Naresh Hiraram Choudhary et al.

/ Journal of Pharmacy Research 2012,5(7),3791-3799

Review Article ISSN: 0974-6943

Available online through www.jpronline.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 Societys, 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 and consequently do not take medications 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 demand for solid dosage forms that can be dissolved and suspended in water, chewed, or rapidly dissolved in the mouth is particularly strong in the pediatric and geriatric markets, with further application to other patients who prefer the convenience of a readily administered dosage form. Because of the increase in the average human life span and the decline, with age, in swallowing ability, oral tablet administration to patients is a significant problem and has become the object of public attention [1]. The problem can be resolved by the creation of Orally Disintegrating Tablets (ODTs). ODTs rapidly disintegrate in the mouth without chewing upon oral administration and without the need for water, unlike other drug delivery systems and conventional oral solid immediate-release dosage form [2]. ODTs dosage forms, also commonly known as fast melt, quick melts, fast disintegrating, or dispersible systems have the unique property of disintegrating the tablet in the mouth in seconds [3]. The dosage forms are placed in the mouth, allowed to disperse or dissolve in the saliva, and then are swallowed in the normal way. Less frequently, they are designed to be absorbed through the buccal and esophageal mucosa as the saliva passes into the stomach. In the latter case, the bioavailability of a drug from fast dispersing formulations may be even greater than that observed for standard dosage forms. Furthermore, side effects may be reduced if they are caused by first pass metabolites [1, 4]. Orally disintegrating dosage forms are often formulated for existing drugs with an intention to extend the patent life of the drug through product differentiation. They are evaluated against the innovator drug in a bioequivalence study in humans to establish comparability of pharmacokinetic parameters.

Despite a surge of orally disintegrating tablets in the market in the recent years, they potentially can be confused with other solid oral dosage forms that are consumed without additional water intake, including lozenges, buccal tablets, chewable tablets and effervescent tablets. Lozenges and buccal tablets are intended to dissolve slowly in the mouth, whereas, ODTs must disperse or dissolve in the mouth quickly, within seconds. Chewable tablets are also different from orally disintegrating tablets because they require manual chewing action by the patient before they can be swallowed. The disintegration times are longer for the chewable tablets as compared to the ODTs. Effervescent tablets require preparatory steps before administration of the drug [5, 6]. One of the greatest benefits of ODTs over conventional tablets is enhanced patient compliance and acceptance related to both feasibility and convenience of dosage administration [7]. Population having difficulty in swallowing intact tablets and hard gelatin capsules include pediatric and geriatric, patients who are bedridden, mentally retarded, uncooperative, nauseous, and those suffering from nervous or anatomical disorder of the larynx or esophagus, or on reduced liquid intake diets also cannot swallow conventional tablets. In such patients practitioners would expect much better compliance and therapeutics outcomes by administering ODTs instead of conventional tablets [8]. Patient compliance can be enhanced by designing orally disintegrating tablets that have pleasant taste and texture because many people simply do not enjoy swallowing solid tablets. People who take medicine such as-needed basis and active people who do not have convenient access to water could easily take them as well [6]. Other advantages includes benefit of liquid medication in the form of solid preparation, more rapid drug absorption from the pre-gastric area i.e. mouth, pharynx and esophagus which may produce rapid onset of action, pregastric absorption can result in improved bioavailability, reduced dose and improved clinical performance by reducing side effect, new business opportunities like product differentiation, line extension and lifecycle management, exclusivity of product promotion and patent-life extension [9,10,11]. Orally disintegrating tablet drug delivery does, however, have certain limitations. Because ODTs require the users to produce their own saliva, those

*Corresponding author.
Naresh Hiraram Choudhary. Department of Pharmaceutics, Sinhgad Technical Education Societys, Smt. Kashibai Navale College of Pharmacy, Kondhwa [Bk], Pune, Maharashtra, India.

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with very dry mouth may not benefit. Production of saliva depends not only on the drug product formulation but the ability and condition of the user. Also, the administration of ODTs to increase compliance in uncooperative patients, such as those being treated for mental illness, does not guarantee compliance. Patients have found various ways of hiding the medication such as sticking the Zydis tablets behind the teeth to avoid swallowing the medication [12]. Nonetheless, ODTs offer practitioners an added tool in enhancing compliance in some patient population [13]. RECENT FDA GUIDANCE ON ODT TECHNOLOGIES The emergence of multiple ODT technology platforms created some regulatory challenges due to increasing variance in the critical product attributes of ODTs, notably disintegration time and tablet size. Hypothetically, in an abbreviated new drug application, the disintegration time of a generic product could be 3045 s, and the disintegration time of a reference product 010 s. Prolonged disintegration times may result in failure to meet the defining performance characteristics of the ODTs dosage form, such that the product might require water for administration or chewing to facilitate swallowing. Where the patient or caregivers expectation is for rapid dispersion in the mouth, larger units with slower disintegration times could result in confusion regarding the product quality and even present a choking hazard. Thus, in addition to product definition, patient safety is also a significant consideration [14]. Freeze-Drying or Lyophilization This technique forms the basis of Zydis (Cardinal Health), Quicksolv (Janssen Pharmaceutica), Lyoc (Pharmalyoc), and NanoCrystal (Elan) technologies which are used to manufacture ODTs [17]. Zydis Technology utilizes a unique freeze-drying process to manufacture finished dosage units which significantly differ from conventional oral systems. The process involves the following steps:

Stage 1 - Bulk preparation of an aqueous drug solution or suspension and its subsequent precise dosing into pre-formed blisters. It is the blister that actually forms the tablet shape and is, therefore, an integral component of the total product package. Stage 2 - Passing the filled blisters through a specially designed cryogenic freezing process to control the ultimate size of the ice crystals which ensures that the tablets possess a porous matrix to facilitate the rapid disintegration property. These frozen units are then transferred to large-scale freeze dryers for the sublimation process, where the majority of the remaining moisture is removed from the tablets. Stage 3 -Sealing the open blisters using a heat-seal process to ensure stability and protection of the product from varying environmental conditions. 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 freezing2008 publication of Guidance for Industry: Orally Disintegrating Tablets [15]. 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 Quicksolv (Janssen Pharmaceutica, Beese, Belgium) and Lyoc (Farmalyoc although the combined influence of tablet weight, size, and component solubility all factor into the acceptability of an ODT for both Laboratorie L., Lefon, Maisons-Alfort, France) are also prepared by the freeze drying method. In the Quicksolv formulation, the matrix composipatients and regulators. 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 subter 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 having a disintegration time of less than 3 min [16]. 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 adequate strength for handling. 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 Technologies, Norman, Oklahoma) are widely known technologies. Table 1 shows summary of technologies used to prepare ODTs. Table 1 Shows summary of Technologies Used to Prepare ODTs
Basic for Technology Lyophilization process Company Cardinal Health Janssen Pharmaceutica Pharmalyoc Elan Biovail (Fuisz) Cima Labs Yamanouchi Elan Corp. Ethypharm Eurand KV Pharmaceutical SPI Pharm Alkina Technology Zydis Quiksolv Lyoc NanoCrystal FlashDose OraSolv/DuraSolv WOWTAB Fast Melt Flashtab AdvaTab/Ziplets OraQuik Pharmburst Frosta

Lyoc In the Lyoc formulation, the porous solid form is obtained by freeze drying an oil-in-water emulsion placed directly in the blister pockets. In order to prevent inhomogeneity by sedimentation during freeze drying, this formulation requires a large proportion of undissolved inert filler to increase the viscosity of the suspension. The high proportion of filler reduces the porosity of the tablet, and as a result, the disintegration is slower. It is also noted that the tablet still has poor mechanical resistance [20]. Advantages of Lyoc compared to other freeze dried dosage forms include absence of preservatives [3]. NanoCrystal technology NanoCrystal technology (Elan, King of Prussia, Pennsylvania) uses orally administered nanoparticles (<2 m) in the form of rapidly disintegrating tablet matrix. The NanoCrystal orally disintegrating tablet dosage form was developed to facilitate the preparation of small-scale clinical supplies. NanoCrystal colloidal dispersions of drug substance are combined with

Cotton candy process Tableting process

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water-soluble ingredients, filled into blisters, and lyophilized. This approach is especially attractive when working with highly potent or hazardous materials because it avoids manufacturing operations such as granulation, blending, and tableting, which generate large quantities of aerosolized powder and present much higher risk of exposure. The freeze-drying approach also enables small quantities of drug to be converted into ODTs because manufacturing losses are negligible. The final tablet is durable enough for conventional blister or bottle packaging and accepts as much as 200 mg of drug per unit[21]. COTTON CANDY PROCESS Fuisz Technologies (Chantilly, Virginia) has introduced the Shearform Technology to make Flashdose. The Shearform Technology uses a unique spinning mechanism to produce a floss-like crystalline structure, much like cotton candy. In this process, the feedstock is subjected to centrifugal force and 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 perimeter of a spinning head. The mass is cooled down as it comes out of the opening to form a discrete fiber structure, as seen in cotton candy. The speed of spinning is about 3,0004000 rpm, and the temperature gradient is about 180250C. The carrier materials include saccharides, polysaccharides, and mixtures thereof [22]. There were two systems used to create the Shearform floss having selfbinding 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 effective self binding properties. The second system used two separate flosses. One was xylitol containing binder flosses and the other was base flosses that contain different sugar alcohols or saccharide. When the two flosses were combined, it was termed a dual floss system. The produced floss needed to be recrystallized to form freely flowing granules with self-binding properties. Two techniques were used in recrystallization. One was using crystallization enhancers including ethanol, polyvinylpyrrolidone, water (e.g.,moisture), glycerin, and radiant energy (e.g., microwaves). The other was using crystallization modifiers, which were included in floss ingredients at 0.0120.0% the weight of the floss. Typical crystallization modifiers were surfactants having an HLB of about 6 or more. TABLET MOULDING Moulded tablets invariably contain water-soluble ingredients due to which the tablets dissolve completely and rapidly. Following are the different tablet moulding techniques: Compression Moulding Process This manufacturing process involves moistening the powder blend with a hydroalcoholic solvent followed by pressing into mould plates to form a wetted mass (compression moulding). The solvent is then removed by air drying, a process similar to the manufacture of tablet triturates. Such tablets are less compact than compressed tablets and possess a porous structure that hastens dissolution [25]. Heat-Moulding Process Heat-moulding process involves setting the molten mass containing a dispersed drug. This process uses agar solution as a binder and a blister packaging well as a mould to manufacture the tablet. A suspension containing drug, agar and sugar is prepared followed by pouring the suspension into the blister packaging well, solidifying the agar solution at room temperature to form a jelly and finally drying at approximately 30 C under vacuum [26]. Moulding by Vacuum Evaporation without Lyophilization This 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 to form a solidified matrix and finally subjecting it to vacuum drying at a temperature within the range of its collapse temperature and equilibrium freezing temperature. This results in the formation of a partially collapsed matrix. This method differs from the lyophilization technique, as in the former the evaporation of free unbound solvent occurs from a solid through the liquid phase to a gas, under controlled conditions, instead of the sublimation which takes place in the latter process. Unlike lyophilization, vacuum drying helps to densify the matrix and thereby improves the mechanical strength of the product. 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 tabletshaped mould to design a ODTs with a disintegration time of about 20 60 secs. Takeda Chemical Industries (Osaka, Japan) and Nippon Shinyaku (Kyoto, Japan) have disclosed compression-molding. The wetted mass was compressed at low pressure and subsequently dried to produce porous tablets with 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 into molds. The solvent was removed from the units usually by heating, pressure reduction, or microwave radiation [30]. In a patent by Okada, the molded tablets contained a drug, a saccharide having a solubility of 30 (w/w) % or less at room temperature (e.g., lactose and mannitol), and a saccharide having a solubility of 30 (w/w) % or more at room temperature (e.g., glucose, fructose, sucrose, xylose, trehalose, xylitol, sorbitol, erythritol, dextrin, and pullulan). The amount of this saccharide was slightly above its solubility. The mixture was a creamy aqueous suspension having both low solubility and high solubility saccharides in water. The moisture was then removed from the suspension to obtain molded tablets [31]. Novartis Consumer Health (Basel, Switzerland) also has filed a patent application for tablets prepared by dispensing the drug solution or suspension into moulds, evaporating the solvent from the units (usually achieved by heating, pressure reduction, or microwave radiation), and then optionally sealing the dried units directly in the mould. The patent application reported only examples of low dose and low-weight forms, although higher amounts are claimed [32]. DIRECT COMPRESSION From the pharmaceutical manufacturers point of view, direct compression is the simplest and most cost-effective tablet manufacturing procedure. Pharmaceutical companies can use conventional manufacturing equipment and commonly available ingredients. This method can be applied to manufacturing ODTs by choosing appropriate combinations of excipients, which can provide fast disintegration and good physical resistance. Sugar-based excipients have been widely used as bulking agents because of their high aqueous solubility and sweetness, pleasing mouth-feel and good taste masking. Nearly all formulations for ODTs incorporate some sugar materials in their formulations [33]. The direct-compression tablets disintegration and solubilization are based on 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) by tablet size and hardness. Large, hard tablets can have a disintegration time greater than that usually required for ODTs. As a consequence, products with optimal disintegration properties often have a mediumsmall 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 the force-equivalent concept (the combined measurement of swelling force development and amount of water absorption). Force equivalence expresses the capability of a disintegrant to transform absorbed water into swelling (or disintegrating) force. The optimization of tablet disintegration was defined by means of the disintegrant critical concentration. Below this concentration, the tablet disintegration time is inversely proportional to the disintegrant concentration. Above the critical concentration, the disintegration time remains approximately constant or even increases [37]. GRANULATION METHODS Wet Granulation Bonadeo et al. [38] described a process of producing ODTs by wet granulation in a fluidized bed. It was found that even with effervescent agents presented 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 using only the acid component of the effervescent couple. In the patent, the formulation includes polyalcohols (e.g., mannitol, xylitol, sorbitol, maltitol, erythritol, and lactitol), 130% of an edible acid, and an active ingredient as the dry mixture. This mixture was wet granulated with an aqueous solution of a water-soluble or water-dispersible polymer (e.g., poly(ethylene glycols), carrageenan, and ethylcellulose), which consisted of 110% of the final 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 rapid disintegration times ranging from 3 to 30 seconds in the saliva. Dry Granulation Eoga and Valia [39] disclosed a method of making ODTs by dry granulation. Higher density alkali earth metal salts and water-soluble carbohydrates usually do not provide quick disintegration and a smooth mouth feel. Lowdensity alkali earth metal salts and water soluble carbohydrates are also difficult to compress and caused inadequate content uniformity. For these reasons, low-density alkali earth metal salts or water-soluble carbohydrates were precompacted, and the resulting granules were compressed into tablets that could dissolve fast. In this process, a powdered material with a density of 0.20.55 g/mL was precompacted to increase the density to 0.40.75 g/ mL by applying a force ranging from 1 to 9 kN/cm. The resulting granules were compressed into tablets. Melt Granulation 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 3337 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 disintegration of the tablets. In case of melt granulation, granules were prepared in a high-speed blade mixer at 4044 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, however, was more than 1 minute. Spray-Drying Allen et al., [41] have used spray-drying for the production of ODTs. The formulations contained hydrolyzed and unhydrolyzed gelatin as a supporting agent for the matrix, mannitol as a bulking agent and sodium starch glycolate/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 to yield a porous powder which was compressed into tablets. Tablets manufactured by this method disintegrated in < 20 seconds in an aqueous medium. Sublimation Sublimation has been used to produce ODTs with high porosity. A porous matrix is formed by compressing the volatile ingredients along with other excipients into tablets, which are finally subjected to a process of sublimation. Inert solid ingredients with high volatility (e.g., ammonium bicarbonate, ammonium carbonate, benzoic acid, camphor, hexamethylene tetramine, naphthalene, phthalic anhydride, urea and urethene) have been used for this purpose [42]. Solvents such as cyclohexane and benzene were also suggested for generating the porosity in the matrix. Makino et al., [43] reported a method using water as pore-forming material. Lo [44] disclosed an efficient method for preparing high-strength, highly porous, fast-dissolving delivery devices. In this method menthol, a water-soluble, menthol soluble polymer, and an active ingredient are mixed at a temperature that insures that the menthol is substantially molten. The formulation is disposed in a mold and solidified, and the menthol is sublimed from the solidified molded formulation. Preferably, the solidification occurs at a temperature sufficient to provide a substantially amorphous menthol structure. Humidity Treatment The mechanical strength of some tablets increased substantially after moisture treatment, compared with the tablets before the treatment. The increase is known to be due to the formation of liquid bridges in the presence of moisture and then formation of solid bridges after drying. Tatara et al. [45] used moisture treatment and devised an apparatus to handle the fragile tablets before moisture treatment. An active ingredient and other excipients were compressed in low pressure, and then the resultant tablets were moisturized and dried to produce a porosity between 20 and 40%. As shown in figure 1, the manufacturing apparatus includes a rotary punchpress, a relay conveyor for transferring tablets, a moisturizing section, a drying section, and a delivery conveyor. In the moisturizing section, the condition was set to allow tablets moisturized at 45 C, 95% relative humidity 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 were gently transferred throughout the process.

Fig. 1 It shows schematic view of the manufacturing apparatus using moisture treatment [45]. The left side of a dotted line shows the conventional compression and dedusting steps, while the right side shows the additional step requiring special chambers for moisture treatment and drying.

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Sintering Lagoviyer et al.[46] disclosed a process that increased tablet strength by sintering the tablet components at high temperatures and then resolidifying them at lower temperatures. The components in this formulation include bulk agents, structure agents, solvent, and binding agents. The suitable structure agents should provide a porous support structure to allow quick dissolution of the tablets in the mouth. The structural agents include agar, gelatin, albumin, and chondroitin. Bulking 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 with a low density. Choice of the solvent is based on its ability to provide a desired porosity to the bead or granulated product upon drying. Solvents can be 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 decreases. Binders are water soluble polymers such as poly(ethylene glycol) (PEG), with a molecular weight of approximately 1000 to 1,000,000. PEG melts at 5090 C. PEG has the advantage of functioning both as a binder and as 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 ODTs The excipients listed for a number of orally disintegrating products are provided in table 2. ODTs typically composed of sweet fillers and flavouring agents. Compressed tabets typically are formulated with highly water soluble fillers and relatively high levels of disintegrants. Insoluble fillers such as microcrystalline cellulose are sometime used in these formulation but the formulator must make sure that their particle sizes are small and that levels in the formulation are not excessive to avoid gritiness or any other unpleasant mouth feel. Like conventional tablets, compressed ODTs need gliadants (e.g. colloidal silicone dioxide) to help the particles flow and lubricants (e.g. magnesium stearate) to prevent sticking of the material the punches and facilitate ejection from dies. [6] Disintegrating Agents The disintegrants have a major role in the disintegration and dissolution process of ODTs made by direct compression. The choice of a suitable type and an optimal amount of disintegrants is paramount for ensuring a high disintegration rate. The addition of other formulation components such as water soluble excipients or effervescent agents (e.g. sodium bicarbonate and citric acid comnination) can further enhance dissolution or disintegration properties. Table 3 shows classification of superdisintegrants along with their trade name. Table 3 Table Shows classification of super disintegrants (partial listing) [65]
Structural type (NF name) Modified starches (Sodium carboxymethyl starch) Croscarmellose, NF (Sodium carboxymethyl cellulose) Trade name (manucturer) Explotab (Edward Mendell Co.) Primogel (Generichem Corp.) Tablo Blanver, Brazil AcDiSol (FMC Corp.) Nymcel ZSX (Nyma, Netherlands) Primellose (Avebe, Netherlands) Solutab (Blanver, Brazil) Crospovidon M (BASF Corp.) Kollidon CL (BASF Corp.) Polyplasdone XL (ISP Corp.)

Cross-linked poly-vinylpyrrolidone (Crospovidone NF)

Inorganic Excipients Used in ODTs Dobetti [48] has developed a formulation using insoluble inorganic excipients as the main component for ODTs. According to the patent, disintegration of a tablet depends on the quantity of the disintegrant and insoluble inorganic excipient used. The disintegration also depends on the relative weight ratio between the water insoluble and soluble excipients, if the water-soluble excipients are used. It was also found that in their formulations, sufficient compression could be applied to form tablets with strong tensile strength and low friability. The disintegration rates were not significantly affected by 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 Zydis Products Claritin Reditab Feldene Melt Maxalt-MLT Pepcid RPD Zyprexa Zydis Name of the Company R.P. Scherer/ Schering Plough, Kenilworth, USA Pfizer Inc, NY, USA. R.P.Scherer / Merck & Co., NY, USA. Merck & CO., NY, USA. R.P.Scherer/Eli Lilly, Indianapolis, USA. Composition Micronized loratidine (10mg), citric acid, mannitol, gelatin, mint flavor Piroxicam (10 or 20 mg), mannitol, gelatin, aspartame, citric anhydrous Rizatriptan (5 or 10 mg), mannitol, gelatin, aspartame, peppermint flavor Famotidine (20 or 40 mg), mannitol, gelatin,aspartame Olanzapine (5, 10, 15 or 20 mg), mannitol, gelatin, aspartame, methyl paraben sodium, propyl paraben sodium Ondansetron (4 or 8 mg), mannitol, gelatin, aspartame, methyl paraben sodium, propyl paraben sodium, strawberry flavor Mirtazepine (15,30 or 45 mg), mannitol, aspartame, citric acid, crosspovidone, Avicel, NaHCO3, HPMC, maagnesium stearate, povidone, PMA, starch, sucrose, orange flavor Acetaminophen (80 or 160 mg), mannitol (currently available in Canada) Hyoscyamine sulphate (0.125mg), aspartame, colloidal silicon dioxidecrospovidone, mint flavor, magnesium stearate, mannitol, Avicel Zolmitriptan (2.5mg), mannitol, aspartame, citric acid anhydrous crospovidone, Avicel, sodium bicarbonate, magnesium stearate colloidal silicon dioxide, orange flavor

Zofran ODT

R.P.Scherer/Glaxo Wellcome, Middlesex, UK.

Orasolv

Remeron Soltab

CIMA / Organon, Glaxo Wellcome, Middlesex, UK.

Tempra First Tabs Durasolv Nulev

CIMA / Mead Johnson, Bristol Myers Squibb, NY, USA. CIMA/Schwarz Pharma.

Zoming ZMT

CIMA / AstraZeneca, Wilmington,USA.

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were used includes substantially water insoluble components (water-insoluble excipients, 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 component decreased. If the active ingredient was only a small portion of the whole formulation, the disintegration time could be optimized by including insoluble fillers (e.g., microcrystalline cellulose and silicon dioxide) or by increasing the amount of insoluble inorganic excipients (e.g., calcium salt such as dibasic calcium phosphate). Sweeteners Sugars, sugar alcohols, and other artificial sweeteners are preferred fillers in ODTs. Sugar and sugar based excipients provide good mouth feel because they are water soluble. Together with other flavouring agents and artificial sweeteners such as aspartame, they help to mask the taste of active ingredients, many of which are bitter even in small doses. Some examples of sugars and sugar based excipients used in ODTs are amorphous sucrose, dextrose, maltitol, mannitol, and xylitol. Sugar alcohols such as maltitol, mannitol, and xylitol have the added advantage of containing fewer calories compared to sucrose and do not promote tooth decay. Mannitol and xylitol have negative heats of solution, thereby imparting a cooling sensation in the mouth. Common 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 an intrabuccally dissolved compressed moulding comprising granules made with saccharides having low and high mouldability, respectively [49]. Wowtab technology employs a combination of low- and high-moldability saccharides to produce fast-dissolving tablets using conventional granulation and tableting techniques [50, 51]. According to the patent, saccharides were divided into two groups: those with high moldability and those with low moldability. Low moldability saccharides produce tablets with hardness between 0 and 2 kg, when 150 mg of such a saccharide is compressed under pressure of 1050 kg/cm2 using a die 8 mm in diameter. The typical low-moldability saccharides include lactose, mannitol, glucose, sucrose, and xylitol. High-moldability saccharides produce tablets with hardness above 2 kg when prepared under the identical conditions. The typical high- moldability saccharides are maltose, maltitol, sorbitol, and oligosaccharides. When tablets are made by compressing a saccharide having low moldability or high moldability alone, the desired properties of adequate hardness and quick disintegration in the mouth cannot be achieved simultaneously. Moreover, if saccharides having low moldability and high moldability are mixed (physical mixture) before tableting, quick disintegration and dissolution in the mouth cannot be obtained. As clearly indicated in the patents, there is no single saccharide that can make tablets having both high strength and fast disintegration properties. For this reason, a saccharide having low moldability was granulated with a saccharide having high moldability as a binder. The low-moldability saccharides were used as the main component. Tablets made by compression of these granules were further treated under moisture condition as described in fgure 1. The tablets show an adequate hardness and fast disintegration and dissolution when put in the mouth. The Wowtab reportedly can accommodate high doses of multiparticulate watersoluble or insoluble drugs, dissolves rapidly, and has an 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 and one or more water-soluble saccharides. Erythritol was found to be the best sugar for this type of formulation, showing rapid disintegration that was negligibly affected by tablet hardness; good tolerability and sweetening; and a refreshing mouth sensation because of its endothermic dissolution heat [53]. Ziplets technology It is evident that the main challenge in developing an ODTs is to achieve both good physical resistance and disintegration properties. Generally, a traditional direct-compression approach is preferred because it offers low production costs and the use of commonly available equipment and materials. On this basis, Eurand (Pessano con Bornago, Italy) recently developed the Ziplets technology, which can be used with water insoluble compounds as both bulk actives and as coated microparticles (the latter containing soluble and/or insoluble drugs). It was found that the addition of a suitable amount of a water-insoluble inorganic excipient combined with one or more effective disintegrants imparted an excellent physical resistance to the ODTs and simultaneously maintained optimal disintegration, even at low compression forces and tablet hardnesses [54]. In fact, handling problems during manufacturing (breakage of the tablet edges or formation of powder,which adversely affects the blistering phase) are avoided because of mechanical resistance. The risk of tablet breakage during the opening of the blister pack is eliminated. The use of water-insoluble inorganic excipients also offers better enhancement of disintegration characteristics than most commonly used water-soluble sugars or salts. In fact, tablets composed primarily of water-soluble components often tend to dissolve rather than disintegrate, resulting in a much longer disintegration time. As the soluble components dissolve on the tablets outer layer, the rate of the water diffusion into the tablet core decreases because of the formation of concentrated viscous solutions [55]. Frosta Technology The core concept of Frosta technology is compressing highly plastic granules at low pressure to produce strong tablets with high porosity. The highly plastic granules comprise three classes of components: a porous and plastic material, a water penetration enhancer, and a binder. A simplified manufacturing process of highly plastic granules and their ODTs is described in figure 2. The highly plastic granules can then be compressed at low pressure to form a fast-melting pharmaceutical tablet. A porous, plastic material is water soluble or water dispersible, sometimes almost instantaneously upon contact with water. Plastic deformation of powders dramatically increases the chance of the interparticle contacts necessary to form bonds between particles. If a porous and plastic material is polymeric, it is essential to prevent formation of a viscous layer of the material at the tablet surface when it dissolves in aqueous medium. One way of making such tablets is to mix porous, plastic material with a water penetration enhancer at certain ratios. In this process, the porous and plastic particles are separated by waterpenetration-enhancing particles, which prevent formation of a viscous layer on the tablet surface. Although the porous and plastic materials can make close contacts to increase the chance of bonding by compression, formation of really strong bonding among granules at low pressures requires a suitable binder. The binder here can also secure the porous material and water penetration enhancer during granulation. These two components can be easily segregated during mixing without the binder. If the binder is in the liquid or semi-solid state, it should not significantly destroy the porous structure of the porous materials. One way of achieving this is to use aqueous binder solutions with very low water activity. The highly plastic granule approach produces ODTs with excellent hardness and fast disintegration time ranging from several seconds to about 30 seconds, depending on the size of the tablets [56].

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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 2025% 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 granules and their ODTs. (API: Active pharmaceutical ingredient) Pharmaburst Technology Pharmaburst technology (SPI Pharma, New Castle, Delaware) uses off the-shelf coprocessed excipients to create an ODTs that, depending on the type of active and loading (up to 700 mg), dissolves within 3040 seconds. The quantity of Pharmaburst required in a formulation depends on the active in the tablet. It is necessary to carry out initial studies on a formulation by varying the amount of Pharmaburst from 50 to 80%, depending on the desired mouth feel and disintegration time. The process involves a dry blend 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 under normal temperature and humanity conditions. The tablets can be packaged in blister packs or bottle [57]. Flashtab Technology Flashtab technology (Ethypharm, France) produces tablets by compression of granular excipients. This technology uses almost the same excipients as do conventional compressed tablets. Excipients used in this technology comprise two groups of components: disintegrating agents, such as carboxymethylcellulose or insoluble reticulated polyvinylpyrrolidone; and swelling agents, such as carboxymethylcellulose, starch, modified starch, carboxymethylated starch, microcrystalline cellulose, and possibly directly compressible sugars. The mixture of excipients is prepared by either dry or wet granulation methods. The produced tablets are known to have satisfactory physical resistance and disintegrate in the mouth within 1 minute [58]. AdvaTab Technology AdvaTab technology (Eurand) produces ODTs tablets based on a proprietary tablet composition that was designed and patented by Kyowa Hakko Kogyo (Tokyo, Japan) [59, 60] in which the lubrication is dispensed onto each tablet by using a spray during the production process. Traditional tablets are produced using an internal lubrication system, which disperses lubricant on the inside and the surface of the tablets. This method can decrease tablet mechanical strength. AdvaTab is produced using 1030 times less hydrophobic lubricant and can be 3040% stronger than conventional tablets. As a 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 particles. Importantly, the technology does not require specialty packaging and, as a result, can be packaged in both standard bottles and push-through blisters. OraSolv and DuraSolv Technology OraSolv technology (Cima Labs) produces tablets by low compression pressure [61, 62]. It uses an effervescent disintegration pair that releases gas upon contact with water. The widely used effervescent disintegration pairs 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 The key ingredients in this formulation are nondirect compression filler and lubricant. The particle size of the nondirect compression filler is preferably between about 20 and 65 m, while for direct compressible fillers at least 85% of the particles are over 100 m in size. These nondirect compression fillers, such as dextrose, mannitol, sorbitol, lactose, and sucrose, have the advantage of quick dissolution and avoid some of the gritty or sandy texture usually present in direct compressible versions of the sugar. The amount of nondirect compression filler is usually about 6095% of the total tablet weight. The tablets have low friability, which is about 2% or less when tested according to the USP, and the hardness of the tablets is at least about 15-20 N. The disintegration time is less than 60 seconds. Thin-film technology Thin-film technology is a relative new area of interest with respect to oral fast-dispersing products. Although not strictly an ODT, the oral thin-film platform provides an alternative to traditional tablet approaches. Oral thin films generally consist of hydrophilic polymers of varying thickness (50 to 200 nm). The manufacturing process is based on liquid casting to control film and weight variability. The dosage required is achieved by manipulating the API concentration in the bulk solution and/or the film-thickness produced. The films are dried by passing through oven(s) to evaporate the solvent used to prepare the film. The dried film is cut into single unit doses before packaging. During manufacture, the dried film must be protected from heat and humidity. The final packaging of the strips also needs careful consideration to protect the product from moisture. Taste-masking options include the use of sweeteners, flavors, and ion-exchange-resin complexes. Encapsulated APIs for taste-masking purposes is challenging because the larger particles can give rise to uniformity issues. Although disintegration of thin films are rapid (< 30 s), their limitation is drug loading (approximately less than 30 mg). Increasing film-thickness or using multiple layers may increase drug loading, but greater thickness can have a negative effect on disintegration. The specific packaging requirements also add complexity and cost to these products, though specific packaging technologies such as Catalents DelStrip pack are being developed to suit the thin film strips. To date, the majority of products have been in the over-thecounter sector (see Table 4) [14]. Table 4 Table shows examples of products using thin film technologies
Supplier Novartis Product Various products under Theraflu and Triaminic brands Sudafed Chloraseptic Active ingredients (dose strength) Phenylehedrine hydrogen chloride (HCl) Dextromethorphan hydrogen bromide (5 to 20 mg) Diphenhydramine HCl (12.5 to 25 mg) Phenylephedrine HCl (10 mg) Benzocaine (3 mg) Menthol (2 mg)

Pfizer MedTech Products/ Prestige Brands

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PACKAGING Selection of a packaging configuration is a crucial part of an ODT dosage form. Unlike conventional tablets, where packaging provides a means of administration/transport, ODTs may require specialized packaging configurations 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 with ODTs is to select a rigid, multilayer foil-based barrier material to protect the dosage form, with the blister actually forming during the tablet formulation process. In many cases, ODTs are very fragile, and regular push through blister packaging may break the tablet upon removing from the blister, so the packaging requires a peelable closure. The most common packaging configuration includes blister packaging and bottle packaging. The final packaged dosage form has to be evaluated to verify packaging integrity. One way to perform this is by immersing blisters in water and subjecting them to a vacuum for a specified period of time. The blisters are then opened manually and checked for presence of water droplets. Additionally, blisters and bottles should be monitored in simulated shipping tests according to American Society for Testing Materials (ASTM) standards. Some ODTs are sensitive to moisture to such an extent that, even during processing or formulation development stages, temperature and humidity have to be controlled to avoid long-term stability issues and may require special packaging. REGULATORY The FDA has set regulations for filing a petition of a Supplemental NDA for a drug that has the same strength and route of administration as a drug listed in the FDAs publication entitled Approved Drug Products with Therapeutic Equivalence Evaluations, but differ in dosage form. This petition generally 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 drug delivery systems fall under this category. Depending on the bioequivalence study, certain products can get approval under this clause or otherwise will need to establish safety and efficacy of the product by conducting further clinical trials. As ODTs products do not require administration of water, it may be required to perform bioequivalence studies with and without water depending upon the nature of the drug. This will depend upon the difference of absorption of drug in the fed and fasted state and in addition may lead to a fed and fasted study [65]. FUTURE The future of ODTs lies in the development of ODTs with controlled release properties. If one ODT can deliver drugs with short half-lives for 1224 hours, it would be a quantum improvement in the ODT technology. The added convenience and compliance of such formulations would be enormous. The future of ODTs also lies in the development of effective taste-masking properties. The use of coating poorly tasting drugs is commonly used, but it increases the total volume of the final formulation. There may be no magic solution to this, but more effective use of existing taste masking technologies is expected to alleviate the problems associated with taste masking. In addition, the ability to formulate drugs in large doses will bring another important technological advance. In general, the ODT formulations require large amount of excipients, and having large doses of drug will only make the final formulation too big to handle. An ODT formulation that would require fewer excipients than the drug itself would be a breakthrough. CONCLUSION The popularity of ODTs has increased tremendously over the last decade. 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Source of support: Nil, Conflict of interest: None Declared

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