aspirin sr tab ..ex 1

EXPERIMENT NO:06

TO PREPARE AND EVALUATE MULTIPLE EMULSION .

1. AIM: To prepare and evaluate multiple emulsion.

2. REFERENCES:1. www.Aaps.pharm sci,2003,5(1),article 72. Multiple emulsion :Technology & application by Abraham Aserin.3. www.wikipedia.com4. Remington:the science & practice of pharmacy volume-1 ;3265. Pak.J.pharm sci,vol 21,no.4 october 2008,pp 430-4376. Bull chem..soc. ethiop .2010,24(1)1-10

3. MATERIALS:

NAME OF THE DRUG COMPANY’S NAME Salicylic acid Aghadi Industrial Estate

Excipients COMPANY’S NAME Span 80 Dextrose Aghadi industrial Estate Tween 80

4. THEORY

Introduction

Spherical crystallization is a particle design technique, by which crystallization andagglomeration can be carried out simultaneously in one step and which has been successfullyutilized for improvement of flowability, compactability and bioavailability of crystallinedrugs. General methods of spherical crystallization are spherical agglomeration, emulsionsolvent diffusion and ammonia diffusion method. The principle steps involved in the processof spherical crystallization are flocculation zone, zero growth zone, fast growth zone andconstant size zone. Factors controlling the process of agglomeration are solubility profile,mode and intensity of agitation, temperature of the system and residence time. Sphericalcrystallization is having wide applications in pharmaceuticals like improvement offlowability and compressibility of poorly compressible drugs, masking bitter taste of drugs

and improving the solubility and dissolution rate of poorly soluble drug.

Parul Institute of Pharmacy 1 of 14

http://www.Aaps.pharm/

5. EVALUATION PARAMETER

1. Type of emulsions. 2. Microscopic Test. 3. Globule size. 4. pH determination. 5. stabilityof multiple emulsion. 6 Centrifuge tests. 7. Electrical conductivity tests.

6. DRUG PROFILE

PARAMETER VALUE

dose 600mgcategory Anti inflammatory,rubefacient,keratolyticBCS classification Class I

solubility Poorly soluble in water 0.2 g/100 mL H2O (20 °C), Chloroform 0.19 M, ethanol 1.84 M, methanol 2.65 M .

Ionization constant 2.97 at 25Ċ

bioavailabilityAfter oral administration 80-100% will be absorbed in stomach and in the small intestine

Steady state conc.Half life 2-4.5 hrsProtein binding 50-80% metabolism Salicylic acid is metabolized 80% in liver

Renal excretionexcreted mainly by the kidney as salicylic acid, salicyluric acid, salicylic glucuronides and gentisic acid.

Tmax 2hrCmaX 1.2 mcg/l

7. FORMULA:-


SR NO.

INGREDIENTS QUANTITY TAKEN

A. FOR W/O : 1ST PHASE:

1 light liquid paraffin oil 30 ml

2 purified water 15 ml

3 span -80 6 ml Dextrose 0.02gm

B. FOR W/O/W: 2ND PHASE:

1 purified water 30 ml

2 tween -80 1.8 ml

3 w/o emulsion 60 ml

4 Blood red color q.s.

8. PROCEDURE:-

1. Preparation of W/O emulsion:

For preparation of primary emulsion , oil phase consisting of paraffin oil and Span 80 ,was heated to 55. Aqueous phase consisting of salicylic acid and dextrose was also heated to the same temperature. Aqueous phase was added to the oil phase drop by drop . (15 min stirr under mechanical stirrer).

2. Preparation of W/O/W emulsion:

Agitation was continued until cooling to room temperature of 25 oC. For obtaining the multiple emulsion, primary emulsion was added to the aqueous phase containing hydrophilic surfactant (Tween 80) while agitating for 10 min. Emulsion was then homogenized at 800 rpm for 5 min and further at 500 rpm for 5 min more.

2. Evaluation Parameters:

EVALAUTION OF SPHERICAL CRYSTALSAs these spherical agglomerated crystals showing significant effect on the formulation andmanufacturing of pharmaceutical dosage forms so it is necessary to evalaute them by using differentparametrs.FLOW PROPERTY


Flow property of the material depends on the force developed between the particle, particle size, particlesize distribution, particle shape, surface texture or roughness and surface area. Flowability of theagglomerates is much improved as the agglomerateexhibits lower angle of repose then that of single crystals. Studies on spherically agglomerated aspirincrystals revealed that, the angle of repose of agglomerated crystals was 31.13 while that ofunagglomerated crystals was 47.12.This improvement in the flowability of agglomerates could beattributed to the significant reduction in inter-particle friction, due to their spherical shape and a lowerstatic electric chargeFollowing are the methods used to determine of flow propertyANGLE OF REPOSEThis is the common method used for determination of flow property. The angle of repose is the anglebetween the horizontal and the slop of the heap or cone of solid dropped from some elevation. Values forangle of repose ≤ 30 usually indicate free flowing material and angle ≥ 40 suggested a poor flowingmaterial. The angle of repose can be obtained from equationTan θ = h/0.5dWhere h- height of the cone and d- diameter of the coneCOMPRESSIBILITY OR CARR INDEXA simple indication of ease with which a material can be induced to flow is given by application ofcompressibility indexI = (1-V/Vo) *100Where v = the volume occupied by a sample of powder after being subjected to a standardized tappingprocedure and Vo = the volume before tapping.The value below 15% indicates good flow characteristics and value above 25% indicate poor flowabilityHAUSNER RATIOIt is calculated from bulk density and tap density.Hausner ratio = Tapped density / Bulk densityValues less than 1.25 indicate good flow (20% Carr Index) and the value greater then 1.25 indicates poorflow ( 33% Carr Index).DENSITYDensity of the spherical crystals is the mass per unit volume.Density = M/VPublication Ref No.: IJPRD/2010/PUB/ARTI/VOV-1/ISSUE-12/FEB/005 ISSN 0974 – 9446International Journal of Pharma Research and Development – Onlinewww.ijprd.com5POROSITYPorosity of granules affects the compressibility. Porosities are of two types “intragranular and


intergranular and these are measured with the help of true and granular densities.Intragranular porosity = 1- Granular density /True density.Intergranular porosity = 1- Bulk density / Granular densityTotal Porosity = 1- Bulk density/ True densityPACKABILITY:Improve packability has been reported for agglomerates prepared by spherical crystallization. The angleof friction, shear cohesive stress and shear indexes are lower then that of single crystals, which canimprove the packability of the agglomerates.The packability of agglomerates improved compared with those of the original crystals and that theagglomerated crystals are adaptable to direct tabletting. The packability assessed by analysis of thetapping process with the Kawakita(I) and Kuno(II) method and using the parameters a, b,1/b, k in theequationN/C = 1/ (ab) +N/a.....................................................IC = (Vo-Vn)/Vo,a =(Vo-V∞) /Vo.ρf- ρn= (ρf- ρo) . exp. (-kn)…………………………IIWhere, N =Number of tappingC =Difference in volume (degree of volume reduction.) and a, b are constant.COMPRESSION BEHAVIOUR ANALYSISGood compactibility and compressibility are essential properties of directly compressible crystals. Thecompaction behavior of agglomerated crystals and single crystals is obtained by plotting the relativevolume against the compression pressure. Sphericalagglomerates possess superior strength characteristics in comparison to conventional crystals. It issuggest that the surface are freshly prepared by fracture during compression of agglomerates, whichenhances the plastic inter particle bonding,resulting in a lower compression force required forcompressing the agglomerates under plastic deformation compared to that of single crystals.Compaction behaviour of agglomerated crystals were evaluated by using following parametersHeckel AnalysisThe following Heckel's equation used to analyze the compression process of agglomerated crystals andassessed their comapctibility.In [1/(1-D)]=KP+AWhere:D is the relative density of the tablets under compression PressureK is the slope of the straight portion of the Heckel PlotThe reciprocal of K is the mean yield is the mean yield pressure (Py).The following equation gives the intercept obtained by extrapolating the straight portion of the plots


A=1n [1/(1-D0)]+BWhere:D0 is the relative density of the powder bed when P=0.The following equation gives the relative densities corresponding to A and B.DA=1-e-ADB=DA-D0Stress Relaxation TestPublication Ref No.: IJPRD/2010/PUB/ARTI/VOV-1/ISSUE-12/FEB/005 ISSN 0974 – 9446International Journal of Pharma Research and Development – Onlinewww.ijprd.com6In this test put specific quantity of spherical agglomerated crystals sample in a die specificdiameter the surface of which is coated with magnesium stearate in advance, then used the universaltensile compression tester to compress the samples at a constant speed. After the certain limit ofpressure attained, the upper punch held in the same position for 20 min, during which measured time forthe reduction amount of the stress applied on the upper punch. The result corrected by subtracting fromthis measurement the relaxation measured without powder in the die under the same conditions.The following equation finds the relationship between relaxation ratio Y(t) and time t, calculated theparameters As and Bs, and assessed relaxation behavior.t/Y(t)=1/AsBs-t/AsY(t)=(P0-Pt)/P0Where:P0 is the maximum compression pressure, and Pt is the pressure at time t.MECHANICAL STRENGTHSpherical crystals should posses’ good mechanical strength as that directly reflects themechanical strength of compact or tablet. It is determine by using the following two methods,Tensile strength:Tensile strength of spherical crystals is measured by applying maximum load required to crush thespherical crystal. This method is a direct method to measure the tensile strength of spherical crystalsCrushing StrengthIt is measured by using 50ml glass hypodermic syringe. The modification includes the removal of the tipof the syringe barrel and the top end of the plunger. The barrel is then used as hallow support and theguide tube with close fitting tolerances to the Plunger. The hallow plunger with open end served as loadcell in which mercury could beadded. A window cut into the barrel to facilitate placement of granule on the base platen. The plungeracted as movable plates and set directly on the granules positioned on the lower platen as the rate of


loading may affect crushing load (gm). Mercury is introduced from reservoir into the upper chamber atthe rate of 10 gm/sec until the single granule crushed; loading time should be <3 minutes. The totalweight of the plunger and the mercury required to fracture a granule is the crushing load.FRIABILITY TESTThe friability of the spherical crystals is the combination of the attrition and sieving process in to asingle operation. Granules along with the plastic balls placed on a test screen. The sieve is thensubjected to the usual motion of a test sieve shaker provided the necessary attrition on the granules. Theweight of powder passing through the sieve is recorded as function of time. The friability index isdetermined from the slop of the plot of % weight of granules remaining on the sieve as a function of timeof shaking.Friability of agglomerates determined by using formulaFriability(X) = {1-W/Wo}/100WhereWo = Initial weight of the crystalline agglomerates placed in sieveW = Weight of the material which does not passed through sieve after 5 min.PARTICLE SIZE AND SIZE DISTRIBUTIONSize of the particle and their distributions can be determined by simply sieve analysis. Now with the helpof Ro-Tap sieve shaker, particle size analysis can be determined. In advance technology image-analyzeris used to determined size and volume of the particle.Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-1/ISSUE-12/FEB/005 ISSN 0974 – 9446International Journal of Pharma Research and Development – Onlinewww.ijprd.com7MOISTURE UPTAKE STUDYThe study indicates the behavior of uptake of moisture by drug and the prepared spherical crystals,which affect the stability. The weighted quantity of drug and spherical crystals placed in crucible ataccelerated condition of temperature and humidity,40 C ± 10C and 75% ± 3%respectively. The gain inweight of drug and spherical crystals is measuredPARTICLE SHAPE / SURFACE TOPOGRAPHYFollowing methods are usedOptical MicroscopyThe shape of the spherical crystals is studied by observing these under a optical microscope. Theobservations are made under the observation like 10X, 45X, 60X etc.Electron Scanning MicroscopyThe surface topography, type of crystals (polymorphism and crystal habit) of the spherical crystals isanalyzed by using scanning electron microscopy.


X-ray Powder DiffractionThis is an important technique for establishing batch-to-batch reproducibility of a crystalline form. Theform of crystal in agglomerates determine by using technique. An amorphous form does not produce apattern. The X-ray scattered in a reproducible pattern of peak intensities at distinct angle (2θ) relative tothe incident beam. Each diffraction pattern is characteristics of a specific crystalline lattice for acompound.SUMMARY AND CONCLUSION

The spherical

2.1 Organoleptic characteristics

.Freshly prepared primary and multiple emulsions were investigated organoleptically (color, liquefaction and phase separation). Organoleptic characteristics of both primary and multiple emulsions kept at different storage conditions, i.e. color, liquefaction and phase separation were noted at various intervals.

2.2 Types of emulsions

Types of emulsions were analyzed by dilution with paraffin oil and water separately and observation under microscope.

2.3 Globules size

In this study, globule sizes of the multiple emulsions prepared were determined using light Microscope fitted with a digital camera for the freshly prepared emulsions and for the emulsions

kept at different conditions for 28 days .

2.4 pH determination

The pH value of the freshly prepared emulsions and the emulsions kept at different conditionswere determined by a digital pH-meter. pH measurements were repeated for multiple emulsions

after 28 days of preparation.

2.5 Microscopic tests

Multiple emulsions were analyzed under the microscope to confirm the multiple characters. A drop of multiple emulsion was placed on the glass slide, diluted with water and covered by a glass cover. A drop of immersion oil was placed on the cover slide and observed under the microscope.

2.6 Stability tests

Stability tests were performed at different storage conditions for both primary and multiple emulsions. The tests were performed on samples kept at 4 ± 0.1 oC (in refrigerator), 25 ± 0.1oC.


2.6 Dye testWater soluble dye was dissolved in the aq.phase of an emulsion while an oil soluble dye taken up by the oil phase .which help ful in determination of type of emulsion.

2.8 In vitro release of drugIn vitro release studies from O/W/O emulsions were conducted using Franz diffusion cell (at room temperature) and UV spectrophotometry. The results showed that in the first four-hour period.

2.9 Assay of salicylic acid

Calibration curve: It was prepared by taking 100 mg salicylic acid then dissolved in 100ml dis. water. Taken 2ml from above and diluted up to 20ml which produced 100µg/ml. then 1ml was taken & diluted to 10ml which produced 10 ug/ml. taken suitable aliquot like,2ml,4ml,6ml,8ml and 10ml dilute up to 10ml which produce concentrations,2,4,6,8 & 10 µg/ml respectively and measured the absorbance by U.V. at 203nm. Plot the graph of Abs v/s Conc and find out the calibration curve equation.

Calibration curve of Aspirin

3 OBSERVATION & CALCULATION


3.1 Organoleptic characteristics Organoleptic characteristics of the primary and multiple emulsions formulated are presented in Table

TIME COLOUR LIQUEFACTION PHASE SEPARATION 0hr milky white No change Not observed 1hr Milky white No change Not observed 24hr Milky white No change Slightly seperation After 1month

3.2 Type of multiple emulsion

(1) Microscopic evaluation shows continuous pink color through out the water phase. (2) We can find out no. of globules of w/o emulsion of various size moving in the continuous water phase. (3) This conforms formation of w/o/w emulsion.

3.3 Globules size

Sr.No Size range Avg.diameter(d) No.of gobules(n) nd 1 0-5 2.5 15 37.5 2 6-10 7.5 35 262.5 3 11-15 12.5 25 312.5 4 16-20 17.5 20 350 5 21-25 22.5 5 112.5

∑n=100 ∑nd=1075 Avg. Diameter = ∑nd/∑n = 1075/100

= 10.75 µm

3.4 pH determination

pH of freshly prepared emulsion was 4.8 observed.

3.5 Microscopic tests

Here multiple emulsion type was o/w/o observed as follow;


3.6 Stability tests

In this work, both primary and w/o/w multiple emulsions were divided into two samples separately and these samples were kept at different storage conditions, i.e. at 4 °C in refrigerator, at 25 °C at room temp.. The samples kept at different storage conditions were observed for a period of 1 month. Samples were observed . separation.

Sr.no parameter Room temperature Temp. 4 °c 1 2 3

3.7 Dye test

Microscopic examination had seen that a water soluble dye had been taken up by continous phase & the inner particles present in globules,which indicated the w/o/w type of emulsion.


3.8 In vitro release of drug

3.9 Assay of salicylic acid Calibration curve

10. RESULT AND CONCLUSION

SR.NO PARAMETER RESULT CONCLUSION1 ORGANOLEPTIC CHARACTERS

(a)COLOUR (b)LIQUEFACTION (c)PHASE SEPARATION

(a)milky white (b)not observed (c)observed after week

2 TYPES OF EMULSION w/o/w3 AVG.GLOBULE SIZE 10.75µm4 PH DETERMINATION 4.8


Sr No. Time (hr)

Absorbance(nm)

1 1 0.234

2 2 0.178

3 3 0.293

Sr No. Cocentration ((ug/ml)

Absorbance(nm)

1 2 0.159

2 4 0.288

3 6 0.359

4 8 0.470

5 10 0.585

5 MICROSCOPIC TEST w/o/w6 STABILITY TEST7 DYE TEST w/o/w

10. RESULTS AND DISCUSSION

Table-1 Blend Evaluation

Sr. No. Parameter F1 (1:1) F2 (1:0.5) F3 (1:1) F4 (1:0.5)

1 Angle of Repose 30.98 35.65 34.70° 33.95°

2 Bulk Density (g/ml) 0.400 0.450 0.559 0.568

3 Tapped Density (g/ml) 0.466 0.500 0.746 0.746

4 Carr’s Index (%) 14.16 10.00 25.06 23.86

5 Hausner’s Ratio (%) 1.16 1.11 1.33 1.31

Table-2 Tablet Evaluation

Sr. No Parameter F1 (1:1) F2 (1:0.5) F3 (1:1) F4 (1:0.5)

1Weight Variation (maximum % Deviation)

3.97 4.10 2.59 4.43

2 Friability (%) 0.555 0.700 0.968 0.682

3 Hardness ± S.D. 10.26 ± 0.21 10.5 ± 0.39 8.7 ± 0.29 7.8 ± 0.22

4 Thickness (mm) ± S.D. 4.0 ± 0.05 4.0 ± 0.05 5.0 ± 0.05 5.0 ± 0.05

5 Diameter (mm) ) ± S.D. 8.0 ± 0.05 8.0 ± 0.05 8.0 ± 0.05 8.0 ± 0.05

6 Drug Content (%) 95.65 % 93.47 % 97.28 % 91.30 %

Dissolution Profile:

Aspirin SR Matrix Tab

0.00

10.00

20.00

30.00

40.0050.00

60.00

70.00

80.00

90.00

0 2 4 6 8Time (Hr)

% D

rug

Rel

ease

EC 1:1 EC 1:0.5 HPMC 1:1 HPMC 1:0.5


Table- 3 Swelling Index:

Time (Hr)% Swelling Index

F1 F2 F3 F40.5 26.67 23.33 30.00 25.811.0 40.00 43.33 46.67 41.942.0 46.67 50.00 53.33 48.393.0 60.00 63.33 56.67 51.614.0 63.33 66.67 63.33 58.065.0 63.33 66.67 63.33 58.066.0 26.67 23.33 30.00 25.81

% Swelling Index

0

10

20

30

40

50

60

70

80

0 1 2 3 4 5 6Time (hr)

% S

wel

lin

g In

dex

F1 F2 F3 F4

11. CONCLUSION

Aspirin sustained release tablets are prepared using two different rate controlling polymers, Ethyl cellulose and HPMC with the drug: polymer ratio (1: 1and 1: 0.5) the evaluation is done both in the blend and the prepared tablets. All the evaluation tests are found to be fall with in the range of standards specified in the pharmacopoeia. The swelling index study indicates that as the concentration of HPMC increases the swelling of the system is increased. And both the systems observed a sudden decrease in the weight after 5 th hour indicates the disintegrations or erosion of the matrix. The dissolution study conducted for all the formulations show the sufficient slow down of the release of the drug achieving the desired target.


aspirin sr tab ..ex 1

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