Tablet Splitting Concerns

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When splitting unscored tablets, the main concerns relate to API dosage control and the potential modification of time-release characteristics. PTE speaks with tableting experts Thierry Menard, Lab Manager, And Bruno Villa, President, both at Medelpharm, about how manufacturers are approaching the challenges.

What are the problems or risks associated with splitting unscored tablets, especially if they are film-coated or modified release tablets?

The main risks are:

  • API dosage control. The risk of uneven pieces and fragments with varying dosages is very high compared with scored tablets. Risks are measured in quality-assurance processes according to the Pharmacopoeias.
  • Modification of timed release characteristics. These characteristics can, in some instances, be totally destroyed when a tablet is broken.

How different is the tabletting process for scored tablets compared with unscored tablets in terms of the technology and equipments involved, quality control and quality assurance protocols, and stability testing requirements?

Precision and reliability are even more critical than usual when producing scored tablets.The sensitivity to variance is increased in upscale process, as well as in tablet production. It is important to take note of the following:

  • Before compression, it is important to ensure that processes are in place to avoid de-mixing, segregation and over-lubrication; classical issues during processing.
  • During compression, there should be tighter tighter regulation control and rejection rules.
  • Uniformity of mass and filling are important parameters. Different weight creates different hardness, which in turn impacts friability and the quality of breaking, as well as uneven filling.

Tooling is also a critical element, although price and fragility increases with their complexity, as well as the ability to detect sticking or other production problems linked to the score line.

Systems such as a “tabletting robot” can be programmed to test a tabletting process, including its sensitivity to variance.

Machines from Medelpharm have key slots as standard to accept shaped tools from production machines. By default, they are also fully instrumented to monitor every phase of the compression event. A laboratory using STYL’One or STYLCAM technology can test the impact of the desired parameters with very small batches (down to 1 tablet) produced at full speed in production conditions.

Fast set-up of experiments (a few minutes to clean and change tooling) also enables shape tests to be performed easily.

To ensure tablets can be split evenly with good dosage content uniformity, what factors do tablet manufacturers need to take into account?

As always, monitoring and knowing key critical parameters are crucial to quality. During research and development of the compression stage, it is important to use final production tools (punches), use similar compression parameters (e.g., forces, compression cycle/speed and pre-compression), and use similar weight regulation systems to control filling and weight homogeneity. Different compression forces or speeds between research and development and production will create different hardness and density inside the tablets, which will impact dissolution and breakage.

Powder flow in the feeding systems, and inside the tablet during compression, is another parameter that should be measured.

What are the common challenges involved in the formulation, manufacturing and testing of scored tablet?

It is challenging for manufacturers to identify a robust formula that creates correct hardness and satisfies quality requirements for splitting. Being able to screen rapidly is key in order to test many formula, formats and options. The challenge here is to perform tests quickly.

How easy is it to ensure that the dosage unit of subdivided tablets fall within the accepted criteria of USP, EP and other current guidance documents?

The content uniformity is even more critical with a dose becoming smaller and an already higher weight variance due to splitting tablets. This variance adds more pressure in scale-up and formulation, requiring more robust processes.

Medelpharm for example did some experiments for a customer with progressive-shape tooling where we examined the ideal shape (angle of indent), as well as single or double side scoring and the benefits of using a “narrow waist” tablet. Producing small batches at production speed, we were able to predict which upper and lower pairs of punches and die selection produced the best tablets for meeting regulatory requirements. At the same time, we tested the efficiency of shaped dies and of different punch tips to find the best compromise between quality acceptance and tooling costs.

Meeting requirements is tricky, however, since quality guidelines take into account human action in breaking tablets. And, as we all know, the regulatory-defined process for breaking a tablet is rarely followed in everyday life!