A Multifunctional Mineral Excipient

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Orally disintegrating tablets (ODTs) are becoming increasingly important in the global pharmaceutical market for both prescription and over-the-counter medications because they can significantly improve patient compliance. They can be swallowed without the need for water, are generally smaller, and have good mouthfeel. Such properties make ODTs particularly convenient for children and the elderly, especially when a flavor is also incorporated into the formulation. In addition, they are the delivery format of choice for people who want to take their medicine “on the go” and are particularly helpful for patients who have difficulty swallowing--a complication associated with a number of age-related conditions, including stroke and Parkinson’s disease. 

ODTs can be manufactured using various different techniques, such as tablet molding, freeze drying, spray drying, or direct compression. The final form--tablet or granule--has to deliver the active ingredients rapidly, but depending on the technique used, it may be associated with low mechanical strength, high production costs, or inferior stability. From the perspectives of cost and simplicity, the preferred method of preparing ODTs is direct compression. However, the disintegration capacity of ODTs produced in this way is limited by the size and hardness of the resulting tablets (1, 2). The challenge, therefore, when compressing ODTs is ensuring a structure that enables fast disintegration without affecting the hardness of the tablets. Developing a dosage form with these properties requires an excipient that offers optimum cohesiveness for compaction. 

Properties

It can be difficult to find multifunctional excipients that do not add to the burden of an already extensive regulatory filing. Functionalized calcium carbonate (FCC) offers the advantage of being a structured mineral comprising calcium carbonate and hydroxyapatite, both of which are monographed minerals. FCC is manufactured from high-purity calcium carbonate that undergoes surface recrystallization (Figures 1 and 2). This process can be controlled to obtain specific surface areas ranging between 30 and 180 m²/g, a median particle size distribution of between 2 and 30 μm, and porosities of higher than 60%. FCC particles are characterized by an external lamellae structure and an internal network of interconnected pores. 

[CLICK FIGURE TO ENLARGE] Figure 1: Micrograph of natural calcium carbonate. (All figures are courtesy of Omya International AG.) 

In contrast to other porous excipients, FCC has a lamellae morphology, which provides plenty of surface contact points among the particles, ensuring interlocking during dry granulation in roller compactors. This structure facilitates the production of granules by dry granulation. After milling and sieving, the granules are ready to be mixed with APIs and can be compressed into ODTs. Thus, ODTs manufactured with FCC feature both high porosity and high levels of hardness.

[CLICK FIGURE TO ENLARGE] Figure 2: Micrograph of functionalized calcium carbonate.

Loading capability

Researchers at the University of Basel in Switzerland investigated the feasibility of using a particular grade of FCC as a carrier for poorly water-soluble APIs. Ibuprofen (IBU), nifedipine (NP), losartan potassium (LP), and metronidazole benzoate (MBZ) were selected as model substances to investigate drug loading (3). The team analyzed the loading capacity of FCC, the dissolution performance of the formulation, and whether the drug was loaded in its amorphous or crystalline form. The four APIs were dissolved in methanol or acetone and mixed with FCC. Using a rotary evaporator to control the pressure, the FCC-API particles were loaded with 25 to 50% (w/w) of each API, and afterwards the solvents were removed. For reference, the scientists also created FCC-API mixtures that contained equivalent API fractions but were not subject to a specific loading strategy. Loading efficiency was assessed using a scanning electron microscope (SEM). The presence of particle agglomerates or drug crystals outside the FCC particles indicated the maximum loading capacity. It was shown that the particles can be successfully loaded with up to 40% (w/w) API. The team also observed a reduction in intraparticle porosity after drug loading (63% for MBZ, 58% for IBU, 50% for NP, and 35% for LP), which provided evidence of pore filling. Drug concentration was quantified by high-performance liquid chromatography (HPLC). In addition, the dissolution rate of FCC loaded with NP and MBZ was found to be faster than that of the FCC-API mixtures. Because only low percentages of amorphous NP (8.9%) and MB (12.5%) were detected, the authors concluded that the faster dissolution was related to the locally increased solubility caused by the larger surface area and not due to the presence of an amorphous API. 

Compressibility

In another study (4), researchers examined the compressibility of tablets made using FCC granules and compared them with tablets made with either FCC in powder form, conventional calcium carbonate, mannitol, or microcrystalline cellulose (MCC). The tensile strength and the porosity of the tablets were analyzed across a broad range of compression forces. At low compression force, the tensile strength of tablets formulated with FCC powder or FCC granules was higher than that of tablets formulated with mannitol or calcium carbonate and was comparable to that of tablets formulated with MCC (see Figure 3). The FCC tablets also had a higher porosity than those containing the other excipients tested. 

Figure 3: Tensile strength vs. mean compression force for tablets made using functionalized calcium carbonate (FCC) and reference excipients. At lower compression forces, FCC tablets reach tensile strengths that are higher than or comparable to that of tablets formulated with other reference excipients. MCC is microcrystalline cellulose.

With FCC in the formulation, tablets were able to reach comparable or higher hardness than other formulations at lower compression forces, which allowed their porosity to remain higher than 50%. This porosity provides a large volume of voids for accommodating APIs.

In a second step, the researchers analyzed tablets formulated with paracetamol and one of the following: FCC powder or MCC. They concluded that despite the presence of an API, the decrease in porosity of the FCC tablets was significantly less than that of tablets formulated with MCC when compression force was increased. Additionally, the tensile strength of the FCC tablets was comparable to that of tablets formulated with MCC (see Figure 4). Finally, the FCC tablets’ combination of high tensile strength and high porosity indicated that FCC is suitable for use in ODTs as a pharmaceutical excipient.

Figure 4: Tensile strength vs. mean compression force for tablets formulated with paracetamol and one of the following: functionalized calcium carbonate (FCC) powder or microcrystalline cellulose (MCC). The tensile strength of FCC tablets was comparable to that of tablets formulated with MCC.

Disintegration

In order to determine residence time, the scientists used a tensiometer to measure mass versus time, which in turn allowed them to study water uptake and disintegration behavior (5). They analyzed the disintegration kinetics of 24 different formulations and identified four patterns. Type I was considered the ideal behavior because it resembled the market formulation. Type II was characterized by very fast water uptake but no disintegration. Type III disintegrated in discrete steps, resulting in tablet pieces, while type IV disintegrated only partially. FCC exhibited a type I disintegration pattern, and its residence time was half that of the market formulation used as a reference.
FCC’s direct compressibility into granules without the use of a binder and its high porosity, which allows faster water uptake, lead to a disintegration time that is twice as fast as the market reference product. In fact, orally disintegrating granules manufactured with FCC disintegrate in 2 seconds and their corresponding ODTs in less than 10 seconds (5).

Conclusion

ODTs manufactured with FCC can be produced by direct compression of a blend of FCC granules and the active of choice. The high porosity of ODTs formulated with FCC results in rapid disintegration and their high mechanical strength enables the use of regular bottles and blisters as packaging, which significantly reduces the overall cost of production compared to other ODT technologies.
Also, from a regulatory point of view, FCC has the advantages of being a co-processed excipient composed of only two monographed minerals. Moreover, it offers the possibility of multiple functionalities with simple chemistry and a straightforward granule and tablet manufacturing process. Additionally, it is possible to tailor the characteristics of FCC, such as specific surface area, particle size distribution, and pore size distribution, according to the requirements of various applications. Furthermore, unlike many similar materials, FCC has the advantage of being highly biocompatible. Its composition is basically that of mineral bone material: hydroxyapatite and calcium carbonate. 
Bearing all of these advantages in mind, FCC is a promising excipient for dry oral dosage forms. It will be interesting to see what kind of formulations this mineral will make possible in the near future. 

References

1. S.A. Sreenivas, Indian J Pharm. Educ. Res. 39 (4) 177-81 (2005).
2. V.D. Kumar, I Sharma, and V. Sharma, J App. Pharm. Sci. 1 (5) 50-8 (2011).
3. D. Preisig et al., Eur J Pharm. Biopharm. 87 (3) 548-58 (2014).
4. T. Stirnimann et al., Int. J Pharm. 466 (1-2): 266-75 (2014).
5. T. Stirnimann et al., Pharm. Res. 30 (7) 1915-25 (2013).  

Article Details

Pharmaceutical Technology
Supplement: Outsourcing Resources
Vol. 41, No. 9
September 2017
Pages: s24-s26

Citation

When referring to this article, please cite it as C. Diaz Quijano, "A Multifunctional Mineral Excipient," Pharmaceutical TechnologyAPIs, Excipients, & Manufacturing 2017 Supplement (September 2017).

About the Author

Carolina Diaz Quijano, PhD, is manager of Innovation and Technical Marketing Nutra/Pharma at Omya International AG, Baslerstrasse 42, 4665 Oftringen, Switzerland, info.pharma@omya.com.