Authors
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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
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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
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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."
