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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2024 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access   Full Text Article                                                                                                                                                              Review Article

Artificial Intelligence-Assisted Fabrication of 3D Printed Technology in Pharmaceutical Development and Its Application

Shruti I. Meshram ¹, Pooja R. Hatwar ¹*, Ravindra L. Bakal ¹, Pooja Vilasrao Raut ²

¹ Department of Pharmaceutics, Shri Swami Samarth Institute of Pharmacy, At Parsodi, Dhamangoan Rly, Dist -Amravati (444709) Maharashtra, India.

² G.H Raisoni Institute of Life Sciences, Shraddha Park, hingna wadi Road Nagpur, India

 

Introduction:

 

Utilizing computer-aided designs (CAD) and printing configurations, three-dimensional (3D) printing technology facilitates medication and formulation development, allowing for the adjustment of medications produced¹. In the realm of drug delivery systems, these platforms offer potential for targeted therapeutic protocols. The effectiveness of this approach hinges on its capability to precisely target specific organs or tissues, optimizing dosage, release duration, and minimizing side effects². Over the past 5-10 years, there has been a significant uptick in utilizing 3D printing directly in patient treatments. Its rapid capacity to generate personalized devices has found favor in medical sectors requiring bespoke solutions³. Since its inception through stereo lithography in 1984 by Charles Hull, 3D printing has expanded rapidly across various medical applications⁴. Termed as Three-Dimensional Printing (3DP), this technology provides numerous advantages such as cost-effective prototyping, manufacturing intricate geometries, and on-demand device production⁵. Biomedical applications commonly employ extrusion-based, Inkjet-based, and laser-assisted bio-printing techniques. Inkjet bio-printing particularly succeeds in printing low-viscosity bio-inks⁶. However, the development of pharmaceutical products through printing remains relatively limited and is still emerging. Given that these materials directly enter the body, there’s a heightened need for caution and innovation in creating 3D printed pharmaceuticals, which also presents vast opportunities⁷. An essential tool for advancing personalized medicine, 3D printing in pharmaceuticals allows the formulation of novel, tailor-made drug delivery systems (DDSs) by leveraging diverse carrier polymers and excipients. This versatility in additive manufacturing holds tremendous promise in pharmaceutics for fabricating advanced patient-specific DDS⁸. In the pharmaceutical industry, 3D printing (3DP) challenges conventional mass manufacturing systems for fixed-dose drugs by enabling customized production⁹. By controlling material layers via computers to develop 3D products, 3D printing technology is recognized as an additive manufacturing process¹⁰. Its unmatched flexibility in designing and manufacturing complex objects aligns well with the goals of personalized and programmable medicine¹¹. Furthermore, AI’s value in the drug discovery market is projected to grow significantly, with a compound annual growth rate of 40.8%, surging from 260 million USD globally in 2019 to an estimated 1.43 billion USD in 2024¹².

 

 

 

Figure 1: 3D printing of colorful cartoon dispersion tablets (A): 1000 mg strength; (B): 250 mg strength¹³.

Figure 2. Structure diagram for the 3D-printed compound LEV-PN multi-compartmental structured dispersible tablet. (A): 1–7 layers; (B): 1–13 layers; (C): 1–38 layers; (D): 1–44 layers; (E): 1–50 layers¹⁴

 

 

History

The roots of 3D printing, or 3DP, trace back to 1981 when Dr. Hideo Kodama applied for a patent for Rapid Prototyping, yet financial constraints hindered completing the process within a year’s deadline. The concept evolved despite setbacks, with Jean-Claude Andre, Oliver De Witte, and Alain Le Mahath attempting a patent in 1984, facing funding issues that led to the project’s abandonment^15,16. Kodama’s concept eventually paved the way for stereolithography (SLA) technology. Charles Hull patented SLA in 1986 and introduced 3D Systems’ first commercial RP system, the SLA-1, in 1987, with the initial system sold in 1988¹⁷. Concurrently, Carl Deckard patented Selective Laser Sintering (SLS) RP process in 1989, licensed to DTM Inc, later acquired by 3D Systems¹⁸. In the late ‘80s, Scott Crump patented fused deposition modeling (FDM) using thermoplastic material for object preparation. Additionally, in the ‘90s, Emanuel Sachs and his MIT team patented 3D printing techniques based on powder binding for object creation¹⁹. Over 30,000 3D printing patents have been reported in the U.S., each technology typically following a three-step process for printlet production: Design, Develop, and Dispense²⁰. Notably, SLS by Carl Deckard and FDM by Sachs et al. emerged in the late 1980s and early 1990s, respectively²¹.

 

Advantages ^22,23,24

1. Eliminates the need for expensive machinery in metal smelting plants and milling processes.
2. Enables swift creation of components with intricate and personalized unconventional structures.
3. Reduces eco-unfriendly waste generation and enhances the recycling process.
4. Cost-effective for small batch and low-volume production.
5. Applications include producing highly porous products (orally disintegrating), toroidal products (near-zero-order release), complex drug-device combination products, personalized dosing (for potent drugs and children), drug-loaded implants (tailored to individual anatomy), polypills (combining different drugs), and ocular implants.

Disadvantages ^22,25

1. Limited capacity for low-speed and low-volume production.
2. Lower surface gloss, accuracy, and strength of printed components.
3. Constraints in materials processing impacting production variety.
4. General limitations on structural dimensions

 

 

 

 

3D printing process: ^25,26,27

First, an object’s simulated 3D modeling with applications of digital design, such as on shape, Solid works, Creo parametric, Autocad, Autodesk, etc.

 

 

The digital model is then modified to the electronic file format (STL) that stands for Stereolithography or standard tessellation language

 

 

In terms of the surface of the 3D model (STL) image, triangle facets provide detail

 

 

The STL file has been transformed into G file, with the aid of specialized software slicer Installed in a 3D printer which slices the design into a series of 2D horizontal cross-sections

 

 

The printer head can now be shifted to the base of the 3D object in the x-y axis. The print Head will now shift into the z-axis, sequentially deposit the layers of the content you like, thereby producing a full 3D object

 

 

Maximum 3DP technology numbers are file format compliant (STL). Few mistakes can arise When the 3D models are converted to a digital file. STL; tools such as Magics (Materialize) May be used to correct the mistakes during the conversion. STL has no detail about material Type, color, texture, characteristics, and other characteristics.

 

Figure 3: Process Of 3D printed formulation²⁸

 

3D printing techniques:

1. Laser based printing ^28,29

The concept of laser-based printing, originating in 1984 by Charles Hull and patented as Stereolithography in 1986, encompasses two main subtypes: stereolithographic (resin reservoir) and powder bed selective laser sintering. This additive manufacturing process has found application in 3D bioprinting for creating intricate biostructures using bioink on a substrate or scaffold, showing promise in regenerative medicine and drug development.

 

SLA (Stereolithography)^{30,31,32,33,34,35,36}

SLA is the pioneer laser-based liquid resin polymerization technology widely employed in rapid prototyping. This computer-controlled method utilizes a laser beam to solidify liquid polymer or resin, layer by layer, forming a 3D structure. In SLA, exposure to ultraviolet or other light sources initiates crosslinking and polymeric matrix formation in a tank filled with photosensitive resin. A digital mirroring device triggers a chemical reaction, leading to gelation in the exposed area. This layering process is repeated to construct the entire object. SLA’s advantages include high-dimensional accuracy, quality, and the ability to produce complex products in a single operation, but the material selection range is limited.

 

Figure 4: Schematic representation of using SLA to print drug loaded tablets with examples of some SLA 3D printed tablets³⁷.

 

 

SLS (Selective Laser Sintering)

SLS, also recognized as powder bed fusion, was initially developed in 1989 by Carl Deckard and Joseph Beaman as a rapid prototyping technique to swiftly convert 3D CAD data into physical parts using powdered materials like nylon 11, Nylon 12, and PEEK³⁸. This method involves the fusion of powdered material particles on a spreading platform, layer-by-layer, through the action of a high-energy laser beam³⁹.

Figure 5: Schematic representation of SLS⁴¹

The essential components of an SLS printer consist of a spreading platform, powder bed, and laser system. During the printing process, the laser is directed to create specific patterns on the powder bed’s surface, binding together the powder particles and forming a 3D structure⁴⁰. SLS stands out for its ability to work with various materials and its rapid prototyping capabilities, enabling the efficient creation of physical prototypes from digital designs.

2. Extrusion Based Printing 

Extrusion-based 3D printing is experiencing significant interest in pharmaceutical manufacturing worldwide. This method, commercially available and widely used for rapid prototyping, is favored due to its affordability, versatility, and compatibility with various ink materials suitable for biofabrication and tissue regeneration⁴².In this process, material is extruded through robotically actuated nozzles, allowing printing on diverse substrates. Contrary to binder deposition that relies on a powder bed, extrusion printing can work on any substrate⁴³. This technology is categorized into two main types: Fused Deposition Modeling (FDM) and Pressure-Assisted Microsyringe (PAM), also known as Nozzle-based deposition systems⁴⁴.

FDM

FDM, a rapidly evolving 3D printing method, utilizes a computer-controlled gantry carrying one or two miniature extruder head nozzles⁴⁵. These nozzles, typically one for modeling material and sometimes another for support material, extrude molten thermoplastic filament onto a platform in a predetermined pattern⁴⁶. This filament, often derived from thermoplastic polymer through hot melt extrusion (HME), serves as the initial material for FDM⁴⁷. FDM involves depositing molten or softened materials on a build plate through a heated printer extrusion head moving along the x and y axes, while the gradual lowering of the build plate allows the Item to grow incrementally from the bottom up⁴⁸.The final 3D object is achieved as the overlaid layers fuse together and bond upon cooling, a common feature shared with hot-processing techniques like HME, observed in FDM, where subsequent layers of molten or softened formulations are deposited⁴⁷.

 

 

Figure 6: schematic representation of FDM⁴⁹

 

PAM (Pressure-Assisted Microsyringe)

Referred to as SSE (pressure-assisted microsyringe) in literature⁵⁰, PAM has been extensively used in tissue engineering to create soft tissue scaffolds and is gaining traction in pharmaceutical applications. This technique involves the continuous extrusion of semi-solids (gels or pastes) layer-by-layer through a syringe-based tool-head⁵¹. A pneumatic, mechanical, or solenoid piston forms the basis for extrusion, propelling a suitable mixture of polymer, solvent, and necessary excipients through the nozzle in an X-Y orientation onto the build plate⁵². After each layer deposition, the build plate is lowered, and the process repeats⁵³.

3. Inkjet Printing

Inkjet-based bioprinting, akin to conventional inkjet printers, involves the precise deposition of picoliter droplets of “bioink” onto a hydrogel substrate or culture dish under computer control. Two primary methods exist: thermal and piezoelectric actuator-based, operating on droplet actuation mechanisms^54,55. This technique utilizes ink deposition similar to commercial printers, offering high-resolution printing by spraying different mixtures of active ingredients and excipients in varying droplet sizes onto a non-powder substrate⁵⁶. Originally stemming from computer-operated inkjet printing, this approach to personalized medicine has been adapted for pharmaceutical applications by replacing ink with drug-containing solutions and paper with edible substrates⁵⁷.

 

 

Figure 7. Schematic of Inkjet-based Bioprinting. Thermal inkjet uses heat-induced bubble nucleation that propels the bioink through the micro-nozzle. Piezoelectric actuator produces acoustic waves that propel the bioink through the micro-nozzle⁵⁸

 

Thermal Ink-Jet Printing 

In thermal inkjet printing, the aqueous ink fluid is transformed to vapours state through heat, expands to push the ink drop out of a nozzle. It is used in the preparation of drug-loaded biodegradable microspheres, Drug-loaded liposomes, patterning microelectrode arrays coating, loading drug eluting stents. It is also an effectual and applied method of Generating films of biologics without negotiating protein activity ^59,60. In this technique, the Ink is deposited onto a substrate either in the form of Continuous Inkjet printing (CIJ) or Drop on Demand (DoD) printing, hence it provides a high-resolution printing capability⁶¹

A piezoelectric actuator 

A piezoelectric actuator is applied in piezoelectric Inkjet bioprinters to generate acoustic waves through the bioink chamber. A voltage pulse is generated to electrostatic inkjet bioprinters to generate droplets by applying between a pressure plate and an Electrode⁶².

Binder Jet printing 

BJ3DP is a powder-based 3D printing process where a binder Solution is jetted onto a powder bed, binding it together to develop A 3D printed structure⁶³.Binder jetting is a layer-by-layer manufacturing process in which powder is first Distributed in a fine layer. The particles are then bound together by a binding fluid applied Via an inkjet printhead⁶⁴.

 

 

Figure 8: Schematic diagram of the principle and mechanism of tablet preparation by BJ-3DP Technology: (A) schematic diagram of the printing principle of BJ-3DP technology; (B) schematic Diagram of the flight state of a droplet after ejection through the nozzle; and (C)schematic diagram of droplet impact on the powder bed⁶⁵

 

 

Application 

1. 3D printing presents a novel approach to pharmaceutical production, allowing precision medicine where treatments are tailored to individual patient needs^67,68,69.
2. The introduction of 3D printers in hospitals for personalized medicine is a significant step forward, but challenges like installation costs, the need for skilled personnel, and ensuring quality control persist⁶⁸.
3. Gastro-retentive drug delivery systems (GRDDS) provide extended drug release in the stomach, enhancing patient compliance. Utilizing 3D printing’s rapid prototyping, various capsular devices with different structures have been efficiently prepared, showing potential for modified-release drug delivery devices^70,71,72.
4. Multilayer tablet preparation often encounters limitations with traditional equipment. 3D printing resolves technical issues, enabling the creation of multilayer slow-release medicines with various shapes and designs⁷³.

1. Compound solid preparations, composed of multiple parts with varying amounts of medicine, undergo processes like pulverization, mixing, screening, drying, and molding to form solid medicine preparations^74,75.
2. 3D drug printing technology ensures dosage accuracy in compound preparations using quantitative pumps and high-precision motors, improving the precision of micro-dosage addition and resembling conventional drug manufacturing processes^76,77.
3. The binding liquid components must be soluble or possess colloidal particle sizes between 10 and 100 nm to prevent sedimentation and ensure uniformity in 3D printing^78,79.
4. In cancer treatment, 3D printing facilitates constructing patches loaded with chemotherapy drugs directly implanted into pancreatic cancer, aiming to reduce side effects⁸⁰.
5. AI assists in developing complex formulations, predicting physicochemical parameters, and optimizing drug stability, solubility, and viscosity for injectables and biologics, enhancing formulation development⁸¹.
6. Professor Cronin’s work from the University of Glasgow demonstrates the potential of transforming 3D printers into automated minilabs for synthesizing pharmaceutical compounds⁸².
7. Preclinical studies, focusing on pharmacology, pharmacokinetics, and toxicology, rely on understanding a drug’s physicochemical properties and ADMET characteristics⁸³.
8. Pediatric patients’ unique needs for safe drug products and adherence require specific considerations in drug design due to limited clinical trials for pediatric applications⁸⁴.

Challenges:

1. Despite the benefits, challenges in technology, dosage form manufacture, safety, quality control, and regulatory aspects hinder the widespread implementation of 3D printing in pharmaceuticals^85,86.
2. The availability of diverse raw materials for 3D printers remains limited, posing physical and technical constraints⁸⁷
3. The FDA acknowledges the emerging issues with 3D printing and is actively researching to gain a comprehensive understanding of the technology⁸⁸.
4. Integrating machine learning with 3D printing faces challenges universal to ML and specific to pharmaceutical 3D printing, emphasizing the need for early identification and mitigation of potential barriers⁸⁹.

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