MDDSMouth dissolving drug delivery

system - a novel drug delivery system achieved by direct compression method

NADANASABAPATHI.P.,M.Pharm

Jr.Research.asstAPEX LABORATORIES (P)LTD,CHENNAI.

WHAT IS MDDS ?

A mouth dissolving drug delivery system, is a tablet that dissolves or disintrigrants in the oral cavity without the need of water or chewing.

Most mouth dissolving delivery system must include substances to mask the taste of the active ingredient. This masked active ingredient is then swallowed by the patient's saliva along with the soluble and insoluble excipients

What the ideal requirements? • On oral administration its dissolve / disperse/ disintegrate in mouth in a matter of seconds without necessitate of water .

• Have a pleasing mouth feel. • Have an acceptable taste masking

property. • Be harder and less friable • Leave minimal or no residue in mouth after

administration • Have physical and environmental stability

what are the advantages over the conventional dosage form?

• Convenient for administration and patient compliant.• No need of water to swallow the dosage from. • Good mouth feels can achieve.• Rapid dissolution of drug and absorption which may

produce rapid, onset of action. • Ability to provide advantages of liquid medication in

the form of solid preparation. • improved bioavailability by pregastric absorption.• New business opportunity like product

differentiation, product promotion, patent extension and life cycle management.

How dissolves faster?

• In fast dissolving tablets, water must moves quickly 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.

What are disintegrant ?

Disintegrants are agents added to tablet (and some encapsulated) formulations to promote the breakup of the tablet (and capsule “slugs’) into smaller fragments in an aqueous environment thereby increasing the available surface area and promoting a more rapid release of the drug substance.

In what mechanisms a disintegrants disintegrates?• Swelling- on contact with water it tendency to swells

and decrease the adhesiveness of the tablet.• Porosity-pathways for the penetration of fluid into

tablets its impart their disintegrating action. • Capillary Action- (Wicking) Liquid is drawn up

through capillary action and rupture the interparticulate bonds causing the tablet to break apart.

• Deformation-the compression forces involved in tableting causes deformation more permanently which on exposure to water leads disintegration.

Example for disintegrants

• Starch• Lactose• Polacrilian K• Sodium alginate• Pregelatinized Starch (Starch 1500)   • Microcrystalline Cellulose (Avicel)   • Chitosan• Docusate sodium etc…

Super Disintegrants ! – which are decreases the disintegration time by various mechanism especially swell to many times their original size when placed in

water while producing minimal viscosity effects 1. Modified Starches- Sodium Carboxymethyl Starch (Chemically treated Potato Starch)     Eg. Sodium Starch Glycolate (Explotab, Primogel)

Mechanism of Action: Rapid and extensive swelling

with minimal gelling.

Effective Concentration: 4-6%. Above 8%, disintegration times may actually increase due to gelling and its subsequent viscosity producing effects.

2. Cross-linked polyvinylpyrrolidone- water insoluble and strongly hydrophilic. Eg. crospovidone (Polyplasdone XL, Kollidon CL) Mechanism of Action: Water wicking, swelling and possibly some deformation recovery. Effective Concentration: 2-5% in both wet & dry granulation.

3. Modified Cellulose- Internally cross-linked form of Sodium carboxymethyl cellulose. Eg. Ac-Di-Sol (Accelerates Dissolution), Nymcel Mechanism of Action: Wicking due to fibrous structure, swelling with minimal gelling. Effective Concentrations: 1-3% (Direct Compression), 2-4% (Wet granulation)

What is mean by direct Compression method?

• The term “direct compression” is defined as the process by which tablets are compressed directly from powder mixture of API with suitable excipients.

• No pretreatment of the powder blend by wet or dry granulation procedure is required.it done by simple mixing of API with suitable additive and compress to tablets.

Merits Demerits

1)Direct compression is more efficient and economical process as compared to other processes

2)The most important advantage of direct compression is economical process

3)Chemical stability problems for API and excipient would be avoided.

4)Prime particle dissolution.

5)Particle size uniformity.

6)The chances of batch-to-

batch variation are negligible

1) Problems in the uniform distribution of low dose drugs.

2) High dose drugs having high bulk volume, poor compressibility and poor flowability are not suitable for direct compression.

3) The choice of excipients for direct compression is extremely critical

4) Many active ingredients are not compressible either in crystalline or amorphous forms

5) Non-uniform distribution of colour, especially in tablets of

deep colours

What are the additives required for direct compression ?

• Directly compressible materials (Spray dried lactose, Anhydrous lactose, Starch-1500, Sorbitol , microcrystalline cellulose, Di-Pac )

• Binders ( Copovidone, Cellulose, Povidone, Starch, HPMC etc)

• Disintegrants (Starch, Lactose, Polacrilian K, Sodium alginate, Pregelatinized Starch,Microcrystalline Cellulose)  

• Lubricants (magnesium stearate, stearic acid, Talc etc...)• Antimicrobial preservatives ( MPS, PPS, Potassium

sorbate)• Sweeteners (Aspartame, Neotame, Saccharin sodium,

Sucralose, etc…)• Some other additives are used depend upon the

formulations.

What are manufacturing steps involved in Direct Compression ?

• Milling of drug and excipients.

• Mixing of drug and excipients.

• Tablet compression.

Sieving Milling Mixing Compression

Evaluation Of Blends Angle of Repose

• the maximum angle possible between the surface of the pile of the powder and the horizontal plane.

• The angle of repose was determined by the funnel method suggested by Newman. Angle of repose is determined by the following formula

Tan θ = h/r Therefore       θ = Tan-1 h/r Where            θ = Angle of repose

h = height of the cone r= Radius of the cone base • Angle of Repose less than 30 ° shows the free flowing

of the material

Bulk Density • Density is defined as weight per unit volume. Bulk

density (pb) is defined as the mass of the powder divided by the bulk volume and is expressed as gm/ cm 3 .

• A sample of about 50 cm 3 (blend) is carefully introduced in a 100ml graduated cylinder. The cylinder is dropped onto a hard wood surface three times from a height of 1 inch at two second interval. The bulk density is then obtained by dividing the weight of sample in gm by final volume in cm 3

Pb = M/ V • Where                        pb = Bulk Density "                                  M = Weight of sample in gm                                  Vo   = initial volume of blend in cm 3 • Bulk density is very important in designing the size of

containers needed for handling, shipping, and storage of raw material and blend.

Bulkiness

Void Volume

• Specific bulk volume or reciprocal of bulk density is called bulkiness or bulk.

• Bulkiness increases with a decrease in particle size. In mixture of material of different sizes, however the smaller particle shifts between the larger particles and tends to reduce the bulkiness.

• The bulkiness can be calculated by the following formula • Bulkiness=      I/ pb where, pb = Bulk Density.

• The volume of the spaces is known as the void volume "v" and is given by the formula

• V= Vo- Vf • Where Vo = Bulk volume (volume before tapping) • Vf   = True volume (volume after tapping

Compressibility index

• Compressibility index is an important measure that can be obtained from the bulk and tapped densities.

• CI = 100 (VO – Vf)

V

% Comp. Index Properties

5-12 Free flowing

12-16 Good

18-21 Fair

23-35 Poor

33-38 Very poor

>40 Extremely poor

Process Related problems occuring in Direct compression ?• Capping, lamination, splitting, or

layering of tablets is sometimes related to air entrapment during direct compression.

• When air is trapped, the resulting tablets expand when the pressure of tablet is released, resulting in splits or layers in the tablet.

What are the parameters evaluation in mouth dissolving tablets ?

1)Shape of Tablets: The compressed tablets were examined under the magnifying lens for the shape of the tablet.

2) Tablet Dimensions: Thickness and diameter were measured using

a calibrated dial caliper. 3) Hardness:

Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using monsanto hardness tester. it is expressed in kg/cm2.

4) Friability Test: It is measured of mechanical strength of tablets.

Roche friabilator was used to determine the friability by following procedure.

A preweighed tablet was placed in the friabilator. friabilator consist of a plastic-chamber that revolves at 25 rpm, dropping those tablets at a distance of 6 inches with each revolution. The tablets were rotated in the friabilator for at least 4 minutes. At the end of test tablets were dusted and reweighed,

The loss in the weight of tablet is the measure of friability and is expressed in percentage as %Friability = loss in weight / Initial weight x 100 Percentage friability of tablets less than 1% is considered acceptable.

.

5)Weight Variation Test:

• Twenty tablets were selected randomly from each batch and weighed individually to check for weight variation. The following percentage deviation in weight variation is allowed.

Average weight of a tablet ±Percentage deviation

130 mg or less 10

>130mg and <324mg 7.5

324 mg or more 5

6) Disintegration test

• The test was carried out on 6 tablets using the apparatus specified in I.P.-1996 distilled water at 37ºC ± 2ºC was used as a disintegration media and the time in second taken for complete disintegration of the tablet with any mass remaining in the apparatus was measured in seconds.

7) Dispersion time • In vitro dispersion time was measured by dropping

a tablet in a beaker containing 50 ml of Sorenson's buffer pH 6.8. Three tablets from each formulation were randomly selected and in vitro dispersion time was performed.

Packaging

• Expensive packaging, specific processing, and special care are required during manufacturing and storage to protect the dosage of other fast-dissolving dosage forms.

• Unlike these other quick-dispersing and/or dissolving oral delivery systems, the system can be packaged using various options, such as single pouch, blister card with multiple units, multiple-unit dispenser, and continuous roll dispenser, depending on the application and marketing objectives

Marketed Fast Dissolving Tablets in India Name of the

Product Active Ingredients

Imodium Lingual Imodium

Pepcidin Rapitab Quick releasing antiulcerpreparation of pepcid

Mosid – MT Mouth melt tablet of Mosapridecitrate.

Calritin Reditabs Immediate Dissolving formulation of Calritin

Nimulid – MD Nimesulide

Zyrof Meltab Rofecoxib

Claritin Reditab micronized loratadine

Feldene Melt piroxicam (10 or 20 mg),

Maxalt-MLT rizatriptan (5 or 10 mg),peppermint flavour

Pepcid RPD famotidine (20 or 40 mg),

Zyprexa Zydis olanzapine (5, 10, 15 or 20 mg),

Zofran ODT ondansetron (4 or 8 mg),strawberry flavor

Remeron Soltab mirtazepine (15, 30, or 45 mg),orange flavor