Liesbeth Meeus

Compressed tablets are the most widely used solid dosage form so they must satisfy a number of physical requirements in terms of hardness, disintegration ability, friability and uniformity. To provide these tablet characteristics in accordance with the chosen ingredients, manufacturers can use three different processing technologies: direct compression, dry granulation and wet granulation.  

Direct compression is a popular choice because it provides the shortest, most effective and least complex way to produce tablets. The manufacturer can blend an API with the excipient and the lubricant, followed by compression, which makes the product easy to process. No additional processing steps are required. 

Moisture or heatsensitive ingredients, which would be contraindicated in wet granulation, can also be used in this type of process. However, it does require a very critical selection of excipients in comparison to granulation processes because the raw materials must demonstrate good flowability and compressibility for successful operation. 

Both high and low doses of API present a challenge in this respect. Most APIs tend to have poor compressibility, which affects the quality of tablets if the formulation calls for a large proportion of API. At the same time, there can also be problems when low amounts of actives need to be incorporated into tablets because it is difficult to accurately blend a small amount of active in a large amount of excipient to achieve the desired uniformity and homogeneity. 

For instance, segregation of the different components can occur. This means there is not a uniform distribution of tablet ingredients being fed to the press, and thus batchtobatch consistency of the manufactured tablet cannot be assured. 

One of the principal risk factors for segregation is the wide particle size distribution in direct compression formulations, in which active ingredients tend to be at the fine end of the range. Where there is a wide range of particle sizes, there is an increased likelihood of sifting, where the smaller particles 'slip through' the bigger ones. 

Other bulk powder properties are also important for successful tabletting, such as good flowability, and all of these factors combine to place a high requirement on the excipients used for direct compression. 

If a powder blend's properties do not suit direct compression tabletting, manufacturers will turn to granulation processes to create the desired flowability and low dustability. These characteristics are required to minimise tablet weight variations, and ensure high density for high tablet filling weight and high moldability for hard tablet manufacture. 

Granulation narrows the particle size distribution of a tablet formulation's bulk powder, eliminating segregation problems. This in turn ensures superior compressibility in the tabletting process, permitting higher quantities of API to be used and ensuring good active distribution in the tablet. However, granulation is a more time-consuming technique compared with direct compression and there is also a risk of product cross-contamination and product loss during the different processing steps (granulation, drying, sieving). All of these factors can increase costs compared with direct compression. 

Dry granulation is more flexible than direct compression. Compared with wet granulation, however, it has a shorter, more cost-effective manufacturing process. Because it does not entail heat or moisture, dry granulation is especially suitable for active ingredients that are sensitive to solvents, or labile to moisture and elevated temperatures. 

As many of us know all too well, the pharma industry is in a state of flux with blockbuster API molecules coming off patent, Big Pharma companies reinventing their business models and generics becoming increasingly prevalent. Pharma manufacturers are extremely focused on cost effectiveness, but are also looking for a much higher level of innovation from excipient providers, recognising that excipients need to be considered alongside the API for a tablet formulation's overall success. 

Often, the challenge for excipient producers is not the creation of new excipients 

, but new and innovative ways of using existing excipients to deliver new functionality or to be more cost-effective. For example, we have developed a way of using glucose monohydrate as a sole excipient (diluent binder) in dry granulation, employing a roller compaction technique to create strong chewable tablets, which would otherwise have required an additional binder such as maltodextrin. In wet granulation, the biggest role is played by the binder because its properties affect granule quality. Wet granulation tabletting methods have been developed that result in good end products. For example the combination of erythritol and isomalt, two polyols with low hygroscopic profiles, results in better stability of the end product.  

Tablet manufacturers are realising that APIs do not have sole responsibility for innovation in their products. Indeed, the creative use of excipients can add significant value to the end formulation; by making it easier to consume a specific dosage form, certain excipients can provide fresh marketing angles for wellestablished APIs in over-the-counter (OTC) formulations, or improve patient compliance in prescribed formulations. 

 is Application Centre Leader for Cargill Pharma & Personal Care EMEA.

This article is part of a special feature on granulation that was published in the March issue of PTE Digital, available at 

Articles

Compressed tablets are the most widely used solid dosage form so they must satisfy a number of physical requirements in terms of hardness, disintegration ability, friability and uniformity.

Direct Compression Versus Granulation

Orally disintegrating tablets (ODTs) are growing in popularity and their market value could exceed $13 billion in sales by 2015, based on current global growth trends.

  Market studies have indicated that more than half of the patient population prefers ODTs to other dosage forms.

  Most consumers would also ask their doctors for ODTs (70%), purchase ODTs (70%) or prefer ODTs to regular tablets or liquids (over 80%).

The growth in the popularity of ODTs reflects the growth in the elderly and infirm population, who often find it difficult or unpleasant to take conventional tablets. ODTs separate in the mouth in contact with saliva, making it easy for a person to swallow the tablet without drinking water. They are also a convenient dosage form for other people, such as business travellers, as they can be taken without water, or for those who need to take tablets to combat travel sickness. 

Over the past few years, there have been several innovations that have improved the appeal of ODTs. Key developments have been improvements in the speed of dispersal of ODTs, as well as the growing use of non-hygroscopic, zero-calorie sweeteners, with taste-masking properties, which have helped ODTs to be more palatable. Improvements in the dispersion speed will, in turn, facilitate higher drug loading. This can be combined with a well-selected binder to retain the non-hygroscopic profile, resulting in hard tablets with a high dilution potential, which will also help improve patient compliance. 

The challenges of developing ODTs are similar to those for conventional solid oral dosage; for instance, one of the main issues for both forms is the need to establish compatibility of the active drug substance with both the excipients and process. For ODTs specifically, the key challenges are producing tablets with rapid disintegration and overcoming the bitter taste exhibited by many actives. These can be overcome, however, by using a good selection of sweetener/binder systems, combined with a super-disintegrant. 

To overcome the bitter taste, sweeteners and flavours are often included to achieve a palatable formulation Additionally, a pleasant mouthfeel is also important. Again, manufacturers are approaching this using a sweetener/binder system with the desired characteristics.  

At Cargill, we've overcome the challenges relating to ODTs by using a wet granulation of erythritol as an excipient. This excipient is non-hygroscopic, contributes to good mouthfeel and has taste-masking properties, and robust tablets can be made 

 wet granulation, combined with a disintegrant to provide faster disintegration. Erythritol also has taste-masking properties and is noncariogenic (toothfriendly), making it an effective ingredient for tablets that need to stay in the mouth for some seconds while dissolving. 

In our research, using a placebo with a hardness of 148 

 our Zerose erythritol and C*Pharm IsoMaltidex formulation, including 2% disintegrant, with the same hardness, there was a significant decrease in disintegration time, from 127 seconds to 95 seconds.

Another challenge is that ODTs are potentially less robust than conventional solid-oral dosage forms, given their formulation to achieve rapid disintegration, so packaging requirements, such as aluminium blister packs need to be considered. 

In the future, innovations and developments in the ara of ODT will be around marketing and awareness relating to ODTs, as much as in particular technological solutions. Raising awareness of ODTs amongst healthcare professionals and developing market segmentation for specific end users will also be crucial. 

Orally Disintegrating Tablet and Film Technologies — 6th Edition 

(Technology Catalysts International, September 2010). 

4. Internal Cargill research conducted by Cargill's Pharma Application Centre team. 