Crystal form DCI of Orforglipron and preparation method thereof

Abstract

The invention discloses Orforglipron crystal form DCI and a preparation method and application thereof. An X-ray powder diffraction spectrum of the crystal form DCI under Cu-Ka radiation comprises peaks at the following 2 theta values: 7.5 + / -0.2 degrees, 8.9 + / -0.2 degrees, 9.9 + / -0.2 degrees, 10.6 + / -0.2 degrees, 10.9 + / -0.2 degrees, 11.9 + / -0.2 degrees, 12.5 + / -0.2 degrees, 13.5 + / -0.2 degrees, 14.0 + / -0.2 degrees, 14.8 + / -0.2 degrees, 15.1 + / -0.2 degrees, 15.5 + / -0.2 degrees, 16.0 + / -0.2 degrees, 16.5 + / -0.2 degrees, 17.7 + / -0.2 degrees, 18.2 + / -0.2 degrees, 19.9 + / -0.2 degrees, 20.3 + / -0.2 degrees, 20.9 + / The invention relates to the technical field of medical instruments, in particular to a novel medical instrument, which is characterized in that the medical instrument is provided with an angle of 25.1 + / -0.2 degrees, an angle of 26.1 + / -0.2 degrees, an angle of 26.6 + / -0.2 degrees, an angle of 27.3 + / -0.2 degrees, an angle of 27.5 + / -0.2 degrees, an angle of 28.2 + / -0.2 degrees, an angle of 28.5 + / -0.2 degrees The Orforglipron crystal form DCI provided by the invention has excellent slurry stability, solid stability and packaging stability, and provides reliable quality guarantee under the condition of medicine storage and placement.

Description

Technical Field

[0001] The present invention relates to the technical field of drug crystal forms, and in particular to an Orforglipron crystal form DCI and a preparation method thereof. Background Art

[0002] Orforglipron is an orally active glucagon-like peptide-1 receptor (GLP-1R) agonist that can improve type 2 diabetes. Currently, literature and patents only report on orforglipron's synthesis and purification process, its dosage forms, and therapeutic approaches. However, there are no reports on orforglipron's polymorphic forms.

[0003] All drugs exhibit polymorphism, which refers to the phenomenon of solid drug molecules existing in two or more different crystal forms. Different crystal forms lead to different physical and chemical properties. Different crystal forms of solid drug molecules face different challenges during storage, such as crystal transformation and deliquescence during transportation and storage, which in turn affect the purity and content of the drug to a certain extent. Especially for hydrates, the stability of the crystal form is even more important. Therefore, drug crystal form is a crucial part of the research and development process of solid-state drugs and a key part of drug quality control.

[0004] The authors of the present invention found that commercially available Orforglipron is amorphous. Compared with crystalline substances, amorphous substances are relatively unstable, hygroscopic, and prone to crystal transformation. Uncontrollable quality risks are likely to occur in the transportation, transfer, storage and preparation of raw materials.

[0005] The present application aims to study Orforglipron crystal forms with good stability in order to solve the problems existing in the prior art. Summary of the Invention

[0006] In view of the above-mentioned deficiencies in the prior art, the present invention provides an orforglipron crystalline form DCI, which exhibits excellent stability. Furthermore, the present invention provides a method for preparing the orforglipron crystalline form DCI. Furthermore, the present invention provides uses of the orforglipron crystalline form DCI.

[0007] In order to solve the above technical problems, the first aspect of the present invention provides an Orforglipron crystal form DCI, wherein the X-ray powder diffraction spectrum of the crystal form DCI under Cu-Ka radiation comprises peaks located at the following 2θ values: 7.5±0.2°, 8.9±0.2°, 9.9±0.2°, 10.6±0.2°, 10.9±0.2°, 11.9±0.2°, 12.5±0.2°, 13.5±0.2°, 14.0±0.2°, 14.8±0.2°, 15.1±0.2°, 15.5±0.2°, 16.0±0.2°. .2°, 16.5±0.2°, 17.7±0.2°, 18.2±0.2°, 19.9±0.2°, 20.3±0.2°, 20.9±0.2°, 21.1±0.2°, 21.9±0.2°, 22.4±0.2°, 22.7±0.2°, 23.6±0.2°, 24.4±0.2°, 25.1±0.2°, 26.1±0.2°, 26.6±0.2°, 27.3±0.2°, 27.5±0.2°, 28.2±0.2°, 28.5±0.2°, 29.5±0.2°.

[0008] As a preferred embodiment, the differential scanning calorimetry spectrum of the crystalline form DCI shows an endothermic peak at 215±2°C.

[0009] As a preferred embodiment, the crystalline form DCI is an anhydrate crystalline form.

[0010] In a second aspect of the present invention, a method for preparing the above-mentioned Orforglipron crystalline form DCI is provided, comprising placing Orforglipron in a mixed solvent of alcohol and water to obtain a suspension, and stirring, separating, and drying the obtained suspension to obtain the crystalline form DCI.

[0011] As a preferred embodiment, the alcohol is selected from a mixture of any one or more of methanol, ethanol, isopropanol, and n-propanol.

[0012] As a preferred embodiment, the mixed solvent ratio is alcohol / water, ranging from 9 / 1 to 1 / 9 (volume ratio).

[0013] As a more preferred embodiment, the ratio of the mixed solvent is n-propanol / water, 1 / 4 (volume ratio).

[0014] As a preferred embodiment, the crystallization temperature is 0-40°C.

[0015] As a more preferred embodiment, the crystallization temperature is 10-20°C.

[0016] The third aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned Orforglipron crystal form DCI.

[0017] Compared with the prior art, the present invention has the following advantages: (1) The Orforglipron crystal form DCI of the present invention has excellent slurry stability, solid-state stability, and mechanical stability, reducing the risk of crystal transformation. (2) The Orforglipron crystal form DCI of the present invention is almost non-hygroscopic. The low hygroscopicity ensures that the sample can maintain a low moisture gain and avoid deliquescence during the subsequent production, processing, storage and transportation, thereby ensuring the stability of the drug quality.

[0018] The concept, specific structure and technical effects of the present invention will be further described below in conjunction with the accompanying drawings to fully understand the purpose, characteristics and effects of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 is the XRPD spectrum of Orforglipron crystal form DCI prepared in Example 1 of the present invention; Figure 2 is the DSC spectrum of Orforglipron crystal form DCI prepared in Example 1 of the present invention; Figure 3 This is the packaging stability XRPD spectrum of Orforglipron crystal form DCI prepared in Example 2 of the present invention; Figure 4 This is the humidity stability XRPD spectrum of the Orforglipron crystal form DCI prepared in Example 2 of the present invention. DETAILED DESCRIPTION

[0020] In order to make the technical means, creative features, objectives and effects of the invention easier to understand, the invention is further described below with reference to specific diagrams. However, the invention is not limited to the following implementation cases.

[0021] It should be noted that the structures, proportions, sizes, etc. illustrated in the drawings in this specification are only used to match the contents disclosed in the specification so that people familiar with this technology can understand and read them. They are not used to limit the conditions under which the present invention can be implemented. Therefore, they have no substantive technical significance. Any modification of the structure, change in the proportion relationship or adjustment of the size should still fall within the scope of the technical content disclosed in the present invention without affecting the efficacy and purpose that can be achieved by the present invention.

[0022] Orforglipron is an orally active glucagon-like peptide 1 receptor (GLP-1R) agonist that can improve type 2 diabetes.

[0023] The present application is based on the perspective of changing the preparation method of Orforglipron to obtain a new crystal form DCI of Orforglipron. The crystal form DCI has good stability and low hygroscopicity, can avoid the risk of crystal transformation, broaden the storage conditions of the raw material drug, and extend the shelf life of the raw material drug.

[0024] XRPD (X-ray powder diffraction) patterns were collected on a Bruker D2 PHASER X-ray powder diffractometer. X-ray powder diffraction parameters were as follows: X-ray source: Cu Ka; Ka1 (A): 1.54060; Ka2 (A) 1.54439; Ka2 / Ka1 intensity ratio: 0.50; voltage: 30 kilovolts (kV); current: 10 milliamperes (mA); scan range: 3.0-40.0°.

[0025] DSC, or differential scanning calorimetry, is a technique used to analyze the surface of a sample using a TA DSC X3. The DSC parameters are as follows: scanning rate: 10 °C / min; protective gas: nitrogen.

[0026] TGA, namely thermogravimetric analysis, the thermogravimetric analysis (TGA) graph of the present application was collected on a TA TGA55, and the method parameters of the thermogravimetric analysis (TGA) were as follows: scanning rate: 10 °C / min; protective gas: nitrogen.

[0027] Unless otherwise specified, the following examples are all operated at room temperature. The “room temperature” is not a specific temperature value, but refers to a temperature range of 10-30°C.

[0028] The "stirring" described in the following examples is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm and the mechanical stirring is preferably 100-300 rpm.

[0029] The "separation" described in the following examples is accomplished by conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation is as follows: the sample to be separated is placed in a centrifuge tube and centrifuged at a speed of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.

[0030] The drying described in the following examples can be performed at room temperature or higher. The drying temperature is from room temperature to about 50°C, or up to 40°C. The drying time can be 2 to 48 hours, or overnight. Drying can be performed in a fume hood, forced air oven, or vacuum oven.

[0031] The "crystals" described in the following examples refer to solids characterized and confirmed by X-ray powder diffraction patterns. It will be understood by those skilled in the art that the physicochemical properties discussed herein can be characterized, and the experimental errors therein depend on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray powder diffraction patterns generally vary with different instrument conditions. It should be noted in particular that the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern may also vary with changes in the experimental conditions, so the order of the diffraction peak intensities cannot be used as the only or decisive factor. In fact, the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals. The diffraction peak intensities shown in the present invention are illustrative and not for absolute comparison. In addition, the experimental error of the diffraction peak position is generally 5% or less, and the errors at these positions should also be taken into account, and an error of ±0.2 is generally allowed. In addition, due to the influence of experimental factors such as sample thickness, the overall offset of the diffraction peak angle will be caused, and a certain offset is generally allowed. Therefore, it will be understood by those skilled in the art that the X-ray powder diffraction pattern of the protected crystal form of the present invention does not necessarily have to be completely consistent with the X-ray powder diffraction patterns in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern that is identical or similar to the characteristic peaks in these patterns falls within the scope of the present invention.

[0032] A person skilled in the art can compare the X-ray powder diffraction patterns listed in the present invention with the X-ray powder diffraction patterns of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.

[0033] The crystalline form DCI of the present invention is pure and substantially free of any other crystalline forms. As used herein, "substantially free," when referring to a new crystalline form, means that the crystalline form contains less than 20% by weight of any other crystalline form, particularly less than 10% by weight of any other crystalline form, more particularly less than 5% by weight of any other crystalline form, and even more particularly less than 1% by weight of any other crystalline form.

[0034] The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5% or ±0.1%.

[0035] Orforglipron as a raw material includes, but is not limited to, solid form (crystalline or amorphous), oily form, liquid form and solution. Preferably, it is in solid form.

[0036] The present invention relates to a method for preparing the orforglipron crystalline form DCI. The method comprises placing orforglipron in a mixed solvent to obtain a suspension, stirring, separating, and drying the resulting suspension to obtain the crystalline form DCI. Specifically, the orforglipron is added to a mixed solvent of an alcohol and water, where the alcohol is a compound containing a hydroxyl group. The alcohol can be selected from a mixture of any one or more of methanol, ethanol, isopropanol, and n-propanol. The ratio of the alcohol to water can range from 9 / 1 to 1 / 9 (volume ratio). The resulting system is a suspension in a non-uniform state.

[0037] The above crystallization process needs to be carried out at a specific temperature. The temperature used in this application is 0-40°C, preferably 10-20°C.

[0038] In the process of preparing Orforglipron crystal form DCI in the present application, there is no strict limit on the amount of Orforglipron and the mixed solvent used. Different amounts of alcohol and water may lead to different crystal yields.

[0039] Different crystallization times also affect the degree of crystallization or crystal yield, and can be flexibly selected according to actual needs.

[0040] The Orforglipron crystalline form DCI obtained in this application can be administered in tablet or capsule form. For patients who have difficulty swallowing solid forms, a liquid formulation can also be used for oral administration. Tablets or capsules can be prepared using conventional excipients and conventional methods. For tablet preparation, for example, the Orforglipron crystalline form DCI obtained in this application is uniformly mixed with excipients, rolled to form thin sheets, crushed into granules, mixed with additional excipients, and then pressed into shape using a suitable mold. For capsule preparation, the Orforglipron crystalline form DCI obtained in this application is uniformly mixed with excipients, rolled to form thin sheets, crushed into granules, mixed with additional excipients, and then canned into capsules of appropriate sizes.

[0041] The Orforglipron crystal form DCI prepared in the present application can be used to treat subjects with type II diabetes.

[0042] Example 1 Weigh 50 mg of Orforglipron and add it to a 1 ml glass bottle. Add 0.5 ml of a mixed solvent of n-propanol and water (1 / 4, volume ratio) to the glass bottle, stir for 16 hours, centrifuge and dry to obtain crystals, namely crystal form DCI. Its XRPD pattern is as follows Figure 1 The XRPD data are shown in Table 1, and the DSC diagram is shown in Figure 2 shown.

[0043] Table 1 Diffraction angle 2θ d value Relative Strength Diffraction angle 2θ d value Relative Strength Diffraction angle 2θ d value Relative Strength 7.55 11.70 29.80% 15.47 5.72 10.10% 22.70 3.91 54.40% 8.86 9.98 17.50% 16.03 5.52 20.80% 23.58 3.77 19.40% 9.93 8.90 6.10% 16.48 5.38 24.20% 24.43 3.64 17.70% 10.60 8.34 69.10% 17.67 5.02 56.10% 25.12 3.54 14.90% 10.95 8.08 10.90% 18.17 4.88 28.10% 26.11 3.41 12.40% 11.95 7.40 16.10% 19.91 4.46 100.00% 26.57 3.35 4.20% 12.49 7.08 26.30% 20.27 4.38 31.50% 27.31 3.26 6.60% 13.50 6.56 87.10% 20.88 4.25 17.20% 27.46 3.25 11.60% 14.05 6.30 73.50% 21.14 4.20 4.20% 28.19 3.16 13.40% 14.81 5.98 19.80% 21.86 4.06 12.70% 28.53 3.13 3.60%

[0044] from Figure 2 It can be seen that the Orforglipron crystal form DCI prepared in Example 1 begins to show an endothermic peak at around 215°C.

[0045] Example 2: Packaging stability of crystalline DCI

[0046] About 5 mg of the crystalline form DCI prepared in the present invention was weighed and sealed in an aluminum foil bag. The bags were then placed under conditions of 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH, respectively, and the crystalline form was determined by XRPD.

[0047] The XRPD comparison diagrams of the crystalline form DCI of the present invention before and after being placed under the above temperature and humidity conditions for 2 months are as follows: Figure 3 As shown, the results show that the crystal form DCI of the present invention is stable and remains unchanged under different ambient temperature and humidity conditions before and after 2 months, which shows that the crystal form DCI has good packaging stability and can be stably stored under conventional storage conditions.

[0048] Example 3: Humidity stability of crystalline form DCI

[0049] About 5 mg of the crystalline form DCI prepared in the present invention was weighed and exposed to the conditions of 25±1°C / 75%RH and 25±1°C / 92.5%RH for 10 days, respectively, and then the crystalline form was determined by XRPD.

[0050] The XRPD comparison diagrams of the crystal form DCI of the present invention before and after exposure to different environmental humidity conditions for 10 days are shown in FIG. Figure 4 As shown, the results show that the crystal form DCI of the present invention is stable and remains unchanged before and after exposure to different environmental humidity conditions for one week, which shows that the crystal form DCI has good humidity stability and can be stably stored at room temperature and different humidity conditions.

[0051] Example 4: Hygroscopicity of Crystalline DCI

[0052] Weigh approximately 20 mg of the crystalline form DCI of the present invention and store it at 25 ± 1°C and 80% relative humidity for 24 hours. The weight of the sample before and after the test is recorded. The results are shown in the table below.

[0053] Table 2 Starting mass (mg) Placement conditions Placement time Mass after placement (mg) Weight gain (mg) Percentage of weight gain 20.50 25 ± 1 ℃, 80% RH 24 hours 20.51 0.01 0.05%

[0054] As can be seen from Table 2, the crystalline DCI of the present invention has no or almost no hygroscopicity, which indicates that the crystalline DCI is not prone to deliquescence during the production and storage of the drug.

[0055] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2020 Edition General Chapter 9103 Guidance for Hygroscopicity of Drugs, experimental conditions: 25 ± 1 ℃, 80% relative humidity): Deliquescent: Absorbs enough water to form a liquid Highly hygroscopic: weight gain due to moisture absorption is not less than 15.0% Hygroscopic: Weight gain due to moisture absorption is less than 15.0% but not less than 2.0% Slightly hygroscopic: weight gain due to moisture absorption is less than 2.0% but not less than 0.2% No or almost no hygroscopicity: weight gain due to moisture absorption is less than 0.2%.

[0056] The preferred embodiments of the present invention have been described in detail above. It should be understood that numerous modifications and variations based on the concepts of the present invention are possible without inventive effort by those skilled in the art. Therefore, any technical solution that can be derived by one skilled in the art through logical analysis, reasoning, or limited experimentation based on the concepts of the present invention and the prior art should be within the scope of protection defined by the claims.

Claims

1. An Orforglipron crystal form DCI, characterized in that: The X-ray powder diffraction spectrum of the crystalline form DCI under Cu-Ka radiation comprises peaks at the following 2θ values: 7.5±0.2°, 8.9±0.2°, 9.9±0.2°, 10.6±0.2°, 10.9±0.2°, 11.9±0.2°, 12.5±0.2°, 13.5±0.2°, 14.0±0.2°, 14.8±0.2°, 15.1±0.2°, 15.5±0.2°, 16.0±0.2°, 16.5±0.2°, 17.7±0. 2°, 18.2±0.2°, 19.9±0.2°, 20.3±0.2°, 20.9±0.2°, 21.1±0.2°, 21.9±0.2°, 22.4±0.2°, 22.7±0.2°, 23.6±0.2°, 24.4±0.2°, 25.1±0.2°, 26.1±0.2°, 26.6±0.2°, 27.3±0.2°, 27.5±0.2°, 28.2±0.2°, 28.5±0.2°, 29.5±0.2°.

2. The Orforglipron crystal form DCI according to claim 1, characterized in that The differential scanning calorimetry spectrum of the crystalline form DCI shows an endothermic peak at 215±3°C.

3. The Orforglipron crystal form DCI according to claim 1 or 2, characterized in that The crystalline form DCI is an anhydrate crystalline form.

4. A method for preparing Orforglipron crystal form DCI, characterized in that: Orforglipron is placed in a mixed solvent of alcohol and water to obtain a suspension, and the obtained suspension is stirred, separated, and dried to obtain crystalline DCI.

5. The method for preparing the Orforglipron crystal form DCI according to claim 4, wherein: The alcohol is selected from any one of methanol, ethanol, isopropanol and n-propanol.

6. The method for preparing Orforglipron crystal form DCI according to claim 4, wherein: The ratio of the alcohol and water mixed solvent ranges from 9 / 1 to 1 / 9 (volume ratio).

7. The method for preparing the Orforglipron crystal form DCI according to claim 4, wherein: The crystallization temperature is 0-40℃.

8. A pharmaceutical composition, characterized in that The Orforglipron crystal form DCI comprises the Orforglipron crystal form DCI according to any one of claims 1 to 4.

9. Use of the Orforglipron crystal form DCI according to any one of claims 1 to 4 in the preparation of a medicament for treating type II diabetes in a subject.

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