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Thursday, May 14, 2009

SUPERDISINTEGRANTS

SUPERDISINTEGRANTS

MubashirHH, Vimal Mathew

National College of Pharmacy, Manassery, Calicut


Disintegrants and superdisintegrants are used in tablets and capsules to ensure that these comparts are rapidly broken down into the primary particles to facilitate the dissolution or release of the active ingredients.


Superdisintegrants which provide improved compressibility compared to prior art superdisintegrants and which does not negatively impact the compressibility of formulations which include high dose drugs, and methods for obtaining the same are disclosed. The superdisintegrants include a particulate agglomerate of coprocessed starch or cellulose and a sufficient amount of an augmenting agent to increase the compatibility of the super disintegrant. T he augmented super disintegrant provides a fast disintegration of a solid dosage form when incorporated in sufficient quality therein, without untowardly affecting the compatibility of the solid dosage form. some superdisintegrants and their properties are listed below:

  1. Croscarmellose sodium (AC-Di-Sol)

    High swelling capacity, effective at low concentration (0.5-2.0 can be used up to 5.0%)

  2. Crospovidone: (Polyplasdone XL, poly plasdone XL 10)

    Completely insoluble in water. rapidly disperses and swells water, but does not gel even after prolonged exposure. Greatest rate of swelling compared to other disintegrants. Greater surface area to volume ratio than other disintegrants. Recommended concentration 1 tp 3%. Available in micromised grades if needed to improve uniform dispersion in the powder blend.

  3. L-HPC: (Low substituted hydroxy propyl cellulose)

    Insoluble in water. rapidly swells in water. grades LH-11 and LH-21 exhibit the greatest degree of swelling. Certain grades can also provide some binding properties while retaining disintegration capacity. Recommended concentration 1-5%.

  4. Sodium starch glycolate: (Primojel)

Absorbs water rapidly, resulting in swelling which leads to rapid disintegrantation of tablets and granules. Recommended concentration 1.0-4% but may need to use upto 6.0%. Gels on prolonged exposure to water. high concentration causes gelling and loss of disintegration.






EVALUATION ASPECTS OF SUPER DISINTEGRATS


Most common tablets are those intended to be swallowed whole and to disintegrate and release their medicaments rapidly in the gastrointestinal tract (GIT). The proper choice of disintegrant and its consistency of performance are of critical importance to the formulation development of such tablets. In more recent years, increasing attention has been paid to formulating not only fast dissolving and/or disintegrating tablets that are swallowed, but also orally disintegrating tablets that are intended to dissolve and/or disintegrate rapidly in the mouth.


Most prior studies have focused on the function-related properties of superdisintegrants with special emphasis on correlating these functional properties to disintegrant efficiency and drug release rate. Water penetration rate and rate of disintegration force development are generally positively related to disintegrant efficiency in nonsoluble matrices.4,5 However, such a positive correlation is not always observed between tablet disintegration time and drug dissolution rate.


The objectives of this study were thus to provide a closer look at the functionality of superdisintegrants in promoting tablet disintegration and to develop a model formulation for discriminating super disintegrant functionality. To those ends, the size distribution of disintegrated dicalcium phosphate-based fast disintegrating tablets was examined with the help of videography and dissolution profiles of aspirin were compared for tablets containing different superdisintegrants at varied levels of addition. Aspirin has been successfully applied by many investigators in studying the mechanisms of tablet disintegrants13-15 and was selected in this study because of its good compactibility and moderately low solubility in water.


Materials and Methods

Materials

Acetylsalicylic acid (aspirin) Dicalcium phosphate dihydrate, Lactose monohydrate (spray-dried NF Fast Flo). The 3 superdisintegrants studied were croscarmellose sodium (Ac-Di-Sol, FMC BioPolymer, Philadelphia, PA), sodium starch glycolate (Primojel, DMV International, Veghel, The Netherlands), and crospovidone NF (Polyplasdone XL and Polyplasdone XL10, ISP Technologies, Ashland, KY). Magnesium stearate (Mallinckrodt, St Louis, MO) was used as the internal lubricant. Dicalcium phosphate and magnesium stearate were sieved through screen No. 45 (354 µm), and aspirin was sieved through screen No. 60 (250 µm) before use. Superdisintegrants were used as received.


Methods

Blending and Tableting

Either dicalcium phosphate or aspirin was premixed with superdisintegrant for 15 minutes in a 500-mL twin shell blender (Patterson Kelly Twin Shell V-Blender, model LB-331, The Patterson-Kelly Co, East Stroudsburg, PA), and then lubricated with magnesium stearate for another 5 minutes. The magnesium stearate level was fixed at 0.5% for all formulations. Superdisintegrants were used at 1% and 2% in dicalcium phosphate tablets, and at 1%, 2%, and 5% in aspirin tablets. Round flat-faced tablets with diameter of 8.8 mm were prepared one at a time on an instrumented rotary press (Stokes B2, Stokes Engineering, Doylestown, PA). The weight of dicalcium phosphate tablets was 445 ± 5 mg, and the weight of aspirin tablets was 300 ± 5 mg. The tablet press setting was kept constant across all formulations. The resulting compression force was 5.1 ± 0.2 kN for dicalcium phosphate tablets and 3.9 ± 0.2 kN for aspirin tablets. Tablets were placed in scintillation vials and the vials were stored in a desiccator for at least 24 hours before testing.

Disintegration and Dissolution Test

Disintegration times were measured in 900 mL purified water according to the USP 24 method without disc at room temperature (20°C ± 2°C). Previous study showed that the tablet disintegration times were linearly increased by reducing the medium temperature from the 37°C required by the USP 24 method to room temperature, as were the differences between tablet disintegration times.16 The disintegration times of 6 individual tablets were recorded and the average was reported.

Dissolution profiles of aspirin tablets were determined using the USP 24 Method II (Vankel VK7000, VanKel Industries, Edison, NJ) with paddle speed at 50 rpm. Dissolution was performed in 900 mL purified water at room temperature (20°C ± 2°C), the same medium as used in the disintegration test. A peristaltic pump (Rainin Instrument Co, Kent, WA) was coupled to a Shimadzu UV-160U UV/visible spectrophotometer (Shimadzu Corp, Tokyo, Japan) to provide a continuous flow of drug solution through the 1-mm cuvettes. The absorbance of aspirin solution at 229 nm was analyzed every 30 seconds for 45 minutes. The data given are the means of 6 individual determinations.




Figure 1. Disintegration of dicalcium phosphate tablets with 1% superdisintegrant in purified water at zero degree of agitation





Figure 2. Disintegration of dicalcium phosphate tablets with 2% super disintegration in purified water at zero degree of agitation


Water Uptake Study by Aspirin Tablets

A modified gravimetric liquid uptake apparatus was used to measure water uptake by the aspirin tablets. The apparatus consists of a sample holder and a liquid holding vessel that is set on an electronic balance. These 2 parts of the apparatus are adjusted to the same horizontal level and connected by a plastic tube so that water can flow freely from one side to the other. When a tablet was placed onto the sample holder, water was then passively withdrawn into the tablet from the feeder. The loss of weight from the liquid holder was read from the electronic balance. The readings were automatically transferred to a PC and collected by a program written in C++ language. Data were collected every second until saturation was reached. Experiments were performed in triplicates at room temperature. All tablets were saturated with water rapidly within 0.5 to 2 minutes. Therefore, only the tablet maximal water uptake amount was reported.


Tablet weight, hardness, and disintegration time are presented in Table 1. All tablets were found uniform in weight and hardness


Table 1. Dicalcium Phosphate Tablets Properties*

Superdisintegrant

Weight
(mg)

Hardness
(kp)

Disintegration Time
(seconds)

1% Disintegrant

Ac-Di-Sol

446 (1)

19.7 (1.0)

15 (0)

Primojel

445 (1)

20.0 (0.8)

132 (65)

Polyplasdone XL

446 (1)

17.9 (1.9)

716 (355)

Polyplasdone XL10

446 (1)

17.6 (1.7)

185 (67)

2% Disintegrant

Ac-Di-Sol

446 (1)

15.2 (1.1)

7 (0)

Primojel

447 (1)

14.6 (0.4)

38 (24)

Polyplasdone XL

442 (1)

15.0 (1.2)

78 (18)

Polyplasdone XL10

442 (1)

15.5 (1.0)

10 (3)


*All values are mean ± SD, n = 6.


All tablets disintegrated rapidly in the USP test. However, the relatively larger fragments generated by tablets containing Primojel and Polyplasdone XL were not small enough to pass through the screen of the disintegration vessels. Accordingly a longer disintegration time and a larger variation were observed for both formulations, especially when the disintegrants were used at the lower concentration (1%). Ac-Di-Sol and Polyplasdone XL10 disintegrated tablets more rapidly. Tablets formulated with 2% of those 2 disintegrants disintegrated nearly immediately, even when tested at room temperature

Aspirin Tablets

The disintegration test is not discriminating since all superdisintegrants appear highly efficient, with disintegration times as short as 30 seconds when used at 2% concentration. However, as discussed above, the videos (Figures 1 and 2) demonstrated differences in the particle size generated in the disintegrated tablets. Those differences could affect drug dissolution since breaking tablets into finer fragments may promote drug dissolution by providing larger total surface areas for drug dissolution to take place. The disintegration times and dissolution profiles of aspirin tablets formulated with 1%, 2%, or 5% Ac-Di-Sol, Primojel, or Polyplasdone XL10 are given in Table 2 and Figure 3. Because of its comparably poorer disintegration efficiency, Polyplasdone XL was not included in this part of study.


Table 2. Aspirin Tablet Properties*

Superdisintegrant

Disintegration Time (seconds)

Q15 (%)

Q30 (%)

Q45 (%)

Maximal Water Uptake (mg/tablet)

0% Disintegrant

Control

N/A†

2.2 (0.4)

4.2 (0.6)

6.1 (1.0)

0.02 (0.00)

1% Disintegrant

Ac-Di-Sol

23 (2)

45.7 (6.4)

82.6 (6.8)

103.7 (6.4)

260 (7)

Primojel

1262 (302)

5.3 (0.8)

10.4 (1.6)

15.3 (2.4)

84 (3)

Polyplasdone XL10

68 (30)

13.8 (2.0)

26.3 (3.4)

38.0 (3.7)

134 (2)

2% Disintegrant

Ac-Di-Sol

20 (3)

61.2 (4.8)

98.6 (3.3)

110.1 (2.2)

295 (5)

Primojel

74 (24)

29.2 (4.1)

49.5 (5.1)

64.6 (4.9)

230 (6)

Polyplasdone XL10

36 (6)

28.6 (4.7)

46.4 (6.5)

61.4 (3.2)

185 (11)

5% Disintegrant

Ac-Di-Sol

17 (7)

71.1 (14.2)

100.9 (10.3)

110.2 (9.1)

346 (6)

Primojel

31 (1)

63.1 (7.0)

92.4 (3.6)

100.9 (4.6)

303 (5)

Polyplasdone XL10

19 (2)

41.8 (7.9)

67.8 (9.7)

83.6 (12.9)

269 (4)


*All values are mean ± SD, n = 6.

†N/A indicates not applicable; tablets fail to disintegrate after 45 minutes.



Figure 3. Dissolution of Aspirin from tablets with different concentration of superdisintegrants (mean ± SD, n = 6).



Figure 4. Correlation between the maximal water uptake by Aspirin tablets and the cumulative percentage of drug dissolved after different period of time


In the present study, 3 disintegrants representing each of the 3 main classes of superdisintegrants differed in their ability to disintegrate model tablets into their primary particles when used at the same wt/wt percentage concentration. Such a difference can potentially affect drug dissolution. The aspirin tablet matrix appeared to successfully discriminate the ability of these superdisintegrants to promote drug dissolution and is proposed as a model formulation for disintegrant performance testing and quality control purposes.


Powder characterisation


The volume median dimeters of superdistinetgrants in different media determined using the Malvern Mastersizer are given in figure 1. according to the volume median diameters, primajel swells only to 20% as much as 0.1N HCl as in water. A significant reduction in swelling capacity is also observed for Ac-Di-Sol in 0.1 N HCl, which swells to half that in water. The strong decrease in swelling capacity of chemically modified starches and celluloses may attribute to the converting of the carboxymethyl sodium moieties to its free acid form in acidic medium for both substances. Since the acid form has less hydration capacity than its salt form, the liquid holding capacity of the disintegrant particles reduces after deionization in the acidic medium. Therefore, the total degree of substitution and the ratio of basic to acidic substituents are potential factors determining the extent of influence of medium pH on the water uptake and swelling properties of disintegrant particles. Unlike the other 2 superdisintegrants, there is no apparent change in the swelling capability of the nonionic polymer Polyplasdone XL10 in both media. The percentage of increase in diameter for Ac-Di-Sol, Primojel, and Polyplasdone XL10 is 104%, 251%, and 29% in water and 51%, 43%, and 33% in 0.1 N HCl, respectively. Therefore, the large difference in swelling capacity between superdisintegrants in water is less significant in acidic medium.




Figure 1. Volume median diameter of superdisintegrants in different media (mean ± 1.96 SE, n = 3 for air; n = 9 for water and 0.1 N HCl).


Generally spherical-shaped Primojel particles more likely absorb water and retain it rather than transfer it to the next particle. In other words, the water-transferring rate between Primojel particles is slower than the swelling rate of individual particles. In addition, Primojel swells in 3 dimensions, whereas Ac-Di-Sol swells preferentially in 2 dimensions only. Assuming the degree of swelling in diameter were reduced to the same extent for both materials in acidic medium, the decrease in volume would be more profound for the former (cubic to diameter) compared with that of the latter (quadratic to diameter). This also partially explains the marked decrease in total water uptake volume by Primojel from acidic medium. Polyplasdone XL10 behaves the same in both media during liquid uptake, which is consistent with the particle size distribution analysis.