3D printing and continuous flow chemistry technology to advance pharmaceutical manufacturing in developing countries

Abstract

The realization of a downward spiralling of diseases in developing countries requires them to become self-sufficient in pharmaceutical products. One of the ways to meet this need is by boosting the local production of active pharmaceutical ingredients and embracing enabling technologies. Both 3D printing and continuous flow chemistry are being exploited rapidly and they are opening huge avenues of possibilities in the chemical and pharmaceutical industries due to their well-documented benefits. The main barrier to entry for the continuous flow chemistry technique in low-income settings is the cost of set-up and maintenance through purchasing of spare flow reactors. This review article discusses the technical considerations for the convergence of state-of-the-art technologies, 3D printing and continuous flow chemistry for pharmaceutical manufacturing applications in developing countries. An overview of the 3D printing technique and its application in fabrication of continuous flow components and systems is provided. Finally, quality considerations for satisfying regulatory requirements for the approval of 3D printed equipment are underscored. An in-depth understanding of the interrelated aspects in the implementation of these technologies is crucial for the realization of sustainable, good quality chemical reactionware.

Keywords: 3D printing; Affordable; Continuous flow chemistry; Developing countries; Pharmaceutical manufacturing; Quality control.

Fig. 1

The generic 3D printing process sequence.

Fig. 2

Typical continuous flow components and systems.

Fig. 3

3D printed continuous flow equipment (Neumaier et al., 2019). (A) R1 CAD drawing, R1 reactor and early stage prototype reactor R2. (B) R3 reactor and reactor rail. (C) R4 microreactor. (D) Continuous stirred tank reactor (CSTR). (E) Syringe pump. The images are reproduced with permission from Neumaier et al. (2019).

Fig. 4

The continuous flow reactions performed in the 3D printed equipment by Neumaier et al. (2019).

Fig. 5

Continuous flow-ESI-MS system with a 3D printed stainless microreactor and a cascade of reactions performed using the reactor. The images are reproduced with permission from Scotti et al. (2019).

Fig. 6

3D printed full continuous flow system. The images are reproduced with permission from Penny et al. (2019).

Fig. 7

S_NAr reactions between 5-nitro-2-chloropyridine 14 and a variety alcohols explored in the 3D printed continuous flow system (Penny et al., 2019).

Fig. 8

3D printed BPR designed and developed by Walmsley and Sellier (2020).

Fig. 9

3D printed continuous flow system. The images are reproduced with permission from Alimi et al. (2019).

Fig. 10

3D printed continuous flow column reactor and morin 18 oxidation (Alimi et al., 2020).

Fig. 11

3D printed continuous flow system consisting of syringe pumps, Pd immobilized alumina monolith and a polypropylene-based flow reactor. The images are reproduced with permission from Alimi et al. (2020).

Fig. 12

3D printed continuous flow reactor. The images are reproduced with permission from Harding et al. (2020).

Fig. 13

Exploded view of the designed calorimeter with the 3D printed modular segments. Reproduced with permission from Maier et al., 2020a, Maier et al., 2020b.

Fig. 14

Grignard oxidation using molecular oxygen investigated in various 3D printed continuous flow reactors (APO3, APO4, SaRR and CSTR cascade). Reproduced with permission from Maier et al., 2020a, Maier et al., 2020b.

Fig. 15

3D printed SaRR incorporated in the multistep continuous flow synthesis of a valsartan precursor 32.

Fig. 16

3D printed CSTR incorporated in the two-step continuous flow synthesis of 4-hydroxystilbene 35. Reproduced with permission from Maier et al., 2020a, Maier et al., 2020b.

Fig. 17

(A) Illustration of printing direction and layer orientation relative to load direction of a vertically printed cylinder, layer oriented perpendicular to load direction. (B) Illustration of printing direction and layer orientation relative to load direction of a horizontally printed cylinder, layer oriented parallel to load direction. Yellow triangles represent the printing support base. Reproduced with permission from Es-Said et al. (2000).

Fig. 18

(A) Strand thickness test design, (B) print accuracy multilayer grid design, (C) printed strand with width analysed using ImageJ and (D) printed grid with dimensions determined using ImageJ. Reproduced with permission from Giuseppe et al. (2018).

Fig. 19

Images of CNF, TOCNF, and AcCNF scaffolds in the wet state soon after printing; at 24 h after freeze-drying and room temperature drying; and after 24 h of rehydration by immersion in water of the freeze-dried samples. Reproduced with permission from Wang et al. (2020).

Fig. 20

Microphotographs of specimens after compressive failure: (a) failure due to buckling and (b) de-bonding between fibers (the surfaces of the test part were examined by scanning electron microscope (SEM) JEOL JSM-6480LV in the LV mode). Reproduced with permission from Gonzalez Ausejo et al. (2018).

Fig. 21

Images of tree-like voids grown in the build direction, with unconsolidated powder trapped inside the closed voids: (a) slice view and (b) 3D rendering. Reproduced with permission from du Plessis et al. (2018).