Better, wetter: an alternative approach to calcium carbonate granulation

Calcium is important for skeletal structure, blood coagulation and nerve functioning. Calcium deficiencies can lead to osteoporosis. The best sources of calcium are dairy products, but for those who cannot consume these, additional calcium is needed. Calcium carbonate is the most widely used and least expensive calcium dietary supplement. As calcium is such an important supplement, it is important to manufacture calcium carbonate tablets as effectively as possible.

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Manufacturing calcium carbonate tablets, as with many other tablets, involves processing steps where powder particles adhere to each other into larger particles or granules (granulation) before being formed into the final tablet. The granulation step has many advantages, such as reducing dust, improving the flow properties of the powder mix and preventing the constituents of the mixture separating.¹

There are two granulation methods: wet and dry. Wet granulation involves agitating the powder, and adding a polymeric binder and liquid to bind the particles together. As the liquid is either water or a mixture of water and alcohol, a drying step is required after granulation.² Dry granulation involves pressing the powder between a tabletting press or the rollers of a compaction or briquetting machine. Since no solvent is added to the powder, a drying step is not required, which is good for moisture- or heat-sensitive drugs,¹ as well as being more environmentally friendly and economical than wet granulation. Powders with temperatures up to 1000 °C can also be compacted. However, dry granulation often produces tablets with low compactability, meaning they have low mechanical strength.³

Methods

Granule preparation. An experiment was conducted to determine whether dry granulation is suitable for producing calcium carbonate tablets. This study used precipitated calcium carbonate and four commonly used excipients: microcrystalline cellulose (Avicel PH101) (MCC), hydroxypropyl cellulose (Klucel) (HPC), maltodextrin (MD) and polyethylene glycol (PEG). All these excipients are widely known and used because of their good binding properties. Two main types of granules were used: granules of calcium carbonate prepared by roller compaction and milling, and granules containing calcium carbonate and maltodextrin prepared by wet granulation and milling.

A Miniroll (Riva SA, Argentina) system was used to compact the powder. The applied force of the rollers was 0–3000 kg, and the diameter and width of the rollers was 135 mm and 26 mm, respectively. The pressure, roll and feeder speed could be varied and stored for further experiments.

The experiment used two combinations of Miniroll, pressure and roll and feeder speeds, which gave the greatest difference in tablet properties. These were picked by compacting 12 samples of calcium carbonate with no excipients added using different combinations of Miniroll settings. After being formed into tablets, their tensile strength and porosity were measured (Table 1). The pressures used ranged from 30 to 75 kg/cm² , the feeder speeds from 18 to 40 rpm and the roll speeds from 6 to 2 rpm. The settings that gave the greatest difference in properties are highlighted in Table 1.

Table 1 Varying parameters during compaction of the different batches.

Four 1000 g batches of calcium carbonate and approximately 10% (w/w) of the four excipients were dry mixed. A fifth batch did not need mixing as it contained only calcium carbonate. The batches were compacted using the Miniroll settings given in Table 1, resulting in two samples of each batch. Details of the 10 samples are given in Table 2. The ribbons produced were milled into granules using a 1.5 mm sieve, and the granules were then separated from fines. Two different references, provided by suppliers, were used in the experiment for comparison between granules prepared by different granulation methods. Reference 1 consisted of granules of calcium carbonate prepared by roller compaction and milling. Reference 2 consisted of granules containing calcium carbonate and approximately 10% (w/w) maltodextrin prepared by wet granulation and milling.

Table 2 Samples with varying parameters and excipients during compaction.

Tablet preparation. The tablets were prepared from 500 mg batches of granules using a single punch press using three different pressures (10, 15 and 20 kN). To manufacture tablets using pressures of 30 and 40 kN, a hydraulic punch was used. Three tablets were produced at each pressure.

Factors affecting tablet strength

In addition to the method of granulation, the mechanical strength of the tablet is affected by factors such as particle size and shape, crystal structure, plastic and elastic deformation, bonding strength and the bonding surface between the particles in the material.^4,5 These factors were examined during the experiment.

During compaction at lower pressures, the particles first shift closer together and then fragment into smaller sizes, which allows them to pack closely together, decreasing their porosity and the volume of the granules, and increasing their density.³ When used, binders help increase the bonding strength by forming a film around the tightly packed particles.³ At higher pressures, plastic and elastic deformation occurs. Elastic deformation is not desirable because it is a reversible process, which can cause the tablets to fall apart. Plastic deformation, in contrast, irreversibly forces the particles together, improving contact and bonding between them.

Measurement

Granule properties. The particle size of the powder and prepared granules was measured using sieves with mesh sizes of 45–1000 μm, which were weighed to calculate the material remaining after sieving.

Scanning electron microscopy (SEM) was used to examine the structure and appearance of the granules. Finally, the crystal structure of the calcium carbonate powder and granules was examined using x-ray diffraction.

Tablet properties. Three factors were measured: tablet porosity, tensile strength and Kawakita parameters. The porosity was calculated from the volume that, for cylindrical tablets, depends on height and diameter. The radial tablet tensile strength was measured by applying diametrical compression on a tablet tester, which caused stresses and eventually led to tensile failure. The strength of the granules was measured at the Royal Institute of Technology in Stockholm (Sweden) using a material tester. The stress of the granules as a function of the strain was calculated for 30 particles from each sample. Finally, Kawakita parameters were calculated. These describe the yield strength of the particles and the stress needed to create particle failure during tablet preparation.⁶

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Results

The study found that the choice of parameters during compaction was not critical to the tablet properties. The excipient also did not significantly affect the tablet properties. The results for Reference 2, which consisted of a wet granulated maltodextrin/calcium carbonate mix, however, differed significantly from the other samples in both tensile strength and porosity at lower and higher pressures (Figures 1 and 2).

Figure 1 Radial tensile strength of the prepared tablets of chosen samples and references as a function of the applied pressure. Error bars show the standard deviation (n=3).

SEM images at 3000× magnification showed that the primary particles of Reference 2 are larger than the other samples and Reference 1 (Figure 3). Smaller particles give granules which behave plastically rather than brittle.⁷ Larger particles fragment during preparation, leading to the formation of new binding surfaces and tablets with higher tensile strength. Only the granules of Reference 2 were found to display brittle behaviours, fragmenting when subjected to a pressure of approximately 5 N/mm² (Figure 4). In contrast, the other samples and Reference 1 did not break when pressure was applied, suggesting they deformed and were softer materials. The difference in the stress among the samples was attributed to the differing particle sizes. The crystals are also more rhombohedral in Reference 2, and more scalenohedral in the other samples, which is another reason why tablets prepared from Reference 2 have a higher tensile strength.

Figure 2 Porosity of the prepared tablets of chosen samples and references as a function of the applied pressure. Error bars show the standard deviation (n=3).

Figure 3 also shows that Reference 2 consists of a smoother material than Reference 1 and the other samples, probably because of the granulation method. In wet granulation, the excipient is better distributed through the material because of the mixing with solvent. The solvent may also partly dissolve the primary particles, encouraging them to stick together during tablet preparation. This explains the high-tensile strength.

Figure 3 Scanning electron micrographs of granules and powder at 3000X magnification: sample 10 (a), calcium carbonate (b) and Reference 2 (c).

The granule particle size and crystal structure were not a critical factor affecting the properties of Reference 2 and the other samples.

Figure 4 Stress of prepared granules of chosen samples and references as a function of strain. Each curve represents an average of the measurements of 30 particles.

Conclusion

This experiment shows that Reference 2, which was manufactured using wet granulation, gave tablets with significantly higher tensile strength and lower tablet porosity than those produced using dry granulation (Reference 1). This was because its granules were more brittle, which was, in turn, attributed to the larger primary particle size. The brittle granules fragmented during tablet production, allowing them to pack closely together, improving the contact between them and, thereby, producing stronger tablets. Wet granulation also uses a solvent, which means the excipient is better distributed and the primary particles have stronger bonds because of the partly dissolved surface areas. The shape of the crystals also differed between Reference 2 and the other samples.

The granule particle size, excipient type, and roller speed and pressure did not affect the tablet properties.

This experiment concludes that using dry granulation to produce granules for tablet production of calcium carbonate gives poorer compactability than using wet granulation.

Lisa Antonsson is Process Engineer at Recipharm (Sweden).

Jonas Berggren is Senior Formulation Scientist at Recipharm (Sweden).

References

1. N.O. Lindberg, "The granulation process," in E. Sandell (Ed.), Industrial Aspects of Pharmaceutics, (Swedish Pharmaceutical Press, Stockholm, Sweden, 1993)

2. R.C. Rowe, P.J. Sheskey and P.J. Weller, Handbook of Pharmaceutical Excipients (Pharmaceutical Press, London, UK, and the American Pharmaceutical Association, Washington, USA, 2003).

3. C. Nyström and G. Alderborn, "The compactability of pharmaceutical powders," in E. Sandell, Ed, Industrial Aspects of Pharmaceutics (Swedish Pharmaceutical Press, Sweden, 1993).

4. G. Alderborn and M. Wikberg, "Granule properties," in G. Alderborn and C. Nyström, Eds, Pharmaceutical Powder Compaction Technology (Marcel Dekker, Inc., New York, NY, USA, 1996).

5. J. Berggren, "Engineering of Pharmaceutical Particles," Ph.D. Thesis, Uppsala University, Sweden (2003).

6. F. Nicklasson and G. Alderborn, Pharm. Res., 17(8), 949–954 (2000).

7. G. Alderborn, "Particle dimensions," in G. Alderborn and C. Nyström, Eds, Pharmaceutical Powder Compaction Technology (Marcel Dekker, Inc., New York, NY, USA, 1996).