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Manufacturing Technologies for Mouth Dissolving Tablets

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Uddhav S. Bagul
Uddhav S. Bagul

Incorporating an existing medicine into a new drug delivery system can significantly improve its performance in terms of efficacy, safety & improved patient compliance.

The need for delivering drugs to patients efficiently and with few side effects has prompted pharmaceutical companies to engage in the development of new drug delivery systems. A solid dosage form that dissolve or disintegrates rapidly in oral   cavity, resulting in solution or suspension without the need of water is known as fast dispersing dosage form or mouth dissolving tablets. When this type of tablet is placed into the mouth, the saliva will serve to rapidly dissolve the tablet.

Many patients find it difficult to swallow tablets and hard gelatin capsules and do not take their medicines as prescribed. The difficulty experienced in particular by pediatrics and geriatrics patients, but this also applies to the patients who are ill in bed or traveling. Other groups that may experience problems using conventional oral dosage form include the mentally ill, developmentally disable and patients who are uncooperative.

A difficulty in swallowing (dysphagia) tablets or capsules is common problem among all age groups, especially in elderly and pediatrics. For this reasons, tablets that can dissolve or disintegrate in oral cavity, have attracted a great deal of attention 1.

Indeed, the mouth dissolving tablet is an important and attractive alternative to liquid dosage form.   Mouth dissolving tablets are not only indicated for people having difficulty in swallowing but also ideal for unfavorable conditions of administration where water is not available 2. Syrups are best for pediatrics but they are bulky and drugs are not as stable in liquid form as in solid form like tablets.

Moth dissolving tablets are also known as fast dissolving, rapid –dissolve, rapimelt, fast melts, porous tablets, EFVDAS or Effervescent Drug Absorption system (Elan Corporation), Orosolv (Cima Labs Inc., USA), Zydis (R.P.Scherer, UK) etc.

Advantages of Mouth dissolving tablets

1.Improved patient compliance

2. Rapid onset of action and may offer an improved bioavailability.

3. Patient having difficulty in swallowing tablet can easily administer this type of dosage form

4. Useful fro pediatric, geriatric and psychiatric patients

5. Suitable during traveling where water is may not be available

6. Gives accurate dosing as compared to liquids

7. Good chemical stability.

8. Free of need of measuring, an essential drawback in liquids.

To ensure the tablet’s fast dissolving attribute, water must quickly egress into the tablet matrix to cause rapid disintegration and instantaneous dissolution of the tablet. Maximizing the porous structure of the tablet matrix and incorporating an appropriate disintegrating agents or highly water soluble excipients in the tablet formulation are the basic approaches used in current fast dissolving tablet technologies. Basically, the disintegrant’s major function is to oppose the efficacy of the tablet binder and the physical forces that act under compression to form the tablet. The mechanism by which tablet is broken down into smaller particles and then produces a homogeneous suspension or solution is based on:

i) Capillary action   ii) High swellabilty of disintegrants  iii) Capillary action and high swellability   iv) Chemical reaction (Release of Gases)

Different types of technologies have been employed for the formulation of mouth dissolving tablets viz freeze-drying, spray drying and sublimation. These technologies require specialized equipment and process.

Tablet Molding

In this technology, water-soluble ingredients are used so that tablet disintegrate and dissolve rapidly. The powder blend is moistened with a hydro alcoholic solvent and is molded in to tablet using compression pressure lower than used in conventional tablets compression. The solvent is then removed by air-drying. Molded tablets have a porous structure that enhances dissolution. Two problems commonly encountered are mechanical strength and poor taste masking characteristics. Using binding agents such as sucrose, acacia or poly vinyl pyrrolidone can increase the mechanical strength of the tablet.

To overcome poor taste masking characteristic Van Scoik 3 incorporated drug containing discrete particles, which were formed by spray congealing a molten mixture of hydrogenated cottonseed oil, sodium bicarbonate, lecithin, polyethylene glycol and active ingredient into a lactose based tablet triturate form.

Direct Compression Method

In this method, tablets are compressed directly from the mixture of the drug and excipients without any preliminary treatment. The mixture to be compressed must have adequate flow properties and cohere under pressure thus making pretreatment as wet granulation unnecessary. Few drugs can be directly compressed into tablets of acceptable quality. A type of disintegrant and its proportion are of prime importance. The other factors to be considered are particle size distribution, contact angle, pore size distribution, tablet hardness and water absorption capacity. All these factors determine the disintegration. The disintegrant addition technology 4,5,6   is cost effective and easy to implement at industrial level.

Cousin et al,7 using carboxymethyl cellulose as disintegrating agent and one swelling agent consisting of modified starch or microcrystalline cellulose formulated rapidly disintegrable multi particular tablets. The tablets disintegrate in the mouth in less than 60 seconds. 

Gas Evolving disintegrants have been used to formulate fast dissolving tablets. The evolution of carbon dioxide as a disintegration mechanism called OROSOLV and DURASOLV have been described in two US Patents assigned to CIMA Labs                   .             

J. Michaelson 8 describe the use of intimate mixture of alginic acid and a water-soluble metal carbonic acid to prepare tablets. When tablet was placed in water, an acid base reaction takes place forming a metal alginic acid salt and carbonic acid. The salt caused the tablet to swell and the carbonic acid produced carbon dioxide within the swelling tablet whereby rapid disintegration of tablet was effected.

Freeze Drying Technology (Zydis Technology 9)

Lyophilization can be used to prepare tablets that have very porous open matrix network into which saliva rapidly moves to disintegrate lyophilized mass after it is placed in mouth.

The drug is entrapped in a water soluble matrix which is freeze dried to produce a unit which rapidly disperses when placed in mouth. Apart from the matrix and active constituents, the final formulation may contain other excipients, which improve the process characteristics or enhance the quality of final product. These include suspending agents, wetting agents, preservatives, antioxidants, colors and flavors. The preferred drug characteristics for freeze drying formulations are water insoluble, low dose, chemically stable, small particle size and tasteless.

Corveleyn and Remon 10, 11 investigated the influence of various formulation and process parameters on the characteristics of rapidly disintegrating tablets in lyophilized form using hydrochlorthiazide as a model drug. They have concluded that maltodxtrins are useful in the formulation of fast dissolving tablets made by freeze-drying.

Lyophilization is relatively expensive and time consuming manufacturing process. Other drawback includes fragility, which make the use of conventional packing difficult and poor stability during storage under stressful condition.

Spray Drying

Spray dryers are widely used in pharmaceuticals and biochemical processes. Due to processing solvent is evaporated rapidly; spray drying can produce highly porous, fine powder. Spray drying can be used to prepare rapidly disintegrating tablets. This technique is based on a particulate support matrix, which is prepared by spray drying an aqueous composition containing support matrix and other components to forma highly porous and fine powder. This is then mixed with active ingredients and compressed into tablets.

Allen et al 12 used a spray drying technique to prepare fast dissolving tablets. The tablets made from this technology are claimed to disintegrate within 20 seconds.                                                                                   

Sublimation Technology

The basis of this technique is to add inert solid ingredients that volatilize readily, (e.g. camphor, ammonium bicarbonate, naphthalene, urea, urethane etc) to other tablet excipients and the mixture is then compressed into tablets. Volatile material is then removed via sublimation, which generate a porous structure.

Koizumi et al 13 applied the sublimation technique to prepare highly porous compressed tablets that were rapidly soluble in saliva. Mannitol and camphor were used as a tablet matrix material and subliming the material respectively.  Camphor was iminated by subliming in vacuum at 80 C for 30 minutes to develop pores in the tablets.

Makino et al 14 described a method of producing a fast dissolving tablet using water as a pore forming material. A mixture containing active ingredient and carbohydrates (glucose, manitol, xylitol etc) were moistened with water (1- 3 %w/w) and compressed into tablets. The water was then removed yielding highly porous tablet that exhibited excellent ;

Sugar Based Excipients

Sugar based excipients e.g. sorbitol, manitol, dextrose, xylitol, fructose, maltose etc. have been used as a bulking agents. Because of their high aqueous solubility and sweetness, which impart a pleasant mouth feel and good taste masking properties, can be used to formulate sugar-based mouth dissolving tablet. However, not all sugar-based material have fast dissolution rate and good compressibility.  

       Table I: Few commercially available mouth dissolving tablets

Trade Name

Technology

Drug

Manufacturer

Feldene Melt

Zydis

Piroxicam 20 mg

Pfizer, New York

Claritin Reditab

Zydis

Loratidine 10 mg

Schering Plough Corp., NJ

Tempra Quicklets

Effervescent (Direct Compression)

Acetaminophen

80 mg

Bristol – Mayers Squibb Co.,

New York

Zomig Rapimelt

Effervescent (Direct Compression

Zolmitriptan

Astra Zenaca Wayne

Conclusion

Recent trends of patient oriented practice demand design of patient oriented dosage form to achieve patient compliance. The number of formulation related factors contributes to the significant amount of non-compliance and hence there is a need to design patient oriented drug delivery system.  Mouth dissolving tablets are ideal for many groups of patients including geriatrics, pediatrics, psychiatrics and for those people who have difficulty in swallowing. By using such manufacturing technologies, many drugs can be formulated in the form of mouth dissolving tablets to provide the advantages of liquid medication in the form of solid preparation. 

References.

1.S. V. Shastry, J. R. Nishdham, and J. A. Fix, Pharmaceutical Science and Technology Today, 13, 138 (2000).

2.R. Chang, X. Guo, B. A. Burnside, and R. A. Couch, Pharmaceutical Technology 24(6), 52 (2000).

3.K. G. Van Scoik “ Solid Pharmaceutical Dosage in Tablet Triturate form”, US patent 5,082,667 (1992).

4.Y. Bi, H, Sunada, Y. Yonezawa, K. Danjo, and K. Lido, Chem.  Pharm. Bull. 44(11), 2121(1996).

5.Y. Watanabe, K. Koizumi, Y, Zama, M Kiriyama, Y. Mastumoto and M. Mastumoto, Bio. Pharm. Bull 18(9), 1308 (1995).

6.Y. Watanabe, T. Ishikawa, N. Yotoguchi, and M. Mastumoto, Chem.  Pharm. Bull. 47(10), 1451(1999).

7.Cousin et al, “ Rapidly Disintegrable Multiparticular Tablets” US patent 5,464,632(1995).

8.J. Machalson, “ Rapidly Disintegrating Tablets Composition and Method ”, US patent 4,414,193(1983).

9.P. Virely, R. Yarhood, “Zydis – a Novel Fast Dissolving Dosage Form” Manufact. Chemist, (2), 37-38 (1989).

10.  S. Corveleyn, J. P. Remon, “ Formulation and Production of rapidly disintegrating tablets by Lyophilization Technique”, Int. J. Pharm.,  152, 215 – 225 (1997).

11. S. Corveleyn, J. P. Remon, US patent 6,010,719(2000). 

12.  L. V. Allen, B. Wang, J. D. Devies, “ Rapidly dissolving Tablets” US patent 6,066,337(2000).

13.  I. K. Koizumi et al, “ New Method of Preparing Highly Porous Rapidly saliva Soluble Tablets by Sublimation Technique”, Int. J. Pharm., 152, 127- 131(1997).

14.  T. Makino, M. Yamado, J. I.  Kikuta, “ Fast Dissolving Tablet” US patent 5,720,974(1998).

  

Author(s):

Mr. Uddhav S. Bagul

Mr. Uddhav S. Bagul * (M. Pharm.  Pharmaceutics) Lecturer,

S.T.E.S.’s Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk), Pune – 411 048, Maharashtra, INDIA

Phone No – 020 26906066 (o), Cell: 9822192443 Email – usbagul@yahoo.co.in

Mr. Nilesh S. Bagul   (B. Pharm.) Quality Assurance Executive,  Glenmark Pharmaceuticals Co., Verna Ind. Area,  Goa, INDIA

Ms. Minal S.  Kulkarni

Ms. Minal S.  Kulkarni   (M. Pharm.  Pharmaceutical Chemistry) Lecturer, S.T.E.S.’s  Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk), Pune – 411 048, Maharashtra, INDIA

Dr. S. D. Sawant

Dr. S. D. Sawant  (M. Pharm. PhD), Principal, S.T.E.S.’s, Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk), Pune, Maharashtra, INDIA

DR. K.N. Gujar

Dr. K. N. Gujar  (M.Pharm PhD), Principal, STES, Sinhgad Institute of Pharmacy, Pune, Maharashtra State, INDIA

Mr. A. A. Bidkar

Mr. A. A. Bidkar (M. Pharm.  Pharmacognosy) Lecturer, S.T.E.S.’s  Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk), Pune – 411 048, Maharashtra, INDIA

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