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4.3 DETERMINATION OF MELTING RANGE AND MELTING TEMPERATURE

      For Pharmacopoeial purposes, the melting range of a substance is defined as the range between the temperature at which the substance begins to collapse or form droplets on the wall of a capillary tube and the temperature at which it is completely melted as shown by the disappearance of the solid phase; the latter temperature is also considered to be the melting temperature, except as defined otherwise for Classes II and III below. Any apparatus or method capable of equal accuracy may be used. The apparatus should be calibrated with appropriate substances of known melting point.¹

      Five procedures for the determination of melting range and melting temperature are given herein, varying in accordance with the nature of the substance. When no class is designated in the monograph, use the procedure for Class Ia. The procedure known as the mixed-melting point determination, whereby the melting range of a solid under test is compared with that of an intimate mixture of equal parts of the solid and an authentic sample of it, may be used as a confirmatory identification test. Agreement of the observations on the original and the mixture constitutes reliable evidence of chemical identity.

¹ Suitable substances are issued by the World Health Organization Collaborating Centre for Chemical Reference Substances, Apotekens Centrallaboratorium, Box 3045, 17103 SOLNA 3, Sweden.

Apparatus I

      An example of a suitable melting range Apparatus I consists of a glass container for a bath of transparent fluid, a suitable stirring device, an accurately standardized thermometer, and a controlled source of heat. The thermometers should cover the range of –10º to +360º, the length of one degree on the scale being not less than 0.8 mm. Each thermometer should preferably be of the mercury-in-glass, solid-stem type with a cylindrical bulb and made of approved thermometric glass suitable for the range covered, and should have a safety chamber. The bath fluid is selected with a view to the temperature required, but liquid paraffin is used generally and certain liquid silicones are well adapted to the higher temperature ranges. The fluid is deep enough to permit immersion of the thermometer to its specified immersion depth so that the bulb is still about 2 cm above the bottom of the bath. The heat may be supplied electrically or by an open flame. The capillary tube is about 10 cm long and 0.8 to 1.2 mm in internal diameter with walls, 0.2 to 0.3 mm in thickness.

      The thermometer is selected for the desired accuracy and range of temperature.

      The procedures for Classes I and Ia are applied to those substances readily reduced to fine powders.

Apparatus II

      An instrument may be used in the procedures for Classes I, Ia, and Ib. An example of a suitable melting range Apparatus II consists of a block of metal that may be heated at a controlled rate, its temperature being monitored by a sensor. The block accommodates the capillary tube containing the test substance and permits monitoring of the melting process, typically by means of a beam of light and a detector. The detector signal may be processed by a microcomputer to determine and display the melting point or range, or the detector signal may be plotted to allow visual estimation of the melting point or range.

Procedure for Class I

      Apparatus I----Reduce the substance under test to a very fine powder. Unless otherwise directed, render it anhydrous when it contains water of hydration by drying at the temperature specified in the monograph. When the substance contains no water of hydration, dry it as directed for Loss on drying in the individual monograph; or if no Loss on drying test is specified, dry it over a suitable desiccant for not less than 16 hours.

      Charge a capillary glass tube, one end of which is sealed, with sufficient quantity of the dry powder to form a column in the bottom of the tube 2.5 to 3.5 mm high when packed down as closely as possible by moderate tapping on a solid surface.

      Heat the bath until the temperature is about 30º below the expected melting point. Remove the thermometer, and quickly attach the capillary tube to the thermometer by wetting both with a drop of the liquid of the bath, and adjust its height so that the material in the capillary is level with the thermometer bulb. Replace the thermometer, and continue the heating, with constant stirring sufficiently to cause the temperature to rise at a rate of about 3º per minute. When the temperature is about 3º below the lowest figure of the melting range for the substance under test, reduce the heating so that the temperature rises at a rate of about 1º to 2º per minute. Continue heating until melting is complete.

      The temperature at which the column of the substance under test is observed to collapse definitely against the side of the tube at any point is defined as the beginning of melting and the temperature at which the test substance becomes liquid throughout is defined as the end of melting or the “melting temperature”. The two temperatures fall within the limits of the melting range.

      Apparatus II----Prepare the substance under test and charge the capillary tube as directed for Class I, Apparatus I. Operate the apparatus according to the manufacturer’s instructions: Heat the block until the temperature is about 30º below the expected melting point. Insert the capillary tube into the heating block, and continue heating at a rate of temperature increase of about 1º to 2º per minute until melting is complete.

      The temperature at which the detector signal first leaves its initial value is defined as the beginning of melting, and the temperature at which the detector signal reaches its final value is defined as the end of melting, or the melting point. The two temperatures fall within the limits of the melting range. 

      In the event of dispute, only the melting range or temperature obtained as directed for Class I, Apparatus I, is definitive.

Procedure for Class Ia

      Apparatus I----Prepare the substance under test and charge the capillary as directed for Class I.

      Heat the bath until the temperature is about 10º below expected melting point and is rising at a rate of 1º±0.5º per minute. Insert the capillary as directed under Class I when the temperature is about 5º below the lowest figure of the melting range for the substance under test and continue heating until melting is complete. Record the melting range as directed for Class I, Apparatus I.

Procedure for Class Ib

      Apparatus I----Place the substance under test in a closed container and cool to 10º, or lower, for at least 2 hours. Without previous powdering, charge the cooled material into the capillary tube as directed for Class I, immediately place the charged tube in a vacuum desiccator and dry at a pressure not exceeding 2.7 kPa (about 20 Torr) for 3 hours. Immediately upon removal from the desiccator, fire-seal the open end of the tube, and as soon as practicable proceed with the determination of the melting range as follows: Heat the bath until a temperature is 10º±1º below the lowest figure of the melting range for the substance under test, introduce the charged tube, and heat at a rate of rise of 3º±0.5º per minute until melting is complete. Record the melting range as directed for Class I, Apparatus I.

      If the particle size of the material is too large for the capillary, pre-cool the test substance as directed above, then with as little pressure as possible gently crush the particles to fit the capillary, and immediately charge the tube.

Procedure for Class II

      This procedure is applied to such substances as fats, fatty acids, paraffins or waxes, that are insoluble in water and not readily reduced to powder. Carefully melt the material under test at as low a temperature as possible, and draw it into a capillary tube, which is left open at both ends, to a height of about 10 mm. Cool the charged tube at 10º, or lower, for 24 hours, or in contact with ice for at least 2 hours. Then attach the tube to the thermometer by a suitable means, adjust it in a waterbath so that the upper edge of the material is 10 mm below the water level, and heat as directed for Class I except, within 5º of the expected melting temperature, to regulate the rate of rise of temperature to 0.5º to 1.0º per minute. The temperature at which the material is observed to rise in the capillary tube is the melting temperature.

Procedure for Class III

      This procedure is applied to petrolatums. Melt a quantity of the substance under test slowly, while stirring, until it reaches a temperature of 90º to 92º. Remove the source of the heat and allow the molten substance to cool to a temperature of 8º to 10º above the expected melting temperature. Chill the bulb of a suitable thermometer to 5º, wipe it dry, and while still cold, dip into the molten substance so that approximately the lower half of the bulb is submerged. Withdraw it immediately, and hold vertically away from the heat until the wax surface dulls. Then dip for 5 minutes into a water-bath having a temperature not higher than 16º.

      Fix the thermometer securely in a test-tube so that the lower end is 1.5 cm above the bottom of the testtube. Suspend the test-tube in a water-bath adjusted to about 16º, and raise the temperature of the bath at a rate of 2º per minute to 30º. Then change to a rate of 1º per minute, and note the temperature at which the first drop of melted substance leaves the thermometer. Repeat the determination twice on a freshly melted portion of the substance under test. If the variation of three determinations is less than 1º, take the average of the three as the melting temperature. If the variation of three determinations is more than 1º, make two additional determinations and take the average of the five.