technical_guide_for_the_elaboration_of_monographs_7th_edition_20151

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Some chemical substances, particularly those obtained from raw materials of natural origin and substances produced by fermentation may not be easily separated from certain related substances (for instance, quinine salts). These may be treated as:

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a chemical product when obtained in a very pure state and when they can be assayed by a physico-chemical method;

a substance accompanied by a certain proportion of related substances, giving an exact definition of the main component only (e.g. neomycin);

a mixture of several components, sometimes difficult to define, where an overall description may suffice (e.g. nystatin).

Where applicable, the origin of the substance must be specified (name and strain of the organism from which the substance is derived). Where applicable, the monograph indicates that the substance is semi-synthetic and derived from a fermentation product [to clarify application of the general monograph Substances for pharmaceutical use (2034)].

II.2.1. Combinations

In therapeutics, more or less well-defined chemical combinations (for instance, theophylline- ethylenediamine) or even mixtures are sometimes used. In such cases, it is necessary to specify precisely each component of the combination or mixture, with its chemical structure and the proportion in which it is present.

II.2.2. Content

The substance described by a monograph is never a wholly pure substance but contains a limited proportion of impurities. The content is therefore an important part of the definition. Assay limits are specified between which the content must fall.

In setting these limits for the active substance content, account is taken of:

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the method of preparation, which determines the degree of purity that may be reasonably required;

the reproducibility and accuracy of the analytical method; current batch data of about 10 production batches at release; the evaluation of batch stability data;

a sufficient number of experimental results obtained on several batches (at least 3), if possible, of different origins and ages.

For a non-specific assay by titrimetry the limits are set according to the table provided in part III.3.7 i.e. usually 99.0-101.0 %. Some monographs still include an assay by UV-Vis spectrophotometry usually bearing wider limits.

For a specific assay using a separation technique (for example, liquid or gas chromatography), the upper assay limit is normally 102.0 %; the lower assay limit will take any necessary account of the impurities present based on the available batch data and approved specifications. It may therefore be lower than 98.0 %.

When the substance to be examined contains only impurities that do not interfere with the

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assay, or when it contains only a very low proportion of impurities interfering with the assay, the results of the assay can be used directly. It will then be stated that: “[the substance] contains not less than x per cent and not more than the equivalent of y per cent (at least 100.5 %, but often a little more) of [chemical definition of the pure product]”. The content of the substance is usually expressed with reference to the anhydrous or dried substance. According to the general monograph Substances for pharmaceutical use (2034) the content of residual solvent is taken into account for calculation of the assay content of the substance, therefore no reference in the DEFINITION section of the individual monograph is made.

In cases where the water content is high (e.g. in the case of disodium phosphate dodecahydrate), limits of content may be expressed with reference to the hydrate form of the substance, taking into account the molecular mass of the hydrate form (only for well-defined hydrates) or with reference to the substance on the anhydrous/dried basis in combination with determination of water content/loss on drying.

When the substance to be examined contains a relatively large proportion (a few %) of impurities, which are determined at the same time as the active ingredient, an appropriate wording is to be used (for instance, in the case of quinine salts: “x per cent of total alkaloid salts, expressed as quinine salts”).

Exceptionally reference is made to only a part of the molecule or to an element (for example assay of magnesium oxide in light magnesium carbonate or assay of magnesium in magnesium stearate).

In the case of antibiotics determined by microbiological assays, the active ingredient content is expressed in International Units, where these exist, and only a minimum value is given. See also under part II.6.

II.3. CHARACTERS As defined in the General Notices, statements under the heading CHARACTERS are not to be interpreted in a strict sense and are not regarded as analytical requirements. The principal items that may be referred to under this heading are the following.

II.3.1. Appearance

This description will normally embrace colour and physical form. The term “white” is not used without qualification since, if viewed against a standard white material, very few pharmaceutical materials will appear truly white. It is, of course, not intended that such a comparison be made but experience shows that certain users of the Ph. Eur. may insist on doing so as part of a purchasing contract. The term “white or almost white” is used instead. Where positive colours are to be described, this is done in terms of primary colours or combinations of primary colours.

Colour: the following descriptive terms are used: black, orange, blue, pink, brown, red, colourless, violet, green, white/almost white, grey, yellow

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Compound terms may be used: English

French bleu-vert vert-bleu rouge-violet violet-rouge rouge-brun brun-rouge

greenish-blue bluish-green violet-red

reddish-violet brownish-red reddish-brown

It can be noted that in English, the dominant is placed second, whereas in French, it is placed first. Expressions such as lemon-yellow, buff, salmon-pink are to be avoided; standard dictionaries give equivalents for such terms as spectral colours with suitable qualifiers (for example, buff is described as “dull yellow”). The following adjectives are also used; light, slight, fluorescent, intense, pale, dull, deep, dark.

It is to be noted that the allowed colours and colour combinations also apply to the description of the colour changes of indicators when used in acid/alkalinity tests or in titrimetric assay procedures.

II.3.2. Taste

The taste is not to be taken into consideration.

II.3.3. Odour

In general, no reference is made to odour. In particular no reference to odour is made for those materials that would constitute a hazard if inhaled. Mention of odour in other cases must be justified.

II.3.4. Solubility

A method recommended for the estimation of solubility is given in general chapter 5.11. Characters section in monographs. All solubilities are quoted in the general terms defined in the General Notices. Solvents quoted are normally confined to water, an alcohol and a lipophilic solvent (e.g. water, ethanol, heptane). Solubilities in chloroform and ether are not mentioned and the use of hexane is discouraged. In special cases the solubility of different samples of a material may vary rather considerably even though their composition is still within the limits set by the monograph. The solubilities in the solvents thereby affected are then given to cover more than one solubility class, e.g. “sparingly soluble to soluble in...”. The solubilities or miscibilities in other solvents with which the material is often combined in practice such as fatty oils, etc., may also be mentioned. In some cases it may be useful to specify solubility in alkalis or acids and, particularly in cases of materials that are very insoluble in the above-mentioned solvents, a special solvent may be indicated, e.g. dimethylformamide or dimethyl sulfoxide. It is not necessary to specify the solubility in every solvent that is used in performing the tests of the monograph itself.

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II.3.5. Stability factors

Evidence of instability due to exposure to air, light and for moisture is to be given, e.g. physostigmine sulfate turns red when exposed to air and light. Any such statement under CHARACTERS is given separately from the description of a pharmacopoeial material.

II.3.6. Hygroscopicity

A pragmatic method recommended for the determination of the tendency of a substance to take up atmospheric water (rather than a true determination of hygroscopicity) is given in general chapter 5.11. Characters section in monographs. Some substances are hygroscopic or deliquescent, which results in difficulties for the analyst during weighing procedures. In such cases, this is indicated using the terminology defined in general chapter 5.11., and serves as an alert to the analyst for precautions to be taken in handling the substance.

II.3.7. Solid-state properties

Solid-state properties include crystallinity, polymorphism, density of solids, particle size of solids and specific surface area of solids. Solid-state properties, particularly polymorphism and pseudopolymorphism, may have an effect on the bioavailability of the substance and for the production of the medicinal product. General chapter 5.9. Polymorphism should be consulted. A method recommended for the determination of crystallinity is given in general chapter 5.11. Characters section in monographs.

Solid-state properties of excipients that are relevant for functionality may be dealt with in the FUNCTIONALITY-RELATED CHARACTERISTICS section (see part II.10).

In a monograph, a statement of polymorphism is intended to alert users of the need to evaluate this phenomenon during the development of a dosage form. When polymorphism is known to exist in the substance, this information is given as a separate statement (“it shows polymorphism”).

Two cases are to be distinguished when polymorphism is known to exist:

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usually, the monograph does not exclude any of the possible crystalline forms;

exceptionally, if the substance is only used in solid dosage forms and one form has been preferred from the point of view of bioavailability or from a better safety/efficacy profile, then the monograph may be limited to that form. The techniques required to identify the form are included in the IDENTIFICATION section.

II.3.8. Other characteristics

Other physical characteristics that may be useful for information but not sufficiently precise to be defined under the headings IDENTIFICATION or TESTS may be stated under the heading CHARACTERS. This will usually apply to a melting point that is insufficiently precise to allow a range to be quoted (if a range can be quoted the melting point may be included under IDENTIFICATION). When decomposition may occur, this must be stated. Other general characteristics that may be of relevance for quotation under the heading CHARACTERS include an indication of direction of optical rotation in a particular solvent or, in the case of radioactive