©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
`
`MARCEL DEKKER, INC. (cid:127) 270 MADISON AVENUE (cid:127) NEW YORK, NY 10016
`
`PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
`Vol. 8, No. 1, pp. 47–59, 2003
`
`RESEARCH ARTICLE
`
`Potential Application of Silicified Microcrystalline Cellulose in Direct-Fill
`Formulations for Automatic Capsule-Filling Machines
`
`Mintong Guo# and Larry L. Augsburger*
`
`School of Pharmacy, University of Maryland, Baltimore, Maryland, USA
`
`ABSTRACT
`
`Silicified microcrystalline cellulose (SMCC) has physico-mechanical properties that may be
`of advantage in hard gelatin capsule formulations. The present research was designed to
`evaluate and compare SMCC’s performance to that of other excipients commonly used in
`hard gelatin capsule direct-fill
`formulations. All capsules were filled using a fully
`instrumented Zanasi LZ-64 automatic capsule-filling machine. Four grades of SMCC [SMCC
`50, SMCC 90, SMCC HD90, and an experimental-grade (SMCC X)] were investigated.
`Anhydrous lactose (direct tableting grade), pregelatinized starch (PGS) (Starch 1500), and
`microcrystalline cellulose (MCC) (Emcocel 90M) were chosen as the control fillers. The
`following properties were measured: capsule fill weight, relative standard deviation of capsule
`fill weight, plug ejection force, plug maximum breaking force (MBF), and the dissolution of
`two marker compounds (acetaminophen and piroxicam). The MBF of capsule plugs increased
`with increases in compression force from 50N to 100N for all excipients. Starch 1500 and
`anhydrous lactose plugs exhibited the lowest MBF values. PGS, anhydrous lactose, SMCC
`HD90, and SMCC X consistently exhibited the lowest ejection forces under the same
`experimental conditions, this difference being most apparent at higher compression forces.
`Different patterns were observed in the way compression force affected the fill weight of the
`materials studied. Overall, there was no clear pattern to the way the relative standard deviation
`(RSD) of capsule fill weight varied with encapsulation conditions. Sodium stearyl fumarate
`(SSF) appeared to be somewhat more efficient at reducing the ejection force than magnesium
`stearate at the same level, this difference being especially apparent at the 14-mm piston
`height. Formulations containing either 5% piroxicam, 30% acetaminophen, or 50%
`acetaminophen exhibited faster drug dissolution when MCC or SMCC was the filler than
`when anhydrous lactose or PGS was the filler. The presence of colloidal silicon dioxide in
`SMCC did not appear to influence the dissolution of these drugs. The data suggest that SMCC
`could be a suitable direct-fill excipient for hard shell capsule formulations.
`
`#Current address: Geneva Pharmaceuticals, Inc., Dayton, NJ, USA.
`*Correspondence: Larry L. Augsburger, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA; Fax: (410) 706-
`0346; E-mail: laugsbur@rx.umaryland.edu.
`
`47
`
`DOI: 10.1081/PDT-120017523
`Copyright q 2003 by Marcel Dekker, Inc.
`
`1083-7450 (Print); 1097-9867 (Online)
`www.dekker.com
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`EXHIBIT D
`
`

`

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`48
`
`Guo and Augsburger
`
`Key Words: Formulation; Capsules; Silicified microcrystalline cellulose; Dissolution;
`Compression; Sodium stearyl fumarate and filler.
`
`INTRODUCTION
`
`Since its introduction in the 1960s, microcrystalline
`cellulose (MCC) has offered great advantages in the
`formulation of solid dosage forms, but some character-
`istics have limited its application, such as relatively low
`bulk density, moderate flowability,
`loss of compact-
`ability after wet granulation, and sensitivity to lubricants.
`Substantial research has been carried out to address these
`limitations and improve the functionality of MCC. This
`effort led to a stream of new grades of MCC with such
`properties as enhanced density, low moisture content,
`and larger particle size.[1]
`Silicification is still another approach to improve
`the functionality of MCC. Silicified microcrystalline
`cellulose (SMCC)
`is manufactured by coprocessing
`colloidal silicon dioxide with MCC. Tableting studies
`have suggested that SMCC has enhanced compact-
`ability, even after wet granulation, and reduced
`lubricant sensitivity, compared to the regular grade of
`MCC. For example, Sherwood and Becker[2] have
`compared the direct-compression tableting performance
`of SMCC 90 with a regular grade of microcrystalline
`cellulose (Avicel PH102) that has similar particle size
`and density. SMCC 90 was , 10 – 40% more compac-
`tible than regular MCC in the absence of drug. The
`SMCC 90 also showed a lower lubricant sensitivity and
`retained , two to three times the compactibility in
`tableting of the comparable MCC grade in a blending
`time study. In another study, the plug-forming ability of
`SMCC was compared to that of common fillers under
`compression conditions similar to those of automatic
`capsule-filling machines in a compaction simulator
`modified to form plugs.[3] Several grades of silicified
`microcrystalline cellulose were found to produce plugs
`having higher maximum breaking force than anhydrous
`lactose and pregelatinized starch (PGS).
`It was
`concluded that the apparently higher compactability of
`these materials might be beneficial
`in developing
`direct-fill
`formulations for automatic capsule-filling
`machines. The present study was intended to test that
`hypothesis in a dosator capsule-filling machine.
`An instrumented Zanasi LZ-64 (IMA North Amer-
`ica, Inc., Fairfield, CT) automatic capsule-filling machine
`was used to compare SMCC with other commonly used
`excipients (controls) as fillers in capsule formulations. A
`dissolution study was also carried out to evaluate and
`
`compare the dissolution of marker compounds from the
`direct-fill capsules formulated with these fillers. The
`drugs selected, acetaminophen[4] and piroxicam,[5] serve
`this study in two ways. First, the broad range of solubility
`represented by these drugs makes them highly suitable
`markers for comparing drug dissolution from these
`matrices. Second, the poor compactibility of acetamino-
`phen[6] provides a substantial challenge to the ability of
`these fillers to serve as direct-fill excipients.
`
`MATERIALS AND METHOD
`
`Materials
`
`Several grades of SMCC (SMCC 50, SMCC 90, and
`SMCC HD90) [Prosolv], MCC [Emcocel 90M], and
`sodium stearyl fumarate (SSF) [PRUV] were obtained
`from Penwest Pharmaceutical Co. (Patterson, NY). In
`addition, an experimental grade of SMCC (SMCC X,
`with a similar particle distribution to SMCC 50 but
`higher density) was supplied by Penwest for comparison
`purposes. The PGS [Starch 1500] was obtained from
`Colorcon (Indianapolis, IN). Anhydrous lactose (direct-
`tableting grade) was purchased from Quest International
`(Norwich, NY). Magnesium stearate (MS) was ordered
`from Spectrum (Gardena, CA). Acetaminophen was
`purchased from BASF (Mt. Olive, NJ) (lot number:
`APBN957). Piroxicam was obtained from Pfizer
`(Groton, CT) (lot number: 21P903A).
`
`Blending Procedure
`
`For formulations without drug markers, all excipi-
`ents were blended with lubricant (0.3% SSF, 0.3% MS,
`or 0.5% MS) for 5 minutes in a 20-liter twin shell dry
`blender (Patterson-Kelly Co., East Stroudsburg, PA) and
`stored in sealed plastic bags before encapsulation. For the
`dissolution study, the seven excipients were first blended
`with active ingredient (5% piroxicam; 30%, 50%, or 75%
`acetaminophen)
`in a twin shell dry blender
`for
`10 minutes. Then MS (0.5% for 5% piroxicam and
`30% acetaminophen, 0.8% for 50% and 75% acetami-
`nophen) was added and mixed for 3 minutes. The
`mixtures were stored in sealed plastic bags before
`loading into the capsule-filling machine.
`
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`SMCC for Automatic Capsule-Filling Machines
`
`49
`
`Encapsulation
`
`All capsules were filled using an instrumented
`Zanasi LZ-64 dosator-type capsule-filling machine.
`Compression and ejection forces were measured from
`strain gages bonded directly to the piston.[7] Data were
`acquired via LabViewR hardware and software (National
`Instruments Corp., Austin, TX) interfaced with a PC.
`In the basic encapsulation study, the powder bed
`height was set at 50 mm, and the piston height was
`maintained at either 12 mm or 14 mm. Compression
`force was adjusted to 40, 80, and 120N. Sufficient time
`was allowed for the system to reach equilibrium by
`monitoring the compression-ejection profiles. Fifty
`sample capsules were collected and stored in sealed
`plastic bags. The average fill weight and fill weight
`variation were calculated from the individual weights of
`20 capsules of each batch. Ejection forces are reported as
`the means of 10 measurements.
`Capsules for the dissolution study were filled under
`similar operating conditions with a powder bed of
`50 mm, a compression force of 120N, and a piston height
`of 12 mm. Plugs for the measurement of maximum
`breaking force were made at a powder bed height setting
`of 50 mm, a piston height setting of 16 mm, and
`compression forces of 50N and 100N. These latter
`conditions assured that coherent plugs could be formed
`from all test materials. Plugs were collected from under
`the bushings by overriding the capsule shell
`feed
`mechanism. The maximum breaking force of the plugs
`was measured within 24 hours, and the means of 10
`determinations are reported.
`
`Maximum Breaking Force Measurement
`
`The maximum breaking force (MBF) of plugs
`was measured using a previously described three-point
`flexure test.[8] A vertically mounted motor-driven
`mechanical
`slide
`assembly
`(Unislide model
`B4009P20J, Velmex, Inc., Bloomfield, NY) was used
`as the platform to hold the plug. The transducer is a
`piezoelectric load cell (Kistler model 9712A5, Kistler
`Instruments
`Inc., Amherst, NY). The
`assembly
`provides a range of up to 2000 g with ^ 1 g resolution.
`All
`values
`reported
`are
`the means
`of
`10
`determinations.
`
`Dissolution Test
`
`Dissolution was carried out on a Vankel VK7000
`apparatus (VanKel, 36 Meridian Road, Edison, NJ).
`
`A peristaltic pump (Rainin Instrument Company Inc.,
`Rainin Road, Woburn, MA) was coupled to a
`Shimadzu UV-160U ultraviolet/visible spectropho-
`tometer
`(Shimadzu Corp., Kyoto 604, Japan) with
`continuous flow to provide the drug dissolution data.
`Dissolution conditions were as prescribed by United
`States Pharmacopeia
`(USP) monographs, which
`specify apparatus I at 50 RPM and simulated gastric
`fluid TS without pepsin for piroxicam, and apparatus
`II at 50RPM and distilled water for acetaminophen.
`(the
`time
`required for 60%
`The T60% values
`dissolution) are reported as
`the means of
`six
`determinations.
`
`RESULTS AND DISCUSSION
`
`Maximum Breaking Force Analysis
`
`Weight variation is an important criterion to monitor
`during capsule production. One potential source of
`weight variation on a dosator machine is powder loss
`during plug transfer. To minimize such losses,
`the
`running mix should have a sufficient degree of
`compactability, as this contributes to the formation of
`coherent plugs and helps assure that a stable arch will be
`formed at the open end of the dosing tube.[9] As shown in
`Fig. 1, under the same experimental conditions (powder
`bed of 50 mm, piston height of 16 mm, compression force
`of 100N, and 0.3% MS), SMCC HD90, SMCC 50, and
`SMCC X exhibited higher MBFs than the other
`materials. Anhydrous lactose and PGS plugs exhibited
`the lowest MBF. With a compression force of 50N, the
`MBF of PGS or anhydrous lactose plugs was not
`measurable, while SMCC and MCC exhibited MBF
`values ranging from 0.6 to 1.3N. Higher MBF values
`indicate that there will be less chance for the plug to
`fracture or collapse when ejected into the capsule body
`and a reduced likelihood of encountering powder loss
`from the open end of the dosator during transfer from the
`powder bed to the ejection station. Excipients with
`greater compactibility have better potential to control
`weight variation in direct-fill formulations when the drug
`being carried by the excipient has a limited ability to
`form plugs under the conditions of low compression
`force that exist in these machines. This is likely to be of
`greatest importance in formulations containing large-
`dose drugs where the percentage of excipient that can be
`added is limited.
`
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`50
`
`Guo and Augsburger
`
`Figure 1. Maximum breaking force of capsule plugs.
`
`Ejection Force Analysis
`
`Ejection force is the maximum force required to
`initiate movement of the plug out of the dosator tube.
`Formulations with low ejection force may permit the
`plug to be ejected cleanly from the dosator and into the
`capsule body,
`thereby reducing dusting and powder
`losses that can contribute to weight variation.[10]
`However, a very low ejection force also could indicate
`that no coherent plug was formed in the dosator tube.
`Such low-density, loosely formed plugs may lose powder
`during transfer,
`thereby leading to poor weight
`variation.[9] Generally,
`increasing the lubricant
`level
`
`will decrease ejection force, but the lubricant potentially
`could also both reduce plug cohesiveness (i.e., MBF) and
`alter the dissolution rate of the final capsule formulation.
`Usually retarded dissolution is observed because of the
`hydrophobicity of lubricants such as MS. Mehta and
`Augsburger[11] studied the relationships of lubricant
`level, dissolution rate, and plug MBF of capsule
`formulations. They found that for the formulations with
`MCC, T60% decreased to a minimum and then increased
`with increased lubricant levels. This was accompanied
`by a dramatic decrease in plug MBF. With lactose, T60%
`increased slightly with the lubricant level while plug
`MBF decreased only slightly. Thus, in the design of
`
`Figure 2. Ejection force—compression force profiles at 14 mm piston height (0.3% MS).
`
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`
`SMCC for Automatic Capsule-Filling Machines
`
`51
`
`lubricated with 0.5% MS, anhydrous lactose exhibited
`nearly the lowest ejection force among the materials
`tested (Figures 4 and 7). Tattawasart and Armstrong
`investigated the formation of lactose plugs by using a
`capsule-filling machine simulator.[13] In their study, the
`level of MS was varied from 0.5 to 1.5%, and the data
`showed that 0.5% MS is enough for lactose. Such experi-
`mental data suggest that, although anhydrous lactose
`apparently requires more lubricant than the other mate-
`rials tested, ejection resistance decreased more rapidly
`once a critical concentration of lubricant was reached.
`A comparison of the ejectability of any single exci-
`pient under different encapsulation conditions reveals that
`SMCC HD90 plugs exhibited the most consistent
`behavior under all conditions (Fig. 8). This observation
`may indicate a low inherent lubricant requirement for this
`excipient. In contrast, Fig. 9 shows how more markedly
`the ejection force of SMCC X changes with different
`levels and types of lubricant under different running
`conditions. It can be seen that the ejection force drama-
`tically decreased with an increase in the MS level from
`0.3% to 0.5%, which could be due to SMCC X’s small
`particle size (50 mm, [14]), which that suggests that this
`filler may require more MS to provide surface coverage.
`When the lubricant was changed from 0.3%
`magnesium to 0.3% SSF, the ejection force decreased
`for all excipients studied, but to different degrees. For
`SMCC X (Figure 9), ejection forces decreased to less
`than half when 0.3% SSF was used. For PGS (Figure 10),
`the formulation containing 0.3% SSF exhibited a lower
`plug ejection force than blends with 0.3% or 0.5% MS.
`
`Figure 3. Ejection force—compression force profiles at
`14 mm piston height (0.3% SSF).
`
`lubricant effects
`
`capsule formulations, such potential
`should be carefully considered.
`The basic encapsulation study (Figs. 2 through 7)
`revealed that the ejection forces of all tested materials
`generally increased with an increase in compression force
`of from 40N to 120N at piston heights of 12 mm and
`14 mm. In most cases, PGS exhibited either the lowest
`ejection force or was among the group exhibiting lower
`ejection forces under the experimental conditions conside-
`red. Similar findings have been previously reported by
`Small and Augsburger.[12] When lubricated with 0.3%
`MS, anhydrous lactose exhibited nearly the highest
`ejection force among all tested materials (Figure 5). With
`0.3% SSF, the compression force versus ejection force
`profile of anhydrous lactose was substantially lowered
`among the materials tested (Figure 6). Interestingly, when
`
`Figure 4. Ejection force—compression force profiles at 14 mm piston height (0.5% MS).
`
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`
`52
`
`Guo and Augsburger
`
`Figure 5. Ejection force—compression force profiles at 12 mm piston height (0.3% MS).
`
`In the investigated compression force range, SSF
`appeared to be more effective than MS in reducing the
`plug ejection force of these materials.
`
`Capsule Fill Weight and Variation
`
`With the dosing-disc type of automatic capsule-
`filling machines, fill weight is expected to increase with
`
`increases in the compression force (or tamping pin
`penetration setting), as this is inherent in their principle of
`operation.[15] However, an increase in fill weight with
`increased compression force may also be observed in
`dosator machines under certain conditions.
`As shown in Figures 11, 12, and 13, the effect of
`compression force on capsule fill weight followed three
`patterns. The first pattern was that exhibited by SMCC
`90, Emcocel 90M, and anhydrous lactose (Figure 11), in
`
`Figure 6. Ejection force—compression force profiles at 12 mm piston height (0.3% SSF).
`
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`
`SMCC for Automatic Capsule-Filling Machines
`
`53
`
`Figure 7. Ejection force—compression force profiles at 12 mm piston height (0.5% MS).
`
`which there was little or no change of capsule fill weight
`with compression force. The second pattern was
`exhibited by SMCC HD90, SMCC 50, and SMCC X,
`in which fill weight increased to a relatively large degree
`with compression force (Figure 12). In the third pattern,
`exhibited by PGS, a decrease in fill weight was observed
`
`when compression force increased (Figure 13). Some
`differences were noticeable among the SMCC group that
`exhibited the greatest weight gain with compression
`force. When compression force increased, the fill weight
`of SMCC X appeared to increase linearly within the
`range studied. For SMCC 50 and SMCC HD90, the fill
`
`Figure 8. Ejection force—compression force profiles for SMCC HD90.
`
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`54
`
`Guo and Augsburger
`
`Figure 9. Ejection force—compression force profiles for SMCC X.
`
`weight also increased, but the percentage gain is smaller.
`Currently there is no clear explanation for
`these
`observations, but
`the results may reflect
`in part on
`differences in compactibility, particle size and/or powder
`adhesiveness among these materials.
`Overall, there was no clear pattern to the way the
`relative standard deviation (RSD) of capsule fill
`weight varied with encapsulation conditions in this
`study (Figure 14).
`
`Tan and Newton[16] also observed different patterns
`in the way compression ratio affected the fill weight of
`various materials using a dosator machine (MG2). For
`example, they found that for different size fractions of
`PGS, increasing the compression settings resulted in only
`slightly lower fill weights for two coarser size fractions,
`while the fill weight of a smaller size fraction decreased
`dramatically. With MCC, fill weight
`sometimes
`increased slightly, decreased slightly, or was unchanged
`
`Figure 10. Ejection force—compression force profiles for PGS.
`
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`SMCC for Automatic Capsule-Filling Machines
`
`55
`
`Figure 11. Capsule fill weights for anhydrous lactose.
`
`depending on the compression ratio and the size fraction.
`Two coarser fractions of lactose exhibited a decrease in
`fill weight with increased compression ratio, but a finer
`particle size grade showed an increase in weight and then
`a decrease as the compression ratio was increased. The
`decreases in fill weight with compression ratio generally
`
`were associated with powder filtering behind the piston
`tip and/or adhering to the wall of the dosator tube,
`depending on the specific powder and its particle size.
`With MCC, fill weight sometimes increased slightly,
`decreased slightly, or was unchanged depending on
`compression and size fraction. The increases in fill
`
`Figure 12. Capsule fill weights for SMCC X.
`
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`56
`
`Guo and Augsburger
`
`Figure 13. Capsule fill weight for pregelatinized starch.
`
`weights with compression ratio observed with MCC
`were attributed to good plug formation and negligible
`losses of powder due to dosing tube wall-coating or
`filtering behind the piston tip.
`
`Dissolution
`
`Any modification of the physicochemical proper-
`ties of an excipient to enhance functionality should not
`compromise drug delivery from the dosage form. To
`compare their effects on dissolution,
`four different
`formulations employing the seven excipients were
`encapsulated with the following drug loadings: 30%,
`
`50%, and 75% acetaminophen; 5% piroxicam. These
`two actives represent a wide range of solubility and
`should give a good assessment of dissolution from
`capsules formulated with the subject excipients. The
`time needed to dissolve 60% of the dose drug (T60%)
`was determined from the dissolution profile, and
`Student’s T-test was applied to determine the
`significance of the differences. Among the capsules
`containing 5% piroxicam (Figure 15), the formulation
`with PGS exhibited the longest T60% (P , 0.02).
`Capsules containing 30% or 50% acetaminophen and
`formulated using either PGS or anhydrous lactose
`exhibited longer T60% values than those formulated
`
`Figure 14. Capsule fill weight variation at piston height of 12 mm (0.3% MS).
`
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`
`SMCC for Automatic Capsule-Filling Machines
`
`57
`
`Figure 15. Dissolution rate (T60%) of formulations with 5% piroxicam.
`
`with SMCC or MCC materials (P , 0.001) (Figure 16).
`For the 75% acetaminophen products, the formulation
`with anhydrous lactose exhibited the slowest dissol-
`ution rate (P , 0.02). Overall,
`formulations with
`anhydrous lactose and PGS exhibited longer T60%
`values than those formulated with the SMCC or MCC
`materials. The faster dissolution rates of formulations
`with SMCC and MCC possibly could be attributed to
`the self-disintegration property of microcrystalline
`cellulose.[17]
`
`Except for the formulation with 50% acetamino-
`phen,
`there is no significant difference in the T60%
`(P . 0.05) among the capsules formulated with the
`SMCC and MCC excipients. This observation suggests
`that the presence of coprocessed colloidal silicon dioxide
`does not affect the dissolution from SMCC excipients
`when compared to original microcrystalline cellulose.
`Buckton et al.[18] and Tobyn et al.[19] studied the
`physicochemical properties of SMCC and found that
`there were no discernible chemical or polymorphic
`
`Figure 16. Dissolution rate (T60%) of formulations with 30%, 50%, and 75% acetaminophen.
`
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`©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
`
`MARCEL DEKKER, INC. (cid:127) 270 MADISON AVENUE (cid:127) NEW YORK, NY 10016
`
`58
`
`Guo and Augsburger
`
`differences between SMCC and MCC. This finding
`indicated that
`the silicification process produced a
`material that was chemically and physically similar to
`regular grade of MCC.[19]
`From Figure 16 it
`is clear that, except for the
`formulations containing PGS, T60% tended to increase
`with increased percentage of acetaminophen, which is
`expected. The formulation with PGS exhibited a
`different pattern: with an increase in acetaminophen
`content, T60% decreased. Because capsule weights were
`held in a small range for each formulation, as the total
`amount of drug to be dissolve increased, the percentage
`of
`the filler
`that could aid dissolution decreased.
`Apparently,
`this effect was compensated by other
`considerations
`in the PGS formulation. With the
`increase of acetaminophen from 30% to 50% and to
`75%, the T60% of the PGS product decreased from 8.46
`to 7.76 and to 5.37 minutes. This pattern of decreasing
`T60% may be due to substantially reduced plug
`cohesiveness, which was derived from both higher
`MS and acetaminophen levels. Reduced plug cohesive-
`ness has been reported to promote more rapid
`dispersion in dissolution fluids.[11,20]
`
`CONCLUSION
`
`The present study revealed that SMCC HD90 and
`SMCC X exhibited relatively higher compactibility
`under the low compression force of a dosator capsule
`filling than either PGS or lactose. PGS, anhydrous
`lactose, SMCC HD90, and SMCC X generally
`exhibited the lowest plug ejection forces under the
`same experimental conditions, especially at higher
`compression forces. Products
`formulated with the
`SMCC materials exhibited faster dissolution rates than
`those formulated with PGS and anhydrous lactose
`when loaded with 5% piroxicam, 30% and 50%
`acetaminophen. Such higher compactibility and fast
`dissolution rates
`suggest
`that SMCC could be a
`suitable alternative excipient for direct-fill formulations
`for hard shell capsules.
`
`REFERENCES
`
`1. FMC Product Brochure (Microcrystalline Cellulose).
`2. Sherwood, B.E.; Beck, J.W. A new class of high-
`functionality excipients: silicified microcrystalline cellu-
`lose. Pharm. Technol. 1998, 22, 78 – 88.
`
`9.
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`3. Guo, M.; Muller, F.X.; Augsburger, L.L. Evaluation of
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`5. Swanepoel, E.; Liebenberg, W.; Villiers, M.D.; Dekker,
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`agglomeration of powders. Drug Dev. Ind. Pharm. 2000,
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`6. Hong-Guang, W.; Ru-Hua, Z. Compaction behavior of
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`8. Shah, K.B.; Augsburger, L.L.; Marshall, K. An
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`291 – 296.
`Jolliffe, I.G.; Newton, J.M.; Walters, J.K. Theoretical
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`the filling of pharmaceutical hard
`gelatin capsules. Powder Tech. 1980, 27, 189 – 195.
`10. Heda, P.K. A comparative study of the formulation
`requirements of dosator and dosing disc encapsulators,
`simulation of plug formation and creation of rules for an
`expert system for formulation design. Ph.D. Thesis,
`University of Maryland, 1998.
`11. Mehta, A.M.; Augsburger, L.L. A preliminary study of
`the effect of slug hardness on drug dissolution from hard
`gelatin capsules filled on an automatic capsule-filling
`machine. Int. J. Pharm. 1981, 7, 327 – 334.
`12. Small, L.E.; Augsburger, L.L. Aspects of the lubrication
`requirements for an automatic capsule filling machine.
`Drug Dev. Ind. Pharm. 1978, 4 (4), 345 – 372.
`13. Tattawasart, A.; Armstrong, N.A. The formation of
`lactose plugs for hard shell capsule fills. Pharm. Dev.
`Tech. 1997, 2 (4), 335 – 343.
`14. Penwest Product Brochure.
`15. Shah, K.B.; Augsburger, L.L.; Marshall, K.P. An
`investigation of some factors influencing plug forma-
`tion and fill weight in a dosing disk-type automatic capsule-
`filling machine. J. Pharm. Sci. 1986, 75 (3), 291 – 296.
`16. Tan, S.B.; Newton, J.M. Influence of compression setting
`ratio on capsule fill weight and weight variability. Int.
`J. Pharm. 1990, 66, 273 – 281.
`17. Patel, R.; Podczeck, F. Investigation of the effect of type
`and source of microcrystalline cellulose on capsule filling.
`Int. J. Pharm. 1996, 128, 123 – 127.
`18. Buckton, G.; Yonemochi, D.; Yoon, W.L.; Moffat, A.C.
`Water sorption and near IR spectroscopy to study the
`differences between microcrystalline cellulose and
`silicified microcrystalline cellulose before and after wet
`granulation. Int. J. Pharm. 1999, 181, 41 – 47.
`
`Pharmaceutical Development and Technology Downloaded from informahealthcare.com by University of Guelph on 08/23/12
`
`For personal use only.
`
`

`

`©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
`
`MARCEL DEKKER, INC. (cid:127) 270 MADISON AVENUE (cid:127) NEW YORK, NY 10016
`
`SMCC for Automatic Capsule-Filling Machines
`
`59
`
`19. Tobyn, M.J.; McCarthy, G.P.; Staniforth, J.N.; Edge, S.
`Physicochemical comparison between microcrystalline
`cellulose and silicified microcrystalline cellulose. Int.
`J. Pharm. 1998, 169, 183 – 194.
`
`20. Nakagwu, H. Effects of particle size of rifampicin and
`addition of magnesium stearate in release of rifampicin
`from hard gelatin capsules. Yakugaku Zasshi 1980, 100,
`1111 – 1117.
`
`Received February 25, 2002
`Accepted May 11, 2002
`
`Pharmaceutical Development and Technology Downloaded from informahealthcare.com by University of Guelph on 08/23/12
`
`For personal use only.
`
`