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Selecting the proper formulation and production parameters for the development of orodispersible tablets on a Prexima 80

1. Introduction

 

During the last decade, orodispersible tablets (ODTs) have drawn a great deal of attention because they are particularly suitable for geriatric and paediatric subjects and for situations where water intake is not possible [1]. The European Pharmacopoeia (EP, 9.0 edition) adopted the term orodispersible tablets for a tablet that disperses and disintegrates in less than 3 minutes in the mouth before swallowing. However, an ODTs disintegration time of less than 30 seconds improves the compliance of patients. Orodispersible tablets combine advantages of both solid and liquid dosage forms. In addition, orodispersible tablets could be very interesting for pharmaceutical industries approaching drug patent expiration [2]. Technologies usually adopted for orodispersible tablet production are lyophilisation, moulding, indirect and direct compression [1]. The production of ODTs by tableting is very appealing as it is based on well established technology. In particular direct compression is preferred in the industry due to the low manufacturing costs and ease in technology transfer [3].

 


 

2. Aim of the study

 

The real challenge of orodispersible tablets produced by direct compression is to find the correct formulation and production parameters that lead to tablets with suitable mechanical strength for the following packaging phase and, at the same time, a low disintegration time.
The aim of this research was to select the proper formulation and production parameters for the development of ODTs by direct compression. In particular the goal of the investigation was to produce tablets having both high mechanical strength and disintegration time less than 30 seconds.

 

 


 

3. Materials and methods

 

Materials

Two different fillers (Sorbitol, Neosorb, Roquette and F-Melt type C, Fuji) and three different super disintegrants (Sodium Carboxymethyl Cellulose, Ac-Di-Sol, FMC; Sodium Starch Gliycolate, Explotab, JRS; Cross Linked PVP, Kollidon CL-SF, BASF) were used. Magnesium Stearate (Polichimica) was employed as a lubricant and Diclofenac Potassium (Polichimica) as the model drug.

 


 

4. Tablets production

 

The powders were mixed using a blender (Cyclops Lab IMA, Italy) at 15 rpm for 15 minutes. All the ODTs were manufactured by a rotary tablet press (Prexima 80, IMA, Italy) using 16 kN or 22kN as the compression force.

 


 

Batch Disint. Type Disint. (%)

Compression force (kN)

Crushing
strength (N)
Friability
(%)
Disint. Time
(sec)
1

Modified Cellulose

(Ac.Di.Sol.)

1 16 69.6 0.21 183
2 22 82.4 0.13 212
3 2 16 72.6 0.28 175
4 22 73.6 0.21 182
5 5 16 54.0 0.97 180
6 22 60.8 0.50 185
7

Cross – Linked
Polyvinyl
Pyrrolidone
(Kollidon CL-SF)

 

 

 

1

16 72.6 0.20 155
8 22 91.2 0.20 148
9 2 16 64.7 0.21 140
10 22 87.3 0.21 145
11 5 16 65.7 0.20 130
12 22 96.1 0.13 135
13

Modified Starch
(Explotab)

 

 

 

 

 

1 16 69.6 0.28 169
14 22 78.5 0.13 178
15 2 16 62.8 1.20 170
16 22 83.4 0.37 169
17 5 16 44.1 2.30 155
18 22 76.6 76.6 158

Table 1: formulative, operative parameters and technological properties of Sorbitol ODTs.

 

The powder was fed through a force feed die feeder equipped with two paddle wheels. The tablets were produced with the following characteristics: round and flat shape, diameter 15 mm, thickness approximately 1 mm and weight 350 mg. The optimized turret rotation speed and the powder dosing wheels speed were 30 and 40 rpm respectively.

 


 

5. Technological characterization

 

The tablets were tested for uniformity of mass (European Pharmacopoeia 9.0 edition), friability (TA 20), crushing strength (TBH 200) and disintegration time (ZT302).


 

6. Results and discussion

 

The preliminary part of the work focused on the optimization of some operating parameters: the speed of both the turret rotation and the powder dosing wheels have been varied between 10 and 85 rpm. The results showed that the ideal speed was 30 and 40 rpm respectively. Subsequently placebo ODT batches were manufactured to investigate the effect of both types of super disintegrants and their concentration on the technological characteristics of the tablets; three disintegrants with different chemical structures were selected. In addition two compression forces were tested (Table 1). 

All the above mentioned batches contained a traditional filler (Sorbitol). The results (Table 1).

showed that the equipment speeds optimized in the preliminary part (for turret rotation and powder dosing wheels) were suitable for the production of tablets as all the batches complied with the uniformity of mass test. As expected, in increasing the compression force, tablets with a higher crushing strength were obtained and 22 kN was defined to be the most suitable to achieve the aim of the study.

As far as the effect of formulative parameters is concerned, it was shown that the best combination leading to both good mechanical properties and low disintegration time was represented by Kollidon CL-SF at 5% (Batch 12). With the aim of further reducing the disintegration time for a better patient compliance, an innovative filler, specifically designed for ODTs, was then evaluated (F-Melt). Six placebo batches were produced using the super disintegrant Kollidon CL-SF (Table 2).

All the batches containing F-Melt demonstrated compliance to the uniformity of mass test and friability lower then 0.01%. Moreover, as for the Sorbitol formulations, the F-Melt tablets showed an increase in crushing strength and disintegration time when the compression force was increased (Table 2): this could be explained by the well known binding properties of Cross-Linked Polyvinylpyrrolidone. In the last part of the study, two batches containing the model drug Diclofenac Potassium, a well known NSAD useful for fast treatment of migraine, were produced using the optimal formulative and operative parameters (Kollidon CL-SF 5%, compression force 22 kN).

Batch

Kollidon CL -SF (%)

Compression
force (kN)

Crushing
strength (N)

Friability
(%)

Disint. Time
(sec)

19

1

16

44.1

<0.01

13

20 22 61.8 67
21 2 16 53 12
22 22 76.5 58
23 5 16 48.1 16
24 22 71.6 25

Table 2: formulative, operative parameters and technological properties of F-Melt ODTs.

The results (Table 3) demonstrated that replacing part of the filler with Diclofenac Potassium did not significantly affect the properties of the tablets.

 

Batch

DiclofenacPotassium
amount (mg)

Filler type

Crushing
strength (N)

Disint. time (sec)

25 50 Sorbitol 77.5 120
26 F-Melt 71.6 32

Table 3: formulative parameters and technological properties of tablets containing Diclofenac Potassium.


 

7. Conclusions

 

The results of the investigation showed that, using Sorbitol as a filler in combination with different types and amounts of disintegrant and by varying the compression force, it was possible to produce tablets with good mechanical properties, uniformity of mass and disintegration time in compliance with the EP limits. However, the Sorbitol ODTs did not achieve a disintegration time below 30 seconds. This was obtained replacing Sorbitol with an innovative filler (F-Melt type C). When Diclofenac Potassium was introduced to the formulation, the optimal tablet characteristics were maintained. In conclusion ODTs providing optimal properties were successfully manufactured by direct compression on pilot scale.

 

References

[1] Fu et al; Crit. Rev. Ther. Drug Carrier Syst.; 21 (6) 433-475, 2004.

[2] Jeong and Park; Int. J. Pharm.; (353) 195-204, 2008.

[3] Schiermeier and Schmidt; Eur. J. Pharm. Sci.; 15, 295-305, 2002.

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