Sample Dossier

1

PRODUCT REGISTRATION DOSSIER

PARACETAMOL TABLET 500 MG

A Product of

:

Neutral Code

:

Marketed/ Imported by

:

:

SCHEDULE

APPLICATION FOR REGISTRATION OF A DRUG

CONFIDENTIAL

DEMOCRETIC REPUBLIC OF---

MINISTRY OF PUBLIC HEALTH

DIRECTION OF PHARMACY, DRUG & LABORATORY

TECHNICAL DIVISION

SECRETARIAT-GENERAL

PART-I

1. NAME OF APPLICANT :

BUSINESS ADDRESS :

TELEPHONE NUMBER :

FAX :

2. NAME OF PRODUCT

TO BE REGISTERED :

3

3. IDENTIFICATION(PHYSICAL

APPERANCE OF THE PRODUCT :

4. THERAPEUTIC CLASSIFICATION

5(a) NAME OF BUSINESS

ADDRESS OF MANUFACTURER :

(b) COUNTRY OF ORIGIN :

(6) NAME OF LOCAL DISTRIBUTOR :

BUSINESS ADDRESS OF LOCAL

DISTRIBUTOR :

TELEPHONE NUMBER :

FAX NUMBER :

(7) NAME AND SIGNATURE OF

THE AUTHORIZE PERSON :

DATE :

SIGNATURE :

OFFICIAL STAMP :

PART I

5

CTD

Module I

ADMINISTRATIVE DATA

(1) SITE MASTER PLAN OF PLANT

(2) COMPANY PROFILE IN SHORT

(3) ATTESTED COPY OF MANUFACTURING LICENCE

(4) ATTESTED COPY OF PRODUCT PERMISSION FROM FDCA

(5) ATTESTED COPY OF COPP

(6) ATTESTED COPY OF WHO/GMP CERTIFICATE

(7) COA OF SAMPLE

(8) ATTESTED COPY OF WHOLE SELL LICENCE.

(9) LETTER OF AUTHORISATION

MODEL

OF

LETTER

OF

AUTHORISATION

C

’

L

LETTER

OF

AUTHORISATION

W

,

___________________________________________________________________

P

O

’

N

A

H

__________________________________________________________

A

’

N

A

T

P

N

,

D

F

S

W

D

R

A

(

)

.

T

PRODUCT

.

SIGNATURE : __________________

7

Department of Health

Food and Drug Administration

Summary Drug Information

NAME ADDRESS PHONE/FAX FOR OFFICIAL USE.

APPLICANT OWNER OF DRUG MANUFACTURER DATE OF APPLICATION: APPLICATION NO.: ASSESSMENT FEES: REGISTRATION CERTIFICATE NO.: DATE OF ISSUE: DATE OF EXPIRY: SALES CATEGORY: VARIATION:

BRAND NAME COMPOSITION (INCLUDING EXCIPIENTS & COLORING

SUBSTANCE)

NON PROPRIETARY NAME PARACETAMOL BP PARACETAMOL BP 500MG

DOSAGE FORM TABLET

STRENGTH 500MG

THERAPEUTIC CATEGORY ANALGESIC AND

ANTIPYRATIC PRESENTATION(TYPE OF PACKING, PACK

SIZE) 1X100T,1X500T,10X10T

INDICATION: Relief mild to moderate pain and fever.

DOSAGE : Adults: One to two tablets every 4 to 6 hours up to a maximum of 8

tablets daily.

Children 6-12 years: One tablet 3 to 4 times daily as required.

Paracetamol is one of the most common analgesics used in children.

The recommended dose for children is 15mg/kg orally every four

hours.50 The maximum daily dose should be limited to 90mg/kg

up to a total of 4000mg. It can also be used rectally in children

with a dose of

0mg/kg.

9

S.NO. TRADE NAME GENERIC NAME OR FORMULA INDICATIONS REMARK

1

EACH TABLET CONTAINS: PARACETAMOL BP 500MG

ANALGESIC & ANTIPYRETIC

PACKING : 1x100T, 10X10T

LIFE : 3Years from the date of manufacturing FOB PRICE : US$

I

A A

1 A 1 PROPOSED TRADE NAME OF THE PHARMACEUTICAL PRODUCT PARACETAMOL TABLET BP 500 MG

EACH UNCOATED TABLET CONTAINS: PARACETAMOL BP ---500 MG EXCIPIENTS---Q.S.

1 A 1.1 NAME OF THE ACTIVE SUBSTANCE(S) PARACETAMOL BP 500 MG

1 A 1.2 PHARMACOTHERAPEUTIC CLASSIFICATION

ANALGESIC & ANTIPYRATICS

1 A 2 PHARMACEUTICAL FORM AND STRENGTH

PHARMACEUTIACLS DOSAGE : ORAL TABLET PARACETAMOL TABLET 500 MG

EACH UN COATED TABLET CONTAINS: PARACETAMOL BP ---500 MG EXCIPIENTS---Q.S.

1 A 2.1 Route of administration ORAL

1 A 2.2 Container

EACH BOX OF 10 X 10TABLETS

200 BOXES IN EACH CORRUGATED BOX Shelf-life

11 I A 4 QUALITATIVE AND QUANTITATIVE COMPOSITION

EACH TABLETS CONTAINS

:

Nº Name Quantity Unity Reference

I ACTIVE SUBSTANCE(S) 1. PARACETAMOL 500.00 mg BP II EXCIPIENT(S) 1 LACTOSE 23.00 mg B P 2 MICRO CRYSTALINE CELLULOSE 50.00 mg B P 3 STARCH 27.00 mg B P 4 MAGNESIUM STEARATE 5.00 mg BP 5 SODIUM STARCH GLYCOLATE 6.00 mg B P 6 COLLOIDAL SILICON DIOXIDE 5.00 mg USP 7 PURIFIED TALC 4.00 mg BP ... 620.00 MG

CTD

Module II & III

SUMMARY OF PRODUCT CHARACTERISTICS

(SPC)

13

II

B

S

(

)

II B 1 SUMMARY OF PRODUCT CHARACTERISTICS (SPC)

II B 1.1 Proposed trade name of the pharmaceutical product

PARACETAMOL TABLET BP 500 MG

EACH TABLETS CONTAINS

Nº Name Quantity Unity Reference

I ACTIVE SUBSTANCE(S) 1. PARACETAMOL 500.00 mg BP II EXCIPIENT(S) 1 LACTOSE 23.00 mg B P 2 MICRO CRYSTALINE CELLULOSE 50.00 mg B P 3 STARCH 27.00 mg B P 4 MAGNESIUM STEARATE 5 .00 mg BP 5 SODIUM STARCH GLYCOLATE 6.00 mg B P 6 COLLOIDAL SILICON DIOXIDE 5.00 mg USP 7 PURIFIED TALC 4.00 mg BP 620.00 MG

15

RAW MATERIAL

SPECIFICATIONS

SUBJECT: RAW MATERIAL SPECIFICATION DEPARTMENT: QUALITY CONTROL

MATERIAL NAME:

PARACETAMOL BP

SPEC NO: RMS/PARA/2004

EFFECTIVE DATE:

REVIEW DATE: Two Years

SR NO

TEST SPECIFICATION

1. CHARACTERS A white, crystalline powder.

2. SOLUBILITY sparingly soluble in water, freely soluble in alcohol, very slightly soluble in ether and in methylene chloride.

3. IDENTIFICATION Complies the test

4. RELATED SUBSTANCE Complies the test

5. 4-AMINOPHENOL Complies the test

6. HEAVY METALS Complies the test

7. LOSS ON DRYING NMT 0.5%

8. SULPHATED ASH NMT 0.1%

17 SUBJECT

:

DEPARTMENT

:

MATERIAL NAME

:

SPEC NO

:

:

REVIEW DATE

:

SR NO TEST SPECIFICATION

1. CHARACTERS A clear liquid, colorless and tasteless

2. pH 5.0-7.0

3. Oxidisable substance To comply the test

4. Chloride To comply the test

5. Nitrate To comply the test

6. Sulphate To comply the test

7. Ammonium To comply the test

8. Calcium & Magnesium To comply the test

9. Heavy metal To comply the test

10. Residue on evaporation NMT 0.0001% 11. Microbial contamination To comply the test

XYZPHARMACEUTICAL

QUALITYASSURANCEDPEARTMENT

RAW MATERIAL SPECIFICATION

Name of Material

:

Lactose BP

no. TEST PARAMETERS SPECIFICATION

1. Description White, crystalline powder

2. Solubility Freely but slowly soluble in water 3. Identification

A. I.R. absorption spectrum To comply B. By TLC To comply

C: Colour test Red colour develops. D: Test for water To comply

4. Appearances of solutionq Solution is clear and colourless. 5. Acdidty or alkalinity NMT 0.4ml of 0.1M NaOH is required. 6. Specific optical rotation +54.4° to +55.9°

7. Absorbance (at 270 to 300 nm)

Not greater than 0.07.

8. Heavy metals (limit test) NMT 1 ppm 9. Water 4.5% to 5.5% 10. Sulphated ash NMT 0.1%

19

Specifications of Microcrystalline Celiulosel02fMCCP) B.P.

Test

Specifications

Description

Solubility

Identification

pH

Conductivity

Ether-soluble substances

Water-soluble substances

Heavy metals Loss on

drying Sulphated ash

White or almost white, fine or

granular powder.

Practically insoluble in water, in

acetone, in ethanol, in toluene, in

dilute acids and in a 50 g/1 solution of

sodium hydroxide.

Complies as per B.P.

5.0 to 7.5 for the supernatant liquid.

Complies as per B.P.

Maximum 0.05 %

Maximum 0.25 %

Maximum 10 ppm.

Maximum 7.0 %

Maximum 0.1 %

Microbial contamination

Complies as per B.P.

Specifications of Maize Starch B.P.

Test

Specifications

Description

Solubility

Matt, white to slightly yellowish,

very fine Powder, which creaks when

pressed between the fingers.

Practically insoluble in cold water

and in ethanol (96 per cent). The

presence of granules with cracks or

irregularities on the edge is

exceptional.

Identification

pH

Foreign matter

Oxidizing substances

Sulphur dioxide

Iron

Loss on drying

Sulphated ash

Microbial contamination

Complies as per B.P.

4.0 to 7.0.

Complies as per B.P.

Maximum 20 ppm.

Maximum 50 ppm.

Maximum 10 ppm.

Maximum 15.0%

Maximum 0.6 %

Total viable aerobic count NMT 10

bacteria and 10

fungi per gram,

21

XYZ PHARMACEUTICAL

QUALITY ASSURANCE DPEARTMENT RAW MATERIAL SPECIFICATION

Name of Material:

Magnesium Stearate BP

Category Lubricant

Status In-active material

Tested as per BP ’

Sample Size 10 GMS. From each container

Qnty for controlled sample 20 GMS.

Time for Re-testing 1 Year

Retention time for controlled sample 1 year after expiry of the material (B) Testing Parameters:

Sr. Test Limit

01 Characters Should Comply as per BP

02 Identification (C), (D), Should comply as per BP ‘

03 Appearance of solution Should Comply as per BP

04 Acidity or Alkalinity Should Comply as per BP

05 Chloride NMT 0.1 % 06 Sulphates NMT 0.5 % 07 Cadmium NMT 3 ppm of Cd 08 Lead NMT 10 ppm of Pb 09 Nickel NMT 5 ppm of Ni 10 Loss on drying NMT 6.0 % 11 Magnesium 4.0 – 5.0%

12 Fatty acid composition NLT 40% of stearic acid

Sum of stearic acid & palmitic acid NLT 90% 13 Microbial Contamination

Total viable aerobic count not more than 103 micro-organisms per gram, determined by plate count. It complies with the test

for Escherichia coli)

14 Assay Should Comply as per BP

15 Fatty acid composition

XYZ PHARMACEUTICAL

QUALITYASSURANCEDPEARTMENT RAW MATERIAL SPECIFICATION

Name of Material:

Sodium Starch Glycollate BP

Category Lubricant

Status In-active material

Tested as per BP

Sample Size 10 GMS. From each container

Qnty for controlled sample 20 GMS.

Time for Re-testing 1 Year

Retention time for controlled sample 1 year after expiry of the material

(B) Testing Parameters:

Sr. Test Limit

01 Characters Should comply as per BP

02

IDENTIFICATION

(A),(B),(C),(D) -should comply as per BP

03 Appearance of gel Should comply as per BP

04 PH 5.5 – 7.5

05 Sodium Glycollate Should comply as per BP

06 Sodium Chloride NMT 1.0 %

07 Heavy Metals NMT 20 ppm

08 Iron NMT 20 ppm

09 Loss on Drying NMT 7.0 %

10 Microbial Contamination It complies with the test for Escherichia coli and Salmonella

23 XYZ PHARMACEUTICAL

QUALITYASSURANCEDPEARTMENT RAW MATERIAL SPECIFICATION Name of Material:

Purified Talc

Sr.

no. TEST PARAMETERS SPECIFICATION

1. Description White coloured fine powder

2. Solubility Practically insoluble in water and in dilute solutions of acids and alkali hydroxides. 3. Identifications

A: I.R. spectrophotometry To comply

B: Precipitate reaction White, crystalline precipitate is formed. C: Reaction of Silicates. To comply

4. pH 7.0 to 9.0

5. Water-insoluble substances NMT 0.2% 6. Aluminium (on atomic

absorption spectrometry)

NMT 2.0%

7. Calcium (on atomic absorption spectrometry)

NMT 0.9%

8. Iron (on atomic absorption spectrometry)

NMT 0.25%

9. Magnesium (on atomic absorption spectrometry)

17.0% to 19.5%

10. Lead (on atomic absorption spectrometry)

NMT 10 ppm

11. Loss on ignition (at 1050°c to 1100°c)

NMT 7.0% w/w

12. Microbial contamination Total visible aerobic count is not more than 102 aerobic bacteria and fungi per gram.

Additional test :

Specifications of Silicon Dioxide U.S.P

Test

Specifications

Description

Solubility

Light, white, nongritty powder of

extremely fine particle size (about 15

nm).

Insoluble in water and in acid (except

hydro fluoride); soluble in hot

solutions of alkali hydroxides

Identification

pH

(in a 1 in 25 dispersion)

To comply as per U.S.P.

3.5 to 5.5

Loss on drying

Loss on ignition

Arsenic

Organic volatile impurities

Assay

NMT 2.5% w/w

NMT 2% w/w

The limit is 8 ug per g

Meets the requirements

25

C12H22O11,H2O 360.3 10039-26-6

Ph Eur

Definition

Lactose monohydrate is the monohydrate of O-b-D-galactopyranosyl-(1®4)-a-D-glucopyranose. It may be modified as to its physical characteristics and may contain varying proportions of amorphous lactose.

Characters

A white or almost white, crystalline powder, freely but slowly soluble in water, practically insoluble in alcohol. Identification First identification A, D. Second identification B, C, D.

A. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with lactose CRS.

Name of Material LACTOSE BP

B. Examine by thin-layer chromatography (2.2.27), using silica gel G R as the coating substance.

Test solution

Dissolve 10 mg of the substance to be examined in a mixture of 2 volumes of water R and 3 volumes of methanol R and dilute to 20 ml with the same mixture of solvents.

Reference solution (a)

Dissolve 10 mg of lactose CRS in a mixture of 2 volumes of water R and 3 volumes of

methanol R and dilute to 20 ml with the same mixture of solvents.

Reference solution (b)

Dissolve 10 mg each of fructose CRS, glucose CRS, lactose CRS and sucrose CRS in a mixture of 2 volumes of water R and 3 volumes of methanol R and dilute to 20 ml with the same mixture of solvents.

Apply separately to the plate 2 ml of each solution and thoroughly dry the starting points. Develop over a path of 15 cm using a mixture of 10 volumes of water R, 15 volumes of

methanol R, 25 volumes of anhydrous acetic acid R and 50 volumes of ethylene chloride R,

measured accurately since a slight excess of water produces cloudiness. Dry the plate in a current of warm air. Repeat the development immediately, after renewing the mobile phase. Dry the plate in a current of warm air and spray evenly with a solution of 0.5 g of thymol R in a mixture of 5 ml of sulphuric acid R and 95 ml of alcohol R. Heat at 130°C for 10 min. The principal spot in the chromatogram obtained with the test solution is similar in position, colour and size to the principal spot in the chromatogram obtained with reference solution (a). The test is not valid unless the chromatogram obtained with reference solution (b) shows four clearly separated spots.

C. Dissolve 0.25 g in 5 ml of water R. Add 5 ml of ammonia R and heat in a water-bath at 80°C for 10 min. A red colour develops.

D. It complies with the test for water (see Tests). Tests

Appearance of solution

Dissolve 1.0 g in water R, heating to 50°C, dilute to 10 ml with the same solvent and allow to cool. The solution is clear (2.2.1) and not more intensely coloured than reference solution BY (2.2.2, Method II).

27 Dissolve 10.0 g in 80 ml of water R, heating to 50°C. Allow to cool and add 0.2 ml of dilute

ammonia R1. Allow to stand for 30 min and dilute to 100.0 ml with water R. The specific

optical rotation is +54.4° to +55.9°, calculated with reference to the anhydrous substance. Absorbance (2.2.25)

Dissolve 1.0 g in boiling water R and dilute to 10.0 ml with the same solvent (solution A). The absorbance of the solution measured at 400 nm is not greater than 0.04. Dilute 1.0 ml of solution A to 10.0 ml with water R. Examine the solution from 210 nm to 300 nm. At wavelengths from 210 nm to 220 nm, the absorbance is not greater than 0.25. At wavelengths from 270 nm to 300 nm, the absorbance is not greater than 0.07.

Heavy metals (2.4.8)

Dissolve 4.0 g in water R with warming, add 1 ml of 0.1M hydrochloric acid and dilute to 20 ml with water R. 12 ml of the solution complies with limit test A for heavy metals (5 ppm). Prepare the standard using lead standard solution (1 ppm Pb) R.

Water (2.5.12)

4.5 per cent to 5.5 per cent, determined on 0.50 g by the semi-micro determination of water, using a mixture of 1 volume of formamide R and 2 volumes of methanol R as the solvent. Sulphated ash

Not more than 0.1 per cent. To 1.0 g add 1 ml of sulphuric acid R, evaporate to dryness on a water-bath and ignite to constant mass.

Microbial contamination

Total viable aerobic count (2.6.12) not more than 102 micro-organisms per gram, determined by plate-count. It complies with the test for Escherichia coli (2.6.13).

Storage

Name of Material MICROCRYSTALLINE CELLULOSE BP

Tested as per BRITISH PHARMACOPEIA

Action and use Pharmaceutical aid. DEFINITION

Microcrystalline cellulose is a purified, partly depolymerised cellulose prepared by treating alpha-cellulose, obtained as a pulp from fibrous plant material, with mineral acids.

CHARACTERS

A white or almost white, fine or granular powder, practically insoluble in water, in acetone, in ethanol, in toluene and in dilute acids and in a 50 g/l solution of sodium hydroxide.

(1) IDENTIFICATION

A. Place about 10 mg on a watch-glass and disperse in 2 ml of iodinated zinc chloride

solution R. The substance becomes violet- blue.

B. Transfer 1.300 g to a 125 ml conical flask. Add 25.0 ml of water R and 25.0 ml of 1M

cupriethylenediamine hydroxide solution. Immediately purge the solution with nitrogen R,

insert the stopper and shake until completely dissolved. Transfer 7.0 ml of the solution to a suitable capillary viscometer (2.2.9). Equilibrate the solution at 25±0.1°C for not less than 5 min. Record the flow time, t1, in seconds, between the two marks on the viscometer.

Calculate the kinematic viscosity n1 of the solution using the formula: t1(k1),

where k1 is the viscometer constant.

Dilute a suitable volume of 1M cupriethylenediamine hydroxide solution with an equal volume of water R and measure the flow time, t2, using a suitable capillary viscometer.

Calculate the kinematic viscosity n2 of the solvent using the formula: t2(k2),

where k2 is the viscometer constant.

29 where m is the mass in grams, of the substance to be examined and b is the loss on drying as a percentage.

The degree of polymerisation is not more than 350. TESTS

(2) Solubility Dissolve 50 mg in 10 ml of ammoniacal solution of copper tetrammine R. It dissolves completely, leaving no residue.

(3) pH (2.2.3). Shake 5 g with 40 ml of carbon dioxide-free water R for 20 min and centrifuge. The pH of the supernatant liquid is 5.0. to 7.5.

(4) Ether-soluble substances Prepare a column using 10.0 g in a tube about 20 mm in internal diameter. Pass 50 ml of peroxide-free ether R through the column. Evaporate the eluate to dryness. The residue weighs not more than 5.0 mg (0.05 per cent).

(5) Water-soluble substances Shake 5.0 g with 80 ml of water R for 10 min. Filter with the aid of vacuum into a tared flask. Evaporate to dryness on a water-bath and dry at 100°C to 105°C for 1 h. The residue weighs not more than 12.5 mg (0.25 per cent).

(6) Starch To 10 g add 90 ml of water R and boil for 5 min. Filter whilst hot. Cool and add to the filtrate 0.1 ml of 0.05M iodine. No blue colour is produced.

(7) Heavy metals (2.4.8). 2.0 g complies with limit test C for heavy metals (10 ppm). Prepare the standard using 2 ml of lead standard solution (10 ppm Pb) R.

Method: (2.4.8)

Test C Place the prescribed quantity (usually not more than 2 g) of the substance being examined in a silica crucible with 4 ml of a 25% w/v solution of magnesium sulphate in 1M

sulphuric acid. Mix using a fine glass rod and heat cautiously. If the mixture is liquid,

evaporate gently to dryness on a water bath. Progressively heat to ignition, not allowing the temperature to exceed 800°, and continue heating until a white or at most greyish residue is produced. Allow to cool, moisten the residue with 0.2 ml of 1M sulphuric acid, evaporate, ignite again and allow to cool. The total period of ignition must not exceed 2 hours. Dissolve the residue using two 5-ml quantities of 2M hydrochloric acid. Add 0.1 ml of phenolphthalein

solution and 13.5M ammonia dropwise until a pink colour is produced. Cool, add glacial acetic acid until the solution is decolorised and add a further 0.5 ml. Filter if necessary and

dilute the solution to 20 ml with water.

To 12 ml of the resulting solution add 2 ml of acetate buffer pH 3.5, mix, add to 1.2 ml of

thioacetamide reagent, mix immediately and allow to stand for 2 minutes. Any brown colour

produced is not more intense than that obtained by treating in the same manner a mixture of 2 ml of the test solution obtained above and 10 ml of the 20 ml of solution obtained by repeating the procedure using the prescribed volume of lead standard solution (10 ppm Pb) in place of the substance being examined, adding 4 ml of a 25% w/v solution of magnesium

sulphate in 1M sulphuric acid and beginning at the words 'Mix with a fine glass rod…'. The

standard solution exhibits a slightly brown colour when compared to a solution prepared by treating in the same manner a mixture of 10 ml of water and 2 ml of the solution being examined.

(8) Loss on drying (2.2.32). Not more than 6.0 per cent, determined on 1.0 g by drying in an oven at 100°C to 105°C for 3 h.

Method (2.2.32)

Place the prescribed quantity of the substance being examined in a weighing bottle previously dried under the conditions prescribed for the substance being examined. Dry the substance to constant weight or for the prescribed time by one of the following procedures. (a) In a desiccator The drying is carried out over phosphorus pentoxide at atmospheric

pressure and at room temperature.

(b) In vacuo The drying is carried out over phosphorus pentoxide at a pressure of 1.5 to

2.5 kPa at room temperature.

(c) In vacuo within a specified temperature range The drying is carried out over phosphorus pentoxide at a pressure of 1.5 to 2.5 kPa within the temperature range specified

in the monograph.

(d) In an oven within a specified temperature range The drying is carried out in an oven

within the temperature range specified in the monograph.

(e) Under high vacuum The drying is carried out over phosphorus pentoxide at a

pressure not exceeding 0.1 kPa at the temperature prescribed in the monograph.

If other conditions are prescribed, the procedure to be used is described in full in the individual monograph.

(9) Sulphated ash (2.4.14). Not more than 0.1 per cent, determined on 1.0 g. Method: (2.4.14)

Heat a silica or platinum crucible to redness for 30 minutes, allow to cool in a desiccator and weigh. Place a suitable quantity of the substance being examined, in the crucible, add 2 ml of 1M sulphuric acid and heat, first on a water bath, then cautiously over a flame and then progressively to about 600°. Continue incineration until all black particles have disappeared and then allow to cool. Add a few drops of 1M sulphuric acid, incinerate as before and allow to cool. Add a few drops of a 15.8% w/v solution of ammonium carbonate, evaporate to dryness and incinerate carefully. Allow to cool, weigh, incinerate for 15 minutes and repeat this procedure to constant weight.

(10) Microbial contamination Total viable aerobic count (2.6.12) not more than 103 micro-organisms per gram and with a limit for fungi of 102 per gram, determined by plate-count. It complies with the tests for Escherichia coli, for Pseudomonas aeruginosa, for

Staphylococcus aureus and for Salmonella (2.6.13).

(2.6.13)

Escherichia coli

Prepare the product to be examined as described in the general method Appendix XVI B2

31 Salmonella

Prepare the product to be examined as described in the general method Appendix XVI B2

(2.6.12), but using broth medium A in place of buffered sodium chloride-peptone solution pH

7.0, homogenise and incubate at 35° to 37° for 18 to 24 hours. Transfer 1 ml of the enrichment culture to 10 ml of broth medium I and incubate at 41° to 43° for 18 to 24 hours. Subculture on at least two different agar media chosen from agar medium J, agar medium K and agar medium L. Incubate at 35° to 37° for 18 to 72 hours. The probable presence of salmonellae is indicated by the growth of cultures having the following appearance:

agar medium J: well-developed, colourless colonies,

agar medium K: well-developed, red colonies, with or without black centres, agar medium L: small, transparent, colourless or pink or opaque-white colonies, often surrounded by a pink or red zone.

Transfer separately a few of the suspect colonies to agar medium M in tubes, using surface and deep inoculation. The presence of salmonellae is provisionally confirmed if in the deep inoculation but not in the surface culture there is a change of colour from red to yellow and usually a formation of gas, with or without production of hydrogen sulphide in the agar. Precise confirmation may be carried out by appropriate biochemical and serological tests. The product passes the test if colonies of the type described do not appear or if the confirmatory biochemical and serological tests are negative.

Pseudomonas aeruginosa

Prepare the product to be examined as described in the general method Appendix XVI B2

(2.6.12) and use 10 ml or the quantity corresponding to 1 g or 1 ml to inoculate 100 ml of

broth medium A, homogenise and incubate at 35° to 37° for 18 to 48 hours. Subculture on a plate of agar medium N and incubate at 35° to 37° for 18 to 72 hours. If no growth of micro-organisms is detected, the product passes the test. If growth of gram-negative rods occurs, transfer some material of morphologically different, isolated colonies to broth medium A and incubate at 41° to 43° for 18 to 24 hours. The product passes the test if no growth occurs at 41° to 43°.

When testing transdermal patches, filter 50 ml of preparation A as described in the general method Appendix XVI B2 (2.6.12) through a sterile filter membrane and place in 100 ml of broth medium A and incubate at 35° to 37° for 18 to 48 hours. After incubation spread on agar medium N.

Staphylococcus aureus

Prepare the product to be examined as described in the general method Appendix XVI B2 (2.6.12) and use 10 ml or the quantity corresponding to 1 g or 1 ml to inoculate 100 ml of broth medium A, homogenise and incubate at 35° to 37° for 18 to 48 hours. Subculture on a plate of agar medium O and incubate at 35° to 37° for 18 to 72 hours. Black colonies of gram-positive cocci, surrounded by a clear zone indicate the presence of S. aureus. Confirmation may be effected by suitable biochemical tests such as the coagulase test and the deoxyribonuclease test. The product passes the test if colonies of the type described do not appear on agar medium O or if the confirmatory biochemical tests are negative.

When testing transdermal transdermal patches, filter 50 ml of preparation A as described in the general method Appendix XVI B2 (2.6.12) through a sterile filter membrane and place in 100 ml of broth medium A and incubate at 35° to 37° for 18 to 48 hours. After incubation spread on agar medium O.

Nutritive and selective properties of the media and validity of the test

The tests described hereafter must be performed at least on each lot of dehydrated media. Proceed as follows. Grow the following test strains separately, in tubes containing suitable media such as those indicated, at 30° to 35° for 18 to 24 hours:

Staphylococcus aureus such as ATCC 6538 (NCIMB 9518, CIP 4.83): broth medium A,

Pseudomonas aeruginosa such as ATCC 9027 (NCIMB 8626, CIP 82.118): broth medium A

Escherichia coli such as ATCC 8739 (NCIMB 8545, CIP 53.126): broth medium A

Salmonella typhimurium no strain number is recommended (a salmonella not pathogenic for man, such as Salmonella abony (NCTC 6017, CIP 80.39), may also be used): broth medium A.

Dilute portions of each of the cultures using buffered sodium chloride-peptone solution pH 7.0 to make test suspensions containing about 1000 viable micro-organisms per millilitre. Mix equal volumes of each suspension and use 0.4 ml (approximately 100 micro-organisms of each strain) as an inoculum in tests for S. aureus, Ps. aeruginosa, E. coli and Salmonellae in the presence and in the absence of the product to be examined. A positive result for the respective microorganisms must be obtained.

Total viable aerobic count (2.6.12) Plate count methods

A. POUR-PLATE METHOD Using Petri dishes 9 cm in diameter, add to each dish 1 ml of the sample prepared as described in the section 'Preparation of the sample' and 15 ml to 20 ml of a liquefied agar medium suitable for the cultivation of bacteria (such as medium B), or 15 ml to 20 ml of a liquefied agar medium suitable for the cultivation of fungi (such as medium C) at not more than 45°. If larger Petri dishes are used the amount of agar is increased accordingly. Prepare for each medium at least two Petri dishes for each level of dilution. Incubate the plates at 30° to 35° (20° to 25° for fungi) for five days, unless a reliable count is obtained in a shorter time. Select the plates corresponding to one dilution and showing the highest number of colonies less than 300 (100 colonies for fungi). Take the

33

Name of Material Magnesium Stearate BP

Tested as per BRITISH PHARMACOPEIA

DEFINITION

Magnesium stearate is a mixture of magnesium salts of different fatty acids consisting mainly of stearic acid [(C17H35COO)2Mg; 591.3] and palmitic acid [(C15H31COO)2Mg; 535.1] and in

minor proportions other fatty acids. It contains not less than 4.0 per cent and not more than 5.0 per cent of Mg (Ar 24.30), calculated with reference to the dried substance. The fatty acid

fraction contains not less than 40.0 per cent of stearic acid and the sum of stearic acid and palmitic acid is not less than 90.0 per cent.

CHARACTERS

A white, very fine, light powder, greasy to the touch, practically insoluble in water and in ethanol.

IDENTIFICATION First identification: C, D. Second identification: A, B, D.

A. The residue obtained in the preparation of solution S has a freezing point not lower than 53°C.

B. The acid value of the fatty acids is 195 to 210, determined on 0.200 g of the residue obtained in the preparation of solution S dissolved in 25 ml of the prescribed mixture of solvents.

C. Examine the chromatograms obtained in the test for fatty acid composition. The retention times of the principal peaks in the chromatogram obtained with the test solution are approximately the same as those of the principal peaks in the chromatogram obtained with the reference solution.

D. 1 ml of solution S gives the reaction of magnesium. TESTS

Solution S: To 5.0 g add 50 ml of peroxide-free ether R, 20 ml of dilute nitric acid R and 20 ml of distilled water R and heat under a reflux condenser until

Name of Material Magnesium Stearate BP

Tested as per BRITISH PHARMACOPEIA

dissolution is complete. Allow to cool. In a separating funnel, separate the aqueous layer and shake the ether layer with two quantities, each of 4 ml, of distilled water R. Combine the aqueous layers, wash with 15 ml of peroxide-free ether R and dilute to 50 ml with distilled water R (solution S). Evaporate the organic layer to dryness and dry the residue at 100°C to 105°C. Keep the residue for identification A and B.

Acidity or alkalinity: To 1.0 g add 20 ml of carbon dioxide-free water R and boil for 1 min with continuous shaking. Cool and filter. To 10 ml of the filtrate add 0.05 ml of bromothymol blue solution R1. Not more than 0.5 ml of 0.01M hydrochloric acid or 0.01M sodium hydroxide is required to change the colour of the indicator.

Chlorides: 0.5 ml of solution S diluted to 15 ml with water R complies with the limit test for chlorides (0.1 per cent).

Sulphates: 0.3 ml of solution S diluted to 15 ml with distilled water R complies with the limit test for sulphates (0.5 per cent).

Cadmium: Not more than 3 ppm of Cd, determined by atomic absorption spectrometry. Test solution. Place 50.0 mg of the substance to be examined in a polytetrafluoroethylene digestion bomb and add 0.5 ml of a mixture of 1 volume of hydrochloric acid R and 5 volumes of cadmium- and lead-free nitric acid R. Allow to digest at 170°C for 5 h. Allow to cool. Dissolve the residue in water R and dilute to 5.0 ml with the same solvent.

Reference solutions. Prepare the reference solutions using cadmium standard solution (10 ppm Cd) R, diluted if necessary with a 1 per cent V/V solution of hydrochloric acid R.

Measure the absorbance at 228.8 nm, using a cadmium hollow-cathode lamp as a source of radiation and an air-acetylene flame.

Lead: Not more than 10 ppm of Pb, determined by atomic absorption spectrometry. Test solution. Use the solution described in the test for cadmium.

35 Name of Material Magnesium Stearate BP

Tested as per BRITISH PHARMACOPEIA

Reference solutions. Prepare the reference solutions using lead standard solution (10 ppm Pb) R, diluted if necessary with water R.

Measure the absorbance at 283.3 nm, using a lead hollow-cathode lamp as a source of radiation and an air-acetylene flame, depending on the apparatus the line at 217.0 nm may be used.

Nickel: Not more than 5 ppm of Ni, determined by atomic absorption spectrometry. Test solution. Use the solution described in the test for cadmium.

Reference solutions. Prepare the reference solutions using nickel standard solution (10 ppm Ni) R, diluted if necessary with water R.

Measure the absorbance at 232.0 nm, using a nickel hollow-cathode lamp as a source of radiation and an air-acetylene flame.

Loss on drying: Not more than 6.0 per cent, determined on 1.000 g by drying in an oven at 100°C to 105°C.

Microbial contamination: Total viable aerobic count not more than 103 micro-organisms per gram, determined by plate count. It complies with the test for Escherichia coli).

ASSAY

Magnesium: To 0.250 g in a 250 ml conical flask add 50 ml of a mixture of equal volumes of butanol R and ethanol R, 5 ml of concentrated ammonia R, 3 ml of ammonium chloride buffer solution pH 10.0 R, 30.0 ml of 0.1M sodium edetate and 15 mg of mordant black 11 triturate R. Heat to 45°C to 50°C until the solution is clear and titrate with 0.1M zinc sulphate until the colour changes from blue to violet. Carry out a blank titration.

1 ml of 0.1M sodium edetate is equivalent to 2.431 mg of Mg. Fatty acid composition: Examine by gas chromatography.

Name of Material Magnesium Stearate BP

Tested as per BRITISH PHARMACOPEIA

Test solution. In a conical flask fitted with a reflux condenser, dissolve 0.10 g of the substance to be examined in 5 ml of boron trifluoride-methanol solution R. Boil under a reflux condenser for 10 min. Add 4 ml of heptane R through the condenser and boil again under a reflux condenser for 10 min. Allow to cool. Add 20 ml of a saturated solution of sodium chloride R. Shake and allow the layers to separate. Remove about 2 ml of the organic layer and dry over 0.2 g of anhydrous sodium sulphate R. Dilute 1.0 ml of the solution to 100.0 ml with heptane R.

Reference solution. Prepare the reference solution in the same manner as the test solution using 50.0 mg of palmitic acid CRS and 50.0 mg of stearic acid CRS instead of magnesium stearate.

The chromatographic procedure may be carried out using:

— a fused-silica column 30 m long and 0.32 mm in internal diameter coated with macrogol 20,000 R (film thickness 0.5 µm),

— helium for chromatography R as the carrier gas at a flow rate of 2.4 ml/min, — a flame-ionisation detector,

with the following temperature programme:

Inject 1 µl of the reference solution. When the chromatograms are recorded in the prescribed conditions, the retention time of methyl palmitate relative to that of methyl stearate is about 0.88. The test is not valid unless, in the chromatogram obtained with the reference solution, the resolution between the peaks corresponding to methyl stearate and methyl palmitate is at least 5.0.

Inject 1 µl of the test solution. Calculate the percentage content of stearic acid and palmitic acid from the areas of the peaks in the chromatogram obtained with the test solution by the normalisation procedure, disregarding the peak due to the solvent.

STORAGE

37 Name of Material

Sodium Starch Glycollate (Type C) BP

Tested as per BRITISH PHARMACOPEIA

DEFINITION

Sodium starch glycollate (type C) is the sodium salt of a cross-linked by physical dehydration, partly O-carboxymethylated starch. It contains not less than 2.8 per cent and not more than 5.0 per cent of Na (Ar 22.99), calculated with reference to the substance

washed with alcohol (80 per cent V/V) and dried.

CHARACTERS

A white or almost white, fine, free-flowing powder, very hygroscopic, soluble in water, practically insoluble in methylene chloride. It gives a translucent gel-like product in water. Examined under a microscope it is seen to consist of granules, irregularly shaped, ovoid or pear-shaped, 30 µm to 100 µm in size, or rounded, 10 µm to 35 µm in size; compound granules consisting of two to four components occur occasionally; the granules have an eccentric hilum and clearly visible concentric striations; between crossed nicol prisms, the granules show a distinct black cross intersecting at the hilum; small crystals are visible at the surface of the granules. The granules show considerable swelling in contact with water.

IDENTIFICATION

A. It complies with the test for pH .

B. Mix with shaking and without heating 4.0 g and 20 ml of carbon dioxide-free water R. The mixture has the appearance of a gel. Add 100 ml of carbon dioxide-free water R and shake: the gel remains stable (difference from types A and B). Keep the gel for the tests for appearance of gel and pH.

C. To 5 ml of the gel obtained in identification test B add 0.05 ml of iodine solution R1. A dark blue colour is produced.

D. Solution S gives reaction (a) of sodium. TESTS

Solution S Place 2.5 g in a silica or platinum crucible and add 2 ml of a 250 g/l solution of sulphuric acid R. Heat on a water-bath, then cautiously over a naked

Name of Material

Sodium Starch Glycollate (Type C) BP

Tested as per BRITISH PHARMACOPEIA

flame, raising the temperature progressively, and then incinerate in a muffle furnace at 600±25°C. Continue heating until all black particles have disappeared. Allow to cool, add a few drops of sulphuric acid R and heat and incinerate as described above. Allow to cool, add a few drops of ammonium carbonate solution R, evaporate to dryness and incinerate cautiously. Allow to cool and dissolve the residue in 50 ml of water R.

Appearance of gel The gel prepared under identification test B is colourless . pH The pH of the gel prepared under identification test B is 5.5 to 7.5.

Sodium glycollate Carry out the test protected from light.

Test solution. Place 0.20 g of the substance to be examined in a beaker. Add 5 ml of acetic acid R

and 5 ml of water R. Stir until dissolution is complete (about 10 min). Add 50 ml of acetone R and 1 g

of sodium chloride R. Filter through a fast filter paper impregnated with acetone R, rinse the beaker and filter with acetone R. Combine the filtrate and washings and dilute to 100.0 ml with acetone R. Allow to stand for 24 h without shaking. Use the clear supernatant liquid. Reference solution. Dissolve 0.310 g of glycollic acid R, previously dried in vacuo over diphosphorus pentoxide R, in water R and dilute to 250.0 ml with the same solvent. To 5.0 ml of this solution, add 5 ml of acetic acid R and allow to stand for about 30 min. Add 50 ml of acetone R and 1 g of sodium chloride R and dilute to 100.0 ml with acetone R.

Heat 2.0 ml of the test solution on a water-bath for 20 min. Cool to room temperature and add 20.0 ml of 2,7-dihydroxynaphthalene solution R. Shake and heat on a water-bath for 20 min. Cool under running water, transfer to a volumetric flask and dilute to 25.0 ml with sulphuric acid R, maintaining the flask under running water. Within 10 min, measure the absorbance at 540 nm using water R as the compensation liquid. The absorbance of the solution prepared with the test solution is not greater than that of a solution prepared at the same time and in the same manner with 2.0 ml of the reference solution (2.0 per cent). Sodium chloride Not more than 1 per cent. Shake 1.00 g with 20 ml of alcohol (80 per cent V/V) R for 10 min and filter. Repeat the operation four times. Dry the residue to constant mass at 100°C and set aside for the assay. Combine the filtrates. Evaporate to dryness, take up the residue with water R and dilute to 25.0 ml with the same solvent. To 10.0 ml of the solution add 30 ml of water R

39 Name of Material

Sodium Starch Glycollate (Type C) BP

Tested as per BRITISH PHARMACOPEIA

and 5 ml of dilute nitric acid R. Titrate with 0.1M silver nitrate, determining the end-point potentiometrically , using a silver indicator electrode.

1 ml of 0.1M silver nitrate is equivalent to 5.844 mg of NaCl.

Iron 10 ml of solution S complies with the limit test for iron (20 ppm).

Heavy metals 1.0 g complies with limit test D for heavy metals (20 ppm). Prepare the standard using 2 ml of lead standard solution (10 ppm Pb) R.

Loss on drying Not more than 7.0 per cent, determined on 1.000 g by drying in an oven at 100°C to 105°C for 4 h.

Microbial contamination It complies with the test for Escherichia coli and Salmonella .

ASSAY

To 0.250 g of the dried and crushed residue obtained in the test for sodium chloride add 80 ml of anhydrous acetic acid R and heat under a reflux condenser for 2 h. Cool the solution to room temperature. Titrate with 0.1M perchloric acid, determining the end-point potentiometrically. Carry out a blank test.

1 ml of 0.1M perchloric acid is equivalent to 2.299 mg of Na. STORAGE

Name of Material COLLOIDAL SILICON DIOXIDE

Tested as per USP

Molecular Formula:SiO2

Mol. Wt. 60.08

Category: Pharmaceutical aid (tablet excipient).

Description: Light, fine, white, amorphous powder. It has a particle size of about 15 nm. Solubility: Practically insoluble in water and in mineral acids with the exception of

hydrofluoric acid. Dissolves in hot solutions of alkali hydroxides. When 1 g is shaken

vigorously with 20 ml of carbon tetrachloride for 3 minutes; a transparent gel is produced. STANDARDS

Colloidal Silicon Dioxide contains not less than 99.0 per cent and not more than 100.5 per cent of SiO2, calculated with reference to the ignited substance.

Identification: About 20 mg gives the reaction of silicates.

pH: Between 3.5 and 5.5, determined in a suspension of 1 g in 30 ml of carbon dioxide-free

water.

Chloride: To 1.0 g add a mixture of 20 ml of 2M nitric acid and 30 ml of water, heat on a water-bath for 15 minutes, shaking frequently, dilute to 50 ml with water if necessary, filter and cool. The filtrate complies with the limit test for chlorides. (250 ppm).

Arsenic: To 2.5 g contained in a round-bottomed flask add 50 ml of 3M hydrochloric acid and heat under a reflux condenser for 30 minutes. Cool, filter with the aid of suction and transfer the filtrate to a 100-ml volumetric flask. Wash the filter with several portions of hot water and add the washings to the volumetric flask. Cool, dilute to volume with water and mix. To 50.0 ml of the solution add 3 ml of hydrochloric acid; the resulting solution complies with the limit test for arsenic, (8 ppm).

Heavy metals: Not more than 25 ppm, determined by Method D on 12 ml of a solution prepared in the following manner. Suspend 2.5 g in sufficient water to produce a semi-fluid slurry and dry at 140o. When the dried substance is white, break up the mass using a glass rod, add 25 ml of 1M hydrochloric acid, boil gently for 5 minutes, stirring frequently with the glass rod, centrifuge for 20 minutes and filter the supernatant liquid through a membrane filter. To the residue in the centrifuge tube add 3 ml of 2M hydrochloric acid and 9 ml of

41 Name of Material COLLOIDAL SILICON DIOXIDE

Tested as per USP

supernatant liquid through the same membrane filter. Wash the residue with small quantities of water, combine the filtrates and washings and dilute to 50.0 ml with water. To 20.0 ml of the solution add 50 mg of L-ascorbic acid and 1 ml of strong ammonia solution, neutralise with 2M ammonia and dilute to 25 ml with water. Use lead standard solution (1 ppm Pb) to prepare the standard.

Loss on ignition: Not more than 5.0%, determined on 0.2 g by igniting at 900o in a platinum crucible for 2 hours

Assay: To the residue obtained in the test for Loss on ignition add 0.2 ml of sulphuric acid and sufficient ethanol (95%) to moisten the residue completely, add 6 ml of hydrofluoric acid and evaporate to dryness on a hot plate at 95o to 105o, avoiding loss from sputtering. Wash the sides of the dish with 6 ml of hydrofluoric acid, evaporate to dryness in a well-ventilated hood, ignite at 1000o, allow to cool in a desiccator and weigh. The difference between the weight of the final residue and that of the residue obtained in the test for Loss on ignition represents the amount of SiO2 in the amount of the substance taken for the test for Loss on

Name of Material

Purified Talc BP

Tested as per BRITISH PHARMACOPEIA

DEFINITION

Talc is a powdered, selected, natural, hydrated magnesium silicate. Pure talc has the formula [Mg3Si4O10(OH) 2; Mr 379.3]. It may contain variable amounts of associated minerals

among which chlorites (hydrated aluminium and magnesium silicates), magnesite (magnesium carbonate), calcite (calcium carbonate) and dolomite (calcium and magnesium carbonate) are predominant.

CHARACTERS

A light, homogeneous, white or almost white powder, greasy to the touch (non abrasive), practically insoluble in water, in alcohol and in dilute solutions of acids and alkali hydroxides. IDENTIFICATION

First identification: A. Second identification: B, C.

A. Examine by infrared absorption spectrophotometry. The spectrum shows absorption bands at 3677 ± 2 cm-1, at 1018 ± 2 cm-1 and at 669 ± 2 cm-1. Examine the substance as discs prepared using potassium bromide R.

B. In a platinum crucible, melt a mixture of 0.2 g of anhydrous sodium carbonate R and 2.0 g of potassium carbonate R. To the melted mass add 0.1 g of the substance to be examined and heat until the mixture is completely melted. Allow to cool and transfer the melted mass into an evaporating dish with 50 ml of hot water R. Add hydrochloric acid R until effervescence ceases. Add 10 ml of hydrochloric acid R and evaporate to dryness on a water-bath. Allow to cool. Add 20 ml of water R, heat to boiling and filter. (The residue is used for identification test C). To 5 ml of the filtrate add 1 ml of ammonia R and 1 ml of ammonium chloride solution R and filter. To the filtrate add 1 ml of disodium hydrogen phosphate solution R. A white, crystalline precipitate is formed.

C. The residue obtained in identification test B gives the reaction of silicates. TESTS

Solution S1: Weigh 10.0 g of the substance to be examined into a conical flask fitted with a reflux condenser, add 50 ml of 0.5M hydrochloric acid gradually while stirring and heat on a water-bath for 30 min. Allow to cool. Transfer the mixture to a beaker and allow the undissolved material to settle. Filter the supernatant through medium-speed filter paper into a 100 ml volumetric flask, retaining as much as possible of the insoluble material in the beaker. Wash the residue and the beaker with three

43 Name of Material

Purified Talc BP

Tested as per BRITISH PHARMACOPEIA

quantities, each of 10 ml, of hot water R. Wash the filter with 15 ml of hot water R, allow the filtrate to cool and dilute to 100.0 ml with the same solvent.

Solution S2: Weigh 0.5 g of the substance to be examined in a 100 ml polytetrafluoroethylene dish, add 5 ml of hydrochloric acid R, 5 ml of lead-free nitric acid R, and 5 ml of perchloric acid R. Stir gently then add 35 ml of hydrofluoric acid R and evaporate slowly to dryness on a hot plate. To the residue, add 5 ml of hydrochloric acid R, cover with a watch-glass, heat to boiling and allow to cool. Rinse the watch-glass and the dish with water R. Transfer into a volumetric flask containing 5 ml of a 25.34 g/l solution of caesium chloride R, rinse the dish with water R and dilute to 50.0 ml with the same solvent.

pH: The pH of the filtrate obtained in the test for water- soluble substances, is 7.0 to 9.0. Read the pH 1 min after inserting the electrode.

Water-soluble substances: To 10.0 g add 50 ml of carbon dioxide- free water R, heat to boiling and maintain boiling under a reflux condenser for 30 min. Allow to cool, filter through a medium-speed filter paper and dilute to 50.0 ml with carbon dioxide-free water R. Take 25.0 ml of the filtrate, evaporate to dryness and heat at 105°C for 1 h. The residue weighs not more than 10 mg (0.2 per cent).

Aluminium: Not more than 2.0 per cent of aluminium, determined by atomic absorption spectrometry.

Test solution. To 5.0 ml of solution S2 add 10 ml of a 25.34 g/l solution of caesium chloride R, 10.0 ml of hydrochloric acid R and dilute to 100.0 ml with water R.

Reference solutions. Into four identical volumetric flasks, each containing 10.0 ml of hydrochloric acid R and 10 ml of a 25.34 g/l solution of caesium chloride R, introduce respectively 5.0 ml, 10.0 ml, 15.0 ml and 20.0 ml of aluminium standard solution (100 ppm Al) R and dilute to 100.0 ml with water R.

Measure the absorbance at 309.3 nm, using an aluminium hollow- cathode lamp as the radiation source and a nitrous oxide- acetylene flame.

Calcium: Not more than 0.9 per cent of calcium, determined by atomic absorption spectrometry.

Test solution. To 5.0 ml of solution S2 add 10.0 ml of hydrochloric acid R, 10 ml of lanthanum chloride solution R and dilute to 100.0 ml with water R.

Reference solutions. Into four identical volumetric flasks, each containing 10.0 ml of hydrochloric acid R and 10 ml of lanthanum chloride solution R, introduce respectively

Name of Material

Purified Talc BP

Tested as per BRITISH PHARMACOPEIA

1.0 ml, 2.0 ml, 3.0 ml and 4.0 ml of calcium standard solution (100 ppm Ca) R1 and dilute to 100.0 ml with water R.

Measure the absorbance at 422.7 nm using a calcium hollow- cathode lamp as the radiation source and a nitrous oxide- acetylene flame.

Iron: Not more than 0.25 per cent of iron, determined by atomic absorption spectrometry. Test solution. To 2.5 ml of solution S1, add 50.0 ml of 0.5M hydrochloric acid and dilute to 100.0 ml with water R.

Reference solutions. Into four identical volumetric flasks, each containing 50.0 ml of 0.5M hydrochloric acid, introduce respectively 2.0 ml, 2.5 ml, 3.0 ml and 4.0 ml of iron standard solution (250 ppm Fe) R and dilute to 100.0 ml with water R.

Measure the absorbance at 248.3 nm using an iron hollow-cathode lamp as the radiation source and an air-acetylene flame. Make a correction using a deuterium lamp.

Magnesium 17.0 per cent to 19.5 per cent of magnesium, determined by atomic absorption spectrometry.

Test solution. Dilute 0.5 ml of solution S2 to 100.0 ml with water R. To 4.0 ml of the solution, add 10.0 ml of hydrochloric acid R, 10 ml of lanthanum chloride solution R and dilute to 100.0 ml with water R.

Reference solutions. Into four identical volumetric flasks, each containing 10.0 ml of hydrochloric acid R and 10 ml of lanthanum chloride solution R, introduce respectively 2.5 ml, 3.0 ml, 4.0 ml and 5.0 ml of magnesium standard solution (10 ppm Mg) R1 and dilute to 100.0 ml with water R.

Measure the absorbance at 285.2 nm using a magnesium hollow- cathode lamp as the radiation source and an air-acetylene flame.

Lead: Not more than 10 ppm of lead, determined by atomic absorption spectrometry. Test solution. Use solution Sl.

Reference solutions. Into four identical volumetric flasks, each containing 50.0 ml of 0.5M hydrochloric acid, introduce respectively 5.0 ml, 7.5 ml, 10.0 ml and 12.5 ml of lead standard solution (10 ppm Pb) R1 and dilute to 100.0 ml with water R.

45 Name of Material

Purified Talc BP

Tested as per BRITISH PHARMACOPEIA

Measure the absorbance at 217.0 nm using a lead hollow-cathode lamp as the radiation source and an air-acetylene flame.

Loss on ignition: Not more than 7.0 per cent, determined on 1.00 g by ignition to constant weight at 1050°C to 1100°C.

Microbial contamination: If intended for topical administration, the total viable aerobic count (2.6.12) is not more than a total of 102 aerobic bacteria and fungi per gram.

If intended for oral administration, the total viable aerobic count is not more than a total of 103 aerobic bacteria and not more than 102 fungi per gram.

LABELLING

The label states, where applicable, that the substance is suitable for oral or topical administration.

Maize starch

Definition

Maize starch is obtained from the caryopsis of Zea mays L.

Characters

■

Appearance

Matt, white to slightly yellowish, very fine powder which creaks when

pressed between the fingers.

■

Solubility

Practically insoluble in cold water and in alcohol.

The presence of granules with cracks or irregularities on the edge is

exceptional.

It is tasteless.

Identification

A. Examined under a microscope, using not less than 20 x

magnification and using equal volumes of glycerol R and water R, it

appears as either angular polyhedral granules of irregular sizes with

diameters ranging from about 2 mm to about 23 mm or as rounded or

spheroidal granules of irregular sizes with diameters ranging from about 25

mm to about 35 mm. The central hilum consists of a distinct cavity or two-

to five-rayed cleft and there are no concentric striations. Between crossed

nicol prisms, the starch granules show a distinct black cross intersecting at

the hilum.

B.

Suspend 1 g in 50 ml of water R, boil for 1 min and cool. A thin,

cloudy mucilage is formed.

47

Tests

■

pH (2.2.3)

4.0 to 7.0.

Shake 5.0 g with 25.0 ml of carbon dioxide-free water R for 60 s. Allow

to stand for 15 min.

■

Foreign matter

Examined under a microscope using a mixture of equal volumes of

glycerol R and water R, not more than traces of matter other than starch

granules are present. No starch grains of any other origin are present.

■

Oxidising substances (2.5.30)

Maximum 20 ppm, calculated as H

0

.

■

Sulphur dioxide (2.5.29)

Maximum 50 ppm.

■

Iron (2.4.9)

Maximum 10 ppm.

Shake 1.5 g with 15 ml of dilute hydrochloric acid R. Filter. The filtrate

Complies with the limit test for iron.

■

Loss on drying (2.2.32)

Maximum 15.0 per cent, determined on 1.000

130°Cfor90min.

■

Sulphated ash (2.4.14)

Maximum 0.6 per cent, determined on 1.0 g.

■

Microbial contamination

Total viable aerobic count (2.6.12) not more than 10

bacteria and 10

fungi per gram, determined by plate count. It complies with the test for

Escherichia coli (2.6.13).

Storage

In an airtight container .

CONCERNING CHEMICAL,

PHARMACEUTICAL AND

BIOLOGICAL DOCUMENTATION FOR

CHEMICAL ACTIVE SUBSTANCE(S)

49

DRUG DESCRIPTION

Generic Name

PARACETAMOL TABLET (Acetaminophen)

Physical Properties Of The Chemical Entity1 a. Structural Formula b. Molecular Formula C8H9NO2 c. Molecular Weight 151.16 d. Macroscopic Appearance

Acetaminophen is a white, crystalline powder.

e. Solubility water 1:70 boiling water 1:20 alcohol 1:10 chloroform 1:50 glycerin 1:40

ether slightly soluble

Chemical Properties

a. Structural Similarities/Differences of the Drug to Other Available Compounds or Groups of Compounds

Acetaminophen is a synthetic, nonopiate, centrally acting analgesic derived from p-aminophenol. The full chemical name is N-acetyl-p-p-aminophenol.

b. pKa

The pKa of acetaminophen is 9.51 at 25°C.

Acetaminophen is stable to temperature, light, and moisture.

d. pH Range Over Which Drug is Stable in Solution

Acetaminophen is stable at a pH between 4 and 7 at 25°C.

e. pH of Commercially Available Liquid Products

Acetaminophen oral solution (ie, elixir, adult liquid) has a pH of 3.8 to 6.1 and the oral suspension (ie, infants' drops, children's suspension) has a pH of 5.4 to 6.9.

f. Osmolarity/Osmolality of Commercially Available Solutions

Extra Strength PARACETAMOL acetaminophen Adult Liquid: 3058 ± 152 mmol/kg Children's PARACETAMOL acetaminophen Elixir: 6040 ± 25 mmol/kg

Because of the nature of suspension formulations, osmolarity of the PARACETAMOL acetaminophen suspension products cannot be determined.

References

1. Remington's Pharmaceutical Sciences. 23rd ed. Easton, PA: Mack Publishing Company; 1995:1109-1110.

*Permission to use the Product Information Form for the American Hospital Formulary Service as modified by McNeil Consumer Healthcare has been granted by the American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, MD 20814. The answers to all questions are prepared and furnished by the manufacturer. The answers were not supplied by the Society nor are they intended to imply the endorsement of the American Society of Health-System Pharmacists; neither does the Society affirm or deny the accuracy of the answers contained herein. Copyright© 1985, American Society of Health-System Pharmacists, Inc., all rights reserved.

INDICATIONS

DOSAGE RANGE

a. Administration

PARACETAMOL acetaminophen products are only administered orally. They are available in a variety of convenient dosage forms as listed in Tables 2 and 3. For ease of administration for young children, Infants' f Concentrated Drops are more concentrated than the Children's PARACETAMOL liquid formulations. Infants' PARACETAMOL Concentrated Drops

51 b. Adult Dosage

For adults and children 12 years of age and older, the recommended dose of acetaminophen is 650 to 1000 mg every 4 to 6 hours as needed, not to exceed 4000 mg in 24 hours (Table 2). For extended-release acetaminophen, the dose is 1300 mg every 8 hours as needed, not to exceed 3900 mg in 24 hours. Some adult products (Extra Strength PARACETAMOL, PARACETAMOL Arthritis Extended Relief Formula) are not intended for use in children under 12 years of age.

c. Pediatric Dosage

For children under 12 years of age, the recommended dose of acetaminophen is 10 to 15 mg/kg every 4 to 6 hours,47 _{not to exceed five doses (50-75 mg/kg) in 24 hours (Table 3).}

Age-Related Dosing Schedule

The age-related schedule is based on standard age divisions proposed by the United States Food and Drug Administration (FDA) and used in the development of an acetaminophen dosing schedule.47

TABLE 4. Recommended pediatric dosing of acetaminophen by weight and age (adapted from reference 47, with permission)*

Weight

lb kg Age

a _doseb _(mg) Single Recommended

daily dose (mg) 6-11 2.0 - 5.4 0-3 monthsc 40 200 12 -17 5.5 - 7.9 4-11 months 80 400 18 -23 8.0 - 10.9 12 - 23 months 120 600 24-35 11.0 - 15.9 2-3 years 160 800 36-47 16.0 - 21.9 4-5 years 240 1200 48-59 22.0 -26.9 6-8 years 320 1600 60-71 27.0 - 31.9 9-10 years 400 2000 72-95 32.0 -43.9 11 years 480 2400

* Refer to package label for more specific information related to dosing.

a _{For adults and children 12 years of age and older see Table 2.}

b _{Doses may be repeated every 4 hours but not more than five times daily} c _{Data not available to define appropriate adjustments, if any, needed for the}

immediate neonatal period. Use of antipyretics in the immediate neonatal period is extremely limited.

Weight-Related Dosing Schedule

This weight-related dosing schedule was developed and recommended by McNeil Consumer Healthcare when dosing by weight. The weight-related schedule is based on weight ranges that are consistent with the use of a standard 80-mg dosage unit.47 Using this method, the weight-related dosage schedule provides a dose of 10 to 15 mg/kg body weight for a single dose. The weight-related schedule most closely approximates this dose, so that when possible, consumers should be instructed to use weight to calculate dose; otherwise, age may be used (Table 4).

The label for Regular Strength PARACETAMOL acetaminophen products recommends that children 6 to 11 years old take 325 mg every 4 to 6 hours, not to exceed five doses in 24 hours.

d. Use of Recommended Doses for Longer Than 10 Days

Clinical studies have evaluated the use of acetaminophen in adult patients with osteoarthritis of the knee at recommended doses of 4000 mg/d for up to 4 weeks.48,49 _{Williams and}

colleagues50 evaluated the use of acetaminophen in doses up to 2600 mg/d for up to 2 years. In these studies, acetaminophen was well tolerated.

The package label for adult PARACETAMOL acetaminophen products instructs adults not to take PARACETAMOL for pain for more than 10 days or for fever for more than 3 days unless directed by a doctor. The package label for Children's PARACETAMOL products instructs parents not to administer PARACETAMOL to children for pain for more than 5 days or for fever for more than 3 days unless directed by a doctor. As with all over-the-counter (OTC) analgesics, this warning is necessary so that patients and parents will seek appropriate medical evaluation of their condition if it persists beyond these time periods.

e. Alternate/Concomitant Dosing

Concomitant or alternate dosing with more than one antipyretic agent is not recommended. There are no studies to support alternate dosing of acetaminophen and ibuprofen or other nonsteroidal anti-inflammatory drugs (NSAIDs). Studies have demonstrated that single-dose concurrent administration of aspirin and acetaminophen produced a more prolonged

temperature decrement than when either antipyretic was given alone.51,52

f. Recommended Storage Conditions

Storage requirements for all PARACETAMOL acetaminophen drops, liquids, and solid formulations are as follows: store at room temperature. It is recommended that high humidity and excessive heat (ie, ≥ 40°C [104°F]) be avoided for the gelatin-coated formulations (eg, gelcaps, geltabs). Freezing of the liquid or suspension formulations should be avoided.

g. Expiration Dating Periods for Commercially Available Products

Under room temperature storage conditions, PARACETAMOL acetaminophen solid

formulations are generally stable for 3 years and liquid formulations are generally stable for 2 years from the date of manufacture. Refer to product package for specific expiration date.

References

47. Temple AR. Pediatric dosing of acetaminophen. Pediatr Pharmacol. 1983;3:321-327. 48. Amadio P, Cummings DM. Evaluation of acetaminophen in the management of osteoarthritis of the knee. Curr Ther Res. 1983;34:59-66.

49. Bradley J D, Brandt KD, Katz BP, Kalasinski LA, Ryan SI. Comparison of an anti-inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the