ABSTRACT
The pharmaceutical industry, whether brand name or generic, has over the past few years been
increasing its focus on developing combination products (1). These products have been a key
component of very successful life cycle management strategies, mainly due to significant
advantages in both therapeutic and commercial aspects, including extension of patent coverage (2). The main therapeutic advantages and rationale for developing fixed-dose combination
products include better long-term patient compliance (3) by decreasing the overall number of
dosage forms to be administered, whether treating one or multiple indications (4-6) and often
decreasing the dose compared to monotherapies due to synergistic effects, thus potentially
minimizing side effects. A wide array of combination products are already available in many
therapeutic areas, including diabetes, hypertension, lipid lowering, pain management, HIV/
AIDS treatments as well as against various types of bacterial infections, with the objective of
maximizing safety and efficacy for the patient’s benefit. From a technical perspective, combination products are challenging. Various formulation
approaches can be considered for the development of tableted combination products. The
preferred approach is a standard/monolayer tablet containing two or more active ingredients
along with excipients. The compaction of these combination product monolayer tablets can be
difficult due to the added complexity and inhomogeneity of the formulation components
compared to mono-active tablets; some critical considerations will be briefly discussed (see
Section “Monolayer Combination Products”). The reader should also refer to other chapters in
this book discussing theory, modeling, and simulation as well as compaction of pharmaceutical powders in general. This chapter will mainly focus on combination products formulation
options and their impact on compaction behavior when a monolayer tablet is not feasible
mainly due to (i) compaction properties, (ii) intended biopharmaceutical performance (e.g., dissolution/bioavailability and/or stability), or (iii) line extension or market differentiation. The majority of this chapter will be addressing multilayer tablet compression (bilayer being the
most common) including tablet strength and layer adhesion strength measurement and
prediction, formulation considerations to optimize compaction properties and manufacturing
considerations during the compression unit operation. Compaction considerations during development and production of minitablets will also be discussed along with a short section on
compression-coated tablets (tablet-in-tablet). While compaction principles discussed in
sections I and II can be extended to combination products, each of these combination
formulation approaches presents some unique advantages as well as hurdles for compaction
measurement, prediction and practical application (1). In addition, it is to be highlighted that
compaction is only one part of developing a tablet: other physicochemical aspects, such as
formulation composition, powder flow mechanics, and chemical and physical stability have to
be considered and balanced with optimal compaction properties. This can be especially challenging for combination products, and is not part of the scope of this chapter.
