Advantages of calcium phosphate based excipients in pharmaceutical formulations development

Daniel Zakowiecki, Marek Lachmann, Vivienne Schaum and Tobias Hess of Budenheim, a Germany based company, discuss the advantages of calcium phosphate based excipients and the developments Budenheim has made in the area

In the series of articles published earlier in the Express Pharma magazine, the authors (Daniel Zakowiecki, Marek Lachmann, Vivienne Schaum and Tobias Hess – BUDENHEIM, Germany) showed the advantages of using calcium phosphate based excipients in pharmaceutical technology, especially in the development of solid dosage oral formulations. [1-6] In the present article we are going to summarise all information and highlight Budenheim new developments which provide further possibilities.

Calcium phosphates based excipients have been present in the pharmaceutical technology for many years. They are widely used for plenty of reasons. First of all, calcium phosphates are inorganic substances of mineral origin, generally recognized as safe (GRAS) by the United States Food and Drug Administration (FDA). They are GMO- and animal-free substances which do not contain any organic residual solvents. They show good chemical and physical stability and are compatible with majority of known active pharmaceutical ingredients. The fact that calcium phosphates are a natural source of such important elements as phosphorus and calcium makes them a very safe solution for patients.

Calcium phosphates as active pharmaceutical ingredients
Owing to the safety and very high quality, some of Budenheim phosphates have recently gone beyond traditional application as excipients and are used as active pharmaceutical ingredients (API) as well – these API grades (calcium, sodium and magnesium phosphates) are registered and offered under the family brand name PharSQ Active.

Benefits for poorly flowable powders
In addition to the benefits related to the safety of use, calcium phosphate based excipient offer many advantages from a technological perspective. Especially attractive are coarse, directly compressible grades. Due to their favorable particle size and shape they exhibit excellent flowability. In many cases they are able to govern the flow pattern of very poorly flowable powders which allows relatively easy preparation of tableting mixtures without a granulation. Very high density of calcium phosphates allows either using of larger amounts of excipients without increasing the size of the dosage form or decreasing it when the same quantity of excipients is used.

Excellent compaction properties
Dibasic calcium phosphates undergo mainly brittle fracture during compression. Thanks to that, they show very good compaction properties as well as low lubricant sensitivity. Increased amounts of lubricants or longer mixing time do not significantly affect the compaction properties of powder mixtures containing calcium phosphate based
excipients.

Physical stability in aqueous media
Calcium salts of orthophosphoric acid do not dissolve in water. Moreover, in contact with aqueous media they do not swell or change their physical properties. Therefore they can be successfully used in any technological operations involving water, e.g. wet granulation, as a completely inert densifier. In this case fine grades are the most frequently used. Another significant advantage is the immaculate white colour that gives the tablets containing calcium phosphates more attractive appearance.

Improved characteristics
Formulation scientists sometimes do not consider calcium phosphate based excipients as the first choice because of a common belief about their abrasive nature which might be problematic for a tablet press tooling. This belief is rather obsolete since the progress in crystal chemistry and technology resulted in the development of new types of phosphates which are devoid of these adverse features. However, it should be remembered that not all phosphates available on the market are the same – more information on this topic will be provided later in this article.

Various types of calcium phosphate based excipients
There are many different grades of calcium phosphate based excipient on the market. Budenheim also offers various forms of specialized calcium phosphates which can be flexibly used in different types of pharmaceutical processes:
Dibasic calcium phosphate dihydrate (USP/NF), Calcium Hydrogen Phosphate Dihydrate (Ph.Eur.) – a coarse grade DI-CAFOS D 160 is the most widely used product for direct compression because of its very good both compaction and flow properties while a fine grade DI-CAFOS D 14 is very popular product used mainly in wet granulation processes. [1,7]
Anhydrous dibasic calcium phosphate (USP/NF), Calcium Hydrogen Phosphate (Ph.Eur.) – directly compressible grade DI-CAFOS A 150 which has a very high binding capacity allowing to significantly increase the mechanical strength of tablets even at high drug concentration. The product is slightly acidic and the possible effect on the microenvironment of the formulation should be considered. DI-CAFOS A 60 is another DC grade which has neutral pH and can be safely processed with pH- sensitive drugs. Owing to elevated density the product helps to reduce the size dosage forms. The level of water sorption is minimal making it ideal partner for water sensitive drugs. DI- CAFOS A 12 is another product with neutral pH and limited water uptake mostly employed in wet granulation processes. Thanks to the very high intrinsic density, it allows to increase the density of obtained granules, as well as final drug products. [1,7] Tribasic Calcium Phosphate (USP/NF), Calcium Phosphate (Ph.Eur.) also known as hydroxyapatite [Ca5(OH)(PO4)3]. Budenheim offers fine grades for wet granulation (TRI-CAFOS 250 and TRI-CAFOS 350) as well as two unique, highly specialized products. First, TRI-CAFOS 500, is a directly compressible material with elevated specific surface area. It is employed in tablet formulations to increase their porosity and consequently shorten disintegration time. Moreover, when used as co-diluent, it enhances the bonding capacity of powder mixtures and allows producing tablets with improved mechanical strength. [1,7] The second very interesting product is, TRI-CAFOS 200-7, thanks its special particle structure and properties it can be used as a flow regulating agent. In comparison to other popular glidants it offers a much higher bulk density which reduces dust formation and increases safety of handling. [2-5]

Comparison of various commercial calcium phosphate based excipients
As mentioned earlier, it should be borne in mind that not all calcium phosphate based excipients available on the market are the same and can be mutually replaced in the formulation. Even types intended for direct compression, although having a similar particle size, may differ significantly in terms of functional properties. Fig.1. shows the comparison of tabletting properties of four calcium phosphate based products for direct compression coming from different vendors. The placebo formulations consisted of 99.5 per cent w/w of anhydrous dibasic calcium phosphates and 0.5 per cent w/w of magnesium stearate. Both substances were blended for 5 min at a rotational speed of 32 rpm using a Turbula mixer (Willy A. Bachofen AG, Muttenz, Switzerland). The powder mixtures were compressed into tablets using the Fette 102i rotary tablet press (Fette Compacting GmbH, Schwarzenbek, Germany) at 62.5 rpm using flat faced punches of 8 mm in diameter under three compaction forces: 10 kN, 20 kN and 30 kN (equivalent to 200 MPa, 400 MPa and 600 MPa respectively).

The comparison shown in Fig.1. reveals some significant differences between products available on the market not only in terms of particle structure and morphology, but what is more important, functional properties. Tablets made of two high quality products: DI-CAFOS A 150 and a product having similar morphology (described as Producer A) give similar results with regard to mechanical strength (hardness expressed as breaking force and friability. Material coming from both Producer B and Producer C are completely different in term of particle shape and structure. It has crucial impact on their performance. Tablets produced using these two materials demonstrate much lower hardness and are very friable. This case study shows how crucial the proper choice of an excipient vendor is. One can imagine how costly could be the replacement of an excipient already used and established in the routine manufacturing with a lower quality material. Tablets produced could not meet the specification requirements which, in turn ended up with rejection of the whole batch produced.

New possibilities with PharSQ Spheres CM starter pellets
It would seem that we already know everything about calcium phosphate excipients. On the market there are many different products available. They have different properties and offer solutions for various formulation challenges. So what new could be still developed?

Well, it turns out that there are still many new possibilities. Last year Budenheim launched a new product: calcium phosphate based starter pellets (PharSQ Spheres CM). These unique inert cores owe their properties to the combination of brittle material – dibasic calcium phosphate anhydrous – and the elastic one – microcrystalline cellulose. In comparison with other commercial inert pellets PharSQ Spheres CM offer many interesting properties which can facilitate production of Multiple Unit Pellet System.(MUPS). [6,8] First of all, PharSQ Spheres CM exhibit much higher unit density compared to other existing starter pellets. This feature can be utilised in preparation of high-density systems which are able to increase the gastric residence time. Moreover, high density in combination with very spherical shape (Fig.2,3) assures excellent flow characteristic as well as good fluidization properties. Another important property is very low friability which is desired as it limits attrition and prevents from dust formation especially at the beginning of coating process.

PharSQ Spheres CM do not dissolve in water and are characterized by low hygroscopicity, which significantly facilitates the technological processes. The high content of anhydrous calcium hydrogen phosphate determines the physicochemical properties of the inert cores and significantly limits the contact of microcrystalline cellulose fibers with particles of drug substances, which in turn eliminates the possibility of unwanted drug absorption.

Summary:
Budenheim is a Germany based company with an over 100- year-old tradition of producing phosphates. This experience allows delivering high quality excipients which help formulation scientists to meet their formulation challenges. Striving to make the pharmaceutical portfolio more attractive for industry partners, Budenheim has introduced the family brand PharSQ. Moreover, the company is strongly committed to develop new innovative products. One can soon expect the introduction of new products which will facilitate existing technological processes and give new opportunities in new drug products development.

REFERENCES
[1] Zakowiecki D, Lachmann M, Hess T. Beyond just a filler – application of calcium phosphates in direct compression formulations. Express Pharma 2017, 13 (3): 90-92
[2] Zakowiecki D, Lachmann M, Hess T. A new perspective on flow enhancement in solid oral dosage formulation – advantages of an unique glidant material TRI-CAFOS® 200-7 – Part 1. Express Pharma, Goa Pharma Summit Special, November 2018: 17 – 19
[3] Zakowiecki D, Lachmann M, Hess T. A new perspective on flow enhancement in solid oral dosage formulation – advantages of an unique glidant material TRI-CAFOS® 200-7 – Part 2. Express Pharma 2018, 14 (4): 142-144
[4] Zakowiecki D, Lachmann M, Hess T. Tribasic calcium phosphate one compound, so many possibilities (Part 1). Express Pharma 2019, 14 (15): 54-57
[5] Zakowiecki D, Lachmann M, Hess T. Tribasic calcium phosphate one compound, so many possibilities (Part 2). Express Pharma 2019, 14 (19): 33-35
[6] Zakowiecki D, Lachmann M, Schaum V, Hess T. Novel starter pellets based on dibasic calcium phosphate anhydrous: properties and application. Express Pharma, November 1-15, 2019: 34-36
[7] Zakowiecki D, Lachmann M, Hess T. Eye on Excipients. Tablets &Capsules Magazine, 2019, 17 (4): 39-43
[8] Zakowiecki D, Lachmann M, Huhn A, Papaioannou M, Hess T, Centkowska K, Milolaszek B, Cal K. Characterization of physical properties of novel calcium-phosphate-based starter pellets (PharSQ Spheres CM). Poster presented at the AAPS Annual Meeting and Exposition, 2019 November 3-6; San Antonio, TX, US

Contact:
E-mail: [email protected]
Webpage: www.budenheim.com