Graphical Abstract First Step Disintegrant Iwao et al. Second Step Available surface area (St) using the data of dissolution study t b F( t) 1 exp ( t / a) C /( C W / V ) df( t) dt S( t) V / k ln s s 0 / 1/ b max ( a( b 1)/ b) 1. C Cs 1 exp ln Cs /( Cs W0 / V ) F( t) 2. S max V / k lnc /( C W / V ) df( t max) dt s s 0 / Final Step Δ tmax t max, 1% t max, 5% ΔS max S max, 5% S max, 1% 1 2 3 4 1
5 6 An easy-to-use approach for determining the disintegration ability of disintegrants by analysis of available surface area 7 8 Yasunori Iwao a, Shoko Tanaka a, Takeaki Uchimoto a, Shuji Noguchi a, Shigeru Itai a,* 9 10 11 12 a Department of Pharmaceutical Engineering, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan 13 14 15 16 17 18 19 20 * Corresponding author: Shigeru Itai, Ph.D., Professor Department of Pharmaceutical Engineering, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Tel.: +81 54 264 5614, Fax: +81 54 264 5615, E-mail: s-itai@u-shizuoka-ken.ac.jp. 21 2
22 Abstract 23 With the aim of directly predicting the functionality and mechanism of 24 disintegrants during the disintegration and dissolution of tablets, we investigated an 25 analysis method based on available surface area, which is the surface area of a drug in a 26 formulation in direct contact with the external solvent during dissolution. We evaluated 27 the following disintegrants in this study: sodium starch glycolate (Glycolys), 28 crospovidone (Kollidon CL), carboxymethylcellulose calcium (CMC-Ca), 29 low-substituted hydroxypropylcellulose (L-HPC), and croscarmellose sodium 30 (Ac-Di-Sol). When disintegrant was added to a 50% ethenzamide tablet formulation, an 31 increase in the dissolution rate dependent on disintegrant concentration was observed, 32 according to the type of disintegrant. In addition, the available surface area also differed 33 between disintegrants. For Glycolys, CMC-Ca, and Ac-Di-Sol, a rapid increase in 34 available surface area and a large increase in maximum available surface area (S max ) 35 were observed due to high swellability and wicking, even when the disintegrant 36 concentration was only 1.0%. In contrast, for Kollidon CL and LH-21, a gradual 37 increase in available surface area was observed, depending on the disintegrant 38 concentration. To evaluate the disintegrant ability, Δt max and ΔS max were calculated by 39 subtracting peak time (t max ) at 5.0% from that at 1.0% and subtracting S max at 1.0% from 40 that at 5.0%, respectively, and it was found that the water absorption ratio had strong 3
41 negative correlations with Δt max and ΔS max. Therefore, this study demonstrates that 42 analysis of only available surface area and parameters thereby obtained can directly 43 provide useful information, especially about the disintegration ability of disintegrants. 44 45 Keywords: disintegrant, available surface area, disintegration mechanism. 46 47 48 49 Abbreviation: ETZ, Ethenzamide; Glycolys, Sodium starch glycolate; K-CL, Kollidon CL; CMC-Ca, carboxymethylcellulose calcium; L-HPC, low-substituted hydroxypropylcellulose; Ac-Di-Sol, croscarmellose sodium; Mg-St, magnesium stearate. 50 4
51 1. Introduction 52 The disintegration of a tablet can be regarded as the first step toward the bioavailability 53 and pharmaceutical action of an active ingredient. To achieve sufficient disintegration, a 54 disintegrant must normally be added to the tablet formulation. Traditional tablet 55 disintegrants can be classified as starches (e.g., corn, wheat, potato, rice, and 56 pregelatinized starches), macromolecules (e.g., alginic acid, sodium alginate, polacrilin 57 potassium, and guar gum), finely divided solids (e.g., colloidal silicon dioxide and 58 magnesium aluminum silicate), and celluloses (e.g., powdered cellulose, 59 microcrystalline cellulose, carboxymethylcellulose, cross-linked sodium 60 carboxymethylcellulose, methylcellulose, and low-substituted hydroxypropylcellulose). 61 Swelling and wicking are the primary mechanisms of action for tablet disintegrants, but 62 other mechanisms such as deformation recovery, particle repulsion, heat of wetting, and 63 gas evolution, may play a role in the disintegration of particular tablet formulations 64 (Kanig and Rudnic, 1984). Another possibility is that several of these mechanisms act 65 simultaneously. 66 Respective of the mechanism of action, water uptake has been identified as the 67 necessary first step in any disintegration process (Van Kamp et al., 1986; Caramella et 68 al., 1986). In addition, Colombo et al. (1981, 1988) and Caramella et al. (1986, 1988) 69 have related the disintegration process to the development of a disintegrating force 5
70 inside the tablet. They concluded that water penetration into an insoluble tablet is 71 accompanied by the development of a proportional force, indicating the relevance of 72 disintegration mechanisms that are capable of force development (Caramella et al., 73 1986). 74 At present, a disintegration test is the standard method for evaluating 75 disintegrant functionality. However, this method provides only limited information 76 about disintegration behavior, but no information about drug dissolution from a tablet. 77 Although water uptake into disintegrants is also measured in combination with the 78 disintegration test, the disintegration mechanism cannot be ascertained with certainty 79 from the results. Therefore, to accurately evaluate the functionality and mechanism of 80 disintegrants in the disintegration of tablets, as well as the dissolution behavior of drugs, 81 an alternative method to reflect both in vitro disintegration and dissolution is needed. 82 Against this background, available surface area (S(t)), which is a 83 physicochemical property that a drug in a formulation directly contacts with the external 84 solvent, has attracted attention and can be estimated by using dissolution test results 85 only, as we have reported previously (Kouchiwa et al., 1985). In general, dissolution of 86 solid dosage forms includes disintegration and deaggregation process. Although these 87 processes are further complicated, the use of S(t) can directly represent the drug 88 dissolution from the tablets including the disintegration process. Using the time course 6
89 of S(t), we elucidated the effect of differences in pharmaceutical processing, such as 90 compression force and formulation, on the dissolution of flufenamic acid (Itai et al., 91 1986). We also reported that when determining whether a lubricant retards the 92 dissolution of a drug, analysis of S(t) enabled prediction of the dissolution and 93 disintegration behavior of acetaminophen tablets formulated using various lubricants 94 (Uchimoto et al., 2011), suggesting that this analysis can allow precise prediction of the 95 disintegration, dispersion and dissolution of the tablet. Therefore, this analysis is also 96 considered to have a potential to evaluate the disintegration ability of disintegrants. 97 In the present study, we used five commercially available disintegrants to 98 evaluate a method for analyzing disintegrant behavior on the basis of available surface 99 area, as an alternative to traditional disintegration tests and water uptake measurements. 7
100 2. Materials and methods 101 2.1. Materials 102 Ethenzamide (ETZ; listed in the Japanese Pharmacopeia 16th Edition (JP16), 103 which was used as the active pharmaceutical ingredient), was kindly provided by Iwaki 104 Pharmaceutical Co., Ltd. (Shizuoka, Japan). Lactose monohydrate (Pharmatose 200M, 105 listed in JP16, used as filler) and microcrystalline cellulose (Avicel PH-102, listed in 106 JP16, used as filler) were kindly provided by DFE Pharmaceutical Co., Ltd. (Tokyo, 107 Japan) and Asahi Kasei Co., Ltd. (Tokyo, Japan), respectively. Hydroxypropylcellulose 108 (HPC-L, listed in JP16, used as binder) was kindly provided by Nippon Soda Co., Ltd. 109 (Tokyo, Japan). Sodium starch glycolate (Glycolys, listed in JP16, Roquette Japan K. K. 110 (Tokyo, Japan)), crospovidone (Kollidon CL (K-CL), listed in JP16, BASF Japan Co., 111 Ltd. (Tokyo, Japan)), carboxymethylcellulose calcium (E.C.G-505 (CMC-Ca), listed in 112 JP16, Gotoku Chemical Co., Ltd. (Tokyo, Japan)), low-substituted 113 hydroxypropylcellulose (LH-21 (L-HPC), listed in JP16, Shin-Etsu Chemical Co., Ltd. 114 (Tokyo, Japan)), and croscarmellose sodium (Ac-Di-Sol, listed in JP16, Dainippon 115 Sumitomo Pharma, Co., Ltd. (Osaka, Japan)) were used as disintegrants. All other 116 reagents used were of the highest grade available from commercial sources, and all 117 solutions were prepared with deionized water. 118 8
119 2.2. Granulation 120 Lactose monohydrate (140 g) and microcrystalline cellulose (60 g) were mixed 121 for 15 min in a mixer (Fuji Medical Equipment Co., Ltd.). ETZ (200 g) was added to 122 this powder and mixed for an additional 15 min. A total of 150 g of 5.0% w/v aqueous 123 solution of HPC-L was then added via a syringe (ss-10sz, Terumo Corporation, Tokyo, 124 Japan), and the mixture was subsequently kneaded for 15 min. Granulation was 125 performed in a rotating squeeze-type granulator with a sieve size of 0.8 mm (Hata Iron 126 Work Co., Ltd. Kyoto, Japan). The granules were dried in an oven at 50 C for 12 16 h. 127 After drying, the granules were sieved through a 1680 µm sieve, and the granules that 128 did not pass through a 350 µm sieve were collected. This process was repeated several 129 times, and the resultant granules were then mixed uniformly and subjected to 130 experimental analysis. 131 132 2.3. Tablet preparation 133 A total of 8 g of mixture composed of granules, magnesium stearate (Mg-St; 134 specified as a lubricant, listed in JP16), and each disintegrant was manually mixed in a 135 polyethylene bag at a rate of 120 times/min for 2 min. The disintegrant concentrations 136 were 1.0%, 3.0% and 5.0%, and the Mg-St concentration was 0.5%. Tablets were 137 prepared with an oil press (JASCO Co., Tokyo, Japan) using a flat-faced punch of 13 9
138 mm in diameter. The tableting force was 10 kn, which was applied for 30 s. 139 140 2.4. Determination of apparent solubility 141 ETZ (1g) was added to ph 6.8 phosphate buffer (200 ml) at 37 C, and the 142 mixture was agitated for 10 h. A 2 ml aliquot of this mixture was withdrawn and 143 filtered through a membrane filter (0.45 m) immediately. The filtered solution was 144 volumetrically diluted, the absorbance at 290 nm was measured on a spectrophotometer 145 (UV-mini, Shimadzu Corporation, Kyoto, Japan), and the concentration of dissolved 146 ETZ was calculated from a calibration curve prepared from standard solutions. 147 148 2.5. Determination of the dissolution rate constant per unit area 149 To determine the dissolution rate constant k, the stationary disk method was 150 used (Agata et al, 2010). An ETZ disk with a diameter of 1.3 cm (surface area: 1.33 151 cm 2 ) was prepared by compressing 400 mg of the drug powder at 10 kn. The disk was 152 placed in a JP16 dissolution test apparatus and rotated at 50 rpm in phosphate buffer at 153 ph 6.8 and 37 ± 0.5 C. Solution (5 ml) was withdrawn at appropriate intervals, and 154 after adequate dilution, the ETZ concentration was determined in the same manner as 155 described in Section 2.4. When the ETZ concentration (C) (mg/l) was plotted versus 156 time (t) (min) and fitted to the experimental data by the least-squares method, the 10
157 following equation was obtained: 158 C = 0.246 t + 1.440 (R 2 =0.9961). (1) 159 From the Noyes Whitney equation, the following equation was derived when the 160 surface area was fixed under sink conditions: 161 k S Cs C t V, (2) 162 where k is the dissolution rate constant per unit area, S is surface area, V is the medium 163 volume, and Cs is the apparent solubility. By comparing the slope between Eqs. (1) and 164 (2), k was then estimated. 165 166 2.6. Dissolution test 167 The dissolution of ETZ from tablets was measured by the paddle method listed 168 in JP16. The test medium was 900 ml phosphate buffer (ph 6.8) at 37.0 ± 0.5 C, and 169 the paddle rotation speed was 50 rpm. At 1.0, 2.5, 5.0, 7.5, 10, 15, 20, 30, 40, 50, 60, 70, 170 80, 90, 100, 120, 140, 160, 180, 200, 240, 280, 320 and 400 min, samples (3 ml) were 171 withdrawn, and 3 ml of fresh medium was added after collecting each sample. The 172 solution was then filtered through a membrane filter (0.45 μm). The ETZ concentration 173 was determined in the same manner as described in Section 2.4. 174 11
175 2.7. Determination of time course of the available surface area during dissolution 176 To determine the time course of the available surface area S(t) as well as the 177 corresponding dissolution rate (C), the following equations reported by Kouchiwa et al. 178 (Kouchiwa et al., 1985), were used: 179 180 C /( C W / V) df( t) dt S( t) V / k ln 0 s s / C C 1 exp ln C /( C W0 / V) F( t) s s s,, (3) (4) 181 where V is the medium volume, Cs is the apparent solubility, W 0 is the initial amount of 182 the drug in solid dosage forms, and F(t) is the ratio of the cumulative surface area that 183 has been made available for dissolution up to time t to the total surface area that is made 184 available during the entire dissolution process. This ratio can be calculated from the 185 experimental dissolution test data by using 186 C /( C C) /lnc /( C W / ) F( t) ln 0 V s s s s. (5) 187 Furthermore, because F(0) = 0 and F( ) = 1, F(t) can be described by a cumulative 188 probability distribution: 189 F( t) ( t) dt 0. t (6) 190 If the Weibull distribution is selected, Eq. (6) can be rearranged to 191 b F( t) 1 exp ( t / a), (7) 192 where a is the scale parameter and b is the shape parameter. 193 By using these equations, both S(t) throughout dissolution and the 12
194 corresponding theoretical dissolution rate (C) of a tablet can be determined. In this 195 study, the best-fitting parameters for the probability distribution of F(t) values for Eq. 196 (7) were found by nonlinear regression with statistical software (Origin 8, Lightstone 197 Corp., Tokyo, Japan), and the fit to the experimental data was estimated in terms of the 198 residual sum of squares. The peak time (t max ) when S(t) was a maximum value (S max ) 199 was determined as 200 t 1/ b max ( a( b 1)/ b), (8) 201 In addition, differences in S max (ΔS max ) and in t max (Δt max ) between tablets 202 containing 5.0% and 1.0% disintegrant were determined as follows: 203 S max S max, 5% S max,1%, (9) 204 t max t max,1% t max, 5%. (10) 205 206 2.8. Determination of tablet disintegration time 207 Six tablets prepared as described for Section 2.3 were selected at random, and 208 disintegration tests were performed in accordance with the protocol set out in JP16 209 using a disintegration tester (Miyamoto Riken Ind. Co., Ltd., Osaka, Japan). Distilled 210 water at 37.0 ± 0.5 C was used as the test fluid. 211 13
212 2.9. Determination of tablet hardness 213 Ten tablets prepared as described for Section 2.3 were selected at random, and 214 compression tests were performed using a hardness meter with a 300 N load cell 215 (precision of 1 N, PC-30, Okada Seiko Co., Ltd., Tokyo, Japan). 216 217 2.10. Determination of water absorption ability of disintegrants 218 To determine the water absorption capacity of disintegrants as previously 219 described (Bi et al, 1996; Fukami et al, 2006), tablets consisting of 100% disintegrant 220 (400 mg) were prepared with an oil press using a flat-faced punch of 13 mm in diameter. 221 The tableting force was 10 kn, which was applied for 30 s. The tablets were placed on 222 filter paper wetted with 6 ml of water, and the appearance of the tablets was observed 223 as water penetrated into them. The water absorption ratio (R w ) was calculated as 224 R w ( Wb Wa ) / Wa. (11) 225 Here, W a is the initial tablet weight and W b is the weight of the tablet after completely 226 wetting. Thus R w is an indicator of swelling. 227 14
228 3. Results and discussion 229 3.1. Effect of disintegrants on the dissolution and S(t) profiles of ETZ tablets 230 Figures 1 and 2 show ETZ release behavior from tablets (weight, 400 mg; 231 thickness, 2.5 mm) containing various disintegrants at concentrations of 0%, 1.0%, 232 3.0%, and 5.0%, and the time courses of S(t), respectively. The disintegrants used in this 233 study are as follows: Glycolys, as a representative of starches; K-CL, as a representative 234 of the cross-linked macromolecules; CMC-Ca and L-HPC, as representatives of 235 celluloses, and Ac-Di-Sol, as a representative of finely divided solids. In addition, the 236 apparent solubility Cs and dissolution rate constant k of ETZ were determined and 237 found to be 1647.5 mg/l and 0.1012 cm/min, respectively. The symbols represent the 238 experimental results, and the curves represent the theoretical dissolution profiles 239 obtained from Eq. (4) (Fig. 1). Good agreement was found between the experimental 240 data (symbols) and the theoretical profile (curves) for dissolution, because each residual 241 sum of squares had a low value (data not shown). Therefore, the time courses of S(t) 242 (Fig. 2) were also deemed to be reasonable. 243 244 3.1.1. Effect of Glycolys 245 When Glycolys was mixed with ETZ granules, faster dissolution of ETZ from 246 the tablets was observed as the Glycolys concentration was increased from 1.0% to 15
247 5.0%; the dissolution of ETZ from the tablets containing 1.0% Glycolys was 248 significantly faster than from tablets containing no disintegrant (Fig. 1A). Although no 249 significant improvement in the dissolution of ETZ was observed when Glycolys 250 concentration was increased from 1.0% and 3.0%, the dissolution of ETZ from tablets 251 containing 5.0% Glycolys was significantly faster. As shown in Fig. 2A, substantial 252 differences in the S(t) profiles were observed in tablets containing various 253 concentrations of Glycolys. Table 1 lists the parameters a, b, S max, and t max, which can 254 be determined for Glycolys by using Eqs. (7) and (8). Generally, when the value of b is 255 less than 1, the Weibull distribution follows a monotonous decreasing curve, where the 256 maximum value is at the start of each experiment, suggesting that, in such a case, a slow 257 decrease in the available surface area occurs because tablets themselves do not 258 disintegrate and instead gradually become smaller. On the other hand, when the value of 259 b is greater than 1, the Weibull distribution has a distinct maximum value, suggesting 260 that tablets disintegrate into granules, and thus that available surface area sharply 261 increases, and then decreases (Itai et al, 1986; Uchimoto et al, 2011). When no 262 disintegrant was used (0%), b was less than 1 (Table 1) and S(t) followed a monotonous 263 decreasing curve (Fig. 2A). At 0% disintegrant, S max and t max were respectively found to 264 be 5.0 cm 2 /tablet and 1.0 min, which was the first sampling time of the dissolution test, 265 because t max could not be calculated by using Eq. (8). From tablet dimensions such as 16
266 the thickness (2.5 mm) and diameter (13.0 mm), the value of the actual tablet surface 267 area (S initial ) was calculated to be 12.9 cm 2 /tablet. Because the tablets contained less than 268 50% ETZ, the surface area of ETZ on the tablet was less than 12.9 cm 2 /tablet (S initial ). 269 S max was slightly smaller than S initial, and thus the tablets did not completely disintegrate. 270 However, at every Glycolys concentration from 1 5.0%, a shape parameter of b > 1 was 271 observed (Table 1) and S(t) initially increased, reached a maximum, and then decreased 272 (Fig. 2A). This result thus suggests that the disintegration and disaggregation of the 273 tablet was induced by Glycolys, which subsequently allowed for rapid dissolution of 274 ETZ into the solvent. At Glycolys concentrations of 1.0% and 3.0%, S max was 27.71 and 275 29.81 cm 2 /tablet, which were about 5- to 6-fold larger than in the case without 276 disintegrant. In contrast, t max was shortened from 15.28 min to 6.20 min, indicating that 277 the practical disintegration of tablets occurred and the speed that Glycolys incorporated 278 water into a tablet would increase as the Glycolys concentration was increased. 279 Interestingly, at a Glycolys concentration of 5.0%, S max was 62.98 cm 2 /tablet (Table 1), 280 more than 12-fold that when no disintegrant was used, and t max was 8.43 min, nearly 281 equal to that when 3.0% Glycolys was used. Taken together, these results indicate that 282 the increase in ETZ dissolution might be attributable to tablet disintegration although 283 the rate of water penetration did not differ between Glycolys concentrations of 3.0% and 284 5.0%. 17
285 286 3.1.2. Effect of K-CL 287 When K-CL was mixed with ETZ granules at a concentration of 1.0%, 3.0%, or 288 5.0%, the rate of ETZ dissolution increased depending on K-CL concentration (Fig. 1B). 289 In addition, substantial differences in the S(t) profiles were also observed in tablets 290 containing the various concentrations of K-CL (Fig. 2B). At 1.0% K-CL, b was greater 291 than 1 (Table 1), but S max was 5.82 cm 2 /tablet, which was almost same as in tablets 292 containing no disintegrant. Furthermore, t max was 55.26 min, which was a much longer 293 peak time than in other formulations. At this concentration, the scale parameter a was 294 considerably higher at 819.57; in other words, K-CL could not sufficiently interact with 295 the external solution and the tablet consequently did not disintegrate. When 3.0% K-CL 296 was added, b was greater than 1 (Table 1) and S(t) initially increased, then reached a 297 maximum, and finally decreased (Fig. 2B). At this concentration, S max was 46.12 298 cm 2 /tablet, which was more than 7-fold that for 1.0% K-CL, and t max was 3.13 min, 299 suggesting that a disintegration property of K-CL was observed. At the K-CL 300 concentration of 5.0%, however, t max could not be calculated by Eq. (8), because b was 301 less than 1 (Table 1). This might be explained by the high disintegration performance of 302 K-CL: because K-CL, unlike the other disintegrants, is considered not to form a gel 303 structure, the tablet disintegration and drug dissolution occurred much more rapidly 18
304 when 5.0% K-CL was added. Therefore, we calculated S max assuming that t max was 1 305 min as well as the case of a tablet containing no disintegrant, and S max was found to be 306 150 cm 2 /tablet. Therefore, the analysis of S(t) can also reflect the characteristics of K-CL 307 that there is a K-CL concentration which optimizes disintegration. 308 309 3.1.3. Effect of CMC-Ca and L-HPC 310 Figs. 1C-D and 2C-D respectively show the ETZ release behavior from tablets 311 containing CMC-Ca and L-HPC, which are cellulose disintegrants, at concentrations of 312 1.0%, 3.0%, and 5.0%, and the time courses of S(t). When either disintegrant was added, 313 the dissolution of ETZ from the tablets increased with increasing disintegrant 314 concentration. In particular, even when CMC-Ca was added at only 1.0%, a remarkable 315 increase in S(t) was observed in comparison with K-CL (Fig. 2C). At this concentration, 316 S max was 40.02 cm 2 /tablet, which was larger than that of 1.0% Glycolys or K-CL, and 317 t max was 12.47 min (Table 1). In addition, when CMC-Ca was added at 3.0% and 5.0%, 318 S max was 60.31 cm 2 /tablet and 80.22 cm 2 /tablet, respectively (Table 1), suggesting that 319 CMC-Ca is a superior disintegrant. Generally, since the recommended concentration 320 range of CMC-Ca in pharmaceutical formulations is 1 15%, tablets containing over 321 5.0% CMC-Ca would exhibit stronger disintegration behavior. In addition, CMC-Ca is a 322 swelling-type disintegrant, and its capacity to absorb the external solution is high. 19
323 Therefore, although the value of t max was almost the same for 3.0% and 5.0% CMC-Ca 324 (because the speed that CMC-Ca absorbs water was unchanged), the tablet rapidly 325 disintegrated due to the characteristics of CMC-Ca. 326 In the case of 1.0% LH-21, although b was greater than 1 (Table 1), S max was 327 4.15 cm 2 /tablet, almost the same as in tablets containing no disintegrant, and t max was 328 54.56 min. A previous report has shown that among cellulose disintegrants, LH-21 has 329 the lowest water absorption and swelling ability (Abdelbary et al, 2009); when a low 330 amount of LH-21 was added, it could not sufficiently interact with the external solution, 331 and consequently the tablets did not disintegrate as when K-CL was used. However, as 332 the LH-21 concentration was increased, the dissolution of ETZ significantly improved, 333 and an increase in S max and a decrease in t max were observed. When 5.0% LH-21 was 334 added, the scale and shape parameters were similar to those when CMC-Ca was used. 335 Therefore, an LH-21 concentration greater than 3.0% might provide a formulation with 336 superior disintegration properties. 337 338 3.1.4. Effect of Ac-Di-Sol 339 When Ac-Di-Sol was mixed with ETZ granules at concentrations of 1.0%, 340 3.0% and 5.0%, faster ETZ dissolution from the tablets was observed in a 341 concentration-dependent manner; even when only 1.0% Ac-Di-Sol was added, S max was 342 57.56 cm 2 /tablet, which is the largest value of S max observed in this concentration, and 20
343 t max was 9.18 min. In addition, when Ac-Di-Sol was added at 3.0% and 5.0%, S max was 344 121.23 cm 2 /tablet and 138.44 cm 2 /tablet, respectively, suggesting that Ac-Di-Sol has the 345 highest water absorption and swelling abilities since it is a well-known swelling-type 346 disintegrant similar to CMC-Ca. 347 348 3.2. Physicochemical properties of tablets containing various disintegrants and 349 relationships between tablet properties and dissolution parameters 350 Table 2 shows the physicochemical properties such as disintegration time and 351 tablet hardness for the prepared tablets. A series of experimental results revealed that as 352 disintegrant concentration was increased, disintegration time decreased, whereas tablet 353 hardness remained over 150 N except for the tablet containing 5.0% K-CL (119 N), 354 which was clearly low compared to the values for the other tablets. Previous studies 355 have reported that incorporation of high amount of K-CL diminished the pressure 356 transmission ratio in tableting (Caramella et al., 1984; Schiermeier and Schmidt., 2002.), 357 and therefore this low compressibility might result in the low tablet hardness for 5.0% 358 K-CL. 359 The relationships between these physicochemical characteristics of tablets and 360 S max and t max obtained by dissolution tests are shown in Fig. 3. Tablet hardness was not 361 significantly related to t max or S max. On the other hand, a strong positive correlation was 21
362 found between disintegration time and t max and a strong negative correlation was found 363 between disintegration time and S max ; that is, as the disintegration time decreased, the 364 values of t max decreased and S max increased accordingly. Therefore, S max and t max 365 obtained through a dissolution test can be directly related to tablet disintegration. 366 367 3.3. Evaluation of disintegrant performance through water absorption experiment 368 To determine the disintegration ability of disintegrants, the time course of the 369 water absorption ratio for each disintegrant was evaluated, as shown in Fig. 4. Glycolys 370 showed good water absorption (R w ) and a fast water absorption rate, which peaked at 10 371 min. In addition, Ac-Di-Sol and CMC-Ca showed moderate water absorption, with R w 372 increasing gradually up to values around 6. On the other hand, LH-21 showed the 373 lowest R w ; when this experiment was continued to 120 min, R w slowly increased to 5.21 374 (data not shown), indicating that LH-21 absorbs water slowly. In addition, the 375 differences in the water absorption ratio among disintegrants might be attributable to the 376 hydrophilicity derived from the substituents of the disintegrants, such as the 377 hydroxypropyl group of LH-21, and the carboxymethyl groups of CMC-Ca and 378 Ac-Di-Sol. 379 380 3.3. Relationship between disintegration ability of disintegrants and available surface 22
381 area 382 To evaluate the dependence of disintegrant concentration on the dissolution 383 parameters, t max and S max, Δt max was calculated by subtracting t max at 5.0% from that at 384 1.0%, and ΔS max was calculated by subtracting S max at 1.0% from that at 5.0%. The 385 results for ΔS max and Δt max are shown in Table 3, together with the R w values from Fig. 4. 386 As mentioned above, except for LH-21, R w was measured at 60 min because, in almost 387 all cases, its value plateaued with that time; however, R w for LH-21 is listed as 5.21 at 388 120 min because the value continued to increase up to 120 min. The relationship of the 389 water absorption ratio with Δt max and ΔS max was evaluated as shown in Fig. 5. Glycolys 390 and Ac-Di-Sol, which exhibit high swellability, have low Δt max and ΔS max, indicating that 391 even if small amounts of these disintegrants are used in the formulation, high tablet 392 disintegration might be observed since these disintegrants have high water absorption 393 ratios. On the other hand, high Δt max and ΔS max values were observed for disintegrants 394 such as K-CL and LH-21 which have a low water absorption ratio, indicating that 395 although these disintegrants exhibit low disintegration performance, high tablet 396 disintegration is possible if a sufficient concentration of the disintegrant is used. In both 397 cases, strong negative correlations of the water absorption ratio with Δt max and ΔS max 398 were found, suggesting that only analysis of available surface area and the parameters 399 thereby obtained can directly provide useful information about the disintegration ability 23
400 of disintegrants. 401 Therefore, this analysis should be a convenient method for predicting the 402 ability of disintegrants as well as other pharmaceutical excipients, without the need to 403 conduct other in vitro experiment for determining the physicochemical properties of 404 tablets. 405 406 4. Conclusions 407 To date, there have been no reports that tablet disintegration due to 408 disintegrants can satisfactorily reflected in the dissolution behavior of a drug. Therefore, 409 to accurately evaluate the functionality and mechanism of disintegrants in relation to the 410 dissolution behavior of drugs, a new method that reflects both in vitro disintegration and 411 dissolution is desirable. Accordingly, in this study we investigated whether the 412 parameters t max and S max obtained by an analysis of available surface area can directly 413 provide useful information about the disintegration functionality of disintegrants. 414 When various types of disintegrants were added to a 50% ETZ formulation, an 415 increase in the dissolution rate was observed depending on the disintegrant 416 concentration. In addition, available surface area differed by disintegrant type. For 417 Glycolys, CMC-CA, and Ac-Di-Sol, a rapid increase in available surface area and the 418 largest increase in S max were observed, owing to swelling and wicking, even when only 419 1.0% disintegrant was added. In contrast, for K-CL and LH-21, a gradual increase in 24
420 available surface area was observed depending on disintegrant concentration. In 421 addition neither t max nor S max were affected by physicochemical properties such as tablet 422 hardness, while these parameters exhibited strong positive correlations with 423 disintegration time. Furthermore, to evaluate the dependence of disintegrant 424 concentration on the dissolution parameters t max and S max, Δt max and ΔS max were 425 calculated. The water absorption ratio was found to have strong negative correlations 426 with Δt max and ΔS max. Therefore, this study demonstrated that analysis of only available 427 surface area and parameters thereby obtained can directly provide useful information 428 about the disintegration ability of disintegrants. 429 430 Acknowledgments 431 The authors sincere thanks are due to the following companies; DFE 432 Pharmaceutical Co., Ltd., Asahi Kasei Co., Ltd., Shin-Etsu Chemical Co., Ltd., Nippon 433 Soda Co., Ltd., Roquette Japan K. K., BASF Japan Co., Ltd., Gotoku Chemical Co., 434 Ltd., Dainippon Sumitomo Pharma, Co., Ltd., and Iwaki Seiyaku Co., Ltd. for kindly 435 providing reagents for this study. 25
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482 Figure legends 483 Figure 1. Effects of disintegrant concentration on the dissolution behavior of ETZ 484 485 486 for (A) Glycolys, (B) K-CL, (C) CMC-Ca, (D) LH-21, and (E) Ac-Di-Sol. Each point represents the mean ± S.D. of three determinations. Cs=1647.5 mg/l, W 0 =200 mg, V=900 ml, k=0.1012 cm/min. 487 488 Figure 2. Effects of disintegrant concentration on the available surface area of ETZ 489 490 491 for (A) Glycolys, (B) K-CL, (C) CMC-Ca, (D) LH-21, and (E) Ac-Di-Sol. Each point represents the mean ± S.D. of three determinations. Cs=1647.5 mg/l, W 0 =200 mg, V=900 ml, k=0.1012 cm/min. 492 493 Figure 3. Relationship between dissolution parameters t max and S max and tablet 494 495 properties (hardness and disintegration time). Each point represents the mean ± S.D. of (a), (b) five and (c), (d) six determinations. 496 497 498 Figure 4. Measurement of water absorption ratio for various disintegrants. Each point represents the mean ± S.D. of three determinations. 499 500 Figure 5. Relationships of dissolution parameters Δt max and ΔS max with water 501 absorption ratio. 502 503 28
% Dissolved % Dissolved % Dissolved Fig. 1 Iwao et al. 100 80 60 40 20 0 100 80 60 40 20 0 A) Glycolys B) K-CL 0 20 40 60 0 20 40 60 Time(min) Time (min) C) CMC-Ca D) LH-21 0 20 40 60 0 20 40 60 Time (min) Time (min) E) Ac-Di-Sol 504 100 80 60 40 20 0 0 20 40 60 Time (min) 0% 1% 3% 5% Experimental data Theoretical curve 29
S(t) (cm 2 /tablet) S(t) (cm 2 /tablet) S(t) (cm 2 /tablet) Fig. 2 Iwao et al. 160 A) Glycolys B) K-CL 120 80 40 0 160 0 20 40 60 0 20 40 60 Time (min) Time (min) C) CMc-Ca D) LH-21 120 80 40 0 160 0 20 40 60 0 20 40 60 Time (min) Time (min) E) Ac-Di-Sol 505 120 80 40 0 0 20 40 60 Time (min) 0% 1% 3% 5% Theoretical curve 30
Disintegration time (min) Disintegration time (min) Fig. 3 Iwao et al. (A) Disintegration time (min) 40 Hardness (N) 250 30 20 R² = 0.1176 200 150 100 Hardness (N) 10 R² = 0.7066 50 0 0 20 40 60 t max (min) 0 (B) Disintegration time (min) 40 Hardness (N) 250 30 20 R² = 0.0016 200 150 100 Hardness (N) 10 R² = 0.5237 50 506 0 0 50 100 150 200 S max (cm 2 /tablet) 0 31
Water absorption ratio (Rw) Fig. 4 Iwao et al. 10 8 6 4 Glycolys Ac-Di-Sol CMC-Ca 2 0 0 20 40 60 K-CL LH-21 507 Time (min) 32
ΔS max (cm 2 /tablet) Δt max (min) Fig. 5 Iwao et al. (A) 60 K-CL LH-21 40 R² = 0.6941 20 0 Ac-Di-Sol CMC-Ca Glycolys 0 2 4 6 8 10 Water absorption ratio (Rw) (B) 160 K-CL R² = 0.821 120 80 Ac-Di-Sol 508 40 0 LH-21 Glycolys CMC-Ca 0 2 4 6 8 10 Water absorption ratio (Rw) 33