Companies can choose among various techniques to manufacture multiparticulates. The simplest manufacturing technique is to
layer the liquid drug onto inert spherical particles made of sugar or microcrystalline cellulose, says Orapin Rubino, director
of formulation and product development at Glatt Pharmaceutical Services (Ramsey, NJ). In this strategy, which is appropriate
for drug loads that are less than approximately 50% w/w, manufacturers use a Wurster column attachment on a fluid-bed processor.
Another common manufacturing method relies on extrusion and spheronization. First, operators force a blended, wet mass of
drug and excipients through a porous plate with an extruder. Then the fragments are loaded onto a revolving disk with a chosen
surface roughness, and the disk's rotation forms rounded pellets, says Oakley. Manufacturers can coat the multiparticulates
or leave them uncoated and fill them into capsules. This method is appropriate for drug loads as high as 90% w/w.
Other common manufacturing techniques include direct pelletization and spray drying. Manufacturers also have developed advanced
techniques such as spray congealing, but they are not yet widely used, says Rubino.
In hot-melt spray congealing, scientists melt a waxy polymer and mix an API into it, says Jochen Farrenkopf, group leader
in pharmaceutical development of solid dosage forms at Abbott (Chicago). The API must be thermally stable enough to withstand
the polymer's melting temperatures of 60–70 °C. Droplets of this molten mixture fall onto a fast-rotating disc and are dispersed
into fine particles that solidify as they travel, within several centimeters. These fine particles become spherical multiparticulates
that can be encapsulated and used for modified release.
Minitabs can be manufactured relatively easily with special tooling using standard tablet presses and compression forces.
At its contract-manufacturing facility in Ludwigshafen, Germany, Abbott uses a punch that incorporates 19 2-mm tips, says
Farrenkopf. Using this tooling requires understanding and experienced operators. Because the 19 small punches have a lot of
surface area, operators must set the tooling up thoroughly and be sensitive to its relatively high punch–die friction. Operators
also must be careful not to break the 2-mm punches by subjecting them to too much compression. Although this manufacturing
process requires care, "it's a pretty stable and forgiving technique that is feasible for long-term commercial manufacture,"
Machines that fill multiparticulates and minitablets into capsules are readily available to pharmaceutical manufacturers.
IMA's (Bologna, Italy) Adapta encapsulator can fill as many as five ingredients into each capsule and check the dosing of
each individual product. Operating the unit requires no special training or maintenance.
Putting multiparticulates to work
Because they are small and easy to swallow, multiparticulates are particularly suited to geriatric formulations. If a patient
breaks a tablet in half so that he or she can swallow it more easily, the tablet's coating layer often is compromised and
it can no longer provide controlled drug release. Multiparticulates avoid this difficulty because they are small enough for
geriatric patients to swallow them easily. These pellets thus are appropriate for treating conditions that impair swallowing
such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, says Oakley.
For similar reasons, multiparticulates also are suitable for pediatric formulations, for which prescription spending increased
10.8% in 2009 (1). Because multiparticulates are one of the best ways of enabling pediatric formulations, the number of drugs
brought to market in this form will surely rise, says Farrenkopf.
Since multiparticulates enable good control of drug release, the dosage form is becoming more popular for drugs that treat
chronic conditions. For these reasons, cardiovascular drugs and blood-pressure medicines could benefit from multiparticulates,