fast disintegrating lorazepam

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PRESENTED BY : K.HAREESH O5-09-20 UNDER THE GUIDANCE OF : N.SRI RAM ASSOCIATE PROFESSOR PHARMACEUTICS SMT. SAROJINI RAMULAMMA COLLEGE OF PHARMACY ; MAHABOOBNAGAR. FORMULATION DESIGN AND OPTIMIZATION OF FAST DISINTEGRATING LORAZEPAM TABLETS BY EFFERVESCENT METHOD

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PRESENTED BY : K.HAREESH O5-09-20

UNDER THE GUIDANCE OF : N.SRI RAM ASSOCIATE PROFESSOR PHARMACEUTICS

SMT. SAROJINI RAMULAMMA COLLEGE OF PHARMACY ; MAHABOOBNAGAR.

FORMULATION DESIGN AND OPTIMIZATION OF FAST DISINTEGRATING LORAZEPAM TABLETS BY EFFERVESCENT METHOD

TABLE OF CONTENTS INTRODUCTION SCOPE AND PLAN OF WORK MATERIALS & METHODS RESULTS AND DISCUSSION CONCLUSION BIBILOGRAPHY

INTRODUCTION Fast dissolving tablet of the drug , rapidly disintegrates in

the mouth without need of water. This type of tablet has good patient compliance and more

bioavailability than the conventional tablets. Lorazepam is a benzodiazopine derivative with anti-epileptic

properties.Fast disintegrating tablets of lorazepam were prepared by EFFERVESCENT METHOD.

The in-vitro disintegration time of the fast disintegrating tablets can be reduced to minimum by

adding the following materials in the formulation: 1. crospovidone (2-8% w/w) as a super disintegrant. 2. mixture of sodium bicarbonate, citric acid & tartaric

acid (6-18% w/w) as effervescent material.

Advantages of effervescent tablets: 1. ease of administration. 2. absorption of the active drug is

improved (as it is in predissolved state). 3. effervescent systems can buffer the

aqueous solution of the drug, so that stomach Ph increases and this prevents the degradation of the active ingredient. This buffering effect induces the stomach to empty quickly( within 20 min) into small intestine and thus the absorption is increased.

4.they retain palatability after lengthy storage.

SCOPE AND PLAN OF WORK. SCOPE : Aim of the present study was to

develop, evaluate and optimize a fast dissolving tablet for lorazepam using simple and cost-effective methodology.

PLAN : A 32 full factorial design was applied to investigate the combined effect of the following two formulation variables on the in vitro dispersion time:

1. amount of crospovidone (superdisintegrant) 2. amount of effervescent material.

MATERIALS AND METHODSMATERIALS : Lorazepam crospovidone directly compressible Mannitol - to enhance mouth feel & other necessary ingredients.METHODS : Effervescent method : various formulations of the lorazepam fast

disintegrating tablets are prepared in the following steps: Lorazepam , mannitol, pineapple flavour, aspartame and crospovidone

were accurately weighed and sifted through sieve no.44. Sodium bi-carbonate and anhydrous citric acid and tartaric acid are pre-

heated at 80 degree celcius to remove moisture. Thoroughly mix this effervescent material in a mortar to get a uniform

powder and then added to the other ingredients. The ingredients after sifting through sieve no.44, were thoroughly mixed in

a geometrical order. The blend thus obtained was directly compressed at 8 mm size to get a

tablet of 150 mg.

Table-1

EVALUATION OF FAST DISSOLVING TABLETS : The evaluation involves the determination of the following parameters :

1. weight variation (by using shimadzu digital balance) 2. thickness variation 3. hardness (by using monsato hardness tester) 4. friability (by using USP type-ll Roche friabilator) 5. drug content uniformity 6. In-vitro dispersion time. 7. wetting time water absorption ratio(R) =100 (wa-wb)/wb

wb=weight of tablet before water absorption

wa= weight of tablet after water absorption.

Table-2

IN-VITRO DRUG RELEASE STUDY : in-vitro dissolution studies of optimized fast dissolving tablets of lorazepam and commercial tablet was performed according to USP XXlll type-ll dissolution apparatus(Electrolab, model TDT-06 N), at 50 rpm & around 37 degree celcius using 900 ml of Ph 6.8 phosphate buffer. Then finally the Absorbance is measured at 233 nm .

STABILITY TESTING : Stability studies on EF- 9 formulation are carried at 40 C / 75% RH for over a period of 3 months.

OPTIMIZATION OF THE FORMULATION : 1. the above performed tests are totally performed in 13

batches. 2. the best combination of effervescent material was used in

the optimization of the formulations. 3. the effect of independent variables x1&x2 on the

dependent variable – invitro dispersion time y1 was evaluated.

x1=amount of crospovidone x2= amount of effervescent material.

RESULTS AND DISCUSSIONS Lorazepam FDT were prepared by effervescent method and evaluated

for different parameters. The tablets obtained were of uniform weight with acceptable variation

as per IP specifications (+or_7.5%) Drug content was found to be in the range of 102-105%, which is

within acceptable limits. Hardness of the tablets was found to be 3.0-3.6 kg/cm 2 Friability below 1% was an indication of good mechanical resistance of

the tablet. In-vitro dispersion time for EF-9 formulation is 13 s, which facilitates

faster dispersion in mouth. So it is called as promising formulation. The optimisation of formulation is done and EF-9 with invitro

dispersion time 13 s is considered as best . It contains 8% w/w crospovidone and 18%w/w mixture of effervescent material.

Short term stability studies of the EF-9 formulation indicated that there are no significant changes in drug content and invitro dispersion time at the end of 3 months.

Invitro drug release study of 3 different formulations(EF-9, EF-0, CCF) provides the following drug profile.

fig-1

table-3

The EF-9 formulation has shown nearly eleven-fold faster drug release( t 50%=2.8 min), when compared to CCF( t 50%> 30 min)

fig-2

Grey =cumulative percent drug release in 10 min

BLACK=Dissolution efficiency after 10 min.

PCP Disso 2000 V3 software was used to develop a polynomial equation for the dependent variable- invitro dispersion time( y)

Y=b0 + b1x1 + b2x2 + b12x1x2 + b11x12 +

b22x22 .

The equation derived for the invitro dispersion time of the factorial formulations is

Y1=33.11-8.83x1-4.33x2

the negative sign for coefficients x1 & x2 indicate that, as the concentration of disintegrants increases, invitro dispersion time decreases.

Validity of above equation was verified by designing two extra design check point formulations( C1 & C2) and determining the invitro dispersion time.

The invitro dispersion time values predicted from the equation for the formulations are 44.73 & 17.73 s, wheras the experimental results are 46.27 & 19.95 s respectively.

The closeness of the predicted and observed values for C1 & C2 in the method indicates the validity of the derived equation.

CONCLUSION The results of a 32 full factorial design reveal that

the amounts of crospovidone and effervescent material significantly effect the invitro dispersion time.

Thus, by adopting a systematic formulation approach, an optimum point can be reached in the shortest time with minimum efforts.

Effervescent technique would be an effective approach compared with the use of more expensive adjuvants in the formulation of fast dissolving tablets with improved drug dissolution, patient complience, convenience and acceptability.

BIBILOGRAPHY1.Seager H. Drug delivry products and Zydis fast dissolving dosage forms. J Pharm Pharmacol 1998;50:375-82.      .

2.Indurwade NH, Rajyaguru TH, Nakhat PD. Novel approach- Fast dissolving tablets. Indian Drugs 2002;39:405-9.       

3.Kuchekar BS, Badhan AC, Mahajan HS. Mouth dissolving tablet: A novel drug delivery system. Pharm Times 2003;35:7-14.       

4.Reddy LH, Ghosh BR. Fast dissolving drug delivery systems: A review of the literature. Indian J Pharm Sci 2002;64:331-6.  

5.Sweetman SC. editor, Martindale: The Complete Drug Reference. 33rd ed. London: Pharmaceutical Press; 2002. p. 688-9.       

6.Kaushik D, Dureja H, Saini TR. Formulation and evaluation of olanzapine mouth dissolving tablets by effervescent formulation approach. Indian Drugs 2002;41:410-2.      

7.Banker GS, Anderson NR. The theory and practice of industrial pharmacy. In: Lachman L, Libermann HA, Kanig JL, editors. 3rd ed. New Delhi: Varghese Publishing House; 1987. p. 293-9.       

8.Ministry of Health and Family Welfare. Indian Pharmacopoeia: New Delhi: Controller of Publications, Govt. of India; 1996. p. 735.