Production of tablets by wet granulation

Wet granulation is still the most widely used technique for preparing a tabletting mixture. There are at least four different variations of the procedure (Table 60).

Water is nowadays the most commonly used solvent. Sometimes, if water cannot be used, as with effervescent tablets, active ingredients that are prone to hydrolysis etc., ethanol or 2-propanol are used as solvents, though fluidized bed granulation technology is preferred.

Table 60. Methods of wet granulation with a binder

1. Granulation of the active substance (+ filler) with a binder solution.

2. Granulation of the active substance (+ filler)-binder mixture with the pure solvent.

3. Granulation of a mixture of the active substance (+ filler) and a portion of the binder with a solution of the remaining binder.

4. Granulation of the active substance (+ filler) with the solution of a portion of the binder followed by dry addition of the remaining binder to the finished granules.

There are a number of factors that dictate which of the methods in Table 60 must be used. With many formulations, Method 1 gives tablets with a shorter disintegration time and quicker release of the active substance than Method 2 [314]. In many cases, Method 1 gives somewhat harder tablets than Method 2. Method 3 in Table 60 is useful if Method 1 cannot be used, as when the tabletting mixture lacks the capacity for the quantity of liquid required (Table 66). If the disintegration time of a tablet presents a problem, it is worth trying Method 4, mixing in about a third of the binder together with lubricant and, last of all, the disinte-grant.

Methods 2 and 3 have proved best for drugs of high solubility, as the quantity of liquid can be kept small to avoid clogging the granulating screens.

Wet granulation with povidone K 25, povidone K 30 or povidone K 90 generally gives harder granules with better flow properties than with other binders [6477,107, 234, 241, 243, 275, 503] with lower friability and higher binding strength. Fig. 40 shows a comparison with cellulose derivatives in placebo tablets, and it can be seen in Fig. 41 that povidone K 30 gives more than the double hardness of hydrochlorothiazide tablets in comparison to maltodextrin [527]. However, not only the hardness or friability can be better, povidone also promotes the dissolution of the active ingredient. As can be seen in Fig. 42, acetaminophen (paracetamol) tablets with 4% povidone K 90 as binder release the drug more quickly than tablets with gelatin or hydroxypropylcellulose as binder, even though the povi-done tablets are harder. Similar results were obtained with 0.6 or 1.0% of povidone K 90 or hydroxypropylcellulose [544].

Povidone can be used in all the current wet granulation techniques, including fluidized bed granulation [82,156, 425] and extrusion-spheronisation [157,

Povidone K 30 Hydroxypropyl Methyl- Hydroxy-

methylcellulose cellulose propyl cellulose

Povidone K 30 Hydroxypropyl Methyl- Hydroxy-

methylcellulose cellulose propyl cellulose

Fig 40. Hardness and friability of calcium phosphate placebo tablets with 3% binder (wet granulation)

Fig. 41. Influence of 5% maltodextrine (Lycatab® DSH) and povidone on the hardness of hydrochlorothiazide tablets [527].

Lycatab® is a registered tradename of Roquettes Frères SA, Lestrem, France

Max. Compression Force, kN

Fig. 41. Influence of 5% maltodextrine (Lycatab® DSH) and povidone on the hardness of hydrochlorothiazide tablets [527].

Lycatab® is a registered tradename of Roquettes Frères SA, Lestrem, France

Fig.42. Dissolution characteristics of acetaminophen tablets containing 4% binder [425]

591, 602] or drying by microwave radiation [561], though with povidone K 90, the viscosity of the granulating solution can be critical if the technique used does not permit the use of an adequate quantity of solvent. In difficult cases, it is actually possible to improve the properties of the granulate by using granulating solutions containing a mixture of different povidone grades instead of a single grade [218] or a mixture with HPMC [581]. The addition of low-molecular polyethylene glycol to the granulating solution can improve the plasticity of the granulate [78-81].

As already shown in Table 59, particle size is increased by granulation with povidone. This increase also depends on the quantity of povidone. If microcrys-talline cellulose is granulated in a range of concentrations of 0-4% of the binder by Methods 1 and 2 in Table 60, the increase in particle size of the cellulose granulate is much the same in both methods (Fig. 43).

However, it has been possible to demonstrate in the production of caffeine tablets, that povidone K 25 increases the particle size and bulk density of the granulate, giving it better flow properties and reducing the friability of the tablets [400].

In wet granulation, the quantity of solvent, usually water, has a definite influence on the tablet properties. Increasing the amount of water as granulation liquid gave naproxen tablets with a significantly higher dissolution rate [534], ace-

Povidone in the granulate, %

Fig.43. Increase in the mean particle size of a cellulose granulate as a function of the binder concentration [362]

Povidone in the granulate, %

Fig.43. Increase in the mean particle size of a cellulose granulate as a function of the binder concentration [362]

taminophen granules that were coarser and had better flowability [549], and calcium hydrogen phosphate tablets with shorter disintegration times (Table 47). The hardness of the calcium tablets remained unchanged if the particle size of the binder was the same. The amount of granulation liquid showed a stronger effect on to the particle size and drug release than the percentage of povidone in phenylbutazone pellets manufactured by extrusion-spheronisation [157] and had an influence on the yield [591].

The optimum quantity of solvent can best be determined from the power consumption of the granulator, though it must be noted that this can vary considerably, even with the same active substance, depending on its origin [484] (Table 61). For the comparison with copovidone see Section 4.4.2.2.

Table 61. Influence of the quantity of granulation liquid (water) on the tablet properties

Povidone K 90 Hardness

Disintegration time

(% per tablet) 31 ml H2O*

52 ml H2O* 31 ml H2O*

52 ml H2O*

1.5% 94 N

99 N 105 min

34 min

3.0% 114 N

110 N 118 min

28 min

* In each case, the quantity of water relates to 515 g of CaHPO4 granules

Table 62. Rifampicin tablets (450 mg) [615]

I Rifampicin

450 g

Corn starch

58 g

II Povidone K 90

9g

Isopropanol

50 ml

III Crospovidone

15 g

Stearic acid

10 g

Magnesium stearate 2 g

Aerosil® 200 2 g

Magnesium stearate 2 g

Aerosil® 200 2 g

Granulate Mixture I with Solution II, dry, sieve and mix in the components of III, then press into tablets on a rotary tablet press using a low compression force.

Properties of tablets obtained in the laboratory:

Weight:

550 mg

Diameter:

12 mm

Hardness:

95 N

Disintegration time (gastric juice):

1-2 min

Friability:

0.6 %

Dissolution in 0.1 N hydrochloric

acid according to USP:

15 min: 86%

30 min: 90%

Aerosil® is a registered trademark of Degussa AG, Düsseldorf, Germany

The function and use of povidone K 30 and povidone K 90 as binders for wet granulation is shown in Tabs. 62-64 for several tablet formulations with drugs, developed on a laboratory scale. They were prepared by Method 1 in Table 60.

Povidone K 25 and povidone K 30 are very good binders for effervescent tablets, as they dissolve rapidly in water to form a clear solution. This particularly applies to effervescent vitamin tablets, e.g. ascorbic acid tablets [368 b]. Tables 65 and 66 give formulations for ranitidine effervescent tablets and multivitamin effervescent tablets as typical examples that were developed on a laboratory scale. For the granulation of multivitamin preparations, it is always preferable to use a fluidized bed.

In Table 66, the vitamin A palmitate should be replaced by a more modern water-dispersible vitamin A acetate dry powder, for better stability.

An interesting application for povidone as a binder lies in the wet granulation of auxiliaries in the manufacture of direct compression auxiliaries (e.g. [376], Table 67) and in the granulation of active substances for direct compression.

Active substances that are marketed in the pre-granulated form for direct compression are almost always substances that are difficult to press into tablets and/ or are prone to hydrolysis. Typical examples are the vitamins and acetaminophen [540]. Table 68 contains details on the production of ascorbic acid for direct compression, which is granulated with povidone K 30 as binder in a fluidized bed granulator.

Table 63. Pyrazinamide tablets (500 mg) [615]

I Pyrazinamide Corn starch

Povidone K 30 Water

III Crospovidone

Magnesium stearate

500 g 50 g

20 g approx. 200 ml

10-11 g 6g

Granulate Mixture I with Solution II, sieve, dry and mix in the components of III, then press into tablets on a rotary tablet press with a low compression force.

Properties of tablets obtained in the laboratory:

Weight:

Diameter:

Hardness:

Disintegration time (gastric juice): Friability:

Dissolution in water (USP method):

610 mg 12 mm 131 N

Table 64. Alpha-methyldopa tablet cores (275 mg) [615]

I Alpha-methyldopa 275 g Lactose monohydrate 55 g

II Povidone K 30 15 g Isopropanol (or water) 80 ml

III Crospovidone 8 g Magnesium stearate 2 g

Granulate Mixture I with Solution II, dry, sieve and mix in the components of III, then press into tablets on a rotary press with a medium compression force (approx. 15 kN).

Properties of tablets obtained in the laboratory:

Weight: 361 mg

Hardness: 118 N

Disintegration time (gastric juice): 5 min

Friability: 0 % Dissolution in 0.1 N hydrochloric acid (USP method): 15 min: 77%

Table 65. Ranitidine effervescent tablets [360]

I

Ranitidine hydrochloride

168 g

Anhydrous monosodium citrate

840 g

Sodium bicarbonate

836 g

Saccharin sodium

11 g

II

Povidone K 30

40 g

Ethanol 96%

q.ü.

III

Lemon flavour (powder)

25 g

Sodium benzoate, siliconized (10%)

80 g

Granulate Mixture I with Solution II, dry, sieve and mix in III, then press into 2-g tablets.

It is essential to carry out the wet granulation of active substances that are prone to hydrolysis on a fluidized bed granulator, to preserve their stability. If an ascorbic acid granulate with 2.5% povidone and 2.5% crospovidone is produced as described in Table 68, and compared with a granulate of the same composition produced by traditional means (Diosna Mixer), only the granulate produced on the fluidized bed granulator proves stable. Figure 44 shows the change in colour of these two granulates after 6 months' storage at room temperature.

The results shown in Fig. 44 demonstrate clearly that reports of incompatibility of povidone with ascorbic acid in a number of publications are based on misinterpretations or the use of inappropriate methods.

Table 66. Multivitamin effervescent tablets [615]

1.

Formulation

I

Thiamine mononitrate

13

g

Riboflavin

4

g

Pyridoxine hydrochloride

11

g

Nicotinamide

66

g

Calcium pantothenate

17

g

Tartaric acid

360

g

Sodium bicarbonate

550

g

Sucrose, crystalline

300

g

Sucrose, powder

300

g

Povidone K 30

35

g

II

Povidone K 30

5

g

2-Propanol

approx. 80

g

III

Riboflavin

6

g

Ascorbic acid, powder

550

g

Cyanocobalamin 0.1% gelatin dry powder

20

g

Vitamin A palmitate 250 000 I.U./g dry powder CWD

12

g

Vitamin E acetate dry powder SDG 50

60

g

PEG 6000, powder

80

g

Crospovidone

100

g

Granulate Mixture I with Solution II, in a fluidized bed granulator, if possible; dry, then mix with the components of III and press into tablets on a rotary tablet press with a relatively high compression force.

2. Properties of the tablets obtained in the laboratory

Weight:

Diameter:

Hardness:

Disintegration time (gastric juice): Friability:

2500 mg

20 mm

140 N

1-2 min

3. Stability (vitamin loss after 12 months at 23 °C, HPLC methods)

Ascorbic acid: Cyanocobalamin: Vitamin A: All other vitamins:

Not more than 6

Table 67. Composition of the Ludipress® direct compression auxiliary

Lactose monohydrate 93.0%

Povidone K 30 3.5%

Crospovidone 3.5%

Ludipress® is a registered trademark of BASF AG, Ludwigshafen, Germany

Table 68. Ascorbic acid granules for direct compression [369]

I Ascorbic acid powder 1920 g

II Povidone K 30 80 g Water 600 ml

Granulate the ascorbic acid (I) with an aqueous solution of povidone K 30 (II) in a 15-kg fluidized bed granulator under the following conditions:

Inlet air temperature: 60°C

Inlet air rate: Maximum setting

Spray pressure: 2-3 bar

Spraying time: 8-10 min

Drying time: 5 min

Final water content: < 0.5%

Stability:

After storage for 3 months at 40°C in airtight containers, the white colour of the product had not changed.

Fig. 44. The influence of different methods of wet granulation on the colour stability of an ascorbic acid granulate with povidone K 30 (after 6 months at room temperature) Left: Fluidized bed granulate. Right: Diosna Mixer granulate
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