Manufacture of Tablets by Dry granulation method

Dry granulation also referred to as precompression or double compression is a size enlargement process designed to improve the flow and compression characteristics of powders that would otherwise be unsuitable for compression. The process involves compaction of powder particles into large pieces or compacts which are subsequently broken down into granules to produce granules that can be further processed into dosage forms.

Dry granulation is typically used in the manufacture of tablets if the formulation ingredients are too fluffy or too susceptible to flowability problems for direct compression to be a viable processing option and/or too susceptible to degradation from heat and/or moisture for wet granulation to be a viable processing option for densification. The process is sometimes chosen as an alternative to wet granulation when direct compression is not feasible not because wet granulation is not feasible but because the manufacturer is more experienced with dry granulation or to reduce processing time and/or equipment requirements to reduce costs.

The manufacture of tablets by dry granulation method eliminates a number of unit operations but still include milling or micronization of drugs, weighing, mixing, slugging, dry screening, lubrication, and compression of granules into tablets.

For successful manufacture of tablets using dry granulation, either the active ingredient or the diluent must have sufficient inherent binding or cohesive properties.

Methods of dry granulation

Formation of granules using dry granulation process is generally achieved either by slugging technique or roller compaction. The two techniques are similar but they can give different results.

Slugging technique

This process involves compression of primary powder particles into large flat tablets or pallets using a tablet press or, more usually, a large heavy-duty rotary press. The resultant compact is then milled using a hammer mill or other conventional milling equipment. The milled slugs are passed through a screen of desired mesh for sizing. Lubricant is added in the usual manner, and the granules compressed into tablets.

Slugging results in considerable dust production which poses a problem for good containment and reduction of cross-contamination. Other main shortcomings of slugging include batch processing, low throughput (30–50 kg/hr), poor process control, frequent maintenance changeovers and poor economy of scale. The method is being replaced by the more modern, and better, roller compaction process.

Roller compaction

Roller compaction (also referred to as ribbon blending) is a relatively simple, more efficient and inexpensive form of dry granulation. It is a process where formulation ingredients are continuously passed between two counter-rotating rollers where it is densified and consolidated into a sheet of solid mass.  Depending on the type of rollers used, the feed material may be compacted into dense ribbon-like materials known as flakes (smooth rolls) or dense briquettes (almond or stick-shaped) if the rollers have grooved or etched surfaces. The compacted materials are further milled, sized, lubricated and compressed into tablets.

Roller compaction offers distinct advantages over wet granulation, particularly for moisture-, solvent-, or heat sensitive formulation ingredients. In the pharmaceutical industry, it is an attractive granulation alternative as it offers considerable cost savings due of its high production throughput (up to 100,000 kg/hr), shorter cycle times and fewer processing steps. Moreover, elimination of a drying step reduces production and development time as well as ease of scale-up.

Excipients used in manufacture of tablets by dry granulation method

The types of excipients used in the manufacture of tablets by dry granulation method and the rationale for their use are similar to those described in the article “Excipients Used in the Manufacture of Pharmaceutical Tablets”. Typically, the following excipients are required:

• Diluent/filler, e.g., Microcrystalline cellulose (MCC), anhydrous lactose or lactose monohydrate, dibasic calcium phosphate, starch etc.
• Disintegrants, e.g., croscarmellose sodium, sodium starch glycolate, pregelatinized starch 1500, crospovidone, starch, MCC, etc.
• Lubricants, e.g., stearates (magnesium stearate, stearic acid), glyceryl fatty acid esters (glyceryl behenate, glyceryl palmitostearate), Polyethylene glycol (PEG), polyoxyethylene stearates, sodium lauryl sulphate.
• Glidants, e.g.: talc, colloidal silicon dioxide.
• Miscellaneous excipients such as colourants, flavourant, sweetening agents, etc.

Read Also: Direct Compression Excipients: Properties and Uses

Steps involved in dry granulation

A summary of the various steps used in the manufacture of tablets by dry granulation method is detailed below.

1. Weighing formulation ingredients

Here, appropriate quantities of formulation ingredients are dispensed. The excipients and the active ingredient(s) must be in finely divided form, otherwise, particle size reduction should be carried out.

2. Mixing of formulation ingredients

The dispensed formulation ingredients are mixed in a powder mixer until a uniform powder mix is achieved. It is worth noting that half amount of lubricant in the formula is added at this stage to enhance powder flow during slugging and to prevent sticking of compressed powder on the die during precompression.

3. Compression of mixed powders into slugs

Here, the mixed ingredients are compressed into flat large tablets or pallets. This step is called precompression (slugging) and the compacts made in the process (typically 25 mm diameter by about 10–15 mm thick) are termed slugs.

Compression of mixed powders into slugs can be achieved either by slugging technique or roller compaction. The pressure used to produce the slugs is usually less than that used in the final compression.

4. Milling and sieving of slugs

Following slugging, the next stage in the manufacture of tablets by dry granulation usually involves breaking of slugs into smaller pieces using a hammer mill or other conventional milling equipment. The milled slugs are screened to produce uniform granules.

5. Mixing with disintegrant and lubricant

After screening, the remaining lubricant and other extragranular excipients such as disintegrant, glidant etc., are added to the granulation and mixed gently to achieve a uniform blend.

6. Compression of granules into tablets

The mixed granules are compressed into tablets using either single or rotary tablet press fitted with appropriate punches and dies.

Similar to wet granulation, tablets manufactured by dry granulation method may be coated if the need arises.

Advantages of dry granulation

As with wet granulation, there are several advantages associated with dry granulation and they include:

1. Dry granulation requires less equipment and minimum floor space.
2. The process eliminates the addition of moisture and allows dry handling of moisture sensitive formulation ingredients.
3. The process is suitable for heat sensitive materials since no drying step is involved.
4. Dry granulation is not generally associated with alterations in drug morphology during formulation process.
5. The process does not require special excipients that is, it makes use of conventional grades of excipients.
6. Tablets manufactured by dry granulation method have improved disintegration time because the dry binder used has less adhesive effect thus fast disintegration.
7. The process is easily scaled up from development to production.
8. It improves blending since there is no migration.

Disadvantages of dry granulation

1. Dry granulation method (roller compaction) require specialized heavy duty equipment for granulation.
2. The process generates considerable dust which may cause cross contamination.
3. Segregation of components may occur post mixing.
4. There may be issues regarding powder flow.
5. Tablets manufactured by dry granulation tend to be softer than those manufactured by wet granulation, rendering them more difficult to process using post-tabletting techniques, e.g. film coating.

Differences between wet granulation and dry granulation methods

1. Typically, wet granulation processes require more equipment and plant space than dry granulation technology.
2. Wet granulation technology makes use of multiple and more expensive equipment technology; thus has higher investment costs compared with dry granulation processes.
3. Cleaning cycles are more frequent with wet granulation equipment trains than dry granulation manufacturing equipment.
4. Scale-up is less complicated with dry granulation compared with wet granulation.
   • Wet granulation scale-up has many more major and minor variables to monitor during wet granulation and drying processes than a dry granulation roller compaction process.
   • Scale-up using wet granulation equipment requires larger bowl and batch sizes— manufacturing capacity is a function of bowl size volume and manufacturing time.
   • Scale-up using roller compaction can be accomplished with development sized equipment—it only requires longer equipment operating hours as manufacturing capacity is primarily a function of operating time providing more capacity and operational flexibility.
5. Wet granulation endpoints can change as the granulator power consumption profile can change when manufacturing multiple consecutive batches during a shift or campaign-requiring more sensor controls to understand the process.
6. The wetting of raw material is more influenced by raw material property changes, for example, particle size distribution, and density than raw material changes affecting roller compaction.
7. In the case of manufacturing a wet granulation batch, if an electrical outage occurs, the probability of losing the batch is high if there is no backup battery system to quickly start up and continue the process; this is not an issue with a roller compaction process.
8. Massing effects and drying capacity issues are key concerns in scale-up for drying granulations produced in separate steps for high- or low-shear wet granulation technologies.

Conclusion

The popularity of dry granulation for the manufacture of tablets has decreased in recent years, having been superseded by direct compression. However, both slugging and roller compaction are still employed in tablet manufacture. While roller compaction is simpler than wet granulation methods in terms of operation, it is still not fully understood or explored.

References

• Allen L. V and Ansel H. C. (2014). Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lipincott Williams and Wilkins.
• Ennis, B. J. and Litster, J. D. (1997). Particle enlargement. In R. Perry and D. Greens (Eds.), Perry’s Chemical Engineer’s Handbook. 7th ed. (pp 20-89). New York: McGraw Hill.
• Jones D. (2008). Fasttrack Pharmaceutics – Dosage Form and Design. London: Pharmaceutical Press.
• Ofoefule, S. I. (2002). Textbook of Pharmaceutical Technology and Industrial Pharmacy. Nigeria: Samakin (Nig) Enterprise.
• Parikh, M. (2010). Handbook of Pharmaceutical Granulation Technology (3rd ed.). USA: Informa Healthcare.
• Shanmugam, S. (2015). Granulation Techniques and Technologies: Recent Progresses. Bioimpacts, 5(1): 55–63. https://dx.doi.org/10.15171%2Fbi.2015.04
• Thejaswini, P., Suguna, B., Sumalatha, N., Umasankar, K. and Reddy, P. (2013). Advanced Granulation Techniques for Pharmaceutical Formulations – Overview. International Journal of Research in Pharmaceutical and Nano Sciences, 2(6), 723 – 732.

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