WO2006092577A1

WO2006092577A1 - Wet granulation process

Info

Publication number: WO2006092577A1
Application number: PCT/GB2006/000701
Authority: WO
Inventors: Jinsheng Fu; Agba D. Salman; Michael J. Hounslow
Original assignee: University Of Sheffield
Priority date: 2005-03-02
Filing date: 2006-02-28
Publication date: 2006-09-08
Also published as: WO2006092577A8

Abstract

A granulation process achieving tight size distribution and homogenous composition comprises: a) adding liquid to a powder in a mixer; b) first mixing the liquid and binder to form intermediate granules; c) selecting intermediate granules while wet that are larger than a predetermined diameter from smaller granules; d) crushing said intermediate granules to a size less than said predetermined diameter; e) second mixing said crushed granules with said smaller granules while still wet until granulation is complete. The crushing of the larger granules serves to redistribute the binder.

Description

Wet Granulation process

This invention relates to a method of granulating a powder .

Granulation can be effected in a number of ways, typically in a high shear mixer. However, if sphericity of the granules is an important criterion, then rolling mixers are used. Other mixers, such as fluidised beds, are common.

The granulation process is only just beginning to be understood. Hitherto, it has been more of an art than a science. Granulation involves the addition of a liquid binder to a powder and mixing them so that the powder binds together forming granules. The granules are used, either as an intermediary for another product, for example, as raw material for forming tablets, such as soap or pharmaceutical tablets, or as an end product itself, such as coffee granules, typically after being dried.

There are many factors that affect the outcome of granulation processes, including the materials employed and the mixing regimes or protocols applied. The desired outcome varies depending on the application of the granules . In the pharmaceutical industry, especially, very close tolerance is required as regard to a number of different aspects of granules, including close size distribution, consistent constituency of the granules, good sphericity and consistent fracture strength.

Indeed, seldom is it a requirement that there be a mix of different sizes, constituents etc, although often such is not a particular problem. The present invention, however, is aimed at a process that achieves better results, at least in the size distribution and granule composition aspects of granulation.

JP-A-06170206 discloses a granulation process in which sphericity and consistent size distribution is desired. This is in the field of grinding beads made of sintered zirconia powder. Here the process involves mixing powder and binder in a high shear mixer, separating larger than 2 mm diameter granules therefrom and rolling the cores formed in the mixer in a rolling granulation process. The outcome is round granules of about 15 mm diameter in a shorter time than would hitherto have been achived using solely a rolling granulation process.

However, there is no discussion of the binder consistency, which in that application is not relevant.

Reynolds et al [1] , establish that, in a mixer granulation process, binder constituency appears to be a function of granule size, where large granules are wet, and tend to get larger, whereas small granules are dry and therefore to do bind with others .

It is an object of the present invention to provide a process which improves both the size distribution and binder constituency of granules .

In accordance with the invention, there is provided a granulation process comprising the steps of: a) adding binder to a powder in a mixer; b) first mixing the powder and liquid binder to form intermediate granules; c) separating intermediate granules while wet that are larger than a predetermined diameter from smaller granules; d) crushing said intermediate granules to a size less than said predetermined diameter; e) second mixing said crushed granules with said smaller granules while still wet until granulation is complete.

Preferably, said predetermined size is calculated on the basis of a predetermined percentage of size relative to a specific size of granule that has the average binder constituency of the mixture as a whole at the time of said separating step. Preferably, said percentage is zero, in which event all intermediate granules of size greater than said specific size are broken into smaller sizes. Thus, by way of example, it may be that, at the separating step, particles of greater diameter than 2 mm have a binder constituency greater than the average binder constituency. In this event, if said percentage is set at zero, all granules greater than 2 mm in diameter are crushed to particles of less than 2 mm diameter. If said percentage is set at 50%, then all particles of greater than 3 mm diameter are crushed.

In many cases, said specific size is 1 mm or less.

The present invention recognises that wet particles grow preferentially to dry particles. Consequently, more even size distribution can be achieved by breaking wet particles. This also has the effect of improving binder distribution. The degree of homogeneity in size and constituency achieved is a matter of choice, depending on the application of the final granules .

Preferably, said first mixing is continued until said specific size has stabilised. That is to say, said specific size tends to grow as mixing progresses but, after a period of time, said specific size tends to stabilise, or at least not change as rapidly as in the first few minutes of said first mixing. Preferably, said first mixing is effected for at least 2 minutes.

Preferably, said second mixing is continued for at least three times as long as said first mixing.

Said binder may be solid when mixed with said powder. The binder in this case is liquified before or during step b) above. The binder may comprise a wax. In this event, said binder is preferably ground to a particle size less than 2 mm in diameter before addition to said powder in step a) above.

The invention is further described hereinafter, by way of example, with reference to the following Example and the accompanying drawings, in which: - Figure 1 is a graphical comparison of size distribution of granules made from a prior art protocol (NP) and the method according to the present invention (SP);

Figure 2 is a graphical comparison between SP and NP of binder content in granules of different size classes;

Figure 3^' is a graphical comparison of the extent of scatter of fracture strength of granules made by NP and SP - strength values of approximately 30 individual granules, as a function of granule size; Figure 4 is as Figure 3, but an average value of strength and standard deviation (the length of error bar represents the calculated standard deviation)

Figures 5 a and b are respectively photographs of granules made by NP and SP. Example

Granule quality can be improved by optimising the operation conditions (protocol) . In order to confirm the improvement, the granule quality of two typical batches to produce granules, based on same binder ratio (0.125) and same granulation time (45 minutes), was compared as between a "normal" protocol and a protocol in accordance with the present invention. The term "normal" protocol refers a typical operation condition found in open literature. The main feature of normal operation protocol is to keep the operation conditions constant throughout the process..

The granule quality concerned in this work involved size distribution, binder distribution, granule strength and appearance.

Experimental Material

Durcal 40 and PEG 1500 were used as dry powder and liquid binder. PEG 1500 is a polyethylene glycol of about 1500 Daltons molecular weight. It is in solid flake form at room temperature. The melting point is about 45⁰C. The density of its liquid is about l.lOβg/ml and its viscosity is 8ImPa. s at 25°C. The characteristic values of Ducal 40 are shown in Table 1.

Table 1. Characteristic value of Durcal 40

Equipment

Granulation was performed in Zanchetta Junior (ZRJ) granulator (10L) . There are two agitators inside the mixer: one is a three-blade impeller that is vertically mounted symmetrically on the centre of the mixer. The other is a chopper which is smaller than impeller (45 mm and 265 mm in diameter, respectively) . The impeller speed could be adjusted in the range of 0-800 rpm, and the chopper up to a speed of 1400 rpm. There is a jacket in the mixer wall and hot water circulates in it to heat the product in the mixer bowel .

Operation protocols

Normal protocol (NP)

The normal protocol consists of following steps :

• Dry powder addition: 3 kg of dry Durcal 40 was added into mixer bowl. • Heating the dry powder: set the boiler temperate at 60 °C and start the impeller speed at 300 rpm and chopper at 1400 rpm.

• Binder addition: when the product (dry powder) in the mixer bowel reached 45⁰C, stop the impeller and open the mixer lid and add the solid binder (flakes) on top of the powder. The amount of binder added was 375g, making the binder ratio was 0.125.

• Granulation: re-start the impeller at 300 rpm and chopper at 1400 rpm and keep the speed until the process termination. The granulation process is undergone at a temperature in the range of 45 -60°C in which the PEG 1500 binder stays in a liquid state .

• Termination of the process: after 45 minutes of mixing, stop the impeller and chopper and collect the product. The collected product dries in open air at room temperature by solidifying the PEG 1500 in the granules.

Special Protocol (SP)

A special protocol (according to the invention) was designed to obtain a specific quality of product involving: a) Smaller span of size distribution; b) Better binder distribution in different size granule; c) Smaller scatter in strength of individual granule in same size class; d) Higher sphericity.

The protocol consisted of the following steps:

• Dry powder addition: 3 kg of dry Durcal 40 was added into the same mixer bowl as in NP. • Grinding the solid flakes PEG to powdery state: grinding the solid PEG1500 flakes can be done using any type of grinder, eg. coffee grinder or food processor. The size to which the flakes are ground depends on what uniformity of product binder and size distribution is required. Generally the higher the uniformity that is required, the smaller the size of solid binder is needed. However, too small size of PEG particle will form loose structured lumps, which adversely affects good distribution of binder in the powder system. In the present case the PEG flakes was grinded to 1.00 μm. However, it is not absolutely necessary to grind the flakes at all to achieve better results than the NP.

• Binder addition: added the ground PEG (375g) onto the top of the powder in the mixer bowel. • Pre-mixing the mixture: after adding the binder, start the mixing process at room temperature for a five minutes at a chopper speed of 1400 rpm and an impeller speed of 750 rpm, allowing good dispersion of PEG in powder system.

• Heating the material in the mixer: set the boiler temperature at 60°C and rotating the impeller at a rotation sped of 300 rpm and chopper at 1400 rpm until the product temperature reaches 45°C, at which point the PEG starts to melt and the granulation imitates .

• Granulation: after the product temperature reaches 45°C, the impeller speed is increased to 750 rpm, the chopper speed being kept at 1400 rpm for 10 minutes. The granulation process takes place in the temperature in the range of 45-60°C.

• Crushing the large granules : remove all products in the mixer bowel and collect that portion of the formed granules larger than 1.00mm diameter by sieving. Crush these larger granules in a grinder to a size less than 425μm and put back to mixer bowl with the rest.

• Restart the granulation process: continue mixing, a) 5 minutes with the chopper at 1400 rpm and impeller at 500 rpm, b) another 10 minutes with the chopper removed and impeller at 500 rpm, and finally c) 5 minutes with no chopper and an impeller speed of 100-150 rpm, stages a) and b) producing granule growth and stage c) finishing the granule surface and shape.

• Stop the impeller and chopper (termination of the process) and collect the product. The collected product dries in open air at room temperature by solidifying the PEG 1500 in the granules. Results

Size distribution

The granule size distribution was measured using a Retsch Camsizer (Kurt Retsch GmbH & co . KG), which is an optical measuring system for determining solid particle sizes of dry, free flowing and harmless bulk products. The total recommended measuring range is 30 μm and 30mm. The operating method of the system is based on digital image processing of a projected area of the particles. The measurement result of the products from the two protocols is shown in Figure 1, and the characteristic value of the size distribution was calculated and is presented in Table 2 below.

Table 2. Comparison of characteristic values of the volume based size distribution between NP and SP

Note : a. X1O%, X50% and X90% are granule sizes corresponding to cumulative distribution of 10%, 50% and 90% of the sample, respectively. b. Span = (X90% - X10%)/X50%

Figure 1 and Table 2 show that the product size distribution of the granule produced using SP was much narrower than one by NP - the span of 0.543 for SP comparing to 1.323 for NP.

Binder distribution

The binder content in the granule with different size classes was determined from the loss in weight after heating a group of granules (0.5-1.Og) for 2 h at 600°C. The measurement results are shown in Figure 2.

Figure 2 shows that the binder distribution in the granule from SP is much close to the theoretical value (0.125), indicating that much uniform binder distribution can be achieved applying SP.

Fracture strength

Granule strength is one of the most important parameters reflecting the granule nature. There are a number of factors that ^' determine granule strength, involving properties of constituent particles and binder, granule size, amount of binder in the granule and porosity etc. For a given granule same size range, primary particle and binder, the granule strength could be regarded as a function of binder content and porosity. Thus, measurement of a number individual granules within the same size range could also reflect the uniformity of the granule nature in terms of binder content and porosity.

The fracture strength of granules was measured using a universal (compression) mechanical tester (Zwick/Roell) . In this test, the upper platen was driven at a constant velocity of 0.1 mm/min. The fracture strength, (the critical stress, σ) to crack a spherical elastic body under diametrically loading, was estimated using an equation developed for the case of irregularly shaped rock pieces [2] . It may be calculated by as follows:

^Q.0 = -D

where σ is granule fracture strength, F_max is the compression force at fracture point, and D is diameter of granule. Approximately 30 granules with sizes in the range of 1.18-1.4mm were tested for the two cases: NP and SP. The measurement results are shown in the Figures 3 and 4.

It can be seen from Figures 3 and 4 that the extent of scatter of fracture strength of granule made from SP is much smaller that one from NP, indicating that there is much higher uniformity in nature for granules from SP than NP.

Appearance

The photos of the product granules are shown in Figures 5a and b. These show that granule quality can be improved significantly by using the special operation protocol (SP) .

Discussion

In most of granulation applications, production quality is of most concern. Small size, narrow size distribution and uniform binder distribution and strength, are generally of highly interest. In some cases, the shape of the granules might be important. However, there are always inevitable scatter in these property terms . Understanding the causes of the scatter and designing an optimised process to obtain good quality granules, is important .

Generally, all granulation process described in open literature undergo constant operation conditions. The considerable extent of scatter of product granule in nature has been highlighted.

The main causes for large scatter could be explained by following: At the beginning of processes, the liquid binder generally is difficult to disperse perfectly in the dry- powder. This is due to capillary forces of the binder, resulting immediately in the formation of granule nuclei containing different levels of liquid binder. As early as 1 minute after mixing has begun, some granules may have binder/powder ratios in the range 0.18-0.2 (binder added ratio being 0.125).

Binder-rich granules reduce their binder content in two ways. First, with extension of the process, the binder rich granules breakdown to create fresh binder-rich surfaces, which will be immediately covered by dry powder surrounding to form a new granule with lower binder. Second, surviving binder-rich granules catch some more dry powder one their surface to average their binder content. Depending on the methods used to add the binder, the extent of forming of the binder-rich granule varies . Pour-on of liquid binder is the worst; melt-in is better, while spray addition of binder droplets is best. However, regardless of the methods employed, the quality of binder dispersion at first place is currently not perfect due to the fact that there is always considerable scatter in granule quality.

Due to the binder scatter, binder-rich granules are likely catch and retain smaller granules, by virtue of sufficient energy of impact and/or contact to ensure adhesion between them. In other words, binder-rich granules are favoured to grow. This biased coalescence is probably the main cause of wide size distribution.

Based on the above analysis, high impeller and chopper speed is expect to enhance the breakage of the binder- rich granules; medium speed during growth to avoid overgrowth due to coalescence; and further low speed during the final stages of the process to avoid granule deformation (assuming the spherical shape of granule is required) . However, at constant impeller speed (normal protocol in open literature) , all these effects are not closely controlled.

In order to achieve uniform properties of product granule, there are three main principles that need to be followed:

1. Dispersion of binder into powder as uniform as possible in the first place. This can be achieved by (a) high impeller and chopper speed, (b) larger chopper size and arrangement of the chopper in the best position to enhance its function, i.e. breakage, and (c) grinding the solid binder to powder first and premixing with dry powder.

2. Whatever methods are used, a certain degree of scatter in the binder distribution is inevitable.

Generally, at an early stage, larger granules contain more binder. In order to reduce the binder scatter still further, the present invention proposes to break larger granules, and so as to share the binder in them with other ones having lower binder content. Collecting these larger ones and crushing them to smaller sizes and putting them back in the mixer is one approach. However, an alternative approach is to grind all products outside the mixer and put them back. 3. Allowing granule growth in a parallel manner

(parallel growth) . Once the binder dispersion is even, granulation can initiate in a parallel manner. That means that all granules grow at the same rate. However, this balance can still be destroyed by over-coalescence. In order to avoid over-coalescence, a medium impeller speed is needed during the growth, or some dry powder needs to be sprayed on to the product to prevent coalescence .

4. Finishing the product granule shape and surface. At the last stage of the process, granule surface and shape can be finished, if necessary. Granule irregular shape and rough surface are related to high impeller and chopper speed. A low impeller speed is required to form spherical granules. At this stage the chopper needs to be removed from the mixer.

References

[1] Reynolds, GK, Biggs, CA, Salman, AD and Hounslow, MJ, 2004, Non-uniformity of binder distribution in high-shear granulation. Powder Technology 140, pp203-208.

[2] Hiramatsu, Y and Oka, Y, 1966, Determination of the tensile strength of rock by a compression test of an irregular test piece. International Journal of Rock Mech. Min. Sci. 3, pp89-99.

Claims

1. A granulation process comprising the steps of: a) adding binder to a powder in a mixer; b) first mixing the powder and liquid binder to form intermediate granules; c) selecting intermediate granules while wet that are larger than a predetermined diameter from smaller granules; d) • crushing said intermediate granules to a size less than said predetermined diameter; e) second mixing said crushed granules with said smaller granules while still wet until granulation is complete.

2. A method as claimed in claim 1, in which said selecting step comprises separating smaller and larger intermediate granules from one another.

3. A method as claimed in claim 1, in which said separation is effected by sieving.

4. A method as claimed in claim 1, 2 or 3, in which said predetermined size is calculated on the basis of a predetermined percentage of size relative to a specific size of granule that has the average binder constituency of the mixture as a whole at the time of said selecting step.

5. A method as claimed in claim 4, in which said percentage is zero.

6. A method as claimed in any preceding claim, in which said all intermediate granules of size greater than said specific size are broken into smaller sizes.

7. A method as claimed in any preceding claim, in which said specific size is 1 mm or less.

8. A method as claimed in any preceding claim, in which said crushing is to a size less than half said specific size.

■ 9. A method as claimed in any preceding claim, in which said crushing is to a size less than 500 μm.

10. A method as claimed in any preceding claim, in which said first mixing is continued until said specific size has stabilised.

11. A method as claimed in any preceding claim, in which said first mixing is continued for at least 2 minutes .

12. A method as claimed in any preceding claim, in which said second mixing is continued for at least three times as long as said first mixing.

13. A method as claimed in any preceding claim, in which said second mixing involves the addition of further powder in order to prevent coalescence of the granules.

14. A^' method as claimed in any preceding claim, in which the mixer is a high-shear mixer comprising a blender impeller and a chopper impeller.

15. A method as claimed in any preceding claim, in which said second mixing is continued for at least 5 minutes .

16. A method as claimed in claim 15, in which the impeller and chopper are run at high speed during said first mixing.

17. A method as claimed in claim 15 or 16, in which said impeller is run at reduced speed and said chopper is switched off for at least a proportion of the said second mixing.

18. A method as claimed in any preceding claim, in which said binder is solid when mixed with said powder in step a) .

19. A method as claimed in claim 18, in which the binder comprises a wax.

20. A method as claimed in claim 18 or 19, in which said binder is ground to a particle size less than 2 mm in diameter before addition to said powder in step a) .