Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 238 _____________________________ _____________________________ Pharmaceutical Binders and Their Function in Directly Compressed Tablets Mechanistic Studies on the Effect of Dry Binders on Mechanical Strength, Pore Structure and Disintegration of Tablets BY SOFIA MATTSSON ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2000 Dissertation for the Degree of Doctor of Philosophy (Faculty of Pharmacy) in Pharmaceutics presented at Uppsala University in 2000 ABSTRACT In this thesis, the strength-enhancing mechanisms of dry binders in direct compression were studied. The systems investigated were binary mixtures containing various compounds and binders. Among the binders used were a series of different molecular weights of polyethylene glycol. The proposed simplified tablet model describing the fracture path in a tablet during strength testing offers an explanation for the increase in tablet strength caused by the binder. The model and results in this thesis indicate that fractures will usually propagate around the tablet particles and through the interparticulate voids during tablet strength testing. One important characteristic of the binder is its ability to be effectively and evenly distributed through the interparticulate voids in a compound tablet. Characteristics such as high plasticity, low elasticity and a small particle size were associated with a more even distribution and a consequent pronounced effect on pore structure and marked improvement in tablet strength. The strength of tablets containing less plastic binders was governed more by the compactibility of the binder. The tablet porosity, bonding mechanisms and volume reduction mechanisms of the compound also influenced the effect of the binder. For example, the plasticity and particle size of the binder had the most significant effects on tablet strength when the tablet porosity of the compound was relatively low. A combination of the plasticity and the compactibility of the binder determined the strength of tablets when the tablet of a compound was more porous. The positive effect of a binder on pore structure and tablet strength resulted in an increase in the disintegration time. Although addition of a superdisintegrant generally improved the disintegration time, the effect was decreased when the formulation included more deformable binders. The choice of a suitable binder for a tablet formulation requires extensive knowledge of the relative importance of binder properties for enhancing the strength of the tablet and also of the interactions between the various materials constituting a tablet. Thus, the increased knowledge of the functionality of a binder obtained in this thesis enables a more rational approach to tablet formulation. Sofia Mattsson, Department of Pharmacy, Division of Pharmaceutics, Uppsala Biomedical Centre, Box 580, SE-75123 Uppsala, Sweden © Sofia Mattsson 2000 ISSN 0282-7484 ISBN 91-554-4857-7 Contents Papers discussed 7 Pharmaceutical tablets 8 Compaction of pharmaceutical powders 9 Volume reduction mechanisms 9 Methods for characterisation of volume reduction mechanisms 10 Bonding mechanisms 11 Methods for characterisation of bonding mechanisms 12 Mechanical strength of tablets 13 Measurements of mechanical strength 13 Theoretical models of mechanical strength 14 Bond summation concept Fracture mechanics concept Percolation theory Effect of particle and powder properties on mechanical strength 15 Effect of compaction process and environment on mechanical strength 16 Pore structure of tablets 17 Disintegration of tablets 18 Binders as strength-enhancing materials in pharmaceutical tablets 18 Distribution of binders - comparison between direct compression and wet granulation 19 Effect of binders on mechanical strength of directly compressed tablets 19 Commonly used binders in direct compression 20 Polyethylene glycol 21 Aims of the thesis 21 Materials and methods 22 Preparation of test materials 22 Model compounds Binder materials Superdisintegrant Choice of model compounds 23 Characterisation of materials 24 Density External surface area Amorphous content Preparation of mixtures 24 Compaction of tablets 25 6 Characterisation of compaction behaviour 25 Deformation properties Fragmentation properties Characterisation of tablets 26 Tensile strength Examination of fracture surfaces Porosity Pore size distribution Degree of binder saturation Disintegration Effect of binders on tablet pore structure 28 Effect of binder deformability and particle size on tablet porosity 28 Effect of amount of binder and compaction pressure on tablet porosity 31 Effect of compound properties on tablet porosity 32 Effect of binder addition on pore size distribution 32 Effect of binders on tablet strength 35 Effect of binder deformability and particle size on tablet strength 36 Effect of amount of binder and compaction pressure on tablet strength 39 Effect of compound properties on tablet strength 40 Tablet model describing the effect of binder addition on tablet strength and pore structure 43 Fracture characteristics 43 Relation between binder saturation and tablet strength 47 Qualitative assessment of the strength of interactions in tablets 48 Effect of binders on tablet disintegration 50 Relation between tablet strength/porosity and disintegration properties 50 Binder properties of importance for optimal function of superdisintegrants 50 Conclusions 53 Acknowledgements 55 References 57 7 Papers discussed This thesis is based on the following papers, which will be referred to by their Roman numerals in the text. I Olsson, H., Mattsson, S., Nyström, C., 1998. Evaluation of the effect of addition of polyethylene glycols of differing molecular weights on the mechanical strength of sodium chloride and sodium bicarbonate tablets. Int. J. Pharm. 171, 31-44. II Mattsson, S., Nyström, C., 2000. Evaluation of strength-enhancing factors of a ductile binder in direct compression of sodium bicarbonate and calcium carbonate powders. Eur. J. Pharm. Sci. 10, 53-66. III Mattsson, S., Nyström, C., 2000. Evaluation of critical binder properties affecting the compactibility of binary mixtures. Drug Dev. Ind. Pharm., accepted for publication. IV Mattsson, S., Nyström, C. The use of mercury porosimetry in assessing the effect of different binders on the pore structure and bonding properties of tablets. Manuscript. V Mattsson, S., Bredenberg, S., Nyström, C. Formulation of high tensile strength rapidly disintegrating tablets – evaluation of the effect of some binder properties. Submitted. Reprints were made with permission from the journals. 8 Pharmaceutical tablets The most commonly used dosage form for pharmaceutical preparations is currently the tablet, available in various forms and administered orally. The advantages of this dosage form are manifold: tablets are cost effective to manufacture, convenient to dispense and store, and easy for the patient to administer, and they provide a versatile means of delivering the drug. Release of drug from the tablet can be controlled by altering the design and content of the formulation. Also, since this is a dry dosage form, tablets provide a supportive environment for drug stability and generally have a relatively long shelf life. Tablets are manufactured by applying pressure to a powder bed, which compresses the powder into a coherent compact. The powder may consist of either primary particles or aggregated primary particles (i.e. granules). When these are compressed, bonds are established between the particles or granules, thus conferring a certain mechanical strength to the compact. The properties of the tablet (e.g. mechanical strength, disintegration time and drug release characteristics) are affected by both the properties of the constituent materials and the manufacturing process. Excipients such as diluents, binders and lubricants are generally needed in a formulation in order to facilitate the manufacturing process, but also to ensure that the resulting tablets have the desired properties. For instance, tablets should be sufficiently strong to withstand handling during manufacturing and usage, but should also disintegrate and release the drug in a predictable and reproducible manner. It is thus important to choose the appropriate excipient and manufacturing process when developing a new tablet formulation. The uniaxial compaction of a pharmaceutical powder results in an anisotropic and heterogeneous tablet with variations in such properties as density, porosity and mechanical strength throughout the tablet (Train, 1956; Kandeil et al., 1977; Nyström et al., 1993). The tablet porosity of most materials is about 5 to 30%. This means that even at relatively high compaction pressures, tablets will rarely be non-porous. Two models have been suggested in an effort to describe the distribution of air in tablets (Nyström et al., 1993). The most appropriate model depends on the compaction and bonding characteristics of a certain material. In the first model, a tablet is described as powder particles dispersed in air, so that the tablet then contains a network of pores. The validity of this model is supported by the applicability of methods such as surface area measurement by air permeametry and measurement with mercury intrusion, since these methods are based on a medium flowing through or penetrating the tablet. As a consequence of this model, the interparticulate bonds are considered weaker than the intraparticulate bonds. In the second model, a tablet is regarded as