Down the Track: Different Speeds with Multiple APIs - Pharmaceutical Technology

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Down the Track: Different Speeds with Multiple APIs
Formulators and manufacturers have many options for modifying release profiles in multiple-API products.


Pharmaceutical Technology
Volume 33, Issue 7, pp. 34-40

Tablets

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.

Single-layer 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.

Multilayer tablets. 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.


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