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Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus
J. DRUG DEL. SCI. TECH., 20 (5) 377-383 2010
Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus T. Harada1*, R. Narazaki2, T. Ohwaki3, T. Uchida4 Eisai Co., Ltd., CEO Office, Planning & Operations Section, Customer Joy Department, Koishikawa 5-5-5, Bunkyo-Ku, Tokyo 112-8088, Japan 2 Eisai Co., Ltd., Formulation Research, CMC Japan, Pharmaceutical Science and Technology CFU, 1 Kawashimatakehaya-machi, Kakamigahara City, Gifu 501-6195, Japan 3 Eisai Co., Ltd., CEO Office, Drug Development Technology Center, Customer Joy Department, 1 Kawashimatakehaya-machi, Kakamigahara City, Gifu 501-6195, Japan 4 School of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien 9-Bancho, Nishinomiya-shi, Hyogo 663-8197, Japan *Correspondence: [email protected] 1
The purpose of this study was to evaluate the usefulness of a new disintegration testing apparatus, ODT-101, and to investigate the effects of the physical properties of orally disintegrating tablets (ODTs) on their disintegration time. We prepared ODTs of different weights and diameters at different tabletting pressures using an excipient Ludiflash. Disintegration times were measured by human sensory evaluation and using the ODT101. The disintegration time measured by the ODT-101 was found to be in good agreement with that measured in the oral cavity. Disintegration time was found to be a function of porosity and weight, regardless of ODT shape, and to be an exponential function of the hardness of the ODT. In conclusion, ODT-101 testing is accurate enough to be a substitute for sensory evaluation and the hardness of the ODT is a good marker for disintegration time. Key words: Orally disintegrating tablet – Disintegration time – Disintegration testing apparatus – ODT-101 – Ludiflash – Porosity – Tensile strength – Tablet hardness.
Orally disintegrating tablets (ODTs) are designed to be easily taken without water, even by elderly people with swallowing difficulties. This requires ODTs to have a range of different properties: they must be capable of rapidly disintegrating in the oral cavity while being strong enough to resist breakage, cracking, and defacement on distribution, dispensing, or opening of PTPs. In addition, if the active ingredient has a bitter (unpleasant) taste, taste masking is required. With such high formulation requirements, ODT design and manufacturing technology are often critical. The FDA introduced guidance for ODTs [1] in 2008. However, the guidance merely recommended that the in vitro disintegration time, a key factor, should be approximately 30 s or less, based on the United States Pharmacopeia (USP). Regulations and details of methods for measuring disintegration time of ODTs were not specified. There are some reports of methods for measuring disintegration time of ODTs [2-5]. However, in these methods, the quantity of test medium is greatly in excess of the volume of the oral cavity and the shear force on the ODT is not loaded. Consequently, the results do not always accurately reflect disintegration time in the oral cavity. We have developed a prototype disintegration testing apparatus in which a small quantity of test medium can be used in a volume similar to that of the oral cavity and shear forces can be modified to reflect the conditions within the oral cavity [6, 7]. In this report, the ability of a further improved oral disintegration apparatus to reflect human oral disintegration time is described. The influence of different physical properties of ODTs manufactured under different conditions on disintegration time are investigated, and the mechanism of disintegration is discussed. There are many patents on additives and manufacturing techniques for ODTs by the direct compression method, but insufficient reports on the use of such additives and techniques [8-10]. Although there are some reports on the mechanism of tablet disintegration and the relationship between disintegration time and manufacturing conditions [11-18], the effects
of physical properties, such as tablet weight, diameter, and thickness, on disintegration time have not been described in detail. The present report also considers these aspects of ODT development.
I. Materials and methods 1. Materials
Ludiflash and magnesium stearate (Mallinckrodt Pharmaceuticals) were used in this study. Ludiflash is a granulated product developed by BASF for production of ODTs by the direct tabletting method. Table I shows the composition of Ludiflash. Mannitol is a diluent base. Crospovidone is added as a disintegrant and sodium dodecyl sulfate as a surface-acting agent. Granulation is carried out using polyvinyl acetate. The composition is designed to achieve excellent fluidity and disintegratability. Table I - Composition of Ludiflash. Composition
Ratio ( %)
D-Mannitol Crospovidone Polyvinyl acetate Polyvinylpyrrolidone Sodium dodecyl sulfate
90.0 5.0 4.5 0.45 0.05
2. Methods
2.1. Preparation of the ODTs The formulation employed in this study is 99 % Ludiflash with 1 % magnesium stearate as a lubricant. Lubrication was carried out using a tumbler mixer (Toyo Packing Co., Ltd.) and tabletting was carried out in a dual-pressurized single-punch tabletting machine (N-30E, Okada Seiko Co., Ltd.). Samples were manufactured with different tablet weights, tablet diameters, and tabletting pressures. The relationship between the disintegration times and physical properties was examined. The production conditions are given in Table II. 377
Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus T. Harada, R. Narazaki, T. Ohwaki, T. Uchida
J. DRUG DEL. SCI. TECH., 20 (5) 377-383 2010
Table II - Manufacturing conditions. Parameter Weight of tablet (mg) Diameter of Punch (mm) Tableting Force (kN)
(a)
Condition 80 6 3
120 7 5
160 8 7
Vertically movable rotating shaft (1) Pump
Drop down
Weight (2)
Compression force
ODT
Guide frame
2.2. Measurement of in vitro disintegration time An ODT testing apparatus ODT-101 (manufactured by Toyama Sangyo Co., Ltd.) was used to evaluate the disintegration time (Tin vitro) of ODTs. This apparatus was prepared by modifying a previously reported [7] apparatus to allow automatic adjustment of the water level of the test medium. Figure 1a shows an illustration of the core structure of the ODT-101. An ODT sample is placed on a stainless-steel porous plate. Weight (2) is provided to the shaft (1) which is capable of moving in the vertical direction and rotating. Before initiating the measurement, the shaft is located above the plate in order to avoid contact between the weight and the ODT. The liquid surface of the test medium (450 mL purified water) is automatically adjusted by a pump so that the water level is slightly below the lower face of the porous plate. Therefore, the ODT does not come into contact with the test medium until the start of measurement. The liquid temperature is set to 37 °C. In this study, a 15-g weight was attached to a shaft and the shaft rotation rate was set at 25 rpm. When the measurement start button is pressed, the shaft goes down. The ODT is sandwiched between the rotating weight and the porous plate such that the load and shear force can be applied to the ODT (disintegration time T = 0). Simultaneously, the block (3) is immersed in the test medium and the water level of the test medium increases. In our previous report [6, 7], the lower part of the ODT was immersed when the porous plate was bent down by the weight. In comparison, in this study the porous plate was kept flat and only the lower face of the ODT was in contact with the test medium. Thus the ODT absorbed the test medium by capillary suction, resulting in disintegration. The effects of load, shear, and wetting, reproduce the conditions in the oral cavity in which an ODT becomes wet with saliva and is lightly ground between the tongue and the upper jaw. Figure 1b shows the mechanism of detection of ODT disintegration. A weight is attached to the shaft such that the weight can freely move in the vertical direction by several millimeters. A sponge is attached to the centre portion of the lower face of the weight, allowing the ODT to rotate without slipping. The outer circumference of the sponge is covered with a conductive metal. The porous plate (punch hole diameter 1 mm; pitch 1.5 mm; thickness 0.1 mm), on which the ODT is placed, is composed of two halves such that electrical resistance between the right and left sides can be measured. When an ODT disintegrates and the resulting slurry particles pass through the porous plate and fall into the test medium, the weight comes into contact with the porous plates, which results in an instantaneous change in electrical resistance between the right and left sides. As a result, ODT disintegration can be detected. The disintegration time is automatically recorded to 1/100th second. In this study, measurement was repeated five times and the average of the five values taken as the disintegration time.
Separated stainless steel plates with multihole
Medium
(b)
Rotating shaft
Vertically movable
Weight Conductive metal Sponge
Separated stainless steel plates
Punched holes L R
L R
Electrodes
Switch to the conducting state between L and R
Figure 1 - Diagram of the new apparatus for measuring the disintegration time of orally disintegrating tablets (ODT-101). (a) The core structure of the ODT-101. (b) A mechanism of detection of ODT disintegration.
freely move the ODT with the tongue. They were not permitted to swallow saliva during the test, 4) when the volunteer noticed the disappearance of the ODT on the tongue, the stopwatch was immediately stopped and the disintegration time was recorded, 5) after the test, the disintegrated ODT was completely spat out and the oral cavity rinsed well, 6) the average of three evaluations was taken as the measurement value. 2.4. Thickness ODT thickness was measured five times with a digital thickness meter (Mitutoyo Co., Ltd., Japan). 2.5. Hardness ODT hardness was the average of five measurement values obtained by applying load along the diameter using a Kiya-type digital hardness tester (Fujiwara Scientific Co., Ltd.). 2.6. Tensile strength Tensile strength (St) was calculated using the following equation [19, 20] where ODT diameter is D, thickness t, and hardness H:
2.3. Sensory evaluation of disintegration time in the oral cavity In vivo disintegration time was measured with the cooperation of five healthy male volunteers. Prior to the test, the test purposes and compositions of samples were explained to the volunteers and informed consent was obtained on paper. The measurement conditions are described below: 1) the oral cavity was rinsed with water before each test, 2) an ODT was placed on the tongue and at the same time the start button of a stopwatch was pushed, 3) volunteers were prohibited from chewing the ODT but allowed to
St = 2H/πDt
Eq. 1
2.7. Porosity Porosity (ε) was calculated using the following equation based on ODT weight (W), diameter, thickness, and particle true density (rt). ε = 1 - [4W/πD2trt] 378
Eq. 2
Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus T. Harada, R. Narazaki, T. Ohwaki, T. Uchida
J. DRUG DEL. SCI. TECH., 20 (5) 377-383 2010
rt was the true density of Ludiflash (1.4748 mg/mm3 measured by BASF), because the percentage of magnesium stearate (1 %) was considered small enough to be ignored.
II. Results and discussion
Table III (formulations 1-27) shows the physical properties of ODTs produced under the tabletting conditions shown in Table II. The effects of the respective tabletting conditions and physical properties on disintegration time shown in the Table are discussed below.
1. In vivo and in vitro correlations
Figure 2 shows the correlations between the results of the sensory evaluation (Tin vivo) and the measurement values using the ODT-101 (Tin vitro). The Tin vitro values are slightly larger than the Tin vivo, but the correlation coefficient between the values is 0.99. This shows that the sensory evaluation can be replaced by the disintegration test using the new apparatus ODT-101. In the pharmacopeial disintegration test, disintegration time is sometimes longer than the oral disintegration time or value of the ODT-101 [7], as no appreciable mechanical shear force is applied to an ODT. In addition, it has been reported that disintegration times one fifth of the actual oral disintegration time, have been obtained using a pharmacopeial apparatus [12]. Therefore, we used the disintegration times obtained using the ODT-101 for analyses and discussions in this paper.
Figure 2 - Relationship between the disintegration time Tin vitro measured by the ODT-101 and the disintegration time Tin vivo in the oral cavity of the ODTs made with Ludiflash. Values are mean ± SD; Tin vitro = 1.1095 Tin vivo; R = 0.990.
Table III - Technological characterization of ODTs. Formulation No.
Diameter (mm)
Tabletting force (kN)
Tabletting pressure (MPa)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 8.0 8.0 8.0 8.0 8.0 8.0 8.0 8.0 8.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 6.0 8.0 9.0
3 5 7 3 5 7 3 5 7 3 5 7 3 5 7 3 5 7 3 5 7 3 5 7 3 5 7 7.5 5.9 4.8 4.3 4.2 3.9 3.8 3.0 4.5 5.0
104.0 173.3 242.6 104.0 173.3 242.6 104.0 173.3 242.6 76.4 127.3 178.3 76.4 127.3 178.3 76.4 127.3 178.3 58.5 97.5 136.5 58.5 97.5 136.5 58.5 97.5 136.5 191.0 150.2 122.2 109.5 107.0 99.3 96.8 104.0 87.7 77.0
Weight mg
CV
77.0 77.6 77.8 122.2 122.6 122.4 159.1 159.4 159.5 78.8 78.3 78.2 122.6 122.1 121.6 160.3 159.9 159.6 80.8 80.3 79.7 119.1 118.9 118.5 160.7 159.5 158.3 73.2 86.0 106.8 134.9 150.7 173.7 201.9 99.3 175.6 218.2
(0.52) (0.87) (0.67) (0.73) (0.62) (0.57) (0.52) (0.45) (0.57) (0.59) (0.70) (0.46) (1.04) (0.38) (0.74) (0.83) (0.53) (0.65) (1.24) (1.69) (1.05) (0.46) (0.87) (0.61) (0.79) (0.63) (1.06) (0.85) (0.84) (0.54) (0.69) (0.56) (0.36) (0.37) (0.69) (0.52) (0.85)
Thickness (mm) 2.31 2.20 2.12 3.56 3.36 3.28 4.66 4.34 4.24 1.82 1.72 1.67 2.77 2.58 2.50 3.59 3.38 3.23 1.52 1.42 1.36 2.21 2.05 1.95 2.98 2.76 2.62 1.55 1.90 2.34 2.97 3.31 3.90 4.55 2.89 3.00 2.95
379
Hardness N
CV
29.1 58.7 76.2 52.5 96.0 112.6 68.3 119.9 156.1 21.6 34.7 49.6 34.3 56.7 78.0 43.5 76.3 106.3 12.1 23.5 32.7 18.6 35.5 52.6 22.0 40.6 56.1 49.2 48.9 48.2 48.8 49.3 45.6 45.8 47.4 49.8 44.5
(0.12) (0.05) (0.17) (0.15) (0.10) (0.32) (0.09) (0.32) (0.34) (0.13) (0.06) (0.09) (0.08) (0.13) (0.09) (0.15) (0.17) (0.16) (0.30) (0.07) (0.05) (0.08) (0.09) (0.09) (0.12) (0.09) (0.12) (0.09) (0.06) (0.05) (0.09) (0.14) (0.14) (0.23) (0.17) (0.05) (0.05)
Tensile strength (MPa)
Porosity (-)
1.34 2.83 3.81 1.56 3.03 3.65 1.56 2.93 3.90 1.08 1.83 2.69 1.13 2.00 2.84 1.10 2.06 2.99 0.63 1.31 1.92 0.67 1.38 2.15 0.59 1.17 1.70 2.89 2.35 1.88 1.50 1.35 1.06 0.92 1.74 1.32 1.07
0.20 0.15 0.12 0.18 0.13 0.10 0.18 0.12 0.10 0.24 0.20 0.18 0.22 0.17 0.14 0.21 0.17 0.13 0.28 0.24 0.21 0.27 0.22 0.18 0.27 0.22 0.19 0.17 0.20 0.19 0.20 0.20 0.21 0.22 0.18 0.21 0.21
Disintegration time in oral cavity (s)
by ODT101 (s)
14.5 25.6 57.0 27.0 58.4 115.9 27.4 84.0 138.9 9.6 13.0 18.9 15.0 22.8 36.9 18.4 30.8 60.9 9.1 8.0 10.3 10.9 13.4 17.5 14.6 16.8 20.4 21.5 19.8 19.4 21.0 25.4 25.2 23.3 17.4 19.5 20.2
19.2 28.0 58.5 33.4 60.4 130.7 37.0 81.7 153.8 12.5 14.1 28.5 24.4 28.1 40.8 34.6 42.1 59.3 10.7 13.1 14.2 14.1 19.9 30.1 20.6 24.9 28.9 19.6 15.2 19.3 22.2 20.1 25.8 27.6 19.0 23.4 27.0
Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus T. Harada, R. Narazaki, T. Ohwaki, T. Uchida
J. DRUG DEL. SCI. TECH., 20 (5) 377-383 2010
2. Effects of thickness on disintegration time
(a)
Figure 3 shows the relationship between the disintegration time and thickness of ODTs at diameters of 6, 7 and 8 mm. The results show that the disintegration time is almost proportional to ODT thickness. Figure 3 also shows that the slope of the regression line tends to be greater as the tabletting pressure becomes higher. Crospovidone, a component of Ludiflash, increases the porosity of the ODT when it comes into contact with water and becomes swollen. Crospovidone is a disintegrant with a wicking mechanism in which the capillary suction force of the pores of an ODT allows water to infiltrate deeply into the tablet, resulting in disintegration [14]. During the disintegration test using the ODT-101, only the lower face of the ODT is in contact with the test medium, and ODT disintegration is completed when water reaches the upper face of the ODT, T seconds after water penetration through the bottom face. The water penetration time, T, in a powder layer is represented by the following equation of Peek et al. [21]: T = 2h [t2/r × gL cosq]
Eq. 3
Figure 4 - Effect of porosity (e) and weight on the disintegration time (T) of the ODT tested. Weight 80 mg (l): T = 0.6809 e-2.0415, R2 = 0.9147. Weight 120 mg (D): T = 0.8864 e-2.0709, R2 = 0.9245. Weight 160 mg (n): T = 1.5464 e-1.8776, R2 = 0.9293.
3. Effects of porosity and weight on disintegration time
Figure 4 shows the relationship between disintegration time and porosity at ODT weights of 80, 120 and 160 mg. The disintegration time was found to be proportional to porosity raised to the power of minus. Although the diameters and thicknesses of ODTs vary, the determination coefficient R2 is more than 0.9 at each weight. This indicates that disintegration time can be predicted by porosity, regardless of ODT shape. Comparing the disintegration time for different weights of tablet, it was found that the disintegration time increases with increasing ODT weight. These results suggest that the disintegration time of ODTs is predicted by the porosity and the weight of the ODT.
(a)
(b)
(c)
Figure 5 - Relationship between the disintegration time of the ODT tested and the tabletting pressure. (a) Weight 80 mg. (b) Weight 120 mg. (c) Weight 160 mg. Diameter of ODT: 6 mm (l), 7 mm (D), 8 mm (n).
4. Effects of tabletting pressure and diameter on disintegration time
Figure 5 shows the relationship between the disintegration time and tabletting pressure at ODT weights of approximately 80, 120 and 160 mg. At all weight levels, the disintegration time increased with increasing tabletting pressure. The disintegration time also increased with decreasing diameter. Figure 6 shows the relationship between porosity and tabletting pressure. The porosity tends to decrease as the diameter decreases. In other words, the disintegration time increases as the diameter decreases, even at identical tabletting pressures. The reason for a decrease in porosity along with a decrease in diameter will be discussed. The equation of Janssen, which is often used for the design of silos or hoppers for discussion of stress in a particle layer in a container, is described as follows: Dρb g Dρb g 4 µ ky + (σ vo − ) exp( − w ) 4µ wk 4µ w k D
(c)
Figure 3 - Relationship between the disintegration time and the thickness of the ODT tested. (a) Diameter 6 mm. Tabletting pressure: 104 MPa(l), 173.3 MPa(D), 242.6 MPa(n); (b) Diameter 7 mm. Tabletting pressure: 76.4 MPa(l), 127.3 MPa(D), 178.3 MPa(n); (c) Diameter 8 mm. Tabletting pressure: 58.5 MPa(l), 97.5 MPa(D), 136.5 MPa(n).
where h represents liquid viscosity coefficient, t ODT thickness, r average capillary radius in the powder layer, γL liquid surface tension, and θ the contact angle. If the ODT disintegration time is based on the degree of water penetration in the powder layer, T should be proportional to t2. However, as shown in Figure 3, disintegration time is directly proportional to thickness. This indicates that ODT disintegration is not caused exclusively by liquid wicking. It is presumed that the rate of sequential disintegration of ODT solid-liquid interfaces and the formation of new interfaces is faster than the rate of liquid penetration. It is considered that the physical shear force, a factor distinct from liquid penetration, accelerates the disintegration of the interface. Therefore, ODT disintegration time cannot be adequately measured without application of shear force.
σv =
(b)
(a)
(b)
(c)
Figure 6 - Relationship between the porosity of the ODT tested and the tabletting pressure. (a) Weight 80 mg. (b) Weight 120 mg. (c) Weight 160 mg. Diameter of ODT: 6 mm (l), 7 mm (D), 8 mm (n).
Eq. 4
380
Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus T. Harada, R. Narazaki, T. Ohwaki, T. Uchida
J. DRUG DEL. SCI. TECH., 20 (5) 377-383 2010
where sv and sh represent the vertical and the horizontal stresses in a columnar ODT, respectively, sv0 represents pressure over the particle layer, D represents ODT diameter, rb represents bulk density in a particle layer, μw represents the coefficient of friction between the inner wall of a die and a particle layer, k represents the Rankin coefficient, and y represents depth from the particle layer surface. The use of the above equation is based on the assumption that a particle layer is not formed. However, the equation is thought to be valid for describing the first half of the course of powder compression. It is possible that 100 % vertical pressure can be transmitted omnidirectionally for a liquid. However, in a powder layer, pressure loss is observed due to inter-particle friction and friction between the powder layer and the die wall. According to the equation of Janssen, an increase in diameter D results in an increase in the vertical stress sv, that is to say, a decrease in the porosity. However, here the experimental results indicate that the porosity tends to decrease as the diameter decreases. In general, horizontal stress sh is proportional to vertical stress sv. Therefore, the following equations are obtained: sh = ksv
Eq. 5
k = (1 - sin fi)/(1 + sin fi)
Eq. 6
Figure 7 - Relationship between the disintegration time (T) and the tensile strength (St) of the ODT tested. Weight 80 mg (l), T = 7.0528 e0.5102 St, R2 = 0.8809. Weight 120 mg (D), T = 9.5223 e0.624 St, R2 = 0.8722. Weight 160 mg (n), T = 14.176 e0.5641 St, R2 = 0.9169.
where fi represents the friction angle on the powder layer. As is apparent from the above equation, k represents a number smaller than 1 and therefore sh is smaller than sv. Specifically, it is presumed that the compression force is applied in the vertical direction; and that pressure is unlikely to be transmitted in the horizontal direction. Therefore, after comparing the effect of diameter size on disintegration time at identical weights, it is clear that porosity increases as the diameter increases, resulting in more rapid disintegration. In conclusion, thinner tablets will achieve more rapid disintegration.
5. Relationship between disintegration time and tensile strength
Figure 7 shows the relationship between disintegration time and tensile strength. It can be seen from this figure that the disintegration time logarithm increases almost linearly with increasing tensile strength. However, these relationships show a positive weight dependence, which suggests that the disintegration time is not predicted only by the tensile strength.
Figure 8 - Relationship between the disintegration time (T) and the hardness (H) of the ODT tested. Weight 80 mg (l), 120 mg (D), 160 mg (n). T = 10.418 e0.0185 H, R2 = 0.9096.
6. Relationship between disintegration time and hardness
Figure 8 shows the relationship between the disintegration time and hardness. It can be seen from this figure that the disintegration time logarithm increases almost linearly with increasing hardness. The exponential approximation is T = 10.418e0.0185 H and the determination coefficient R2 is 0.9096. Unlike tensile strength, which also depends on weight, disintegration time is found to be a function of only the hardness. The relationship between hardness and porosity is shown in Figure 9. The figure shows that the hardness logarithm decreases almost linearly with increasing porosity. An important finding in this figure is that the porosity increases when the weight increases at identical hardness. When we estimate the disintegration time based on this result and the results described in 3.3. above, we find that the effect of weight on the disintegration time is balanced out. Thus: 1) disintegration time is a function of porosity. The disintegration time becomes shorter, when the porosity increases, 2) disintegration time is also a function of weight. The disintegration time becomes longer, when the weight increases. In conclusion, the disintegration time was found to be predicted by hardness, regardless of ODT weight. In addition, the following calculation also shows that disintegration time is an exponential function of hardness. The Heckel analysis [22,
Figure 9 - Relationship between the hardness and the porosity of the ODT tested. Weight 80 mg (l), 120 mg (D), 160 mg (n).
381
Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus T. Harada, R. Narazaki, T. Ohwaki, T. Uchida
J. DRUG DEL. SCI. TECH., 20 (5) 377-383 2010
23] is routinely performed to study the effect of applied pressure P on the porosity ε of a powder bed during compaction. We confirmed that the following Heckel equation could be applied to the results of this study: ln(1/e) = k1P + A1
* ODTs with different weights and diameters were manufactured at different tabletting pressures using Ludiflash. Disintegration times in the oral cavity were compared with those measured using the new disintegration apparatus, ODT-101, developed by the authors. There was a good correlation between the values obtained by ODT-101 and those obtained by sensory testing. This confirms the usefulness of the ODT-101. Physical properties that influence ODT disintegration time were examined. From the results, we can conclude that: 1) the disintegration time is almost proportional to the thickness at identical diameters, 2) the disintegration time is predicted by the porosity and the weight, regardless of ODT shape, 3) the disintegration time increases with decreasing diameter even at identical tabletting pressures, 4) the disintegration time correlates with the tensile strength of the ODT. However, this relationship shows positive ODT weight dependence, 5) the disintegration time correlates with the hardness of the ODT. This relationship is unaffected by ODT weight. Therefore, hardness is more suitable as a marker to predict disintegration time of a formulation than tensile strength.
Eq. 7
where k is a proportional constant and A is an intercept coefficient. From the result of 3.3., the disintegration time T can be indicated as a function of porosity e as follows: T = k2ek3
Eq. 8
lne = k4 lnT + A2
Eq. 9
In addition, we found that the hardness H was a linear function of the compaction pressure P in this study. Then we have the following equation: P = k5H
Eq. 10
Substituting Equations 9 and 10 into Equation 7, we obtain the following equation: lnT = k6H + A3
Eq. 11
References
which is derived from the Heckel equation and experimental results. In order to experimentally verify this assumption, ODTs with a hardness of 45-50 N were prepared with different weights, diameters, tabletting forces, and thicknesses. Table III (formulations 28-37) shows the physical properties of the prepared ODTs, and Figure 10 shows the disintegration time results for these samples, in addition to the data obtained above. It can be seen that the disintegration times of ODTs with a hardness of 45-50 N converge to a constant value of approximately 20 s, even when they have different weights, diameters, compression forces, and thicknesses. These results confirm that the disintegration time can be predicted by hardness. However, this result appears to be excipient-specific and the possible extension and application of Equation 11 to generic formulations requires further study.
1. 2.
3.
4. 5.
6. 7.
8. 9. 10. 11.
Figure 10 - Effect of hardness on the disintegration time of the ODTs under various manufacturing conditions. Hardness: 12~156 N (l), 45~50 N (D).
12. 13.
382
Food and Drug Administration, Center for Drug Evaluation and Research. - Guidance for Industry: Orally Disintegrating Tablets. - December 2008. Bi Y., Sunada K., Yonezawa Y., Danjo K., Otsuka A., Iida K. - Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity. - Chem. Pharm. Bull., 44 (11), 2121-2127, 1996. Morita Y., Tsushima Y., Yasui M., Termoz R., Ajioka J., Takayama K. - Evaluation of the disintegration time of rapidly disintegrating tablets via a novel method utilizing a CCD camera. - Chem. Pharm. Bull., 50 (9), 1181-1186, 2002. El-Arini S.K., Clas S.D. - Evaluation of disintegration testing of different fast dissolving tablets using the texture analyzer. Pharm. Dev. Technol., 7 (3), 361-371, 2002. Abdelbary G., Eouani C., Prinderre P., Joachim., Reynier J., Piccerelle P. - Determination of the in vitro disintegration profile of rapidly disintegrating tablets and correlation with oral disintegration. - Int. J. Pharm., 292, 29-41, 2005. Narazaki R., Harada T., Takami N., Kato Y., Ohwaki T. - A new method for disintegration studies of rapid disintegrating tablet. - Chem. Pharm. Bull., 52, 704-707, 2004. Harada T., Narazaki R. Nagira S., Ohwaki T., Aoki S., Iwamoto K. - Evaluation of the disintegration properties of commercial famotidine 20 mg orally disintegrating tablets using a simple new test and human sensory test. - Chem. Pharm. Bull., 54 (8), 1072-1075, 2006. Verley P., Yarwood R. - Zydis - a novel fast dissolving dosage form. - Manuf. Chem., 61, 36-37, 1990. Kato H., Tsushima Y., Ohwaki T., Nakajima M., Morita Y. - Method and apparatus for manufacturing tablets. - US Patent, 5603880, 1997. Bi Y., Sunada.H., Yonezawa Y., Danjo K. - Evaluation of rapidly disintegrating tablets prepared by a direct compression method. - Drug Dev. Ind. Pharm., 25 (5), 571-581, 1999. Fukami J., Ozawa A., Yoshihashi Y., Yonemochi E., Terada K. - Development of fast disintegrating compressed tablets using amino acid as disintegratation accelerator: evaluation of wetting and disintegration of tablet on the basis of surface free energy. - Chem. Pharm. Bull., 53, 1536-1539, 2005. Li C., Sakamoto M. - Development of oral rapidly disintegrating tablets. - Yakuzaigaku, 67 (2),133-141, 2007. Yamada Y., Yonezawa Y., Sunada H. - Evaluation of rapidly dis-
Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus T. Harada, R. Narazaki, T. Ohwaki, T. Uchida
14. 15. 16. 17. 18.
J. DRUG DEL. SCI. TECH., 20 (5) 377-383 2010
integrating tablet in the oral cavity prepared by dry compression method. - Yakuzaigaku, 68 (6), 445-451, 2008. Fukami J., Yonemochi E., Yoshihashi Y., Terada K. - Evaluation of rapidly disintegrating tablets containing glycine and carboxymethylcellulose. - Int. J. Pharm., 310, 101-109, 2006. Fassihi A.R. - Mechanisms of disintegration and compatibility of disintegrants in a direct compression system. - Int. J. Pharm., 32, 93-96, 1986. Wu C., Best S. M, Bentham A.C., Hancock B.C., Bonfield W. - A simple predictive model for the tensile strength of binary tablets. - Eur. J. Pharm. Sci., 25, 331-336, 2005. Kumar V., Reus-Medina M.L., Yang D. - Preparation, characterization, and tabletting properties of a new cellulose-based pharmaceutical aid. - Int. J. Pharm., 235, 129-140, 2002. Moroshima K., Kawashima Y., Takeuchi H., Niwa T., Hino T., Kawashima Y. - Tabletting properties of bucillamine agglomerates prepared by the spherical crystallization technique. - Int. J. Pharm., 105, 11-18, 1994.
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Manuscript Received 24 July 2009, accepted for publication 3 September 2009.
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Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus T. Harada1*, R. Narazaki2, T. Ohwaki3, T. Uchida4 Eisai Co., Ltd., CEO Office, Planning & Operations Section, Customer Joy Department, Koishikawa 5-5-5, Bunkyo-Ku, Tokyo 112-8088, Japan 2 Eisai Co., Ltd., Formulation Research, CMC Japan, Pharmaceutical Science and Technology CFU, 1 Kawashimatakehaya-machi, Kakamigahara City, Gifu 501-6195, Japan 3 Eisai Co., Ltd., CEO Office, Drug Development Technology Center, Customer Joy Department, 1 Kawashimatakehaya-machi, Kakamigahara City, Gifu 501-6195, Japan 4 School of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien 9-Bancho, Nishinomiya-shi, Hyogo 663-8197, Japan *Correspondence: [email protected] 1
The purpose of this study was to evaluate the usefulness of a new disintegration testing apparatus, ODT-101, and to investigate the effects of the physical properties of orally disintegrating tablets (ODTs) on their disintegration time. We prepared ODTs of different weights and diameters at different tabletting pressures using an excipient Ludiflash. Disintegration times were measured by human sensory evaluation and using the ODT101. The disintegration time measured by the ODT-101 was found to be in good agreement with that measured in the oral cavity. Disintegration time was found to be a function of porosity and weight, regardless of ODT shape, and to be an exponential function of the hardness of the ODT. In conclusion, ODT-101 testing is accurate enough to be a substitute for sensory evaluation and the hardness of the ODT is a good marker for disintegration time. Key words: Orally disintegrating tablet – Disintegration time – Disintegration testing apparatus – ODT-101 – Ludiflash – Porosity – Tensile strength – Tablet hardness.
Orally disintegrating tablets (ODTs) are designed to be easily taken without water, even by elderly people with swallowing difficulties. This requires ODTs to have a range of different properties: they must be capable of rapidly disintegrating in the oral cavity while being strong enough to resist breakage, cracking, and defacement on distribution, dispensing, or opening of PTPs. In addition, if the active ingredient has a bitter (unpleasant) taste, taste masking is required. With such high formulation requirements, ODT design and manufacturing technology are often critical. The FDA introduced guidance for ODTs [1] in 2008. However, the guidance merely recommended that the in vitro disintegration time, a key factor, should be approximately 30 s or less, based on the United States Pharmacopeia (USP). Regulations and details of methods for measuring disintegration time of ODTs were not specified. There are some reports of methods for measuring disintegration time of ODTs [2-5]. However, in these methods, the quantity of test medium is greatly in excess of the volume of the oral cavity and the shear force on the ODT is not loaded. Consequently, the results do not always accurately reflect disintegration time in the oral cavity. We have developed a prototype disintegration testing apparatus in which a small quantity of test medium can be used in a volume similar to that of the oral cavity and shear forces can be modified to reflect the conditions within the oral cavity [6, 7]. In this report, the ability of a further improved oral disintegration apparatus to reflect human oral disintegration time is described. The influence of different physical properties of ODTs manufactured under different conditions on disintegration time are investigated, and the mechanism of disintegration is discussed. There are many patents on additives and manufacturing techniques for ODTs by the direct compression method, but insufficient reports on the use of such additives and techniques [8-10]. Although there are some reports on the mechanism of tablet disintegration and the relationship between disintegration time and manufacturing conditions [11-18], the effects
of physical properties, such as tablet weight, diameter, and thickness, on disintegration time have not been described in detail. The present report also considers these aspects of ODT development.
I. Materials and methods 1. Materials
Ludiflash and magnesium stearate (Mallinckrodt Pharmaceuticals) were used in this study. Ludiflash is a granulated product developed by BASF for production of ODTs by the direct tabletting method. Table I shows the composition of Ludiflash. Mannitol is a diluent base. Crospovidone is added as a disintegrant and sodium dodecyl sulfate as a surface-acting agent. Granulation is carried out using polyvinyl acetate. The composition is designed to achieve excellent fluidity and disintegratability. Table I - Composition of Ludiflash. Composition
Ratio ( %)
D-Mannitol Crospovidone Polyvinyl acetate Polyvinylpyrrolidone Sodium dodecyl sulfate
90.0 5.0 4.5 0.45 0.05
2. Methods
2.1. Preparation of the ODTs The formulation employed in this study is 99 % Ludiflash with 1 % magnesium stearate as a lubricant. Lubrication was carried out using a tumbler mixer (Toyo Packing Co., Ltd.) and tabletting was carried out in a dual-pressurized single-punch tabletting machine (N-30E, Okada Seiko Co., Ltd.). Samples were manufactured with different tablet weights, tablet diameters, and tabletting pressures. The relationship between the disintegration times and physical properties was examined. The production conditions are given in Table II. 377
Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus T. Harada, R. Narazaki, T. Ohwaki, T. Uchida
J. DRUG DEL. SCI. TECH., 20 (5) 377-383 2010
Table II - Manufacturing conditions. Parameter Weight of tablet (mg) Diameter of Punch (mm) Tableting Force (kN)
(a)
Condition 80 6 3
120 7 5
160 8 7
Vertically movable rotating shaft (1) Pump
Drop down
Weight (2)
Compression force
ODT
Guide frame
2.2. Measurement of in vitro disintegration time An ODT testing apparatus ODT-101 (manufactured by Toyama Sangyo Co., Ltd.) was used to evaluate the disintegration time (Tin vitro) of ODTs. This apparatus was prepared by modifying a previously reported [7] apparatus to allow automatic adjustment of the water level of the test medium. Figure 1a shows an illustration of the core structure of the ODT-101. An ODT sample is placed on a stainless-steel porous plate. Weight (2) is provided to the shaft (1) which is capable of moving in the vertical direction and rotating. Before initiating the measurement, the shaft is located above the plate in order to avoid contact between the weight and the ODT. The liquid surface of the test medium (450 mL purified water) is automatically adjusted by a pump so that the water level is slightly below the lower face of the porous plate. Therefore, the ODT does not come into contact with the test medium until the start of measurement. The liquid temperature is set to 37 °C. In this study, a 15-g weight was attached to a shaft and the shaft rotation rate was set at 25 rpm. When the measurement start button is pressed, the shaft goes down. The ODT is sandwiched between the rotating weight and the porous plate such that the load and shear force can be applied to the ODT (disintegration time T = 0). Simultaneously, the block (3) is immersed in the test medium and the water level of the test medium increases. In our previous report [6, 7], the lower part of the ODT was immersed when the porous plate was bent down by the weight. In comparison, in this study the porous plate was kept flat and only the lower face of the ODT was in contact with the test medium. Thus the ODT absorbed the test medium by capillary suction, resulting in disintegration. The effects of load, shear, and wetting, reproduce the conditions in the oral cavity in which an ODT becomes wet with saliva and is lightly ground between the tongue and the upper jaw. Figure 1b shows the mechanism of detection of ODT disintegration. A weight is attached to the shaft such that the weight can freely move in the vertical direction by several millimeters. A sponge is attached to the centre portion of the lower face of the weight, allowing the ODT to rotate without slipping. The outer circumference of the sponge is covered with a conductive metal. The porous plate (punch hole diameter 1 mm; pitch 1.5 mm; thickness 0.1 mm), on which the ODT is placed, is composed of two halves such that electrical resistance between the right and left sides can be measured. When an ODT disintegrates and the resulting slurry particles pass through the porous plate and fall into the test medium, the weight comes into contact with the porous plates, which results in an instantaneous change in electrical resistance between the right and left sides. As a result, ODT disintegration can be detected. The disintegration time is automatically recorded to 1/100th second. In this study, measurement was repeated five times and the average of the five values taken as the disintegration time.
Separated stainless steel plates with multihole
Medium
(b)
Rotating shaft
Vertically movable
Weight Conductive metal Sponge
Separated stainless steel plates
Punched holes L R
L R
Electrodes
Switch to the conducting state between L and R
Figure 1 - Diagram of the new apparatus for measuring the disintegration time of orally disintegrating tablets (ODT-101). (a) The core structure of the ODT-101. (b) A mechanism of detection of ODT disintegration.
freely move the ODT with the tongue. They were not permitted to swallow saliva during the test, 4) when the volunteer noticed the disappearance of the ODT on the tongue, the stopwatch was immediately stopped and the disintegration time was recorded, 5) after the test, the disintegrated ODT was completely spat out and the oral cavity rinsed well, 6) the average of three evaluations was taken as the measurement value. 2.4. Thickness ODT thickness was measured five times with a digital thickness meter (Mitutoyo Co., Ltd., Japan). 2.5. Hardness ODT hardness was the average of five measurement values obtained by applying load along the diameter using a Kiya-type digital hardness tester (Fujiwara Scientific Co., Ltd.). 2.6. Tensile strength Tensile strength (St) was calculated using the following equation [19, 20] where ODT diameter is D, thickness t, and hardness H:
2.3. Sensory evaluation of disintegration time in the oral cavity In vivo disintegration time was measured with the cooperation of five healthy male volunteers. Prior to the test, the test purposes and compositions of samples were explained to the volunteers and informed consent was obtained on paper. The measurement conditions are described below: 1) the oral cavity was rinsed with water before each test, 2) an ODT was placed on the tongue and at the same time the start button of a stopwatch was pushed, 3) volunteers were prohibited from chewing the ODT but allowed to
St = 2H/πDt
Eq. 1
2.7. Porosity Porosity (ε) was calculated using the following equation based on ODT weight (W), diameter, thickness, and particle true density (rt). ε = 1 - [4W/πD2trt] 378
Eq. 2
Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus T. Harada, R. Narazaki, T. Ohwaki, T. Uchida
J. DRUG DEL. SCI. TECH., 20 (5) 377-383 2010
rt was the true density of Ludiflash (1.4748 mg/mm3 measured by BASF), because the percentage of magnesium stearate (1 %) was considered small enough to be ignored.
II. Results and discussion
Table III (formulations 1-27) shows the physical properties of ODTs produced under the tabletting conditions shown in Table II. The effects of the respective tabletting conditions and physical properties on disintegration time shown in the Table are discussed below.
1. In vivo and in vitro correlations
Figure 2 shows the correlations between the results of the sensory evaluation (Tin vivo) and the measurement values using the ODT-101 (Tin vitro). The Tin vitro values are slightly larger than the Tin vivo, but the correlation coefficient between the values is 0.99. This shows that the sensory evaluation can be replaced by the disintegration test using the new apparatus ODT-101. In the pharmacopeial disintegration test, disintegration time is sometimes longer than the oral disintegration time or value of the ODT-101 [7], as no appreciable mechanical shear force is applied to an ODT. In addition, it has been reported that disintegration times one fifth of the actual oral disintegration time, have been obtained using a pharmacopeial apparatus [12]. Therefore, we used the disintegration times obtained using the ODT-101 for analyses and discussions in this paper.
Figure 2 - Relationship between the disintegration time Tin vitro measured by the ODT-101 and the disintegration time Tin vivo in the oral cavity of the ODTs made with Ludiflash. Values are mean ± SD; Tin vitro = 1.1095 Tin vivo; R = 0.990.
Table III - Technological characterization of ODTs. Formulation No.
Diameter (mm)
Tabletting force (kN)
Tabletting pressure (MPa)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 8.0 8.0 8.0 8.0 8.0 8.0 8.0 8.0 8.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 6.0 8.0 9.0
3 5 7 3 5 7 3 5 7 3 5 7 3 5 7 3 5 7 3 5 7 3 5 7 3 5 7 7.5 5.9 4.8 4.3 4.2 3.9 3.8 3.0 4.5 5.0
104.0 173.3 242.6 104.0 173.3 242.6 104.0 173.3 242.6 76.4 127.3 178.3 76.4 127.3 178.3 76.4 127.3 178.3 58.5 97.5 136.5 58.5 97.5 136.5 58.5 97.5 136.5 191.0 150.2 122.2 109.5 107.0 99.3 96.8 104.0 87.7 77.0
Weight mg
CV
77.0 77.6 77.8 122.2 122.6 122.4 159.1 159.4 159.5 78.8 78.3 78.2 122.6 122.1 121.6 160.3 159.9 159.6 80.8 80.3 79.7 119.1 118.9 118.5 160.7 159.5 158.3 73.2 86.0 106.8 134.9 150.7 173.7 201.9 99.3 175.6 218.2
(0.52) (0.87) (0.67) (0.73) (0.62) (0.57) (0.52) (0.45) (0.57) (0.59) (0.70) (0.46) (1.04) (0.38) (0.74) (0.83) (0.53) (0.65) (1.24) (1.69) (1.05) (0.46) (0.87) (0.61) (0.79) (0.63) (1.06) (0.85) (0.84) (0.54) (0.69) (0.56) (0.36) (0.37) (0.69) (0.52) (0.85)
Thickness (mm) 2.31 2.20 2.12 3.56 3.36 3.28 4.66 4.34 4.24 1.82 1.72 1.67 2.77 2.58 2.50 3.59 3.38 3.23 1.52 1.42 1.36 2.21 2.05 1.95 2.98 2.76 2.62 1.55 1.90 2.34 2.97 3.31 3.90 4.55 2.89 3.00 2.95
379
Hardness N
CV
29.1 58.7 76.2 52.5 96.0 112.6 68.3 119.9 156.1 21.6 34.7 49.6 34.3 56.7 78.0 43.5 76.3 106.3 12.1 23.5 32.7 18.6 35.5 52.6 22.0 40.6 56.1 49.2 48.9 48.2 48.8 49.3 45.6 45.8 47.4 49.8 44.5
(0.12) (0.05) (0.17) (0.15) (0.10) (0.32) (0.09) (0.32) (0.34) (0.13) (0.06) (0.09) (0.08) (0.13) (0.09) (0.15) (0.17) (0.16) (0.30) (0.07) (0.05) (0.08) (0.09) (0.09) (0.12) (0.09) (0.12) (0.09) (0.06) (0.05) (0.09) (0.14) (0.14) (0.23) (0.17) (0.05) (0.05)
Tensile strength (MPa)
Porosity (-)
1.34 2.83 3.81 1.56 3.03 3.65 1.56 2.93 3.90 1.08 1.83 2.69 1.13 2.00 2.84 1.10 2.06 2.99 0.63 1.31 1.92 0.67 1.38 2.15 0.59 1.17 1.70 2.89 2.35 1.88 1.50 1.35 1.06 0.92 1.74 1.32 1.07
0.20 0.15 0.12 0.18 0.13 0.10 0.18 0.12 0.10 0.24 0.20 0.18 0.22 0.17 0.14 0.21 0.17 0.13 0.28 0.24 0.21 0.27 0.22 0.18 0.27 0.22 0.19 0.17 0.20 0.19 0.20 0.20 0.21 0.22 0.18 0.21 0.21
Disintegration time in oral cavity (s)
by ODT101 (s)
14.5 25.6 57.0 27.0 58.4 115.9 27.4 84.0 138.9 9.6 13.0 18.9 15.0 22.8 36.9 18.4 30.8 60.9 9.1 8.0 10.3 10.9 13.4 17.5 14.6 16.8 20.4 21.5 19.8 19.4 21.0 25.4 25.2 23.3 17.4 19.5 20.2
19.2 28.0 58.5 33.4 60.4 130.7 37.0 81.7 153.8 12.5 14.1 28.5 24.4 28.1 40.8 34.6 42.1 59.3 10.7 13.1 14.2 14.1 19.9 30.1 20.6 24.9 28.9 19.6 15.2 19.3 22.2 20.1 25.8 27.6 19.0 23.4 27.0
Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus T. Harada, R. Narazaki, T. Ohwaki, T. Uchida
J. DRUG DEL. SCI. TECH., 20 (5) 377-383 2010
2. Effects of thickness on disintegration time
(a)
Figure 3 shows the relationship between the disintegration time and thickness of ODTs at diameters of 6, 7 and 8 mm. The results show that the disintegration time is almost proportional to ODT thickness. Figure 3 also shows that the slope of the regression line tends to be greater as the tabletting pressure becomes higher. Crospovidone, a component of Ludiflash, increases the porosity of the ODT when it comes into contact with water and becomes swollen. Crospovidone is a disintegrant with a wicking mechanism in which the capillary suction force of the pores of an ODT allows water to infiltrate deeply into the tablet, resulting in disintegration [14]. During the disintegration test using the ODT-101, only the lower face of the ODT is in contact with the test medium, and ODT disintegration is completed when water reaches the upper face of the ODT, T seconds after water penetration through the bottom face. The water penetration time, T, in a powder layer is represented by the following equation of Peek et al. [21]: T = 2h [t2/r × gL cosq]
Eq. 3
Figure 4 - Effect of porosity (e) and weight on the disintegration time (T) of the ODT tested. Weight 80 mg (l): T = 0.6809 e-2.0415, R2 = 0.9147. Weight 120 mg (D): T = 0.8864 e-2.0709, R2 = 0.9245. Weight 160 mg (n): T = 1.5464 e-1.8776, R2 = 0.9293.
3. Effects of porosity and weight on disintegration time
Figure 4 shows the relationship between disintegration time and porosity at ODT weights of 80, 120 and 160 mg. The disintegration time was found to be proportional to porosity raised to the power of minus. Although the diameters and thicknesses of ODTs vary, the determination coefficient R2 is more than 0.9 at each weight. This indicates that disintegration time can be predicted by porosity, regardless of ODT shape. Comparing the disintegration time for different weights of tablet, it was found that the disintegration time increases with increasing ODT weight. These results suggest that the disintegration time of ODTs is predicted by the porosity and the weight of the ODT.
(a)
(b)
(c)
Figure 5 - Relationship between the disintegration time of the ODT tested and the tabletting pressure. (a) Weight 80 mg. (b) Weight 120 mg. (c) Weight 160 mg. Diameter of ODT: 6 mm (l), 7 mm (D), 8 mm (n).
4. Effects of tabletting pressure and diameter on disintegration time
Figure 5 shows the relationship between the disintegration time and tabletting pressure at ODT weights of approximately 80, 120 and 160 mg. At all weight levels, the disintegration time increased with increasing tabletting pressure. The disintegration time also increased with decreasing diameter. Figure 6 shows the relationship between porosity and tabletting pressure. The porosity tends to decrease as the diameter decreases. In other words, the disintegration time increases as the diameter decreases, even at identical tabletting pressures. The reason for a decrease in porosity along with a decrease in diameter will be discussed. The equation of Janssen, which is often used for the design of silos or hoppers for discussion of stress in a particle layer in a container, is described as follows: Dρb g Dρb g 4 µ ky + (σ vo − ) exp( − w ) 4µ wk 4µ w k D
(c)
Figure 3 - Relationship between the disintegration time and the thickness of the ODT tested. (a) Diameter 6 mm. Tabletting pressure: 104 MPa(l), 173.3 MPa(D), 242.6 MPa(n); (b) Diameter 7 mm. Tabletting pressure: 76.4 MPa(l), 127.3 MPa(D), 178.3 MPa(n); (c) Diameter 8 mm. Tabletting pressure: 58.5 MPa(l), 97.5 MPa(D), 136.5 MPa(n).
where h represents liquid viscosity coefficient, t ODT thickness, r average capillary radius in the powder layer, γL liquid surface tension, and θ the contact angle. If the ODT disintegration time is based on the degree of water penetration in the powder layer, T should be proportional to t2. However, as shown in Figure 3, disintegration time is directly proportional to thickness. This indicates that ODT disintegration is not caused exclusively by liquid wicking. It is presumed that the rate of sequential disintegration of ODT solid-liquid interfaces and the formation of new interfaces is faster than the rate of liquid penetration. It is considered that the physical shear force, a factor distinct from liquid penetration, accelerates the disintegration of the interface. Therefore, ODT disintegration time cannot be adequately measured without application of shear force.
σv =
(b)
(a)
(b)
(c)
Figure 6 - Relationship between the porosity of the ODT tested and the tabletting pressure. (a) Weight 80 mg. (b) Weight 120 mg. (c) Weight 160 mg. Diameter of ODT: 6 mm (l), 7 mm (D), 8 mm (n).
Eq. 4
380
Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus T. Harada, R. Narazaki, T. Ohwaki, T. Uchida
J. DRUG DEL. SCI. TECH., 20 (5) 377-383 2010
where sv and sh represent the vertical and the horizontal stresses in a columnar ODT, respectively, sv0 represents pressure over the particle layer, D represents ODT diameter, rb represents bulk density in a particle layer, μw represents the coefficient of friction between the inner wall of a die and a particle layer, k represents the Rankin coefficient, and y represents depth from the particle layer surface. The use of the above equation is based on the assumption that a particle layer is not formed. However, the equation is thought to be valid for describing the first half of the course of powder compression. It is possible that 100 % vertical pressure can be transmitted omnidirectionally for a liquid. However, in a powder layer, pressure loss is observed due to inter-particle friction and friction between the powder layer and the die wall. According to the equation of Janssen, an increase in diameter D results in an increase in the vertical stress sv, that is to say, a decrease in the porosity. However, here the experimental results indicate that the porosity tends to decrease as the diameter decreases. In general, horizontal stress sh is proportional to vertical stress sv. Therefore, the following equations are obtained: sh = ksv
Eq. 5
k = (1 - sin fi)/(1 + sin fi)
Eq. 6
Figure 7 - Relationship between the disintegration time (T) and the tensile strength (St) of the ODT tested. Weight 80 mg (l), T = 7.0528 e0.5102 St, R2 = 0.8809. Weight 120 mg (D), T = 9.5223 e0.624 St, R2 = 0.8722. Weight 160 mg (n), T = 14.176 e0.5641 St, R2 = 0.9169.
where fi represents the friction angle on the powder layer. As is apparent from the above equation, k represents a number smaller than 1 and therefore sh is smaller than sv. Specifically, it is presumed that the compression force is applied in the vertical direction; and that pressure is unlikely to be transmitted in the horizontal direction. Therefore, after comparing the effect of diameter size on disintegration time at identical weights, it is clear that porosity increases as the diameter increases, resulting in more rapid disintegration. In conclusion, thinner tablets will achieve more rapid disintegration.
5. Relationship between disintegration time and tensile strength
Figure 7 shows the relationship between disintegration time and tensile strength. It can be seen from this figure that the disintegration time logarithm increases almost linearly with increasing tensile strength. However, these relationships show a positive weight dependence, which suggests that the disintegration time is not predicted only by the tensile strength.
Figure 8 - Relationship between the disintegration time (T) and the hardness (H) of the ODT tested. Weight 80 mg (l), 120 mg (D), 160 mg (n). T = 10.418 e0.0185 H, R2 = 0.9096.
6. Relationship between disintegration time and hardness
Figure 8 shows the relationship between the disintegration time and hardness. It can be seen from this figure that the disintegration time logarithm increases almost linearly with increasing hardness. The exponential approximation is T = 10.418e0.0185 H and the determination coefficient R2 is 0.9096. Unlike tensile strength, which also depends on weight, disintegration time is found to be a function of only the hardness. The relationship between hardness and porosity is shown in Figure 9. The figure shows that the hardness logarithm decreases almost linearly with increasing porosity. An important finding in this figure is that the porosity increases when the weight increases at identical hardness. When we estimate the disintegration time based on this result and the results described in 3.3. above, we find that the effect of weight on the disintegration time is balanced out. Thus: 1) disintegration time is a function of porosity. The disintegration time becomes shorter, when the porosity increases, 2) disintegration time is also a function of weight. The disintegration time becomes longer, when the weight increases. In conclusion, the disintegration time was found to be predicted by hardness, regardless of ODT weight. In addition, the following calculation also shows that disintegration time is an exponential function of hardness. The Heckel analysis [22,
Figure 9 - Relationship between the hardness and the porosity of the ODT tested. Weight 80 mg (l), 120 mg (D), 160 mg (n).
381
Effect of physical properties of orally disintegrating tablets on disintegration time as determined by a new apparatus T. Harada, R. Narazaki, T. Ohwaki, T. Uchida
J. DRUG DEL. SCI. TECH., 20 (5) 377-383 2010
23] is routinely performed to study the effect of applied pressure P on the porosity ε of a powder bed during compaction. We confirmed that the following Heckel equation could be applied to the results of this study: ln(1/e) = k1P + A1
* ODTs with different weights and diameters were manufactured at different tabletting pressures using Ludiflash. Disintegration times in the oral cavity were compared with those measured using the new disintegration apparatus, ODT-101, developed by the authors. There was a good correlation between the values obtained by ODT-101 and those obtained by sensory testing. This confirms the usefulness of the ODT-101. Physical properties that influence ODT disintegration time were examined. From the results, we can conclude that: 1) the disintegration time is almost proportional to the thickness at identical diameters, 2) the disintegration time is predicted by the porosity and the weight, regardless of ODT shape, 3) the disintegration time increases with decreasing diameter even at identical tabletting pressures, 4) the disintegration time correlates with the tensile strength of the ODT. However, this relationship shows positive ODT weight dependence, 5) the disintegration time correlates with the hardness of the ODT. This relationship is unaffected by ODT weight. Therefore, hardness is more suitable as a marker to predict disintegration time of a formulation than tensile strength.
Eq. 7
where k is a proportional constant and A is an intercept coefficient. From the result of 3.3., the disintegration time T can be indicated as a function of porosity e as follows: T = k2ek3
Eq. 8
lne = k4 lnT + A2
Eq. 9
In addition, we found that the hardness H was a linear function of the compaction pressure P in this study. Then we have the following equation: P = k5H
Eq. 10
Substituting Equations 9 and 10 into Equation 7, we obtain the following equation: lnT = k6H + A3
Eq. 11
References
which is derived from the Heckel equation and experimental results. In order to experimentally verify this assumption, ODTs with a hardness of 45-50 N were prepared with different weights, diameters, tabletting forces, and thicknesses. Table III (formulations 28-37) shows the physical properties of the prepared ODTs, and Figure 10 shows the disintegration time results for these samples, in addition to the data obtained above. It can be seen that the disintegration times of ODTs with a hardness of 45-50 N converge to a constant value of approximately 20 s, even when they have different weights, diameters, compression forces, and thicknesses. These results confirm that the disintegration time can be predicted by hardness. However, this result appears to be excipient-specific and the possible extension and application of Equation 11 to generic formulations requires further study.
1. 2.
3.
4. 5.
6. 7.
8. 9. 10. 11.
Figure 10 - Effect of hardness on the disintegration time of the ODTs under various manufacturing conditions. Hardness: 12~156 N (l), 45~50 N (D).
12. 13.
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Manuscript Received 24 July 2009, accepted for publication 3 September 2009.
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