European Pharmacopoeia Volume 2 Pdf

[Coleman John]

TheEuropean Pharmacopoeia (Ph.Eur) is a pharmacopoeia published by the European Directorate for the Quality of Medicines and Healthcare (EDQM) under the auspices of the Council of Europe and all the signatory states to Treaty Number 050. The Ph.Eur is the de facto official pharmacopoeia of the European Union.

Through its monographs and general chapters, the Ph.Eur fosters public health by elaborating and communicating scientifically-valid standards required for assessing and controlling quality of medicines and excipients.

The European Pharmacopoeial Commission is the decision-making body at the EQQM responsible elaboration and maintenance of the Ph.Eur content, including revision and updates of different monographs and general chapters.

The Ph.Eur traces its origins to 1963, when the Public Health Committee of the Council of Europe adopted a draft Convention that lay the legal, technical and administrative foundations of the Ph.Eur. The following year, the Committee of Ministers adopted the Convention and the Rules of Procedure that would govern the European Pharmacopoeia Commission.

Between 1965 and 1966, a Technical Secretariat was expanded and a Commission appointed. Three years later, the first edition of the Ph.Eur was published, and contained just over 100 monographs. Six years later in 1975, the European Union adopted Council Directive 75/318/EEC, which made compliance with Ph.Eur monographs mandatory when applying marketing authorisations.

Now in its 10th edition, the Ph.Eur as well as the Convention has 39 signatory parties from across Europe, including the European Union, that participate and vote on sessions of the European Pharmacopoeia Commission.

All these standards are designed to meet the information needs of scientists and managers involved in research and quality control of medicines, regulatory authorities and those involved in the manufacture of medicinal products or individual components.

The Ph.Eur is available as a single reference volume that covers all relevant articles featured. The 10th Edition was released in July 2019 and will be updated with eight periodic supplements over the following three years (10.1 to 10.8).

Available in either English or French, the print version contains a subscription key (EPID code) that allows access to online archives. The compendium can also be accessed online via a licence (individual or shared access).

The European Pharmacopoeia is a listing of a wide range of active substances and excipients used to prepare pharmaceutical products in Europe. The 2005 edition includes 1800 specific and general monographs, including various chemical substances, antibiotics, biological substances; Vaccines for human or veterinary use; Immunosera; Radiopharmaceutical preparations; Herbal drugs; Homoeopathic preparations and homoeopathic stocks. It also contains Dosage forms, General monographs, Materials and Containers, Sutures; 268 General methods with figures or chromatograms and 2210 reagents are described.The monographs give quality standards for all the main medicines used in Europe. All medicines sold in the 36 Member States of the European Pharmacopoeia must comply with these quality standards so that consumers have a guarantee for products obtained from pharmacies and other legal suppliers.

The European Pharmacopoeia is developed by the European Directorate for the Quality of Medicines (EDQM) and is a part of the Council of Europe, Strasbourg, France. It bases on the Convention on the elaboration of a European Pharmacopoeia from 1964. [1]

In these countries and European Union the Ph. Eur. is the official pharmacopoeia. Additional local pharmacopoeias may exist (e. g. in United Kingdom and Germany). Not all of these countries are member states of the European Union.

Since 5th edition the pharmacopoeia is published in 2 volumes. Volume 1 contains general chapters and monographs (e .g on dosage forms, methods of analysis, reagents), volume 2 contains all substance monographs. During runtime of current edition several supplements are published. Electronic versions are also available (CD-ROM and online version).

This paper describes a chemical method for the recovery and separation of narcotine and papaverine on an industrial scale from a crude mixture of these alkaloids as well as their individual purification to meet pharma copoeial standards. A process for the removal of traces of cryptopine from papaverine using aluminium oxide is also discussed.

Narcotine is the second most abundant alkaloid in opium[1] [2] [3] [4] . Opium from Madhya Pradesh, India, contains, on average, 7 per cent narcotine [5] . Narcotine is a non-narcotic and non-toxic alkaloid with no ill effects on blood pressure and respiration. It is used as an antitussive drug, particularly in wet cough, and is included in the British pharmacopoeia (BP), British Pharmaceutical Codex (B.P.C.) and Japanese Pharmacopoeia (J.P.) under the name of noscapine[6] [7] [8] [9] [10] [11] [12] . Cotarnine chloride B.P.C. 1934, State Pharmacopoeia of the Union of Soviet Socialist Republics (USSph), a styptic, and tritoqualine, an antihistamine, are synthetically prepared from narcotine[13] [14] [15] . Narcotine has no analgesic action and does not induce sleep or produce constipation. It is further used in the treatment of bronchial asthma and pulmonary emphysema. Noscapine B.P. and noscapine hydrochloride, United States National Formulary (U.S.N.F. XII) and J.P. are administered in the form of lozenges, linctus, syrup, tablets and resin-bound products.

Papaverine and papaverine hydrochloride and sulphate are described in the pharmacopoeiae of many countries. Papaverine occurs in opium collected in Madhya Pradesh, India [16] . Papaverine is a smooth-muscle relaxant. It is used as an antispasmodic in the treatment of intestinal, ureteric and biliary colic and of dysmenorrhoea. Being also a vasodilator, it is used to relieve pain in coronary and cerebral thrombosis; as a bronchodilator spray to relieve asthma and for the prevention of post-operative pulmonary collapse. Papaverine and narcotine hydrochloride are required in the production of Papaveretum B.P.C. [17] (pantopon and omnopon), which is used to relieve severe or prolonged labour pain. Papaverine from natural sources is supplemented by synthetic papaverine[18] [19] . India requires 1,350 kg per year of this alkaloid for medical purposes. The entire amount is presently imported.

In the Government Opium and Alkaloid Works, Neemuch, India, where opium collected from Madhya Pradesh (Malwa Opium) is used for the production of opium alkaloids, narcotine and papaverine are extracted as a crude mixture from the opium broth. No processes were available in the factory for the separation of narcotine and papaverine from this crude mixture or for their individual purification to meet pharmacopoeial specifications.

The purpose of the work described in this paper was to develop these processes. The literature mentions that narcotine is soluble in hot alkali [1] . Therefore, using a sodium hydroxide solution, the optimum conditions required for the formation of sodium narcotinate were investigated. The parameters of the reaction were studied in the laboratory and scaled up in the plant for industrial production of narcotine B.P.

papaverine, insoluble in alkaline solution, was filtered off and purified first as the oxalate. Technical grade papaverine of natural origin can contain up to 4 per cent of cryptopine [20] , which when present even at a 0.2 per cent level gives a purple colour with cold sulphuric acid [21] . The literature on opium alkaloids mentions the use of aluminium oxide [22-26]. Details of the experiments carried out in this study in order to remove traces of cryptopine in papaverine, using aluminium oxide, are described below.

The organic solution obtained from the opium broth and containing narcotine and papaverine together with other weakly basic alkaloids was stirred three times with 5% sulphuric acid. The combined acid extracts were made alkaline to pH 10 with 50% sodium hydroxide, under agitation, when the crude mixture of narcotine and papaverine precipitated out. The precipitate was filtered, washed with water and dried, to yield a brown crystalline product melting in the range 147- 169C. An amount of 220 kg of opium at vat consistency yielded, on average, 13 kg of the dry crude mixture of narcotine and papaverine.

The narcotine and papaverine content in the crude alkaloid mixture was estimated following the method given for Papaveretum B.P.C. [17] . The narcotine percentage was also determined by another published method [5, 30]. The results are reported in table I.

An amount of 200 g of the crude narcotine and papaverine mixture was dissolved in hot toluene, decolourized over activated carbon and filtered. The volume of the filtrate was reduced to one third by distillation and the alkaloids were allowed to crystallize. They were then filtered, washed with cold toluene and dried, yielding 170 g of an off-white crystalline product melting between 162 and 169C.

Using the same procedure on an industrial scale, 50 kg of the dry crude narcotine and papaverine mixture yielded, upon crystallization from toluene, 35 kg of technical grade off-white crystalline material. The content of the two alkaloids in the mixture thus obtained are indicated in table 2.

The separation of narcotine from papaverine in the technical grade mixture of the two alkaloids was extensively investigated. However, on the basis of the results obtained with many of the methods studied, they could not be recommended for industrial application.

The use of sodium hydroxide for the separation of narcotine from papaverine was therefore thoroughly investigated. In a series of experiments, such parameters as the strength of the aqueous sodium hydroxide solution, the temperature at which it was to be heated with the alkaloid mixture, the heating time required to make the narcotine go into solution, and the degree of dilution of the reaction mixture with water were studied. Also investigated were the optimum conditions for the opening and closing of the lactone ring and precipitation of narcotine using sodium hydroxide or ammonium salt. The aqueous sodium hydroxide solutions used were at concentrations of 50, 40, 30, 20 and 15 g per 100 ml and the temperatures studied were 95, 90, 85, 80 and 75C. Heating of the mixed alkaline-alkaloid solution was carried out for 2, 1.5, 1 and 0.5 h. In addition, consideration was given to the simplicity of the process and economy in respect of use of chemicals and energy. Thus the optimum conditions required for the recovery of the two alkaloids in high yield were arrived at in the laboratory experiment described below.

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