Tablet Aminofilin

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3 Tablets obtained by wet granulation

– granulation in which some of the Kollidon is mixed with the active substance and the rest of Kollidon is dissolved in the solution used for granulation

3.1 Size of formulations

The last the of the three alternatives is preferred if the amount of liquid required for granulation is restricted and therefore does not suffice to obtain a solution of reasonable viscosity with all of the Kollidon.

The formulations were developed on a laboratory scale in which case 200 –1,000 g of the mixtures to be tabletted were used. Normally, the amounts weighed out in the formulations correspond to the amount in the tablets multiplied by a factor of 1,000.

3.2 Wet granulation technology Great significance is still attached to wet granulation, because direct compressing is not the most suitable technology for many active substances that are in high dosages or in fine powder form. Even if the active substance is sensitive to hydrolysis, modern equipment, e.g. in a fluidized bed, eliminates all problems in wet granulation. The granules for tabletting were mostly produced by traditional means, i.e. moistening, screening, drying, and again screening. Fluidized-bed granulation was resorted to only in exceptional cases in view of the amounts needed. Various alternatives to wet granulation in general are offered by BASF pharmaceutical excipients: – granulation with a Kollidon solution – granulation of a dry mixture of the active substance and (filler and) Kollidon with water/solvent

Other alternatives consist of using different grades of Kollidon. Substituting Kollidon 25 or Kollidon 30 by Kollidon 90 F would be particularly interesting for obtaining greater hardness without increasing the pressure. The example of a placebo tablet illustrated in Fig. 3 shows that tablets of twice the hardness of those obtained by Kollidon 25 can be achieved by using Kollidon 90 F at low pressures. Conversely, there would be some point in changing over from Kollidon 90 F to Kollidon 25 or 30 if the viscosity of the solution used in granulation is too high. In practice, however, the same hardness is usually achieved by increasing the amount of Kollidon.

3.3 Effect of the physical properties of the excipients Characterization of the physical properties of excipients is also important. This is demonstrated in Table 2 in the light of the example of hydrochlorothiazide. Tablets of greater hardness are obtained if fine instead of coarse Povidone K 90 is taken. To a certain extent, the disintegration and the release are also affected.

BASF Pharma Ingredients Generic Drug Formulations 2005

Hardness N

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Kollidon 25 Kollidon 30 Kollidon 90 F

90 80 70 60 50 40 4

6

8

10 12 Compression force kN

14

16

Fig. 3 Hardness of lactose tablets containing various Kollidon products (wet granulation)

Table 2 Influence of the particle size of Povidone K 90 on the properties of hydrochlorothiazide tablets (solvent granulation) Formulation

I

II III

Hydrochlorothiazide ............... 50.0 Povidone K 90 ......................... 7.5 Lactose monohydrate ........... 422.5 Water .................................... 37.5 Magnesium stearate ................. 2.5

mg mg mg mg mg

Tablet properties Binder

Hardness

Disintegration time

Dissolution (30 min)

Povidone K 90 95 % > 250 µm

66 N

18 min

23 %

Povidone K 90 15 % > 250 µm

97 N

22 min

19 %

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3.4 Methods of measuring the properties of tablets The general instructions for the determination of the corresponding properties of tablets (hardness, disintegration, friability, dissolution) are contained the Pharmacopoeiae Ph.Eur. or USP. If it is not stated to the contrary, the disintegration time is measured in artificial gastric juice. The release is determined by the conditions laid down in the corresponding monographs for the tablets (usually USP) and in the prescribed medium.

3.5 Information on dissolution of active substance Nowadays it is standard practice and/or laid down that the in-vitro release of active substance be checked. Unfortunately, these data cannot be given for all formulations. This is particularly the case when the active substance is sufficiently soluble or when the formulation was developed in a time when this parameter was not yet demanded.

3.6 Formulations The formulations in this chapter have been arranged in the alphabetic order of their active substances.

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3.6 Tablet formulations obtained by wet granulation (Lab Scale)

Acetylsalicylic Acid + Paracetamol (= Acetaminophen) + Caffeine Tablets (250 mg + 250 mg + 50 mg) 1. Formulation I.

Acetylsalicylic acid, crystalline (Merck) ......250 g Paracetamol, crystalline (Merck) ...............250 g Caffeine (BASF) .........................................50 g II. Kollidon 90 F [1] ........................................50 g Isopropanol ...............................................q. s. III. Magnesium stearate [2] ...............................5 g Kollidon CL [1]...........................................16 g

2. Manufacturing (Wet granulation) Granulate mixture I with solution II, dry and sieve through a 0.8 mm screen, add the components III and press with high compression force.

3. Tablet properties Weight .................................................670 mg Form ...................................................biplanar Diameter ...............................................12 mm Hardness..................................................45 N Disintegration ..........................................6 min Friability...................................................0.7 %

4. Physical stability (12 months, 20–25 °C) Weight .................................................670 mg Hardness..................................................65 N Disintegration ..........................................4 min Friability...................................................0.9 %

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3.6 Tablet formulations obtained by wet granulation (Lab Scale)

Adhesive Buccal Tablets (Basic Formulation)

1. Formulations No. 1

No. 2

Active Ingredient .............................................q.s. Lactose monohydrate ....................................76 g Carbopol ® 934 (Goodrich) .................................4 g Carbopol 980/981 1+1 (Goodrich)....................... – Kollidon VA64 [1] ............................................19 g II. Ethanol 96 % ..................................................15 g III. Magnesium stearate [2] ....................................1 g

q.s. 76 g – 4g 19 g 10 g 1g

I.

2. Manufacturing (Wet granulation) Mix intensively the components I, granulate mixture I with ethanol II, pass through a 0.8 mm sieve, dry, sieve again through a 0.5 mm sieve, mix with the component III and press with medium compression force to tablets.

3. Tablet properties Diameter ......................................................8 mm Weight ......................................................200 mg Hardness...................................................>180 N Disintegration ...........................................>30 min Friability......................................................