Powder Characterization for Formulation and Processing

The current trend within the pharmaceutical industry toward more efficient development, manufacturing, and specification is fueling demand for analytical tools that provide highly relevant information. Effective powder characterization has a valuable role to play.
May 01, 2008

Freeman Technology
Despite advances in alternative methods, tablets remain the most widely used method of drug delivery. Well-manufactured tablets are extremely stable, provide excellent dose uniformity, and are well accepted by users. Formulation development is, however, challenging, with the apparent simplicity of a tablet belying the challenges of its manufacture.

Tablet production demands the transformation of a relatively free-flowing powder into a compressed solid form. Stability is a defining performance characteristic, but rapid dissolution is also essential for efficient in vivo delivery. Other properties such as taste, smoothness, and shape must also be taken into account. As a result, tablets are complex multicomponent blends of binders, glidants, lubricants, disintegrants, sweeteners, flavors, pigments and, of course, active pharmaceutical ingredients (APIs).

Tableting has a long history, and substantial experience has been gained over many decades. Processors and formulators have traditionally relied heavily on this experience, taking an empirical, as opposed to knowledge-based, approach. Now, with the introduction of quality by design, the situation is changing. There is recognition of the importance of more fundamental knowledge and of investing heavily in its development.

Taking tableting as an example unit operation, this article explores how modern powder characterization techniques can provide valuable information that enhances understanding. Measuring dynamic, bulk, and shear properties of powders allows identification of the parameters that best define product performance, both during processing and in final application. This knowledge underpins fast, successful formulation development and effective process control.

The demands of the tableting process

Direct-compression tableting is a common method of solid dosage form manufacture. With this approach, the constituents of the tablet are blended and are then fed directly to the press. In most cases, however, the formulation cannot be used without first completing several preprocessing steps such as a wet or dry granulation. Granulating the blend reduces problems such as segregation and improves flow behavior by densifying and increasing the size of "particles."

Figure 1
Figure 1 shows a schematic of a single-sided rotary tablet press. Powder flows from the hopper or intermediate bulk container, down the transfer chute, and onto the table. The blend is distributed through the feeder and flows gravimetrically into the die. As the table rotates, excess powder is scraped away from the top of the die before the punches apply compression to create the tablet. The tablets are ejected before the dies reach the filling point again.

Because the aim is to produce tablets of defined weight, geometry, hardness, and composition, consistent flow from the hopper onto the table and through the feeder into the die is necessary. A free-flowing powder may avoid blockages and intermittent flow, but it also may be more prone to flooding or segregation (the separation of dissimilar-sized particles).

During the compression stage, the goal is to produce a stable form that can be cleanly ejected from the press with minimal force. Achieving this objective makes other aspects of powder behavior important. For example, if excess air is retained in the die and compressed along with the powder, then it may expand once the compression force is removed, causing the tablet to burst or cap. Blends that release air relatively easily are therefore preferred. Tablet strength also is directly affected by cohesivity—compressive strength. A blend with low cohesivity may form a weak, unstable tablet, while highly cohesive materials may adhere to the tablet press and cause variability in fill weight.

This brief analysis highlights some of the compromises involved in addressing just a few of the issues connected with processing and final product quality. Other performance criteria overlay additional and often conflicting priorities. For example, fines may be attractive to a formulator because they help achieve rapid dissolution and increase tablet-compression strength but are problematic during processing because they increase the risk of cohesive behavior and affect productivity. Balancing these variables is the formulator's art.

Experience-based formulation is possible, and indeed still common, but greater emphasis on effective processing and early definition of the design space is reducing the scope for error. Formulators need tools that provide relevant data at an early stage, thereby allowing rationalization of experience in terms of quantifiable parameters. This result gives insight and understanding, promoting a knowledge-based approach. Processors too require data to understand the reasons for both good and poor performance at the press. Such knowledge feeds back into formulation development and facilitates the successful processing of challenging blends.