Emerging Trends In The Development Of Orally Disintegrating Tablet Technology

Dr. Avani F. Amin

The demand for orally disintegrating tablets has enormously increased during
the last decade, particularly for geriatric and pediatric patients who have
difficulty in swallowing conventional tablets and capsules.

This new formulation trend is emerging and gaining popularity because it is
easy to administer and leads to better patient compliance. These dosage forms
are placed in the mouth, allowed to disperse or dissolve in the saliva, and
release the drug as soon as they come in contact with the saliva, thus obviating
the need for water during administration.

The aim of this article is to review the progress of the evolving technologies
in the formulation, manufacturing and evaluation of these tablets. Orally disintegrating
tablets are prepared by using various approaches like freeze drying, compression
molding, direct compression, spray drying, sublimation and other techniques.
Many patented technologies like Durasolv, Flash Dose, Flashtab, Oraquick, Orasolv,
Wowtab, and Zydis have also gained importance in the international market. This
article also discusses the new evaluation methodologies for these orally disintegrating
tablets.  Various modifications in the conventional evaluation and use
of specialized instruments are found to be essential in the testing of these
dosage forms.

INTRODUCTION

Tablets and hard gelatin capsules constitute a major portion of the drug delivery systems that are currently available. However, many patient groups such as elderly, children, and patients mentally retarted, uncooperative, nauseated, or on reduced liquid intake diets have difficulty in swallowing these dosage forms. Many elderly persons face difficulties in administering conventional oral dosage forms because of hand tremors and dysphagia. Swallowing problem is common in children because of their underdeveloped muscular and nervous systems¹. In some cases like motion sickness, sudden episodes of allergic attack or coughing, and during unavailability of water, swallowing conventional tablets is difficult.  To fulfill these medical needs, formulators have devoted considerable efforts for developing a novel type of dosage form for oral administration known as orally disintegrating tablets (ODT). This is an innovative technology where the dosage form containing active pharmaceutical ingredients disintegrates rapidly, usually in a matter of seconds, without the need for water, providing optimal convenience to the patient. Innovators and inventor companies have given these tablets various names such as mouth dissolving, fast melting, fast dissolving or orodisperse². The European Pharmacopoeia defines Orodisperse as a tablet that can be placed in the mouth where it disperses rapidly before swallowing.

Researchers have formulated ODT for various categories of drugs, which are
used for therapy in which rapid peak plasma concentration is required to achieve
desired pharmacological response. These include neuroleptics, cardiovascular
agents, analgesics, anti-allergic and drugs for erectile dysfunction.

CHARACTERISTICS OF ODT³

Orally disintegrating tablets have many advantages over other dosage forms such as effervescent tablets, dry syrups, chewing gums, or chewable tablets, which are commonly used to enhance patient compliance. Administration of effervescent tablets, granules or dry syrups require intake of water. Chewing large pieces of gum or tablet is difficult for elderly patients and sometimes experience the bitter or unpleasant taste of drug if the taste masking coatings rupture during mastication. The various characteristics of orally disintegrating tablets are: 

• Convenient and easy to administer as does not require water for oral administration
  yet disintegrates and dissolves in the mouth within a few seconds
• Durable and sufficient strength to withstand the rigors of the manufacturing
  process and manufacturing handling
• Pleasant mouthfeel
• Insensitive to environmental conditions such as humidity and temperature.
• Improved taste without any residue in the mouth after disintegration
• Adaptable and amenable to existing processing and packaging machinery
• Cost effective
• Compatible with taste masking

Ideally an ODT should allow high drug loading, be compatible with taste masking and have a pleasing mouth feel and should have sufficient strength. 

VARIOUS TECHNOLOGIES USED IN THE MANUFACTURE OF ODT

The performance of ODT depends on the technology used in their manufacture. The orally disintegrating property of the tablet is attributable to a quick ingress of water into the tablet matrix, which creates porous structure and results in rapid disintegration. Hence, the basic approaches to develop ODT include maximizing the porous structure of the tablet matrix, incorporating the appropriate disintegrating agent & using highly water-soluble excipients in the formulation⁴. Following technologies have been used by various researchers to prepare ODT: -

• Freeze-Drying or Lyophilization
• Tablet Molding
• Spray Drying
• Sublimation
• Direct Compression
• Cotton Candy Process
• Mass-Extrusion

Freeze-Drying or Lyophilization

 Freeze drying is the process in which water is sublimed from the product after it is frozen. This technique creates an amorphous porous structure that can dissolve rapidly. Commonly used excipients with their uses & examples employed in manufacturing of ODT using Freeze drying are listed in Table 1.

A typical procedure involved in the manufacturing of ODT using this technique is mentioned here. The active drug is dissolved or dispersed in an aqueous solution of a carrier/polymer. The mixture is dosed by weight and poured in the wells of the preformed blister packs. The trays holding the blister packs are passed through liquid nitrogen freezing tunnel to freeze the drug solution or dispersion. Then the frozen blister packs are placed in refrigerated cabinets to continue the freeze-drying. After freeze-drying the aluminium foil backing is applied on a blister-sealing machine. Finally the blisters are packaged and shipped.

The freeze-drying technique has demonstrated improved absorption and increase in bioavailability. Jaccard and Leyder⁵ employed lyophilization technique in making an oral pharmaceutical preparation and found increased absorption and bioavailability of drugs like spiranolactone, nicergoline and trolendomycin in comparison to their conventional formulation. Remon and Corveleyn⁶ in one of their study found maltodextrins very useful in preparing fast-dissolving tablets by lyophilization. Scherer⁷ developed Zydis technology on the basis of patent granted to Georgy et al.⁸ and Yarwood et al⁹. The Zydis formulations consist of a drug physically trapped in a water-soluble matrix (saccharide mixture and polymer), which is freeze dried to produce a product that dissolves rapidly when placed in mouth. The ideal candidate for Zydis technology should be chemically stable and water insoluble and particle size preferably less than 50 mm. Water soluble drugs might form eutectic mixtures and not freeze adequately, so dose is limited to 60 mg & the maximum drug limit is 400 mg for water insoluble drug as large particle sizes might present sedimentation problems during manufacture¹⁰ .

The major disadvantages of lyophillization technique are that it is expensive and time consuming; fragility makes conventional packaging unsuitable for these products and poor stability under stressed conditions.

Tablet Molding

The preparation of ODT using molding technology employs water-soluble ingredients so that the tablet dissolves completely and rapidly. The active ingredients in most cases are absorbed through the mucosal lining of the mouth. Molding process is of two types i.e. solvent method and heat method. Solvent method involves moistening the powder blend with a hydroalcoholic solvent followed by compression at low pressures in molded plates to form a wetted mass (compression molding). The solvent is than removed by air-drying. The tablets manufactured in this manner are less compact than compressed tablets and posses a porous structure that hastens dissolution.

The heat molding process involves preparation of a suspension that contains
a drug, agar and sugar (e.g. mannitol or lactose) and pouring the suspension
in the blister packaging wells, solidifying the agar at the room temperature
to form a jelly and drying at 30˚ under vacuum. The mechanical strength
of molded tablets is a matter of great concern. Binding agents, which increase
the mechanical strength of the tablets, need to be incorporated. Taste masking
is an added problem to this technology. To overcome this, Van Scoik¹¹
incorporated taste masked drug particles. The taste masked drug particles were
prepared by spray congealing a molten mixture of hydrogenated cottonseed oil,
sodium carbonate, lecithin, polyethylene glycol, and an active ingredient into
a lactose based tablet triturate form. Compared to the lyophillization technique,
tablets produced by the molding technique are easier to scale up for industrial
manufacture¹². Masaki uses an agar solution as a binding agent and
a blister packaging as well as a mold to prepare an intrabuccally fast disintegrating
tablet¹³.

Spray Drying

Spray drying is used in pharmaceutical industries to produce highly porous powders. The processing solvent is evaporated rapidly by spray drying, which renders the product highly porous and thus can be used in manufacturing ODT.

In this technique, gelatin can be used as a supporting agent and as a matrix, mannitol as a bulking agent and sodium starch glycolate or cross carmellose or crospovidone are used as superdisintegrants. Tablets manufactured from the spray-dried powder have been reported to disintegrate in less than 20 seconds in aqueous medium¹⁴.

Allen and Wang^15-18  have reported this technique for preparing fast dissolving tablets. The formulation contained bulking agent like mannitol and lactose, a superdisintegrant like sodium starch glycolate & crosscarmellose sodium and acidic ingredient (citric acid) and/or alkaline ingredients (e.g. sodium bicarbonate). This spray-dried powder, which compressed into tablets showed rapid disintegration and enhanced dissolution.

Sublimation

The key to rapid disintegration of ODT is preparation of a porous structure in the tablet matrix. To generate such a porous matrix, volatile ingredients are incorporated in the formulation that is later subjected to a process of sublimation. Highly volatile ingredients like ammonium bicarbonate, ammonium carbonate, benzoic acid, camphor, naphthalene, urea, urethane and phthalic anhydride may be compressed along with other excipients into a tablet. This volatile material is then removed by sublimation leaving behind a highly porous matrix. Tablets manufactured by this technique have reported to usually disintegrate in 10-20 sec. Even solvents like cyclohexane, benzene can be used as pore forming agents.

Vacuum drying technique has been very often used by researchers to sublime the volatile ingredients and thus maximize the porous structure in the tablet matrix^19-24. It is likely that a porous hydrophilic matrix will easily pick up the disintegrating medium and break quickly.

Direct Compression

Direct compression represents the simplest and most cost effective tablet manufacturing technique. This technique can now be applied to preparation of ODT because of the availability of improved excipients especially superdisintegrants & sugar based excipients.

(a) Superdisintegrants:

In many orally disintegrating tablet technologies based on direct compression, the addition of superdisintegrants principally affects the rate of disintegration and hence the dissolution. The presence of other formulation ingredients such as water-soluble excipients and effervescent agents further hastens the process of disintegration. Bi et al²⁵ and Wantanbe et al ²⁶ have used microcrystalline cellulose (MCC) and low substituted hydroxyl propyl cellulose (HPC) to manufacture ODT. The ratio of MCC to HPC varied from 8:2 to 9:1. Ito and Sugihara²⁷ investigated use of agar powder as a disintegrant because the powder absorbs water and swells without forming gel at physiological temperature. Ethylpharm (France) has introduced a Flash- dose technology, which contains coated crystals and micro granules along with the disintegrants. In this technology, two types of granules are used; a disintegrating agent (e.g. modified cellulose- cross carmellose) which has a high swelling force, and a swelling agent (e.g. starch) which has a low swelling force.

The basis of Orasolv^{28, 29} technology in a US patent assigned to Cima Labs have also developed effervescent tablets in which disintegration is aided by evolution of carbon dioxide. Saliva activates the effervescent agent, causing the tablet to disintegrate. Second-generation technology developed by Cima Labs is the Durasolv technology used for the production of robust, mouth dissolving tablets. Care should be observed because effervescent excipients and final product require higher protection against humidity conditions. Tempra Quicklets (Bristol Myers Squibb, NY, USA) containing Paracetamol, and Zoming Rapimelt³⁰ (AstraZeneca, Wilmington, USA), which contains Zolmitriptan are examples of orally disintegrating tablets that contain effervescent agents.

 J. Michaelson³¹ suggested combination of alginic acid and metal carbonic acid, which on contact with aqueous medium causes swelling of the tablets and carbon dioxide is, generated which leads to disintegration of the tablet.

Shirwaikar and coworkers³² prepared atenolol tablets by dry granulation method using three superdisintegrants, cross carmellose sodium (Ac-Di-Sol), cross povidone and sodium starch glycolate, and they found that Ac-Di-Sol was the best superdisintegrant among the three.

(b) Sugar Based Excipients^33-37:

This is another approach to manufacture ODT by direct compression. The use of sugar based excipients especially bulking agents like dextrose, fructose, isomalt, lactilol, maltilol, maltose, mannitol, sorbitol, starch hydrolysate, polydextrose and xylitol, which display high aqueous solubility and sweetness, and hence impart taste masking property and a pleasing mouthfeel.

Mizumito et al³⁸ have classified sugar-based excipients into two types on the basis of molding and dissolution rate.

Type 1 saccharides (lactose and mannitol) exhibit low mouldability but high dissolution rate.

Type 2 saccharides (maltose and maltilol) exhibit high mouldability and low dissolution rate. Mouldability is defined as the capacity of the compound to be compressed/molded. The mouldability of type 1 saccharide can be improved by granulating it with type 2 saccharides. WOWTAB technology used in Benadryl fast melt tablets uses this technique. Most commercial ODTs have been developed using mannitol as the bulk excipient of choice. Mannitol is overwhelmingly preferred over lactose because of its extremely low hygroscopicity, excellent chemical and physical compatibility, good compressibility and better sweetness. ODT formulators prefer to use a directly compressible mannitol, which enables the preparation of robust tablets that can withstand processing and transportation. Specially textured directly compressible, spray-dried, or granulated mannitol excipients have been designed to meet these needs. These excipients under defined manufacturing conditions gives a highly porous structure and friable exterior structure which helps in faster disintegration of ODT, they also provide a satisfactory mouth feel and so suitable for use in preparation of harder ODT by direct compression at low pressure ³⁹.

Cotton Candy Process

The cotton candy process is also known as the “candy floss” process and forms
the basis of the technologies such as Flash Dose³⁰ (Fuisz Technology).
An ODT is formed using a candyfloss or shear form matrix; the matrix is formed
from saccharides or polysaccharides processed into amorphous floss by a simultaneous
action of flash melting and centrifugal force. The matrix is then cured or partially
recrystallised to provide a compound with good flow properties and compressibility.
The candyfloss can then be milled and blended with active ingredients and other
excipients and subsequently compressed into ODT. However the high processing
temperature limits the use of this technology to thermostable compounds only⁴⁰.

Mass-Extrusion

This technology involves softening the active blend using the solvent
mixture of water-soluble polyethylene glycol and methanol and subsequent expulsion
of softened mass through the extruder or syringe to get a cylinder of the product
into even segments using heated blade to form tablets⁴¹. The dried
cylinder can also be used to coat granules for bitter drugs and thereby achieve

NEW ORALLY DISINTEGRATING DOSAGE FORMS

Oral films and wafers

Oral films and wafers are the newer technologies in the manufacturing of orally disintegrating dosage forms. They are thin elegant films of edible water-soluble polymers of various sizes and shapes like square, rectangle or disc. The strips may be flexible or brittle, opaque or transparent. They are designed to provide rapid disintegration on the tongue without the need for water. They have the advantage of a large specific surface area for disintegration. One or a combination of the following processes like hot-melt extrusion, solid dispersion extrusion, rolling and solvent casting are used to manufacture these films. A major limitation of these dosage forms is low drug loading capacity and limited taste masking option⁴².

Some US patented technologies^{43, 44} are mentioned in Table 2 and
patented products available in market are listed in Table 3.

EVALUATION OF ORALLY DISINTEGRATING TABLETS ^{1, 45}

Evaluation parameters of tablets mentioned in the pharmacopoeia need to be assessed, but some, which require special concern or need to be modified, are discussed here. 

Crushing Strength

A significant strength of ODT is difficult to achieve due to the specialized processes and ingredients used in the manufacturing. The limit of crushing strength for an ODT is usually kept in a lower range to facilitate early disintegration in the mouth. The crushing strength of the tablet may be measured using conventional hardness testers.

Friability of tablet

To achieve % friability within limits for an ODT is a challenge to the formulator since all methods of manufacturing of ODT are responsible for increasing the % friability values. Thus, it is necessary that this parameter should be evaluated and the results are within bound limits (0.1 to 0.9%).

Wetting time

Wetting time of dosage form is related with the contact angle. Wetting time of the ODT is another important parameter, which needs to be assessed to give an insight into the disintegration properties of the tablets, a lower wetting time implies a quicker disintegration of the tablet.

The wetting time of the tablets can be measured using a simple procedure. Five circular tissue papers of 10 cm diameter are placed in a petridish with a 10 cm diameter. Ten millimeters of water-containing Eosin, a water-soluble dye, is added to petridish. A tablet is carefully placed on the surface of the tissue paper. The time required for water to reach upper surface of the tablet is noted as a wetting time.

Modified disintegration test

The time for disintegration of ODTs is generally less than one minute and actual disintegration time that patient can experience ranges from 5-30 seconds. The standard procedure of performing disintegration test for these dosage forms has several limitations and they do not suffice the measurement of very short disintegration times. The disintegration time for ODT needs to be modified as disintegration is required without water, thus the test should mimic disintegration in salivary contents. For this purpose, a petridish (10 cm diameter) was filled with 10 ml of water. The tablet was carefully put in the center of petridish and the time for the tablet to completely disintegrate into fine particles was noted. Various scientists ⁴⁶ have developed new in-vitro methods that allow an accurate determination of disintegration test. The disintegration test performed using a texture analyzer instrument as shown in Fig.1. In this test, a flat ended cylindrical probe penetrates into the disintegrating tablet immersed in water. As the tablet disintegrates, instrument is set to maintain a small force for a determined period of time. The plots of the distance traveled by the probe generated with the instrument’s software provide a disintegration profile of the tablets as a function of time. The plot facilitates calculation of the start and end point of the tablet disintegration.

Dissolution test

The development of dissolution methods for ODTs is comparable to the approach taken for conventional tablets, and is practically identical.

Dissolution conditions for drugs listed in a pharmacopoeia monograph, is a good place to start with scouting runs for a bioequivalent ODT. Other media such as 0.1N HCl and buffers (pH - 4.5 and 6.8) should be evaluated for ODT much in the same way as their ordinary tablet counter parts.

Klancke⁴⁷ have suggested the USP 2 Paddle apparatus which is the most suitable and common choice for orally-disintegrating tablets, with a paddle speed of 50 rpm commonly used. Typically the dissolution of ODT is very fast when using USP monograph conditions; hence slower paddle speeds may be utilized to obtain a profile. The USP 1 Basket apparatus may have certain applications but sometimes tablet fragments or disintegrated tablet masses may become trapped on the inside top of the basket at the spindle where little or no effective stirring occurs, yielding irreproducible dissolution profiles.

As with all oral solid dosage forms, dissolution serves as a control test. The same is true for taste-masked bulk drug. For batch-to-batch consistency can be assured, and dissolution data on the taste-masked drug is frequently predictive of dissolution of the tableted product. The USP 2 Paddle apparatus at 50-100 rpm is suitable for dissolution testing of taste-masked drug as well. The media used for the taste-masked drug should match that of the finished product to maximize the value of the test. HPLC is often required to analyze dissolution aliquots due to presence of UV absorbing components, specifically flavors and sweetener. Excipient to drug ratio may be higher since the formulation is designed to have good taste and mouth feel, decreasing the signal of the drug to background (excipient) in the UV spectrophotometric technique. .

Moisture uptake studies

Moisture uptake studies for ODT should be conducted to have an insight into the stability of the formulation. Ten tablets from each formulation were kept in a desiccator over calcium chloride at 37˚C for 24 h. The tablets were then weight and exposed to 75% RH, at room temperature for two weeks. Required humidity was achieved by keeping saturated sodium chloride solution at the bottom of the desiccator for three days. One tablet as control (without superdisintegrant) was kept to assess the moisture uptake due to other excipients. Tablets were weighed and the percentage increase in weight was recorded.

SUMMARY

• Orally disintegrating tablets are formulated to drug delivery system aims
  to improve patient compliance and convenience.
• They are a very good alternative for drug delivery to geriatric and pediatric
  patients.
• As a result of the variety of technologies for its formulation, several
  commercial products are available in the market.
• Thus, looking at the advances and advantages in this therapeutic approach,
  the pharmaceutical formulator need not restrict his choice in the development
  of conventional dosage forms but should also try to develop these fast dissolving
  drug delivery systems.

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Table 1: Excipients and their uses in the manufacture of ODT using Freeze
Drying technique

Table 2: A list of Patented Technologies using manufacturing techniques

 Table 3:  List of some patented products available in
the market ^{30, 43}

 Figure 1: Texture Analyzer for Disintegration testing.

About Authors

A. F. Amin*, T. J. Shah, M. N. Bhadani and M. M. Patel

Department of Pharmaceutics, Institute of Pharmacy,Nirma University of Science
& Technology,Sarkhej-Gandhinagar Highway,Ahmedabad- 382 481,Gujarat, India.

For Correspondence*

*Dr. Avani F. Amin has 11 years of teaching & research
experience and 2 years of industrial experience. She has about 24 research publications
in international and national pharmaceutical journals. She has also presented
papers at various conferences. She is the recipient of the Motan Devi Dandiya
Prize in Pharmacy, the Prof. M. L. Khurana Memorial Prize in Pharmaceutics,
the G. P. Nair IDMA award and other state level prizes.

Contact Info:
Dr. Avani F. Amin

M. Pharm. (Pharmaceutics), Ph.D.
Assistant Professor in Pharmaceutics, Department of Pharmaceutics,Institute
of Pharmacy,Nirma University of Science & Technology,Sarkhej-Gandhinagar
Highway,Ahmedabad- 382 481,Gujarat, India.

Phone No: (02717) 241900-904,Fax No: (02717) 241916, E-mail: avanifamin@yahoo.com

Ms. Tejal Shah
Asst. Professor in Pharmaceutics
M.Pharm. (Pharmaceutics)

Prof. Tejal Shah has 9 years of teaching experience. She has national &
international publications and a chapter written by her in a multi-authored
book on Novel Drug Delivery Systems. She is recipient of the Best Paper Award
2004 granted by Association of Pharmaceutical Teacher’s of India for publishing
paper in Indian Journal of Pharmaceutical Education. She is actively working
for her Ph.D. degree at Sardar Patel University

Mr. Manish Bhadani
M. Pharm Sem IV (Pharmaceutics)

Manish Bhadani graduated from Rofel, College of Pharmacy, Vapi and currently
he is pursuing Masters in Pharmacy with specialization in Pharmaceutical Technology
and Biopharmaceutics. He got distinction in Bachelor of Pharmacy program. He
also got 97.04 percentile in Graduate Aptitude Test in Engineering 2004, which
was conducted by Indian Institute of Technology, Delhi. He area of interests
are formulation development and novel drug delivery systems.

Mr. Mayur Patel
M. Pharm Sem IV (Pharmaceutics)

Mayur graduated from A.R college of pharmacy, Vallabh vidyanagar and currently
he is pursuing his Masters in Pharmacy with specialization in Pharmaceutical
Technology and Biopharmaceutics. He got first class in Bachelor of Pharmacy
program. and 98.65 percentile in Graduate Aptitude Test in Engineering 2004,
which was conducted by Indian Institute of Technology, Delhi. He is interested
in formulation development and novel drug delivery systems.