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Journal of Pharmacy Research Vol.5 Issue 7.July 2012

Naresh Hiraram Choudhary et al. / Journal of Pharmacy Research 2012,5(7),3791-3799

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Review ArticleISSN: 0974-6943

Available online throughwww.jpronline.info

*Corresponding author.Naresh Hiraram Choudhary.Department of Pharmaceutics, SinhgadTechnical Education Society’s, Smt. KashibaiNavale College of Pharmacy, Kondhwa [Bk],Pune, Maharashtra, India.

Orally Disintegrating Drug Delivery SystemsNaresh Hiraram Choudhary*, Manoj Shivaji Kumbhar, Deepak Annasaheb Dighe,

Anita Prakash Sapkale, Meera Chandradatt SinghDepartment of Pharmaceutics, Sinhgad Technical Education Society’s,

Smt. Kashibai Navale College of Pharmacy, Kondhwa [Bk], Pune, Maharashtra, India.

Received on:07-04-2012; Revised on: 12-05-2012; Accepted on:16-06-2012

ABSTRACTMany patients have difficulty in swallowing tablets and hard gelatin capsules and consequently do not take medicine as prescribed. It is estimated that 50%of the population is affected by this problem, which results in a high incidence of noncompliance and ineffective therapy. The difficulty is experienced inparticular by pediatric and geriatric patients, but it also applies to people who are ill in bed and to those active working patients who are busy or travelling,especially those who have no access to water. Such problems can be resolved by means of Orally Disintegrating Tablets (ODTs) which does not require waterto aid swallowing. ODTs are placed on the tongue, allowed to disperse or dissolve in the saliva, and then swallowed without the need of water. Some drugsare absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. In these cases, the bioavailability of drug is significantlygreater than those observed from standard dosage forms. ODTs can be formulated using different techniques like freeze drying, cotton candy process,moulding, sublimation, and direct compression. The various patented technology includes Zydis®, QuickSolv®, Lyoc®, Flashdose®, OraSolve®, Ziplettechnology, Frosta®, DuraSolve®, and Wowtab®. ODTs offer many advantages like improved patient compliance, rapid onset of action, improved bioavailability.The future of ODTs lies in the development of ODTs with controlled release properties.

Key words: Orally Disintegrating Tablets (ODTs), Zydis®, Cotton candy process, Moulding, Direct compression, Superdisintegrants.

INTRODUCTIONMany patients have difficulty swallowing tablets and hard gelatin capsulesand consequently do not take medications as prescribed. It is estimated that50% of the population is affected by this problem, which results in a highincidence of noncompliance and ineffective therapy. The demand for soliddosage forms that can be dissolved and suspended in water, chewed, orrapidly dissolved in the mouth is particularly strong in the pediatric andgeriatric markets, with further application to other patients who prefer theconvenience of a readily administered dosage form. Because of the increase inthe average human life span and the decline, with age, in swallowing ability,oral tablet administration to patients is a significant problem and has becomethe object of public attention [1]. The problem can be resolved by the creationof Orally Disintegrating Tablets (ODTs). ODTs rapidly disintegrate in themouth without chewing upon oral administration and without the need forwater, unlike other drug delivery systems and conventional oral solid imme-diate-release dosage form [2]. ODTs dosage forms, also commonly known asfast melt, quick melts, fast disintegrating, or dispersible systems have theunique property of disintegrating the tablet in the mouth in seconds [3].

The dosage forms are placed in the mouth, allowed to disperse or dissolve inthe saliva, and then are swallowed in the normal way. Less frequently, theyare designed to be absorbed through the buccal and esophageal mucosa as thesaliva passes into the stomach. In the latter case, the bioavailability of a drugfrom fast dispersing formulations may be even greater than that observed forstandard dosage forms. Furthermore, side effects may be reduced if they arecaused by first pass metabolites [1, 4]. Orally disintegrating dosage forms areoften formulated for existing drugs with an intention to extend the patent lifeof the drug through product differentiation. They are evaluated against theinnovator drug in a bioequivalence study in humans to establish comparabil-ity of pharmacokinetic parameters.

Despite a surge of orally disintegrating tablets in the market in the recentyears, they potentially can be confused with other solid oral dosage formsthat are consumed without additional water intake, including lozenges, buccaltablets, chewable tablets and effervescent tablets. Lozenges and buccal tab-lets are intended to dissolve slowly in the mouth, whereas, ODTs mustdisperse or dissolve in the mouth quickly, within seconds. Chewable tabletsare also different from orally disintegrating tablets because they require manualchewing action by the patient before they can be swallowed. The disintegra-tion times are longer for the chewable tablets as compared to the ODTs.Effervescent tablets require preparatory steps before administration of thedrug [5, 6].

One of the greatest benefits of ODTs over conventional tablets is enhancedpatient compliance and acceptance related to both feasibility and conve-nience of dosage administration [7]. Population having difficulty in swallow-ing intact tablets and hard gelatin capsules include pediatric and geriatric,patients who are bedridden, mentally retarded, uncooperative, nauseous, andthose suffering from nervous or anatomical disorder of the larynx or esopha-gus, or on reduced liquid intake diets also cannot swallow conventional tab-lets. In such patients practitioners would expect much better compliance andtherapeutics outcomes by administering ODTs instead of conventional tab-lets [8]. Patient compliance can be enhanced by designing orally disintegratingtablets that have pleasant taste and texture because many people simply donot enjoy swallowing solid tablets. People who take medicine such as-neededbasis and active people who do not have convenient access to water couldeasily take them as well [6]. Other advantages includes benefit of liquid medi-cation in the form of solid preparation, more rapid drug absorption from thepre-gastric area i.e. mouth, pharynx and esophagus which may produce rapidonset of action, pregastric absorption can result in improved bioavailability,reduced dose and improved clinical performance by reducing side effect, newbusiness opportunities like product differentiation, line extension and life-cycle management, exclusivity of product promotion and patent-life exten-sion [9,10,11].

Orally disintegrating tablet drug delivery does, however, have certain limita-tions. Because ODTs require the users to produce their own saliva, those



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Basic for Technology Company Technology

Lyophilization process Cardinal Health Zydis®Janssen Pharmaceutica Quiksolv®Pharmalyoc Lyoc®Elan NanoCrystal™

Cotton candy process Biovail (Fuisz) FlashDose®Tableting process Cima Labs OraSolv®/DuraSolv®

Yamanouchi WOWTAB®Elan Corp. Fast Melt®Ethypharm Flashtab®Eurand AdvaTab™/Ziplets®KV Pharmaceutical OraQuik®SPI Pharm Pharmburst™Alkina Frosta

Table 1 Shows summary of Technologies Used to Prepare ODTs

FORMULATION PROCESSES FOR MAKING ODTs

There are several technologies that produce commercially available ODTs.Zydis® (Cardinal Health, Dublin, Ohio), OraSolv® /DuraSolv® (Cima Labs,Eden Prairie, Minnesota), and WOWTAB® (Yamanouchi Pharma Technolo-gies, Norman, Oklahoma) are widely known technologies. Table 1 showssummary of technologies used to prepare ODTs.

Despite the publication of the FDA guidance for ODTs, this category ofdosage form lacks globally harmonized nomenclature and criteria. For ex-ample, the European Pharmacopeia defines orodispersible dosage forms ashaving a disintegration time of less than 3 min [16]. Such differences do notresult in inconsistent regulation of ODTs in different regions, but greaterharmonization would be preferable.

1. ODTs should have an in vitro disintegration time of approximately30 s or less (using United States Pharmacopeia disintegration testor equivalent).

2. Generally, the ODTs tablet weight should not exceed 500 mg,although the combined influence of tablet weight, size, and compo-nent solubility all factor into the acceptability of an ODT for bothpatients and regulators.

3. The guidance serves to define the upper limits of the ODTs cat-egory, but it does not supersede or replace the original regulatorydefinition mentioned. In other words, disintegration within a mat-ter of seconds remains the target for an ODT.

The US Food and Drug Administration responded to this challenge with the2008 publication of Guidance for Industry: Orally Disintegrating Tablets [15].Three main points stand out in the final guidance:

Freeze-Drying or LyophilizationThis technique forms the basis of Zydis (Cardinal Health), Quicksolv (JanssenPharmaceutica), Lyoc (Pharmalyoc), and NanoCrystal™ (Elan) technologieswhich are used to manufacture ODTs [17]. Zydis Technology utilizes a uniquefreeze-drying process to manufacture finished dosage units which signifi-cantly differ from conventional oral systems. The process involves the fol-lowing steps:

Stage 1 - Bulk preparation of an aqueous drug solution or suspension and itssubsequent precise dosing into pre-formed blisters. It is the blister thatactually forms the tablet shape and is, therefore, an integral component of thetotal product package.Stage 2 - Passing the filled blisters through a specially designed cryogenicfreezing process to control the ultimate size of the ice crystals which ensuresthat the tablets possess a porous matrix to facilitate the rapid disintegrationproperty. These frozen units are then transferred to large-scale freeze dryersfor the sublimation process, where the majority of the remaining moisture isremoved from the tablets.Stage 3 -Sealing the open blisters using a heat-seal process to ensure stabil-ity and protection of the product from varying environmental conditions.The maximum drug loading capacity for water insoluble and soluble drugs are400 mg and 60 mg respectively. The primary problems associated with watersoluble drugs are the formation of eutectic mixtures resulting in freezing-point depression and the formation of a glassy solid on freezing which mightcollapse on drying due to loss of supporting structure during sublimationprocess [18, 1].

Quicksolv®

Quicksolv® (Janssen Pharmaceutica, Beese, Belgium) and Lyoc® (FarmalyocLaboratorie L., Lefon, Maisons-Alfort, France) are also prepared by thefreeze drying method. In the Quicksolv® formulation, the matrix composi-tions are dissolved in the first solvent (usually water), and then the solutionis frozen. At the temperature at which the first solvent will remain in thesolid form, the frozen solution contacts the second solvent, which is sub-stantially miscible with the first solvent. For example, ethanol, menthol, oracetone is used as the second solvent with water as the first solvent. Thematrix composition should be immiscible to the second solvent. Thus, thefirst solvent is substantially removed after a few hours of contacting thesecond solvent to result in a usable matrix [19].The final product disintegratesalmost instantly. This method is claimed to prevent or reduce the incidenceof cracking during the final preparation, having uniform porosity and ad-equate strength for handling.

Lyoc®

In the Lyoc® formulation, the porous solid form is obtained by freeze dryingan oil-in-water emulsion placed directly in the blister pockets. In order toprevent inhomogeneity by sedimentation during freeze drying, this formula-tion requires a large proportion of undissolved inert filler to increase theviscosity of the suspension. The high proportion of filler reduces the poros-ity of the tablet, and as a result, the disintegration is slower. It is also notedthat the tablet still has poor mechanical resistance [20]. Advantages of Lyoccompared to other freeze dried dosage forms include absence of preserva-tives [3].

NanoCrystal™ technologyNanoCrystal™ technology (Elan, King of Prussia, Pennsylvania) uses orallyadministered nanoparticles (<2 µm) in the form of rapidly disintegratingtablet matrix. The NanoCrystal™ orally disintegrating tablet dosage formwas developed to facilitate the preparation of small-scale clinical supplies.NanoCrystal™ colloidal dispersions of drug substance are combined with

with very dry mouth may not benefit. Production of saliva depends not onlyon the drug product formulation but the ability and condition of the user.Also, the administration of ODTs to increase compliance in uncooperativepatients, such as those being treated for mental illness, does not guaranteecompliance. Patients have found various ways of hiding the medication such

RECENT FDA GUIDANCE ON ODT TECHNOLOGIESThe emergence of multiple ODT technology platforms created some regula-tory challenges due to increasing variance in the critical product attributes ofODTs, notably disintegration time and tablet size. Hypothetically, in anabbreviated new drug application, the disintegration time of a generic prod-uct could be 30–45 s, and the disintegration time of a reference product 0–10s. Prolonged disintegration times may result in failure to meet the definingperformance characteristics of the ODTs dosage form, such that the productmight require water for administration or chewing to facilitate swallowing.Where the patient or caregiver’s expectation is for rapid dispersion in themouth, larger units with slower disintegration times could result in confusionregarding the product quality and even present a choking hazard. Thus, inaddition to product definition, patient safety is also a significant consider-ation [14].

as sticking the Zydis tablets behind the teeth to avoid swallowing the medi-cation [12]. Nonetheless, ODTs offer practitioners an added tool in enhancingcompliance in some patient population [13].



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water-soluble ingredients, filled into blisters, and lyophilized. This approachis especially attractive when working with highly potent or hazardous mate-rials because it avoids manufacturing operations such as granulation, blend-ing, and tableting, which generate large quantities of aerosolized powder andpresent much higher risk of exposure. The freeze-drying approach also en-ables small quantities of drug to be converted into ODTs because manufac-turing losses are negligible. The final tablet is durable enough for conventionalblister or bottle packaging and accepts as much as 200 mg of drug per unit [21].

COTTON CANDY PROCESSFuisz Technologies (Chantilly, Virginia) has introduced the Shearform Tech-nology to make Flashdose. The Shearform Technology uses a unique spin-ning mechanism to produce a floss-like crystalline structure, much like cot-ton candy. In this process, the feedstock is subjected to centrifugal force andto a temperature gradient simultaneously. An internal flow is created by thiscondition to force the flowing mass out of the opening provided in theperimeter of a spinning head. The mass is cooled down as it comes out of theopening to form a discrete fiber structure, as seen in cotton candy. The speedof spinning is about 3,000–4000 rpm, and the temperature gradient is about180–250°C. The carrier materials include saccharides, polysaccharides, andmixtures thereof [22].

There were two systems used to create the Shearform floss having self-binding properties [23, 24]. The first system was named a single floss or unifloss.Typical flosses of this kind, made of sucrose, sorbitol, and xylitol, yieldedeffective self binding properties. The second system used two separateflosses. One was xylitol containing binder flosses and the other was baseflosses that contain different sugar alcohols or saccharide. When the twoflosses were combined, it was termed a dual floss system.

The produced floss needed to be recrystallized to form freely flowing gran-ules with self-binding properties. Two techniques were used in recrystalliza-tion. One was using crystallization enhancers including ethanol, polyvi-nylpyrrolidone, water (e.g.,moisture), glycerin, and radiant energy (e.g., mi-crowaves). The other was using crystallization modifiers, which were in-cluded in floss ingredients at 0.01–20.0% the weight of the floss. Typicalcrystallization modifiers were surfactants having an HLB of about 6 or more.

TABLET MOULDINGMoulded tablets invariably contain water-soluble ingredients due to whichthe tablets dissolve completely and rapidly. Following are the different tabletmoulding techniques:

Compression Moulding ProcessThis manufacturing process involves moistening the powder blend with ahydroalcoholic solvent followed by pressing into mould plates to form awetted mass (compression moulding). The solvent is then removed by airdrying, a process similar to the manufacture of tablet triturates. Such tabletsare less compact than compressed tablets and possess a porous structurethat hastens dissolution [25].

Heat-Moulding ProcessHeat-moulding process involves setting the molten mass containing a dis-persed drug. This process uses agar solution as a binder and a blister packag-ing well as a mould to manufacture the tablet. A suspension containing drug,agar and sugar is prepared followed by pouring the suspension into theblister packaging well, solidifying the agar solution at room temperature toform a jelly and finally drying at approximately 30 °C under vacuum [26].

Moulding by Vacuum Evaporation without LyophilizationThis process involves pouring of the drug excipient mixture (in the form of a

slurry or paste) into a mould of desired dimension, freezing the mixture toform a solidified matrix and finally subjecting it to vacuum drying at a tem-perature within the range of its collapse temperature and equilibrium freezingtemperature. This results in the formation of a partially collapsed matrix.This method differs from the lyophilization technique, as in the former theevaporation of free unbound solvent occurs from a solid through the liquidphase to a gas, under controlled conditions, instead of the sublimation whichtakes place in the latter process. Unlike lyophilization, vacuum drying helpsto densify the matrix and thereby improves the mechanical strength of theproduct. Pebley et al. [27], evaporated the frozen mixture containing a gum(e.g., acacia, carageenan, guar, tragacanth or xanthan), a carbohydrate (e.g.,dextrose, lactose, maltose, mannitol or maltodextrin) and solvent in a tablet-shaped mould to design a ODTs with a disintegration time of about 20– 60secs.

Takeda Chemical Industries (Osaka, Japan) and Nippon Shinyaku (Kyoto,Japan) have disclosed compression-molding. The wetted mass was com-pressed at low pressure and subsequently dried to produce porous tabletswith sufficient mechanical strength. The disintegration time was about 30–50 seconds in the mouth [28, 29]. In a patent by Novartis Consumer Health(Basel, Switzerland), the drug solution or suspension was dispersed intomolds. The solvent was removed from the units usually by heating, pressurereduction, or microwave radiation [30].

In a patent by Okada, the molded tablets contained a drug, a saccharidehaving a solubility of 30 (w/w) % or less at room temperature (e.g., lactoseand mannitol), and a saccharide having a solubility of 30 (w/w) % or more atroom temperature (e.g., glucose, fructose, sucrose, xylose, trehalose, xylitol,sorbitol, erythritol, dextrin, and pullulan). The amount of this saccharide wasslightly above its solubility. The mixture was a creamy aqueous suspensionhaving both low solubility and high solubility saccharides in water. Themoisture was then removed from the suspension to obtain molded tablets [31].

Novartis Consumer Health (Basel, Switzerland) also has filed a patent appli-cation for tablets prepared by dispensing the drug solution or suspensioninto moulds, evaporating the solvent from the units (usually achieved byheating, pressure reduction, or microwave radiation), and then optionallysealing the dried units directly in the mould. The patent application reportedonly examples of low dose and low-weight forms, although higher amountsare claimed [32].

DIRECT COMPRESSIONFrom the pharmaceutical manufacturer’s point of view, direct compression isthe simplest and most cost-effective tablet manufacturing procedure. Phar-maceutical companies can use conventional manufacturing equipment andcommonly available ingredients. This method can be applied to manufactur-ing ODTs by choosing appropriate combinations of excipients, which canprovide fast disintegration and good physical resistance. Sugar-based excipi-ents have been widely used as bulking agents because of their high aqueoussolubility and sweetness, pleasing mouth-feel and good taste masking. Nearlyall formulations for ODTs incorporate some sugar materials in their formula-tions [33].

The direct-compression tablet’s disintegration and solubilization are basedon the single or combined action of disintegrants, water-soluble excipients,and effervescent agents. The disintegration time is, in general, satisfactory,although the disintegrating efficacy is strongly affected (and limited) bytablet size and hardness. Large, hard tablets can have a disintegration timegreater than that usually required for ODTs. As a consequence, productswith optimal disintegration properties often have a medium–small size (weight)and/or a low physical resistance (high friability and low hardness) [34].



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Caramella et al. [35, 36] found that disintegration efficiency is based on theforce-equivalent concept (the combined measurement of swelling force de-velopment and amount of water absorption). Force equivalence expressesthe capability of a disintegrant to transform absorbed water into swelling (ordisintegrating) force. The optimization of tablet disintegration was definedby means of the disintegrant critical concentration. Below this concentration,the tablet disintegration time is inversely proportional to the disintegrantconcentration. Above the critical concentration, the disintegration time re-mains approximately constant or even increases [37].

GRANULATION METHODS

Wet GranulationBonadeo et al. [38] described a process of producing ODTs by wet granulationin a fluidized bed. It was found that even with effervescent agents presentedin the tablet with lower than 5%, quick disintegration times could be achieved.Furthermore, it was also found that fast disintegration time could be achievedusing only the acid component of the effervescent couple. In the patent, theformulation includes polyalcohols (e.g., mannitol, xylitol, sorbitol, maltitol,erythritol, and lactitol), 1–30% of an edible acid, and an active ingredient asthe dry mixture. This mixture was wet granulated with an aqueous solutionof a water-soluble or water-dispersible polymer (e.g., poly(ethylene gly-cols), carrageenan, and ethylcellulose), which consisted of 1–10% of the finalweight of the granule in a fluid bed. Granules with high porosity and lowapparent density were obtained, and the tablets made by such granules hadrapid disintegration times ranging from 3 to 30 seconds in the saliva.

Dry GranulationEoga and Valia [39] disclosed a method of making ODTs by dry granulation.Higher density alkali earth metal salts and water-soluble carbohydrates usu-ally do not provide quick disintegration and a smooth mouth feel. Low-density alkali earth metal salts and water soluble carbohydrates are alsodifficult to compress and caused inadequate content uniformity. For thesereasons, low-density alkali earth metal salts or water-soluble carbohydrateswere precompacted, and the resulting granules were compressed into tabletsthat could dissolve fast. In this process, a powdered material with a densityof 0.2–0.55 g/mL was precompacted to increase the density to 0.4–0.75 g/mL by applying a force ranging from 1 to 9 kN/cm. The resulting granuleswere compressed into tablets.

Melt GranulationAbdelbary et al. [40] described a new approach of preparing ODTs withsufficient mechanical strength, involving the use of a hydrophilic waxy binder(Superpolystate®, PEG-6-stearate) by melt granulation or wet granulation.Because Superpolystate® is a waxy material with a melting point of 33–37°C and a hydrophilic to lipid balance (HLB) value of 9, it will not only act asa binder and increase the physical strength of tablets but also help the disin-tegration of the tablets. In case of melt granulation, granules were prepared ina high-speed blade mixer at 40–44 °C, according to the conventional hot-meltprocedure. For wet granulation, an oil-in-water emulsion of Superpolystate®

was used as the granulating agent. Then, granules were blended withcroscarmellose, aspartame, and magnesium stearate and compressed intotablets. The melt granulation ODTs had better hardness results than the wetgranulation ODTs. The disintegration times of melt granulation tablets, how-ever, was more than 1 minute.

Spray-DryingAllen et al., [41] have used spray-drying for the production of ODTs. Theformulations contained hydrolyzed and unhydrolyzed gelatin as a support-ing agent for the matrix, mannitol as a bulking agent and sodium starchglycolate/croscaramellose as a disintegrant. Disintegration and dissolution

were further enhanced by adding an acid (e.g., citric acid) or an alkali (e.g.,sodium bicarbonate). The suspension of above excipients was spray-dried toyield a porous powder which was compressed into tablets. Tablets manufac-tured by this method disintegrated in < 20 seconds in an aqueous medium.

SublimationSublimation has been used to produce ODTs with high porosity. A porousmatrix is formed by compressing the volatile ingredients along with otherexcipients into tablets, which are finally subjected to a process of sublima-tion. Inert solid ingredients with high volatility (e.g., ammonium bicarbonate,ammonium carbonate, benzoic acid, camphor, hexamethylene tetramine, naph-thalene, phthalic anhydride, urea and urethene) have been used for this pur-pose [42]. Solvents such as cyclohexane and benzene were also suggested forgenerating the porosity in the matrix. Makino et al., [43] reported a methodusing water as pore-forming material.

Lo [44] disclosed an efficient method for preparing high-strength, highly po-rous, fast-dissolving delivery devices. In this method menthol, a water-soluble,menthol soluble polymer, and an active ingredient are mixed at a temperaturethat insures that the menthol is substantially molten. The formulation isdisposed in a mold and solidified, and the menthol is sublimed from thesolidified molded formulation. Preferably, the solidification occurs at a tem-perature sufficient to provide a substantially amorphous menthol structure.

Humidity TreatmentThe mechanical strength of some tablets increased substantially after mois-ture treatment, compared with the tablets before the treatment. The increaseis known to be due to the formation of liquid bridges in the presence ofmoisture and then formation of solid bridges after drying.

Tatara et al. [45] used moisture treatment and devised an apparatus to handlethe fragile tablets before moisture treatment. An active ingredient and otherexcipients were compressed in low pressure, and then the resultant tabletswere moisturized and dried to produce a porosity between 20 and 40%. Asshown in figure 1, the manufacturing apparatus includes a rotary punch-press, a relay conveyor for transferring tablets, a moisturizing section, adrying section, and a delivery conveyor. In the moisturizing section, thecondition was set to allow tablets moisturized at 45 °C, 95% relative humid-ity for 60 seconds. In the drying section, the temperature was set to 50 °C for60 seconds. With this apparatus the fragile tablets before moisture treatmentwere gently transferred throughout the process.

Fig. 1 It shows schematic view of the manufacturing apparatus usingmoisture treatment [45].

The left side of a dotted line shows the conventional compression anddedusting steps, while the right side shows the additional step requiringspecial chambers for moisture treatment and drying.



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SinteringLagoviyer et al.[46] disclosed a process that increased tablet strength by sin-tering the tablet components at high temperatures and then resolidifyingthem at lower temperatures. The components in this formulation includebulk agents, structure agents, solvent, and binding agents. The suitable struc-ture agents should provide a porous support structure to allow quick disso-lution of the tablets in the mouth.

The structural agents include agar, gelatin, albumin, and chondroitin. Bulkingand structural agents were dissolved in a suitable solvent, and the dissolvedmixture was spray dried or dispersed to obtain a bead or granulated productwith a low density. Choice of the solvent is based on its ability to provide adesired porosity to the bead or granulated product upon drying. Solvents canbe chosen from water, ethyl alcohol, isopropyl alcohol, or a mixture thereof.The binders need to melt at the sintering stage, form bonding among granules,and resolidify as the temperature of the final sintering or heating step de-creases. Binders are water soluble polymers such as poly(ethylene glycol)(PEG), with a molecular weight of approximately 1000 to 1,000,000. PEGmelts at 50–90 °C. PEG has the advantage of functioning both as a binder andas a capillary attractant. The amount of binding polymer ranged from 0.5%to 25% of the weight of the final product.

EXCIPIENTS USED IN FORMULATION OF ODTsThe excipients listed for a number of orally disintegrating products are pro-vided in table 2. ODTs typically composed of sweet fillers and flavouringagents. Compressed tabets typically are formulated with highly water solublefillers and relatively high levels of disintegrants. Insoluble fillers such asmicrocrystalline cellulose are sometime used in these formulation but theformulator must make sure that their particle sizes are small and that levels inthe formulation are not excessive to avoid gritiness or any other unpleasantmouth feel. Like conventional tablets, compressed ODTs need gliadants (e.g.colloidal silicone dioxide) to help the particles flow and lubricants (e.g. mag-nesium stearate) to prevent sticking of the material the punches and facilitateejection from dies. [6]

Table 2 Table shows US FDA approved products available in the Market along with inactive ingredient in ODTs [47]

PatentedTechnology Products Name of the Company Composition

Zydis® Claritin Reditab R.P. Scherer/ Schering Plough, Kenilworth, USA Micronized loratidine (10mg), citricacid, mannitol, gelatin, mint flavor

Feldene Melt Pfizer Inc, NY, USA. Piroxicam (10 or 20 mg), mannitol,gelatin, aspartame, citric anhydrous

Maxalt-MLT R.P.Scherer / Merck & Co., NY, USA. Rizatriptan (5 or 10 mg), mannitol, gelatin,aspartame, peppermint flavor

Pepcid RPD Merck & CO., NY, USA. Famotidine (20 or 40 mg), mannitol,gelatin,aspartame

Zyprexa Zydis R.P.Scherer/Eli Lilly, Indianapolis, USA. Olanzapine (5, 10, 15 or 20 mg), mannitol,gelatin, aspartame, methyl parabensodium, propyl paraben sodium

Zofran ODT R.P.Scherer/Glaxo Wellcome, Middlesex, UK. Ondansetron (4 or 8 mg), mannitol, gelatin,aspartame, methyl paraben sodium,propyl paraben sodium, strawberry flavor

Orasolv® Remeron Soltab CIMA / Organon, Mirtazepine (15,30 or 45 mg),Glaxo Wellcome, Middlesex, UK. mannitol, aspartame, citric acid, crosspovidone,

Avicel, NaHCO3, HPMC, maagnesium stearate,povidone, PMA, starch, sucrose, orange flavor

Tempra First Tabs CIMA / Mead Johnson, Bristol Myers Acetaminophen (80 or 160 mg),Squibb, NY, USA. mannitol (currently available in Canada)

Durasolv® Nulev CIMA/Schwarz Pharma. Hyoscyamine sulphate (0.125mg), aspartame,colloidal silicon dioxidecrospovidone,mint flavor, magnesium stearate,mannitol, Avicel

Zoming ZMT CIMA / AstraZeneca, Wilmington,USA. Zolmitriptan (2.5mg), mannitol, aspartame,citric acid anhydrous crospovidone,Avicel, sodium bicarbonate, magnesiumstearate colloidal silicon dioxide, orange flavor

Disintegrating AgentsThe disintegrants have a major role in the disintegration and dissolutionprocess of ODTs made by direct compression. The choice of a suitable typeand an optimal amount of disintegrants is paramount for ensuring a highdisintegration rate. The addition of other formulation components such aswater soluble excipients or effervescent agents (e.g. sodium bicarbonate andcitric acid comnination) can further enhance dissolution or disintegrationproperties. Table 3 shows classification of superdisintegrants along withtheir trade name.

Table 3 Table Shows classification of ‘‘super disintegrants’’ (partiallisting) [65]

Structural type (NF name) Trade name (manucturer)

Modified starches Explotab® (Edward Mendell Co.)(Sodium carboxymethyl starch) Primogel® (Generichem Corp.)

Tablo® Blanver, Brazil

Croscarmellose, NF AcDiSol (FMC Corp.) (Sodium carboxymethyl cellulose) Nymcel ZSX® (Nyma, Netherlands)

Primellose® (Avebe, Netherlands)Solutab® (Blanver, Brazil)

Cross-linked poly-vinylpyrrolidone Crospovidon M® (BASF Corp.)(Crospovidone NF) Kollidon CL® (BASF Corp.)

Polyplasdone XL (ISP Corp.)

Inorganic Excipients Used in ODTsDobetti [48] has developed a formulation using insoluble inorganic excipientsas the main component for ODTs. According to the patent, disintegration ofa tablet depends on the quantity of the disintegrant and insoluble inorganicexcipient used. The disintegration also depends on the relative weight ratiobetween the water insoluble and soluble excipients, if the water-solubleexcipients are used. It was also found that in their formulations, sufficientcompression could be applied to form tablets with strong tensile strengthand low friability. The disintegration rates were not significantly affected bythe high compression force. In the formulation, three major components



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were used includes substantially water insoluble components (water-insolubleexcipients, water-insoluble drugs, and water- insoluble lubricant and glidant),substantially soluble components (compressible sugars, flavoring agents,sweeteners, binders, and surfactants) and disintegrants.

The disintegration time increased as the amount of insoluble componentdecreased. If the active ingredient was only a small portion of the wholeformulation, the disintegration time could be optimized by including in-soluble fillers (e.g., microcrystalline cellulose and silicon dioxide) or by in-creasing the amount of insoluble inorganic excipients (e.g., calcium salt suchas dibasic calcium phosphate).SweetenersSugars, sugar alcohols, and other artificial sweeteners are preferred fillers inODTs. Sugar and sugar based excipients provide good mouth feel becausethey are water soluble. Together with other flavouring agents and artificialsweeteners such as aspartame, they help to mask the taste of active ingredi-ents, many of which are bitter even in small doses. Some examples of sugarsand sugar based excipients used in ODTs are amorphous sucrose, dextrose,maltitol, mannitol, and xylitol. Sugar alcohols such as maltitol, mannitol, andxylitol have the added advantage of containing fewer calories compared tosucrose and do not promote tooth decay. Mannitol and xylitol have negativeheats of solution, thereby imparting a cooling sensation in the mouth. Com-mon artificial sweeteners in ODTs are acesulfame potassium, aspartame,sucralose and saccharin sodium [6].

ORALLY DISINTEGRATING TABLETS TECHNOLOY

Wowtab®

The Wowtab ® manufactured by Yamanouchi (Tokyo, Japan) is anintrabuccally dissolved compressed moulding comprising granules made withsaccharides having low and high mouldability, respectively [49]. Wowtab®

technology employs a combination of low- and high-moldability saccharidesto produce fast-dissolving tablets using conventional granulation and tabletingtechniques [50, 51].

According to the patent, saccharides were divided into two groups: thosewith high moldability and those with low moldability. Low moldabilitysaccharides produce tablets with hardness between 0 and 2 kg, when 150 mgof such a saccharide is compressed under pressure of 10–50 kg/cm2 using adie 8 mm in diameter. The typical low-moldability saccharides include lac-tose, mannitol, glucose, sucrose, and xylitol. High-moldability saccharidesproduce tablets with hardness above 2 kg when prepared under the identicalconditions. The typical high- moldability saccharides are maltose, maltitol,sorbitol, and oligosaccharides. When tablets are made by compressing asaccharide having low moldability or high moldability alone, the desiredproperties of adequate hardness and quick disintegration in the mouth cannotbe achieved simultaneously. Moreover, if saccharides having low moldabilityand high moldability are mixed (physical mixture) before tableting, quickdisintegration and dissolution in the mouth cannot be obtained. As clearlyindicated in the patents, there is no single saccharide that can make tabletshaving both high strength and fast disintegration properties. For this reason,a saccharide having low moldability was granulated with a saccharide havinghigh moldability as a binder. The low-moldability saccharides were used asthe main component. Tablets made by compression of these granules werefurther treated under moisture condition as described in fýgure 1. The tabletsshow an adequate hardness and fast disintegration and dissolution when putin the mouth. The Wowtab® reportedly can accommodate high doses ofmultiparticulate watersoluble or insoluble drugs, dissolves rapidly, and hasan adequate hardness [51, 52].

Daiichi (Tokyo, Japan) performed a series of experiments to develop an

ODTs of moderate strength, using a combination of starch or cellulose andone or more water-soluble saccharides. Erythritol was found to be the bestsugar for this type of formulation, showing rapid disintegration that wasnegligibly affected by tablet hardness; good tolerability and sweetening; anda refreshing mouth sensation because of its endothermic dissolution heat [53].

Ziplets technologyIt is evident that the main challenge in developing an ODTs is to achieve bothgood physical resistance and disintegration properties. Generally, a tradi-tional direct-compression approach is preferred because it offers low pro-duction costs and the use of commonly available equipment and materials.On this basis, Eurand (Pessano con Bornago, Italy) recently developed theZiplets technology, which can be used with water insoluble compounds asboth bulk actives and as coated microparticles (the latter containing solubleand/or insoluble drugs). It was found that the addition of a suitable amount ofa water-insoluble inorganic excipient combined with one or more effectivedisintegrants imparted an excellent physical resistance to the ODTs andsimultaneously maintained optimal disintegration, even at low compressionforces and tablet hardnesses [54].

In fact, handling problems during manufacturing (breakage of the tablet edgesor formation of powder,which adversely affects the blistering phase) areavoided because of mechanical resistance. The risk of tablet breakage duringthe opening of the blister pack is eliminated. The use of water-insolubleinorganic excipients also offers better enhancement of disintegration charac-teristics than most commonly used water-soluble sugars or salts. In fact,tablets composed primarily of water-soluble components often tend to dis-solve rather than disintegrate, resulting in a much longer disintegration time.As the soluble components dissolve on the tablet’s outer layer, the rate of thewater diffusion into the tablet core decreases because of the formation ofconcentrated viscous solutions [55].

Frosta® TechnologyThe core concept of Frosta® technology is compressing highly plastic gran-ules at low pressure to produce strong tablets with high porosity. The highlyplastic granules comprise three classes of components: a porous and plasticmaterial, a water penetration enhancer, and a binder. A simplified manufac-turing process of highly plastic granules and their ODTs is described in figure2. The highly plastic granules can then be compressed at low pressure toform a fast-melting pharmaceutical tablet. A porous, plastic material is watersoluble or water dispersible, sometimes almost instantaneously upon con-tact with water. Plastic deformation of powders dramatically increases thechance of the interparticle contacts necessary to form bonds between par-ticles. If a porous and plastic material is polymeric, it is essential to preventformation of a viscous layer of the material at the tablet surface when itdissolves in aqueous medium. One way of making such tablets is to mixporous, plastic material with a water penetration enhancer at certain ratios.In this process, the porous and plastic particles are separated by water-penetration-enhancing particles, which prevent formation of a viscous layeron the tablet surface. Although the porous and plastic materials can makeclose contacts to increase the chance of bonding by compression, formationof really strong bonding among granules at low pressures requires a suitablebinder. The binder here can also secure the porous material and water pen-etration enhancer during granulation. These two components can be easilysegregated during mixing without the binder. If the binder is in the liquid orsemi-solid state, it should not significantly destroy the porous structure ofthe porous materials. One way of achieving this is to use aqueous bindersolutions with very low water activity. The highly plastic granule approachproduces ODTs with excellent hardness and fast disintegration time rangingfrom several seconds to about 30 seconds, depending on the size of thetablets [56].



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Fig. 2 It shows a simplified manufacturing process of highly plasticgranules and their ODTs. (API: Active pharmaceutical ingredient)

Pharmaburst™ TechnologyPharmaburst technology™ (SPI Pharma, New Castle, Delaware) uses off -the-shelf coprocessed excipients to create an ODTs that, depending on thetype of active and loading (up to 700 mg), dissolves within 30–40 seconds.The quantity of Pharmaburst™ required in a formulation depends on theactive in the tablet. It is necessary to carry out initial studies on a formulationby varying the amount of Pharmaburst™ from 50 to 80%, depending on thedesired mouth feel and disintegration time. The process involves a dry blendof a drug, flavor, and lubricant that are compressed into tablets on a standardtablet press with stock tooling. The manufacture process can be carried outunder normal temperature and humanity conditions. The tablets can be pack-aged in blister packs or bottle [57].

Flashtab® TechnologyFlashtab® technology (Ethypharm, France) produces tablets by compres-sion of granular excipients. This technology uses almost the same excipientsas do conventional compressed tablets. Excipients used in this technologycomprise two groups of components: disintegrating agents, such as car-boxymethylcellulose or insoluble reticulated polyvinylpyrrolidone; and swell-ing agents, such as carboxymethylcellulose, starch, modified starch,carboxymethylated starch, microcrystalline cellulose, and possibly directlycompressible sugars. The mixture of excipients is prepared by either dry orwet granulation methods. The produced tablets are known to have satisfac-tory physical resistance and disintegrate in the mouth within 1 minute [58].

AdvaTab™ TechnologyAdvaTab™ technology (Eurand) produces ODTs tablets based on a propri-etary tablet composition that was designed and patented by Kyowa HakkoKogyo (Tokyo, Japan) [59, 60] in which the lubrication is dispensed onto eachtablet by using a spray during the production process. Traditional tablets areproduced using an internal lubrication system, which disperses lubricant onthe inside and the surface of the tablets. This method can decrease tabletmechanical strength. AdvaTab™ is produced using 10–30 times less hydro-phobic lubricant and can be 30–40% stronger than conventional tablets. As aresult, the tablets are hard and durable yet do not impede liquid entry uponcontact with saliva. AdvaTab™ can handle high drug loading and coated drugparticles. Importantly, the technology does not require specialty packagingand, as a result, can be packaged in both standard bottles and push-throughblisters.

OraSolv® and DuraSolv® TechnologyOraSolv® technology (Cima Labs) produces tablets by low compressionpressure [61, 62]. It uses an effervescent disintegration pair that releases gasupon contact with water. The widely used effervescent disintegration pairsusually include an acid source and a carbonate source. The acid sourcesinclude citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, andsuccinic acids. The carbonate sources include sodium bicarbonate, sodium

carbonate, potassium bicarbonate, and potassium carbonate. The carbondioxide evolved from the reaction may provide some “fizzing” sensation,which is a positive organoleptic sensation. The amount of effervescent agentis in general about 20–25% of the total weight of the tablet. Because of thesoft and fragile nature of OraSolv® tablets, a special packaging system, knownas PakSolv®, was developed to protect the tablets from breaking duringtransport and storage [63]. PakSolv® is a “dome-shaped” blister package thatprevents the vertical movement of the tablet within the depressions, becausethe diameter of the lower portion of the dome is too narrow to accommodatethe tablet. PakSolv® also offers light, moisture, and child resistance. [64].

The key ingredients in this formulation are nondirect compression filler andlubricant. The particle size of the nondirect compression filler is preferablybetween about 20 and 65 µm, while for direct compressible fillers at least85% of the particles are over 100 µm in size. These nondirect compressionfillers, such as dextrose, mannitol, sorbitol, lactose, and sucrose, have theadvantage of quick dissolution and avoid some of the gritty or sandy textureusually present in direct compressible versions of the sugar. The amount ofnondirect compression filler is usually about 60–95% of the total tabletweight. The tablets have low friability, which is about 2% or less when testedaccording to the USP, and the hardness of the tablets is at least about 15-20N. The disintegration time is less than 60 seconds.

Thin-film technologyThin-film technology is a relative new area of interest with respect to oralfast-dispersing products. Although not strictly an ODT, the oral thin-filmplatform provides an alternative to traditional tablet approaches. Oral thinfilms generally consist of hydrophilic polymers of varying thickness (50 to200 nm). The manufacturing process is based on liquid casting to control filmand weight variability. The dosage required is achieved by manipulating theAPI concentration in the bulk solution and/or the film-thickness produced.The films are dried by passing through oven(s) to evaporate the solvent usedto prepare the film. The dried film is cut into single unit doses before pack-aging. During manufacture, the dried film must be protected from heat andhumidity. The final packaging of the strips also needs careful considerationto protect the product from moisture. Taste-masking options include the useof sweeteners, flavors, and ion-exchange-resin complexes. Encapsulated APIsfor taste-masking purposes is challenging because the larger particles can giverise to uniformity issues.

Although disintegration of thin films are rapid (< 30 s), their limitation isdrug loading (approximately less than 30 mg). Increasing film-thickness orusing multiple layers may increase drug loading, but greater thickness canhave a negative effect on disintegration. The specific packaging requirementsalso add complexity and cost to these products, though specific packagingtechnologies such as Catalent’s DelStrip pack are being developed to suit thethin film strips. To date, the majority of products have been in the over-the-counter sector (see Table 4) [14].

Table 4 Table shows examples of products using thin film technologies

Supplier Product Active ingredients (dose strength)

Novartis Various products Phenylehedrine hydrogen chloride (HCl)under Theraflu Dextromethorphan hydrogen bromide (5 to 20 mg)and Triaminic brands Diphenhydramine HCl (12.5 to 25 mg)

Pfizer Sudafed Phenylephedrine HCl (10 mg)MedTech Chloraseptic Benzocaine (3 mg)Products/ Prestige Menthol (2 mg)Brands



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PACKAGINGSelection of a packaging configuration is a crucial part of an ODT dosageform. Unlike conventional tablets, where packaging provides a means ofadministration/transport, ODTs may require specialized packaging configu-rations owing to their relative high moisture sensitivity and fragility. In fact,the cost of packaging can be significant for commercialization.

One approach used to overcome the moisture and physical issues withODTs is to select a rigid, multilayer foil-based barrier material to protect thedosage form, with the blister actually forming during the tablet formulationprocess. In many cases, ODTs are very fragile, and regular push throughblister packaging may break the tablet upon removing from the blister, so thepackaging requires a peelable closure.

The most common packaging configuration includes blister packaging andbottle packaging. The final packaged dosage form has to be evaluated toverify packaging integrity. One way to perform this is by immersing blistersin water and subjecting them to a vacuum for a specified period of time. Theblisters are then opened manually and checked for presence of water drop-lets. Additionally, blisters and bottles should be monitored in simulatedshipping tests according to American Society for Testing Materials (ASTM)standards. Some ODTs are sensitive to moisture to such an extent that, evenduring processing or formulation development stages, temperature and hu-midity have to be controlled to avoid long-term stability issues and mayrequire special packaging.

REGULATORYThe FDA has set regulations for filing a petition of a Supplemental NDA fora drug that has the same strength and route of administration as a drug listedin the FDA’s publication entitled ‘‘Approved Drug Products with Thera-peutic Equivalence Evaluations,’’ but differ in dosage form. This petitiongenerally can be filed pursuant to section 505(b) (2) of the Federal Food,Drug and Cosmetic Act and 21 CFR x 314.93. Most of the ODT drugdelivery systems fall under this category. Depending on the bioequivalencestudy, certain products can get approval under this clause or otherwise willneed to establish safety and efficacy of the product by conducting furtherclinical trials. As ODTs products do not require administration of water, itmay be required to perform bioequivalence studies with and without waterdepending upon the nature of the drug. This will depend upon the differenceof absorption of drug in the fed and fasted state and in addition may lead toa fed and fasted study [65].

FUTUREThe future of ODTs lies in the development of ODTs with controlled releaseproperties. If one ODT can deliver drugs with short half-lives for 12–24hours, it would be a quantum improvement in the ODT technology. Theadded convenience and compliance of such formulations would be enormous.The future of ODTs also lies in the development of effective taste-maskingproperties. The use of coating poorly tasting drugs is commonly used, but itincreases the total volume of the final formulation. There may be no magicsolution to this, but more effective use of existing taste masking technologiesis expected to alleviate the problems associated with taste masking. In addi-tion, the ability to formulate drugs in large doses will bring another importanttechnological advance. In general, the ODT formulations require large amountof excipients, and having large doses of drug will only make the final formu-lation too big to handle. An ODT formulation that would require fewerexcipients than the drug itself would be a breakthrough.

CONCLUSIONThe popularity of ODTs has increased tremendously over the last decade.The key to ODTs formulations is fast disintegration, dissolution, or melting

in the mouth and this can be achieved by producing the porous structure ofthe tablet matrix or adding superdisintegrant and/or effervescent excipients.ODTs prepared by direct compression usually have good mechanical prop-erties, and the strength can be enhanced further by subsequent treatment,such as moisture treatment. The clinical studies show ODTs can improvepatient compliance, provide a rapid onset time of action, and increasebioavailability.

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Source of support: Nil, Conflict of interest: None Declared

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