CN113372331B - Novel crystal form of Orientinib monohydrate - Google Patents
Novel crystal form of Orientinib monohydrate Download PDFInfo
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention belongs to the technical field of organic drug crystal forms, and discloses a novel crystal form of an octreotide monohydrate. The novel crystal form of the octreotide monohydrate uses Cu-K alpha radiation, and an X-ray diffraction spectrum shown by 2 theta has characteristic diffraction peaks at 5.9+/-0.2 degrees, 7.3+/-0.2 degrees, 9.1+/-0.2 degrees, 11.2+/-0.2 degrees, 25.2+/-0.2 degrees and 25.41 +/-0.2 degrees. Compared with the prior art, the crystal form provided by the invention has the advantages of simple preparation method and low cost, and has important value for optimizing and developing the medicine in the future. The novel crystal form of the oriatinib monohydrate prepared by the invention has high yield and purity, and good stability and dissolution.
Description
Technical Field
The invention belongs to the technical field of organic drug crystal forms, and particularly relates to an octreotide monohydrate crystal form.
Background
Orditinib, its chemical name is: n- [2- [ [2- (dimethylamino) ethyl ]](methyl) amino group]-4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl]Amino group]Phenyl group]The molecular formula of the prop-2-enamide is as follows: c (C) 28 H 33 N 7 O 2 The molecular weight is: 499.61. the structure is shown as 1:
ornitinib, the third generation oral, irreversible selective EGFR mutation inhibitor developed by the company Allicon, was approved in advance by the United states FDA on 11/13/2015 with accelerated approval, and was also the first tumor drug in China to be used for EGFR T790M mutation positive locally advanced or metastatic non-small cell lung cancer.
For advanced non-small cell (NSCLC) patients, targeted therapy of Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) mutations is the standard therapeutic regimen of today. The efficacy of these drugs is then generally short, and resistance occurs in 9-11 months, as cancer cells can escape the therapeutic activity of EGFR or ALK inhibitors by mutation and modification of growth patterns.
Ornitanib, developed by the company Alikang, is a third generation oral, irreversible selective EGFR mutation inhibitor that can be used for both active and resistant mutant EGFR, i.e., 50% of the acquired resistance to EGFR therapy in patients with advanced non-small cell lung cancer is caused by the T790M mutation, which could negate this challenging mutation. Ornitinib has better therapeutic effect on NSCLC patients with resistance to existing EGFR-receptor tyrosine kinase inhibitor (EGFR-TKI) and T790M mutation. The original research company used the oritinib mesylate for clinical studies. However, methanesulfonic acid salts have the problems of high toxicity, high hygroscopicity and deliquescence at high humidity, and are not suitable for use in patent medicine in the alternative. Therefore, the development of other salts which have high bioavailability, low toxicity and are suitable for medical use is necessary.
For drugs of the same molecular structure but different crystalline forms, it is possible to have different bioavailability, solubility, dissolution rate, chemico-physical stability and dissolution. These properties can directly affect the handling or production of the drug substance and formulation. Therefore, the polymorphism of the medicine has important significance for the quality, safety and effectiveness of the medicine preparation.
The existing polymorphic forms of the oritinib, the current Chinese patent CN103702990A discloses the crystal form characterization data of the polymorphic forms A, B, C, D (1 hydrate), E (1.25 hydrate), F (0.25 hydrate), K, A and B of the oritinib mesylate and the preparation method thereof; another chinese patent CN107778295a discloses an 1.5 hydrate of octenib and a method for preparing the same.
Although the crystal forms of the hydrate of the octreotide have been reported, there is still an urgent need for a crystal form of the octreotide which is excellent in physical and chemical properties and stable in properties and is easy to be industrially produced. Since it is important to obtain this compound in good purity, with well-defined crystal forms and excellent reproducibility, the result is that it exhibits valuable properties in terms of formulation and is stable enough to allow it to be stored for a long period of time.
Disclosure of Invention
The invention aims to provide the Orientinib monohydrate, which has the advantages of simple preparation process, excellent hygroscopicity and stability and suitability for industrial production.
The specific technical content of the invention is as follows:
in a first aspect of the present invention, there is provided a novel crystalline form of octreotide monohydrate, the novel crystalline form having a molar ratio of octreotide to water of 1:1.
the novel crystal form of the Ornitinib monohydrate uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic diffraction peaks at 5.9+/-0.2 degrees, 7.3+/-0.2 degrees, 9.1+/-0.2 degrees, 11.2+/-0.2 degrees, 25.2+/-0.2 degrees and 25.41 +/-0.2 degrees.
Preferably, the novel crystal form of the oritinib monohydrate uses Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic diffraction peaks at 5.9+/-0.2 degrees, 7.3+/-0.2 degrees, 9.1+/-0.2 degrees, 11.2+/-0.2 degrees, 13.5+/-0.2 degrees, 15.1+/-0.2 degrees, 18.4+/-0.2 degrees, 24.7+/-0.2 degrees, 25.2+/-0.2 degrees and 25.4+/-0.2 degrees.
Further preferably, the novel crystal form of the oritinib monohydrate uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic diffraction peaks at 5.9+/-0.2 degrees, 7.3+/-0.2 degrees, 9.1+/-0.2 degrees, 11.2+/-0.2 degrees, 11.8+/-0.2 degrees, 12.5+/-0.2 degrees, 13.5+/-0.2 degrees, 15.1+/-0.2 degrees, 16.3+/-0.2 degrees, 18.4+/-0.2 degrees, 19.1+/-0.2 degrees, 20.4+/-0.2 degrees, 21.7+/-0.2 degrees, 22.4+/-0.2 degrees, 24.7+/-0.2 degrees, 25.2+/-0.2 degrees, 25.4+/-0.2 degrees, 26.1+/-0.2 degrees and 28.2+/-0.2 degrees.
Preferably, the novel crystal form of the Ornitinib monohydrate uses Cu-K alpha radiation, and the characteristic peak accords with X-ray powder diffraction detection data and a graph shown in figure 1.
Preferably, the novel crystalline form of octreotide monohydrate exhibits a Differential Scanning Calorimetry (DSC) peak at 102.29 ℃.
Preferably, the novel crystal form of the oritinib monohydrate has the following crystallographic parameters: triclinic system, chiral space group: p-1; the unit cell parameters are:α= 66.278 (3) °, β= 88.222 (4) °, γ= 61.856 (5) °, unit cell volume +.>
In a second aspect, the present invention provides a process for preparing the novel crystalline form of octreotide monohydrate, comprising the steps of:
(1) Adding N- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-yl ] amino ] phenyl ] prop-2-enamide into an organic solvent, and slowly heating to obtain a solution;
(2) Dripping the solution into purified water, and uniformly stirring;
(3) Slowly reducing the temperature for crystallization;
(4) And (5) performing vacuum drying after crystallization.
The organic solvent is selected from one or more of methanol, ethanol, acetone, acetonitrile and tetrahydrofuran; preferably, the organic solvent is selected from ethanol or acetonitrile; more preferably, the organic solvent is acetonitrile.
Preferably, the mass ratio of the volume of the organic solvent to the mass ratio of N- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] prop-2-enamide is 3 to 10 in terms of volume mL/mass g: 1.
the heating temperature is 40-60 ℃.
The volume ratio of the purified water to the organic solvent is 1:1-10.
The temperature of the cooling crystallization is 0-30 ℃.
The crystallization time is as follows: 3-6 h.
The vacuum drying temperature is 30-40 ℃ and the drying time is 4-8 h.
In a third aspect the present invention provides a pharmaceutical composition comprising the novel crystalline form of octreotide monohydrate according to the present invention and further comprising other pharmaceutically acceptable auxiliary material components.
Preferably, the pharmaceutical composition of the present invention is prepared as follows: the compounds of the present invention are formulated into useful dosage forms by combining them with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable adjuvants and excipients, using standard and conventional techniques.
Preferably, the additional components include additional active ingredients, excipients, fillers, and the like, which may be used in combination.
Preferably, the pharmaceutical composition is spray, tablet, capsule, powder injection, liquid injection and the like.
The fourth aspect of the invention provides an application of the novel crystal form of the octreotide monohydrate as an active ingredient in preparing medicaments for treating lung cancer, in particular to an application in preparing medicaments for treating non-small cell lung cancer.
Confirmation of Crystal Structure
The X-ray powder diffraction test instrument and test conditions in the test of the novel crystal form of the Orientinib monohydrate are as follows: an X-ray powder diffractometer of the panaceae family; the laser comprises a light source copper target, a flat sample table, a BBHD incident light path, a PZXCEL diffraction light path, a voltage of 45kv, a current of 40mA, a divergence slit of 1/4 DEG, an anti-scattering slit of 1 DEG, a Sorption slit of 0.04rad, a counting time of 0.5s per step and a scanning range of 3-50 deg.
The TGA/DSC thermal analysis test conditions for the novel crystal form of the octreotide monohydrate are as follows: mertrer-tolidol TGA/DSC thermogram (model: TGA/DSC 3+), dynamic temperature profile: 30-200 ℃, heating rate: 10 ℃/min, procedure gas N 2 Flow rate: 50ml/min, crucible: 40 μl of aluminum crucible.
The X-ray single crystal diffraction test instrument and test conditions for the novel crystal form of the Orientinib monohydrate are as follows: a physical XtaLAB Synergy X-ray single crystal diffractometer; the light source copper target has the temperature of 293K, the voltage of 50kv and the current of 1mA, and the data collection is carried out by adopting Cu-K alpha target ray scanning, and the collection method is an orthogonal method.
The novel crystal form of the Orientinib monohydrate has the following crystal parameters: triclinic system, chiral space group: p-1; the unit cell parameters are:α= 66.278 (3) °, β= 88.222 (4) °, γ= 61.856 (5) °, unit cell volume +.>The molecular formula is: c (C) 28 H 35 N 7 O 3 The molecular weight is: 517.63. ORTE of the novel crystal form of the Orntinib monohydrate of the present inventionThe P diagram shows that the crystal form contains one molecule of Ornitinib and one molecule of water, and no solvent exists in the crystal form, as shown in figure 3.
TABLE 1 Crystal data for novel crystal forms of octreotide monohydrate
According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in the accompanying figures 1 and 2.
Table 2 PXRD data for novel crystalline forms of octreotide monohydrate
All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns as described above.
The result of the differential scanning calorimetric curve (DSC) of the novel crystal form of the oritinib monohydrate prepared by the invention is shown in figure 2, the starting point of the detected endothermic peak is 85.80 ℃, and the peak appears at 102.29 ℃. The novel crystal form of the Ornitanib monohydrate has a TGA/DSC spectrum shown in figure 2.
Compared with the prior art, the crystal form provided by the invention has the advantages of simple preparation method and low cost, and has important value for optimizing and developing the medicine in the future. The novel crystal form of the oritinib monohydrate prepared by the invention has high yield and purity and good stability.
Drawings
Fig. 1: PXRD pattern of the new crystalline form of octreotide monohydrate.
Fig. 2: TGA/DSC profile of the new crystalline form of octreotide monohydrate.
Fig. 3: ORTEP diagram of the novel crystal form of Orditinib monohydrate.
Detailed Description
The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. Modifications of the preparation method and the apparatus used may be made by those skilled in the art within the scope of the claims, and such modifications should also be considered as the scope of the invention. The starting materials or reagents used in the examples were all commercially available.
Example 1
(1) 10.0g of N- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] prop-2-enamide was added to 70mL of acetonitrile, and the mixture was slowly heated to 50℃until the solution was clear;
(2) Dropwise adding the solution into 14mL of purified water, and stirring while adding;
(3) Slowly reducing the temperature to 25 ℃, and controlling Wen Xijing h;
(4) Vacuum drying is carried out for 5 hours after crystallization, the drying temperature is 35 ℃, the yield is 97.23 percent, and the method comprises the following steps of: 99.98%.
Example 2
(1) 10.0g of N- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] prop-2-enamide was added to 80mL of ethanol, and slowly heated to 55deg.C until the solution was dissolved;
(2) Dropwise adding the solution into 12mL of purified water, and stirring while adding;
(3) Slowly reducing the temperature to 30 ℃, and controlling Wen Xijing h;
(4) Vacuum drying is carried out for 7h after crystallization, the drying temperature is 35 ℃, the yield is 96.57 percent, and the method comprises the following steps of: 99.98%.
Example 3
(1) 10.0g of N- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] prop-2-enamide was added to 50mL of methanol, and slowly heated to 45℃until the solution was dissolved;
(2) Dropwise adding the solution into 17mL of purified water, and stirring while adding;
(3) Slowly reducing the temperature to 15 ℃, and controlling Wen Xijing h;
(4) Vacuum drying is carried out for 5 hours after crystallization, the drying temperature is 30 ℃, the yield is 95.84 percent, and the HPLC is carried out: 99.97%.
Example 4
(1) 10.0g of N- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] prop-2-enamide was added to a mixed solvent of 50mL of tetrahydrofuran and 50mL of acetonitrile, and the mixture was slowly heated to 60℃until the solution was dissolved;
(2) Dropwise adding the solution into 10mL of purified water, and stirring while adding;
(3) Slowly reducing the temperature to 30 ℃, and controlling Wen Xijing h;
(4) Vacuum drying is carried out for 8 hours after crystallization, the drying temperature is 40 ℃, the yield is 94.36 percent, and the method comprises the following steps of: 99.96%.
Example 5
(1) 10.0g of N- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] prop-2-enamide was added to 30mL of tetrahydrofuran, and the mixture was slowly heated to 40℃until the solution was clear;
(2) Dropwise adding the solution into 30mL of purified water, and stirring while adding;
(3) Slowly reducing the temperature to 0 ℃ and controlling Wen Xijing h;
(4) Vacuum drying is carried out for 4 hours after crystallization, the drying temperature is 30 ℃, the yield is 92.55 percent, and the method comprises the following steps of: 99.97%.
Example 6
(1) 10.0g of N- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] prop-2-enamide was added to 120mL of acetone, slowly heated to 40℃and the solution was allowed to dissolve;
(2) Dropwise adding the solution into 120mL of purified water, and stirring while adding;
(3) Slowly reducing the temperature to 30 ℃, and controlling Wen Xijing h;
(4) Vacuum drying is carried out for 4 hours after crystallization, the drying temperature is 35 ℃, the yield is 90.43 percent, and the method comprises the following steps of: 99.96%.
Example 7
(1) 10.0g of N- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] prop-2-enamide was added to 25mL of isopropanol, and the mixture was slowly heated to 65℃until the solution was dissolved;
(2) Dropwise adding the solution into 12mL of purified water, and stirring while adding;
(3) Slowly reducing the temperature to-3 ℃ and controlling Wen Xijing h;
(4) Vacuum drying is carried out for 5 hours after crystallization, the drying temperature is 40 ℃, the yield is 88.70 percent, and HPLC:99.95%.
The polymorphic form A, B, C, D, E, F, K of octenib and polymorphic form a of octenib mesylate were prepared according to prior art patent CN201280033773.9 and the 1.5 hydrate of octenib was prepared according to prior art patent CN 201610708704.3.
1. Moisture permeability test
The prior art preparation of the polymorphic form A, B, C, D, E, F, K of octreotide, polymorphic form a of octreotide mesylate, and the 1.5 hydrate of octreotide were used as comparative examples 1-9, namely: comparative example 1 octreotide polymorph a, comparative example 2 octreotide polymorph B, comparative example 3 octreotide polymorph C, comparative example 4 octreotide polymorph D, comparative example 5 octreotide polymorph E, comparative example 6 octreotide polymorph F, comparative example 7 octreotide polymorph K, comparative example 8 octreotide mesylate polymorph a, comparative example 9 octreotide 1.5 hydrate.
Comparative study on hygroscopicity was carried out with the novel crystal form of the Ornittinib monohydrate prepared in example 1 of the present invention, and the results are shown in Table 3 according to the method of appendix 9103 of four parts of the edition 2015 of Chinese pharmacopoeia:
table 3 results of moisture wicking comparison
From the above results, it is understood that the novel crystal form of the octreotide monohydrate of example 1 of the present invention and the octreotide 1.5 hydrate of comparative example 9 are less hygroscopic than comparative examples 1 to 8 at relative humidity of 92.5% and 80% and are significantly different. Although comparative example 9 of the 1.5 hydrate of octreotide has less hygroscopicity, the wettability is greater as compared to the novel crystalline form of the monohydrate of octreotide of example 1 of the present invention.
2. Stability test
Comparative experiments were performed on polymorphs of octreotide prepared in inventive example 1 and comparative examples 1 to 9. The specific stability test method is carried out by referring to the guidance method of the fourth section related to stability investigation of the Chinese pharmacopoeia 2015 edition, the purity detection is carried out by using an HPLC method, and the specific test results are shown in tables 4 and 5.
(1) Acceleration test
Packaging on the market, and standing at 40+ -2deg.C and relative humidity of 75% + -5% for 6 months. Samples were taken once at the end of each of the 0, 1, 2, 3, 6 months during the test.
TABLE 4 accelerated test purity data
(2) Long-term test
The samples were packaged on the market, placed at 25.+ -. 2 ℃ and 60%.+ -. 10% relative humidity for 12 months, and sampled once at the end of each of the 0 th, 3 th, 6 th, 9 th and 12 th months during the test.
TABLE 5 long-term test purity data
As is clear from the results of the above acceleration test and long-term test data, the purity of the novel crystal form of the octreotide monohydrate of the embodiment 1 of the present invention is not significantly changed, and the stability of the novel crystal form of the octreotide monohydrate of the embodiment 1 of the present invention is better.
Experiments prove that the novel crystal forms of the octreotide monohydrate prepared in the examples 2-7 can achieve the similar hygroscopicity and stability effects as the novel crystal forms of the octreotide monohydrate prepared in the example 1.
Claims (6)
1. A novel crystalline form of octreotide monohydrate, characterized by: the characteristic peaks of the Cu-K alpha radiation are consistent with the X-ray powder diffraction detection data and the graph shown in figure 1.
2. The novel crystalline form of octreotide monohydrate of claim 1, characterized by the crystallographic parameters: triclinic system, chiral space group: p-1; the unit cell parameters are: α= 66.278 (3) °, β= 88.222 (4) °, γ= 61.856 (5) °, unit cell volume v= 1393.96 (12) a 3 。
3. The novel crystalline form of octreotide monohydrate of claim 1, wherein the novel crystalline form of octreotide monohydrate exhibits a differential scanning calorimetry trace exhibiting an endothermic peak at 102.29 ℃.
4. A process for preparing a new crystalline form of octreotide monohydrate according to any one of claims 1 to 3, comprising the steps of:
(1) Adding N- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] prop-2-enamide into an organic solvent, and slowly heating to dissolve;
(2) Dripping the solution into purified water, and uniformly stirring;
(3) Slowly reducing the temperature for crystallization;
(4) Vacuum drying is carried out after crystallization;
the organic solvent is selected from one or more of methanol, ethanol, acetone, acetonitrile and tetrahydrofuran; the volume ratio of the purified water to the organic solvent is 1:1-10; the heating temperature is 40-60 ℃.
5. The method of claim 4, wherein: the mass ratio of the volume of the organic solvent to the mass ratio of N- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] prop-2-enamide is 3-10 in terms of volume mL/mass g: 1.
6. use of the novel crystalline form of octreotide monohydrate as claimed in any one of claims 1 to 3 as an active ingredient in the manufacture of a medicament for the treatment of lung cancer.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN106699736A (en) * | 2015-11-17 | 2017-05-24 | 惠州信立泰药业有限公司 | Crystal form gamma of compound A mesylate and pharmaceutical composition containing the same |
| CN107778295A (en) * | 2016-08-24 | 2018-03-09 | 天津市汉康医药生物技术有限公司 | Mai Rui replaces Buddhist nun's compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN106699736A (en) * | 2015-11-17 | 2017-05-24 | 惠州信立泰药业有限公司 | Crystal form gamma of compound A mesylate and pharmaceutical composition containing the same |
| CN107778295A (en) * | 2016-08-24 | 2018-03-09 | 天津市汉康医药生物技术有限公司 | Mai Rui replaces Buddhist nun's compound |
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