Tablets, still the most common dosage form, are manufactured in various ways to deliver multiple APIs. For each tablet-method,
companies have several options for controlling the release of the APIs. Although certain pairs of APIs could be incompatible,
formulators generally can prevent adverse interactions by coating powder particles and adding excipients. But multidrug tablets
do require a longer and more expensive formulation process than do traditional tablets.
The simplest manufacturing method is to mix APIs together through high-shear or fluid-bed granulation into a single-layer
tablet. By coating the tablet with one or more layers of polymers such as methyl acrylates, the release of multiple APIs can
be controlled, says Nic Michel, vice-president of the process division at Oystar USA (Fairfield, NJ). The coating solution
can ensure that the APIs dissolve over time, thus providing sustained release, or in a specific place in the intestinal tract.
Modifying the polymer coating on beads of APIs such as those used in capsules sustains the rate of release. Coatings tend
to result in a drug "dumping," and release is controlled according to the thickness of the coating. In contrast, a polymer-matrix
mixture creates tunnels through which a drug slowly travels out. The matrix option is useful for high drug-loading applications.
Various triggers (e.g, pH sensitivity or enzymatic action) also can be incorporated to control the release (e.g., enteric-coated
aspirin). For drug formulations containing multiple APIs, more than one polymer or more than one trigger may be used to control
the release of each drug.
Traditional multilayer tablets include one active layer sandwiched between two inactive layers. These tablets can be coated
for controlled release. sanofi-aventis's (Paris) Ambien product is a bilayer tablet with two separate release profiles (i.e.,
immediate release and controlled release). Bilayer tablets such as Ambien could also incorporate a different API in each layer,
each with its own release profile, says Doug Becker, senior director of process technology at Wyeth (Madison, NJ). A bilayer
tablet could not, however, release drugs sequentially because the alimentary canal would affect each API immediately.
Although the compression technique is the same for single-layer and multilayer tablets, adding and controlling multiple tablet
layers can present engineering challenges such as interfacial bonding problems. For example, formulators must ensure that
the two API layers have similar expansion and contraction coefficients so that they do not separate. Some layers don't adhere
to each other, so manufacturers may have to use a three-sided press to incorporate a boundary layer, says Becker. This method
can improve the tablet's structural integrity during coating and handling.