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

Transcription

1 Pharmaceutical Development and Technology, 7(3), (2002) 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 School of Pharmacy, University of Maryland, 20 N. Pine Street, Baltimore, MD 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) ; laugsbur@rx.umaryland.edu Copyright q 2002 by Marcel Dekker, Inc

2 346 Shah and Augsburger (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.

3 Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 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 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 ) 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 or 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) % % % 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, mm in size, or rounded, 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.

4 348 Shah and Augsburger 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.

5 Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 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 Primojel Tablo Super-Disintegrants d gw (mm) s g d nl,a (mm) R 2 Geometric Mean Diameter and Standard Deviation (Sieve Analysis) Explotab Primojel Tablo 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.

6 350 Shah and Augsburger 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).

7 Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 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 Primojel Tablo 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 (0.005) a 0.53 (0.03) 10.7 (0.9) 41.3 (3.2) Primojel (0.004) 0.59 (0.01) 11.8 (2.1) 48.1 (3.3) Tablo (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.

8 352 Shah and Augsburger 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 Figure 8. SEM of Primojel. Magnification ¼ 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.

9 Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 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 (0.1) a 4.1 (0.1) 3.3 (0.5) (0.1) 5.1 (0.1) 3.9 (0.2) (0.2) 5.2 (0.2) 4.1 (0.1) (0.3) 17.0 (0.3) 23.0 (0.7) (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 lactose (Filler) Super-disintegrant (sodium starch 3.0 glycolate, NF) Magnesium stearate (Lubricant) 3.0 Total tablet weight 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:

10 354 Shah and Augsburger 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 (0.14) b (0.42) (0.59) Explotab (2.73) (3.75) (2.00) Primojel (1.25) (2.11) (1.56) Tablo (1.78) (1.56) (1.05) Filler: Fast Flo lactose Control a (0.34) b (0.93) (2.02) Explotab (2.95) (3.70) (3.17) Primojel (4.15) (4.64) (3.99) Tablo (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*

11 Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 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 Primojel Tablo Explotab (75 53 mm) Explotab (45 38 mm) 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.

12 356 Shah and Augsburger 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

13 Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 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 (0.018) a (0.015) (0.019) (0.100) (0.190) (0.019) Primojel (0.091) (0.026) (0.023) (0.100) (0.018) (0.120) Tablo (0.030) (0.011) (0.018) (0.064) (0.077) (0.099) Explotab (75 53 mm) (0.024) (0.033) (0.043) (0.024) (0.051) (0.033) Explotab (45 38 mm) (0.010) (0.017) (0.014) (0.017) (0.012) (0.020) Primojel ( mm) (0.006) (0.021) (0.017) (0.011) (0.029) (0.015) Primojel (38 20 mm) (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 a (0.020) (0.011) (0.054) (0.010) (0.009) (0.087) Primojel (0.003) (0.026) (0.023) (0.010) (0.038) (0.029) Tablo (0.045) (0.023) (0.008) (0.050) (0.017) (0.043) a 95% confidence interval ðn ¼ 3Þ:

14 358 Shah and Augsburger 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 (0.22) a (0.03) (0.31) (0.32) (0.04) (0.61) Primojel (0.42) (0.06) (0.52) (0.39) (0.04) (0.83) Tablo (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.

15 Functional Equivalence of Sodium Starch Glycolate, NF from Multiple Sources 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, Shangraw, R.F.; Mitrevej, A.M.; Shah, M.N. A New Era of Tablet Disintegrants. Pharm. Technol. 1980, 4, Marshall, K.; Rudnic, E.M. Tablet Dosage Forms. In Modern Pharmaceutics; Banker, G.S., Rhodes, C.T., Eds.; Marcel Decker: New York, 1990; 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, 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), 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), Handbook of Pharmaceutical Excipients, 3rd Ed.; American Pharmaceutical Association, Washington, DC and Pharmaceutical Press: UK, Carr, R.L. Particle Behavior Storage and Flow. Br. Chem. Eng. 1970, 15, Technical Information on Explotab w, Penwest, Patterson, NY.