According to the different properties of the test samples, the determination methods are classified into the following three types. Unless otherwise specified under each variety item, the first method shall be referred to.

The first method is for the determination of easily crushed solid drugs

Heat transfer liquid heating method

Take an appropriate amount of the test sample, grind it into fine powder. Unless otherwise specified, it should be dried in accordance with the drying weight loss conditions under each drug item. If the reagent is a test sample without checking for drying weight loss, with a lower limit of the melting point range above 135℃ and no decomposition when heated, it can be dried at 105℃. Test samples with a melting point below 135℃ or decomposing upon heating can be dried overnight in a phosphorus pentoxide dryer or by other suitable drying methods, such as constant temperature and reduced pressure drying.

Take an appropriate amount of the test sample and place it in a capillary tube for melting point determination (referred to as the capillary tube, made of neutral hard glass tube, with a length of more than 9cm, an inner diameter of 0.9 to 1.1mm, and a wall thickness of 0.10 to 0.15mm, with one end sealed; When the thermometer used is immersed in the heat transfer liquid for more than 6cm, the length of the tube should be appropriately increased to expose more than 3cm above the liquid surface. Gently tap the tube wall or use a clean glass tube of appropriate length to place it vertically on a surface dish or other suitable hard object. Insert the capillary tube from the upper opening and let it fall freely. Repeat this several times to ensure that the powder is closely concentrated at the sealed end of the capillary tube. The height at which the test sample is loaded is approximately 3mm.

In addition, place the glass thermometer (immersion type, with a 0.5℃ scale, calibrated with reference substances for melting point determination) into the temperature transfer liquid (if the melting point is below 80℃, use water; For those with a melting point above 80℃, use a container filled with silicone oil or liquid paraffin, ensuring that the bottom end of the mercury bulb of the thermometer is more than 2.5cm away from the bottom of the container (for containers with internal heating, the distance between the mercury bulb of the thermometer and the upper surface of the heater is more than 2.5cm), or use a resistance digital thermometer calibrated with reference substances. Add the heat transfer liquid so that the liquid level after heating is exactly at the immersion line of the thermometer.

Heat the temperature transfer liquid. When the temperature rises to approximately 10℃ lower than the specified lower limit of the melting point, immerse the capillary tube containing the test sample into the temperature transfer liquid and attach it to the thermometer (it can be fixed with a rubber ring or a capillary tube clamp). The position must be such that the contents of the capillary tube are exactly in the middle of the measurement area of the thermometer. Continue heating and adjust the temperature increase rate to 1.0 to 1.5℃ per minute. During heating, stir constantly to keep the temperature of the heat transfer liquid uniform. Record the temperature of the test sample from the initial melting to the final melting. Repeat the measurement three times and take the average value.

"Initial melting" refers to the temperature at which the test sample begins to partially liquefy in the capillary tube and obvious droplets appear.

"Final melting" refers to the temperature at which the test sample is completely liquefied.

The "melting distance" refers to the temperature difference between the initial melting and the final melting. The melting distance value can reflect the chemical purity of the test sample. When the test sample has a polymorphic phenomenon, on the basis of ensuring chemical purity, the size of the melting distance value can also reflect the purity of its crystal form.

When determining the test sample that melts and decomposes simultaneously, the method is as described above, but the heating rate is adjusted to increase by 2.5 to 3.0 degrees Celsius per minute. The temperature at which the test sample begins to partially liquefy (or when bubbles start to form) is taken as the initial melting temperature. The temperature at which the solid phase of the test sample disappears and is completely liquefied is taken as the final melting temperature. When the solid phase does not disappear significantly, the temperature at which the decomposition products of the test sample start to expand and rise should be taken as the final melting temperature. When it is impossible to distinguish between the initial and final melting points of certain drugs, the temperature at which the sudden change occurs can be taken as the melting point.

"B. Electric heating block air heating method

It is a melting point determination method using an automatic melting point apparatus. The automatic melting point apparatus has two light measurement methods: one is the transmitted light method, and the other is the reflected light method. Some instruments have two photometric methods. Most automatic melting point apparatus can be equipped with multiple capillaries for simultaneous determination.

Take an appropriate amount of the test sample that has undergone drying treatment (as in Method A) and place it in the capillary tube used for melting point determination (as in Method A). When the heating block of the automatic melting point apparatus is heated to approximately 10℃ lower than the specified lower limit of the melting point, insert the capillary tube containing the test sample into the heating block, continue heating, adjust the heating rate to 1.0 to 1.5℃ per minute, repeat the measurement three times, and take the average value, which is the result.

When determining the test sample that melts and decomposes simultaneously, the method is as described above, but the heating rate is adjusted to increase by 2.5 to 3.0 degrees Celsius per minute.

When encountering test samples with colored powders, melting and decomposition simultaneously, with insignificant disappearance of the solid phase and the formation of decomposition products causing volume expansion, or containing crystalline water (or crystalline solvents), the instrument parameters can be appropriately adjusted to improve the accuracy of judging the change in melting point. When the transmission and reflection photometric methods are significantly interfered with, visual observation of the melting point change is allowed. The melting process is recorded through the camera system and retrospectively evaluated. When necessary, the accuracy of the measurement results needs to be verified by Method A.

The temperature indication of the automatic melting point apparatus (recommended instrument: Shanghai Jiahang AIpol-M80 drug Automatic melting point Apparatus) should be regularly calibrated with melting point standard products. When necessary, the test sample determination should be carried out simultaneously with the calibration of the instrument using standard samples.

If there are any objections to the determination results of Method B, the determination results of Method A shall prevail.

The second method for determining solid substances that are difficult to crush (such as fats, fatty acids, paraffin, lanolin, etc.)

Take the test sample. Note that after melting it at the lowest possible temperature, draw it into the capillary tube with openings at both ends (the same as the first method, but the tube ends are not sealed), making it approximately 10mm high. Let it stand in a cold place at 10℃ or below for 24 hours, or place it on ice to cool for no less than 2 hours. After solidification, tightly bind the capillary tube to the thermometer with a rubber band (as in the first method), so that the contents of the capillary tube are exactly in the middle of the mercury bulb of the thermometer.

Immerse the capillary tube along with the thermometer into the heat transfer liquid as per the first method. The upper end of the test sample should be exactly about 10mm below the liquid surface of the heat transfer liquid. Heat carefully. When the temperature rises to about 5℃ lower than the specified lower limit of the melting point, adjust the heating rate so that the increase does not exceed 0.5℃ per minute. When the test sample begins to rise in the capillary tube, read the temperature displayed on the thermometer, and the result is obtained.

Method 3: Determination of Vaseline or other similar substances

Take an appropriate amount of the test sample, stir it slowly and heat it to a temperature of 90 to 92℃. Then place it in a flat-bottomed heat-resistant container to make the thickness of the test sample reach 12mm±1mm. Let it cool to a temperature 8 to 10℃ higher than the upper limit of the specified melting point. Take a thermometer with a scale of 0.2℃, a mercury bulb length of 18 to 28mm, and a diameter of 5 to 6mm (with a cork pre-attached to the top and a small groove made along the edge of the stopper). Let it cool to 5℃, dry it, and carefully insert the mercury bulb of the thermometer vertically into the molten test sample until it touches the bottom of the container (submerged by 12mm). Then remove it and suspend it upright When the surface of the test sample adhering to the mercury bulb of the thermometer becomes turbid, immerse the thermometer in water below 16℃ for 5 minutes, take it out, and then insert the thermometer into a test tube with an outer diameter of about 25mm and a length of 150mm, tightly plug it so that the thermometer is suspended in it, and the bottom end of the mercury bulb of the thermometer is about 15mm away from the bottom of the test tube. Immerse the test tube in a water bath at approximately 16℃, and adjust the height of the test tube so that the immersion line on the thermometer is level with the water surface. Heat to raise the water bath temperature at a rate of 2℃ per minute to 38℃, and then increase it at a rate of 1℃ per minute until the first drop of the test sample separates from the thermometer. The temperature displayed on the thermometer can be used as the approximate melting point of the test sample.

Take the test sample again and repeat the determination several times according to the previous method. If the melting points measured in three consecutive times differ by no more than 1℃, the average of the three times can be taken as the melting point of the test sample. If the melting points measured three times differ by more than 1℃, two more measurements can be made, and the average of the five measurements should be taken as the melting point of the test sample.