1

Oral Disintegrating Tablets- a review

Presented by: Niketkumar Patel

2

Outline…

Introduction. Advantages. Formulation properties. Formulation methods. Subsequent treatments. Excipients Future trends for oral disintegrating tablets. Summary.

3

Introduction…Dysphagia which means difficulty in swallowing - is common problem

occur with oral formulations.

35% of the general population, 30-40% of elderly institutionalized patients and 18-22% of all persons in the long-term care facilities.

The common complaints related to swallowing tablets are mainly tablet size, surface, dosage form and taste.

Geriatric and pediatric patients - frequent administration of water

is difficult. For traveling patients - ready access to water is difficult.

Need for easy swallowing dosage forms.

4

Definition… A single unit dose that disintegrate in the oral cavity.

According to USFDA - Center for Drug Evaluation and Research (CDER) :"A solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue“.

European Pharmacopoeia recognizes ODTs as “orodispersible tablets” or tablets intended to be placed in the mouth that subsequently disperses rapidly before being swallowed.

They are also known as fast dissolving, rapid dissolving, rapid melting and/or quick disintegrating tablets

5

Characteristics… They disintegrate in the oral cavity.

(GI fluid, intestinal fluid) They melt in the mouth or form gel like structure allowing easy

swallowing by the patients.

Disintegration time is 15 sec for ideal ODT.Usually it is up to 60 sec.

Tensile strength is more than 0.5 MPa.

Several formulation changes or addition of excipients has to be carried out in order to achieve these characteristics.

6

Advantages… ODTs provide a good solution –

Patients have swallowing problems. Patients with persistent nausea. Pediatric, geriatric and bedridden patient – frequent administration

of water is difficult.

ODTs can be swallowed as a form of soft paste or liquid; it eliminates the risk of suffocation due to physical obstruction of formulation when swallowed.

More accurate dosing, Better stability, compare to conventional tablets.

7

Continue… ODTs disintegrate in the oral cavity and dissolve easily in the

saliva, which will be absorbed from the mouth, pharynx and oesophagus so bioavaibility is greater than conventional tablets.

From the pharmaceutical industry's point of view, ODTs provide new dosage forms for those drugs which are near to the end of their patent life. Manufacturers can extend their market exclusivity by extending a patent by providing new dosage forms.

8

Choosing an active ingredient… They should not have bitter taste.

Dose should lower than 20 mg.

They should have small to moderate molecular weight.

They should have good solubility in water and saliva

They should partially nonionized at the oral cavity's pH.

They should have ability to diffuse and partition into the epithelium of the upper GIT.

They should have ability to penetrate oral mucosal tissue

9

Formulation properties… Fast disintegration :

ODTs should disintegrate in oral cavity so that they should provide good mouth feel and smooth swallowing.It can be achieved with some formulation changes and use of specified disintegrating agents.

Taste of the Active Ingredients :Should be tasteless or without undesirable taste.Taste masking techniques can be used.

Tablet strength and porosity :Maximum porosity should be achieved to ensure water absorption to achieve fast disintegration but it affects the tablet strength.

Changes in the conventional formulation processes.

10

Formulation methods… Lyophilization method (not used for conventional tablets)

Principle : Conversion of solid to vapor phase (sublimation).Zydis technology Quicksolv technologyLycov technology Nanocrystal technology

Tablet molding method

Formulation mixture containing drug and excipients are molded with a punch.

Compaction method (used with some modification). Granulation method Direct compression

11

Lyophilization… In this method, solvent is removed from a frozen drug solution or a

suspension containing structure-forming excipients.(freeze drying)

That creates an amorphous porous structure of the drug that can dissolve rapidly in the saliva.

The freeze-drying process may result in a glassy amorphous structure of excipients as well as the drug substance, leading to enhance dissolution rate.

The entire freeze drying process should be carried out at non elevated temperature to eliminate adverse thermal effects that may affect drug stability during processing.

12

Continue…Lyophilization for ODT is carried out as shown below :

Dispersion of active drug in a carrier or polymer.↓

Pouring of mixture to blister packs.↓

Pass them through nitrogen freezing tunnel.↓

Refrigeration to achieve freeze drying.↓

Apply backing of an aluminium foil to seal it.↓

Blisters are ready to ship.

Expensive and time consuming. Fragility makes the conventional packing unsuitable for ODT

produced by lyophilization.

13

Tablet molding method…

1. Loading of the cavity 2. Actual molding process3. Ejection of upper punch.

Fig. demonstrate how tablet molding works for ODTs.

This method employs mainly for water-soluble ingredients.

14

Continue… Solvent method

Mainly involves compression of moistened mass with a hydroalcoholic solution (water and alcohol).

Moistening of powder with a solvent↓

Molding of the mixture into tablets under pressure↓

Solvent can be removed by air drying.↓

Highly porous structure can be obtained.

Heat method :Involves preparation of a suspension that contains a drug, agar and sugar and agar is solidified.

15

Compaction…

Conventional tablet press is used to make ODTs. Low manufacturing cost and Ease in technology transfer makes this method attractive.

Applied pressure is the critical step because formulation may loose its property as a ODT.

Various modifications has been carried out in the process and excipients.

Mainly used methods Granulation method Direct compression method

16

Granulation Methods… Wet GranulationWet granulation with water soluble polymers is carried out.

Dry GranulationAddition of low density alkali earth metal salts is done.

Melt GranulationAddition of hydrophilic waxy binder.

Spray DryingSpray of matrix containing polypeptide components is done.

Flash heat processA unique spinning mechanism to produce floss is involved.

17

Wet Granulation… Active ingredients is wet granulated with water soluble or

water miscible polymer. Granules are compressed to produce tablets.

Polymers mainly used Poly (ethyleneglycol) Ethyl cellulose

Addition of effervescent agents is a common practice to achieve rapid disintegration.

Granules of high porosity and low density can be obtained.

Optimization of various parameters is necessary.

18

Preparation of tablets: ODTs can be mainly characterized by

Tensile Strength Disintegration time

Tensile Strength :

Ability to tablet to resist against mechanical stress.Should greater than 0.5 MPa.

Disintegration Time :

Time required for a tablet to disintegrate in a given media.

For ideal ODT disintegration time would be 15 sec.Practically it is more than 15 sec (up to 60 sec).

Tensile strength and disintegration time is mainly depend on porosity of tablets.

19

Continue…..

Effect of log porosity on tensile strength and disintegration time is shown for wet granulation of lactose.M.contant 8.56%

Thus porosity of the tablets decide the tablet properties.

20

Continue… Porosity of the tablet depends on compaction of the wet granules.

Applied compression force decides the porosity which ultimately affects disintegration time and tensile strength.

Compression pressure is high then resulting porosity would be less.

Porosity is in inverse relationship with Tensile strength and Disintegration time.

Thus compression pressure increase both Tensile Strength and Disintegration time.

21

Continue…

Effect of compression force on Crushing strength (Tensile strength) and Disintegration time.

22

Optimization…

Better ODT formulation requires two parametersTensile strength…greater than 0.5 MPa.Disintegration time …less than 15 sec.

If we increase compression force in order to achieve tensile strength 0.5 Mpa…Leads to increase disintegration time also. (unwanted).

Compression force should be applied in a amount in order to achieve both characteristics in the range.

23

Continue…

Effect of compression force on porosity which decides Tensile strength and Disintegration time of the tablet.

COMPRESSION FORCE > 500 KN and < 280 KN REQUIRED.

24

Other parameters… Other parameters which decide the Tensile strength and

Disintegration time are

Particle shape of a raw material. Partice size of a raw material. Moisture content of granules.

Lactose 450M Lactose 200M Lactose 80M

Particle size(μm) 13.2 23.9 61.4SF= (A/ML) 0.52 0.52 0.56Particle Density

(g/cm3)1.52 1.52 1.52

Comparison of various properties of different grades of Lactose in given.

Whereas SF is shape factor which decide the shape of the lactose.

25

Continue… So two factors which decide the tensile strength and disintegration

time Particle size and Moisture content

Lower the particle size…Higher the tensile strengthHigher the disintegration time (due to better compaction)

Higher the moisture content…Higher the tensile strengthHigher the disintegration time (due to better compaction)

26

Optimization… We again need optimization between tensile strength and

disintegration time.

For laboratory scale – “plotting a graph” is the method commonly used.

For better result :

Multiple regression analysis and artificial neural network (ANN) is used.

The relation of a dependent variable (response variable) to specified independent variables

Computational model to get the relationship.

27

Tensile strength…

Graph shows the effect of particle size and moisture content on tensile strength using a multiple regression analysis.

28

Disintegration time…

Graph shows the effect of particle size and moisture content on disintegration time.

29

Optimization…

Optimization of water content(%) and particle size( µm) to get the desired properties using counter plots.

30

Direct compression… Simplest and most effective approach for tablet manufacturing.

Active ingredients are directly compressed with disintegrating agents.

Choosing excipients is the most important step in direct compression.

Getting the required porosity is the most critical step in direct compression.(Low porosity due to compaction force results into decrease water penetration into the matrix which affects disintegration.)

31

Sublimation…

Manufacturing involves volatilizing agents using direct compression

Involve incorporation of volatilizing agents in the mixture for direct compression.

Volatilization provides increase the porosity to the matrix as shown in the figure and decrease the disintegration time without affecting tensile strength.

32

Continue… Volatilizing agents mainly includes

Menthol CamphorThymol

Most widely used is menthol.

Tablet weight and the size remain same after addition of volatilizing agent.

Ratio of volatilizing agent to mannitol is very important.

Higher amount of volatilizing agents can not be added due to problems in manufacturating of tablets.

33

Continue…

Effect of addition of volatilizing agent is shown on porosity and crushing strength. Closed bars shows the results before sublimation. Open bars shows the results after sublimation.

34

Subsequent treatments… After formulation of ODTs several processes are carried out in

order to get better formulaion.

Basically involve 3 processes…

SublimationUse of volatilizing agents.

Humidity treatmentMoisture treatment substantially increase the tablet strength.

SinteringSintering is melting the tablet components at high temperatures and

resolidify them.

35

Humidity treatment…

A moisture sorption model explaining the mechanical strength of ODTs after humidity treatment.

After the formulaiton of oral disintegrtating tablets moisture is applied in order to increase the tablet strength.

36

Continue… Water is absorbed on the surface and form a moisture layer with a

vapor pressure Pb.

Solid starts to dissolve in this layer which will lead to decrease in Pb.

Decrease in Pb offset by increase in temperature of film and solid caused by heat released on the condensation of vapor.

Moisture sorption occurs and film grows.

After drying solid bridging believes to occur which increase the bonding between particles which provide additional strength to tablets.

37

Structural change in sugar… Certain type of sugars change from amorphous state to crystalline

state due to humidity.

So at the time of manufacturating sugar is in amorphous form which gets converted to crystalline form on storage.

Transformation of amorphous sugar to crystalline form upon storing upon a certain relative humidity.

38

Continue… Sugars that shows this type of behavior are

Glucose lactoseMaltose sorbitol

Amorphous form has a low critical relative humidity so they can absorb water even at low moisture level.

Transformation from amorphous to crystalline is irreversible so after storage remains in the crystalline form.

Sugars in crystalline form has high critical moisture point so less susceptible to moisture

39

Continue..

Figure shows change in tensile strength with respect to porosity after storage in a humid area.Closed triangle before storage.Open triangle after storage.

Remarkable increase in Tensile strength can be observed whereas porosity almost remain unchanged.

40

Continue…

Figure shows changes in disintegration time and in tensile strength upon storage.Closed triangle shows before storage.Open triangle shows after storage.

After storage tensile strength of tablet increase remarkably. With 10 sec increase in disintegration time tensile strength increase from 0.4 to 1.2 MPa.

41

Exicipients used for ODTs… Formulation process is similar to conventional tablets.

A direct-compression ODT formulation usually contains excipients such as diluent, lubricant, disintegrant, flavor, sweetener, and often color.

Main two types of excipients are

Diluents :Which are used to impart bulkiness to the formulation.

Disintegrating agents :help to disintegration which is necessary to achieve the characteristics of the ODTs.

42

Diluents… Various agents are added which act as a filler to the formulation

and impart bulkiness to the formulation which are known as diluents.

Several sugar-based excipients are mainly used as diluentbecause of their high aqueous solubility and sweetness in ODT formulations

Mainly used diluents are . Sorbitol, Mannitol, Dextrose,

Xylitol, Fructose, Maltose, Starch hydrolysate, and Polydextrose.

They also impart pleasing mouth-feel and good taste masking effect to the formulation.

43

Mannitol as a diluent… In a currently marketed ODTs mannitol is commonly used as a

diluent.

The reasons for extensive use of mannitol are

Availability in directly compressible grade. Rapid dispersibility due to wicking action. Better solubility. Impart sweetness. Negative heat of solution which gives cooling effect in the oral

cavity.

Mannitol has gained popularity for ODTs over other diluents as lactose typically used in direct compression.

44

Disintegrating Agents : Helps the tablets to disintegrate.

Mainly two types : Effervescent disintegrating agents. Non effervescent disintegrating agents.

Newer advancement : Super disintegrating agents.

45

Effervescent disintegrating agents.. When these agents come in contact with water they absorb water

and disintegrate very quickly and impart fast dissolving property to the tablets.

An effervescent agent cause high digestion of ODTs in mouth, which is activated by saliva and provides a distinct, pleasant sensation of effervescence in the mouth of the patient which is an additional advantage of these agents.

Excipients shows inability to prevent moisture absorption so manufacturing requires a controlled environment at low relative humidity and special packaging.

The cost of ODTs is higher than the cost of standard tablets made by direct compression.

46

Non effervescent disintegrating agents : They have their own property which makes them enable to cause

disintegration of tablets.

Starch and modified starches :

Directly compressible starches (such as starch 1500) Modified starches (such as carboxy methyl starches and sodium

starch glycolate) Starch derivatives (such as amylose)

Cross linked polyvinylpyrolidone. Cross linked sodium carboxymethylcellulose. Alginic acid and sodium alginate. Microcrystalline cellulose.

47

Super disintegrating agents… As these agents have property to disintegrate very well nowadays

to achieve rapid disintegration mainly in direct-compression ODT formulations high levels of a super disintegrant is added.

The levels of super disintegrant used can be around 10–20 wt % of the formulation

Various super disintegrating agents used are :

Crospovidone A1 (standard particle-size grade) (Polyplasdone XL) Crospovidone A2 (fine particle-size grade) (Polyplasdone XL-10) Crospovidone B (Kollidon CL) Sodium starch glycolate (Explotab) Croscarmellose sodium(Ac-Di-Sol).

48

Life cycle management… From the pharmaceutical industry's point of view, ODTs provide

new dosage forms for those drugs which are near to the end of their patent life.

So Manufacturers can extend their market exclusivity by

extending a patent by providing new dosage forms as OTD.

The higher cost for the development of ODTs may be absorbed by increased revenue of market exclusivity.

So oral disintegrating tablets are a subject of interest for pharmaceutical industry also.

49

Limitations of ODTs… Dosage form having a short half-life and which will need frequent

dosing can not be formulated as ODT.

Drugs having a very bitter or unacceptable taste because taste masking cannot be achieved without losing desired property.

Drugs which require controlled or sustained release.

Newer developments have been carried out in order to overcome these limitations.

50

Future trends… A new technologies being developed to incorporate higher doses

of hydrophobic drugs without affecting the fast disintegrating property too severely.

The tablet hardness, friability, and stability can be further

improved to such a level that multi-tablet packaging in conventional bottles becomes a norm.

ODTs may be suitable for the oral delivery of drugs such as protein and peptide-based therapeutics that have limited bioavailability when administered by conventional tablets due to degradation in the stomach.

51

New generation of ODTs… They are developed to overcome the sited limitations for ODT in

the formulation

Tablets are manufactured using an external tablet lubrication method in which direct compression of rapidly dispersing microgranules has been carried out.

They have friability of less than 0.5 % can be packed in bottles or blister pack.

Tablet dissolves in 15 to 30 sec and produce a smooth and pleasant tasting.

52

Taste masking… As we have seen formulation of bitter drug with ODT is not

possible due to low patient compliance so overcome this problem two approaches may be used.

Combination of micro-encapsulation technique with ODT technology effectively taste-masks the most bitter API.

Another technology is based on coacervation technique that encapsulates individual drug particles completely and provides superior taste masking.

In the coacervation process a uniform coating of polymeric membranes of various thicknesses and porosities directly place onto dry crystals or granules of bitter drugs which are micronised.

This coacervation technique can taste-mask a wide range of extremely poor-tasting drugs like zolpidem, sumatriptan, ranitidine, and cetirizine.

53

Bio-equivalency… The polymers used for taste masking can impede API release which results in delaying the onset of action. The use of micro-encapsulation technique which restricts dissolution of the API in the mouth, but allows rapid dissolution as the formulation reach the GI tract

Figure shows how microencapsulation helps to achieve bioequivalency.

54

ODT with Sustain Release…

Figure shows how sustained release is achieved with ODT.

Combination of ODTs with specialized functional polymers and variation in coating processes can lead to formation of ODTs with sustained, modified, and customized release profiles.

Micro encapsulation and

Multiparticulate coating are the two techniques used for this purpose.

55

Oral films and wafers… They are the most current advancements in the manufacturing of

orally disintegrating dosage forms.

Oral films and wafers are mainly thin elegant films of edible water-soluble polymers of various sizes and shapes like square, rectangle or disc. The strips may be opaque, flexible , brittle, or transparent.

They have the advantage over ODTs of a large specific surface area for disintegration.

Oral Wafer

A major limitation of these dosage forms is their low drug loading capacity and limited taste masking option.

56

Summary… As we have seen that by carrying out several formulation changes we can

easily formulate oral disintegrating agents.

Patients acceptability for this formulation is also relatively high which shows the potential market for these formulation.

Companies are also interested in formulating oral disintegrating tablets as the reason shown for that.

Thus, involvement of all the parts predicts the better future for oral disintegrating tablets.

Kinam Park, a professor in Purdue university and his phD student Y. fu has mentioned

“Time is not far when all the oral formulation would be available in the form of fast dissolving tablets”looks meaningful.

57

Thank you…