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Abstract 0The effects of number of tampsand tamping force on drug Products Division, Philadelphia, PA) a~ disintegrant. Batches of
dissolution from capsulesfilled on an instrumenteddosing-diskautomat- 3000 g (anhydrous lactose filler) or 4000 g (dicalcium phosphate
ic capsule filling machine (Hofliger-Karg)were studied using hydrochlo- filler) were blended in a 15.1-L twin-shell blender (Patterson-Kelly
rothiazide as a model, low dose, poorly soluble drug. Generally, there Co., East Stroudsburg, PA) for 10 min. The weight difference allowed
was a trend toward slower dissolution rate with increasing numbers of a charge of approximately equivalent volumes in the twin-shell
tamps, the effect being most marked when insoluble dicalcium phos- blender.
phate dihydrate was the filler. Higher compression forces improved drug Size #1 capsules were filled on a model GKF 330 Hofliger-Karg
release when anhydrous lactose was the filler, but adversely affected automatic capsule-filling machine (Bosch Packaging Machinery Di-
the dicalcium phosphate-based capsules. Inclusion of 4% croscarmel- vision, Piscataway, NJ) which had been instrumented with strain
lose sodium disintegranttended to nullify the effects of number of tamps gauges to monitor tamping forces, a~ previously described.1.2 The
or tamping force with both fillers; however, the disintegrantalso marked- machine speed was held constant at 100 strokes per min, and a 1.58-
ly enhanced drug dissolution from the dicalcium phosphate-based cm thick dosing disk was used in all runs. Either one tamp or up to
formulation. Hydrochlorothiazidedissolution from the latter formulation three consecutive tamps (i.e., stations #5, #5 and #4, and X5, #4,
without disintegrant appeared to follow a “diffusion from insoluble and #3) a t a given compression force were utilized during encapsula-
matrix” model regardlessof number of tamps or their intensity. Mercury tion to study the multiple tamp effect. Separate runs were made
intrusion pore size distribution data for some plugs suggested that for using compression forces of 100 and 200 N to assess any possible
tamps of equal force (100 or 200 N), further powder consolidation after compression force effect.
two tamps does not occur. 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
I n dosing-disk type automatic capsule filling machines, the was well below the 10-152 of solubility limit considered satisfactory6
plugs of powder to be filled i n t o capsules are progressively for approximating sink conditions.
built up in dosing-disk cavities through a series o f tamps. In Dissolution-The dissolution rate of hydrochlorothiazide was de-
previous the tamping stations o f a model GKF 330 termined by USP method 11, with paddles.6 A six-head dissolution
apparatus equipped with a multiple-drive stirrer (model 2000 Disso-
Hofliger-Karg machine were instrumented by installing a lution System; Distek, Inc., Somerset, NJ) was employed. The
strain-gauged piston in each station. It was shown t h a t dissolution medium was 900 mL of dilute hydrochloric acid (1:lOO)
although there was a provision for five consecutive tamps in maintained at 37 “C. The paddles were positioned 2.5 cm above the
that machine, a m a x i m u m of three would normally be bottop of the flasks and rotated a t 50 2 2 rpm. Six randomly selected
required to achieve the desired fill weight for a given disk capsules of each formulation were tested. The capsules were held in
thickness. However, both the number o f tamps and the stainless steel spirals to prevent their floating. Dissolution runs
tamping force, as well as formulation variables, could influ- were carried out for 64 min. One set from each of the four formula-
ence the drug release rate from an encapsulated dosage form, tions was tested for 100 (? 5)% release by increasing the paddle
particularly if the drug had a low dose and was poorly speed to 250 rpm. A sequential flow system (Dissograph Flow
System, model 49-200-000; Hanson Research Corporation, North-
soluble. It has been shown on the simpler dosator machines, ridge, CA) was used. This system provides for serial withdrawal of
in which plugs are formed by a single compression, that drug filtered samples from each flask a t preset time intervals for spectral
dissolution can be affected by manipulating plug compac- analysis and for return of the sample to the corresponding flask
t i ~ nThus,
. ~ the experiments described below were designed following absorbance measurement. To avoid disturbance of the
to investigate the influence o f compression force, tamping stirring medium during runs, a pneumatically driven automatic
history, filler type, and presence o f disintegrant o n the sampler (model 27-700-000; Hanson Research Corporation, North-
dissolution o f a model, low dose, slightly soluble drug, hydro- ridge, CA), which inserts sampling probes only for the specified
chlorothiazide. sampling time, was employed. The withdrawn samples were
pumped, single file, through a 0.1-cm flow cell (model 170; Helma
Experimental Section Cells, Inc., Jamaica, NY)that was mounted in a dual-beam, micro-
processor-controlled spectrophotometer (model Lambda 3B; Perkin
Formulations and Capsule Manufacture-The general formula- Elmer Corporation, Oak Brook, IL). All absorbance8 were read at
tion consisted of 6% hydrochlorothiazide, USP (Pro Farmaco, Bolo- 272 nm7 against dissolution medium in the reference flow cell. The
gna, Italy), magnesium stearate (Amend Drug and Chemical Compa- reference dissolution medium was replenished between dissolution
ny, Irvington, NJ) as lubricant, and filler. Direct tableting-grade runs from a reservoir container, using a peristaltic pump. The
anhydrous lactose (Sheffield Products, Memphis, TN) and unmilled spectrophotometer was interfaced through a serial port with a
dicalcium phosphate dihydrate (Ditab; Staufer Chemical Company, desktop computer (IBM PC; IBM Corporation, Armonk, NY). The
Westport, CT) were used as “soluble” and “insoluble” fillers, respec- sobware calculates percent drug dissolved based on drug content of
tively. Magnesium stearate was used a t the 1.5%level for the soluble individual dosage units and takes into account the actual fill weight
filler and a t the 0.50%level for the insoluble filler. Two formulations of the test capsules.
were designed for each filler, one without and the other with 4% The mean percents dissolved and standard errors appear in Tables
croscarmellose sodium (AcDiSol; FMC Food and Pharmaceutical I-IV.
Table 11-Effect of Multiple Tamps and Compression Force on Hydrochlorothlazide Dissolution from Anhydrous Lactose-Based
Capsules Containing 4% Croscarmellose Sodlum'
Table Ill-Effect of Multiple Tamps and Compression Force on Hydrochlorothlazlde Dissolution from Dlcalclum Phosphate-Based
Capsules'
Table IV-Effect of Multiple Tamps and Compression Force on Hydrochlorothlazlde Dlssolutlon from Dlcalclum Phosphate-Based
Capsules Containing 4% Croscarmellose Sodium'
80
B
3
2 00
v,
0
Q
2 40
0
s
20
A
0 , . . I . . .
0 13 20 38 61 66 Lo 10 4 I 0.2
TIME (mid
PORE SIZE (urn)
Figure 1--Effect of multiple tamps at low compression force (100 N) on
hydrochlorothiazide dissolution from anhydrous lactose-basedcapsules Flgure 3-Hfect of multiple tamps at low cornpression force (100 N) on
(7.5% magnesium stearate). Key: (0) tamping at station #5; (0) pore size distributions of plugs (anhydrous lactose-based formulation of
tamping at station #5,4; (A)tamping at station 15, 4, 3. 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
80 -
e3
g 80-
td 60-
CL
0
0
a
2 40- w
I
0 I-
be Q s-
5
20 -
u
f
1
4a 10 4 1 0.2
01 I 1
0 13 28 38 62 86
TIME (mid PORE SIZE (urn)
Flgure 2-€ffect of multiple tamps at high compression force (200 N) on Flgure 4-Effect of multiple tamps at high compression force (200 N) on
hydrochlorothiazidedissolution from anhydrous lactose-based capsules pore size distributions of plugs (anhydrous lactose-based formulation of
( 1 5% magnesium stearate). Key: see Figure 1. hydrochlorothiazide, 7.5% magnesium stearate). Key: see Figure 3.
80
e3
0 60
v)
v,
0
c7
2 40
n
z
20
01 I 1 , 1
0 13 26 3e 62 65
TIME (mid
0
0 13 26 38 62 66
Figure 7-€ffect of multiple tamps at low compression force (100 N) on
TIME (mid
hydrochlorothiazidedissolution from anhydrous lactose-based capsules
containing 4% croscannellose sodium disintegrant (1.5% magnesium
Figure 5-€ffect of compression force on hydrochlorothiazide dissolu-
stearate). Key: see Figure 7.
tion from anhydrous lactose-based capsules (7.5% magnesium stea-
700 N; (0)
rate) utilizing only a single tamp. Key: (0) 200 N.
W
5
I . O I , 1 I
40 10 4 1 0.2 0 13 20 38 62 05
TIME (mid
PORE SlZE(um)
Figure 8-.€ffect of multiple tamps at high compression force (200 N) on
Figure 6--Effect of compression force on pore size distributions of hydrochlorothiazidedissolution from anhydrous lactose-basedcapsules
plugs (anhydrous lactose formulation of hydrochlorothiazide, 1.5% containing 4 % croscarmellose sodium disintegrant (1.5% magnesium
magnesium stearate). Key: (A)700 N; (A)200 N. stearate). Key: see Figure 1 .
40
B
23 30
0
2 20
n
*I
zp
10
10
0
0 13 26 39 62 66 01 , I I I
TIME (mid 0 13 26 30 62 66
TIME (mid
Figure +Effect of multiple tamps at low compression force (100 N) on
hydrochlorothiazide dissolution from dicalcium phosphate-based cap- Figure 11-Effect of compression force on hydrochlorothiazidedissolu-
sules (0.50%magnesium stearate). Key: (0) tamping at station #5; (0) tion from dicalcium phosphate-based capsules (0.50% magnesium
tamping at station X5, 4; (A) tamping at station #5, 4, 3; open symbols: 100 N;(0)
stearate) utilizing only a single tamp. Key: (0) 200 N;open
x-axis = time; closed symbols: x-axis = time "? symbols: x-axis = time; closed symbols: x-axis = time l'?
’””1
80 -
lo0l
ow 601
60 -
v,
0
40 -
0
I
13 ze 39 62 e6
!i 401
20
0 13 26 39 62
I 1
66
TIME (mid TIME (mid
Flgure 12-€ffect of multiple tamps at low compression force ( 1 00 N) on Figure 14-Effect of compression force on hydrochlorothiazidedissolu-
hydrochlorothiazide dissolution from dicalcium phosphate-based cap- tion from dicalciurn phosphate-based capsules containing 4% croscar-
sules containing 4% croscarmellose sodium (0.50% magnesium stea- mellose sodium filled using a single tamp (0.50% magnesium stearate).
rate). Key: see figure l. Key: (0) 100 N; (3) 200 N.