(230f) Bilayer Tablet Compaction: Translation From a Single Stage Compaction Simulator to a Rotary Press

Fixed dose combination products (FDC) are formulations containing two or more active pharmaceutical

ingredients (API) combined within a unit dose. In recent years, FDCs have become increasingly popular in

several therapeutic areas because they offer convenience, a reduced pill burden, and cost savings for patients.

In cases when the APIs are chemically incompatible or multiple release profiles are desired, the dose must

be formulated as a layered tablet. However, layered tablets pose unique development and manufacturing

risks because of the fine balance required between maintaining sufficient physical separation between the layers

to mitigate chemical incompatibilities and ensuring that the tablet remains intact (i.e. avoid layer delamination)

throughout the manufacturing process and product shelf life. Challenges during the manufacture of layered

tablets can be difficult to resolve due to the limited mechanistic understanding of the compaction process. Thus,

the development process for layered tablet formulations has been largely trial-and-error, requiring significant

resource investments, especially when considering that layered tablet production on a rotary press requires

kilogram-quantities of materials.

In this work, the authors have sought to gain mechanistic understanding of the compaction process for layered

tablets to minimize resources required during product development, more specifically to better understand how

experimental factors (i.e. material selection, compaction conditions) impact layer interface strength. Since the

failure of layered tablets typically occurs due to delamination at the interface, a fundamental appreciation of

the governing mechanisms that impact interface strength is crucial in order to improve the overall mechanical

integrity of that layered tablet. A single station compaction simulator, fitted with a three-sensor instrumented die,

was used as a material-sparing tool (requires only grams of material) for the development of bilayer tablets and

to increase fundamental understanding of the compaction process. The instrumented die was used to measure the

die-wall pressure exerted by each layer of the bilayer tablet during the compaction process.

Bilayer combinations of placebo and active granulations over a range of compaction forces were examined in

this study. Young’s moduli and Poisson’s ratios, as well as additional elastic material properties described by

the Drucker-Prager-Cap model, were determined using measured die-wall pressure profiles for each material in

the study. Analysis of the die-wall pressure profiles during bilayer compaction yielded a correlation between

the residual stress within each of the layers after compaction and the interface strength of the bilayer tablet. The

level of residual stress experienced by different materials, when compressed as either the first or second layer in a

bilayer tablet, was related back to elastic material properties. Using this knowledge, select material combinations

were compressed as bilayer tablets on a rotary tablet press. The trends in tablet interface strength for tablets

produced on the compaction simulator were similar for those manufactured on the rotary press. However, it was

noted that for certain material combinations, tablets made on the compaction simulator and the rotary press did

not possess the same solid fraction when compacted under the same forces. When tablet strength was examined

as a function of solid fraction instead of compaction force, the compaction simulator was found to adequately

emulate the rotary press. Discrepancies between press compaction force and corresponding solid fractions were

related back to elastic material properties. In conclusion, the compaction simulator was found to be a useful

tool to develop bilayer tablet formulations at small scales, providing results that may be translated to larger scale

production on a rotary press.