Analytical Approaches in 3D Printing Technology for Pharmaceutical Formulation Development & Printed Dosage Forms

What is 3D Printing:

3D Printing means the process which involves the formation of Three-dimensional solid objects from a computerized or digital (ordinal) files [1]. The process of Spraying or the laying down of additives continues unless successive layers Create an object. The thinly sliced horizontal cross-sections of the eventual object have been seen in every layer.

Terminology Related to 3D Printing (Drug Products:

The drug product in which the finished dosage forms like capsule, tablet, solution, emulsion, suspension, etc.) containing active pharmaceutical ingredients. 3D printing can fabricate other regulated products materials, which have well defined quality purpose & regulation [2].

Drug Development can be defined as an approach through which systems, technology, & formulation can be developed which helps to explicitly in drug transportation within the biological fluid & Successive desired biological effects [3,4]. With the increased development of science and technologies in the pharmaceutical field they have been new concepts in the design of drugs, manufacturing technology, processes, and for the better understandings which helps to achieve a high quality of dosage forms [5]. Within the last few decades, the development of drug product has been under study & numerous novel dosage forms and they technological process has been developed [6]. Noticeably in most of the cases special consideration was given for the physical-chemical properties of APIs and regulatory requirements during each stage of product development [7]. Now days different ethnic background, food habits, different circadian cycles, an inter-individual difference of patients propagates creates some enormous challenges for pharmaceutical scientists to deliver uniformity in medicine. They personalization of medicine is in hike for the last few years [8]. Over the years, scientists are stressing to optimize treatments according to the pharmacogenetics of the populations and individual pharmacokinetic profiles [9]. In the field of customized medicine 3DP technology is emerging out to the blockbuster in personalized medicine. Scientists are developing 3D printing technology as powerful tool for designing novel formulations and disease modelling [10]. Computer based drug design along with 3D printing technology quickens manufacturing of personalized pharmaceutical drug products [11]. Using inkjet printing, in which the semi-liquid binding solution was mixed with power bed to produces adhesive particles. The 3D printing pharmaceutical formulations are successfully prepared in recent years [12]. For obtaining the desired shape & size of the formulation, optimization of tools & techniques is pre-requisite. The first 3D printed drug that was approved by FDA (August 2015) is SPRITAM (Levetiracetam) [13]. In pharmaceutical applications, 3D printing allows for the design of dosage form that are not only functional but also highly personalized addressing individual patient needs & therapeutic requirements. A key driver for adopting 3D printing in pharmaceutical manufacturing is the growing demand for personalized medicine. Traditional drug formulations are generally manufactured in fixed doses, which may not be optimal for all patient populations. Inter individual variability in genetics, metabolism, age, weight, & disease states often necessary dose adjustment that are not readily available in standard commercial products. 3D printing enables the on-demand production of dosage forms with tailored drug quantity, release profiles, & physical characterisation, aligning with the principle of individualized therapy [14].

This customization is particularly beneficial for special populations such the paediatrics & geriatrics, where swallowing difficulties & variable dosing needs are common. For instance, flexible dosage forms like mini tablets, chewable tablets, Oro-dispersible films can be easily fabricated using 3D printing technology [15]. 3D printing supports the creation of complex and multi-functional dosage forms that are difficult or impossible to produce with conventional methods. This include polypills containing multiple active pharmaceutical ingredients (API) with compart mentalized release profiles, as well as devices engineered for site-specific or timed drug release [16]. The efficiency and flexibility of 3D printing also enhance the early stages of drug development. Traditional pharmaceutical manufacturing often requires extensive formulation trials and re-tooling which are time-consuming and resource intensive. In contrast, 3D printing allows researchers to rapidly prototype and rate dosage designs with minimal material wastage and reduced lead times [17]. This accelerated development process is especially valuable in clinical settings, compassionate use programs or market where demand for customized treatments is high but commercial incentives may be limited. Another significant advantage of 3D printing is its alignment with on demand & decentralized manufacturing models. As healthcare systems move toward localized treatment solutions & precision healthcare, 3D printing offers the potential for point-of-care drug manufacturing in hospitals, pharmacy, or even home settings [18]. This decentralized could mitigate supply chain disruptions, reduce storage needs & enable real time customization based on current patient data. Moreover, 3D printing opens avenues for integrating digital health technology into pharmaceutical care. Coupled with electronic health records, wearable sensors, & pharmacogenomic information, 3D printers could theoretically adjust dosage forms based on real time patient monitoring ushering in an era of smart medicine where therapy dynamically responds to physiological feedback [19].

Figure 1: 3D Printing Technology in Formulation Development & Dosage Forms.

Ongoing advancements in formulation science, material engineering, & regulatory policy are gradually addressing these limitations. As more data emerge regarding the stability, safety & efficacy of 3D printed dosage forms it is anticipated that the adoption of this technology will expand across the pharmaceutical value chain from research & development to manufacturing and Personalized delivery [20]. The referred to as additive manufacturing technique because of the process involved in its fabrication which generally includes deposition of material layer by layer till the end product is formed they formulation development & Dosage forms. In this technique solid 3D object is fabricated by deposition of multiple layers over layers of the required material (drug). The technique has capability to fabricate most of the typical dimensions, preparation of which was not possible by traditional methods. In first step of the 3DP structure is planned on digital 3D file using computer aided design (CAD) software which makes it easier to prepare complex designs. After preparation of digital file suitable 3D printer is used according to object requirements. Basically, there are four different technique which was adapted by pharma industry for preparing 3DP products such as fused deposition modelling (FDM), Stereolithography (SLA), selective laser sintering (SLS), & Zip dose [21]. In this review the focus has been done on certain 3DP technology that are suited for pharmaceutical designing suitability in the development of dosage forms. The broad regulatory acceptance & demonstration of technological viability in commercial production. They also focus on Analytical Methods or Aspects in 3DP for formulation Development & Printed Dosage Forms.

A. ADVANTAGES

1. New Formulations for Improved Drug: New Dosage Forms in the traditional method of drug preparation, some tablets are difficult to swallow. But with 3D printing, the pills can be designed according to the patient preferences [22].
2. Innovative Dosage Forms: Facilitates printing of porous, complex, or hollow structures not possible with conventional methods.
3. Accurate & precise dosing of potent drugs which are administered at small doses.
4. Reduces cost of production due to lesser material wastage.
5. High drug loading ability when compared to conventional dosage forms.
6. In case of multi drug therapy with multiple dosing regimen, treatment can be customized to improve patient adherence.
7. Narrow therapeutic window [23,24].

B. DISADVANTAGES

1. The 3D Printing technology is currently limited by size limitations.
2. Very large objects are still not possible when built using 3D printers.
3. Regulatory & GMP challenges – Lack of standardized global guidelines & complex quality control requirements [25].
4. Material limitations – few pharmaceutically acceptable excipients & API stability issues [26].
5. Low production speed, not suitable for large-scale manufacturing.
6. High costs & expertise needs – expensive equipment & skilled personnel shortage.
7. Slow production & scalability issues [27].

HISTORY OF 3D DRUG PRINTING TECHNOLOGY

3D Printing posed as a possible platform for personalized medicine in the 1990s. There are major achievements in 3D printed medical devices, FDA centre for device & Radiological Health (CDRH) has reviewed & cleared 3DP medical devices. In 1989, Scott Crump, field the patent on another 3D printing technology. Fused deposition modelling, where extruded polymer filaments heated into semi-liquid state were extruded through a heated nozzle & deposited into a build platform layer by layer to harden [28,29].

Table 1: Historical Development of the 3D Printing Technology [30].

WORKING OF 3D PRINTER

The basic process involves 3D prototyping of layer-by-layer fabrication to drug excipients to formulate into the desired dosage forms. It begins with making a virtual design is for instance CAD (computer aided design) file. This CAD file is created using a 3D modelling application or with 3D scanner (to copy an existing object). The 3D scanner can make the 3D digital copy of an object [31]. The Process OR working of the 3D Printer are specifically first in Design digitally in 3D dimensional with Computer Aided design software then conversion of the design to a machine readable, next process as raw material processing and then finally printing these layer by layer produced the desired product. After these removable & post processing the printing products may require drying sintering, polishing or other post processing steps. The 3D printer by taking design from computer, cut into thin layers, then printing those layers one by one using materials like resin. Each layer sticks to previous one until the full object is built. Then finally object may need little cleaning or finishing. The shortly Process of 3D drug printing in (Design, Slice, Print, Fuse, Layers, Finish product) [32].

• Steps Involved in 3D Printing
  1. Design: The intended product design is digitally rendered. Design can be rendered in Three-Dimensional with Computer Aided Design Software (CAD).
  2. Conversion of the design to machine readable: 3D Design are typically converted to the STL. File format, which describe the external surface of 3D model.
  3. Raw Material Processing: Raw material may be process into granules filaments, or binder solutions to facilitate the printing process.
  4. Printing: Raw materials are added & solidified in an automatic, layer-by-layer manner to produce the desired product.
  5. Removable & Post Processing: After printing products may require drying, sintering, polishing or other post processing steps.

3D DRUG PRINTING TECHNIQUES IN PHARMACEUTICAL FORMULATION & DOSAGE FORMS

There are numerous varieties of manufacturing practices intricate in 3D printing, which are grounded on digitally organized depositing of materials (layer-by-layer) to create free form geometries.

1. Thermal ink-jet printing.
2. Inkjet printing.
3. Fused Deposition Modelling.
4. Extrusion 3D printing.
5. Zip Dose Technology.
6. Hot Melt Extrusion (HME).
7. Powder bed 3D printing.
8. Stereo-Lithographic 3D printing.
9. Selective Laser Sintering.

[1] THERMAL INK-JET PRINTING

The thermal inkjet printing, the aqueous ink fluid is transformed to vapours state through heat, expands to push the ink drop out of nozzle [33]. It is used in the preparation of drug-loaded bio-degradable microspheres, drug-loaded liposomes, patterning microelectrode arrays coating, loading drug eluting stents [34,35]. Thermal inkjet printing (TIJP) is an advanced technique used in pharmaceutical formulation development & printed dosage forms. It works by rapidly heating a resister to generate a vapour bubble which ejects precise micro-droplets of drug solution or suspension into a substrate such as polymer films, tablets, or patches. This method enables accurate dose control & rapid prototyping & personalized medicine by adjusting drug quantity & combinations. TIJP is applied in Oro-dispersible films, surface-modified tablet & microdosing. It is also an efficient & practical method of producing films of biologics without compressing activity [36].

Figure 2: Thermal ink-jet Printing.

Table 2: Some of the drug prepared by Thermal ink-jet 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 substrate either in the form of continuous inkjet printing (CIJ) or Drop on Demand (DOD) printing, hence it provides high-resolution printing capability [37]. Advantages of inkjet printing is that it has low processing cost, rapid processing rates, generation of minimal waste, it gives CAD information in direct Write manner & its process material over large areas with minimal contamination [38].

Table 3: Some of the drug prepared by Ink-jet Printing.

Fused deposition modelling (FDM) is commonly used method in 3D printing the materials are softer or melt by heat to create objects during printing [39]. Fused deposition modelling 3D printing helps in manufacturing delayed release print lets without an outer enteric coating & also provides personalised medicines doses. The 3DP indicates some limitations for system like lack of suitable polymers [40]. Slow & ten incomplete drug Release, because of the drug remain trapped in the polymers, miscibility of drug & additives with the polymers used was not evaluated [41].

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.

Figure 3: Fused Deposition Modelling (FDM)

Table 4: Some of the Drug prepared by Fused Deposition Modelling (FDM)

This method the material is extruded from the automated nozzle into the substrate without any higher support material. It is only utilized to fabricate tablet containing Guaifenesin act as expectorating. The components that can be extruded are molten polymers, suspensions, semisolids, pastes [42,43].

Table 5: Some of the drug prepared by Extrusion 3D Printing

Zip dose is the world’s initial & only FDA-Approved, commercial-scale 3DP in current therapeutic areas for pharmaceutical manufacturing areas. It has distinctive digitally coded layering & zero compression practices, used for tablet formulation with large dosage & prompt dis integration. Hence it helps in overwhelming difficulty in swallowing [44]. Spritam-R (anti-epilepsy drug) is an oral dispersible tablet, that the marketed by

Pharmaceuticals based on powder bed fusion by layer-by-layer production system. In which it consists of the active ingredient, excipients & binder liquid to produce matrix tablet [45]. The first step, powder blending material thin layer are spread on conveyor belts. Then, they move to print fluid areas, where fluids are sprayed. The overall interaction of printing fluid & powder blend results makes thin layer of dosage form then this process is repeated several times & makes powder layer by layer. During each cycle end drying step is conducted to solidify the wet until doses at control temperature, relative humidity, & time. This technology liquid binder is sprayed into powder and makes uniform solid dosage form that reason that technology also called binder jetting 3D printing technology, also here wetting powder binds horizontally & vertically & makes layer by layer 3D structure that reason. The part of 3D printing. Finish Dosage forms are collected & unbound powder are removed by using air. The finished solid dosage form is like towel tablet [46].

1. Powdered Blend is deposited as single thin layer on a platform.
2. A binding fluid is deposited in bind this powered blend together.
3. Repeat 1 & 2 several times to add more layers based on the dosage to form a pill. 

Figure 4: Zip-Dose Technology Machine Process

5. 5. Process of formulate tablet using 3D printing Zip-Dose Technology
    

   

   [6] HOT MELT EXTRUSION (HME)

Hot melt extrusion (HME) is the method of melting polymer & drug at elevated temperature & the pressure is employed in the instrument sequentially for blending [47]. It is continuous manufacturing technique that involves feeding, heating, mixing & shaping [48]. In recent years, it has proved that hot melt extrusion capable to optimize the solubility & bioavailability of moderately soluble drugs [49].

Table 6: Some of drug prepared by HME

The technique powder jetting or power bed is used to spread thin layers of power & simultaneously applying liquid binder drops with the help of inkjet printers. The ink (binders & APIs binder solution) is sprinkled over a powder bed in 3D fashion to make the final product in the layer-by-layer fashion [50]. The adaption of this technique into pharmaceutical manufacturing is easier than other techniques as powder & binder solution are widely used in the pharmaceutical industry.

5. This method it has its own disadvantages as follows:

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

[8] STEREO-LITHOGRAPHY 3D PRINTING

This technique involves the curing of photosensitive materials (photo polymerization to produce 3D object. Scanning 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 and therefore layer formation is done. Post printing processing is usually required to further curve the final product to improve its mechanical integrity and to polish or remove the attached supports to the fabricated objects [51]. This technique however possesses a health hazard in the form of potential carcinogenic resins. This is very slow process in SLA printers are composed of an UV light beam. The form a laser which transfer the energy into a liquid photopolymerisable resin. The UV light beam is aided by baffles, axis X and Y to transverse the surface of the liquid resin in order to accurately represent the 3D model previously designed. When layer solidifies the lifting platform descends its position to the night of a new layer of a liquid resin, again beginning the procedure until manufacturing of 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 a human use with ability to solidify upon exposure to laser beam [52].

Figure 5: 3DP of Stereo-Lithography

[9] SELECTIVE LASER SINTERING

Selective leaser sintering (SLS) act as a way in the powder bed to bind. The leaser is designed to draw a specific pattern on the surface of the powdered bed during the printing process, thus creating a 3D structure. For example, Paracetamol is an Oro-dispersible tablet prepared by the manner. It currently used for industrial manufacturing of plastic, metallic and ceramic objects [53].

Figure 6: 3DP of Selective Laser Sintering

SLS Technology was invented by Carl Deckard & Joe Beaman in 1984 [54]. It is one of the latest & most advanced technology for the preparation of solid dosage forms. In this process, 3D objects are built by the fusion of powder particles which are selectively heated by the laser. SLS is manufacturing process involving a laser to selectively sinter the powder particles layer by layer to form the 3D object. The SLS printer consists of powder bed, powder reservoir & roller with a laser source. The powder containing drug & polymer is loaded in the powder reservoir & is spread evenly on the powder bed from the powder reservoir by the roller. Depending on the design of the object in the CAD file. The laser is directed to draw a specific defined pattern on the surface of the power bed & sinters the powder particles. After the first layer of the object is sintered the powder bed moves downwards & the powder reservoir moves upwards so that another layer of these a

Powder can be distributed on top of the first layer & hence printing the object layer by layer which can be recovered from the powder bed once it cools down [55]. The pharmaceutical grade polymers commonly used in SLS are polyethylene glycol, Kolli-coat IR, Kolli-don VA 64, polyvinyl alcohol, ethyl cellulose, hydroxymethyl cellulose [54]. In the pharmaceutical field SLS 3D printing has been recently used to prepare orally disintegrating tablets & immediate release tablet drug delivery lattice structures & drug delivery devices [56]. 

• Pharmaceutical Preparation OR Formulation That Were Developed by 3D Printing Technology

3D PRINTING IN PHARMACEUTICAL DOSAGE FORMS

[A] ORAL DOSAGE FORMS

Oral dosage forms belong to the most common dosage forms & include dosage forms that are swallowed & dosage forms that are placed in the oral cavity. Solid oral dosage forms for human use listed in the European pharmacopoeia include powders, granules, capsules, tablets, medicated chewing gums & Oro-mucosal preparations such as films & lozenges. Oral dosage forms identified from the literature tablets, pellets & minitablets, capsules, & films. Furthermore, dosage forms with a specific feature are described separately such as gastro-retentive dosage forms (GRDF) chewable dosage forms and other very specialized dosage forms including dental devices. In general, for oral dosage forms, 3D printing is mainly applied in order to individualize the dose of drugs to influence the drug release behaviour, or in some cases to promote patient adherence. The 3D printing techniques used for this purpose showed high variability. However, some trends were detectable such as the use of solvent-free techniques for Oro-dispersible forms and MEX methods for extended release peroral tablets. The excipients used for oral dosage forms are often classical excipients that are also used with established production methods. An exception from this was the printing of capsule shells for which mainly poly (VINYL ALCOHOL) was used an excipient as opposed to traditional capsules typically made from gelatine.

[1] TABLETS

Tablets are solid dosage forms containing a single dose often derived from powders or granules via compression but also other techniques as mol-ding or extrusion can be used. Tablets often have a cylindrical shape with either flat or convex end surfaces. Several characteristics regarding the disintegration & drug release behaviour as well as other properties or methods of administration may be used to differentiate among different types of tablets. The distinguishes between immediate-release & modified release the latter group is further divided into prolonged release (often also referred to as extended release) delayed release & pulsatile release for the purpose of this review the following categories will be distinguished: Oro-dispersible tablets (ODT), immediate release (IR) tablets, extended release (ER) tablets, and delayed-release tablets. Delayed-release tablets for this purpose are defined as tablets in which the onset of release has been modified. This group included gastro-resistant tablets. The differentiation between IR & ER tablets was based on the recommendations on dissolution testing [76]. Which specifies a typical acceptance criterion for IR tablets f 80% release within 45 min for the first test level. In additions the ph. Eur. Describes an IR dosage form as one that is not deliberately modified by a special formulation design & manufacturing method [77]. It also mentions that for solid dosage forms the dissolution profile of the active ingredient essentially depends on the intrinsic properties. This means that even comparatively slow release can be classified as immediate release dosage forms if they contain for example, active ingredients that possess low dissolution speed.

[2] PELLETS & MINITABLETS

While pellets & minitablets describes different dosage forms & their conventional production is very different, they will be described together in this review due to their similar dimensions and the resulting requirements & challenges. The related manuscripts are also listed together in the supplementary materials A & B shows two examples of dosage forms belonging to this category. The 3D printing of pellets & minitablets is an alternative, additive manufacturing method. The size of the dosage forms is challenges for

The process depending on the additive manufacturing technique chosen. Sizes of less than 2 mm, for example, which are required for unimpeded passage through the pylorus even in the fed stomach state with given mechanical stability pose challenges for some printing methods [78].

[3] CAPSULES

Capsules are single-dose solid pharmaceutical dosage forms which are usually intended for oral administration. The distinguishes between hard & soft capsules. Traditionally, capsule shells for hard capsules are usually manufactured industrially using the dipping pin process. The animal product gelatine is mainly used but vegan & vegetarian alternatives such as Hypromellose and pullulan are also used [79]. Soft capsules are formed and filled in single production step. PVA & PLA based filaments not only promise a certain potential for the printing of dosage forms for humans in addition to their already established application in technical 3D printing but could also be used for the production of veterinary medicines.

Figure 7: 3D Printed Pellets & Capsules

[B] PARENTERAL DOSAGE FORMS

Defines parenteral as sterile preparations designed to be administered via injection, infusion, or implantation & distinguishes between injections, infusions, concentrates for injections or infusions, powders for injections or infusions, gels for injection, implants & intravitreal preparations. Parenteral dosage forms include liquid, semi-solid & solid dosage forms. For the 3D printing applications solid dosage forms are relevant even though during the printing process often semi-solid states are necessary.

Figure 8: 3D Printed Parenteral Dosage Forms

ANALYTICAL ASPECTS OF [3D PRINTING FOR FORMULATION DEVELOPMENT & DOSAGE FORMS]

1. Pre-Formulation Analytical Approaches
2. In-Process Analytical Approaches
3. Post-Printing Analytical Approaches

[A] PRE-FORMULATION ANALYTICAL APPROACHES

Pre-formulations studies aim to evaluate the compatibility, stability, & printability of APIs & excipients before printing. Pre-formulation is the first step in the drug development process. It involves the systematic evaluation of the physicochemical & biopharmaceutical properties of a drug candidate (API) & excipients to design a stable, effective, & manufacturable dosage forms. Analytical approaches in pre-formulation help identify potential formulation challenges early & guide the development strategy. (Key Analysis: Solubility Studies, pKa Determination, Partition Coefficient (Log P/Log D), hygroscopicity, Polymorphism & Crystallinity, Particle size & Morphology etc. [80].

[1] THERMAL ANALYSIS: Differential Scanning Calorimetry (DSC): Evaluates melting point, glass transition temperature, and crystallinity. Determines suitable printing temperatures & polymer selection. Thermogravimetric Analysis (TGA): Monitors thermal stability & decomposition temperatures to prevent API degradation during printing.

[2] SPECTROSCOPIC TECHNIQUES: Fourier Transform Infrared Spectroscopy (FTIR): Detects interactions between APIs & excipients. Raman Spectroscopy: Maps API distribution in polymer blends at microscopic levels. Near-Infrared (NIR) Spectroscopy: Allows rapid evaluation of content uniformity & excipient distribution.

[3] CRYSTALLINITY & MORPHOLOGY: X-Ray Diffraction (XRD): Determines crystalline versus amorphous state of APIs. Scanning Electron Microscopy (SEM): Analyse particle size, shape & surface morphology.

[4] RHEOLOGY & PRINTABILITY ASSESSMENT: Rheological studies assess Viscosity, Flow Behaviour, & Filament Extrusion Properties for FDM & SSE. Ensures optimal printing fidelity, prevents nozzle clogging, & maintains layer uniformity. Critical for FDM & SSE techniques to ensure layer deposition accuracy.

Table 7: Pre-Formulation Analytical Techniques

In-Process analytical monitor real-time printing quality & minimize batch variability & Maintain Consistency & detect defects.

[1] REAL-TIME MONITORING TECHNIQUES: Process Analytical Technology (PAT) the Integrates sensors for temperature extrusion pressure, & layer deposition monitoring. NIR & Raman Spectroscopy the allows non-destructive, in-line monitoring of API content & uniformity across printed layers. Optical/imaging systems the detect structural defects, layer misalignment, or void formation during printing.

[2] RHEOLOGY & FLOW MONITORING: Continuous monitoring of filament extrusion or semi-solid flow ensures print precision. Essential for preventing defects like layer gaps, uneven dosing, or nozzle clogging.

Table 8: In-Process Analytical Techniques