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2018-2019 Quality Assurance Assignment-02

DECCAN SCHOOL OF PHARMACY

DARUSSALAM, AGHAPURA

HYDERABAD – 500 001, TELANGANA STATE

QUALITY ASSURANCE

ASSIGNMENT - 02

STUDY OF COMPENDIA AND PARTS LIKE POLICIES, MONOGRAPHS, GENERAL NOTICES,

COMPARTIVE PICTURE OF IP, BP, USP

SUBMITTED TO:

Mr. Syed Tabraiz Ullah Hussaini

M.Pharm

ASSISSTANT PROFESSOR

(DEPARTMENT OF PHARMACEUTICAL ANALYSIS AND QUALITY ASSURANCE)

PREPARED BY: 170716881-084, 086, 087, 091, 092, 093, 096, 097, 100, 301, 302

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B.Pharmacy 3rd Year VI Sem, Section - B

STUDY OF COMPENDIA

PHARMACOPOEIA:

The word is derived from the ancient Greek (pharmakopoiia), from (pharmako-) ″drug″, followed by the verb-stem (poi-) ″make″and finally the abstract noun ending (-ia). These three elements together can be rendered as ″drug-mak-ing″ or ″to make a drug″.

A pharmacopoeia/pharmacopeia, in its modern sense, is a legally binding collection, prepared by a national or regional authority,of standards and quality specifications for medicines used in that country or region. A quality specification is composed of a set ofappropriate tests that will confirm the identity and purity of the product, ascertain the strength (or amount) of the active substanceand, when needed, its performance characteristics.

Reference substances, i.e. highly-characterized, physical specimens, are used in testing to help ensure the quality, such as identity,strength and purity, of medicines. The texts cover pharmaceutical starting materials, excipients, intermediates and finishedpharmaceutical products (FPPs). General requirements may also be given in the pharmacopoeia on important subjects related tomedicines quality, such as analytical methods, microbiological purity, dissolution testing, stability, etc.

MONOGRAPHS:

A monograph includes the name of the ingredient or preparation; the definition; packaging, storage, and labeling requirements;and the specification. The specification consists of a series of tests, procedures for the tests, and acceptance criteria. These testsand procedures require the use of official USP Reference Standards.

Medicinal ingredients and products will have the stipulated strength, quality, and purity if they conform to the requirements of

the monograph and relevant general chapters.

During the International meeting of world pharmacopoeias, there were examples of types of monographs with less frequent

occurrence than other types. For example,

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https://www.usp.org/reference-standards


Monographs for Blood Products were presented by Argentina (12), Brazil (20) and India (21) Monographs for Vaccines were presented by Argentina (21), India (57), Kazakhstan (15) and Ukraine (26). Homeopathic preparations described in monographs were presented mainly by France (320), Germany (120) and Mexico

(558) Monographs for Traditional Medicine were given as an example by China (2165).

A total of 92 herbal, traditional herbal and homeopathic monographs are present in the British Pharmacopoeia 2012.

Supplementary information is included in some of the pharmacopoeias, for example general texts, reference tables, and texts onmethods of analysis, reagents, materials/containers, sutures, and references substance used in national monographs.

GENERAL NOTICES:

The General Notices provide definitions for terms used in the monographs, as well as information that are necessary to interpret themonograph requirements.

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INDIAN PHARMACOPEIA (IP)

EVOLUTION, MONOGRAPHS AND GENERAL NOTICES:

As per the Drugs and Cosmetics Act 1940, the Indian Pharmacopeia is the legally recognized book of Standards for the quality of the drug substances and the preparations included therein for India.

FORMATION:

First official Pharmacopeia of India appeared in 1868 which was edited by Edward John Waring. In pre independence days, BritishPharmacopeia was used in India. The colonial addendum of BP 1898 was published in 1900 appeared as Government of Indiaedition in 1901.

In 1946 Government of India issued one list known as ‘The Indian Pharmacopeial list’. Committee under chairmanship of Sir R.N. Chopra alongwith other nine members prepared ‘The Indian Pharmacopeial list’. It was prepared by Dept. of Health, Govt. ofIndia, Delhi in 1946.

In 1948 Government of India appointed an Indian Pharmacopeia committee for preparing ‘Pharmacopeia of India’. Tenure of thiscommittee was five years. Indian Pharmacopeia committee under chairmanship of Dr. B. N. Ghosh published first edition of IP in1955.

VISION:

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To promote the highest standards of drugs for use in humans and animals within practical limits of the technologies available formanufacturing and analysis; to promote public health in India by bringing out authoritative and officially accepted standards forquality of drugs including APIs, excipients and dosage forms used by health professionals, patients.

OBJECTIVE:

To develop comprehensive monographs for drugs to be included in Indian Pharmacopoeia, including APIs, excipients,

pharmaceutical aids, dosage forms To develop monographs for herbal drugs included in the National Essential Drugs List and their dosage forms. Regular upgradation of monographs but consistent with the level and degree of sophistication acceptable to the majority of

manufacturers. Harmonization of IP standards with international acceptance criteria for drug quality.

Special efforts have been made to safeguard the interests of the weaker sectors of the industry without compromising the safetyand efficacy of the medicines included in the Indian Pharmacopoeia.

Edition YearChairmans

hipFeatures

(Monographs, General notices)

Supplement/

AddendumFeatures

1st Edition 1955Dr. B. N.

Ghosh

written in English & official titles of monographs given in Latin

covers 986 monographs

Supplement1960

-

2nd Edition 1966 Dr. B.Mukkerji

official titles of monographs given in English

doses were expressed in Metric system For Tablets and Injections “USUAL

STRENGTH” have been given. formulations of the drugs were given

immediately after the monograph of drugs 274 monographs from IP 55 & their

supplement were deleted. 93 new monographs were added.

Supplement1975

126 new monographs havebeen included & 250

monographs have beenamended.

Cholera vaccine has beendeleted

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3rd Edition 1985Dr. Nitya

Nand

published with two volumes & nine appendices

261 new monographs have been added. 450 monographs were deleted.

Addendum1989

46 new monographs added and126 amended

Addendum1991

62 new monographs added and110 amended

4th Edition 1996 Dr. Nityanand

made effective from 1st December 1996 covered 1149 monographs and 123

appendices includes 294 new monographs & 110

monographs have been deleted

Addendum2000

made effective from 31st

December 2000 42 new monographs have

been addedVet

Supplement2000

contains 208 monographs &four appendices

Addendum2002

made effective from 30th

June 2003 19 new monographs have

been addedAddendum

2005-

5th Edition 2007

Presented in 3 volumes: Volume I: general notices and general

chapters Volume II and III: general monographs on

drug substances, dosage forms, pharmaceutical aids

Addendum2008

-

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6th Edition 2010

effective from 1st September, 2010Presented in 3 volumes: Volume I: the Notices, Preface, the Structure

of the IPC, Acknowledgements, Introduction, and the General Chapters.

Volume II: the General Notice, General Monographs on Dosage Forms and Monographs on drug substances, dosage forms and pharmaceutical aids (A to M).

Volume III: Monographs on drug substances, dosage forms and pharmaceutical aids (N to Z).

Addendum2012

-

7th Edition 2014

Present in 4 volumes 2550 monographs of drugs out of which

577 are new monographs consisting of APIs, excipients, dosage forms and herbal products etc.

Addendum2015

-

Addendum2016

-

The IP 2010 6th Edition:

Monographs on Vaccines and Immunosera for Human use, Herbs and Herbal products, Blood and blood-related products,Biotechnology products and Veterinary product are included.

The number of monographs of Excipients, Anticancer drugs, Herbal products and antiretroviral drugs has been increased inthis edition.

Monographs of Vaccines and Immunosera are also upgraded in view of development of latest technology in the field. A new chapter on Liposomal products and a monograph of Liposomal Amphotericin B injection is an added advantage in

view of latest technology adopted for drug delivery.

The IP 2014, 7th Edition incorporates,

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A list of 577 New Monographs along with the 19 new General Chapters, not included in IP-2010 and its Addendum-2012.

313 New Monographs on drug substances, Dosage forms & Pharmaceutical aids (A to Z), 43 New Drugs Substances Monographs, 10 Antibiotic Monographs, 31 Herbal Monographs, 05 Vaccines & immunosera for human use, 06 Insulin Products, 07 Biotechnology Products

19 New Radiopharmaceutical Monographs & 1 General chapter is first time being included in this edition.

BRITISH PHARMACOPOEIA (BP)


British Pharmacopeia is an annual published collection of quality standards fro UK medicinal substances, by the British Pharmacopoeia Commission, a non-profit organization that owns the trademark and copyright.

FORMATION:

The inconvenience resulting from the existence of three different pharmacopoeias in the UK and Ireland was considerable, andwhen the Medical Act of 1858 established the General Council of Medical Education and Registration, it enjoined the Councilamong other things to publish a single Pharmacopoeia to supersede those of London, Edinburgh and Dublin. Immediately after itsconstitution, therefore, a committee of the Council was setup to take the necessary steps for the preparation of BritishPharmacopeia.

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First edition of BP was published in 1864. It was an attempt to harmonize pharmaceutical standards, through merger of threePharmacopoeias.

Since its first publication back in 1864, the distribution of BP has grown throughout the world. It is now used in over 100countries. Australia and Canada are two of the countries that have adopted the BP as their national standard alongside the UK.

MISSION AND PREFACE:

The BP contributes to the overall control of the quality of medicinal products by providing an authoritative statement of the qualitythat a product, material or article is expected to meet any time during its period of use.

1st Edition of BP, 1864, consists of two sections

Part I: Materia Medica Part II:- Preparation & compounds

2nd Edition of BP was published in 1867.

3rd Edition of BP was published in 1885.

4th Edition of BP was published in 1898 (with an Indian Edition in 1901)..

5th Edition of BP was published in 1914.


7th Edition of BP was published in 1948. Since 1948, revision of BP was every 5 years.


In this edition titles of drugs & preparations were in English instead of Latin and metric system.

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After 1973 BP was published in 1980 and 1988 with including extracts, galanicals and other drugs.

It is being published annually now.

In BP 2007,

Monographs have been introduced for material specifically used in preparation of Traditional Chinese medicines Term ‘Prolonged release’ has been replaced the term ‘Slow’ and the term ‘Gastro-resistant’ has been replaced with

‘Enteric coated’ in number of monographs

BP 2008

Contains approximately 3100 monographs for substances, preparations and articles used in practice Has been made effective from 1st January 2008

BP 2007 -2009 were given in Six Volumes i.e. Volume I to Volume VI.

Volume I – medicinal substances (Monographs A-I). Volume II – medicinal substances (Monographs A-I). Volume III – formulated preparations, blood related products, immunological products, radiopharmaceutical

preparations, surgical materials & homoeopathic preparations. Volume IV – supplementary chapters, IR spectra etc. Volume V – veterinary. Volume VI – CD ROM version.

BP 2010

Effective from 1st January 2010

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New: 40 monographs for formulated preparations, including veterinary medicines and additional standards for

widely used unlicensed formulations. All European Pharmacopoeia 6th edition material, up to and including Supplement 6.5, is integrated into the text of

the BP 2010. In addition to the expanding number of monographs for licensed formulated products, the BP supports the regulatory

work in the fields of herbal and complementary medicines by providing additional new and revised monographs forherbal medicinal products and for homeopathic stocks and mother tinctures.

The print edition comprises four volumes of the BP 2010 and a single volume of the BP (Veterinary) 2010.

The BP 2013 includes:

Six volume printed edition including the BP (Veterinary) 2013 New for 2013:

o 41 new BP monographso 40 new European Pharmacopoeia monographso 619 amended monographso 6 new and 1 amended Infrared Reference Spectra

BP 2014:

Effective from 1 January 2014 The 2014 edition includes almost 3500 monographs which are legally enforced by the Human Medicines Regulations

2012. Comprises five volumes of the BP 2014 and a single volume of the BP (Veterinary) 2014, along with a fully

searchable CD-ROM. New for 2014: 40 new BP monographs, 272 amended monographs 3 new Supplementary Chapters, 4 new BP (Vet)

monographs, 1 new BP (Vet) Supplementary Chapter

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The BP remains an essential reference for all individuals and organisations working within pharmaceutical research

and development, manufacture and testing around the globe.

UNITED STATES PHARMACOPOEIA (USP)


The United States Pharmacopeia (USP) is the official pharmacopeia of the United States, published annually with the NationalFormulary as the USP-NF.

The United States Pharmacopoeial Convention (Usually also called the USP) owns the trademark and copyright to the USP-NFand publishes it every 5 years.

All Prescription and over–the–counter medicines and other health care products manufactured or sold in the United States arestandardized to the USP-NF USP also sets recognized standards for food ingredients and dietary supplements. USP standards arerecognized and used in more than 130 countries.

FORMATION:

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First edition of United States Pharmacopeia was published on 15th December 1820 in both Latin & English. First NationalFormulary of the united state appeared in 1888 by APhA. In 1975 USP acquires National Formulary and Drug StandardsLaboratory from APhA. In 1977 USP and NF scope was redefined: USP specifies standards for drug substances and dosage forms;NF specifies standards for excipients. In 1980 USP and NF were published under same cover.

The USP-NF and its supplements will become official in six months after being released to public. The USP-NF, publishedannually since 2002, is released on November 1 of each year, and will become official on May 1 of the next year.

MISSION AND PREFACE:

The United States Pharmacopoeia promotes the public health and benefits practitioners and patients by disseminating authoritative standards and information developed by its volunteers for medicines, other health care technologies, and related practices used to maintain and improve health and promote optimal health care delivery working with many constituencies and stakeholders around the world

2nd Edition was published in 1830.

From 1820 to 1942, it was published at 10 years intervals.

From 1942 to 2000, it was published at 5 years intervals.

From 2002, it was published annually.

USP21-NF16

It has eight supplements. First appeared in January 1985 & last in November 1988.

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USP22-NF17 1990 is the third revision that consolidates USP & NF into a single volume.

Electronic version of USP-NF on floppy disks was introduced in 1992.

USP23-NF18 was published in Mumbai as an Asian edition at the end of 1994.

USP23 has ten supplements. First supplement was published in January 1995 & Last in May 1999.

USP24-NF19 appeared from first January 2000.

USP25-NF20 appeared in 2002, since when it has been published annually.

USP26-NF21 (2003), USP27-NF22 (2004), USP28-NF23 (2005), USP29-NF24 (2006) were published.

USP30-NF25 appeared from May 2007. USP published USP-NF as 3 volume set.

It contains scientific standards for drugs, dietary substances, biological products & excipients used in dosage forms. It contains 4,100 monographs and 200 general chapters. It has been printed in three volume set.

o Volume I contains general chapters, general notices, dietary supplement chapters, reagent reference tables,

dietary supplement monographs, monographs for drug substances and preparationso Volume II contains monographs A to L.o Volume III contains monographs M to Z.

First supplement to USP30-NF25, appeared from August 2007 & second supplement from November 2007 which

will be considered official from May 2008.

From 2006, Spanish edition of USP is also being published.

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USP - NF CONTENT

USP31-NF26Monographs for drug substances and preparations (in the USP), monographs for dietary supplements

and ingredients (separate section of the USP), excipient monographs (in the NF).

USP32-NF27 More than 4200 monographs, over 200 general chapters covering general tests and assays



USP35-NF30 Applicable from 1 May 2012 to 30 April 2013

COMPARATIVE PICTURE: EXCIPIENT (Magnesium Stearate)

Property IP BP USP

Formula Mg [C18 H35 O2]2 Mg [C18 H35 O2]2 Mg [C18 H35 O2]2

Definition

Magnesium Stearate consists mainly ofmagnesium stearate with variableproportions of magnesium palmitate,and magnesium oleate.

Magnesium stearate is a mixture ofmagnesium salts of different fattyacids consisting mainly of stearic(octadecanoic) acid[(C17H35COO)2Mg] and palmitic(hexadecanoic) acid[(C15H31COO)2 Mg] with minorproportions of other fatty acids.

Magnesium Stearate is a compoundof magnesium with a mixture ofsolid organic acids, and consistschiefly of variable proportions ofmagnesium stearate and magnesiumpalmitate. The fatty acids are derivedfrom edible sources.

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Content

Magnesium Stearate contains not lessthan 3.8 per cent and not more than 5.0per cent of Mg. calculate on the driedbeds. The fatty acid fraction containsnot less than 40.0 per mat of stearicacid and the sum of stearic acid andpalmitic acid is not less than 90.0 percent.

It contains not less than 4.0 per centand not more than 5.0 per cent ofMg, calculated with reference to thedried substance. The fatty acid fraction contains notless than 40.0 per cent of stearic acidand the sum of stearic acid andpalmitic acid is not less than 90.0per cent.

It contains not less than 4.0 percentand not more than 5.0 percent ofMg, calculated on the dried basis.

Description/Characters

A very fine, light, white powder;odorless with a very faint odour ofstearic acid; unctuous and free fromgrittiness.

Appearance: A white or almostwhite, very fine, light powder,greasy to the touchSolubility: practically insoluble inwater and anhydrous ethanol.

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

Identification To 5.0 g add 50 ml of peroxide-free ether, 20 ml of dilute nitric acid and 20 ml of water and heat under reflux condenser until dissolution is complete.Allow to cool. In a separating funnel, separate the aqueous layer and shake the ether layer with 2 quantities, each of 4 ml, of water. Combine the aqueouslayers, wash with 15 ml of peroxide-free ether and dilute to 50 ml with water (solution A). Evaporate the organic layer to dryness and dry the residue at 105°. A. The residue obtained in the

preparation of solution A has a freezing point not less than 53°.

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

A. The residue obtained in the preparation of solution S (see Tests) has a freezing point not less than 53⁰C.

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

A. Mix 5.0 g Magnesium stearate with 50 mL of peroxide-free ether, 20 mL of diluted nitric acid, and 20 mL of water in a round-bottom flask. Connect the flask to a reflux condenser, and reflux until dissolution is complete. Cool, transfer the contents to a separator. Shake, allow the layers to separate, and transfer the aqueous layer to a flask. Extract the ether layer withtwo 4-mL portions of water; add these aqueous extracts to the main aqueous extract. Wash the aqueous extract with 15 mL of

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B. The acid value of the fatty acids is 195 to 210, determined on 0.2g of residue obtained in the preparation of solution A, dissolved in 25 ml prescribed mixture of solvents.

C. In the test for fatty acid composition, the principal peak in the chromatogram obtained with the test solution corresponds to the peak in the chromatogram obtained with the reference solution.

D. 1 ml of solution A gives the reaction of magnesium.

of the principal peaks in the chromatogram obtained with the test solution are approximately the same as those of the principalpeaks in the chromatogram obtained with the reference solution.

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

peroxide-free ether, transfer to a 50-mL volumetric flask, dilute with water to volume, mix. Retain solution for the Limit of chloride sulfate tests. This solution responds to the test for Magnesium.

B. The retention time of the peaks corresponding to stearic and palmitic acid in the chromatogram of the test solution correspond to those in the chromatogram of the system suitability solution, as obtained in the relative content of stearic, palmitic acid test.

Tests Appearance of solution: solution A isnot more intensely colored thanreference solution YS6.

Appearance of solution of fatty acid:Dissolve 0.5 g of the residue obtainedin the preparation of solution A in 10ml of chloroform. The solution is clearand not more intensely colored thanreference solution YS5.

Acidity or alkalinity: Mix 1.0 g with20 ml of carbon dioxide free water, boilfor 1 minute, shaking continuously,cool and filter. To 10 ml of filtrate add0.05 ml of bromothymol blue solution.Not more than 0.05 ml of 0.1M HCl or

Solution S- To 5.0 g Magnesiumstearate add 50 ml of peroxide-freeether, 20 ml of dilute nitric acid and20 ml of distilled water and heatunder a reflux until dissolution iscomplete. Allow to cool. In aseparating funnel, separate theaqueous layer and shake the etherlayer with 2 quantities, each of 4 ml,of distilled water. Combine theaqueous layers, wash with 15 ml ofperoxide-free ether and dilute to 50ml with distilled water R (solutionS). Evaporate the organic layer todryness and dry the residue at 100-105°C. Keep the residue foridentification tests A and B.

Acidity or alkalinity: Transfer 1.0g Magnesium stearate to a 100-mLbeaker, add 20 mL of carbondioxide-free water, boil on a steambath for 1 minute with continuousshaking, cool, and filter. Add 0.05mL of bromo thymol blue TS to 10mL of the filtrate: not more than 0.05mL of 0.1 N hydrochloric acid or 0.1N sodium hydroxide is required tochange the color of the indicator.

Loss on drying: Dry it at 105 toconstant weight: it loses not morethan 6.0% of its weight.

Limit of chloride: A 10.0-mL

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0.1M NaOH is required to change thecolour of solution.

Acid value of the fatty acids: 195 to210, determined on 0.2g of the residueobtained in the preparation of solutionA dissolved in 25 ml of the prescribedmixture of solvents.

Chlorides: 10.0 ml of solution Adiluted to 15 ml complies with the limittest for chlorides (250 ppm). Sulphate: dilute 5.0 ml of solution Ato 50.0 ml with water. 2.5 ml of thissolution diluted to 15 ml with watercomplies with the limit test for sulphate(0.6 per cent)

Zinc stearate: Heat 5.0 g with shakingin a mixture of 50 ml of water and 50ml of dilute sulphuric acid until thefatty acids separate as an oily layer.Cool, filter the aqueous layer and washthe residue with two successivequantities, each of 5 ml, of hot water,combine the filtrate and the washingsand dilute to 100 ml with water. To 5ml of the resulting solution add 0.5 mlof ammonium mercury thiocyanatesolution and 0.05 ml of copper sulphatesolution. Scratch the walls of containerwith glass rod and allow standing for15 minutes, no violet ppt is formed.

Acidity or alkalinity- To 1.0 gMagnesium stearate add 20 ml ofcarbon dioxide-free water R and boilfor 1 min with continuous stirring.Cool and filter. To 10 ml of thefiltrate add 0.05 ml of bromothymolblue solution. Not more than 0.5 mlof 0.01 M hydrochloric acid or 0.01M sodium hydroxide is required tochange the color of the indicator.

Chlorides- 0.5 ml of solution Sdiluted to 15 ml with water Rcomplies with the limit test forchlorides (0.1 per cent).Sulphates: 0.3 ml of solution Sdiluted to 15 ml with distilled watercomplies with the limit test forsulphates (0.5 per cent).

Cadmium: Not more than 3.0 ppmof Cd, determined by atomicabsorption spectrometry.

Nickel- Not more than 5.0 ppm ofNi, determined by atomicabsorption.

Lead - Not more than 10.0 ppm ofPb, determined by atomic absorptionspectrometry

portion of the aqueous solutionobtained in Identification test Ashows no more chloride thancorresponds to 1.4 mL of 0.020 Nhydrochloric acid (0.1%)

Limit of sulfate: A 3.0 mL portionof the aqueous solution obtained inIdentification test A shows no moresulfate than corresponds to 3.0 mLof 0.020 N sulfuric acid (1.0%).

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Loss on drying (2.4.19): not more than6.0 percent, determined on 1.0 g bydrying in an oven at 105°.

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

Assay ofMagnesium

Weigh 0.75 g, add 50 ml of a mixture of equal volumes of l-butanol and ethanol. 5 ml of strong ammonia solution, 3 ml of ammonia buffer pH 10.0, 30.0 ml of 0.1 M disodium edetate and 15 mg of mordant black II mixture, heat to 45° to 50° and titrate with 0.1M zinc sulphate until the color changes from blue to violet.

Repeat the operation without the substance under examination. The difference between the titrations represents the amount of disodium edetate required.

1 ml of 0.1 M disodium edetate is equivalent to 0.002431 g of Mg.

To 0.500 gm in a 250 mL conical flask, add 50 mL of a mixture of equal volumes of anhydrous ethanol R and butanol R, 5 mL concentrated ammoia R, 3 mL ammonium chloride buffer solution pH 10.0 R, 30.0 mL of 0.1M sodium edentate and 15 mg of mordant black II triturate R.

Heat at 45-50⁰C until the solution is clear and titrate with 0.1 zinc sulphate until the colour changes from blue to violet. Carry out a blank titration.

1 mL of sodium edentate is equivalent to 2.431 mg of Mg.

Ammonium chloride pH 10 buffer solution: Dissolve 5.4 g of ammonium chloride in water, add 21mL of ammonium hydroxide, and dilute with water to 100 mL.

Analysis: Transfer about 500 mg of Magnesium Stearate, accurately weighed, to a 250 mL conical flask. Add 50 mL of a mixture of butyl

alcohol and dehydrated alcohol (1:1), 5 mL of ammonium hydroxide, 3 mL of Buffer, 30.0 mL of 0.1 M edetate disodium VS, and 1or 2 drops of Eriochrome black TS.

Heat at 45 –50 until the solution is clear. Cool, and titrate the excess edetate disodium with 0.1 M zinc sulfate VS until the solution color changes from blue to violet. Performa blank determination, and make anynecessary correction. Each mL of 0.1 M edetate disodium is equivalent to 2.431 mg of Mg.

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Content ofStearic and

Palmitic acid(fatty acids)

Determined by gas chromatographyDetermined by gaschromatography

The stearate peak comprises not less than 40% and the sum of the stearate and palmitate paks is not less than 90% of the total area of all fatty acid esters in the chromatogram

AdditionalCategory: Pharmaceutical aid

(lubricant). Action and use: ExcipientPackaging and storage: Preserve in

tight containers

COMPARATIVE PICTURE: DRUG / API (Paracetamol)

Property IP BP USP

Mol. Formula C8H9NO2 C8H9NO2 C8H9NO2

Sructure

Mol. Weight 151.2 151.2 151.16

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Actions/Uses Pain reliever, fever reducer Analgesic and antipyretic ______

Definition

Paracetamol is 4-hydroxyacetanilide.Paracetamol contains not less than 99.0

% and not more than 101.0% ofC8H9NO2, calculated on the dried basis.

Paracetamol contains not less than99.0 % and not more than theequivalent of 101.0% of N-(4-

hydroxyphenyl) acetamide,calculated with reference to the

dried substance.

It contains not less than 98.0% andnot more than 101.0% of C8H9NO2,calculated on the anhydrous basis. Itis Acetamide, N-(4-hydroxyphenyl)-

4’-Hydroxyacetanilide.

Description/Characters

White crystals or a white crystallinepowder.

A white, crystalline powder,sparingly soluble in water, freelysoluble in alcohol, very slightly

soluble in ether and in methylenechloride.

------

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Identification

Melting point: 169°C (336°F).

Test A may be omitted if B, C and D are carried out.Test B, C and D may be omitted if A is carried out.

A. By infrared absorption spectrophotometery. Compare the spectrum with that obtained with paracetamol RS or with the reference spectrum of paracetamol

B. Dissolve 50 mg in sufficient methanol to produce 100 ml. To 1ml of this solution add 0.5ml of 0.1M hydrochloric acid & dilute to 100ml with methanol. Protect the resulting solution from bright light and immediately measure the absorbance at the maximum about 249nm, about 0.44.

C. Boil 0.1g in 1ml of hydrochloric acid for 3 min, add 10 ml of water & cool. No precipitate is produced. Add 0.05ml of 0.0167 M potassiumdichromate, a violent colour develops which does not turn red.

D. Gives the reaction of acetyl groups.

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

A. M.P: 168⁰ - 172⁰CB. Examine by infrared absorption

spectrophotometery, comparing with the spectrum obtained with Paracetamol CRS

C. Dissolve 50 mg in methanol R and dilute to 100 ml with the same solvent. To 1ml of methanol solution add 0.5ml of 0.1M hydrochloric acid & dilute to 100ml with methanol. Protect the resulting solution from brightlight and immediately measure the absorbance at the maximum about 249nm. The specific absorbance at the maximum is 860 to 980.

D. To 0.1g add 1ml of hydrochloric acid R, heat to boiling for 3 min, add 10 ml of H2O & cool. No precipitate is produced. Add 0.05ml of 0.0167 M potassium dichromate, a violent colour develops which does not change to red.

E. It gives the reaction of acetyl. Heat over a naked flame.

A. Infrared Absorption <197K>. B. Ultraviolet Absorption <197U>

Solution: 5 μ g per mL. Medium: 0.l N hydrochloric acid in methanol (1 in 100).

C. It responds to the Thin-layer Chromatographic Identification Test <201>, a test solution in methanol containing about 1 mg per mL and a solvent system consisting of a mixture of methylene chloride and methanol(4:1) being used.

D. Melting range: between 168° and172⁰C

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Tests4-aminophenol: Dissolve 0.5g insufficient methanol (50%) to produce10ml. Add 0.2ml of freshly preparedalkaline sodium nitroprusside solution,mix and allow standing 30 min. Anyblue color in the solution is not moreintense than that in 10ml of solutionprepared at the same time containing0.5g of 4-aminophenol-freeparacetamol and 0.5ml of a 0.005%w/vsolution of 4-aminophenol in methanol(50%) (50ppm).

Related substances: Determine by thinlayer chromatography, coating the platewith silica gel.

Mobile phase: A mixture of 65volumes of chloroform, 25 volumes ofacetone and 10 volumes of toulene.

Test solution (a): Transfer 1g ofsubstance under examination, finelypowdered to a ground glass stoppered15ml centrifuge tube, add 5ml ofperoxide free ether, shake mechanicallyfor 30min and centrifuge at 1000rpmfor 15min or until a clear supernatantliquid is obtained.

Test solution(b): Dilute 1ml of the testsolution to 1ml with ethanol.(95%)

Related substances: Determine bythin layer chromatography, usingsilica gel HF254 R as coatingsubstance.

Test solution (a): Transfer 1.0g ofthe finely powdered substance to beexamined to a stoppered 15ml glassor polytetrafluoroethylene centrifugetube, add 0.5ml of peroxide freeether R, shake by mechanical meansfor 30 min and centrifuge for 15 minor until a clear supernatant liquid isobtained.

Test solution (b): Dissolve 0.10g ofthe substance to be examined inmethanol R and dilute to 4.0ml withthe same solvent.

Reference solution (a): Dissolve50mg of choloacetanilide R inmethanol R and dilute to 10.0mlwith same solvent. Dilute 2ml of thissolution to 100ml with methanol R.

Reference solution (b): Dilute 5.0mlof reference solution (a) to 8.0mlwith methanol R.

Reference solution (c): Dissolve0.25g of chloroacetanilide R and 0.1g of substance to be examined inmethanol R and dilute to 100ml withsame solvent.

Free p-aminophenol: Transfer 5.0 gto a 100-mL volumetric flask, and dissolve in about 75 mL of a mixtureof equal volumes of methanol and water. Add 5.0 mL of alkaline nitroferricyanide solution, dilute with a mixture of equal volumes of methanol and water to volume, mix, and allow standing for 30 minutes. Concomitantly determine the absorbance of this solution and of a freshly prepared solution of p-aminophenol prepared at a conc.of 2.5 μg per mL using the same quantities of the same reagents, in l-cm cells, at the maximum at about 710 nm with a suitable spectrophotometer using 5.0 mL of alkaline nitroferricyanide solution diluted with a mixture of equal volumes of methanol and water to 100 mL as the blank: the absorbance of the test solution does not exceed that of the standard solution corresponding to not more than 0.005% of p-aminophenol.

Limit of p-chloroacetanilide: Transfer 1.0 g to 15 ml centrifuge tube, add 5.0 mL of ether, shake by mechanical means for 30 minutes and centrifuge at 1000 rpm for 15

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Reference solution (a): A 0.005% w/vsolution of 4-chloroacetanilide inethanol (95%).

Reference solution (b): Dissolve 0.25gof 4-chloroacetanilide and 0.1g of thesubstance under examination insufficient ethanol (95%) to produce100ml.

Apply to the plate 200μl of test solution(a) and 40μl of each of the test solution(b) and reference solutions (a) & (b).After development, dry the plate incurrent of warm air and examine inultraviolet light at 254nm. Any spotcorresponding to 4-chloroacetanilide inchromatogram obtained with the testsolution (a) is not more intense than thespot in the chromatogram obtainedwith reference solution (a). Any othersecondary spot in the chromatogramobtained with test solution (b) is notmore intense than the spot in thechromatogram obtained with thereference solution (a). Thechromatogram obtained with referencesolution (b) shows two clearlyseparated spots, the spot correspondingto Paracetamol having the lower Rfvalue.

Apply separately to the plate 200μlof test solution (a), 20μl of referencesolution (a) 20μl of test solution (b),20μl of reference solution (b) and20μl of reference solution (c).Develop immediately in anunsaturated tank, over a path of10cm using a mixture of 10 volumesof methanol R, 40 volumes of 1,1,1-trichloroethane R and 50 volumes ofdi-isopropyl ether R. Allow the plateto dry in air and examine inultraviolet light at 254nm. Any spotcorresponding to chloroacetanilidein the chromatogram obtained withthe test solution (a) is not moreintense than the spot in thechromatogram obtained withreference solution (a) (0.005%). Anyspot in the chromatogram obtainedwith the test solution (b), apart fromthe principle spot and any spotcorresponding to chloroacetanilide isnot more intense than the spot in thechromatogram obtained withreference solution (b) (0.25%). Thetest is not valid unless thechromatogram obtained withreference solution (c) shows twoclearly separated spots.

mins or until a clean separation is obtained. Apply 200 μl of the supernatant liquid. In 40- μl portions to obtain a single spot not more than to mm m diameter to a suitable thin layer chromatographic plate coated with a 0 25-mm layer ofchromatographic silica gel mixture. Similarly apply 40 μl of a standard solution in ether containing l0 μg of p-chloroacetanilide per mL and allow the spots to dry. Develop the chromatogram in unsaturated chamber with a solvent system consisting of a mixture of solvent hexane and acetone (75:25, until the solvent front has moved three-fourths of the length of the plate. Remove the plate from the developing chamber, mark the solvent front and allow the solvent toevaporate. Locate the spots in the chromatogram by examination undershort-wavelength ultraviolet light: any spot obtained from the solution under test, at an Rf value corresponding to the principal spot from the Standard solution is not greater in size or intensity than the principal spot obtained from the Standard solution corresponding to not more than 0.001% of p-chloroacetanilide.

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Heavy metals: 2.0g complies with thelimit test for heavy metals, Method B(10ppm).

Sulphated Ash: not more than 0.1%.

Loss on drying: not more than 0.5%,determined on 1.0g by drying in anoven at 105°.

4-aminophenol Dissolve 0.50g in amixture of equal volumes ofmethanol R and water R and diluteto 10.0ml with same mixture ofsolvents. Add 0.2ml of freshlyprepared solution containing 10g/l ofsodium carbonate R, mix and allowto stand for 30min. Prepare astandard at the same time using 10.0ml of the mixture of methanol R,water R and 0.5ml of 0.05h/ksolution of 4-aminophenol R in amixture of equal volumes ofmethanol R and water. Any bluecolour in test solution is not moreintense than that in a standard(50ppm).

Heavy metals: Dissolve 1.0g inmixture of 15 vol. of water R and 85vol. of acetone R, dilute to 20ml.12ml of solution complies with limittest B for heavy metals (20ppm).Prepare the standard using leadstandard solution (1ppm pb)

Loss on drying: Not more than0.5%, determined on 1.000g bydrying in an oven at 100°c to 105°c.

Sulphated Ash: not more than 0.1%determined on 1.0g.

Water, Method I <921>: not more than 0.5%.

Residue an ignition <281>: not more than 0.1%.

Chloride: No more chloride than corresponds to 0.20 mL of 0.020 N hydrochloric acid (0.014%).

Sulfate: No more sulfate than corresponds to 0.20 mL of 0.020 N sulfuric acid (0.02%).

Sulfide: Place about 2.5 g in a 50-mL beaker. Add 5 mL of alcohol andl mL of 3 N HCl. Moisten a piece of lead acetate test paper with water, fixto the underside of a watch glass. Cover the beaker with the watch glass so that part of the lead acetate paper hangs down near the pouring spout of the baker Heat the contents, no coloration or spotting of the test paper occurs.

Heavy metals, Method II (231): 0.001%.

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Assay

Weigh accurately about 0.5g dissolve in mixture of 10ml water and 50ml of 1M sulfuric acid. Boil under reflux condenser for 1hr, cool and dilute to 100.0ml with water. To 20.0ml of the solution, add 40ml of water, 40g of water in form of ice, 15ml of 2M HCl and 0.1 ml of ferroin solution. Titrate with 0.1M ceric ammonium sulphate until a yellow color is obtained. Carry out a blank titration.

1ml of 0.1M ceric ammonium sulphate is equivalent to 0.00756 g of C8H9NO2

Dissolve 0.300g in a mixture of10ml of water R and 30ml of dil.sulfuric acid. Boil under refluxcondenser for 1hr, cool and dilute to100.0 ml with water R. To 20.0 mlof the solution, add 40ml of water R,40g of ice, 15ml of Dil. HCl acid Rand 0.1 ml of ferroin R. Titrate with0.1M ammonium and ceriumsulphate until a yellow color isobtained. Carry out a blank titration.

1ml of 0.1M ammonium and ceriumsulphate is equivalent to 7.56mg ofC8H9NO2

Dissolve about 120 mg of acetaminophen, accurately weighed, in 10 mL of methanol in a 500-mL volumetric flask, dilute with water tovolume, and mix. Transfer 5.0 mL ofthis solution to a 100-mL volumetricflask, dilute with water to volume, and mix. Concomitantly determine the absorbance of this solution and of a Standard solution of USP Acetaminophen RS, in the same medium at a concentration of about 12 μg per mL in l-cm cells, at the wavelength of maximum absorbanceat about 244 nm, with a suitable spectrophotometer, using water as the blank. Calculate the quantity in mg of C8H9NO2 in the Acetaminophen taken by the formula: 10C(AU/AS)

C is the concentration (μg per mL of USP Acetaminophen RS in the Standard solution), and AU and AS are the absorbances of the solution of Acetaminophen and the Standard solution respectively.

StorageStore protected from light and

moisture.Store in a well closed container,

protected from light.Preserve in tight, light-resistant

containers

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Reference:

Indian Pharmacopoeia 2014, 7th Edition, Volume II. Page no: British Pharmacopoeia 2013, Volume II. Page no: The Official Compendia of Standards, USP 24-NF 19, U.S.Pharmacopoeia and National Formulary, Asian Edition.

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