Leading the way in effervescent tablets manufacturing

Introduction

Conventionally defined as the most popular way of taking medication, oral dosage forms have some disadvantages compared with other pharmaceutical forms. One of this is the risk of slow absorption of the active pharmaceutical ingredient (API), which can be overcome by administering the drug in liquid form. However, because many APIs show a limited stability in liquid form, effervescence application has provided a good solution: drug dissolution and consumption and, at the same time, faster and more complete absorption compared to conventional tablets. Therefore, several advantages should be considered: improved patient compliance since there is no need to swallow tablets, less stomach and intestinal irritation, accurate dosing and more reproducible pharmacokinetics are a few examples. However, process manufacturing and blend formulation need some specific arrangements in effervescent field: larger tablets, complex production and need for specialist packaging materials as well as non-toxic, tasteless and water-soluble lubricant. Lubricant is, for this reason, a critical feature that needs to be deeply evaluated: magnesium stearate, as other water-insoluble lubricants, avoids obtaining a clear transparent solution and retards the disintegration and dissolution which is required to be rapid in effervescent tablets.
The aim of this case study, in cooperation with IASIS PHARMA, is manufacturing of round effervescent tablets on a rotary tablet press model Prexima 300 according to customer’s specification. In addition, the focus was placed on process feasibility by inserting lubricant externally in order to reduce at minimum the quantity provided and improve the technological characteristics of the tablets such as disintegration. IASIS PHARMA is a privately-owned company with 24 years of solid experience in pharmaceuticals manufacturing currently exporting in 25 countries. The addition of a second state-of-the-art manufacturing site, fully operational in year 2020, increases substantially IASIS PHARMA capability to carry out CMO/CDMO projects of very high specifications. The flagship of the new plant is a Pharma Grade Effervescent Unit capable to produce in both tube and strip presentations. All operations and functions in the new site are fully supported by a highly sophisticated IT system ensuring the data integrity of every single process.

Materials and methods

Acetylcysteine effervescent granules, used for this case study, are obtained through single-pot granulation in Roto Cube 600.
The API Acetylcysteine is firstly granulated with a binding solution of polyvinypyrrolidone dissolved in ethanol and finally mixed with the rest of granulated excipients, responsible of effervescence added with extra granular excipients in Cyclops bin tumbler.

• API Acetylcysteine 13.8%.
• Excipients (77.2%): sodium hydrogen carbonate, citric acid anhydrous, sodium sulphate anhydrous, sodium cyclamate, sodium saccharin, simethicone emulsion, povidone.
• Other excipients (9.0%): sodium carbonate anhydrous, lemon flavor, macrogol 6,000.

This final blend is free-flowable (iCarr 14%) with a very low content of residual moisture (LOD 0.16%). Lubricant used was Magnesium Stearate provided by external lubrication unit (LUMS, IMA).

The unit was equipped with a 12 mm screw to provide the necessary quantity of lubricant.
The trials were performed on Prexima 300, equipped accurately for customer need:

• 18 stations format IMA-32 round Ø 18 mm, punches specially designed with an increased head that is useful to rise dwell time without sacrificing tablet press speed;
• Punches with teflon insert that reduce sticking and picking to punches and dies.

Different experiments were performed, all with the aim to achieve the maximum tablet press speed and with the minimum lubricant quantity provided. Parameters found can be summarized in Table 1.
At the end, tablets were analyzed in terms of weight, thickness, hardness, content uniformity and lubricant quantity.

Table 1: final process parameters on Prexima 300.

Results and discussion

Blend processability is excellent and the good process optimization allows to obtain high production output without any particular need: feeder system is standard with no particular paddle shape mounted in. Tablets’ analysis completely satisfy the customers’ request (as summarized in Table 2):

Table 2: results of tablets’ analysis.

It is important to underline that it is recommendable to work in the upper part of the dies (upper punch penetration 1 mm in pre-compression and 1 mm in compression) in order to lubricate properly punches and dies surface. This process optimization, with the use of IMA 32 punches model, allows high production in terms of tablets per hour without reducing tablets’ quality. Magnesium stearate analytical detected was confirming the possibility to reduce lubricant quantity compared with a normal internal lubrication where magnesium stearate is usually around 0.5%. Visually, disintegration and dissolution of tablets in water release completely transparent solution without any residues of magnesium stearate.