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PIROXICAM GEL

No 1. 2. 3. 4 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Description Drug Authority Application form Name and Address of Applicant *& Manufacturer Name of the Product Free Sale certificate Certificate Certificate of the composition of the product giving in detail the chemistry of the active ingredient / ingredient of the product. Detailed specification and standards laid down by the manufacturer for each product together with its method of analysis in details. A certificate of sterility and absence of pyrogen wherever it is applicable Six samples of the product applied for registration in their original pack. Certificate of Analysis Reference Sample Bioavailability studies I Safety and Tolerance studies & Test Detailed Reports covering a) Pharmacological b) Toxicological c) Clinical aspects Storage Date Authenticated price list Name of the competitive drugs manufactured by other firms Other countries where the product is Registered Date of introduction of the product to the market in the country of origin. Section No

I II ill IV V VI VII VIII IX X XI XII XIII XIV XV XIV

COMPOSITION OF THE PRODUCT

PRODUCT : ROXICAM GEL Batch No. :01

Batch Size : 300.0 kgs

NO 1 2 3 4 5 6 7 8 9

INGREDIENTS Piroxicam Carbomer 934 Glycerin Propylene glycol Potassium Hydroxide Disodium Edetate Methyl Paraben Propyi Paraben D.M.Water Q.S. to

SPEC. IP USP IP IP IP IP IP IP IP

LABEL CLAIM W/W 0.50 % 0.90 % 10.00 % 20.00 % 0.80 % 0.01 % 0.16% 0.04 %

OVER AGES 5.0 %

QTY IN KGS 1.575 2.700 30.000 60.000 2.400 0.030 0.480 0.120 300.000

CHEMICAL NAME & STRUCTURAL FORMULA OF EACH ACTIVE INGREDIENT

DRUG NAME SYNONYM MOLECULAR FORMULA CHEMICAL NAME

Piroxicam

: :

C15Hi3N304S 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2benzothiazine -3-carboxamide-l,l-dioxide I.P - 1996 ; Page No. 600

SPECIFICATION OR REFERENCE TEXT

INACTIVE INGREDIENTS
PRODUCT: ROXICAM GEL Batch No. :01

Batch Size : 300.0 kgs

NO 1 2 3 4 5 6 7 8

INGREDIENTS Carbomer 934 Glycerin Propylene glycol Potassium Hydroxide Disodium Edetate Methyl Paraben Propyi Paraben D.M.Water Q.S.to

SPE. USP IP IP IP IP IP IP IP

LABEL CLAIM 0.90 % 10.00% 20.00% 0.80% 0.01% 0.16% 0.04%

OVER AGES

QTY IN KGS 2.700 30.000 60.000 2.400 0.030 0.480 0.120 300.00

REASON FOR INCLU. Suspending & gelling agent Humectant Humectant & solvent PH adjuster Chelating/com plexing agent. Antimicrobial preservative Antimicrobial Preservative Solvent

RAW MATERIAL SPECIFICATION AND ANALYTICAL CONTROL PROCEDURE

RAW MATERIAL : PIROXICAM PROTOCOL : IP - 1996

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C15H13N304S

Mol.Wt. 331.35

Piroxicam is 4-hydroxy-2-metfayl-N-(2-pyridyl)-2H-l,2- benzothiazine -3-carboxamide1,1- dioxide. CATEGORY: Analgesic; antiinflammatory; antipyretic. DOSE : 10 to 20 mg daily. DESCRIPTION : Off-white to light tan or light yellow powder; odourless. SOLUBILITY: Slightly soluble in ethanol (95%) and in aqueous alkaline solutions; very slightly soluble in water, in dilute acids and in most organic solvents. STORAGE: Store in tightly-closed, light resistant containers . STANDARDS: Piroxicam contains not less than 97.0 per cent and not more than 103.0 percent ofC15H13N3O4S, calculated with reference to the anhydrous substance.

RAW MATERIAL : PIROXICAM PROTOCOL : IP - - 1996 IDENTIFICATION : A. B.

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The infrared absorption spectrum. Appendix 5.4, is concordant with the reference spectrum of piroxicam or with the spectrum obtained from piroxicam RS. The light absorption in the range 230 to 360 nm of a 0.001% w/v Solution in 0.01 M methanolic hydrochloric acid exhibits two maxima, at about 242 nm and 334 nm and a minimum at about 270 nm; absorbance at about 334 nm, about 0.87, Appendix 5.5. Carry out the method for thin layer chromatography. Appendix 4.6, using silica gel GF254 as the coating substances and a mixture of 95 volumes of toluene and 5 volumes of acetic acid as the mobile phase but allowing the solvent front to ascend 15 cm above the line of application. Apply separately to the plate 20 jul of each of the two solutions in a mixture of equal volumes of chloroform and methanol containing (1) 0.1 % w/v of the substance being examined, (2) 0.1 % w/v of piroxicam RS . Allow it to dry and develop again. After removal of the plate allow it to dry in air and examine under ultra-violet light (254 nm). The principal spot in the chromatogram obtained with solution (1) corresponds to that in the chromatogram obtained with solution (2).

C.

HEAVY METALS: Not more than 50 ppm, determined on 0.4 g by Method B, Appendix 3.12. SULPHATED ASH : Not more than 0.3 %, Appendix 3.22.

RAW MATERIAL : PIROXICAM PROTOCOL : IP - 1996

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WATER: Not more than 0.5 %w/w, determined on 2.0 g, Appendix 3.24. ASSAY: Carry out the method for high performance liquid chromatography, Appendix 4.3, using die following solutions in 0.1 M methanolic hydrochloric acid containing (1) 0.005% w/v of the substance being examined and (2) 0.005 % w/v of piroxicam RS. The Chromatographic procedures may be carried out using (a) a stainless steel column packed with stationary phase LCI, (b) a degassed mixture of 45 volumes of methanol and 55 volumes of a buffer solution prepared by diluting a mixture of 7.72 g of anhydrous citric acid in 400 ml of water and 5.35 g of sodium phosphate in 100 ml of water to 1000 ml with water as the mobile phase with a flow rate of 1.2 ml per minute and (c) a detection wavelength of about 254 run. The column efficiency determined using solution (2) is not less than 500 theoretical plates, the tailing factor is not more than 1.5. The test is not valid unless the relative standard deviation for replicate injections is not more than 2.0 %. Calculate me content of C15H13N3O4S in piroxicam RS.

TEST CERTIFICATE (THE DRUGS AND COSMETICS ACT 1940 AND THE RULES THEREUNDER FORM 39 ) RAW MATERIAL : PIROXICAM IP Party : Universal Impex A.R.NO. : UIR 257/98-99 G.R.N.no. : UI/RM/250/989 Pub. Lab. T.R.NO. : R07556 Batch No. : PX-036/98 Mfg. Date : Dec' 1998 Batch Size : 1x5 kg = 5 kg Exp. Date : Nov'2003 Manufacturer: Ramdev Chem Dt of Receipt : 24/01/99 Supplier : ReamdevChem Dtof Completion : 30/01/99 Ch.No./Dt : 243/24-01-99 Qty sampled : 2x5g RESULTS OF ANALYSIS & PROTOCOLS OF TEST APPLIED AS PER IP-96 Protocols Description Solubility Identification A,B,C Heavy metals. Sulphated ash Water Assay as C15H13N3O4S Results Complies with IP Complies with IP Complies with IP Complies with IP 0.03989 % 0.2975 % w/w 98.7 % OAB Claim / Limit Off-white to light tan or light yellow powder; odourless. NMT 50 PPM NMT 0.3 % NMT 0.5% w/w 97.0% to 103.0%

OPINION : In the opinion of the undersigned, the sample referred to above is of standard quality as defined in the act and the rules thereunder with respect to the tests carried out and mentioned above as per IP-96.

Date

: 30/01/99

Analyst

Q.C. Incharge.

RAW MATERIAL : CARBOMER 934 PROTOCOL : USP

PAGE: 01 OF 04

Carbomer 934 is a high molecular weight polymer of acrylic acid cross-linked with allyl ethers of sucrose. Carbomer 934, previously dried in vacuum at 80 deg for 1 hour, contains not less than 56.0 percent and not more than 68.0 percent of carboxylic acid (-COOH) groups. The viscosity of a neutralised 0.5 percent aqueous dispersion of Carbomer 934 is between 30,500 and 39,400 centipoises. PACKAGING AND STORAGE : Preserve in tight containers. LABELLING : Label it to indicate that it is not intended for internal use. IDENTIFICATION :A. Prepare a 1 in 100 dispersion of it To one portion of the dispersion add thymol blue TS: an orange color is produced. To another portion of the dispersion add cresol red TS: a yellow color is produced. Adjust a 1 in 100 dispersion of it with 1 N sodium hydroxide to about Ph 7.5: a very viscous gel is produced.

B.

RAW MATERIAL : CARBOMER 934 PROTOCOL : USP

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VISCOSITY ; (911) Carefully add 2.5 gm , previously dried in vacuum at 80 deg for 1 hour, to 500 ml of water in a 1000 ml beaker, while stirring continuously at 1000 +/- 10 rpm, with the stirrer shaft set at an angle of 60 deg and to one side of the beaker , with the propeller positioned near the bottom of the beaker. Allow 45 to 90 seconds for the addition of the test preparation at a uniform rate, being sure that loose aggregates of powder are broken up, and continue stirring at 1000 +/- 10 rpm for 15 minutes. Remove the stirrer, and place the beaker containing the dispersion in a 25 +/- 0.2 deg water bath for 30 minutes. Insert the stirrer to a depth necessary to ensure that air is not drawn into the dispersion, and while stirring at 300 +7- 10 rpm, titrate (see Titrimetry (541) with a calomel-glass electrode system to a pH of between 7.3 and 7.8 by adding sodium hydroxide solution (18 in 100) below the surface, determining the end point potentiometrically. The total volume of sodium hydroxide solution (18 in 100) used is about 6.2 ml . Allow 2 to 3 minutes before the final pH determination. [ Note If the final pH exceeds 7.8, discard the mucilage , and prepare another using a smaller amount of sodium hydroxide for titration ] Return the neutralized mucilage to 25 deg water-bath for 1 hour, then perform the viscosity determination without delay to avoid slight viscosity changes that occur 75 minutes after neutralization. Equip a suitable rotational viscometer with a spindle having a cylinder 1.47 cm in diameter and 0.16 cm high attached to a shaft 0.32 cm in diameter, the distance from the top of the cylinder to the lower tip of the shaft being 3.02 cm, and the immersion depth being 4.92 cm (No. 6 spindle). With the spindle rotating at 20 rpm, observe and record the scale reading. Calculate the viscosity , in centipoises, by multiplying the scale reading by the constant for the spindle used at 20 rpm. LOSS ON DRYING: (731)Dry it in a vacuum at 80 deg for 1 hour; it loses not more than 2.0 % of its weight.

RAW MATERIAL : CARBOMER 934 PROTOCOL : USP HEAVY METALS: Method II (231): 0.002% BENZENE:

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Standard preparation : Transfer 5.7 ul (5 mg ) of benzene to a 500 ml volumetric flask, add water to volume, and mix until homogeneous. Dilute 10.0 ml of this mixture with water to 500 ml , and mix. Pipet 5 ml of this solution into a suitable 10 ml serum-type vial, insert a tight rubber stopper, and seal with a metal cap. Test preparation : Accurately weigh about 10 mg of carbomer into a suitable 10 ml serum-type vial, add 5 ml of water, insert the stopper without delay, seal the vial, and mix to dissolve the specimen. Chromatographic system : (see Chromatography (621) The gas chromatograph is equipped with a flame-ionization detector and a 2-mm x 1.8-m column packed with 0.2 % phase G39 on support S7. The injector and detector are maintained at temperatures of about 200 deg. The column temperature is maintained at 80 deg for 4 minutes, then raised at the rate of 5 deg per minute to 150 deg. The carrier gas is nitrogen, flowing at a rate of 20 ml per minute. Treat and inject the Standard preparation as directed under procedure, and measure the peak response for benzene. The relative standard deviation for replicate injection is not more than 5.0 % PROCEDURE : - [ In the following chromatographic procedure, the use of headspace apparatuses that automatically transfer the measured amount of headspace is preferable to handling heated syringes for injecting the heated specimen.] Immerse the vials up to the rim of the cap in a thermostatic bath, maintained at a temperature of 85 deg , for at least 30 minutes. Using a 2 ml of gas syringe preheated in an oven at 100 +/- 2 deg, inject rapidly 1.0 ml of the gaseous phase from each vial separately into the chromatograph, and measure the peak responses for benzene. Calculate the quantify , in ug , of benzene in the weight of specimen taken by the formula : ru/rs,

RAW MATERIAL : CARBOMER934 PROTOCOL : USP

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in which ru and rs, are the responses obtained from the Test preparation and Standard preparation , respectively. The weight of benzene found is not more than 0.01 % of the weight of the specimen taken. ASSAY FOR CARBOXYLIC ACID CONTENT : Slowly add about 400 mg previously dried and accurately weighed , to 400 ml of water in 1000 ml beaker, while stirring continuously at about 1000 rpm, with the stirrer shaft set at an angle of 60 deg and at the side of the beaker, with the propeller positioned near the bottom of the beaker, and continue stirring for 15 minutes. Reduce the stirring speed, and titrate potentiometrically with 0.25 N sodium hydroxide VS, using calomel glass electrode system. Allow 1 minute for mixing , after each addition of 0.25 N sodium hydroxide VS, before recording the pH. Calculate the carboxylic acid content as a percentage of carboxylic acid groups taken by the formula 100 (45.02VN/W ), in which V is the volume in ml, of sodium hydroxide consumed, N is the normality of sodium hydroxide solution , W is the weight, in mg, of the specimen taken , and 45.02 is the molecular weight of the carboxylic acid (- COOH) group.

TEST CERTIFICATE (THE DRUGS AND COSMETICS ACT 1940 AND THE RULES THEREUNDER FORM 39) Rawmaterial : Carbomer 934 USP Party : Universal Impex G.R.N. No. : UI/RM/279/989 Batch No. : KK832KA459 Batch Size : lx22.68kg-22.68kg Manufacturer: Goodrich Supplier : Hemlin Chemicals Ch.No./Dt : 22-03-99

A.R.NO. : UIR 287/98-99 Pub. Lab. T.R.NO. Mfg. Date Exp. Date Dt of Receipt Dt of Completion Qty sampled

: R10400 : Mar'1999 : : 23/03/99 ; 28/03/99 : 2xl5g

RESULTS OF ANALYSIS & PROTOCOLS OF TEST APPLIED AS PER USP Protocols Description Results Complies with USP Claim / Limit White, fluffy powder having a slight characte- ristic odour, hygroscopic, the pH of a 1 in 100 dispersion is 3.20. 30500 39400 cps NMT 0.5 % NMT 2.0 % NMT 0.002 % 56.0 % - 68.0 %

Solubility Identification A, B Viscosity Benzene Loss on drying Heavy metals Content ofcarboxylic acid

Complies with USP Complies with USP 31060cps Test Passes 0.45 % Complies with USP 66.11%ODB

OPINION : In the opinion of the undersigned, the sample referred to above is of standard quality' as defined in the act and the rules thereunder with respect to the tests carried out and mentioned above as net USP Date : 28-03-99 Analysis Q.C. Incharge.

RAW MATERIAL : GLYCERIN PROTOCOL : IP - 1996 GLYCEROL Glycerin is propane- 1,2,3-triol

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CATEGORY: Lubricant; laxative; pharmaceutical aid (humectant) DESCRIPTION : Clear, colourless or almost colourless, syrupy liquid; odourless; very hygroscopic. SOLUBILITY: Miscible with water and with ethanol (95 %); slightly soluble in acetone; practically insoluble in ether and in fixed oils and volatile oils. STORAGE: Store in tightly-closed containers. STANDARDS: Glycerin contains not less than 98.0 per cent and not more than 101.0 per cent of C3H8O3, calculated with reference to the anhydrous substances. IDENTIIFCATION : Test A be omitted if test B,C and D are carried out. Test B and C may be omitted if test A and D are carried out. A : To 5 ml add 1 ml of water and mix carefully. The infra-red absorption spectrum of the resulting solution. Appendix 5.4, is concordant with the reference spectrum of glycerin (85 %) or with the spectrum obtained from glycerin (85 %) RS.

RAW MATERIAL : GLYCERIN PROTOCOL : IP - 1996 B:

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Mix 1 ml with 0.5 ml of nitric acid and superimpose 0.5 ml of potassium dichromate solution; a blue ring develops at the interface of the two liquids. Allow to stand for 10 minutes ; the blue colour does not diffuse into the lower layer. Heat 1 ml with 2 g of potassium hydrogen sulphate in an evaporating dish. Irritant vapours are evolved which blacken filter paper moistened with alkaline potassium mercuri-iodide solution. Refractive index, between 1.470 and 1.475, determined at 20 , Appendix 8.13.

C:

D:

ACIDITY OR ALKALINITY: To 50 ml of a 50.0 % w/v solution in carbon-dioxide free water ( solution A) add 0.5 ml of phenolphthalein solution. The solution is colourless and not more than 0.2 ml of 0.1 M sodium hydroxide is required to produced a pink colour. Reserve the final solution for the test for Ester CLARITY AND COLOUR OF SOLUTION : Solution A is clear. Appendix 6.1. Dilute 10 ml of solution A to 25 ml with water . The solution is colourless. Appendix 6.2 HEAVY METALS: Not more than 5 ppm, determined by Method A on a solution of 4.0 g in 2 ml of 0.1 M hydrochloric acid and sufficient water to produce 25 ml, Appendix 3.12. IRON: 10 g complies with the limit test for iron. Appendix 3.13 (4 ppm).

RAW MATERIAL : GLYCERIN PROTOCOL : IP - 1996

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CHLORIDE: 20 ml of solution A complies with the limit test for chlorides , Appendix 3.10(25ppm). SULPHATE: 10 ml of solution A complies with the limit test for sulphates , Appendix 3.15(30ppm). ALDEHYDES AND REDUCING SUBSTANCES : To 7.5 ml of solution A in a glass stoppered flask add 7.5 ml of water and 1 ml of decolorised pararosaniline solution, close the flask and allow to stand for 1 hour. Any color produced is not more intense than that obtained in a standard prepared at the same time and in the same manner but using 7.5 ml of formaldehyde standard solution ( 5 ppm CH2O) in place of solution A. The test is not valid unless the standard solution is pink. ESTER: Add 0.1 M sodium hydroxide to the solution reserved in the test for Acidity or alkanity until a total of 10.0 ml has been added and boil under reflux condenser for 5 minutes . Cool, add 0.5 ml of phenolphthalein solution and titrate with 0,1 M hydrochloric acid. Not less than 8.0 ml of 0.1 M hydrochloric acid is required to decolorise the solution. GLYCOLS AND RELATED SUBSTANCES : Carry out the method for thin-layer chromatography. Appendix 4.6, using silica gel G as the coating substance and a freshly prepared mixture of 55 volumes of chloroform , 35 volumes of acetone and 10 volumes of ethanol (95%) as the mobile phase. Apply separately to the plate 5 pi of each of the following solution. Solution (1) is a 2.0 % w/v solution of the substances being examined. Solution (2) contains 0.02 % w/v each ofdiethylene glycol RS, ethylene glycol RS and propylene glycol RS in ethanol (95 %) .

RAW MATERIAL : GLYCERIN PROTOCOL : IP - 1996

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After removal of the plate, allow it to dry in air for 1 hour, spray with a 0.1 % w/v solution of sodium metaperiodate and dry me plate in a current of warm air. Spray with a solution prepared by dissolving 1.8 g ofbenzidine in 50 ml of etfaanol (95 %), adding 50 ml of water followed by 20 ml of acetone and 10 ml of 0.2 M hydrochloric acid. Allow the plate to dry in air. Any secondary spot in the chromatogram obtained with solution (1) is not more intense than any of the spots in the chromatogram obtained with solution (2). SUGARS : Heat 10 ml of solution A with 1 ml of 1 M sulphuric acid on a water bath for 5 minutes . Add 3 ml of 2 M Sodium hydroxide ( Carbonate-free), mix and add dropwise 1 ml of freshly prepared copper sulphate solution; a clear blue solution is produced. Continue heating on the water-bath for 5 minutes; me solution remains blue and no precipitate is produced. SULPHATE ASH: Not more than 0.01 %, determined on 5 g, appendix 3.22. WATER: Not more than 2.0 % w/w, determined on 1.5 g. Appendix 3.24. ASSAY: Weigh accurately about 0.1 g, mix throughly with 45 ml of water, add 25.0 ml of a 2.14 % solution of sodium periodate and 1 ml of 1 M sulphuric acid and allow to stand protected from light for 15 minutes. Add 5 ml of a 50 % w/v solution of ethylene glycol, allow to stand protected from light for 20 minutes and titrate with 0.1 M sodium hydroxide using 0.5 ml of phenolphthalein solution as indicator. Perform a blank determination and make any necessary correction. Each ml of 0.1 M Sodium hydroxide is equivalent to 0.00921 g of C3H8O

TEST CERTIFICATE ( THE DRUGS AND COSMETICS ACT 1940 AND THE RULES THEREUNDER FORM 39 ) Rawmaterial : Glycerine IP Party : Universal Impex G.R.N.No. : UI/RM/223/989 Batch No. : E0804-14 Qty received : 1 x 250 kg. = 250.0 kg. Manufacturer: Supplier : Sneha chemicals Ch.No*/Dt : Proforma / 02-12-98

A.R.NO. : UIR 228/98-99 Pub. Lab. T.R.NO. Mfg. Date Exp. Date Dt of Receipt Dt of Completion Qty sampled

06/12/98 15/12/98 2 x 100 ml

RESULTS OF ANALYSIS & PROTOCOLS OF TEST APPLIED AS PER IP -96. Protocols Description Results Complies with IP Claim / Limit Clear, colourless, syrupy liquid; odourless; very hygroscopic. 1.470 to 1.475 NMTSppm NMT 4 ppm NMT 25 ppm NMT 30 ppm

Solubility Identification - B,C, D Acidity & alkalinity Clarity & colour of sol. Heavy metals Iron Chloride Sulphate Aldehydes & Reducing sub. Esters Glycols & Related sub Sugars Sulphated ash Water Assay as C3H8O.

Complies with IP Complies with IP D-1.474 Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP 0.01996 % 0.88499 % w/w 98.6141 % OAB

NMT 0.01 % NMT 2.0% w/w 98.0 % to 101.0 %

OPINION : In the opinion of the undersigned, the sample referred to above is of standard quality as defined in the act and the rules thereunder with respect to the tests carried out and asestiened above as per IP-96 - 96 Date : 15-12-98 Analyst Q.C. Incharge.

RAW MATERIAL : PROPYLENE GLYCOL PROTOCOL : IP - 1996 1,2-PROPANEDIOL C3 H8O Propylene glycol is (RS)-propane-l,2-diol. CATEGORY : Pharmaceutical aid (humectant; solvent)

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MOL. WT .75.09

DESCRIPTION : Clear, colourless, viscous liquid; practically odourless ; hygroscopic. SOLUBILITY : Miscible with water, with ethanol (95 %) , with acetone and with chloroform. Store in tightly-closed containers.

RAW MATERIAL : PROPYLENE GLYCOL PROTOCOL IP STANDARDS: IDENTIFICATION : A.

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To 0.5 ml of a 0.01 % w/v solution , cooled in ice add 5 ml of a cooled mixture of 10 ml of water and 90 ml of sulphuric acid. Heat for 10 minutes on a water bath at 70 deg, cool and add 0.2 ml of a 3 % w/v solution ninhydrin in a 2.5 % w/v solution of sodium metabisulphite; a violet colour slowly appears. Heat 0.15 ml with 0.1 g of boric acid; a pleasant odour develops. Add 1 ml to 0.5 g of potassium bisulphate and heat gently; a fruity odour develops And when me solution is heated to dryness, no sharp, acrid smell ofacrolein is perceptible.

B. C.

ACIDITY : Mix 10 ml with 40 ml of water and add 0.1 ml of bromothymol blue solution. The solution is greenish yellow and not more than 0.05 ml of 0.1 M sodium hydroxide is required to change the colour to blue. CLARITY AND COLOUR: The substance being examined is clear. Appendix 6.1, and colourless, Appendix 6.2. BOILING RANGE : Between 184 deg and 189 deg. Appendix 8.1 RELATIVE DENSITY: Between 1.035 and 1.040, Appendix 8.15.

RAW MATERIAL : PROPYLENE GLYCOL PROTOCOL : IP REFRACTIVE INDEX: Between 1.431 and 1.433, Appendix 8.13.

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HEAVY METALS: Not more than 5 ppm , determined by method D on 3 ml diluted to 12 ml with water. Appendix 3.12. Use lead standard solution (Ippm Pb) to prepare me standard. OXIDISING SUBSTANCES : To 10 ml add 5 ml of water, 2 ml of potassium iodide solution and 2 ml of 1 M sulphuric acid and allow to stand in a ground-glass-stoppered flask protected from light for 15 minutes. Titrate the liberated iodine with 0.05 M sodium tmosulphate using 1 ml of starch solution , added towards the end of the titration, as an indicator. Not more than 0.2 ml of 0.05 M sodium thiosulphate is required. REDUCING SUBSTANCES : Mix 1 ml with 1 ml of 6 M ammonia and heat in a water bath at 60 deg for 5 minutes; the solution is not yellow. Immediately add 0.15 ml of 0.1 M silver nitrate; me solution does not change its appearance within 5 minutes.

RAW MATERIAL : PROPYLENE GLYCOL PROTOCOL : IP

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OTHER GLYCOLS: Carry out the method for thin layer chromatography, Appendix 4.6, using silica gel G as the coating substance and a freshly prepared mixture of 55 volumes of chloroform, 35 volumes of acetone and 10 volumes of efhanol (95 %) as the mobile phase. Apply separately to the plate 5 ul of each of the following solutions. Solution (1) is a 2.0 % w/v solution of the substance being examined. Solution (2) contains 0.02 % w/v each of diethylene glycol RS, ethylene glycol RS and propylene glycol RS in ethanol (95 %). After removal of the plate, allow it to dry in air for 1 hour, spray with a 0.1 % w/v solution of sodium metaperiodate and dry the plate in a current of warm air. Spray with a solution prepared by dissolving 1.8 gm of benzidine in 50 ml of ethanol (95%) , adding 50 ml of water followed by 20 ml of acetone and 10 ml of 0.2 M hydrochloric acid. Allow the plate to dry in air. Any secondary spot in the chromatogram obtained with the solution ( 1 ) is not more intense than any of the spots in the chromatogram obtained with solution (2). SULPHATED ASH : Not more than 0.01 % w/w, determined by the following method. Heat 50 g until it bums, and ignite. Allow to cool, moisten the residue with sulphuric acid and ignite; repeat the operations. WATER : Not more than 0.2 % w/w, determined on 5 g, Appendix 3.24.

TEST CERTIFICATE ( THE DRUGS AND COSMETICS ACT 1940 AND THE RULES THEREUNDER FORM 39 ) Rawmaterial : Propylene glycol IP Party : Universal Impex G.R.N. No. : UI/RM/265/989 Batch No. : 11902071 Qty received : 3x215 kg. =645.0 kg. Manufacturer : Spic Organics Supplier : Sneha Chemicals Ch. No. / Dt : 1562 / 03-03-99

A.R.NO. : UIR 272/99-2000 Pub. Lab. T.R.NO. : - Mfg. Date : Feb' 1999 Exp. Date : ------Dt of Receipt : 06/03/99 Dt of Completion : 07/03/99 Qty sampled : 2 x 100 ml

RESULTS OF ANALYSIS & PROTOCOLS OF TEST APPLIED AS PER IP-96 Protocols Description Solubility Identification - A,B,C Acidity Clarity & colour of sol. Boiling Range Relative Density Refractive Density Heavy metals Oxidising Substances Reducing substances Other Glycols Sulphated ash Water Results Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP 187C 1.03820 1.431 Complies with IP Complies with IP Complies with IP Complies with IP 0.00145 %w/w 0.14875% w/w Claim / Limit Clear, colourless, viscous liquid; practically odourless hygroscopic.

184C to 189 C 1.035 to 1.040 1.431 to 1.433

NMT0.01% w/w NMT 0.2 %w/w

OPINION : In the opinion of the undersigned, the sample referred to above is of standard quality as defined in the act and the rules thereunder with respect to the tests carried out and mentioned above as per IP-96

Date : 07-03-99

Analy

Q.C. Incharge:

RAW MATERIAL : POTASSIUM HYDROXIDE PROTOCOL : IP-1966 KOH Caustic Potash.

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STANDARDS: Potassium hydroxide contains not less than 85 % of total alkali, calculated as KOH and not more man 4.0 per cent of K2CO3. DESCRIPTION: Dry, white sticks,pellets or fused mass; hard, brittle and showing a crystalline fracture. Very deliquescent. Strongly alkaline and corrosive. SOLUBILITY: Soluble in 1 part of water, in 3 parts of alcohol (90%), and in about 2.5 parts of glycerin; very soluble in boiling ethyl alcohol. IDENTIFICATION : Gives the reactions characteristic of potassium, page 928. ALUMINIUM, IRON, AND MATTER INSOLUBLE IN HCL : Boil 5 g with 40 ml of dilute HCL , cool, make alkaline with dilute ammonia solution, boil, filter, and wash athe residue with 2.5 per cent w/v solution of ammonium nitrate; the insoluble residue, after ignition to constant weight, weighs not more than 5 mg. ARSENIC : Not more than 4 ppm, page 971

RAW MATERIAL : POTASSIUM HYDROXIDE PROTOCOL : IP-1966

PAGE : 01 OF 02

CHLORIDE: 0.5 g dissolved in water with the addition of 1.6 ml of nitric acid, complies with the limit test for chlorides, page 930. HEAVY METALS: Dissolve 1 g in a mixture of 5 ml of water and 7 ml of dilute HCL. Heat to boiling, add 1 drop of phenolpthalein solution and dilute ammonia solution dropwise to produce a faint pink colour. Add 2 ml of acetic acid and water to make 25 ml; the limit of heavy metals is 30 ppm, page 931. SULPHATE: Dissolve 1 g in water with the addition of 4.5 ml of hydrochloric acid; the solution complies with limit test for sulphates, page 931. SODIUM : To 3 ml of a 10 per cent w/v solution add 1 ml of water, 1.5 ml of alcohol, and 3 ml of potassium antimonate solution and allow to stand; no white crystalline precipitate or sediment is visible to the naked eye within fifteen minutes ASSAY: Weigh accurately about 2 g, and dissolve in 25 ml of water, add 5 ml of barium chloride solution, and titrate with 1 N hydrochloric acid, using phenolphfhalein solution as indicator. To the solution in me flask add bromophenol blue solution, and continue the titration with 1 N hydrochloric acid. Each ml of 1 N hydrochloric acid, used in the second titration is equivalent to 0.06911 g of K2C03. Each ml of 1 N hydrochloric acid, used in the combined titration is equivalent to 0.05611 g of total alkali, calculated as KOH. STORAGE: KOH should be kept in a well closed container.

TEST CERTIFICATE (THE DRUGS AND COSMETICS ACT 1940 AND THE RULES THEREUNDER FORM 39 ) RAW MATERIAL : POTASSIUM HYDROXIDE IP Party : Universal Impex G.R.N. No. : UI/RM/ Batch No, : Qty received : lx50kg.-50.0kg. Manufacturer : The National Che. Cor Supplier : Ch.No./Dt : 0037 / 98-99

A.R.NO. : UIR 141/98-99 Pub. Lab. T.R.NO. : - Mfg.Date : - Exp. Date : Dt of Receipt : 02/09/98 Dt of Completion : 06/09/98 Qty sampled : 2 x 20 g

RESULTS OF ANALYSIS & PROTOCOLS OF TEST APPLIED AS PER IP-66 Protocols Description Results Complies with IP Claim / Limit Dry, white pellets or fused mass; hard brittle and showing crystalline fracture; very deliquescent; strongly alkaline & corrosive. NMT: 5 mg NMT4PPM NMT 30 PPM NLT 85.0 % NMT 4.0%

Solubility Identification Aluminium, Iron & matter insoluble in HC1 Arsenic Chloride Heavy metals Sulphate Sodium Assay as KOH K2C03

Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP 85.486 % 1.394 %

OPINION : In the opinion of the undersigned, the sample referred to above is of standard quality as defined in the act and the rules thereunder with respect to the tests carried out and mentioned above as per IP-66

Date : 06-09-98

Anatyst

Q.C. Incharge.

RAW MATERIAL : DISODIUM EDETATE PROTOCOL : IP - 1996 CioH14N2Na2O8,2H2O

PAGE : 01 OF 02

Mol. Wt. 372.24

Disodium Edetate is disodium ethylenediaminetetra acetate dihydrate. CATEGORY: Pharmaceutical aid; dictating agent in metal poisoning. DOSE : By intravenous injection, 50 mg per kg of body weight, upto a maximum of 3 g per day. DESCRIPTION: White, crystalline powder; odourless. SOLUBILITY: Soluble in water, sparingly soluble in ethanol (95%); practically insoluble in chloroform and in ether. STANDARD: Disodium Edetate contains not less than 98.5 % and not more than 101.0 per cent of CioHi4N2Na208,2H20. IDENTIFICATION : A. The infra-red absorption spectrum. Appendix 5.4, is concordant with the reference spectrum of disodium edetate or with the spectrum obtained from disodium edetate RS. Dissolve 2 g in 25 ml of water, add 6 ml of lead nitrate solution, shake and add 3 ml of potassium iodide solution; no yellow precipitate is produced. Make alkaline to red litmus paper with 2 M ammonia and add 5 ml of ammonium oxalate solution ; no preciptate is produced.

B.

RAW MATERIAL : DISODIUM EDETATE PROTOCOL : IP C.

1996

PAGE: 01 OF 02

Dissolve 0.5 g in 10 ml of water, add 0.5 ml of a 10 % w/v solution of calcium chloride, make alkaline to red litmus paper with 2 M ammonia and 3 ml of ammonium oxalate solution ; no precipitate is produced. Gives the reaction of sodium salts. Appendix 3.1.

D.

pH: Between 4.0 and 5.5, determined in a 5 % w/v solution. Appendix 8.11. CLARITY AND COLOUR OF SOLUTION : A 5.0 % w/v solution in carbondioxide-free water is clear. Appendix 6.1, and colourless. Appendix 6.2. HEAVY METALS: Not more than 20 ppm, determined on 1.0 g by Method A, Appendix 3.12. Use 2 ml of lead standard solution (10 ppm Pb) to prepare the standard. IRON: 10ml of a2.5% w/v solution complies with the limit test for iron, Appendix 3.13 (80 ppm). Add 0.25 g of calcium chloride to each solution before adding mercaptoacetic acid. ASSAY: Weigh accurately about 0.5 g, dissolve in sufficient water to produce 300 ml and add 2 g ofhexamine and 2 ml of 2M hydrochloric acid. Titrate with 0.1 M lead nitrate using about 50 mg of xylenol orange triturate as indicator. Each ml of 0.1 M lead nitrate is equivalent to 0.03722 g of CioH14N2Na2O8,2H2O.

TEST CERTIFICATE ( THE DRUGS AND COSMETICS ACT 1940 AND THE RULES THEREUNDER FORM 39 ) RAW MATERIAL : DISODIUM EDETATE IP Party : Universal Impex A.R.NO. : UIR 6/96-97 G.R.N. No. : UI/RM/ Pub. Lab. T.R.NO. : 0/A8888 Batch No. : 0116 Mfg. Date ; July 96 Qty received : 1x5 kg. =5.0 kg. Exp. Date : . Manufacturer: Alliance Dyechem P.L Dt of Receipt : 22/03/97 Supplier Smeeta traders Dt of Completion : 28/03/97 Ch.No./Dt : 345/ 22-3-97 Qty sampled : 2x25g RESULTS OF ANALYSIS & PROTOCOLS OF TEST APPLIED AS PER IP -96. . Protocols Description Solubility Identification A,B,C,& D PH Clarity and colour of sol Heavy metals Iron Assay C10H14N2Na208,2H2O Results Complies with IP Complies with IP Complies with IP 4.59 Complies with IP Complies with IP 0.05989 % 100.665 % Claim / Limit White, crystalline powder; odourless Bet. 4.0 and 5.5 NMT 20 PPM NMT80PPM Bet. 98.5% and 101.0%

OPINION : In the opinion of the undersigned, the sample referred to above is of standard quality as defined in the act & the rules thereunder with respect to the tests carried out & mentioned above as perJP96 specifiction

Date : 28/03/97

Analyst

Q.C. Incharge

RAW MATERIAL : METHYLPARABEN PROTOCOL : IP-1996 C8H8O3 Mol.Wt.l52.15

PAGE: 01 OF 03

Methyl Hydroxybenzoate Methyl paraben is methyl 4- hydroxybenzoate. CATEGORY: Pharmaceutical aid ( antimicrobial preservative) DESCRIPTION : Colourless crystals or white, crystalline powder. SOLUBILITY: Freely soluble in ethanol (95%), in ether and in methanol; very slightly in water. STORAGE: Store in well closed containers. STANDARDS Methylparaben contains not less than 99.0 per cent and not more than 101.0 per cent of C8H8O3. IDENTIFICATION : Test A may be omitted if test B,C, D and E are carried out. Tests B,C and D may be omitted if test A and E are carried out. A. The infra-red absorption spectrum. Appendix 5.4, is concordant with the reference spectrum of methylparaben or with the spectrum obtained from methylparaben RS.

RAW MATERIAL : METHYLPARABEN PROTOCOL : IP-1996 B.

PAGE : 02 OF 03

The light absorption in the range 230 to 360 nm of a 0.0005% w/v in ethanol (95%) exhibits a maximum at about 258 nm; absorbance at about 258 nm, 0.52 to 0.56, Appendix 5.5. Boil 10 mg with 10 ml of water, cool and add 0.05 ml of ferric chloride solution; a reddish violet colour is produced. Dissolve 0.1 g in 2 ml of ethanol (95%), boil and add 0.5 ml ofmercuric nitrate solution; a precipitate is formed and the supernatant liquid becomes red. Melts between 125 and 128, Appendix 8.8.

C. D. E.

ACIDITY: Dissolve 1.0 g in sufficient ethanol (95%) to produce 10 ml. To 2 ml of the solution add 3 ml of ethanol (95%), 5 ml of carbon dioxide-free water and 0.1 ml of bromocresol green solution. Not more than 0.1 ml of 0.1 M sodium hydroxide is required to change the colour of solution. CLARITY AND COLOUR OF SOLUTION : A 10 % w/v solution in ethanol (95%) is clear. Appendix 6.1, and not more intensely coloured than reference solution BYS6, Appendix 6.2. CHLORIDE: Heat 2 g with 100 ml of water, cool, add sufficient water to restore the original volume, and filter. 25 ml of the filtrate complies with the limit test for chlorides. Appendix 3.10 (500 ppm).

RAW MATERIAL : METHYLPARABEN PROTOCOL : IP-1996

PAGE: 03 OF 03

SULPHATE: To 10 ml of the filtrate obtained in the test for chloride add 0.15 ml of dilute hydrochloric acid and 0.1 ml of barium chloride solution; no turbity is produced within 10 minutes. RELATED SUBSTANCES: Carry out the method for thin-layer chromatography. Appendix 4.6, using silica gel HF254 as the coating substance and a mixture of 88 volumes of dichlormethane, 10 volumes of ethyl acetate and 2 volumes of anhydrous formic acid as the mobile phase. Apply separately to the plate 5 ul of each of two solutions of me substance being examined in methanol containing (1) 2.0 % w/v and (2) 0.02 % w/v respectively. After removal of the plate, dry it in a current of hot air and examine under ultra-violet light (254 nm). Any secondary spot in the chromatogram obtained with solution (1) is not more intense than me spot in the chromatogram obtained with solution (2). SULPHATED ASH: Not more than 0.1%, Appendix 3.22. ASSAY: Weigh accurately about 80 mg, transfer to a glass-stoppered flask, add 25 ml of 2 M sodium hydroxide and boil gently under reflux condenser for 30 minutes. Cool and add 25.0 ml of 0.0333 M potassium bromate, 5 ml of a 12.5 % w/v solution of potassium bromide and 40 ml of glacial acetic acid, cool in ice, add 10 ml of hydrochloric acid, immediately stopper the flask and allow to stand for 15 minutes. Add 15 ml of potassium iodide solution, mix and titrate athe liberated iodine with 0.1 M sodium thiosulphate using 2 ml of starch solution, added towards the end of the titration, as indicator. Repeat the operation without the substance being examined. The difference between the titrations represents the amount of potassium bromate required. The volume of 0.0333 M potassium bromate is equivalent to half of the volume of 0.1 M sodium thiosulphate required for the titration. Each ml of 0.0333 M potassium bromate is equivalent to 0.005072 g of C8H8O3.

TEST CERTIFICATE (THE DRUGS AND COSMETICS ACT 1940 AND THE RULES THEREUNDER FORM 39 ) RAW MATERIAL : METHYL PARABEN IP Party : Universal Impex G.R.N. No. : UI/RM/167/989 Batch No. : M/098/998 Qty received : 1x10 kg. =10.0 kg. Manufacturer : Salicylates & Chemical Supplier : Harish Enterprises Ch. No. / Dt : 899 / 14-10-98

A.R.NO. : UIR 173/98-99 Pub. Lab. T.R.NO Mfg. Date ; Sep'1998 Exp. Date Aug' 2003 Dt of Receipt 17/10/98 Dt of Completion : 31/10/98 Qty sampled '2x20g

RESULTS OF ANALYSIS & PROTOCOLS OF TEST APPLIED AS PER IP -96 Protocols Description Solubility Identification A,B,C,D & E Acidity Clarity and colour of sol Chloride Sulphate Related substances Sulphated ash Assay as C8H8O3. Results Complies with IP Complies with IP Complies with IP C. 0.542 E. 126 Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP 0.03989 % 100.068 % Claim / Limit White, crystalline powder; odourless. C. 0.52 to 0.56 E. 125to 128 NMT 500 PPM NMT 0.1 % Bet. 99.0% & 101.0%

OPINION : In the opinion of the undersigned, the sample referred to above is of standard quality- as defined in the act & the rules thereunder with respect to the tests carried put & mentioned above as get IP-96 specification

Date : 31/10/98

Analyst

Q.C. Incharge

RAW MATERIAL : PROPYLPARABEN PROTOCOL : IP-1996 C10H12O3 Mol. Wt. 180.20

PAGE: 01 OF 03

Propyi Hydroxybenzoate Propyi paraben is propyi 4- hydroxybenzoate. CATEGORY: Pharmaceutical aid ( antimicrobial preservative) DESCRIPTION : Colourless crystals or white, crystalline powder. SOLUBILITY: Freely soluble in ethanol (95%), in acetone, in ether and in methanol; very slightly in water. STORAGE: Store in well closed containers. STANDARDS Propylparaben contains not less than 99.0 per cent and not more than 101.0 per cent of C10H12O3, calculated with reference to the dried substance. IDENTIFICATION: A. The light absorption in the range 230 to 360 nm of a 0.0005% w/v in ethanol (95%) exhibits a maximum at about 258 nm; absorbance at about 258 nm, 0.44 to 0.47, Appendix 5.5.

RAW MATERIAL : PROPYLPARABEN PROTOCOL : IP-1996 B.

PAGE : 02 OF 03

To about 10 mg in a test tube add 1 ml of sodium carbonate solution, heat it to boiling for 30 seconds and cool (solution A). To a further 10 mg in a test tube add 1 ml of sodium carbonate solution; the substance partly dissolves (solution B). Add at the same time to each of solution A and B 5 ml of aminophenazone solution and 1 ml of potassium ferricyanide solution and mix. Solution B is yellow to orange - brown. Solution A is orange to red and the colour is clearly more intense than any similar colour that may obtained with solution B. Melts between 96 and 99, Appendix 8.8.

C.

CLARITY AND COLOUR OF SOLUTION : A 10 % w/v solution in ethanol (95%) is clear. Appendix 6.1, and not more intensely coloured than reference solution BYS6, Appendix 6.2. ACIDITY : Dissolve 1.0 g in sufficient ethanol (95%) to produce 10 ml. To 2 ml of the solution add 3 ml of ethanol (95%), 5 ml of carbon dioxide-free water and 0.1 ml of bromocresol green solution. Not more than 0.1 ml of 0.1 M sodium hydroxide is required to change the colour of solution. CHLORIDE: Heat 2 g with 100 ml of water, cool, add sufficient water to restore the original volume, and filter. 25 ml of the filtrate complies with the limit test for chlorides. Appendix 3.10 (500 ppm). SULPHATE: To 10 ml of the filtrate obtained in the test for chloride add 0.15 ml of dilute hydrochloric acid and 0.1 ml of barium chloride solution; no turbity is produced within 10 minutes.

RAW MATERIAL : PROPYLPARABEN PROTOCOL : IP 1996

PAGE: 03 OF 03

RELATED SUBSTANCES : Carry out the method for thin-layer chromatography. Appendix 4.6, using silica gel HF254 as the coating substance and a mixture of 88 volumes of dichlormethane, 10 volumes of ethyl acetate and 2 volumes of anhydrous formic acid as the mobile phase. Apply separately to the plate 5 ul of each of two solutions of the substance being examined in methanol containing (1) 2.0 % w/v and (2) 0.02 % w/v respectively. After removal of the plate, dry it in a current of hot air and examine under ultra-violet light (254 nm). Any secondary spot in the chromatogram obtained with solution (1) is not more intense than the spot in the chromatogram obtained with solution (2). SULPHATED ASH: Not more man 0.1%, Appendix 3.22. LOSS ON DRYING: Not more than 0.5 %, determined on 1 g by drying over silica gel for 5 hours. Appendix 8.6. ASSAY: Weigh accurately about 80 mg, transfer to a glass-stoppered flask, add 25 ml of 2 M sodium hydroxide and boil gently under reflux condenser for 30 minutes. Cool and add 25.0 ml of 0.0333 M potassium bromate, 5 ml of a 12.5 % w/v solution of potassium bromide and 40 ml of glacial acetic acid, cool in ice, add 10 ml of hydrochloric acid, immediately stopper the flask and allow to stand for 15 minutes. Add 15 ml of potassium iodide solution, mix and titrate athe liberated iodine with 0.1 M sodium thiosulphate using 2 ml of starch solution, added towards the end of the titration, as indicator. Repeat the operation without the substance being examined. The difference between the titrations represents the amount of potassium bromate required. The volume of 0.0333 M potassium bromate is equivalent to half of the volume of 0.1 M sodium thiosulphate required for me titration. Each ml of 0.0333 M potassium bromate is equivalent to 0.006007 g of C10H12O3.

TEST CERTIFICATE ( THE DRUGS AND COSMETICS ACT 1940 AND THE RULES THEREUNDER FORM 39 ) RAW MATERIAL : PROPYL PARABEN IP : Universal Impex A.R.NO. : : UI/RM/ Pub.Lab.TR.NO : : P/015/698 Mfg. Date : 1 x 10 kg. = 10.0 kg. Exp. Date : Salicylates & Chemical Dt of Receipt : Harish Enterprises Dt of Completion : 29/07/98 : 492/21-07-98 Qty sampled

Party G.R.N. No. Batch No. Qty received Manufacturer Supplier Ch. No. / Dt

UIR 98/98-99 : June' 1998 : May'2003 : 27/07/98 : 2xl0g

RESULTS OF ANALYSIS & PROTOCOLS OF TEST APPLIED AS PER IP -96. Protocols Description Solubility Identification A,B,C Acidity Clarity and colour of sol Chloride Sulphate Related substances Sulphated ash Loss on drying Assay as C8H8O3. Results Complies with IP Complies with IP Complies with IP A- 0.452 C- 97 Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP 0.04% 0.44% 100.07% Claim / Limit White, crystalline powder; odourless. A- 0.44 to 0.47 E. 96to 99

NMT500PPM

NMT 0.1 % NMT0.5% Bet. 99.0%& 101.0%

OPINION : In the opinion of the undersigned, the sample referred to above is of standard quality' as defined in me act & the rules thereunder with respect to the tests carried out & mentioned above as per IP96 specifiction Date : 29/07/98 Analyst Q.C. Incharge

RAW MATERIAL : PURIFIED WATER IP PROTOCOL : IP H2O

1996 PAGE: 01 OF 03 Mol.Wt. 18.02

Purified water is prepared by distillation by means of ion exchange or by any other appropriate means from suitable potable water mat complies with all relevant statutory regulations. CATEGORY: Pharmaceutical aid (solvent) DESCRIPTION : Clear, colourless liquid; odourless and tasteless. STORAGE: Store in well closed containers of a material that does not alter the properties of the water. STANDARD: ACIDITY OR ALKALINITY: To 10 ml, freshly boiled and cooled in a borosuicate glass flask, add 0.05 ml of methyl red solution; me resulting solution is not red. To 10 ml add 0.1 ml ofbromothymol blue solution; the resulting solution is not blue.

RAW MATERIAL : PURIFIED WATER IP PROTOCOL : IP-1996 AMMONIUM :

PAGE: 02 OF 03

To 20 ml add 1 ml of alkaline potassium mercuri-iodide solution and allow to stand for 5 minutes. When viewed vertically the solution is not more intensely coloured than a solution prepared at the same time by adding 1 ml of alkaline potassium mercuri-iodide solution to a solution containing 2.5 ml of dilute ammonium chloride solution and 7.5 ml of the liquid being examined. CALCIUM AND MAGNESIUM: To 100 ml add 2 ml of ammonia buffer pH 10.0, 50 mg of mordant black II mixture and 0.5 ml of 0.01 M disodium edetate; a purple blue colour is produced. HEAVY METALS: Not more than 0.1 ppm, determined by Method D on 12 ml of a solution prepared in the following manner. In a glass evaporating dish evaporate 150 ml to 15 ml on a water bath. Use lead standard solution (1 ppm Pb) to prepare the standard , Appendix 3.12. CHLORIDE: To 10 ml add 1 ml of 2 M nitric acid and 0.2 ml of 0.1 M silver nitrate; the appearance of the solution does not change for at least 15 minutes.

RAW MATERIAL : PURIFIED WATER IP PROTOCOL IP - 1996 NITRATE :

PAGE: 03 OF 03

To 5 ml in a test-tube immersed in ice add 0.4 ml of 10 % w/v solution of potassium chloride, 0.1 ml of diphenylamine solution and, dropwise with shaking, 5 ml of sulphuric acid. Transfer the tube to a water-bath at 50 and allow to stand for 15 minutes. Any blue colour in the solution is not more intense than that in a solution prepared at the same time and in the same manner using a mixture of 4.5 ml of nitrate-free water and 0.5 ml of nitrate standard solution (2 ppm N03) (0.2 ppm). SULPHATE: To 10 ml add 0.1 ml of 2 M hydrochloric acid and 0.1 ml of barium chloride solution. The appearance of the solution does not change for at least 1 hour. OXIDISABLE SUBSTANCES: To 100 ml add 10 ml of 1 M sulphuric acid and 0.1 ml of 0.02 M potassium permanganate and boil for 5 minutes ; the solution remains faintly pink. RESIDUE ON EVAPORATION: Evaporate 100 ml to dryness on a water-bath and dry to constant weight at 105. The residue weighs not more than 1 mg (0.001 %).

TEST CERTIFICATE (THE DRUGS AND COSMETICS ACT 1940 AND THE RULES THEREUNDER FORM 39 ) RAW MATERIAL : PURIFIED WATER IP Party : UniversalImpex A.R.NO. : PWR 12/97-98 Batch No. : 12/98-99 Dt of Completion : 16/05/99 Qty sampled : Hit. Dt of Completion : 16/05/99 RESULTS OF ANALYSIS & PROTOCOLS OF TEST APPLIED AS PER IP-96 Protocols Description Acidity or alkalinity Ammonium Calcium & magnesium Heavy metals Chloride Nitrate Sulphate Oxidisable matter Residue on evaporation Results Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Complies with IP Claim / Limit Clear colourless liquid; odouless and tasteless.

NMT 0-1 ppm NMT 0.2 ppm NMT 0.001%

OPINION : In the opinion of the undersigned, the sample referred to above is of standard quality as defined in the act and the rules thereunder with respect to the tests carried out and mentioned above as per IP specifications.

Date : 16/05/98

Analyst

Q.C. Incharge

SECTION IV DETAILS OF SPECIFICATIONS AND STANDARDS LAID DOWN BY THE MANUFACTURER FOR EACH PRODUCT TOGETHER WITH ITS METHOD OF ANALYSIS

RAW MATERIAL REQUISITION PRODUCT :ROXICAMGEL BATCH NO. : 01 BATCH SIZE : 300 KGS MFG.DATE : APR. 1999 EXP.DATE : MAR.2001
No 1 2 3 4 5 6 7 8 9 INGREDIENTS Piroxicam Carbomer 934 Glycerin Propylene glycol Potassium Hydroxide Disodium Edetate Methyl Paraben Propyi Paraben D.M.WaterQ.S.to SPEC IP USP IP IP IP IP IP IP IP

UNIVERSAL IMPEX 89,PeerbhoyBldg., Mumbai-400002 India

MFC.NO. : MF/UI-02 SR. N0 :23 PACK SIZE :30GM DT. OF STARTING : 22/4/99 DT OF COMPLETION : 27/4/99
A.R NO. UIR QTY IN KGS THEOR. ACTUAL 257/98-99 1.575 1,575 8/99-2000 287/98-99 2.700 2.700 228/98-99 30.000 30.000 272/98-99 60.000 60.000 141/98-99 2.400 2.400 6/96-97 0.030 0.030 173/98-99 0.480 0,480 98/98-99 0.120 0.120 300.00 300.00 0 WT. BY CH K BY

LABEL CLAIM % w/w 0.50% 0.90 % 10.00% 20.00% 0.80% 0.01% 0.16% 0.04%

OVER AGES % w/w 5.0

STORES INCHARGE

PRODUCTION INCHARGE

QUALITY CONTROL INCHARGE

A.

LIST OF VESSELS AND EQUIPMENT USED SR. NO. 1 2 3 4 5 6 DESCRIPTION Main mixing vessel Mechanical Sifter Colloid Mul Homogenisor S.S. Storage vessels Filling Machine MAKE Aerolite Industries Smitact Equipments Clit Industries Remi Industries S.S Mechanical Works Precitech Industries CAPACITY 300 Kgs 1400 rpm 200 Kgs 25000 tubes per shift

A.........

MANUFACTURING PROCESS

PRODUCT : ROXICAM GEL BATCH NO. : 01 BATCH SIZE : 300 KGS

PAGE : 01 OF 03

A. Cleaning & General Instructions Ensure the following before commencing the production. 1. 2. The floor and ceilings of the area should be thoroughly cleaned and should not contain any foreign material attached to it. All equipments are cleaned and washed thoroughly. No material of previously run material should stick to these. When machine is ready for use, approval should be obtained from Quality Control Department after checking the wash water content. The raw materials required must be previously checked for labels and weight. Proper temperature records should be maintained throughout me processing as per the instructions. Equipments and containers should be labelled at each and every stage of manufacturing. All processing should be carried out under strict supervision of a Qualified Competent staff. Production personnel should wear gloves and masks before they enter the manufacturing area while handling the material.

3. 4. 5. 6. 7.

A.........

MANUFACTURING PROCESS PRODUCT : ROXICAM GEL BATCH SIZE : 300 KGS BATCH NO. : 01 PAGE : 02 OF 03

A. PREPARATION OF CARBOMER GEL. Main Mixing Vessel cleaned by : Homogeniser cleaned by Checked by : : ____________ _____________ ________________

STEP I Transfer Propylene Glycol ( 59.000 Kgs ), Glycerin ( 30.000 Kgs ) in a jacketted main mixing tank and start heating. Hold temperature around 55 C to 60 C. Add carbomer -934 ( 2.700 Kgs ) slowly with constant high speed stirring to form a uniform gel. Continue stirring for 15-20 minutes and allow to stand over night. Temp. of water: __________ Checked By; ___________

Note : Add Carbomer-934 into the vortex caused by high speed stirring. STEP II Transfer 180 litres of D.M water into the main mixing tank. Add disodium Edetate. Start heating and hold temp. around 50 -55 C. Temp. of water phase :- 55C Checked By:- __________ STEP III Transfer 90 Lit of D.M. Water from STEP II to STEP I under high speed stirring. Continue stirring for 20-30 min. STEP IV In a separate container dissolve Methyl Paraben (0.480 Kgs) Propyi paraben (0.120 kgs) in propylene Glycol (1.00 Kg) by heating, till solution is clear. Add the clear solution to STEP I. Checked by :A.........

PRODUCT : ROXICAM GEL BATCH SIZE : 300 KGS

BATCH NO. : 01 PAGE : 03 OF 03

STEP V Add and dissolve potassium Hydroxide pellets (1.900 Kgs) in 6.0 litres of D.M. water. Filter and add to STEP I. STEP VI Transfer the contents of the S.S vessel from STEP I onto the main mixing tank under constant stirring and continue stirring for 30 min. Start cooling. Check pH (Range 7.0 to 8.0) B. DISSOLUTION AND ADDITION OF PIROXICAM : Add and dissolve potassium hydroxide (0.500 Kgs) in 6.00 kgs of D.M. water. Add Piroxicam (1.575 kgs). Stir well to get a clear solution. Filter and add to the main mixing tank and mix for about 20 minutes. Check pH (range 7.0 to 8.0). Make up the volume of the bulk, by addition of remaining D.M.water (about 11 .00 kgs)> C. UNLOADING: 1. Transfer the bulk in the S.S. Storage vessel with proper label. 2. Check for the theoretical yield : _________ 3. Manufacturing Chemist : _____________ 4. Manufacturing operator : _____________ 5. Manufacturing started on : Date : ______ Time: ___________ 6. Manufacturing completed on : Date : _________ Time : _________ 7. Inform Q.C. to draw Sample . A.........

FILLING PROCESS

A. 1. 2. 3. 4. 5. 6. B. 1. 2. 3. 4. 5.

FILLING INSTRUCTION: Assemble the filling machine as per instruction. After getting the approval from Quality Control Department take the cream for filling, A required information should be sent to Quality Control Department immediately after the commencement of the filling. Adjust the filling machine to get the desired weight. Only one product is to be filled at a time. Single batch should start and finish at a time. FILLING IN-PROCESS : Check for parameters such as crimping, coding, leakage , Wt. Variation. A filling chart should be maintained during the filling of the batch. All the crates and machines should be labelled property indicating the product name. Batch No., Quantity processing stage. Date and initials of the supervising authority. After the completion of filling or during online, the intimation should be given the packing department for packing. All filled tubes should be transferred to the Packaging Department alongwith me transfer slip and complete records

A.........

PACKING PROCESS A. 1. 2. PRIMARY PACKING : The tube is packed in the carton from right hand side. The carton is unfolded and sealed from left hand side by the flaps. The tube is carefully put in the carton by right hand holding the carton in the left hand. The side on which details ofMfg. Lie., No., Batch No., Mfg . Date, Exp. Date & Retail price are given should be treated as a front side. Finally the right hand side flaps on me carton should be folded and sealed. The carton should be placed with inside tube in upright position. SECONDARY PACKING : The outer cartons should be overprinted with Mfg. Lie. No., Batch No. Mfg. Date., Exp Date & Retail price. FOR 30 G : Twenty carton boxes are placed in 5 rows , 4 in each row. The rows are placed vertically one after the another. Finally the opening flap is closed. TERTIARY PACKING: The master shipper is formed with upper lids opened and the lower lids sealed by 3 inch BOPP tapes For 30 g :- The secondary outer are placed in two rows one above the another. One row consists of 5 x 2 outer. Thus 20 such outer are packed in one shipper. Finally the master shipper is sealed by 3 inch BOPP tape with H type sealing to cover all end. An overprinted label with Product Name, Batch No., Mfg. Date, Exp. Date & Packing is pasted in the middle of the master shipper.

B. 1. 2.

C. 1. 2. 3.

A........

ANALYTICAL CHECKS PERFORMED DURING FILLING AND PACKING PROCESS SR.NO. 1 2 3 4 5 6 7 8 CHECKS Average weight Individual weight Coding Crimping Leak test Carton/Outer overprinting Shipper packing Labelling DURATION After every 30 min After every 60 min After every 30 min After every 30 min After every 30 min After every 30 min After every 30 min Each & every shipper

THEORETICAL YIELD
PROCESS Mixing Filling Packaging MINIMUM 99.00 98.50 98.00 RESPONSIBILITY 1 2 Production In-Process Quality Control Mfg. Chemist/Operators Quality Control Chemist

A .

FINISHED PRODUCT : PROTOCOL : INHOUSE

PAGE: 01 OF 02

FINISHED PRODUCTS SPECIFICATIONS, STANDARDS & ANALYTICAL CONTROL LIMITS

DESCRIPTION: Yellow coloured homogeneous transparent gel. IDENTIFICATION: pH: 7.0 to 8.0 Determine directly on the cream using a suitable calibrated pH meter. LEAICTEST: Limit: No leakage is observed in any of the 10 tubes tested. Select 10 tubes of the gel with seal applied thoroughly. Clean and dry the exterior surfaces of the tube with absorbent cloth. Place the tubes in a horizontal position on a sheet of filter in an oven maintained at 45C 3C for 8 hours. No significant leakages occur during or at the completion of the test in all samples . ( Disregard traces of cream near the crimp or thread of the cap. MINIMUM FILL TEST: The average net weight of the content of the 10 tubes is not less than 15 g and the net weight of content of any of the tube is between 15.0 to 15.5 g. Select a sample of 10 filled tubes and remove any labelling. Thoroughly clean and dry the outside of the tubes by suitable means and weigh individually. Quantitatively remove the content of each tube by cutting it open and washing with a suitable solvent, if necessary taking care to retain the closure and other parts of each tube. Dry and reweigh each empty tube along with its corresponding parts. Difference between the two weights is the net weight of the content of the tube. The average net weight of the content of the 10 tubes is not less than labelled amount. A.........

FINISHED PRODUCT : ROXICAM GEL PROTOCOL : INHOUSE ASSAY: The method is based on differential spectroscopy. REAGENTS : 1. 0.01 N methanolic hydrochloric acid. 2. 0.01 N methanolic sodium hydroxide

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STANDARD SOLUTION: 10 mcg/ml of piroxicam in 0.01 methanolic hydrochloric acid and methanolic sodium hydroxide. SAMPLE SOLUTION : Accurately weighed quantity of the sample equivalent to 10 mg of the substance was extracted with methanol to get solution of 100 mcg/ml. Further dilution were done as given under standard solution. PROCEDURE : Measure the absorbance of acidic solution of both sample and standard at 326 nm using respective alkaline solution as blank and calculate the result by comparision. The method obeys Beer's law in the concentration range of 4-22 mcg/ml

A.........

SECTION V CERTIFICATE OF STERILITY AND ABSENCE OF PROGEN : WHEREVER IT IS APPLICABLE

SECTION VI SAMPLES OF THE PRODUCT APPLIED FOR REGISTRATION IN THEIR ORIGINAL PACK

SPECIFICATIONS OF THE PACKAGING MATERIAL

A. PRIMARY PACKING: The tube is packed in the carton from right hand side. The carton is unfolded and sealed from left hand side by the flaps. The tube is carefully put in the carton by right hand holding the carton in the left hand. The side on which details ofMfg. Lie., No., Batch No., Mfg . Date, Exp. Date & Retail price are given should be treated as a front side. Finally the right hand side flaps on the carton should be folded and sealed. The carton should be placed with inside tube in upright position. SECONDARY PACKING: The outer cartons should be overprinted with Mfg. Lie. No., Batch No. Mfg. Date., Exp Date & Retail price. FOR 30 G : Twenty carton boxes are placed in 5 rows , 4 in each row. The rows are placed vertically one after the another. Finally the opening flap is closed. TERTIARY PACKING: The master shipper is formed with upper lids opened and the lower lids sealed by 3 inch BOPP tapes For 30 g :- The secondary outer are placed in two rows one above the another. One row consists of 5 x 2 outer. Thus 20 such outer are packed in one shipper. Finally the master shipper is sealed by 3 inch BOPP tape with H type sealing to cover all end. An overprinted label with Product Name, Batch No., Mfg. Date, Exp. Date & Packing is pasted in the middle of the master shipper.

C.

SPECIFICATION FOR PACKING MATERIAL TUBES 30 G 1 Description Three colour tube , with proper impression of logo and readable printing in English language as per the art work. (* The colour of the tube should match with the standard colour of the carton. 120.0mm (lmm) 22.0 mm ( 1 mm ) 137.0mm (lmm) 5.0 g ( .250 g) Should be complied as per IS specification Should be complied as per IS specification CARTONS 30 G 1 Description Three colour carton made out of 300 gsm Board, with proper impression of logo and readable Printing in English language as per the art work. (* The colour of the carton should match with the standard colour of the tube. Both side open 145.0mm ( 1 mm) 32.0mm (lmm) 24.0 mm ( 1 mm) 300 gsm ( 5 gsm )

2 3 4 5 6 7

Length upto Shoulder Shoulder diameter Length upto cap Weight of empty tube Lacquering Porosity

2 3 4 5 6

Design Length Height Width Grammage

A.

SPECIFICATION FOR PACKING MATERIAL OUTERS FOR 30 G 1 Description Three colour Outer made out of 350 gsm Board , with proper impression of logo and readable printing in English language as per the art work. (* The colour of the outer should match with the standard colour of the tube & carton. One side open 165.0mm ( 1 mm ) 151.0mm (lmm) 105.0mm (lmm) Not less than 350 gsm 5 PLY SHIPPERS FOR 30 G 1 2 3 4 5 6 Description Design Length Height Width Grammage Five ply Master Shipper of 115 gsm each sheet. Both side open 54.0cm (0.5 cm) 38.5cm (0.5 cm) 38.5cm (0.5 cm) Not less man 575 gsm

2 3 4 5 6

Design Length Height Width Grammage

SECTION - VII CERTIFICATE OF ANALYSIS

TEST CERTIFICATE ( THE DRUGS AND COSMETICS ACT 1940 AND THE RULES THEREUNDER FORM 39 ) Party Product Batch No. Batch Size Mfg. Date Exp. Date : Universal Impex : Roxicam gel : 01 : 300 kgs : Apr'1999 : Mar'2001 A.R.NO. : UIF 17/99-2000 Dt of the Receipt : 24/04/99 Dt of the Completion : 27/04/99 Public lab T.R. No. : 0/C 11828 Qty drawn for sampling : 15x30g Packing details : 9878x 15g

RESULTS OF ANALYSIS AND PROTOCOLS OF TEST APPLIED AS PER INHOUSE SPECIFICATION. A Pale yellow coloured homogenous gel. 1. 2. 3. 4. 5. No DESCRIPTION IDENTIFICATION pH at 40C LEAK TEST MINIMUM FILL TEST Wt of Filled Tube in g 35.3890 35.4701 35.3849 35.3564 35.5322 Wt of Empty Tube in g 5.3856 5.4627 5.3782 5.3479 5.5285 : : : : : A Pale yellow coloured homogenous gel. Positive for Piroxicam. 7.47 Limit 7.00 to 8.00 Complies Complies Sr No 6 7 8 9 10 Wt of Filled Tube in g 35.4427 35.4331 35.5395 35.5766 353826 Wt of Empty Tube in g 5.4384 5.4255 5.5347 5.5709 53741 Wt of net Content of Tube in G 30.0043 30.0076 30.0048 30.0057 30.0085

1 2 3 4 5

Wt of net Content of Tube in g 30.0034 30.0074 30.0067 30.0085 30.0037

6. ASSAY: Complies Ingredients Piroxicam IP Lab. Content % w/w contains 0.5

Limit : 90.0% to 110.0% Actual content % w/w contains 0.5049 Percentage 100.97 %

OPINION : In the opinion of the undersigned, the sample referred to above is of standard quality as defined in the act and the rules thereunder with respect to the tests carried out and mentioned above as per inhouse Specification Date : 27/04/99 Analyst Q.C. Incharge.

SECTION - VII REFERENCE SAMPLES

REFERENCE SAMPLES

Ref. Sample Batch No Manufacturer Mfg. Date Exp. Date Water Assay

: : : : : : :

Piroxicam IP PX 028 / 200 Ramdev Chem Sept. 2000 Aug 2005 0.098% w/w 99.38% OAB

SECTION IX BIOAVAILABILITY STUDIES

SECTION X SAFETY AND TOLERANCE STUDIES

BIOAVAILABILITY STUDIES
Babar et al prepared gels and ointment bases containing piroxicam 1% in order to study the in-vitro release of the drug. The gel contained hypromellose, propylene glycol, sodium hydroxide, methyl and propyi hydroxybenzoates and purified water. The modified hydrophilic bases contained white soft parrafin, stearyl alcohol, sodium lauryl sulphate, propylene glycol, sodium hydroxide, methyl and propyi hydroxybenzoates and purified water. The emulsion basis contained liquid paraffin, isopropyi lanolate, stearic acid TP, cetyl alcohol, self emulsifying glyceryl monostearate, triethanolamine, glycerol, sodium hydroxide, methyl and propyi hydroxybenzoates and purified water. The general rank order of in- vitro drug release through a cellulose membrane from all bases evaluated was: gel basis>hydrophillic basis>emulsion basis. Drug release was adversely affected by inclusion of ethanol or macrogol 400. The gel basis (containing also dimethylsulphoxide) produced best in - vitro drug release both through me cellulose membrane and hair less mouse skin. Tsai et al found that the percutaneous absorbtion of piroxicam from an oil-in-water ointment bases (university of California Hospital basis containing 12 % propylene glycol), in rabbits was superior to that from three other USP ointments ( Simple ointment, macrogol ointment, and petrolatum rose water ointment). When the water (pH 7.2 ) in the oil-in-water ointment basis was replaced by sodium bicarbonate-buffered solution (pH 9.2), percutaneous absorbtion of piroxicam was increased. The optimal effect was attained with the addition of 5 % urea. The relative bioavailabilities of two commercially available piroxicam 20 mg suppositories in dogs were found to be similar and greater than the oral bioavailability of a piroxicam capsule following administration of single doses of the preparation. Marked inter individual and intra-individual difference in absorption were noted.

SAFETY & TOLERANCE

SPECIAL PRECAUTIONS It should not be applied over broken skin or wounds. Products containing salicylates should be avoided or used with caution in patients with liver disease, pre-existing hypothrombinemia, vitamin K deficiency and before surgery. They are for external use only and contact with eyes or mucous membranes should be avoided. To be used only under close medical supervision during last three months of pregnancy and lactation. PAEDIATRICS : Not recommended in age below 6 years. OVER 60: Reduced dose necessary due to increased likelihood of adverse effects. BREAST FEEDING: Contraindicated as present in breastmilk & safety not established. PREGENANCY: Contraindicated as it may affect the developing foetus. ALCOHOL: Avoid . Increase the risk of stomach irritation.

SECTION XI DETAILED REPORTS COVERING PHARMACOLOGICAL ASPECTS TOXICOLOGICAL ASPECTS CLINICAL ASPECTS

PHARMACOLOGICAL ASPECTS

Piroxicam is a non-steroidal anti-inflammatory agent used in musculoskeletol and joint disorders . Piroxicam is well absorbed from the gastro-intestinal tract; peak plasma concentrations area reached 3 to 5 hours after oral dose. It is metabolised in the liver by hydrosylation and conjugation with glucuronic acid and excreted predominantly in the urine with smaller amounts in the faeces. Enterohepatic recycling occurs. Less than 5 % of the dose is excreated unchanged. Piroxicam is extensively bound to plasma proteins (about 99%) and has a long plasma half-life of approximately 50 hours.

TOXICOLOGICAL DATA
ADVERSE EFFECTS The most frequent adverse effect occuring with Piroxicam are local irritation and erythema , pruritus, dermatitis, photosensitivity. Oedema, Vomiting, Nausea, Heartburn, Epigastric distress, tinnitus, skin rash. A report of the adverse reactions associated with piroxicam received by the Medicines Safety Centre in South Africa including two reactions, paraesthesia and hair loss, not previously recorded in the literature - Gerver D. Adverse reaction of piroxicam. Drug intell din Pharm 1987 ; 21: 707-10 EFFECT ON SKIN; As with other NSAIDs, rash has occurred in patients taking piroxicam. Phototoxic reactions have been described, Seroius skin reaction attributed to piroxicam therapy include toxic epidermal necrolysis and pemphigus vulgaris. EFFECTS ON THE BLOOD : Decrease in haemoglobin and haematocrit not associated with obvious gastro-intestinal bleeding, have occurred in patients taking piroxicam. Thrombocytopenia, thrombocytopenic purpura and aplastic anaemia have been described in patients on piroxicam. EFFECTS ON THE ELECTROLYTES : Reversible hyperkalaemic hyperchloraemic acidosis in patients receiving piroxicam. EFFECTS ON GASTRO-INTESTINAL TRACT ; In the past it has been suggested that piroxicam may have a higher incidence of gastrointestinal adverse effects than other NSAIDs. However, while the commonest side effects of piroxicam are indeed gastro-intestinal, it would appear from the present evidence that the overall incidence of such reactions is not appreciably higher with piroxicam than with other non-steroidal anti- inflammatory agents.

EFFECTS ON KIDNEYS ; Acute nephropathy with characteristic features of Henoch-Schonlein purpura, acute renal failure, uraemia with hyperkalaemia, and acute intestinal nephritis have been associated with piroxicam. EFFECTS ON LIVER: A report of a patient who presented with features of acute hepatocellular injury after taking piroxicam 40 mg daily for 3 days; the liver disorder progressed to subacute hepatic necrosis and the patient died. DRUG INTERACTION : Anticoagulants : Potentiation. Diuretics : Increased risk of renal damage. Aspirin : Reduces serum piroxicam. Corticosteroids, oral anticoagulants and NSAIDs : Increased risk of bleeding. Lithium : Incresed serum lithium, Antihypertensives : reduces the beneficial effects pf piroxicam. OVERDOSAGE mx Emesis, Gastric lavage, Activated Charcoal. Monitor vital functions. General supportive and symptomatic treatment.

PARTICULARS OF CLINICAL ASPECTS OF DRUGS INDICATIONS : i. ii. iii. iv. v. vi. vii. Ankylosing spondylitis. Rheumatoid arthritisOesteoarthritis of superficial joints. Acute musculoskeletal injuries, periathritis & tendinitis. Postoperative pains Acute gout. Dysmenorrhoea.

DOSAGE: ADULTS : Rheumatoid arthritis, ankylosing spondylitis, osteoarthritis : 20 mg. OD. Maintenance : 10-30 mg. OD Acute musculoskeletal disorder : 40 mg OD/BD for 7-14 days. Maintenance : 40 mg OD/BD for 4-6 days. CHILDREN : Over 6 yr<15 kg : 5 mg OD, 15-25 kg : 10 mg OD, 26-45 Kg: 15mgOD. APPLICATION : Topical analgesic are to be applied to me affected area and rubbed lightly until the cream vanishes do not massage-do not apply bandages or heat on the affected areas following applications. ONSET OF EFFECT : Analgesia : 3-4 hr. Arthritis : Full anti-inflammatory effect. Gout : Over 4-5 days. DURATION OF ACTION : Upto 2 days. Some effects may last 7-10 days after the treatment has been stopped.

SECTION XII STORAGE DATA

STORAGE DATA Piroxicam should be preserved in tight, light-rsistant containers Piroxicam gel should be Stored below 30. Hydroxyalkylated cyclodextrin derivatives were found to reduce the stability ofpiroxicam (0.5 mg in pH 7.4 that contained a 10-fold excess of the cyclodextrin, stored at 21 to 71

SHELF LIFE : STABILITY DATA REFERENCE SAMPLES FOR STABILITY TESTING The reference samples are picked from the hold store using the random sampling technique. They are kept on clean pallets in the stability room. Product Batch No, Batch Size : Roxicam Gel : 01 : 300 kgs A.R.No. Mfg. Date Exp. Date : UIFS 9/99-2000 : APR. 1999 : MAR.2001

Results of analysis & protocols of Test applied as per inhouse specification. Storage Condition : Store in cool dry dark place. Test Stability Description PH Identification Assay Analyst Date Spec / Pharmacopeial Limit Pale yellow coloured homogenous gel 7.0 to 8.0 Positive Piroxicam IP 0.5 % w/w Imth Ok 7.47 Ok 0.5049 g -100.97 % 27/4/99 12mth Ok 7.35 Ok 0.4839 g =96.78 % 25/4/00 24mth Ok 7.20 Ok 0.4721 g = 94.42 % 30/4/2001

The samples are observed for any changes in physical properties after every three months and full analyticals testing is done after each year duration. OPINION: The product is stable for 24 months.

SHELF LIFE : STABILITY DATA REFERENCE SAMPLES FOR STABILITY TESTING The reference samples are picked from the hold store using the random sampling technique. They are kept on clean pallets in the stability room. Product Batch No. Batch Size : Roxicam Gel : 02 : 300 kgs A.R.No. Mfg. Date Exp. Date : UIFS 13/99-2000 : MAY. 1999 : APR .2001

Results of analysis & protocols of Test applied as per inhouse specification. Storage Condition : Store in cool dry dark place. Test Stability Description PH Identification Assay Analyst Date Spec / Pharmacopeial Limit Pale yellow coloured homogenous gel 7.0 to 8.0 Positive Piroxicam IP 0.5 % w/w Imth Ok 7.59 Ok 0.5003 g =100.06 % 16/5/1999 12mth Ok 7.46 Ok 0.4941 g =98.82 % 22/5/00 24 mm Ok 7.31 Ok 0.4784 g = 95.68 % 27/5/2001

The samples are observed for any changes in physical properties after every three months and fall analyticals testing is done after each year duration. OPNION: The product is stable for 24 months.

SECTION XIII AUTHENTICATED PRICE LIST

THE FOLLOWING IS THE AUTHENTICATED PRICE LIST

SR. A B C D *E

DESCRIPTION Ex-Factory Price Price to pharmacy in the country of origin Public price in the country of origin C I F price to U.A.E. main ports Export price (C I F ) to the neighbouring countries

PRICE

* Photo copy of Certificate (Authenticated)

SECTION XVI NAME OF THE COMPETITIVE DRUG MANUFACTURED BY OTHER FIRMS

THE FOLLOWING ARE THE NAMES OF THE COMPETITIVE DRUG MANUFACTURED BY OTHER FIRMS.

BRAND MINICAM GEL 0.5 % MOVON GEL 0.5 % DOLONEX GEL 0.5 % PIROX GEL 0.5 % FELCAM GEL 0.5 % PANCAMGEL 1.0%

COMPANY BLUE CROSS IPCA PFIZER CIPLA SUNPHARMA TALENT LAB

PACKING 30 gm gel 30 gm gel 15 gmgel 30 gm gel 30 gm gel 30 gm gel

PRICE 28.20 26.50 26.24 27.00 30.00 1 29.00

A.

SECTION XV OTHER COUNTRIES WHERE THE PRODUCT IS REGISTERED

Photo copy of the certificate of registration of product in other country NOT REGISTERED IN OTHER COUNTRIES

SECTION - XVI DATE OF INTRODUCTION OF THE PRODUCT TO THE MARKET IN THE COUNTRY OF ORIGIN