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Multiple Tamping Effects on Drug Dissolution From Capsules Filled on a Dosing-Disk Type Automatic Capsule Filling Machine
Multiple Tamping Effects on Drug Dissolution from Capsules Filled on a Dosing-Disk Type Automatic Capsule Filling Machine K. B. SHAH**, L. L. AUGSBURGER“,AND K. MARSHALL§ Received August 29. 1986, from the ‘De artmenf of Phamaceufics, School of Pharmacy, University of Maryland, Baltimore, MD 21201, and Accepted for publication June 6, 1987. §Smifh Kline and French Laboratories, Pkladelphia, PA 19101. Present address: SSearle Research and Development, Skokie, IL 60077. Abstract 0The effects of number of tampsand tamping force on drug dissolution from capsulesfilled on an instrumenteddosing-diskautomatic capsule filling machine (Hofliger-Karg)were studied using hydrochlorothiazide as a model, low dose, poorly soluble drug. Generally, there was a trend toward slower dissolution rate with increasing numbers of tamps, the effect being most marked when insoluble dicalcium phosphate dihydrate was the filler. Higher compression forces improved drug release when anhydrous lactose was the filler, but adversely affected the dicalcium phosphate-based capsules. Inclusion of 4% croscarmellose sodium disintegranttended to nullify the effects of number of tamps or tamping force with both fillers; however, the disintegrantalso markedly enhanced drug dissolution from the dicalcium phosphate-based formulation. Hydrochlorothiazidedissolution from the latter formulation without disintegrant appeared to follow a “diffusion from insoluble matrix” model regardlessof number of tamps or their intensity. Mercury intrusion pore size distribution data for some plugs suggested that for tamps of equal force (100 or 200 N), further powder consolidation after two tamps does not occur. -... ~ . _ _
I n dosing-disk type automatic capsule filling machines, the plugs of powder to be filled i n t o capsules are progressively built up in dosing-disk cavities through a series o f tamps. In previous the tamping stations o f a model GKF 330 Hofliger-Karg machine were instrumented by installing a strain-gauged piston in each station. It was shown t h a t although there was a provision for five consecutive tamps in that machine, a m a x i m u m of three would normally be required to achieve the desired fill weight for a given disk thickness. However, both the number o f tamps and the tamping force, as well as formulation variables, could influence the drug release rate from an encapsulated dosage form, particularly if the drug had a low dose and was poorly soluble. It has been shown on the simpler dosator machines, in which plugs are formed by a single compression, that drug dissolution can be affected by manipulating plug compact i ~ nThus, . ~ the experiments described below were designed to investigate the influence o f compression force, tamping history, filler type, and presence o f disintegrant o n the dissolution o f a model, low dose, slightly soluble drug, hydrochlorothiazide.
Experimental Section Formulations and Capsule Manufacture-The general formulation consisted of 6% hydrochlorothiazide, USP (Pro Farmaco, Bologna, Italy), magnesium stearate (Amend Drug and Chemical Company, Irvington, NJ) as lubricant, and filler. Direct tableting-grade anhydrous lactose (Sheffield Products, Memphis, TN) and unmilled dicalcium phosphate dihydrate (Ditab; Staufer Chemical Company, Westport, CT) were used as “soluble” and “insoluble” fillers, respectively. Magnesium stearate was used a t the 1.5%level for the soluble filler and a t the 0.50%level for the insoluble filler. Two formulations were designed for each filler, one without and the other with 4% croscarmellose sodium (AcDiSol; FMC Food and Pharmaceutical
0022-3549/87/0800-0639$01.00/0 0 7987, American Pharmaceufical Association
Products Division, Philadelphia, PA) a~ disintegrant. Batches of 3000 g (anhydrous lactose filler) or 4000 g (dicalcium phosphate filler) were blended in a 15.1-L twin-shell blender (Patterson-Kelly Co., East Stroudsburg, PA) for 10 min. The weight difference allowed a charge of approximately equivalent volumes in the twin-shell blender. Size #1 capsules were filled on a model GKF 330 Hofliger-Karg automatic capsule-filling machine (Bosch Packaging Machinery Division, Piscataway, NJ) which had been instrumented with strain gauges to monitor tamping forces, a~ previously described.1.2 The machine speed was held constant at 100 strokes per min, and a 1.58cm thick dosing disk was used in all runs. Either one tamp or up to three consecutive tamps (i.e., stations #5, #5 and #4, and X5, #4, and #3) a t a given compression force were utilized during encapsulation to study the multiple tamp effect. Separate runs were made using compression forces of 100 and 200 N to assess any possible compression force effect. The inclusion of hydrochlorothiazide at a fixed concentration of 6% resulted in a 7-27-mg range in drug content, since fill weights varied with the number and intensity of tamps, as well a~ with the density of the filler. Based on the solubility of hydrochlorothiazide (0.106% in 1:lOO hydrochloric acid at 37 “(29, even the maximum drug content resulted in a drug concentration during dissolution that was well below the 10-152 of solubility limit considered satisfactory6 for approximating sink conditions. Dissolution-The dissolution rate of hydrochlorothiazide was determined by USP method 11, with paddles.6 A six-head dissolution apparatus equipped with a multiple-drive stirrer (model 2000 Dissolution System; Distek, Inc., Somerset, NJ) was employed. The dissolution medium was 900 mL of dilute hydrochloric acid (1:lOO) maintained at 37 “C. The paddles were positioned 2.5 cm above the bottop of the flasks and rotated a t 50 2 2 rpm. Six randomly selected capsules of each formulation were tested. The capsules were held in stainless steel spirals to prevent their floating. Dissolution runs were carried out for 64 min. One set from each of the four formulations was tested for 100 (? 5)% release by increasing the paddle speed to 250 rpm. A sequential flow system (Dissograph Flow Hanson Research Corporation, NorthSystem, model 49-200-000; ridge, CA) was used. This system provides for serial withdrawal of filtered samples from each flask a t preset time intervals for spectral analysis and for return of the sample to the corresponding flask following absorbance measurement. To avoid disturbance of the stirring medium during runs, a pneumatically driven automatic sampler (model 27-700-000; Hanson Research Corporation, Northridge, CA), which inserts sampling probes only for the specified sampling time, was employed. The withdrawn samples were pumped, single file, through a 0.1-cm flow cell (model 170; Helma Cells, Inc., Jamaica, NY)that was mounted in a dual-beam, microprocessor-controlled spectrophotometer (model Lambda 3B; Perkin Elmer Corporation, Oak Brook, IL). All absorbance8 were read at 272 nm7 against dissolution medium in the reference flow cell. The reference dissolution medium was replenished between dissolution runs from a reservoir container, using a peristaltic pump. The spectrophotometer was interfaced through a serial port with a desktop computer (IBM PC; IBM Corporation, Armonk, NY). The sobware calculates percent drug dissolved based on drug content of individual dosage units and takes into account the actual fill weight of the test capsules. The mean percents dissolved and standard errors appear in Tables I-IV. Journal of Pharmaceutical Sciences / 639 Vol. 76,No. 8,August 1987
Porosity Measurement-The effect of compression force and the number of tamps on powder consolidation was further studied by determining the porosity and pore size distribution of anhydrous lactose-based plugs containing hydrochlorothiazide. A mercury intrusion porosimeter (model 9305 Pore Sizer; Micromeritics, Norcross, GA)was used. Data acquisition and reduction was largely automated through serial interfacing with the desktop computer. Intrusion readings up to 168 Mpa were taken. Visual examination ofthe plugs revealed no apparent physical damage as a result of the intrusion pressure. Moreover, total pore volumes calculated from true densities and plug dimensions agreed to within 22%with total intrusion volumes.
Results and Discussion These studies were designed to identify the influence of the
number of tamps and the extent of tamping, if any, on in vitro drug release. The formulation variables considered were filler type and the presence (or absence) of a distintegrant. Anhydrous L ~ ~ ~ ~~ ~ ~ ~ ~~ effect l ~of ~ - i number Of tamps (up three tampsp each at the same compression force) on hydrochlorothiazide dissolution at low (100 N) and high (200 N)ComPression force may be seen in Figures 1 and 2, respectively. The pore size distributions for these capsule plugs appear in Figures 3 and 4. It is apparent that regardless of compression force (high o r low), multiple tamping adversely affected the dissolution profile. This observation is surprising in light of a previous finding2 on similar placebo formulations that the mechanical strength of
''
Table I-Effect of Multiple Tamps and Compression Force on Hydrochlorothiazlde Dissolution from Anhydrous Lactose-Based Capsules'
Compression Force, N
Number of Tamps
100
1
200
2 3 1 2 3
Percent Drug Dissolved at Various Times, min 8 25.4 (1.99) 21.2(2.24) 15.0(0.88) 26.0(1.22) 17.8(1.25) 15.4(0.79)
16
24
45.6(2.11) 41.8(0.79) 35.4(1.28) 48.9 (0.52) 40.1 (1.11) 35.7(0.95)
56.5 (1.69) 52.3 (0.69) 46.9 (1.06) 59.4 (0.78) 51.4 (0.83) 47.8(0.91)
32 63.1 (1.59) 58.9 (0.82) 54.8 (1.34) 67.2(1.00) 59.1 (0.95) 55.5 (1.04)
40
48
56
68.4(1.63) 64.9 (0.74) 60.3(1.56) 73.4(1.13) 64.8(1.07) 61.5 (1.10)
74.1 (1.66) 69.6(0.84) 65.1 (1.73) 78.3 (1.19) 69.9 (1.14) 66.0 (1.18)
78.6 (1.72) 73.8(0.92) 69.0(1.90) 82.4(1.26) 74.2(1.21) 70.2 (1.22)
64 82.1 (1.58) 77.3 (1.06) 72.6(2.02) 86.0 (1.41) 77.3(1.20) 73.7(1.27)
'Magnesium stearate (1 5%)as lubricant. bMean of 6 determinations; standard error of mean in parentheses. Table 11-Effect of Multiple Tamps and Compression Force on Hydrochlorothlazide Dissolution from Anhydrous Lactose-Based Capsules Containing 4% Croscarmellose Sodlum'
Compression Force, N
Number of Tamps
100
1 2 3 1 2 3
200
Percent Drug Dissolved at Various Times, min 8 38.0(1.16) 35.9(1.19) 34.3 (2.10) 38.0(1.27) 36.2(1 .lo) 31.3 (1.44)
16 51.6(0.51) 49.8(0.44) 48.8(1.67) 53.4 (0.83) 51.3 (0.53) 47.5 (0.57)
24 58.7(0.29) 57.2(0.22) 56.7(1.53) 61.7(0.65) 58.4(0.52) 54.8 (0.31)
32 64.3(0.38) 62.7(0.35) 62.2(1.71) 67.9(0.72) 64.5(0.51) 60.4(0.32)
40
48
56
69.3(0.50) 68.0(0.39) 67.0(1.76) 72.9(0.77) 69.5(0.49) 65.0(0.32)
73.7(0.54) 72.5 (0.48) 71.5 (1.87) 77.2 (0.88) 73.8 (0.49) 68.9 (0.35)
77.7(0.56) 75.8(0.62) 75.0 (1.87) 81.0 (0.90) 77.3 (0.38) 72.4(0.40)
64 80.7(0.66) 79.2(0.75) 78.0(1.82) 84.0(0.96) 80.4(0.44) 75.3(0.40)
'Magnesium stearate (1.5%)as lubricant. Mean of 6 determinations; standard error of mean in parentheses. Table Ill-Effect Capsules'
Compression Force, N
a
of Multiple Tamps and Compression Force on Hydrochlorothlazlde Dissolution from Dlcalclum Phosphate-Based
Percent Drug Dissolved at Various Times, min
Number
of Tamps
100
1
200
2 3 1 2 3
8 12.1 (0.60) 9.2(0.29) 8.9(0.23) 10.6(0.55) 7.6(0.10) 7.7(0.32)
16 20.5 (0.91) 16.0(0.45) 15.6(0.42) 17.8(0.68) 13.0(0.23) 13.4(0.34)
24 26.9 (1.19) 21.1 (0.55) 20.5(0.53) 22.7(0.72) 17.3(0.24) 17.4(0.41)
32 32.0 (1.43) 25.4 (0.74) 24.5(0.64) 27.0(0.75) 20.7(0.29) 20.7(0.42)
40
48
56
37.0(1.57) 29.4 (0.92) 28.2 (0.71) 30.5 (0.86) 24.0 (0.31) 23.8 (0.54)
41.3 (1.84) 32.9 (1.06) 31.3 (0.87) 33.8 (1.00) 27.0(0.35) 26.6(0.57)
45.2(1.93) 36.3 (1.12) 34.6 (0.92) 37.2 (1.12) 29.6(0.39) 29.5 (0.61)
64 48.8(2.07) 39.7(1.25) 37.5(1.00) 40.2(1.26) 32.4 (0.44) 32.1 (0.71)
Magnesium stearate (0.5%)as lubricant. bMean of 6 determinations; standard error of mean in parentheses.
Table IV-Effect of Multiple Tamps and Compression Force on Hydrochlorothlazlde Dlssolutlon from Dlcalclum Phosphate-Based Capsules Containing 4% Croscarmellose Sodium'
Compression Force, N 100 200
a
Percent Drug Dissolved at Various Times, min
Number of Tamps
1 2 3 1 2 3
8 28.8 (1.74) 28.4 (0.94) 27.7 (1.58) 31.0 (1.72) 28.7 (1.24) 28.4(1.72)
16 41.9(1.76) 40.8(1.47) 41.5 (1.82) 44.2(1.83) 40.3(1.41) 41.3(1.89)
24 51.9 (1.56) 50.0 (1.19) 51.1 (1.72) 53.6 (1.54) 49.6(1.30) 51.1 (1.97)
32 59.4 (1.63) 57.3 (0.94) 59.3 (1.58) 61.7(1.39) 56.1 (1.04) 59.6(1.96)
40 66.0(1.54) 63.9(0.80) 66.2(132) 68.4(1.23) 62.0(0.94) 66.5(1.92)
48
56
70.6(1.57) 68.9(0.39) 72.2 (1.06) 73.6 (1.07) 67.5(0.85) 72.0(1.86)
75.0(1.50) 74.2(0.46) 77.2(0.83) 78.0(1.03) 72.5(0.73) 76.6(1.70)
Magnesium stearate (0.50%)as lubricant. Mean of 6 determinations; standard error of mean in parentheses.
640 /Journal of Pharmaceutical Sciences Vol. 76, No. 8, August 1987
64 78.4(1.50) 78.8(0.30) 81.3(0.67) 81.0(1.06) 76.3(0.73) 79.9(1.60)
the large, initially formed plug segment did not change after a second or third tamp a t the same compression force. If plug mechanical strength is a good indicator of powder consolidation, that finding would suggest that multiple tamping does not cause further compaction. However, the results of the present study reveal a uniform decrease in pore size distribution at both force levels from the first tamp to the second tamp which does, indeed, point to further consolidation. Evidently, the previously reported mechanical strength measurements were not sensitive enough to detect these relatively small changes in porosity. At the low compression force (Figure 3), it may be seen that the median pore diameter decreases from 12.8 pm with one tamp to 10.8 Fm with two tamps, although no change was apparent between two tamps and three tamps. In considering the dissolution data (Figure 11, it is interesting to note that the differences in percent dissolved at any time between the curves representing one, two, and three tamps were constant. Although small, these differences were statistically significant (p < 0.05) at 32 min, 100
but not a t 64 min, based on a two-sided t-test for the two extremes (one tamp versus three tamps). The trend toward decreasing dissolution rate with increases in the number of tamps is even more clear in the high compression force data (Figure 2). While the differences in percent drug dissolved a t various times still remained more or less constant for the three tamping conditions, a significantly (p < 0.05) higher percent of hydrochlorothiazide dissolved at the 32- and 64-min marks from the plugs obtained with one tamp than from plugs obtained with two or three tamps. The pore size distribution (Figure 41, as before, shifted toward a smaller size when the number of tamps increased from one to two, but was not greatly affected by the third tamp. The consistent differences a t all times in percent release a t both low and high compression forces among the three tamping groups, with maximum release occurring when only a single tamp was employed, points to an initial “burst” effect in drug release. This burst effect probably results from the loose powder that fills the disk cavity after the last tamp and prior to ejection, and is likely to be most significant in the
80
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Figure 1--Effect of multiple tamps at low compression force (100 N) on hydrochlorothiazide dissolution from anhydrous lactose-basedcapsules (7.5% magnesium stearate). Key: (0) tamping at station #5; (0) tamping at station #5,4; (A)tamping at station 15, 4, 3.
Flgure 3-Hfect of multiple tamps at low cornpression force (100 N) on pore size distributions of plugs (anhydrous lactose-based formulation of hydrochlorothiazide, 7.5% magnesium stearate). Key: ( 0 )tamping at station #5; (a)tamping at station #5, 4; (A)tamping at station #5, 4, 3.
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Flgure 2-€ffect of multiple tamps at high compression force (200 N) on hydrochlorothiazidedissolution from anhydrous lactose-based capsules ( 1 5% magnesium stearate). Key: see Figure 1.
PORE SIZE (urn)
Flgure 4-Effect of multiple tamps at high compression force (200 N) on pore size distributions of plugs (anhydrous lactose-based formulation of hydrochlorothiazide, 7.5% magnesium stearate). Key: see Figure 3. Journal of Pharmaceutical Sciences I641 Vol. 76, No. 8, August 7987
case where only one tamp is employed. Previous work2 showed that the full plug length is not realized with just a single tamp, and that a void volume remains which is filled volumetrically from the powder head over the dosing disk prior to the scrape-offwhich precedes ejection. Since complete plug length is realized when two tamps are employed, capsules filled when employing two tamps will contain no loose powder. Assuming the intact plug to release drug a t the same rate in all cases, this initial burst could account for the consistently higher dissolution profiles of these capsules. The amount of loose fill would be less at the low compression force (i.e., less consolidation of the intact plug, thereby leaving less room for the loose fill) than it would be at the high compression force. This latter point thus could account for the greater (but consistent with time) differences in percent dissolved between the single-tamp and two-tamp data at the higher (Figure 1) and lower compression forces (Figure 2). The effect of single-tamp compression force on hydrochlorothiazide dissolution is shown in Figure 5, and the pore size distribution data for those capsule plugs are given in Figure 6. An examination of these pore size distribution data indi-
cates that a greater consolidation of the powder mass occurred with an increase in compression force. Curiously, however, the increased densification resulted in an improved dissolution rate for this soluble system. A similar observation has been reported by Botzolakis et aL8 for a similar hydroch1orothiadize:anhydrous lactose formulation filled on a dosator machine, and by Greenberg regarding an unspecified formulation, also filled on a dosator machine. Exactly why dissolution rate increased with increased compression force is not clear, but the effect in part may be related to greater particle fracture or frictional shearing a t higher compression force resulting in more clean surfaces uncontaminated with hydrophobic lubricant. For these lactose formulations, both the burst effect and greater consolidation, together, yield overall improved dissolution profiles a t higher compression forces. That the curves in Figure 5 do not show equal spacing at all time points is not inconsistent with the discussion of 100
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62
38
66
TIME (mid
Figure 5-€ffect of compression force on hydrochlorothiazide dissolution from anhydrous lactose-based capsules (7.5% magnesium stea700 N; (0) 200 N. rate) utilizing only a single tamp. Key: (0)
Figure 7-€ffect of multiple tamps at low compression force (100 N) on hydrochlorothiazidedissolution from anhydrous lactose-based capsules containing 4% croscannellose sodium disintegrant (1.5% magnesium stearate). Key: see Figure 7.
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40
O 10
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PORE SlZE(um) Figure 6--Effect of compression force on pore size distributions of plugs (anhydrous lactose formulation of hydrochlorothiazide, 1.5% magnesium stearate). Key: (A)700 N; (A)200 N. 642 /Journal of Pharmaceutical Sciences Vol. 76, No. 8, August 7987
Figure 8-.€ffect of multiple tamps at high compression force (200 N) on hydrochlorothiazidedissolution from anhydrous lactose-basedcapsules containing 4 % croscarmellose sodium disintegrant (1.5% magnesium stearate). Key: see Figure 1 .
Figures 1 and 2. In the early stages, dissolution from both capsules is primarily due to the dissolution of the faster dissolving loose powder. Thus, one would expect little or no difference between the two capsules initially, with the curves gradually diverging to a fairly constant difference at later times, owing to the different amounts of loose powder fill as well as to the effect of the two different compression forces on the intact plug. This is exactly what the data in Figure 5 show. The effects of disintegrant (4% croscarmellose sodium) and multiple tamps a t low and high compression force on the dissolution of hydrochlorothiazide from anhydrous lactosebased capsules are summarized in Figures 7 and 8. The presence of disintegrant at low compression force yielded essentially identical dissolution patterns for the capsules filled using any of one, two, or three tamps. The burst effect, observed previously in the absence of disintegrant, was not evident here. It is likely that rapid plug dispersal and initial dissolution, resulting from the presence of disintegrant, overshadowed any such effect. A comparison between Figures 1 and 7 clearly indicates that for any tamping combination, a significantly (p < 0.05) higher percent of hydrochlorothiazide dissolved in 8 min when the disintegrant was included in the formulation than was released in 8 min from the formulation without disintegrant. Figures 7 and 8 also reveal that an increase in the number of tamps tends to retard dissolution from the disintegrantcontaining lactose formulations. This effect is most clearly obvious at the high compression force (Figure 8). Dicalcium Phosphate-Based Formulations-The effects of the number of tamps and the extent of compression on hydrochlorothiazide dissolution from the dicalcium phosphate-based formulations may be seen in Figures 9-11. Increasing the number of tamps slowed drug release at both the low (Figure 9) and high (Figure 10) compression forces, but only when up to two tamps were employed. When a third tamp was applied at the low compression force (Figure 91, the dissolution rate appeared to decay further; however, the differences were not significant (p < 0.05) at 32 and 64 min. The application of a third tamp at the higher compression force had no apparent effect on drug dissolution (Figure 10).
From the previously noted porosimetry data (anhydrous lactose, Figures 3 and 41, it is clear that consolidation occurred only up to two tamps. With both the anhydrous lactose and dicalcium phosphate formulations, fill weight also increased with up to only two tamps. Thus, it seems reasonable to infer that even for the dicalcium phosphate formulations, consolidation and porosity reduction occurred with up to only two tamps. Based on these results (Figures 9 and lo), it is apparent that in vitro drug release depends on the extent of consolidation for this "insoluble" system. A comparison of Figures 9 and 10 also reveals that dissolution rate decreased (regardless of the number of tamps) a t the higher compression force. This compression force effect is most clearly evident in the single-tamp data (Figure 11). Overall, the differences in dissolution profiles generally increased with time as a function of both the number of tamps and the extent of tamping. SOUARE ROOT OF TIME (rnin"')
I
lo
1
0
0
26
13
39
62
66
TIME (rnin) Figure lO-€ffect of multiple tamps at high compression force (200 N) on hydrochlorothiazide dissolution from dicalcium phosphate-based capsules (0.50%magnesium sfearate). Key: see Figure 9.
SOUARE ROOT OF TIME (min"') 2
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SOUARE ROOT OF TIME (min"')
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TIME (mid Figure +Effect of multiple tamps at low compression force (100 N) on hydrochlorothiazide dissolution from dicalcium phosphate-based captamping at station #5; (0) sules (0.50%magnesium stearate). Key: (0) tamping at station X5, 4; (A) tamping at station #5, 4, 3; open symbols: x-axis = time; closed symbols: x-axis = time "?
01
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TIME (mid Figure 11-Effect of compression force on hydrochlorothiazidedissolution from dicalcium phosphate-based capsules (0.50% magnesium 100 N;(0) 200 N;open stearate) utilizing only a single tamp. Key: (0) symbols: x-axis = time; closed symbols: x-axis = time l'? Journal of Pharmaceutical Sciences / 643 Vol. 76, No. 8, August 1987
Interestingly, all dicalcium phosphate-based plugs remained intact even after the last dissolution sample was taken at 64 min. HiguchilO has described the following model for diffusion-controlled drug release from a heterogeneous matrix in which diffusion takes place in the intergranular pores:
(1) where Q is the amount of drug released per unit surface area after time t , D is the diffusion coefficient of the drug in the dissolution medium, c is the porosity of the matrix, r is the tortuosity of the matrix, A is the concentration of the drug in the compact, and Cs is the solubility of the drug in the dissolution medium. This equation holds as long as 2A >> E c s , and predicts a linear fit for the amount released per unit area versus t”2. A capsule fill weight range of 0.369 to 0.505 g, containing drug at 6% (w/w) in a disc cavity volume of 0.396cm3, corresponds to a range of A of 5.6-7.6% (w/v).The solubility of the drug in the dissolution medium has been reported to be 0.106% (w/v) a t 37 0C.4Furthermore, from the lactose data and an earlier report,” the porosity of the plugs could reasonably be expected to be in the range of 0.4 to 0.5. Thus, it is quite reasonable that the condition 2A >> E c s holds in this case. However, the surface area is not held constant in a typical dissolution study. Nevertheless, the fact
that the plug did remain intact throughout the dissolution run suggests a possible fit to the Higuchi model, with the limitation noted above. As may be seen in Figures 9-11, when the dissolution data were regressed and plotted as percent dissolved against t1’2, an excellent fit of the model was found in all cases (coefficient of determination 2 0.999). The squared x-intercept ranged from 0.82-1.6 min (Table V) which could represent the time taken for the capsule shell to dissolve in the release medium and for the initial direct exposure of the plug to the dissolving fluid. Decreasing slopes with increases in the extent and frequency of tamps could be a function of resultant greater consolidation and, thus, decreasing porosity. The addition of disintegrant improved drug dissolution over that of the control dramatically, regardless of the number of tamps andlor the tamping force. As may be seen in Figures 12 and 13, the number of tamps did not adversely affect drug dissolution. Neither was there any specific effect 100 7
80 -
8
3
Table V-Regresslon Parameters Using A “Diffusion from lsoluble Matrlx” Model for HydrochlorothlazldeDlssolutlon from Dlcalclum Phosphate-BasedCapsules’
0 3
Compression Number
ae
Forces N
Of
100
Regression Parameterb
Tamps Slope, %/min”z
F
1.26 1.65 1.40 0.82 1.62 1.37
0.9999 0.9997 0.9998 0.9996 0.9996 0.9994
7.1 1 5.86 5.49 5.65 4.78 4.66
1 2 3 1 2 3
200
(x-intercept)Z,rnin
Magnesium stearate (0.5%) as lubricant. bObtained by regressing mean (n = 6) percent dissolved against timeo2from 64-min dissolution runs. a
IE
60-
40-
n 20
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01
0
I
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13
26
39
1
1
62
66
TIME (mid
Figure 13-.€ffect of multiple tamps at high compression force (ZOO N) on hydrochlorothiazide dissolution from dicalciurn phosphate-based capsules containing 4% croscarmellose sodium (0.50% magnesium stearate). Key: see Figure 7.
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601
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0
401
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62
e6
Flgure 12-€ffect of multiple tamps at low compression force ( 1 00 N) on hydrochlorothiazide dissolution from dicalcium phosphate-based capsules containing 4% croscarmellose sodium (0.50% magnesium stearate). Key: see figure l. 644 /Journal of Pharmaceutical Sciences Vol. 76, No. 8,August 1987
20
0
13
26
39
62
1
66
TIME (mid
Figure 14-Effect of compression force on hydrochlorothiazidedissolution from dicalciurn phosphate-based capsules containing 4% croscarmellose sodium filled using a single tamp (0.50% magnesium stearate). Key: (0) 100 N; (3) 200 N.
due to compression force (Figure 14). Four,percent croscarmellose sodium may be sufficient for this insoluble system to provide disintegration and deaggregation sufficiently rapid to overcome any effects resulting from multiple tamps or increased tamping force within the range of these experiments.
Conclusions Formulators are called upon to optimize formulations not only with respect to the performance characteristics of the finished dosage form, but also with respect to the manufacturing operation, and a study of the interplay of process variables as related to the formulation performance is essential to attaining that goal. In our previous study,2 certain machine operating variables and formulation factors affecting plug formation and fill weight were studied for a dosingdisk automatic capsule filling machine. The present study focused on the effects of certain of these variables on drug release. The implications of the two important dosing-disk machine operating variables (i.e., the tamping force and the number of tamps) on drug release were explored in a dissolution study using hydrochlorothiazide as a model, low dose, poorly soluble drug. Anhydrous lactose and dicalcium phosphate were chosen to represent soluble and insoluble fillers, respectively. Generally, there was a tendency toward slower drug release with an increase in number of tamps. This effect was more dramatic for the insoluble system than for the soluble system; however, that variable could be eliminated in either case when 4% croscarmellose sodium, a tablet disintegrant, was included in the formulation. Drug release improved slightly from the anhydrous lactose-based capsules when a higher tamping force was applied, but dissolution was adversely affected by compression force when dicalcium phosphate was the filler. Hydrochlorothiazide dissolution from this latter matrix appeared to fit a “diffusion from insoluble matrix” model through the dissolu-
tion times studied. The decreasing slopes of the square-rootof-time dissolution plots based on that model point to decreasing porosity andlor increasing tortuosity a t high compression force or with multiple tamps. This latter observation could be used advantageously to control drug release from an insoluble, nondisintegrating matrix since the same fill weight may be obtainable with varying degrees of consolidation by adjustment of the number of tamps and the tamping force.
References and Notes 1. Shah, K. B.; Augsburger, L. L.; Small, L. E.; Polli, G. P. Pharm. Technol. 1983, 7(4), 42. 2. Shah, K.B.; Augsburger, L. L.; Marshall, K. J . Pharm. Sci. 1986. 75. 291. 3. Mehta, A.M.; Augsburger, L. L. Int. J . Pharm. 1981, 7, 327. 4. Augsbur er, L.L.; Shangraw, R. F.; Giannini, R. P.; Shah, V. P.; F’rasad, K.; Brown, D. J . Pharm. Sci. 1983, 72, 876. 5. Levy, G. In Papers Presented Before the Industrial Pharmacy Section, A.Ph.A. 113th Annual Meeting, Dallas, TX, A ril 1966; American Pharmaceutical Association: Washington, 8C,1966; 289-293. 6. VS. Phurmacopeia XXIlNational Formulary XVI; The US. Pharmacopeial Convention: Rockville, MD, 1985; 1244. 7. US. Phurmacopeiu XXIlNational Formulary X h ; The US. Pharmacopeial Convention: Rockville, MD, 1985; p 497. 8. Botzolakis, J. E.;Small, L. E.; Augsburger, L. L. Int. J . Pharm. 1982,12, 341. 9. Greenber R. Proc. 88th National Meeting, Am. Inst. Chem. Engrs.; Pkladel hia, PA, June 8-12, 1980, Fiche 29. 10. Higuchi, T. J . P L r m . Sci. 1963,52, 1145. 11. Botzolakis, J. E.,Ph.D. Thesis, University of Maryland, Baltimore, MD, 1985.
f.
Acknowledgments University of Maryland, in partial fulfillment of the Doctor of Philosophy degree requirements. ’
Journal of Pharmaceutical Sciences / 645 Vol. 76, No. 8, August 1987
I n dosing-disk type automatic capsule filling machines, the plugs of powder to be filled i n t o capsules are progressively built up in dosing-disk cavities through a series o f tamps. In previous the tamping stations o f a model GKF 330 Hofliger-Karg machine were instrumented by installing a strain-gauged piston in each station. It was shown t h a t although there was a provision for five consecutive tamps in that machine, a m a x i m u m of three would normally be required to achieve the desired fill weight for a given disk thickness. However, both the number o f tamps and the tamping force, as well as formulation variables, could influence the drug release rate from an encapsulated dosage form, particularly if the drug had a low dose and was poorly soluble. It has been shown on the simpler dosator machines, in which plugs are formed by a single compression, that drug dissolution can be affected by manipulating plug compact i ~ nThus, . ~ the experiments described below were designed to investigate the influence o f compression force, tamping history, filler type, and presence o f disintegrant o n the dissolution o f a model, low dose, slightly soluble drug, hydrochlorothiazide.
Experimental Section Formulations and Capsule Manufacture-The general formulation consisted of 6% hydrochlorothiazide, USP (Pro Farmaco, Bologna, Italy), magnesium stearate (Amend Drug and Chemical Company, Irvington, NJ) as lubricant, and filler. Direct tableting-grade anhydrous lactose (Sheffield Products, Memphis, TN) and unmilled dicalcium phosphate dihydrate (Ditab; Staufer Chemical Company, Westport, CT) were used as “soluble” and “insoluble” fillers, respectively. Magnesium stearate was used a t the 1.5%level for the soluble filler and a t the 0.50%level for the insoluble filler. Two formulations were designed for each filler, one without and the other with 4% croscarmellose sodium (AcDiSol; FMC Food and Pharmaceutical
0022-3549/87/0800-0639$01.00/0 0 7987, American Pharmaceufical Association
Products Division, Philadelphia, PA) a~ disintegrant. Batches of 3000 g (anhydrous lactose filler) or 4000 g (dicalcium phosphate filler) were blended in a 15.1-L twin-shell blender (Patterson-Kelly Co., East Stroudsburg, PA) for 10 min. The weight difference allowed a charge of approximately equivalent volumes in the twin-shell blender. Size #1 capsules were filled on a model GKF 330 Hofliger-Karg automatic capsule-filling machine (Bosch Packaging Machinery Division, Piscataway, NJ) which had been instrumented with strain gauges to monitor tamping forces, a~ previously described.1.2 The machine speed was held constant at 100 strokes per min, and a 1.58cm thick dosing disk was used in all runs. Either one tamp or up to three consecutive tamps (i.e., stations #5, #5 and #4, and X5, #4, and #3) a t a given compression force were utilized during encapsulation to study the multiple tamp effect. Separate runs were made using compression forces of 100 and 200 N to assess any possible compression force effect. The inclusion of hydrochlorothiazide at a fixed concentration of 6% resulted in a 7-27-mg range in drug content, since fill weights varied with the number and intensity of tamps, as well a~ with the density of the filler. Based on the solubility of hydrochlorothiazide (0.106% in 1:lOO hydrochloric acid at 37 “(29, even the maximum drug content resulted in a drug concentration during dissolution that was well below the 10-152 of solubility limit considered satisfactory6 for approximating sink conditions. Dissolution-The dissolution rate of hydrochlorothiazide was determined by USP method 11, with paddles.6 A six-head dissolution apparatus equipped with a multiple-drive stirrer (model 2000 Dissolution System; Distek, Inc., Somerset, NJ) was employed. The dissolution medium was 900 mL of dilute hydrochloric acid (1:lOO) maintained at 37 “C. The paddles were positioned 2.5 cm above the bottop of the flasks and rotated a t 50 2 2 rpm. Six randomly selected capsules of each formulation were tested. The capsules were held in stainless steel spirals to prevent their floating. Dissolution runs were carried out for 64 min. One set from each of the four formulations was tested for 100 (? 5)% release by increasing the paddle speed to 250 rpm. A sequential flow system (Dissograph Flow Hanson Research Corporation, NorthSystem, model 49-200-000; ridge, CA) was used. This system provides for serial withdrawal of filtered samples from each flask a t preset time intervals for spectral analysis and for return of the sample to the corresponding flask following absorbance measurement. To avoid disturbance of the stirring medium during runs, a pneumatically driven automatic sampler (model 27-700-000; Hanson Research Corporation, Northridge, CA), which inserts sampling probes only for the specified sampling time, was employed. The withdrawn samples were pumped, single file, through a 0.1-cm flow cell (model 170; Helma Cells, Inc., Jamaica, NY)that was mounted in a dual-beam, microprocessor-controlled spectrophotometer (model Lambda 3B; Perkin Elmer Corporation, Oak Brook, IL). All absorbance8 were read at 272 nm7 against dissolution medium in the reference flow cell. The reference dissolution medium was replenished between dissolution runs from a reservoir container, using a peristaltic pump. The spectrophotometer was interfaced through a serial port with a desktop computer (IBM PC; IBM Corporation, Armonk, NY). The sobware calculates percent drug dissolved based on drug content of individual dosage units and takes into account the actual fill weight of the test capsules. The mean percents dissolved and standard errors appear in Tables I-IV. Journal of Pharmaceutical Sciences / 639 Vol. 76,No. 8,August 1987
Porosity Measurement-The effect of compression force and the number of tamps on powder consolidation was further studied by determining the porosity and pore size distribution of anhydrous lactose-based plugs containing hydrochlorothiazide. A mercury intrusion porosimeter (model 9305 Pore Sizer; Micromeritics, Norcross, GA)was used. Data acquisition and reduction was largely automated through serial interfacing with the desktop computer. Intrusion readings up to 168 Mpa were taken. Visual examination ofthe plugs revealed no apparent physical damage as a result of the intrusion pressure. Moreover, total pore volumes calculated from true densities and plug dimensions agreed to within 22%with total intrusion volumes.
Results and Discussion These studies were designed to identify the influence of the
number of tamps and the extent of tamping, if any, on in vitro drug release. The formulation variables considered were filler type and the presence (or absence) of a distintegrant. Anhydrous L ~ ~ ~ ~~ ~ ~ ~ ~~ effect l ~of ~ - i number Of tamps (up three tampsp each at the same compression force) on hydrochlorothiazide dissolution at low (100 N) and high (200 N)ComPression force may be seen in Figures 1 and 2, respectively. The pore size distributions for these capsule plugs appear in Figures 3 and 4. It is apparent that regardless of compression force (high o r low), multiple tamping adversely affected the dissolution profile. This observation is surprising in light of a previous finding2 on similar placebo formulations that the mechanical strength of
''
Table I-Effect of Multiple Tamps and Compression Force on Hydrochlorothiazlde Dissolution from Anhydrous Lactose-Based Capsules'
Compression Force, N
Number of Tamps
100
1
200
2 3 1 2 3
Percent Drug Dissolved at Various Times, min 8 25.4 (1.99) 21.2(2.24) 15.0(0.88) 26.0(1.22) 17.8(1.25) 15.4(0.79)
16
24
45.6(2.11) 41.8(0.79) 35.4(1.28) 48.9 (0.52) 40.1 (1.11) 35.7(0.95)
56.5 (1.69) 52.3 (0.69) 46.9 (1.06) 59.4 (0.78) 51.4 (0.83) 47.8(0.91)
32 63.1 (1.59) 58.9 (0.82) 54.8 (1.34) 67.2(1.00) 59.1 (0.95) 55.5 (1.04)
40
48
56
68.4(1.63) 64.9 (0.74) 60.3(1.56) 73.4(1.13) 64.8(1.07) 61.5 (1.10)
74.1 (1.66) 69.6(0.84) 65.1 (1.73) 78.3 (1.19) 69.9 (1.14) 66.0 (1.18)
78.6 (1.72) 73.8(0.92) 69.0(1.90) 82.4(1.26) 74.2(1.21) 70.2 (1.22)
64 82.1 (1.58) 77.3 (1.06) 72.6(2.02) 86.0 (1.41) 77.3(1.20) 73.7(1.27)
'Magnesium stearate (1 5%)as lubricant. bMean of 6 determinations; standard error of mean in parentheses. Table 11-Effect of Multiple Tamps and Compression Force on Hydrochlorothlazide Dissolution from Anhydrous Lactose-Based Capsules Containing 4% Croscarmellose Sodlum'
Compression Force, N
Number of Tamps
100
1 2 3 1 2 3
200
Percent Drug Dissolved at Various Times, min 8 38.0(1.16) 35.9(1.19) 34.3 (2.10) 38.0(1.27) 36.2(1 .lo) 31.3 (1.44)
16 51.6(0.51) 49.8(0.44) 48.8(1.67) 53.4 (0.83) 51.3 (0.53) 47.5 (0.57)
24 58.7(0.29) 57.2(0.22) 56.7(1.53) 61.7(0.65) 58.4(0.52) 54.8 (0.31)
32 64.3(0.38) 62.7(0.35) 62.2(1.71) 67.9(0.72) 64.5(0.51) 60.4(0.32)
40
48
56
69.3(0.50) 68.0(0.39) 67.0(1.76) 72.9(0.77) 69.5(0.49) 65.0(0.32)
73.7(0.54) 72.5 (0.48) 71.5 (1.87) 77.2 (0.88) 73.8 (0.49) 68.9 (0.35)
77.7(0.56) 75.8(0.62) 75.0 (1.87) 81.0 (0.90) 77.3 (0.38) 72.4(0.40)
64 80.7(0.66) 79.2(0.75) 78.0(1.82) 84.0(0.96) 80.4(0.44) 75.3(0.40)
'Magnesium stearate (1.5%)as lubricant. Mean of 6 determinations; standard error of mean in parentheses. Table Ill-Effect Capsules'
Compression Force, N
a
of Multiple Tamps and Compression Force on Hydrochlorothlazlde Dissolution from Dlcalclum Phosphate-Based
Percent Drug Dissolved at Various Times, min
Number
of Tamps
100
1
200
2 3 1 2 3
8 12.1 (0.60) 9.2(0.29) 8.9(0.23) 10.6(0.55) 7.6(0.10) 7.7(0.32)
16 20.5 (0.91) 16.0(0.45) 15.6(0.42) 17.8(0.68) 13.0(0.23) 13.4(0.34)
24 26.9 (1.19) 21.1 (0.55) 20.5(0.53) 22.7(0.72) 17.3(0.24) 17.4(0.41)
32 32.0 (1.43) 25.4 (0.74) 24.5(0.64) 27.0(0.75) 20.7(0.29) 20.7(0.42)
40
48
56
37.0(1.57) 29.4 (0.92) 28.2 (0.71) 30.5 (0.86) 24.0 (0.31) 23.8 (0.54)
41.3 (1.84) 32.9 (1.06) 31.3 (0.87) 33.8 (1.00) 27.0(0.35) 26.6(0.57)
45.2(1.93) 36.3 (1.12) 34.6 (0.92) 37.2 (1.12) 29.6(0.39) 29.5 (0.61)
64 48.8(2.07) 39.7(1.25) 37.5(1.00) 40.2(1.26) 32.4 (0.44) 32.1 (0.71)
Magnesium stearate (0.5%)as lubricant. bMean of 6 determinations; standard error of mean in parentheses.
Table IV-Effect of Multiple Tamps and Compression Force on Hydrochlorothlazlde Dlssolutlon from Dlcalclum Phosphate-Based Capsules Containing 4% Croscarmellose Sodium'
Compression Force, N 100 200
a
Percent Drug Dissolved at Various Times, min
Number of Tamps
1 2 3 1 2 3
8 28.8 (1.74) 28.4 (0.94) 27.7 (1.58) 31.0 (1.72) 28.7 (1.24) 28.4(1.72)
16 41.9(1.76) 40.8(1.47) 41.5 (1.82) 44.2(1.83) 40.3(1.41) 41.3(1.89)
24 51.9 (1.56) 50.0 (1.19) 51.1 (1.72) 53.6 (1.54) 49.6(1.30) 51.1 (1.97)
32 59.4 (1.63) 57.3 (0.94) 59.3 (1.58) 61.7(1.39) 56.1 (1.04) 59.6(1.96)
40 66.0(1.54) 63.9(0.80) 66.2(132) 68.4(1.23) 62.0(0.94) 66.5(1.92)
48
56
70.6(1.57) 68.9(0.39) 72.2 (1.06) 73.6 (1.07) 67.5(0.85) 72.0(1.86)
75.0(1.50) 74.2(0.46) 77.2(0.83) 78.0(1.03) 72.5(0.73) 76.6(1.70)
Magnesium stearate (0.50%)as lubricant. Mean of 6 determinations; standard error of mean in parentheses.
640 /Journal of Pharmaceutical Sciences Vol. 76, No. 8, August 1987
64 78.4(1.50) 78.8(0.30) 81.3(0.67) 81.0(1.06) 76.3(0.73) 79.9(1.60)
the large, initially formed plug segment did not change after a second or third tamp a t the same compression force. If plug mechanical strength is a good indicator of powder consolidation, that finding would suggest that multiple tamping does not cause further compaction. However, the results of the present study reveal a uniform decrease in pore size distribution at both force levels from the first tamp to the second tamp which does, indeed, point to further consolidation. Evidently, the previously reported mechanical strength measurements were not sensitive enough to detect these relatively small changes in porosity. At the low compression force (Figure 3), it may be seen that the median pore diameter decreases from 12.8 pm with one tamp to 10.8 Fm with two tamps, although no change was apparent between two tamps and three tamps. In considering the dissolution data (Figure 11, it is interesting to note that the differences in percent dissolved at any time between the curves representing one, two, and three tamps were constant. Although small, these differences were statistically significant (p < 0.05) at 32 min, 100
but not a t 64 min, based on a two-sided t-test for the two extremes (one tamp versus three tamps). The trend toward decreasing dissolution rate with increases in the number of tamps is even more clear in the high compression force data (Figure 2). While the differences in percent drug dissolved a t various times still remained more or less constant for the three tamping conditions, a significantly (p < 0.05) higher percent of hydrochlorothiazide dissolved at the 32- and 64-min marks from the plugs obtained with one tamp than from plugs obtained with two or three tamps. The pore size distribution (Figure 41, as before, shifted toward a smaller size when the number of tamps increased from one to two, but was not greatly affected by the third tamp. The consistent differences a t all times in percent release a t both low and high compression forces among the three tamping groups, with maximum release occurring when only a single tamp was employed, points to an initial “burst” effect in drug release. This burst effect probably results from the loose powder that fills the disk cavity after the last tamp and prior to ejection, and is likely to be most significant in the
80
B
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2
00
v, 0 Q
2 0 s
40
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A 0 0
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61
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TIME (mid
, .
.
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I
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.
I
.
.
0.2
PORE SIZE (urn)
Figure 1--Effect of multiple tamps at low compression force (100 N) on hydrochlorothiazide dissolution from anhydrous lactose-basedcapsules (7.5% magnesium stearate). Key: (0) tamping at station #5; (0) tamping at station #5,4; (A)tamping at station 15, 4, 3.
Flgure 3-Hfect of multiple tamps at low cornpression force (100 N) on pore size distributions of plugs (anhydrous lactose-based formulation of hydrochlorothiazide, 7.5% magnesium stearate). Key: ( 0 )tamping at station #5; (a)tamping at station #5, 4; (A)tamping at station #5, 4, 3.
100 7
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-
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td CL
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38
62
86
TIME (mid
Flgure 2-€ffect of multiple tamps at high compression force (200 N) on hydrochlorothiazidedissolution from anhydrous lactose-based capsules ( 1 5% magnesium stearate). Key: see Figure 1.
PORE SIZE (urn)
Flgure 4-Effect of multiple tamps at high compression force (200 N) on pore size distributions of plugs (anhydrous lactose-based formulation of hydrochlorothiazide, 7.5% magnesium stearate). Key: see Figure 3. Journal of Pharmaceutical Sciences I641 Vol. 76, No. 8, August 7987
case where only one tamp is employed. Previous work2 showed that the full plug length is not realized with just a single tamp, and that a void volume remains which is filled volumetrically from the powder head over the dosing disk prior to the scrape-offwhich precedes ejection. Since complete plug length is realized when two tamps are employed, capsules filled when employing two tamps will contain no loose powder. Assuming the intact plug to release drug a t the same rate in all cases, this initial burst could account for the consistently higher dissolution profiles of these capsules. The amount of loose fill would be less at the low compression force (i.e., less consolidation of the intact plug, thereby leaving less room for the loose fill) than it would be at the high compression force. This latter point thus could account for the greater (but consistent with time) differences in percent dissolved between the single-tamp and two-tamp data at the higher (Figure 1) and lower compression forces (Figure 2). The effect of single-tamp compression force on hydrochlorothiazide dissolution is shown in Figure 5, and the pore size distribution data for those capsule plugs are given in Figure 6. An examination of these pore size distribution data indi-
cates that a greater consolidation of the powder mass occurred with an increase in compression force. Curiously, however, the increased densification resulted in an improved dissolution rate for this soluble system. A similar observation has been reported by Botzolakis et aL8 for a similar hydroch1orothiadize:anhydrous lactose formulation filled on a dosator machine, and by Greenberg regarding an unspecified formulation, also filled on a dosator machine. Exactly why dissolution rate increased with increased compression force is not clear, but the effect in part may be related to greater particle fracture or frictional shearing a t higher compression force resulting in more clean surfaces uncontaminated with hydrophobic lubricant. For these lactose formulations, both the burst effect and greater consolidation, together, yield overall improved dissolution profiles a t higher compression forces. That the curves in Figure 5 do not show equal spacing at all time points is not inconsistent with the discussion of 100
100
80
80
e3
0
60
v)
v,
0 c7
2
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n
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,
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TIME (mid
Figure 5-€ffect of compression force on hydrochlorothiazide dissolution from anhydrous lactose-based capsules (7.5% magnesium stea700 N; (0) 200 N. rate) utilizing only a single tamp. Key: (0)
Figure 7-€ffect of multiple tamps at low compression force (100 N) on hydrochlorothiazidedissolution from anhydrous lactose-based capsules containing 4% croscannellose sodium disintegrant (1.5% magnesium stearate). Key: see Figure 7.
W
5
I .
40
O 10
4
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I 0
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, 20
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PORE SlZE(um) Figure 6--Effect of compression force on pore size distributions of plugs (anhydrous lactose formulation of hydrochlorothiazide, 1.5% magnesium stearate). Key: (A)700 N; (A)200 N. 642 /Journal of Pharmaceutical Sciences Vol. 76, No. 8, August 7987
Figure 8-.€ffect of multiple tamps at high compression force (200 N) on hydrochlorothiazidedissolution from anhydrous lactose-basedcapsules containing 4 % croscarmellose sodium disintegrant (1.5% magnesium stearate). Key: see Figure 1 .
Figures 1 and 2. In the early stages, dissolution from both capsules is primarily due to the dissolution of the faster dissolving loose powder. Thus, one would expect little or no difference between the two capsules initially, with the curves gradually diverging to a fairly constant difference at later times, owing to the different amounts of loose powder fill as well as to the effect of the two different compression forces on the intact plug. This is exactly what the data in Figure 5 show. The effects of disintegrant (4% croscarmellose sodium) and multiple tamps a t low and high compression force on the dissolution of hydrochlorothiazide from anhydrous lactosebased capsules are summarized in Figures 7 and 8. The presence of disintegrant at low compression force yielded essentially identical dissolution patterns for the capsules filled using any of one, two, or three tamps. The burst effect, observed previously in the absence of disintegrant, was not evident here. It is likely that rapid plug dispersal and initial dissolution, resulting from the presence of disintegrant, overshadowed any such effect. A comparison between Figures 1 and 7 clearly indicates that for any tamping combination, a significantly (p < 0.05) higher percent of hydrochlorothiazide dissolved in 8 min when the disintegrant was included in the formulation than was released in 8 min from the formulation without disintegrant. Figures 7 and 8 also reveal that an increase in the number of tamps tends to retard dissolution from the disintegrantcontaining lactose formulations. This effect is most clearly obvious at the high compression force (Figure 8). Dicalcium Phosphate-Based Formulations-The effects of the number of tamps and the extent of compression on hydrochlorothiazide dissolution from the dicalcium phosphate-based formulations may be seen in Figures 9-11. Increasing the number of tamps slowed drug release at both the low (Figure 9) and high (Figure 10) compression forces, but only when up to two tamps were employed. When a third tamp was applied at the low compression force (Figure 91, the dissolution rate appeared to decay further; however, the differences were not significant (p < 0.05) at 32 and 64 min. The application of a third tamp at the higher compression force had no apparent effect on drug dissolution (Figure 10).
From the previously noted porosimetry data (anhydrous lactose, Figures 3 and 41, it is clear that consolidation occurred only up to two tamps. With both the anhydrous lactose and dicalcium phosphate formulations, fill weight also increased with up to only two tamps. Thus, it seems reasonable to infer that even for the dicalcium phosphate formulations, consolidation and porosity reduction occurred with up to only two tamps. Based on these results (Figures 9 and lo), it is apparent that in vitro drug release depends on the extent of consolidation for this "insoluble" system. A comparison of Figures 9 and 10 also reveals that dissolution rate decreased (regardless of the number of tamps) a t the higher compression force. This compression force effect is most clearly evident in the single-tamp data (Figure 11). Overall, the differences in dissolution profiles generally increased with time as a function of both the number of tamps and the extent of tamping. SOUARE ROOT OF TIME (rnin"')
I
lo
1
0
0
26
13
39
62
66
TIME (rnin) Figure lO-€ffect of multiple tamps at high compression force (200 N) on hydrochlorothiazide dissolution from dicalcium phosphate-based capsules (0.50%magnesium sfearate). Key: see Figure 9.
SOUARE ROOT OF TIME (min"') 2
0
6
4
8
SOUARE ROOT OF TIME (min"')
60
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8
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TIME (mid Figure +Effect of multiple tamps at low compression force (100 N) on hydrochlorothiazide dissolution from dicalcium phosphate-based captamping at station #5; (0) sules (0.50%magnesium stearate). Key: (0) tamping at station X5, 4; (A) tamping at station #5, 4, 3; open symbols: x-axis = time; closed symbols: x-axis = time "?
01
,
I
I
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I
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TIME (mid Figure 11-Effect of compression force on hydrochlorothiazidedissolution from dicalcium phosphate-based capsules (0.50% magnesium 100 N;(0) 200 N;open stearate) utilizing only a single tamp. Key: (0) symbols: x-axis = time; closed symbols: x-axis = time l'? Journal of Pharmaceutical Sciences / 643 Vol. 76, No. 8, August 1987
Interestingly, all dicalcium phosphate-based plugs remained intact even after the last dissolution sample was taken at 64 min. HiguchilO has described the following model for diffusion-controlled drug release from a heterogeneous matrix in which diffusion takes place in the intergranular pores:
(1) where Q is the amount of drug released per unit surface area after time t , D is the diffusion coefficient of the drug in the dissolution medium, c is the porosity of the matrix, r is the tortuosity of the matrix, A is the concentration of the drug in the compact, and Cs is the solubility of the drug in the dissolution medium. This equation holds as long as 2A >> E c s , and predicts a linear fit for the amount released per unit area versus t”2. A capsule fill weight range of 0.369 to 0.505 g, containing drug at 6% (w/w) in a disc cavity volume of 0.396cm3, corresponds to a range of A of 5.6-7.6% (w/v).The solubility of the drug in the dissolution medium has been reported to be 0.106% (w/v) a t 37 0C.4Furthermore, from the lactose data and an earlier report,” the porosity of the plugs could reasonably be expected to be in the range of 0.4 to 0.5. Thus, it is quite reasonable that the condition 2A >> E c s holds in this case. However, the surface area is not held constant in a typical dissolution study. Nevertheless, the fact
that the plug did remain intact throughout the dissolution run suggests a possible fit to the Higuchi model, with the limitation noted above. As may be seen in Figures 9-11, when the dissolution data were regressed and plotted as percent dissolved against t1’2, an excellent fit of the model was found in all cases (coefficient of determination 2 0.999). The squared x-intercept ranged from 0.82-1.6 min (Table V) which could represent the time taken for the capsule shell to dissolve in the release medium and for the initial direct exposure of the plug to the dissolving fluid. Decreasing slopes with increases in the extent and frequency of tamps could be a function of resultant greater consolidation and, thus, decreasing porosity. The addition of disintegrant improved drug dissolution over that of the control dramatically, regardless of the number of tamps andlor the tamping force. As may be seen in Figures 12 and 13, the number of tamps did not adversely affect drug dissolution. Neither was there any specific effect 100 7
80 -
8
3
Table V-Regresslon Parameters Using A “Diffusion from lsoluble Matrlx” Model for HydrochlorothlazldeDlssolutlon from Dlcalclum Phosphate-BasedCapsules’
0 3
Compression Number
ae
Forces N
Of
100
Regression Parameterb
Tamps Slope, %/min”z
F
1.26 1.65 1.40 0.82 1.62 1.37
0.9999 0.9997 0.9998 0.9996 0.9996 0.9994
7.1 1 5.86 5.49 5.65 4.78 4.66
1 2 3 1 2 3
200
(x-intercept)Z,rnin
Magnesium stearate (0.5%) as lubricant. bObtained by regressing mean (n = 6) percent dissolved against timeo2from 64-min dissolution runs. a
IE
60-
40-
n 20
-
01
0
I
I
13
26
39
1
1
62
66
TIME (mid
Figure 13-.€ffect of multiple tamps at high compression force (ZOO N) on hydrochlorothiazide dissolution from dicalciurn phosphate-based capsules containing 4% croscarmellose sodium (0.50% magnesium stearate). Key: see Figure 7.
’””1
lo0l
80 -
ow
601
60 -
v,
0
40 -
0
401
!i
I
13
ze 39 TIME (mid
I
62
e6
Flgure 12-€ffect of multiple tamps at low compression force ( 1 00 N) on hydrochlorothiazide dissolution from dicalcium phosphate-based capsules containing 4% croscarmellose sodium (0.50% magnesium stearate). Key: see figure l. 644 /Journal of Pharmaceutical Sciences Vol. 76, No. 8,August 1987
20
0
13
26
39
62
1
66
TIME (mid
Figure 14-Effect of compression force on hydrochlorothiazidedissolution from dicalciurn phosphate-based capsules containing 4% croscarmellose sodium filled using a single tamp (0.50% magnesium stearate). Key: (0) 100 N; (3) 200 N.
due to compression force (Figure 14). Four,percent croscarmellose sodium may be sufficient for this insoluble system to provide disintegration and deaggregation sufficiently rapid to overcome any effects resulting from multiple tamps or increased tamping force within the range of these experiments.
Conclusions Formulators are called upon to optimize formulations not only with respect to the performance characteristics of the finished dosage form, but also with respect to the manufacturing operation, and a study of the interplay of process variables as related to the formulation performance is essential to attaining that goal. In our previous study,2 certain machine operating variables and formulation factors affecting plug formation and fill weight were studied for a dosingdisk automatic capsule filling machine. The present study focused on the effects of certain of these variables on drug release. The implications of the two important dosing-disk machine operating variables (i.e., the tamping force and the number of tamps) on drug release were explored in a dissolution study using hydrochlorothiazide as a model, low dose, poorly soluble drug. Anhydrous lactose and dicalcium phosphate were chosen to represent soluble and insoluble fillers, respectively. Generally, there was a tendency toward slower drug release with an increase in number of tamps. This effect was more dramatic for the insoluble system than for the soluble system; however, that variable could be eliminated in either case when 4% croscarmellose sodium, a tablet disintegrant, was included in the formulation. Drug release improved slightly from the anhydrous lactose-based capsules when a higher tamping force was applied, but dissolution was adversely affected by compression force when dicalcium phosphate was the filler. Hydrochlorothiazide dissolution from this latter matrix appeared to fit a “diffusion from insoluble matrix” model through the dissolu-
tion times studied. The decreasing slopes of the square-rootof-time dissolution plots based on that model point to decreasing porosity andlor increasing tortuosity a t high compression force or with multiple tamps. This latter observation could be used advantageously to control drug release from an insoluble, nondisintegrating matrix since the same fill weight may be obtainable with varying degrees of consolidation by adjustment of the number of tamps and the tamping force.
References and Notes 1. Shah, K. B.; Augsburger, L. L.; Small, L. E.; Polli, G. P. Pharm. Technol. 1983, 7(4), 42. 2. Shah, K.B.; Augsburger, L. L.; Marshall, K. J . Pharm. Sci. 1986. 75. 291. 3. Mehta, A.M.; Augsburger, L. L. Int. J . Pharm. 1981, 7, 327. 4. Augsbur er, L.L.; Shangraw, R. F.; Giannini, R. P.; Shah, V. P.; F’rasad, K.; Brown, D. J . Pharm. Sci. 1983, 72, 876. 5. Levy, G. In Papers Presented Before the Industrial Pharmacy Section, A.Ph.A. 113th Annual Meeting, Dallas, TX, A ril 1966; American Pharmaceutical Association: Washington, 8C,1966; 289-293. 6. VS. Phurmacopeia XXIlNational Formulary XVI; The US. Pharmacopeial Convention: Rockville, MD, 1985; 1244. 7. US. Phurmacopeiu XXIlNational Formulary X h ; The US. Pharmacopeial Convention: Rockville, MD, 1985; p 497. 8. Botzolakis, J. E.;Small, L. E.; Augsburger, L. L. Int. J . Pharm. 1982,12, 341. 9. Greenber R. Proc. 88th National Meeting, Am. Inst. Chem. Engrs.; Pkladel hia, PA, June 8-12, 1980, Fiche 29. 10. Higuchi, T. J . P L r m . Sci. 1963,52, 1145. 11. Botzolakis, J. E.,Ph.D. Thesis, University of Maryland, Baltimore, MD, 1985.
f.
Acknowledgments University of Maryland, in partial fulfillment of the Doctor of Philosophy degree requirements. ’
Journal of Pharmaceutical Sciences / 645 Vol. 76, No. 8, August 1987