A New Hypromellose Excipient for Direct-Compression, Controlled-Release Applications

The authors examine the use of a hypromellose-based product as an excipient in a controlled release formulation using direct-compression tableting.
Mar 31, 2009

Direct compression (DC) is becoming a preferred manufacturing method for tablets. This process is less complicated than dry- or wet-granulation processes and therefore offers shorter product-development timelines and reduced cost to manufacture through the elimination of granulation unit operations. In addition, DC can be used for heat- and/or moisture-sensitive active pharmaceutical ingredients (APIs) because it has a low heat history and does not require water during processing. Excipients used in DC processing, however, must have a combination of properties, including good flow, compressibility, minimal segregation tendency, and good physical and chemical compatibility—a combination not usually associated with controlled-release (CR) excipients. A new family of hypromellose (HPMC) products (Methocel cellulose ethers, Dow Chemical, Midland, MI) was developed that combines these properties with the ability to provide controlled-drug release.

HPMC products are widely used rate-controlling polymers in oral controlled-release drug-delivery applications. These excipients offer flexibility in formulation and function for preparation of oral solid-dosage forms. However, their application in DC tableting processes is limited in some cases and complicated in others because of their poor powder flow properties. Recent product development efforts have improved powder flow while maintaining suitable compressibility and CR performance and minimizing segregation.

DC and the use of CR excipients

Figure 1
DC is a tableting process in which a dry blend of ingredients is placed into a tablet hopper and compressed into tablets. It is a much simpler process than wet or dry granulation, eliminating several unit operations and resulting in a more straightforward manufacturing system (see Figure 1). This results in lower manufacturing costs and shorter development times for new formulations. DC has the added advantage of being less harsh on heat- and moisture-sensitive APIs.

The main parameters for an ideal DC excipient are flowability, compressibility, minimal tendency to segregate, and physical and chemical compatibility with APIs and other ingredients. Reliable flow of pharmaceutical mixtures out of tablet-press hoppers is particularly important for problem-free tablet-press operation and consistent tablet properties. Failure to ensure reliable flow can result in both considerable manual interventions for the tablet-press hopper and poor tablet physical properties, such as high tablet-to-tablet weight variability and tablet hardness.

Because HPMC has generally poor flow properties and is often present in formulations at high levels (up to 30%), it can have a serious effect on formulation flow in a DC process. As a result, preparing CR formulations with a DC process can be difficult, usually requiring compromises such as flow enhancers or slower production rates. Typically, CR formulations are processed using wet granulation to achieve adequate mixing and improved flow. If the flow properties of HPMC could be improved, the less costly DC process could be used.

Influence of material properties and environmental factors on powder flow

Figure 2
Powder flow can be a difficult property to quantify because it is influenced by so many factors. Material properties such as particle size and distribution, bulk density, particle shape, moisture content, and cohesiveness all have a role in determining powder flow (1). In addition, environmental factors such as humidity, particle-to-wall interactions, bin and hopper design and dimensions, consolidation time, and load affect powder processing. Measuring powder flow with conventional bench-scale tests can be deceptive because small-scale processes primarily show the effects of particle-to-particle cohesion. If two products have the same chemistry, the particle-to-particle cohesion will be similar. At a larger scale, however, more relevant to production processes, there is an increased influence of gas permeability of the bulk solid. If the gas permeability of the bulk solid is low, the flowing solid is unable to dilate in the conical section of the hopper, a phenomenon referred to as "limiting flow rate."