Under Pressure

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Broadly speaking, oral solid dosage forms remain the most popular choice for drug developers and patients, offering convenience, simplicity, cost-effectiveness, and higher rates of compliance. Tablets have maintained the top position in terms of dosage form popularity for some time, yet according to certain reports, the rising trend of more complex, specialized medicines in development is leading to the necessity of more flexible and sophisticated manufacturing approaches (1).

Additionally, growth in emerging markets has placed pressure on solid dose manufacturers to accelerate production while also managing to keep costs at an efficient level. To learn more about the challenges associated with tableting and these industry trends, Pharmaceutical Technology spoke with Michael Oxford, research & design engineer at I Holland. 

Challenges facing manufacturers

PharmTech:Could you highlight the main challenges drug manufacturers face when trying to quickly and cost-efficiently process oral solid-dosage forms/tablets while also maintaining high quality?

Oxford (I Holland):In order to efficiently manufacture a quality tablet, design is key. Details including shape, profile, and features such as a blended land are just some of the factors that must be considered.

Let’s initially look at the shape. A round shape is the most common as it is the easiest to produce. Non-round shapes are more complex and can require specialized tool manufacturing capability. Once the basic shape has been decided, take time to look at the size. Look at the type of press available for tablet manufacture as this can limit the size of the tablet. Also, if production has to be fast, consider using multi-tip tooling, which can also affect the size of the tablet.

An important element of successful tablet design is ensuring that the blended land works. If a blended land is applied incorrectly, a range of issues can ensue during compression. For example, the tablet land can chip during take-off, and coating can build up on the edge of the tablet and eventually chip.

Finding the correct blended land will increase tablet strength and performance, therefore resulting in higher volumes. It’s important to remember that a correctly selected and applied blended land provides benefits in terms of handling, loading, setting, tooling strength, and the visual appearance of the tablet.

Also consider the tablet profile. The profile is affected by several aspects including the granule, embossing requirements, coating process, packaging, and the branding required. Additionally, think about the volume of the tablet and if it will be coated as this can present challenges for the tablet designer. Successful coating is dependent on the tablet profile. Because the core of a tablet has reduced hardness compared to the peripheral of a tablet, core erosion can occur during the coating process. Erosion is caused when the tablet comes into contact with the coating pan and other tablets, leading to wear. This weakness can be reduced by avoiding very deep concaves. 

An expert tooling designer will be able to design and add appropriate strengthening features, such as blended lands and profile changes, resulting in a robust tablet that can be quickly and cost-effectively produced.

Dwell time and its impact

PharmTech:What about dwell time and its impact on the tableting process?

Oxford (I Holland):In a nutshell, dwell time is the amount of time that the punch head remains under full load when in contact with the compression roller. It will have a huge impact on production as some tablet formulations are dwell-sensitive, therefore they require longer compression.

It is important that the correct amount of force is used for the right amount of time. Too much or too little of either can result in tableting problems. Excessive force or over-pressuring of the punch can cause failure of the tool and will damage the press. For this reason, it is vital to understand how to optimize dwell time correctly.  

Influences that can affect dwell time include the punch head flat diameter and shape, use of precompression, and revolutions per minute used during production. It is important to remember that dwell time plays a significant part in determining if a tablet can be produced successfully, especially those incorporating formulations that are challenging to compress. Not all formulations are dwell sensitive, as some will compress effectively at any speed; the majority, however, are very susceptible to even the slightest change. 

When understanding the dwell time required for a formulation, research of the characteristics of the formulation is essential-is it plastic or elastic? Does it have a high moisture content? All these elements will affect the dwell time. 

Dwell time can also play a part in stopping common problems like sticking, capping, or friability during manufacture, for example, using specific tooling that can be used without slowing the press, so production runs satisfactorily. Innovative new punches on the market allow tablet manufacturers to achieve higher press speeds with challenging products and formulations without the significant capital expenditure of a new press. 

All formulation factors must be considered

PharmTech:You mentioned that the drug formulation can affect dwell time; does it have other implications in other aspects of the tableting process?

Oxford (I Holland):The formulation can have a huge impact on the quality of the tablet and the overall process. You must look at every element of the formulation; for example, does the formulation have a high moisture content or does it have abrasive or corrosive ingredients? There are a whole host of factors to consider. The overall formulation composition has to be studied so the correct tooling can be used to reflect the formulation being compressed and ensure a quality fault-free end product.

One of the main problems encountered is that of a sticky or abrasive formulation. Looking at the latter problem, some formulations contain unrefined, hard, abrasive ingredients, which makes production a challenge. Formulations with this composition, when repeatedly compressed, can scrape away or penetrate the surface of the tool. The abrasion can lead to the erosion of punch tip detail such as logo embossing and other identification specifications. Eventually this wear can lead to weight variation, sticking, and other issues, resulting in the scrapping of the punch. 

Abrasion can be resolved through the use of wear-resistant premium steel. It is important to fully understand the differences between the selection of steels as they have a variety of advantages and disadvantages. One example is that some wear-resistant steel can be less resilient to fracture in some applications due to reduced toughness and tensile strength. If the changeover to a premium steel does not offer the extra wear resistance required, then a powder metallurgy steel will provide greater wear resistance. 

If the selection of a wear-resistant steel is not enough, then a wear-resistant coating can be applied to the tooling to offer more strength and prolong its life. The correct coating will not only add wear resistance, but will also offer benefits in terms of corrosion protection and anti-stick properties. There are coatings on the market that are around five times harder than normal tablet-tooling steels. These coatings can increase wear resistance to tooling in comparison to uncoated tooling and can extend tool life by over 900%, following research and working examples from I Holland.

Tablet sticking

PharmTech:As you have highlighted earlier, tablet sticking can be a common problem; what options are available to help overcome this issue?

Oxford (I Holland):Sticking is the most common problem and one we come across daily. Because it is such a dominant issue in tablet production, I Holland investigated the cause of formulation sticking and developed ‘TSAR Predict’. It is an algorithmic predictive model that calculates the optimal anti-stick coating to apply to compression tooling based on the properties and characteristics of the formulation. We can identify the most appropriate punch or die coating for sticky formulations, which can eliminate the need to conduct in-the-field testing.

There can be many reasons for the cause of sticking, from Van der Waals forces to capillary action associated with high moisture content, or conversely, sticking due to static electricity generated in very dry conditions. Because the physical properties of any sticky formulation are unique, there is no one-size-fits-all anti-stick solution. Applying a predictive tool specifically developed to recognize the correct punch or die coating solution for a sticky formulation is the answer and one that will save a lot of time and money.

Tool selection

PharmTech:What are some of your key tips and tricks for the best tool selection?

Oxford (I Holland):The correct choice of tool steel can make a huge impact on production and is one of the most important considerations. The tool material must be balanced to give optimum tooling performance and durability. Good steel selection will achieve the best possible balance of a number of properties including abrasion and corrosion resistance, compressive strength, hardness and resistance to chipping and cracking, a clean structure, and good machinability and formability. Tablet punches and dies are the main components to interface with the powders and granules, so they must be metallurgically robust. If the wrong choice of tooling steel is used, the compression of, for example, abrasive formulations, will result in numerous problems.

To select the right tool, consult with a tablet tooling expert and provide as much information as possible. With years of experience, they can offer advice on the most suitable tooling for the job.

Tableting trends

PharmTech:Have you witnessed any significant trends in tableting over the past decade that have had a positive/negative impact on the industry, and what are your predictions for the coming decade?

Oxford (I Holland):Perhaps one of the most significant trends in the past 10 years is the use of multi-tips. Oral solid-dose drug manufacturing is increasing. To keep up with demand, manufacturers need to implement production process improvements to efficiently manufacture tablets. Multi-tip tooling has transformed the way tablets are produced, and it is now considered one of the most productive forms of tablet manufacture. 

Successful implementation of multi-tipped tooling can reduce the need to invest in additional tablet presses, therefore reducing the overall capital spend. The number of tool set-ups required per production batch can also be reduced and product batches are completed quickly, decreasing the overall production time. It also benefits tablets that need to be compressed within a very short time of the formulation being prepared. 

Over the coming decade, shorter lead times and cost implications will put pressure on manufacturers to invest in new technologies and processes. There are also stringent quality requirements that the pharmaceutical industry must apply. These requirements are leading to the need to improve production through durable tablet tooling and the associated maintenance equipment.

The implementation of continuous manufacturing to increase volume will be an important trend in the future and one which will help reduce reaction time and time to market. At I Holland, we have recently designed a product that aims to maximize uptime. The XDF (eXtended Dwell Flat), a novel patented elliptical head form, has been created to increase dwell time on existing presses without the need for modifications. As the importance of increased productivity continues to grow, accommodative solutions, such as XDF, will afford tablet manufacturers the ability to meet future industry demands and trends. 

Reference

1. ISR Reports, “Oral Dosage Forms Market Overview and Outlook (2nd Edition),” ISRreports.com (April 2017), Accessed March 9, 2019. 

Article Details 

Pharmaceutical Technology
Supplement: Solid Dosage Drug Development and Manufacturing
April 2019
Pages: s14–s16

Citation 

When referring to this article, please cite it as F. Thomas, “Under Pressure,” Solid Dosage Drug Development and Manufacturing Supplement (April 2019).