CN111487266A - Quantitative determination method for monohydrate crystal form in medicinal crystal form of canagliflozin hemihydrate - Google Patents
Quantitative determination method for monohydrate crystal form in medicinal crystal form of canagliflozin hemihydrate Download PDFInfo
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- CN111487266A CN111487266A CN202010366052.6A CN202010366052A CN111487266A CN 111487266 A CN111487266 A CN 111487266A CN 202010366052 A CN202010366052 A CN 202010366052A CN 111487266 A CN111487266 A CN 111487266A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
- G01N23/20—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
- G01N23/20—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials
- G01N23/20008—Constructional details of analysers, e.g. characterised by X-ray source, detector or optical system; Accessories therefor; Preparing specimens therefor
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
- G01N23/20—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials
- G01N23/20008—Constructional details of analysers, e.g. characterised by X-ray source, detector or optical system; Accessories therefor; Preparing specimens therefor
- G01N23/2005—Preparation of powder samples therefor
Abstract
The invention discloses an X-ray powder diffraction method for determining monohydrate crystal form content in a medicinal crystal form of canagliflozin hemihydrate, which selects 2 theta =3.8 +/-0.1 degrees as a reference characteristic peak of the canagliflozin hemihydrate crystal form, selects 2 theta =4.2 +/-0.1 degrees and 8.4 +/-0.1 degrees as quantitative detection peaks of the canagliflozin monohydrate crystal form, selects the intensity ratio of the quantitative diffraction peaks of the two crystal forms as quantitative parameters, establishes a standard curve, and determines the quantification of the monohydrate crystal form in the canagliflozin hemihydrate. The method provided by the invention is used for determining the content of the monohydrate crystal form in the canagliflozin hemihydrate, is high in accuracy, is rapid and convenient, and can be used for effectively controlling the content of the monohydrate crystal form in the canagliflozin hemihydrate.
Description
Technical Field
The invention relates to a quantitative determination method of a compound, in particular to a determination method of monohydrate crystal form content in a pharmaceutical crystal form of canagliflozin hemihydrate based on an X-ray powder diffraction technology, and belongs to the technical field of medicines.
Background
Canagliflozin (Canagliflozin) is the first SG L T2 FDA-approved inhibitor for treating type II diabetes in adult patients, is a novel sodium-glucose cotransporter 2 (SG L T2) inhibitor drug, and increases glucose excretion by inhibiting reabsorption of glucose by kidneys, thereby reducing the elevated blood glucose level of diabetic patients.
WO2008069327a1 and CN101573368 disclose a crystalline form of canagliflozin hemihydrate and its XRD profile, and CN201480019637 discloses a crystalline form of canagliflozin monohydrate and its XRD profile. Generally speaking, different crystal forms of the same drug have certain difference in solubility, so that the in vitro dissolution and in vivo bioavailability of different crystal form drugs have obvious difference, and particularly, the crystal forms have larger influence on the solubility of the drugs which are difficult to dissolve in water. In addition, different crystal forms of the same drug often have certain differences in stability, thereby affecting storage and use of the drug. The crystal form of canagliflozin used clinically is a hemihydrate pharmaceutical crystal form (ACN 103896930A). In order to better control the quality and curative effect of the canagliflozin hemihydrate, the method has very important significance for researching the purity of the medicinal crystal form of the canagliflozin hemihydrate.
Disclosure of Invention
The invention aims to solve the technical problem of providing a method for measuring the content of the monohydrate crystal form in the medicinal crystal form of canagliflozin hemihydrate, which has high accuracy, is rapid and convenient, aiming at the defects of the prior art.
The invention aims to solve the technical problem by the following technical scheme, and the invention provides a quantitative determination method of a monohydrate crystal form in a pharmaceutical crystal form of canagliflozin hemihydrate based on an X-ray powder diffraction technology, which is characterized by comprising the following steps of: selecting 2 theta =3.8 +/-0.1 degrees as a reference characteristic peak of a canagliflozin hemihydrate crystal form, selecting 2 theta =4.2 +/-0.1 degrees and 8.4 +/-0.1 degrees as quantitative characteristic peaks of the canagliflozin monohydrate crystal form, selecting a quantitative diffraction peak intensity ratio of the two crystal forms as quantitative parameters, establishing a standard curve, and determining the content of the monohydrate crystal form in the canagliflozin hemihydrate.
The method for quantitatively determining the monohydrate crystal form in the medicinal crystal form of the canagliflozin hemihydrate further preferably adopts the technical scheme that an X-ray powder diffractometer is used during determination, CuK α rays are used as a diffraction source, lambda =1.5406A is adopted, working voltage is 40KV, working current is 40mA, step length is 0.02 degrees, scanning speed is 0.10S per step, slit width is 0.2mm, sorafen is 2.5 degrees, and a nickel optical filter is adopted, wherein the scanning angle range is 3-40 degrees.
The method for quantitatively determining the monohydrate crystal form in the medicinal crystal form of the canagliflozin hemihydrate further preferably adopts the technical scheme that: before measurement, crystal forms of canagliflozin hemihydrate and canagliflozin monohydrate are respectively taken, after full grinding, the crystal forms are sieved by a 100-mesh sieve, a proper amount of samples are weighed and placed in a sample tray, scanning is respectively carried out, 2 theta =3.8 +/-0.1 degrees is selected as a reference characteristic peak of the canagliflozin hemihydrate, and 2 theta = 8.4 +/-0.1 degrees and 4.2 +/-0.1 degrees are selected as quantitative characteristic peaks of the canagliflozin monohydrate.
The method for quantitatively determining the monohydrate crystal form in the medicinal crystal form of the canagliflozin hemihydrate further preferably adopts the technical scheme that: the method comprises the following steps:
(1) respectively taking crystal forms of canagliflozin hemihydrate and monohydrate, fully grinding, sieving by a 100-mesh sieve, taking a proper amount of samples, placing the samples in a sample tray for sample preparation, and respectively carrying out X-ray diffraction test;
(2) the measurement parameters comprise an X-ray powder diffractometer, CuK α rays as a diffraction source, lambda =1.5406A, working voltage of 40KV, working current of 40mA, step length of 0.02 degrees, scanning speed of 0.10S per step, slit width of 0.2mm, cable of 2.5 degrees and a nickel filter, wherein the scanning angle range is 3-40 degrees;
(3) selecting characteristic peaks for hemihydrate as 2 theta =3.8 ± 0.1 °, and characteristic peaks for monohydrate as 2 theta = 8.4 ± 0.1 ° and 4.2 ± 0.1 °; the X-ray powder diffraction method for determining the crystal form content of the monohydrate in the canagliflozin hemihydrate selects the ratio of the characteristic diffraction peak intensity of the monohydrate to the characteristic diffraction peak intensity of the hemihydrate as a quantitative parameter, establishes a standard curve and calculates.
Compared with the prior art, the method has the following beneficial effects:
(1) the method of the invention adopts a powder X-ray powder diffraction analysis method to research the content of the monohydrate crystal form in the canagliflozin hemihydrate, and because the method belongs to nondestructive testing, the content of various crystal forms in a sample can be truly reflected.
(2) The method for determining the crystal form content of the monohydrate in the canagliflozin hemihydrate is high in accuracy, fast and convenient, and can effectively control the crystal form content of the monohydrate in the canagliflozin hemihydrate.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of canagliflozin hemihydrate;
FIG. 2 is a DSC of canagliflozin hemihydrate;
FIG. 3 is an X-ray powder diffraction pattern of canagliflozin monohydrate;
FIG. 4 is a DSC chart of canagliflozin monohydrate.
Detailed Description
The invention is further illustrated by the following description of specific embodiments in conjunction with the accompanying drawings. It is to be understood that the following examples are for purposes of further illustrating the features and advantages of the present invention and that various changes and modifications may be made by one skilled in the art without departing from the spirit and scope of the invention. All falling within the scope of the present invention.
Example 1, a method for quantitative determination of a monohydrate crystal form of a pharmaceutical crystal form of canagliflozin hemihydrate comprising the steps of:
(1) respectively taking crystal forms of canagliflozin hemihydrate and monohydrate, fully grinding, sieving by a 100-mesh sieve, taking a proper amount of samples, placing the samples in a sample tray for sample preparation, and respectively carrying out X-ray diffraction test;
(2) the measurement parameters comprise an X-ray powder diffractometer, CuK α rays as a diffraction source, lambda =1.5406A, working voltage of 40KV, working current of 40mA, step length of 0.02 degrees, scanning speed of 0.10S per step, slit width of 0.2mm, cable of 2.5 degrees and a nickel filter, wherein the scanning angle range is 3-40 degrees;
(3) selecting characteristic peaks for hemihydrate as 2 theta =3.8 ± 0.1 °, and characteristic peaks for monohydrate as 2 theta = 8.4 ± 0.1 ° and 4.2 ± 0.1 °; the X-ray powder diffraction method for determining the crystal form content of the monohydrate in the canagliflozin hemihydrate selects the ratio of the characteristic diffraction peak intensity of the monohydrate to the characteristic diffraction peak intensity of the hemihydrate as a quantitative parameter, establishes a standard curve and calculates.
Example 2, method for quantitative determination of monohydrate crystal form in canagliflozin hemihydrate pharmaceutical crystal form:
the test method comprises the following steps:
a Bruker D8 Advance X-ray powder diffractometer takes CuK α rays as a diffraction source, lambda =1.5406A, working voltage is 40KV, working current is 40mA, step length is 0.02 degrees, scanning speed is 0.10S per step, slit width is 0.2mm, sorafe is 2.5 degrees, and a nickel filter is in a scanning angle range of 3-40 degrees.
Differential scanning calorimetry analysis (DSC) instrument: NETZSCH DSC 204 type differential thermal analyzer, temperature range: 30-230 ℃, heating rate: 10 ℃/min.
1 sample preparation
1.1 preparation of Canagliflozin hemihydrate crystal form standard substance
Taking a crystal form sample of the canagliflozin hemihydrate, fully and uniformly grinding, firstly sieving the crystal form sample by a 100-mesh sieve, collecting the sample which passes through the 100-mesh sieve, then sieving the sample by a 200-mesh sieve, and collecting the sample which cannot pass through the 200-mesh sieve, so that the granularity of the sample is kept consistent as much as possible, and the detection error caused by preferred orientation is reduced. PXRD detection is carried out on the sample, and a characteristic peak at 3.8 +/-0.1 degrees is obvious (refer to a No. 1 peak in the figure); the sample has only one absorption peak (shown in figure 2) at the temperature of 92.6 ℃ and the moisture content is 2.1 percent by DSC detection, and is used as a pure canagliflozin hemihydrate medicinal crystal form standard substance.
1.2 preparation of Canagliflozin monohydrate crystal form reference substance
Taking a crystal form sample of canagliflozin monohydrate, fully and uniformly grinding, firstly sieving with a 100-mesh sieve, collecting the sample passing through the 100-mesh sieve, then sieving with a 200-mesh sieve, and collecting the sample failing to pass through the 200-mesh sieve, so that the granularity of the sample is kept consistent as much as possible. Sampling for PXRD detection (see fig. 3); there was only one absorption peak by DSC, with a moisture content of 3.9% at around 100.5 ℃ (see figure 4), which was used to formulate the mixed sample as pure canagliflozin monohydrate form.
2 selection of characteristic peaks
2.1 comparing the canagliflozin hemihydrate crystal form X-ray diffraction pattern (shown in figure 1) with the canagliflozin monohydrate crystal form X-ray diffraction pattern (shown in figure 3), finding that characteristic peaks of the canagliflozin monohydrate crystal form at the 2 theta positions of 8.4 +/-0.1 degrees (shown in figure 3, diffraction peak No. 2) and 4.2 +/-0.1 degrees (shown in figure 3, diffraction peak No. 1) have no interference of other diffraction peaks at corresponding positions of the canagliflozin hemihydrate crystal form X-ray diffraction pattern, and the two peaks are the strongest diffraction peak and the second strongest diffraction peak of the canagliflozin monohydrate crystal form.
2.2 selection of reference characteristic peaks
Comparing a canagliflozin hemihydrate crystal form X-ray diffraction pattern (shown in figure 1) with a canagliflozin monohydrate crystal form X-ray diffraction pattern (shown in figure 3), finding that the canagliflozin hemihydrate crystal form with the 2 theta position of 3.8 +/-0.1 degrees has a characteristic peak, and in the corresponding position of the canagliflozin monohydrate crystal form X-ray diffraction pattern, the 2 theta position of 3.8 +/-0.1 degrees has no interference of other characteristic peaks, so that the characteristic peak at the position is selected as a reference characteristic peak.
2.3 drawing of Standard Curve
Adding canagliflozin monohydrate crystal form into canagliflozin hemihydrate crystal form by equivalent incremental method to prepare 7 samples (containing 1%, 2%, 3%, 5%, 7%, 9% and 10% of canagliflozin monohydrate respectively), shaking and mixing by a shaker, preparing samples, measuring X-ray powder diffraction condition, and calculatingThe ratio of the intensity of a selected characteristic peak with the 2 theta position of 8.4 +/-0.1 degrees to the intensity of a reference characteristic peak (the 2 theta is 3.8 +/-0.1 degrees) in a sample is taken as the abscissa, the content percentage of the monohydrate crystal form in the sample is taken as the ordinate, a standard curve is drawn according to the principle of the least square method, and the linear equation of y =0.0141x +0.0108 (r is obtained2=0.9932）。
2.4 accuracy survey
The content of the monohydrate crystal form in the pseudo-canagliflozin hemihydrate is not more than 3%, 3 groups of samples with quality level crystal form purity (the content of the monohydrate crystal form is 1.5%, 3% and 4.5% respectively) are prepared according to the preparation method of the canagliflozin standard product with known crystal form purity content, each sample is detected for 3 times, and the recovery rate is calculated. The average recovery was 96.3% and RSD was 4.6% (n = 9).
The foregoing is merely an example of the embodiments of the present invention, and it should be noted that, for those skilled in the art, the determination method of crystal form content in canagliflozin described in the present invention is modified or appropriately changed and combined to implement the technology of the present invention without departing from the content, spirit and scope of the present invention, and all similar modifications and variations will be obvious to those skilled in the art, which are deemed to be included in the content, spirit and scope of the present invention.
Claims (3)
1. A quantitative determination method for a monohydrate crystal form in a pharmaceutical crystal form of canagliflozin hemihydrate based on an X-ray powder diffraction technology is characterized by comprising the following steps: selecting 2 theta =3.8 +/-0.1 degrees as a reference characteristic peak of a canagliflozin hemihydrate crystal form, selecting 2 theta =4.2 +/-0.1 degrees and 8.4 +/-0.1 degrees as quantitative characteristic peaks of the canagliflozin monohydrate crystal form, selecting a quantitative diffraction peak intensity ratio of the two crystal forms as quantitative parameters, establishing a standard curve, and determining the content of the monohydrate crystal form in the canagliflozin hemihydrate.
2. The method according to claim 1, wherein the measurement is carried out by using an X-ray powder diffractometer using CuK α radiation as a diffraction source, λ =1.5406A, operating voltage of 40KV, operating current of 40mA, step size of 0.02 °, scanning speed of 0.10S per step, slit width of 0.2mm, cable of 2.5 °, nickel filter, and scanning angle of 3 ° -40 °.
3. The method for measuring according to claim 1, wherein: before measurement, crystal forms of canagliflozin hemihydrate and canagliflozin monohydrate are respectively taken, after full grinding, the crystal forms are sieved by a 100-mesh sieve, a proper amount of samples are weighed and placed in a sample tray, scanning is respectively carried out, 2 theta =3.8 +/-0.1 degrees is selected as a reference characteristic peak of the canagliflozin hemihydrate, and 2 theta = 8.4 +/-0.1 degrees and 4.2 +/-0.1 degrees are selected as quantitative characteristic peaks of the canagliflozin monohydrate.
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