Make more of moisture-activated dry granulation

Moisture-activated dry granulation (MADG) is a simple, cost-effective way to create granules that can offer specific solutions to formulation issues. In the face of an industry resistant to change, Aesica argues that MADG deserves greater consideration

In the pharmaceutical industry, the three common granulation processes for solid dosage form production are wet granulation, dry granulation (roller compaction) and direct blending. Yet despite being well-established techniques, each has drawbacks. Moisture-activated dry granulation (MADG) was developed in response to the difficulties experienced with wet granulation in terms of endpoint, drying and milling, and offers an efficient, cost-effective process that does not require a drying step.

Manufacturers are increasingly aware of processing steps, production costs, safety issues and time-to-market, not withstanding the absolute requirement for quality and reliability. In tablet manufacture, direct compression has always been the traditional first choice, followed by granulation, which adds time and cost to the process (and formula).

MADG is a growing but, as yet, not widely adopted process. Because minimal moisture is needed in this speciality granulation process, no drying time is required, significantly shortening the processing time. It is a simple and innovative process in which granules are created with water and a granulating binder, as in wet granulation, but they are not heat-dried or milled, which also helps to minimise endpoint sensitivity.

Where MADG comes to the fore is that it is an efficient, cost-effective granulating process that does not require a drying step

In addition, it works in situations when wet granulation or dry compression will not (such as water- or heat-sensitive products). And, along with reduced steps, the equipment required is the same as that used in traditional wet granulation – which is what most manufacturing sites are equipped with – so mass implementation would be relatively easy to achieve.

The benefits of wet granulation are well known, and include good particle size distribution and good flow. It is a flexible technique that offers good uniformity and a wide range of applications, yet it lacks robustness, requires multiple steps, milling, an expensive drying step and carries a risk of over-granulation.

Where MADG comes to the fore is that it is an efficient, cost-effective granulating process that does not require a drying step – i.e. moisture is used to activate granulation, but the granules are not heat-dried. Essentially, the process comprises two major steps: agglomeration and moisture distribution (see Figure 1). During agglomeration, the active pharmaceutical ingredient (API) is dry blended with a binder or combination of binders in a typical high shear granulator. A limited amount of moisture (8%) is then added to granulate the powder mixture, but not enough to over wet it. The water droplets hydrate the dry binder(s) and create tacky nuclei or a tacky wet mass, and the dry powder particles adhere to the tacky nuclei/mass to create moist agglomerates.

Figure 1 The moisture-activated dry granulation process

During the moisture distribution stage, an absorbent excipient is added to distribute the moisture evenly and ‘dry’ the granulation. At this stage, it is still possible to add in any remaining drug or, if required, a lubricant or disintegrant. Finally, the contents can be lubricated, sieved/sized and blended, although in reality limited or no sizing is required in this process because the particles are small and uniform.

The process takes only about 10–15 minutes and the final granulation looks like a direct blend formulation with fine particle size distribution. In this process, the drug is bound with the ingredients, as in wet granulation, which minimises the potential for segregation. In short, MADG has the best attributes of dry blending and wet granulation, with the caveat that it is just a simpler process to create granules without heat drying and milling. As with any solid dosage form, granulation and any resulting tablet and capsule characteristics will depend on the formula composition.

In terms of equipment, a high shear granulator is more suitable for MADG, and an ideal machine should have efficient impellers/blades and choppers to allow good mass movement and proper mixing. It should also allow water to be sprayed only on the powder bed and not on the blades, choppers or granulator wall. Also, the blades and bowl configuration should be such that it does not allow ‘wet pockets’ or ‘dead spots’ to remain after the moisture distribution or absorption stage, which would then necessitate additional sizing and shifting of the granulation.

Traditional granulation techniques

Wet Granulation

The process of adding a liquid solution to powders involves the massing of a mix of dry primary powder particles using a granulating fluid. The fluid contains a solvent that must be volatile, so that it can be removed by drying, and be non-toxic. Typical liquids include water, ethanol and isopropanol, either alone or in combination. The liquid solution can be either aqueous-based (safer) or solvent-based.

Water mixed into the powders can form bonds between powder particles that are strong enough to lock them together. However, once the water dries, the powders may fall apart. Therefore, water may not be strong enough to create and hold a bond. In such instances, a liquid solution that includes a binder is required.

Once the solvent/water has been dried and the powders have formed a more densely held mass, then the granulation is milled.

The process can be very simple or very complex depending on the characteristics of the powders and the available equipment. In the traditional wet granulation method, the wet mass is forced through a sieve to produce wet granules that are subsequently dried.

Dry Granulation

Dry granulation is used to form granules without using a liquid solution, because the product to be granulated may be sensitive to moisture and heat. It involves compacting and densifying the powders. The primary powder particles are aggregated under high pressure using swaying or high shear mixer-granulators.

Dry granulation can be achieved in two ways: either a large tablet (slug) is produced in a heavy duty tableting press or the powder is squeezed between two rollers to produce a sheet of materials (roller compactor/chilsonator).

When a tablet press is used for dry granulation, the powders may not possess enough natural flow to feed the product uniformly into the die cavity, resulting in varying degrees of densification. The roller compactor (granulator-compactor) uses an auger-feed system that will consistently deliver powder uniformly between two pressure rollers.

The powders are compacted into a ribbon or small pellets between these rollers and milled through a low shear mill. When the product is compacted properly, then it can be passed through a mill and final blend before tablet compression.

Manufacturers are increasingly aware of processing steps, production costs, safety issues and time-to-market

Advantages and benefits

Dr Gerard Thone, North/Latin America Technical Services Manager, FMC Biopolymer, in his presentation, ‘MADG: A low cost/high efficiency approach to wet granulation’, observed that MADG produces granules that are very homogenous and free-flowing, that the amount of remaining water was comparable with a direct compression granulation and that the amount of time saved (compared with a typical wet granulation process) was in the order of hours not minutes. Other notable advantages include its suitability for continuous processing, the very few variables involved – resulting in less need for expensive process analytical technology (PAT) – and its applicability to a number of formulations, including high or low drug load formulations, polymer matrix-type controlled release formulations and both soluble and insoluble drug formulations. Using very little energy, it is a ‘green’ technology with extremely wide scope in the life science manufacturing industries. It is reproducible and scalable, lean and as it provides good content uniformity it is a better option than conventional wet or dry granulation processes with which to implement the US Food and Drug Administration’s Quality by Design concepts (Table 1).

Table 1: A summary of MADG benefits
MADG vs Wet GranulationPrimary benefitSecondary benefit
Lower amount of added moisture (4–8% total)No dryingFaster process, increased efficiencies, lower production costs
Single production equipment (high shear granulator)Lower investments and maintenanceIncreased efficiencies, lower production costs
No equipment changeReduced process timeLower production costs, faster product development, faster to market
No milling requiredNo finesHigher yields, lower costs
Reduced risk of cappingLower tablet rejection rateHigher yields, lower costs
No over or under granulationFewer scrapped batchesHigher asset utilisation, lower costs

Although many MADG proponents see no downside to the process and believe it to be a superior alternative to traditional granulation techniques, it is not without drawbacks. There is still some discussion concerning its use for moisture-sensitive drugs or high drug load moisture-absorbing APIs and there could be other issues with the API, with high drug load formulations being particularly difficult to develop.

However, at a less tangible level, there is still some industry resistance to change; being less familiar with the process, there is some apprehension towards adoption. Big Pharma is traditionally risk averse and MADG goes against perceived knowledge and wisdom. But, conversely, there are major benefits for companies looking to scale up; there is a much lower chance of failure compared with wet granulation, which users and customers will find very attractive. It also offers greater control over the formulation and solves a number of dissolution problems because of the amount of water involved.

Formulation benefits

Robert Armstrong, a Formulation Development Scientist at Aesica, explains: ‘A client tried to produce some really small tablets using pneumatic dry granulation and failed. We used MADG and succeeded. And, to cite a specific example, MADG also made it possible to produce Metformin tablets when other techniques failed.’ Metformin hydrochloride is an API that not only exhibits batch-to-batch variability but also demonstrates different physical characteristics between suppliers. The challenge was to produce a sustained release tablet that was smaller or, at best, no bigger than what was currently available on the market.

Cost was the second factor; therefore, process time and processing technology would also have an impact on how successful the end result would be. The variable nature of the API ruled out a simple blend and direct compression process. Although this is by far the cheapest process, the tablet size would have been too large to accommodate the amount of excipients required to dilute out any API effects.

Wet granulation was an option, but processing time and cost of processing was an issue. Metformin hydrochloride is widely available as a generic tablet and is therefore in a competitive marketplace. Newer dry granulation technologies did prove to be partially successful; however, the tablet size was slightly larger than target and the yields were quite low, pushing up the cost of manufacture. In addition, the granule characteristics were suboptimal as flowability was not as desired.

MADG offers quantifiable benefits regarding waste reduction, energy use and overall efficiency

Using the MADG process, Aesica was able to produce tablets successfully from two different sources of API. The tablets produced weighed 1190mg in total – containing 750mg of active – and measured 17 x 9mm. Currently available 750mg extended release formulations are 19–21mm diameter round tablets, which are physically much larger and very difficult to swallow.

Commercially, MADG offers quantifiable benefits regarding waste reduction, energy use and overall efficiency. In clinical trials or bulk manufacturing, MADG can halve the production time to manufacture compressible granules. The requirement for fluid bed drying is completely removed. Benefits include significantly reduced processing times compared with traditional wet granulation, improved yields with no losses in transfer or fluid bed drying and reduced costs in terms of both energy and work hours.

Big Pharma is traditionally risk averse and MADG goes against perceived knowledge and wisdom

Offering a simple, ‘one pot’ processing approach, less equipment is needed and, therefore, set up is both simpler and more cost-effective. As Armstrong further illustrates: ‘A small-scale development batch was manufactured for a particular product; traditional wet granulation took the best part of a day to manufacture the granule and finish processing it to a point whereby it could be compressed the following day. The MADG process for this product enabled us to manufacture the granule and compress it during the same morning.’

MADG is a simple, economical, clean, lean and robust process that creates granulation with very good physical properties and finished products with satisfactory quality attributes. It is applicable to many of the industry’s granulation needs for solid dosage form development and can be described as a ‘one pot’ granulation process. MADG also offers energy savings, a short manufacturing time and fewer critical formulation and process variables.

Future work

As with any ‘new’ technology, there is still room for improvement. This could be in the form of multifunctional excipients, which would simplify the process and make it even more economical. For instance, an excipient could be developed that is both a moisture absorbent and a disintegrant, or a moisture absorbent, a disintegrant and a dry binder. And, the development of specialised granulators for MADG, as well as continuous processors and feeders, will also be beneficial.

In short, MADG increases manufacturing efficiencies, achieves higher asset utilisation, decreases costs and achieves higher yields with fewer fines. Based on these criteria, traditional granulation techniques have a serious alternative.


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