A Review and Experimental Study on 3D Printed Pharmaceutical Tablets

The 3D Printing technology has caught the attention of medical devices industry and pharmaceutical industry due to its application on various platform in health care industry. 3D printing technology promises a future of drugs & medicine printed on demand, personalized with customized doses. The potential of 3D printing is about being able to deliver what you want, how much & when you want.This technology will definitely help Doctors & pharmacists to provide “Tailor made” medicine for each patient.^(1,13)

3D printing in pharmaceutical drug delivery would excel greatly in the domain of personalized medicine, where the medication could be customized as per the need of treatment, & not “one fits all” approach. 3D printing can play a significant role in multiple active ingredients dosage forms, where the formulations can be as a single blend or multilayer printed tablets with sustained release properties. This reduces the frequency and no. of dosage forms units consumed by the patient on a daily routine. 3D printing technology has high potential in individualized dosage forms concept called the polypill concept. This brings about the possibility of all the drugs required for the therapy into a single dosage form unit.^(1,11)

Three dimensional printing technology is a novel rapid prototyping technique in which solid objects are constructed by depositing several layers in sequence. The rapid prototyping involves the construction of physical models using computer – aided design in three dimension. It is also known as additive manufacturing and solid free form fabrication.3D printing relies on computer aided designs to achieve almost flexibility, time saving, & exceptional manufacturing capability of pharmaceutical medicines which can be utilized in personalized and programmed medicine.⁽¹⁾

Challenges in the mass production of dosage forms and limitations in the availability of different types of dosage forms have all restricted the traditional pharmaceutical manufacturing process. However, a game-changing technology that can get beyond these restrictions is 3D printing. 3D printing holds enormous potential for personalized medicine, complex medication formulations, and customized dosages by utilizing computer-aided design (CAD) models and exact layer-by-layer deposition of active pharmaceutical ingredients (APIs).⁽²⁾

Long-standing mass production techniques have been used in the pharmaceutical manufacturing process, which has limited dosage forms and delayed medication delivery. But a ground-breaking innovation called 3D printing has arisen as a disruptive force that can get through these restrictions.^(2,4)

The potential for 3D printing to revolutionize the pharmaceutical business is enormous because it allows for precise layer-by layer deposition of active pharmaceutical ingredients and the use of computer-aided design models. This novel strategy gives up fresh possibilities for complex pharmacological formulations, personalized dosing, and personalized therapy.⁽⁵⁾

Furthermore, 3D printing technology makes it easier to produce complicated medicine compositions that were previously difficult to make using traditional techniques. Since several pharmaceuticals can be combined into a single dosage form by the layer-by-layer deposition of APIs, complex diseases or disorders that call for a cocktail of treatments can be treated more successfully. Additionally, 3D printing’s fine control enables the creation of drug delivery systems with unique release profiles, guaranteeing precise dosing and lasting therapeutic benefits.⁽²⁾

HISTORY

The concept of three-dimensional printing (or 3DP) originated in the early 1970s when Pierre A. L. Giraud described applying powdered material and then solidifying each layer using a high-intensity beam. In this scenario, melting materials like plastic or metal might hypothetically be utilized to prepare the object. Early in the 1980s, Ross Householder described the idea of binding sand with various materials in a patent entitled “A molding process for forming a three-dimensional article in layers”, and Carl Deckard created a technique for solidifying powdered beds with laser beams known as selective laser sintering (SLS). Stereo lithography (SLA) was the first technique that Chuck Hull developed and marketed .This technique was based on the UV light-induced photo polymerization of liquid resin .For fused deposition modelling (FDM), a process that utilized thermoplastic material for object preparation, Scott Crump submitted a patent at the end of the 1980s. Emanuel Sachs, an MIT scientist, developed “Three-dimensional printing techniques” in the 1990s based on combining the chosen powder regions with a binding substance.^(4,6)

The Advantages of 3D Printing Technology in Pharmaceuticals

1. Personalized Medicine for Special Populations

 The health and safety of medication for special populations such as the elderly and children has long been an issue of concern. Children are in a period of growth and development and have a particular reactivity and sensitivity to medication; the elderly have a reduced absorption and metabolism capacity, and the coexistence of multiple diseases and combined medication is very common.  Where as current drug dosages are standardized, there are few specialized drugs for special populations, and children’s medication is often administered by manually breaking tablets, which is not only inaccurate but may also damage the particular structure of the preparation and cause adverse reactions. Three-dimensional printing technology is highly flexible and can be used to print targeted medicines by adjusting model parameters such as size, shape, or fill rate. For pediatric patients, 3D printing technology can be used to produce low-dose personalized medicines suitable for children, and can also be used to improve the appearance and taste of the medicines to increase the compliance of pediatric patients ; for elderly patients who have difficulty swallowing, 3D printing technology can prepare loose and porous preparations, thus, helping them to take medication; for patients who take multiple drugs at the same time, different drugs can be partitioned and combined into a single tablet to avoid errors or missed drugs, which can increase the safety and effectiveness of medication; in addition, specially shaped preparations can be printed or special symbols can be printed on the surface of the preparation to provide convenience for patients with visual impairment . The advantages of 3D printing technology for personalized drug delivery provide technical support for people to achieve personalized medicine, and some 3Dprinted drug companies are moving towards the goal of personalized medicine, such as Fab Rx in the UK, which prepares personalized drugs for children with maple diabetes, and has placed SSE printers in the pharmacy of a Spanish hospital and conducted clinical trials on the subject. ^(3,7)

2. Precise Control of Drug Release

 As the most widely used solid oral dosage form, tablets account for 70% of all dosage form production. Traditional manufacturing processes enable tablets to be produced at a lower cost, but they have been less creative in preparation development, with long development times and less ability to manufacture personalized preparations on demand. Compared to conventional tablets, controlled-release preparations allow for precise control of drug release, avoiding side effects and improving efficacy. However, traditional manufacturing processes pose greater challenges in the development and manufacture of controlled-release preparations due to their limitations. Three-dimensional printing technology is highly flexible and is well suited to the development and manufacture of complex preparations through the combination of different drugs, the design of complex models, and the adjustment of printing parameters.

For example, Tri astek’s 3D printed product, T19, which received IND approval from the FDA in January 2021, is a controlled release preparation designed for the circadian rhythm of rheumatoid arthritis, where patients take it at bedtime and blood concentration peaks in the morning with the most severe symptoms of pain, joint stiffness, and dysfunction, and maintains daytime blood concentration for optimal therapeutic effect, providing better medication options for patients.⁽³⁾

AIM AND OBJECTIVE

Aim

To explore and develop 3D printing technologies for pharmaceutical applications, focusing on creating personalized drug delivery systems that improve patient compliance, therapeutic efficacy, and manufacturing efficiency in the pharmaceutical industry.

Objectives

1. Technology Exploration:
   • To study different 3D printing techniques (e.g., Fused Deposition Modeling, Inkjet Printing, Stereolithography) applicable in pharmaceuticals.
2. Personalized Medicine:
   • To design patient-specific dosage forms with controlled release, multi-drug combinations, or complex geometries that conventional methods cannot easily achieve.
3. Material Selection:
   • To evaluate suitable pharmaceutical-grade polymers, excipients, and active pharmaceutical ingredients (APIs) for compatibility with 3D printing.
4. Formulation Development:
   • To optimize process parameters (temperature, layer thickness, printing speed) for achieving uniformity, stability, and reproducibility of 3D-printed dosage forms.
5. Therapeutic Efficacy:
   • To assess the drug release profile, bioavailability, and stability of 3D-printed formulations compared to conventional dosage forms.
6. Regulatory & Industrial Feasibility:
   • To identify regulatory considerations, scalability, and cost-effectiveness of integrating 3D printing in pharmaceutical manufacturing.
7. Case Application:

• To highlight examples like Spritam® (first FDA-approved 3D-printed drug) and explore potential applications in orphan drugs, pediatrics, geriatrics, and polypills

DESIGN OF 3D PRINTING TECHNOLOGY

WORKING OF 3D PRINTER  

The basic process involves 3D prototyping of layer by layer fabrication to drug excipients to formulate into the desired dosage form. It begins with making a virtual design is for instance a CAD (Computer aided Design) file. This CAD file is created using a 3D modelling application or with a 3D scanner (to copy an existing object). A 3D scanner can make a 3D digital copy of an object.

Steps involved in 3D printing:

Design : The intended product design is digitally rendered. Design can be rendered in 3 dimensional with Computer Aided Design Software (CAD)

Conversion of the design to a machine readable:

3D design are typically converted to the STL file format, which describe the external surface of a 3D model.

Raw material processing: Raw material may be proceed into granules filaments, or binder solution to facilitate the printing process.

Printing: Raw materials are added and solidified in an automatic, layer –by-layer manner to produce the desired product.

Removable & post processing: After printing products may require drying, sintering, polishing or other post processing steps.

Techniques in 3D Printing

3D printing includes a wide variety of manufacturing techniques, which are based on digitally – controlled depositing of material (layer- by – layer) to create freeform geometries.

The widely used 3D printing technologies are as follows:-

1. Thermal inkjet printing.
2. Inkjet printing
3. Fused Deposition Modelling
4. Extrusion 3D printing
5. 3D printer
6. Hot Melt Extrusion (HME)
7. Powder bed 3D printing.
8. Stereo-lithographic 3D printing

 1. THERMAL INKJET PRINTING

In thermal inkjet printing, the aqueous ink fluid is converted to vapour form through heat and expands to push the ink drops out of a nozzle. It is used in the preparation of drug loaded biodegradable microspheres, drug loaded liposomes, pattering microelectrode arrays coating and loading drug eluting stents. It is also an efficient and practical method of producing films of biologics without compressing activity.

Fig. 1: Thermal Inkjet Printing

Table 1- Some of the drug prepared by Thermal Inkjet Printing

2. INKJET PRINTING

Inkjet printing is also called as ‘mask-less’ or ‘tool-less’ approach because the formation of desired structure mainly depends upon the movement of inkjet nozzles or movement of the substrate for an accurate & reproducible formation. 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 capability. Advantages of inkjet printing is that it has low processing cost, rapid processing rates, generation of minimal waste, it gives CAD information in a ‘ direct write’ manner & it process material over large areas with minimal contamination.

Fig. 2: Inkjet printer

Table 2 –Some of the drug prepared by Inkjet Printing

3. FUSED DEPOSITION MODELLING

It is an commonly used technique in 3D printing, in which the materials are soften or melt by heat to create objects during printing. There are several dosage forms available by using FDM. FDM 3D printing helps in manufacturing delayed release print lets without an outer enteric coating, & also provides personalised dosed medicines.

Limitations –  

FDM 3D printing indicates several limitations of the system,

• • • Lack of suitable polymers
    • Slow & often incomplete drug release because the drug remains trapped in the polymers & the miscibility of the drug & additives with the polymers used was not evaluated

Fig .3: Fused Deposition Modelling (FDM)

Table 3 – Some of the drug prepared by Fused Deposition Modelling (FDM).

4. EXTRUSION 3D PRINTING

Extrusion is the most widely used 3D printing technology. In an extrusion process, material is extruded from robotically –actuated nozzles. Unlike binder deposition, which requires a powder bed, extrusion methods can print on any substrate. A variety of materials can be extruded for 3D printing, including molten polymers, pastes & colloidal suspension, silicones, & other semisolids. A particularly common type of extrusion printing is fused filament fabrication (FFF). It is only used to fabricate tablet containing Guaifenesin as expectorant.

Table 4- Some of the drug prepared by Extrusion 3D printing

5. 3D PRINTER :

3D printer is a valuable tool which is used to create customized medication with tailored release profiles & the medication is changed as per the patient comfort.

Fig.4: 3D Printer.

Table5- Some of the drug prepared by 3D printer technology

6. HOT MELT EXTRUSION(HME):

Hot melt extrusion is the process of melting polymer & drug at high temperature & the pressure is applied in the instrument continuously for blending. It is a continuous manufacturing process that includes several operations such as feeding, heating, mixing, & shaping. In recent years, it has proved that HME has the ability to improve the solubility&  BA of poorly soluble drugs. 

Fig.5 – Hot Melt Extrusion

Table 6 - some of the drug prepared by HME

7. POWDER BED 3D PRINTING:

Hot melt adhesion In that technique powder jetting or power bed is used to spread thin layer of power and simultaneously applying liquid binder drops with the help of inkjet printers. The ink (binders & APIs binder solution) is sprinkled over a powder bed in 2D fashion to make the final product in a layer-by-layer fashion. The adaption of this technique into pharmaceutical manufacturing is easier than other techniques as powder and binder solution are widely used in the pharmaceutical industry. This method is has its own disadvantages as follows-

• • • Additional drying is required to remove solvent residues.
    • Excess powder accumulates during printing leading to wastage.

Polypill concept

The polypill is also known as “zip dose”. It refers to a single tablet that includes the combination of several drugs. This concept is highly beneficial for geriatric population, as patient of this age category are prone to multiple disorders and hence multiple therapy.

The technology has been realised through the research of Khalid et al, where 5 different active pharmaceutical ingredients (APIs) with different release profiles have been formulated in a single 3D dosage from. Three drugs (pravastatin, atenolol, & ramipril) were printed in the extended release compartment. The drugs were physically separated by a permeable membrane of hydrophobic cellulose acetate.

Fig.6: 3D printed polypill

An immediate release compartment containing aspirin and hydrochlorothiazide was deposited on top of the extended release compartment.

8. STEREO-LITHOGRAPHIC 3D PRINTING

This technique involves the curing of photosensitive materials (photo polymerization to produce a 3D object. Scanning a focused UV laser over the top of a photopolymerisable liquid is a layer-by-layer fashion, SLA employs a digital mirroring device to initiate a chemical reaction in the photopolymer which causes the gelation of the exposed area. This process is repeated layer after layer to build the entire part of the object. This occurs as unreacted functional groups on the solidified structure in the first layer polymerises with the illuminated resin in the next layer insuring adhesion & therefore, layer formation is done. Post printing processing is usually required to further curve the final product, to improve its mechanical integrity & to polish or remove the attached supports to the fabricated objects. This technique however possesses a health hazard in the form of potential carcinogenic resins. This is also a very slow process.

SLA printers are composed of an UV light beam, in the form of a laser, which transfer the energy into a liquid photo polymerisable resin. The UV light beam is aided by baffles, axis X&Y, to transverse the surface of the liquid resin, in order to accurately represent the 3D model, previously designed. When a layer solidifies, the lifting platform descends its position to the night of a new layer of a liquid resin, again beginning the procedure, until the manufacturing of the 3D product is finished in a layer –by-layer way. Here thickness of the cured layers depends upon the energy of the UV light to which resin exposed. The resin should be FDA approved for human use with the ability to solidify upon exposure to laser beam.^(1,4,5)

Fig.7: Stereo lithographic 3D printing