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 significant impact on the course of the coating process as well as on the thickness and uniformity of the coating layer and thus on the quality of the final medicinal product. 11,15 A comparison of some of the properties of selected starter pellets is given in Fig. 1 – 4 as well as in Table 1. The results are part of research carried out in cooperation with the Pharmaceutical Department of the Medical University of Gdansk (Poland), which were accepted for presentation at the AAPS 2019 PharmSci 360 conference organized by the American Association of Pharmaceutical Scientists. It should be noted that the inert cores offered by different manufacturers differ in particle size ranges. That is why before testing, the samples were screened between 500 µm and 710 µm sieves to obtain grains of similar size and to avoid impact of particle size on the measurement result.

The analysis results presented in Table 1 show significant differences in the properties of the analyzed inert cores. First of all, the pellets based on microcrystalline cellulose and dibasic calcium phosphate are insoluble in water, unlike sugar and isomalt beads. PharSQ Spheres CM pellets are characterized by very low moisture content and elevated density (both bulk and tapped) which, in combination with high grain sphericity (Fig.1.), results in excellent flowability. The flowability of all tested products is very good, however, a much lower Carr index of sugar and isomalt pellets can be observed when compared to cellulose and calcium phosphate spheres. pH of the liquid obtained by dissolving / suspending 10 per cent w/w of the inert cores in water is close to neutral except for isomalt pellets, where the pH is shifted into an acidic region. These pellets also had the lowest sphericity compared to other products (Fig.1-4).

The results of hardness (expressed as breaking force and tensile strength) of calcium phosphate based pellets appear to be relatively low compared to the other products tested. This is due to the properties of calcium hydrogen phosphate which is a brittle material and undergoes brittle fracture when compressed. However, it should be noted that despite this, the friability of calcium phosphate spheres is similar to that of cellulose pellets, and much lower than that of sugar or isomalt beads. This effect can be observed during the friability test in an oscillating apparatus. After four minutes of the test carried out with the 400 oscillations/min. the glass walls of the friabilator vessel are clean for waterinsoluble pellets (microcrystalline cellulose and calcium phosphate) and are covered with fine, hard-to-remove dust in the case water-soluble pellets (sugar and isomalt).

3. The prospect of compressing calcium phosphate based pellets into tablets
Although the basic form of Multiple Unit Pellet Systems are hard gelatin capsules, tableting of pellets coated with a thin polymeric coating is becoming increasingly popular. This modern technology makes it possible to obtain a very convenient drug form, especially in terms of dosage, for the patient and is considered more advantageous than hard gelatin capsules. Tablets are the most common solid oral dosage forms and their production is significantly easier and cheaper than encapsulation. The tablets containing pellets can be freely divided and taken in smaller pieces without influencing dissolution pattern of a drug, e.g. delayed release. The proper mechanical properties of both inert cores as well as polymer coatings have significant effect on durability of pellets during compression. The type of fillers/diluents in the composition of the tabletting mass is also of fundamental importance. The combination of fillers/diluents having both brittle and plastic properties seems to be particularly beneficial. 16 In the case study described below the possibility of compression of the calcium phosphate based pellets into tablets was evaluated. PharSQ Spheres CM were coated with two types of polymeric coatings: fast-dissolving AquaPolishP blue and enteric AquaPolishP red (Biogrund, Hünstetten, Germany). The coated pellets were used to prepare two tabletting masses, each comprising 50 per cent w/w of the pellets, 47.5 per cent w/w of the 1: 1 mixture of anhydrous dibasic calcium phosphate (DI-CAFOS A150) and microcrystalline cellulose (type 102), 2 per cent w/w of disintegrant (crospovidone) and 0.5 per cent w/w of lubricant (magnesium stearate). All ingredients without lubricant were mixed for 10 min in a Turbula mixer (Willy A. Bachofen AG, Muttenz, Switzerland) at 32 rpm which was followed by five min lubrication step carried out in the same conditions. The obtained tablet masses were pressed into tablets using a Fette 102i rotary tablet press (Fette Compacting GmbH, Schwarzenbek, Germany) equipped with round, flat punches having the diameter of 12 mm. Compression force of 25 kN, which is maximum compression force for this kind of punches and a rotor speed of 62.5 rpm were applied. Fig.5 shows a cross section of tablets containing two kinds of coated pellets. It can be noticed that in both cases the pellet coating has not been damaged and there are no visible abrasions, cracks etc. It is also evident that some pellets have strained plastically during compression (photo on the left) which compensated the compression pressure and protected the coating against the damage during tabletting.

Summary
Innovative starter pellets based on dibasic calcium phosphate anhydrous (PharSQ Spheres CM) are a very good alternative to other commercially available inert cores used in the production of Multiparticulate Drug Delivery Systems. Due to their high density, good mechanical strength and spherical shape they show excellent fluidization properties. The exceptionally high density of these inert cores gives the possibility of preparing drug products with increased density which can stay longer in the stomach. Low water content and neutral pH make phosphate pellets an ideal carrier for medicinal substances sensitive to moisture.

References
1 Nihad Al-Hashimi, Nazish Begg, Raid G. Alany, Hany Hassanin, Amr Elshaer. Oral Modified Release Multiple-Unit Particulate Systems: Compressed Pellets, Microparticles and Nanoparticles. Pharmaceutics. 2018; 10(4): 176
2 Janicki S. Making the idea of a Multiple Unit Dosage Form a reality. Farm Pol. 1999; 55(3): 139 – 148
3 Stawarski T, Sieradzki E, Bartos N, Stawarska A. Comparison of the rate of release of pantoprazole from gastro-resistant tablets and multicompartment systems. Farm Pol. 2014, 70(5): 231 – 234
4. Haznar D, Garbacz G. Selected aspects of technologies for modified-release dosage forms. Farm Pol. 2009; 65(10): 749 – 757
5. US Food and Drugs Administration Guidance for Industry: Size of beads in drug products labeled for sprinkle. (https://www.fda.gov/media/79676/download)
6. Ranmal SR, Barker SA, Tuleu C. Paediatric solid formulations. In: Pediatric Formulations – A Roadmap (eds.: Bar-Shalom D, Rose K). AAPS Springer 2014: 153 – 170
7. Ho L, Cuppok Y, Muschert S, Gordon KC, Pepper M, Shen Y, Siepmann F, Siepmann J, Taday PF, Rades T. Effects of film coating thickness and drug layer uniformity on in vitro drug release from sustained-release coated pellets: a case study using terahertz pulsed imaging. Int J Pharm. 2009; 382(1-2): 151 – 159.
8. Patel P, Godek E, O’Callaghan C, Jones I. Predicting multiparticulate dissolution in real time for modified- and extended-release formulations: Process analytical technology based on monitoring particle size distribution and tracking coating thickness measurements in real time can be used to predict the dissolution of polymer-coated multiparticulates. Pharmaceutical Technology Europe 2017, 29(7): 15 – 21
9. Tschopp P. Starter pellets: materials, manufacturing methods, and applications. Tablets &Capsules, 2015, 13 (5): 10 – 13
10. Sidwell R, Hansell J, Rane M, Rajabi-Siahboomi AR. Characterization of Inert Cores for Multiparticulate Dosage. In: Multiparticulate Drug Delivery (ed.: Rajabi-Siahboomi AR). Springer 2017: 5 – 36
11. Kallai N, Luhn O, Dredan J, Kovacs K, Lengyel M, Antal I. Evaluation of drug release from coated pellets based on isomalt, sugar, and microcrystalline cellulose inert cores. AAPS PharmSciTech. 2010; 11(1): 383 – 391
12. Werner D. Sugar spheres: a versatile excipient for oral pellet medications with modified release kinetics. Pharmaceut Tech Eur. 2006; 18: 35 – 41
13. Dukic-Ott A, Thommes M, Remon JP, Kleinebudde P, Vervaet C. Production of pellets via extrusion-spheronisation without the incorporation of microcrystalline cellulose: a critical review. Eur J Pharm Biopharm. 2009; 71(1): 38 – 46
14. 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
15. Czajkowska M, Kowalec-Pietrenko B, Sznitowska M. Program control of air flow during fluidized bed coating of pharmaceutical preparations. Inz. Ap. Chem. 2015; 54(6): 312 – 313
16. Al-Hashimi N, Begg N, Alany RG, Hassanin H, Elshaer A. Oral Modified Release Multiple-Unit Particulate Systems: Compressed Pellets, Microparticles and Nanoparticles. Pharmaceutics. 2018; 10 (4): 176
Contact-
E-mail: [email protected]
Webpage: www.budenheim.com