Combining Multiparticulates and 3DP for Patient-Centric Dosage Forms

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-05-02-2021, Volume 45, Issue 5
Pages: 30-31

Aprecia and Glatt investigate manufacturing technologies to widen the formulation design space for oral delivery.

Pharmaceutical manufacturers use a wide range of technologies, such as tablet coating, fixed-dosage combination drug products, multiparticulates, and orally disintegrating tablets (ODT), to make it easier for different patient populations to take their medicines. “Addressing barriers to adherence, such as pill burden, dosing frequency, and ease of administration, are necessary to ensure treatment success for many therapies and indications,” says Chris Gilmore, CEO of Aprecia Pharmaceuticals.

Aprecia has applied its three-dimensional printing (3DP) manufacturing technology to create an orally disintegrating dosage form for patient populations that have difficulty swallowing conventional tablets or capsules. Gilmore says that conventional ODT formulations are limited by dose load, taste, and disintegration time, and that Aprecia’s ZipDose technology overcomes these limitations. “The majority of available ODT formulations contain less than 50 mg of active ingredient due to overall product weight limitations,” notes Gilmore. “These limitations also hinder the ability to add other inactive ingredients to improve mouth-feel and taste.” Gilmore says that Spritam (levetiracetam tablets), the first commercial application of the ZipDose technology, can achieve higher dose strengths—approved strengths range from 250 mg up to 1000 mg tablets. “In standard tablets, such dose strengths would be among the largest tablets or capsules and still need to be swallowed wholly intact. For example, the size of the most commonly dispensed 1000 mg tablet is 23 mm by 10 mm. The length exceeds the maximum size recommended by the FDA for generic tablets. For perspective, this tablet has a length as long as a nickel’s diameter. But in ZipDose tablets, these strengths can be achieved in tablets that fully disintegrate in the mouth with a sip of water before swallowing, eliminating the impact of tablet size on swallowing,” he says.

The technology could also be used to combine multiple drugs to reduce pill count. In addition, notes Gilmore, Aprecia has begun working with various clients to extend ZipDose technology to payloads having modified-release particles, which could have various benefits, such as enabling lower frequency of dosing for certain medicines.

In February 2021, Glatt and Aprecia announced a collaboration to combine Glatt’s multiparticulate technologies, produced using its fluidized bed technology, with Aprecia’s 3DP manufacturing systems. “We see interesting opportunities in the field of ODTs and multiparticulate systems,” says Philippe Tschopp, head of business development at Glatt Pharmaceutical Services. He notes that multi-unit pellet system (MUPS) formulas are rarely used in ODTs, but that this use would open up the ability to address swallowing issues. “Incorporating multiparticulates in 3DP tablets gives the opportunity to have a fast dissolving ‘transport agent’ with the full flexibility of multiparticulates in dosing and dose combinations, with controlled-release profiles by functional coating of the multiparticulates.” Another benefit of combining 3DP and multiparticulates is enabling a flexible dosing regimen to adapt to patients’ needs without manipulation by the patient or caregiver, suggests Tschopp.

“Use of multiparticulates allows us to expand the range of drug delivery options from the final dosage form in order to include modified release functionality. It addresses formulation design in modular fashion, by providing certain functionality at the particle level and providing additional functionality at the finished dosage form level,” adds Thomas West, vice-president of pharmaceutical development at Aprecia.

Combining multiparticulates and 3DP

A unique aspect of 3DP manufacturing is that it eliminates the mechanical stress on the tablets due to the compressive forces needed in conventional tablet production. In Aprecia’s patented binder-jetting 3DP manufacturing system, tablets are built layer by layer—this process of adding layers to create a product is why 3DP is also called “additive manufacturing” in some industries.

“Incorporation of multiparticulates into 3DP tablets overcomes the issue of traditional MUPS tablets as there are no compression forces applied to the film coated pellets that could deform and destroy the functional coatings and therefore alter the release profiles,” explains Tschopp. 

“Avoiding mechanical stresses on the multiparticulates helps protect the multiparticulate integrity until it reaches the patient and reduces the risk of dose dumping for modified-release dosage forms,” agrees West. “The biggest challenge of multiparticulates in tableting is the act of compaction, which initially causes localized friction (heat) and then deformation or fragmentation of the pellets or coating. Cracks or other imperfections in the pellets on the surface can alter the dissolution profile, making it challenging to have a batch-to-batch consistency.”

Another novel benefit of 3DP is blend consistency. When feeding multiparticulates and excipients into a conventional tableting press, there is a tendency for demixing, says Tschopp. The system for feeding multiparticulates into the 3DP process is more controllable; it is important to have consistent quality of the pellet population, but Tschopp says this is achievable. He says that pellets should be consistent in size and, depending on the dosing device, in weight or bulk density. Tschopp explains that pelletization equipment, such as Wurster technology or Glatt’s micropelletizing technology (MicroPX), can produce a narrow particle size distribution, a smooth surface area and, if needed, small particle sizes.


In Aprecia’s additive manufacturing process where the tablets are built layer by layer, this method of tablet forming provides a greater degree of localized control than in conventional tablet presses, adds West. “For example, the design of a 3DP tablet can include regions of greater or lesser binding based upon the regional density of liquid droplets. Since a 3DP tablet is built layer by layer, the regional droplet density may be tailored within each 2D ‘slice’ of the tablet design,” he explains. The primary considerations for this manufacturing platform are material uniformity (i.e., avoiding segregation) and wetting and drying in the open-bed process. “Multiparticulates are larger and generally flow better than finer powders, but there are fewer excipient options for size-matching in blends. The material should be amenable to water-alcohol exposure for short periods and drying at 40–60 °C,” West notes.

Recirculation is another parameter to be tested during process design. “Open-bed systems collect and refeed the unprinted powder, so the potential impact of these conditions must be evaluated through repetitive exposure with the scaled batch size in mind,” says West.

Although much of Aprecia’s commercial work has used dry powder blends, West says the company has now proven the capability of incorporating granulated APIs and functionally coated particles, such as drug-layered beads, at small scale on the commercially available open-bed platform. Gilmore adds that Glatt and Aprecia’s joint projects are underway, and multiparticulate ZipDose demonstrator tablets will be available in the coming months.

Investigating other 3DP systems

Aprecia is also developing a patent-pending printing platform in which tablets are formed, using binder jetting directly in a blister-package cavity, rather than free-standing on the open bed. This platform further expands the capability of what types of materials can be used in 3DP manufacturing, because the wetting and drying requirements are less stringent than in the open-bed system, and desegregation is less of a concern. This process also eliminates recirculation. “The in-cavity systems do not have recirculated powder, providing better precision in dosing the multiparticulates in measured amounts,” reports West.

“In the in-cavity platform, we’re looking at a wider range of material inputs and the ability to incorporate both single and multi-material inputs in a single dosage form,” West adds. For example, the in-cavity printing system can use two powder blends as inputs. “This multipowder approach can allow separate addition of a multiparticulate payload and of the other excipients used to build the product. Direct wetting of the payload can be avoided in some instances,” he says.

“We are also working on a new product design that allows for dry, ambient filling of virtually any payload into a rapidly disintegrating unit. That approach yields true minimum process stress for payloads such as multiparticulates, because it avoids direct wetting, vapor exposure, and oven exposure,” notes West. This product design is achieved using open bed 3DP with certain downstream modifications. Aprecia expects to disclose more about it later this year.

Although Aprecia is looking at these alternative 3DP systems and designs, the company continues to enhance its open-bed binder-jetting process. A collaboration with the non-profit research group, Battelle, announced in December 2020, will focus on formulation and production breakthroughs in the binder-jetting process design for pharmaceutical applications, says Jae Yoo, senior vice-president and chief technology officer at Aprecia Pharmaceuticals. “[This work will seek to] expand formulation capabilities, reduce formulation time, streamline supply chains, reduce stability risks and requirements, increase production throughput, eliminate production waste, and enhance flexibility,” says Yoo.

The objective of all these novel manufacturing technology combinations is to enable formulators to design better products and expand the possibilities for patient-focused dosage forms, concludes Gilmore.

About the Author

Jennifer Markarian is manufacturing editor at Pharmaceutical Technology.

Article details

Pharmaceutical Technology
Vol. 45, No. 5
May 2021
Pages: 30-31


When referring to this article, please cite it as J. Markarian, “Combining Multiparticulates and 3DP for Patient-Centric Dosage Forms,” Pharmaceutical Technology 45 (5) 2021.