Naresh Hiraram Choudhary et al. / Journal of Pharmacy Research 2012,5(7),3791-3799 Review Article Available online through ISSN: 0974-6943 http://jprsolutions.info Orally Disintegrating Drug Delivery Systems Naresh Hiraram Choudhary*, Manoj Shivaji Kumbhar, Deepak Annasaheb Dighe, Anita Prakash Sapkale, Meera Chandradatt Singh Department 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

ABSTRACT Many 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 in particular 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 water to 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 drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. In these cases, the bioavailability of drug is significantly greater 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®, Ziplet technology, 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.

INTRODUCTION Many patients have difficulty swallowing tablets and hard gelatin capsules Despite a surge of orally disintegrating tablets in the market in the recent and consequently do not take medications as prescribed. It is estimated that years, they potentially can be confused with other solid oral dosage forms 50% of the population is affected by this problem, which results in a high that are consumed without additional water intake, including lozenges, buccal incidence of noncompliance and ineffective therapy. The demand for solid tablets, chewable tablets and effervescent tablets. Lozenges and buccal tab- dosage forms that can be dissolved and suspended in water, chewed, or lets are intended to dissolve slowly in the mouth, whereas, ODTs must rapidly dissolved in the mouth is particularly strong in the pediatric and disperse or dissolve in the mouth quickly, within seconds. Chewable tablets geriatric markets, with further application to other patients who prefer the are also different from orally disintegrating tablets because they require manual convenience of a readily administered dosage form. Because of the increase in chewing action by the patient before they can be swallowed. The disintegra- the average human life span and the decline, with age, in swallowing ability, tion times are longer for the chewable tablets as compared to the ODTs. oral tablet administration to patients is a significant problem and has become Effervescent tablets require preparatory steps before administration of the the object of public attention [1]. The problem can be resolved by the creation drug [5, 6]. of Orally Disintegrating Tablets (ODTs). ODTs rapidly disintegrate in the mouth without chewing upon oral administration and without the need for One of the greatest benefits of ODTs over conventional tablets is enhanced water, unlike other drug delivery systems and conventional oral solid imme- patient compliance and acceptance related to both feasibility and conve- diate-release dosage form [2]. ODTs dosage forms, also commonly known as nience of dosage administration [7]. Population having difficulty in swallow- fast melt, quick melts, fast disintegrating, or dispersible systems have the ing intact tablets and hard gelatin capsules include pediatric and geriatric, unique property of disintegrating the tablet in the mouth in seconds [3]. patients who are bedridden, mentally retarded, uncooperative, nauseous, and those suffering from nervous or anatomical disorder of the larynx or esopha- The dosage forms are placed in the mouth, allowed to disperse or dissolve in gus, or on reduced liquid intake diets also cannot swallow conventional tab- the saliva, and then are swallowed in the normal way. Less frequently, they lets. In such patients practitioners would expect much better compliance and are designed to be absorbed through the buccal and esophageal mucosa as the therapeutics outcomes by administering ODTs instead of conventional tab- saliva passes into the stomach. In the latter case, the bioavailability of a drug lets [8]. Patient compliance can be enhanced by designing orally disintegrating from fast dispersing formulations may be even greater than that observed for tablets that have pleasant taste and texture because many people simply do standard dosage forms. Furthermore, side effects may be reduced if they are not enjoy swallowing solid tablets. People who take medicine such as-needed caused by first pass metabolites [1, 4]. Orally disintegrating dosage forms are basis and active people who do not have convenient access to water could often formulated for existing drugs with an intention to extend the patent life easily take them as well [6]. Other advantages includes benefit of liquid medi- of the drug through product differentiation. They are evaluated against the cation in the form of solid preparation, more rapid drug absorption from the innovator drug in a bioequivalence study in humans to establish comparabil- pre-gastric area i.e. mouth, pharynx and esophagus which may produce rapid ity of pharmacokinetic parameters. onset of action, pregastric absorption can result in improved bioavailability, reduced dose and improved clinical performance by reducing side effect, new *Corresponding author. business opportunities like product differentiation, line extension and life- Naresh Hiraram Choudhary. cycle management, exclusivity of product promotion and patent-life exten- Department of Pharmaceutics, Sinhgad sion [9,10,11]. Technical Education Society’s, Smt. Kashibai Navale College of Pharmacy, Kondhwa [Bk], Orally disintegrating tablet drug delivery does, however, have certain limita- Pune, Maharashtra, India. tions. Because ODTs require the users to produce their own saliva, those

Journal of Pharmacy Research Vol.5 Issue 7.July 2012 3791-3799 Naresh Hiraram Choudhary et al. / Journal of Pharmacy Research 2012,5(7),3791-3799 with very dry mouth may not benefit. Production of saliva depends not only Freeze-Drying or Lyophilization on the drug product formulation but the ability and condition of the user. This technique forms the basis of Zydis (Cardinal Health), Quicksolv (Janssen Also, the administration of ODTs to increase compliance in uncooperative Pharmaceutica), Lyoc (Pharmalyoc), and NanoCrystal™ (Elan) technologies patients, such as those being treated for mental illness, does not guarantee which are used to manufacture ODTs [17]. Zydis Technology utilizes a unique compliance. Patients have found various ways of hiding the medication such freeze-drying process to manufacture finished dosage units which signifi- as sticking the Zydis tablets behind the teeth to avoid swallowing the medi- cantly differ from conventional oral systems. The process involves the fol- cation [12]. Nonetheless, ODTs offer practitioners an added tool in enhancing lowing steps: compliance in some patient population [13].

RECENT FDA GUIDANCE ON ODT TECHNOLOGIES Stage 1 - Bulk preparation of an aqueous drug solution or suspension and its The emergence of multiple ODT technology platforms created some regula- subsequent precise dosing into pre-formed blisters. It is the blister that tory challenges due to increasing variance in the critical product attributes of actually forms the tablet shape and is, therefore, an integral component of the ODTs, notably disintegration time and tablet size. Hypothetically, in an total product package. abbreviated new drug application, the disintegration time of a generic prod- Stage 2 - Passing the filled blisters through a specially designed cryogenic uct could be 30–45 s, and the disintegration time of a reference product 0–10 freezing process to control the ultimate size of the ice crystals which ensures s. Prolonged disintegration times may result in failure to meet the defining that the tablets possess a porous matrix to facilitate the rapid disintegration performance characteristics of the ODTs dosage form, such that the product property. These frozen units are then transferred to large-scale freeze dryers might require water for administration or chewing to facilitate swallowing. for the sublimation process, where the majority of the remaining moisture is Where the patient or caregiver’s expectation is for rapid dispersion in the removed from the tablets. mouth, larger units with slower disintegration times could result in confusion Stage 3 -Sealing the open blisters using a heat-seal process to ensure stabil- regarding the product quality and even present a choking hazard. Thus, in addition to product definition, patient safety is also a significant consider- ity and protection of the product from varying environmental conditions. ation [14]. The maximum drug loading capacity for water insoluble and soluble drugs are 400 mg and 60 mg respectively. The primary problems associated with water The US Food and Drug Administration responded to this challenge with the soluble drugs are the formation of eutectic mixtures resulting in freezing- [15] 2008 publication of Guidance for Industry: Orally Disintegrating Tablets . point depression and the formation of a glassy solid on freezing which might Three main points stand out in the final guidance: collapse on drying due to loss of supporting structure during sublimation 1. ODTs should have an in vitro disintegration time of approximately process [18, 1]. 30 s or less (using United States Pharmacopeia disintegration test

or equivalent). ® 2. Generally, the ODTs tablet weight should not exceed 500 mg, Quicksolv ® ® although the combined influence of tablet weight, size, and compo- Quicksolv (Janssen Pharmaceutica, Beese, Belgium) and Lyoc (Farmalyoc nent solubility all factor into the acceptability of an ODT for both Laboratorie L., Lefon, Maisons-Alfort, France) are also prepared by the patients and regulators. freeze drying method. In the Quicksolv® formulation, the matrix composi- 3. The guidance serves to define the upper limits of the ODTs cat- tions are dissolved in the first solvent (usually water), and then the solution egory, but it does not supersede or replace the original regulatory is frozen. At the temperature at which the first solvent will remain in the definition mentioned. In other words, disintegration within a mat- solid form, the frozen solution contacts the second solvent, which is sub- ter of seconds remains the target for an ODT. stantially miscible with the first solvent. For example, ethanol, menthol, or Despite the publication of the FDA guidance for ODTs, this category of acetone is used as the second solvent with water as the first solvent. The dosage form lacks globally harmonized nomenclature and criteria. For ex- matrix composition should be immiscible to the second solvent. Thus, the ample, the European Pharmacopeia defines orodispersible dosage forms as first solvent is substantially removed after a few hours of contacting the [16] having a disintegration time of less than 3 min . Such differences do not second solvent to result in a usable matrix [19].The final product disintegrates result in inconsistent regulation of ODTs in different regions, but greater almost instantly. This method is claimed to prevent or reduce the incidence harmonization would be preferable. of cracking during the final preparation, having uniform porosity and ad- FORMULATION PROCESSES FOR MAKING ODTs equate strength for handling.

There are several technologies that produce commercially available ODTs. Lyoc® Zydis® (Cardinal Health, Dublin, Ohio), OraSolv® /DuraSolv® (Cima Labs, In the Lyoc® formulation, the porous solid form is obtained by freeze drying Eden Prairie, Minnesota), and WOWTAB® (Yamanouchi Pharma Technolo- an oil-in-water emulsion placed directly in the blister pockets. In order to gies, Norman, Oklahoma) are widely known technologies. Table 1 shows prevent inhomogeneity by sedimentation during freeze drying, this formula- summary of technologies used to prepare ODTs. tion requires a large proportion of undissolved inert filler to increase the Table 1 Shows summary of Technologies Used to Prepare ODTs viscosity 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 noted Basic for Technology Company Technology that the tablet still has poor mechanical resistance [20]. Advantages of Lyoc compared to other freeze dried dosage forms include absence of preserva- Lyophilization process Cardinal Health Zydis® [3] Janssen Pharmaceutica Quiksolv® tives . Pharmalyoc Lyoc® Elan NanoCrystal™ NanoCrystal™ technology Cotton candy process Biovail (Fuisz) FlashDose® Tableting process Cima Labs OraSolv®/DuraSolv® NanoCrystal™ technology (Elan, King of Prussia, Pennsylvania) uses orally Yamanouchi WOWTAB® administered nanoparticles (<2 µm) in the form of rapidly disintegrating Elan Corp. Fast Melt® tablet matrix. The NanoCrystal™ orally disintegrating tablet dosage form Ethypharm Flashtab® Eurand AdvaTab™/Ziplets® was developed to facilitate the preparation of small-scale clinical supplies. KV Pharmaceutical OraQuik® NanoCrystal™ colloidal dispersions of drug substance are combined with SPI Pharm Pharmburst™ Alkina Frosta

Journal of Pharmacy Research Vol.5 Issue 7.July 2012 3791-3799 Naresh Hiraram Choudhary et al. / Journal of Pharmacy Research 2012,5(7),3791-3799 water-soluble ingredients, filled into blisters, and lyophilized. This approach slurry or paste) into a mould of desired dimension, freezing the mixture to is especially attractive when working with highly potent or hazardous mate- form a solidified matrix and finally subjecting it to vacuum drying at a tem- rials because it avoids manufacturing operations such as granulation, blend- perature within the range of its collapse temperature and equilibrium freezing ing, and tableting, which generate large quantities of aerosolized powder and temperature. This results in the formation of a partially collapsed matrix. present much higher risk of exposure. The freeze-drying approach also en- This method differs from the lyophilization technique, as in the former the ables small quantities of drug to be converted into ODTs because manufac- evaporation of free unbound solvent occurs from a solid through the liquid turing losses are negligible. The final tablet is durable enough for conventional phase to a gas, under controlled conditions, instead of the sublimation which blister or bottle packaging and accepts as much as 200 mg of drug per unit [21]. takes place in the latter process. Unlike lyophilization, vacuum drying helps to densify the matrix and thereby improves the mechanical strength of the COTTON CANDY PROCESS product. Pebley et al. [27], evaporated the frozen mixture containing a gum Fuisz Technologies (Chantilly, Virginia) has introduced the Shearform Tech- (e.g., acacia, carageenan, guar, tragacanth or xanthan), a carbohydrate (e.g., nology to make Flashdose. The Shearform Technology uses a unique spin- dextrose, lactose, maltose, mannitol or maltodextrin) and solvent in a tablet- ning mechanism to produce a floss-like crystalline structure, much like cot- shaped mould to design a ODTs with a disintegration time of about 20– 60 ton candy. In this process, the feedstock is subjected to centrifugal force and secs. to a temperature gradient simultaneously. An internal flow is created by this condition to force the flowing mass out of the opening provided in the Takeda Chemical Industries (Osaka, Japan) and Nippon Shinyaku (Kyoto, perimeter of a spinning head. The mass is cooled down as it comes out of the Japan) have disclosed compression-molding. The wetted mass was com- opening to form a discrete fiber structure, as seen in cotton candy. The speed pressed at low pressure and subsequently dried to produce porous tablets of spinning is about 3,000–4000 rpm, and the temperature gradient is about with sufficient mechanical strength. The disintegration time was about 30– 180–250°C. The carrier materials include saccharides, polysaccharides, and 50 seconds in the mouth [28, 29]. In a patent by Novartis Consumer Health mixtures thereof [22]. (Basel, Switzerland), the drug solution or suspension was dispersed into molds. The solvent was removed from the units usually by heating, pressure There were two systems used to create the Shearform floss having self- reduction, or microwave radiation [30]. 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, yielded In a patent by Okada, the molded tablets contained a drug, a saccharide effective self binding properties. The second system used two separate having a solubility of 30 (w/w) % or less at room temperature (e.g., lactose flosses. One was xylitol containing binder flosses and the other was base and mannitol), and a saccharide having a solubility of 30 (w/w) % or more at flosses that contain different sugar alcohols or saccharide. When the two room temperature (e.g., glucose, fructose, sucrose, xylose, trehalose, xylitol, flosses were combined, it was termed a dual floss system. sorbitol, erythritol, dextrin, and pullulan). The amount of this saccharide was slightly above its solubility. The mixture was a creamy aqueous suspension The produced floss needed to be recrystallized to form freely flowing gran- having both low solubility and high solubility saccharides in water. The ules with self-binding properties. Two techniques were used in recrystalliza- moisture was then removed from the suspension to obtain molded tablets [31]. tion. One was using crystallization enhancers including ethanol, polyvi- nylpyrrolidone, water (e.g.,moisture), glycerin, and radiant energy (e.g., mi- Novartis Consumer Health (Basel, Switzerland) also has filed a patent appli- crowaves). The other was using crystallization modifiers, which were in- cation for tablets prepared by dispensing the drug solution or suspension cluded in floss ingredients at 0.01–20.0% the weight of the floss. Typical into moulds, evaporating the solvent from the units (usually achieved by crystallization modifiers were surfactants having an HLB of about 6 or more. heating, pressure reduction, or microwave radiation), and then optionally sealing the dried units directly in the mould. The patent application reported TABLET MOULDING only examples of low dose and low-weight forms, although higher amounts Moulded tablets invariably contain water-soluble ingredients due to which are claimed [32]. the tablets dissolve completely and rapidly. Following are the different tablet moulding techniques: DIRECT COMPRESSION From the pharmaceutical manufacturer’s point of view, direct compression is Compression Moulding Process the simplest and most cost-effective tablet manufacturing procedure. Phar- This manufacturing process involves moistening the powder blend with a maceutical companies can use conventional manufacturing equipment and hydroalcoholic solvent followed by pressing into mould plates to form a commonly available ingredients. This method can be applied to manufactur- wetted mass (compression moulding). The solvent is then removed by air ing ODTs by choosing appropriate combinations of excipients, which can drying, a process similar to the manufacture of tablet triturates. Such tablets provide fast disintegration and good physical resistance. Sugar-based excipi- are less compact than compressed tablets and possess a porous structure ents have been widely used as bulking agents because of their high aqueous that hastens dissolution [25]. solubility and sweetness, pleasing mouth-feel and good taste masking. Nearly all formulations for ODTs incorporate some sugar materials in their formula- Heat-Moulding Process tions [33]. Heat-moulding process involves setting the molten mass containing a dis- persed drug. This process uses agar solution as a binder and a blister packag- The direct-compression tablet’s disintegration and solubilization are based ing well as a mould to manufacture the tablet. A suspension containing drug, on the single or combined action of disintegrants, water-soluble excipients, agar and sugar is prepared followed by pouring the suspension into the and effervescent agents. The disintegration time is, in general, satisfactory, blister packaging well, solidifying the agar solution at room temperature to although the disintegrating efficacy is strongly affected (and limited) by form a jelly and finally drying at approximately 30 °C under vacuum [26]. tablet size and hardness. Large, hard tablets can have a disintegration time greater than that usually required for ODTs. As a consequence, products Moulding by Vacuum Evaporation without Lyophilization with optimal disintegration properties often have a medium–small size (weight) This process involves pouring of the drug excipient mixture (in the form of a and/or a low physical resistance (high friability and low hardness) [34].

Journal of Pharmacy Research Vol.5 Issue 7.July 2012 3791-3799 Naresh Hiraram Choudhary et al. / Journal of Pharmacy Research 2012,5(7),3791-3799 Caramella et al. [35, 36] found that disintegration efficiency is based on the were further enhanced by adding an acid (e.g., citric acid) or an alkali (e.g., force-equivalent concept (the combined measurement of swelling force de- sodium bicarbonate). The suspension of above excipients was spray-dried to velopment and amount of water absorption). Force equivalence expresses yield a porous powder which was compressed into tablets. Tablets manufac- the capability of a disintegrant to transform absorbed water into swelling (or tured by this method disintegrated in < 20 seconds in an aqueous medium. disintegrating) force. The optimization of tablet disintegration was defined by means of the disintegrant critical concentration. Below this concentration, Sublimation the tablet disintegration time is inversely proportional to the disintegrant Sublimation has been used to produce ODTs with high porosity. A porous concentration. Above the critical concentration, the disintegration time re- matrix is formed by compressing the volatile ingredients along with other mains approximately constant or even increases [37]. excipients into tablets, which are finally subjected to a process of sublima- tion. Inert solid ingredients with high volatility (e.g., ammonium bicarbonate, GRANULATION METHODS ammonium carbonate, benzoic acid, camphor, hexamethylene tetramine, naph- thalene, phthalic anhydride, urea and urethene) have been used for this pur- Wet Granulation pose [42]. Solvents such as cyclohexane and benzene were also suggested for Bonadeo et al. [38] described a process of producing ODTs by wet granulation generating the porosity in the matrix. Makino et al., [43] reported a method in a fluidized bed. It was found that even with effervescent agents presented using water as pore-forming material. in the tablet with lower than 5%, quick disintegration times could be achieved. Furthermore, it was also found that fast disintegration time could be achieved Lo [44] disclosed an efficient method for preparing high-strength, highly po- using only the acid component of the effervescent couple. In the patent, the rous, fast-dissolving delivery devices. In this method menthol, a water-soluble, formulation includes polyalcohols (e.g., mannitol, xylitol, sorbitol, maltitol, menthol soluble polymer, and an active ingredient are mixed at a temperature erythritol, and lactitol), 1–30% of an edible acid, and an active ingredient as that insures that the menthol is substantially molten. The formulation is the dry mixture. This mixture was wet granulated with an aqueous solution disposed in a mold and solidified, and the menthol is sublimed from the of a water-soluble or water-dispersible polymer (e.g., poly(ethylene gly- solidified molded formulation. Preferably, the solidification occurs at a tem- cols), carrageenan, and ethylcellulose), which consisted of 1–10% of the final perature sufficient to provide a substantially amorphous menthol structure. weight of the granule in a fluid bed. Granules with high porosity and low apparent density were obtained, and the tablets made by such granules had Humidity Treatment rapid disintegration times ranging from 3 to 30 seconds in the saliva. The mechanical strength of some tablets increased substantially after mois- ture treatment, compared with the tablets before the treatment. The increase Dry Granulation is known to be due to the formation of liquid bridges in the presence of Eoga and Valia [39] disclosed a method of making ODTs by dry granulation. moisture and then formation of solid bridges after drying. Higher density alkali earth metal salts and water-soluble carbohydrates usu- ally do not provide quick disintegration and a smooth mouth feel. Low- Tatara et al. [45] used moisture treatment and devised an apparatus to handle density alkali earth metal salts and water soluble carbohydrates are also the fragile tablets before moisture treatment. An active ingredient and other difficult to compress and caused inadequate content uniformity. For these excipients were compressed in low pressure, and then the resultant tablets reasons, low-density alkali earth metal salts or water-soluble carbohydrates were moisturized and dried to produce a porosity between 20 and 40%. As were precompacted, and the resulting granules were compressed into tablets shown in figure 1, the manufacturing apparatus includes a rotary punch- that could dissolve fast. In this process, a powdered material with a density press, a relay conveyor for transferring tablets, a moisturizing section, a of 0.2–0.55 g/mL was precompacted to increase the density to 0.4–0.75 g/ drying section, and a delivery conveyor. In the moisturizing section, the mL by applying a force ranging from 1 to 9 kN/cm. The resulting granules condition was set to allow tablets moisturized at 45 °C, 95% relative humid- were compressed into tablets. ity for 60 seconds. In the drying section, the temperature was set to 50 °C for 60 seconds. With this apparatus the fragile tablets before moisture treatment Melt Granulation were gently transferred throughout the process. Abdelbary et al. [40] described a new approach of preparing ODTs with sufficient 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 as a 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 in a high-speed blade mixer at 40–44 °C, according to the conventional hot-melt procedure. For wet granulation, an oil-in-water emulsion of Superpolystate® was used as the granulating agent. Then, granules were blended with croscarmellose, aspartame, and magnesium stearate and compressed into tablets. The melt granulation ODTs had better hardness results than the wet granulation ODTs. The disintegration times of melt granulation tablets, how- ever, was more than 1 minute. Fig. 1 It shows schematic view of the manufacturing apparatus using Spray-Drying moisture treatment [45]. [41] Allen et al., have used spray-drying for the production of ODTs. The The left side of a dotted line shows the conventional compression and formulations contained hydrolyzed and unhydrolyzed gelatin as a support- dedusting steps, while the right side shows the additional step requiring ing agent for the matrix, mannitol as a bulking agent and sodium starch special chambers for moisture treatment and drying. glycolate/croscaramellose as a disintegrant. Disintegration and dissolution

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

Sintering Disintegrating Agents [46] Lagoviyer et al. disclosed a process that increased tablet strength by sin- The disintegrants have a major role in the disintegration and dissolution tering the tablet components at high temperatures and then resolidifying process of ODTs made by direct compression. The choice of a suitable type them at lower temperatures. The components in this formulation include and an optimal amount of disintegrants is paramount for ensuring a high bulk agents, structure agents, solvent, and binding agents. The suitable struc- disintegration rate. The addition of other formulation components such as ture agents should provide a porous support structure to allow quick disso- water soluble excipients or effervescent agents (e.g. sodium bicarbonate and lution of the tablets in the mouth. citric acid comnination) can further enhance dissolution or disintegration properties. Table 3 shows classification of superdisintegrants along with The structural agents include agar, gelatin, albumin, and chondroitin. Bulking their trade name. and structural agents were dissolved in a suitable solvent, and the dissolved mixture was spray dried or dispersed to obtain a bead or granulated product Table 3 Table Shows classification of ‘‘super disintegrants’’ (partial with a low density. Choice of the solvent is based on its ability to provide a listing) [65] desired porosity to the bead or granulated product upon drying. Solvents can be chosen from water, ethyl alcohol, isopropyl alcohol, or a mixture thereof. Structural type (NF name) Trade name (manucturer) 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- Modified starches Explotab® (Edward Mendell Co.) creases. Binders are water soluble polymers such as poly(ethylene glycol) (Sodium carboxymethyl starch) Primogel® (Generichem Corp.) Tablo® Blanver, Brazil (PEG), with a molecular weight of approximately 1000 to 1,000,000. PEG Croscarmellose, NF AcDiSol (FMC Corp.) melts at 50–90 °C. PEG has the advantage of functioning both as a binder and (Sodium carboxymethyl cellulose) Nymcel ZSX® (Nyma, Netherlands) as a capillary attractant. The amount of binding polymer ranged from 0.5% Primellose® (Avebe, Netherlands) to 25% of the weight of the final product. Solutab® (Blanver, Brazil) Cross-linked poly-vinylpyrrolidone Crospovidon M® (BASF Corp.) (Crospovidone NF) Kollidon CL® (BASF Corp.) EXCIPIENTS USED IN FORMULATION OF ODTs Polyplasdone XL (ISP Corp.) The excipients listed for a number of orally disintegrating products are pro- vided in table 2. ODTs typically composed of sweet fillers and flavouring Inorganic Excipients Used in ODTs agents. Compressed tabets typically are formulated with highly water soluble Dobetti [48] has developed a formulation using insoluble inorganic excipients fillers and relatively high levels of disintegrants. Insoluble fillers such as as the main component for ODTs. According to the patent, disintegration of microcrystalline cellulose are sometime used in these formulation but the a tablet depends on the quantity of the disintegrant and insoluble inorganic formulator must make sure that their particle sizes are small and that levels in excipient used. The disintegration also depends on the relative weight ratio the formulation are not excessive to avoid gritiness or any other unpleasant between the water insoluble and soluble excipients, if the water-soluble mouth feel. Like conventional tablets, compressed ODTs need gliadants (e.g. excipients are used. It was also found that in their formulations, sufficient colloidal silicone dioxide) to help the particles flow and lubricants (e.g. mag- compression could be applied to form tablets with strong tensile strength nesium stearate) to prevent sticking of the material the punches and facilitate and low friability. The disintegration rates were not significantly affected by ejection from dies. [6] the high compression force. In the formulation, three major components

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), citric acid, 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 paraben sodium, 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, magnesium stearate colloidal silicon dioxide, orange flavor

Journal of Pharmacy Research Vol.5 Issue 7.July 2012 3791-3799 Naresh Hiraram Choudhary et al. / Journal of Pharmacy Research 2012,5(7),3791-3799 were used includes substantially water insoluble components (water-insoluble ODTs of moderate strength, using a combination of starch or cellulose and excipients, water-insoluble drugs, and water- insoluble lubricant and glidant), one or more water-soluble saccharides. Erythritol was found to be the best substantially soluble components (compressible sugars, flavoring agents, sugar for this type of formulation, showing rapid disintegration that was sweeteners, binders, and surfactants) and disintegrants. negligibly affected by tablet hardness; good tolerability and sweetening; and a refreshing mouth sensation because of its endothermic dissolution heat [53]. The disintegration time increased as the amount of insoluble component decreased. If the active ingredient was only a small portion of the whole Ziplets technology formulation, the disintegration time could be optimized by including in- It is evident that the main challenge in developing an ODTs is to achieve both soluble fillers (e.g., microcrystalline cellulose and silicon dioxide) or by in- good physical resistance and disintegration properties. Generally, a tradi- creasing the amount of insoluble inorganic excipients (e.g., calcium salt such tional direct-compression approach is preferred because it offers low pro- as dibasic calcium phosphate). duction costs and the use of commonly available equipment and materials. Sweeteners On this basis, Eurand (Pessano con Bornago, Italy) recently developed the Sugars, sugar alcohols, and other artificial sweeteners are preferred fillers in Ziplets technology, which can be used with water insoluble compounds as ODTs. Sugar and sugar based excipients provide good mouth feel because both bulk actives and as coated microparticles (the latter containing soluble they are water soluble. Together with other flavouring agents and artificial and/or insoluble drugs). It was found that the addition of a suitable amount of sweeteners such as aspartame, they help to mask the taste of active ingredi- a water-insoluble inorganic excipient combined with one or more effective ents, many of which are bitter even in small doses. Some examples of sugars disintegrants imparted an excellent physical resistance to the ODTs and and sugar based excipients used in ODTs are amorphous sucrose, dextrose, simultaneously maintained optimal disintegration, even at low compression maltitol, mannitol, and xylitol. Sugar alcohols such as maltitol, mannitol, and forces and tablet hardnesses [54]. xylitol have the added advantage of containing fewer calories compared to sucrose and do not promote tooth decay. Mannitol and xylitol have negative In fact, handling problems during manufacturing (breakage of the tablet edges heats of solution, thereby imparting a cooling sensation in the mouth. Com- or formation of powder,which adversely affects the blistering phase) are mon artificial sweeteners in ODTs are acesulfame potassium, aspartame, avoided because of mechanical resistance. The risk of tablet breakage during sucralose and saccharin sodium [6]. the opening of the blister pack is eliminated. The use of water-insoluble inorganic excipients also offers better enhancement of disintegration charac- ORALLY DISINTEGRATING TABLETS TECHNOLOY teristics than most commonly used water-soluble sugars or salts. In fact, tablets composed primarily of water-soluble components often tend to dis- Wowtab® solve rather than disintegrate, resulting in a much longer disintegration time. The Wowtab® manufactured by Yamanouchi (Tokyo, Japan) is an As the soluble components dissolve on the tablet’s outer layer, the rate of the intrabuccally dissolved compressed moulding comprising granules made with water diffusion into the tablet core decreases because of the formation of saccharides having low and high mouldability, respectively [49]. Wowtab® concentrated viscous solutions [55]. technology employs a combination of low- and high-moldability saccharides to produce fast-dissolving tablets using conventional granulation and tableting Frosta® Technology techniques [50, 51]. The core concept of Frosta® technology is compressing highly plastic gran- ules at low pressure to produce strong tablets with high porosity. The highly According to the patent, saccharides were divided into two groups: those plastic granules comprise three classes of components: a porous and plastic with high moldability and those with low moldability. Low moldability material, a water penetration enhancer, and a binder. A simplified manufac- saccharides produce tablets with hardness between 0 and 2 kg, when 150 mg turing process of highly plastic granules and their ODTs is described in figure of such a saccharide is compressed under pressure of 10–50 kg/cm2 using a 2. The highly plastic granules can then be compressed at low pressure to die 8 mm in diameter. The typical low-moldability saccharides include lac- form a fast-melting pharmaceutical tablet. A porous, plastic material is water tose, mannitol, glucose, sucrose, and xylitol. High-moldability saccharides soluble or water dispersible, sometimes almost instantaneously upon con- produce tablets with hardness above 2 kg when prepared under the identical tact with water. Plastic deformation of powders dramatically increases the conditions. The typical high- moldability saccharides are maltose, maltitol, chance of the interparticle contacts necessary to form bonds between par- sorbitol, and oligosaccharides. When tablets are made by compressing a ticles. If a porous and plastic material is polymeric, it is essential to prevent saccharide having low moldability or high moldability alone, the desired formation of a viscous layer of the material at the tablet surface when it properties of adequate hardness and quick disintegration in the mouth cannot dissolves in aqueous medium. One way of making such tablets is to mix be achieved simultaneously. Moreover, if saccharides having low moldability porous, plastic material with a water penetration enhancer at certain ratios. and high moldability are mixed (physical mixture) before tableting, quick In this process, the porous and plastic particles are separated by water- disintegration and dissolution in the mouth cannot be obtained. As clearly penetration-enhancing particles, which prevent formation of a viscous layer indicated in the patents, there is no single saccharide that can make tablets on the tablet surface. Although the porous and plastic materials can make having both high strength and fast disintegration properties. For this reason, close contacts to increase the chance of bonding by compression, formation a saccharide having low moldability was granulated with a saccharide having of really strong bonding among granules at low pressures requires a suitable high moldability as a binder. The low-moldability saccharides were used as binder. The binder here can also secure the porous material and water pen- the main component. Tablets made by compression of these granules were etration enhancer during granulation. These two components can be easily further treated under moisture condition as described in fýgure 1. The tablets segregated during mixing without the binder. If the binder is in the liquid or show an adequate hardness and fast disintegration and dissolution when put semi-solid state, it should not significantly destroy the porous structure of in the mouth. The Wowtab® reportedly can accommodate high doses of the porous materials. One way of achieving this is to use aqueous binder multiparticulate watersoluble or insoluble drugs, dissolves rapidly, and has solutions with very low water activity. The highly plastic granule approach an adequate hardness [51, 52]. produces ODTs with excellent hardness and fast disintegration time ranging from several seconds to about 30 seconds, depending on the size of the Daiichi (Tokyo, Japan) performed a series of experiments to develop an tablets [56].

Journal of Pharmacy Research Vol.5 Issue 7.July 2012 3791-3799 Naresh Hiraram Choudhary et al. / Journal of Pharmacy Research 2012,5(7),3791-3799 carbonate, potassium bicarbonate, and potassium carbonate. The carbon dioxide evolved from the reaction may provide some “fizzing” sensation, which is a positive organoleptic sensation. The amount of effervescent agent is in general about 20–25% of the total weight of the tablet. Because of the soft and fragile nature of OraSolv® tablets, a special packaging system, known as PakSolv®, was developed to protect the tablets from breaking during transport and storage [63]. PakSolv® is a “dome-shaped” blister package that prevents the vertical movement of the tablet within the depressions, because the diameter of the lower portion of the dome is too narrow to accommodate the tablet. PakSolv® also offers light, moisture, and child resistance. [64].

Fig. 2 It shows a simplified manufacturing process of highly plastic The key ingredients in this formulation are nondirect compression filler and granules and their ODTs. (API: Active pharmaceutical ingredient) lubricant. The particle size of the nondirect compression filler is preferably between about 20 and 65 µm, while for direct compressible fillers at least Pharmaburst™ Technology 85% of the particles are over 100 µm in size. These nondirect compression Pharmaburst technology™ (SPI Pharma, New Castle, Delaware) uses off - fillers, such as dextrose, mannitol, sorbitol, lactose, and sucrose, have the the-shelf coprocessed excipients to create an ODTs that, depending on the advantage of quick dissolution and avoid some of the gritty or sandy texture type of active and loading (up to 700 mg), dissolves within 30–40 seconds. usually present in direct compressible versions of the sugar. The amount of The quantity of Pharmaburst™ required in a formulation depends on the nondirect compression filler is usually about 60–95% of the total tablet active in the tablet. It is necessary to carry out initial studies on a formulation weight. The tablets have low friability, which is about 2% or less when tested by varying the amount of Pharmaburst™ from 50 to 80%, depending on the according to the USP, and the hardness of the tablets is at least about 15-20 desired mouth feel and disintegration time. The process involves a dry blend N. The disintegration time is less than 60 seconds. of a drug, flavor, and lubricant that are compressed into tablets on a standard tablet press with stock tooling. The manufacture process can be carried out Thin-film technology under normal temperature and humanity conditions. The tablets can be pack- Thin-film technology is a relative new area of interest with respect to oral aged in blister packs or bottle [57]. fast-dispersing products. Although not strictly an ODT, the oral thin-film platform provides an alternative to traditional tablet approaches. Oral thin Flashtab® Technology films generally consist of hydrophilic polymers of varying thickness (50 to Flashtab® technology (Ethypharm, France) produces tablets by compres- 200 nm). The manufacturing process is based on liquid casting to control film sion of granular excipients. This technology uses almost the same excipients and weight variability. The dosage required is achieved by manipulating the as do conventional compressed tablets. Excipients used in this technology API concentration in the bulk solution and/or the film-thickness produced. comprise two groups of components: disintegrating agents, such as car- The films are dried by passing through oven(s) to evaporate the solvent used boxymethylcellulose or insoluble reticulated polyvinylpyrrolidone; and swell- to prepare the film. The dried film is cut into single unit doses before pack- ing agents, such as carboxymethylcellulose, starch, modified starch, aging. During manufacture, the dried film must be protected from heat and carboxymethylated starch, microcrystalline cellulose, and possibly directly humidity. The final packaging of the strips also needs careful consideration compressible sugars. The mixture of excipients is prepared by either dry or to protect the product from moisture. Taste-masking options include the use wet granulation methods. The produced tablets are known to have satisfac- of sweeteners, flavors, and ion-exchange-resin complexes. Encapsulated APIs tory physical resistance and disintegrate in the mouth within 1 minute [58]. for taste-masking purposes is challenging because the larger particles can give rise to uniformity issues. AdvaTab™ Technology AdvaTab™ technology (Eurand) produces ODTs tablets based on a propri- Although disintegration of thin films are rapid (< 30 s), their limitation is etary tablet composition that was designed and patented by Kyowa Hakko drug loading (approximately less than 30 mg). Increasing film-thickness or Kogyo (Tokyo, Japan) [59, 60] in which the lubrication is dispensed onto each using multiple layers may increase drug loading, but greater thickness can tablet by using a spray during the production process. Traditional tablets are have a negative effect on disintegration. The specific packaging requirements produced using an internal lubrication system, which disperses lubricant on also add complexity and cost to these products, though specific packaging the inside and the surface of the tablets. This method can decrease tablet technologies such as Catalent’s DelStrip pack are being developed to suit the mechanical strength. AdvaTab™ is produced using 10–30 times less hydro- thin film strips. To date, the majority of products have been in the over-the- phobic lubricant and can be 30–40% stronger than conventional tablets. As a counter sector (see Table 4) [14]. result, the tablets are hard and durable yet do not impede liquid entry upon contact with saliva. AdvaTab™ can handle high drug loading and coated drug Table 4 Table shows examples of products using thin film technologies particles. Importantly, the technology does not require specialty packaging Supplier Product Active ingredients (dose strength) and, as a result, can be packaged in both standard bottles and push-through blisters. Novartis Various products Phenylehedrine hydrogen chloride (HCl) under Theraflu Dextromethorphan hydrogen bromide (5 to 20 mg) OraSolv® and DuraSolv® Technology and Triaminic brands Diphenhydramine HCl (12.5 to 25 mg) ® OraSolv technology (Cima Labs) produces tablets by low compression Pfizer Sudafed Phenylephedrine HCl (10 mg) pressure [61, 62]. It uses an effervescent disintegration pair that releases gas MedTech Chloraseptic Benzocaine (3 mg) upon contact with water. The widely used effervescent disintegration pairs Products/ Prestige Menthol (2 mg) Brands usually include an acid source and a carbonate source. The acid sources include citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, and succinic acids. The carbonate sources include sodium bicarbonate, sodium

Journal of Pharmacy Research Vol.5 Issue 7.July 2012 3791-3799 Naresh Hiraram Choudhary et al. / Journal of Pharmacy Research 2012,5(7),3791-3799 PACKAGING in the mouth and this can be achieved by producing the porous structure of Selection of a packaging configuration is a crucial part of an ODT dosage the tablet matrix or adding superdisintegrant and/or effervescent excipients. form. Unlike conventional tablets, where packaging provides a means of ODTs prepared by direct compression usually have good mechanical prop- administration/transport, ODTs may require specialized packaging configu- erties, and the strength can be enhanced further by subsequent treatment, rations owing to their relative high moisture sensitivity and fragility. In fact, such as moisture treatment. The clinical studies show ODTs can improve the cost of packaging can be significant for commercialization. patient compliance, provide a rapid onset time of action, and increase bioavailability. One approach used to overcome the moisture and physical issues with ODTs is to select a rigid, multilayer foil-based barrier material to protect the REFERENCES dosage form, with the blister actually forming during the tablet formulation 1. Seager H. Drug Delivery Products and the Zydis Fast-Dissolving process. In many cases, ODTs are very fragile, and regular push through Dosage Form. J. Pharm. Pharmacol. 1998. 50: 375-382. blister packaging may break the tablet upon removing from the blister, so the 2. Habib W, Khankari R, Hontz J. Fast-dissolve drug delivery sys- packaging requires a peelable closure. tems. Crit. Rev. Thera. Drug Carrier Syst. 2000; 17(1):61-72. 3. Hirani JJ, Rathod DA, Vadalia KR. Orally Disintegrating Tablets: The most common packaging configuration includes blister packaging and A Review, Tropical Journal of Pharmaceutical Research, April 2009; bottle packaging. The final packaged dosage form has to be evaluated to 8 (2): 163 verify packaging integrity. One way to perform this is by immersing blisters 4. Yarwood R. Zydis — A Novel, Fast Dissolving Dosage Form. in water and subjecting them to a vacuum for a specified period of time. The Man. Chem. 1990. 36–37. blisters are then opened manually and checked for presence of water drop- 5. Dobetti L. Fast-melting tablets: developments and technologies. lets. Additionally, blisters and bottles should be monitored in simulated Pharmaceutical Technology Drug Delivery 2001; 44-49. shipping tests according to American Society for Testing Materials (ASTM) 6. Augsburger LL, Hoag SW, Pharmaceutical dosage forms: Tablets, standards. Some ODTs are sensitive to moisture to such an extent that, even third edition, vol-2, rational design and formulation, Informa during processing or formulation development stages, temperature and hu- healthcare, New York, londan, 2007; 293-311. midity have to be controlled to avoid long-term stability issues and may 7. Chue P, Welch R, Binder C. Acceptability and disintegration rate require special packaging. of orally disintegrating risperidone tablets in patients with schizo- phrenia or schizoaffective disorder. Can J Psych 2004; 49(10):701- REGULATORY 703 The FDA has set regulations for filing a petition of a Supplemental NDA for 8. Shen Y, Lee M, Lin C, et al. Orally disintegrating olanzapine for the a drug that has the same strength and route of administration as a drug listed treatment of a manic patient with esophageal stricture plus chronic in the FDA’s publication entitled ‘‘Approved Drug Products with Thera- pharyngitis. Progress Neuro Psychopharmacol & Bio Psych 2007; peutic Equivalence Evaluations,’’ but differ in dosage form. This petition 31: 541-542 generally can be filed pursuant to section 505(b) (2) of the Federal Food, 9. Fix JA. Advances in quick-dissolving tablets technology employ- Drug and Cosmetic Act and 21 CFR x 314.93. Most of the ODT drug ing Wowtab. Paper Presented at: IIR Conference on Drug Delivery delivery systems fall under this category. Depending on the bioequivalence Systems. 1998 Oct.; Washington DC, USA. study, certain products can get approval under this clause or otherwise will 10. Virely P, Yarwood R. Zydis – a novel, fast dissolving dosage form. need to establish safety and efficacy of the product by conducting further Manuf Chem. 1990; 61: 36–37. clinical trials. As ODTs products do not require administration of water, it 11. Jaccard TT, Leyder J. A new galenic form: lyoc. Ann Pharm Fr. may be required to perform bioequivalence studies with and without water 1985; 43: 123–131. depending upon the nature of the drug. This will depend upon the difference 12. Freudenreich O. Letter to the editor: Treatment of noncompliance of absorption of drug in the fed and fasted state and in addition may lead to with orally disintegrating olanazepine tablets. Can J Psych 2003: a fed and fasted study [65]. 48(5). http://ww1.cpaapc.org:8080/Publications/Archives/CJP/ 2003/june/lettersTreatment.asp. accessed on September 2007 FUTURE 13. Bogner R, Wilkosz M. Fast-dissolving tablets. U.S. Pharmacist The future of ODTs lies in the development of ODTs with controlled release 2002; 27:3 properties. If one ODT can deliver drugs with short half-lives for 12–24 14. McLaughlin R, Banbury S, Crowley K. Orally disintegrating tab- hours, it would be a quantum improvement in the ODT technology. The lets: The effect of recent FDA guidance on ODT technologies and added convenience and compliance of such formulations would be enormous. applications, Pharmaceutical technology, supplement to the Sep- The future of ODTs also lies in the development of effective taste-masking tember 2009 issue. properties. The use of coating poorly tasting drugs is commonly used, but it 15. FDA, Guidance for Industry: Orally Disintegrating Tablets increases the total volume of the final formulation. There may be no magic (Rockville, MD, Dec. 2008), www.fda.gov/OHRMS/ DO CKETS/ solution to this, but more effective use of existing taste masking technologies 98fr/ FDA-2007-D-0365-gdl.pdf, accessed Aug. 20, 2009. is expected to alleviate the problems associated with taste masking. In addi- 16. European Pharmacopeia, Version 6.5, 2009. tion, the ability to formulate drugs in large doses will bring another important 17. Mishra B, Singh S, Chakraborty S, Shukla D. Mouth dissolving technological advance. In general, the ODT formulations require large amount tablets I: An overview of formulation technology, Sci Pharm. 2009; of excipients, and having large doses of drug will only make the final formu- 77: 309-326 lation too big to handle. An ODT formulation that would require fewer 18. Catalent Pharm Solutions. Zydis® fast dissolve technology-Opti- excipients than the drug itself would be a breakthrough. mize your product’s market potential in less than 3 seconds. http:www.catalent.com/drug,oral,zydis/zydis.pdf CONCLUSION 19. Gole DJ, Levinson RS, Carbone J, Davies JD. Preparation of phar- The popularity of ODTs has increased tremendously over the last decade. maceutical and other matrix systems by solid-state dissolution. The key to ODTs formulations is fast disintegration, dissolution, or melting 1993. US Patent 5,215,756.

Journal of Pharmacy Research Vol.5 Issue 7.July 2012 3791-3799 Naresh Hiraram Choudhary et al. / Journal of Pharmacy Research 2012,5(7),3791-3799 20. Lafon L. Galenic form for oral administration and its method of material. Int J Pharm. 1997; 152: 127–131. preparation by lyophilization of an oil-in-water emulsion. 1986. 43. Makino T, Yamada M, Kikuta JI. Fast-dissolving tablet and its US Patent 4,616,047. production. 1998. US Patent 5,720,974. 21. Kaushik D, Dureja H, Saini TR. Orally disintegrating tablets-an 44. Lo JB. Method of producing porous delivery devices. 1993. WO overview of melt-in mouth tablet technologies and techniques. Patent 9,318,757. Tables Capsules 2004; 2(4):30–36. 45. Tatara M, Matsunaga K, Shimizu T. Method and apparatus for 22. Myers GL, Battist GE, Fuisz RC. Process and apparatus for manufacturing tablet capable of quick disintegration in oral cavity. making rapidly dissolving dosage units and product thereform. 2001. US Patent 6,316,026. 1999. US Patent 5,866,163. 46. Lagoviyer Y, Levinson RS, Stotler D, Riley TC. Means for creating 23. Misra TK, Currington JW, Kamath SV, Sanghvi PP, Sisak JR, a mass having structural integrity. 2002. US Patent 6,465,010. Raiden MG. Fast-dissolving comestible tablets formed under high- 47. Goel H, Rai P, Rana V, Tiwary AK. Orally Disintegrating Systems: speed/high-pressure conditions. 1999. US Patent 5,869,098. Innovations in Formulation and Technology, Recent Patents on 24. Misra TK, Currington JW, Montwill B, Kamath SV, Sanghvi PP, Drug Delivery & Formulation 2008; 2: 258-274. Sisak JR, Raiden M. Fast-dissolving comestible units formed un- 48. Dobetti L. Fast disintegrating tablets. 2003. US Patent 6,596,311. der high-speed/high-pressure conditions. 2000. US Patent 49. Mizumoto T, Masuda Y, and Fukui M. (Yamanouchi Pharmaceu- 6,048,541. tical Co. Ltd), Intrabuccally Dissolving Compressed Moldings 25. Parakh SR, Gothoskar AV. A review of mouth dissolving tablet and Production Process Thereof. 1996. US Patent 5,576,014 technologies. Pharm Technol. 2003; 27: 92-100. 50. Mizumoto T, Masuda Y, Kajiyama A, Yanagisawa M, Nyshadham 26. Masaki K. Intrabuccally disintegrating preparation and produc- JR. Tablets quickly disintegrating in the oral cavity and process for tion thereof. 1995. US Patent 5,466,464. producing the same. 2003. US Patent 6,589,554. 27. Pebley WS, Jager NE, Thompson SJ. Rapidly disintegrating tab- 51. Mizumoto T, Masuda Y, Fukui M. Intrabuccally dissolving com- let. 1994. US Patent 5, 298, 261. pressed moldings and production process thereof. 1996. US Patent 28. Makino T, Yamada M, Kikuta J. Fast dissolving tablet and its 5,576,014. production. 1993. EP Patent 0,553,777 A2. 52. Dor JM, Fix JA, and Johnson MI. A New In Vitro Method to 29. Nakamichi K, Izumi S, Yasuura H. Fast soluble tablets. 1994. EP Measure the Disintegration Time of a Fast-Disintegration Tablet. Patent 0,627,218 A1. Proc. Intl Symp. Control. Rel. Bioact. Mater.1996; 26, 939–940. 30. Humber-Droz P, Seidel M, Martani R. Fast disintegrating oral 53. Murakami T. et al., Rapidly Disintegrating Tablets with Saccha- dosage form. 1997. WO Patent 9,738,679. rides. Proc. Intl Symp. Control. Rel. Bioact. Mater.1999; 26: 855– 31. Okada M, Ikeda Y, Ono K, Kurazumi T, Kasai S, Imamori K. 856. Quickly soluble solid preparations. 2002. US Patent 6,455,053. 54. Dobetti (Eurand International). Fast Disintegrating Tablets. 1999. 32. Humber-Droz P, Seidel M, and Martani R. (Novartis Consumer PCT Patent WO 99/44580-A1 Health), Fast Disintegrating Oral Dosage Form.1997. PCT Patent 55. Shangraw R, Mitrevej A, and Shah M. A New Era of Tablet WO 97/38679-A1. Disintegrants. Pharm. Technol. 1980; 4 (10): 49–57 33. Chang R-K, Guo X, Burnside BA, Couch RA. Fast-dissolving 56. Jeong SH, Fu Y, Park K. Frosta®: a new technology for making tablets. Pharm TechnolN Am 2000; 24(6):52–58. fast-melting tablets. Expert Opinion on Drug Delivery 2005; 2 (6): 34. Shangraw R, Mitrevej A, Shah M. A New Era of Tablet 1107–1116. Disintegrants, Pharm. Technol. 1980; 4 (10): 49–57. 57. Kaushik D, Dureja H, Saini TR. Orally disintegrating tablets-an 35. Caramella et al., Disintegrants in Solid Dosage Forms, Drug Dev. overview of melt-in mouth tablet technologies and techniques. Ind. Pharm.1990; 16 (17): 2561–2577. Tables Capsules 2004; 2(4):30–36. 36. Caramella et al., The Role of Swelling in the Disintegration Pro- 58. Cousin G, Bruna E, Gendrot E. Rapidly disintegratable cess. Int. J. Pharm. Technol. Prod. Mfr. 1984; 5 (2), 1–5 multiparticular tablet. 1995. US Patent 5,464,632. 37. Ringard J, and Guyot-Hermann AM. Calculation of Disintegrant 59. Ohta M, Hayakawa E, Ito K, Tokuno S, Morimoto K, Watanabe V. Critical Concentration in Order to Optimize Tablets Disintegra- Intrabuccally rapidly disintegrating tablet. 1997. WO Patent tion. Drug Dev. Ind. Pharm. 1988; 14 (15–17): 2321–2339. 9,747,287. 38. Bonadeo D, Ciccarello F, Pagano A. Process for the preparation of 60. Hayakawa E, Ito K, Ohta M, Tokuno S, Morimoto K, Watanabe V. a granulate suitable to the preparation of rapidly disintegrable Intrabuccally rapidly disintegrating tablet. 1999. EU Patent mouth-soluble tablets and compositions obtained thereby. 1998. 0,914,818. US Patent 6,149,938. 61. Wehling F, Schuehle S. Base coated acid particles and effervescent 39. Eoga AB, Valia KH. Method for making fast-melt tablets. 1999. formulation incorporating same. 1996. US Patent 5,503,846. US Patent 5,939,091. 62. Wehling F, Schuehle S, Madamala N. Effervescent dosage form 40. Abdelbary G, Prinderre P, Eouani C, Joachim J, Reynier JP, with microparticles. 1993. US Patent 5,178,878. Piccerelle P. The preparation of orally disintegrating tablets using 63. Amborn J, Tiger V. Apparatus for handling and packaging friable a hydrophilic waxy binder. Int J Pharm 2004; 278(2):423–433. tablets. 2001. US Patent 6,311,462. 41. Allen LV, Wang B, Davis JD. Rapidly dissolving tablet. 1998. US 64. Khankari RK, Hontz J, Chastain SJ, Katzner L. Rapidly dissolv- Patent 5,807,576. ing robust dosage form. 2000. US Patent 6,024,981. 42. Koizumi KI, Watanabe Y, Morita K, Utoguchi N, Matsumoto M. 65. Swarbrick J. Encyclopedia of pharmaceutical technology, Third New method for preparing high porosity rapidly saliva soluble edition, volume 2, Informa healthcare, New York, Londan. 2007. compressed tablets using mannitol with camphor, a subliming 3554, 1108-1110

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

Journal of Pharmacy Research Vol.5 Issue 7.July 2012 3791-3799