(550d) A Drop-on-Demand Manufacturing System for the Production of Amorphous Drug Products

Innovation is the key to success within the pharmaceutical industry. However, it has been largely sought through new drug discovery and development, while the development of more efficient manufacturing methods has received inadequate attention. Recently, as a result of encouragement from the regulatory authorities, the advent of globalization and the increasing awareness of environmental impact, the pharmaceutical industry has been reconsidering the way drug products are developed and manufactured. The US Food and Drug Administration (FDA) has promoted the Quality by Design (QbD) approach to increase process understanding and improve quality and efficiency while minimizing risk [1]. The Process Analytical Technology (PAT) guidance introduced by the FDA encouraged the monitoring of critical quality and performance attributes during processing with the goal of ensuring final product quality [2,3].

As part of this renewed emphasis on improvement of manufacturing and under the US National Science Foundation supported Engineering Research Center for Structured Organic Particulate Systems; we have developed a dropwise additive manufacturing process for solid oral dosage production. The process utilizes the drop-on-demand (DoD) inkjet printing technology for predictable and highly controllable deposition of active pharmaceutical ingredients (API) onto an edible substrate, such as a polymeric film or placebo tablet [4, 5]. This process uses fluid operations suitable for low volume production of personalized dosage forms. The advantages of liquid processing and reproducible production of small droplets create the special opportunity for the production of high potency, low dose drugs, which are difficult to produce with consistent quality via conventional powder processing methods.

Using the developed drop on demand manufacturing process for pharmaceuticals, different drug formulations including solvent based systems [4], i.e. solvent-polymer-API solutions, as well as melt based systems [5], i.e. polymer-API melts, can be printed. Melt-based printing applications eliminate the solvent evaporation step after drop deposition and thus allow on demand production of individual dosage forms with good control of drug solid state and morphology.

In this paper, we present the controlled production of amorphous dosages by the deposition of melt-based formulation using the DoD manufacturing system. Producing dosage forms in which the active ingredient is in amorphous forms can enhance the dissolution of low-solubility drugs. Amorphous drug forms are produced with alternative choice of polymers, which inhibit crystallization, along with suitable choice of operating conditions. Polymers are added to the printing material to help control drug morphology, material properties and the formulation composition [6]. Addition of crystallization inhibiting polymers, such as PVP, to the formulation, can result in the formation of dosage forms containing amorphous or semi-crystalline API. Operating conditions, i.e. crystallization temperature, are controlled using substrate temperature controller, which is used to achieve the desired product quality by influencing the dissolution behavior and therefore the bioavailability of the drug [7]. Since stability of amorphous drug forms can be challenging, design of crystallization temperature profile and precise control of substrate temperature profile are even more important than in the case of crystalline API formulations. The amorphous dosage forms are achieved by controlling the cooling profile of the deposits to solidify the drug in the amorphous form before crystallization occurs.

1. Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK, et al. Understanding pharmaceutical quality by design. AAPS J. 2014;16(4):771–83.
2. Food and Drug Administration CDER. Guidance for Industry PAT - A Framework for Innovative Pharmaceutical. 2004.
3. Simon LL, Pataki H, Marosi G, Meemken F, Hungerbu K, Baiker A, et al. Assessment of Recent Process Analytical Technology (PAT) Trends: A Multiauthor Review. Org Process Res Dev. 2015;19(1):3–62.
4. Hirshfield L, Giridhar A, Taylor LS, Harris MT, Reklaitis G V. Dropwise additive manufacturing of pharmaceutical products for solvent-based dosage forms. J Pharm Sci. 2014;103(2):496–506.
5. Içten E, Giridhar A, Taylor LS, Nagy ZK, Reklaitis G V. Dropwise Additive Manufacturing of Pharmaceutical Products for Melt-Based Dosage Forms. J Pharm Sci. 2015;104(5):1641-49.
6. Trasi NS and Taylor LS. Effect of Additives on Crystal Growth and Nucleation of Amorphous Flutamide. Crystal Growth & Design 2015; 12(6): 3221–3230.
7. Içten E, Nagy ZK, Reklaitis GV. Supervisory Control of a Drop on Demand Mini-manufacturing System for Pharmaceuticals. Comp. Aided Process Eng., 2014; 33: 535-540.