As aconsequence, the complexities of the manufacturing process, particularly forcomplex dosage forms, are often not recognized Yu,2008. As the major goal ofusing SFF techniques is to produce individual dosage forms, these could pushthe boundaries of mass medication to personalized medicine. Probably due to theincreased interest of therapeutic biological and sensitive (e.g. anticancerdrugs) molecules, which often need specific formulation processes, the FDAinitiated quality-by-design and processanalytical technology in 2003 to buildquality into the product right from the beginning of the manufacturing.

Thiswas done to decrease unpredictability in scaling up and rejection of batches thatdo not comply with specification, and consequently to increase effectiveness bydecreasing cost Charro et al., 2012. Such an approach is more suitable foridentifying critical process parameters of new manufacturing methods, such asthree-dimensional printing. In the future, much effort should be made to adaptgood manufacturing practice, standard of operating procedures and qualitycontrol to individual production lines.

Nevertheless, the recent approval of theprinted product Spritam® by the FDAdemonstrates that the industrial production of a printed drug delivery systemis already possible and recent developments of 3DP technologies seems to indicatethat both improvement of the current SFF processes to make adjustment of theactual formulation limitations and the ability to industrially produce printeddrug delivery systems will be achieved.  dosage forms totargeted-release drug delivery systems. Indeed, the necessity of controllingthedrug releaseprofile to modulate the absorption, the distribution, the metabolization andtheelimination ofthe drug rapidly appeared as a key factor for improving product efficacy andsafety as well as to increase the compliance of the patients.Therefore,conventional fabrication methods used to produce immediate-release systems(e.

g.directtableting, capsule filling) progressively evolved towards multi-stepmanufacturingtechnologies,including granulation, extrusion or coating processes, to allow the developmentofcontrolled-releasesystems. Then, due to recent advances in biotherapy and personalized medicine,novelconcepts of formulation have emerged (e.g.

nano-scale medicines, biomimeticparticles, functionalized liposomes) as well as more sophisticatedmanufacturing methods. In parallel, the development of new carriers seems to bemandatory to reach individualized treatments but it could lead to industrialissues due to safety and regulatory considerations.Nowadays, globalregulatory, manufacturing and consumer trends are driving a need for change in currentpharmaceutical sector business models, with specific focus on the inherentlyexpensiveresearch costs,high-risk capital-intensive scale-up and the traditional centralized batchmanufacturingparadigm. Rapid prototyping (RP) naturally appeared to be an essential tool inresearch anddevelopment area to fit with actual industrial directions of reducing both timeandcosts in theearly stage of a novel manufacturing concept, reducing the inherent risk of newdevelopment tofail at later stages.Originally, RPwas developed to produce prototypes of new products to increase the speed ofproductionsignificantly, especially during the development stage Melchels et al.

, 2010.Today,RP could easilybe confused with the general term “3D printing process” (3DP), which is one ofthe numerousexisting RP techniques. Therefore, RP should preferably be defined as anumbrellaterm thatincludes a plethora of manufacturing processes using three-dimensional computeraideddesign (CAD)data where no tooling is required Wang et al 2013. Because all RP techniquesarebased ondigitally-controlled depositing of materials layer-by-layer to create freeformgeometry,RP could bereferred as additive manufacturing (AM) or, more preferably, as solid freeformfabrication(SFF) processes.In order tobetter define RP, the common element in all the SFF techniques – i.e. how alayeredsolid structureis designed – may be used.

Briefly, underlying all current RP techniques is theconstruction ofa CAD model, which is exported in rapid prototyping stereolitography (.stl)file5format. Whilethe CAD-file describes the geometry and size of the parts to be built, the .stlformatfile lists thecoordinates of triangles that together make up the surface of the designed 3DstructureMelchels etal., 2010. The RP machine then processes the .

stl file by creating slicedlayers of themodel. Threedimensions are built by subsequent overprinting and, when the first layer isdeposited, themodel is reduced by the thickness of the next layer. The process is repeateduntilcompletion ofthe desired structure; for this to work, every layer must solidify.The first RPmethod became available in the early ’90s from Sachs et al.

at MIT (Cambridge,MA)Sachs et al,1993. It was used to produce prototype models quickly, easily, cheaply andautomatically.They patented a powder-based freeform fabrication method in which, using astandard inkjetprint head, binders are printed onto loose powders in a powder bed. In the abstractof their patent,the authors described their technique as “a process for making a component bydepositing afirst layer of a fluent porous material, such as powder, in a confined regionand thendepositing abinder material to selected regions of the layer of powder material at theselectedregion. Suchsteps are repeated a selected number of times to produce successive layers ofselectedregions of boundpowder material so as to form the desired component. The unbound powdermaterial is thenremoved”.

This invention aimed to increase industrial productivity as well ascompetitivenessby reducing the time needed to make a new product flexibly in small quantities.Due to the easeof utilization and the evident economic benefits of RP, more than 30 differenttechniques havebeen applied in diverse industries such as plastic, wood, ceramic or metalproductmanufacturingChu et al., 2008. Charles Hull isconsidered the pioneer of 3D printing, as hedeveloped, patented andcommercialized the first apparatus for the3D printing of objects in the mid1980s10–12, as well as developedthe STL file format that interfaced withexisting CAD software. Hull’stechnique,stereolithography (SL), consists of a laser that movesacross the surface of aliquid resin, curing the resin, before the stageis again submerged to allow forthe curing of another layer; thisprocess isrepeated layer by layer until the desired geometry isprinted.Thebasic needs of a man are food, Shelter, Clothes. But is it really in thesedays? No. Not for sure.

Because no man is satisfied with what they have. Peoplehave always been wanted and needed something extraordinary. This is why may bewe are at the stage of where we are. In the world of computers andtechnologies. Everything is getting computerized at this stage. Man hasachieved so much with the god gifted brains that we can see the satellite fromhome.

           If we focus onto medical field,technology has changed medical field too very extensively. People startedtreating themselves not in the hospital but at their own houses. Pharmaceuticalcompanies and researchers have made the medical solutions easier for peoplebyintroducing 3D Printing.3D printing is also known as additive manufacturing 3D printing is the type of manufacturing oftablets or capsules, or a dosage by composition of chemistry with high accuracyand precision to cure disease. There are three most common Printer technologiesin medical applications : Selective laser Sintering, Thermal Inkjet printing&  Fused Deposition Modeling. Thereare about two dozen 3D printing processes, which use varying printertechnologies, speeds, and resolutions, and hundreds of materials.9 These technologies can build a 3D object in almost anyshape imaginable as defined in a computer-aided design (CAD) file.

            It is a prototyping technology thathas advantages of customizing solid dosages.3D Printing is flexible and Timesaving for not only to the pharmaceutical companies but also for generalpeople. This also gives ease manufacturing in pre formulation to validate drugdelivery. The ability to modulate the dose simply by adjusting the volume ofthedosage form without modifying the formulation reveals real advantages. 3DPshould already be interestingly used in pre-development or pre-clinicalandclinical studies.

Formulation3Dprinting involves making solid objects from a digital file by thinly sliced,horizontal layers in any shape. Atthe first, visual design of the drug creates using CAD software or animationmodeling software. Then the file is sent to the 3D printer. The 3d printerthrows material softly on the build plate and creates layers. Within the powderit drops liquid into the material to createsdherence to the final product onthe build plate.

FDAapproval of the first3D printed tablet, Spritam_, there is now precedence set for theutilizationof3D printing for the preparation of drug delivery systems. The capabilities fordispensing low volumes withaccuracy,precise spatial control and layer-by-layer assembly allow for the preparationof complexcompositionsand geometries. The high degree of flexibility and control with 3D printingenables thepreparationof dosage forms with multiple active pharmaceutical ingredients with complexand tailoredreleaseprofiles. A unique opportunity for this technology for the preparation of personalizeddoses toaddressindividual patient needs.

This review will highlight the 3D printingtechnologies being utilized forthefabrication of drug delivery systems, as well as the formulation and processingparameters forconsideration.This article will also summarize the range of dosage forms that have beenprepared usingthesetechnologies, specifically over the last 10 years.AdvantageThe benefits of using additive manufacturing techniques fordosage form design include the ability to accurately control thespatial distribution of an active pharmaceutical ingredient (API)within a dosage form, produce complex geometries, deposit verysmall amounts of API, reduce waste and allow for rapid fabricationofvarying compositions to allow for screening activities orpreparationof individualized dose strengths5–8. Business incentivesassociatedwith printing pharmaceuticals include moving away fromtraditionallycomplex, slow and expensive supply chains, reducing manufacturingand inventory waste, as well as allowing for moreindividualized dosage forms (i.

e. varying dose strengths) withouttheneed for a high volume manufacture9.Formulation3D inkjet printing and FDM techniques have found their way intodrug product research and development. The implementation ofthese technologies in dosage form design has spurred thefabricationof novel, multifunctional and customizable dosage forms.

3D inkjet and 3D powder bed printingInkjet printing is based on the Lord Rayleigh’s instability theorydeveloped in 1878, which explains the breaking of a liquid streamorjet into droplets17. This concept was used to develop continuous jet(CJ) and drop on demand (DOD) printing, both of which are used intraditional desktop printing18. CJ printing utilizes apressurized flowto produce a continuous stream of droplets. The droplets arecharged upon exiting the nozzle and directed by electrostaticplatesto the substrate or to waste to be recirculated, as shown in Figure 1.DOD is considered more precise and less wasteful in that it canproduce droplet volumes as low as 1–100 pL at very high speeds,but only as needed. The two most common types of actuation withDOD printing are thermal (sometimes called bubble) and piezoelectric.

Micro-electro-mechanical systems, electrostatic and othermethods of droplet actuation are available or under investigationbut will not be discussed here.A thermal print head utilizes a resister that upon receipt ofelectrical pulses rapidly heats and forms a vapor bubble in theinkreservoir, as shown in Figure 2(a).This bubble then forces ink out ofthe print head; the bubble then collapses, producing a negativepressure that draws ink from the reservoir to refill the chamber.Thermal inkjet printing can produce high local temperatures nearthe resistor.

Although the short duration and small contact areamakes thermal degradation of the ink a low risk, it is somethingtobe considered. Additionally, the thermal print heads requirethe useof a high vapor pressure orvolatile solvent, which may limit itspharmaceutical application7.Piezoelectricprint heads utilize a piezoelectric element, such ascrystalor ceramic that produces a mechanical movement when avoltageis applied, as shown in Figure 2(b). The deformation of theelementcreates a pressure wave that ejects the fluid from thenozzle20. Piezoelectric printing hasbeen shown to allow for morecontrolof droplet formation and does not operate by heatgeneration,making it more desirable for use in drugdevelopment4,21.

3Dpowder bed printing is the deposition of a liquid or ”ink” ontoapowder bed to bind the powder. The powder bed is then lowered,a newpowder layer is spread, and the process repeated to bindpowderlayer-by-layer to produce the final geometry, as shown inFigure 3.Formulation and process parameters for consideration3D inkjet printing can be separated into three parts: (1)dropletformation, (2) droplet impactand spreading and (3) drying orsolidification.

Note that the majority of DOD printing conductedforpreparation of pharmaceutical dosage forms utilizes piezoelectricactuation, as thermal actuation requires the use of high vaporpressure or volatile materials. Droplet formation is a complexprocess, which is influenced by fluid viscosity, density andsurfacetension, among other factors.Many dimensionless values have beendeveloped to predict fluidbehavior, including Reynolds (Re),Weber(We), and Ohnesorge (Oh) numbers, shown in Equation (1),Equation (2), and Equation (3), respectively. The inverse of theOhnumber, Z¼1/Oh, as a function of Re number was used to defineareas for stable drop generation and We number was used todetermine areas where energy was sufficient to eject a drop fromthe nozzle19,22,23,as represented in Figure 4. Generally speaking, Zvalues of 1–10 are classified as printable fluids23.

Hon et al.summarized some of the performance and fluid properties usedwith typical commercial inkjet systems, which is shown in Table 124.Reynolds (Re) numberRe ¼__a_ð1ÞWeber (We) numberWe ¼_2_a_ð2ÞEarly work with 3D printing of tablet dosage forms was conductedusing 3D powder bed printing5,8,80. Katstra et al.

highlightedtheability to achieve appreciably low drug deposition, measuring 10_12moles or 0.34 ng per droplet, using a 10.6 mg/mL activesolution. Healso conducted physical characterization of the resulting tabletsshowing the ability to obtain comparable hardness and friabilitytoDRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1023compressed dosage forms byincreasing polymer/binder concentrations8; however, 3D inkjet printinggenerally produces moreporous and therefore morefriable tablets that those prepared bycompression81.The increased porosity with 3D inkjet printing hasbeen attributed to incomplete interaction with the printed bindersolution, leading to areas of ”unbound” particles18.ApreciaPharmaceuticals took advantage of this increased porosity tocreateorodispersible tablets that rapidly dissolve (10 s) withverysmall amounts of water (15 mL or less)82. Their patented ZipDose_technology is adapted from the powder bed printing technologydeveloped at MIT and boasts the ability to support drug loading upto 1000 mg.

This technology led to the development and approvalofSpritam_ (levetiracetam) for the treatment of epilepsy,particularlyin pediatric and geriatric patient populations that havedifficulty swallowing tablets. The rapid dissolution allows forrapidonset of action with Tmaxachieved in as little as 9 min82.Rowe et al.

emphasized theability of 3D fabrication to producecomplex dosage forms byproducing tablets with IR and extendedrelease (ER) components, delayedrelease, pulsatory drug release,inclusion of multiple APIs, andbreakaway tablets that generatesmaller fixed geometries withtailored erosion rates5. Using thisflexibility for the printing ofgeometries that are not readilyprepared through tabletcompression, Yu et al.prepared tablets ina doughnut shape, as shown in Figure 783.

This shape had beenpreviously shown to produce zero-order release by controllingsurface area during erosion84,85; however, manufacturing thesetablet geometries required complex compression processes. Yuet al. made a structure with the top and bottom layers comprisedethylcellulose (EC) to produce impermeable layers; the inner corewas prepared using an active blend of acetaminophen (APAP) withthe binder used for the outer surface (shown in gray in Figure 7)consisting of 2% EC to create a slower release rate from the outersurface. 3D inkjet printing allowed for the fabrication of verythin,but functional barrier layers on the top and bottom, as well as anEC-containing outer surface. Theoretically, this geometry allowsforthe decrease in the surface area due to the outward releasingportion and the increase in the surface area of the inward releasingportion to be more synchronized to produce a zero-order release.Zero-order release was seen for the printed tablet with thereleaserate varying with the thickness of the rate-controlling membraneand tablet height. Moreover, no burst release was seen, as can betheissue with many sustained release formulations.

after printing40, further emphasizing the need for an appropriatesolvent system selection.With 3D powder bed printing, the binder concentration may becritical to the strength of the final structure. Patirupanusara etal.investigated the impact of binder concentration of maltodextrinandpolyvinyl alcohol (PVA) as binders for a polymethyl methacrylatestructure41. With this system, at least 10% binder was neededin thepowder bed for successful fabrication. Increase in binderconcentrationled to decreased porosity andincreased strength;however,at over 40%, deformation in the structure shape was seen.

Patirupanusaradescribed the mechanism of binding as dissolutionof binder in the printed liquid,followed by infiltration into thepowder bed, and finallysolidification upon drying.Alternatively, onecould print with binder in the ink solution, as the spraying ofwettedbinder can lead to more efficient migration in the powder bed andpotentially enhanced mechanical properties42–44. In this case,oneshould evaluate fluid properties of the ink, as polymer solutionscanhave complex rheology. Particle size of thepowder bed also effectsbinderdistribution and ultimately the final structure porosity andstrength.Typical layer thickness during powder be inkjet printingcan be50–200 mm,therefore, average particle size is recommendedto be50–150 mm45.

Other processing parameters thatshould be considered includenozzle diameter, dropletspacing, print head speed, and dropletfrequency and velocity, whichcan be controlled by the amplitude ofthe piezoelectric actuation pulse.LimitationAn alternativewas quickly proposed and was based on the dispersion of the drug in thepolymer using anHME process to create loaded filaments before printing Pietrzak et al., 2015.

Theincorporation of another material (i.e. a drug) in a polymer modified itsthermoplasticproperties andmay lead to technical issues such as nozzle clogging or unsuitable flexibilityof thefilament. Furthermore, as well asprinting-based inkjet systems,     FutureProspect and scopeAs3d printing entered into the pharmaceutical industry it has been changing thestructure of traditional pharmaceutical system. It changes the way of medicinemanufacturing.

Because of 3d printing is new in this industry we couldn’t seethe fast growth. maybe because of research and development. But it steadilymoving ahead. It came up with big vision.It’snot just for any pharmaceutical industry or any hospitals. It will be availablefor all of us. So it is a big vision and requires big amount of money tofulfill the every pharma need.

Because now it’s not only question of similardosage to everyone, here they are providing different dosage for geneticallydifferent person. and if that printerare going to available to each and everyperson then their price matters it should be affordable for everyone.Alsowith this technology we don’t need to go anywhere for medicine. It can beeasily available at home.Butsales of medicine in shop will reduce and it will be greatly impact on shops ormedical store.

After use of machine cleaning is very important and also achemical which is important in this also made available easily and theirformula for combination. Because without chemical we cant make itand also theyhave to find out different techniques to simplify this work.             ProfessorsatMIT were credited with first using the term ”3D printer” withtheirinvention of a layering technique using a standard inkjet printheadto deposit ”ink” or a binder solution onto a powder bed to bindpowder, again repeating this process layer-by-layer to produce adesired geometry. The un-bonded or loose powder, which acts as asupport during processing, is then removed. The structure can befurther treated, for example with heat, to enforce the bonding14.

Thisprocess is generally referred to as 3D printing. In this review,thistechnique will be referred to as 3D powder bed or powder bedinkjetprinting.Theincreased use of 3D printing technologies in the preparation ofdrugdelivery systems is driven by a myriad of factors.

Thetechnologyallows for the preparation of multifaceted dosageformswith accurate deposition of materials, greater spatial controlandgeometric flexibility. These features allow for the formulationandmanufacture of highly innovative products, such as combinationdrugproducts with multimechanism release behaviors, whichcangreatly increase compliance by patients with complex dosingregimens.3D printing systems are inherently scalable, with theabilityto be set up as semi-continuous or continuous manufacturinglines,to address small volume (e.g. orphan products) to commercialscale(e.g. generics) manufacturing.

The capabilities of accurate, lowdosedispensing can lead to better control, uniformity and safetywithlow dose and/or potent compounds. In a pharmacy orambulatorysetting, 3D printing allows for the preparation ofvariousdose strengths, providing an unprecedented ability toindividualizedose per patient needs. Additionally, the ability to printdosageforms at the point of care may allow for more therapeuticoptionsavailable for patients.Future work to enable drug product manufacture using 3Dprintingtechnologies should include the identification and characterizationofadditional pharmaceutical materials amenable toprocessing.

Polymeric materials for FDM, specifically, should beinvestigatedto allow a wider formulation design space. Bothprocesses,powder bed inkjet printing and FDM, can yield porousand/orpartially fused structures with a relatively rough surfacefinish,which have implications on the mechanical strength of thefinalstructure. It may be possible to address this by optimizing theformulation(i.

e. decrease particle size of powder in powder bed,increasebinder ink concentration) or process parameters (i.e.increaseenvelope temperature during FDM fabrication).Withan exceptionally high degree of control and flexibility, 3Dprintingtechnologies are well suited for pharmaceuticalmanufacturingof customized, complex and innovate dosageforms.Their use in the screening, development and manufacturingofdrug delivery systems will only increase as there is moreunderstandingof and need for tailored drug release profiles andpersonalizeddose strengths to better address complex dosingregimens andheterogeneous patient populations.

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