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Compression of enteric-coated pellets to disintegrating tablets: uniformity of dosage units
POWDER TECHNOLOGY ELSEVIER
Pov, dcr T c c h n u l o g y 96 ( 1998 ) 2 4 8 - 2 5 4
Compression
of
enteric-coated pellets to disintegrating tablets: uniformity of dosage units
Thomas E. Beckert ~"~",Klaus Lehmann b, Peter C. S c h m i d t ~'* "' l)ep~ r m e ,
~t,rt~h~ - u , , , tlic~ I T c t
olo~.v 1:t; rl ~ l lk'~ rl~ ~; ', vii3 Tiihin~,e ,~ ,/ I~'r ,VI ~ %,~,t ~'tell " ,~', 7 2 0 7 6 ?'iibi ~ge~. G e n m m v t, Rg~hm G m h t t , 0427.5 I)arm,~tadl, G e r m a n y
Received 5 July 1'-)96:rcxiscd 29 September 1997
Abstract
Enteric-coated bisacodyl pellets were compressed into tablets using granules and powders as filler.--bindersof difterenl particle size and cohcsiveness. The effucts on the uniformity of content and mass were investigated. The mixtures contained between 10 and 709 mass/mass pellets with a particle size in the range 0.8 1.25 ram. Egermann's equations were used to calculate the coefficients of random variation of conlenl. Tablets containing 10% mass/mass pellets showed pronotmced w~riationsin mass and content. This was attributed to the large particle size of the pellets as compared with the tablet size. Mixtures with 3()9~ mass/mass pellets showed good uniformity of mass and of conlenl if addilional granules were used as excipients. Segregation c.ccttrrcd if only liner excipients were used. With 50-70% mass/mass pellets in a tabl~et, good content uniformity was found with all tiller binders used. This can be explained by lhe formation of a percolating cluster ol the pellets, ~ hich prevented segregation. With 50% mass/mass, corresponding to 3t)9,: w~l./vol., and more pellets in the mixture, the coefficient of variation of c~mtent agreed well with the values calculated according to Egermann's equations. ~) 1998 Elsevier Science S.A. All rights reserved. Key~,ord.w
Pellets: Tablt:ls: ('ontttnt unifolnlily: Mas~, tunif~ulnil'~
1. I n t r o d u c t i o n
Controlled-release and gastroresistant preparations can be administered orally in single-unit or multiple-unit dosage lk)rms. Single-unit dosage forms contain the active ingredient within a single tablet, capsule or fihn-coated tablet, while multiple-unit dosage forms consist of a number of subunits incorporated in a capsule or tablet. Single-unit preparations show higher variations in gastric residence time, causing a prolonged lag tirne, enhanced side effects or stability problems in the case of gastroresistant formulations and wniations in bioavailability of sustained-release preparations. h-I contrast, multiple-unit products distribulc readily over a large surface area in the intestine. At less than 2 mm in diameter, the particles behave like liquids, leaving the stomach within a short period of time [ I I. This results in fewer adverse effects, better bioavailability of the drug and less pronounced variations in drug release 12-41. Multiple-unit dosage forms are normally administered its capsules containing pellets or granules as suhunits. Unfortunately, prnduction (7oncsponding authok Tel.: + 4 9 7071 29 ._46_ ~ "~ lax: f 4 u 7071 "~9
5531. 0(}3_ 5 )10 '),S, $1 ~.Ot) ~', 1908 Elsevier Science S.A. All rights re
costs lot capsules are high compared with those of tablets. This is due to the lower output of capsule-filling machines and to the higher cost of the capsules themselves. Moreover, capsules cannot be divided into subunits in the same way as tablets. These disadwmtages can be overcome by compressing coated pellets into rapidly disintegrating tablets. In general, the compression of pellets into tablets together with excipients of a smaller particle size causes high variations in mass and content, duc to the segregation phenomenon. If pellets with a narrow size distribution are compressed together with additives of similar size and shape, uniformity of mass and content according to the pharmacopoeias can be achieved [ 5 ]. Disintegrating tablets containing particles of about I mm in diameter necd to be compressed with a certain amount of excipient, otherwise the mixture will not form stable tablets, and cracking will occur in the filnl coatings ] 6 ] on the pellets. Addition of excipients makes it possible to form solid compacts which, upon addition ofa disintegrant, disintegrate rapidly and allow the particles to sepa,ate. The most pragmatic way to achieve high homogeneity with conslituents of different parficlc size may be seen in the use of an "ordered' mixlure, as proposed by Hersey [7] in 1975. Unfortunately, however, ordered mixtm'es with a proportion
T.E. Beckerr el al. / P o w d e r 7echm~logy 96 (1998) 248-254
of fine constituents of more than 20% mass/mass 18,9] are difficult to obtain. More: recently, Egermann 110-13] has derived equations for predicting the homogeneity of binary random mixtures. He used these equations to optimize tablet formulations with respect to high dose unilbrmity and fixed the limits of their application based on percolation thresholds as explained by Stauffer [ 14 ]. As Egermann rightly supposed, a unique equation for the quality of random mixtures is not available. He found that different equations and assumptions are needed, depending on the ratio of the components in a mixture [ 15 ]. On the one hand, his system is based on Lacey's [ 161 assumption that the highest attainable degree of mixing contbrms to a completely disordered system with random distribution of all particles, following a binomial distribution. Dosing of tablets is performed by filling a mixture into the die of a tableting machine by volume. Egcrmann [10] modified the Stange Poole equation [17], which is based on the mass of the particles and constituent proportions by applying the corresponding parameters by apparent volume. In addition, he changed Johnson's [18] equation, which is valid for spherical drug particles, to apply to particles of any shape. This equation is based on a Poisson distribution and wdid only for small proportions of drug below 10% v ol./vol. [ 13 ]. He also showed that the highest attainable degree of homogeneity of an interactive mixture equals the quality of the ntminteractive random system [ 191. This makes the equations applicable m pharmaceutical systems, which are often partially interactive mixtures. The aim of the present investigation was to develop tablets of 10 mm diameter, containing pellets of approximately 1 mm diameter, that conform to the uniformity of content and of mass required according to the US Pharmacopoeia version 23 [ 201 and to the German Pharmacopoeia [ 21 ]. Egermann's system of equations was used to compare the values found with theory. Based on the percolation theory, a syslem is presented that allows pellets to be compressed into disintegrating tablets with sufficient uniformity of content and mass.
2. Theory 2.1. Equations of binary random mixtures The random content variation Cm,B of a coarse component A in a mixture with a tint.' powder B. expressed as the coef-
249
licient of variation of the mean volume proportion a, of A, is given by the following equation [ 101 based on a binomial distribution: CR~,B= 100[ (I),ca)/ (a, V) ]1,,2
(1)
a~ and b, are the mean proportions by volume of component A or B in the mixture: CA is the representative mean particle volume of the coarse component A, and Vthe constant volume per sample of the random mixture. The proportions by volume of the components may be estimated from the quotients of poured and tap density of the components A and B, respectively, and linear extrapolation between these quotients to the quotient of the working densities of A and B [10]. The working density is the apparent density that a powder assumes in the die of a tableting machine. The range of validity of Eq. ( 1 ) was found to be between the two percolation thresholds ( see below and Table 1 ) of a binary mixture where a bicoherenl system of A and B exists [ 12 ]. If the ratio of the coarse component A is lower, an equation based on the Poisson distribution [ 13 ] applies: (["RAP = I {)0 ( l' A / V A ) I / 2
(2 )
VA is the apparent volume of A per sample of total volume V. According to Egermann, the validity of Eq. (2) is limited to a ratio of 10% vol./vol, of the coarse ingredient, which corresponds to 3(1% mass/mass in his publication [ 13 ].
2.2. Percolation theory Stauffer [ 14 ] used the term percolation to describe continuous structures (clusters) formed throughout the length, width and height of a system. When a binary system is considered, it depends on the concentration of each component, whether only one or both components percolate. The minimum concentration of a component at which a percolating cluster may be found is called the percolation threshold, P~:. Below this concentration only isolated clusters of one component can exist. These clusters are termed finite. Infinite clusters form above the percohttion threshold. A bicoherent structure builds up if both components percolate. The possibilities are shown in Table 1. As far as pharmaceutical mixtures or tablets are concerned, the concentration by volume, rather than by mass, of the components has to be taken into consideration. The two main types of percolation are site and bond percolation. In site percolation, a group of neighboring occupied sites is considered to belong to a cluster. Sites are occupied or unoccupied. Bonds (or interactions)
Table 1 T y p e s o f p e r c o l a t i o n in a binary mixture, a s s u m i n g that both c o m p o n e n t s h a v e p e r c o l a t i o n thresh{flds PeA a n d P ~ l o w e r than 0.5. C \ indicates the c o n c e n t r a t i o n of c o n l p o n e n t A Concentration of component A
Concentration ol component B
Percolating systems
C , <. P~,x
( 1 -- ( ' \ ) > P,I~
component B
(':, > P,,\ C'x 2>P , \
{ I - (',,) 2> P , ( I - (',, ! < P~ i~
c o m p o n e n t s A and B. b i c o h e r e n l ~,ystem component A
250
T.t:'. Beckerl et al. / Powder gechm~logy 96 (1998) 248-254
Table 2 Site percolation thresholds of binary powder mixtures: theoretical resuhs by Stauffer ] 14] Latl ice t 3,pe
P,
Single cubic Body centered cubic Face-centered cubic
0.312 0.245 0.198
Merck (Darmstadt, Germany), sucrose pellets type 841 from Werner (Tornesch, Germany) and polysorbate 80 from ICI ( Essen, Germany ).
3.2. Methods
between occupied sites are formed as soon as one site is occupied. In bond percolation, bonds may be formed between neighboring sites that happen to be occupied. Holman and Leuenberger J22] estimated the percolation thresholds for binary systems of lactose or dicalcium phosphate dihydrate and microcrystalline cellulose. Amongst other types of pen.olation (e.g. bond or site percolation), they found that the conditions existing in a loose powder bed can be described by site percolation theory. Different percolation thresholds can be observed, depending on the geometrical a,Tangement olthe particles. Theoretical values for three types of cubic lattice are given in Table 2. Hohnan and l,euenberger found that the value of the percolation threshold was closer to that of the :dngle cubic lattice when a binary mixture of varying particle size was used. In the binary mixture of uniform particle size the percolation threshold was closer to that of the body-centered cubic lattice, which indicates final the geometrical ammgement of particles depends on the particle size ratio and on the shape and size distribution of the components. Percolation thresholds of binary pharmaceutical powder mixtures can only be determined experimentally and may lie in a range i)etween those of the single cubic lattice and the body-centered cubic lattice with a value of approximately 0.3. The differences in particle size and the concentration by volume ¢~1"each component deline the equation to be used for calculation of the uniformity of contenl.
3. Experimental
3.2. l. Preparation ~?lthe drug-loaded pellets Sucrose pellets were coated in a fluidized bed processor (GPCG1 and WSG5, Glatt, Binzen, Germany), using approximately 4% mass/mass bisacodyl in the form of a 20% mass/vol, aqueous dispersion comprising a binder solution of 33.3~ mass/mass Eudragit L 30 D-55 dry substance on bisacodyl content, 1()'/~ mass/mass triethyl citrate as tt plasticizer and 50c/, mass/mass talc as a antiadherent on dry polymer substance. The dispersion was stirred with a magnetic stirrer throughout the coating process. The inlet air temperature was kept constant at 45°C. After completion of the coating, the pellets were dried in the fluidized bed processor for another 5 minutes. Between 77 and 1(10% of the theoretical amount of 5c~ mass/mass bisacodyl was found on the pellets. The lihn coating was made of Eudragit L 30 I)-55. 25% mass/mass of dry polymer, calculated on bisacodyl pellets, was applied. The pellets were dried m the lluidized bed processor for 5 minutes, and in a tray drier for 24 hours at 40°C.
3.2.2. Preparation o/Avicel granules 2 kg of Avicel PH 102 were blended with 50 g of Kollidon 30 lot 10 minutes in a planetary mixer. 2 kg of the granulation liquid containing 5% mass/vol. Kollidon 30 in demineralized water were added in four portions of 500 g. After each addition, mixing was carried on for 10 minutes. The wet mass was passed through the 2.0 mm sieve of a sieve granulator (Alexanderwerk, Remscheid, Germany) and dried to 705~ RH in a tray drier (Memmert, Schwabach, Germany). A second granulation step was performed with the same granulator, using a 1.5 mm sieve. The granules were dried to 40c~ RH. The desired size fractions between 0.5 and 1.0 mm were obtained by sieving.
3.1. Materials 3.2.3. Prel~aration q[dieah'ium l~hosphate granules Avicel PH 101, Avicel PH 102 and Avicel PH200 (all are microcrystalline celluloses) were supplied by Lehmann and Voss (Hamburg, Germany), Eudragit L 30 D-55 (methacrylic acid copolymer type C USP/NF), and triethyl citrate by R6hm (Darmstadt, Germany), Kollidon 30 (povidone) and Kollidon CL (crospovidone) by BASF (Ludwigshafen, Germany). Cellactose (excipient for direct compression made of 75% mass/mass lactose and 25c)f mass/mass cellulose) was supplied by Meggle (Wasserburg, Germany), Dicafos AN (anhydrous dicalcium phosphate, USP 23) by Chemische Fabrik Eudenheim ( Budenheim, Germany ). Bisacodyl was purchased from MS Chemicals (Milan, Italy), magnesium stcarate from B~rlocher (Munich, Germany), glycerol monostearate from Htils( Troisdorf, Germany) : citric acid, hydrochloric acid. sodium hydroxide and talc from
10 kg of anhydrous dicalcium phosphate were blended for 10 minutes with 0 . 2 5 ~ mass/mass magnesium stearate and compacted on a Pharmapaktor L200/50 (Bepex, Leingarten, Germany) at 80 kN. The compacts were broken down through the 1.6 mm sieve of a sieve granulator (Erweka, Heusenstamm, Germany), and the desired size fraction between 0.5 and 1.0 mm was obtained by sieving.
3.2.4. Blending and tabletiH~ The particle size of the excipients used for tableting is given in Table 3. Different amounts of pellets were blended for 5 minutes with 4% mass/mass Kollidon CL as a disintegrant, using a Turbula T2C mixer (Bachofen, Basel, Switzerland) at 42 rpm. Then the excipients were added and mixed for 10 minutes. Finally, 0.25c7, mass/mass magnesium stearate was
T.A. Beck
Table 3 Particle size of excipients and pellets Material
Mean particle size/particle sizc range ( I~,m )
Avicel PH 101 Avicel PH 1()2 AviceI PH200 Cellaciose Avicel granules Dicalcium phosphate granules Bisacodyl pellets
50 100 190 231,; 50(I 1000 500-100() 1050
added through a 315 mm sieve to the mixture and blended for 5 minutes. Batches of 400 g each were prepared. Mixing vessels were filled between 40 and 70% of their capacity to ensure proper mixing. In order Io prevent the effects of powder densification at the beginning and bed expansion at the end of the tableting process, both of which promote separation of the mixture. 200 g from the 400 g mixture were compressed and the tablets collected. Tablets of 400__+ 20 mg and 10 mm in diameter were compressed on an instrumented singlepunch machine (EK0, Korsch, Berlin, Germany) al 15 kN. The machine speed was set to 35 rpm. The lower punch holder was instrumented with four strain gauges ( 3/120 LY I I. Hottinger Baldwin Megtechnik, Darmstadt, Germany) in a ten> perature-compensated full bridge. Data acquisition occurred via a D A S H I 6 A / D converter board (Keithley, Munich. Germany) on an IBM AT03 personal computer ( IBM, Stuttgart, Germany). Data analysis was performed using Me61i x programmed by Herzog [ 231. Calibration against a piezoelectric load washer ( 9021, Kistler, Winterthur, Switzerhmd ) proved linearity of the system from 0 to 35 kN with a correlation coefficient of 0.9998. The first Ill0 tablets were withdrawn. The fl)llowing 500 tablets were sampled iri fractions of 100 tablets each. These ~amples were carefully hand-mixed before sampling single tablets for mass analysis. Ten tablets out of each 100 were weighed on a Merrier AE200 balance (Gie/3en, Germany) to evaluate the mean mass and standard deviation. The radial crushing strength of the tablels was determined 24 h after coalpaction using a Schleuniger 6[) hardness tester (Schleuniger, Solothurn, Switzerland). All tablets showed a crushing strength above 50 N and a friability below 0.5c/c. The disintegration time in 0.1 N HCI was below 15 min. Scale-up was performed on an instrumented rotary press ( PH230, Korsch, Berlin, Germany ). Data for the instrumentation of this machine are given elsewhere [ 241.5 kg of a mixture prepared in a tumbling ROhnrad mixer as staled above were compressed on the rotary press at various machine speeds. .¢.2.5. Determination ( f bisacodyl content
Five tablets from the first 100 and five tablets from the last 100 per batch were assayed. Each tablet was suspended in 250 mL 0. I M HCI and extracted with an Ultra-Turrax (Janke and Kunkel, Staufen, Germany). Three l0 ml aliquots were
251
removed and filtered through a cellulose acetate membrane filter (order no. 1110%25-N, pore size 0.2 l,zm, Sartorius, G¢$ttingen, Germany). All samples were assayed three times by UV spectrophotometric analysis at 264 nm, using a Lambda 16 U V - V I S spectrophotometer (Perkin-Elmer, Llberlingen, Germany'). Calibration proved that the system was linear from 0.57 to 56.5 ~ g / m l , with a correlation coefficient of 0.9997. The results of these ten tablets were evaluated to ensure homogeneity of mass according to the requirements of the German Pharmacopoeia [ 21 I and a standard F-test fin homogeneity of variance 125/ as well as a standard t-test for homogeneity of the means 125 ] showed no significant difference between the samples. When the sampies were statistically different, ten additional tablets were assayed from the total of 500 tablets sampled.
4. R e s u l t s a n d d i s c u s s i o n 4.1. Acceptance c r i t e r i a j b r content and mass
Criteria of acceptance were set according to USP 23 "Uniformity of Dosage Units, Content Uniformity' [ 20], allowing not a single one in ten bisacodyl tablets to deviate more than 10% from the declared content. The relative standard deviation must be less than 6%. Uniformity of mass according to the German Pharmacopoeia 121[ calls for 20 tablets to be w'eighed per batch. The mass of not more than two of the bisacodyl tablets is allowed to differ from the average rnass by more than 59~, and no tablet mass is permitted to deviate more than I(Y'J. In the present study, the relative standard deviation of the tablet mass was used as a critical parameter for mass uniformity and set to 1.67+./~. Under nomml distribution conditions+ 99.7g{ of all single values will be located within ± 5 ~ of the mean tablet mass. For a more accurate estimate of the relative standard deviation, 50 tablets were weighed. 4.2. 10~/~ mass~mass pellets (Table 4j
The relative standard deviation of the tablet mass was not within specification unless granules were used as filler-binders in pellet compression at this level. With fine powders, segregation occurred and the requirements were not met. High relative standard deviations of content were found for all batches. This was attributed to segregation of fine powders and large pellets. Approximately 47 pellets were present in one tablet. Thus a "standard deviation' of four pellets per tablet resulted in a relative standard deviation of the bisacodyl content of 8.5% - - being a value too high for acceptance. It seems to be easily possible that within the tablet mass four pellets more or less may be lilled into the die during tableting. Thus, a proportion of 10% mass/mass of pellets did not seem to be suitable fl~r compression. The use of larger-sized granules did not improve the uniformity of the compact either, although the coefficient of variation of content was found to
I2E. Beckerl et ul. / Powder li, ch,ology 96 (1998) 248-254
252
Table 4 10% mass/mass pellets: coeflicients of variation of mass and content found and calculated coeflicents of variation ol content. Values in bold print do not meet the requirements of the pharmacopeias Excipient
Coeflicient of varialion o1": Mass
Avicel PH I{}1 Aviccl PH 211() Avicel granules Dicalcium phosphate granules
1.6',;: 2.1% 0.9% 0.8%
('ontenl
16.4% 16.3% 9.6% 9.9'~{
CoucenUation of pellets ( vol./vol. } Calculated content Binomial
P{/iss{rn
11.6% 11.5% 11.2% 111.3%
I i .9% ! 1.8% I 1.7% 111.8%
4. I ~,,~: 5.39.: 7.2% I{}. I ~,'i
b e l o w e r . T h i s w a s a s s u m e d to be i n f l u e n c e d by the c l u s t e r
d u e to the a b s e n c e o f a p e r c o l a t i n g s y s t e m o f c o a r s e p a r t i c l e s .
f o r m a t i o n o f the c o a r s e p a r t i c l e s w i t h i n the m i x t u r e w h i c h
G i v e n a p e r c o l a t i n g s y s t e m o f c o a r s e e x c i p i e n t s , e.g. if the g r a n u l e s w e r e u s e d as d i l u e n t s , t h e b i n o m i a l d i s t r i b u t i o n
prevented segregation.
y i e l d e d a fair p r e d i c t i o n o f the c o e f f i c i e n t o f v a r i a t i o n o f c o n t e n t , a l t h o u g h t h e p r e d i c t e d v a l u e s are h i g h e r t h a n the
4.3. 31)~ mass/ma.ss pellets (Table 5) Segregation occmTed when mixtures of pellets with coarse o r fine d i l u e n t p a r t i c l e s w e r e c o m p r e s s e d into tablets, w h i c h
v a l u e s f o u n d . T h i s m i g h t p r o b a b l y be d u e to i n a c c u r a c i e s in the p r e d i c t i o n o f an a v e r a g e p a r t i c l e size o f the m i x t u r e o f granules and pellets.
w a s i n d i c a t e d by h i g h c o e f f i c i e n t s o f v a r i a t i o n o f c o n t e n t . W i t h a l a r g e r m e a n p a r t i c l e size o f the d i l u e n t c o m p o n e n t ,
4.4. 5 0 % m a s s / m a s s pellet.s (Table 6)
better uniformity of mass was obtained. Mixtures containing g r a n u l e s r e s u l t e d in g o o d u n i f o r m i t y o f m a s s a n d c o n t e n t . A s w i t h 10% m a s s / m a s s pellets, the e q u a t i o n b a s e d on the P o i s son distribution yielded better predicted values forlhecontent o f a m i x t u r e o f c o a r s e a n d fine p a r t i c l e s , w h i c h s e e m s to b e
Mixtures containing granules or coarse excipients resulted in g o o d u n i f o r m i t y o f m a s s a n d c o n t e n t . T h i s w a s c a u s e d b y the f o r m a t i o n o f a p e r c o l a t i n g c l u s t e r o f t h e p e l l e t s a c c o r d i n g to p e r c o l a t i o n t h e o r y . S t a r t i n g f r o m a c o n c e n t r a t i o n o f
Table 5 3(19~ m/n3 pellets: coefticients of ;'ariation of mass arid content and calculated coeliiccnts of variation of content Values in bold print do not nteet the requircments of the pharmacopeias Excipient
Coeflicient {}1variation of: Mass
Avicel PH 101 Avicel PH 1{}2 Avicel PH200 Cellaclose Avicel granules Dicalcium phosphate granules
2.3% 1.49; 1.6~,,i 1.4g {).9~,~ I. I%
Concentration of pellets ( vol./v{}l. )
('onlent
9.9% 16.7% 15.4% 1{1.11% 3.2',i 3.694
Calculated c,mtenl Binolnial
Poisson
6.3% 6.6% 5.99; 5.9~,~ 5.9~,4 5.2%
6.8% 7.2% 6.5% 6.5 % 6.7% 6.3%
14.5'/,: 16.694 17.1~,4 17.891 22.9r,~ 30.6G
Tabh: 6 509; inass/mass pellets: t:oeflicients of'variation of mass arid conlenl and calculated coellicents of variation of content ~according to the binomial distribution I. Values in hold print do not meet the requirements of the pharmacopeias Excipiel~t
Avicel PHI01 Avicel PH 1(12 Avicel PH200 Cellactose Avicel sranules Dicalcium phosphate granules
Coellicient o f \ariation {fl:
Concenmition of pellets (vol./vol.)
Mas~,
Contenl
Calculated content
5.4 % 2.1% 1.3','; 1.4',,~ 0.99~ I. 11,4
5.4'// 4.7g 3 6{,'~ 3.5g 4.0g d.69~
5,0V, 469~ 4.39~ 4.35{ 3.9~A 3.59~
26. I ¢4 29.4c/i 32.8% 33.3e/i 4(}. 1% 48.8~7,:
T.L. Beclert eta/./PowUer Teclmolo.g,~ 90 (199h') 24,Y 254
253
Table 7 7[)c)~ m a s s / m a s s
pellets: coeflicienls of variation tit" m a s s and conleni alld calculated cocl'licents of variation of contenl ( according t,.)the binomial distribution )
Excipienl
Coefficient of varialion o1:
Concentrali~m of pellets ( vol./vol.
Avicel PH 101 A', icel PH20[) Avicel granules Dicalcium phosphate granules
Mass
CunteTiI
Calculated content
1.6<,4 1.2c~;: 0.9'~: fOl-lnsbrittle tablets
2.15'~ 2.79~ 2.3<,4
3.8
)
41.25'~ 51 .S<,4 61.4
Table 8 Influence ofgranulcs and 159~ mass/mass microcrystalline cellulosc( !kvicel PH 102 ) as lhc segregation preventing excipienl: coefficients of variation of mass aild content. Vahles in bold print do nol meet the requirements of the pharmac{~peias Concentration of pcllcts
Without Avicel PH 102
Witll Avicel PHI02
[.?o¢l'ficieilt of variation of:
Ct)elliclenl of wu-iation of 2
{ [l/aSS/!lldS'~ ]
105'} 30c'~
5(1% 7(1'/~
}ILISS
Cl.)lltell t
bl~.lS'~
('Olllent
().9~'i ().%~ 0.9<4 0.9<4
7.2% 3.2<,i 4.()
().99~ 0.9~,~ 0.9% 0.8%
7.7% 3.691 2.5% 2.3%
Fable 9 Scale up on a Pharma 230 roltiry tablet press with 5(E4 m/m pellets and/\vicel PH2(t(): coeflicients of variation of mass alld content I'romdiflereni batches Excipient
Coefficient of variation oil
Concentration ol pellets [ vol./vol.
Single-punch machine Rotary press, batch 1 Rotary press, batch It
Mass
(7ontcnl
Calculated contenl
1.3c~ 1.5c;,~ 1.49/
3.6'; 4.2',: 3.8
4.3~,;; 4.4~)i 4.59,
approximately 3 0 ~ v o l . / v o l , coiTesponding to 5()0~ mass/ mass of pellets, a percolatirlg cluster has to be formed according to Stauffer's calculations. This prevents segregation by lhe coarse diluent, ensuring suitable uniformity of contcnl and mass. When fine particles were used as excipients, segregation was observed. A c c o r d i n g to T o m a s [ 26]. this may be attributed to the appearance o f particles behaving like Schl6ipfkugel" particles, which can percolate (in the sensc of p o w d e r segregation) through the cluster o f pellets. ELl . 1), which is based on a binomial distribution, served for calculating variations of content. Ira Poisson distribution ,xas assumed, the resultant calculated values were too high. 4.5. 70f4: mass/mas's pelle,s (Table 7) No stable tablets could be prepared with granulated anhydrous dicalcium phosphate, as the excipient did not form a compact at this pellet concentration because the binding capacities of these brittle granules were too low. G o o d unilorl-nity of content was found with all other formulations. which can again be attributed to the formation of a percolating cluster of pellets in the mixture. Only the mixture containing
)
32.8~,4 34.4cf 34.55,~:
Avicel PH I01 showed a high relative standard deviation of mass. This can again be attributed to the appearance of "Schltiplkugel' particles, which cause segregation. Thus. very fine particles like the Avicel PHI01 as well as brittle excipients like the phosphate granules seem not to be suitable for the compression of particles at this pellet concentration level. Eq. ( 1 ), which is based on a binomial distribution, served for the calculation of content variations. 4.6. At'icel P H I 0 2 as an e.rcipienl preventing segregation Avicel P H I 0 2 was evaluated as an agent preventing segregation. It was assumed that Avicel PH 102 filled up the w)ids between the pellets. Unlbrtunately. however, it was not poss i n e to improve the quality of a mixture by adding this finely powdered material. The results shown in Table 8 indicatc that there was no significant difference between the values lound with and without Avicel P H I 0 2 . These results are not in agreement with those of Beyer [9], who described an i m p r o v e m e n t in the quality of a mixture of E l c e m a P l 0 0 (microfine cellulose) and glass beads, but can be explained by E g e r m a n n ' s equations, according to which the highest
254
T.E. Beckert ez at. /Powder Technolo~,,x 90 (I 998) 248-254
a t t a i n a b l e d e g r e e o f h o m o g e n e i t y o f an i n t e r a c t i v e m i x t u r e
Acknowledgements
e q u a l s the quality o f a n o n i n t e r a c t i v e r a n d o m s y s t e m [ 191. 4.7. S c a l e - u p
A s s h o w n in T a b l e 9 the results o b t a i n e d on a s i n g l e - p u n c h m a c h i n e can be r e p r o d u c e d on a rotary press using 5 kg b a t c h e s of 5 0 % m a s s / m a s s pellets and A v i c e l P H 2 0 0 as the d i l u e n t excipient. In t h e s e cases Eq. ( 1 ) m e e t s the true values. It can be seen that l:he pellets o c c u p y a larger p r o p o r t i o n by v o l u m e in m i x t u r e s c o m p r e s s e d on a rotary m a c h i n e . T h i s is attributed to the d e n s i f y i n g effect o f a rotary feeder on the p o w d e r m a s s w h i c h will m a i n l y effecl the line diluent particles.
5. Conclusions Pellets o f 1 m m in d i a m e t e r c o u l d be c o m p r e s s e d into 10 m m tablets w i t h a c c e p t a b l e u n i f o r m i t y o f c o n t e n t w h e n a p e r c o l a t i n g cluster o f coarse material ( p e l l e t s or a m i x t u r e of pellets and suitable g r a n u l e s ) o c c u p i e d at least 30c~ v o l . / v o l . in the mixture. In o u r e x a m p l e , 3 0 % v o l . / v o l , e q u a l s a p p r o x imately 5 0 % m a s s / m a s s . If less than 30cJ~ v o l . / v o l , pellets were c o m p r e s s e d , suitable g r a n u l e s had to be a d d e d until 30r~ v o l . / v o l , was r e a c h e d to form a p e r c o l a t i n g cluster, l f a conc e n t r a t i o n o f 10~7, m a s s / m a s s pellets was c o m p r e s s e d into tablets, u n i f o r m i t y al" c o n t e n t c o u l d not be a c h i e v e d . F i l l e > b i n d e r s for direct c o m p r e s s i o n , like A v i c e l P H 2 0 0 , can be used in tablet m a n u f a c t u r e if a p e r c o l a t i n g cluster of the coarse c o m p o n e n t s is ensured. T h e particle size o f these e x c i p i e n t s s h o u l d not differ too m u c h from that of the coarse COlnponents, i.e. the pellets or granules. T h i s also permils addition o f d i s i n t e g r a n t s , for e x a m p l e , or o t h e r functional substances. T h e resulting tablets c o m p l y with the requirem e n t s o f U S P 23 for c o n t e n t u n i f o r m i t y and o f the G e r m a n P h a r m a c o p o e i a for u n i f o r m i t y of weight. Thus, fast disintegrating n m l t i p l e - u n i t tablets w h i c h c o n f o r m to the p h a r m a c o p o e i a s can be o b t a i n e d via direct c o m p r e s s i o n .
W e gratefully a c k n o w l e d g e technical a n d material support from R6hm GmbH, Darmstadt, Germany.
References [ 1 ] G.M. Clarke, J.M. Newton and M.D. Short, Int. J. Pharm., 100 ( 1993 ) 81. [2] T. May and B. Rambeck, Ther. Drug M,anit., I 1 (1989) 21. [3 I A. Sandberg, I, Blomqvi~t. U.E. Jonsson and P. Lundborg, Eur. J. elm. Pharmacol., 33 ( 1988 ) 9, [ 41 A. Sandberg, G. Ragnarsson. U.E. Jonsson and J. Sj{igrcn, Eur. J. Clin. F'harmacol., 33 (1988) $3. 15 ] M.P. Flament, P. Leterlne, A. Gayot, E. Gendrot and E. Bruna, Pharm. Tech. E,ur., 6 (1994) 19. 161 T.E. Becken, K Lehmalm and P.C. Schmidt. Int. J. Pharm., 143 q 1996) 13. 71 J.A. Hersey, Powder Technol.. I I ( 1975 ) 419. 8] P.C. Schmidl and E.S. Ben, Phann. Ztg., 132 (1987) 2550. 9] C. Beyer, Ph.D. Thesis. University of Ttibingen, Germany, 1975. I0] H. Egermann and P. Frank. J. Pharm. Sci., 81 (1992) 551, I1 I H. Egermann and P. Frank, J. Pharm. Sci., 81 (1992) 667. 121 H. Egermann. A. Krumphuber and P. Frank. J. Pharm. Sci., 81 ( 1992 ) 773. 13] H. Egennann, P. Frank and A. Krumphuher, Pharm. Res., 9 (1992) 385. 14 J D. Staul]ier, An Introduction to Percolation Theory, Taylor and Francis, London, 1985. 15 I H. Egermann and E. Pithier. Acta Pharm. Jugosl., 38 ( 1988 ) 279. 161 P.M.C. l,acey, Trans. Inst. Chem. Eng., 21 ( 19431 5:~. 171 K.R. Poole, R,F. Taylor and GP. Wall, Trans. Inst. Chem. E'ng.. 42 ( 1964 ) T305. 181 H. Egermann, J. Pharm. Pharrnacol., 37 (1985) 491. 191 H. Egermann. I. Kempmcr and F,. Pithier, [)rug Dev. Ind. Pharm., 11 (1985) 663. 201 tAN Pharmacopoeia, 23rd re':., US Pharmacopoeial Convention. Rockville, MD, 1994, p. 1838. 121 I Deutsches Arzneibuch, 10th rev., Deutscher Apothekerverlag, Stuttgart, Germany, 1991. 1221 L.E. Hohnan and H. Leuenherger. Powder Technol.. 60 (1990) 249. 1231 R. Herzog, Ph.D. Thesis. Univel+sityof Ttibingen, Germany, 1991. 1241 P. Vogel, Ph.D. Thesis. University of T0bingen, Germany, 1992. 125 I k Sachs, Angewandte Statistik, Springer, Berlin, 1992, p. 266. [ 261 J. Tomas, Ph.D. Thesis B, Bergakademie Freiberg, Germany 1992.
Pov, dcr T c c h n u l o g y 96 ( 1998 ) 2 4 8 - 2 5 4
Compression
of
enteric-coated pellets to disintegrating tablets: uniformity of dosage units
Thomas E. Beckert ~"~",Klaus Lehmann b, Peter C. S c h m i d t ~'* "' l)ep~ r m e ,
~t,rt~h~ - u , , , tlic~ I T c t
olo~.v 1:t; rl ~ l lk'~ rl~ ~; ', vii3 Tiihin~,e ,~ ,/ I~'r ,VI ~ %,~,t ~'tell " ,~', 7 2 0 7 6 ?'iibi ~ge~. G e n m m v t, Rg~hm G m h t t , 0427.5 I)arm,~tadl, G e r m a n y
Received 5 July 1'-)96:rcxiscd 29 September 1997
Abstract
Enteric-coated bisacodyl pellets were compressed into tablets using granules and powders as filler.--bindersof difterenl particle size and cohcsiveness. The effucts on the uniformity of content and mass were investigated. The mixtures contained between 10 and 709 mass/mass pellets with a particle size in the range 0.8 1.25 ram. Egermann's equations were used to calculate the coefficients of random variation of conlenl. Tablets containing 10% mass/mass pellets showed pronotmced w~riationsin mass and content. This was attributed to the large particle size of the pellets as compared with the tablet size. Mixtures with 3()9~ mass/mass pellets showed good uniformity of mass and of conlenl if addilional granules were used as excipients. Segregation c.ccttrrcd if only liner excipients were used. With 50-70% mass/mass pellets in a tabl~et, good content uniformity was found with all tiller binders used. This can be explained by lhe formation of a percolating cluster ol the pellets, ~ hich prevented segregation. With 50% mass/mass, corresponding to 3t)9,: w~l./vol., and more pellets in the mixture, the coefficient of variation of c~mtent agreed well with the values calculated according to Egermann's equations. ~) 1998 Elsevier Science S.A. All rights reserved. Key~,ord.w
Pellets: Tablt:ls: ('ontttnt unifolnlily: Mas~, tunif~ulnil'~
1. I n t r o d u c t i o n
Controlled-release and gastroresistant preparations can be administered orally in single-unit or multiple-unit dosage lk)rms. Single-unit dosage forms contain the active ingredient within a single tablet, capsule or fihn-coated tablet, while multiple-unit dosage forms consist of a number of subunits incorporated in a capsule or tablet. Single-unit preparations show higher variations in gastric residence time, causing a prolonged lag tirne, enhanced side effects or stability problems in the case of gastroresistant formulations and wniations in bioavailability of sustained-release preparations. h-I contrast, multiple-unit products distribulc readily over a large surface area in the intestine. At less than 2 mm in diameter, the particles behave like liquids, leaving the stomach within a short period of time [ I I. This results in fewer adverse effects, better bioavailability of the drug and less pronounced variations in drug release 12-41. Multiple-unit dosage forms are normally administered its capsules containing pellets or granules as suhunits. Unfortunately, prnduction (7oncsponding authok Tel.: + 4 9 7071 29 ._46_ ~ "~ lax: f 4 u 7071 "~9
5531. 0(}3_ 5 )10 '),S, $1 ~.Ot) ~', 1908 Elsevier Science S.A. All rights re
costs lot capsules are high compared with those of tablets. This is due to the lower output of capsule-filling machines and to the higher cost of the capsules themselves. Moreover, capsules cannot be divided into subunits in the same way as tablets. These disadwmtages can be overcome by compressing coated pellets into rapidly disintegrating tablets. In general, the compression of pellets into tablets together with excipients of a smaller particle size causes high variations in mass and content, duc to the segregation phenomenon. If pellets with a narrow size distribution are compressed together with additives of similar size and shape, uniformity of mass and content according to the pharmacopoeias can be achieved [ 5 ]. Disintegrating tablets containing particles of about I mm in diameter necd to be compressed with a certain amount of excipient, otherwise the mixture will not form stable tablets, and cracking will occur in the filnl coatings ] 6 ] on the pellets. Addition of excipients makes it possible to form solid compacts which, upon addition ofa disintegrant, disintegrate rapidly and allow the particles to sepa,ate. The most pragmatic way to achieve high homogeneity with conslituents of different parficlc size may be seen in the use of an "ordered' mixlure, as proposed by Hersey [7] in 1975. Unfortunately, however, ordered mixtm'es with a proportion
T.E. Beckerr el al. / P o w d e r 7echm~logy 96 (1998) 248-254
of fine constituents of more than 20% mass/mass 18,9] are difficult to obtain. More: recently, Egermann 110-13] has derived equations for predicting the homogeneity of binary random mixtures. He used these equations to optimize tablet formulations with respect to high dose unilbrmity and fixed the limits of their application based on percolation thresholds as explained by Stauffer [ 14 ]. As Egermann rightly supposed, a unique equation for the quality of random mixtures is not available. He found that different equations and assumptions are needed, depending on the ratio of the components in a mixture [ 15 ]. On the one hand, his system is based on Lacey's [ 161 assumption that the highest attainable degree of mixing contbrms to a completely disordered system with random distribution of all particles, following a binomial distribution. Dosing of tablets is performed by filling a mixture into the die of a tableting machine by volume. Egcrmann [10] modified the Stange Poole equation [17], which is based on the mass of the particles and constituent proportions by applying the corresponding parameters by apparent volume. In addition, he changed Johnson's [18] equation, which is valid for spherical drug particles, to apply to particles of any shape. This equation is based on a Poisson distribution and wdid only for small proportions of drug below 10% v ol./vol. [ 13 ]. He also showed that the highest attainable degree of homogeneity of an interactive mixture equals the quality of the ntminteractive random system [ 191. This makes the equations applicable m pharmaceutical systems, which are often partially interactive mixtures. The aim of the present investigation was to develop tablets of 10 mm diameter, containing pellets of approximately 1 mm diameter, that conform to the uniformity of content and of mass required according to the US Pharmacopoeia version 23 [ 201 and to the German Pharmacopoeia [ 21 ]. Egermann's system of equations was used to compare the values found with theory. Based on the percolation theory, a syslem is presented that allows pellets to be compressed into disintegrating tablets with sufficient uniformity of content and mass.
2. Theory 2.1. Equations of binary random mixtures The random content variation Cm,B of a coarse component A in a mixture with a tint.' powder B. expressed as the coef-
249
licient of variation of the mean volume proportion a, of A, is given by the following equation [ 101 based on a binomial distribution: CR~,B= 100[ (I),ca)/ (a, V) ]1,,2
(1)
a~ and b, are the mean proportions by volume of component A or B in the mixture: CA is the representative mean particle volume of the coarse component A, and Vthe constant volume per sample of the random mixture. The proportions by volume of the components may be estimated from the quotients of poured and tap density of the components A and B, respectively, and linear extrapolation between these quotients to the quotient of the working densities of A and B [10]. The working density is the apparent density that a powder assumes in the die of a tableting machine. The range of validity of Eq. ( 1 ) was found to be between the two percolation thresholds ( see below and Table 1 ) of a binary mixture where a bicoherenl system of A and B exists [ 12 ]. If the ratio of the coarse component A is lower, an equation based on the Poisson distribution [ 13 ] applies: (["RAP = I {)0 ( l' A / V A ) I / 2
(2 )
VA is the apparent volume of A per sample of total volume V. According to Egermann, the validity of Eq. (2) is limited to a ratio of 10% vol./vol, of the coarse ingredient, which corresponds to 3(1% mass/mass in his publication [ 13 ].
2.2. Percolation theory Stauffer [ 14 ] used the term percolation to describe continuous structures (clusters) formed throughout the length, width and height of a system. When a binary system is considered, it depends on the concentration of each component, whether only one or both components percolate. The minimum concentration of a component at which a percolating cluster may be found is called the percolation threshold, P~:. Below this concentration only isolated clusters of one component can exist. These clusters are termed finite. Infinite clusters form above the percohttion threshold. A bicoherent structure builds up if both components percolate. The possibilities are shown in Table 1. As far as pharmaceutical mixtures or tablets are concerned, the concentration by volume, rather than by mass, of the components has to be taken into consideration. The two main types of percolation are site and bond percolation. In site percolation, a group of neighboring occupied sites is considered to belong to a cluster. Sites are occupied or unoccupied. Bonds (or interactions)
Table 1 T y p e s o f p e r c o l a t i o n in a binary mixture, a s s u m i n g that both c o m p o n e n t s h a v e p e r c o l a t i o n thresh{flds PeA a n d P ~ l o w e r than 0.5. C \ indicates the c o n c e n t r a t i o n of c o n l p o n e n t A Concentration of component A
Concentration ol component B
Percolating systems
C , <. P~,x
( 1 -- ( ' \ ) > P,I~
component B
(':, > P,,\ C'x 2>P , \
{ I - (',,) 2> P , ( I - (',, ! < P~ i~
c o m p o n e n t s A and B. b i c o h e r e n l ~,ystem component A
250
T.t:'. Beckerl et al. / Powder gechm~logy 96 (1998) 248-254
Table 2 Site percolation thresholds of binary powder mixtures: theoretical resuhs by Stauffer ] 14] Latl ice t 3,pe
P,
Single cubic Body centered cubic Face-centered cubic
0.312 0.245 0.198
Merck (Darmstadt, Germany), sucrose pellets type 841 from Werner (Tornesch, Germany) and polysorbate 80 from ICI ( Essen, Germany ).
3.2. Methods
between occupied sites are formed as soon as one site is occupied. In bond percolation, bonds may be formed between neighboring sites that happen to be occupied. Holman and Leuenberger J22] estimated the percolation thresholds for binary systems of lactose or dicalcium phosphate dihydrate and microcrystalline cellulose. Amongst other types of pen.olation (e.g. bond or site percolation), they found that the conditions existing in a loose powder bed can be described by site percolation theory. Different percolation thresholds can be observed, depending on the geometrical a,Tangement olthe particles. Theoretical values for three types of cubic lattice are given in Table 2. Hohnan and l,euenberger found that the value of the percolation threshold was closer to that of the :dngle cubic lattice when a binary mixture of varying particle size was used. In the binary mixture of uniform particle size the percolation threshold was closer to that of the body-centered cubic lattice, which indicates final the geometrical ammgement of particles depends on the particle size ratio and on the shape and size distribution of the components. Percolation thresholds of binary pharmaceutical powder mixtures can only be determined experimentally and may lie in a range i)etween those of the single cubic lattice and the body-centered cubic lattice with a value of approximately 0.3. The differences in particle size and the concentration by volume ¢~1"each component deline the equation to be used for calculation of the uniformity of contenl.
3. Experimental
3.2. l. Preparation ~?lthe drug-loaded pellets Sucrose pellets were coated in a fluidized bed processor (GPCG1 and WSG5, Glatt, Binzen, Germany), using approximately 4% mass/mass bisacodyl in the form of a 20% mass/vol, aqueous dispersion comprising a binder solution of 33.3~ mass/mass Eudragit L 30 D-55 dry substance on bisacodyl content, 1()'/~ mass/mass triethyl citrate as tt plasticizer and 50c/, mass/mass talc as a antiadherent on dry polymer substance. The dispersion was stirred with a magnetic stirrer throughout the coating process. The inlet air temperature was kept constant at 45°C. After completion of the coating, the pellets were dried in the fluidized bed processor for another 5 minutes. Between 77 and 1(10% of the theoretical amount of 5c~ mass/mass bisacodyl was found on the pellets. The lihn coating was made of Eudragit L 30 I)-55. 25% mass/mass of dry polymer, calculated on bisacodyl pellets, was applied. The pellets were dried m the lluidized bed processor for 5 minutes, and in a tray drier for 24 hours at 40°C.
3.2.2. Preparation o/Avicel granules 2 kg of Avicel PH 102 were blended with 50 g of Kollidon 30 lot 10 minutes in a planetary mixer. 2 kg of the granulation liquid containing 5% mass/vol. Kollidon 30 in demineralized water were added in four portions of 500 g. After each addition, mixing was carried on for 10 minutes. The wet mass was passed through the 2.0 mm sieve of a sieve granulator (Alexanderwerk, Remscheid, Germany) and dried to 705~ RH in a tray drier (Memmert, Schwabach, Germany). A second granulation step was performed with the same granulator, using a 1.5 mm sieve. The granules were dried to 40c~ RH. The desired size fractions between 0.5 and 1.0 mm were obtained by sieving.
3.1. Materials 3.2.3. Prel~aration q[dieah'ium l~hosphate granules Avicel PH 101, Avicel PH 102 and Avicel PH200 (all are microcrystalline celluloses) were supplied by Lehmann and Voss (Hamburg, Germany), Eudragit L 30 D-55 (methacrylic acid copolymer type C USP/NF), and triethyl citrate by R6hm (Darmstadt, Germany), Kollidon 30 (povidone) and Kollidon CL (crospovidone) by BASF (Ludwigshafen, Germany). Cellactose (excipient for direct compression made of 75% mass/mass lactose and 25c)f mass/mass cellulose) was supplied by Meggle (Wasserburg, Germany), Dicafos AN (anhydrous dicalcium phosphate, USP 23) by Chemische Fabrik Eudenheim ( Budenheim, Germany ). Bisacodyl was purchased from MS Chemicals (Milan, Italy), magnesium stcarate from B~rlocher (Munich, Germany), glycerol monostearate from Htils( Troisdorf, Germany) : citric acid, hydrochloric acid. sodium hydroxide and talc from
10 kg of anhydrous dicalcium phosphate were blended for 10 minutes with 0 . 2 5 ~ mass/mass magnesium stearate and compacted on a Pharmapaktor L200/50 (Bepex, Leingarten, Germany) at 80 kN. The compacts were broken down through the 1.6 mm sieve of a sieve granulator (Erweka, Heusenstamm, Germany), and the desired size fraction between 0.5 and 1.0 mm was obtained by sieving.
3.2.4. Blending and tabletiH~ The particle size of the excipients used for tableting is given in Table 3. Different amounts of pellets were blended for 5 minutes with 4% mass/mass Kollidon CL as a disintegrant, using a Turbula T2C mixer (Bachofen, Basel, Switzerland) at 42 rpm. Then the excipients were added and mixed for 10 minutes. Finally, 0.25c7, mass/mass magnesium stearate was
T.A. Beck
Table 3 Particle size of excipients and pellets Material
Mean particle size/particle sizc range ( I~,m )
Avicel PH 101 Avicel PH 1()2 AviceI PH200 Cellaciose Avicel granules Dicalcium phosphate granules Bisacodyl pellets
50 100 190 231,; 50(I 1000 500-100() 1050
added through a 315 mm sieve to the mixture and blended for 5 minutes. Batches of 400 g each were prepared. Mixing vessels were filled between 40 and 70% of their capacity to ensure proper mixing. In order Io prevent the effects of powder densification at the beginning and bed expansion at the end of the tableting process, both of which promote separation of the mixture. 200 g from the 400 g mixture were compressed and the tablets collected. Tablets of 400__+ 20 mg and 10 mm in diameter were compressed on an instrumented singlepunch machine (EK0, Korsch, Berlin, Germany) al 15 kN. The machine speed was set to 35 rpm. The lower punch holder was instrumented with four strain gauges ( 3/120 LY I I. Hottinger Baldwin Megtechnik, Darmstadt, Germany) in a ten> perature-compensated full bridge. Data acquisition occurred via a D A S H I 6 A / D converter board (Keithley, Munich. Germany) on an IBM AT03 personal computer ( IBM, Stuttgart, Germany). Data analysis was performed using Me61i x programmed by Herzog [ 231. Calibration against a piezoelectric load washer ( 9021, Kistler, Winterthur, Switzerhmd ) proved linearity of the system from 0 to 35 kN with a correlation coefficient of 0.9998. The first Ill0 tablets were withdrawn. The fl)llowing 500 tablets were sampled iri fractions of 100 tablets each. These ~amples were carefully hand-mixed before sampling single tablets for mass analysis. Ten tablets out of each 100 were weighed on a Merrier AE200 balance (Gie/3en, Germany) to evaluate the mean mass and standard deviation. The radial crushing strength of the tablels was determined 24 h after coalpaction using a Schleuniger 6[) hardness tester (Schleuniger, Solothurn, Switzerland). All tablets showed a crushing strength above 50 N and a friability below 0.5c/c. The disintegration time in 0.1 N HCI was below 15 min. Scale-up was performed on an instrumented rotary press ( PH230, Korsch, Berlin, Germany ). Data for the instrumentation of this machine are given elsewhere [ 241.5 kg of a mixture prepared in a tumbling ROhnrad mixer as staled above were compressed on the rotary press at various machine speeds. .¢.2.5. Determination ( f bisacodyl content
Five tablets from the first 100 and five tablets from the last 100 per batch were assayed. Each tablet was suspended in 250 mL 0. I M HCI and extracted with an Ultra-Turrax (Janke and Kunkel, Staufen, Germany). Three l0 ml aliquots were
251
removed and filtered through a cellulose acetate membrane filter (order no. 1110%25-N, pore size 0.2 l,zm, Sartorius, G¢$ttingen, Germany). All samples were assayed three times by UV spectrophotometric analysis at 264 nm, using a Lambda 16 U V - V I S spectrophotometer (Perkin-Elmer, Llberlingen, Germany'). Calibration proved that the system was linear from 0.57 to 56.5 ~ g / m l , with a correlation coefficient of 0.9997. The results of these ten tablets were evaluated to ensure homogeneity of mass according to the requirements of the German Pharmacopoeia [ 21 I and a standard F-test fin homogeneity of variance 125/ as well as a standard t-test for homogeneity of the means 125 ] showed no significant difference between the samples. When the sampies were statistically different, ten additional tablets were assayed from the total of 500 tablets sampled.
4. R e s u l t s a n d d i s c u s s i o n 4.1. Acceptance c r i t e r i a j b r content and mass
Criteria of acceptance were set according to USP 23 "Uniformity of Dosage Units, Content Uniformity' [ 20], allowing not a single one in ten bisacodyl tablets to deviate more than 10% from the declared content. The relative standard deviation must be less than 6%. Uniformity of mass according to the German Pharmacopoeia 121[ calls for 20 tablets to be w'eighed per batch. The mass of not more than two of the bisacodyl tablets is allowed to differ from the average rnass by more than 59~, and no tablet mass is permitted to deviate more than I(Y'J. In the present study, the relative standard deviation of the tablet mass was used as a critical parameter for mass uniformity and set to 1.67+./~. Under nomml distribution conditions+ 99.7g{ of all single values will be located within ± 5 ~ of the mean tablet mass. For a more accurate estimate of the relative standard deviation, 50 tablets were weighed. 4.2. 10~/~ mass~mass pellets (Table 4j
The relative standard deviation of the tablet mass was not within specification unless granules were used as filler-binders in pellet compression at this level. With fine powders, segregation occurred and the requirements were not met. High relative standard deviations of content were found for all batches. This was attributed to segregation of fine powders and large pellets. Approximately 47 pellets were present in one tablet. Thus a "standard deviation' of four pellets per tablet resulted in a relative standard deviation of the bisacodyl content of 8.5% - - being a value too high for acceptance. It seems to be easily possible that within the tablet mass four pellets more or less may be lilled into the die during tableting. Thus, a proportion of 10% mass/mass of pellets did not seem to be suitable fl~r compression. The use of larger-sized granules did not improve the uniformity of the compact either, although the coefficient of variation of content was found to
I2E. Beckerl et ul. / Powder li, ch,ology 96 (1998) 248-254
252
Table 4 10% mass/mass pellets: coeflicients of variation of mass and content found and calculated coeflicents of variation ol content. Values in bold print do not meet the requirements of the pharmacopeias Excipient
Coeflicient of varialion o1": Mass
Avicel PH I{}1 Aviccl PH 211() Avicel granules Dicalcium phosphate granules
1.6',;: 2.1% 0.9% 0.8%
('ontenl
16.4% 16.3% 9.6% 9.9'~{
CoucenUation of pellets ( vol./vol. } Calculated content Binomial
P{/iss{rn
11.6% 11.5% 11.2% 111.3%
I i .9% ! 1.8% I 1.7% 111.8%
4. I ~,,~: 5.39.: 7.2% I{}. I ~,'i
b e l o w e r . T h i s w a s a s s u m e d to be i n f l u e n c e d by the c l u s t e r
d u e to the a b s e n c e o f a p e r c o l a t i n g s y s t e m o f c o a r s e p a r t i c l e s .
f o r m a t i o n o f the c o a r s e p a r t i c l e s w i t h i n the m i x t u r e w h i c h
G i v e n a p e r c o l a t i n g s y s t e m o f c o a r s e e x c i p i e n t s , e.g. if the g r a n u l e s w e r e u s e d as d i l u e n t s , t h e b i n o m i a l d i s t r i b u t i o n
prevented segregation.
y i e l d e d a fair p r e d i c t i o n o f the c o e f f i c i e n t o f v a r i a t i o n o f c o n t e n t , a l t h o u g h t h e p r e d i c t e d v a l u e s are h i g h e r t h a n the
4.3. 31)~ mass/ma.ss pellets (Table 5) Segregation occmTed when mixtures of pellets with coarse o r fine d i l u e n t p a r t i c l e s w e r e c o m p r e s s e d into tablets, w h i c h
v a l u e s f o u n d . T h i s m i g h t p r o b a b l y be d u e to i n a c c u r a c i e s in the p r e d i c t i o n o f an a v e r a g e p a r t i c l e size o f the m i x t u r e o f granules and pellets.
w a s i n d i c a t e d by h i g h c o e f f i c i e n t s o f v a r i a t i o n o f c o n t e n t . W i t h a l a r g e r m e a n p a r t i c l e size o f the d i l u e n t c o m p o n e n t ,
4.4. 5 0 % m a s s / m a s s pellet.s (Table 6)
better uniformity of mass was obtained. Mixtures containing g r a n u l e s r e s u l t e d in g o o d u n i f o r m i t y o f m a s s a n d c o n t e n t . A s w i t h 10% m a s s / m a s s pellets, the e q u a t i o n b a s e d on the P o i s son distribution yielded better predicted values forlhecontent o f a m i x t u r e o f c o a r s e a n d fine p a r t i c l e s , w h i c h s e e m s to b e
Mixtures containing granules or coarse excipients resulted in g o o d u n i f o r m i t y o f m a s s a n d c o n t e n t . T h i s w a s c a u s e d b y the f o r m a t i o n o f a p e r c o l a t i n g c l u s t e r o f t h e p e l l e t s a c c o r d i n g to p e r c o l a t i o n t h e o r y . S t a r t i n g f r o m a c o n c e n t r a t i o n o f
Table 5 3(19~ m/n3 pellets: coefticients of ;'ariation of mass arid content and calculated coeliiccnts of variation of content Values in bold print do not nteet the requircments of the pharmacopeias Excipient
Coeflicient {}1variation of: Mass
Avicel PH 101 Avicel PH 1{}2 Avicel PH200 Cellaclose Avicel granules Dicalcium phosphate granules
2.3% 1.49; 1.6~,,i 1.4g {).9~,~ I. I%
Concentration of pellets ( vol./v{}l. )
('onlent
9.9% 16.7% 15.4% 1{1.11% 3.2',i 3.694
Calculated c,mtenl Binolnial
Poisson
6.3% 6.6% 5.99; 5.9~,~ 5.9~,4 5.2%
6.8% 7.2% 6.5% 6.5 % 6.7% 6.3%
14.5'/,: 16.694 17.1~,4 17.891 22.9r,~ 30.6G
Tabh: 6 509; inass/mass pellets: t:oeflicients of'variation of mass arid conlenl and calculated coellicents of variation of content ~according to the binomial distribution I. Values in hold print do not meet the requirements of the pharmacopeias Excipiel~t
Avicel PHI01 Avicel PH 1(12 Avicel PH200 Cellactose Avicel sranules Dicalcium phosphate granules
Coellicient o f \ariation {fl:
Concenmition of pellets (vol./vol.)
Mas~,
Contenl
Calculated content
5.4 % 2.1% 1.3','; 1.4',,~ 0.99~ I. 11,4
5.4'// 4.7g 3 6{,'~ 3.5g 4.0g d.69~
5,0V, 469~ 4.39~ 4.35{ 3.9~A 3.59~
26. I ¢4 29.4c/i 32.8% 33.3e/i 4(}. 1% 48.8~7,:
T.L. Beclert eta/./PowUer Teclmolo.g,~ 90 (199h') 24,Y 254
253
Table 7 7[)c)~ m a s s / m a s s
pellets: coeflicienls of variation tit" m a s s and conleni alld calculated cocl'licents of variation of contenl ( according t,.)the binomial distribution )
Excipienl
Coefficient of varialion o1:
Concentrali~m of pellets ( vol./vol.
Avicel PH 101 A', icel PH20[) Avicel granules Dicalcium phosphate granules
Mass
CunteTiI
Calculated content
1.6<,4 1.2c~;: 0.9'~: fOl-lnsbrittle tablets
2.15'~ 2.79~ 2.3<,4
3.8
)
41.25'~ 51 .S<,4 61.4
Table 8 Influence ofgranulcs and 159~ mass/mass microcrystalline cellulosc( !kvicel PH 102 ) as lhc segregation preventing excipienl: coefficients of variation of mass aild content. Vahles in bold print do nol meet the requirements of the pharmac{~peias Concentration of pcllcts
Without Avicel PH 102
Witll Avicel PHI02
[.?o¢l'ficieilt of variation of:
Ct)elliclenl of wu-iation of 2
{ [l/aSS/!lldS'~ ]
105'} 30c'~
5(1% 7(1'/~
}ILISS
Cl.)lltell t
bl~.lS'~
('Olllent
().9~'i ().%~ 0.9<4 0.9<4
7.2% 3.2<,i 4.()
().99~ 0.9~,~ 0.9% 0.8%
7.7% 3.691 2.5% 2.3%
Fable 9 Scale up on a Pharma 230 roltiry tablet press with 5(E4 m/m pellets and/\vicel PH2(t(): coeflicients of variation of mass alld content I'romdiflereni batches Excipient
Coefficient of variation oil
Concentration ol pellets [ vol./vol.
Single-punch machine Rotary press, batch 1 Rotary press, batch It
Mass
(7ontcnl
Calculated contenl
1.3c~ 1.5c;,~ 1.49/
3.6'; 4.2',: 3.8
4.3~,;; 4.4~)i 4.59,
approximately 3 0 ~ v o l . / v o l , coiTesponding to 5()0~ mass/ mass of pellets, a percolatirlg cluster has to be formed according to Stauffer's calculations. This prevents segregation by lhe coarse diluent, ensuring suitable uniformity of contcnl and mass. When fine particles were used as excipients, segregation was observed. A c c o r d i n g to T o m a s [ 26]. this may be attributed to the appearance o f particles behaving like Schl6ipfkugel" particles, which can percolate (in the sensc of p o w d e r segregation) through the cluster o f pellets. ELl . 1), which is based on a binomial distribution, served for calculating variations of content. Ira Poisson distribution ,xas assumed, the resultant calculated values were too high. 4.5. 70f4: mass/mas's pelle,s (Table 7) No stable tablets could be prepared with granulated anhydrous dicalcium phosphate, as the excipient did not form a compact at this pellet concentration because the binding capacities of these brittle granules were too low. G o o d unilorl-nity of content was found with all other formulations. which can again be attributed to the formation of a percolating cluster of pellets in the mixture. Only the mixture containing
)
32.8~,4 34.4cf 34.55,~:
Avicel PH I01 showed a high relative standard deviation of mass. This can again be attributed to the appearance of "Schltiplkugel' particles, which cause segregation. Thus. very fine particles like the Avicel PHI01 as well as brittle excipients like the phosphate granules seem not to be suitable for the compression of particles at this pellet concentration level. Eq. ( 1 ), which is based on a binomial distribution, served for the calculation of content variations. 4.6. At'icel P H I 0 2 as an e.rcipienl preventing segregation Avicel P H I 0 2 was evaluated as an agent preventing segregation. It was assumed that Avicel PH 102 filled up the w)ids between the pellets. Unlbrtunately. however, it was not poss i n e to improve the quality of a mixture by adding this finely powdered material. The results shown in Table 8 indicatc that there was no significant difference between the values lound with and without Avicel P H I 0 2 . These results are not in agreement with those of Beyer [9], who described an i m p r o v e m e n t in the quality of a mixture of E l c e m a P l 0 0 (microfine cellulose) and glass beads, but can be explained by E g e r m a n n ' s equations, according to which the highest
254
T.E. Beckert ez at. /Powder Technolo~,,x 90 (I 998) 248-254
a t t a i n a b l e d e g r e e o f h o m o g e n e i t y o f an i n t e r a c t i v e m i x t u r e
Acknowledgements
e q u a l s the quality o f a n o n i n t e r a c t i v e r a n d o m s y s t e m [ 191. 4.7. S c a l e - u p
A s s h o w n in T a b l e 9 the results o b t a i n e d on a s i n g l e - p u n c h m a c h i n e can be r e p r o d u c e d on a rotary press using 5 kg b a t c h e s of 5 0 % m a s s / m a s s pellets and A v i c e l P H 2 0 0 as the d i l u e n t excipient. In t h e s e cases Eq. ( 1 ) m e e t s the true values. It can be seen that l:he pellets o c c u p y a larger p r o p o r t i o n by v o l u m e in m i x t u r e s c o m p r e s s e d on a rotary m a c h i n e . T h i s is attributed to the d e n s i f y i n g effect o f a rotary feeder on the p o w d e r m a s s w h i c h will m a i n l y effecl the line diluent particles.
5. Conclusions Pellets o f 1 m m in d i a m e t e r c o u l d be c o m p r e s s e d into 10 m m tablets w i t h a c c e p t a b l e u n i f o r m i t y o f c o n t e n t w h e n a p e r c o l a t i n g cluster o f coarse material ( p e l l e t s or a m i x t u r e of pellets and suitable g r a n u l e s ) o c c u p i e d at least 30c~ v o l . / v o l . in the mixture. In o u r e x a m p l e , 3 0 % v o l . / v o l , e q u a l s a p p r o x imately 5 0 % m a s s / m a s s . If less than 30cJ~ v o l . / v o l , pellets were c o m p r e s s e d , suitable g r a n u l e s had to be a d d e d until 30r~ v o l . / v o l , was r e a c h e d to form a p e r c o l a t i n g cluster, l f a conc e n t r a t i o n o f 10~7, m a s s / m a s s pellets was c o m p r e s s e d into tablets, u n i f o r m i t y al" c o n t e n t c o u l d not be a c h i e v e d . F i l l e > b i n d e r s for direct c o m p r e s s i o n , like A v i c e l P H 2 0 0 , can be used in tablet m a n u f a c t u r e if a p e r c o l a t i n g cluster of the coarse c o m p o n e n t s is ensured. T h e particle size o f these e x c i p i e n t s s h o u l d not differ too m u c h from that of the coarse COlnponents, i.e. the pellets or granules. T h i s also permils addition o f d i s i n t e g r a n t s , for e x a m p l e , or o t h e r functional substances. T h e resulting tablets c o m p l y with the requirem e n t s o f U S P 23 for c o n t e n t u n i f o r m i t y and o f the G e r m a n P h a r m a c o p o e i a for u n i f o r m i t y of weight. Thus, fast disintegrating n m l t i p l e - u n i t tablets w h i c h c o n f o r m to the p h a r m a c o p o e i a s can be o b t a i n e d via direct c o m p r e s s i o n .
W e gratefully a c k n o w l e d g e technical a n d material support from R6hm GmbH, Darmstadt, Germany.
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