Wet Granulation

Good viscosity, abrasion resistance and compressibility... Some features like these enables products made through wet granulation to be widely applied in pharmaceutical industry. In the next part, we will share some knowledge about wet granulation with you.

 

At first, we need to know that products of wet granulation is granules, while the main material is powders. Therefore, wet granulation is a process to transform powders to granules. Then, some differences between powders and granules should be learned. Powders is actually a mixture of solid, liquid and air. The particle force of them mainly consists of van der Waals force, Coulomb force, and capillary force. Besides, amount of air existing among particles also make them a system linked by air. However, when adhesive is added, powders will change to be linked by liquid and then to be linked by solid. After drying, granules can be formed.

 

1.Micro wet granulation

1)Primary stage: Particles of powders and powders themselves are linked by air.

2)Medium stage: As adhesive/moisturizer is added, air linkage is replaced by liquid linkage. Strong capillary force generated then will promote primary granulation.

3)Later stage: Since liquid is added continuously and collision strength between primary granules increases, granule system is totally linked by liquid. But the liquid will be dried later and firm particle system can be formed then.

Of course, material nature and adhesive/moisturizer will influence the final form of granules.

 

2.Macro wet granulation

Macro wet granulation also is made up of the following three stages:

1)Premixing. All material needed are fed into the wet granulation pot for mixing.

2)Adhesive/moisturizer adding. As wet granulating paddle rotates, adhesive will be sprayed into bucket and granules preliminary form.

3)During formation of wet granules, mixing paddle and mixing paddle both operate in high speed after spraying, which increases water distribution uniformity and forces between granules. Therefore, steady wet granules can be formed.

 

3.Influence of macro parameters on micro granulation

Actually, granulation can be divided into two major steps:

1)Liquid crowd air and is distributed uniformly on the surface.

2)Appropriate physical collision between granules. 

 

Through analysis, we can learn that what macro parameters will influence the above steps:

1)Macro factors influencing uniform distribution

Wet granulation is a process where multiple materials are bond and granulated. Since different materials have different binding capacity to adhesive, full mixing before adhesive spraying can make sure that adhesive can be added uniformly. Materials are mainly driven by rotating main paddle in granulating pot , which also guarantees uniform distribution of sprayed liquid. Besides, to meet above requirements, materials in pot should be turnover towards pot mouth. If equipment cannot meed requirements, cutter should be operated to assist material turnover. Liquid adding mode will also affect distribution. Spraying and atomization can improve uniformity of liquid. However, the size of sprayed area should be controlled to prevent material from binding on the wall or central axis.

2)Macro factors influencing particle collision

Continuous collision between particles can increase particles’ physical strength. Both elastic materials and brittle materials can form firm granules only after collision. Therefore, paddle rotating speed, pot design and cutter speed can all be the factors to influence particle collision and furthermore, granule quality.

 

4.Magnification and control strategies of wet granulation

Magnification of wet granulation applies Froude parameter (Froude=n2*r/g) inevitably. This parameter, a non-dimensional parameter, owns absolute guiding significance at the level of theory. It is meaningful for wet granulating equipment of the same series to refer to this parameter in magnification. It can also be a primary reference to equipment of different series.

 

Some control strategies can be as follows: Any magnification of techniques and industrial transfer are not simple parameter shifting. The core of it is actually the parameter shifting aiming to keep intermediate material nature consistent. Therefore, during research, we should learn more about the influence of technical parameters on intermediate material nature.

 

1)Technical parameters of wet granulation:

Adhesive adding mode, adhesive adding speed, mixing shaft rotating speed, cutter rotating speed, premixing time, mixing time after granulation and expected granulating result. 

Some parameters of intermediate particles should include particle size, tightness, tap tensity, moisture content and viscosity. It seems easy to get these parameters in practical research or production, but actually methods are not enough to get them. Besides, for more needs, shape of particles can be studied.

 

Next, some examples of particle size distribution will be introduced. In wet granulation, PSD will affect fluidity of intermediate particles, filling uniformity and further content and nature of pressed products. However, content is only one of the CQAs (critical quality attributes), so PSD is used as the key nature of intermediate material for full research and control strategies making. At first, PSD measuring method should be primarily made during test in lab and the nature of intermediate material, which meets CQAs can be obtained. Therefore, standard can be built for intermediate material nature.

 

Afterwards, magnification researches can be carried out on the basis of the standard made in test in lab. Meanwhile, sampling method and sampling quantity can be optimized for better and more scientific test plan. For PSD test, the nature researched in the test in lab might represent the nature of the whole particle system due to the small batch. However, it becomes more important to guarantee sample representative in magnification. Therefore, sampling plan in magnification should be made carefully, too. PSD standard of intermediate material can be formed when statistics and analysis to PSD of multiple batch of intermediate materials are combined with quality information of products in pilot test and key batch.

 

The above control is debated from the point of view of particle nature standard. In other words, the statistic parameters of particle nature is an impotent constituent of product control strategies. Likewise, we can evaluate all natures to justify if they conform to CQA of intermediate particles. And then effect of input parameters on natures can be studied. In practical research process, monofactor research or orthogonal research can be applied. In my opinion, only after some failures are experienced and detailed intermediate particle quality control suggestions are accumulated during wet granulation in lab, magnification transfer can be better controlled.

 

5.Something else

Actually, people always talk about three points, namely, end justification, excessive granulation and liquid feeding method. How to justify the end of granulation? Granulating time, granule status, current value and torque value can all be for reference with priority to the former two items. Take the bottom driving granulating machine as an example. The current can only indirectly indicates work of paddle on particles, while in fact current suggests the resistance on paddle. The resistance is composed of resistances from machine, as well as particles. In the whole period, resistance from machine must change. Therefore, current value can only serve as secondary standard.

 

Nest, excessive granulation always occurs when materials are of good plasticity or viscosity. As granulation time is extended and particles continue collision, some auxiliary materials will beset into or bind to material of plasticity and form denser particles. Such a motion, on one hand, will delay drug release in human body. On the other hand, it will reduce the risk of excessive punching for viscous material tablets.

 

Research to liquid feeding method always appear to soluble material granulation. It can be flexible to feed liquid to materials of strong water absorption, while to some soluble materials (such as sorbitol or xylitol) or materials which can gel (such as HPC, HPMC, and HEC), water shouldn’t be fed or can be sprayed into only if inevitably. However, spraying causes challenge to the feeding speed and equipment.

 

All in all, granulation is a large topic. It needs our insistent research and study, as well as some exchange between researches.