Preparation method of omariglitazone dispersoid and crystal form quantitative detection method of omariglitazone dispersoid
By preparing omaglione dispersions using spray drying and combining this with X-ray powder diffraction for quantitative crystal form detection, the problems of omaglione crystal form conversion and degradation were solved, achieving efficient preparation and accurate detection, thus ensuring the stability and efficacy of the drug.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- HAIHUA LIFE (XIAMEN) TECH CO LTD
- Filing Date
- 2026-02-06
- Publication Date
- 2026-05-19
AI Technical Summary
During drug production and storage, the crystal form transformation and degradation products of oxaliplatin are difficult to control, affecting the stability and bioavailability of the drug. Efficient preparation methods and quantitative detection methods are needed to ensure the efficacy and safety of the drug.
Oligol dispersions were prepared by spray drying, using copovidone or hydroxypropyl methylcellulose acetate succinate as dispersants. Crystallization was quantitatively detected by X-ray powder diffraction, and crystallinity was calculated by the ratio of characteristic peak areas.
This technology enables the efficient preparation of oxaliplatin dispersions and accurate quantitative detection of crystal forms, improving the sensitivity and efficiency of detection and ensuring the stability and efficacy of the drug.
Smart Images
Figure CN122056836A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical chemical purification, specifically to a method for preparing an augerilon dispersion and a method for quantitative detection of the crystal form of the augerilon dispersion. Background Technology
[0002] Orforglipron is an oral small molecule GLP-1 receptor agonist developed by Eli Lilly. As a non-peptide compound, it can exert an effective anti-diabetic effect by enhancing glucose-dependent insulin secretion and improving energy balance. It has excellent oral bioavailability and does not require dietary restrictions.
[0003]
[0004] The original research company disclosed the semi-calcium salt crystal form of omega-3 and its preparation method in patent CN109790161A.
[0005] The original manufacturer disclosed in patent CN119497611A that the oligomeryne formulation dispersion has an amorphous crystal form.
[0006] Different crystal forms of the same drug may exhibit significant differences in appearance, solubility, melting point, dissolution rate, and bioavailability, thus affecting the drug's stability, bioavailability, and efficacy. This phenomenon is particularly pronounced in oral solid dosage forms. Drug polymorphism is one of the important factors affecting drug quality and clinical efficacy; therefore, when developing drugs with polymorphism, special attention should be paid to crystal form analysis.
[0007] However, improper conditions during drug production and storage can easily lead to crystal transformation and degradation products. Therefore, to ensure the efficacy and safety of drugs, it is necessary to determine non-target crystal forms in active pharmaceutical ingredients or formulations, and appropriate methods are required for quantitative analysis of crystal forms. Summary of the Invention
[0008] To address the aforementioned technical problems, this invention provides a method for preparing an augeriton dispersion and a method for quantitatively detecting the crystal form of the augeriton dispersion. The dispersion preparation method provided by this invention is highly efficient, and the crystal form quantitative detection method is convenient, rapid, highly sensitive, and accurate.
[0009] The objective of this invention is achieved through the following technical solution: A method for preparing an oxaliplatin dispersion involves dissolving crystalline oxaliplatin hemicalcium salt (active drug) and a dispersant in an alcohol solvent in a specific ratio, and then preparing the dispersion by spray drying.
[0010] The mass ratio of the crystalline oxaliplatin hemicalcium salt (active drug) to the dispersant is 3:7.
[0011] The dispersant is one of copovidone and hydroxypropyl methylcellulose acetate succinate, preferably copovidone.
[0012] The alcohol solvent is one of methanol and ethanol, preferably methanol.
[0013] The inlet temperature of the drying gas in the spray drying system is 110 to 130°C, preferably 120°C; the outlet temperature of the spray dryer is 70°C to 80°C, preferably 75°C.
[0014] This invention also provides a method for quantitative detection of the crystal form of oxaliplatin dispersions, which includes the following steps: (1) Determine the peak area of the reference standard: Perform X-ray powder diffraction on the reference standard and determine the peak area of the reference standard; (2) Determine the peak area of the test sample (Oglionene dispersion): Perform X-ray powder diffraction on the test sample and determine the peak area of the test sample; (3) Compare the peak areas of the test sample and the reference sample, and calculate the crystallinity of the omega-3 hemicalcium salt in the test sample according to the following formula;
[0015] Where Wr is the mass fraction of the reference standard, % Ar represents the average peak area in the X-ray powder diffraction pattern of the reference standard; Ax represents the peak area in the X-ray powder diffraction pattern of the sample. The reference standard is a mixture of crystalline oliquilon hemicalcium salt and a dispersant; The peak area is the sum of the peak areas in the region from 6.55 ± 0.2° to 6.95 ± 0.2° in the X-ray powder diffraction pattern represented by 2θ using Cu-Kα radiation.
[0016] The mass of the crystalline omega-3 hemicalcium salt in the reference standard is 3-30% of the mass of the dispersant.
[0017] X-ray powder diffraction tests were performed on a Bruker D8 X-ray powder diffractometer or a Rigaku X-ray powder diffractometer. The test conditions were as follows: tube voltage was set to 20-55 kV, for example 40-55 kV, preferably 40 kV; tube current was set to 20-55 mA, for example 40-55 mA, preferably 40 mA; step size was set to 0.001-0.04°, for example 0.001-0.02°, preferably 0.01°; and scan speed was set to 1-10° / min, for example 4-8° / min, preferably 4° / min.
[0018] Compared with the prior art, the advantages of the present invention are as follows: The method for preparing the augerilon dispersion of the present invention has a good inclusion effect, and the resulting dispersion does not contain crystalline augerilon hemicalcium salt.
[0019] The quantitative detection method for augeritron dispersion crystal form established in this invention has high sensitivity, meets the requirements for qualitative and quantitative detection, has good stability, short detection time, and effectively improves detection efficiency. Attached Figure Description
[0020] Figure 1 This is a characteristic peak spectrum of the quantitative detection of the crystal form of the oxaliplatin dispersion in the method optimization of Embodiment 2 of the present invention.
[0021] Figure 2 This is the XRPD spectrum of the oxaliplatin dispersion in the sample detection of Example 3 of the present invention.
[0022] Figure 3 This is an overlay image of the XRPD of blank excipient, test sample, and spiked test sample in the specificity test of Example 4 of the present invention.
[0023] Figure 4 This is a typical XRPD pattern from the system applicability experiment in Embodiment 5 of the present invention.
[0024] Figure 5 This is the working curve in the linear experiment of Embodiment 7 of the present invention. Detailed Implementation
[0025] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.
[0026] Example 1 Sample Preparation This invention provides a method for preparing an oxaliplatin dispersion, comprising the following steps: dissolving crystalline oxaliplatin hemicalcium salt active pharmaceutical ingredient and a dispersant in an alcohol solvent in a certain proportion, and then preparing the dispersion by spray drying, thereby obtaining the oxaliplatin dispersion. The dispersant is copovidone; the mass ratio of the crystalline oxaliplatin hemicalcium salt active pharmaceutical ingredient to the dispersant is 3:7; the alcohol solvent is methanol; the inlet temperature of the drying gas in the spray drying is 120°C; and the outlet temperature of the spray dryer is 75°C.
[0027] Example 2: Optimization of sample detection method: Screening of characteristic peaks and selection of instrument parameters This invention provides a method for quantitative detection of the crystal form of oxaliplatin dispersions, comprising the following steps: (1) Determine the peak area of the reference standard: Perform X-ray powder diffraction on the reference standard and determine the peak area of the reference standard; (2) Determine the peak area of the test sample (Oglionene dispersion): Perform X-ray powder diffraction on the test sample and determine the peak area of the test sample; (3) Compare the peak areas of the test sample and the reference sample, and calculate the crystallinity of the omega-3 hemicalcium salt in the test sample according to the following formula;
[0028] Where Wr is the mass fraction of the reference standard, % Ar represents the average peak area in the X-ray powder diffraction pattern of the reference standard; Ax represents the peak area in the X-ray powder diffraction pattern of the sample. The reference standard is a mixture of crystalline oliquilon hemicalcium salt and a dispersant; The peak area is the sum of the peak areas in a specific region of an X-ray powder diffraction pattern represented by 2θ using Cu-Kα radiation.
[0029] To select the optimal characteristic peaks, the inventors conducted a characteristic peak screening process, the specific screening method of which is as follows: Sample (equivalent to 30% crystallinity sample): Accurately weigh 30 mg of crystalline augeritron hemicalcium salt and 70 mg of copovidone, place them in a centrifuge tube, and shake thoroughly to mix evenly.
[0030] Three parallel samples (50 mg each, named Sample 1, Sample 2, and Sample 3) were taken for analysis. Peak area selection regions were screened, and the peak areas of different regions are summarized as follows:
[0031] Among the three selected characteristic peak regions, the region from 6.55±0.2° to 6.95±0.2° exhibits higher sensitivity and better reproducibility, and was therefore selected as the characteristic peak for the quantitative detection of oxaliplatin dispersion crystal forms. Taking sample 1 as an example, the peaks in the regions of 6.55±0.2° to 6.95±0.2°, 15.75±0.2° to 16.15±0.2°, and 11.85±0.2° to 12.25±0.2° are as follows: Figure 1 As shown.
[0032] Based on the above comparison results and the separation of characteristic peaks in each region, it can be concluded that the characteristic peak region of 6.55±0.2° to 6.95±0.2° exhibits better durability.
[0033] In addition, X-ray powder diffraction tests on the samples were performed on a Bruker D8 X-ray powder diffractometer or a Rigaku X-ray powder diffractometer. Test settings: pipe voltage 20-55kV; pipe current 20-55mA; step size 0.001-0.04°; The scanning speed is 1-10° / min.
[0034] Within the above-mentioned instrument setting parameters, the sample detection showed good reproducibility. Preferably, the optimal parameters for using the Rigaku Smartlab X-ray diffractometer are: tube voltage 40 kV, tube current 40 mA, step size 0.01°, and scanning speed 4° / min.
[0035] As can be seen from the above, the following methods can be used to quantitatively detect the crystal form of oxaliplatin dispersions: (1) Determine the peak area of the reference standard: Perform X-ray powder diffraction on the reference standard and determine the peak area of the reference standard; (2) Determine the peak area of the test sample (Oglionene dispersion): Perform X-ray powder diffraction on the test sample and determine the peak area of the test sample; (3) Compare the peak areas of the test sample and the reference sample, and calculate the crystallinity of the omega-3 hemicalcium salt in the test sample according to the following formula;
[0036] Where Wr is the mass fraction of the reference standard, % Ar represents the average peak area in the X-ray powder diffraction pattern of the reference standard; Ax represents the peak area in the X-ray powder diffraction pattern of the sample. The reference standard is a mixture of crystalline oligomerylon hemicalcium salt raw material reference standard and dispersant; The peak area is the sum of the peak areas in the region from 6.55 ± 0.2° to 6.95 ± 0.2° in the X-ray powder diffraction pattern represented by 2θ using Cu-Kα radiation.
[0037] The X-ray powder diffraction test was performed using a Rigaku Smartlab X-ray diffractometer from Japan. The optimal parameters were: tube voltage 40 kV, tube current 40 mA, step size 0.01°, and scanning speed 4° / min.
[0038] Example 3 Sample Detection: The test sample was tested using the optimized detection method from Example 2. This invention provides a method for quantitative detection of the crystal form of oxaliplatin dispersions, comprising the following steps: (1) Determine the peak area of the reference standard: Perform X-ray powder diffraction on the reference standard and determine the peak area of the reference standard; (2) Determine the peak area of the test sample (the oligomerylon dispersion obtained in Example 1): Perform X-ray powder diffraction on the test sample and determine the peak area of the test sample; (3) Compare the peak areas of the test sample and the reference sample, and calculate the crystallinity of the omega-3 hemicalcium salt in the test sample according to the following formula;
[0039] Where Wr is the mass fraction of the reference standard, % Ar represents the average peak area in the X-ray powder diffraction pattern of the reference standard; Ax represents the peak area in the X-ray powder diffraction pattern of the sample. The reference standard is a mixture of crystalline omaglineline hemicalcium salt active pharmaceutical ingredient reference standard and a dispersant; the dispersant is povidone. The mass ratio of the crystalline omaglineline hemicalcium salt active pharmaceutical ingredient reference standard to the dispersant is 7:3.
[0040] The peak area is the sum of the peak areas in the region from 6.55 ± 0.2° to 6.95 ± 0.2° in the X-ray powder diffraction pattern expressed as 2θ using Cu-Kα radiation. The X-ray powder diffraction experimental conditions used are shown in Table 1.
[0041] Table 1 Instrument Conditions
[0042] like Figure 2 The image shows the spectrum of the oxaliplatin dispersion obtained in Example 1 in the region from 6.55 ± 0.2° to 6.95 ± 0.2°, with a peak area of 0. The average peak area of the reference standard was 95.5. The mass fraction of the reference standard was 30%. Substituting into the above calculation formula, the crystallinity of the oxaliplatin dispersion obtained in Example 1 is 0%.
[0043] This demonstrates that the augerilon dispersion prepared by the method described in Example 1 of this invention has good inclusion effect and does not contain crystalline augerilon hemicalcium salt.
[0044] Example 4: Specificity Blank excipient: Accurately weigh 50 mg of blank excipient copovidone powder and place it on a collection glass plate for detection.
[0045] Test sample: Accurately weigh 50 mg of the test sample (the augerilon dispersion prepared by the method described in Example 1) and place it on the collection glass plate for detection.
[0046] Spiked test sample (equivalent to a 30% crystallinity sample): Accurately weigh 30 mg of crystalline augeritron hemicalcium salt and 70 mg of the augeritron dispersion obtained in Example 1, place them in a centrifuge tube, and shake thoroughly to mix evenly.
[0047] Determination method: Under the detection conditions in Table 1, blank excipients, test samples (Ogliflozin dispersion prepared by the method described in Example 1), and spiked test samples were tested and the XRPD chromatograms were recorded. Figure 3 This is a superimposed graph of the XRPD patterns of the blank excipient, the test sample (the aoglieron dispersion prepared by the method described in Example 1), and the spiked test sample (equivalent to a 30% crystallinity sample). Figure 3 It can be seen that the crystallization peak of oxaliplatin has good specificity, and the blank excipient did not interfere with its test.
[0048] Example 5: System Applicability Spiked test sample (equivalent to 6% crystallinity sample): Accurately weigh 6 mg of crystalline augeritron hemicalcium salt and 94 mg of the augeritron dispersion obtained in Example 1, place them in a centrifuge tube, and shake thoroughly to mix evenly. Prepare 6 parallel samples for testing.
[0049] Determination method: The spiked test sample was tested under the test conditions in Table 1, and the XRPD spectrum was recorded.
[0050] Experimental results: The system applicability verification results are shown in Table 2. Figure 4 The typical XRPD spectrum for system applicability shows that this method has high sensitivity.
[0051] Table 2 System Applicability Verification Results
[0052] The results show that the RSD of the peak area for the 6% crystallinity sample is no greater than 10.0%. The results demonstrate that the method has high sensitivity and good reproducibility, and can fully meet the requirements for quantitative detection of the crystal form of oxaliplatin dispersion.
[0053] Example 6: Detection Limit Spiked test sample (equivalent to 2% crystallinity sample): Accurately weigh 2 mg of crystalline omaglione hemicalcium salt raw material reference standard and 98 mg of omaglione dispersion, place them in a centrifuge tube, and shake thoroughly to mix evenly. Prepare 6 parallel tests.
[0054] Determination method: The spiked test sample was tested under the test conditions in Table 1, and the XRPD spectrum was recorded.
[0055] Experimental results: The detection limit verification results are shown in Table 3.
[0056] Table 3. Detection Limit Validation Results
[0057] The results show that the RSD of the peak area for the 2% crystallinity sample is no greater than 20.0%; the results demonstrate that the method has high sensitivity and can fully meet the requirements for quantitative detection of the crystal form of oxaliplatin dispersion.
[0058] Example 7: Linear Prepare different linear test samples according to the composition in Table 4, and shake thoroughly to mix evenly.
[0059] The linear validation results are shown in Table 5. A standard curve was plotted with crystallinity (%) on the x-axis and peak area on the y-axis, and the regression equation was calculated. The line graph is shown in [Table 5]. Figure 5 .
[0060] Table 4 Composition of linear test sample
[0061] Table 5 Linearity Validation Results
[0062] The results show that oxaliplatin exhibits a good linear relationship with peak area in the crystallinity range of 6-45%, with a correlation coefficient R0. 2 All are not less than 0.99.
[0063] Example 8: Accuracy Crystallized oxaliplatin hemicalcium salt and oxaliplatin dispersion were mixed to prepare mixed samples containing 15%, 30%, and 45% by mass of crystalline oxaliplatin hemicalcium salt, respectively. Three samples of each concentration were prepared and thoroughly shaken to ensure homogeneity. The crystallinity of each sample was calculated under the detection conditions in Table 1, and the recovery rate of each sample was calculated. The accuracy verification results are shown in Table 6.
[0064] Table 6 Accuracy Verification Results
[0065] The results showed that the recovery rate of the oxaliplatin dispersion was between 80% and 120% within the crystallinity range of 50%-150%, and the RSD of the recovery rate was less than 10.0%, indicating good method accuracy.
[0066] The above-described embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention to the scope of the described embodiments. The method of the present invention is also not limited to the quantitative detection of the osiglione dispersion crystal form; any quantitative determination of the osiglione crystal form using the method of the present invention falls within the scope of the present invention.
Claims
1. A method for preparing an augeridol dispersion, characterized in that: The crystalline octagon hemicalcium salt active pharmaceutical ingredient and dispersant were dissolved in an alcohol solvent in a certain proportion and then spray-dried to form a dispersion.
2. The preparation method according to claim 1, characterized in that: The mass ratio of the crystalline octagon hemicalcium salt active pharmaceutical ingredient to the dispersant is 3:
7.
3. The preparation method according to claim 1, characterized in that: The dispersant is one of copovidone and hydroxypropyl methylcellulose acetate succinate.
4. The preparation method according to claim 1, characterized in that: The alcohol solvent is one of methanol and ethanol.
5. The preparation method according to claim 1, characterized in that: The spray drying system has an inlet temperature of 110 to 130°C and an outlet temperature of 70 to 80°C.
6. A method for quantitative detection of the crystal form of an augeritron dispersion, characterized in that: It includes the following steps: (1) Determine the peak area of the reference standard: Perform X-ray powder diffraction on the reference standard and determine the peak area of the reference standard; (2) Determine the peak area of the test sample (Oglionene dispersion): Perform X-ray powder diffraction on the test sample and determine the peak area of the test sample; (3) Compare the peak areas of the test sample and the reference sample, and calculate the crystallinity of the omega-3 hemicalcium salt in the test sample according to the following formula; 7. Wherein, Wr is the mass fraction of the reference standard, % . Ar represents the average peak area in the X-ray powder diffraction pattern of the reference standard; Ax represents the peak area in the X-ray powder diffraction pattern of the sample. The reference standard is a mixture of crystalline oligomerylon hemicalcium salt raw material reference standard and dispersant; The peak area is the sum of the peak areas in the region from 6.55 ± 0.2° to 6.95 ± 0.2° in the X-ray powder diffraction pattern represented by 2θ using Cu-Kα radiation.
8. The quantitative detection method according to claim 6, characterized in that: The mass of crystalline omega-3 in the reference standard is 3-30% of the mass of the dispersant.
9. The quantitative detection method according to claim 6, characterized in that: X-ray powder diffraction tests were performed on a Bruker D8 X-ray powder diffractometer or a Rigaku X-ray powder diffractometer. The test conditions were as follows: tube voltage 20-55 kV; tube current 20-55 mA; step size 0.001-0.04°; and scanning speed 1-10° / min.