NON SYNTHETIC DISINTEGRANTS SELECTION FOR PHARMACEUTICAL AND NUTRACEUTICAL ORAL DISINTEGRATING TABLETS (ODT)

Carmen POPESCU1, Hong LIU3, Alain FRANCOIS2, Delphine DAMOUR2, Liuming ZHOU1, Ashish JOSHI1 and Philippe LEFEVRE2

1 Roquette America Inc., Geneva, IL 60134, 2 Roquette Frères, Lestrem, France, 3 Western Illinois University, Macomb, IL 61455Popescu, C., Zhou, L., Joshi, A., Liu, H., Francois, A., Damour, D., and LeFevre, P. Selection of non-synthetic disintegrants for pharmaceutical and nutraceutical orally disintegrating tablets. Tablets & Capsules. Volume 8, number 5. pp. 14-20.

INTRODUCTIONOral Disintegrating Tablets (ODT) became very popular due to both increased patient compliance (especially for geriatric and pediatric populations), portability (no need for water, take them on the go), extended product life cycle and broadening the use towards macromolecules incorporation.FDA is recommending that ODT “disintegrate rapidly in the oral cavity with an in vitro disintegration time of approximately 30 seconds or less and the weight should not exceed 500mg”. The excipients selection is critical in reaching these main attributes: rapid in vitro disintegration, a pleasant mouth feel and robust tablets that can withstand processing and transportation. The purpose of this study was to broaden the mannitol based ODT applications by screening disintegrants suitable for pharmaceutical and nutraceutical applications and comparing their abilities to quickly disintegrate directly compressed placebo tablets. Formulations developed in this study meet the demands for nutraceutical market on claims such as no animal source, natural source, reduced calories and non-synthetic.

ODT disintegration mechanism As illustrated in Fig 1 and Table 1 the key element in inducing the fast disintegration of ODT in the mouth is the superdisintegrant. The superdisintegrant is a hydrophilic product that weakens the tablet when adsorbing water by creation of a hydrophilic tablet network upon (and then) swelling. The amount of saliva in the mouth is low (about 2ml). In order to reach an optimal disintegration effect in a very short time interval a maximum amount of aqueous milieu is required to be available for the superdisintegrant particle growth. Therefore the filler has to have less affinity for water than the superdisintegrant. But for a pleasant mouth feel (to avoid grittiness) the filler should be water soluble too. Mannitol is often used in ODT as it has these two opposite characteristics: a low affinity for water and a high solubility. These properties are facilitating the fast water penetration through the channels to the superdisintegrant. The excipients selection is critical for quick ODT disintegration by providing high hydrophilicity, wetability, porosity and a low viscosity through channels during the disintegration step.

Fig 1 ODT disintegration model

Table 1 Superdisintegrant Strong hydrophilic character, facilitates water

penetration and creates a continuous hydrophilic matrix

Low solubility that does not increase the viscosity Fast swelling or particles regeneration to the initial

form

Filler

DC hydrophilic excipient

DC non hydrophilic excipient

As little hydrophilic as possible in order to reduce interaction with the water penetration/ absorption

Soluble but not spontaneously in order to allow saliva to reach the superdisintegrant and to avoid filling the pore network with a viscous matter.

Lubricant A hydrophobic compound

MATERIAL and METHODS

1. Excipient selectionSpray-dried mannitol (PEARLITOL® 200SD, Roquette) with an average particle size 200 µm, soluble but with a low affinity for water, pleasant mouthfeel and sweetness and superior tableting properties was selected as a filler. The following disintegrants were screened: Crospovidone (Kollidon, BASF, (as a reference), Na croscarmellose (Ac-Di-Sol, FMC BioPolymer).Low substituted hydroxypropyl cellulose (L-HPC: LH 11 and LH 31 grades, ShinEtsu),Calcium silicate (Rxcipients), Silicone dioxide (Cab-O-Sil, Eager Polymers). Mg Stearate (Peter Greven)

2. ODT preparation and evaluationODT placebo formulation was as follows:

12

31: to ease the liquid penetration2 : to target the superdisintegrant3 : to not hamper the liquid penetration

Filler (Mannitol) +Disintegrant + Sweetener (0.5%Sucralose) + 0.35% Flavor +1.5% Lubricant (Mg Stearate)For all screened formulations the amount of sucralose, flavor and lubricant was kept constant and mannitol amounts were adjusted in correlation with the disintegrant concentration (table2). Crospovidone (a synthetic disintegrant, not allowed in nutraceutical applications) extensively used in ODT for its rapid swelling capability was used as a reference. The screened disintegrants sodium croscarmellose, L-HPC (LH 11 and LH31 grades), calcium silicate and silicone dioxide as such or in combination ( see table 2 ) were compared to crospovidone (as a reference, a superdisintegrant mainly used in pharmaceutical formulations ). The ODT placebos (500mg, 10 mm diameter, convex shape) were compressed on a Korsch XP1 single punch press. The tablets were evaluated using the USP methods for: hardness (Schleuniger Pharmatron Tablet Hardness Tester), friability (VanKel) and in vitro disintegration time (Schleuniger Pharmatron Disintegration Tester, Model DTG 2000) . To estimate in vivo disintegration timean in house method ( in vitro) was developed (see 3.)

3. Development of an in vitro predictive test for ODT oral (in vivo) disintegration time evaluation (INSTRON method)

The critical parameter for ODT evaluation is the disintegration time. There are many drawbacks for the in vivo tests: a low reproducibility, constraints for the testers, risks involved when using actives. The USP in vitro disintegration method does not have a good correlation with the in vivo test ( Fig 2).

Fig 2: In vitro (USP method): in vivo disintegration time correlation for an average of 9 subjects

Disintegration time

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60

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140

0 50 100 150 200 250 300 350 400 450

In vitro (s)

In V

ivo

(s)

To get a better evaluation of the disintegration time we developed for our study a disintegration predictive test of oral disintegration time using a universal testing machine INSTRON. This equipment is able to record the applied forces through specific probes. The ODT is placed in a specially designed cup (Fig 3). INSTRON probe (5mm diameter) is applied on the surface of the tablet till a force of 3N is reached. Then 2 ml of water (approximating the amount of saliva) are added to the cup and simultaneously the evolution of the force is recorded for a 200seconds time interval (Fig 4).

Fig 3 Sample setting for INSTRON method

Fig 4 Swelling and Relaxation (collapse) curve

When for ODT the selected filler is mannitol there is an initial increase of the force due to the swelling of the tablet followed by a quick drop ( relaxation time) corresponding to the tablet disintegration process (Fig 4). The oral disintegration time of the tablet is estimated through the collapse time which is the time required for the initial force to decrease from 3N to 1.5N. The collapse time was selected because it shows the best correlation with the in vivo disintegration test (Fig 5). But this test appears to be relevant only for ODT formulated with mannitol. Switching to spray-dried lactose as filler the method becomes irrelevant.

Fig 5 Collapse time (in vitro) and in vivo oral disintegration time correlation for mannitol based ODT

RESULTS and DISCUSSION

The ODT formulation and characterization are summarized in table 2. Based on these data we reached to the following preliminary conclusions:1. The ranking of the screened superdisintegrants (as such or in combination) is as follows: L-HPC LH 11+ Croscarmellose + Calcium Silicate > L-HPC LH 11+Croscarmellose > L-HPC LH 11 + Calcium Silicate > L-HPC LH 11 + Calcium Silicate+SiO2 2. For a better evaluation of the in vivo disintegration time using INSTRON method we have selected several formulations from Table2 (2, 3, 4, 8, 9 and 12). As per tables 3 and 4 with this INSTRON method we can better evaluate the disintegrant contribution (as such or in combination) in speeding up the disintegration process.3. The best formulation with the minimum disintegration time is: 5% L-HPC LH 11+ 2%Croscarmellose +2% Calcium Silicate

y = 0,4353x + 15,046R2 = 0,9223

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0 50 100 150 200 250 300 350 400 450 500

Time of collapse (s)

Ora

l dis

inte

grat

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time

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4. The most promising formulation using a combination of disintegrants (L-HPC LH 11+ Croscarmellose + Calcium Silicate) was evaluated by 1/3 fractionated 3x3 factorial design of experiment (DoE) for robustness. Table 2

No. Mannitol%

Croscarmellose%

L-HPCLH 31

%

L-HPCLH 11

%

Calcium Silicate

%

Silicon Dioxide

%

Crospovidone %

Forcek N

HardnessN

Friability≤ 1%

in vitro(USP)

Disintegration≤ 30sec

1 89.65 8.00 8.4 97 Yes yes

2 92.65 5.00 3.2 55 Yes Yes92.65 5.00 4.4 65 Yes Yes

389.65 8.00 3.1 44 Yes Yes89.65 8.00 4.0 51 Yes Yes89.65 8.00 5.5 57 Yes Yes

4 92.65 5.00 3.3 41 Yes Yes92.65 5.00 4.5 74 Yes No

5 90.65 2.00 5.00 3.5 47 Yes No90.65 2.00 5.00 4.6 50 Yes Yes

6 88.65 4.00 5.00 3.3 46 Yes Yes88.65 4.00 5.00 4.2 52 Yes No

790.65 2.00 5.00 2.8 40 Yes Yes90.65 2.00 5.00 4.3 51 Yes Yes90.65 2.00 5.00 8.8 71 Yes Yes

888.65 2.00 5.00 2.00 2.0 35 Yes Yes88.65 2.00 5.00 2.00 3.4 41 Yes Yes88.65 2.00 5.00 2.00 4.8 45 Yes Yes

990.65 5.00 2.00 2.5 31 Yes Yes90.65 5.00 2.00 3.4 41 Yes Yes90.65 5.00 2.00 6.0 55 Yes Yes

10 89.85 5.00 2.00 0.80 1.4 52 Yes Yes89.85 5.00 2.00 0.80 2.9 63 Yes Yes

11 92.15 5.00 0.50 2.1 35 Yes Yes92.15 5.00 0.50 4.5 47 Yes No

1290.15 2.00 5.00 0.50 2.5 20 Yes No90.15 2.00 5.00 0.50 3.5 37 Yes No90.15 2.00 5.00 0.50 5.5 45 Yes No

Table 3: Evaluation of Disintegration time for selected formulations using INSTRON method

FormulationMannitol

% Croscarmellose

%L-HPC

LH31 %L-HPC

LH 11 %

Calcium Silicate

%

Silicon Dioxide

%Relaxation

time (s)Swelling

(N)2 92.65   5       43 0.093 89.65   8       39 0.104 92.65     5     70 0.098 88.65 2   5 2   26 0.0797 90.65 2   5     32 0.09

1210 89.85     5 2 0.8 56 0.08

Table 4 Influence of disintegrant on the relaxation time (disintegration)

Formulation Disintegrant Relaxation time2, 3 Addition of L-HPC LH31 Decrease 4,7,84, 8, 9 Addition of L-HPC LH11 Decrease +++88, 12 Addition croscarmellose Decrease +++

8, 10 8, 9 Addition calcium silicate Decrease +2, 4 L-HPC LH31 or L-HPC-LH 11 LH 31 grade more efficient than LH11 grade 7,88, 9 L-HPC-LH 11 LH11 grade is working better in combination

with croscarmellose and calcium silicate

4. DoE ScreeningAs per Table 5 spray dried mannitol, sodium croscarmellose, L-HPC L11 and calcium silicate were selected for further evaluation by a 1/3 fractionated 3x3 factorial design of experiment (DoE) and the influence of their concentration on hardness, friability and disintegration time was evaluated as follows:

Table 5 Fractional Factorial Design

1/3 of the full design CroscarmelloseL-HPC LH-11 Ca Silicate

0 0 0 2 0 00 1 2 2 2.5 20 2 1 2 5 11 0 2 5 0 21 1 1 5 2.5 11 2 0 5 5 02 0 1 8 0 12 1 0 8 2.5 02 2 2 8 5 2

Influence on hardness:

Influence on friability:

Influence on disintegration time (USP method, 6tablets)

Summarizing DoE results we can conclude that L-HPC LH 11 and Ca Silicate have less influence on disintegration time ( USP method, 6 tablets) within the studied concentration interval while croscarmellose should be kept at less than 5%. The friability was 0.3-0.7% for all three disintegrants within their range of tested concentrations. For all tested excipients in the concentration range it is possible to reach a good hardness level. Using L-HPC LH 11+ Croscarmellose + Calcium Silicate combination as disintegrant for ODT placebo formulation it is advisable to keep their concentration variation within following intervals: 2-5%Croscarmellose; 2.5-5% L-HPC LH-11 and 0-2% Ca silicate

Conclusion:For ODT extension towards nutraceutical market, a superdisintegrant combination of 5% L-HPC LH 11with 2% croscarmellose and 2% calcium silicate offers a good balance of hardness, friability and disintegration time (< 30 sec) without any alteration of mannitol characteristics.. This study conforms that DC mannitol due to its properties (pleasant mouth feel, sweetness, particle size, low water affinity and very good compressibility) is the best ODT filler for both Pharmaceutical and Nutraceutical applications. Using a non synthetic disintegrant this formulation is an excellent tool for nutraceutical ODT adding on its behalf claims like: non animal source, natural, reduced calories and non-synthetic.