(1994; 140 pages) [French] [Spanish]
4. Determination of melting characteristics
Determination of melting point
The melting point is determined in a capillary tube. The expression "melts about..." means that the temperature at which the substance is completely melted, as indicated by the disappearance of the solid, will be in the range ± 4°C from the stated value, unless otherwise indicated.
Details of the procedure
The following technique is adequate for the determination of melting point:
Grind about 50 mg of the substance to be tested in a small mortar. Place the ground substance in a vacuum desiccator over silica gel or phosphorus pentoxide at room temperature and dry for about 24 hours (unless another drying procedure is given in the test sheet). Place the substance in a dry capillary tube of 1-mm internal diameter forming a column about 3 mm high. Heat the melting-point apparatus to a temperature 5-10°C below the expected temperature of melting and adjust the heating so that the temperature in the chamber rises about 1°C per minute. Introduce the capillary with the substance into the heated chamber and note the temperature when the sintered substance becomes completely transparent; this is considered to be the melting point.
The difference between the purely theoretical definition of the melting temperature and the results obtained in practice is now widely recognized. A precise physical definition exists only for the so-called triple point, i.e., the temperature at which all three phases (solid, liquid and gaseous) are in equilibrium. The measurement of the triple point is achieved in a highly complicated experiment. Many compendia do not use this temperature, but describe melting intervals as observed in practice, when the formation of droplets, the softening of the substance or its sintering are considered to be the beginning of the melting process, while the formation of a clear and transparent drop of liquid is taken to be the end of the melting process.
In the case of pure substances that melt without decomposition, the beginning of melting can be observed with some certainty. For impure substances, the beginning of the melting process will vary, depending on the nature of the impurities. Therefore it has been proposed that in the basic tests the following definition of melting point be used. This definition is similar to that used in The International Pharmacopoeia, to describe melting temperature:
The melting point denotes the temperature at which the substance has just completely melted; this is indicated by the disappearance of the solid phase and complete transparency of the melt.
This approach has the disadvantage that, if impurities are present, their presence can only be deduced from the lowering of the melting-point value, as no observation is made of the melting interval. An increase in the latter usually indicates low purity of a substance. These considerations, however, have less importance for basic test identification, where this disadvantage is fully offset by increased reproducibility of the values of melting point determined according to the above procedure.
The expression "melting behaviour" used in the basic tests denotes the melting point of substances that melt with decomposition. It is also used for melting points above 250°C to indicate that the reproducibility of the value may be low.
It is necessary to bear in mind that a difference exists between true melting points (or melting ranges) and the temperature of decomposition. Ideally, in the case of a true melting point, no chemical change occurs in the substance. However, when some substances are heated, decomposition takes place either before or during the process of melting, being indicated by a change in the colour of the substance or by the evolution of a gas. In such situations, the observed temperature of melting is not a true melting point of the substance but the melting point of a mixture with decomposition products. It is obvious that the temperature of decomposition cannot be considered as a physical property of a substance as the amount of decomposition products, and consequently the temperature of decomposition, depend on the length of the period of heating and therefore have low reproducibility, even if a standardized procedure is used.
Determination of eutectic temperature
Eutectic temperature is given as a single value only and designates the beginning of melting, i.e., the temperature at which the solid collapses or forms drops on the wall of the capillary tube. The mixture to be used in the test is usually prepared by thorough mixing of approximately equal parts of the test substance and the accessory substance, unless the use of strictly equal amounts of both substances is specially indicated in the test procedure.
Details of the procedure
The following technique is adequate for the determination of eutectic temperature:
Grind equal parts (by weight) of the substance to be tested and the accessory substance, both of them previously dried for about 24 hours at room temperature in a vacuum desiccator over silica gel or phosphorus pentoxide. Fill a dry capillary tube, of 1-mm internal diameter, with the mixture, forming a column about 3 mm high. Heat the melting-point apparatus to a temperature 5-10°C below the expected temperature of melting and adjust the heating so that the temperature in the chamber rises about 1°C per minute. Introduce the capillary with the mixture into the heated chamber, and note the temperature at which the solid collapses or forms droplets on the wall of the capillary tube.
The measurement of eutectic temperature has been introduced in the basic tests as an additional criterion of identity. An exact determination of the eutectic melting point requires a set of measurements carried out on mixtures prepared in different ratios. The eutectic melting point thus measured is thermodynamically exactly defined and may be used as a criterion of both identity and purity. Such a procedure is not, however, practical for the basic test project, as it requires a long time and adequate laboratory facilities. For the purpose of basic tests, the determination is carried out at a constant ratio of 1:1. However, this has the disadvantage that in some cases the melt will not become transparent, so that the reproducibility of the measurement is low owing to individual errors. Nevertheless, the eutectic temperatures given in the basic tests are usually reproducible to within ±5°C.
It should be noted that during eutectic temperature determination the beginning of the process of melting is observed, whereas during melting-point determination it is the end of the process that is surveyed.
Mixed melting point
The determination of a mixed melting point is carried out in a glass capillary as described under "Determination of melting point", page 6. Equal amounts of the substance to be tested and the authentic substance are mixed and placed in a capillary. A separate capillary is filled with the substance to be tested and a further capillary with the authentic substance. All three capillaries are simultaneously heated in the melting-point apparatus. The melting point of the mixture should not differ by more than ±4°C from the melting points of the single substances.
Although mixed melting-point determinations are not included in the basic tests, this procedure is a highly reliable criterion in deciding whether two substances are identical. The general introduction of mixed melting-point determination as an identity test would require a wide accessibility of appropriate reference substances, which can sometimes only be arranged on a national basis. Each laboratory can, however, gradually create for itself a collection of authentic substances from incoming consignments of materials of good quality and can then use the mixed melting point as a strong additional criterion of identity. Such a collection, once established, may further be used in identity tests using the thin-layer chromatography technique.
Type of apparatus
A number of types of melting-point apparatus are produced. A review of those that are commercially available is given by Büchi & Hasler.a
a Büchi, J. & Hasler, C. Pharmaceutica acta Helvetiae, 49:47 (1974).
The apparatus employed in the determination should be equipped with a magnifying glass, have a controlled heating arrangement that permits a heating rate of 1-2°C/min around the temperature of melting, and be equipped to be used with capillaries of 1-mm inner diameter.
The heating arrangement can take the form of a stirred bath, such as the Thiele apparatus and its modifications,b or a heated block, e.g., the Lindström or Culatti modifications.c
b Skan, E.L. & Arthur, J.C. Jr. In: Weissberger, A., ed. Technique of organic chemistry, New York, Interscience, 1971, Vol. 1, p. 105.
c Kienitz, H. In: Houben-Weyl, Methoden der organischen Chemie, Stuttgart, Georg Thieme Verlag, 1953, Vol. 2, p. 788.
Calibration of thermometers
For the various measurements of melting characteristics to be of any value, it is essential to use accurate thermometers. The thermometer used should preferably be certified by a duly recognized body. Alternatively, it could be calibrated against such a thermometer. Another method of checking the accuracy of the thermometer is by measuring the melting points of a set of WHO melting-point reference substances using a 1-mm capillary; if the observed melting points of the reference substances lie within ±2°C of the melting temperature indicated for that substance, the thermometer may be considered satisfactory. An important requisite, however, is that the geometrical arrangement of the thermometer and capillaries in the apparatus is practically identical in every determination. The length of the column of mercury in the thermometer exposed to room temperature can introduce significant error particularly at high temperature. It is therefore desirable to use thermometers with narrow ranges of temperature such as 0-110°C, 110-210°C or 200-300°C. If this is not possible, a correction factor should be introduced according to the formula given in The International Pharmacopoeia, third edition (volume 1, page 22).
The expression "heating behaviour" used in the basic tests denotes the behaviour of the substance (such as colour changes or evolution of gas) when heated in an open test-tube in a flame or in an electrical heater.