Tableting: How Understanding Material Deformation Characteristics Can Improve Tableting Process Scale-up

The tablet is the most popular dosage form for prescribed and over-the-counter medications. Tablets are a simple and convenient way to accurately dose active pharmaceutical ingredients and are flexible enough in their design to address many of the patient-compliance challenges currently facing the pharmaceutical industry. However, to help ensure the success and acceptance of a tablet product, it’s vital to study each phase of the tablet development, design, and manufacturing process in great detail.

Tablet manufacturing poses many challenges. It’s common to develop what appears to be a robust formulation on an R&D tablet press but then find that the formulation performs poorly when transferred to production- scale equipment. This article discusses ways to improve the tableting scale-up process at the development stage where materials may be costly and difficult to come by. It is important to understand what developers and scientists need to research about a formulation for successful production. If the goal is to manufacture the product on a high-speed tablet press, you must understand the process dynamics at high speed and anticipate the production conditions during development. 

A material’s deformation properties are key attributes to evaluate when developing a product for high-speed production. To study these properties in the lab, Natoli Scientific uses a Presster compaction emulator (Photo 1). A compaction emulator, also referred to as a compaction simulator, is a good technology for studying a material’s deformation properties, because the machine mimics the manufacturing compaction process while collecting data that a standard, rotary tablet press does not. 

The Presster is a single-station machine in which the punches travel through cams and rollers as in a production- scale rotary tablet press, but in a linear fashion. The machine is instrumented to measure dosing height, upper and lower pre- and main compression force, ejection force, radial die-wall force, and take-off sticking force. The punch holders are equipped with linear displacement sensors allowing real-time punch position measurements during the compaction process. This enables users to study work curves, elastic recovery, Heckel plots for product yield pressure, and other characterizing data. 

Material deformation characteristics 

All solid materials change in shape and volume when subjected to mechanical forces. The force per unit area, or pressure, applied to the material is referred to as stress, and the material’s relative change in geometry is referred to as strain. When upper and lower punches travel through the compression rollers of a tablet press, they apply a load to the tablet formulation, which repacks and deaerates the particles, resulting in a higher bulk density. With continued increased pressure, the particles will deform via one or more of the following mechanisms:

Brittle fracture 

With brittle fracture, the particle structure fails and breaks into two or more pieces. A commonly used excipient that exhibits this behavior is dicalcium phosphate. 

Elastic deformation

Elastic deformation resembles the action of a spring. The applied stress causes a matching strain response, but when the stress is removed, the material immediately recovers and returns to its original shape. Pregelatinized starch and some active ingredients behave in this manner.

Plastic deformation

With plastic deformation, the strain caused from applied stress will continue to increase until the load is removed. Therefore, the amount of strain is time-dependent. A material that exhibits this behavior is microcrystalline cellulose. 

In practice, most materials possess a combination of these characteristics, resulting in some degree of viscoelastic behavior. In time-dependent deformation processes, if the particles aren’t given enough time to deform, the material will react in some other way. This is a common source of problems for products being scaled up from an R&D tablet press to a high-speed production tablet press, where less time is given to make each individual tablet. 

Furthermore, the material will undergo some degree of time-dependent recovery after the compression load is released, and if the tablet was not sufficiently formed at the point of maximum compression force, this recovery may result in tablet structure failure. 

Planning for scale-up 

Identifying material deformation characteristics at the development level allows developers to formulate a drug product to withstand the compression dynamics of a high-speed production tablet press. Figure 1 depicts Heckel plots for the commonly used excipients microcrystalline cellulose (Emcocel 90M, JRS Pharma), pregelatinized starch (Starch 1500, Colorcon), mannitol (Parteck M 200, MilliporeSigma), and dicalcium phosphate (Emcompress, JRS Pharma). The Heckel plot measures the log of 1/porosity as the compression force is increased. From the Heckel plot, the yield pressure of plastic deformation (YPpl) and yield pressure of elastic deformation (YPel) were derived. 

Table 1 shows the work of compaction (WoC), work of elasticity (WoE), yield pressure of plastic deformation (YPpl), yield pressure of elastic deformation (YPel), ejection force, porosity, and tensile strength (TS) values for the four excipients at 50, 100, and 150 megapascals of compression force. Material-predominant deformation was identified using principal component analysis (PCA). It was observed that brittle materials are associated with high YPpl and YPel values, plastic materials are associated with high WoC values, and elastic materials are associated with high WoE values. 

Figure 2 depicts a PCA score plot that groups the different materials by deformation mechanism. The results show Starch 1500 with dominant elastic deformation, Emcompress and Parteck M200 with dominant brittle fracture deformation, and Emcocel 90M with dominant plastic deformation. 

Using these evaluation techniques can help developers with: 

• selecting formulation ingredients; 
• designing tablets, including concavity and profile shape; 
• choosing punch-head options to provide longer or shorter consolidation or dwell times; 
• determining whether precompression and tapered dies are needed to exhaust entrapped air from the material in the die; and 
• reducing tablet press wear and tear from excessive compression forces and friction.

The driving force for choosing a particular excipient is its functionality, such as diluting the formulation, enhancing the API’s therapeutic performance, enhancing solubility, facilitating powder flow, reducing sticking and picking potential, and more. However, understanding the mechanical characteristics of a drug product’s excipients under known tableting conditions can pay long-term dividends when the product is ready to be scaled up for high-speed production.