Selection of non-synthetic disintegrants for ...

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Tablets & Capsules July 2010

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excipients Selection of non-synthetic disintegrants for pharmaceutical and nutraceutical orally disintegrating tablets

Carmen Popescu, Liuming Zhou, and Ashish Joshi

Roquette America Hong Liu

Western Illinois University Alain Francois, Delphine Damour, and Philippe Lefevre

Roquette Frères

The purpose of this study was to broaden the applications of mannitol-based orally disintegrating tablets (ODTs) by screening disintegrants suitable for pharmaceutical and nutraceutical applications and comparing their abilities to quickly disintegrate directly compressed (DC) placebo tablets. Formulations developed in this study meet nutraceutical market claims such as “non-animal source,” “natural source,” “reduced calories,” and “non-synthetic.”

O

DTs are popular because they increase patient compliance (especially for pediatric and geriatric populations), improve portability (since they require no water), and extend product life-cycles. The FDA recommends that ODTs “disintegrate rapidly in the oral cavity, with an in vitro disintegration time of approximately 30 seconds or less” and that their weight not exceed 500 milligrams (mg) [1]. Selection of excipients for ODTs is critical in achieving rapid in vivo disintegration, a pleasant mouthfeel, and robust tablets that can withstand processing and transportation.

ODT disintegration mechanism

Materials and methods

The super-disintegrant is the key element in inducing fast disintegration of the ODT. See Figure 1 and Table 1. The super-disintegrant is a hydrophilic product that weakens the tablet by creating a hydrophilic tablet network upon swelling. Since the amount of saliva in the mouth is low (about 2 milliliters (ml)), a maximum amount of aqueous milieu should be available to allow super-disintegrant particle growth and quickly achieve optimal tablet disintegration. Therefore, the filler must have less affinity for water than the super-disintegrant. But to achieve a pleasant mouth-feel (to avoid grittiness), the filler should be water soluble. Mannitol is often used in ODTs since it has these two opposite characteristics: low affinity for water and high solubility. These characteristics facilitate fast water penetration through the channels to the super-disintegrant.

Excipient selection. A spray-dried mannitol [2] with an average particle size of 200 microns was selected as a filler. Mannitol is water soluble and has a low affinity for water (low hygroscopicity). It also has a pleasant mouth-feel and sweetness, as well as good tabletting properties. The following disintegrants were also screened: crospovidone [3], sodium croscarmellose [4], low-substituted hydroxypropyl cellulose (L-HPC) grade LH-11 [5], L-HPC grade LH-31 [6], calcium silicate [7], and silicon dioxide [8]. The lubricant magnesium stearate [9] from a vegetable source was also used. ODT preparation and evaluation. The ODT placebo formulation comprised filler (mannitol) + disintegrant + sweetener (0.5 percent sucralose) + flavor (0.35 percent) + lubricant (1.5 percent magnesium stearate). For all screened formulations, the amounts of sweetener, flavor, and lubricant were kept constant while the amount of mannitol was adjusted in correlation with the disintegrant concentration (Table 2). Crospovidone—a synthetic disintegrant used extensively in ODTs for its rapid swelling capability but not preferred in nutraceutical applications due to its synthetic nature—was used as a reference. The screened disintegrants (alone or in combination) sodium croscarmellose, L-HPC (both grades), calcium silicate, and silicon dioxide were compared to crospovidone. The ODT placebos (500 mg, 10-millimeter (mm) diameter, convex) were compressed on a single-punch tablet press [10]. The tablets were evaluated using the USP methods for hardness [11], friability [12], and in vitro disintegration time [13]. To estimate in vivo disintegration time, an in-house in vitro method was developed. Development of an in vitro disintegration predictive test. Disintegration time is the critical parameter for ODT evaluation. There are many drawbacks to the in vivo tests: low reproducibility, tester constraints, and risks associated with APIs. In addition, the USP in vitro disintegration method does not correlate well with the in vivo test (Figure 2). To better evaluate the disintegration time, we developed a test using a texture analyzer [14], which records applied forces through probes. The ODT is placed in a specially designed cup (Figure 3), then a 5-mm-diameter probe applies force to the tablet surface until it reaches 3 newtons (N). Then 2 ml of water (representing the amount of saliva) are added to the cup and, simultaneously, the change in force is recorded for 200 seconds (Figure 4). When mannitol was used as the filler, an initial increase in force occurred due to tablet swelling, followed by a quick drop (relaxation time) due to tablet disintegration. The oral disintegration time of the tablet was estimated via collapse time, which is the time required for the initial force to decrease from 3 N to 1.5 N. The collapse time was selected because it shows the best correlation with the in vivo disintegration test (Figure 5). This test, however, appears to be relevant only for ODTs formulated with mannitol.

Figure 1

ODT disintegration model

2

1

3 1: To ease the liquid penetration 2: To target the super-disintegrant 3: To not hamper the liquid penetration

Table 1

Key for ODT disintegration model Super-disintegrant

• Strong hydrophilic character that facilitates water penetration and creates a continuous hydrophilic matrix • Low solubility that does not increase the viscosity

Filler

DC non-hygroscopic excipient DC hydrophilic excipient

Lubricant

• Fast swelling or particle regeneration to the initial form • As little hydrophilicity as possible in order to reduce interaction with the water penetration/absorption

• Soluble, but not spontaneously soluble, in order to allow saliva to reach the super-disintegrant and to avoid filling the pore network with a viscous matter • A hydrophobic compound

Table 2

ODT placebo formulations at different force and hardness

Formulation 1 2

Sodium L-HPC Mannitol croscarmellose LH-31 (%) (%) (%) 89.65 92.65 92.65 89.65 89.65 89.65 92.65 92.65 90.65 90.65 88.65 88.65 90.65 90.65 90.65 88.65 88.65 88.65 90.65 90.65 90.65 89.85 89.85 92.15 92.15 90.15 90.15 90.15

3 4 5 6 7 8 9 10 11 12

L-HPC LH-11 (%)

8.00

5.00 5.00 8.00 8.00 8.00 2.00 2.00 4.00 4.00 2.00 2.00 2.00 2.00 2.00 2.00

Calcium Silicon silicate dioxide Crospovidone Force (%) (%) (%) (kN) 8.4 3.2 4.4 3.1 4.0 5.5 3.3 4.5 3.5 4.6 3.3 4.2 2.8 4.3 8.8 2.0 3.4 4.8 2.5 3.4 6.0 1.4 2.9 2.1 4.5 2.5 3.5 5.5

5.00 5.00

5.00 5.00 5.00 5.00

5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00

2.00 2.00 2.00

2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00

Results and discussion Based on the data in Table 2, we reached the following preliminary conclusions: • The ranking of the screened super-disintegrants (alone or in combination), from best to worst, is 1. L-HPC grade LH-11 ⫹ sodium croscarmellose ⫹ calcium silicate

Figure 2

0.80 0.80 0.50 0.50 0.50 0.50 0.50

Hardness (N)

In vitro (USP) Friability disintegration (≤ 1%) (≤ 30 s)

97 55 65 44 51 57 41 74 47 50 46 52 40 51 71 35 41 45 31 41 55 52 63 35 47 20 37 45

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Yes Yes Yes Yes Yes Yes Yes No No Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No No No

2. L-HPC grade LH-11 ⫹ sodium croscarmellose 3. L-HPC grade LH-11 ⫹ calcium silicate 4. L-HPC grade LH-11 ⫹ calcium silicate + silicon dioxide

Figure 4

Swelling and relaxation (collapse) curve for mannitol-based ODTs

Correlation of in vitro (USP method) and in vivo disintegration time for an average of nine subjects

3.0 2.5

Force (N)

140 120

In vivo (s)

100

80 60 40

1.5 1.0 0.5

20 10 0

2.0

0

50

100

150

200

250

In vitro (s)

300

350

400

450

0.0

0

10

20

30

40

50

Time (s)

60

70

80

90

• For a better evaluation of the in vivo disintegration time using the texture analyzer method, we selected several formulations from Table 2 (2, 3, 4, 7, 8, and 10). As shown in tables 3 and 4, using the texture analyzer method we can better evaluate the degree to which the disintegrant (alone or in combination) accelerates the disintegration process. • The formulation with the fastest disintegration time is 5 percent L-HPC grade LH-11 ⫹ 2 percent sodium croscarmellose ⫹ 2 percent calcium silicate

for an ODT placebo formulation, it is advisable to keep their concentration variation within the following intervals: 2.5 to 5 percent L-HPC, 2 to 5 percent sodium croscarmellose, and 0 to 2 percent calcium silicate.

Conclusion

For a nutraceutical ODT, a super-disintegrant combination of 5 percent L-HPC grade LH-11, 2 percent sodium croscarmellose, and 2 percent calcium silicate offers a good balance of hardness, friability, and disintegration time (less than 30 seconds) without altering the characteristics of the mannitol. This study confirms that DC mannitol was the best ODT filler for both pharmaceutical and nutraceutical applications due to its pleasant mouth-feel and sweetness, low affinity for water, and good compressibility. Since it uses a non-synthetic disintegrant, this formulation is an excellent tool for nutraceutical ODTs because it meets nutraceutical market claims such as “non-animal source,” “natural source,” “reduced calories,” and “non-synthetic.” T&C

Design of experiments (DoE) screening. Spray-dried mannitol and the disintegrant formulation with the fastest disintegration time were selected for further evaluation by a one-third-fractionated 3⫻3 factorial DoE (Table 5). The influence of their concentration on hardness, friability, and disintegration time was evaluated. See figures 6-8. We conclude that for all tested excipients within the concentration range, it is possible to reach a good hardness level. Friability ranged from 0.3 to 0.7 percent for all three disintegrants. L-HPC grade LH-11 and calcium silicate had little influence on disintegration time (USP method, six tablets) within the studied concentration interval, while sodium croscarmellose should be kept at less than 5 percent. When using a disintegrant combination of L-HPC grade LH-11, sodium croscarmellose, and calcium silicate

Figure 5

Correlation of in vitro collapse time and in vivo oral disintegration time for mannitol-based ODTs

Figure 3

250

Sample test setup for texture analyzer method [14] before (left) and after (right) probe is applied and water is added

y ⫽ 0,4353x ⫹ 15,046 2 R ⫽ 0.9223

Oral disintegration time (s)

200 150 100 50 0

0

50

100

150

200

250

300

Time of collapse (s)

350

400

450

Table 3

Evaluation of disintegration time for selected formulations using texture analyzer method [14] Formulation

Mannitol (%)

2 3 4 7 8 10

92.65 89.65 92.65 90.65 88.65 89.85

Sodium croscarmellose (%)

L-HPC LH-31 (%) 5 8

2 2

L-HPC LH-11 (%) 5 5 5 5

Calcium silicate (%)

2 2

Silicon dioxide (%)

Relaxation time (s)

Swelling (N)

0.8

43 39 70 32 26 56

0.09 0.10 0.09 0.09 0.07 0.08

500

Table 5

Table 4

Fractional factorial DoE

Influence of disintegrant on the relaxation time (disintegration) Formulation

Disintegrant

2, 3

Addition of L-HPC LH-31

8, 12

Addition sodium croscarmellose

2, 4

L-HPC LH-31 or L-HPC-LH-11 L-HPC-LH-11

4, 8, 9 8, 9

Relaxation time Decrease

Addition of L-HPC LH-11

Decrease +++

Addition calcium silicate

Decrease +

8, 9

1/3 of the full design 0 0 0 1 1 1 2 2 2

Decrease +++

LH-31 grade more efficient than LH-11 grade LH-11 works better in combination with sodium croscarmellose and calcium silicate

0 1 2 0 1 2 0 1 2

90 Percentage mannitol

95

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 80

100

4 6 Percentage sodium croscarmellose

8

10

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Friability (%) 2

3 Percentage L-HPC LH-11

4

5

6

0

2

Friability (%) 1 1.5 Percentage calcium silicate

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

0

1

2

2

2.5

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

0

0.5

Compression force 5.5 kN

Compression force 4.5 kN Compression force 4 kN

8

3 4 Percentage L-HPC LH-11

1 1.5 Percentage calcium silicate

d. Calcium silicate

d. Calcium silicate Compression force 6 kN


10

5

6

c. L-HPC LH-11

Hardness (N)

0.5

100

95

b. Sodium croscarmellose

Hardness (N)

1


Friability (%)

Hardness (N)

2

85

c. L-HPC LH-11

0

0 2 1 2 1 0 1 0 2

a. Mannitol

b. Sodium croscarmellose

80 70 60 50 40 30 20 10 0

0 2.5 5 0 2.5 5 0 2.5 5

Friability (%)

Hardness (N)

85

0

0

2 2 2 5 5 5 8 8 8

Influence of different disintegrants on friability

a. Mannitol

80 70 60 50 40 30 20 10 0

Calcium silicate

Figure 7

Influence of different disintegrants on hardness

80 70 60 50 40 30 20 10 0

L-HPC LH-11

0 2 1 2 1 0 1 0 2

Figure 6

80 70 60 50 40 30 20 10 0 80

Sodium croscarmellose

Compression force 6 kN



2

2.5

Figure 8

Number of tablets undissolved in 30 seconds

Influence of different disintegrants on disintegration time (USP method, six tablets) 7 6 5 4 3 2 1 0

80

85


95

100


a. Mannitol 7 6 5 4 3 2 1 0

2

0


8

10


b. Sodium croscarmellose 7 6 5 4 3 2 1 0

0

2

1

4 3 Percentage L-HPC LH-11

5

6


c. L-HPC LH-11 7 6 5 4 3 2 1 0

0

0.5

1 1.5 Percentage calcium silicate

2

2.5

d. Calcium silicate Compression force 6 kN



References 1. Guidance for Industry, Orally Disintegrating Tablets, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, December 2008. 2. Pearlitol 200SD from Roquette, Geneva, IL. 3. Kollidon from BASF, Florham Park, NJ. 4. Ac-Di-Sol from FMC BioPolymer, Philadelphia, PA. 5. L-HPC grade LH-11 from Shin-Etsu and distributed by Biddle Sawyer, New York, NY. 6. L-HPC grade LH-31 from Shin-Etsu and distributed by Biddle Sawyer.

7. Rxcipients FM 1000 from Huber Engineered Materials, Havre de Grace, MD. 8. Cab-o-Sil from Cabot, Boston, MA. 9. Magnesium stearate from Peter Greven, Venlo, The Netherlands. 10. XP1 tablet press from Korsch America, South Easton, MA. 11. Tablet hardness tester from Dr. Schleuniger Pharmatron, Manchester, NH. 12. VanKel friability tester from Varian, Palo Alto, CA. 13. Model DTG 2000 disintegration tester from Dr. Schleuniger Pharmatron. 14. Texture analyzer from Instron, Norwood, MA.

Carmen Popescu is project coordinator of pharmaceutical applications, Liuming Zhou is senior department manager of application technology, and Ashish Joshi is pharmaceutical technicalsales coordinator at Roquette America, 2000 South Batavia Ave., Geneva, IL 60134. Tel. 630 208 5223, fax 630 463 9440. Website: www.roquette.com. Hong Liu is associate professor in the engineering technology department at Western Illinois University, Malcolm, IL. Alain Francois is orodispersible tablets supervisor in the pharmaceutical applications laboratory, Delphine Damour is pharmaceutical applications laboratory manager, and Philippe LeFevre is pharmaceutical applications development coordinator at Roquette Frères, Lestrem, France. This article was adapted from a poster presented at the American Association of Pharmaceutical Scientists Annual Meeting and Exposition, Los Angeles, CA, November 2009.