Novel starter pellets based on dibasic calcium phosphate anhydrous: properties and application

Daniel Zakowiecki, Marek Lachmann, Vivienne Schaum and Tobias Hess of Chemische Fabrik BUDENHEIM give an insight on various types of starter pellets which are frequently used for the production of MDDS

Multiparticulate Drug Delivery Systems (MDDS) also called Multiple Unit Dosage Forms (MUDF) are modern pharmaceutical drug products which have been gaining more and more popularity in recent years. These multiple unit dosage forms are created by many independent subunits (microparticles), each of which is an autonomous reservoir of a drug and releases the drug in a planned manner, independently of the other subunits. In the case of solid oral dosage forms, multiparticulates such as granules, minitablets or pellets are usually enclosed in hard capsules or compressed into tablets which increases the comfort of taking medicines by patients.

In comparison to single unit doses such as conventional tablets and capsules, MUDF offer many benefits to pharmaceutical scientists in order to best fulfil actual patient requirements. For example, they give new possibilities of achieving target drug delivery or controlling a drug release characteristic which consequently impact on bioavailability of medicinal products. Furthermore, modified-release multiparticulate formulations can be divided into smaller parts and then taken with food or liquid without altering the release characteristics of a drug substance. This functionality is particularly beneficial in the case of pediatric or geriatric patients having difficulty in swallowing. An interesting solution presents commercially available MDDS which simultaneously contains microparticulates having different drug release patterns, e.g. immediate- and extended-release. In the case of pain treatment, such solution brings the patient a quick relief of pain shortly after taking the preparation and then a long-lasting analgesic effect. The need to take the drug less often increases patient compliance and increases the safety of pharmacotherapy. The issue of drug safety is particularly relevant for extended-release formulations which contain usually very high doses of a drug. Multiparticulate systems are considered to be the most resistant to dose dumping phenomenon in the event of drug product damage (e.g. accidental chewing) or consumption of alcohol (alcohol-induced dose dumping). 1,2,3,4 At present, the most common form of multiparticulates are pellets placed into hard gelatin capsules or compressed into tablets (Multiple Unit Pellet System, MUPS). Pellets are spherical grains (beads, microspheres), most often made of a core coated with at least one layer of polymer film. The coating can play various roles, e.g. protection of a drug substance against the acidic environment of the stomach, regulation of the release rate of an active pharmaceutical ingredient. Usually pellets with diameters from 0.2 to 1.5 mm are used, although grains of other sizes are also available. The FDA (US Food and Drug Administration) suggests that the maximum pellet size should not exceed 2.5 – 2.8 mm. 5,6 On an industrial scale multiparticulates are usually produced by one of two processes: either direct pelletization or coating of inert cores. In the first case, a drug substance is granulated with one or more excipients and subjected to extrusion and spheronisation. As the result the pellets containing a medicinal substance incorporated into the core are obtained. After drying, such spherical grains are usually coated with a thin polymer-based coat. Pelleting by coating of inert cores (indirect) requires the use of so-called starter pellets which do not contain a drug substance. The drug particles are deposited to the outside of the cores in the form of a solution, suspension or powder moistened with a binder. After drug layering, the pellets are usually coated with one or more layer(s) of polymeric film. For modified-release formulations, the release pattern is regulated by the type of polymer used and the thickness of the layer.7,8 This article presents various types of starter pellets (inert cores containing no drug substance), which are frequently used for the production of MDDS. Their physicochemical and functional properties, which normally are not part of the specification, may prove to be important factors determining the course of the drug layering process as well as the properties of the finished drug product. It is worth giving them some consideration before starting the development works.

1. Types of starter pellets (inert cores)
Inert cores are made of excipients commonly used in the pharmaceutical industry, which themselves do not show any pharmacological activity nor interact with the drug substance in a way that may adversely affect its stability and / or effectiveness. There are many types of starter pellets on the market which contain various compounds such as sucrose, starch, microcrystalline cellulose, lactose, various polyalcohols or silica.9,10
Sugar pellets were first introduced to the market and applied as inert cores in production of MUPS. It was related to the introduction of hard gelatin capsules and the development of the biopharmaceutical concept of the modified-release dosage forms in the 1950s. Sugar spheres consist of sucrose, which usually constitutes up to 92 per cent of the abovementioned product, and a corn starch. A wide range of sugar pellets are available on the market and the proportions between the amount of sucrose and starch may vary depending on the manufacturer. Sugar pellets are water-soluble and hygroscopic which often presents challenge during coating. Absorbed water is retained and may impact stability of moisture sensitive drugs. That is why alternative products have been introduced to the market. The most commonly used alternative are cellulose pellets consisting of 100 per cent microcrystalline cellulose. They are insoluble in water and are characterized by high sphericity and good mechanical strength. Thanks to that, the drug layering can be carried out faster, which in turn shortens the coating time and reduces production costs. However, problems such as the absorption of certain drugs on the surface of cellulose fibers which affects their dissolution are frequently reported. Another solution available on the market are starter pellets consisting of polyalcohols such as isomalt, mannitol, xylitol. They are promoted due to their low glycemic index and lack of cariogenic effect. Similarly to sugar pellets, however, they are watersoluble and hygroscopic. 10,11,12,13 Starter pellets based on dibasic calcium phosphate are new on the market and offered by the company Budenheim under the brand name PharSQ Spheres CM. Calcium phosphate based pellets are co-processed product consisting of two commonly used excipients: 80 per cent w/w of anhydrous calcium dihydrogen phosphate and 20 per cent w/w of microcrystalline cellulose. Similarly to cellulose pellets, they 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 cores14 and significantly limits the contact of microcrystalline cellulose fibers with particles of a drug substances which eliminates the possibility of unwanted drug absorption.

2. Comparison of the properties of selected starter pellets
Coating of inert cores is the first stage in the production of Multiple Unit Dosage Forms and its course is determined not only by the appropriate selection of process parameters but also by the physicochemical properties of the starter pellets themselves. The most important factors are the shape of grains, their particle size distribution, roughness of the surface, specific surface area as well as density and mechanical strength of the spheres. All these features have a