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Process Efficiency How to Enhance Tableting Production with a Paracetamol Based Formulation?

| Editor: Ahlam Rais

Recognised as the most stable and economic pharmaceutical forms, tablets are produced in general with an instant release (IR) formulation comprising 500 or 1000 mg of API content. This article aims to enhance the tableting production process.

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Ima’s Prexima 800 is an industrial large-scale double-side rotary tablet press equipped with an Euro-D turret hosting 53 stations and biconvex oblong Euro-D punches.
Ima’s Prexima 800 is an industrial large-scale double-side rotary tablet press equipped with an Euro-D turret hosting 53 stations and biconvex oblong Euro-D punches.
(Source: Ima)

Acetaminophen, commonly known as paracetamol, has analgesic and antipyretic properties and also exhibits weak anti-inflammatory activity. It is used in the symptomatic management of moderate pain and fever: in adults, 500 mg are recommended in case of fever and 1g for moderate pain.

When taken at recommended doses it has an excellent safety profile, notably lacking the gastrointestinal side effects of aspirin and ibuprofen: for this reason this molecule also well known as paracetamol is widely used in the pediatric and geriatric field. However, acute over dosage with acetaminophen, whether accidental or deliberate, is relatively common and can be extremely serious: ingestion of 10–15 g of acetaminophen by adults may cause severe hepatocellular necrosis and doses of 20–25 g are potentially fatal.

The excellent tolerability of therapeutic doses of paracetamol is a major factor in the wide use of the drug: solid oral dose including tablets, capsules, granules as well as syrup and suppositories manufacturing is of big interest in the pharmaceutical field.

Recognised as the most stable and economic pharmaceutical forms, tablets are produced in general with an instant release (IR) formulation comprising 500 or 1000 mg of API content. This article aims to enhance the tableting production process.

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Materials & Methods

A paracetamol based formulation is used for process optimisation: it contains 90 % of API and includes electrostatic, adhesive and cohesive inter-particles.

An industrial large-scale double-side rotary tablet press (Prexima 800, Ima Italy) is used to enhance production. It is equipped with an Euro-D turret hosting 53 stations and biconvex oblong Euro-D punches.

Gallery

The blend was sieved through a 1,2 mm sieve to homogenise the particle distribution and increase the flowability of the powder. A pneumatic loading system was selected to continuously feed the die feeder that was mounting flat shaped paddles.

Production was increasing step by step: three different tests were performed (test 1, test 2 and test 3) at 318,000 tablets per hour (tph), 381600 tph and 508800 tph respectively (Table 1).

At the end, the tablets were checked from a technological point of view to confirm the compliance with the quality required by customers: analysis was focused on weight and hardness variation by comparing all the trials with each other.

Table 1: Tableting process parameters for paracetamol production in Prexima 800.
Table 1: Tableting process parameters for paracetamol production in Prexima 800.
(Source: Ima)

Results & Discussion

Correct up-stream processes allow a smooth tableting process: tablets produced fit will always be the quality required by the Pharmacopeia thanks to the combination of good sieving and mechanical choices on the tablet press.

Attention was also deeply focused on weight variation and its relative standard deviation over time: good and reproducible results were achieved for both equipment sides and all the speeds explored on the tablet press (Figure 1).

Figure 1: Weight variation of test 1, test 2 and test 3 in Prexima 800.
Figure 1: Weight variation of test 1, test 2 and test 3 in Prexima 800.
(Source: Ima)

This graph compares both sides of Prexima 800 for each test: the trend is always comparable and relative standard deviation is less than 1 %, confirming process stability independent of the tablet press speed chosen.

To confirm and strengthen the results, the tablet strength was also monitored: robust structure of the Prexima 800 allows it to maintain stability independent of the peripheral speed performed (Figure 2).

Figure 2: Tablet strength variation of test 1, test 2 and test 3 in Prexima 800.
Figure 2: Tablet strength variation of test 1, test 2 and test 3 in Prexima 800.
(Source: Ima)

As before, the same approach was followed to evaluate the tensile strength: this graph shows both sides of Prexima 800 for each test. As before, tablet hardness is reproducible and comparable monitoring is carried out on two sides of the same tests. On evaluating the increase in tablet press speed, it was observed that tablet strength slightly decreases showing stability and robustness of the process performed.

Conclusions

The paracetamol blend can be tableted smoothly in the Prexima 800, hitting all the target requests made by customers. A high-dose API often shows an unstable process due to the occurrence of bridges and lumps, thus reducing production. Exploring the process enables one to understand that introducing sieving before tableting, improves the whole homogeneity of the blend. Thanks to the combination of mechanical and technological choices as a feeding system, paddle shape and upper punch-penetrations, production quality is reproducible also at enhanced speeds such as 508,800 tph.

Robustness of the process makes the tablets’ technological characteristics stable over time: the relative standard deviation (RSD) on weight is under 1 % in all trials. The tablets strength confirms this theory and does not signal any significant impact at high speed and low dwell times.

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