effect of tabletting compaction pressure on alginate microspheres
TRANSCRIPT
Eå ect of tabletting compaction pressure on alginatemicrospheres
P. W. S. HENG*, L. W. CHAN, C. V. LIEW and T. Y. NG
Department of Pharmacy, National University of Singapore, 10 Kent RidgeCrescent, Singapore 119260
(Received 3 August 1999; revised 7 October 1999; accepted 25 October 1999 )
Alginate and alginate-hydroxypropylmethylcellulose (HPMC) microsphereswere prepared by the emulsi® cation method. The compaction of microspheresfor producing tablet dosage forms raises concerns about possible damage tomicrosphere walls with subsequent unpredictable dissolution rates. The eå ectof diå erent compaction pressures on the integrity of the microspheres wasinvestigated. The addition of a diluent, microcrystalline cellulose (MCC), wasrequired to make compacts containing alginate and alginate-HPMC micro-spheres. Compacts containing alginate-HPMC (7:3) microspheres had thehighest crushing strength followed by compacts containing alginate-HPMC(9:1) microspheres and alginate microspheres. However, compact crushingstrength did not vary signi® cantly with increased compaction pressures overthe range of compaction pressures investigated. Diå erences in the drug releasepro® les of the original non-compacted and compacted alginate and alginate-HPMC microspheres were slight and not marked. Although dentation anddistortion of the microspheres were observed with increasing compactionpressures, the microspheres generally remained intact, with minimal rupture/fracture.
Keywords: Alginate, hydroxypropylmethylcellulose, microspheres, compac-tion, tablet.
Introduction
Microencapsulation is a process by which small solid particles, liquid droplets
and gases are enveloped by a polymeric coat. The objectives are to protect,
separate and stabilize the encapsulated material. It is also used to control the
rate of release of the encapsulated material. Microencapsulated products have been
formulated in dosage forms such as suspensions, gels and hard gelatin capsules.
Another attractive presentation of microencapsulated products may be in tablet
dosage forms. Indeed, tablets containing a multiparticulate system are fast gaining
popularity over capsule dosage forms because of their lower production cost and
ease in swallowing (Yao et al. 1997). However, only a few investigations of tablet
formulations from microspheres have been reported (Chiao and Price 1994).
Sustained release tablets containing coated microspheres must be able to disin-
tegrate into many discrete subunits instantly after oral administration to maintain
the characteristics of the coated particles. The compaction of microspheres raises
legitimate concerns about possible damage to microsphere walls, with subsequent
J. MICROENCAPSULATION , 2000, VOL. 17, NO. 5, 553± 564
* To whom correspondence should be addressed. e-mail: [email protected]
Journal of Microencapsulation ISSN 0265± 2048 print/ISSN 1464± 5246 online # 2000 Taylor & Francis Ltdhttp://www.tandf.co.uk/journals
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unpredictable dissolution rates. Chiao and Price (1994) studied the eå ect of
compaction pressure on the physical properties and dissolution characteristics of
disintegrating tablets of propranolol microspheres and noted that the drug release
rate increased at higher compaction pressures due to the rupture of a greaterproportion of microspheres. The present study was carried out to investigate the
eå ect of diå erent compaction pressures on the integrity of alginate and alginate-
hydroxypropylmethylcellulose (HPMC) microspheres.
Materials and methods
Materials
The materials, sodium alginate (viscosity approximately 250 cps measured at
258C for a 2%solution, Sigma, USA), hydroxypropylmethylcellulose (HPMC, 90
SH Type 2208, viscosity grade 100 cps measured at 208C for a 2%solution, Shin-Etsu, Japan), iso-octane (GR grade, Merck, Germany) and calcium chloride
(Merck, Germany) were used as supplied. The surfactants used were sorbitan
trioleate (Span 85, Nacalai Tesque, Japan) and polyoxyethylene (20) sorbitan
trioleate (Tween 85, Fluka Chemika-Biochemika, Switzerland). The other
materials used were lactose (Pharmatose1 200M, DMV, The Netherlands) and
microcrystalline cellulose (MCC, Celex1 101, ISP Technologies, USA). Themodel drug, sulphaguanidine (BP grade), was milled and passed through a
75 mm sieve before use.
Methods
Preparation of alginate microspheres. Alginate microspheres were prepared ac-cording to the method of Wan et al. (1992). One hundred millilitres of iso-octane
containing 1.7 g of Span 85 was added into 50 g of aqueous solution containing 3%
w/w of sodium alginate and 1% w/w of sulphaguanidine, and the mixture was
stirred using a turbine stirrer at 1000 rpm for 10 min. With continuous stirring, 5 g
of aqueous solution containing 0.9 g of Tween 85 was next added and the
dispersion was stirred for another 5 min. This was followed by the addition of
20 g of aqueous solution containing 35% w/w of calcium chloride, which wasallowed to react with the dispersed sodium alginate globules for 30 min. The
microspheres were collected by ® ltration and washed with 20 mL of distilled water
three times before being air blown dried.
The above procedure was repeated by replacing 3%w/w sodium alginate with
sodium alginate-HPMC blends in the ratios of 9:1 and 7:3. Four diå erent types ofmicrospheres were prepared: (i) alginate microspheres without drug, (ii) alginate
microspheres with drug, (iii) alginate-HPMC (9:1) microspheres with drug, and
(iv) alginate-HPMC (7:3) microspheres with drug.
Compaction of alginate microspheres. Compacts of 200 mg each were prepared
using a universal-testing machine (Autograph AGE-100, Shimadzu, Japan) with a10 mm diameter ¯ at-face punch and die set. The forces used to compact the
microsphere-diluent mixtures into compacts were about 10, 30, 60 and 90 kN. The
diluents used in this study were MCC and lactose. The mixtures used for
compaction into compacts consisted of plain microspheres, microspheres with
lactose (1:1) and microspheres with MCC (1:1).
554 P. W. S. Heng et al.
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Determination of drug release pro® les. Dissolution testing was carried out in
1000 mL deaerated distilled water at 378C using the paddle method (USP
Apparatus 2, VanKel VK6010, USA). The paddle was rotated at 50 rpm. Filtered
5 mL samples were collected using an auto sample collector (VanKel VK 6000,USA) at speci® ed intervals of time (0, 2, 5, 10, 15, 20, 25, 30, 40, 50 and 60 min)
and assayed spectrophotometrically at 260 nm (Hewlett Packard HP8452A, USA).
After 1 h, the rate of rotation was increased to 250 rpm for 5 min. This was done to
ensure complete dissolution of all the drug from the microspheres. For each batch,
three dissolution runs were carried out and the results were averaged.
Evaluation of physical characteristics of microspheres. The shape and surfacecharacteristics of the microspheres were examined using a scanning electron
microscope (Jeol JSM-5200, Japan). The microspheres were coated (Sputter
Coater, Bio-Rad SC 502, USA) with gold before scanning electron microscopy
studies were conducted.
Determination of compact crushing strength. The crushing strength of the
compacts was measured with a tablet tester (Schleuniger 6D, Germany) which
applied compression force diametrically to the compacts. For each formulation,compacts were prepared at diå erent pressures to determine the average force
required to crush the compact. The purpose of determining the crushing strength
was to ensure that the compacts formed were of suæ cient integrity. For each
compaction pressure, crushing strength determination was duplicated and results
averaged.
Results and discussion
Crushing strength of compacts
Compacts of microspheres formed using MCC as a diluent (1:1) were the
hardest. In comparison, compacts formed using lactose as the diluent had lower
crushing strength. It was observed that good compacts containing microspheres
could not be prepared without the addition of a diluent. Compacts formed without
any diluent were very fragile and broke upon application of a small force.
For microspheres (with drug)-MCC compacts, compacts containing alginate-
HPMC (7:3) microspheres were found to have the highest crushing strength
followed by compacts containing alginate microspheres and compacts containing
alginate-HPMC (9:1) microspheres. Compacts containing alginate microspheres
without drug were the least strong among the diå erent types of compacts formed
(® gure 1). However, for all four types of compact formed, it was observed that the
crushing strength of the compacts did not vary signi® cantly with an increase in
compaction pressure over the range of compaction pressures investigated. When
the constituents of the compacts were examined, the alginate microspheres
contained insoluble calcium alginate, which formed the backbone of the micro-
sphere matrix and was responsible for the strength of the alginate microspheres
(Chan et al. 1997). When compacted, the microspheres without drug were poorly
adhering and strongly elastic, producing compacts of lower crushing strength. Foralginate-HPMC microspheres, less sodium alginate was available to form calcium
alginate, resulting in a matrix that was relatively less rigid. Hence, the more plastic
Eå ect of tabletting compaction pressure on alginate microspheres 555
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and adhesive alginate-HPMC (7:3) microspheres formed compacts with higher
crushing strength. For the alginate-HPMC (9:1) microspheres, the crushing
strength± compaction pressure curve showed a maxima around 460 MPa. A
reason for this could be that when microspheres containing small amounts of
HPMC were subjected to compaction pressure, some of the HPMC below the
surfaces of the microspheres would be extruded and would contribute to increased
adhesiveness and compact strength. Surface HPMC in alginate-HPMC (9:1)
microspheres was low due to washing during the preparation of the microspheres.
As the content of HPMC in alginate-HPMC (9:1) microspheres was limited,
and as compaction pressure was further increased, a reduction in compact strength
was obtained due to strong elastic recovery of the compacted microspheres
(® gure 1).
556 P. W. S. Heng et al.
Figure 1. Crushing strength of compacts of alginate microspheres without drug andalginate and alginate-HPMC microspheres containing drug compacted at variouscompaction pressures with MCC as a diluent. Alginate microspheres without drug(&), alginate microspheres containing drug (&), alginate-HPMC (9:1) microspherescontaining drug (~), and alginate-HPMC microspheres (7:3) containing drug (!).
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Although microsphere-lactose compacts had relatively lower crushing strength
compared to microsphere-MCC compacts, similar trends were observed with
microsphere-lactose compacts containing alginate-HPMC (7:3) with drug having
the highest crushing strength and compacts containing alginate microspheres
without drug having the lowest crushing strength.
Drug release studies
The intact compacts containing microspheres with drug were ® rst ground
using a mortar and pestle to break the compact up to a ground form containing the
compacted microspheres. The drug release pro® les of ground compacted micro-
spheres were used for comparison with the drug release pro® les of non-compacted
microspheres to investigate the eå ects of compaction pressure on drug release from
the microspheres. Dissolution studies were carried out on compacted microspheres
in the ground form rather than as intact compacts, because drug release from
compacts was also dependent on the rate of disintegration of the intact compact
into discrete units.
It was necessary to evaluate the eå ect of the grinding action employed for
breaking up the compacts into discrete units, as it may cause the walls of the
microspheres to rupture or fracture signi® cantly. This eå ect was ® rst investigated
by carrying out dissolution studies on non-compacted microspheres without
grinding, and on non-compacted microspheres which were ground. The dissolu-
tion characteristics of the ground and unground microspheres showed similar ® rst
order drug release rates. These observations indicated that the grinding action did
not rupture the microspheres signi® cantly nor did it change the drug dissolution
pro® les of the microspheres.
Drug release kinetics of subsequent batches of discrete compacted and non-
compacted microspheres were determined using ® rst order (equation 1), Hixson
Crowell (equation 2) and Higuchi (equation 3) drug release models,
ln W ˆ ln W0 ¡ k1t …1†
W1=3 ˆ W1=30 ¡ k2t …2†
Q ˆ k3t1=2 …3†
where W and W0 were the amount of drug (%w/w) not released at time t and t ˆ 0
respectively, k1 was the ® rst order dissolution rate constant, k2 was the Hixson
Crowell release rate constant, Q was the amount of drug (%w/w) released at time t,and k3 was the Higuchi release rate constant. The equation ® ts were calculated in
the region of drug release from 20± 80% of the drug dissolution pro® les. Initial
portions of the dissolution pro® les which showed a faster release of unencapsulated
drug on the surface of the microspheres were not taken into account. Washing of
the microspheres during preparation would probably have removed the drug on
the surface. Therefore, any unequal distribution of drug was caused by water
¯ uxes which carried dissolved drug particles to the surface when the microspheres
were dried. This would be re¯ ected as an increase of drug particles on or just
beneath the surface of the dry microspheres. Other workers (Jalil and Nixon 1990)
observed a similar biphasic release.
Eå ect of tabletting compaction pressure on alginate microspheres 557
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For the three types of drug-loaded microspheres, that is, plain alginate,
alginate-HPMC (9:1) and alginate-HPMC (7:3), better ® ts for the drug release
data were generally obtained using the ® rst order equation (table 1). Aslani and
Kennedy (1996) reported similar ® ndings in which the release of paracetamol from
alginate beads parallelled ® rst order kinetics.
The drug incorporated in the microspheres was likely to be distributed
throughout the microsphere matrix. When placed in the dissolution media,
dissolution began with drug on/near the surface of the microsphere being released
® rst into the surrounding dissolution media. As the microspheres were porous, the
dissolution ¯ uid permeated into the microspheres through the pores. The uptake
of the dissolution ¯ uid took place in a radially inward manner from the micro-
sphere surface into the microsphere interior. With the entry of the dissolution
¯ uid, drug particles inside the microspheres dissolved and diå used out through the
water-logged pores. With the passage of time, the diå usional pathlength for the
drug to leach out increased as the drug in the outer regions was depleted. Hence,
® rst order release kinetics were expected.
At higher compaction pressures, correlation coeæ cients …r2† for drug release
from alginate-HPMC (7:3) microspheres were generally lower than those for plain
alginate and alginate-HPMC (9:1) microspheres. This might be due to non-
conformity to the assumptions of an ideal ® rst order drug release kinetics model
(Jalil and Nixon 1990). One of these assumptions was that the diå usional matrix
must be non-swelling and non-eroding. The extent of polymer swelling for the
microspheres during dissolution testing has not been investigated in this present
study. However, previous studies have shown that HPMC matrices swelled and
eroded when placed in the dissolution ¯ uid (Wan et al. 1991). Other workers have
also reported that alginate beads can swell when hydrated (Lin and Ayres 1992,
Aslani and Kennedy 1996). Microspheres prepared by emulsi® cation were
generally much smaller in size than alginate beads or HPMC matrices. In the
558 P. W. S. Heng et al.
Table 1. Correlation coeæ cients for ® rst order, Higuchi and Hixson Crowell drug releasemodels.
Compaction pressure (MPa)
0 170 460 860 1240
Release model Correlation coeæ cient, r2
Alginate microspheresFirst order 0.9985 0.9991 0.9991 0.9981 0.9986Higuchi 0.9935 0.9787 0.9800 0.9774 0.9831Hixson Crowell 0.9914 0.9877 0.9881 0.9854 0.9876
Alginate-HPMC (9:1) microspheresFirst order 0.9991 0.9983 0.9991 0.9992 0.9998Higuchi 0.9785 0.9714 0.9827 0.9710 0.9810Hixson Crowell 0.9986 0.9897 0.9910 0.9865 0.9919
Alginate-HPMC (7:3) microspheresFirst order 0.9930 0.9929 0.9848 0.9890 0.9808Higuchi 0.9479 0.9734 0.9746 0.9798 0.9742Hixson Crowell 0.9672 0.9762 0.9679 0.9749 0.9641
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laboratory, preliminary studies with alginate microspheres showed that swelling
appeared to be related to particle size, with swelling being less signi® cant for
smaller microspheres.
In general, drug release from the plain alginate and alginate-HPMC micro-
spheres was rapid, with the addition of HPMC giving rise to a slightly faster
release for the non-compacted microspheres (® gure 2 and table 2). In a study on
the eå ect of cellulose derivatives on alginate microspheres, Chan et al. (1997)
reported that alginate microspheres were highly porous, allowing the rapid release
of drug entrapped within. The incorporation of HPMC 100 cps into alginate
microspheres was also found to increase the rate of drug release.
Eå ect of tabletting compaction pressure on alginate microspheres 559
Figure 2. Drug release from (a) alginate microspheres, (b) alginate-HPMC (9:1) micro-spheres, and (c) alginate-HPMC (7:3) microspheres compacted at diå erent compac-tion pressures. 0 (&), 170 (£), 460 (~), 860 (!) and 1240 (*) MPa.
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For the alginate-HPMC microspheres, besides permeation of water into the
microspheres, drug release may also be in¯ uenced by the rate of formation of
HPMC gel and the diå usion rate of the drug in the gel (Wan et al. 1991). The
microsphere structure can be altered, with the incorporation of HPMC into the
alginate microspheres. Firstly, there was comparatively less sodium alginate to
form the calcium alginate backbone. During the microsphere hardening stage, the
presence of the swollen HPMC reduced the extent of cross-linking of the calcium
alginate in the microspheres. This was likely to give rise to the formation of a more
porous microsphere. With reduced structural integrity coupled with the likelihood
of a strongly swelling HPMC when wetted, to loosen the microsphere structure, a
slightly faster drug release rate was obtained for the non-compacted alginate-
HPMC microspheres when compared to non-compacted alginate microspheres
without HPMC (table 2).
For compacted drug-loaded microspheres, in comparison to plain alginate and
alginate-HPMC (9:1) microspheres, the alginate-HPMC (7:3) microspheres ex-
hibited a relatively slower drug release rate (® gure 2 and table 2). The rate of drug
release appeared to decrease slightly with an increase in compaction pressure to
¹460 MPa. A further increase in compaction pressures from 460± 1240 MPa did
not have a marked eå ect on the drug release rates. A corresponding weakening of
the integrity of the microsphere structure based on the calcium alginate backbone
took place with an increase in the content of HPMC in the microsphere. Upon
compaction, a comparatively denser polymeric matrix packing could be formed,
resulting in a less porous structure. This would lead to a decrease in the
permeability of the matrix for drug diå usion to occur. HPMC in the matrix can
also hydrate and swell on contact with the dissolution ¯ uid, giving rise to the
560 P. W. S. Heng et al.
Table 2. First order dissolution rates, correlation coeæ cients, T50%and T75%of themicrospheres.
Compaction First order dissolution rate T50% T75%pressure (MPa) {[ln (%w/w)]/min} r2
(min) (min)
Alginate microspheres0 0.0975 0.9985 3.14 10.25
170 0.1421 0.9991 2.25 7.13460 0.1397 0.9991 2.33 7.29860 0.1347 0.9981 2.34 7.49
1240 0.1265 0.9986 2.55 8.03
Alginate-HPMC (9:1) microspheres0 0.1458 0.9991 2.01 6.76
170 0.1725 0.9983 2.07 6.09460 0.1424 0.9991 2.45 7.32860 0.1608 0.9992 1.90 6.21
1240 0.1591 0.9998 2.14 6.49
Alginate-HPMC (7:3) microspheres0 0.1655 0.9930 3.78 7.97
170 0.1134 0.9929 3.10 9.21460 0.0888 0.9848 3.93 11.73860 0.0873 0.9890 3.92 11.86
1240 0.0805 0.9808 4.34 12.95
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formation of a gel layer. With a less porous microsphere, this diå usional gel layer
may be more eå ective in retarding drug release.
Comparing drug release rates from non-compacted plain alginate microspheres
with that from the compacted microspheres, a marginally slower release rate wasobserved for non-compacted microspheres (® gure 2(a) and table 2). Super® cially,
it appeared that compaction may have caused some fracturing of the compacted
microspheres. However, as it can be seen, the increased compaction pressure failed
to increase the rate of drug release further. The more probable reason for increased
release rate of compacted microspheres was that the process of compactingmicrospheres was successful at breaking up microsphere aggregates present.
This action required relatively low shear forces. Thus, the lowest compaction
pressure used was suæ cient to de-aggregate the microspheres and higher pressures
did not confer additional advantage. It was also evident that the microspheres were
able to withstand the compaction forces and did not show signs of extensive
fracture (® gure 3).However, on the whole, the microspheres generally exhibited relatively rapid
drug release, as shown by the T50%and T
75%values (table 2), and the diå erences
between the drug release pro® les of the original non-compacted and compacted
plain alginate and alginate-HPMC microspheres were slight and not marked. The
drug release kinetics of the microspheres were also not altered by increasingcompaction pressures. First order release kinetics were observed for the original
non-compacted microspheres and for the discrete units of compacted micro-
spheres. Hence, it could be concluded that an increase in compaction pressure
over the range of compaction pressures investigated did not appear to cause
signi® cant changes in the rate of drug release from the microspheres. Thisconclusion was supported by scanning electron microscopy studies of non-
compacted and compacted microspheres.
Scanning electron photomicrography
Under the scanning electron microscope, the original non-compacted micro-
spheres were observed as discrete spherical particles (® gure 4). Scanning electron
photomicrographs of discrete units of compacted microspheres showed that theirwalls remained relatively intact after compaction up to 1240 MPa (® gure 4). With
increasing compaction pressures, the microspheres merely became dented and
distorted from their original spherical shape. From these observations (® gures 3
and 4), the alginate and alginate-HPMC microspheres appeared to be relativelystrong. Moreover, good compacts were formed with the addition of MCC as a
diluent. The high compressibility of MCC also conferred a cushioning eå ect and
protected the microspheres. Therefore, little or no fracture of the microspheres
resulted. These observations were also supported by the ® ndings of GuÈ rsoy et al.(1998). They reported that the integrity of dipyridamole alginate-Eudragit micro-
spheres was not changed after dissolution of tabletted microspheres and that nocracks were observed on the surface or cross section of the microspheres.
Conclusions
The addition of a diluent was required to make compacts containing plain
alginate or alginate-HPMC microspheres. Microcrystalline cellulose was a suitable
Eå ect of tabletting compaction pressure on alginate microspheres 561
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diluent. Besides conferring disintegrant properties to the compacts, it has cush-
ioning properties which protect the microspheres from fracture during compac-
tion. Discrete units of compacted plain alginate and alginate-HPMC microspheres
retained the ® rst order release kinetic properties of the original non-compacted
562 P. W. S. Heng et al.
(a)
(b)
(c)
Figure 3. Photomicrographs of drug-loaded microspheres of alginate and alginate-HPMCcompacted at 1240 MPa. (a) Alginate [with drug], (b) Alginate-HPMC (9:1) [withdrug], (c) Alginate-HPMC (7:3) [with drug].
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microspheres. Although the microspheres tend to become dented and distorted
from their original spherical shape with increasing compaction pressures, the
microspheres generally remained intact with minimal rupture/fracture. Hence, the
microspheres can be subjected to compaction without signi® cant alterations to
their original drug release rates.
Eå ect of tabletting compaction pressure on alginate microspheres 563
(a)
(b)
(c)
Figure 4. Photomicrographs showing the eå ect of compaction pressure on alginatemicrospheres wihtout drug. (a) 0 MPa, (b) 170 MPa, (c) 1240 MPa.
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References
ASLANI, P., and KENNEDY, R. A., 1996, Eå ect of gelation conditions and dissolution mediaon the release of paracetamol from alginate beads. Journal of Microencapsulation, 13,601± 614.
CHAN, L. W., HENG, P. W. S., and WAN, L. S. C., 1997, Eå ect of cellulose derivatives onalginate microspheres prepared by emulsi® cation. Journal of Microencapsulation, 14,545± 555.
CHIAO, C. S. L., and PRICE, J. C., 1994, Eå ect of compression pressure on physicalproperties and dissolution characteristics of disintegrating tablets of propranololmicrospheres. Journal of Microencapsulation, 11, 161± 170.
GURSOÈ Y, A., KALKAN, F., and OKAR, I., 1998, Preparation and tabletting of dipyridamolealginate-Eurdragit microspheres. Journal of Microencapsulation, 15, 621± 628.
JALIL, R., and NIXON, J. R., 1990, Microencapsulation using poly (DL-lactic acid) III: Eå ectof polymer molecular weight on the release kinetics. Journal of Microencapsulation,7, 357± 374.
LIN, S. Y., and AYRES, J. W., 1992, Calcium alginate beads as core carriers of 5-aminosalicylic acid. Pharmaceutical Research, 9, 1128± 1131.
WAN, L. S. C., HENG, P. W. S., and CHAN, L. W., 1992, Drug encapsulation of alginatemicrospheres by emulsi® ction. Journal of Microencapsulation, 9, 309± 316.
WAN, L. S. C., HENG, P. W. S., and WONG, L. F., 1991, The eå ect of hydroxypropylmethylcellulose on water penetration into a matrix system. InternationalJournal of Pharmaceutics, 73, 111± 116.
YAO, T., YAMADA, M., YAMAHARA, H., and YOSHIDA, M., 1997, Tableting of coated particles.I., Small particle size chitosan as an agent protecting coating membrane frommechanical damage of compression force. Chemical and Pharmaceutical Bulletin, 45,1510± 1514.
564 Eå ect of tabletting compaction pressure on alginate microspheres
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