Pharmaceutical Tablet formulation and process development
An Orthogonal approach to Oral Solid Dosage development
Why Tablets?
Oral Solid Dosage medications (OSDs) continue to constitute the majority of all pharmaceuticals currently on the market, offering ease of administration and long shelf-life at room temperature. OSDs are often relatively inexpensive to manufacture, as long as constituent Active Pharmaceutical Ingredients (APIs) and excipients are physicochemically optimized. Blend uniformity must be optimized so that the correct amount of API is distributed evenly across tablets produced, which must be tough enough for easy handling during distribution and use. To achieve this in the first place, the powder must have the correct flow properties to allow predictable and efficient movement. The fine balances involved in optimizing these metrics can complicate tablet-development, with powder behavior notoriously difficult to predict. Powders exhibit a spectrum of behaviors, from liquid-like flow to solid-like compaction depending on the external forces applied at different points of the manufacturing process.
Making Tablets
Powder flowability must be characterized in order to define a powder’s behavior during manufacturing. The complexity of these flow characteristics makes an orthogonal, multi-metric approach essential to optimizing the manufacturing process. Such analysis may also help maximize drug delivery in the cases of nasal sprays and inhalers. Powder flow can be directly measured using powder rheology, while particle size and shape have a major impact, their characterization giving a means of predicting flow.
Dynamic Flowability
Powder rheometers, such as the Micromeritics FT4, allow direct measurement of dynamic flow, bulk and shear properties. Using dedicated accessories and measurement techniques to simulate process conditions, such as mixing, fluidization, shearing or air permeability testing, the rheometer allows tablet developers to assess and optimize the processability of their powders.
The dynamic test, for instance, uses a cylindrical vessel with a blade rotating at several different speeds. The energy expended by the blade’s movement from the top to the bottom of the powder bed is then calculated for further indicative values. The Basic Flowability Energy (BFE), for instance, is used to assess dynamic mixing behavior, acting as a measure of agglomeration within the sample. The Flow Rate Index (FRI) is used to predict mixing homogeneity, while Specific Energy (SE) assesses the friction and interlock within the powder. Stability Index, on the other hand, is a key measure of friability and stability. Permeability, the ability of air to flow through the powder bed, can also be measured with the FT4 rheometer as a bulk property. Both permeability and direct compressibility are critical to tablet die filling and compaction, and therefore product quality.
Shear testing, on the other hand, is very different to dynamic testing, as it characterizes the powder in a consolidated, more static, state. This allows measurement of Flow Function (FF) and Wall Friction Angle (WFA), indicative of the cohesion between particles and adhesion to specific wall-types. The use of these methods to characterize pharmaceutical powder flow is now detailed in USP <1174>, as well as corresponding chapters in the European and Japanese Pharmacopeias.
Particle size and shape
Though measuring flowability in response to force is a key means of predicting manufacturing success for pharmaceutical OSD products, it tells us less about the underlying factors for flow characteristics. Knowledge of such factors allows prediction of how a powder will flow, helping us further optimize our therapeutic at the earliest stages of development.
Particle size measurements, for instance, allow us to predict cohesion. Smaller particles result in greater cohesion, all else being equal. This has to be balanced with flowability, however, which is reduced by cohesion. Ease of powder processing must be balanced with the stability of the final tablet, and Laser Diffraction (LD) gives a simple and easy means with which to achieve this. The Mastersizer 3000+ is used across the pharmaceutical industry to understand and control processability and tablet uniformity and stability, based on accurate, precise and rapid acquisition of Particle Size Distributions (PSDs). Adaptive Diffraction, a technique patented to Mastersizer Xplorer software, differentiates and separately displays data from outside influences, helping customers optimize their tablet development and manufacturing more rapidly and with greater confidence.
In addition to particle size, particle morphology is also a key factor in particle flowability, and therefore in final tablet quality. Perfectly spherical particles, in principle, impart the highest flowability (due to reduced friction and interlocking). But perfection is rare, certainly in the case of API. Morphology measurements using the Morphologi automatic static image analysis system gives the data required to optimize sphericity and scores of other morphological parameters, giving a detailed description of the particle’s shape. A Raman spectrometer accessory for the Morphologi 4 allows identification of particles (e.g. API or excipient) where needed, helping users assign morphological metrics to each population.
The Orthogonal approach to Characterization
Taken separately, the parameters outlined above are highly valuable to OSD developers. It is when they are used together, however, that they come into their own. Customers for whom the FT4 demonstrates low flowability can assess particle size and shape in order to understand why. For instance, if powder rheometry results suggest vertical compression of the powder bed, PSD and morphology are measured to confirm if fine particle aggregation or interlocking, irregularly-shaped particles might be the cause. Conversely, the predictive capabilities of the Morphologi 4 and Mastersizer 3000+ may be used early in the development process to help optimize particle size and shape, with the FT4 used to confirm the desired flowability before moving to the next stage.
Summary
Though tablets have long been a mainstay of pharmaceutical production, processing the ingredients in a way that leads to quality tableting must be optimized on a case-by-case basis. Every powder is different, and Malvern Panalytical has decades of experience using its technology and expertise to support customers through the OSD development process. From prediction of powder flowability, to more direct measurement of cohesive forces and aeration within the powder, to troubleshooting, our products and knowledge are used to enhance the efficiency of OSD development whilst minimizing the risk of costly failure.