International Journal of Pharmacy and Pharmaceutical Sciences

Print ISSN: 2656-0097 | Online ISSN: 0975-1491 Vol 11, Issue 9, 2019

Review Article
INSIGHTS INTO FORMULATION TECHNOLOGIES AND NOVEL STRATEGIES FOR THE DESIGN
OF ORALLY DISINTEGRATING DOSAGE FORMS: A COMPREHENSIVE INDUSTRIAL REVIEW

AHMED M. AGIBAa*, AHMED B. ELDINb

aFormulation Department, Research and Development Directorate, SIGMA Pharmaceutical Industries, Egypt, bMethodology Department,
Research and Development Directorate, SIGMA Pharmaceutical Industries, Egypt
Email: [Link]@[Link]
Received: 09 Jul 2019, Revised and Accepted: 10 Aug 2019
ABSTRACT
Among the various routes of administration, the oral route remains the most convenient and commonly employed route for drug delivery. The oral
conventional drug delivery systems have some drawbacks, such as possibility of gastrointestinal destruction of labile molecules, low absorption of
macromolecules, slow onset of action, and unavoidable fluctuation in the concentration of drugs which can either lead to under-or over medication with
concomitant adverse effects, especially for drugs with small therapeutic index. Therefore, it became essential to design novel oral drug delivery systems
to achieve quick dissolution, absorption, rapid onset of action and reduction of drug dose. Among those novel drug delivery systems are oral
disintegrating tablets (ODTs). The purpose of this review article is to report the recent advances in ODT systems with emphasis on their preparations,
characterizations and applications. Also, it highlights future prospects and possible challenges in the development of an ideal ODT system.
Keywords: Oral disintegrating tablets, Preparations, Characterizations, Applications, Future prospects, Challenges
© 2019 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license ([Link]
DOI: [Link]

INTRODUCTION where (P) is the permeability coefficient, (A) is the amount of drug
absorbed via oral mucosa, (D) is the diffusion coefficient of the drug,
The oral mucosal cavity is a very attractive and feasible site for local (Kp) is the partition coefficient of the drug in between the oral
and systemic drug delivery, since the mucosal membranes, upon mucosa and the specific medium used to deliver the drug, (h) is the
which drug delivery systems are placed, are readily accessible by the thickness of the oral mucosa, (C) is the free drug concentration in the
patients [1]. The oral mucosal drug delivery exhibits many medium used to deliver the drug, (S) is the surface area of the oral
advantages over other routs of drug administration, which include mucosa, and (t) is the duration or time of drug interacting the oral
increased accessibility by the patients as the dosage form can be mucosa.
accurately placed on the desired oral cavity membrane location and
can be easily removed in order to terminate delivery if signs of There must be a balance between partition coefficient and drug’s
adverse reactions are observed during treatment which increases solubility for a suitable oral mucosal delivery. In general, the
patient acceptability [1-3]. Moreover, the oral mucosa is a well- permeability coefficient of lipophilic drugs is higher than hydrophilic
vascularised tissue directly draining into the jugular vein [4], hence, drugs, and vice versa for solubility (i.e. the aqueous solubility of
allowing direct delivery into the systemic circulation and avoidance lipophilic drugs are usually lower than the hydrophilic drugs). Thus,
of first-pass hepatic degradation. Oral mucosal delivery also avoids the amount of drug absorbed via oral mucosa may be low for high
the gastrointestinal tract (GIT) environment preventing possible lipophilic drugs. As a result, permeation enhancers are subsequently
drug hydrolysis in the GIT, in addition to avoiding enzymatic used to enhance drug absorption and permeation [7].
barriers; i.e. low gastric pH and protease enzymes. However, the oral
mucosal drug delivery represents a challenging area because of the Understanding the physicochemical and solid-state properties of a
inherent functions of the oral cavity as swallowing, chewing, and drug substance is essential to obtain a rational formulation process.
speaking [5]. Furthermore, saliva is constantly secreted into the The desirable physicochemical and solid-state properties for drug
buccal cavity from both major and minor salivary glands, causing delivery through oral mucosa are shown in table 1 [3]. Two factors
severe dilution of the drug or excessively fast erosion of dosage mainly affect the effectiveness of oral drug delivery systems; the
forms. Furthermore, salivation leads to swallowing which removes retention time of the drug delivery system in contact with the oral
the drug from the targeted site of absorption. Moreover, the oral mucosa and its permeation rate.
mucosa has a smaller absorptive surface area which is The need for development of oral disintegrating tablets
approximately 214 cm2 [6] compared to the gastrointestinal mucosa
(350.000 cm2). Despite the aforementioned limitations, oral mucosal Conventional oral dosage forms like tablets and capsules pose a
delivery remains a viable option for drug delivery [3]. great swallowing problem for paediatrics and geriatrics.
Approximately 35% of the general population suffers from
There are two major routes of drug absorption via oral mucosa; the dysphasia [8]. Oral disintegrating tablets (ODTs) are tablets which
transcellular (where drugs permeate directly through the cells) and are placed in the mouth and then get dispersed in saliva without the
paracellular (where drugs permeate by passive diffusion through the need of water [9-11]. ODTs are considered the dosage form of choice
spaces between the cells) routes. The drug absorption process by for psychiatric patients, patients requiring fast intervention as well
passive diffusion is best expressed by Fick’s first law [7], which as patients suffering from nausea, vomiting and motion sickness
states that drug molecules diffuse from a region of higher to lower [12], since the ODT system presents a patient friendly dosage form
concentration until equilibrium is achieved. which ensures patient compliance and adherence to treatment.
ODTs combine the advantages of solid and liquid dosage forms. Like
(Eq. 1) conventional tablets, ODTs present accurate drug dosing, ease of
both manufacturing and packaging, good chemical stability, as well
as ease of handling by patients [13]. They also exhibit the smooth
(Eq. 2) mouth feel and avoidance of swallowing problems encountered with
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liquid dosage forms. Additionally, ODTs provide rapid onset of (5) has sufficient hardness and acceptable friability limit, (6) leaves
action and improvement of the bioavailability of poorly absorbed minimal or no residue in mouth after oral administration, (7)
drugs [14]. An ideal ODT exhibits the following characteristics [15]: exhibits low sensitivity to environmental conditions, (8) is
(1) requires no water for oral administration, (2) dissolves, manufactured using conventional manufacturing methods, and (9)
disperses or even disintegrates in the mouth in a matter of seconds, utilizes cost effective production method. Table 2 shows the
(3) has a pleasant mouth feel, (4) has good taste-masking potential, suitability of drug candidates for ODTs [15].

Table 1: The desirable physicochemical and solid-state properties of a drug delivery through oral mucosa [3]
Property Normal range
Aqueous solubility >1 mg/ml
Lipophilicity 10<oil: water partition coefficient<1000
Molecular weight <500 Da
Melting point <200 °C
pH of saturated aqueous solution pH 5–9
Required dose deliverable <10 mg/day
Irritation potential No irritation to buccal tissue

Table 2: Choice of drug candidates for oral disintegrating tablets [15]

Suitable drug candidates for ODTs Unsuitable drug candidates for ODTs
No bitter taste Short half-life and frequent dosing
Good stability in water and saliva Drug having very bitter taste
Taken in small doses Required controlled or sustained release

The new generation of oral disintegrating tablets Freeze-drying or lyophilization technique

The first generation ODTs suffered from many undesirable traits, Freeze-drying, also known as lyophilization or cryodesiccation, is a
mainly low density, poor mechanical strength, brittleness and technique that yields amorphous highly porous structures with
difficulty in handling. This necessitated blister packaging, which is rapid disintegration and dissolution. Orodispersible tablets made by
not patient friendly, and causes increase in production expenses lyophilization are prepared by dissolving the drug substance in an
[16]. Another disadvantage of first generation ODTs was the aqueous mixture of carrier/polymer, the solution is then poured into
difficulty of masking the taste of bitter active ingredients loaded the holes of blister packs which are subsequently frozen in order to
within these tablets [17], which led to the emergence of new continue the freeze-drying cycle, followed by blistering and finally
generation ODTs that overcame the problems of taste masking, packaging. Lyophilization technique is very suitable for heat-
allowed for modified release of medications, solved solubility and sensitive drugs (i.e. thermo-labile substances). Although ODTs
bioavailability problems, resulted in ODT tablets with excellent prepared by freeze-drying process showed rapid disintegration and
physical and mechanical robustness, mouth feel sensation, dissolution properties, but their industrial applications are limited
disintegration and dissolution properties. since it is a high cost technique particularly in equipment and
packing materials [34].
Challenges in formulating and developing oral disintegrating
tablets Spray-drying technique
There are several challenges in formulating and developing ODTs, Spray-drying is widely used in pharmaceutical industries nowadays.
such as: (1) palatability and acceptability [18], (2) mechanical It provides a fast, efficient and economical way of removing solvents
strength [19], (3) the amount of drug that can be incorporated into and producing free flowing, highly porous particles. In this process,
an ODT system [19], (4) size of tablet [20], (5) hygroscopicity [21], gelatin is commonly used as a supporting agent, mannitol as a
(6) aqueous solubility [22, 23], (7) physical and chemical stability. bulking agent, and sodium starch glycolate, crosscarmellose sodium
and/or crospovidone as superdisintegrants. Orodispersible tablets
Taste-masking of bitter and unpleasant taste of drugs is essential in made by spray-drying have been reported to disintegrate and
order to achieve patient acceptability and compliance. Different dissolve in less than 20 seconds [35, 36].
techniques were developed and introduced for bitterness masking
[24-32]. One of the most commonly used techniques for taste- Interestingly, Allen and Wang [54] fabricated a particulate support
masking of bitter and unpleasant APIs or drugs is the coacervation matrix for preparing ODTs by spray-drying, consisting of supporting
process [33]. Coacervation process has successfully taste-masked a agents of two polypeptide components from gelatin, a bulking agent
wide variety of bitter drugs, including but not limited to, (mannitol) and a volatilizing agent (ethyl alcohol). In order to
acetaminophen, cetirizine, ibuprofen, pseudoephedrine, ranitidine, maintain the net charges of both polypeptide components, a buffer
sumatriptan, theophylline and zolpidem [33]. Coupling controlled system of an acidifying agent (citric acid) and an alkalinizing agent
release behaviour with specialized functional polymers and efficient (sodium bicarbonate) is prepared and added to the tablet mixture.
coating processes creates ODT systems with modified and sustained The mixture of the aforementioned components is then spray-dried
release profiles. to obtain porous granules. By incorporating a volatilizing agent as
ethyl alcohol, the surface tension of the droplets is further reduced,
Formulation processes for developing oral disintegrating tablets and more porous structures are created. An effervescent agent could
be optionally added to further enhance the dissolution.
Various pharmaceutical techniques are used in the manufacture of
ODTs, including: (1) freeze-drying or lyophilization [34], (2) spray- Molding method
drying [35, 36], (3) molding [37, 38], (4) phase transition process [39],
(5) melt-granulation [40-42], (6) sublimation [43, 44] (7) mass Molding is a solid dispersion method, involving the dispersion of APIs
extrusion [45], (8) cotton candy process [46, 47], (9) nanonization in an inert water-soluble carrier or matrix at solid-state form,
[48], and (10) direct compression [40, 49-53]. Admittedly, direct prepared by solvent or heat method. Solvent method involves
compression is the most commonly used technique in the manufacture moistening the powder mixture with alcoholic or hydroalcoholic
of ODTs, owing to its easy-implementation and cost-effectiveness [40, solvent, then molding into tablets under reduced pressure to form wet
53]. These techniques are described below in detail. paste. This process is known as compression molding. The solvent is

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then removed from the wet paste by air-drying. The resulting tablets crystalline structure, which is then mixed with active/inactive
possess fine powders and highly porous structures. Solid dispersions ingredients and compressed into ODTs. This process can easily
are prepared directly from a molten matrix in which the drug is accommodate large doses of APIs with an improved mechanical
dispersed in or by vaporizing the solvent at ambient pressure (no strength. However, high-process temperature limits its use [46, 47].
vacuum lyophilization). The drug molecule can be in the form of
discrete-particles or microparticles, completely or partially dispersed Nanonization
in the molten matrix. Because of their composition, molded tablets Nanomelt is a recently developed nano-based drug delivery system,
offer rapid disintegration, dissolution and improved taste, but they involving a reduction of drug particle size to be in nano-scale range
suffer the disadvantage of poor mechanical strength. Compared to by using a proprietary wet-milling technique. APIs usually present in
freeze-drying, molded tablets are simpler in production and easier for the form of nanoparticles or nanocrystals are stabilized against
industrial scale-up, although disintegration times may not be possible agglomeration by surface adsorption onto preselected
comparable to those of lyophilized forms [37, 38]. stabilizing agents incorporated into ODT systems. This technique is
Phase transition process suitable for poorly water-soluble drugs, and the produced tablets
exhibit rapid disintegration and dissolution [48].
This process involves a combination of low-and high melting point
sugar alcohols. Optimizing the phase transition in the manufacturing Direct compression
process is important for formulating tablets without the need of any Direct compression is the simplest, easiest and most widely used
equipment. Kuno et al. [39] prepared ODTs by phase transition technique in ODT manufacturing, owing to its easy-implementation
process using compressible powder mixture of erythritol (a sugar and cost-effectiveness. It involves using a blend of ingredients, which
alcohol with melting point: 122 °C) and xylitol (a sugar alcohol with can provide rapid disintegration, as well as high physical integrity
melting point: 93-95 °C), followed by heating at 93 °C for a period of and stability. Sugar-based excipients as mannitol, sorbitol and
15 min. As a result of heating, the median pore size of tablets lactose are commonly used as bulking agents, because of their high
increased, as well as tablet hardness. aqueous solubility and good taste-masking properties [40, 49-53].
Melt-granulation technique In general, any tablet dosage form contains one or more of
The melt-granulation technique is based on incorporating a diluents/fillers, binders/adhesives, disintegrants,
hydrophilic melting binder in the formulation, which increases the superdisintegrants, glidant/flowing agent and lubricant.
physical resistance of tablets and helps their disintegration and Disintegrants and superdisintegrants are mainly incorporated into
dissolution. In comparison with other granulation techniques as dry- tablet formulations to promote their disintegration and dissolution.
and wet-granulation, melt-granulation is advantageous as no As the ability of the tablet to rapidly disintegrate is a prerequisite in
aqueous, alcoholic or even organic solvents are required. Melt- ODT systems, ODTs usually contain high concentrations of
granulation is less time-consuming, cost-effective and easy to disintegrants and superdisinetgrants. Examples of disintegrants and
perform [40-42]. superdisintegrants are listed below.

Interestingly, Abdelbary et al. [41] described a new approach for the Disintegrants and superdisintegrants
preparation of ODTs of high mechanical strength involving the use of Various disintegrants and superdisintegrants are available in the
a hydrophilic waxy binder, PEG-6-stearate, commercially known as pharmaceutical market and are readily used for the manufacture of
Superpolystate® by melt-granulation. Moreover, Agiba et al. [40] ODTs.
developed high-dose nutraceutical ODTs of glucosamine sulphate
and chondroitin sulphate using a blend of hydrophilic melting Starch and modified starch
binders as high molecular weight polyethylene glycols (PEG-4000
Starch is a versatile excipient with many applications in oral solid
and PEG-6000). Although ODTs weighed around 1.30 gm with 60%
dosage forms as a diluent, binder, and disintegrant. Starch acts as a
drug load, they showed quick disintegration and dissolution
disintegrant at a concentration of 3-25% (w/w), with an optimum
properties, as well as a high mechanical strength.
concentration of 15% (w/w) [58-61]. However, before using starch,
Sublimation method a prior granulation step is required to avoid problems associated
with low flowability and compressibility that can cause powder
In this method, a sublimating agent like camphor is removed from segregation. Examples of the most commonly used starches as
the compressed tablets by sublimation. Highly porous structures are disintegrants are maize, potato, rice, tapioca and wheat starch.
created as a result of removing camphor from the compressed
tablets. The resulted tablets, characterized by high porous Directly compressible and modified starches have been introduced
structures, could achieve fast disintegration in saliva. Examples of to overcome the problems associated with the conventional starches
other volatile materials are adipic acid, ammonium carbonate, as pregelatinized starch (disintegrant) and sodium starch glycolate
ammonium bicarbonate, arachidic acid, capric acid, camphor, (superdisintegrant). Pregelatinized starch is a modified starch that
menthol, myristic acid, and palmitic acid, thymol and urea. The has been mechanically and chemically modified through breaking all
sublimation temperature range is from 40 to 60 °C [43, 44]. or part of the starch granules. Partially-pregelatinized starch,
commercially known as Starch 1500® is a modified starch, mainly
Interestingly, Heinemann [55] prepared a highly porous tablet used in oral solid dosage forms as a diluent, binder [62, 63] and
structure by using a mixture of volatile adjuvant, which was disintegrant [64]. Comparing conventional starches with partially-
removed at the end by heating. On the other hand, Roser and Blair pregelatinized starch, partially-pregelatinized starch has better
[56] removed the volatile materials by using vacuum, which reduced flowability and compressibility; therefore, it may be used as a binder
the dissolution-time from 15 min for the tablets containing trehalose and disintegrant in direct compression. It also has self-lubricating
(a disaccharide composed of 2 glucose units) alone to less than 1 property. However, when it is used with other excipients, the
minute. Moreover, Lo [57] developed an efficient method for the addition of a lubricant as magnesium stearate (0.25%) (w/w) is
preparation of fast-dissolving tablets with highly porous structures. necessary taking into consideration that concentrations greater than
0.25% (w/w) may have adverse effects on tablet disintegration and
Mass extrusion technique dissolution.
In mass extrusion, the active and inactive ingredients are first softened Sodium starch glycolate, commercially known as Explotab® or
using PEGs mixture and methanol as organic solvent, followed by Primojel®, is also used in oral solid dosage forms as a
extrusion and division into tablets using heated blades [45]. superdisintegrant. It is commonly used at a concentration of 2 to 8%
(w/w), with an optimum concentration of 4% (w/w) [58].
Cotton candy process
Disintegration occurs by rapid uptake of water followed by rapid
This technique involves the formation of a matrix of poly-or swelling [65-67]. Increasing the tablet compression pressure did not
monosaccharides using flash melting and spinning to form floss like seem to influence the disintegration time [68, 69].

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Cellulose and modified cellulose compact) [77, 81, 82]. As other water-soluble ingredients rather
than disintegrants can contribute to improving disintegration by
Microcrystalline cellulose, commercially known as Avicel PH®, is increasing tablet porosity as high-molecular weight polyethylene
widely used in oral solid dosage forms as a binder or diluent in both glycols, so wicking cannot be classified as a primary disintegration
direct-compression, dry-and wet-granulation methods, with some mechanism. However, water penetration into the tablet compact is
lubricant and disintegrant properties [58]. essential for disintegrant activation [79]. Thus, the penetration rate
Croscarmellose sodium or cross-linked carboxymethylcellulose will mainly depend on the balance between capillary and opposite
sodium, commercially known as Ac-Di-Sol®, Explocel® or viscous forces [83].
Primellose® is widely used in oral solid dosage forms as a tablet Strain recovery (process of deformation)
superdisintegrant in both direct-compression, dry-and wet-
granulations [58]. In wet-granulation, it can be added intra-and In tabletting process, tablet components are subjected to a high
extragranularly, so that the wicking and swelling ability of the compaction pressure. During compaction, particles deform and
superdisintegrant is optimized [70, 71]. interparticulate bonds are disturbed. Strain recovery is a reversible
viscoelastic deformation process [84]. It elucidates the process of
Low-substituted hydroxypropyl cellulose (L-HPC) is primarily used mechanical activation of disintegrant polymer chains when getting
as a disintegrant in both dry-and wet-granulations, also used in the into contact with the aqueous media, causing a partial recovery into
preparation of ODTs prepared by direct compression [58]. There are their original shapes [77]. Moreover, disintegration media
different grades of L-HPC that have different substitution levels and contributes to the plasticization of disintegrant polymer chains and
particle sizes. For example, LH-11 has the longest fibrous particles, assists their accommodation into the most energetically stable
and is typically used as a disintegrant for tablets prepared by direct positions. The resulting pressure could help in tablet disintegration
compression method, while LH-21 is less fibrous and used in case of [79]. Strain recovery process is unidirectional and exists in the
tablets prepared by wet-granulation method. LH-31 is a small opposite direction of exerted compaction force [78]. The recovery
particle size grade and mainly used in extrusion process to produce and relaxation of the stressed particles promotes rapid movement
granules. LH-B1 is non-fibrous, high-density grade, typically and volume expansion, causing the breakage of bonding bonds.
produced for fluid-bed granulation. Low substitution grades LH-22
and LH-32 are usually used for enhancing the disintegration, and Interruption of particle-particle bonds
their concentrations are mainly depending on the characteristics of
Interruption of particle-particle bonds is considered one of the most
APIs [72]. The typical concentration of L-HPC in a solid formulation
important mechanisms for tablet disintegration. Some previous
ranges from 5–50% (w/w) [58].
studies suggested three different possible bonding mechanisms
Crospovidone [58] involved in tableting which are solid bridges, mechanical
interlocking, and intermolecular forces [85]. Among those three
Crospovidone or cross-linked povidone (commercially known bonding mechanisms, intermolecular forces are considered the most
Kollidon CL-M®; Polyplasdone XL®) is a tablet superdisintegrant prevalent bonding mechanism in tablet disintegration [85, 86].
used at a concentration of 2–5% (w/w) in tablets prepared by direct Various techniques have been introduced to identify the
compression, dry-or wet-granulations [73]. Crospovidone can also intermolecular bonds involved in the interruption of the tablet
be used as a solubility enhancer for increasing the solubility and matrix. Luangtana-Anan et al. [87] showed a correlation between the
dissolution of poorly absorbed drugs by coevaporation technique. intermolecular forces present in tablets and the disintegration time.
Resin and its derivatives Heat of interaction
Ion exchange resins have been introduced as tablet disintegrants. Two types of interactions result from the interaction of materials
The most commonly used ion exchange resin is polacrilin potassium. with aqueous media; endothermic (heat absorption) and exothermic
Polacrilin potassium is a highly hydrophilic cation exchange resin (heat generation) [77]. Exothermic interactions are obtained from
having good swelling properties [74] as well as wicking and strain interacting disintegrants with the aqueous media, either water or
recovery characteristics [75, 76]. It is usually used in a concentration buffer compartment [88], hence the heat generated causes localized
of 2-10% (w/w) in tablet formulations, although 2% (w/w) was stress within tablets which is usually associated with an expansion
reported to be sufficient. of air retained in the tablet compact, and subsequently increased
disintegration time. Lowenthal [87] illustrated the importance of
Mechanisms of disintegrants heat generation as an important mechanism in tablet disintegration.
Swelling However, Luangtana-Anan et al. [88] explained the changes in
enthalpy for different disintegrants and concluded that the amount
The most common mechanism of tablet disintegration is swelling. of heat generated by wetting is rather small and insufficient to cause
Swelling is basically a dimensional-expansion process in which effective expansion of the entrapped air in the tablet compact.
particles enlarge in every direction to push apart tablet components, Furthermore, Caramella et al. [89] studied the relation between the
thereby initiating the process of breaking-up of the tablet matrix [77, temperature of the disintegration media and disintegration time and
78]. The swelling property of a disintegrant depends on many concluded that increasing the temperature of the aqueous media did
factors including chemical structure and degree of crosslinking [79]. not necessarily improve the disintegration process. Therefore, it is
Porosity of the tablet compact plays also a significant role in necessary to further study the mechanism of heat of interactions to
determining the performance rate of swelling disintegrants. A tablet identify its impact on tablet disintegration.
matrix with low porosity and void spaces would reduce liquid
penetration and thereby delay or prolong the disintegration time, Coprocessed and multifunctional excipients
and vice versa [77]. Therefore, tablets should be prepared at an Developing a robust tablet formulation that can be easily scaled up
optimal porosity to provide adequate mechanical integrity and good to a drug product without any problematic issues is a big challenge.
disintegrability [80]. There is a positive correlation between the Today, there are many challenges in product manufacturing and
disintegration force development rate and the disintegration time, scaling up; therefore, the need of new pharmaceutical techniques
while there is no correlation between the extent of swelling of a and novel excipients are necessary for manufacturing a high-quality
disintegrant and the maximum disintegration force. Thus, the product. Coprocessed and multifunctional excipients are designed to
disintegration force development rate is essential for rapid tablet improve the formulation experience and performance. They are
matrix disintegration [80] high-functionality excipients containing one or more diluents,
Wicking (capillary action) binders, disintegrants, superdisintegrants and/or lubricants that
could provide superior binding, high mechanical strength, quick
Wicking is a process of liquid penetration by capillary action into the disintegration and dissolution. The basic principle of coprocessing is
microstructured spaces in the tablet compact to displace the based on particle engineering technologies. Any powdered
entrapped air (i.e. through porous structures within the tablet substance is characterized by three different levels of solid-state;

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molecular level (individual molecule level), particle level (individual compressibility. All these levels are essential for evaluating the
solid particle level) and bulk level (as assembly of particulate performance of excipients.
species) [90]. These different levels are closely connected to each
other in which changing in one level affects the other levels. The Methods of coprocessing include spray-drying, granulation,
molecular level involves the arrangement of individual molecules in extrusion/spheronization, melt-extrusion, solvent-evaporation and
the crystal lattice and represented by polymorphism, pseudo- crystallization. Examples of commonly used coprocessed and
polymorphism, and the amorphous state. Particle level involves multifunctional excipients are listed in table 3. Coprocessed and
individual solid particle properties like arrangement, shape, size, multifunctional excipients represent the ultimate solution in
surface area, and porosity. The bulk level involves large numbers of developing orodispersible tablets with very few excipients and high
particles together and their properties like flowability and functionalities and physicomechanical properties.

Table 3: The most common examples of high-functionality excipients

Excipient Composition Manufacturer
Prosolv® SMCC Silicifed Microcrystalline Cellulose JRS Pharma
Prosolv® EASYtab SP Microcrystalline Cellulose JRS Pharma
Colloidal Silicon Dioxide
Sodium Starch Glycolate
Sodium Stearyl Fumarate
Prosolv® EASYtab Nutra CM Microcrystalline Cellulose JRS Pharma
Silicon Dioxide
Croscarmellose Sodium
Magnesium Stearate
Prosolv® EASYtab Nutra GM Microcrystalline Cellulose JRS Pharma
Silicon Dioxide
Sodium Starch Glycolate
Magnesium Stearate
Prosolv® EASYtab Nutra CP Microcrystalline Cellulose JRS Pharma
Silicon Dioxide
Croscarmellose Sodium
Sodium Stearyl Fumarate
Prosolv® ODT G2 Microcrystalline Cellulose JRS Pharma
Silicon Dioxide
Mannitol
Fructose
Crospovidone
Mannogem® EZ Spray-dried Mannitol SPI Pharma
Mannogem® XL Spray-dried Mannitol SPI Pharma
Compressol® SM Mannitol, Sorbitol SPI Pharma
Advantose® 100 Spray-dried Maltose SPI Pharma
Advantose® FS95 Spray-dried Fructose SPI Pharma
Lubripharm® SSF Sodium Stearyl Fumarate SPI Pharma
Pharmaburst® C1 Mannitol SPI Pharma
Sorbitol
Crosspovidone
Colloidal silicone dioxide
Tabulose® Colloidal Microcrystalline Cellulose Roquette Pharma
Pearlitol® Spray-dried Mannitol Roquette Pharma
Pearlitol® Flash Mannitol, Starch Roquette Pharma
Starlac® Starch, Lactose Roquette Pharma
Xylisorb® Xylitol Roquette Pharma
Ludipress® Lactose BASF Pharma
Povidone
Crospovidone
Ludiflash® D-mannitol BASF Pharma
Crospovidone
Polyvinyl acetate
Povidone
Soluplus® Polyethylene glycol BASF Pharma
polyvinyl acetate
Polyvinylcaprolactame
Sepitrap™ 80 Magnesium Aluminometasilicate SEPPIC
Polysorbate 80
Sepitrab™ 4000 Magnesium Aluminometasilicate SEPPIC
Polyoxyl 40 Hydrogenated Castor Oil
HiCel™ HFE Microcrystalline Cellulose, Mannitol Sigachi Industries Pvt. Ltd
HiCel™ CE15 Microcrystalline Cellulose, Guar gum Sigachi Industries Pvt. Ltd
HiCel™ SMCC Microcrystalline Cellulose Sigachi Industries Pvt. Ltd
Colloidal Silicon dioxide
HiCellac™ 80 and 100 Microcrystalline Cellulose Sigachi Industries Pvt. Ltd
Lactose Monohydrate
HiCel™ DG Microcrystalline Cellulose Sigachi Industries Pvt. Ltd
Dicalcium phosphate

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Patented technologies AdvaTab® technology [97], (8) FlashDose® technology [98], (9)
OraQuick® technology [14], (10) Nanocrystal® and EFVDAS® and
Several patented technologies are introduced for the manufacture FastMelt® technologies [14, 99], (11) QuickDis® technology, and
of ODTs [14, 25, 53], including: (1) Zydis® technology [22], (2) (12) Pharmabrust™ technology [14]. Table 4 summarizes the
Lyoc® technology [92], (3) WowTab® technology [93, 94], (4) patented techniques used for the manufacture of ODTs and table 5
FlashTab® technology and Multiflash® [49], (5) Durasolv® and shows examples of globally marketed oral disintegrating tablets
Orasolv® technologies [95, 96], (6) Frosta® technology [14], (7) products.

Table 4: Patented technologies used to produce ODTs

Technology Company Description Novelty aspect Advantages Disadvantages
Zydis® [22] R. P. Scherer - Lyophilizing the drug in a water-soluble First marketed - Self- - Expensive manufacturing
Corporation matrix usually consisting of mannitol (a new tablet preservative process
crystalline sugar) and gelatin (a water- technology - Rapid - Require special packaging
soluble polymer). disintegration materials
- Other excipients can be used depending on and dissolution - Unstable at higher
the properties of the drug. - Improved temperature and humidity
bioavailability - Incompatible with high
drug doses
Lyoc® [92] Cephalon - A freeze drying process but differ from A modified - Self- - Expensive manufacturing
Corporation Zydis where the drug product is frozen on form of Zydis preservative process
freeze dryer shelves. - Require high amounts of
- The homogeneous liquid or suspension is fillers to prevent possible
placed into blister cavities and subjected to sedimentation
freeze drying. - The high amounts of fillers
- The homogenous liquid or suspension can reduce tablet porosity
contains one or more of water-soluble fillers, and prolong disintegration
thickening agents, surfactants and the drug - Incompatible with high
substance. drug doses
WowTab® Yamanouchi - Wow means without water Combination of - Rapid - No significant change in
[93, 94] Pharma - This process involves granulating low- low-and high- disintegration drug bioavailability
Technologie moldable sugars (e. g. mannitol, lactose, moldable sugars and dissolution
s sucrose and glucose) that show rapid
dissolution with high-moldable sugars (e. g.
sorbitol, maltitol and maltose) with the drug
substance.
FlashTab® Prographar - This process involves coating a drug with a A compressed - Conventional ---
[49] m polymer as Eudragit to provide a rapid drug tablet dosage tabletting
release in the stomach and formulating this form containing process
microencapsulated drug with an effervescent a drug as - Easy to
base to produce a flash dispersible tablet. microcrystals or perform
- This technology comprises the granulation microgranules - Tablets
of a drug and excipients by either dry-or wet- dissolve within
granulation then compressed into tablets. 1 minute.

DuraSolv® Cima Labs, - Conventional tabletting process (i.e. a Second - Higher - Incompatible with high
[95, 96] Inc. direct compression method using higher generation oral mechanical drug doses because the
compaction pressures during tabletting) disintegrating - strength than formulations are subjected
tablets Orasolv to high compaction
- Good tablet pressures. Unlike OraSolv,
rigidity the structural integrity of
- Easy to any taste-masking may be
perform compromised with high drug
- Low cost doses.
- Packaged in - No significant change in
blisters, foil or drug bioavailability
bottles
OraSolv® - Conventional tabletting process (i.e. direct Unique taste- - Taste- - Low mechanical strength
[95, 96] compression method using an effervescent masking masking is two- - Soft and fragile
base and taste masked drug.) process fold - Tablets; therefore, a
- Effervescence agents cause the tablet to - Rapid special packing material
disintegrate rapidly in less than 1 min once dissolution system is required
contact with water or saliva, leaving coated - No significant change in
drug powder. drug bioavailability
- Effervescent agents include carbonates such
as sodium bicarbonate, sodium carbonate,
potassium bicarbonate and potassium
carbonate, magnesium carbonate, and acids
like citric, tartaric, fumaric, adipic and succinic.
Frosta®[14 Akina - This technique comprises formulating Formation of - High ---
] plastic granules and compressing them at low highly porous, mechanical
compaction pressure to produce tablets with plastic granules strength
high porosity - Rapid

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Int J Pharm Pharm Sci, Vol 11, Issue 9, 8-20

- Plastic granules may contain porous and disintegration

plastic materials, penetration enhancers and
binders
- The manufacturing process includes mixing
the porous plastic materials with penetration
enhancers, followed by granulating with the
aid of binders
AdvaTab® Eurand - A microencapsulation process for coating A - Rapid ---
[97] the drug particles with gastro soluble microencapsula disintegration
polymer to mask the bitter taste along and tion process in mouth cavity,
prevent the drug dissolution in mouth cavity. typically within
- It can be combined with Eurand’s 30 seconds
complimentary particle technologies as
Microcaps® (taste-masking technology) and
Diffucaps® (controlled release technology).
FlashDose® Fuisz - This technique comprises a unique spinning A unique - Good taste- - Require special packing
[98] Technologie mechanism to produce a floss-like crystalline spinning masking materials as tablets are
s, Ltd. structure, much like cotton candy process. mechanism and - High surface highly friable.
- This crystalline sugar-based matrix (floss) an alternative area for drug - Require high temperature
can incorporate the active drug and be method of taste dissolution to melt the matrix; therefore,
compressed into tablets. masking it cannot be used with heat
- Instead of a floss-like crystalline sugar, and moisture sensitive drugs
small spheres of saccharides can be used as a - It is suitable for doses up
carrier for the drug. to 600 mg
OraQuick®[ KV - Taste masking process is done by Unique taste- - appropriate ---
14] Pharmaceut incorporating drug into matrix microsphere. masking for heat-
ical Co., Inc. - In this technique, tablets are prepared by process sensitive
dissolving the sugar (e. g. mannitol, sorbitol (microencapsul drugs
or sucrose) and protein (gelatin or albumin) ated drug
in a aqueous, alcoholic or hydroalcoholic particles)
solvent. The matrix is then spray dried,
yielding highly porous granules.
- The formed granules are mixed with the
drug and other excipients then compressed
at low compression force.
NanoCryst Elan - The main concept of this technology is Wet-milling - Easy to ---
al ® [14] Corporation decreasing drug particle size and increasing technique perform
surface area for drug absorption. - Cost-effective
- Nanocrystal particles are small particles of manufacturing
the drug substance, typically less than 1000 process
nm in diameter, which are - Use
- Manufactured by milling the drug substance conventional
using a suitable wet-milling method. packaging
- Nanocrystal colloidal dispersions of drug materials
substances have been combined with water- - suitable for
soluble ingredients as mannitol and sorbitol, doses up to 200
filled into blisters, and freeze-dried. The mg of API per
resultant blisters are remarkably robust yet unit
dissolve in very small quantities of water in
matter of seconds. This approach is suitable
with highly potent or hazardous materials.
EFVDAS®[1 - Known as Effervescent Drug Absorption Effervescent - Used for OTC
4] System (EFVDAS) Drug and
- Examples of EFVDAS products are Absorption prescription
acetaminophen, cimetidine, ibuprofen and System drugs
naproxen. - Also, for hot
drink sachet
products
Fast Melt® - Combine the advantages of liquid Highly porous, --- ---
[14] formulations with those of solid dosage micro-fine
forms matrix tablet
- Characterized by highly porous, micro-fine
matrix tablet
- Once placed onto the oral cavity, the
matrix tablet rapidly absorbs water and
disintegrates, and the drug is released into
the oral cavity.
Pharmabru SPI Pharm - Tablets are manufactured by direct Direct --- ---
st™ [14] compression of drug substances, compression
pharmabrust, flavours, colorants and a using
lubricant. Pharmabrust as
- Tablets dissolve within 30-40 seconds. a novel
- Tablets have sufficient strength and can be multifunctional
packed in blister packs and bottles excipient

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Int J Pharm Pharm Sci, Vol 11, Issue 9, 8-20

Table 5: A list of marketed orally disintegrating tablet products

Commercial product Active ingredient Indication Manufacturer Technology
Abilify® Aripiprazole Anti-psychotic Otsuka America Zydis®
Pharmaceutical, Inc.
Children’s Dimetapp® ND Loratadine Anti-histaminic Wyeth Consumer Healthcare
Claritin® RediTabs® Loratadine Anti-histaminic Bayern Schering Corporation
Feldene Melt™ Piroxicam Anti-inflammatory Pfizer
Grastek® Sublingual Tablets Pollen allergen extract from Timothy grass or related Catalent Pharma Solutions
Timothy grass (Phleum grass-pollen allergies for ALK-Abelló A/S
pratense)
Grazax 75,000 SQ-T Oral Pollen allergen extract from Timothy grass or related ALK-Abelló A/S
Lyophilisate Timothy grass (Phleum grass-pollen allergies
pratense)
Imodium® Instant Loperamide HCl Anti-diarrheal Johnson and Johnson
Melts/Imodium® Lingual/
Imodium® Quick Dissolve
Klonopin® Wafers Clonazepam Anti-convulsive and Roche
Anxiolytic
Maxalt-MLT® Rizatritpan benzoate Anti-migraine Merck
Motilium® Domperidone Anti-emetic Johnson and Johnson
Ondansetron-RL Zydis® Wafers Ondansetron HCl Anti-emetic GlaxoSmithKline
Ondaz Zydis® Wafers Ondansetron HCl Anti-emetic Sandoz
Pepcid® Famotidine Anti-ulcer Merck
Ragwitek® Sublingual Tablets Pollen allergen extract from Ragweed pollen allergies ALK-Abelló A/S
Short Ragweed (Ambrosia
artemisiifolia)
Risperdal® M-Tab™ Risperidone Anti-psychotic Johnson and Johnson
Zelapar™ Selegiline HCl Parkinson’s disease Elan/Amarin Corporation
Zofran® ODT Ondansetron HCl Anti-emetic GlaxoSmithKline
Zubrin® Tepoxalin Anti-inflammatory Schering Corporation
Zyprexa® Olanzapine Anti-psychotic Eli Lilly
Loperamide® Lyoc® Loperamide chlorhydrate Anti-diarrheal Teva Lyco®
Paralyoc® Paracetamol Analgesic, anti-pyretic Teva
Proxalyoc® Piroxicam Anti-inflammatory Teva
Seglor® Lyoc® Dihydroergotamine mesylate Migraine UCB Pharma
Sermion® Lyco® Nicergoline Potent vasodilator Pfizer
Spasponlyoc® Phloroglucinol dihydrate Anti-spasmodic Teva
Vogalene® Lyoc® Metopimazine Anti-emetic Teva
Reminly® OD Tablets Galantamine Alzheimer's disease Janssen/Takeda Quicksolv®
Risperdal® M-Tab Risperidone Anti-psychotic Janssen Pharma
Allegra® Fexofenadine Anti-histaminic Aventis Pharmaceuticals OraSolv®
Clarinex RediTab® Desloratadine Anti-histaminic Schering-Plough
Fluxid™ Famotidine Anti-ulcer Azur Pharma
Orapred® ODT Prednisolone sodium phosphate Asthma Concordia Pharmaceuticals
Remeron® SolTab Mirtazapine Anti-depressant Organon Inc.
Tempra® Quicklets/ Acetaminophen Analgesic Bristol-Myers Squibb
Tempra® FirsTabs
Triaminic® Cold Cough Chlorpheniramine maleate, Cold cough Novartis Consumer Health
Softchews Dextromethorphan HBr,
Pseudoephedrine HCl
Zomig® Rapimelt Zolmitriptan Migraine AstraZeneca
Alavert® Loratadine Anti-histaminic Wyeth Consumer Healthcare DuraSolv®
Dimetapp® ND Loratadine Anti-histaminic Wyeth Consumer Healthcare
FazaClo® LD (low dose) Clozapine Schizophrenia Alamo Pharmaceuticals
and FazaClo® HD (high dose)
Kemstro™ Baclofen Anti-spastic analgesic Schwarz Pharma
Niravam™ Alprazolam Anxiety Schwarz Pharma
NuLev® Hyoscyamine sulfate Antispasmodic Schwarz Pharma
Benadryl® Fastmelt Diphenhydramine Citrate Anti-histaminic Pfizer WowTab®
Gaster® D Famotidine Anti-ulcer Yamanouchi
Harnal® D Tamsulosin HCl Benign prostatic Astellas Pharma Inc.
hyperplasia
Irribow® OD Ramosetron HCl Irritable bowel syndrome Astellas Pharma Inc.
Nasea® OD Ramosetoron HCl Anti-emetic Yamanouchi
Vesicare® OD Solifenacin succinate Overactive bladder Astellas Pharma Inc.
Calpol® Six Plus Fastmelts Paracetamol Analgesic, anti-pyretic McNeil Products Ltd Flashtab®
Dolflash® Acetaminophen Analgesic, anti-pyretic Sanofi-Aventis
Excedrin Quicktabs Acetaminophen, Caffeine Analgesic, anti-pyretic Bristol-Myers Squibb
Nurofen® Flashtab Ibuprofen Analgesic, anti-pyretic Boots Healthcare
Ondansetron Flashtab® Ondansetron Anti-emetic Teva
OxynormOro® Oxycodone chlorhydrate Cancer related pain Mundipharma
Paracetamol Flashtab® Paracetamol Analgesic, anti-pyretic Ranbaxy

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Prevacid® SoluTab Lansoprazole Gastroesophageal reflux Takeda

(Delayed release ODT) disease
Solupred Orodispersible Tablet Prednisolone Asthma Sanofi-Aventis
Tachipirina Flashtab® Paracetamol Analgesic, anti-pyretic Angelini
Tramalene® Flashtab® Tramadol HCl Potent analgesic Ethypharm
Trambax® MD Tramadol HCl Potent analgesic Ranbaxy
Zamadol® Melt Tramadol HCl Potent analgesic MEDA Pharma
Citalopram® ODT Citalopram hydrobromide Anti-depressant Biovail FlashDose®
Fluoxetine® ODT Fluoxetine Anti-depressant Biovail
Ralivia FlashDose® Tramadol HCl Potent analgesic Biovail
Tovalt™ ODT Zolpidem tartrate Insomnia Biovail
Lamictal® ODT Lamotrigine Bipolar disorders GlaxoSmithKline AdvaTab®
Unisom® SleepMelt Diphenhydramine HCl Anti-histaminic Chattem, Inc.
Caffe Magia® Vitamin B and Caffeine Stimulant Akina Frosta®
Ceto-Q® Mannitol, Calcium carbonate, Toothpaste tablet Akina
Xylitol, Yucca extract
Hyoscyamine Sulfate ODT Hyoscyamine sulfate Anti-ulcer Perrigo OraQuick®

Characterizations of oral disintegrating tablets

(Eq. 4)
Evaluation of powders or granules (pre-compression
parameters evaluation) Hausner ratio and carr's compressibility index
Bulk and tapped density Hausner ratio and carr's compressibility index are calculated based
on bulk and tapped density results using equations 5 and 6,
Ten gm of a dry powder or granular sample is placed in a 100 ml respectively.
graduated cylinder. The volume occupied by the powder or granules
is measured and the bulk density is calculated using equation 3.
Tapped density is determined by a tapped density tester. The (Eq. 5)
volume occupied by the powder or granules after tapping is used to
calculate the tapped density using equation 4 [40, 100].
(Eq. 6)
Flowability is determined based on the results of hausner ratio and
(Eq.3) carr's compressibility index as shown in table 6.

Table 6: Specification for hausner ratio and carr's compressibility index

Hausner ratio Carr's compressibility index (%) Flowability
1.00-1.11 0-10 Excellent
1.12-1.18 11-15 Good
1.19-1.25 16-20 Fair
1.26-1.34 21-25 Passable
1.35-1.45 26-31 Poor
1.46-1.59 32-37 Very poor
>1.60 >38 Very, very poor

Table 7: Specification of angle of repose (Ɵ)

Angle of repose (degree) Flowability
25–30 Excellent
31-35 Good
36-40 Fair
40-45 Passable
46-55 Poor
56-65 Very poor
>66 Excellent

Angle of repose (Ɵ) Flowability is determined based on the results of angle of repose as
shown in table 7.
Angle of repose (Ɵ) is determined by the fixed funnel and free-
standing cone method. The method employed a funnel that is fixed at Porosity (ε)
a certain height (h) on a graph paper placed on a flat horizontal
surface. The powder or granules sample is carefully passed through Porosity (ε) is calculated from apparent density (ρapp) and true
the funnel till the apex at the conical pile touched the tip of the density (ρtrue) as in equation 8 [40].
funnel. Thus, with (r) being the radius of the base of the conical pile
as shown in equation 7 [101].
(Eq. 8)
(Eq. 7) The true density (ρtrue), which is the density of the particles that
Where, (h) and (r) are the height and radius of the base of the make up a powder or particulate solid, is measured by gas
conical pile displacement using a pycnometer [102].

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Evaluation of tablets (post-compression parameters percentage of weight variation is calculated using equation 9 [40,
evaluation) 103].
(1) Weight uniformity or % of weight variation
(Eq. 9)
Twenty tablets were randomly selected from the production batch
and weighted individually to check their weight uniformity. The The percentage of tablet weight deviation is shown in table 8.

Table 8: Uniformity of weight of tablets

Average tablet weight (mg) % Deviation
Less than 80 mg ±10
More than 80 mg but less than 250 mg ±7.5
250 mg and more ±5

Tablet hardness purified water kept at 37±0.5 °C. The time required for complete
Tablet hardness is measured by the hardness tester in newton (N) or disintegration is in seconds [40, 103].
kilopond (kP) per unit tablet. Each tablet is placed individually in the
In-vitro and comparative dissolution
hardness tester and the crushing load is measured. In general, the
hardness of ODTs is set to be lower than conventional tablets Four dissolution medias are commonly used for evaluating in vitro
because of increasing hardness results in decreasing tablet and comparative dissolution, namely 0.1N HCl (pH 1.2), acetate
disintegration rate [40, 103]. buffer (pH 4.5), phosphate buffer (pH 6.8) and artificial saliva
solution (pH 7.0). Dissolution tester is used for experimental
Tablet friability
evaluation following the USP paddle (most common). All dissolution
Twenty tablets are accurately weighted and placed in the friabilator tests are usually conducted in 900 ml of each dissolution media
chamber, then allowed to rotate at 25 rpm for 4 min. Tablets are maintained at a constant temperature of 37 °C±0.5 °C with paddle
collected and reweighted. The percentage of weight loss in tablet is rotation speed of 25, 50, 75 or 100 rpm. Comparative dissolution
calculated using equation 10 and taken as a measure of friability. studies is mainly conducted against the reference marketed product.
Tablets pass the friability test if not more than 1% of the tablets Dissolution profiles are compared with the reference marketed
weight was lost [40, 103]. product using the similarity factor (f2) defined by the following
equation 12 [40, 103].

W0: initial weight of tablets (Eq. 12)

Wf: final weight of tablets Where (n) is the number of sampling time points, (Rt) and (Tt) are
the mean percent dissolved of the reference product and the
Tablet thickness and diameter prepared ODTs respectively, up to each time point (t), (f2) represents
Tablet thickness and diameter are measured by using a micrometer a logarithmic transformation of the sum-squared error of difference
caliper in millimeter (mm) per unit tablet [40]. between the reference and the test products over all time points. In
order to consider similar dissolution profiles, (f2) values should be
Uniformity of dispersion higher than 50.
Twenty tablets are placed in a beaker containing 100 ml of purified Novel formulations of oral disintegrating tablets
water and stirred gently for 2 min. The dispersion is allowed to pass
through 22 mesh screen. Tablets would pass the test if no residue Many reported applications of ODTs have been described in the
remained on the screen [104]. literature. Agiba et al. [40] incorporated a high dose of
nutraceuticals glucosamine sulphate (GluS) and chondroitin
Water absorption ratio sulphate (CS) into ODTs in order to improve their disintegration,
dissolution and subsequent their bioavailability. GluS/CS ODTs were
A small piece of tissue paper folded twice is placed in a small prepared by direct compression and melt-granulation techniques,
petridish containing 6 ml of purified water. A tablet is placed onto using a blend of conventional and coprocessed multifunctional
the tissue paper and the time required for completely wetted is excipients as Pharmaburst™ C1. Pharmaburst™ C1 turned out to be
measured. The wetted tablet is then re-weighed. Water absorption the key excipient in improving the tablet characteristics,
ratio (R) is calculated by using equation 11 [104]. disintegration and dissolution profile. Kumar and Saharan [101]
developed ODTs of salbutamol sulphate, using a combination of
(Eq. 11) three different superdisinetgrants in different ratios. They
concluded that the binary combination of superdisintegrants was
Wb: is the weight of tablet before water absorption more effective in disintegration and dissolution than the individual
use of one superdisintegrant. Dave et al. [105] developed ODTs of
Wa: is the weight of tablet after water absorption
chlorpheniramine maleate based on lyophilization technique, using
Wetting time superdisinetgrants as croscarmellose sodium and crospovidone for
faster disintegration and dissolution. Türkmen et al. [106] developed
Five circular tissue papers of 10 cm diameter are placed in a fexofenadine hydrochloride ODTs by direct compression using high
petridish with a 10 cm diameter. Ten millimeters of water functionality excipients as F-Melt®, Pearlitol® Flash, Pharmaburst®
containing Eosin, a water-soluble dye, is added to petridish. A tablet 500, Prosolv® Easytab SP, Ludiflash® and Parteck® ODT. ODTs
is carefully placed on the surface of the tissue paper. The time formulated with Pharmaburst® 500 were the most promising
required for water to reach upper surface of the tablet is noted as a formulation with respect to physical characteristics and dissolution
wetting time [50, 101]. rate. Shoormeij et al. [107] developed meloxicam ODTs using solid
In-vitro disintegration time dispersions followed by direct compression. Meloxicam solid
dispersions were prepared by the melting method, using poloxamer
Disintegration time is evaluated using the disintegration tester 188 as a hydrophilic carrier and crospovidone as a
without disk. The disintegration medium is usually 900 ml of superdisintegrant. Moqbel et al. [108] developed ODTs of

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Int J Pharm Pharm Sci, Vol 11, Issue 9, 8-20

chlorzoxazone using two different approaches; co-processed doses drugs is still a problematic issue and need further new and
excipients or liquisolid technique. F-melt®, Pearlitol® flash, advanced technologies.
Pharmaburst® 500, Prosolv® ODT and Starlac® were used as co-
processed multifunctional excipients, whereas in liquisolid method, CONCLUSION
Avicel® PH101, Cellactose® 80 and Microcelac® 100 were used as The popularity of ODTs has increased dramatically over the last few
carriers, while Aerosil® 200 was a coating material. Both approaches decades. There are many globally marketed products that have been
were capable of producing ODTs with ease and low cost of formulated into ODT dosage forms. The most important parameters
manufacture. ODTs formulated with Pharmaburst® 500 showed the in ODT formulations are rapid onset of action, very fast drug release,
best results in terms of palatability, mechanical strength, quick disintegration and dissolution, and these could be achieved by
disintegration and dissolution. Ibrahim and El Sayeh [109] formulating tablets with high porous structures or by adding a blend
formulated orally disintegrating tablets containing furosemide; a of disintegrants, superdisintegrants, effervescent systems, and/or
potent diuretic used mainly in the management of hypertension. coprocessed multifunctional excipients. ODTs prepared by direct
ODTs were prepared by direct compression method for taste- compression technique usually have good mechanical properties but
masking purposes. Nishiyama et al. [110] prepared taste-masking could be further improved by using high functionality excipients.
granules of lafutidine for ODTs using water-insoluble/water-soluble Considering many advantages and benefits of ODT systems, it is only
polymers combinations. Lafutidine taste-masking granules were a matter of time till the majority of oral solid dosage forms become
prepared by coating lafutidine granules with a taste-masking layer ODT formulations.
prepared by combining ethylcellulose (water-insoluble polymer)
and hypromellose (water-soluble polymer), and ODTs were ACKNOWLEDGEMENT
prepared by direct compression method using mannitol as a diluent,
The authors would like to thank Dr Sherif Lashin, R&D Director, Dr
low-substituted hydroxypropyl cellulose as a disintegrant and
Abla Abdel Aziz, R&D Senior Manager, SIGMA Pharmaceutical
sodium stearyl fumarate as a water-soluble lubricant. Desai et al.
Industries; Dr Wageeh Abdel Hakeem, R&D Deputy Manager,
[111] developed β-cyclodextrin (β-CD) solid dispersion-based ODTs
October Pharma; Dr Maha Nasr, Associate Professor of
of eslicarbazepine acetate (ESL), for improving the dissolution and
Pharmaceutics and Industrial Pharmacy, Ain Shams University in
providing rapid anti-epileptic action. ESL-β-CD solid dispersion was
Cairo and Mutah University in Jordan; and Dr Hanan Refai, Professor
prepared by solvent evaporation method and then compressed into
of Pharmaceutics and Industrial Pharmacy, Cairo University and
ODTs by direct compression, using superdisintegrants as
Misr University for Science and Technology in Egypt for their fruitful
crosspovidone, sodium starch glycolate, pregelatinzed starch and
discussions on the theme of the review article.
croscarmellose. Microcrystalline cellulose was further added to aid
in tabletting. Yıldız et al. [112] developed new ODTs containing AUTHORS CONTRIBUTIONS
mirtazapine; an antidepressant drug molecule having bitter taste by
coacervation followed by direct compression using different fillers All the authors have contributed equally.
(Ludiflash®, Phamaburst™ C1, Galen® IQ, F-Melt® and Mannitol
CONFLICT OF INTERESTS
Parteck® M100), disintegrants (Kollidon® CL, Ac-Di-Sol®, Explotab®
and Kollidon® CL/Amberlit® IRP-88 mixture), glidant (Aerosil® 200), The authors report no conflicts of interest
citric acid and sodium carbonate (effervescent mixture). Chen et al.
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