of 20% spheronizing agent (standard grade MCC or modified types with 6% or 8% of low viscosity grade SCMC) and 80% of ascorbic acid, ibuprofen or lactose monohydrate. The introduction of SCMC changed all rheological parameters assessed. It produced more rigid systems, requiring more stress to induce and maintain flow. Degree of non-Newtonian flow, angle of convergence, extensional viscosity, yield and die land shear stress at zero velocity, and static wall friction were increased, but recoverable shear and compliance were decreased. The presence of SCMC did not remove the influence of the type of drug. The mixture of ibuprofen and standard MCC had the lowest values for shear stress as a function of the rate of shear, extensional viscosity, and angle of convergence, but the highest values for recoverable shear and compliance. The findings indicate that the system has insufficient rigidity to form pellets.     

Release of propranolol hydrochloride from matrix tablets containing sodium carboxymethylcellulose and hydroxypropylmethylcellulose.

Hydroxypropylmethylcellulose (HPMC) and three viscosity grades of sodium carboxymethylcellulose (NaCMC), namely NaCMC (Blanose 7H 4XF), NaCMC (Courlose P 800), and NaCMC (Courlose P 350), were investigated for their ability to provide a sustained release of propranolol hydrochloride from matrices. The rank order of release rate, in the absence of HPMC, was NaCMC (Blanose) < NaCMC P 800 < NaCMC P 350 for matrices containing 95-285 mg NaCMC, and was dependent on their viscosity grades. The effects of changing the ratio of HPMC to NaCMC (Blanose) and the drug/total polymer ratio were examined. The release rates decreased as the proportion of NaCMC in the matrices increased. Zero-order release of propranolol hydrochloride was obtained from matrices containing 285 mg 3:1 NaCMC (Blanose)/HPMC. Differential scanning calorimetry was used to quantify the moisture uptake by the polymers at 37 degrees C. Wafers containing NaCMC (Blanose) or 1:1 HPMC/NaCMC (Blanose) absorbed water similarly. A study of the erosion rates of matrices containing polymer only indicated that NaCMC (Blanose) eroded more quickly than HPMC. When propranolol hydrochloride was included in matrices containing NaCMC (Blanose), the erosion was reduced as a result of the insolubility of a complex formed between NaCMC and propranolol hydrochloride. The interaction between propranolol hydrochloride and NaCMC (Blanose) was confirmed by both dialysis and by monitoring the release of sodium ions from the matrices.     

Water uptake and relaxation processes in mixed unlimited swelling hydrogels

The rheological oscillatory test parameters have been observed for highly concentrated hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose-sodium (NaCMC) and mixed HPMC/NaCMC hydrogels obtained by swelling of matrix tablets in 0.1 mol cm(-3) HCl and pH 6.8 phosphate buffer. The mechanical spectra of the gels have been analysed using theoretical models, i.e. a generalised Maxwell model and an adapted Maxwell model, both based on Ferry and Williams approximations. The relaxation time spectra as well as the parameters characteristic of linear viscoelastic behaviour have been calculated: zero shear viscosity (eta(0)), plateau moduli (G(N)(0), G(0)' and G(0)"), zero-relaxation time (tau(0)) and mean relaxation time (θ). The mechanical spectra of mixed HPMC/NaCMC hydrogels differ considerably from those of the pure ones, the type of the spectrum depending on the two polymers' ratios. In both media, the rheological models applied define the HPMC gels as homogeneous entangled networks, and those of NaCMC and mixed HPMC/NaCMC as heterogeneous physical gels. The relationship between the kinetic constants of water penetration and the mean relaxation times suggests that the molecular relaxation controls the water uptake velocity. With all the systems tested irrespective of pH of the aqueous phase, an inversely proportional dependence between the viscosity and the water penetration velocity has been noted. Since the degree of hydration is one of the factors determining the degree and velocity of drug release from the hydrogel matrices, the relation between the kinetic parameters of water penetration and the viscosity is a characteristic indicator for the gel structure, the degree of swelling and the drug release rate.     

Use of a capillary rheometer to evaluate the rheological properties of microcrystalline cellulose and silicified microcrystalline cellulose wet masses

The influence of microcrystalline cellulose (MCC) type and water content on the rheological properties of the wet powder masses were studied using two different MCC grades (Avicel and Emcocel) and silicified microcrystalline cellulose (SMCC, Prosolv). A ram extruder was used as a capillary rheometer and unique flow curves for each cellulose grade and moisture content were derived. In addition, the elastic parameters of recoverable shear and compliance were determined. From different flow curve models evaluated, it was not possible to obtain clear evidence, which model best described the rheological properties of each cellulose grade at each water level. Furthermore, the residuals were shear rate dependent, which indicates that the models do not perfectly agree with physical properties of the wet masses. The elastic properties of wet masses increased with increasing water content and decreased with increasing shear stresses. SMCC grade proved to be more elastic than the simple MCC grades at each moisture content. Thus, the rheological properties of MCC and SMCC wet masses were different and changed with water content. Consequently, it was not possible to achieve similar rheological properties between different grades of cellulose by altering the water content of the wet mass.     

Rheological synergism between ionic and non-ionic cellulose gums

The rheological properties of 50:50 mixtures of an ionic (sodium carboxymethylceliulose (NaCMC)) and various non-ionic cellulose gum solutions have been assessed using a rotational cup and bob viscometer and the apparent viscosities at each shear rate compared with their calculated mean. All the non-ionic celluloses studied gave an increase in viscosity over the calculated value.The greatest increase in viscosity was exhibited by a combination of methylcellulose (MC) with NaCMC and an optimum viscosity grade ( chain length) of HPMC was found.The interaction of xanthan gum with NaCMC was also investigated and they were shown to be incompatible.The mechanisms by which synergism occurs is discussed at the molecular level in relation to side chain configuration, degree of substitution cross linking and polymer chain length. The combination of an ionic (NaCMC) and a non-ionic cellulose gum produces an increased viscosity due to cross-linking and allows the use of cellulose gums at reduced concentrations in formulated products.     

Quantifying effects of particulate properties on powder flow properties using a ring shear tester

Effects of particle size, morphology, particle density, and surface silicification, on powder flow properties were investigated using a ring shear tester. Flow properties were quantified by flow function (FF), that is, unconfined yield strength, f(c), as a function of major principal stress. A total of 11 powders from three series of microcrystalline cellulose (MCC): Avicel (regular MCC, elongated particles), Prosolv (silicified MCC, elongated particles), and Celphere (spherical MCC), were studied. Particle size distribution in each type of MCC was systematically different. Within each series, smaller particles always led to poorer powder flow properties. The slope of FF line was correlated to degree of powder consolidation by external stress. A key mechanism of the detrimental effect of particle size reduction on flow properties was the larger powder specific surface area. Flow properties of Celphere were significantly better than Avicel of comparable particles size, suggesting spherical morphology promoted better powder flow properties. Flow properties of powders different in densities but similar in particle size, shape, and surface properties were similar. When corrected for density effect, higher particle density corresponded to better flow behavior. Surface silicification significantly improved flow properties of finer MCC, but did not improve those of coarser.     

Drug release and washability of mucoadhesive gels based on sodium carboxymethylcellulose and polyacrylic acid

This study investigated the relationship of the washability of gels based on two mucoadhesive polymers (sodium carboxymethylcellulose [NaCMC] and polyacrylic acid [PAA]) and their mixtures to their physical properties such as consistency and hydration/dissolution. The mucoadhesive properties of the two polymers and the effect of mucus-polymer interaction on gel washability at the mucoadhesive interface were also investigated using mixtures of PAA and NaCMC gels with increasing mucin amounts. Release and wash-away properties of the gels were assessed by means of a simultaneous release and wash-away test, whereas the consistency and hydration/dissolution properties of the gels were investigated by rheological analysis (viscosity and dynamic viscoelastic tests) and liquid uptake measurements, respectively. The results showed that PAA was characterized by lower release and wash-away properties than those of NaCMC. Mixing of two gels at different ratios allowed modulation of the release and wash-away properties. A relationship between washability and hydration/dissolution properties was found. Gel consistency by itself did not always provide a complete explanation of the wash-away process. The two polymers investigated showed different rheological interaction properties with mucin. Depending on the extent of such interaction, gel-mucin mixture had hydration/dissolution and washability properties that were quite different with respect to the initial gel.     

Influence of methyl-beta-cyclodextrin and liposomes on rheological properties of Carbopol 974P NF gels

The influence of positively-charged and sterically stabilized liposomes and/or methyl-beta-cyclodextrin on rheological properties of Carbopol 974P NF hydrogels was investigated. All formulations have displayed a shear-thinning behavior of Carbopol gels, and the rate stress as a function of the shear rate was fitted using the Cross equation. An important loss of viscosity was observed when 1.5% Carbopol gels were formed in Hepes/NaCl buffer or in a 5% aqueous solution of methyl-beta-cyclodextrin. Nevertheless, when methyl-beta-cyclodextrin was dissolved in buffer at 5% there was no additional effect on gel viscosity reduction. The incorporation of positively-charged and sterically stabilized liposomes at 2 mM of lipid concentration had no incidence on rheological properties of the Carbopol gels, whereas gel viscosity was significantly increased in the presence of positively-charged liposomes at 10 mM of lipid concentration. Finally, the viscosity of hydrogels containing both liposomes and methyl-beta-cyclodextrin tended to be close to control gels, remaining high and relevant for a topical delivery.     

Area under rheogram as multi-point viscosity characteristic of the sterilized hypromellose hydrogels

In this work, the cone and plate rheological viscometry readings of the sterilized hydrogels of hypromellose 4000 (60 g/L) were investigated by using of the three-parameter Herschel a nd Bulkley powerlaw and the new empirical two-parameter model. In it, the independent variable of shear rate was transformed by logarithm and the dependent variable of shear stress by square root. The two-parameter model showed only non-significantly lower mean value of the coefficient of determination when compared with the results of the three-parameter power law model being of good promise in other investigation of the near pseudoplastic rheograms of hypromellose hydrogels. To express the influence of the addition of the isotonic concentration of sodium chloride and/or pilocarpine hydrochloride, respectively, on the viscosity of sterilized hydrogels of hypromellose, the area under rheogram (AUR) data was employed as a multi-point theological characteristic. No significant differences were noted between AUR calculated using three parameters of the power law model and those calculated using two parameters of the proposed one. The significant increase in viscosity was observed in the presence of the isotonic concentration of sodium chloride in comparison to the hydrogel without additives. In the opposite, the addition of the isotonic concentration of pilocarpine hydrochloride resulted in the significant viscosity decrease. In conclusion, the proposed empirical two-parameter model could be used as the rheological model in investigation of the near pseudoplastic rheograms of the sterilized hypromellose hydrogels.     

Mono-N-carboxymethyl chitosan (MCC), a polyampholytic chitosan derivative, enhances the intestinal absorption of low molecular weight heparin across intestinal epithelia in vitro and in vivo

The synthesis and evaluation of mono-N-carboxymethyl chitosan (MCC) as an intestinal permeation enhancer for macromolecular therapeutics is presented. MCCs were synthesized from two different viscosity grade chitosans to yield both high and low viscosity grade products. These MCCs were tested on Caco-2 cells for their efficiency to decrease the transepithelial electrical resistance (TEER) and to increase the paracellular permeability of the anionic macromolecular anticoagulant low molecular weight heparin (LMWH). For in vivo studies, LMWH was administered intraduodenally with or without MCC to rats. Both types of experiments were performed at pH 7.4. Results show that both viscosity grade MCCs managed to significantly decrease the TEER of Caco-2 cell monolayers when they were applied apically at concentrations of 3-5% (w/v). Transport studies with Caco-2 cells revealed substantial increases of LMWH permeation in the presence of both viscosity grade MCCs compared with controls. In rats, 3% (w/v) low viscosity MCC significantly increased the intestinal absorption of LMWH, reaching the therapeutic anticoagulant blood levels of LMWH. Both in vitro and in vivo results indicate that the polyampholytic chitosan modification MCC is a suitable and functional polymer for the delivery and intestinal absorption of anionic macromolecular therapeutics like LMWH.     

Formulation and in vitro evaluation of prednisolone buccoadhesive tablets

In this research, the effect of mucoadhesive polymers such as hydroxyl propyl methyl cellulose (HPMC) with viscosity grade 60 and 500 mPas, sodium carboxy methyl cellulose (NaCMC) and carbopol 934 (Cp 934) alone or in combination with each other on the release profile of prednisolone was studied and mucoadhesion strength of these buccoadhesive formulations was evaluated. The results showed that the release of prednisolone from HPMC with viscosity grade 60 mPas and Cp 934 alone was fast and their mucoadhesion strengths was low. On the other hand, the release rates of prednisolone from the HPMC viscosity grade 500 mPas and NaCMC and mucoadhesion strengths were moderate and suitable. The results showed that with different blends of HPMC viscosity grade 500 mPas or NaCMC and Cp 934 with increasing in HPMC or NaCMC/Cp 934 ratio a remarkable decrease in the rate of drug release and an appreciable increase in the mucoadhesion strength was observed. Except from the formulations prepared with HPMC viscosity grade 60 and 500 mPas, other formulation had more fluctuations in release profiles and their kinetics of release were not fitted to zero order model.     

The evaluation of the rheological properties of lactose/microcrystalline cellulose and water mixtures by controlled stress rheometry and the relationship to the production of spherical pellets by extrusion/spheronization.

The consistency of wet powder masses produced from two ratios (7:3 and 8:2) of alpha-lactose monohydrate (L) and microcrystalline cellulose (MCC) mixed with a range of water contents has been assessed with a parallel plate controlled stress rheometer. The range of water contents, which could be studied, was restricted to those, which could be extruded uniformly by a ram extruder. In the creep mode, the instantaneous compliance increased as the water content increased for both L:MCC ratios illustrating the increasing deformability of the mixtures with increasing water content. The derived apparent viscosity of the mixtures as a function of shear rate, increased as the water content decreased and the values for all the systems fell on a common line. This indicates that the measurements are providing a reliable assessment of the mixtures and that the change in water content and L:MCC ratio provides systems, whose change of viscosity with rate of shear is consistent at low rates of shear. The values of the storage and loss moduli obtained from oscillatory measurements, increased with a decrease in water content but this time the two ratios of L:MCC were not on a common line when related to the water content of the mixtures. There was a range of water levels over which both the values of the storage and loss moduli were approximately constant. This corresponded to the level of water, which produced the pellets of the smallest diameter and range of diameters and were of the most spherical shape when produced by a ram extruder and spheronization. For 8:2 L:MCC ratio, there appeared to be a value for both the storage and the loss moduli above which the wet mass could not produce good pellets. For the 7:3 L:MCC these limiting levels were not achieved before extrusion with steady state conditions could be maintained without the mass being too wet or too dry. Instead, there appeared to be minimum levels of the moduli required to ensure that the mixtures were able to produce good pellets.     

Importance of excipient wettability on tablet characteristics prepared by moisture activated dry granulation (MADG)

For moisture activated dry granulation (MADG), microcrystalline cellulose (MCC) or silicon dioxide is recommended for the moisture absorption stage. The aim of this study was to assess the suitability of alternative excipients as moisture absorbents with regard to the disintegration mechanism of resulting lactose based placebo formulations. Beside high and low moisture MCC grades, the additions of magnesium aluminometasilicate (MAMS), pregelatinized starch (S1500), crospovidone (Kollidon CL) and carmellose calcium (ECG 505) were evaluated. High shear granulation (HSG) was conducted as a reference process. The overall disintegration time of all tablets produced by MADG was significantly faster whereas hardness yield and mass-variability were equal or superior compared to the HSG process. Powder wettability of the different moisture absorbents was identified to be a key driver for rapid disintegration, whereas tablet porosity had only a minor influence on the target hardness of the tablets.     

Influence of degree of polymerization on behavior of cellulose during homogenization and extrusion/spheronization

The study objective was to investigate the influence of the degree of polymerization (DP) of cellulose materials (microcrystalline cellulose [MCC] and powder cellulose [PC]) on the behavior of these materials during homogenization and extrusion/spheronization processes. Suspensions of the cellulose types with different DP values were homogenized using a high-pressure homogenizer. The particle size, agglomeration index, and apparent viscosity of these suspensions was determined at different times after pouring. Additionally, these different cellulose types were processed into pellets using the extrusion/spheronization, method, and the water content and power consumption as a function of the DP were determined. Cellulose types with a high DP value showed greater particle size after homogenization, than the types with a low DP value. In contrast, no relevant relationship between the apparent viscosity and DP could be observed. During the extrusion process, water content in the extrudate and pellet porosity were increased as the DP was increased for the extrudates produced at the same level of power consumption. MCC types with various DPs compared with PC provided a novel way of understanding the role of cellulose in the extrusion process. The DP showed a remarkable influence on the physicochemical properties of the cellulose materials and, consequently, on the behavior of these materials during the extrusion/spheronization process. It is postulated that the sponge model is more appropriate for the cellulose type with high DP (PC), whereas the gel model is more applicable to cellulose types with lower DP (MCC).     

Spray-dried microparticulate systems containing acetaminophen

The present work investigates the preparation and the release of acetaminophen from spray-dried microparticles. Two cellulose derivatives were tested as sustaining agents: microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (NaCMC). In-vitro dissolution studies were carried out in dissolution media of different pH. With MCC, the adsorption of acetaminophen on the surface or in the pores of the polymer does not allow a significant sustained release of the drug, which completely dissolves in 1 h. Conversely, the use of NaCMC retards the release of acetaminophen over a period of 6-8 h. The drug release depends on the plasticizer used and on the pH of the dissolution medium, and the mechanism consists essentially in the diffusion of the drug through the swollen polymeric matrix. The pH dependence observed can be correlated with a lower hydrophylicity of the polymer in acidic medium, which retards gel formation.     

Spray-dried microparticulate systems containing acetaminophen

The present work investigates the preparation and the release of acetaminophen from spray-dried microparticles. Two cellulose derivatives were tested as sustaining agents: microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (NaCMC). In-vitro dissolution studies were carried out in dissolution media of different pH. With MCC, the adsorption of acetaminophen on the surface or in the pores of the polymer does not allow a significant sustained release of the drug, which completely dissolves in 1 h. Conversely, the use of NaCMC retards the release of acetaminophen over a period of 6-8 h. The drug release depends on the plasticizer used and on the pH of the dissolution medium, and the mechanism consists essentially in the diffusion of the drug through the swollen polymeric matrix. The pH dependence observed can be correlated with a lower hydrophylicity of the polymer in acidic medium, which retards gel formation.     

The rheological properties of self-emulsifying systems, water and microcrystalline cellulose.

The rheological properties of mixtures of equal parts of a range of ratios of a self-emulsifying system (MP) and water (W) added to microcrystalline cellulose (MCC), have been measured by an extrusion capillary rheometer. These measurements allow assessment of both the shear and tension components of flow plus the elastic behaviour of the wet powder masses, although the results for the estimation of shear stress require careful interpretation due to the limitation of the measuring system and the assumptions made in their derivation. The results indicate that there are three regions of behaviour of the systems, which are all significantly different from the mixtures containing only W and MCC. At low MP contents (1.5--23%), the masses increase in their resistance to shear and elongational flow and have lower elasticity. These similarities in behaviour occur in spite of considerable increase in the viscosity of the MPW mixtures and a change to non-Newtonian flow of the fluid. The behaviour of the 46% MP system is intermediate between these systems and the high MP concentrations (69, 80 and 92%). These latter systems show less resistance to shear and elongational flow than the first group of concentrations, but show considerably higher levels of elasticity. As the resistance to shear decreases, so does the impairment of the surface of the extrudate. There is clear evidence of a systematic change in behaviour of the wet powder masses as the values for the angle of entry of the wet mass into the die when plotted against the ratio of the resistance to die entry (upstream pressure loss) to the shear stress within the die, is linear on a log/log scale. Also, the values of compliance of the systems as a function of shear stress fall on a common curve. Changes in the ratio of the MPW to MCC for a system for a single level of MP (46%) resulted in a change in the values of the rheological parameters but not the type of behaviour. As all these wet powder masses had been shown previously to form pellets by the process of extrusion/spheronization, it is clear that systems with a wide range of rheological characteristics can be processed and no single rheological parameter can be used to provide complete characterisation of the processability of such systems.     

Torque rheological parameters to predict pellet quality in extrusion-spheronization

This study explored the feasibility of predicting the quality of microcrystalline cellulose (MCC) pellets prepared by extrusion-spheronization using torque rheological characterization. Rheological properties of eleven MCC grades as well as their binary mixtures with lactose (3:7) at various water contents were determined using a mixer torque rheometer (MTR). Derived torque parameters were: maximum torque and cumulative energy of mixing (CEM). CEM values of MCC powders (CEM((MCC))) could be attributed to their physical properties such as crystallinity, V(low P) and V(total) (volumes of mercury intruded in their pores at low pressure and the total intrusion volume), bulk and tapped densities. For both MCC powders and their binary mixtures, strong correlation was observed between their torque parameters and the properties of their pellets formed with 30 and 35% (w/w) water. Since this relationship was valid over a broad water content range, rheological assessment for pre-formulation purposes need not be performed at optimized water contents. These results demonstrated the usefulness of torque rheometry as an effective means of comparing and evaluating MCC grades especially when substitution of equivalent grades is encountered. In so doing, the tedious and expensive pre-production (pre-formulation and optimization) work can be considerably reduced.