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Drop-on-Demand Pharmaceutical Manufacturing

Test bed lead:      Gintaras (Rex) Reklaitis, Purdue             


Testbed 3 Participants
(Past and Present)
Basaran, Harris, Nagy, Reklaitis, Takhistov, Taylor 
Post-doctoral Associates
Bhat, Giridhar, Huynh
Anthony, Brown, Hirshfield, Hsu, Icten, Radcliffe
Rahman, Bhat, Davis, Huber, Lighty, Loehr, Sacksteder, Wallace
Burcham , Clarke,  Fiesser, Jerzewski , McHugh, Rumondor

The Drop on Demand Pharmaceutical Manufacturing test bed is intended to exploit liquid phase processing as a means of avoiding the complexities associated with the powder and granule handling operations conventionally used to manufacture solid oral products.  Applications of particularly high potential are highly active, low dose drug products whose manufacture using conventional powder-based processes is very challenging. 

The drop on demand manufacturing mode has the flexibility of accommodating a variety of fluid phase formulations as well as alternative substrates onto which the drop (s) is deposited. It has the potential for enabling a transition from manufacturing of large quantities of identical product to manufacturing of small lots of the product with flexible drug substance loading.  Moreover, this technology can provide a platform for early clinical trial dosage manufacture as well as for individualized medicine application.  In one embodiment of the platform, the test bed has been configured as a compact, self-contained, automated bench-top unit suitable for deployment in hospital dispensaries, clinics and compounding pharmacies for point of use delivery of dosages individualized to the patient.  Thus, this platform could facilitate a paradigm shift in the drug product supply chain from one in which the manufacture of the final dosage form is centralized to one in which the supply chain is distributed with the final product produced at the point of use. The role of the pharmaceutical manufacturer would be to provide a formulation intermediate, packaged in pouch or cassette form, which would serve as “ready-made” input to the drop on demand unit.


The main goal of this test bed is to implement and demonstrate an integrated platform based on drop-on-demand technology for manufacturing solid oral dosage products with precisely controlled release profiles. 


  1. To investigate alternative families of liquid formulations of API and various carriers, their rheology and processing characteristics. 

  2. To investigate the available modes of driving the formation of drops and establish their strengths and limitations. 

  3. To determine the reproducibility of the drop-wise deposition mode for these formulations and different fluid drivers.

  4. To establish the capabilities of depositing onto several types of different substrates.

  5. To demonstrate the capability of controlling the morphology and solid state of the deposit upon solidification.

  6. To develop fully automated prototypes of the DOD technology with on-line monitoring and integrated  control systems. 

  7. To design and implement an informatics infrastructure to allow the complete provenance of each manufactured  dose to be fully documented.

  8. To pursue commercialization of the technology with medical device manufacturers and  pharmaceutical manufacturing partners.

Key Accomplishments

Major accomplishments for this test bed are highlighted below:


  • The processing characteristics of solution- and melt-based formulations have been investigated, including drop formation dynamics and stability, both through free-boundary FEM simulations as well as experimentally.  

  • The strengths and limitations of different drop formation drivers have been established, including piezo-driven and positive displacement (Purdue) as well as syringe pump and gas pressure driven modes (Rutgers).

  • Feasibility of reproducible dispensing of dilute suspensions and emulsions for capsule/vial filling has been demonstrated (Rutgers).

  • Using high speed imaging and gravimetric means the reproducibility of drop formation of solution and melt based formulations has been demonstrated to exceed established content uniformity requirements.

  • Precision deposition of drops has been demonstrated on polymer films, inert tablets with convex face (Purdue) and wells/capsules  (Rutgers) in automated fashion for production runs of multiple deposits.  

  • The solid state, amorphous or amorphous and predominant crystal forms if any, of the deposits has been investigated using Raman spectroscopy and hot stage microscopy. 

  • Temperature monitoring and controls have been implemented for the fluid processing line from formulation reservoir to deposit stage. 

  • Temperature control of the crystallization / solidification of the deposit has been implemented to achieve consistent solid properties. Both on-line measurement of substrate surface temperature and IR-based deposit temperature measurement have been demonstrated.

  • A Labview based user interface has been implemented to integrate the various elements  for initiation, execution and termination of production runs.

  • A design tool has been developed that allow model based prediction of operating conditions based on experimentally determined aggregate nucleation and growth  kinetics.

  • Model based supervisory control of crystallization temperature profile to achieve target dissolution performance has been developed, implemented and demonstrated.

  • An informatics infrastructure based on the KProMS system developed under Project D3 has been implemented and demonstrated. The system records the nozzle, formulation and substrate properties, all system operating parameters, and all on-line measured attributes, such as drop image, temperature time series data, and solid state related measurements such as Raman output. 

  • Most recently, preliminary results have been reported that demonstrate the use of self-emulsifying formulations to produce stable amorphous API deposits with sub-micron sized particles. 

  • The IP related to the work on melt-based formulations has been disclosed to the Purdue Research Foundation, a provisional patent has been issued and patent filing is being pursued.


The C -SOPS funding has resulted in a viable platform whose further development has received attention and support from several sources. The C-SOPS research has led to a two-year grant from the IN MaC program, a State of Indiana initiative to support Next Generation Manufacturing Competitiveness. PhD student support has been obtained under a recent multi-year Department of Education, Graduate Assistance in Areas of National Needs Grant. The drop on demand facility is part of a recently awarded DARPA project, “Analytic-directed Multi-scale synthesis system”, for flexible and small scale, end-to-end small molecule manufacturing platform. Moreover, targeted projects are under negotiation with two companies.

The use of printing based product manufacture, including 3-D printing technology and roll-to-roll printing onto polymeric films, are receiving increased attention in the pharmaceutical industry. For instance, FDA approval of a 3D printed drug product has recently been announced.

There are many drug products, especially in oncology, which exhibit high inter-patient therapeutic variability and thus the dosage regimens of such drug products need to be tuned carefully to the individual patient. This is generally true for geriatric and pediatric patients and particularly for drugs with narrow therapeutic window. Such tuning of drug administration has hitherto been performed empirically: the doctor prescribes the recommended base line dosage regimen, and then adjusts it higher or lower over the next 2 to 6 months based on the trade-off between therapeutic benefit and side effects. This approach requires a relatively long time to achieve the most beneficial therapeutic range, especially for cancer patients for whom quality of life is important in the lifespan they have remaining. A recent area of research in individualized medicine, in which members of the Purdue TB3 team have been involved, has been to use patient-specific data combined with population-based pharmaco-metric models to rapidly optimize individual patient dosing regimens. A doctor can use this methodology to determine and prescribe customized dosage regimens in an evidence-based manner and thus to arrive at optimized treatment much sooner. A key missing piece has been the ability to readily and conveniently make such customized drug products for individual patients on demand. The drop on demand facility provides this capability. The combined  prediction and on demand manufacturing capability thus has the potential for high societal impact by dramatically improving the treatment of patients.

Future Plans

There are three primary areas for technical developments for the next several years that will be pursued: 

  1. Printing using additional fluid formulation types, such as high solids loading suspensions and self-emulsifying and polymer melt–based formulations to create amorphous deposits; 

  2. Demonstration of automation and control system modifications which will result in precision deposition into alternative substrates such capsules, and onto tablets with multiple wells or multilayered structures for combination products; 

  3. Re-engineering of the prototype unit to a commercialization prototype with improve robustness, compactness, portability, simplified cleaning and improved ease of use.

Efforts towards commercialization of the technology will continue to be pursued through the Purdue Foundry program, federal small business grants, State technology commercialization programs such as IN MaC, as well as DARPA and BARDA programs. A commercialization advisory team consisting of an experienced entrepreneur in the medical instrumentation domain, a Foundry Entrepreneur-in-Residence and a representative of the Office of Technology Commercialization is working with the TestBed 3 team.

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