741 MELTING RANGE OR TEMPERATURE
For Pharmacopeial purposes, the melting range, melting temperature, or melting point is defined as those points of temperature within which, or the point at which, the first detectable liquid phase is detected to the temperature at which no solid phase is apparent, except as defined otherwise for Classes II and III below. A melting transition may be instantaneous for a highly pure material, but usually a range is observed from the beginning to the end of the process. Factors influencing this transition include the sample size, the particle size, the efficiency of heat diffusion, and the heating rate, among other variables, that are controlled by procedure instructions. In some articles, the melting process is accompanied by simultaneous decomposition, which is visually evidenced as a side event like darkening of the material, charring, bubbling, or other incident. The visual impact of this side reaction frequently obscures the end of the melting process, which it may be impossible to accurately determine. In those circumstances, only the beginning of the melting can be accurately established; and it is to be reported as the melting temperature. The accuracy of the apparatus to be used as described below should be checked at suitable intervals by the use of one or more of the six USP Melting Point Reference Standards, preferably those that melt nearest the melting temperatures of the compounds being tested (see USP Reference Standards 11).
Five procedures for the determination of melting range or 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 for crystalline or amorphous substances and the procedure for Class II for waxy substances.
The procedure known as the mixed-melting point determination, whereby the melting range or temperature of a solid under test is compared with that of an intimate mixture of equal parts of the solid and an authentic specimen of it, e.g., the corresponding USP Reference Standard, if available, may be used as a confirmatory identification test. Agreement of the observations on the original and the mixture constitutes reliable evidence of chemical identity.
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 accurate thermometer (see Thermometers 21),* and a controlled source of heat. The bath fluid is selected with a view to the temperature required, but light 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 by an open flame or electrically. 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.
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, and, unless otherwise directed, render it anhydrous when it contains water of hydration by drying it at the temperature specified in the monograph, or, when the substance contains no water of hydration, dry it over a suitable desiccant for not less than 16 hours.
Charge a capillary glass tube, one end of which is sealed, with a sufficient amount 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 30 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 or otherwise, 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 3 per minute. When the temperature is about 3 below the lower limit of the expected melting range, reduce the heating so that the temperature rises at a rate of about 1 to 2 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 indicates the beginning of melting, and the temperature at which the test substance becomes liquid throughout corresponds to the end of melting or the melting point. The two temperatures fall within the limits of the melting range. If melting occurs with decomposition, the melting temperature corresponding to the beginning of the melting is within the range specified.
Procedure for Class Ia, Apparatus I Prepare the test substance and charge the capillary as directed for Class I, Apparatus I. Heat the bath until the temperature is about 10 below the expected melting point and is rising at a rate of 1 ± 0.5 per minute. Insert the capillary as directed under Class I, Apparatus I when the temperature is about 5 below the lower limit of the expected melting range, 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 test substance in a closed container and cool to 10, or lower, for at least 2 hours. Without previous powdering, charge the cooled material into the capillary tube as directed for Class I, Apparatus I, then immediately place the charged tube in a vacuum desiccator and dry at a pressure not exceeding 20 mm of mercury 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 10 ± 1 below the expected melting range is reached, then introduce the charged tube, and heat at a rate of rise of 3 ± 0.5 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 above directed, then with as little pressure as possible gently crush the particles to fit the capillary, and immediately charge the tube.
Procedure for Class I, 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 30 below the expected melting point. Insert the capillary tube into the heating block, and continue heating at a rate of temperature increase of about 1 to 2 per minute until melting is complete.
The temperature at which the detector signal first leaves its initial value indicates the beginning of melting, and the temperature at which the detector signal reaches its final value corresponds to 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. If melting occurs with decomposition, the melting temperature corresponding to the beginning of the melting is within the range specified. In the event of dispute, only the melting range or temperature obtained as directed for Class I, Apparatus I, is definitive.
Procedure for Class II Carefully melt the material to be tested at as low a temperature as possible, and draw it into a capillary tube, which is left open at both ends, to a depth of about 10 mm. Cool the charged tube at 10, or lower, for 24 hours, or in contact with ice for at least 2 hours. Then attach the tube to the thermometer by suitable means, adjust it in a water bath so that the upper edge of the material is 10 mm below the water level, and heat as directed for Class I, Apparatus I except, within 5 of the expected melting temperature, to regulate the rate of rise of temperature to 0.5 to 1.0 per minute. The temperature at which the material is observed to rise in the capillary tube is the melting temperature.
Procedure for Class III Melt a quantity of the test substance slowly, while stirring, until it reaches a temperature of 90 to 92. Remove the source of the heat and allow the molten substance to cool to a temperature of 8 to 10 above the expected melting point. Chill the bulb of a suitable thermometer (see Thermometers 21) to 5, wipe it dry, and while it is still cold dip it into the molten substance so that approximately the lower half of the bulb is submerged. Withdraw it immediately, and hold it vertically away from the heat until the wax surface dulls, then dip it for 5 minutes into a water bath having a temperature not higher than 16.
Fix the thermometer securely in a test tube so that the lower point is 15 mm above the bottom of the test tube. Suspend the test tube in a water bath adjusted to about 16, and raise the temperature of the bath at the rate of 2 per minute to 30, then change to a rate of 1 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 test substance. If the variation of three determinations is less than 1, take the average of the three as the melting point. If the variation of three determinations is 1 or greater than 1, make two additional determinations and take the average of the five.
* ASTM Method E77 deals with Verification and Calibration of Liquid-in-glass Thermometers.
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