JPH04127057A - Method for measuring degree of crystallization of drug preparation - Google Patents

Abstract

PURPOSE:To simply measure the degree of crystallization of a drug preparation of every kind, especially, a beta-lactam compound with high accuracy by measuring the intensity of extremely weak chemiluminescence of the drug preparation. CONSTITUTION:It is said that there is predetermined relation between the value of extremely weak chemiluminescence CL of a predetermined compound, especially, a beta-lactam compound and the degree of crystallization thereof when temp. is constant. Then, in order to measure the degree of crystallization of a drug preparation, especially, the beta-lactam compound, a first, the CL value of a compound whose degree of crystallization is known is measured, for example, by a chemiluminescence measuring apparatus amplifying the receiving quantity of the light from a compound within a predetermined time to be capable of measuring, displaying and recording the same as a photoelectron pulse to prepare a calibration curve wherein a degree of crystallization is set to a horizontal axis and luminous intensity is set to a vertical axis. When the luminous intensity of a compound whose degree of crystallization is unknown is measured, the degree of crystallization thereof can be easily calculated and the stability thereof can be evaluated.

Description

[Detailed description of the invention] (Industrial application field) The present invention is a method for measuring the degree of crystallinity of a pharmaceutical preparation.

In particular, it relates to a method for measuring the degree of crystallinity of a β-lactam compound.

(Prior Art) Many compounds used as pharmaceuticals are first isolated as crystals. The main reason for this is that crystalline compounds generally have a higher degree of purification and are more stable than amorphous compounds. In the case of oral preparations, they are often formulated as they are, but in the case of injection preparations, there is a risk of contamination with foreign substances during powder filling, so first, the crystalline powder is made into an aqueous solution and filtered. A method of freeze-drying after removing foreign substances is often adopted.

Although the freeze-drying method is optimal for removing foreign substances, it has the disadvantage of increasing the proportion of amorphous substances, and various freeze-drying methods have been proposed to increase the degree of crystallinity (the ratio of crystalline compounds to the total amount of compounds). . For example, cephalothin sodium (trade name: Kefrin■, Shionogi & Co., Ltd.) has a crystallinity of approximately 10.
Supplied as a 0% lyophilized formulation.

As described above, there is a close relationship between the crystallinity and stability of various pharmaceutical compounds, and a method for measuring the crystallinity easily and with high accuracy has been desired.

Conventionally, these measurements have been carried out by X-ray analysis, thermal analysis, etc., but these have disadvantages such as complicated operations and relatively long time requirements.

(Problems to be Solved by the Invention) The present invention is intended to solve the above-mentioned conventional problems, and its purpose is to provide various pharmaceutical preparations.

In particular, it is an object of the present invention to provide a method for easily and accurately measuring the crystallinity of a β-lactam compound.

By using the method of the present invention, it is possible to easily control the quality of the product immediately after freeze-drying, and it is also possible to easily track and check product deterioration that occurs during product storage.

(Means for solving problems) A method for measuring the degree of crystallinity of a pharmaceutical formulation of the present invention is as follows.

It includes measuring the extremely weak chemiluminescence intensity of the pharmaceutical formulation.

In a preferred embodiment, the pharmaceutical formulation is:

A β-lactam compound, preferably cephalothin sodium.

In order to measure the crystallinity of a pharmaceutical formulation, particularly a β-lactam compound, by the method of the present invention, firstly, the ultraweak chemiluminescence (extraweak chemiluminescence) of the compound of known crystallinity is measured.
eluminescence; CL) is measured by an appropriate means. For example, a chemiluminescence measurement device that can amplify the amount of light received from the compound in a predetermined time using a photomultiplier tube and measure, display and record the photoelectron pulse number can be used. Examples of such devices include 1, for example, Chemiluminescence manufactured by Tohoku Denshi Sangyo ■.
Analyzer model 0X-70 can be used. The crystallinity of the above compound can be measured in advance using a known crystallinity measuring device 1, such as an X-ray analyzer or a thermal analysis crystallinity analyzer.

The crystallinity and chemiluminescence intensity have a predetermined relationship.

For example, the crystallinity is plotted on the horizontal axis, and the luminescence intensity (e.g.
If the vertical axis is the average amount of light emitted per hour, a straight line as shown in FIG. 1 is obtained.

Using this as a calibration curve, the luminescence intensity of a sample of the above compound with unknown crystallinity is measured.

It becomes possible to easily calculate the degree of crystallinity.

It has been known that the above C'L exists in individual compounds. This was thought to be because the compound is oxidized by oxygen in the atmosphere and universally produces chemiluminescence. For example, Water Pillar et al.

Pharmaceutical Journal 105 (4) 401-406 (1985
), the ['L values of various pharmaceutical compounds were measured at various temperatures, and the relationship between CL and the oxidizing properties of the compounds was devised. Furthermore, Mizuhira et al., Tohoku Electronic Industry Report, Tohoku Electronic Industry Co., Ltd., Sendai, 1985, 1-6.
Page shows that the CL value differs depending on the type of compound and the measurement temperature, that the CL value of unstable compounds is high, and that the higher the measurement temperature, the higher the CL value.

The authors concluded that the above phenomenon occurs on the same principle as that of fats and oils and foods that produce CL due to deterioration, and that the CL value of pharmaceuticals also increases because their components undergo oxidation and release CL. in this way.

It was known that CL is mainly produced by oxidation reactions, and that the higher the temperature, the higher the CL value.

The relationship between the CL produced by a specific compound and the crystallinity of the compound was completely unknown.

In contrast, the inventors discovered that the CL value and crystallinity of a given compound, especially a β-lactam compound, have a certain relationship as long as the temperature is constant, which was completely unknown in the past. Find the facts.

The present invention has now been completed. It is known that general pharmaceuticals, especially β-lactam compounds, are more unstable as the degree of crystallinity is lower. Therefore, if the CL value of a certain compound can be measured by the method of the present invention and the degree of crystallinity can be calculated, it becomes possible to evaluate the stability of that compound. The method of the present invention will be explained in the following examples using cephalothin sodium as an example. The method of the present invention is not limited to cephalothin sodium, but can be applied to other β-lactam compounds and even other pharmaceuticals. If the relationship between crystallinity and the drug is clear for other drugs, the CL value can be measured using two methods to evaluate the crystallinity and further the stability of the drug. becomes possible.

(Example) Examples of the present invention are shown below.

Example 1 Purified bulk powder of cephalothin sodium (provided by Shionogi & Co., Ltd.) was sieved through a 120 mesh standard sieve.

This was designated as sample 1. Next, 280 g of the above cephalothin sodium bulk powder from the same lot was added to 720 g of pharmacopoeically distilled water.
The mixture was heated and dissolved at 50°C. This solution was immediately cooled to 5° C. and filtered under pressure through a 0.22 μm membrane filter to obtain a 28% aqueous solution. Add this aqueous solution to a volume of 14
- Dispense 3.3 mf into each vial.

It was freeze-dried by the following method. First, freeze by holding at -40°C for 1 hour (first freezing step), then hold at -5°C for a predetermined time (0, 0, 5, 10, or 15 hours) (crystallization step). The sample was then kept at -40° C. for 2 hours (second freezing step) and then dried at 30° C. (temperature) for 25 hours under a reduced pressure of 0.2 ml J bar (drying step). The time required for the crystallization process was 15 hours, 10 hours, and 0.
The 5 hour and 0 hour samples were labeled as samples 2.3.4., respectively. and 5.

The crystallinity of samples 1 to 5 was determined by thermal analysis according to Pharmaceutical Journal v
9 according to the method of OL, 109.388 (1988).
It was measured as follows. As a measuring instrument, TG-DTA manufactured by Rigaku Denki ■ was used. 5 mg of each of the above samples 1 to 5 was weighed out, and the amount of weight loss due to thermal decomposition during a constant temperature increase process of 1.25° C./min was measured by the TG method.

Crystallinity is determined by the following formula: (αg) was calculated.

βg=(△Gl+ΔG2)/Σ△G1-3αg= (1
-βg) △G1. ΔG2: Amount of weight loss due to thermal decomposition of each component of the amorphous and pseudocrystal of the sample Σ△G1-3: Total value of weight loss due to thermal decomposition of each component of the pseudocrystal and crystal of the sample As a result, each sample The crystallinity of sample 1: 99.0, sample 2: 92.
3%, sample 3 near 5.0%; sample 4: 58.0
%; Sample 5: 4.0%.

Next, the chemiluminescence intensity (amount of luminescence per unit time; shown as a CL value) of these samples was measured by the following method. First, the sample was placed in a stainless steel plate with a diameter of 53 mm and a height of 13 mm.
The sample was set in an inescence analyzer 0X-70 model, and measurements were performed at 23° C. in the following manner.

First, after setting the sample, measurements were taken 10 times in a row at 10 second intervals with the ventilation shutter closed.
(dark count) was determined, and then measurements were taken continuously for 5 minutes at 10 second intervals with the shutter open, and after reaching a steady state, measurements were taken 6 times in a row, and the average value was determined. The value obtained by subtracting the dark count from the measured value (average value) at this time was defined as the CL value of the sample.

Table 1 shows the CL values of samples Nα1 to Nα5.

(Space below) Table 1 Results of regression analysis: Standard error of Y intercept Y evaluation value R square Number of samples Degrees of freedom 21578, 610 813, 50771 0.9925069 X coefficient Standard error of X coefficient 213, 5030 10, 710436 Each sample above The relationship between the degree of crystallinity and the CL value is expressed as
As shown in the figure. From Figure 1, the lower the crystallinity of the sample, the more C
The L value increases, and what is the crystallinity and CL value?

It can be seen that a good linear relationship is shown. If this is used as a calibration curve, it becomes possible to calculate the degree of crystallinity by measuring the CL value of cephalothin sodium with an unknown degree of crystallinity.

Example 2 Three new samples each of samples NrJ, 1.2 and 5 of the example were prepared. The CL values of these samples were measured at 27°C, 47°C and 67°C.

However, in measuring the CL value, continuous measurements were taken at 10 second intervals for 10 minutes after setting the sample, and then the values measured 10 times were used. The results are shown in Table 2.

Furthermore, the relationship between the measured temperature (1/TX 103) and the CL value is shown in FIG.

(Margins below) Table 2 From Table 2 and FIG. 2, it can be seen that the reciprocal of the absolute temperature and the logarithm of the CL value show a linear relationship. Therefore, we applied the Arrhenius equation to calculate the activation energy of the chemiluminescent reaction. The results are shown in Table 3.

Table 3 10.94 11.36 6.05 From Table 3, it is clear that cephalothin sodium with low crystallinity has a lower activation energy and is unstable to heat than crystalline cephalothin sodium. .

(Effects of the Invention) According to the present invention, as described above, by measuring the extremely weak chemiluminescence intensity of a pharmaceutical preparation, particularly a β-lactam compound, the degree of crystallinity of the compound can be measured with high precision in a short time. Ru. In general, compounds with a high degree of crystallinity have high stability, so by measuring the degree of crystallinity of a pharmaceutical preparation using a single method, it is possible to evaluate the stability of the drug preparation.

[Brief explanation of the drawing]

Figure 1 is a graph showing the relationship between the crystallinity of cephalothin sodium and the amount of chemiluminescence per unit time of the compound, and Figure 2 is a graph showing the relationship between the crystallinity of cephalothin sodium and the amount of chemiluminescence per unit time of the compound, and Figure 2 shows the temperature when cephalothin sodium was measured at various temperatures. It is a graph showing the relationship between the amount of chemiluminescence and the amount of chemiluminescence per unit time. that's all

Claims (1)

[Scope of Claims] 1. A method for measuring crystallinity of pharmaceutical preparations, which includes measuring extremely weak chemiluminescence intensity. 2. The measuring method according to claim 1, wherein the pharmaceutical preparation is a β-lactam compound. 3. The measuring method according to claim 2, wherein the β-lactam compound is cephalothin sodium.