Preparation by solubility enhancement of domperidone oro dispersible tablets (od ts) using sds with inclusion complexations technique and their evaluation.ppt

PRESENTED BY :

Mr. Mahendra Pratap SwainB.PHARM, 7th SEMESTER,REGD. NO:- 1103267027

UNDER THE ESTEEMED GUIDANCE OF :

Prof. M.E. Bhanoji RaoPrincipal, M.Pharma, Ph.D., HOD of Pharmaceutics Roland Institute of Pharmaceutical Sciences

Mahendra Pratap Swain Friday, 15-May-2015

PREPARATION BY SOLUBILITY ENHANCEMENT OF DOMPERIDONE ORO-DISPERSIBLE TABLETS (ODTs) USING SDS

WITH INCLUSION COMPLEXATIONS TECHNIQUE AND THEIR EVALUATION

SONY

CONTENTS

Friday, 15-May-2015Mahendra Pratap Swain

INTRODUCTION

OBJECTIVE OF THE STUDY

PLAN OF WORK

MATERIALS & METHOD

A. PRE-FORMULATION STUDIES & RESULTS

B. POST-FORMULATION STUDIES & RESULTS (OR) EVALUATION OF ODTs

CONLUSION

REFERANCES

Propose Of Work


The aim and objective of the proposed study is to develop and evaluate ODTs of a model drug and enhance the onset of action & also to study the influence of excipients on the physical characteristics of the tablets.

The study is intended to select the best possible diluents and the superdisintegrants.

The impact of the diluents ratio and superdisintegrants on various properties of the tablet will be determined.

Croscarmellose, sodium starch glycolate, crospovidone, polacrallin potassium are the best used superdisintegrants globally, so In this study all the above mentioned superdisintegrants are selected.

Mahendra Pratap Swain

Plan Of Work

Friday, 15-May-2015

•Selection of an ideal drug for study (Was selected Domperidone).

•Preformulation studies done.

•Design a prototype Oro-Dispersible tablet (ODTs) formulation.

•Selection of a superdisintegrant in development of ODTs.

•Optimization of superdisintegrant for ODTs.

•Evaluation.

Oro-Dispersible Tablets (ODTs)

Dispersible Tablets (DTs) are uncoated or film-coated tablets intended to be dispersed in water before administration giving a homogeneous dispersion. Dispersible tablets disintegrate within 3 min when examined by the test for disintegration of tablets and capsules, by using water at 15-25 °C.

Oro-dispersible tablets (ODTs) are uncoated tablets intended to be placed in the mouth where they disperse rapidly before being swallowed. ODTs disintegrate within 30 sec. It is a NDDS because they are easy to administer and lead to better patient compliance so its should named OD-NDDS.

E.g.: The trend toward formulation of dispersible tablets is evident in Europe (159-162) and is becoming more commonplace in the United states with over-the counter preparation available in the form of the following technologies: Zydis® (Scerer DDS), Lyoe® (Farmalyoc), WOW® Tab (Yamanouchi), FlashDose® (Fuisz technologies), OraSolv® (CIMA), and DuraSolv® (CIMA). These tablets are either placed in mouth where they quickly dissolve or are placed in a glass of water prior to ingestion and provide consumers with a dosage form that is both potable and easy to swallow.




An orally disintegrating tablets or Oro-Dispersible Tablets (ODTs) is a drug dosage form available for limited amount of over-the-counter (OTC) & Prescription Medications.

ODTs serves as an Alternative dosage form those have Dysphagia (Difficulties in Swallowing).

Common among all age groups, dysphagia is observed in 35% of the general population as well as elderly institutionalized population & 12-18% patient in long term facilities.

Last decade seen that ODTs are well used in both OTC & Prescription medication. And important cause to take ODTs because these are very convenience as it can taken without Water.



Advantages OF ODTs


As per European Pharmacopoeia defined the term “Oro-disperse” as “a tablet that can be place in the mouth where it disperses rapidly before swallowing.” so ODTs are preparations which conveniences to those patients who are suffered dysphagia.

Good for pediatric medication.

Convenience to use during work.

Pre-Gastric Absorption leading to increase the Bioavaibility / Rapid absorption in Pharynx, Mouth, Esophagus leads to avoiding Hepatic Metabolism.

Convenient to those doesn't accesses water during journey as well as in busy work.

Excellent mouth feel properties produces by Flavor & Sweeteners leads to decrease the ppt. of ‘Medication as bitter pill’ especially in pediatrics.

Rapid On-Set-Of-Action due to absorption is rapid.

ODTs possesses all advantages of Liquid as well as Solid Dosage form.

Etc.


Drug Selection Criteria ODTs:

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The ideal characteristics of drug for consideration :

Ability to permit the oral mucosa.

At least partially non ionized at oral cavity pH.

Have a ability to diffuse or partition in to epithelium of the upper GIT.

Small to moderate molecular weight.

Low dose drug preferably less then 50mg.

Short T1/2 & frequent dosing drugs are unstable for DTs.

Drug should have good stability in saliva & water.

Very bitter & unacceptable test & odor drugs are unsuitable for DTs.


Drug Choice:

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Domperidone Systematic (IUPAC) name :5-chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl]piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

Pharmacokinetic data:Bioavailability : HighProtein binding : 91–93%Metabolism : Hepatic and intestinal (first-pass)Half-life : 7 hoursExcretion : Breast milk, renal

Chemical data:Formula : C22H24ClN5O2

Molecular mass : 425.911 g/molDomperidone is widely used anti-emetic drug acting by an inhibition of the dopaminergic receptor. Domperidone does not cross blood brain barrier. Domperidone is also effective in gastroparesis, pediatrics gastro-esophageal reflux (infant vomiting). Domperidone also prescribed for the treatment of gastro paresis a stomach motility condition.

http://en.wikipedia.org/wiki/International_Union_of_Pure_and_Applied_Chemistry_nomenclature

http://en.wikipedia.org/wiki/Bioavailability

http://en.wikipedia.org/wiki/Plasma_protein_binding

http://en.wikipedia.org/wiki/Drug_metabolism

http://en.wikipedia.org/wiki/Liver

http://en.wikipedia.org/wiki/Intestine

http://en.wikipedia.org/wiki/First_pass_effect

http://en.wikipedia.org/wiki/Biological_half-life

http://en.wikipedia.org/wiki/Excretion

http://en.wikipedia.org/wiki/Chemical_formula

http://en.wikipedia.org/wiki/Carbon

http://en.wikipedia.org/wiki/Hydrogen

http://en.wikipedia.org/wiki/Chlorine

http://en.wikipedia.org/wiki/Nitrogen

http://en.wikipedia.org/wiki/Oxygen

http://en.wikipedia.org/wiki/Molecular_mass

Significance of Oro-Dispersible New Drug delivery systems (OD-NDDS):


They are stable, easy to manufacture, possible to administer accurate dose.

They provide rapid absorption, which causes rapid onset of action.

Use of flavor and sweeteners enhance the mouth feel property by masking the bitter taste of the drug.

They have increased bioavailability compared to conventional oral tablets.

They are convenient to patients who refuse to swallow a tablet.

It is very much convenient to administer accurate dosing as compared to liquid formulations.

There is no need of water to swallow the dosage from.


Important Criteria For Selection Of Excipients For Used In Formulation Of

DTs

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It must be able to disintegrate quickly.

Their individual properties must not affect the formulation of ODTs.

It should be not interact with excipients & IPA.

It should not interfere in efficacy & organoleptic properties of products.

When selection of binder a care must be taken in final stability & integrity of products.

Binders may be liquid, semi liquid, solid or polymorphic mixtures. ( e.g.: Polyethylene glycol, Cocoa butter, Hydrogenated vegetable oils )


Formulation of DTS. :

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Active ingredients

Disintegrating agents

Binders

Sweeteners

Flavoring agents

Glidants

lubricants

Anti-adherants



FORMULATION


Domperidon Domperidon + +

INGRADIENTS HP- -Cyclodextrinβ PEG-6000

(In mg) (In mg)

F1 F2 F3 F4 F5 F61.Domperidon Inclusion Complex (API)

36.64 36.64 36.64 20 20 20

2. Tween-80 0.2 0.2 0.2 0.2 0.2 0.23. SDs

Ø SSG 18 - - 18 - -Ø Crospovidone - 18 - - 18 -

Ø Croscarmellose - - 18 - - 18

4. Sod. Saccarine 1 1 1 1 1 1

5. Starch-1500 20 20 20 20 20 20

6. Mg-Sterate 1 1 1 1 1 17. Talc 1 1 1 1 1 18. PVP 10 10 10 10 10 109. Flavour & Colour 2 2 2 2 2 2

10. PerLitol 120.16 120.16 120.16 136.8 136.8 136.8 TOTAL (In mg.) 210 210 210 210 210 210

FORMULATION


All the materials were passed through 20# screens prior to mixing. Domperidone, Mg-Stearate, Talc, Starch-1500, Sodium Starch Glycolate (SSG)/ Crospovidon/ Cros-carmellose, Na-Sacarin, PVP and Mannitol were mixed using a glass mortar and pestle. All the materials were directly compressible so this uniformly mixed blend was compressed into tablets using concave face round tooling on a Rimek-Mini Pres-11MAT (Multi Station Tablet Compression Machine, KARNAVATI).

Technologies Used For Preparing ODTs


Freeze drying or Lyophilization

Sublimation

Mass extrusion

Melt Granulation

Spray drying

Molding

Nanonization

Direct compression

Cotton candy process

Phase transition process

From that I selected Direct Compression method i.e. given below .


Direct compression

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Easiest way to Mfg. Of tablets by this technique.

Low mfg. cost, conventional equipments & limiting no. of processing steps led this technique to be a preferable one. How over disintegration & dissolution of directly compressed tablets depends on single or combine effect of disintegrant, water soluble excipients & effervescing agents.

It is essential to choose a suitable & optimum concen. Of disintgrants to ensure quick disintegration & dissolution.

Superdisintgrants are newer substances which are more effective at lower concen. At greater disintgrating efficiency & mechanical strength.

Studied revealed that water insoluble Superdisintgrants like Sod. Starch glycolate & Croscarmellose sod. Show better disintegration properties then the slightly water soluble agents like Crospovidone sod. they do not have tendency to Swell.



Evaluation Study:

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Evaluation of powder blends/Pre Formulation study : Bulk density Tapped density Angle of repose Compressibility index Melting point test Compatibility study Flow property of API’s Solubility study

Evaluation of Dispersible Tablets (DTs/ODTs) : Hardness Test Friability Thickness Weight Variation Test Disintegration test Water Absorption Ratio Wetting time Dissolution test

Pre-Formulation Studies


Bulk Tapped Flow Properties determination

Batch No. Density Density

( b=M/Vb)ρ ( t=M/Vt)ρ Angle of Repose Compressibility index

Hausner’s Ratio

F1 1 1.18 24 (Excellent) 15.25 (Good) 1.18 (Excellent)

F2 0.8 1.15 25 (Good) 30.43 (Poor) 1.43 (Poor)F3 1 1.18 30 (Good) 15.25 (Good) 1.18

(Excellent)F4 1.01 1.28 33 (Passable) 20.31

(Passable)1.26 (Passable)

F5 1.02 1.3 33 (Passable) 21.53 (Poor) 1.27 (Passable)

F6 1.03 1.26 43 (Poor) 18.25 (Passable)

1.22 (Passable)


Result & Discussion on Pre-formulation Studies:

Friday, 15-May-2015

After preparation of bulk powder blend, Flow study of blend;

Angle of Repose: In all Formulation found α value that 24, 25, 30, 33, 33, & 43 in F1, F2,…, F6 respectively. So as for Standard found that in formulation F1, F2, F3 were show good type flow, where F3 & F4 passable type and F5 give Very poor type flow.

Carr’s Index: In all Formulation found %C value that 15.25, 30.43, 15.25, 20.31, 21.53, & 18.25 in F1, F2,…, F6 respectively. Where found, according to standard F1 & F3 show good Flow and poor flow property given by F2 other are Passable.

Hausner’s Ratio: In all Formulation found Hausner’s ratio that 1.18, 1.43, 1.18, 1.26, 1.27, & 1.22 in F1, F2,…, F6 respectively but with respect to standard in case of F1 & F3 were given excellent Flow where F2 given very-very-poor flow & other are in good as well as passable type flow property.

From above studies concluded that F1, F3, F4 have Good flow property.


Post-Formulation Studies


Batch No. Disintegration

Wetting time (sec.)

Hardness Friability Weight Drug Release

time (sec.) (n=10) kg/cm2

(%) variation Q30 (%)

F1 29 32 3.9 ±0.122 0.39 199±1.33 96.21

F2 27 30 3.9 ±0.128 0.41 200±1.56 92.21

F3 30 33 4.0 ±0.365 0.41 200±1.59 89.65

F4 31 34 4.2 ±0.126 0.4 198±1.33 96

F5 30 35 3.9 ±0.152 0.38 210±1.62 91.54

F6 29 32 4.9 ±0.360 0.41 302±1.57 92.53


Result and Discussion Post-formulation i.e. ODTs:

Friday, 15-May-2015

As per study Table:3 was prepare in Post formulation studies from that following discussions obtained;

General appearance: In all Formulation (F1, F2, …, & F6) found visually that all were good appearance with pale yellowish small (8mm diameter) tablets had mint odor and test of sweeter due to presence of Sodium Saccharine.

Weight Variation: In prepared Formulation found weight variation that 199±1.33, 200±1.56, 200±1.59, 198±1.33, 210±1.62, 302±1.57 in F1, F2,…, F6 respectively and with respect to standard (210±7.5%) all Formulation are in Good weight Variation.

Hardness: In prepared all Formulation found good hardness in Kg/cm2 (n=10). Approx. 3.5+2 Kg/ cm2 in F1, F2, F3, …, F6. But good shown by F1, F4 & F6 and best Hardness shown by PEG-6000 inclusion complex as compare to HP--CD complex.

Friability: In all Formulation found Friability value that 0.39, 0.41, 0.41, 0.40, 0.38 & 0.41 in F1, F2,…, F6 respectively. Where found, according to standard (0.1%-0.9%), all were within the limit so all passed the test.

Disinigration: In all Formulation found Disintgration time (DT) (in Second) that 29, 27, 30, 31, 30 & 29

in F1, F2,…, F6 respectively. Where concluded that, according to standard (with in rang 30±2 sec.) all formulation were show good DT.

Wetting time: In all formulation found that 32, 30, 33, 34, 35 & 32 in F1, F2,…, F6. And all are Passed the evaluation test of wetting time as like as Diintigration.

Result and Discussion Post-formulation i.e. ODTs:


From the above, From above Post formulation data found that all formulations were good in preparation. Prepare Drug Inclusion complex with PEG-6000 & other HP-β-Cyclodextrin and the use of superdisintegrants (SDs) for preparation of Oro-Dispersible tablets (ODTs) was highly effective and commercially feasible. These superdisintegrants (SDs) accelerate disintegration of tablets by virtue of their ability to absorb a large amount of water when exposed to an aqueous environment. The absorption of water results in breaking of tablets and therefore faster disintegration. This disintegration is reported to have an effect on dissolution characteristics as well. Prepared of Dispersible tablets (ODTs) tablet gets dispersed in the mouth quickly and releases the drug early as compared to its formulated conventional tablet. Domperidone released from formulated tablet with Sodium Starch Glycolate (SSG)/ Crospovidon/ Cros-carmellos is very acceptable is about 96+%. It is clear that the dissolution of domperidone has improved in F1, F2, F3, as compare to F4, F5 & F6 tablets and showed good dissolution efficiency and rapid dissolution. The study shows that the dissolution rate of Domperidone can be enhanced to a great extent by direct-compression technique with the addition of super-disintegrants(SDs), which gives quick relief from emesis.


Conclusion

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In formulations best effects were seen of superdisintigrants (SDs) for increase in disintegration.

Inclusion complex of HP-β-CD & PEG-6000 with drug both ↑se solubility but HP-β-CD was seen better enhancer.

All formulations were had good disintegration time as well as the wetting time especially in F1 & F6.

Release of drug was good as 90+%.All had good Hardness as well as friability.


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Mahendra pratap Swain

MPS-JSR-MP

Friday, 15-May-2015

Mr. Mahendra pratap Swain

Health & Medicine

Preparation by solubility enhancement of domperidone oro dispersible tablets (od ts) using sds with inclusion complexations technique and their evaluation.ppt