RESHMA VEMULAMS. INDUSTRIAL

PHARMACEUTICS

o Introductiono Objectives of The Studyo Review of literatureo Plan Of Worko Materials & Methods:

• Pre-formulation• Formulation &• Evaluation

o References

Def :-Orally disintegrating tablets (ODTs) were defined as a solid dosage form containing medicinal substances that disintegrate within a matter of seconds when placed on tongue.

According to EUROPEAN PHARMACOPEIA, ODTs were defined as orodisperse that can be placed in mouth where it disperses rapidly before swallowing.

These are appropriate dosage form for older people, children, and bedridden patients because it can be difficult for these patients to swallow conventional tablets or capsules.

In these patients, medication compliance and therapeutic effect could be improved by taking ODTs that can rapidly and easily disintegrate in oral cavity.

Oral route ofadministration

Solid dosage formSolid dosage form

Rapiddisintegrationon the tongue

Rapiddisintegrationon the tongue

Fast DissolveDosage Form

A stable, oral dosage formwith the dosing ease of a liquid

A stable, oral dosage formwith the dosing ease of a liquid

What are ODTs?

Regulatory Definitions

US Definition

• Orally Disintegrating Tablet

• A solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds when placed upon the tongue.

• Tablet weight <500mg. In-vitro USP disintegration test <30 seconds.

• FDA Guidance for Industry -Orally Disintegrating Tablets (Dec 2008)

EU Definition

• Orodispersible tablets

• Orodispersible tablets are uncoated tablets intended to be placed in the mouth where they disperse rapidly before being swallowed

• Disintegration Test: Orodispersible tablets disintegrate within 3 mins when examined by the test for disintegratioN.

• European Pharmacopoeia (Ph.Eur.)

Why use ODT?

• Clinical Formulation Marketing

• Pregastric delivery

• Faster onset

• Better S&E

• Bioequivalence

• Local delivery

• Compliance

• Convenience

• Stability

• Ease of use

• New presentation

• Extend exclusivity

• Broader application

• USP

ODT

CLASSIFICATION OF ODTsFirst generation ODTs

SECOND generation ODTs

THIRD generation ODTs

Preparation method • Prepared by freeze –drying method.• Drug suspension along with specific additives was filled into the pockets of press through packing.

• Wet granulation method• Drying the drug and additives after tabletting their wet mass(TUSHIMA 2001).

• Dry granulation method• Dry mass including the drug and saccharides were tabletted.

ADVANTAGES • RAPID DISINTEGRATION of ODTs

• Rapid disintegration of ODTs

• Rapid disintegration of ODTs• Less friable then first generation ODTs

DISADVANTAGES • Handling was difficult because the tablets were very friable• Highly sensitive to moisture• No Taste masking compounds applied for bitter tasting drugs•Low density and hardness

• LOW HARDNESS OF TABLETS• High porosity• Low density

• High porosity• Low hardness• Low density

Need for ODTs

Orally disintegrating dosage forms are particularly suitable for patients find it inconvenient to swallow traditional tablets and capsules with glass of water.

Pediatric and geriatric patients

Patients who are unwilling to take solid preparation due to fear of choking

A patient with persistent nausea, who may be in journey, or has little or no access to water

Increased bioavailability and faster onset of action are a major claim of these formulations.

Advantages of ODT’s

1. Good for patients with swallowing difficulties.

2. Good for paediatric compliance

3. Convenient to administer during travelling or working without need of water

4. The pre-gastric drug absorption avoids the first-pass metabolism.

5. Pregastric absorption leading to increased bioavaibility/ rapid absorption of drugs from mouth, pharynx and oesophagus as saliva passes down to stomach, also avoids hepatic Metabolism.

6. Convenient for administration to traveling patients and busy people who do not have accesses to water.

7. Excellent mouths feel property produced by use of flavours and sweetners help to change the perception of “medication as bitter pill” especially in pediatric population.

8. Fast disintegration of tablets leads to quick dissolution and rapid absorption which may produce rapid onset of action.

9. ODTs offer all the advantages of solid dosage forms and liquid dosage forms.

10. Convenience of administration and accurate dosing compared to liquids.

Drug selection criteria

The ideal characteristics of a drug for oral dispersible tablet include:

Ability to permeate the oral mucosa.

At least partially non-ionized at the oral cavity pH.

Have the ability to diffuse and partition into the epithelium of the upper GIT.

Small to moderate molecular weight.

Low dose drugs preferably less than 50mg.

Short half life and frequent dosing drugs are unsuitable for ODT.

Drug should have good stability in saliva and water.

Very bitter or unacceptable taste and odor drugs are unsuitable for ODT.

IMPORTANT CRITERIA FOR EXCIPIENTS USED IN THE FORMULATION OF ODTs:

• It must be able to disintegrate quickly.

• Their individual properties should not affect the ODTs.

• It should not have any interactions with drug and other excipients.

• It should not interfere in the efficacy and organoleptic properties of the product.

• When selecting binder a (single or combination of binders) care must be taken in the final integrity and stability of the product.

• The binders may be in liquid, semi liquid, solid or polymeric mixtures11. (Ex: Polyethylene glycol, coca butter, hydrogenated vegetable oils)

Formulation of ODT’sFormulation of ODT’s

• Active ingredient

• Disintegrating agents

• Binders

• Sweeteners

• Flavoring agents

• Glidants, lubricants, anti-adherents.

Formulation of ODT’sDisintegrating agents:Disintegrating agents: Starch and modified starches (e.g. – Primogel, Carboxy methyl Starches,

Pregelatinized, Starch USP, Starch 1500 ) Cross-linked polyvinylpyrrolidone (eg. Povidone). Modified celluloses such as cross-linked sodium carboxymethylcellulose

(eg. Ac-Di-Sol) Alginic acid and sodium alginate Microcrystalline cellulose e.g. - Avicel DG, Avicel PH-101. Super disintegrants - Crosscarmellose®

Ac-Di-Sol®

Primellose®  Vivasol®

Crosspovidone - Sodium Starch Glycolate - Soy polysaccharides

Emcosoy

Swelling is in two dimensions.-Direct compression or granulation-Starch free

Water insoluble and spongy in nature so get porous tablet

Rapid dissolving.Does not contain any starch or sugar. Used in nutritional products.

Formulation of ODT’sFormulation of ODT’sBinders :

SMCC (Silicified microcrystalline cellulose )

SMCC1 SMCC2 SMCC3

Starch paste , Natural Gums, Liquid Glucose , etc. )

Flavors:

A bitter product - mint, cherry or anise may be used

A salty product – peach, apricot or liquorice may be used

A sour product - raspberry or liquorice may be used

An excessively sweet product - vanilla may be used

TECHNOLOGIES FOR PREPARING ODT’STECHNOLOGIES FOR PREPARING ODT’S

The various technologies adopted to prepare ODTs are:

a)Freeze drying / Lyophilizationb)Mouldingc)Sublimationd)Spray dryinge)Mass extrusionf)Direct compression

Direct compression

• Easiest way to manufacture tablets is direct compression.• Low manufacturing cost, conventional equipments and limited number of processing steps led this technique to be a preferable one. However disintegration and dissolution of directly compressed tablets depend on single or combined effect of disintegrant, water soluble excipients and effervescing agents.

• It is essential to choose a suitable and an optimum concentration of disintegrant to ensure quick disintegration and dissolution.

• Superdisintegrants are newer substances which are more effective at lower concentrations with greater disintegrating efficiency and mechanical strength.

• On contact with water, the superdisintegrants swell, hydrate, change volume or form and produce a disruptive change in the tablet. Effective superdisintegrants provide improved compressibility, compatibility and have no negative impact on the mechanical strength of formulations containing high dose drugs.

• The type of disintegrants and its proportion are of prime importance.

• Also factors to be considered are particle size distribution, contact angle, pore size distribution and water absorption capacity.

• Studies revealed that the water insoluble superdisintegrants like sodium starch glycolate and Croscarmellose sodium show better disintegration property than the slightly water soluble agents like Crospovidone, since they do not have a tendency to swell.

• Superdisintegrants that tend to swell show slight retardation of the disintegration property due to formation of viscous barrier. There is no particular upper limit regarding the amount of superdisintegrant as long as the mechanical properties of the tablet are compatible with its intended use. The superdisintegrant may be used alone or in combination with other superdisintegrants.

Freeze DryingA process in which water is sublimated from the product after freezing. Lyophilization is a pharmaceutical technology which allows drying of heat sensitive drugs and biological at low temperature under conditions that allow removal of water by sublimation.

Lyophilization results in preparations, which are highly porous, with a very high specific surface area, which dissolve rapidly and show improved absorption and bioavailability.

MouldingIn this method, molded tablets are prepared by using water-soluble ingredients so that the tablets dissolve completely and rapidly.

The powder blend is moistened with a hydro-alcoholic solvent and is molded into tablets under pressure lower than that used in conventional tablet compression.

The solvent is then removed by air-drying. Molded tablets are very less compact than compressed tablets. These possess porous structure that enhances dissolution.

• SublimationThe slow dissolution of the compressed tablet containing even highly water-soluble ingredients is due to the low porosity of the tablets. Inert solid ingredients that volatilize readily (e.g.  urea,  ammonium  carbonate,  ammonium  bicarbonate, camphor etc.) were added to the other tablet ingredients and the mixture is compressed into tablets.

The volatile materials were then removed via sublimation, which generates porous structures.

Additionally, several solvents (e.g. cyclohexane, benzene) can be also used as pore forming agents.

Patented Technologies For Fast Dissolving Patented Technologies For Fast Dissolving TabletsTablets

Zydis TechnologyA Zydis tablet is produced by lyophilizing or freeze-drying the drug in a matrix usually consisting of gelatin.

The product is very lightweight and fragile, and must be dispensed in a special blister pack.

Patients should be advised not to push the tablets through the foil film, but instead peel the film back to release the tablet.

The Zydis product is made to dissolve on the tongue in 2 to 3 seconds.

Feldene Melt (Piroxicam 20 mg )

Claritin Reditab (Loratidine 10 mg )

• Durasolv TechnologyThe tablets made by this technology consist of a drug, fillers and a lubricant.

Tablets are prepared by using conventional tableting equipment and have good rigidity.

These can be packed into conventional packaging system like blisters.

Durasolv is an appropriate technology for products requiring low amounts of active ingredients.

Parcopa® (levodopa and carbidopa)

NuLev® (hyoscyamine)

• Orasolv TechnologyIn this system active medicament is taste masked.

It also contains effervescent disintegrating agent.

Tablets are made by direct compression technique at low compression force in order to minimize oral dissolution time.

Conventional blenders and tablet machine is used to produce the tablets.

The tablets produced are soft and friable and packaged in specially designed pick and place system.

FazaClo® (clozapine)

Orapred ODT®** (prednisolone sodium phosphate)

Drugs Formulated Into ODT’sDrugs Formulated Into ODT’s

• Analgesics and Anti-inflammatory Agents:

e.g. Azapropazone, Meclofenamic Acid, Indomethacin, Phenylbutazone, etc.

• Anthelmintics

e.g. Albendazole, Mebendazole, Dichlorophen, etc.

• Anti-coagulants:

e.g.Dicoumarol, Nicoumalone, Phenindione, etc.

• Anti-bacterial Agents:

e.g. Penicillin, Ciprofloxacin, Clarithromycin, Clofazimine, Cloxacillin, Demeclocycline, Doxycycline, Erythromycin, Ethionamide,

• Anti-Epileptics:

e.g. Carbamazepine, Clonazepam, Ethotoin, Methoin, etc.

• Anti-Fungal Agents:

e.g. Amphotericin, Clotrimazole, Econazole Nitrate, Fluconazole, Fiucytosine, Griseofulvin, Itraconazole, Ketoconazole, Miconazole, Natamycin, Nystatin. Etc.

• Formulation and evaluation of oral disintegrating tablets of Sertraline : Suhas M. Kakade1*, Vinod S. Mannur1,Ravindra V. Kardi1, Ketan B. Ramani1, Ayaz A. Dhada11, Department of Pharmaceutics, K.L.E. University’s college of pharmacy, J.N.M.C. Campus, Belgaum – 590010, India. Orally disintegrating tablets prepared by direct compression and using super disintegrants like crospovidone, croscarmellose sodium and sodium starch glycolate designate, designated as three different groups of formulation ( A, B and C) respectively were prepared and evaluated for the pre-compression parameters such as bulk density, compressibility, angle of repose etc.

• Formulation and evaluation of oral disintegrating tablets of Ondasetron hydrochloride using natural superdisintegrants: Nitin Bansal*, Govind Sharma, College of Pharmacy, IPS Academy, Indore (M. P.),India.

Tablets containing the drug were prepared by dry granulation method using different concentrations of superdisintegrants such as modified gum karaya, modified natural agar, crosscarmellose sodium and sodium starch glycollate. The formulations were evaluated for weight variation, hardness, friability, drug content, wetting time, in vitro disintegration time and in vitro dissolution study.

• Formulation and evaluation of oral disintegrating tablets of Salbutamol sulphate by cost-efficient | direct compression method : Reeta Rani Thakur*1, Vipin Sardana1, M.M College of Pharmacy, M.M. University, Mullana, Ambala-133001, India Disintegrating Tablet of Salbutamol sulphate was selected as model drug In the present study, an attempt had been made to prepare oral disintegrating tablets of the drug using various superdisintegrates crospovidone, sodium starch glycolate, crosscarmellose sodium following bydirect compression technique. Nine formulations having different superdisintegrants atdifferent concentration levels were prepared to assess their efficiency and criticalconcentration level.

• Formulation and In-vitro Evaluation of Orally Disintegrating Tablets of Olanzapine-2- Hydroxypropyl-β-Cyclodextrin Inclusion Complex : Kulkarni Ajit Shankarrao*, Ghadge Dhairysheel Mahadeo and Kokate Pankaj Balavantrao, Depatment of Pharmaceutics, Satara College of Pharmacy, Satara, M.S. India. The aim of this study was to design orally disintegrating tablets of Olanzapine and to complex Olanzapine with 2-hydroxypropyl-β- cyclodextrin with special emphasis on disintegration and dissolution studies.

• Formulation and In-vitro Evaluation of taste masked oral disintegrating tablets of predisolone : V. Ananda, *, R. Kandarapub, S. Gargc, Department of Pharmaceutics, Seth G. L. Bihani S. D. College of Technical Education, Sri Ganganagar, Rajasthan, India b Research and Development, Dr. Reddy’s Laboratories Ltd. (Generics), Bachupally, Hyderabad, India c School of Pharmacy, University of Aukland, New Zealand Received 20 June 2007; Revised 18 September 2007; Accepted 13 October 2007 To prepare taste-masked orally disintegrating tablets (ODTs) of prednisolone (PDL) by incorporation of microspheres in the tablets for use in specific populations viz. pediatrics, geriatrics and patients experiencing difficulty in swallowing.

• Formulation and evaluation of Rizatriptan Benzoate Orally Disintegrating Tablets : Mothilal. M*, Srikanth Kota, Sivagirish babu G, Gnanendra Kumar, Manimaran. V and Damodharan. N Department of Pharmaceutics, SRM College of Pharmacy, SRM University, Kattankulathur 603 203, Tamil Nadu, India. Orally disintegrating benzoate were prepared by direct compression method to provide faster relief from pain to migraine sufferers. About twelve formulations for tablets of Rizatriptan

• Formulation, Evaluation and Optimization of Orally Disintegrating Tablet of Piroxicam : *Bhupendra G.Prajapati, Bhaskar Patel, S.K.Patel College of Pharmaceutical Education and Research,Ganpat University, Kherva-382711, Mehsana, Gujarat State, INDIA Objective of this study was to formulate directly compressible orally disintegrating tablets of piroxicam with sufficient mechanical integrity, content uniformity, and acceptable palatability to assist patients of any age group for easy administration. Effect of varying concentrations of different superdisintegrants such as crospovidone, croscarmellose sodium, and sodium starch glycolate on disintegration time was studied.

• Formulation And Evaluation Of Enalapril Maleate Orodispersible Tablet : S.Jayaprakash, K.Kulathuran Pillai, S.Mohamed Halith*, Ganesh Doifode, Abirami, P.U.Mohamed Firthouse Department of Pharmaceutics, K.M.College of Pharmacy, Madurai-625107, Tamilnadu, India.

In the present work Enalapril maleate tablet have been developed in an orodispersible tablets formulation (ODT). Which was designed to facilitate tablet disintegration and drug dispersion. Orodispersible tablet of Enalapril maleate which, when placed in the tongue disintegrates or dissolve rapidly in the saliva without water.

To formulate Oral disintegrating tablets for new generation drugs of Anti- migraine for treating migraine. Formulation Designing : 2n factorial design technique was used for formulation designing. In this “2” is factor i.e. combination of two super disintegrants at a time and “n” indicates level i.e. higher and lower concentration

To Characterize interaction between the drugs & the excipients used.

To Evaluate the prepared Oral disintegrating tablets.

To Select an optimized formulation and compare it with the marketed products & find the F2 value.

API’s :

Avitriptan, Clonidine Hydrochloride, Ergotamine Tartrate, Naratriptan.

Excipients :

Sodium starch glycolate, Cross povidone, Crosscarmellose sodium, Mannitol, Aerosil, Mg stearate, Aspartame, Flavours, MCC

AvitriptanAvitriptan

IUPAC Name –IUPAC Name – 1-[3-[3-[4-(5-methoxypyrimidin-4yl)piperazin-1-yl]propyl]-1H-indol-5-yl]-N-methyl-methanesulfonamide . .

Molecular formula - Molecular formula - C22H30N6O3S

Molecular Weight - Molecular Weight - 458.577

CatergoryCatergory -- I Indolylpiperazine compound with abortive antimigraine properties.

MOAMOA - - Avitriptan interacts with vascular 5-HT11-like receptors to constrict cerebral blood

vessels and reduce carotid artery blood flow by closing AV anastomoses (AV shunts)that have been implicated in causing migraine pain .

The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring at 0.5 hr postdose. Absolute bioavailability was 19.3% in rats and 17.2% in humans.

Clonidine HydrochlorideClonidine Hydrochloride

IUPAC Name –IUPAC Name – N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine

Molecular formula - Molecular formula - C9H10Cl3N3 HclMolecular Weight - Molecular Weight - 266.5548

CatergoryCatergory -- Adrenergic alpha-2 Receptor Agonists.

MOAMOA - - Stimulates central alpha-adrenergic receptors to inhibit sympathetic cardioaccelerator and vasoconstrictor centers.

T1/2 - T1/2 - 6-20 hours; 40-60% is excreted in urine unchanged, 20% is excreted in feces. Less than 10% is excreted by p-hydroxyclonidine.

Bioavailability - 75-95%

Protein binding - 20-40%

Ergotamine TartrateIUPAC Name –IUPAC Name – (6aR,9R)-N-((2R,5S,10aS,10bS)- 5-benzyl-10b-hydroxy-2-methyl- 3,6-dioxooctahydro-2H-oxazolo[3,2-a] pyrrolo[2,1-c]pyrazin-2-yl) -7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg] quinoline-9-carboxamideMolecular formula - Molecular formula - C33H35N5O5)2, C4H6O6Molecular mass - Molecular mass - 1312.4 g/mol

CatergoryCatergory -- Vasoconstrictor Agents, Sympatholytics, Adrenergic, alpha-Agonists, Analgesics, Non-Narcotic.MOAMOA - - Avitriptan interacts with vascular 5-HT1

1-like receptors to constrict cerebral blood vessels and reduce carotid artery blood flow by closing AV anastomoses (AV shunts)that have been implicated in causing migraine pain .

T1/2 - Is approximately 2 h; 90% of metabolites are excreted in the bile. Unmetabolized ergotamine is erratically excreted in the saliva, and trace amounts are excreted in the feces and urine.Bioavailability - Intravenous: 100%, Intramuscular: 47%, Oral: <1% (Enhanced by co- administration of caffeine

Naratriptan

IUPAC Name –IUPAC Name – N-methyl-2-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]ethanesulfonamide

Molecular formula - Molecular formula - C17H25N3O2Molecular Weight - Molecular Weight - 335.465 [[gram g/mol

CatergoryCatergory -- 5HT (serotonin) agonist.

MOAMOA - - Endogenous compounds and drugs that specifically stimulate SEROTONIN 5- HT1 RECEPTORS. Included under this heading are agonists for one or more of the specific 5-HT1 receptor subtypes.

Bioavailability - 74%Metabolism - Hepatic T1/2 - 5-8 hours Excretion - Renal

• Minipress - II DL – Rimek

• Dissolution Tester(USP) - Electrolab

• Disintegration Tester(USP) - Electrolab

• Friabulator (USP) - Electrolab

• UV-Visible spectrometer - PG instruments LTD

• Digital pH meter – Systronics

• Digital balance

• Monsanto hardness tester

• Melting point test

• Solubility study

• Compatibility study

• Flow properties of API’s