Characteristics of Pharmaceutical Grade Phyllosilicate Compacts

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1 Pharmaceutical Development and Technology, 5(1), (2000) RESEARCH ARTICLE Characteristics of Pharmaceutical Grade Phyllosilicate Compacts César Viseras, 1 Africa Yebra, 2 and Alberto López-Galindo 2 1 Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Granada, Granada, Spain 2 IACT, CSIC-University of Granada, Faculty of Sciences, University of Granada, Granada, Spain Received August 5, 1998; Accepted June 30, 1999 ABSTRACT The purpose of this paper was to determine the possible employment of three groups of phyllosilicates (two smectites, three palygorskites, and two sepiolites) as direct-compression tablet excipients. Compact lots of each material were obtained after application of three different compression loads and the elastic recoveries and tensile strengths of each lot were then determined. The results showed that, in comparison with laminar minerals (smectite samples), fibrous minerals (palygorskites and sepiolites) were found to have lower elastic recovery, regardless of the compression load. Almost all elastic recovery happened immediately after the ejection of the compacts. Then, and at least during the next 24 hr, smectite compacts maintained their dimensions without any significant variation, whereas fibrous compacts tended to continue increasing slightly their dimensions. On the other hand, compacts made with laminar particles had higher mechanical strength than those made with fibrous particles, except for one sepiolite sample in which the strength was similar. Both particle morphologies and the presence or absence of hydration water molecules were taken into account in order to explain these differences. According to the compact properties measured, at least two of the noncommercial samples (smectite from Gádor, Spain, and sepiolite from Vicálvaro, Spain) would be useful as direct-compression tablet excipients. KEY WORDS: Compactibility; Compressibility; Palygorskite; Sepiolite; Smectite. INTRODUCTION Tablets are the most common form of drug administration. A tablet (or compact) can be defined as a special kind of disperse system (gas/solid) where the interactions between solid phase constituents are the main factors re- sponsible for compact stability and mechanical properties. Compaction is defined as the transformation of a powder into a coherent specimen (compact) of defined shape by powder compression, compression being the reduction in volume of the powder bed due to the application of a Address correspondence to César Viseras Iborra, Instituto Andaluz de Ciencias de la Tierra, CSIC-University of Granada, Facultad de Ciencias. Avda. Fuentenueva, s/n Granada, Spain. Fax: cviseras@platon.ugr.es 53 Copyright 2000 by Marcel Dekker, Inc.

2 54 Viseras, Yebra, and López-Galindo stress (1). A limited number of pharmaceutical studies have discussed the relationship between particle shape and compact properties. The mechanical strength of pharmaceutical compacts depends both on particle bond mechanics and active surface area for these bonds (2). Both factors are difficult to measure and frequently compact strength refers to indirect parameters such as particle and aggregate sizes (3), particle shape (4,5), both size and shape (6), or volume reduction profiles (7,8). The main objective of this work was to evaluate the applicability of three groups of phyllosilicates as directcompression tablet excipients. To evaluate the predominant bonding mechanism, the mechanical strength of some compacts elaborated with materials were measured and related to the specific surface area (bonding surface area). The presence of hydration and structural water molecules was established previously (9) and is also expected to affect bonding mechanics during compaction. MATERIALS AND METHODS Materials Two sepiolites (SV from Vicálvaro, Madrid, Spain, and SY from Yunclillos, Toledo, Spain), one palygorskite (PCR from Turón, Ciudad Real, Spain), and one bentonite (BG from Cabo de Gata, Almería, Spain) were studied. For comparative purposes, two fibrous clays used as pharmaceutical products (Pharmasorb regular [PHR] and colloidal [PHC]), and one commercial bentonite (Benthopharm [BTP]) were also included in the study. For each sample the sieve fraction between 75 and 125 µm was selected by dry sieving and then stored at 40% relative humidity and room temperature (22 25 C) for at least 48 hr before any study was performed. Elaboration of Compacts Compacts of each material were made up using a compaction simulator. The compression chamber consisted of a steel fixture equipped with a flat-faced punch, 12.3 mm in diameter, designed to be mounted in an automated hydraulic press (Instron automated testing system series IX, model 1250). One hundred milligrams of each material was individually weighed on an analytical balance and then manually filled into the die. Maximum punch pressures used were 165, 413, and 825 MPa. Distance between punches was continually measured during compaction and these data were used to calculate compressibility of the powder bed during the loading phase. At least 15 compacts were obtained at each pressure and then stored at 40% relative humidity and room temperature (20 25 C) for at least 48 hr before testing. Dimensions of Compacts A caliper was used to measure thickness and diameter of compacts immediately after ejection and after 24 and 48 hr in the conditions mentioned above. The values obtained were used to determine elastic recovery of the compacts following Spiegel et al. (10). Porosity and Specific Surface Areas Porosity and specific surface areas were analyzed to attempt to explain differences in the tensile strengths of each material. As mentioned above, compact dimensions were measured and used to evaluate porosity of the compacts as follows: %ε (ρ a /ρ b 1) 100 (1) where the density values were obtained by mercury intrusion and bulk density measurements. Specific surface areas of each set of compacts were measured by the same porosimeter (Autoscan 60, Quantachrome, Boynton Beach, FL) working at 60,000 psi with a resolution of 1 psi. Density values obtained by mercury intrusion were used as true densities, even if those values were always an approximation. Mechanical Strength Radial tensile strength of five compacts was measured by diametric compression following Fell and Newton (11). Results are mean values of five measurements. Values of tensile strength were divided by the correspondent surface area of the compacts to obtained the surfacespecific compact strength (SSCS) in Kpa/cm 2. RESULTS AND DISCUSSION Dimensions and Elastic Recovery of Compacts Results of elastic recovery just after ejection (R 0 ) and 24 hr after ejection (R 24 ) are shown in Table 1. We have also included the compression values at maximum stress obtained by %C 100(d c d 0 )/d c (2)

3 Characteristics of Phyllosilicate Compacts 55 Table 1 Compressibility, Elastic Recovery, Tensile Strength, and Surface Specific Compact Strength (SSCS) of the Materials Tensile Applied Stress Compressibility R 0 R 24 Strength SSCS (MPa) Sample (%) (%) (%) (MPa) (KPa/cm 2 ) 165 BG BTP PCR PHC PHR SV SY BG BTP PCR PHC PHR SV SY BG BTP PCR PHC PHR SV SY where d c is the apparent density of the powder when a maximum load was applied, and d 0 is the initial value of bulk density of the powder in the compression chamber. As expected, volume reduction (compressibility) and elastic recovery increased with stress, being affected by the shape of aggregates and fiber lengths. Figures 1(a) (c) show the relations between percentages of compression and elastic recovery of compacts immediately after ejection (0 hr) for each group of materials as a function of the three different applied stresses. In all cases we observed a linear relationship between both parameters, with a tendency for elastic recovery to increase as compression increased. The slope of this increase indicates the tendency to laminate. The slopes corresponding to the laminar samples have, in general, higher values than those of fibrous materials. Axial elastic recovery is an indirect measure of the elasticity of the particles forming the compact, and a high value of this is associated with a decrease in tablet strength because of the resulting reduction in bonding surface area. Particle shape and type of aggregates could explain this difference. All samples are formed of particles of similar sizes (between 2 and 5 µm), but with diverse geometrical shapes (laminar or fibrous). It is clear that laminar particles are more easily compressed than fibrous particles, for which a readjustment is necessary prior to the volume reduction. On the other hand, the samples consisting of fibrous particles can also be classified according to their particle surface geometry or surface textures. When pressure is applied to sepiolite aggregates, which have more cracks and defects, the aggregates tend to fragment into smaller particles that compress more efficiently. Palygorskite samples, on the other hand, form more compact aggregates that are difficult to separate. This could contradict with the fact that as the external surface roughness of a granule or particle aggregate increases, angle of repose will increase (i.e., flowability decreases). The possibility of particle interlocking should be taken into account, as this would cause zones of dilatant behavior resulting in nonuniform die-filling. Aggregate homogeneity may be high, but the fibrous aspect and/or fiber length pose problems for increasing the packing density of the powder.

4 56 Viseras, Yebra, and López-Galindo Figure 2. Ratios of elastic recovery, 0 versus 24 hr. (a) All samples; (b) samples grouped according to their nature: : sepiolites; : palygorskites; : smectites. Figure 1. Compressibility (%) versus elastic recovery (%) of the studied samples. (a) Smectites just after ejection; (b) palygorskites just after ejection; (c) sepiolites just after ejection. : BG; : BTP; : PCR; : PHC; : PHR; : SV; : SY. Finally, when we compare the results of elastic recovery obtained just after ejection and after 24 hr storage, we can see that almost all recovery occurs immediately after ejection [Fig. 2(a)]. When regression lines are adjusted to each type of material [Fig. 2(b)] we can see that the slopes are arranged in the same order as above, i.e., smectites palygorskites sepiolites. When extrapolated to zero, the lines cross the y-axis at 0.1, 5, and 10%. These values can be interpreted as the tendency of each group of compacts to increase its dimensions when stored. Smectite compacts maintained their dimensions without any significant variation from 0 to 24 hr, whereas fibrous compacts tended to continue increasing their dimensions for at least this period. The mechanical strength of compacts can change dramatically during a limited period of time after compaction, and elastic recovery is an important factor to be considered in this change. Analysis of their mechanical behavior is therefore required. Mechanical Strength The nature of particle particle interactions was measured indirectly by means of estimations of the SSCS,

5 Characteristics of Phyllosilicate Compacts 57 i.e., the ratio between radial tensile strength and surface area of the powders before compacting. Results from tensile strength and the resultant SSCS as a function of applied stress are shown in Figs. 3(a) (c) and in Table 1 (only SSCS values have been included in the figures because those of tensile strength resulted in identical plots). Both smectite samples gave compacts of similar mechanical behavior. The particles presented good adhesion and thus, even when compressed at 165 MPa, compactibility increased as the compression load increased and after a certain load remained at similar values. In the paligorskite compacts mechanical interlocking required high compression forces and the compacts had low compact strength when compressed at 413 MPa. Sepiolitic compacts behaved very differently. SV gave high-strength compacts at 165 MPa, increasing with load, and then decreasing between 413 and 825 MPa; SY behaved similarly to the palygorskite samples. Both particle morphologies and the presence of hydration water molecules must be taken into account in order to explain these results. BG compacts may present nonfreely movable binder bridges resulting from the adsorption layers of water between adjacent particles. This effect is not present in BTP compacts because this material has Na as an interlaminar cation. Several authors have mentioned the effect of particle shape on compact strength, establishing that when the material fragmented to a limited extent, particle shape was affected, i.e., particle irregularity improved compactibility. On the other hand, if the material fragmented significantly, initial particle shape did not affect the final compact properties. In palygorskite compacts the increase in compactibility with load increase may be due to the fragmentation of the original aggregates followed by plastic deformation of the former particles. This deformation would be mainly on the edges and corners of the fibers and could be further enhanced by lattice defects, even if the packing properties of the particles are similar. The sepiolite samples gave strikingly different results. SV aggregates were more irregular, and consequently were more easily fragmented, because corners and defects correspond to weak parts that can be fractured or separated from the rest of the aggregate. This would increase the number of possible interparticulate attraction zones, and as a result, would increase the mechanical strength of the compact. When almost all of the aggregates were broken, a new increase in load caused a reduction of compact strength due to the breaking of isolate fibers and a consequent decrease in particle dimensions. CONCLUSIONS Figure 3. Surface-specific compact strengths as a function of applied pressure. (a) : smectites; (b) : palygorskites; (c) : sepiolites. When compacted, fibrous materials were found to have lower elastic recovery than laminar materials. Compacts made with laminar particles had higher mechanical strength than those made of fibrous particles, except for one sepiolite sample in which strength was similar. According to the characteristics of compacts, just two of the noncommercial samples (smectite from Gádor and sepio-

6 58 Viseras, Yebra, and López-Galindo lite from Vicalvaro) would be useful products as directcompression tablet excipients; none of the commercial materials would be useful as direct-compression tablet excipients. Recently, a substantial amount of research has been directed to improved understanding of particle packing and compaction, and to factors such as size distribution or particle shape that affect the properties of the final product. The choice of materials was adequate for evaluation of the influence of shape on compaction. In our opinion, fragmentation of particles does not always lead to an increase in homogeneity. Indeed, for aggregates of fibrous particles, the opposite is true. Control of the increase in surface area as a result of increasing loads allows us to determine whether significant fragmentation occurs during compression. This kind of material allows the use of nonmilled samples, with the advantage of avoiding the effects of milling on particle surface irregularities. ACKNOWLEDGMENTS This work was supported by the DGES project PB C REFERENCES 1. G. Alderborn and C. Nyström, Nomenclature, in Pharmaceutical Powder Compaction Technology (G. Alderborn and C. Nyström, eds.), Marcel Dekker, New York, 1996, pp. vii viii. 2. C. Nyström, G. Alderborn, M. Duberg, and P. G. Harehill, Bonding surface area and bonding mechanism two important factors for the understanding of powder compactability, Drug Dev. Ind. Pharm., 19, (1993). 3. N. Kaneniwa, K. Imigaw, and J. Ichikawa, The effect of particle size on the compaction properties and compaction mechanism of sulfadimethoxine and sulfaphenazole, Chem. Pharm. Bull., 36, (1988). 4. L. W. Wong, N. Pilpel, and S. Ingham, Effect of particle shape on the compaction of powders, J. Pharm. Pharmacol., 40, 69P (1988). 5. G. Alderborn and C. Nyström, Studies on direct compression of tablets. III. The effect on tablet strength of changes in particle shape and texture obtained by milling. Acta Pharm. Suec., 19, (1982). 6. M. Çelik, J. T. H. Ong, Z. T. Chowhan, and G. J. Samuel, Compaction simulator studies of a new drug substance: Effect of particle size and shape, and its binary mixtures with microcrystalline cellulose, Pharm. Dev. Technol., 1, (1996). 7. J. K. Yliruusi and O. K. Antikainen, New parameters derived from tablet compression curves. Part I. Force-time curve, Drug Dev. Ind. Pharm., 23, (1997). 8. O. K. Antikainen and J. K. Yliruusi, New parameters derived from tablet compression curves. Part II. Forcedisplacement curve, Drug Dev. Ind. Pharm., 23, (1997). 9. C. Viseras, Caracterización de distintos materiales de origen mineral para su empleo en la elaboración de medicamentos: esmectitas, paligorskitas, sepiolitas, Ph.D. dissertation, Granada University, Granada, Spain, J. T. Fell and J. M. Newton, Determination of tablet strength by the diametral-compression test, J. Pham. Sci., 59, (1970). 11. P. E. L. Spiegel and G. F. Limbrunner, Stresses and strains, in Applied Statics and Strength of Materials, (P. E. L. Spiegel and G. F. Limbrunner, eds.), MacMillan Publishing, New York, 1994, pp

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