JP2005127999A - Crystal determinating method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a crystal determinating method of high precision for preparing a standard mixed powder, wherein crystals are ground to be mixed, to form a calibration curve. <P>SOLUTION: This crystal determinating method includes a step (a) for grinding at least two kinds of crystals different in crystal form or degree of crystallization by an air flow type grinder to obtain ground crystals, a step (b) for weighing the ground crystals by a predetermined amount to put them in a hollow container of which the outer surface is provided with an elastomer mixed medium and vibrating or rotating the hollow container to obtain a plurality of standard mixed powders different in crystal containing ratio or degree of crystallization, a step (c) for subjecting the standard mixed powders to powder X-ray diffraction measurment to form the calibration curve of the correlation with the weights of the respective crystals in the standard mixed powders or the degrees of crystallization of the standard mixed powders, a step (d) for grinding the crystal mixture to be determinated, and a step (e) for calculating the contents of the respective crystals in the crystal mixture or the degree of crystallization of the crystal mixture from the calibration curve formed in the step (c) by subjecting the ground crystal mixture to powder X-ray diffraction measurement. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a crystal quantification method.

  A compound having a crystalline polymorph has various properties depending on the crystal form, and even if it has the same chemical composition, for example, physicochemical properties such as solubility, dissolution rate, stability, hygroscopicity, In many cases, various properties such as degradation products, metabolites, toxicity, and formulation characteristics are different. Therefore, when a compound having a crystalline polymorph is used, for example, as a drug substance, it naturally does not contain a different crystal form or the composition ratio of the polymorph is constant due to the characteristics of the drug substance. It is required to provide a controlled drug substance, and in the development of the manufacturing process, whether or not a compound having a crystal form different from the target crystal form is generated in the process is determined in the obtained drug substance. That the compound does not contain a compound with a crystal form different from the intended crystal form, the composition ratio of the polymorph is constant, and during the storage of the manufactured drug substance and the formulation process Therefore, it was extremely important to confirm the presence or absence of crystal polymorphism, the polymorph content, etc. In addition, even when the crystallinity is different, as in the case of the crystalline polymorph, the physicochemical properties and characteristics are often different, and the drug substance is controlled so that the crystallinity is constant. Similarly, in the manufacturing process, it is confirmed whether the compound with the desired crystallinity is obtained, and whether there is no change in the crystallinity in the storage process after the manufacturing. It was extremely important.

  Conventionally, a powder X-ray diffraction measurement method has been used as a method for quantifying such crystal polymorphs and crystallinity. This is because a crystal of a specific crystal form or crystallinity is ground using an agate mortar, and the ground crystal powder is sampled and mixed in predetermined amounts, and then subjected to powder X-ray diffraction measurement to determine the size of the intrinsic peak of the crystal. X-ray diffraction profile obtained by preparing a calibration curve of the correlation between the weight of each crystal powder in the mixed powder and the crystallinity and then grinding the crystal mixture of unknown content in the same manner and measuring the powder X-ray diffraction It is a method for quantifying the content of each crystal form in the crystal mixture and the crystallinity of the crystal mixture from the size of the intrinsic peak in the medium and the calibration curve. It is said that the limit is about 5 to 10%, and there is a possibility that crystal form transition, non-crystallization, crystallization, etc. may occur during grinding. , As a method of analyzing a crystal or presence of amorphous amounts such as not be said to be necessarily suitable. Furthermore, since the crystal content itself in the preparation is small, the lower limit of quantification is further increased, and the crystal form content and the crystallinity of the crystal sample can be accurately quantified. was difficult.

  In order to reduce the limit of quantification and create a more reliable calibration curve, prepare a standard mixed powder by uniformly crushing the crystals as much as possible without changing the crystal form, crystallinity, etc., and mixing them evenly. However, it is necessary to prepare a calibration curve using the standard mixed powder, but until now, the crystals are homogenized as much as possible without causing crystal form transition, non-crystallization, crystallization, etc. The method for preparing the standard mixed powder is not known, and the method for quantifying crystals with unknown contents having a smaller lower limit of quantification has not been known.

  Under such circumstances, the present inventor can prepare a standard mixed powder that is pulverized and mixed as homogeneously as possible without causing crystal transformation, amorphization, crystallization, etc. A highly calibrated calibration curve was created, and intensive studies were conducted to develop a method for quantifying crystals with a smaller quantification limit. Two or more crystals with different crystal forms or crystallinity levels were pulverized using an airflow pulverizer. By doing so, a fine powder crystal is obtained, and the fine powder crystal is placed in a hollow container provided with a mixing medium having at least an outer surface formed of an elastic body, and the hollow container is vibrated or rotated to pulverize the fine powder crystal. By mixing the crystals, it is possible to obtain a mixed fine powder having a homogeneous mixed state without causing a change in crystal form, a change in crystallinity, etc., and using the mixed fine powder as a standard mixed powder, Line diffraction measurement Thus, the correlation between the weight of each crystal form in the mixed fine powder or the crystallinity of the mixed powder and the size of the intrinsic peak of each crystal in the obtained powder X-ray diffraction profile is more reliable. It has been found that a calibration curve can be prepared, and by using such a calibration curve, crystals with unknown contents can be quantified more precisely, leading to the present invention.

That is, the present invention includes (a) a step of pulverizing two or more types of crystals having different crystal forms or crystallinity levels independently using an airflow pulverizer to obtain respective pulverized crystals;
(B) Each of the pulverized crystals is weighed in a predetermined amount, placed in a hollow container provided with a mixed medium having at least an outer surface formed of an elastic body, and the pulverized crystal is vibrated or rotated. Performing a mixing process of crystals to obtain a plurality of standard mixed powders having different crystal content or crystallinity;
(C) Powder X-ray diffraction measurement of the standard mixed powder, the size of the intrinsic peak of each crystal in the obtained powder X-ray diffraction profile, the weight of each crystal form in the standard mixed powder, or the standard mixed powder Creating a calibration curve for correlation with crystallinity of
(D) crushing the crystal mixture to be quantified;
(E) Powder X-ray diffraction measurement of the pulverized crystal mixture, from the size of the intrinsic peak of each crystal in the obtained powder X-ray diffraction profile and the calibration curve created in the step (c), A step of calculating the content of each crystal form in the crystal mixture to be quantified or the crystallinity of the crystal mixture, a method of preparing a standard mixed powder used in the quantification method, and the method The present invention provides a method for preparing a calibration curve used in a quantitative method.

  According to the present invention, since the lower limit of quantification is smaller and precise quantification is possible, of course, the field of medicine that requires precise quantification such as quantification of a small amount of crystal polymorphs, quantification of a small amount of amorphous, etc. It is also useful in other fields.

The crystal quantification method of the present invention is characterized by including the following steps (a) to (e), and a calibration curve with a smaller quantification limit can be created by such a quantification method. The crystal form and amorphous contained in a trace amount in the crystal mixture can be quantified.
(A) Two or more kinds of crystals having different crystal forms or crystallinity levels are independently pulverized using an airflow pulverizer to obtain respective pulverized crystals (hereinafter abbreviated as step (a)). ), (B) weighing each of the pulverized crystals by a predetermined amount, placing them in a hollow container provided with a mixed medium having at least an outer surface formed of an elastic body, and vibrating or rotating the hollow container, Steps of mixing the pulverized crystals to obtain a plurality of standard mixed powders having different crystal form content ratios or crystallinity (hereinafter abbreviated as step (b)), (c) the standard mixed powders as powders X-ray diffraction measurement and calibration of correlation between the size of the intrinsic peak of each crystal in the obtained powder X-ray diffraction profile and the weight of each crystal form in the standard mixed powder or the crystallinity of the standard mixed powder line Creating step (hereinafter abbreviated as step (c)), (d) crushing crystal mixture to be quantified (hereinafter abbreviated as step (d)), (e) crushing treatment The crystal mixture is subjected to powder X-ray diffraction measurement. From the size of the intrinsic peak of each crystal in the obtained powder X-ray diffraction profile and the calibration curve created in the step (c), A step of calculating the content of the crystal form or the crystallinity of the crystal mixture (hereinafter abbreviated as step (e)).

  Hereafter, it demonstrates in order for every step based on the flowchart of the fixed_quantity | assay method of this invention shown in FIG.

  In step (a), as described above, two or more types of crystals having different crystal forms or crystallinity levels are independently pulverized using an airflow pulverizer to obtain respective pulverized crystals (FIG. 1, S1). ). By this step, fine and non-oriented crushed crystals are obtained.

  As an air-flow type pulverizer for independently pulverizing two or more types of crystals having different crystal forms or crystallinity, the crystal to be crushed is contained in a jet stream generated by compressed air or compressed inert gas ejected from a nozzle. There is no particular limitation as long as it is a pulverizer that supplies and pulverizes crystals by collision of crystals in a jet stream or collision of crystals with a collision plate. Examples of such airflow type pulverizers include jet mills, and commercially available ones are used. Commercially available jet mills include, for example, A-O jet mill (manufactured by Seishin Enterprise Co., Ltd.), spiral jet mill (manufactured by Hosokawa Micron Corporation), counter jet mill (manufactured by Hosokawa Micron Corporation), and single track jet mill (Stock of Hosokawa Micron Corporation). Company-made), super single track jet mill (manufactured by Hosokawa Micron Corporation), current jet (manufactured by Nissin Engineering Co., Ltd.), and the like.

  There are no particular restrictions on the material of the mill part where the crystals are pulverized, and examples include stainless steel, alumina, zirconia, silicon carbide, silicon nitride, and the like.

In the pulverization process, from the viewpoint of the accuracy of the calibration curve described later, the air flow rate of the airflow pulverizer, compressed air for generating a jet airflow, or a non-compressed air is generally used so that a crushed crystal having a D ₉₀ of about 10 μm or less is obtained. The pulverization conditions such as the pressure of the active gas and the amount of crystals charged into the airflow pulverizer can be determined as appropriate.

  When the pulverized crystals discharged from the airflow pulverizer are collected and the pulverization process is completed for a predetermined number of crystals (S2 in FIG. 1), the process proceeds to the next step (b). The collected crushed crystals may be further put into an airflow pulverizer, and the pulverization treatment may be performed twice or more.

  In step (b), the pulverized crystals obtained in step (a) are weighed in predetermined amounts, respectively, and placed in a hollow container provided with a mixing medium having at least an outer surface formed of an elastic body. In this step, the pulverized crystals are mixed by vibrating or rotating the container to obtain a plurality of standard mixed powders having different crystal content and crystallinity (FIG. 1, S3).

  By this step (b), the fine, non-oriented pulverized crystals obtained in the step (a) can be uniformly mixed without causing crystal form transition, change in crystallinity, etc. It is possible to obtain a standard mixed powder capable of creating a highly calibrated calibration curve.

  A plurality of standard mixed powders having different content ratios or crystallinity levels of two or more crystal forms are prepared. The number of standard mixed powders may be two or more. Of course, as the number increases, a more accurate calibration curve can be created. Therefore, the number may be determined according to the purpose or the like. In addition, for example, when the content of each crystal form contained in the crystal mixture to be quantified in step (d) described later or the crystallinity of the crystal mixture can be predicted, it is close to or expected from the expected content. A calibration curve in the vicinity of the degree of crystallinity may be created.

  For weighing the crushed crystals obtained in the step (a), for example, a weighing instrument such as an electronic balance is used, and a predetermined amount is weighed by the weighing instrument. The predetermined amount to be weighed is not particularly limited as long as a calibration curve can be created.

  Each ground crystal weighed is placed in a hollow container provided with a mixing medium having at least an outer surface formed of an elastic body, and the hollow container is vibrated or rotated, whereby the ground crystal is mixed. A plurality of standard mixed powders having different crystal form contents or crystallinity levels are obtained.

  The hollow container may be a hollow sealed container provided with an inlet for supplying the pulverized crystals and an outlet for discharging the mixed powder after mixing, and the size is not particularly limited. The input port and the discharge port may be provided separately, or one input / discharge port serving as the input port and the discharge port may be provided.

  The material of the hollow container is not particularly limited, and examples thereof include stainless steel, alumina, zirconia, and ceramic. In addition, if a hollow container in which the inner surface of a hollow container that is in contact with the pulverized crystal or the mixing medium is formed of an elastic material can be used, the impact on the pulverized crystal during mixing can be further reduced. This is preferable because the crystal form transition, crystallinity change and the like are less likely to occur.

  The mixing medium may be any shape that can mix the pulverized crystals in contact with the pulverized crystals, such as spherical or columnar shapes, and the number of the mixed media is not particularly limited as long as the mixed medium can move within the hollow container. .

  At least the outer surface of such a mixing medium is formed of an elastic body, so that even when in contact with the pulverized crystal, it can be mixed without causing a transition of the crystal form of the pulverized crystal, a change in crystallinity, or the like. it can.

  As described above, at least the outer surface of the mixed medium is formed of an elastic body and has a certain degree of elasticity, and the entire mixed medium may be formed of an elastic body. In the case of a mixed medium in which the outer surface is formed of an elastic body and the inside is formed of a hard material other than an elastic body such as ceramic, the outer surface layer formed of the elastic body is It is only necessary to have a thickness having elasticity that does not change the crystal form or crystallinity of the crushed crystals.

  As the elastic body, an elastic body having a rubber hardness of 20 to 90 as measured by a type A durometer normally defined in JIS K6253 is used, and preferably the rubber hardness is in the range of 40 to 85. An elastic body is used.

  Examples of the material of the elastic body include natural rubber, synthetic rubber, resin, elastomer, cork and the like, and synthetic rubber and resin are preferable. Examples of synthetic rubber include silicon rubber, urethane rubber, fluorine rubber, polysulfide rubber, acrylic rubber, butadiene rubber, styrene rubber, styrene butadiene rubber, acrylonitrile butadiene rubber, isoprene isobutylene rubber, ethylene propylene rubber, chloroprene rubber, and chlorosulfonated. Examples thereof include polyethylene rubber, and silicon rubber and urethane rubber are preferable. Examples of the resin include vinyl chloride resin and polyethylene resin.

  As the elastic body, for example, an elastic body having conductivity such as a conductive rubber obtained by mixing a conductive material such as carbon or iron into the elastic body may be used. By using a mixed medium formed of an elastic body having at least the outer surface having conductivity, adhesion of the powder to the mixed medium can be reduced and the mixed powder can be taken out more easily. In addition, for example, when mixing electrostatically charged powder or easily charged electrostatic powder, it is preferable to use a mixed medium in which at least the outer surface is formed of an elastic body having conductivity.

  What is necessary is just to determine the magnitude | size and the number of use of a mixing medium suitably according to the magnitude | size of the hollow part of a hollow container.

  The vibration or rotation of the hollow container may be performed artificially or mechanically. From the viewpoint of reproducibility of the mixing process, it is preferable to mechanically vibrate or rotate. There is no particular limitation on the number of vibrations or the number of rotations per unit time. The mixing time may be appropriately determined according to the number of mixing media, the number of vibrations or the number of rotations, the type of pulverized crystal, and the like.

  Examples of the device that mechanically vibrates or rotates the hollow container include a mixing device including a vibration or rotating device that vibrates or rotates the hollow container. Examples of the mixing device provided with the vibration or rotation device for vibrating or rotating the hollow container include a cylindrical mixer, a V-type mixer, a vibration mill, a rotary mill, a rolling mill, and the like, and are usually commercially available. Things are used.

  In addition, as described above, by using a hollow container in which at least the inner surface of the hollow container is formed of an elastic body, it is possible to further weaken the impact on the pulverized crystal during the mixing process. The transition of the crystal form of the crystal, the change in crystallinity and the like are less likely to occur, and are more preferable.

  When the mixing process is completed for a predetermined number of crushed crystals (S4 in FIG. 1), the process proceeds to the next step (c).

  In step (c), the standard mixed powder obtained in step (b) is subjected to powder X-ray diffraction measurement (FIG. 1, S5 and S6), and the size of the intrinsic peak of each crystal in the obtained powder X-ray diffraction profile is determined. This is a step of creating a calibration curve correlating with the weight of each crystal form in the standard mixed powder or the crystallinity of the standard mixed powder (S7 in FIG. 1).

  As a method for powder X-ray diffraction measurement of the standard mixed powder, a normal powder X-ray diffraction method may be used. Usually, a certain amount of each standard mixed powder is weighed and measured by a powder X-ray diffractometer. As a scanning mode in the powder X-ray diffraction method, a continuous mode in which measurement is performed while driving the shaft at a constant speed may be used, or a step mode in which the shaft is fed at a constant angle and counted in a stationary state is used. Also good. The step mode is preferable in that the statistical error of the intensity of the peak in the low content range is small. In the case of the step mode, the diffraction angle of the selected intrinsic peak which will be described later is usually selected.

  For each crystal, the powder X-ray diffraction measurement was performed alone in advance, the specific peak of each crystal was selected, the size of each selected specific peak was determined from the obtained powder X-ray diffraction profile, and the obtained specific peak A calibration curve is created by plotting the data with the peak size on the vertical axis and the weight of each crystal form in the standard mixed powder or the crystallinity of the standard mixed powder on the horizontal axis (Fig. 1 S7). Examples of the size of the intrinsic peak at the time of plotting include the intensity of the intrinsic peak, the peak area of the intrinsic peak, the relative intensity of the intrinsic peak, and the sum of the intrinsic peaks when there are a plurality of intrinsic peaks. In addition, when a standard mixed powder is prepared using two or more types of crystals having different crystal forms, each crystal form has a specific diffraction peak, that is, is detected in any one crystal form, and other crystals. A diffraction peak unique to each crystal form that is not detected in the form may be regarded as an intrinsic peak. In addition, when a standard mixed powder is prepared using two or more types of crystals having different crystallinity levels, any of the detected diffraction peaks may be an intrinsic peak, but a diffraction peak having a large change in intensity is inherent. A peak is preferable.

  In the present invention, the crystallinity is normally defined as 100% crystallinity of the crystal sample and 0% crystallinity of the amorphous sample in which no diffraction peak is detected in the powder X-ray diffraction profile. In other words, the crystallinity of the standard mixed powder may be obtained from the crystallinity of crystals having different crystallinity when preparing the standard mixed powder and the mixing weight ratio thereof. For example, a crystal having a crystallinity of 100% and a crystal having a crystallinity of 10%, that is, an amorphous material are used, and a crystal having a crystallinity of 100% / a crystal having a crystallinity of 10% (weight ratio) is 100/0, 80 When the five standard mixed powders of / 20, 50/50, 20/80 and 0/100 were prepared, the crystallinity of each standard mixed powder was 100%, 82%, 55%, 28% and 10%, respectively. %.

  The powder X-ray diffraction measurement (FIG. 1 S5) may be performed at least once for each standard mixed powder. Of course, each standard mixed powder may be measured twice or more from the viewpoint of making the measurement error smaller and creating a calibration curve with higher accuracy.

  When powder X-ray diffraction measurement is completed for a predetermined number of standard mixed powders (FIG. 1 S6), a calibration curve is created (FIG. 1 S7). The calibration curve represents, for example, the size of the intrinsic peak of each crystal in the obtained powder X-ray diffraction profile, the weight of each crystal form in the standard mixed powder, or the crystallinity of the standard mixed powder. A graph in which data is plotted on the horizontal axis, for example, a correlation between the two is represented by an approximate expression such as a linear equation or a quadratic equation, for example. An example of a calibration curve graph is shown in FIG.

  If a calibration curve is created, the process proceeds to the next step (d).

  Step (d) is a step of pulverizing the crystal mixture to be quantified (S8 in FIG. 1).

  The pulverization may be performed, for example, by placing the crystal mixture to be quantified into an agate mortar and grinding it artificially or mechanically. Alternatively, the pulverization may be performed by the same method using the airflow pulverizer as in step (b). May be. It is preferable to carry out the pulverization by the same method using the airflow pulverizer as in the latter step (b), since there is less possibility of crystal form transition, change in crystallinity, and the like.

  When the pulverization of the crystal mixture to be quantified is completed, the process proceeds to the next step (e).

  In step (e), the crystal mixture pulverized in step (d) is subjected to powder X-ray diffraction measurement, and the size of the intrinsic peak of each crystal in the obtained powder X-ray diffraction profile is determined. This is a step of calculating the content of each crystal form in the crystal mixture to be quantified or the crystallinity of the crystal mixture from the calibration curve created in (S9 in FIG. 1).

  What is necessary is just to implement the powder X-ray-diffraction measurement of the crystal | crystallization mixture grind | pulverized by the said step (d) by the normal powder X-ray-diffraction method. The measurement amount used for the measurement is usually approximately the same as the amount of the standard mixed powder used in the powder X-ray diffraction measurement in the step (c).

  The crystal mixture is subjected to powder X-ray diffraction measurement, and the content or crystal of each crystal form is determined from the size of the intrinsic peak of each crystal in the obtained powder X-ray diffraction profile and the calibration curve created in the step (c). The degree of conversion is calculated. The size of the intrinsic peak is the same as that used when the calibration curve was created in step (c). The content or crystallinity of each crystal form is, for example, when the vertical axis of the calibration curve graph is the size of the intrinsic peak and the horizontal axis is the content or crystallinity of the crystal form, Plot the size of the intrinsic peak of the crystal mixture on the vertical axis, draw a horizontal line from the plot position, find the intersection of the horizontal line and the calibration curve, subtract the vertical line from the intersection, the vertical line and the horizontal axis What is necessary is just to read the intersection of. When the calibration curve is expressed by an approximate expression, the content or crystallinity of the crystal form may be calculated by substituting the size of the intrinsic peak into the approximate expression.

  Further, by using the quantification method of the present invention, the content of each crystal contained in the produced crystal or preparation or the crystallinity of the crystal is measured, and according to the change in the content or crystallinity. By controlling and managing the factor conditions affecting the generation or crystallinity of crystal polymorphs in the process of producing the crystal or the formulation process of producing a preparation containing the crystal, the content of each crystal or A crystal having a stable crystallinity or a preparation containing the crystal can be produced.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to this Example.

Example 1
<Acquisition of ground crystals>
Using α-O jet mill (Venturi pressure 0.5 MPa, grounding pressure 1 0.5 MPa and grounding pressure 2 0.5 MPa) manufactured by Seishin Corporation, α-form indomethacin crystals are pulverized (supply of crystals to the jet mill) The speed was 30 to 40 g per hour), and α-type pulverized crystals having a particle diameter of about 10 μm or less were obtained. Similarly, γ-type indomethacin crystals were pulverized to obtain γ-type crushed crystals having a particle size of about 10 μm or less.

<Preparation of standard mixed powder>
The α-type crushed crystal and the γ-type crushed crystal are weighed in predetermined amounts, respectively, and a urethane rubber ball (diameter: about 20 mm, weight: about 4-5 g, rubber hardness measured with a type A durometer) 70) in a hollow container of a vibration mill (TI-100 type, manufactured by CMT Scientific Co., Ltd.) using a mixed medium (number: 3), and vibrated for 3 minutes at a vibration rotational speed of 1730 rpm / 60 Hz and an amplitude of 7 mm. Standard mixed powders 1 to 10 (about 2 g each) having different content ratios of 10 types of α forms shown in Table 1 were prepared.

<Creation of calibration curve>
The prepared standard mixed powders 1 to 10 were each subjected to powder X-ray diffraction measurement. The scanning mode was a continuous mode (scanning speed: 2.0 ° / min, sampling width: 0.02 °), and about 200 mg of each standard mixed powder was refilled and measured three times. Further, about 200 mg of each standard mixed powder was refilled and measured three times by setting the scanning mode to the step mode (diffraction angle of intrinsic peak (2θ) = 8.4 °, counting time: 20 seconds, sampling width: 0.01 °). . In any scanning mode, the standard mixed powder 2 was measured by refilling 5 times.

  The diffraction profile obtained by measurement in the continuous mode is shown in FIG. 2, and the average value of the peak intensity of the intrinsic peak (diffraction angle (2θ) = 8.4 °) from the diffraction profile is shown in Table 2. In addition, FIG. 3 shows the diffraction profile obtained by measurement in the step mode (diffraction angle of intrinsic peak (2θ) = 8.4 ° vicinity), and the average value of the peak intensity of the intrinsic peak is calculated from the diffraction profile. It is shown in Table 3.

  The calibration curve was created by plotting the data in Table 3 with the abscissa representing the α-form content (% by weight) in each standard mixed powder and the ordinate representing the average value of the peak intensity of the intrinsic peak. The prepared calibration curve is shown in FIG. When the calibration curve in FIG. 4 is expressed by an approximate linear equation, the slope is 1675.6 and the intercept is 10554.

<Quantification of mixed crystals of unknown composition>
The α-form and γ-form indomethacin mixed crystals of unknown composition were carefully ground in an agate mortar and pulverized. When the obtained pulverized powder was measured by powder X-ray diffraction (scanning mode: step mode), the peak intensity at a diffraction angle (θ) = 8.4 ° was 12924 cps. From the calibration curve shown in FIG. 4, the composition of indomethacin crystal having an unknown composition was obtained, and it was a mixed crystal having a composition ratio of α-form crystal / γ-form crystal = 1.4 / 98.6 (weight ratio). I understood.

Example 2
<Acquisition of ground crystals>
Γ-type indomethacin crystals were pulverized using an A-O jet mill (Venturi pressure 0.5 MPa, grounding pressure 1 0.5 MPa and grounding pressure 2 0.5 MPa) manufactured by Seishin Corporation (supply of crystals to the jet mill) The speed was 30 to 40 g per hour), and γ-type crushed crystals (with a crystallinity of 100%) having a particle size of about 10 μm or less were obtained. Further, after melting the γ-type indomethacin crystal at 180 ° C., it is rapidly cooled with liquid nitrogen to obtain an indomethacin amorphous, the amorphous is pulverized, and a pulverized amorphous having a particle diameter of about 10 μm or less (crystallinity 0%) Was obtained.

<Preparation of standard mixed powder>
γ-type crushed crystals and crushed amorphous were weighed in predetermined amounts, and a urethane rubber ball (diameter of about 20 mm, weight of about 4 to 5 g, rubber hardness of 70 measured with a type A durometer) was formed entirely with urethane rubber. ) In a hollow container of a vibration mill (TI-100, manufactured by CMT Science Co., Ltd.) using a mixed medium (number: 3), and vibrated for 3 minutes at a vibration rotational speed of 1730 rpm / 60 Hz and an amplitude of 7 mm. Different kinds of mixed powders were obtained. A predetermined amount of mannitol (9 times by weight with respect to the mixed powder) was added to each mixed powder to prepare nine types of standard mixed powders 1 ′ to 9 ′ having different crystallinity levels shown in Table 4.

<Creation of calibration curve>
About the obtained standard mixed powders 1 ′ to 9 ′, powder X-ray diffraction analysis (collected about 200 mg of mixed powder, scanning mode: continuous mode, diffraction angle of intrinsic peak (2θ) = 11.6 °, scanning speed: 2) (Degree / min, sampling width: 0.02 °). From the obtained X-ray diffraction profile, the relationship between the average value of the peak intensity of the diffraction peak of the intrinsic peak of the γ-type indomethacin crystal (2θ) = 11.6 ° and the crystallinity is shown in Table 5. A calibration curve was prepared by plotting the data in Table 5 with the crystallinity (%) of each standard mixed powder on the horizontal axis and the average value of the peak intensity of the intrinsic peak on the vertical axis. The prepared calibration curve is shown in FIG. When the calibration curve in FIG. 5 is expressed by an approximate linear equation, the slope is 29.236, and the intercept is −171.52.

  By using the calibration curve shown in FIG. 5, the crystallinity of the γ-type indomethacin crystal whose crystallinity is unknown can be measured.

Example 3
<Acquisition of ground crystals>
In the same manner as in Example 1, α-type crystal / amorphous mixed indomethacin and γ-type crystal / amorphous mixed indomethacin were each pulverized to obtain respective powders. The crystallinity of the α-type crystal / amorphous mixed indomethacin powder was 43.9%, and that of the γ-type crystal / amorphous mixed indomethacin powder was 53.4%. It was.

<Preparation of standard mixed powder>
The obtained α-form crystal / amorphous mixed indomethacin powder and γ-form crystal / amorphous mixed indomethacin powder were weighed in predetermined amounts, respectively, to prepare standard mixed powders a to f shown in Table 6. In the table, α-form content (content ratio of α-form indomethacin crystal) and γ-form content ratio (content ratio of γ-form indomethacin crystal) are α-form crystal / amorphous mixed indomethacin powder and γ-form crystal / amorphous. Calculated from the mixing ratio of the mixed indomethacin powder and the crystallinity of the α-form crystal / amorphous mixed indomethacin powder and the γ-form crystal / amorphous mixed indomethacin powder, the amorphous content is the α-form content and the γ-form content The sum of the values was subtracted from 100.

<Creation of calibration curve>
The standard mixed powders a to f were subjected to powder X-ray diffraction analysis (collected about 50 mg of mixed powder, scanning mode: continuous mode). From the obtained X-ray diffraction profile, the diffraction angle of the intrinsic peak of α-form indomethacin crystal (2θ) = the sum of the peak intensities of the three diffraction peaks at 8.4 °, 11.8 ° and 14.4 ° Average value and diffraction angle (2θ) of intrinsic peak of γ-type indomethacin crystal = 12.5 °, 16.6 °, and average value of total value of peak intensity of three diffraction peaks of 21.8 ° are calculated respectively. A calibration curve graph was prepared by taking the α-form content or γ-form content on the horizontal axis and the average on the vertical axis, and the results are shown in FIGS. 6 (a) and 6 (b), respectively. When the calibration curve shown in FIG. 6 (a) is expressed by an approximate linear equation, the slope is 287.23 and the intercept = 736.39, and the calibration curve shown in FIG. 6 (b) is expressed by an approximate linear equation. The slope was 580.48 and the intercept was 2719.7.

  Further, when the crystallinity of the standard mixed powders a to f was measured by the Luland method, as shown in Table 7, the mixing ratio of the α-type crystal / amorphous mixed indomethacin powder and the γ-type crystal / amorphous mixed indomethacin powder was obtained. It was also confirmed that there was almost no difference between the calculated value calculated based on this and the actual value measured by the Roland method.

<Quantification of mixed crystals of unknown composition>
A mixture of α-form and γ-form indomethacin of unknown composition (the degree of crystallinity is also unknown) was carefully ground in an agate mortar and pulverized. The obtained pulverized powder is subjected to powder X-ray diffraction measurement (scanning mode: continuous mode), and the contents of α form and γ form are calculated based on the calibration curves shown in FIGS. 6 (a) and 6 (b). did. The value obtained by subtracting the sum of the calculated α-form content and γ-form content from 100 was taken as the amorphous content. As a result, it was found that the composition of the indomethacin mixture whose composition was unknown was α-form crystal / γ-form crystal / amorphous = 10.5 / 32.9 / 56.6 (weight ratio).

It is a flowchart of the fixed_quantity | assay method of this invention. It is an X-ray diffraction profile obtained by conducting powder X-ray diffraction analysis of standard mixed powders 1 to 10 in a continuous mode. It is an X-ray diffraction profile (diffraction profile in the vicinity of an intrinsic peak diffraction angle (2θ) = 8.4 °) obtained by performing powder X-ray diffraction analysis of standard mixed powders 1 to 10 in a step mode. It is a calibration curve graph created by plotting the data shown in Table 3. 6 is a calibration curve graph created by plotting the data shown in Table 5. (A) It is the graph which plotted the result, taking the average value of the total value of the peak intensity of three diffraction peaks on the horizontal axis | shaft, and making the vertical axis | shaft the content rate of (alpha) -form indomethacin crystal. (B) A graph in which the content of γ-type indomethacin crystals is plotted on the horizontal axis and the average value of the total peak intensities of three diffraction peaks is plotted on the vertical axis.

Claims (5)

(A) two or more kinds of crystals having different crystal forms or crystallinity levels are independently pulverized using an air-flow pulverizer to obtain respective pulverized crystals;
(B) Each of the pulverized crystals is weighed in a predetermined amount, placed in a hollow container provided with a mixed medium having at least an outer surface formed of an elastic body, and the pulverized crystal is vibrated or rotated. Performing a mixing process of crystals to obtain a plurality of standard mixed powders having different crystal content or crystallinity;
(C) Powder X-ray diffraction measurement of the standard mixed powder, the size of the intrinsic peak of each crystal in the obtained powder X-ray diffraction profile, the weight of each crystal form in the standard mixed powder, or the standard mixed powder Creating a calibration curve for correlation with crystallinity of
(D) crushing the crystal mixture to be quantified;
(E) Powder X-ray diffraction measurement of the pulverized crystal mixture, from the size of the intrinsic peak of each crystal in the obtained powder X-ray diffraction profile and the calibration curve created in the step (c), A method for quantifying a crystal, comprising the step of calculating the content of each crystal form in the crystal mixture to be quantified or the crystallinity of the crystal mixture. The crystal quantification method according to claim 1, wherein in step (d), the crystal mixture to be quantified is pulverized using an airflow pulverizer. (A) two or more kinds of crystals having different crystal forms or crystallinity levels are independently pulverized using an air-flow pulverizer to obtain respective pulverized crystals;
(B) Each of the pulverized crystals is weighed in a predetermined amount, put into a hollow container provided with a mixing medium having at least an outer surface formed of an elastic body, and the hollow container is vibrated or rotated to pulverize the crushed crystals. And a step of obtaining a plurality of standard mixed powders having different crystal form content ratios or crystallinity degrees. (A) two or more kinds of crystals having different crystal forms or crystallinity levels are independently pulverized using an air-flow pulverizer to obtain respective pulverized crystals;
(B) Each of the pulverized crystals is weighed in a predetermined amount, placed in a hollow container provided with a mixing medium having at least an outer surface formed of an elastic body, and the pulverized crystal is vibrated or rotated. Performing a mixing process of crystals to obtain a plurality of standard mixed powders having different crystal content or crystallinity;
(C) Powder X-ray diffraction measurement of the standard mixed powder, the size of the intrinsic peak of each crystal in the obtained powder X-ray diffraction profile, the weight of each crystal form in the standard mixed powder, or the standard mixed powder A method for creating a calibration curve for quantifying the content or crystallinity of each crystal form in a crystal mixture, comprising the step of creating a calibration curve having a correlation with the crystallinity of the crystal. Using the crystal quantification method according to claim 1 or 2, the content of each crystal or the crystallinity of the crystal contained in the produced crystal or preparation is determined, and the content or crystal A method for managing the production of a crystal or a preparation, comprising controlling a production process of a crystal or a preparation process for producing a preparation containing the crystal according to a change in the degree of conversion.

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