Compaction mechanism and tablet strength of unlubricated and lubricated (silicified) microcrystalline cellulose.

This paper describes the differences in compaction properties between microcrystalline cellulose (MCC) and microcrystalline cellulose co-processed with colloidal silicon dioxide (SMCC). The different compaction parameters are not only compared for the pure materials, but also for the lubricated powders with magnesium stearate. Neither magnesium stearate, nor colloidal silicon dioxide, facilitates extensively the densification of (silicified) microcrystalline cellulose during compaction. The difference in tablet relaxation of MCC and SMCC indicates a small negative effect of colloidal silicon dioxide on the interparticle bonding strength of unlubricated MCC. However, for lubricated MCC a larger increase in tablet relaxation at a high compression speed was found than for lubricated SMCC tablets. Accordingly, the decrease in tablet strength was larger for the MCC tablets than for the SMCC tablets when lubrication was applied. The examination of the tablet strengths of tablets compressed from physical mixtures of MCC with increasing concentrations of colloidal silicon dioxide proved the slightly negative influence of silicon dioxide on the tablet strength of unlubricated MCC tablets and the positive effect of colloidal silicon dioxide addition on the tensile strength of lubricated MCC tablets. Co-processing of MCC with colloidal silicon dioxide showed no extra contribution on the tablet strength of lubricated tablets above the physical mixtures. The interactions between the different materials were further supported by the interaction parameters based on partial solubility parameters.

On the employment of lambda carrageenan in a matrix system. III. Optimization of a lambda carrageenan-HPMC hydrophilic matrix.

The lambda carrageenan/HPMC ratio in matrix tablets has been optimized in order to obtain pH-independent release profiles of chlorpheniramine maleate, a freely soluble drug. Release profiles in acidic (pH1.2) and neutral (pH 6.8) media were fitted according to the Weibull and the power law models. Model independent parameters(t50% and the percentage of drug released after 2 h) were also calculated. The Weibull parameters were found suitable to describe the dependence of the release profiles on matrix composition. Preparation and testing of the optimized formulation showed linear and pH-independent release profiles lasting about 24 h, in good accordance with the values predicted by the optimization procedure.

Effect of microcrystalline cellulose on liquid penetration in and disintegration of directly compressed tablets.

The penetration of isooctane and water into tablets of microcrystalline cellulose, dibasic calcium phosphate dihydrate, spray-crystallized maltose-dextrose, and blends of microcrystalline cellulose with one of the other excipients were studied. The isooctane penetrations occurred according to the Washburn equation and were not affected by the presence of 0.5 or 1.0% magnesium stearate. The inhibition of aqueous penetration into tablets resulting from hydrophobic magnesium stearate was less pronounced for vehicles like dibasic calcium phosphate, which exhibited extensive brittle fracture under compression. Microcrystalline cellulose tablets, both with and without magnesium stearate, exhibited extremely fast aqueous penetration even at low porosities, caused by breaking of the hydrogen bonds and subsequent widening of the pores. Ratios between water uptake and original pore volume up to 20 were obtained for microcrystalline cellulose tablets. This unique property was, however, suppressed by the presence of fast dissolving and highly soluble excipients like dextrose, resulting in an antagonistic disintegration behavior of tablets compressed at pressures over 10,000 N/cm2. Improved disintegration properties were obtained by blending microcrystalline cellulose with an insoluble vehicle such as dibasic calcium phosphate dihydrate.

Interaction of tablet disintegrants and magnesium stearate during mixing I: Effect on tablet disintegration.

The effect of magnesium stearate on the disintegration of tablets was studied. Three different preblends, containing a slightly or a strongly swelling disintegrant, were mixed before compression with magnesium stearate for different time periods. The results show that a strongly swelling disintegrant, such as sodium starch glycolate in contrast to potato starch, can reduce the deteriorating effect of hydrophobic lubricants on tablet disintegration. However, the interaction between magnesium stearate and potato starch or sodium starch glycolate and the resulting differences in disintegration characteristics can be masked by the use of disks in the USP disintegration apparatus.

The influence of particles of a minor component on the matrix strength of sodium chloride.

This paper deals with the matrix strength of sodium chloride particles in pure sodium chloride tablets and in tablets compressed from binary mixtures of sodium chloride with low concentrations of pregelatinised starch. Because this study concerns the strength of the sodium chloride matrix, the tablet strength is reflected as a function of the sodium chloride volume fraction in the tablet. Starch particles in the mixture tablets decrease the sodium chloride volume fraction-tensile strength relationship compared with that of pure sodium chloride tablets. To determine the contribution of the sodium chloride matrix to the tablet strength, the starch particles were removed from the mixture tablets by heat treatment. Determination of the strengths of these heat-treated tablets reveals that the sodium chloride matrix strength determines the tablet strength of mixture tablets containing a single matrix of sodium chloride particles. The decrease of the sodium chloride matrix density in the three different tablets (pure sodium chloride tablets, mixture tablets and heat-treated tablets) is reflected by an increase of the median pore size. The matrix in sodium chloride tablets shows a higher tensile strength to median pore size relation than the matrices in the mixture and heat-treated tablets. Based on calculations according to the theory of elastic-brittle fracture, it is suggested that the initial presence of starch particles during tablet compaction causes the pores in the matrices of the mixtures and heat-treated tablets to be relatively more flat and longer. These pores weaken the sodium chloride matrix in the mixture and heat-treated tablets to a larger extent than the shorter, more spherical pores formed during compaction of pure sodium chloride.

Pore formation in tablets compressed from binary mixtures as a result of deformation and relaxation of particles.

This paper describes the internal structure of tablets compressed from binary mixtures of sodium chloride and pregelatinised starch. The minimum particle diameter of pregelatinised starch inside tablets compressed from mixtures was calculated from the difference between the initial pore size distribution and the pore size distribution after removal of the starch particles by burning. Subsequently, the tablets were carefully crushed. These powders, consisting of almost only sodium chloride particles, were measured by laser diffraction. It was found that the diameter of the sodium chloride particles hardly changed, whereas the minimum diameter of starch particles strongly decreased during the compaction process. As an effect of the difference in yield pressure, the harder sodium chloride particles cause deformation of the softer starch particles, resulting in a change in particle shape. The pore size distribution of tablets compressed from mixtures of sodium chloride and starch is typically that of viscoelastic materials; the larger pores (>5 microm) change, while the small pores stay constant in number and size. The median pore diameter in tablets compressed from the mixtures is higher than the median pore diameter in tablets compressed from the pure materials. This paper shows that the formation of large pores was the result of the extra porosity expansion of tablets compressed from binary mixtures of sodium chloride and pregelatinised starch.

DC calcium lactate, a new filler-binder for direct compaction of tablets.

In this paper, a directly compressible form of calcium lactate is introduced as a filler-binder for direct compaction of tablets. Calcium lactate is one of the most important calcium sources and has, in comparison with other organic calcium salts, a good solubility and bioavailability. Two different modifications, calcium lactate trihydrate and calcium lactate pentahydrate are described in the main pharmacopoeias. This paper describes that the compaction properties of calcium lactate pentahydrate (Puracal DC) are much better than those of the calcium lactate trihydrate (Puracal TP). Calcium lactate pentahydrate has better compaction properties than dicalcium phosphate dihydrate, even if lubricated with magnesium stearate. Moreover, as a consequence of its crystalline structure, calcium lactate pentahydrate has a low compaction speed sensitivity. This means that, in combination with its excellent flow properties, calcium lactate pentahydrate is a suitable filler-binder in tablets prepared by high-speed compaction. In a number of formulation examples it will be illustrated that tablets containing calcium lactate pentahydrate as main or additional filler-binder have a short disintegration time and a fast drug release. Directly compressible calcium lactate can be considered as a promising excipient in both pharmaceutical tablets and tablets for the nutraceutical market.

Effect of magnesium stearate on bonding and porosity expansion of tablets produced from materials with different consolidation properties.

The negative effect of magnesium stearate on tablet strength is widely known. This strength reduction is always considered to be the result of reduction of interparticle bonding. It is also known that interparticle bonding affects relaxation of tablets. Relaxation increases with decreasing bonding. Microcrystalline cellulose is an example of a material with a high lubricant sensitivity, which effect is caused by its plastic deformation behavior during compression. This paper shows for microcrystalline cellulose that the porosity under pressure was equal for unlubricated tablets and for tablets containing 0.5% magnesium stearate. This points to equal densification properties. The lubricated tablets show, however, a much larger relaxation than the tablets without magnesium stearate. This difference can be ascribed to the reduction of interparticle bonding by the lubricant, because a strong interparticle bonding counteracts tablet relaxation. In contrast to microcrystalline cellulose, aggregated gamma-sorbitol (Karion Instant) has a low lubricant sensitivity. Both porosity under pressure and tablet relaxation were found to be equal for lubricated and unlubricated sorbitol tablets. This phenomenon is caused by the particle structure of gamma-sorbitol. During compression, a lubricant film will be destroyed by fragmentation of the sorbitol aggregates. For this reason, magnesium stearate will hardly affect the interparticle bonding between sorbitol particles and hence have only a small or no effect on tablet relaxation.

Tensile strength of tablets containing two materials with a different compaction behaviour.

The tensile strength of tablets compressed from binary mixtures is in general not linearly related to the strength of tablets prepared from single materials; in many cases it shows a decreased tensile strength relative to interpolation. The materials used in this study, sodium chloride and pregelatinised starch, are both plastically deforming materials, but have a different densification and relaxation behaviour. The yield pressure of the binary mixtures shows an almost linear relationship. As an effect of their lower yield pressure, starch particles yield earlier than sodium chloride particles. The following enclosure prevents some sodium chloride particles to yield or crack. The relaxation of the tablets is higher than the relaxation calculated by linear interpolation of the relaxation behaviour of the two pure materials. The difference between the measured porosity expansion and the data obtained by linear interpolation can be considered as a measure for the reduced interparticle bonding. SEM-photographs indicate that the reduced interparticle bonding is caused by the low adhesive forces. The measured decrease of the tensile strength of the tablets is also considered to be the result of reduced interparticle bonding. In this paper it is shown that there exists a similar relationship between the tensile strength reduction and the percentage of starch on the one hand and the extra porosity expansion and the starch percentage on the other hand.

Optimization of a formulation for direct compression using a simplex lattice design.

In this paper it is demonstrated how the optimum composition of a mixture for direct compression consisting of alpha-lactose monohydrate, roller-dried beta-lactose and microcrystalline cellulose can be found using a systematic optimization technique. The experiments were chosen according to a simplex lattice design. The results of these experiments were used to fit a mathematical model, which then can predict the properties of all possible mixture compositions and enables a graphic representation of these properties in the form of contour plots. At a level of 4% the effect of three disintegrants (sodium starch glycolate, croscarmellose sodium and crospovidone) on the properties of the tablets compressed from these filler-binders, was evaluated by superimposing the contour plots of the different tablet responses. It was found that all the disintegrants used were effective in this combination of filler-binders. In order to evaluate drug dissolution rate an extra experiment with crospovidone as the disintegrant was performed, in which oxazepam was used as a test drug.

Native starch in tablet formulations: properties on compaction.

Maize, potato, rice and tapioca (cassava) starch were evaluated with respect to their properties on direct compression. Rice starch showed much better compactibility as compared to maize, potato and tapioca starch. Moreover, its binding capacity proved to be almost insensitive to mixing with magnesium stearate. This in contrast to the dramatic decrease in crushing strength of potato starch tablets containing the lubricant. The compactibility of the starches was found to be strongly affected by the equilibrium moisture content of the starches, which is dependent on the relative humidity of the atmosphere under which the powders were stored. All starches showed adequate capacity for water uptake to act as a disintegrant. Rice starch exhibited worst flowability, caused by its fine particle size as compared to the other starches. Granulation of rice starch changed it into a potential filler-binder in tablets prepared by direct compression.

Improvement by super disintegrants of the properties of tablets containing lactose, prepared by wet granulation.

The crushing strength, disintegration and dissolution properties of tablets, made by wet granulation with lactose as filter, gelatin as binder, potato starch as disintegrant and magnesium stearate as lubricant can be markedly improved when the potato starch (20%) is replaced by a much lower concentration (4%) of an insoluble super disintegrant, such as sodium starch glycolate (Primojel) or crospovidone (Polyplasdone XL). The incorporation of partially water soluble super disintegrants such as low-substituted sodium carboxymethylcellulose (Nymcel, ZSD 16), causing a viscous barrier in the tablets when containing water, is shown to be deleterious for both tablet disintegration and drug release. In contrast to potato starch, the position of the super disintegrants (intragranular, extragranular or equally distributed) had hardly any effect on the tablet properties. The improved properties of the tablets containing insoluble super disintegrants, when compared to tablets with potato starch, are the result of the use of a much lower concentration of disintegrant, but especially of the difference in effect of magnesium stearate on the disintegration capacity of the slightly swelling potato starch and the strongly swelling super disintegrants, respectively. The latter cause, even in the presence of the liquid penetration inhibiting hydrophobic magnesium stearate, a chain reaction of opening of the tablet, starting at the outside and resulting in a fast disintegration.

Influence of plasticizers on tableting properties of polymers.

This study relates tablet formation with relaxation properties of two polymers on the basis of the stress-deformation curve. The mechanical properties of the polymers were varied by changing tableting temperature, adding varying amounts of plasticizer, and incorporating a monomer with plasticizer effect on the polymer chain. The crucial parameter appeared to be the difference between the glass transition temperature and the tableting temperature. This temperature difference was found to determine the amount of energy stored during densification. The energy is manifested as the stress relaxation propensity of the material. Large stress relaxation yields porous and consequently weak tablets. At a low temperature difference (i.e., tableting temperature is much lower than the glass transition temperature), the amount of stored energy is large. An increase in tableting temperature, or a decrease in glass transition temperature, yields a decrease in stored energy as a result of a decrease in yield strength. Consequently, production of less porous and stronger tablet is possible. However, if the tableting temperature is higher than the glass transition temperature, the stress relaxation propensity of the deformed polymers is extremely high because the elastic modulus of the materials is low under these circumstances. This results is porous and even capped tablets. From the data it is concluded that, independent of the type of polymer and the method of plasticizing, compaction at a temperature of about 20 K under the glass transition temperature yields circumstances for which the amount of stored energy has a minimum. Consequently, tablet porosity has a minimum and tablet strength has a maximum. These circumstances are created by changing both the tableting temperature and the glass transition temperature of the powder.

Dissolution enhancement of an insoluble drug by physical mixture with a superdisintegrant: optimization with a simplex lattice design.

The aim of the present work was to optimize a tablet formulation containing a physical mixture of a practically insoluble drug (prednisone) with a superdisintegrant (croscarmellose sodium) and two filler-binders characterized by differing water solubility (dicalcium phosphate dihydrate and anhydrous beta-lactose). Crushing strength, disintegration, and dissolution were measured for 10 formulations distributed over a factor space according to a simplex lattice design for a special cubic model. Multiple linear regression analysis was used to assess the best fit for each variable. The model predicted that increasing the amount of disintegrant to a critical amount (50%) would result in reduced disintegration time for dicalcium phosphate/beta-lactose ratios > 0.3, no changes in disintegration time for ratios < 0.3, and for all ratios an improvement in dissolution at 10 min. Crushing strength values of dicalcium phosphate increased with increasing disintegration concentration but not for beta-lactose tablets. The physical mixture of a practically insoluble drug with a superdisintegrant was confirmed as a valid approach to the improvement of dissolution, even in presence of other components. The solubility of the filler-binders influenced the minimum amount of disintegrant needed; when a soluble diluent was used, the amount of disintegrant required was reduced.

Studies on tableting properties of lactose. Part III. The consolidation behaviour of sieve fractions of crystalline alpha-lactose monohydrate.

The consolidation and compaction behaviour of sieve fractions of crystalline alpha-lactose monohydrate were studied. From mercury porosimetry measurements tablet pore surface areas were derived. At a certain compaction load it appeared that tablets compressed from small particles were generally stronger and showed a larger surface area than compacts prepared from coarse sieve fractions. By plotting compact strength against pore surface area, a unique linear relationship was obtained. From these results it can be concluded that the actual tablet surface area, being a function of both the initial particle size and applied compaction pressure, is responsible for the compact strength.

Development and optimization of pharmaceutical formulations using a simplex lattice design.

The composition of pharmaceutical formulations is often subject to trial and error. This approach is time consuming and unreliable in finding the best formulation. Optimization by means of an experimental design might be helpful in shortening experimenting time. Such a design with the concomitant mathematical models, reveals effects and interactions of the variables. The independent variables are the different compositions of the mixtures of the chosen ingredients [drug(s) and excipients]. The dependent variables are the properties (responses) of the formulation. When all responses of interest have been expressed in models that describe the response as a function of the composition of the mixture, the models can be combined graphically or mathematically to find a composition satisfying all demands. In this paper an introduction to the use of mixture designs will be given by means of a theoretical part and an example: optimizing a tablet formulation consisting of excipients only.

Studies on tableting properties of lactose. Part 2. Consolidation and compaction of different types of crystalline lactose.

Lactose is available in several crystalline forms, which differ in binding properties. A new method of estimating the fragmentation propensity was applied to investigate the consolidation and compaction behaviour of this excipient for direct compression. Mercury porosimetry was used to demonstrate that crystalline lactose fragments during compaction. Tablet strength was found to be dependent on the degree of fragmentation only. This finding indicates that the nature of the actual binding must be the same for the different types of crystalline lactose.