From Current to Future Trends in Pharmaceutical Technology

From Current to Future Trends in Pharmaceutical Technology explores the current trends of this field and creates a multi-aspect framework for the reader. The book covers topics on pharmaceutics, pharmaceutical engineering, pre-formulation protocols, techniques, innovative excipients, bio-printing techniques, scale-up based on formulas on-a-chip, and regulatory aspects based on new scientific achievements. Modified dosage forms, new aspects on the compatibility of drug excipients interactions, and drug release by various dosage forms are included. Physical pharmacy (physical and biological stability of dosage forms), innovative excipients, patents on innovative formulations and regulatory issues related to the approval process of medicines are also discussed.

The book is a valuable resource for a wide audience of academics, industrial researchers and professionals working in this field as the development of efficient and safe medicines is critical to future needs.

• Includes innovative excipients/advanced materials in pharmaceutics
• Covers modified release delivery platforms
• Explores new elements of drug development

• Language: English
• Publisher: Academic Press
• Release date: Nov 30, 2023
• ISBN: 9780323914390

Book preview

Preface

Pharmaceutical technology is a critical field in the development of efficient and safe medicines as innovative dosage forms, and it is involved in all steps of their development process and production. It is a dynamic, multidisciplinary field that is continuously evolving, as it is always necessary and applicable in every new medicine development and pharmaceutical manufacturing process. From Current to Future Trends in Pharmaceutical Technology explores the current trends in this field and creates a multiaspect framework for the reader.

Chapter 1 deals with the fundamentals of 3D printing of pharmaceuticals. This chapter provides an overview of recent progress in the development of dosage forms for specific populations and with tailored drug release. It places a special emphasis on process parameters and material qualities necessary for each technique. Before widespread 3D printing of dosage forms, several challenges need to be resolved, including the creation of printers for the pharmaceutical industry and the adoption of a standardized approach to evaluate the printability of materials.

The ability to identify the key variables and investigate various operational situations makes modeling any process a formidable tool for improving its design. This very interesting topic is discussed in Chapter 2. To understand how excipients and manufacturing processes can affect the limiting steps of drug absorption, as well as to accomplish for a specific drug its maximum rate and extent of absorption, modeling pharmaceutical oral formulation performance is used. This chapter provides an overview of in silico, in vitro, and in vivo models and their incorporation into mathematical models. Focus on the expert system for excipient selection in the section on in silico approaches. In vivo predictive dissolution models (IPD) and cell models for permeability assessment are examples of in vitro models.

Excipients have a central role in pharmaceutical research and development. Chapter 3 focuses on the impact of co-processing attributes of innovative pharmaceutical excipients. There is a wide literature review, including several examples of preformulation and formulation studies and techniques.

The difficulties in formulating new drugs are briefly discussed in Chapter 4, and it is stressed how important the molecular simulations (including molecular dynamics) method may be in this situation. The characteristics of using molecular simulations to build formulations are examined and contrasted with those of other cutting-edge technologies.

The characteristics and working ideas of several 3D printing technologies, as well as the benefits and drawbacks of each in terms of printing speed and material utilization, are also presented in Chapter 5. This chapter also summarizes developments in 3D printing technologies for applications in the treatment of wounds, including the use of various materials with antibacterial and antioxidant properties as well as the incorporation of peptides and pharmacological compounds. The use of bioprinting for cell delivery and skin tissue engineering is another development.

Artificial intelligence (AI) and machine learning (ML) have attracted considerable attention in a variety of sectors, including pharmaceutical sciences, and have led to a rapid rise in new applications for machine learning in numerous areas of pharmaceutical sciences. In computational chemistry, deep learning models have been used to predict drug-target interactions, develop new compounds, and predict pharmacokinetics. AI, robotics, and advanced computing have applications in drug repurposing, quality by design, 3D printing, and nanomedicine. When used properly, AI techniques can improve patient treatment, detection and reduction of risk factors, and identification of complications. This important topic is analyzed in depth in Chapter 6.

Chapter 7 focuses on the relevant principles applied in the preclinical, clinical, preformulation, and formulation development studies in light of recently introduced tools and techniques. The development of high-throughput screening, computer-aided design, in silico screening, and combinatorial chemistry has accelerated the drug discovery process and made it possible to identify a lead candidate with the ideal balance of pharmacokinetic, pharmacodynamic, and biopharmaceutical properties and a high likelihood of success. Early clinical and proof-of-concept studies often employ a formulation that is suited for purpose. The formulation employed during the clinical stage would be identical to the final, marketed dosage form if thorough preformulation and formulation development work had been done. The formulation should exhibit acceptable stability, dissolution, and other pertinent quality features to be considered fit for purpose.

Chapter 8 also includes the current status and the challenges of implementing 3D printing technologies in pharmaceutical manufacturing. The 3D-printed dosage forms can be submitted and reviewed for FDA approval using the current regulatory paradigm.

The scope of Chapter 9 is to summarize the different strategies and categories of modified-release systems, focusing on orally administrated dosage forms. Modified release systems are regarded as a leading area of pharmaceutical manufacturing and technology, leading to the creation of novel, safe, and effective new dosage forms, the enhancement of existing therapeutics, the reduction of drug toxicity, and patient compliance. Different technologies are highlighted, including coated tablets, matrixes, multiple-unit solid dosage forms, minitablets, and gastroretentive drug delivery systems.

The field of 3D printing, contemporary medical applications, 3D-printed dosage forms, and drug delivery systems, as well as the advantages and drawbacks of this technology, are all covered in Chapter 10. It focuses on the potential and drivers of this additive manufacturing technique, as well as the difficulties and potential benefits it may have for the future of medicine and pharmaceuticals.

Chapter 11 deals with the use of polymersomes for drug delivery purposes. Polymersomes are amphiphilic block copolymers that self-assemble into vesicles to form a bilayer and are used as medication delivery devices. As a result, both hydrophilic and hydrophobic active pharmaceutical ingredients (APIs) can be encapsulated using these carriers. The goal of the current chapter is to examine a wide variety of factors and variables that impact the polymersomes’ encapsulated APIs’ release profile. The results of a thorough analysis of the body of prior research were used to present the factors that affect drug release behavior in a methodical and in-depth manner.

This book includes several interesting topics in the field of pharmaceutical technology. Special attention is given to 3D printing technologies, modified release dosage forms, and pharmaceutical excipients. The book is a valuable resource for a wide audience of academics, industrial researchers, formulation scientists, and professionals working in this field.

The Editors

Natassa Pippa

Costas Demetzos

Maria Chountoulesi

Chapter 1 Fundamentals of 3D printing of pharmaceuticals

Djordje Medarevića,∗; Mirjana Krstićb; Svetlana Ibrića    a Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia

b Zdravlje AD, Leskovac, Serbia

∗ [e-mail]

Abstract

Need for adjustment of therapy to individual patient’s characteristics forced the pharmaceutical industry to seek for alternative techniques for production of personalized products. Numerous studies demonstrated suitability of three-dimensional (3D) printing for fabrication of different kinds of dosage forms, with tailored drug dose, architecture, and drug release patterns, whereas the Food and Drug Administration (FDA) approval of the first 3D-printed drug Spritam showed that this technique can be implemented also on the large scale when conventional techniques may not be feasible. Numerous issues should be overcome before routine fabrication of dosage forms by 3D printing, such as development of printers for pharmaceutical use and standardized methodology to assess material printability, with adoption of regulatory framework. This chapter overviews current achievement in 3D printing of drugs, with particular emphasis on process parameters and material characteristics important for each technique and recent progress in the development of dosage forms for specific population and with tailored drug release.

Keywords

Additive manufacturing; 3D printing; Personalized drug delivery systems; Tailored drug release; Printability; Printing parameters

Acknowledgments

This research was funded by the Ministry of Education, Science and Technological Development, Republic of Serbia through Grant Agreement with University of Belgrade-Faculty of Pharmacy No: 451-03-47/2023-01/ 200161.

1 Introduction

With the progress in medicine during the last several decades, it became clear that the course of the disease and response to applied therapy differ to a great extent between patients due to differences in genetic, anatomical, and physiological characteristics of the patients. This brought into question the current concept of therapy, so-called one size fits all, where similar drug doses have been prescribed to a huge number of patients, with neglect of interindividual differences between patients. The possibility for dose adjustment was mostly limited to the subdivision of tablets as the most commonly used dosage forms, which can lead to dose inaccuracy and also affects product stability and drug release pattern (Richey et al., 2017). In addition, acceptability of therapy for an individual patient, concerning dosing frequency, the number of medications in the therapy, the appearance, size, color, taste, and textural properties of the dosage form is becoming an increasingly important factor in providing optimal pharmacotherapy, especially in pediatric and geriatric populations. Inadequate organoleptic properties and appearance of the drug significantly reduce patient adherence to therapy in pediatric patients, whereas taking multiple drugs, which disrupt the daily activities of patients, is one of the main causes of nonadherence to therapy in the geriatric population (Menditto et al., 2020). Therefore, in drug development, it is necessary to consider whether the final preparation, in addition to established quality requirements, will also meet the specific requirements and needs of patients. Although it is indisputable that mass pharmaceutical production provided an access to cheap drugs with high quality, safety, and efficiency, above-mentioned limitations have encouraged scientists to work intensively on the development of a new strategy, which will enable the patient therapy with drugs that fit his genetic, anatomical and physiological characteristics, and personal requirements.

Three-dimensional printing (3D printing) is an additive manufacturing process that enables the production of different kinds of objects from constructed 3D model file by sequential deposition of material layer by layer (Prasad & Smyth, 2016). Objects for printing are designed by computer-aided-design (CAD) software packages and further transferred to the printing system. Early works in the field of additive manufacturing date back to the 1970s, when Pierre Ciraud in his patent described the production of an object from layers of powder material, where the melting of material was induced by a high-energy laser beam (Ciraud, 1972). In 1986, in an attempt to improve lengthy and less accurate process of prototype fabrication in the plastic industry, Charles Hull, a pioneer of 3D printing, developed stereolithography as the technique where liquid photopolymerizable resin is solidified according to a predefined 3D model upon irradiation by UV light (Hull, 1986). This is considered as the beginning of today’s 3D printing. Hull’s company 3D Systems introduced the first commercially available 3D printer SLA-250, for the fabrication of objects by stereolithography (Kalaskar, 2017). Carl Deckard, a graduate student of the University of Texas patented in 1989 selective laser sintering (SLS), as a 3D printing technique where the desired object is produced by solidification of layers of powder material after irradiation by laser beam within the areas defined by CAD file (Deckard, 1989). In 1992 Scott Crump developed fused deposition modeling (FDM) printing which involves heating of thermoplastic filaments and deposition of melt in a layer-by-layer fashion (Crump, 1992). The term 3D printing was introduced in 1993 by the group of Emanuel Sachs from the Massachusetts Institute of Technology, who described inkjet printing by spreading of liquid binder over layers of powder material (Sachs et al., 1993).

From its appearance, 3D printing has evolved from its original purpose to fabricate industrial prototypes to a scalable technique suitable for large-scale production on the one side and method for production of small batches with unique characteristics that match specific requirements of customers on the other side. Despite most of the currently available 3D printing techniques have been invented during the 1980s and 90s, expansion of research in this field and the wider practical application started much later. The reason for this delay in wider application of 3D printing lies in the patent protection of most 3D printing techniques, which expired until the end of the first decade of the 21st century. Due to patent protection of most of the 3D printing techniques, available equipment was very expensive, which made impossible development of the cost-effective production processes. The expiration of these patents was followed by the rapid development of affordable user-friendly desktop printers suitable for mass production of custom-made objects in a cost-effective manner (Capel et al., 2018; Melocchi et al., 2021). Till now, 3D printing found applications in various areas, such as automotive, aerospace, and consumer goods industries and biomedical and pharmaceutical research and industry (N. Dumpa et al., 2021).

Capability for rapid production of any type of designed architecture introduced 3D printing to the pharmaceutical field, as a promising technique to address growing needs for personalized drug delivery systems. The particular advantage of the application of 3D printing in dosage form design is production of complex architecture with spatially controlled material deposition, which enables the development of delivery systems with multiple drugs (polypills), different drug doses, and different drug release profiles. Another benefit of 3D printing is the suitability for on-demand manufacturing at the point of care or hard-to-reach area, thus enabling prompt access to needed medications, with minimizing costs and risks associated with storage and transport (Caballero-Aguilar et al., 2019; N. Dumpa et al., 2021). Although the application of 3D printing in drug delivery has been reported as early as 1996 (Wu et al., 1996), the interest of scientists from both academia and the pharmaceutical industry culminated after the Food and Drug Administration (FDA) approved the first 3D-printed drug, Spritam, orodispersible tablets with 1000 mg of levetiracetam, produced by patented ZipDose binder jetting technique (Lim et al., 2018; Souto et al., 2019). Fast disintegration in the oral cavity makes this product particularly suitable for the treatment of epilepsy in patients with swallowing difficulties, which is common in pediatric and geriatric populations (Prasad & Smyth, 2016). Even in patients without swallowing difficulties, swallowing of conventional tablets containing 1000 mg of drug with the additional amount of required excipients would be unpleasant. Despite 3D printing being introduced in the pharmaceutical field mainly due to its unique capability to provide small batches of personalized dosage forms, Spritam was produced in large batches by 3D printing as a mass production technique. FDA approval of this product confirmed that 3D printing can be used as an alternative to the conventional tablet manufacturing process. Three-dimensional printing of Spritam tablets enabled the incorporation of a large dose of levetiracetam in a highly porous single tablet, with fast disintegration, which is often impossible to achieve with conventional tablet production either by direct compression or wet granulation. In February 2021, Triastek, a pharmaceutical company specializing in 3D printing of drug products, received approval of the investigational new drug (IND) application for their product T19—3D-printed chronotherapeutic drug delivery system for the treatment of rheumatoid arthritis (Triastek, 2021). This product was prepared using melt extrusion deposition (MED) 3D printing technology where the mixture of drug and excipients are firstly processed by hot-melt extrusion (HME) and then conveyed directly to a heated printing station where molten or softened mass is deposited layer by layer (Zheng et al., 2021).

2 The basic principles of 3D printing

Although each 3D printing technique has its unique mechanism for the fabrication of objects, the basic principle is the same for all techniques. The first stage in the 3D printing process is the design of the object by a suitable CAD software. Progress in 3D printing with the development of affordable desktop printers run in parallel with evolving of user-friendly software packages for 3D design. Selection of appropriate CAD software is based on hardware requirements, the complexity of architecture that needs to be constructed, level of user expertise in 3D modeling, available budget (free or paid software), and suitability for exporting the 3D model in a file compatible with 3D printers. While objects of simple shape like tablets, capsules, films, and patches can be easily constructed in any software, the design of more complex architectures, such as tablets with multiple compartments, and drug delivery systems that fit anatomy of the application site requires more complex software packages and personnel with advanced skills in 3D design (Melocchi et al., 2021). Using of 3D scanners or medical imaging data acquired by computed tomography or magnetic resonance imaging enabled the creation of 3D models, which precisely fit patient anatomical characteristics. This makes 3D printing the most promising technique for the production of bespoke prostheses and implants with or without the incorporated drugs (Ashish et al., 2019; Trenfield, Awad, et al., 2019). Goyanes et al. (2016), demonstrated that this concept can be used for the fabrication of antiacne patches and face masks with salicylic acid, which perfectly fit patient face anatomy (Goyanes et al., 2016).

A created digital model is then converted to standard tessellation language or stereolithography (STL) digital file format, which serves as an instruction for printing. The STL file comprises coordinates of the triangles, which make up an external surface of the object (Melchels et al., 2010; Melocchi et al., 2021). Although STL file can be automatically created in most CAD software, conversion process sometimes resulted in defective STL file, particularly in the case of complex architectures, which further requires the application of repair tools (Melocchi et al., 2021). Although STL format has become a standard type for transferring information between CAD software and 3D printers during the last several decades, progress in the development of 3D printing, together with customers’ demands for more complex objects produced from multiple materials with higher printing resolution, brought to the fore some important drawbacks of this file type. An STL file describes only the surface geometry of the objects but lacks information about color, texture, material, substructure, and other properties of the fabricated object. Limitations of STL format led to the introduction of novel file formats, such as additive manufacturing file format (AMF) or 3D manufacturing format (3MF). These formats keep the benefits of STL format, such as simplicity and technology independence, with additional data about object structure, color and texture, and material properties. STL format can be easily converted to AMF or 3MF formats, while backward conversion to STL format is also possible with losing advanced features of AMF and 3MF formats. Particular benefits of AMF and 3MF formats are their high versatility, which enables the inclusion of additional features as 3D printing technology evolves, with maintaining compatibility with older hardware (3MF consortium, 2021; ISO/ASTM 52915:2020, 2020). Although additive manufacturing is still based mostly on the use of STL format, additional features offered by the novel formats will certainly lead to their wider acceptance, with the future progress in the 3D printing industry.

The final step before the printing process is the processing of STL or alternative file with slicing software, which converts an object into series of 2D layers and creates so-called G-Code, i.e., detailed instructions for the printing process in a numerically controlled programming language. According to the instructions written in G-Code, each layer of material is printed in the X–Y direction. After completion of each layer, the building platform is moved in a Z-direction, allowing deposition of the next layer on a previous one (Melocchi et al., 2021). Mechanisms of layer deposition and solidification are specific for each 3D printing technology.

In a response to the intensive development of 3D printing, American Society for Testing and Materials (ASTM) in 2009 formed Committee F42 on Additive Manufacturing Technologies, which is dedicated to the development of standards in additive manufacturing to support the implementation of this technology in different kinds of industry. ASTM standard 2792-12a, which was later replaced by a jointly accepted ISO/ASTM 52900:2021 introduced standard terminology in additive manufacturing and classified all techniques into seven groups: binder jetting, VAT polymerization, powder-bed fusion, material jetting, material extrusion, direct energy deposition, and sheet lamination (ISO/ASTM 52900:2021, 2021). In the following text, only techniques which can be applied in the fabrication of drug delivery systems will be described.

3 Extrusion-based 3D printing

3.1 Fused deposition modeling 3D printing

FDM 3D printing (also known as fused filament fabrication [FFF]) is a method for the fabrication of 3D objects using thermoplastic material in the form of solid filaments. The thermoplastic filament is fed by the pinch roller mechanism toward a heated nozzle where filament melts at increased temperature into semisolid viscous mass. Layers of melted material are deposited on a building platform by moving the printing head in the X–Y direction. Promptly after deposition, the layer of material solidifies in contact with air, and the building plate is moved in Z-direction, leaving the space for deposition of the next layer (Fig. 1.1).

Fig. 1.1

Fig. 1.1 Schematic illustration of FDM 3D printer (left) and the printing head (right). (Reprinted from: Parulski, C., Jennotte, O., Lechanteur, A. & Evrard, B. (2021). Challenges of fused deposition modeling 3D printing in pharmaceutical applications: Where are we now? Advanced Drug Delivery Reviews, 175, 113810, with permission from Elsevier.)

In the case of printing some complex structures or using materials with poor adhesion to the building plate, deposition of supporting layers of other material may be required. After completion of printing process, supporting material is removed mechanically or by dissolving with a suitable solvent, which must not dissolve the material used for printing the main structure (N. Dumpa et al., 2021; Parulski et al., 2021). Two types of FDM 3D printers can be distinguished based on the design of the feeding mechanism. In the direct extrusion printers, the feeding system is an integrated part of the printing head, and it is placed close to the heated nozzle. In Bowden extrusion systems, the feeding mechanism is dislocated from the printing head usually on the frame of the printer, and the filament is pushed through the PTFE Bowden tube to the heated nozzle (P. Xu, Li, et al., 2020). The wide availability of commercial filaments and low-cost desktop printers made FDM a dominant 3D printing technology for the fabrication of custom-made objects as consumer goods, or use in some specific application. However, the vast majority of commercial filaments contain polymers and additives, which are not approved for medical application, while filaments made of medical grade of polymers are mostly intended for the preparation of prosthetic and orthodontic implants. Till now, there are no available filaments containing both polymer and drug. This makes materials preprocessing by HME essential for FDM 3D printing, making the whole process of object fabrication more complex. Drug-loaded filaments are produced using single-screw or twin-screw extruders, whereby more efficient mixing, lower residence time and lower temperature in the process give preference to the use of twin-screw extruders (Tan et al., 2018). In the early studies, dealing with the application of FDM for the fabrication of drug delivery systems, simple and cheap small-scale single-screw extruders intended for recycling of plastics (e.g., Filabot) have been used for the production of drug-loaded filaments, in line with the proposed low-cost concept of 3D printing. Despite filaments produced by these extruders have been successfully printed, further understanding that the printing process is strongly dependent on the filament properties moved focus toward using twin-screw extruders, particularly developed for pharmaceutical applications (Melocchi et al., 2021). Drug-loaded filaments can be also prepared by immersion of polymeric filaments into drug solution in a volatile solvent, followed by solvent removal in a drying step. This method of drug loading is simple and is feasible with high-quality commercially available filaments made from medical grade of polymers, thus enabling avoidance of extrusion of the drug–polymer mixture. In this way, exposure of the drug to increased temperatures is limited only to the printing step. Because of prolonged residence time, drug degradation is more likely to occur in the extrusion step than in the printing stage, so avoiding extrusion can significantly reduce the extent of drug degradation. However, the main limitation of this process is low drug loading (commonly up to 3% w/w) that can be derived, limiting its application only to low-dose drugs (Parhi, 2021; Parulski et al., 2021). Drug loading efficiency is markedly affected by the choice of solvent for the preparation of drug solution. Chew et al. (2019) demonstrated that using methanol instead of ethanol increases the loading of polyvinyl alcohol (PVA) filament with fluorescein sodium and 5-aminosalicylic acid. Loading with ∼6% (w/w) of fluorescein sodium and ∼ 3% (w/w) of 5-aminosalicylic acid was achieved in the same filament, enabling the straightforward formulation of fixed-dose combination tablets. Although the loading process by immersion of filament in drug solution decreased the mechanical strength of the filaments, printability was still maintained (Chew et al., 2019). Additional drawbacks include long process duration (12 h to 4 days), wastage of unloaded drug, and safety concerns due to the presence of residual solvents. Swelling in the solvent can also affect filament dimensions, surface texture, and mechanical properties, which can make it unsuitable for printing (Parhi, 2021). Supercritical impregnation can be also used as an environmentally friendly solvent-free technique for drug loading of polymeric filaments. In this process, it is possible to tune drug loading by changing temperatures and pressures. Supercritical impregnation was successfully used for impregnation of polylactic acid (PLA) filaments with mango leaves extract. Although increased pressures in this process on the one side increase the diffusion of drug in the polymeric filament and make loading more efficient, on the other side, it negatively affects dimensions, surface characteristics, and mechanical properties of the filaments (Rosales et al., 2021).

Despite FDM 3D printing gained huge popularity as an affordable 3D printing technique, its application for the fabrication of drug delivery systems is still challenging due to numerous factors, which affect final product characteristics. Similar to conventional pharmaceutical production processes, FDM 3D printing is affected by material properties, process parameters, and equipment-related factors. Since FDM used filaments prepared from thermoplastic polymers, drugs, and other additives, as a feedstock material, in the product development it is necessary to consider the thermal, mechanical, and rheological properties of all ingredients as well as of the prepared filaments. As HME is a well-established technique in the development of a formulation for improving solubility and bioavailability of poorly soluble drugs, pharmaceutical thermoplastic polymers suitable for extrusion of filaments can be easily found on the market. PVA, polyvinylpyrrolidone (PVP), PLA, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), ethyl cellulose (EC), poloxamers, polyethylene glycol (PEG), polyethylene oxide (PEO), polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus) acrylate copolymers (Eudragit), vinylpyrrolidone-vinyl acetate copolymers (PVPVA) have been evaluated concerning suitability for filament production and further 3D printing (Parulski et al., 2021). Thermostability, melt viscosity, and miscibility of components are important material factors to consider in the extrusion step. Miscibility of polymer with a drug is particularly important in the development of the formulation for solubility and bioavailability improvement of poorly soluble drugs, where it is desirable to attain molecular dispersion of drug in the polymeric matrix to avoid drug recrystallization and ensure product long-term stability (Medarević et al., 2019). Although the aforementioned polymers are suitable for extrusion of filaments, most of them alone are not suitable for 3D printing because they do not meet either mechanical characteristics of the filaments or melt viscosity. It is not surprising that extrusion of commonly used pharmaceutical polymers does not result in filaments that can withstand mechanical stress in the printer feeding mechanism, since extrudates produced by HME are mostly intended to be milled into powder for further compression in tablets or filling in capsules (Nasereddin et al., 2018). Therefore the brittleness of HME products, which is a common problem in FDM 3D printing, is even desirable in the conventional HME process. For a successful FDM 3D printing process, filaments should pose both suitable mechanical characteristics to ensure transfer through the printer feeding mechanism and suitable rheological characteristics to achieve sufficient melt flow from the heated nozzle and deposition of molten material in layers (Cailleaux et al., 2021; N. Dumpa et al., 2021). Zhang, Xu, et al. (2019) identified flexibility, brittleness, and stiffness as critical mechanical attributes of filaments for a successful 3D printing process. They proposed Repka-Zhang methodology for mechanical characterization of filaments, which includes a three-point bend test for determination of flexibility and brittleness, and additional stiffness test. In the three-point bend test, filament cut to a defined length is placed on the two supporting pins with a gap between them, and force is applied centrally by moving blade until the predefined displacement (Fig. 1.2A). Breaking stress (or force) and breaking distance are recorded during the test. Flexibility is defined as the tolerance of filament to bending without breakage, whereas brittleness describes materials that break without significant deformation. According to this method, the flexibility of the filament is determined by the breaking distance, as the distance which the blade travels from the first contact with the filament until the maximum force is recorded. Flexible filaments exhibit a high breaking distance (J. Zhang, Hu, et al., 2019). Toughness is often used for the mechanical characterization of filaments as resistance to fracture. Tough filament can absorb a high amount of energy before the fracture (Samaro et al., 2020). High breaking stress in the three-point bend test was used as an indicator of high filament toughness, i.e., resistance to fracture under applied stress. In the stiffness test, the filament is placed on a solid flat surface and the blade is directed to penetrate up to a defined distance in the filament (Fig. 1.2B). Stiffness is the resistance of the filament to deformation under applied force, whereby stiff filaments require high breaking force in the stiffness test. To avoid the effect of variations in filament diameter, breaking stress (ratio of breaking force to filament cross-sectional area) is commonly used instead of breaking force. According to Zhang, Xu, et al. (2019), printable filaments should pose adequate flexibility (breaking distance >0.61 mm), toughness (breaking stress >635.5 g/mm²), and stiffness (20,758.3 g/mm²). Brittle filaments break when moved between feeding gears, whereas soft filaments deform under pressure between feeding gears, which both results in obstruction of the feeding mechanism (J. Zhang, Hu, et al., 2019).

Fig. 1.2

Fig. 1.2 Illustration of testing methodology for filaments mechanical characterization (A) three-point bend test; (B) resistance test; (C) stiffness test. (Reprinted from: Xu, P., Li, J., Meda, A., Osei-Yeboah, F., Peterson, M. L., Repka, M. & Zhan, X. (2020). Development of a quantitative method to evaluate the printability of filaments for fused deposition modeling 3D printing. International Journal of Pharmaceutics, 588, 119760, with permission from Elsevier.)

A tensile test was also used for mechanical characterization of the filaments (Korte & Quodbach, 2018b; Samaro et al., 2020; Shi et al., 2021; Tabriz et al., 2021). In this test, the filament is oriented vertically, fixed with two grippers, and stretched vertically until the filament breaks or until the set distance for filaments that do not break (Samaro et al., 2020). Testing of each sample results in a unique stress–strain diagram, which enables the determination of characteristic parameters, such as Young’s modulus, maximum (or ultimate) tensile strength, and elongation at break. The slope of the linear part of the stress–strain curve is equal to Young’s modulus, which represents filament stiffness, i.e., resistance to deformation under an applied force. Elongation at break is calculated as an increase of filament length upon stretching relative to the original length, where higher values are an indication that the filament undergoes deformation but does not break. Maximum tensile strength is the maximal force recorded during filament elongation, above which fracture occurs (Tabriz et al., 2021). Toughness can be calculated as an area under the stress–strain curve up to the fracture point (Samaro et al., 2020). Although Korte and Quodbach demonstrated by tensile test successful printability when Young’s modulus exceeds 300 N/mm² and the elongation at break exceeds 1.125 mm (Korte & Quodbach, 2018b), Tabriz et al. (2021) recently showed that these parameters failed to distinguish printable from nonprintable filaments. According to Tabriz et al., maximum tensile strength was the most suitable parameter derived from the tensile test for determination whether the filament is printable or not (Tabriz et al., 2021). Nasereddin et al. (2018) proposed a screening test for the determination of filament feedability where the filament is compressed axially by moving probes of the texture analyzer with compression speed, which corresponds to roller rotation speed in the chosen commercial FDM 3D printer (Fig. 1.2B). Most of the feedable filaments did not break under compression but showed characteristic bending, with at least partial recovery after cessation of compression force. Most of the nonfeedable filaments exhibit brittle fracture with the absence of bending, plastic, or elastic deformation after reaching the maximum force. Some filaments that were too flexible to stand vertically during testing were also nonfeedable, as filaments deform when moving to the heated nozzle and block printing head (Nasereddin et al., 2018). Xu, Robles-Martinez, et al. (2020) compared three different texture analysis methods, the three-point bend test and the stiffness test, proposed in the Repka-Zhang method and the resistance test proposed by Nasereddin et al. (2018) (Fig. 1.2) in predicting the printability of filaments. Filaments with high toughness, brittleness, and resistance generally exhibited better printability, but toughness, calculated from the results of the stiffness test, was the only parameter that could distinguish printable from nonprintable filaments (P. Xu, Li, et al., 2020). Since there are no universally accepted scales for parameters that are used as indicators of feedability and/or printability, obtained values are commonly compared to those obtained for commercial printable filaments, such as PLA. Although some authors proposed threshold values for parameters that describe mechanical properties of the filaments, it should be borne in mind that filaments that are nonprintable on one type of 3D printer might be printable on some other printer.

Rheological properties of the material are of particular importance for both extrusion and the FDM printing process. Materials with high melt viscosity are difficult to extrude and the inclusion of additives or increase in processing temperature is often necessary to produce filaments. In addition, extrusion of these materials may result in the production of filaments with a rough surface and therefore increase the risk for printing failure (Bandari et al., 2021). The low shear rate in the printing head makes a melt viscosity as a more critical factor in the FDM 3D printing than in the HME step. During the FDM printing process, melt viscosity should be sufficiently low to allow uniform flow and avoid nozzle clogging but sufficiently high to ensure accurate material deposition according to the predefined design and to prevent the collapse of printed layers under the weight of succeeding layers (Parulski et al., 2021). Determination of the melt flow index (MFI) which represents the flow rate of material in the molten state is a useful parameter in the preformulation screening of material printability in FDM. MFI is determined by the capillary rheometer which closely resembles the design and shear force characteristic for the printing head of FDM printers (Fuenmayor et al., 2018; S. Wang et al., 2018). Wang et al. (2018) determined on commercial PLA grades that MFI should be greater than 10 g/10 min to achieve printability (S. Wang et al., 2018). Melt viscosity can be lowered by the setting of a higher printing temperature, but this can also increase the extent of drug degradation. The addition of plasticizers, such as PEG, polysorbate 80, poloxamers 188, triethyl citrate (TEC), triacetin, stearic acid, and sorbitol is a common approach to decrease melt viscosity and improve material processability by HME and FDM (Cailleaux et al., 2021). Plasticizers decrease polymer glass transition temperature (Tg) by embedding between the polymer chains and thus increase the mobility of the polymer chains and the free volume (Crowley et al., 2007). This enables processing by HME and FDM 3D printing at significantly lower temperatures and thus decreases the risk of thermal degradation. In addition, plasticizers improve filament flexibility and often enable printing with filaments that will otherwise break in the feeding mechanism. An excessive amount of plasticizer can make filament overflexible and unsuitable for printing due to deformation in the feeding mechanism (Nasereddin et al., 2018). In the printed products where a drug is in an amorphous state or dissolved in the polymeric matrix, a decrease of mixture Tg by added plasticizer, increases the risk for drug recrystallization, which may consequently affect drug dissolution rate and bioavailability. Pereira et al. (2019) demonstrated using of water as a temporary plasticizer, which can facilitate the HME process in the lower range of temperatures, but produced filaments were too flexible to be printed. Postprocessing of the filaments by drying removed the excess water and makes filaments less flexible and suitable for printing (Pereira et al.,