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The tabletting properties of a new coprocessed excipient for direct compression were compared with a physical mixture of its components (separately and with drugs) and the individual constituents. The compaction properties were also investigated. Results indicated that the new excipient has excellent flow properties and demonstrates enhanced compressibility.
Although it is probably the oldest excipient used in solid dosage form formulations, lactose is still one of the most important, particularly as a diluent in tabletting. However, the inadequate compactability of a-lactose monohydrate at particle sizes that provide good flow properties of the powder mixture limits the use of crystalline a-lactose monohydrate as a filler-binder for direct tabletting. Because of the need for direct compression excipients, to accompany the progress being made on high speed rotary tablet presses, many researchers and excipient manufacturers modified crystalline a-lactose monohydrate to achieve a product exhibiting good compactability, reduced capping tendency and good flow properties.
Two approaches were taken: the first was to process lactose by itself. For example, agglomeration of small a-lactose monohydrate crystal fractions, which display a large specific surface and have better compactability led to granules with good flowability such as Tablettose (Meggle GmbH, Wasserburg, Germany) or Pharmatose DCL 15 (DMV Pharma, Veghel, The Netherlands). The large granules fractionate at low pressure, releasing small crystals that demonstrate adequate compactability. Spray drying increased the amorphous portion of lactose in the agglomerates, resulting in improved tabletting properties compared with the granules. However, alteration of amorphous lactose to a-lactose monohydrate may change the tabletting properties of the spray dried products during storage.
Table I: Properties of the excipients.
The limitations of improving the properties of lactose-only direct compression excipients led to the second approach: combinations of a-lactose monohydrate and binding and/or plastifying agents. Binary mixtures of crystalline a-lactose monohydrate with microcrystalline cellulose, povidone or starch generally increase the compressibility of the mixtures compared with pure a-lactose monohydrate. However, these mixtures do not improve flowability; hence, coprocessed materials were developed. Agglomeration of a-lactose monohydrate with povidone and cross-povidone (Ludipress, BASF AG, Ludwigshafen, Germany), for example, led to a suitable filler for direct tabletting on high speed presses. Additionally, coprocessing crystalline a-lactose monohydrate with powdered cellulose (Cellactose, Meggle) or microcrystalline cellulose (MicroceLac, Meggle) resulted in improved bonding ability and excellent flow properties. The latest material on the market is StarLac (SL), a coprocessed filler-binder consisting of 85% a-lactose monohydrate and 15% native corn starch. Exhibiting the lowest elastic recovery at high binding capacity compared with other starches, corn starch seems almost destined to form a filler-binder with a-lactose monohydrate with excellent compactability. A further advantage of starch is its bifunctionality as a binder and disintegrant. Thus, out of just two components (a-lactose monohydrate and starch) a product with good flow properties, compactibility and disintegrant functionality has been developed. The objectives of this study were, therefore, to check the tabletting properties of the pure filler-binder and its mixtures with two active ingredients (acetaminophen and vitamin C) under formulation conditions. As a comparison, all the experiments were also performed with a physical mixture of a-lactose monohydrate and corn starch.
Table II: Composition of powder mixtures and apparent yield pressure (YP).
SL, a coprocessed compound containing 15% (w/w) corn starch and 85% (w/w) a-lactose monohydrate (Meggle, Wasserburg, Germany and Roquette Freres, Lestrem, France), spray dried lactose (FlowLac 100 [FL], Meggle), Aerosil 200 (Degussa, Frankfurt am Main, Germany), magnesium stearate (Baerlocher, Unterschleißeim, Germany), Maisstarke extra-white corn starch (Roquette Freres), Paracetamol DC acetaminophen (Hartington, Chesterfield, UK) and C 97/Ascorbinsaure DT vitamin C (BASF AG).
Powder characterization. Powder flowability was measured as the angle of repose and flow-through time of 100 g of powder using Pfrengle's funnel (DIN 53 916). True density was determined using a Beckman air comparison pycnometer (Model 930, Beckman Instruments, Fullerton, California, USA).
Figure 1: Scanning electron micrographs of StarLac (1a, 1b) and a physical mixture of 85% FlowLac and 15% corn starch (2a, 2b) at a magnification of 5003 (a) and 10003 (b).
Bulk and tapped density were measured according to the European Pharmacopoeia (4th edition) using a 250 mL graduated cylinder and an Engelsmann tap meter (JEL ST 2, Engelsmann, Ludwigshafen, Germany).
Particle size distribution was determined by laser diffraction (Mastersizer 2000, Malvern Instruments, Malvern, UK) applying the dry dispersion module Scirocco 2000 (Mastersizer 2000, Malvern Instruments) at a dispersion pressure of 0.1 bar. All values were averaged from three repetitions, and the standard deviation is given in parentheses. The properties of the excipients are listed in Table I.
Blending. SL or a respective physical mixture (PM) of 15% corn starch and 85% spray dried lactose was blended for 15 min with the active ingredient (paracetamol [P] or ascorbic acid [AA]). Finally, 0.5% magnesium stearate was passed through a 315 mm sieve onto the mixture and mixing was continued for another 5 min. All batches were 1.5 kg and are listed in Table II. The shortened form for each mixture consists of the abbreviation of the filler (SL or PM) followed by the active ingredient (AA or P) and ends with the percentage of the active ingredient (30-70), for example SLAA30 is the shorted form of a mixture consisting of SL as a filler and 30% ascorbic acid as an active ingredient.
Rotary tablet press. Tablets of 400630 mg were compressed on a Kilian RL-H instrumented rotary tablet press (Kilian, Koln-Niehl, Germany) at a speed of 25 rpm using a gravity feeder. Five out of 15 punch stations were equipped with 10 mm flat-face bevelled-edge tooling. Tablets were compressed at 5, 10, 15 and 20 kN and the data were recorded and processed by the Messfix software.
Figure 2: Heckel plots of FlowLac, a physical mixture of 85% FlowLac and 15% corn starch, StarLac and corn starch.
Single punch tablet press. Tablets were compressed on an instrumented single punch tablet press Korsch EK II (Korsch Pressen, Berlin, Germany) at a compression pressure of 200 MPa using 10 mm flat tooling. The upper punch displacement was measured using a digital incremental displacement transducer MT 2571 (Heidenhain, Traunreut, Germany). Data were acquired using the MGC Plus system including an ML 10 B voltage amplifier (HBM, Darmstadt, Germany) and the Catman software (HBM). The displacement error caused by distortion of the tooling and frame of the machine was obtained from 10 punch-to-punch compressions, which led to a linear function giving the displacement error versus the force. That function was implemented into the data acquisition software, thus correcting displacement according to the compression force.
Compression analysis. Heckel plots were calculated using the corrected upper punch displacement data (method "in die"). All parameters were calculated for each plot and are presented as an average value of 10 single plots. The slope of the linear compression part of each Heckel plot, as well as its reciprocal (yield pressure), was determined using a stepwise linear regression from 300 data points.14 R-values represent the maximum force ratio of lower to upper punch compression force (n510). The confidence interval at a level of 95% is given in parentheses.
Figure 3: R-values and ejection force results from tablet mixtures containing StarLac, or a physical mixture (PM) of 85% Flowlac and 15% corn starch, together with various proportions of active ingredient (AA = ascorbic acid; P = paracetamol). Single punch tablet press at 200 MPa. P-70% was externally lubricated.
Tablet parameters. The mass of 20 tablets was measured using an AE 200 balance (Mettler-Toledo, Gießn, Germany). The crushing strength of 10 tablets was determined using a TBH-30 tester (Erweka GmbH, Heusenstamm, Germany) at a punch velocity of 1.00 mm/s. Friability and disintegration time were both determined according to the European Pharmacopoeia (4th edition). The friability was determined in a PTF tester (Pharma Test, Hainburg, Germany) and the disintegration time was measured in demineralized water using a PTZ 1 tester (Pharma Test). All tests on the tablets were performed 24 h and 7 days after compression.
Powder properties. All the SL batches investigated showed excellent flow properties, because of the coarse (d[0.5]=156-195.5 Âµm) sphere-shaped particles (Figure 1) and the narrow particle size distribution (Table I), where d is the diameter. The flow-through time was, therefore, always less than 7 s for all the SL batches, which resulted in angles of repose between 26Â° and 27Â°. By contrast to the SL results, PMs of 85% spray dried lactose and 15% native corn starch did not flow at all; the entire test according to DIN 59 316 failed. Although spray dried lactose particles exhibited similar morphology (Figure 1) and flow properties (Table I) as SL, the fine starch particles (d[0.5]=13.3 Âµm) prevented the mixture of spray dried lactose and corn starch from flowing. Because a non-flowing filler was inappropriate to use in a comparison for direct compression excipients, 0.3% Aerosil 200 was added to the PM, thus a moderate flow-through time (10.5 s) for the mixture was obtained. The bimodal particle size distribution of the PM (d[0.5]=13.3 Âµm for corn starch and 132.8 Âµm for spray dried lactose) consequently led to higher bulk and tapped densities of the PM compared with SL, as a result of the ability of small starch particles to travel into the large inter-particular pores of coarse spray dried lactose.
Figure 4 and Figure 5.
Compaction properties. The resistance against deformation or apparent yield pressure, which is calculated as the reciprocal of the slope (k) of the linear part of the Heckel plot15 (Figure 2), decreased in the order FL.PM.SL.corn starch (Table I). However, the low value for the yield pressure of native corn starch of 58.3 MPa needs some extra explanation, related to the Heckel equation (Equation 1). The closer the apparent density approximates the true density of the powder (the porosity gravitates towards 0), the higher the value for ln(1/[12D]). When the value of the apparent density is higher than the measured true density, the entire model becomes invalid. However, true densities are not necessarily pressure independent18 and materials such as starch may exhibit their true density even at the pressures applied during the tabletting experiment. Consequently, calculating a Heckel plot for starch employing a constant true density leads to increasingly false higher values for ln(1/[12D]) at increasing compression pressures. Thus, in the absence of a "true" true density, and considering the density of starch determined using an air comparison pycnometer is definitely not the true one, the slope of the starch Heckel plots are too steep. Nevertheless, even if the determined slope is not precise, the Heckel plot of corn starch indicates a highly plastic deforming material with an increasing elastic proportion at high compression pressure, which is in accordance with other reports.12 The lower yield pressure of SL compared with the PM (Figure 2 and Table I) shows that starch, which is bound within the SL compound (Figure 1), improved the deformation properties to a greater extent than starch, which was just physically mixed with large spray dried lactose particles. Small starch particles may travel into the pores of the spray dried lactose lattice, whereas starch particles within the compound remain in place.
Additionally, the proportion of small starch particles in the PM decreased lubricant efficiency because of a higher specific surface area. Hence, R-values of SL compacts were higher than those of the PM (Table I) at a constant lubricant concentration of 0.5% magnesium stearate, indicating a more even stress distribution within the SL tablets. This trend is highlighted when various proportions of active ingredient (AA or P) were added (Table II, Figure 3). The PM R-values decreased with increasing proportions of active ingredient, and the ejection force increased significantly. At proportions of 70% active ingredient, the die had to be externally lubricated to reduce the ejection force on the single punch tablet press and hence led to lower values. By contrast, mixtures of SL with either AA or P in any proportion exhibited constant R-values of approximately 0.925 and ejection forces of less than half the values of the mixtures compressed with PM as a filler-binder (Figure 3).
Figure 6 and Figure 7.
Tablets of pure filler-binder. SL tablets of sufficient crushing strength (50 N) could be compressed at a compaction force of 10 kN and greater (Figure 4). The 5 kN force level led to weak tablets for both SL and PM, which displayed crushing strength values of less than 20 N. The crushing strength for SL tablets increased almost linearly by increasing the compaction force and reached a value of 173 N at 25 kN. By contrast, tablets compressed with the PM started capping at compression forces exceeding 15 kN. This capping tendency was also apparent in the friability test, wherein the PM tablets compressed with a force exceeding 15 kN failed the test. However, PM tablets prepared at compression forces of 10-20 kN exhibited acceptable friability values of just less than 0.2%. SL tablets did not tend to cap, either during the crushing strength test or the friability test, which the tablets passed with friability values of less than 0.02% for force levels between 10 and 25 kN (Figure 4). The reason for the better mechanical properties of the SL compacts was the enhanced compressibility of SL compared with the PM (Figure 2) as a result of the higher effectiveness of starch particles as subunits within the SL granules. Thus, starch particles could locate between the small a-lactose monohydrate crystals as a dry binder, increasing plastic deformation at the time the SL particles are fractioning (at an early stage of the compression). The good mechanical properties of the SL tablets did not affect disintegration. The disintegration time of SL tablets was approximately 30 s less than the tablets compressed with the PM, which varied between 2-3 min. The different batches of SL (1-3) did not show significant differences in their tablet properties.
Tablets containing active ingredient. Mixtures of SL or PM containing ascorbic acid in proportions between 30-70% behaved poorly whilst being compressed into tablets. Together with SL, the main problem was capping, even though the type of AA used was designed for direct compression (96% ascorbic acid and 4% polyvinylpyrrolidone [PVP]). However, SL was a suitable filler for tablets containing 30-70% ascorbic acid (SLAA30-70). The only force level that could be used without capping was 10 kN. The resulting tablets displayed a tolerable crushing strength of 50 N, independent of the ascorbic acid proportion, but rather high friability (0.3-0.55%, after 24 h) (Figures 5-7), that increased at higher ascorbic acid proportions. Storing the tablets for one week resulted in reduced friability values of 0.10% for SLAA30, 0.16% for SLAA50 and 0.35% for SLAA70. Crushing strengths, however, remained unchanged. As a result of the increasing effect of hardening at higher SL proportions, the effect could be related to an alteration of amorphous lactose, which is used as a binder for the SL particles, towards a-lactose monohydrate.7 The disintegration time was always much shorter (2-6 min) than the 15 min required by the European Pharmacopoeia (Figures 5-7).
Tabletting mixtures containing ascorbic acid and the PM were even harder to compress than the physical mixtures containing SL. Physical mixtures that exceeded a proportion of 30% ascorbic acid immediately started sticking to the tooling and no further tabletting could be performed. Nevertheless, the PMAA30 showed decreased capping; hence force levels up to 20 kN could be applied, resulting in a crushing strength of 140 N, a friability of 0.17% and a disintegration time of 470 s (Figure 5). Repeating the tablet tests after 1 week, the same hardening effect as was seen for the SLAA tablets was displayed. Additionally, the crushing strength increased; thus values of 0.09% for the friability and 157 N for the crushing strength were determined.
Tabletting mixtures containing the active ingredient P exhibited even more capping tendency when compressed with SL as a filler compared with mixtures containing ascorbic acid. As a result, only tablets compressed at 5 kN passed the friability test uncapped. However, they showed sufficient crushing strength (66 N) at low friability (0.1%) for SLP70 tablets. By contrast to the SL tablets with ascorbic acid, the tablets with paracetamol showed higher mechanical strength at increasing paracetamol proportions. Thus, the paracetamol for direct compression dominates the tablet properties. This result also explains the drastically increased capping compared with tablets of pure SL, as paracetamol is a well-known drug that causes capping.19 However, PM mixtures containing paracetamol had a reduced dependence of the paracetamol proportion on the compactability than SL mixtures: the PMP tablet properties were similar to the tablets of pure PM (Figures 4-7). That means shorter disintegration times, higher crushing strength and less friability compared with the SLP tablets (Figures 5-7).
SL is a compound of excellent flow properties and enhanced compressibility compared with spray dried a-lactose monohydrate (FL). Binding small starch particles together with a-lactose monohydrate crystals into compound particles increased the starch-related effects of enhanced binding capacity and compressibility compared with a physical mixture of corn starch and spray dried lactose. Additionally, the small starch particles within the physical mixture prevented powder flow, thus 0.3% Aerosil had to be added to make a comparison of the two filler-binders possible.
Ascorbic acid could be tabletted at all tested proportions up to 70% together with SL, whereas sticking prevented the compression of mixtures exceeding 30% AA together with the PM.
Paracetamol tabletted with SL proved to be a greater challenge. At a P level of 70%, tablets of good crushing strength and friability could be obtained. For P the PM had advantages of better mechanical tablet properties, particularly at P levels below 70%. Generally, all tablets hardened slightly during storage during the examined period of 1 week. None of the tabletting mixtures required the addition of a disintegrant, whereas tablets that contained SL exhibited a faster disintegration than tablets that contained the PM.