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Novel divisible tablet designs for sustained release formulations
179
Journal of Controlled Release, 14 (1990) 179-185 Elsevier Science Publishers B.V., Amsterdam
NOVEL DIVISIBLE
TABLET
DESIGNS
FOR SUSTAINED
RELEASE FORMULATIONS
A.C. Shah and N.J. Britten Drug Delivery Research and Development, (Received December
The Upjohn Company, 30 1 Henrietta Street, Kalamazoo, MI 4900 1 (U.S.A.)
18, 1989; accepted in revised form April 16, 1990)
Keywords: sustained release; divisible dose matrix tablets; lateral and transverse scores; minimum increase in new surface area; equivalent whole- and half-tablet release rates
Novel divisible tablet designs have been developed, which minimize the formation of new surface area upon division and thereby provide a means of administering a portion of the sustained release dose without appreciably altering the rate of drug release. A U.S. patent has been issued, claiming these divisible tablets for fractional dosing of sustained release medications [l]. Basic design features include lateral grooves on the top and bottom tablet surfaces at each line of division, which may be of variable depth, and a tablet shape that produces deep transverse grooves on the side of the tablet. Tablet shape, as well as the depth and angle of the dividing grooves, may be varied depending on the number of divisions desired, tablet size, weight, mechanical strength, and other formulation considerations. Distinctive features of oval bi-dosage tablets, oval tri-dosage tablets, and elliptical bi-dosage tablets are examined. Divisible oval bi-dosage sustained released 400 mg Motrin tablets were evaluated. Cleavage resulted in tablet segments containing half the dosage of the whole tablet (within < 0.2%). An increase in surface area, upon division, of only 2.49% was observed. In vitro drug release rates for the Motrin half tablets were essentially equivalent to those of the whole tablets.
INTRODUCTION The use of divisible tablets, with lateral grooves, for fractional dosing of conventional rapid release formulations is well established [2-81. The function of these lateral grooves is solely to facilitate tablet breakage. Since separation of conventional divisible tablets exposes a substantial amount of new surface area, these tablets are not suitable for multiple dosing of sustained release preparations. Divisible sustained release matrix tablet designs have been *To whom correspondence about this paper should be addressed.
016%3659/90/$03.50
0 1990 -
reported [ 91, but appreciable new surface is exposed upon tablet division, thus altering the drug release rate. Comparable sustained drug release rates for segments and whole tablets have been achieved by arranging the drug in longitudinal layers within the divisible tablet [lo]. The manufacturing methodology however, precludes its application to simple matrix tablets, or easy conversion of an existing single dose formulation to a multiple dose tablet. Although the literature contains a variety of divisible tablet designs for rapid and sustained release formulations, none have attempted effectively to minimize the amount of new surface area exposed upon division. Novel tablet
Elsevier Science Publishers B.V.
180
designs have been developed which minimize the new surface area created after division, providing tablet segments displaying drug release rates equivalent to those of the whole tablet. These designs may also be used for divisible sustained release tablets possessing a coating which partially or totally controls the rate of drug release. With conventional coated tablets, division results in fragments with fairly large portions of coating broken away, exposing unprotected surface which dissolves at a more or less uncontrolled rate. This report examines a number of divisible tablet designs. The preparation and evaluation of sustained release oval bi-dosage 400 mg Motrin tablets are also presented.
MATERIALS
AND METHODS
Ibuprofen used in this study was obtained from Boots Pharmaceutical Company (Nottingham, U.K.).
Tablet preparation
Tablet preparation consisted of the compression of 400 mg of ibuprofen in a bi-oval divisible tablet punch (3/16 stainless steel), on a Carver press, at 5000 p.s.i. for 60 s. Tablet dimensions were measured with a Simmonds Model 2000 micrometer. Dissolution
Dissolution
procedure
Dissolution studies were conducted in a medium of 0.05 M phosphate buffer, pH 7.2, temperature 37”C, and at a stirring speed of 300 rpm. Drug release rates were determined by spectrophotometric analysis, at 220 nm, of dissolved drug at 10 min intervals over an 8 h period. Studies were performed in duplicate for each batch of tablets. Data were plotted as the percentage of drug dissolved as a function of time.
RESULTS
AND DISCUSSION
Divisible tablet designs as described in this paper are applicable to sustained release formulations, including non-swelling matrix and coated tablets. A U.S. patent has recently been issued claiming these divisible tablet designs for fractional dosing of sustained release medicaments [ 11. Basic design features include lateral grooves on the top and bottom tablet surfaces, at each line of division, which may be of variable depth, and a tablet shape which produces deep transverse grooves on the side of the tablet. Design features can be utilized to prepare sustained release tablets which are divisible into any number of discrete segments. The shape of the individual segments and whole tablet, as well as the depth and angle of the dividing grooves, may be varied depending on the number of divisions desired per tablet, tablet size,
apparatus
Tablets were subjected to dissolution rate testing using an automated six place rotating filter-stationary basket system [ 111 a water bath with Tecam C-400 circulator, a 10 place Master Flex pump, a Perkin-Elmer Lambda 3 UV-Visible spectrophotometer, and an IBMAT computer.
Fig. 1. Oval bi-dosage tablet.
181
weight, mechanical strength, and other formulation considerations. An oval bi-dosage tablet is illustrated in Fig. 1. Transverse grooves A and B, and lateral grooves C and D, are set at a maximum angle and depth. A cross-sectional diagram, showing the rectangular new surface area created upon division of an oval bi-dosage tablet with constant groove depth, is presented in Fig. 2. Areas E and F, which would be exposed new surface area in conventional divisible tablets, are eliminated by the deep transverse grooves A and B. To further diminish the new surface area created after division, the depth of lateral grooves C and D may be varied along the tablet surface. Figure 3 details the new surface area generated on division of an oval bi-dosage tablet where the depth of grooves C and D is greatest at the tablet center. New surface area for a bi-dosage tablet with lateral grooves deepest at the tablet edges is pictured in Fig. 4. A maximum increase in surface area upon division of 8.66% (for both tablet halves) was calculated for the oval bidosage tablet. Constant lateral groove depth was assumed. Dimensions of the largest possible oval bi-dosage tablet and a representative tablet are specified in Table 1. Divisible sustained release 400 mg Motrin tablets were prepared by direct compaction of
IFUE I
f
\
Fig. 2. Cross-section constant
I
TABLE 1 Oval bi-dosage tablets Tablet dimensions Tablet dimensions for representative for maximum increase in surface examples area Diameter of circular half tablet segment Tablet thickness Lateral groove depth Transverse groove depth Lateral groove length Thickness at groove Whole tablet surface area Total new surface area
2.0 mm 6.0 mm 2.0 mm
Divisible
600 mm2 24.0 mm*
1105 mm* 95.7 mm2
Increase in surface area upon division (for both halves 1
TABLE
9.7 mm 5.0 mm
17.7 mm 7.5 mm 1.0 mm
4.00%
8.66%
2 sustained release 400 mg Motrin tablets
Half tablet radius Short diameter of half tablet
4.7752 mm 9.0246 mm
Tablet thickness
2.753 mm
Lateral groove length
5.00 mm
Lateral groove thickness Whole tablet surface area Total new surface area
1.00 mm 401.779 mm2 10.00 mm2
I
of divided oval bi-dosage
groove depth. Shaded portion
tablet with
is the new surface
Increase in surface area after division (for both
2.49%
halves)
area created upon division.
Fig. 3. Cross-section
of divided oval bi-dosage
tablet with
groove depth greatest at tablet center. Shaded portion new surface produced after division.
is
Fig. 4. Cross-section of divided oval bi-dosage tablet with grooves deepest at tablet edges. New surface is shaded.
ibuprofen in an oval bi-dosage punch. Selected tablets were manually separated along the line of division. A 400.00 mg tablet was divided into essentially equal segments of 199.63 mg and 200.16 mg. An increase in surface area upon division of 2.49% (for both halves) was calculated. Table 2 lists tablet measurements. Dissolution studies were conducted on whole and half tablet segments. As seen in Table 3, whole tablets and half tablet segments released
182 TABLE 3 Dissolution of divisible sustained release 400 mg Moth Time (min)
30 60 90 120 180 240 300 360
tablets
Percent drug dissolved Half Tablet Beaker1
Half Tablet Beaker2
Half Tablet Average
Whole Tablet Beaker3
Whole Tablet Beaker4
Whole Tablet Average
12.27 26.31 39.64 51.66 71.65 86.42 96.41 100.16
12.29 27.52 41.76 54.59 76.19 91.92 100.19 101.09
12.28 26.91 40.70 53.12 73.92 89.17 98.30 100.63
12.97 27.35 40.97 53.41 74.31 88.34 96.21 89.31
13.15 28.77 43.17 55.82 77.03 91.72 99.39 100.54
13.06 28.06 42.07 54.61 75.67 90.03 97.80 99.42
drug at a nearly constant rate for over 5 h. Good reproducibility is evident (Fig. 5), with little tablet to tablet variation. Average drug release profiles for the half and whole divisible 400 mg Motrin tablets are plotted in Fig. 6. Within experimental error, drug release rates for the Motrin half tablets are equivalent to those of the whole tablet. An oval tri-dosage tablet is shown in Fig. 7. Deep transverse grooves G, H, and I greatly re-
duce the amount of new surface area produced upon tablet division. Lateral grooves, on both sides of the tablet, are set at a maximum angle and depth. The depth of the lateral grooves may also be varied along the faces of the tablet to reduce the amount of new surface area. Figure 8 gives a cross-sectional representation of the new surface area found on division of an oval tri-dosage tablet with groove depth greatest at the tablet center. Area N, which would be exposed new surface area in conventional divisible tablets, is eliminated by deep transverse grooves G, H, and I. Areas M and 0, new surface area after separation of conventional tablets, are not present in our divisible tablets. A maximum increase in surface area upon division of 13.98% (for all three sections) was calculated for the oval tri-dosage tablet. A representative increase in surface area of 9.32% was also estimated. Constant lateral groove depth was assumed in both cases. Dimensions of the largest possible oval tri-dosage tablet and a representative example are furnished in Table 4. Elliptical bi-dosage tablet designs, with constant groove depth, may have either a rectan-
70.0 P 2 60.0 : 2 50.0 0 6 40.0 P Cl a 30.0
0.0 0.0
96.0
192.0
286.0
364.0
460.0
Time IminI
Fig. 5. Dissolution tablet, (---------)
profile
of individual
half tablet.
Motrin
whole
and half tablets:
(- - - ) whole
tablet,
(-.
- ) whole tablet,
(
) half
183
0.0 0.0
96.0
1 192.0 Time
Fig. 6.
Average drug release profiles
of Motrin
whole tablets
(-)
I 298.0
I 384.0
.
I 490.0
(mid
and half tablet
TABLE
(-------).
4
Oval tri-dosage tablets Tablet dimensions for maximum increase in surface area
Fig. 7. Oval tri-dosage
Fig. 8. Cross-section
tablet.
of divided oval tri-dosage
tablet with
groove depth greatest at tablet center. New surface is shaded.
gular or a circular new surface area upon tablet division. An elliptical bi-dosage tablet with a rectangular new surface area is depicted in Fig.
Largest diameter I/3 tablet segment 6.5 mm Tablet thickness 7.5 mm Radius of each l/3 circular section 3.5 mm Lateral groove 2.25 mm depth Thickness at lateral grooves 3.0 mm Whole tablet surface 495 mm’ area Total new surface area 69.2 mm2 Increase in surface area upon division (for all three sections)
13.98%
Tablet dimensions for representative example
6.5 mm 1.5 mm 3.5 mm 2.75 mm
2.0 mm 495 mm2
46.1 mm2 9.32%
TABLE Elliptical
Fig. 9. Elliptical
bi-dosage
tablet with rectangular
5 bi-dosage tablets with rectangular new surface Tablet dimensions for maximum increase in surface area
new sur-
face area.
Fig. 10. Cross-section of divided elliptical bi-dosage tablet with constant groove depth. Shaded portion is new surface.
Fig. 11. Cross-section
of divided elliptical
with groove depth greatest
at tablet
bi-dosage
center.
tablet
New surface
Whole tablet length Width and diameter of l/2 tablet Lateral groove depth Transverse groove depth Whole tablet surface area Total new surface area Increase in surface area upon division (for both halves )
15.0 mm
Tablet dimensions for representative example
15.0 mm
6.35 mm 1.0 mm
6.35 mm 1.5 mm
1.0 mm
1.5 mm
299 mm2 37.9 mm* 12.7%
299 mm2 2.5 mm* 7.50%
created is shaded. TABLE Elliptical
6 bi-dosage tablets with circular new surface Tablet dimensions for maximum increase in surface area
Fig. 12. Elliptical
bi-dosage
tablet with circular
new surface
area.
Fig. 13. Cross-section Shaded portion
of divided elliptical
bi-dosage
tablet.
is new surface.
9. Figure 10 shows the rectangular new surface created after division for a tablet with constant lateral groove depth. As seen in Fig. 11, a bow tie shaped new surface is produced when the lateral groove depth is greatest at the middle of the tablet. Figures 12 and 13 illustrate an elliptical bi-dosage tablet having a circular new surface on tablet separation. Tables 5 and 6, respectively, give the dimensions for elliptical bidosage tablets with rectangular and circular new
Whole tablet length Width and diameter of l/2 tablet Groove depth Length of center section Whole tablet surface area Total new surface area Increase in surface area upon division (for both halves )
15.0 mm
Tablet dimensions for representative example
15.0 mm
6.35 mm 1.0 mm
6.35 mm 1.425 mm
4.0 mm
4.0 mm
294 mm2 29.7 mm2 10.1%
327 mm2 19.2 mm2 5.88%
surfaces. A maximum increase in surface area upon division of 12.7% (for both halves) and a representative increase of 7.50% were calculated for an elliptical bi-dosage tablet with rectangular new surface area. The elliptical bidosage tablet having a circular new surface yielded a 10.1% maximum increase and an ex-
185
emplary increase in new surface area of 5.88%. The use of divisible tablet designs described in this paper should provide a simple, reliable, cost effective means for precise fractional dosing of many sustained release medications.
3 4
5 6 7
ACKNOWLEDGEMENTS 8
The authors would like to acknowledge the assistance of Joseph Badalamenti and Dan Martin in the manufacture of the oval bi-dosage tablet punch.
9
10
REFERENCES 11 1
2
A.C. Shah, N.J. Britten and J.N. Badalamenti, Grooved tablets for fractional dosing of sustained release medications, U.S. Patent 4,824,677,1989. Ives Laboratories, Deeply grooved tablets formulation for easy breaking into predetermined portions, U.S. Patent 3,883,647, 1972.
Union Chimique-Chemische Bedrijven, Pharmaceutical tablets, Dutch Patent 294,190,1964. Ives Laboratories, Easily divisible tablet for obtaining correct dosage - with a groove in flat surface and a convex opposite surface, U.K. Patent 1,368,574,1971. T.L. Cooper, Tablets, German Patent 1,200,790,1961. A.G. Geigy, Tablet with a breaking groove, N.E. Patent 68,16240,1967. Ciba-Geigy, Maltese-cross scored tablet of medicament, U.S. Patent 3,723,614-5, 1968. Mead Johnson Company, Accurately divisible tablet - scores in top and bottom sides for breaking into two or three pieces, U.S. Patent 4,215,104, 1979. Bristol Myers Company, Theophylline tablet giving prolonged releaseover 12 hours, U.S. Patent 4,249,787, 1980. Ciba-Geigy, Divisible tablet having controlled and delayed release of the active substance, U.S. Patent 4,353,887,1981. A.C. Shah, C.B. Peot and J.F. Ochs, Design and evaluation of a rotating filter-stationary basket in uitro dissolution of test apparatus. I. Fixed fluid volume system, J. Pharm. Sci., 62 (1973) 671.
Journal of Controlled Release, 14 (1990) 179-185 Elsevier Science Publishers B.V., Amsterdam
NOVEL DIVISIBLE
TABLET
DESIGNS
FOR SUSTAINED
RELEASE FORMULATIONS
A.C. Shah and N.J. Britten Drug Delivery Research and Development, (Received December
The Upjohn Company, 30 1 Henrietta Street, Kalamazoo, MI 4900 1 (U.S.A.)
18, 1989; accepted in revised form April 16, 1990)
Keywords: sustained release; divisible dose matrix tablets; lateral and transverse scores; minimum increase in new surface area; equivalent whole- and half-tablet release rates
Novel divisible tablet designs have been developed, which minimize the formation of new surface area upon division and thereby provide a means of administering a portion of the sustained release dose without appreciably altering the rate of drug release. A U.S. patent has been issued, claiming these divisible tablets for fractional dosing of sustained release medications [l]. Basic design features include lateral grooves on the top and bottom tablet surfaces at each line of division, which may be of variable depth, and a tablet shape that produces deep transverse grooves on the side of the tablet. Tablet shape, as well as the depth and angle of the dividing grooves, may be varied depending on the number of divisions desired, tablet size, weight, mechanical strength, and other formulation considerations. Distinctive features of oval bi-dosage tablets, oval tri-dosage tablets, and elliptical bi-dosage tablets are examined. Divisible oval bi-dosage sustained released 400 mg Motrin tablets were evaluated. Cleavage resulted in tablet segments containing half the dosage of the whole tablet (within < 0.2%). An increase in surface area, upon division, of only 2.49% was observed. In vitro drug release rates for the Motrin half tablets were essentially equivalent to those of the whole tablets.
INTRODUCTION The use of divisible tablets, with lateral grooves, for fractional dosing of conventional rapid release formulations is well established [2-81. The function of these lateral grooves is solely to facilitate tablet breakage. Since separation of conventional divisible tablets exposes a substantial amount of new surface area, these tablets are not suitable for multiple dosing of sustained release preparations. Divisible sustained release matrix tablet designs have been *To whom correspondence about this paper should be addressed.
016%3659/90/$03.50
0 1990 -
reported [ 91, but appreciable new surface is exposed upon tablet division, thus altering the drug release rate. Comparable sustained drug release rates for segments and whole tablets have been achieved by arranging the drug in longitudinal layers within the divisible tablet [lo]. The manufacturing methodology however, precludes its application to simple matrix tablets, or easy conversion of an existing single dose formulation to a multiple dose tablet. Although the literature contains a variety of divisible tablet designs for rapid and sustained release formulations, none have attempted effectively to minimize the amount of new surface area exposed upon division. Novel tablet
Elsevier Science Publishers B.V.
180
designs have been developed which minimize the new surface area created after division, providing tablet segments displaying drug release rates equivalent to those of the whole tablet. These designs may also be used for divisible sustained release tablets possessing a coating which partially or totally controls the rate of drug release. With conventional coated tablets, division results in fragments with fairly large portions of coating broken away, exposing unprotected surface which dissolves at a more or less uncontrolled rate. This report examines a number of divisible tablet designs. The preparation and evaluation of sustained release oval bi-dosage 400 mg Motrin tablets are also presented.
MATERIALS
AND METHODS
Ibuprofen used in this study was obtained from Boots Pharmaceutical Company (Nottingham, U.K.).
Tablet preparation
Tablet preparation consisted of the compression of 400 mg of ibuprofen in a bi-oval divisible tablet punch (3/16 stainless steel), on a Carver press, at 5000 p.s.i. for 60 s. Tablet dimensions were measured with a Simmonds Model 2000 micrometer. Dissolution
Dissolution
procedure
Dissolution studies were conducted in a medium of 0.05 M phosphate buffer, pH 7.2, temperature 37”C, and at a stirring speed of 300 rpm. Drug release rates were determined by spectrophotometric analysis, at 220 nm, of dissolved drug at 10 min intervals over an 8 h period. Studies were performed in duplicate for each batch of tablets. Data were plotted as the percentage of drug dissolved as a function of time.
RESULTS
AND DISCUSSION
Divisible tablet designs as described in this paper are applicable to sustained release formulations, including non-swelling matrix and coated tablets. A U.S. patent has recently been issued claiming these divisible tablet designs for fractional dosing of sustained release medicaments [ 11. Basic design features include lateral grooves on the top and bottom tablet surfaces, at each line of division, which may be of variable depth, and a tablet shape which produces deep transverse grooves on the side of the tablet. Design features can be utilized to prepare sustained release tablets which are divisible into any number of discrete segments. The shape of the individual segments and whole tablet, as well as the depth and angle of the dividing grooves, may be varied depending on the number of divisions desired per tablet, tablet size,
apparatus
Tablets were subjected to dissolution rate testing using an automated six place rotating filter-stationary basket system [ 111 a water bath with Tecam C-400 circulator, a 10 place Master Flex pump, a Perkin-Elmer Lambda 3 UV-Visible spectrophotometer, and an IBMAT computer.
Fig. 1. Oval bi-dosage tablet.
181
weight, mechanical strength, and other formulation considerations. An oval bi-dosage tablet is illustrated in Fig. 1. Transverse grooves A and B, and lateral grooves C and D, are set at a maximum angle and depth. A cross-sectional diagram, showing the rectangular new surface area created upon division of an oval bi-dosage tablet with constant groove depth, is presented in Fig. 2. Areas E and F, which would be exposed new surface area in conventional divisible tablets, are eliminated by the deep transverse grooves A and B. To further diminish the new surface area created after division, the depth of lateral grooves C and D may be varied along the tablet surface. Figure 3 details the new surface area generated on division of an oval bi-dosage tablet where the depth of grooves C and D is greatest at the tablet center. New surface area for a bi-dosage tablet with lateral grooves deepest at the tablet edges is pictured in Fig. 4. A maximum increase in surface area upon division of 8.66% (for both tablet halves) was calculated for the oval bidosage tablet. Constant lateral groove depth was assumed. Dimensions of the largest possible oval bi-dosage tablet and a representative tablet are specified in Table 1. Divisible sustained release 400 mg Motrin tablets were prepared by direct compaction of
IFUE I
f
\
Fig. 2. Cross-section constant
I
TABLE 1 Oval bi-dosage tablets Tablet dimensions Tablet dimensions for representative for maximum increase in surface examples area Diameter of circular half tablet segment Tablet thickness Lateral groove depth Transverse groove depth Lateral groove length Thickness at groove Whole tablet surface area Total new surface area
2.0 mm 6.0 mm 2.0 mm
Divisible
600 mm2 24.0 mm*
1105 mm* 95.7 mm2
Increase in surface area upon division (for both halves 1
TABLE
9.7 mm 5.0 mm
17.7 mm 7.5 mm 1.0 mm
4.00%
8.66%
2 sustained release 400 mg Motrin tablets
Half tablet radius Short diameter of half tablet
4.7752 mm 9.0246 mm
Tablet thickness
2.753 mm
Lateral groove length
5.00 mm
Lateral groove thickness Whole tablet surface area Total new surface area
1.00 mm 401.779 mm2 10.00 mm2
I
of divided oval bi-dosage
groove depth. Shaded portion
tablet with
is the new surface
Increase in surface area after division (for both
2.49%
halves)
area created upon division.
Fig. 3. Cross-section
of divided oval bi-dosage
tablet with
groove depth greatest at tablet center. Shaded portion new surface produced after division.
is
Fig. 4. Cross-section of divided oval bi-dosage tablet with grooves deepest at tablet edges. New surface is shaded.
ibuprofen in an oval bi-dosage punch. Selected tablets were manually separated along the line of division. A 400.00 mg tablet was divided into essentially equal segments of 199.63 mg and 200.16 mg. An increase in surface area upon division of 2.49% (for both halves) was calculated. Table 2 lists tablet measurements. Dissolution studies were conducted on whole and half tablet segments. As seen in Table 3, whole tablets and half tablet segments released
182 TABLE 3 Dissolution of divisible sustained release 400 mg Moth Time (min)
30 60 90 120 180 240 300 360
tablets
Percent drug dissolved Half Tablet Beaker1
Half Tablet Beaker2
Half Tablet Average
Whole Tablet Beaker3
Whole Tablet Beaker4
Whole Tablet Average
12.27 26.31 39.64 51.66 71.65 86.42 96.41 100.16
12.29 27.52 41.76 54.59 76.19 91.92 100.19 101.09
12.28 26.91 40.70 53.12 73.92 89.17 98.30 100.63
12.97 27.35 40.97 53.41 74.31 88.34 96.21 89.31
13.15 28.77 43.17 55.82 77.03 91.72 99.39 100.54
13.06 28.06 42.07 54.61 75.67 90.03 97.80 99.42
drug at a nearly constant rate for over 5 h. Good reproducibility is evident (Fig. 5), with little tablet to tablet variation. Average drug release profiles for the half and whole divisible 400 mg Motrin tablets are plotted in Fig. 6. Within experimental error, drug release rates for the Motrin half tablets are equivalent to those of the whole tablet. An oval tri-dosage tablet is shown in Fig. 7. Deep transverse grooves G, H, and I greatly re-
duce the amount of new surface area produced upon tablet division. Lateral grooves, on both sides of the tablet, are set at a maximum angle and depth. The depth of the lateral grooves may also be varied along the faces of the tablet to reduce the amount of new surface area. Figure 8 gives a cross-sectional representation of the new surface area found on division of an oval tri-dosage tablet with groove depth greatest at the tablet center. Area N, which would be exposed new surface area in conventional divisible tablets, is eliminated by deep transverse grooves G, H, and I. Areas M and 0, new surface area after separation of conventional tablets, are not present in our divisible tablets. A maximum increase in surface area upon division of 13.98% (for all three sections) was calculated for the oval tri-dosage tablet. A representative increase in surface area of 9.32% was also estimated. Constant lateral groove depth was assumed in both cases. Dimensions of the largest possible oval tri-dosage tablet and a representative example are furnished in Table 4. Elliptical bi-dosage tablet designs, with constant groove depth, may have either a rectan-
70.0 P 2 60.0 : 2 50.0 0 6 40.0 P Cl a 30.0
0.0 0.0
96.0
192.0
286.0
364.0
460.0
Time IminI
Fig. 5. Dissolution tablet, (---------)
profile
of individual
half tablet.
Motrin
whole
and half tablets:
(- - - ) whole
tablet,
(-.
- ) whole tablet,
(
) half
183
0.0 0.0
96.0
1 192.0 Time
Fig. 6.
Average drug release profiles
of Motrin
whole tablets
(-)
I 298.0
I 384.0
.
I 490.0
(mid
and half tablet
TABLE
(-------).
4
Oval tri-dosage tablets Tablet dimensions for maximum increase in surface area
Fig. 7. Oval tri-dosage
Fig. 8. Cross-section
tablet.
of divided oval tri-dosage
tablet with
groove depth greatest at tablet center. New surface is shaded.
gular or a circular new surface area upon tablet division. An elliptical bi-dosage tablet with a rectangular new surface area is depicted in Fig.
Largest diameter I/3 tablet segment 6.5 mm Tablet thickness 7.5 mm Radius of each l/3 circular section 3.5 mm Lateral groove 2.25 mm depth Thickness at lateral grooves 3.0 mm Whole tablet surface 495 mm’ area Total new surface area 69.2 mm2 Increase in surface area upon division (for all three sections)
13.98%
Tablet dimensions for representative example
6.5 mm 1.5 mm 3.5 mm 2.75 mm
2.0 mm 495 mm2
46.1 mm2 9.32%
TABLE Elliptical
Fig. 9. Elliptical
bi-dosage
tablet with rectangular
5 bi-dosage tablets with rectangular new surface Tablet dimensions for maximum increase in surface area
new sur-
face area.
Fig. 10. Cross-section of divided elliptical bi-dosage tablet with constant groove depth. Shaded portion is new surface.
Fig. 11. Cross-section
of divided elliptical
with groove depth greatest
at tablet
bi-dosage
center.
tablet
New surface
Whole tablet length Width and diameter of l/2 tablet Lateral groove depth Transverse groove depth Whole tablet surface area Total new surface area Increase in surface area upon division (for both halves )
15.0 mm
Tablet dimensions for representative example
15.0 mm
6.35 mm 1.0 mm
6.35 mm 1.5 mm
1.0 mm
1.5 mm
299 mm2 37.9 mm* 12.7%
299 mm2 2.5 mm* 7.50%
created is shaded. TABLE Elliptical
6 bi-dosage tablets with circular new surface Tablet dimensions for maximum increase in surface area
Fig. 12. Elliptical
bi-dosage
tablet with circular
new surface
area.
Fig. 13. Cross-section Shaded portion
of divided elliptical
bi-dosage
tablet.
is new surface.
9. Figure 10 shows the rectangular new surface created after division for a tablet with constant lateral groove depth. As seen in Fig. 11, a bow tie shaped new surface is produced when the lateral groove depth is greatest at the middle of the tablet. Figures 12 and 13 illustrate an elliptical bi-dosage tablet having a circular new surface on tablet separation. Tables 5 and 6, respectively, give the dimensions for elliptical bidosage tablets with rectangular and circular new
Whole tablet length Width and diameter of l/2 tablet Groove depth Length of center section Whole tablet surface area Total new surface area Increase in surface area upon division (for both halves )
15.0 mm
Tablet dimensions for representative example
15.0 mm
6.35 mm 1.0 mm
6.35 mm 1.425 mm
4.0 mm
4.0 mm
294 mm2 29.7 mm2 10.1%
327 mm2 19.2 mm2 5.88%
surfaces. A maximum increase in surface area upon division of 12.7% (for both halves) and a representative increase of 7.50% were calculated for an elliptical bi-dosage tablet with rectangular new surface area. The elliptical bidosage tablet having a circular new surface yielded a 10.1% maximum increase and an ex-
185
emplary increase in new surface area of 5.88%. The use of divisible tablet designs described in this paper should provide a simple, reliable, cost effective means for precise fractional dosing of many sustained release medications.
3 4
5 6 7
ACKNOWLEDGEMENTS 8
The authors would like to acknowledge the assistance of Joseph Badalamenti and Dan Martin in the manufacture of the oval bi-dosage tablet punch.
9
10
REFERENCES 11 1
2
A.C. Shah, N.J. Britten and J.N. Badalamenti, Grooved tablets for fractional dosing of sustained release medications, U.S. Patent 4,824,677,1989. Ives Laboratories, Deeply grooved tablets formulation for easy breaking into predetermined portions, U.S. Patent 3,883,647, 1972.
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