Mechanistic Study of the Effect of Roller Compaction and Lubricant on Tablet Mechanical Strength

Transcription

1 Mechanistic Study of the Effect of Roller Compaction and Lubricant on Tablet Mechanical Strength XIAORONG HE, PAMELA J. SECREAST, GREGORY E. AMIDON Pfizer, Inc, Ann Arbor, Michigan Received 30 September 2005; revised 7 July 2006; accepted 16 July 2006 Published online in Wiley InterScience ( DOI /jps ABSTRACT: Heckel analysis, tablet tensile strength, and indentation hardness were determined for a series of sieved and roller compacted microcrystalline cellulose mixtures under both unlubricated and lubricated conditions with magnesium stearate. These results have been used to evaluate the loss of reworkability following roller compaction for microcrystalline cellulose and show the extent of impact on tableting properties when magnesium stearate is added intragranularly prior to roller compaction. While results consistent with traditional work-hardening are observed as shown by a modest increase in dynamic hardness and mean yield pressure for unlubricated, roller compacted microcrystalline cellulose, it is overshadowed by the overlubrication effect seen during roller compaction and in particular, the subsequent milling step. The common practice of lubricating the feedstock with magnesium stearate to avoid sticking of the material to the compaction rolls appears to be the major cause of decreased mechanical strength of the final compressed tablets. ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: , 2007 Keywords: roller compaction; mechanical properties; compaction; tableting; lubrication; dry granulation; Heckel analysis; tensile strength; yield pressure; workhardening INTRODUCTION Roller compaction is commonly used in the pharmaceutical industry to densify material to enhance its flow properties and improve content uniformity. Unlike wet granulation, roller compaction does not require water during the processing steps. Therefore, it is highly desirable to use roller compaction to improve the processability of moisture sensitive materials that are not conducive to direct compression. One of the disadvantages associated with roller compaction is its loss of reworkability. 1,2 Here, Xiaorong He s present address is GlaxoSmithKline, Research Triangle Park, NC, USA. Correspondence to: Xiaorong He (Telephone: ; Fax: ; xiaorong.x.he@gsk.com) Journal of Pharmaceutical Sciences, Vol. 96, (2007) ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association reworkability is defined as the ratio of a material s tensile strength at a given solid fraction (SF) before and after roller compaction. It is often observed that a material tends to lose its mechanical strength after being roller compacted. A popular hypothesis for loss of reworkability is work-hardening, a phenomenon often observed in the metal industry, where the metal becomes more difficult to plastically deform after being worked multiple times. 1,3 5 It is hypothesized that work-hardening occurs due to entanglement of new dislocations or random defects formed during the initial plastic deformation phase. This entanglement makes further plastic deformation more difficult. Therefore, the stress needed to produce further deformation is increased. Workhardening is often used to explain the loss of reworkability after roller compaction. However, there has been little or no direct evidence to support this hypothesis. Therefore, it is of interest 1342 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

2 EFFECT OF ROLLER COMPACTION AND LUBRICANT 1343 to study if work-hardening indeed contributes to the loss of reworkability after roller compaction, and if so, to what extent. Microcrystalline cellulose is chosen as a model compound because it is a widely used pharmaceutical excipient and its mechanical properties are well understood. There have been a number of publications that studied the effect of roller compaction on microcrystalline cellulose 5 7 as well as the physical, chemical, and mechanical properties of microcrystalline cellulose The objective of this study was to utilize out-of-die Heckel analysis, tablet tensile strength data, and indentation hardness data to evaluate the reasons for the loss of reworkability seen in microcrystalline cellulose. Experiments were designed to systematically study the impact of roller compaction on the material properties of MCC with and without magnesium stearate after minimizing the impact of particle size. MATERIALS AND METHODS Materials Microcrystalline cellulose (Avicel PH-102, FMC, Philadelphia, PA) and magnesium stearate (Mallinkrodt Inc., St. Louis, MO) were used in this study. Sieving Microcrystalline cellulose was sieved using a rotary tapping sieve apparatus (Rotap) and the mesh cut of mm ( mesh) was used for all studies. The sieved microcrystalline cellulose was either used as-is or roller compacted as described below. By restricting the use of as-is and roller compacted material to a narrow particle size range, the effect of particle size on the compressibility, compactibility, and tabletability of the compacts and tablets could be minimized. Lubrication To study the effect of lubrication on the reworkability of roller compacted granules, microcrystalline cellulose (44 75 mm) was lubricated with 0.5% magnesium stearate for 2 min in a V blender before roller compaction and milling and then sieved following the same procedure as above. True Density The true densities of all lots were determined by helium air pycnometry (AccuPyc 1330, Micromeritics, Norcross, GA). The average density values were determined in duplicate without drying the material and the results averaged Roller Compaction Microcrystalline cellulose PH-102 (44 75 mm sieve fraction corresponding to mesh) was fed into a roller compactor (Vector TF-Mini roller compactor) fitted with interlocking serrated rolls that are horizontally placed. The feed rate, roll speed, and roll pressure were varied to produce ribbons with three different SF of 0.50, 0.65, and A segment of ribbon was cut into a rectangular shape and its dimensions were measured using a caliper. The surface of the ribbon is lined with narrow serration. The volume of the serration was considered negligible compared to the volume of the ribbon sample. Care was taken to measure the thickness between serrations. Due to the asymmetric feed, the ribbon thickness varied slightly from one edge to another. Therefore, the average thickness of both edges was used for calculation of the ribbon SF. The ribbon SF was calculated by dividing the weight of the ribbon by its length, width, thickness, and true density. The average SF was taken from the measurement of three samples that were collected randomly throughout the run. Ribbon SF remained reasonably constant during the run. To size ribbons into granules, ribbons were fed into a conventional impact mill (Fitzpatrick model L1A) equipped with a rotor bar oscillating at 300 rpm against a 20-mesh rasping screen. Granules that passed through the rasping screen were further sieved (Rotap). The sieve fraction of mm mesh was chosen so that the granule size matched that of the stock that was fed into the roller compactor. Tablet Compaction Properties Tablet Compaction A high-speed tablet press emulator (Presster, Metropolitan Computing Corporation, East Hanover, NJ) designed to mimic the displacement profile of a rotary press was used for all tableting operations. Tablets were manufactured using a 10 mm flat face round tooling at a dwell time of DOI /jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

3 1344 HE ET AL. 27 ms using 250 mm diameter compression rolls corresponding to 30 rpm on a Killian RTS 16 station tablet press. The compression forces on both upper and lower punches were recorded for each tablet. Determination of Solid Fraction The out-of-die tablet dimensions were measured with a caliper immediately after ejection of the tablet. Tablet SF was calculated by dividing tablet weight by tablet volume and true density of the tableting material. Determination of Tablet Tensile Strength A tablet was placed between two platens of a conventional hardness tester (Schleuniger tablet tester 6D). The resulting hardness was then converted to tensile strength using the equation: Tensile Strength ¼ 2F p thickness diameter The sharp, linear fracture plane through the center of the tablets indicated that failure was in tension. Mechanical Property Characterization Samples for mechanical testing were approximately 4.5 g rectangular compacts measuring 1.9 cm 1.9 cm 1.0 cm. Compacts were formed by rapid uniaxial compression followed by maintenance of the compression pressure for 90 s using a custom-built hydraulic press. Tri-axial decompression at a constant rate was achieved over 2 min using a split-die and a computer-controlled hydraulic system. 17 The punch and die surfaces were sparingly lubricated with magnesium stearate suspended in methanol. Square compacts were prepared and tested at SF ranging from 0.6 to 0.75 and properties estimated at SF ¼ 0.7 using log-linear regression analysis. Tensile strength and dynamic hardness measurements were completed for several lots of lubricated and unlubricated virgin microcrystalline cellulose as well as for the processed (roller compacted, milled, and sieved) material. This quasi-static, out-of-die mechanical property testing makes it possible to evaluate and separate out each of several mechanical properties in a way that is difficult or impossible with dynamic in-die testing using the compaction emulator. For this study, it offers an independent method for JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 estimating the dynamic hardness, bonding index (BI) (a measure of bonding efficiency), and tensile strength. Dynamic Indentation Hardness The dynamic indentation hardness using a pendulum impact device as described by Hiestand and Smith 17 (H) was determined for three compacts. Compacts were prepared at SF from 0.6 to 0.8 and regression analysis used to assess the indentation hardness at a SF of 0.7. The reference SF of 0.7 was chosen, as it is within the typical range for ribbon SF. H ¼ 4 mgrh r h i pa 4 3 h r 8 where m ¼ mass of the indenter, g ¼ gravitational constant, r ¼ radius of indenter, h i ¼ initial height of indenter, h r ¼ rebound height of indenter, and a ¼ radius of curvature. Tensile Strength The tensile strength of a solid compact was determined in triplicate. The tensile strength was measured by transverse compression of square compacts using the method of Hiestand and Smith. 17 A rectangular platen (width ¼ 0.76 cm and height ¼ 1.59 cm) was used to apply force to 40% of the total available compact edge. The tensile strength is related to the transverse compression force as follows. 17 where s T ¼ 0:16s C s T ¼ tensile strength and s C ¼ compression force. Statistical Analysis A one-factor ANOVA analysis was run for each tablet SF (0.60, 0.70, and 0.80) made from virgin and roller compacted microcrystalline cellulose (0.50, 0.65, and 0.84). The purpose of the ANOVA analysis was to detect if there are any statistical differences in tensile strength and yield pressure among virgin and roller compacted materials. If the overall F-test for material was DOI /jps

4 EFFECT OF ROLLER COMPACTION AND LUBRICANT 1345 significant (p < 0.05), the different materials were compared using contrasts (t-tests). Multiple comparisons of this type are often made using this technique called the protected F-test. The analysis was done using JMP statistical software. RESULTS AND DISCUSSION Compactibility, Compressibility, and Tabletability The data obtained from the compaction emulator were used to generate compactibility, compressibility, and tabletability plots. 18 Compactibility reflects a material s ability to produce compact strength (tensile strength) as a function of SF. Compressibility reflects a material s ability to undergo volume reduction under pressure. Tabletability reflects the compact strength (tensile strength) of the material as a function of compression pressure. Compactibility Figure 1 shows the tensile strength as a function of SF for several lots of unlubricated microcrystalline cellulose. A modest decrease in compactibility of the roller compacted material is seen compared Figure 1. Compactibility profile of compressed tablets of unlubricated microcrystalline cellulose (45 75 mm sieve fraction) ^, unlubricated, roller compacted (SF ¼ 0.50), unlubricated, roller compacted (SF ¼ 0.65) ~ unlubricated, roller compacted (SF ¼ 0.82). to that of the virgin (e.g., not roller compacted) unlubed microcrystalline cellulose. The change in compactibility seems to show a trend. A small decrease in compactibility was observed for compacts prepared with milled soft ribbons (SF ¼ 0.50), followed by greater decreases for regular ribbons (SF ¼ 0.65) and highly compacted ribbons (SF ¼ 0.82). The tensile strength of a compact prepared with granules made from a ribbon whose SF is 0.82 was reduced by about 30% as compared to the virgin stock (i.e., unworked) material of the same particle size. Since the data were somewhat scattered, ANOVA analysis was performed to determine if differences in compactibility are statistically significant between these ribbon SF (nonroller compacted virgin material, ribbon SF ¼ 0.50, ribbon SF ¼ 0.65, and ribbon SF ¼ 0.82). Table 1 lists tablet tensile strength at three-selected tablet SF (SF ¼ 0.60, SF ¼ 0.72, and SF ¼ 0.80). As shown in Tables 2a, 2c, and 2e, the compactiblity differences of unlubricated microcrystalline cellulose are statistically significant among virgin MCC and three ribbon SF ( p 0.001) for all three tablet SF. Protected F-test was run to determine which groups are statistically significant from each other. As shown in Tables 2b and 2d, at tablet SF of 0.60 and 0.72, the tensile strength of the virgin MCC is statistically different from that of the roller compacted MCC. Among the three ribbon SF, there is no statistical difference in tablet tensile strength between ribbon SF of 0.52 and 0.64, but there is a statistical difference between ribbon SF of 0.64 and When the virgin and roller compacted materials were compressed under a high enough compression force to form a tablet SF of 0.80, there is no statistical difference in tablet tensile strength between the virgin MCC and the ribbon SF of 0.52 and 0.64, as shown in Table 2f. However, the tensile strength of the hardest roller compacted material (SF ¼ 0.84) is significantly different from the rest of the three groups of materials. Overall, the ANOVA analysis implies that the extent of roller compaction does have a statistically significant impact on the compactibility of unlubricated microcrystalline cellulose. As shown in Figure 2, the effect of incorporating 0.5% lubricant into roller compacted microcrystalline cellulose is much more dramatic. The tablet tensile strength decreases significantly with increasing ribbon SF. For example, at a tablet SF of 0.70, the tablet tensile strength made of the virgin stock is 4 MPa, which is twice as much as that made of granules that were obtained from a DOI /jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

5 1346 HE ET AL. Table 1. Compactibility of Unlubricated Microcrystalline Cellulose at Various Tablet Solid Fractions a Roller Compaction Ribbon Solid Fraction Tablet Tensile Strength at Tablet SF of 0.60 (KN/cm 2 ) Tablet Tensile Strength at Tablet SF of 0.72 (KN/cm 2 ) Tablet Tensile Strength at Tablet SF of 0.80 (KN/cm 2 ) No NA Yes Yes Yes a For each ribbon solid fraction, tablet tensile strength was determined from triplicate of compacts at each given tablet solid fraction. soft ribbon (ribbon SF ¼ 0.52). As the ribbon SF increases to 0.64, the resulting granules produced a weak compact with tensile strength (0.4 MPa at a tablet SF ¼ 0.70) of only 10% of that of the tablet made of virgin material. As the ribbon SF further increases to 0.84, there is little additional reduction in the granule s mechanical strength. It is significant that lubrication of the feedstock caused microcrystalline cellulose tablets to lose 90% of its compactibility after roller compaction, whereas the pure unlubed microcrystalline cellulose retained almost all of it, at least for ribbons with SF of less than ANOVA analysis was again performed on virgin and three ribbon SF (ribbon SF¼ 0.52, ribbon SF ¼ 0.64, and ribbon SF ¼ 0.84) of lubricated microcrystalline cellulose for three selected tablet SF. As shown in Tables 3, 4a, 4c, and 4e, the compactibilty differences are statistically significant between ribbon SF ( p 0.001) for all three tablet SF. Protected F-test was run to determine if the differences between each of the two groups are statistically significant. As shown in Tables 4b and 4f, there is a statistical difference in tensile strength among all groups at tablet SF of 0.60 and As shown in Table 4d, except for the groups between ribbon SF of 0.64 and 0.84, every pair of the groups are statistically significant. The ANOVA analysis shows that the extent of roller compaction does have a statistically significant impact on the compactibility of lubricated microcrystalline cellulose. The proposed cause for the observed loss of compactibility is the additional time required for the ribbon-milling process to occur (mill retention time) as ribbon SF was increased. Increased mill retention time appears to have caused microcrystalline cellulose to be so well mixed with magnesium stearate that overlubrication occurred. Overlubrication occurs when the surface of the material is so well covered with the poorly bonding magnesium stearate that it can lead to a significant reduction of the bonding strength of the original material, especially for a plastically deforming material such as microcrystalline cellulose. At higher ribbon SF, a ribbon becomes harder to mill and remains for a longer period in the milling chamber. During milling, intensive mixing and chopping of the ribbons creates intimate contacts between microcrystalline cellulose and magnesium stearate. The longer the residence time, the better is the mixing between microcrystalline cellulose and magnesium stearate. As will be seen in the subsequent discussion, this rather than classical work-hardening seems to explain why the tensile strength decreases dramatically as ribbon SF increases. Even though it is well known that microcrystalline cellulose is sensitive to overlubing, 19 it has never been reported that overlubing actually occurs during roller compaction and subsequent milling. In fact, it is a common practice in the pharmaceutical industry to lubricate the feedstock with magnesium stearate prior to roller compaction to avoid sticking of the material to the roll surface. Equipment vendors often advise against such a practice, but for a different reason. Table 2a. ANOVA Analysis of Data Listed in Table 1 (Tablet Solid Fraction of 0.60) Ribbon solid fraction <0.001 Residual Total JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI /jps

6 EFFECT OF ROLLER COMPACTION AND LUBRICANT 1347 Table 2b. of 0.60) a Roller Compaction Compare All Groups (Tablet Solid Fraction Ribbon Solid Fraction Level Level Level Mean No NA A Yes 0.50 B Yes 0.65 B Yes 0.82 C a Levels not connected by the same letter are significantly different. They reason that addition of magnesium stearate to the formulation lowers the nip angle (an angle defined as the point at which the feed stock no longer slides relative to the roll surface), thereby, reducing the process efficiency. This work shows that the common practice of lubrication may negatively impact the mechanical strength of the resulting tablet. While changes in mill temperature were not monitored, a comparison of lubricated and unlubricated ribbons indicates that mill temperature is not an explanation for the dramatic decrease in compact tensile strength of lubricated material compared to unlubricated material roller compacted to the same SF. Compressibility As shown in Figures 3 and 4, roller compaction did not significantly change the compressibility of either lubed or unlubed microcrystalline cellulose with the exception of the dry granules made from ribbons with a SF of The compressibility of these granules was slightly decreased. Tabletability Figure 5 shows the effect of compression force on the tensile strength when unlubricated microcrystalline cellulose is used. Without lubrication, the tabletability of microcrystalline cellulose is only slightly reduced for tablets made of ribbons with a SF of 0.50 and However, the tabletability of microcrystalline cellulose was significantly reduced after microcrystalline cellulose was overcompacted to form a ribbon with a SF of Figure 6 illustrates how lubrication might facilitate the reduction of tabletability. The higher the ribbon SF, the more pronounced the reduction in tabletability. The microcrystalline cellulose granules become well coated with magnesium stearate during roller compaction and milling and form weaker tablets. The reduction of tabletability Table 2c. ANOVA Analysis of Data Listed in Table 1 (Tablet Solid Fraction of 0.72) Ribbon solid fraction <0.001 Residual Total Table 2d. Compare All Groups (Tablet Solid Fraction of 0.72) a Roller Compaction Ribbon Solid Fraction Level Level Level Mean No NA A Yes 0.50 B Yes 0.65 B Yes 0.82 C a Levels not connected by the same letter are significantly different. Table 2e. ANOVA Analysis of Data Listed in Table 1 (Tablet Solid Fraction of 0.80) Ribbon solid fraction Residual Total DOI /jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

7 1348 HE ET AL. Table 2f. of 0.80) a Roller Compaction Compare All Groups (Tablet Solid Fraction Ribbon Solid Fraction Level Level Level Mean No NA A Yes 0.50 A Yes 0.65 A Yes 0.82 B a Levels not connected by the same letter are significantly different. is mainly caused by a reduction in compactibility because the compressibility of microcrystalline cellulose stays relatively constant as shown in Figures 3 and 4. Heckel Analysis Out-of-die Heckel analysis of the tableting data was also performed to determine the mean yield pressure of the virgin microcrystalline cellulose and roller compacted microcrystalline cellulose Figure 2. Compactibility profile of compressed tablets of lubricated microcrystalline cellulose (45 75 mm sieve fraction) ^, lubricated, roller compacted (SF ¼ 0.52) &, lubricated, roller compacted (SF ¼ 0.64) ~, lubricated, roller compacted (SF ¼ 0.84). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 granules. Out-of-die analysis was used as it provides an estimate of mean yield pressure that is less affected by elastic deformation in comparison to in-die Heckel analysis and hence is suitable for microcrystalline cellulose compacts. The Heckel equation 20,21 was derived assuming solids undergo plastic deformation under pressure, analogous to a first-order reaction, where pores in the mass constitute the reactant. The Heckel equation is described as: lnðeþ ¼K y P c þ K r where P c is the compression pressure, E is the porosity in the mass, and K is a constant that reflects the initial repacking stage. K y is considered a material-dependent constant inversely proportional to its yield strength, 22 Y (K y ¼ 1/3Y) and mean yield pressure, 23 P (K y ¼ 1/P). Two regions characterize a typical out-of-die Heckel plot: the initial curved region represents the initial repacking stage and the subsequent linear region represents subsequent plastic deformation. The point of intersection corresponds to the lowest force at which a coherent mass is formed. Data in the linear region were fit with linear regression to obtain an estimate of the mean yield pressure (P ¼ 1/K y ). A popular hypothesis for loss of reworkability is work-hardening, where a material becomes less prone to plastic deformation after being worked or in this case, roller compacted. However, this hypothesis has not been directly supported in the literature. The mean yield pressure is often used to reflect the ability of a material to undergo plastic deformation. The higher the mean yield pressure (or more shallow the slope), the more difficult the material is to plastically deform. If work-hardening is the mechanism for loss of reworkability, one would expect to see an increase in the material s mean yield pressure after roller compaction. Data on unlubricated microcrystalline cellulose shown in Table 5 and Figure 7 seems to suggest that the tensile strength reduction correlates well with a modest increase in mean yield pressure indicative of work-hardening. The decrease in the tensile strength is not surprising given this increase in the mean yield pressure. Data on lubricated microcrystalline cellulose shown in Table 7 and Figure 8 indicate that there are at least two factors affecting the tablet tensile strength. One is hypothesized to be overlubrication of microcrystalline cellulose with magnesium stearate during the milling step and perhaps to a DOI /jps

8 EFFECT OF ROLLER COMPACTION AND LUBRICANT 1349 Table 3. Compactibility of Lubricated Microcrystalline Cellulose at Various Tablet Solid Fractions a Roller Compaction Ribbon Solid Fraction Tensile Strength at Tablet SF of 0.60 (KN/cm 2 ) Tablet Tensile Strength at Tablet SF of 0.70 (KN/cm 2 ) Tablet Tensile Strength at Tablet SF of 0.80 (KN/cm 2 ) No NA Yes Yes Yes 0.84 NA NA lesser extent the roller compaction step as well, which reduces the interparticle bonding strength and dramatically decreases the tensile strength of the resulting compacts. The other is workhardening, which appears to be substantially less important compared to the former in these studies and is indicated by the modest increase in the mean yield pressure. These two factors may not be entirely independent of each other. The extent of mean yield pressure increase was less significant for lubricated granules than for nonlubricated microcrystalline cellulose granules. Lubrication may facilitate interparticle movement thereby reducing the mean yield pressure. ANOVA analysis was performed on the mean yield pressure for both unlubricated and lubricated microcrystalline cellulose. As shown in Tables 6 and 8, the mean yield pressure of unlubricated and lubricated microcrystalline cellulose is statistically significant among virgin and different ribbon SF (the statistical significance is defined as p-value <0.05). This indicates that the extent of roller compaction has a significant impact on the yield pressure of microcrystalline cellulose. It is important to keep in mind that workhardening and overlubing may not be the only causes for microcrystalline cellulose s loss of reworkability and that different lubricants and roller compaction conditions, including use of different rolls, may influence results. In this study, the granule size is deliberately kept the same as the virgin stock to minimize Table 4a. ANOVA Analysis of Data Listed in Table 3 (Tablet Solid Fraction of 0.60) Ribbon solid fraction <0.001 Residual Total Table 4b. Compare All groups (Tablet Solid Fraction of 0.60) a Roller Compaction Ribbon Solid Fraction Level Level Level Mean No NA A Yes 0.52 B Yes 0.64 C a Levels not connected by the same letter are significantly different. Table 4c. ANOVA Analysis of Data Listed in Table 3 (Tablet Solid Fraction of 0.70) Ribbon solid fraction <0.001 Residual Total DOI /jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

9 1350 HE ET AL. Table 4d. Compare All Groups (Tablet Solid Fraction of 0.70) a Roller Compaction Ribbon Solid Fraction Level Level Level Mean No NA A Yes 0.52 B Yes 0.64 C Yes 0.84 C a Levels not connected by the same letter are significantly different. Table 4e. ANOVA Analysis of Data Listed in Table 3 (Tablet Solid Fraction of 0.80) Ribbon solid fraction <0.001 Residual Total Table 4f. Compare All groups (Tablet Solid Fraction of 0.80) a Roller Compaction Ribbon Solid Fraction Level Level Level Level Mean No NA A Yes 0.52 B Yes 0.64 C Yes 0.84 D a Levels not connected by the same letter are significantly different. Figure 3. Compressibility profile of compressed tablets of unlubricated microcrystalline cellulose (45 75 mm sieve fraction) ^, unlubricated, roller compacted (SF ¼ 0.50) &, unlubricated, roller compacted (SF ¼ 0.65) ~, unlubricated, roller compacted (SF ¼ 0.82). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 Figure 4. Compressibility profile of compressed tablets of lubricated microcrystalline cellulose (45 75 mm sieve fraction) ^, lubricated, roller compacted (SF ¼ 0.52) &, lubricated, roller compacted (SF ¼ 0.64) ~, lubricated, roller compacted (SF ¼ 0.84). DOI /jps

10 EFFECT OF ROLLER COMPACTION AND LUBRICANT 1351 Figure 5. Tabletability profile of compressed tablets of unlubricated microcrystalline cellulose (45 75 mm sieve fraction) ^, unlubricated, roller compacted (SF ¼ 0.50) &, unlubricated, roller compacted (SF ¼ 0.65) ~, unlubricated, roller compacted (SF ¼ 0.82). particle size effects. In reality, roller compaction results in size enlargement, which may cause additional changes in the mechanical properties of the microcrystalline cellulose (e.g., further reduction in compactibility due to particle size enlargement). Mechanical Properties Table 9 summarizes the mechanical properties measured or calculated at a SF of 0.7. Materials were the same as those used for the Heckel and tensile strength data analyses. Also reported is the standard error of the estimate for each value from regression analysis for dynamic hardness, tensile strength, and BI at a SF of 0.7. These results are consistent with typical standard errors observed in our laboratory. For 40 materials tested in 2004, the percent standard error of the estimate was: 13% for dynamic hardness, 9% for tensile strength, and 17% for dynamic BI. As seen in Table 9, microcrystalline cellulose that is not roller compacted before compaction into tablets has similar dynamic hardness (H d ), tensile strength (s T ), and dynamic BI 17 with and without lubrication. Though similar, differences in s T and BI trends in the direction are expected. One would expect tensile strength to be lower for a material containing magnesium stearate since it is a poor bonding material and, when well mixed, will disrupt microcrystalline cellulose interparticle bonding. As magnesium stearate coats the individual particles, it inhibits the formation of interparticle bonds and lowers the strength of the resulting compact. Tensile strength for both lubed and unlubed microcrystalline cellulose is good however. BI is also lower for lubed microcrystalline cellulose as would be expected since BI is a calculated value. Bonding Index ¼ Tensile Strength Dynamic Hardness Figure 6. Tabletability profile of compressed tablets of lubricated microcrystalline cellulose (45 75 mm sieve fraction) ^, lubricated, roller compacted (SF ¼ 0.52) &, lubricated, roller compacted (SF ¼ 0.64) ~, lubricated, roller compacted (SF ¼ 0.84). However, once microcrystalline cellulose has been lubricated with magnesium stearate, roller compacted to ribbon SF at 0.52, 0.64, and 0.84, milled and compacted into tablets, significant differences begin to appear. The decrease in hardness and tensile strength of compacts made from roller compacted material is relatively small for a soft ribbon (SF ¼ 0.52) material compared to the virgin lubed microcrystalline cellulose. Both compact hardness and tensile strength drop dramatically when microcrystalline cellulose is roller compacted to higher SF of 0.64 or When the microcrystalline cellulose is roller compacted, it undergoes volume reduction as the ribbon is compressed and pressure must be increased to form ribbons with a higher SF. After the ribbons are roller compacted to a SF ¼ , milled and then compacted to form tablets, there is not a great DOI /jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

11 1352 HE ET AL. Table 5. Tablet Tensile Strength and Mean Yield Pressure of Unlubricated Microcrystalline Cellulose Determined From Regression Analysis of Terminal Region of Out-of-die Heckel Plot Roller Compaction Ribbon Solid Fraction Mean Yield Pressure (MPa) a Correlation Coefficient (r 2 ) Tensile Strength (MPa) b No NA 81.7 ( Yes (0.6) Yes (.2) Yes (0.8) a Standard deviation in estimate of MPa is included in parenthesis. b Tensile strength estimated at a tablet solid fraction of deal of tabletability remaining and the mechanical strength of the compact decreases. For example, the tensile strength of lubed virgin microcrystalline cellulose is 2.8 MPa while the tensile strength of roller compacted, SF ¼ 0.64 microcrystalline cellulose has dropped to 0.5 MPa. The tensile strength drops slightly more at SF¼ 0.82 microcrystalline cellulose to 0.3 MPa. For unlubed microcrystalline cellulose there is an increase in the dynamic hardness of the compact after the microcrystalline cellulose is roller compacted to SF ¼ 0.84 (85 98 MPa). Dynamic hardness is an indication of a material s ability to plastically deform and is therefore a measure of the mean yield pressure of the material. The more resistant a material is to plastic deformation, the harder the material will be. Increase of hardness after roller compaction can be attributed to work-hardening and is seen to some degree here just as was observed in Figures 7 and 8. For lubed microcrystalline cellulose there is a decrease in dynamic hardness of the compact after the microcrystalline cellulose is roller compacted to SF ¼ 0.82 (90 30 MPa). Microcrystalline cellulose is known for its sensitivity to lubrication time with magnesium stearate. The tensile strength of microcrystalline cellulose is significantly reduced as blending time with magnesium stearate increases. Ribbons prepared to a higher SF are harder to mill and tend to stay in the milling chamber for longer periods. Therefore microcrystalline cellulose ribbons at higher SF are more intimately mixed with magnesium stearate during milling, become more thoroughly coated, and are therefore more subject to overlubrication. Figure 7. Yield pressure, MPa (^) and tensile strength 10, MPa (&) of compressed tablets of unlubricated microcrystalline cellulose as a function of ribbon solid fraction. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 Figure 8. Yield pressure (^) and tensile strength (&) of compressed tablets of lubricated microcrystalline cellulose as a function of ribbon solid fraction. DOI /jps

12 EFFECT OF ROLLER COMPACTION AND LUBRICANT 1353 Table 6. ANOVA Analysis of Mean Yield Pressure of Unlubricated Microcrystalline Cellulose Determined From Regression Analysis of Terminal Region of Out-of-Die Heckel Plot Ribbon solid fraction <0.001 Residual Total Table 7. Tablet Tensile Strength, True Density, and Mean Yield Pressure of Lubricated Microcrystalline Cellulose Determined From Regression Analysis of Terminal Region of Out-of-Die Heckel Plot Roller Compaction Ribbon Solid Fraction Mean Yield Pressure (Mpa) a Correlation Coefficient (r 2 ) Tensile Strength (MPa 2 ) b True Density (g/cm 3 ) No NA 85.2 (2.6) Yes (1.5) Yes (2.0) Yes (2.0) a Standard deviation in estimate of MPa is included in parenthesis. b Tensile strength estimated at a tablet solid fraction of To determine dynamic hardness, a steel ball impacts the compact and the resulting dent measured. 17 For a compact prepared using high SF milled ribbons, one can envision the individual microcrystalline cellulose particles as being near their maximum compression (i.e., no additional volume reduction is possible), however, because of the magnesium stearate which has thoroughly coated the individual microcrystalline cellulose granules, the particles may have reduced bonding with each other and may, in fact, slip past each other when force is applied, creating a larger dent in the material. Thus the decrease in material hardness may be due to overlubricating. This measurement reflects the behavior of the bulk material, not the individual particles. Figure 9 compares the dynamic hardness (mechanical properties) and mean yield pressure data (Heckel analysis) for unlubricated microcrystalline cellulose. For the unlubricated microcrystalline cellulose, there is an excellent correlation between dynamic hardness and mean yield pressure at a SF of 0.7. Figure 10 compares the dynamic hardness and mean yield pressure data for lubricated microcrystalline cellulose. While results are similar for virgin lubed microcrystalline cellulose and compacts made with soft ribbons (SF ¼ 0.52), for harder ribbons (SF ¼ 0.6, 0.8), the dynamic hardness is drastically reduced compared to the mean yield pressure. As discussed above, this may reflect the greater mobility of the particles that is possible in the dynamic indentation test. Based on this, the mean yield pressure obtained from the Heckel analysis appears to be less affected by interparticle movement than the dynamic hardness. CONCLUSIONS Out-of-die Heckel analysis, tablet tensile strength data, and dynamic indentation test data Table 8. ANOVA Analysis of Mean Yield Pressure of Lubricated Microcrystalline Cellulose Determined From Regression Analysis of Terminal Region of Out-of-Die Heckel Plot Ribbon solid fraction Residual Total DOI /jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

13 1354 HE ET AL. Table 9. Mechanical Properties of Microcrystalline Cellulose and Roller Compacted Materials at SF ¼ 0.7 (Estimated by Regression) Magnesium Stearate (%) Roller Compaction Ribbon SF True Density (g/cm 3 ) Dynamic Hardness, MPa (Std. Error of Estimate) Tensile Strength, MPa (Std. Error of Estimate) Dynamic Bonding Index, BI 10 2 (Std. Error of Estimate) 0 No NA (5) 3.0 (0.01) 3.5 (0.2) 0 Yes (17) 2.0 (0.1) 2.0 (0.4) 0.5 No NA (20) 2.8 (0.1) 3.2 (0.7) 0.5 Yes (3) 2.1 (0.01) 2.4 (0.1) 0.5 Yes (5) 0.5 (0.1) 1.5 (0.3) 0.5 Yes (9) 0.3 (0.2) 1.1 (0.8) have been completed on a series of sieved and roller compacted microcrystalline cellulose mixtures under both unlubricated and lubricated conditions with magnesium stearate. These data have been used to evaluate the reasons of loss of reworkability seen for microcrystalline cellulose and shows the extent of impact seen when magnesium stearate is added intragranularly and then roller compacted. While traditional work-hardening may occur as shown by the increase in dynamic hardness and mean yield pressure when comparing unlubricated microcrystalline cellulose and unlubricated, roller compacted microcrystalline cellulose, it is overshadowed by the overlubrication effect seen during roller compaction and in particular, the subsequent milling step. The common practice of lubricating the feedstock with magnesium stearate to avoid sticking of the material to the compaction rolls appears to be the major cause of decreased mechanical strength of the final tablets. Figure 9. Dynamic hardness, MPa (&) and mean yield pressure, MPa (^) from Heckel analysis of compressed compacts of unlubricated microcrystalline cellulose as a function of ribbon solid fraction. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 Figure 10. Dynamic hardness, MPa (&) and mean yield pressure, MPa (^) from Heckel analysis of compressed compacts of lubricated microcrystalline cellulose as a function of ribbon solid fraction. DOI /jps

14 EFFECT OF ROLLER COMPACTION AND LUBRICANT 1355 ACKNOWLEDGMENTS The authors would like to acknowledge Changquan Sun for many helpful discussions regarding this research project. REFERENCES 1. Miller RW Roller Compaction Technology. In: Parikh DM, editor. Handbook of Pharmaceutical Granulation Technology, ed. New York: Marcel Dekker. p He X Application of roller compaction in solid formulation development. Am Pharm Rev 6: Malkowska SK, Khan KA Effect of recompression on the properties of tablets prepared by dry granulation. Drug Dev Ind Pharm 9: Li LC, Peck GE Effect of agglomeration methods on the micromeritic properties of a maltodextrin product, Maltrin 150. Drug Dev Ind Pharm 16: Bultmann JM Multiple compaction of microcrystalline cellulose in a roller compactor. Eur J Pharm Biopharm 54: Inghelbrecht S, Remon JP Roller compaction and tableting of microcrystalline cellulose/drug mixtures. Int J Pharm 161: Grulke R, Kleinebudde P, Shlieout G Mixture experiments on roll compaction Part 1. Pharmazeutische Industrie 66: van Veen B, Bolhuis GK, Wu YS, Zuurman K, Frijlnk HW Compaction mechanism and tablet strength of unlubricated and lubricated (silicified) microcrystalline cellulose. Eur J Pharm Biopharm 59: Kachrimanis K, Malamataris S Compact size and mechanical strength of pharmaceutical diluents. Eur J Pharm Sci 24: Cunningham JC, Sinka IC, Zavaliangos A Analysis of tablet compaction. I. Characterization of mechanical behavior of powder and powder/tooling friction. J Pharm Sci 93: Gupta A, Peck GE, Miller RW, Morris KR Nondestructive measurements of the compact strength and the particle-size distribution after milling of roller compacted powders by near-infrared spectroscopy. J Pharm Sci 93: Kaerger JS, Edge S, Price R Influence of particle size and shape on flowabiltiy and compactibility of binary mixtures of paracetamol and microcrystalline cellulose. Eur J Pharm Sci 22: Kiekens F, Debunne A, Vervaet C, Baert L, Vanhoutte F, Assche IV, Menard F, Remon JP Influence of the punch diameter and curvature on the yield pressure of MCC-compacts during Heckel analysis. Eur J Pharm Sci 22: Gustafsson C, Lennholm H, Iversen T, Nystroem C Evaluation of surface and bulk characteristics of cellulose I powders in relation to compaction behavior and tablet properties. Drug Dev Ind Pharm 29: Westermarck S, Juppo AM, Kervinen L, Yliruusi J Microcrystalline cellulose and its microstructure in pharmaceutical processing. Eur J Pharm Biopharm 48: Edge S, Steele DF, Tobyn MJ, Staniforth JN, Chen A Directional bonding in compacted microcrystalline cellulose. Drug Dev Ind Pharm 27: Hiestand EN, Smith DP Indices of tableting performance. Powder Tech 38: Tye CK, Sun C, Amidon GE Evaluation of the effects of tableting speed on the relationships between compaction pressure, tablet tensile strength, and tablet solid fraction. J Pharm Sci 94: Bolhuis GK, Reichman G, Lerk CF, Van Kamp HV, Zuurman K Evaluation of anhydrous alphalactose, a new excipient in direct compression. Drug Dev Ind Pharm 11: Heckel RW An analysis of powder compaction phenomena. Trans Metallurgical Soc of AIME 221: Heckel RW Density pressure relationships in powder compaction. Trans Metallurgical Soc of AIME 221: Hersey JAR, Rees J nd Particle Size Analysis Conference. University of Bradford, Bradford, UK, Hersey J, Rees J Deformation of particles during briquetting. Nature 230:96. DOI /jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007