Monolaurin-cyclosporine co-crystals, methods of making and using the same

Abstract

This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a monopravir-caprolactam cocrystal, its preparation method, and its applications. The monopravir-caprolactam cocrystal is composed of monopravir and caprolactam in a molar ratio of 1:1.9-2.1. X-ray powder diffraction was performed using Cu-Kα radiation, with angles expressed as 2θ±1, at 6.91, 7.09, 8.38, 11.24, 12.52, 13.26, 13.87, 14.24, 15.22, 16.82, 17.31, and 1... Characteristic peaks are observed at 9.73, 20.22, 20.53, 20.84, 21.90, 22.28, 22.52, 22.95, 23.51, 23.75, 24.00, 24.31, 24.86, 25.35, 26.44, 27.41, 28.02, 28.69, 29.22, 29.84, and 30.33. Monopravir-caprolactam cocrystals can be successfully prepared by grinding and / or solution methods, and grinding and / or melting methods. The preparation process is simple, and the obtained product has high purity. Characterization has confirmed it to be a new cocrystal. Powder flowability and tableting tests revealed that the monopravir-caprolactam cocrystals provided by this invention have better flowability and tableting properties compared to monopravir crystal form I, meeting the requirements of formulation and manufacturing processes.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a monorapir-caprolactam cocrystal, its preparation method, and its application. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Molnupiravir is a broad-spectrum anti-RNA virus drug that can inhibit the replication of various RNA viruses, including equine encephalitis virus, mouse hepatitis virus (MHV), MERS, and 2019-nCoV. The commercially available crystalline form of Molnupiravir is Crystallized Form I. However, Crystallized Form I has poor flowability and poor tableting properties, which is unfavorable for formulation processes and severely affects the bioavailability of the oral drug in humans.

[0004] Drug cocrystals refer to single-phase crystalline drugs formed by the interaction of the active pharmaceutical ingredient (API) and cocrystal forgings (CCFs) in a certain proportion through non-covalent bonds such as hydrogen bonds, van der Waals forces, and π-π stacking. Drug cocrystals can significantly improve the physicochemical properties of APIs, such as melting point, solubility, flowability, and bioavailability, without disrupting covalent bonds. Furthermore, drug cocrystals also show promise in masking drug taste and improving tableting performance. Currently, there are no reports on monoravir drug cocrystals. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a monorapir-caprolactam cocrystal, its preparation method, and its applications. Caprolactam is recognized by the U.S. Food and Drug Administration (FDA) as a good flavoring agent or adjuvant that meets the safety standards for drug cocrystal forming products (CCFs). This invention utilizes the preparation of drug cocrystals to improve the physicochemical properties of monorapir, providing a drug cocrystal form that improves the flowability and tableting properties of monorapir, which is beneficial for meeting the requirements of formulation and manufacturing processes.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0007] In a first aspect, the present invention provides a monopravir-caprolactam eutectic, composed of monopravir and caprolactam in a molar ratio of 1:1.9-2.1. Using Cu-Kα radiation, X-ray powder diffraction at angles of 2θ±1 is performed at 6.91, 7.09, 8.38, 11.24, 12.52, 13.26, 13.87, 14.24, 15.22, and 16.82. Characteristic peaks are observed at 17.31, 19.73, 20.22, 20.53, 20.84, 21.90, 22.28, 22.52, 22.95, 23.51, 23.75, 24.00, 24.31, 24.86, 25.35, 26.44, 27.41, 28.02, 28.69, 29.22, 29.84, and 30.33.

[0008] Preferably, an asymmetric unit of the monopravir-caprolactam eutectic contains one monopravir molecule and two caprolactam molecules, belonging to the monoclinic crystal system, space group C2, with unit cell parameters of... α=γ=90°, β=106.459±0.002°, and the unit cell volume is The R-factor is 0.0606.

[0009] Preferably, the monopravir-caprolactam eutectic loses 35.36% of its weight when the temperature rises to 154.5°C; and loses 47.82% of its weight when the temperature rises to 600°C.

[0010] Preferably, the monoravir-caprolactam eutectic differential scanning calorimetry curve shows a unique endothermic peak at 92.4℃.

[0011] Preferably, the angle of repose of the monopravir-caprolactam eutectic is 41°-43°.

[0012] In a second aspect, the present invention provides a method for preparing monopravir-caprolactam cocrystal as described in the first aspect, comprising the following steps:

[0013] Monopravir and caprolactam were mixed and dissolved in a solvent to obtain a clear solution. After the clear solution evaporated, the monopravir-caprolactam eutectic was obtained.

[0014] Preferably, the solvent includes at least one selected from ethyl acetate, acetonitrile, acetone, water, and n-butanol.

[0015] Thirdly, the present invention provides a method for preparing monopravir-caprolactam cocrystal as described in the first aspect, comprising the following steps:

[0016] Monopravir and caprolactam are mixed, heated to melt, and then cooled to obtain the monopravir-caprolactam eutectic.

[0017] Preferably, monopravir and caprolactam are mixed by co-grinding or direct mixing.

[0018] Fourthly, the present invention provides the use of monopravir-caprolactam cocrystal as described in the first aspect in the preparation of anti-RNA virus drugs.

[0019] Preferably, the anti-RNA virus drug is monoravir.

[0020] The beneficial effects achieved by one or more technical solutions of the present invention are as follows:

[0021] Monopravir-caprolactam cocrystals can be successfully prepared by grinding and / or solution methods, and grinding and / or melting methods. The preparation process is simple, and the obtained product has high purity. Characterization by XRPD, X-ray single crystal diffraction, DSC, and TG confirmed it as a novel cocrystal. Powder flowability and tableting tests revealed that the monopravir-caprolactam cocrystal provided by this invention has better flowability and tableting properties than monopravir crystal form I, meeting the requirements of formulation and manufacturing processes. Attached Figure Description

[0022] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0023] Figure 1 XRPD diagram of monopravir-caprolactam eutectic;

[0024] Figure 2 X-ray single-crystal diffraction structure of the monopravir-caprolactam eutectic;

[0025] Figure 3 Thermogravimetric analysis (TG) plot of monoravir-caprolactam eutectic;

[0026] Figure 4 Differential scanning calorimetry (DSC) plot of monoravir-caprolactam eutectic;

[0027] Figure 5 This is a graph showing the compressibility test of monoravir-caprolactam eutectic. Detailed Implementation

[0028] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments and comparative examples.

[0029] The testing instruments used in this invention:

[0030] 1. X-ray powder diffractometer

[0031] Model: SmartLab X-ray powder diffractometer manufactured by Rigaku Corporation, Japan

[0032] Test conditions: room temperature 25℃, copper target, output power 9kW, scanning range 5-50°, scanning speed 20° / minute.

[0033] 2. X-ray single crystal diffractometer

[0034] Model: Smart-APEX II single crystal diffractometer manufactured by Bruker GmbH, Germany

[0035] Test conditions: Data was collected using Cu Kα rays at room temperature of 25℃, and the data was restored and corrected using APEX3 Software Suite. SHELXL was used to analyze and refine the structure.

[0036] 3. DSC thermal analysis

[0037] Model: DSC 214 Polyma thermal analyzer manufactured by Netzsch GmbH, Germany

[0038] Test conditions: Nitrogen purging, heating rate of 10℃ / min.

[0039] 4. TG thermal analysis

[0040] Model: TG 209F3 Tarsus thermogravimetric analyzer manufactured by Netzsch GmbH, Germany

[0041] Test conditions: Nitrogen purging, heating rate of 10℃ / min.

[0042] 5. Grinding machine

[0043] Model: Retsch MM200 grinder manufactured by Retsch GmbH, Germany

[0044] Test conditions: Test frequency is 25Hz, grinding time is 30 minutes.

[0045] The raw materials and solvents used in this invention are all commercially available products or prepared by known methods.

[0046] Example 1

[0047] Preparation and identification of monopravir-caprolactam eutectic

[0048] At room temperature, accurately weigh 20.00 mg of the ground mixture of monopravir and caprolactam (molar ratio 1:2) into a clean, transparent glass bottle (10 ml), and add 2 ml of ethyl acetate. Place a clean magnetic stir bar in the bottle containing the solution, stir at 500 rpm for 30 minutes, and then filter to obtain a clear solution. Place the glass bottle in a fume hood and allow it to evaporate naturally for 2 days to obtain the monopravir-caprolactam eutectic with a purity of 100% and a yield of 95.6%.

[0049] The grinding process includes the following steps:

[0050] Accurately weigh a certain amount of monoravir and caprolactam (1:2) and mix them in a grinding jar. Then place the grinding jar in a ball mill and grind for 30 minutes at a grinding rate of 25 Hz.

[0051] like Figure 1 As shown, XRPD results indicate that the monopravir-caprolactam eutectic exhibits diffraction angles (2θ, °) of 6.91±1, 7.09±1, 8.38±1, 11.24±1, 12.52±1, 13.26±1, 13.87±1, 14.24±1, 15.22±1, 16.82±1, 17.31±1, 19.73±1, 20.22±1, 20.53±1, and 20. Characteristic peaks are found at 84±1, 21.90±1, 22.28±1, 22.52±1, 22.95±1, 23.51±1, 23.75±1, 24.00±1, 24.31±1, 24.86±1, 25.35±1, 26.44±1, 27.41±1, 28.02±1, 28.69±1, 29.22±1, 29.84±1, and 30.33±1.

[0052] like Figure 2 As shown, X-ray single-crystal diffraction results indicate that an asymmetric unit of the monopravir-caprolactam eutectic contains one monopravir molecule and two caprolactam molecules, belonging to the monoclinic crystal system, space group C2, with cell parameters of... α=γ=90°、β=106.459(2), the unit cell volume is The R-factor is 0.0606. The numbers in parentheses in the above data represent the error value of the last digit.

[0053] like Figure 3 As shown, the TG results indicate that the monopravir-caprolactam eutectic weight loss was 35.36% at 154.5℃ and 47.82% at 600℃.

[0054] like Figure 4As shown, the DSC curve has a unique endothermic peak at 92.4℃, which corresponds to the melting of the monopravir-caprolactam eutectic.

[0055] Powder flowability test:

[0056] For ground powder, the angle of repose is a characteristic parameter related to the friction between powder particles or the relative motion resistance between powder particles. The smaller the angle of repose, the better the powder flowability.

[0057] The crystalline sample (monoravir-caprolactam eutectic prepared in Example 1) was ground into powder and pre-passed through a sieve with a pore size of 0.45 mm. The powder flowability was then measured using the fixed funnel method; the sample formed a powder cone after passing through the funnel. The angle of repose α was calculated by measuring the height of the powder cone.

[0058] The calculation formula is as follows: tan(α) = cone height / chassis radius.

[0059] The pure monoravir-caprolactam cocrystal provided by this invention exhibits good flowability, meeting the requirements of formulation and manufacturing processes. Test results are shown in Table 1.

[0060] Table 1. Measurement results of the angle of repose

[0061] Components / Number of measurements 1 2 3 average value Monoravir Crystal Form I 48.24° 49.96° 48.49° 48.90° Monopravir-caprolactam eutectic 41.67° 42.92° 41.67° 42.09°

[0062] Test results show that the monopravir-caprolactam eutectic provided by this invention has an angle of repose of less than 43°, which is much smaller than the 48.90° angle of repose corresponding to crystal form I. Research indicates that an angle of repose between 41° and 45° can meet the powder flowability requirements of the production process. When the angle of repose exceeds 45°, the powder flowability is very poor, requiring stirring and vibration during production, which is difficult to meet the formulation and production process requirements. Therefore, compared to crystal form I, the monopravir-caprolactam eutectic provided by this invention significantly improves powder flowability, making it more beneficial for subsequent industrial production and processing.

[0063] Powder tableting performance test:

[0064] The compressibility of a drug is closely related to the research on its formulation process. Good compressibility is beneficial to the development and application of its oral solid dosage forms.

[0065] The crystalline sample (monoravir-caprolactam eutectic prepared in Example 1) was ground into powder and pre-passed through a sieve with a pore size of 0.45 mm. 120 mg of the sieved sample was weighed and placed into a mold with a diameter of 10 mm. The mold was compressed at pressures of 190 MPa, 228 MPa, and 254 MPa, respectively. After maintaining the pressure for 30 seconds, the tablets were removed and sealed for equilibration for 24 hours. Figure 5As shown, the monopravir-caprolactam eutectic did not break after compression and maintained its shape, demonstrating good compressibility.

[0066] Example 2

[0067] Preparation and identification of monopravir-caprolactam eutectic

[0068] At room temperature, 20.00 mg of a ground mixture of monopravir and caprolactam (1:2) was accurately weighed and placed in a clean, transparent glass bottle (10 ml). 4 ml of acetonitrile was added. A clean magnetic stir bar was placed in the bottle containing the solution, and the mixture was stirred at 500 rpm for 30 minutes. The mixture was then filtered to obtain a clear solution. The glass bottle was then placed in a fume hood and allowed to evaporate naturally for 2 days to obtain a monopravir-caprolactam cocrystal with a purity of 100% and a yield of 90.2%. XRPD testing was performed on the obtained crystals, and the results were consistent with... Figure 1 The results were consistent, and it was determined to be a monopravir-caprolactam eutectic.

[0069] Example 3

[0070] Preparation and identification of monopravir-caprolactam eutectic

[0071] At room temperature, 15.00 mg of a 1:2 mixture of ground monopravir and caprolactam was accurately weighed and placed in a clean, transparent glass bottle (10 ml). 2 ml of acetone was added. A clean magnetic stir bar was placed in the bottle containing the solution, and the mixture was stirred at 500 rpm for 30 minutes. The mixture was then filtered to obtain a clear solution. The glass bottle was then placed in a fume hood and allowed to evaporate naturally for 2 days to obtain a monopravir-caprolactam cocrystal with a purity of 100% and a yield of 88.6%. XRPD testing was performed on the obtained crystals, and the results were consistent with... Figure 1 The results were consistent, and it was determined to be a monopravir-caprolactam eutectic.

[0072] Example 4

[0073] Preparation and identification of monopravir-caprolactam eutectic

[0074] At room temperature, 10.00 mg of monopravir and 6.90 mg of caprolactam were accurately weighed and placed in a clean, transparent glass bottle (10 ml volume). 4 ml of ethyl acetate was added. A clean magnetic stir bar was placed in the bottle containing the solution, and the mixture was stirred at 500 rpm for 2 hours. The mixture was then filtered to obtain a clear solution. The bottle was then placed in a fume hood and allowed to evaporate naturally for 2 days to obtain a monopravir-caprolactam cocrystal with a purity of 100% and a yield of 93.6%. XRPD analysis of the obtained crystals yielded results consistent with... Figure 1 The results were consistent, and it was determined to be a monopravir-caprolactam eutectic.

[0075] Example 5

[0076] Preparation and identification of monopravir-caprolactam eutectic

[0077] At room temperature, 5.00 mg of a finely ground mixture of monopravir and caprolactam (1:2) was accurately weighed and evenly placed on a glass slide. The slide was then heated on a hot stage (heating rate: 10 °C / min). When the temperature reached 100 °C, the sample completely melted. The hot stage temperature was then lowered to 70 °C, and after 2 hours, a monopravir-caprolactam eutectic crystal with 100% purity and 99% yield was obtained. XRPD analysis of the obtained crystals yielded results consistent with... Figure 1 The results were consistent, and it was determined to be a monopravir-caprolactam eutectic.

[0078] Example 6

[0079] Preparation and identification of monopravir-caprolactam eutectic

[0080] At room temperature, 5.00 mg of monoravir and 3.45 mg of caprolactam were accurately weighed, mixed thoroughly, and placed on a glass slide. The slide was then heated on a hot stage (heating rate: 10 °C / min). When the temperature reached 100 °C, the sample completely melted. The hot stage temperature was then lowered to 70 °C, and after 2 hours, a monoravir-caprolactam eutectic crystal with 100% purity and a yield of 97.6% was obtained. XRPD analysis of the obtained crystals yielded results consistent with... Figure 1 The results were consistent, and it was determined to be a monopravir-caprolactam eutectic.

[0081] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A monopravir-caprolactam eutectic, characterized in that, Composed of monopravir and caprolactam in a molar ratio of 1:1.9-2.1, the X-ray powder diffraction, expressed in 2θ±1 angles using Cu-Kα radiation, exhibits characteristic peaks at 6.91, 7.09, 8.38, 11.24, 12.52, 13.26, 13.87, 14.24, 15.22, 16.82, 17.31, 19.73, 20.22, 20.53, 20.84, 21.90, 22.28, 22.52, 22.95, 23.51, 23.75, 24.00, 24.31, 24.86, 25.35, 26.44, 27.41, 28.02, 28.69, 29.22, 29.84, and 30.

33.

2. The monopravir-caprolactam eutectic as described in claim 1, characterized in that, An asymmetric unit of the monopravir-caprolactam eutectic contains one monopravir molecule and two caprolactam molecules, and it belongs to the monoclinic crystal system. C 2 The space group has the following cell parameters: a = 13.0036 ± 0.0003 Å, b = 8.6033 ± 0.0002 Å, c = 13.3224 ± 0.0003 Å, α = γ = 90°, β = 106.459 ± 0.002°, and the cell volume is 1429.36 ± 0.06 Å. 3 The R factor is 0.0606.

3. The monopravir-caprolactam eutectic as described in claim 1, characterized in that, The monopravir-caprolactam eutectic exhibited a weight loss of 35.36% when the temperature reached 154.5 °C, and a weight loss of 47.82% when the temperature reached 600 °C.

4. The monopravir-caprolactam eutectic as described in claim 1, characterized in that, The monoravir-caprolactam eutectic differential scanning calorimetry curve showed an endothermic peak at 92.4 °C.

5. The monopravir-caprolactam eutectic as described in claim 1, characterized in that, The repose angle of the monopravir-caprolactam eutectic is 41°-43°.

6. A method for preparing the monopravir-caprolactam eutectic as described in any one of claims 1-5, characterized in that, Includes the following steps: Monopravir and caprolactam are mixed and dissolved in a solvent to obtain a clear solution. After the clear solution evaporates, the monopravir-caprolactam eutectic is obtained. The solvent includes at least one of ethyl acetate, acetonitrile, acetone and n-butanol.

7. A method for preparing the monopravir-caprolactam eutectic as described in any one of claims 1-5, characterized in that, Includes the following steps: Monopravir and caprolactam are mixed, heated to melt, and then cooled to obtain the monopravir-caprolactam eutectic.

8. The preparation method according to claim 6 or 7, characterized in that, Monopravir and caprolactam can be mixed by grinding together or by direct mixing.

9. The use of the monopravir-caprolactam cocrystal as described in any one of claims 1-5 in the preparation of anti-RNA virus drugs.

10. The application as described in claim 9, characterized in that, The anti-RNA virus drug is monoravir.

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