Journal of Controlled Release 51 (1998) 289–299

Film-forming polymer-granulated excipients as the matrix materialsfor controlled release dosage forms

*Tsuimin Tsai, Yu-Ping San, Hsiu-O Ho, Jen-Sen Wu, Ming-Thau SheuGraduate Institute of Pharmaceutical Sciences, Taipei Medical College, 250 Wu-Hsing Street, Taipei, Taiwan, ROC

Received 18 March 1997; received in revised form 1 August 1997; accepted 19 September 1997

Abstract

Lactose and dibasic calcium phosphate (DCP) were granulated with various concentrations of film-forming polymers by astepwise spraying method to prepare a directly compressible matrix excipient. The film-forming polymeric latex of EudragitRS-30D, Eudragit RL-30D, and Surelease (ethylcellulose) were used in this study as the source of the granulating materials.Better flowability and compressibility were observed for all the granulated particles than the polymer-free granules. Mosttablets prepared from the polymer-granulated particles exhibited satisfactory friability of less than 1% except for thoseprepared from lactose particles granulated with low concentrations of ethylcellulose and from plain lactose granules. Changein tensile strength and tablet thickness were in good agreement with the plasticity of the granulating polymer. Polymer-granulated lactose and DCP provided for controlled release of captopril from matrix tablets. This investigation suggests thatconventional excipients can be modified by a simple granulating procedure to provide better physical properties for beingused as a matrix material. 1998 Elsevier Science B.V.

Keywords: Eudragit; Ethylcellulose; Lactose; Dibasic calcium phosphate; Spraying granulation; Direct compression

1. Introduction viscosity grades of hydroxypropyl methylcellulose(HPMC’s) and their chemically modified derivatives

Controlled release tablets have been widely used are the most popular choice [1,2]. However,for decades. There are several ways to prepare these granulating is usually necessary to improve thetablets such as direct compression, wet granulation flowability when HPMC is used as the matrixand the slugging method. Incorporation of the drug material, especially when a high-speed tablettinginto a matrix tablet by a direct compression tech- machine is used. Modification of excipient function-nique is an easy and economical way to formulate a ality to provide tabletting materials with ideal prop-controlled release dosage form. However, the fact erties for tablet production on modern machines hasthat some commonly used excipients have poor gained a lot of interest. There are three approachesflowability and compressibility may limit their appli- commonly used to obtain a better matrix-formingcations as direct compression matrix materials. material with improved functionality: chemical

Among the reported matrix materials used, various modification, physical modification and co-process-ing [3–5]. Modification by co-processing is attractive

*Corresponding author. because the products physically modified in a special

0168-3659/98/$19.00 1998 Elsevier Science B.V. All rights reserved.PII S0168-3659( 97 )00183-1

290 T. Tsai et al. / Journal of Controlled Release 51 (1998) 289 –299

way do not lose their chemical structure and stabili- 2.2. Methodsty. This type of modification is cost-effective fordeveloping a product, with the added value of its 2.2.1. Preparation of granulated excipientsfunctionality. A type of aqueous-based coating to Lactose and DCP were sieved through a 100-meshcarry matrix materials, either containing drug only or screen (150 mm), separately, prior to use as coredrug with suitable excipients, has been thoroughly materials. Eudragit RS-30D and RL-30D were usedreviewed by Kawashima et al. [6]. as received in the form of latex dispersions for the

On the other hand, the selection of excipients granulation of lactose and DCP. TEC and Tween 80sometimes can dramatically affect the processing were added into the colloidal dispersions of Eudragitconditions and overall characteristics of the final and stirred for 30 min prior to use. Surelease wasproduct. Hence, a number of tests have been de- also used as received and was diluted with anveloped to evaluate whether the excipient is suitable appropriate amount of water to a concentration ofas a directly compressible diluent. Most of the 10% w/w based on the polymer content. Granulatedparameters studied in the tests can be divided into powder was prepared by spraying the coating latextwo categories: the rheological properties and the onto the surface of lactose or DCP in a KitchenAidtabletting characteristics. Mixer (Model K5SS, KitchenAid, USA). The wet

In this investigation, a simple spraying method slurry was then passed through a 50-mesh screenwas used in preparing granulated excipients as a (0.297 mm) by hand and dried in a forced-air oven atdirectly compressible diluent. Polymeric materials 608C. The dried granules were then passed through aselected for the granulation in this study were 50-mesh screen and were sprayed repeatedly in theEudragit RS-30D, Eudragit RL-30D and ethylcellul- same manner with the same latex solution at 2.5%ose, which have been used in tablet and pellet weight gain increments to obtain granulated particlescoatings to provide membrane- or diffusion-con- with a polymer content of either 2.5, 5.0, 7.5 ortrolled release characteristics [7,8]. The purpose of 10.0% w/w.this investigation was to develop a simple granulatedexcipient and to evaluate the rheological properties 2.2.2. Physical and rheological properties ofand tabletting characteristics of these granulated granulesexcipients as matrix material for the direct compres- Particle size distribution for each sample wassion of tablets. measured with a standard method of sieve analysis.

After sieving, the amount retained on each sieve wasweighed and the distribution of the particle size wasplotted on normal–probability axes. The arithmetic

2. Materials and methodsmean diameters (d ) corresponded to 50% of theg

cumulative percentage of weight. The arithmetic2.1. Materials standard deviations (d ) were calculated as theg

particle size at 50% subtracted by the particle size atEudragit RS-30D and RL-30D were purchased 16% undersized. The angle of repose (8), bulk

from Rohm Pharma (Darmstadt, Germany). density, and tapped density for each powder wasSurelease containing 25% ethylcellulose in a pseudo- determined by an A.B.D. Fine Particle Characteris-latex form in an aqueous medium was obtained from tics Measuring Instrument (Tsutsui Scientific Instru-Colorcon (Bexley, UK). Triethyl citrate (TEC), ments, Japan). Compressibility of the powder wasTween 80, acetonitrile and phosphoric acid were calculated using Carr’s index [9].supplied by Merck–Schuchardt (Germany). Lactosemonohydrate (200 mesh) came from DMV (Veghel, 2.2.3. Tablet compression and tensile strengthNL). Dibasic calcium phosphate dihydrate (DCP) Tablets were compressed using a Carver labora-was from BK Ladenburg (Germany). Captopril was tory press (Fred S. Carver) utilizing standard 7.5-mmpurchased from Farmhispania S. (lot 100.25.26.01). concave punches and die tooling at compressionDeionized water was used in this study. forces of 500, 1000, 1500, 2000 and 2500 kg. A

T. Tsai et al. / Journal of Controlled Release 51 (1998) 289 –299 291

raising speed of 0.5 cm/s and a zero contact time 2.2.5. Drug dissolutionwere used to form tablets. The punches and die wall The USP paddle method was used to measurewere cleaned with a facial paper and the tooling was dissolution rates of captopril. The dissolutionlubricated with a thin film of magnesium stearate medium was pH 1.2 simulated gastric fluid (withoutapplied from an acetone solution. Then the die was enzymes) maintained at 378C with a stirring rate offilled with 200 mg of powder being either pure 50 rpm. The sample was withdrawn at fixed timepolymer-granulated excipients or a mixture (3:1) of intervals and analyzed for the drug using a HPLCpolymer-granulated excipients and the model drug method. The samples were injected directly into acaptopril. Twenty replicate compacts were prepared m-Bondapak C column (3.93300 mm) using18

at the same compression force. The tablet thickness deionized water (containing 0.05% H PO )/acetoni-3 4

and crushing strength were determined using a trile575:25 as the mobile phase. The detectionPharma Test Model PTB-311 (GMBH, Germany). wavelength was 218 nm and the flow-rate was 1Tablet tensile strength was calculated as defined by ml /min. This HPLC method has been validated withFell and Newton [10]. The friability of the compacts an acceptable coefficient of variation for accuracywas evaluated from the weight loss of 10 tablets and precision (0.13–2.29% and 0.04–1.21% fortumbled for 100 revolutions using a Roche type inter-day and 0.03–3.70% and 0.14–2.29% for intra-Friabilator (All-Trans Ent., ROC). day).

2.2.4. Scanning electron microscopy (SEM) 3. Results and discussionThe surface and cross-section morphologies were

examined under a Hitachi model S-2400 SEM The particle size of all granulated excipients was(Department of Pathology, Taipei Medical College). found to be normally distributed. The values of theSamples were loaded on aluminum studs and coated arithmetic mean diameters (d ) and standard devia-g

with gold for 3 min at 8 mA under a pressure of 0.1 tions (d ) calculated from the graphs are listed ing

torr. The samples were scanned and the micrographs Tables 1 and 2 for lactose and DCP, respectively. Aswere examined. the amount of granulating materials increased, the

Table 1Rheological properties of lactose granules

Granules Angle of Bulk density Tapped density Compressibility Mean diameter,arepose (8) (g /c.c.)3100 (g /c.c.)3100 index (%) d (d , mm)g g

bLactose 56.1 (0.6) 40.22 (2.48) 66.87 (1.42) 39.88 (2.71) 45.36 (62.50)With water 49.4 (1.0) 44.35 (0.68) 56.92 (0.27) 22.08 (0.81) 118.41 (50.76)

2.5% EC 39.5 (0.8) 47.88 (0.28) 56.80 (1.41) 18.63 (2.38) 119.00 (58.03)5.0% EC 39.3 (0.4) 48.84 (1.54) 58.10 (0.86) 19.03 (2.21) 127.84 (53.63)7.5% EC 40.4 (0.6) 48.29 (0.89) 57.15 (1.49) 18.34 (1.30) 135.61 (48.75)

10.0% EC 40.7 (1.1) 48.92 (0.61) 57.71 (1.09) 17.97 (2.14) 140.37 (46.51)

2.5% RS 43.2 (0.7) 44.24 (2.29) 56.10 (2.13) 27.00 (2.27) 94.99 (60.76)5.0% RS 45.1 (1.5) 44.77 (3.13) 56.42 (4.63) 20.78 (2.83) 116.78 (45.79)7.5% RS 47.4 (1.7) 41.97 (4.02) 51.41 (5.66) 22.22 (1.72) 116.91 (45.38)

10.0% RS 61.6 (0.6) 41.25 (0.90) 46.91 (0.55) 13.78 (2.83) 153.51 (33.37)

2.5% RL 43.3 (0.9) 44.40 (0.54) 54.48 (1.52) 22.69 (2.04) 118.80 (54.29)5.0% RL 45.2 (1.3) 43.81 (3.15) 54.74 (4.21) 24.96 (2.44) 114.05 (55.86)7.5% RL 45.6 (1.0) 45.15 (2.10) 56.04 (2.01) 24.18 (1.78) 128.61 (46.65)

10.0% RL 46.5 (1.9) 46.93 (1.23) 56.22 (1.21) 21.45 (3.37) 133.88 (45.01)a

d : Arithmetic standard deviation of size distribution.gb Standard deviation shown in parenthesis.

292 T. Tsai et al. / Journal of Controlled Release 51 (1998) 289 –299

Table 2Rheological properties of dibasic calcium phosphate granules

Granules Angle of Bulk density Tapped density Compressibility Mean diameter,arepose (8) (g /c.c.)3100 (g /c.c.)3100 Index (%) d (d , mm)g g

bDCP 52.3 (0.6) 59.31 (1.37) 95.25 (0.42) 37.74 (1.16) ,104 nmWith water 58.0 (0.0) 50.99 (0.36) 84.02 (0.24) 39.31 (0.44) ,104 nm

2.5% EC 44.3 (1.4) 75.17 (0.89) 100.10 (1.15) 24.88 (1.67) 15.51 (91.74)5.0% EC 41.6 (1.7) 76.86 (0.91) 98.79 (5.97) 22.20 (2.86) 41.72 (84.03)7.5% EC 38.6 (1.0) 74.20 (0.43) 95.31 (1.89) 22.14 (1.46) 70.78 (71.94)

10.0% EC 38.4 (1.4) 74.93 (1.22) 96.84 (2.31) 22.63 (2.20) 88.34 (67.15)2.5% RS 42.0 (1.8) 69.78 (0.64) 90.43 (2.81) 22.84 (1.46) 17.48 (86.21)5.0% RS 39.4 (0.3) 65.81 (1.10) 83.96 (0.96) 21.62 (1.90) 71.12 (72.46)7.5% RS 38.5 (0.7) 61.13 (0.22) 75.11 (1.72) 18.62 (3.11) 97.89 (62.50)

10.0% RS 38.4 (0.6) 59.99 (0.71) 71.35 (0.96) 15.03 (0.75) 116.78 (63.60)2.5% RL 49.2 (0.4) 63.42 (1.63) 94.02 (1.85) 32.53 (1.77) 28.48 (100.1)5.0% RL 41.4 (0.5) 64.69 (1.46) 85.30 (2.02) 24.18 (0.96) 77.30 (69.49)7.5% RL 39.4 (0.7) 66.98 (1.10) 85.47 (1.22) 21.63 (0.66) 98.77 (69.49)

10.0% RL 37.0 (1.5) 67.13 (0.85) 84.24 (2.18) 19.34 (1.30) 118.36 (67.40)a

d : Arithmetic standard deviation of size distribution.gb Standard deviation shown in parenthesis.

arithmetic mean diameter of the granules increased. surface as well as the cross-section of lactose andThe particle size increments showed different pat- DCP tablets made with powder only (PO) andterns for lactose and DCP granulated with three powder granulated with water (PW). It indicates thatdifferent polymers. In the case of lactose, the mean the particles of lactose in the cross-section weregranule size increased from 45.4 mm to 118.4 mm more uniform after granulation with water, but thatwhen water was involved in the granulation. Further DCP tablets maintain a similar size range andinvolvement of granulated polymers only contributed identical shape. This confirms the different charac-to a small increment in the particle size. However, teristics of two materials when granulated withthe mean size of DCP appeared to be unchanged water.when granulated with water only, whereas the mean Fig. 3 displays SEM photomicrographs of tabletssize increased gradually with increasing amounts of in the cross-section for lactose (A) and DCP (B)the polymer used. granulated with either Eudragit RL (1), Eudragit RS

The water solubility of lactose is sufficient to (2), or Surelease (3) at a 10% level. It is inconclu-allow the partial dissolution in the granulating solu- sive if the coating could occur during granulationtion as a secondary binder during the granulation when only employing such a simple spraying meth-process. It is likely that the formation of lactose od. Comparing relatively, however, the edge ofgranules during this process is mainly controlled by particles after compression seems to be softer forthe bridge formed from the soluble portion of lactose particles granulated with Eudragit RL, the next isin the latex solution, which results in smaller differ- Eudragit RS and the last is Surelease. A plasticizerences in the mean particle size between those may function like a glue to bind particles togethergranulated with water and those granulated with even if it forms a thin film on the surface ofvarious concentrations of the latex solutions. Due to particles. Therefore, a definite or less soft edgethe insolubility of DCP and the coating materials in would be possibly seen for less plasticizing particles.water, agglomeration of the particles occurs as a It illustrates that particles granulated with Eudragitresult of the bridge connection between DCP and the RL seem to possess the highest extent of plasticitypolymers. This agglomeration resulted in an increase compared with the other two materials.in the mean particle size as the amount of granulat- The results shown in Tables 1 and 2 reveal thating polymer was increased. granules produced by granulation had an angle of

Figs. 1 and 2 show SEM photomicrographs on the repose less than that of the original powder. How-

T. Tsai et al. / Journal of Controlled Release 51 (1998) 289 –299 293

Fig. 1. The SEM photomicrographs of lactose tablets on the surface (S) and in the cross-section (C) for powder only (PO) and powdergranulated with water (PW).

ever, the values were still above 378 indicating repose with the increase in the granulating amountacceptable flowability. On the other hand, all Com- was observed for DCP.pressibility Indices (Carr’s index values) calculated The angle of repose is usually affected by thefrom the density data were smaller for the granulated particle size of the powder and usually increases withpowders. Hence, this indicated a good flow potential a decrease in the particle size [11]. This generalfor all granulated excipients. For lactose granules, statement holds provided that the component of thethe angle of repose increased slightly with the powder is the same. When the powder is granulatedincrease in the granulating amount of all three coated with different materials, the surface morphology andmaterials used. Furthermore, the effect on the angle cohesive forces between the particulate may beof repose was more profound for Eudragit RS and greatly affected. As described above, the growth ofRL than for Surelease at the same amount of lactose granules is mainly due to the binding effectgranulation. However, a decrease in the angle of of the soluble portion of lactose in the latex solution.

294 T. Tsai et al. / Journal of Controlled Release 51 (1998) 289 –299

Fig. 2. The SEM photomicrographs of DCP tablets on the surface (S) and in the cross-section (C) for powder only (PO) and powdergranulated with water (PW).

A mixture of lactose and granulating materials may The cohesive force is expected to be similar for allappear on the surface of the treated granules and, as granules with different granulating amounts. It ap-a result, the retardation of the flowability of the pears that the size of the granules is responsible forgranules by the cohesive effect of the granulated the flowability of DCP granules. The flowability ofmaterials is a determining factor. This retardation of DCP granules increases with the increase in granulethe flowability will be more significant as the size.granulating amount increases. Since the cohesive The data on the thickness, friability and tensileforce is larger for Eudragit RS and RL than strength of the tablets compressed from all powdersSurelease as a result of a plasticizing effect, inferior at different compression forces (500, 1000, 1500,flowability for granules treated with Eudragit RS and 2000, 2500 kg) are listed in Tables 3 and 4 forRL than those with Surelease is expected. On the lactose and DCP, respectively. As expected, tabletother hand, the growth of DCP granules is due to the thickness decreased as the compression force in-binding effect of the coated materials as the nucleus. creased, but except for lactose tablets made with

T. Tsai et al. / Journal of Controlled Release 51 (1998) 289 –299 295

Fig. 3. The SEM photomicrographs of lactose (A) and DCP (B) tablets in the cross-section for powder granulated with Eudragit RL 30D (1),Eudragit RS 30D (2), and ethylcellulose (3) at a 10% level.

296 T. Tsai et al. / Journal of Controlled Release 51 (1998) 289 –299

Table 3Compression properties of lactose tablets

Compression Compression Lactose Surelease (Ethylcellulose %) Eudragit RS (%) Eudragit RL (%)

properties force (kg) Plain Water 2.5 5.0 7.5 10.0 2.5 5.0 7.5 10.0 2.5 5.0 7.5 10.0

Thickness 500 3.81 3.84 3.80 3.80 3.81 3.80 3.82 3.81 3.82 3.83 3.84 3.85 3.85 3.86

(mm) (0.02) (0.01) (0.02) (0.01) (0.01) (0.01) (0.03) (0.01) (0.02) (0.03) (0.01) (0.01) (0.01) (0.01)

1000 3.75 3.74 3.74 3.74 3.75 3.77 3.75 3.74 3.76 3.77 3.74 3.75 3.75 3.78

(0.02) (0.02) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01)

1500 3.68 3.69 3.74 3.72 3.74 3.76 3.70 3.70 3.72 3.74 3.68 3.71 3.72 3.75

(0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.02) (0.01) (0.02) (0.01) (0.01)

2000 3.67 3.66 3.76 3.73 3.73 3.75 3.67 3.65 3.69 3.71 3.66 3.68 3.70 3.73

(0.02) (0.04) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01)

2500 — — 3.75 3.75 3.73 3.75 3.64 3.66 3.68 3.70 3.62 3.66 3.68 3.72

(0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01)

Friability (%) 500 0.3 0.3 0.4 0.3 0.2 0.2 5.0 0.1 0.2 0.1 0.2 0.4 0.2 0.2

1000 0.3 0.4 0.4 0.3 0.2 0.2 0.2 0.2 0.1 0.1 0.2 0.2 0.2 0.1

1500 0.3 0.4 15.7 0.4 0.3 0.3 0.2 0.2 0.2 0.2 0.3 0.2 0.2 0.2

2000 7.1 8.7 31.6 7.4 0.3 0.2 0.2 0.2 0.2 0.1 0.3 0.2 0.2 0.2

2500 — — 33.4 15.3 0.3 0.3 0.2 0.2 0.2 0.1 0.3 0.2 0.2 0.2

Tensile 500 17.64 14.41 10.08 13.35 11.07 11.63 21.01 27.39 29.28 31.18 20.19 19.86 23.70 21.75

strength (0.76) (1.39) (0.77) (0.61) (0.60) (0.99) (2.51) (1.15) (2.41) (1.22) (1.92) (3.59) (3.02) (1.91)

1000 24.71 16.67 12.73 14.05 13.41 13.23 26.59 31.32 34.90 35.85 27.20 28.19 32.80 31.37

(1.04) (1.75) (1.14) (0.68) (0.49) (0.64) (0.83) (2.71) (1.16) (1.82) (1.36) (2.02) (1.63) (2.21)

1500 27.61 16.70 9.54 14.76 13.79 13.31 30.71 35.82 35.96 36.89 34.18 33.90 35.67 33.93

(1.72) (4.50) (1.15) (0.75) (0.48) (0.72) (1.60) (1.36) (1.68) (1.98) (2.08) (1.42) (2.97) (0.82)

2000 24.32 23.12 8.06 8.85 13.70 13.31 32.91 33.84 34.07 33.27 28.73 33.05 36.05 33.72

(3.67) (4.48) (0.52) (0.91) (0.92) (0.84) (1.50) (1.96) (1.09) (1.34) (2.80) (1.39) (0.59) (0.91)

2500 — — 6.66 7.92 13.24 11.96 34.99 33.84 35.00 35.15 26.29 31.36 35.40 33.84

(0.58) (1.50) (0.93) (0.87) (1.16) (1.17) (1.40) (1.05) (2.51) (3.80) (1.07) (0.84)

granules treated with smaller amounts of ethylcellul- DCP granules, the tensile strength of the tabletsose. Most of the tablets demonstrated an acceptable increased with increasing compression force nofriability (less than 1%). However, 2.5% and 5.0% matter which polymers were used in the granulation.ethylcellulose granulated lactose along with un- However, the increase was less profound at highertreated lactose produced tablets showing a relatively compression forces. The tablets made from DCPhigh friability when the compression force was high. particles granulated with ethylcellulose also pos-

The tensile strengths of the tablets relative to the sessed a smaller tensile strength than those fromfive different compression forces are shown in Fig. 4. Eudragit RS and RL. Furthermore, the tensileFor lactose granules, the tensile strength of the strength of the tablets made with granules treatedtablets made with ethylcellulose granulated particles with either Eudragit RS and RL showed no signifi-showed only a minor change with increasing com- cant difference, but both were higher than thosepression force, as well as with increasing amounts of made with ethylcellulose treated granules. This wasgranulation. However, for tablets made with Eudragit more obvious at a higher granulating amounts.RS- and RL-treated granules, changes in the tensile Both lactose and DCP are deformed by brittlestrength relative to the compression force was simi- fracture during tabletting [12,13]. However, thelar, both of which initially increased with increasing fracture patterns were different for these two materi-compression force and then reached a plateau. How- als. Microscopic observation has shown that theever, the effect of granulating amount on the change surface of lactose tablets contains brittle particles,in the tensile strength seems to be insignificant. With while a cross-section of the tablets showed more

T. Tsai et al. / Journal of Controlled Release 51 (1998) 289 –299 297

Table 4Compression properties of DCP tablets

Compression Compression DCP Surelease (ethylcellulose %) Eudragit RS (%) Eudragit RL (%)

properties force (kg) Plain Water 2.5 5.0 7.5 10.0 2.5 5.0 7.5 10.0 2.5 5.0 7.5 10.0

Thickness 500 2.95 2.99 2.93 2.94 2.95 2.96 2.94 2.95 2.96 2.97 2.95 2.99 2.97 2.99

(mm) (0.02) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01)

1000 2.86 2.89 2.84 2.85 2.88 2.90 2.86 2.86 2.88 2.89 2.85 2.90 2.90 2.92

(0.01) (0.03) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01)

1500 2.79 2.81 2.76 2.79 2.83 2.86 2.80 2.82 2.83 2.86 2.79 2.84 2.86 2.89

(0.01) (0.01) (0.01) (0.01) (0.00) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01)

2000 2.73 2.75 2.73 2.77 2.80 2.84 2.75 2.78 2.81 2.84 2.74 2.79 2.82 2.84

(0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01)

2500 2.70 2.72 2.72 2.76 2.79 2.83 2.71 2.76 2.79 2.82 2.70 2.76 2.79 2.81

(0.01) (0.02) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01) (0.01)

Friability (%) 500 0.4 0.4 0.4 0.3 0.3 0.2 0.3 0.2 0.1 0.3 0.3 0.2 0.1

1000 0.3 0.4 0.3 0.3 0.2 0.2 0.2 0.2 0.1 0.1 0.2 0.2 0.2 0.1

1500 0.3 0.8 0.3 0.3 0.3 0.3 0.2 0.2 0.1 0.2 0.3 0.2 0.2 0.2

2000 0.3 0.2 0.3 0.3 0.3 0.2 0.3 0.2 0.2 0.2 0.3 0.3 0.2 0.2

2500 0.3 5.7 0.4 0.3 0.3 0.2 0.2 0.2 0.2 0.2 0.5 0.2 0.2 0.2

Tensile 500 15.42 12.28 10.74 10.21 10.45 11.65 15.20 18.93 25.36 29.84 16.36 17.62 20.97 24.08

strength (1.76) (1.11) (1.19) (0.67) (0.92) (1.46) (1.37) (1.37) (1.27) (1.41) (0.43) (0.57) (1.24) (1.01)

1000 24.74 22.09 17.50 15.20 13.86 13.92 24.47 28.80 32.78 38.44 26.39 26.36 29.91 34.07

(0.54) (3.91) (1.79) (0.84) (0.95) (0.82) (1.73) (1.07) (1.01) (0.79) (1.45) (0.95) (0.96) (1.51)

1500 35.15 32.50 24.61 20.46 19.39 18.60 33.51 34.43 40.15 42.23 32.38 32.41 34.57 36.00

(2.37) (3.11) (2.27) (1.02) (1.17) (0.90) (1.98) (1.45) (2.48) (1.34) (1.79) (1.88) (1.05) (0.89)

2000 39.27 40.48 31.94 25.65 22.75 20.65 42.55 40.17 43.11 43.75 42.98 39.56 39.80 41.07

(6.63) (7.97) (1.04) (1.42) (1.08) (0.89) (2.31) (0.89) (1.20) (1.51) (1.16) (1.13) (1.74) (2.01)

2500 30.87 34.51 31.55 28.61 23.95 21.24 45.83 45.24 45.26 46.70 43.07 44.20 44.42 45.74

(3.77) (13.7) (6.02) (1.03) (0.52) (0.85) (2.31) (1.92) (1.42) (1.00) (5.54) (1.40) (1.03) (1.65)

particles in their intact form (Fig. 1). The sameresults were demonstrated by Hess [14]. Hence, it islikely that the same compression force would bedistributed less evenly for lactose. The brittle par-ticles on the surface of lactose tablets are responsiblefor the cohesion of the tablet as well as the frictionbetween the tablet surface and the die wall. On theother hand, the fracture of DCP particles seems to bemore even on both the surface and in the cross-section. The strength of the cohesion forces and thebonding area of these fractured particles will be themain determining factor of the tablet strength ofDCP.

The presence of granulated materials will exertdifferent patterns of influence on tabletting for

Fig. 4. The effect of applied compression force on tensile strength lactose and DCP. Both ethylcellulose and Eudragitof tablets made with granules of (A) lactose and (B) DCP. The

RS/RL are film-forming materials and are expectedgranules were coated with polymers of ethylcellulose (s), Eud-to undergo plastic deformation during tabletting. Theragit RS 30D (h) and Eudragit RL 30D (n) at four different

amounts. plastic deformation will enhance the cohesion of

298 T. Tsai et al. / Journal of Controlled Release 51 (1998) 289 –299

particles resulting in an increase in tablet strength. under pressure, therefore, are a function of theThe plasticity of these materials is a function of the original excipient, the granulating material and theadded amount of plasticizer, which can be evaluated association between the excipient and the granulatingbased on its T (glass transition temperature). It has material. This is part of the reason why the granu-g

been shown that ethylcellulose possesses a higher T lated excipients have different tabletting characteris-g

than either Eudragit RS-30D or Eudragit RL-30D tics that probably would be more suitable than usingwhen the same plasticizer (TEC) was added at the the original excipients.same concentration (20%). T of the former is about The ability of these granulated excipients tog

358C and of the latter two, less or equal to 308C provide for controlled drug release was tested using a[7,15]. It is thus speculated that given the same highly water-soluble drug, captopril, as the modelconditions at room temperature, ethylcellulose would drug. A matrix tablet containing a fixed amount ofbe more glassy and a larger amount would be captopril (50 mg of drug/per 200 mg tablet) wasnecessary to provide sufficient cohesion by plastic compressed at a constant force of 1000 kg. Typicaldeformation. When a suitable range of compression dissolution profiles for selected examples producedforces are applied, the lactose formed would general- with both granulated lactose and DCP are presentedly show a decrease in friability with increasing in Fig. 5. It was found that the effect of Eudragit RLcompression force, since the extent of friction is only on retardation of the drug release was poor comparedmoderate. However, when lactose is subjected to to that using the other two materials at all granulat-higher compression forces, the brittle particulate ing levels. The release rate decreased with angenerated on the outermost area will exert more increase in granulating amount for both Eudragit RSfriction against the die wall. Without sufficient and ethylcellulose, but their effects were different onlubrication, the formation of capping tablets with a different excipients. Eudragit RS worked better forhigh percentage of friability after ejection is expected the drug release from DCP tablets, whereas ethylcel-if there is not enough cohesion to bind particlestogether. This speculation is supported by our findingthat the friability of lactose tablets, ungranulated orgranulated with less than 5% ethylcellulose, in-creased with an increase in the compression force.The reduction in tensile strength and the increase intablet thickness for these lactose tablets (ungranu-lated and granulated with less than 5% ethylcellul-ose) at higher compression forces also suggests thatthese tablets were weaker in strength than thoseproduced at an appropriate compression force.

Since Eudragit RS/RL possesses a lower T thang

ethylcellulose, the plasticity of the former two willbe higher than that of the latter. As a result, thegranulating amount of 2.5 and 5% Eudragit RS/RLwill provide enough cohesion to prevent the lactosetablets from capping when compressed at a higherpressure. Because DCP tablets cause less frictionagainst the die wall than lactose tablets, the cohesiveforce developed by the plastic deformation of thesecoated materials will be sufficient to bond particlestogether. As indicated, the strength of DCP tabletsincreases with increasing amounts of granulation.Also, the extent of the increase in tablet strength isparallel to the plasticity of the coated materials. The Fig. 5. The dissolution profiles of captopril from selected exam-overall mechanisms of the deformation for tablets ples of matrix tablets produced with granulated lactose and DCP.

T. Tsai et al. / Journal of Controlled Release 51 (1998) 289 –299 299

lulose showed a better control on the drug release National Science Council of ROC (NSC 83-0412-B-from these lactose tablets. Regardless, the effect of 038-005 and NSC 84-2331-C-038-001-B).granulated excipients on sustaining drug release wasdemonstrated in comparison with that from bothplain lactose and DCP tablets.

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