The desire to create more targeted, effective therapeutics with fewer side effects has driven drug formulators to expand into more technically-demanding areas over the past decade. Microtablets are one result of this burst of creativity and engineering expertise. Going small opens up numerous new delivery options, but also creates additional challenges for drug formulators and manufacturers.
Microtablets — which are typically defined as being smaller than 5mm in diameter — enable therapeutic options that are very difficult or impossible to achieve using other delivery formats. The size is the key differentiator. Tablets that are just a few millimeters in diameter have a much greater surface area to volume ratio than standard oral dosage forms. As such, tiny tablets have a radically different dissolution profile.
Whereas a standard tablet will break down slowly as it passes through the gastrointestinal (GI) tract, a microtablet undergoes rapid particle dissolution. Complete release of the API within 10 minutes is achievable. When combined with a formulation that only breaks down when exposed to pH levels found after a certain point in the GI tract, the abbreviated release window of microtablets allows drug developers to deliver high therapeutic loads to very specific areas of the digestive system.
Microtablets can also be used for multiparticulate forms, either to deliver several different APIs or one drug with multiple release profiles. This is achieved by filling a capsule with multiple microtablets that have different dissolution profiles or APIs. If a company decides to adjust the proportion of the different APIs or release profiles during the development, formulators just have to adjust the mix inside the capsule. Companies using single, multiparticulate tablets would face a tricky reformulation.
Alternative routes to multiparticulate and controlled-release tablets have other disadvantages, too. The use of extrusion, for example, is undermined by the difficulty of getting the controlled-release polymers to form spheres. Equally, including multiple APIs in a single dosage form can create stability problems and raises the risk of dose dumping if the release coating fails. The microtablet approach of multiple, separate tablets in one capsule makes stability and dose dumping less of a concern.
Assessing The Pitfalls Of Microtablet Production
Microtablets offer other benefits to formulators — such as the ability to deliver high concentrations of poorly-compressible APIs — but also create their own set of challenges. Again, many of these difficulties relate to the size of the tablets. Small, lightweight tablets are liable to become stuck by static forces when passing through a standard feeder system. Manufacturers must use special feed systems to prevent blockages.
Uniformity is also an issue. The small weights of APIs involved mean there is no margin for error. Even a small difference in the amount of active ingredient from tablet to tablet can translate into a significant variation in percentage terms. To uniformly fill 2mm die holders, the materials must have excellent flow properties. This limits the ingredients that are suitable for microtableting to those which have innately good flow properties or ones that can be improved through processing.
Operating at such small scales also affects tablet punches. A punch for a 2mm tablet is by necessity very delicate. To compensate for this inherent weakness, equipment manufacturers have developed punches that feature multiple tips. These designs reinforce the rigidity of the punch and cut the risk of an equipment failure slowing production. When combined with a design that limits the travel of the punch and used by a skilled operator, such equipment is as effective and reliable as full-sized tools.
Once a microtablet has been filled, punched, and moved along the feed, it comes to the final hurdle: Quality control. Visible measurements are harder to make when working with microtablets than normal sized drugs. The process requires more dexterous operators — forceps are often used to manipulate microtablets — and special equipment. Microtablet-tailored machinery is particularly important for measuring hardness, a process that can be impossible without dedicated tools.
Picking The Perfect Microtableting Operation
When establishing an in-house microtableting operation or choosing a third-party manufacturer with which to work, it is important to consider all of the aforementioned challenges. Microtablets are just small tablets, but in this instance size really matters. Production steps that are simple when working with full-sized tablets can be very demanding when the products are scaled down to just a few millimeters in diameter.
The best microtableting sites combine the dedicated equipment needed to fill, punch, and process the products with manufacturing line workers who have the skills to operate at such small scales. Ideally, such an operation will possess the ability to take a microtablet from early-stage development through to commercial production. Working with such an integrated, end-to-end development and production team cuts the risk of encountering problems when scaling up manufacturing of microtablets.
Companies that acquire access to such capabilities are well placed to reap the benefits offered by microtablets. The ability to target specific areas of the GI tract, easily combine multiple APIs, and deliver consistent doses regardless of food consumption make microtablets an attractive dosage form for developers of new molecules and improvers of existing products across a wide range of therapeutic areas.
About CoreRx, Inc.
CoreRx, a contract formulator and manufacturer of complex pharmaceutical products, announced that the Company has completed a placement of Series A Preferred Stock with Signet Healthcare Partners.
Brian McMillan, V.P. of Formulations is a valuable asset to CoreRx. He brings many years of experience and talent and is a driving force in the success of CoreRx. With that aside, it's easy for any conversation with Brian to gravitate to his beloved "Buckeyes." It's very clear that Brian loves his roots. As an Ohio State University (OSU) alumni, he holds the school close to his heart. Based on an article posted in 2012, it's clear the feelings are mutual. CoreRx is honored to share an article posted by OSU where the spotlight is on Brian and his past and future accomplishments. We're happy to report that Brian did earn his M.S. in Pharmaceutical Chemistry from the University of Florida in 2013 and continues his relationship teaching at the University of South Florida, College of Pharmacy. We're fortunate at CoreRx to have such talented and skilled professionals among us.
Read the OSU article here: http://artsandsciences.osu.edu/alumni/experience/spotlights2012/mcmillan
Companies to Invest in New Facility, Increase Workforce
Tampa, FL (June 24, 2013) – The University of South Florida College of Pharmacy and CoreRx, Inc., a research-based drug development firm, received a $200,000 award from the Florida High Tech Corridor to bolster the training needed to prepare students for innovation and technology in the pharmaceutical industry.
Company to Invest Approximately $2 Million, Increase Workforce