Multiple Sources of Sodium Starch Glycolate, NF: Evaluation of Functional Equivalence and Development of Standard Performance Tests

Pharmaceutical Development and Technology, 7(3), 345 359 (2002) 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 38 39 40 41 42 43 44 45 46 47 48 49 50 51 RESEARCH ARTICLE Multiple Sources of Sodium Starch Glycolate, NF: Evaluation of Functional Equivalence and Development of Standard Performance Tests Umang Shah 1 and Larry Augsburger 2, * 1 Pfizer Global Research and Development, Morris Plains, NJ 07950 2 School of Pharmacy, University of Maryland, 20 N. Pine Street, Baltimore, MD 21201 ABSTRACT Sodium starch glycolate is a commonly used super-disintegrant employed to promote rapid disintegration and dissolution of IR solid dosage forms. It is manufactured by chemical modification of starch, i.e., carboxymethylation to enhance hydrophilicity and cross-linking to reduce solubility. It has been reported in the literature that the source of starch, particle size, amount of sodium chloride (reaction by-product), viscosity, degree of substitution and cross-linking effect the functionality of sodium starch glycolate. Compendial assays provide an accurate representation of the chemical quality of an excipient, but they are not useful in describing the physical properties associated with the excipients. Physical characterization of sodium starch glycolate, NF revealed differences in particle size, surface area, porosity, surface morphology, and viscosity between two of the three sources examined. An automated liquid uptake test (in neutral and acidic medium) demonstrated similar initial rates of uptake, however, the extent of liquid uptake differed for the disintegrant powders examined. Settling volume was also observed to be different for the disintegrant from two sources. Lowering the ph of the medium reduced the rate and extent of liquid uptake and the settling volume in all instances. The extent of liquid uptake and settling volume was observed to be higher for the smaller sieve fractions in either medium. Although differences were also observed in the axial and radial disintegration force measurements of the pure disintegrant compacts, disintegration and dissolution of a model drug *Corresponding author. Fax: (410) 706-0346; E-mail: laugsbur@rx.umaryland.edu Copyright q 2002 by Marcel Dekker, Inc. 345 www.dekker.com

346 Shah and Augsburger 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 (hydrochlorothiazide) from either the soluble or insoluble core did not reveal any significant differences between the multiple sources. Key Words: Disintegration force; Functionality; Liquid uptake; Physical characterization; Settling volume; Sodium starch glycolate, NF INTRODUCTION Starch, a traditional disintegrant has largely been replaced by a new class of disintegrants, commonly known as super-disintegrants. One such super-disintegrant is sodium starch glycolate. It is manufactured by chemical modification of starch, by substituting the hydroxyl group of the glucose units, which makes it more hydrophilic, and cross-linking, which reduces the solubility of the carboxymethylated starch thereby preventing the formation of a gel. It has been reported in the literature that the type of starch, [1] particle size after the chemical modification, [2] degree of substitution and cross-linking, [3] and the amount of soluble byproduct of the reaction [4] can affect its performance. It has been observed that the particle size and porosity of loose crospovidone powder, [5,6] another class of superdisintegrant, effected the disintegration time and dissolution rate of a model drug (hydrochlorothiazide) from an insoluble tablet core. On the basis of these observations, factors that could affect the functionality of the disintegrant such as particle size and distribution, surface area, porosity, surface morphology, and viscosity were characterized. Measurement of simultaneous rate and extent of liquid uptake for the loose disintegrant powders, as well as, axial and radial disintegration forces generated by the wetting of the pure disintegrant compacts were performed, to corelate with the differences in physical properties observed. Finally, disintegration and dissolution tests on tablets using both soluble and insoluble matrices were performed to co-relate any differences observed in physical properties with actual dissolution of a model drug (hydrochlorothiazide). SODIUM STARCH GLYCOLATE, NF Sodium starch glycolate, NF is cross-linked sodium F1 carboxymethyl starch (Fig. 1). It is prepared by both cross-linking and substitution of starch. [7] Cross-linking is carried out by either chemical methods, using reagents like phosphorus oxytrichloride, sodium trimetaphosphate, etc., or by physical methods. Carboxymethylation (substitution) is carried out as a Williamson ether synthesis, i.e., starch is reacted with sodium chloroacetate in an alkaline medium and subsequently neutralized with acid such as citric or acetic acid. About 25% of the glucose units are carboxymethylated (degree of substitution). This degree of substitution is the sum of the acid and salt substituted values. The synthesis results in sodium chloride, sodium glycolate, and sodium citrate or acetate as the by-products. [7] The process of substitution and cross-linking increases the particle size of the final product. [2] The salts are partially washed out. However, the final product retains some soluble components of the reaction process. Three commercially available sodium starch glycolates were evaluated (Table 1). T1 The NF and European monograph requirements are T2 shown in Table 2. The European Pharmacopoeia has specifications for particle size, whereas, U.S. Pharmacopoeia has none. There are no requirements for the total soluble content or degree of substitution, for either monographs. Settling volume test in water is included in the monograph of croscarmellose sodium (USP24NF19), another super-disintegrant, however, it is not a requirement for the sodium starch glycolate monograph. Figure 1. Structural formula of sodium starch glycolate.

Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 347 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 Materials EXPERIMENTAL Sodium starch glycolate, NF Explotab from Penwest, NY, Primojel from Avebe Chem., Foxhol, Netherlands, and Tablo from Pharmaceutical Ingredients, Belle Mead, NJ; hydrochlorothiazide USP (Lot 778) from Ciba- Q1 Geigy; dicalcium phosphate dihydrate, unmilled USP Di- Tab w (Lot 3375) from Rhône-Poulenc Pharmaceutical Ing., Cranbury, NJ; lactose, spray-dried NF Fast Flo w Table 1 Sources and Grades of Sodium Starch Glycolate, NF Explotab a Penwest, Patterson, NY Lot E5158X Primojel b Avebe Chem, Foxhol, Netherlands Lot 932162870 Tablo c Pharmaceutical Ingredients Ltd., Belle Mead, NJ Lot 9176/93 a Three grades, Explotab CLV (low visocity), Explotab LpH (low ph), and Explotab V17 (high viscosity), are also available. Explotab certificate of analysis includes additional tests such as sulfated ash, tapped density, swelling (water), viscosity (water), and particle size. All grades are potato starch based. b A low viscosity grade (LV) is available. Both grades are potato starch based. c Corn starch based (name changed to Pilsol). (Lot 1RLO26) from Foremost Farms USA, Baraboo, WI; magnesium stearate NF (Grade 2255, Lot 413503) from Mallinckrodt Inc., St. Louis, MO. Methods Particle Size Measurement Microscopic Analysis Q1 A microscope (Leitz Wetzlar, Germany) fitted with a video camera (MTI 65, Dage-MTI Inc., Michigan City, Table 2 Sodium Starch Glycolate, NF (Monograph Requirements) Ph Eur a Type Test USP23 NF18 A B Characters 2 þ b þ b Identification þ þ þ Microbial limits þ þ þ Acidity or alkalinity 3.0 5.0 or 5.5 27.5 5.5 7.5 3.0 5.0 Heavy metals, 0.002%, 0.002%, 0.002% Iron,0.002 %,0.002%,0.002% Sodium chloride c,7.0%,7.0%,7.0% Sodium glycolate d 2 2% 2% Loss on drying,10.0%,10.0%,10.0% Assay (of Na) 2.8 4.2% 2.8 4.2% 2.0 3.4% a Ph Eur defines sodium starch glycolate as the sodium salt of a cross-linked O-carboxymethylated potato starch. b A white or almost white, fine, free-flowing powder, very hygroscopic, practically insoluble in methylene chloride. It gives a translucent suspension in water. Examined under the microscope it is seen to consist of: granules, irregularly shaped, ovoid or pearl shaped, 30 100 mm in size, or rounded, 10 35 mm in size; compound granules consisting of 2 4 components occur occasionally; the granules have an eccentric hilum and clearly visible concentric striations; between crossed nicol prisms, the granules show a distinct black cross intersecting at the hilum; small crystals are visible at the surface of the granules. The granules show considerable swelling in contact with water. c The sodium chloride specification in NF XVII was higher (,10%). d Penwest and Avebe certificate of analysis indicates that they also comply with Ph Eur Type A requirements.

348 Shah and Augsburger 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 IN) was cabled directly into a microcomputer (Apple IIe w, Apple Computer, Cupertino, CA). The microscopic field was displayed on the computer monitor and particle size measurements were made as described elsewhere. [5] Sieve Analysis The particle size distribution of the disintegrants was determined by sieve analysis using an Allen-Bradley sonic sifter apparatus (Model L3 PF Series A, Fischer Scientific Company, Pittsburgh, PA) as described elsewhere. [5] Density Determination True Density True density of the disintegrants were determined in triplicate by helium displacement using a helium densitometer (Multivolume Pycnometer 1305, Micromeritics Instrument Corp., Norcross, GA). [5] Bulk and Tap Density The loose bulk densities of the samples were determined using a Scott Volumeter (Fisher Scientific Company, Pittsburgh, PA) which complies with the ASTM standard. [5] Surface Area Determination The weight specific surface area was determined using a balanced adsorption apparatus (Gemini 2375, Micromeritics Instrument Corp., Norcross, GA). [5] Mercury Porosimetry Study The determination of powder porosity and pore size distribution was performed using a mercury intrusion porosimeter (Pore Sizer Model 9305, Micromeritics Instrument Corp., Norcross, GA). [5] Scanning Electron Microscopy The disintegrant samples were photographed under a scanning electron microscope (Model: JSM-T200, Jeol Ltd., Tokyo, Japan). [5,6] Viscosity Study Viscosity was measured over 1 hr (readings were taken immediately and then at 1, 10, 30, and 60 min intervals). [5,9] Disintegration and Dissolution Study Direct compression formulation containing hydrochlorothiazide and either dicalcium phosphate or spraydried lactose (Fast Flo lactose) as fillers was prepared. Tablets were compressed on a single station of an instrumented rotary tablet press (Stokes RB-2, Stokes Engineering, Philadelphia, PA) using 7.9 mm diameter flat-faced punches. The tablets were compressed at 600- kg (5880 N) compression force. Tablet thickness and hardness were found similar for all the tablets containing sodium starch glycolate, NF from different sources. Disintegration times were measured in 900 ml of 0.1 N HCl solution at 37 ^ 18C; using the USP 23 method without using the discs. The final value reported is the average of six tablets. Dissolution studies were performed using the USP 23 apparatus 1 (basket method, Vanderkamp 600, Van-Kel Industries Inc., Edison, NJ) at 100 rpm as described elsewhere. [5] An average of six tablets containing no disintegrant (control) in both filler systems is also reported. Settling Volume Study Settling volume studies were performed in both distilled water and 0.1 N HCl at room temperature and the results were noted at 4 and 24 hr. The following method was employed for the settling volume test as stated in NF 18 for croscarmellose sodium: To 75 ml water in a 100-mL graduated cylinder add 1.5 g of croscarmellose sodium in 0.5 g portions, shaking vigorously after each addition. Then add water to make it 100 ml. Shake again until all of the powder is homogeneously distributed, and allow it to stand for 4 hr. Note the volume of the settled mass. Liquid Uptake Study In order to facilitate the measurement of liquid uptake in disintegrant powders, a gravimetric liquid uptake apparatus was used, described elsewhere. [6] Disintegration Force Study A system to simultaneously monitor disintegration forces and water uptake was employed. [6] The disintegrating force apparatus was designed to measure the compacts liquid uptake and disintegrating force in both the axial and radial directions, while holding the tablet volume constant.

Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 349 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 RESULTS AND DISCUSSION Microscopic and Sieve Analysis Particle size of super-disintegrants can have a profound effect on their efficiency, [5] and it is also reported that larger sized disintegrant particles are more efficient than smaller particles of the same material. [6] Microscopic particle size analysis was performed on T3 sodium starch glycolate from different sources (Table 3, F2 Fig. 2). The following is the rank order for the d nl,m : Primojel, Explotab. Tablo ðp, 0:05Þ* * indicates a one-way analysis of variance was performed using the Bonferroni test as the multiple comparison test. Sieve analysis was also performed and the mean number length diameter for the weight distribution (d nl,a ) F3 was calculated from the sieve analysis (Table 3, Fig. 3). The rank order of the d nl,m from microscopic and d nl,a from the sieve analysis was found to be similar. Density Determinations Loose and tap bulk densities were measured for the materials as received and the Carr Index, [8] which is a measure of flowability, was calculated from these values T4 (Table 4). Based on the Carr Index, Explotab and Primojel have superior flow characteristics, compared to Tablo. However, the contribution of the disintegrant to the bulk flow properties of a total formulation may not be significant because of the typically low concentration of super-disintegrants employed in tablet formulations. Surface Area Determination T5 Table 5 shows the surface area of sodium starch glycolate per gram of material. Specific surface area is an indirect measure of particle size distribution for relatively nonporous materials. Generally, the larger the specific surface area, the smaller is the average particle size and the greater is the proportion of smaller particles. The following rank order can be assigned to the specific surface area of sodium starch glycolates: Table 3 Tablo. Explotab. Primojel ðp, 0:05Þ* Greater surface area means more particles in the formulation, however, the total contribution to disintegration force, wicking, or structure recovery could be less. Mercury Porosimetry Study Geometric Mean Diameter of Sodium Starch Glycolate, NF As liquid uptake studies were performed on loose disintegrant powders, it was important to determine both the interparticle and intraparticle porosities (Table 5). It was noted that Primojel has the highest porosity, however, no differences were observed between Tablo and Explotab. Super-Disintegrants d gn (mm) s g d nl,m (mm) R 2 Geometric Mean Diameter and Standard Deviation (Microscopic Analysis) Explotab 40 1.3 41.7 0.949 Primojel 42 1.4 44.2 0.950 Tablo 23 1.5 24.2 0.913 Super-Disintegrants d gw (mm) s g d nl,a (mm) R 2 Geometric Mean Diameter and Standard Deviation (Sieve Analysis) Explotab 38 1.26 33.29 0.950 Primojel 38 1.60 35.98 0.960 Tablo 28 1.71 13.63 0.979 d gn, geometric mean diameter for the number distribution; d gw, geometric mean diameter for the weight distribution; s g, geometric standard deviation; d nl,m, mean number length diameter for the number distribution; d nl,a, mean number length diameter for the weight distribution.

350 Shah and Augsburger 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 F4 F5 F6 F7 F8 F9 Scanning Electron Microscopy Figure 2. From the SEM of disintegrant particles, it can be observed that the surface morphology and particle shapes differ greatly. These disintegrants are spherical or donut shaped (Figs. 4 9). Both Explotab and Primojel particles appear to be spherical; however, the entire surface of the former is covered with sodium chloride (a reaction by-product). Figure 3. Particle size distribution (microscopic analysis). Tablo particles are also spherical or donut shaped and covered with sodium chloride crystals, however, some particles are fused. Viscosity Study The viscosity that develops in a slurry with time is an indirect measure of cross-linking. Researchers in the past have compared the efficiency of several disintegrants Particle size distribution (sieve analysis).

Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 351 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 with the increase of viscosity over time. A method similar to that employed to determine the viscosity of Explotab [9] was used. The initial viscosities of all three disintegrants are T6 similar (Table 6, Fig. 10), however, the following rank F10 order was observed after 30 min: Explotab. Tablo. Primojel ðp, 0:05Þ* Table 4 Density of Sodium Starch Glycolate, NF Loose Powder ðn ¼ 3Þ Super-Disintegrant True Density (g/cm 3 ) Loose Bulk Density (g/cm 3 ) Tapped Bulk Density (g/cm 3 ) Carr Index Explotab 1.51 0.75 0.88 0.15 Primojel 1.56 0.81 0.98 0.17 Tablo 1.49 0.67 0.83 0.20 Super-Disintegrant Table 5 Surface Area and Porosity of Sodium Starch Glycolate, NF Loose Powder Surface Area (m 2 /g) Total Intrusion Volume (cm 3 /g) Median Pore Diameter (mm) Disintegration and Dissolution Study Porosity (Inter- and Intraparticle) (%) Explotab 0.202 (0.005) a 0.53 (0.03) 10.7 (0.9) 41.3 (3.2) Primojel 0.185 (0.004) 0.59 (0.01) 11.8 (2.1) 48.1 (3.3) Tablo 0.335 (0.010) 0.60 (0.04) 11.1 (1.8) 42.5 (2.9) a 95% confidence interval ðn ¼ 3Þ: To evaluate the effect of sodium starch glycolate, NF on disintegration and dissolution from different T7 sources, direct compression formulations (Table 7) containing the model drug and either a soluble filler (Fast Flo lactose) or an insoluble filler (dibasic calcium phosphate, unmilled) were made on an Figure 4. SEM of Explotab. Magnification ¼ 150. Figure 5. SEM of Primojel. Magnification ¼ 150.

352 Shah and Augsburger 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 Figure 6. SEM of Tablo. Magnification ¼ 150. instrumented tablet press. No significant differences in tablet size or hardness were observed for the tablets containing the disintegrant from any of the sources. For tablet cores containing the insoluble filler, no significant differences in disintegration time were T8 observed (Table 8). However, for the soluble filler system, the overall disintegration times increased and tablets containing Tablo took the longest time to disintegrate. Dissolution of hydrochlorothiazide from insoluble cores was observed to be slower than cores made from the soluble filler. The following rank order can be assigned to the initial rate of dissolution from an Figure 7. SEM of Explotab. Magnification ¼ 1200. Figure 8. SEM of Primojel. Magnification ¼ 1200. T9 F11 F12 insoluble tablet core (Table 9, Figs. 11 and 12): T9 Primojel. Explotab. Tablo ðp, 0:05Þ* F11 F12 These differences disappear at the later time-points (i.e., 15 and 25 min). No differences in the rates were observed for the initial or later time-points in the dissolution rate from the soluble cores. Settling Volume Study The glycolates are anionic, and it has been reported that lower ph reduces the settling volume. [2] It was also reported that the settling volume of Explotab and Primojel was found to be different. [2] Figure 9. SEM of Tablo. Magnification ¼ 1200.

Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 353 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 In the present study, settling volume in water F13 (Table 10, Fig. 13) revealed no differences between T10 Primojel and Explotab, however, Tablo has a considerably lower settling volume. All three disintegrants show reduced settling volume in acidic ph (0.1 N HCl). Interestingly, lower particle size fractions of Explotab have a higher settling volume, compared to the larger sieve cuts of the same lot. Liquid Uptake Study Table 6 Viscosity Study Minute Explotab Primojel Tablo 0 4.0 (0.1) a 4.1 (0.1) 3.3 (0.5) 1 4.0 (0.1) 5.1 (0.1) 3.9 (0.2) 10 6.2 (0.2) 5.2 (0.2) 4.1 (0.1) 30 31.0 (0.3) 17.0 (0.3) 23.0 (0.7) 60 73.0 (1.0) 62.0 (1.1) 62.0 (0.6) a 95% confidence interval ðn ¼ 3Þ: In the present study, an automated gravimetric liquid uptake system [5] was used to compare the disintegrants. The liquid uptake characteristics of the loose disintegrant powders allowed for an evaluation of the intrinsic hydrophilicity as well as to determine any differences in Figure 10. Viscosity study. Table 7 Direct Compression Formulation Containing 1% Super- Disintegrant Ingredients Quantity (mg/tablet) Hydrochlorothiazide (Active) 45.0 Dicalcium phosphate or Fast Flo 249.0 lactose (Filler) Super-disintegrant (sodium starch 3.0 glycolate, NF) Magnesium stearate (Lubricant) 3.0 Total tablet weight 300.0 Table 8 Disintegration Time of Tablets Containing Model Drug Sodium Starch Glycolate, NF Filler: Dicalcium Phosphate Disintegration Time (sec) Filler: Fast Flo Lactose Explotab 39 (3) a 64 (4) Primojel 35 (2) 56 (2) Tablo 40 (1) 80 (4) a 95% confidence interval ðn ¼ 6Þ:

354 Shah and Augsburger 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 Table 9 Dissolution Results (Tablets Containing Model Drug) % Dissolved in Super-Disintegrant 7.5 min 15 min 25.5 min Filler: dicalcium phosphate Control a 1.50 3.67 5.83 (0.14) b (0.42) (0.59) Explotab 45.46 77.88 96.08 (2.73) (3.75) (2.00) Primojel 54.83 77.25 96.26 (1.25) (2.11) (1.56) Tablo 38.25 66.38 85.58 (1.78) (1.56) (1.05) Filler: Fast Flo lactose Control a 4.76 11.37 22.14 (0.34) b (0.93) (2.02) Explotab 76.56 93.05 98.15 (2.95) (3.70) (3.17) Primojel 78.63 93.15 98.55 (4.15) (4.64) (3.99) Tablo 78.9 92.72 97.5 (3.41) (4.14) (3.69) a No disintegrant in the control tablets. b 95% confidence interval ðn ¼ 6Þ: Figure 11. the chemically equivalent materials. As the swelling capacities of certain super-disintegrants were found to be reduced or restricted in low ph medium, [2] it was of interest to evaluate the liquid uptake in both water and in a low ph medium. T11 The initial rate of liquid uptake (Table 11, Fig. 14) F14 using water as the medium, indicated no differences between the disintegrants, however, the following rank order can be assigned to the extent of water uptake: Primojel. Explotab. Tablo ðp, 0:05Þ* The extent of uptake for the smaller sieve fractions of Explotab and Primojel was higher compared to their respective larger sieve fractions (Table 11). No significant differences were observed among T12 the three disintegrants, in acidic medium (Table 12, F15 Fig. 15). Disintegration Force Study All disintegration tests were performed using distilled T13 water (Table 13). The following rank order can be assigned to the maximum axial force generated: Primojel. Explotab. Tablo Dissolution of hydrochlorothiazide (filler: dicalcium phosphate dihydrate, unmilled). ðp, 0:05Þ*

Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 355 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 Figure 12. Table 10 Settling Volume Study of Sodium Starch Glycolate, NF Loose Powder in Distilled Water and 0.1 N HCl ðn ¼ 3Þ Distilled Water (ml) This rank order is similar to the extent of liquid uptake (water) observed. The disintegration test does not go to completion, because the disintegrant is allowed to swell in a constant volume, which eventually prevents further liquid uptake. SUMMARY AND CONCLUSIONS The objective of this study was to evaluate the functional equivalence of sodium starch glycolate, NF from multiple sources and to determine if the monograph tests related in any way to the functionality. Dissolution of hydrochlorothiazide (filler Fast Flo lactose). 0.1 N HCl (ml) Super-Disintegrant 4 hr 24 hr 4 hr 24 hr Explotab 38 39 10 10 Primojel 38 40 7 7 Tablo 28 31 7 8 Explotab (75 53 mm) 34 35 7.0 7.5 Explotab (45 38 mm) 41 43 8 9 It is interesting to note that although differences were observed in the physical characteristics of glycolates from multiple sources, these differences did not translate into differences in disintegration or dissolution of the model drug from either the soluble or insoluble cores. Microscopy and sieve analysis revealed some differences among the disintegrants. Tablo has the smallest geometric mean diameter as indicated by both the sieve and microscopy analysis, whereas Explotab and Primojel were found to have similar mean particle size. Based on the Carr Indices, Explotab w is the best flowing disintegrant (lower Carr Index value) within its category. Scanning electron microscopy reveals differences in the surface morphology among the glycolates. Although the NF monograph for sodium starch glycolate does not indicate limits for total water soluble content, probable differences in sodium chloride were evident from the appearance of crystals on Explotab w and Tablo w particle surfaces (NF XVII specifications for sodium chloride were 3% higher than the current NF 19 specifications). There are no specifications for degree of substitution or degree of cross-linking for sodium starch glycolate in the NF monograph. Although no major differences were observed in the initial 5 min for the viscosity of a suspension of the disintegrant from various sources, later time-points indicate that viscosity of the Explotab suspension is significantly higher compared to Primojel or Tablo.

356 Shah and Augsburger 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 Figure 13. Settling volume is a physical test included in the monograph for croscarmellose sodium (cellulose-based super-disintegrant). Settling volume can provide an indirect measure of swelling. Although this monograph requires the use of water for the test, both water and 0.1 N HCl were used for the present study to evaluate the glycolates. It was observed that the settling volumes were Settling volume study: effect of ph. Figure 14. Water uptake study. significantly greater in water compared to acidic ph in all instances. One major drawback of the settling volume test is that one cannot tell whether the settled volume is due to swelling or gelling unless the total soluble fraction of the material to be tested is known. As this is not a requirement for the monograph, it is difficult to tell

Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 357 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 whether the settled volume is due to swelling or gelling. Therefore, limits of solubility for the starch glycolate are recommended to be included in the monograph. Another drawback of the settling volume study is also that it takes more time to conduct the test than it usually takes a tablet to disintegrate. However, due to the lack of a more appropriate test, the settling volume test is recommended for inclusion in the monograph. As the starch derivatives show a higher settling volume in water possibly due to gelling, a standard viscosity measurement test needs to be added to its monograph. Table 11 Liquid Uptake Parameters of Sodium Starch Glycolate, NF Loose Powder (Distilled Water) Liquid Uptake (g) Super-Disintegrant 20 sec 50 sec 100 sec 150 sec 200 sec Mean Maximum Liquid Uptake (g) Time to 50% Maximum Uptake (sec) Explotab 1.610 2.931 4.040 4.269 4.190 4.260 30 (0.018) a (0.015) (0.019) (0.100) (0.190) (0.019) Primojel 1.820 3.032 4.424 5.155 5.444 5.450 43 (0.091) (0.026) (0.023) (0.100) (0.018) (0.120) Tablo 1.700 2.920 3.611 3.575 3.430 3.523 24 (0.030) (0.011) (0.018) (0.064) (0.077) (0.099) Explotab (75 53 mm) 1.362 1.640 1.645 1.594 1.552 1.659 11 (0.024) (0.033) (0.043) (0.024) (0.051) (0.033) Explotab (45 38 mm) 1.877 2.106 2.050 1.985 1.933 2.106 7 (0.010) (0.017) (0.014) (0.017) (0.012) (0.020) Primojel (106 90 mm) 1.355 1.876 2.213 2.169 2.164 2.171 14 (0.006) (0.021) (0.017) (0.011) (0.029) (0.015) Primojel (38 20 mm) 1.355 2.414 2.562 2.561 2.538 2.566 12 (0.066) (0.016) (0.036) (0.023) (0.029) (0.004) a 95% confidence interval ðn ¼ 3Þ: Table 12 Liquid uptake by sodium starch glycolates reveals no differences in the initial rate of uptake in either medium. If the tablet disintegrates within this initial period, differences in settling volume or rate and extent of liquid uptake are not relevant. Smaller particle size fractions of sodium starch glycolate show a higher rate and extent of liquid uptake, indicating that for a given degree of cross-linking and substitution, greater surface area per unit weight leads to a faster and more extensive liquid uptake. However, swelling of larger particle would open greater voids in the tablet, further promoting greater liquid penetration Liquid Uptake Parameters of Sodium Starch Glycolate, NF Loose Powder (0.1 N HCl) Liquid Uptake (g) Super-Disintegrant 20 sec 50 sec 100 sec 150 sec 200 sec Mean Maximum Liquid Uptake (g) Time to 50% Maximum Uptake (sec) Explotab 1.382 a 1.911 2.084 2.052 2.023 2.085 12 (0.020) (0.011) (0.054) (0.010) (0.009) (0.087) Primojel 1.321 1.797 2.077 2.163 2.192 2.197 15 (0.003) (0.026) (0.023) (0.010) (0.038) (0.029) Tablo 1.247 1.651 1.688 1.671 1.654 1.691 10 (0.045) (0.023) (0.008) (0.050) (0.017) (0.043) a 95% confidence interval ðn ¼ 3Þ:

358 Shah and Augsburger 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 into the tablet. The European pharmacopoeia includes a particle size test in the monograph for both types of glycolates. These specifications are however not included in NF 19. As the settling volume study is unable to distinguish between swelling or gelling, a higher value may not necessarily mean a higher disintegrating force being generated. However, for all disintegrants studied, although the simultaneous disintegration force and water uptake study do not go to completion, the initial Table 13 Disintegration Force, Maximum Pressure, and Liquid Uptake Parameters of Sodium Starch Glycolate, NF Compacts Super-Disintegrant Axial Force Force (N) 60 sec 1800 sec Radial Force Axial Force Radial Force Average Maximum Liquid Uptake (mg) AP max (MPa) RP max (MPa) AP max /RP max Explotab 1.50 0.87 31.80 20.94 0.389 0.84 0.28 2.99 (0.22) a (0.03) (0.31) (0.32) (0.04) (0.61) Primojel 1.68 0.96 34.13 23.53 0.415 0.85 0.27 3.16 (0.42) (0.06) (0.52) (0.39) (0.04) (0.83) Tablo 0.51 0.30 29.29 19.77 0.298 0.64 0.19 3.30 (0.11) (0.03) (0.33) (0.27) (0.02) (0.31) a 95% confidence interval ðn ¼ 3Þ: Figure 15. values indicate that the disintegration force developed is directly proportional to the extent of liquid uptake. In conclusion, it could be argued that the model formulation failed to be discriminating for sodium starch glycolate because tablet matrices disintegrated (dicalcium phosphate) or dissolved (lactose) so rapidly that dissolution was the rate-limiting step. As a practical matter, the ability to elicit rapid disintegration is a highly desirable attribute. Although this model formulation was unable to detect functional differences in these cases, it is 0.1 N HCl uptake study.

Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 359 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 also possible that manufacturers are doing a good job in meeting equivalent functionally related specifications. If it were desirable to contrive a direct compression tablet formulation that might distinguish between these sources of disintegrants, several steps may be taken. For example, although the level of disintegrant used was half the lowest recommended use level of any disintegrant, it is possible that a still lower concentration would result in better discrimination. Ensuring that disintegration rate is the limiting factor for drug release by using a drug having higher solubility than hydrochlorothiazide and/or modifying the matrix to resist liquid uptake also should enhance discrimination. The rapid disintegration of these tablets suggests that the use of a more soluble drug alone would be impractical. Incorporation of a drug of sufficiently high solubility may still result in a nondiscriminating formulation. However, if a more soluble drug were combined with a high concentration of magnesium stearate and/or an extended magnesium stearate blending time, the tablet is more likely to exhibit disintegration rate-limited dissolution. Within a certain range, an increase or decrease in compression force may also help discrimination by slowing down disintegration. ACKNOWLEDGMENTS The authors would like to thank FMC Corporation for the funding of this research, Dr. Ralph Shangraw for his valuable suggestions, and Ms. Lynn DiMemmo (FMC Co.) for the excellent SEMs which helped better characterize the disintegrants. REFERENCES 1. Gadalla, M.F.; El-Hameed, M.A.; Ismail, A.A. A Comparative Evaluation of Some Starches as Disintegrants for Double Compressed Tablets. Drug Dev. Ind. Pharm. 1989, 15, 427 446. 2. Shangraw, R.F.; Mitrevej, A.M.; Shah, M.N. A New Era of Tablet Disintegrants. Pharm. Technol. 1980, 4, 49 57. 3. Marshall, K.; Rudnic, E.M. Tablet Dosage Forms. In Modern Pharmaceutics; Banker, G.S., Rhodes, C.T., Eds.; Marcel Decker: New York, 1990; 355 421. 4. Bolhuis, G.K.; van Kamp, H.V.; Lerk, C.F. Effect of Variation of Degree of Substitution, Crosslinking and Purity of the Disintegration Efficiency of Sodium Starch Glycolate. Acta Pharm. Technol. 1984, 30, 24 32. 5. Augsburger, L.L.; Shah, U. Evaluation of the Functional Equivalence of Crospovidone, NF from Different Sources. Part 1. Physical Characterization. Pharm. Dev. Technol. 2001, 6 (1), 39 51. 6. Augsburger, L.L.; Shah, U. Evaluation of the Functional Equivalence of Crospovidone, NF from Different Sources. Part 2. Standard Performance Tests. Pharm. Dev. Technol. 2001, 6 (3), 447 465. 7. Handbook of Pharmaceutical Excipients, 3rd Ed.; American Pharmaceutical Association, Washington, DC and Pharmaceutical Press: UK, 1995. 8. Carr, R.L. Particle Behavior Storage and Flow. Br. Chem. Eng. 1970, 15, 1541 1549. 9. Technical Information on Explotab w, Penwest, Patterson, NY.