Lamivudine-orthophthalate and a process for its preparation

Abstract

This invention belongs to the field of pharmaceutical chemistry, specifically relating to a lamiditam-phthalate salt and its preparation method. The crystal of this salt consists of two molecules of lamiditam and three molecules of phthalic acid as its basic unit. The specific crystal form of this salt not only exhibits excellent chemical stability but also effectively improves the bioavailability of lamiditam, thus providing a more stable pharmaceutical raw material for clinical applications.

Description

Technical Field

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

[0002] Migraine is a common neurological disorder characterized by episodic unilateral or bilateral throbbing headaches, often accompanied by symptoms such as nausea, vomiting, photophobia, and phonophobia, severely interfering with patients' quality of life and work ability. Calcitonin gene-related peptide (CGRP) plays a central role in the pathological mechanism of migraine; abnormally elevated levels of CGRP can lead to vasodilation and neurogenic inflammation, thereby triggering pain.

[0003] In the treatment of acute migraines, triptans have been the traditional medications for decades. However, triptans primarily exert their vasoconstrictive effects by stimulating 5-HT1B / 1D receptors. This mechanism leads to significant cardiovascular risks in patients with hypertension, coronary artery disease, peripheral vascular disease, or a history of stroke, limiting their safe use in a broad population. Therefore, there is an urgent clinical need for a novel therapeutic agent that can effectively relieve pain and related symptoms without vasoconstrictive activity.

[0004] Lasmiditan, also known chemically as COL-144 or LY573144, is the first approved specific serotonin 1F (5-HT1F) receptor agonist, representing a significant breakthrough in the acute treatment of migraine. Unlike traditional triptans, lamiditan not only has high receptor selectivity but also does not cause vasoconstriction at therapeutic doses. It exerts its analgesic effect by stimulating 5-HT1F receptors in the central nervous system, inhibiting the release of pain-inducing substances such as CGRP and glutamate from the trigeminal nerve terminals. Clinical data show that lamiditan has a rapid onset of action, effectively relieving headaches and improving accompanying symptoms such as photophobia and nausea, filling a treatment gap for high-risk cardiovascular migraine patients.

[0005] Although lamiditan has shown excellent clinical potential, the drug has extremely low solubility in water. This low solubility results in a slow dissolution rate in the gastrointestinal tract and low oral bioavailability. To overcome the low solubility problem, existing formulation technologies often require complex processes such as micronization and solid dispersions or the addition of large amounts of solubilizers, which significantly increases the difficulty of formulation development and production costs, and can easily lead to unstable product quality and large differences in bioavailability between individuals.

[0006] Despite its high potential for clinical application, lamiditan's extremely low water solubility limits its widespread clinical use. This low solubility results in slow gastrointestinal dissolution and limited oral bioavailability. To address these technical challenges, current formulation technologies often employ complex processes such as micronization and solid dispersions, or involve large amounts of solubilizers. This inevitably increases research and development costs and makes the product more susceptible to instability and significant inter-individual variability in bioavailability.

[0007] Currently, existing technologies mainly focus on the polymorphism research of lamiditam hemisuccinate. Patents US8697876B and IN201941034052 disclose its polymorphs A, B, C, amorphous form, and pharmaceutical composition, respectively, while CN201780075750 discloses dihydrate polymorph D, trihydrate polymorph F, and polymorph E. However, the above-mentioned known polymorphs generally suffer from stability shortcomings: polymorph A depends on specific environmental conditions such as anhydrous ethanol for stability, polymorph E is metastable, while polymorphs D and F are prone to crystal transformation under low humidity, making it difficult to meet the stringent requirements of drug production and storage.

[0008] Regarding stability issues, CN202510581608.6 discloses lamiditan's hemisuccinate and acetate. Although the acetate slightly improves solubility, its poor water solubility remains due to the inherent properties of the active pharmaceutical ingredient. Therefore, there is an urgent need to develop a novel crystal form to simultaneously improve the stability, solubility, and bioavailability of lamiditan, thereby providing a better active pharmaceutical ingredient option for clinical formulation development. Summary of the Invention

[0009] In view of the deficiencies in the prior art, the present invention provides a lamiditan-phthalate and a method for preparing the same. The specific crystal form of the salt not only exhibits excellent chemical stability, but also effectively improves the bioavailability of lamiditan, thereby providing a more stable pharmaceutical raw material for clinical application.

[0010] The technical solution of this invention is as follows:

[0011] A lamiditam-phthalate crystal form, using Cu-Kα radiation, exhibits characteristic peaks in its 2θ X-ray diffraction pattern at 3.68±0.2°, 11.77±0.2°, 13.83±0.2°, 17.75±0.2°, 19.11±0.2°, 23.89±0.2°, 25.43±0.2°, and 26.87±0.2°.

[0012] Preferably, the lamiditam-phthalate crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (expressed as 2θ) at at least 3.68±0.2°, 11.77±0.2°, 13.83±0.2°, 17.75±0.2°, 19.11±0.2°, 19.87±0.2°, 23.89±0.2°, 24.72±0.2°, 25.43±0.2°, 26.03±0.2°, 26.87±0.2°, and 42.91±0.2°.

[0013] Preferably, the lamiditam-phthalate crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks conforming to the following... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0014] Preferably, the lamiditam-phthalate crystal form has an endothermic peak at 193.28°C in the differential scanning calorimetry (DSC) curve.

[0015] Preferably, the lamiditam-phthalate crystal form is composed of two molecules of lamiditam and three molecules of phthalic acid as basic units.

[0016] Preferably, the crystallographic parameters of the lamiditan-phthalate crystal form are: monoclinic crystal system, space group P21 / c; cell parameters are: a = 7.9057(2) Å, b = 15.0937(6) Å, c = 48.9648(15) Å, α = 90.00°, β = 91.084(3) °, γ = 90.00°, z = 4, and cell volume V = 5841.7(3) Å. 3 .

[0017] In a second aspect, the present invention provides a method for preparing the lamiditam-phthalate crystal form as described above, comprising the following steps: adding lamiditam and phthalic acid to a mixture of a good solvent and water to form a suspension with a solid content of 10-27 mg / mL; heating and stirring the suspension until it is completely converted into the lamiditam-phthalate crystal form; filtering; and vacuum drying to obtain the lamiditam-phthalate crystal form.

[0018] Preferably, the benign solvent is selected from one or more of methanol, acetone, acetonitrile, and trifluoroethanol.

[0019] Preferably, in the mixed solvent, the volume ratio of water to good solvent is 1:1~2.

[0020] Preferably, the heating temperature is 35~43℃.

[0021] Preferably, the mass-to-volume ratio of lamiditan to the mixed solvent is 37.7:3~8, more preferably 37.7:4~6; wherein the mass is expressed in mg and the volume in mL.

[0022] Preferably, the mass-to-volume ratio of phthalic acid to the mixed solvent is 41.7:3~8, more preferably 41.7:4~6; wherein the mass is expressed in mg and the volume in mL.

[0023] Preferably, the drying temperature is 30~35℃ and the drying time is 10~12h.

[0024] The present invention also provides a pharmaceutical composition comprising the aforementioned lamiditan-phthalate crystal form. The pharmaceutical composition consists of the lamiditan-phthalate crystal form and pharmaceutically acceptable excipients. The excipients may be selected from conventional pharmaceutical excipients in the art, specifically including one or more of diluents, binders, disintegrants, lubricants, flow aids, release modifiers, plasticizers, preservatives, and antioxidants. The pharmaceutical composition may be formulated into various dosage forms suitable for oral administration, such as tablets, capsules, granules, powders, or pills, according to clinical needs. Furthermore, the present invention provides the use of the lamiditan-phthalate crystal form or the pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of acute migraine.

[0025] Crystal structure confirmed:

[0026] The lamiditam-phthalate crystal form described in this invention was tested using X-ray crystal data collected on a Rigaku XtaLAB Synergy instrument at a temperature of 293(2) K. The data was collected and processed using Cu-Ka radiation in an ω-scan manner. Lp Correction. The structure was analyzed using the direct method, and all non-hydrogen atoms were identified using the difference Fourier method. All hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation. The structure was then refined using the least squares method.

[0027] The lamiditam-phthalate crystal form described in this invention has the following crystallographic parameters: monoclinic crystal system, space group P21 / c; cell parameters: a = 7.9057(2) Å, b = 15.0937(6) Å, c = 48.9648(15) Å, α = 90.00°, β = 91.084(3) °, γ = 90.00°, z = 4, cell volume V = 5841.7(3) Å. 3 The ORTEP diagram of the lamiditam-phthalate crystal of the present invention shows that the crystal consists of two molecules of lamiditam and three molecules of phthalic acid as the basic unit, as shown in the attached diagram. Figure 3As shown. A packing diagram of the lamiditam-phthalic acid of the present invention is attached. Figure 4 As shown.

[0028] Table 1. Main crystallographic data of lamiditam-phthalate crystal forms

[0029] The X-ray powder diffraction testing instrument and testing conditions in this invention are as follows: X-ray powder diffractometer: PANalyticalEmprem; Cu-Kα; sample stage: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage: 45 kV; current: 40 mA; divergence slit: 1 / 4; anti-scattering slit: 1; Solar slit: 0.04 rad; step size: 0.5 s; scanning range: 3~50°.

[0030] Based on crystallographic data, the characteristic peaks in the X-ray powder diffraction (Cu-Kα) pattern corresponding to the lamidetan-phthalate crystal form described in this invention are detailed in the appendix. Figure 1 And Table 2.

[0031] Table 2. Major PXRD peaks of lamiditam-phthalate crystal forms

[0032] All lamiditam-phthalate crystal form samples prepared in the embodiments of the present invention conform to the appendix. Figure 1 The X-ray powder diffraction pattern shown is shown.

[0033] The TGA / DSC thermal analysis instrument and testing conditions in this invention: TGA / DSC thermal analyzer: METTLER TOLEDOTGA / DSC 3+ Dynamic temperature range: 30~300℃; heating rate: 10℃ / min; programmed gas N2; gas flow rate: 50 mL / min; crucible: 40 μL aluminum crucible.

[0034] The TGA / DSC test results of the lamiditam-phthalate crystal form prepared by the method of the present invention are as follows: Figure 2 As shown, the DSC detection results show an endothermic peak, corresponding to a temperature of 193.28℃. The TGA detection results indicate the presence of a weight loss step, and calculations suggest that this lamiditam-phthalate crystal form lacks solvent.

[0035] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0036] The lamiditam-phthalate crystal form provided by this invention not only exhibits high chemical stability but also significantly improved bioavailability, providing a more stable and reliable pharmaceutical raw material for clinical applications. Furthermore, the preparation method for this crystal form is simple, the crystallization process is easy to scale up and control, and it possesses good reproducibility, making it easy to achieve industrial-scale production. Attached Figure Description

[0037] Figure 1 PXRD pattern of lamiditam-phthalate crystal form.

[0038] Figure 2 TGA / DSC spectrum of lamiditam-phthalate crystal form.

[0039] Figure 3 ORTEP diagram of lamiditam-phthalate crystal form.

[0040] Figure 4 Stacking diagram of lamiditam-phthalate crystal forms. Detailed Implementation

[0041] The following specific embodiments further illustrate the present invention, but do not limit the scope of the present invention in any way. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not depart from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0042] Example 1

[0043] 37.7 mg lamiditam and 41.7 mg phthalic acid were added to a mixed solvent of 2 mL methanol, 1 mL acetone and 2 mL water to form a suspension. The suspension was heated and stirred at 38 °C until it was completely converted into lamiditam-phthalate crystal form. After filtration, the solution was dried under vacuum at 33 °C for 10 h to obtain lamiditam-phthalate crystal form with a yield of 88.67% and an HPLC purity of 99.92%.

[0044] Example 2

[0045] 37.7 mg lamiditam and 41.7 mg phthalic acid were added to a mixed solvent of 2 mL acetonitrile and 1 mL water to form a suspension. The suspension was heated and stirred at 35 °C until it was completely converted into lamiditam-phthalate crystal form. After filtration, the solution was dried under vacuum at 30 °C for 11 h to obtain lamiditam-phthalate crystal form with a yield of 88.16% and an HPLC purity of 99.87%.

[0046] Example 3

[0047] 37.7 mg lamiditam and 41.7 mg phthalic acid were added to a mixed solvent of 3 mL methanol, 2 mL trifluoroisopropanol and 3 mL water to form a suspension. The suspension was heated and stirred at 43 °C until it was completely converted into lamiditam-phthalate crystal form. After filtration, the solution was dried under vacuum at 35 °C for 12 h to obtain lamiditam-phthalate crystal form with a yield of 87.33% and an HPLC purity of 99.90%.

[0048] Example 4

[0049] 37.7 mg lamiditam and 85.3 mg phthalic acid were added to a mixed solvent of 2 mL methanol, 1 mL acetone and 2 mL water to form a suspension. The suspension was heated and stirred at 38 °C until it was completely converted into lamiditam-phthalate crystal form. After filtration, the solution was dried under vacuum at 33 °C for 10 h to obtain lamiditam-phthalate crystal form with a yield of 71.53% and an HPLC purity of 99.84%.

[0050] Example 5

[0051] 37.7 mg lamiditam and 41.7 mg phthalic acid were added to a mixed solvent of 5 mL methanol, 4 mL acetone and 6 mL water to form a suspension. The suspension was heated and stirred at 38 °C until it was completely converted into lamiditam-phthalate crystal form. After filtration, the solution was dried under vacuum at 33 °C for 10 h to obtain lamiditam-phthalate crystal form with a yield of 68.51% and an HPLC purity of 99.86%.

[0052] Comparative Example 1

[0053] 2,4,6-Trifluoro-N-(6-(piperidin-4-formyl)pyridin-2-yl)benzamide trifluoroacetate (200 g) was dissolved in formic acid (600 mL), and 37% formaldehyde (46 mL) was added with stirring. The reaction was carried out at about 90 °C until complete. Water was then added at about 30 °C, and the mixture was extracted with dichloromethane and washed with sodium hydroxide aqueous solution. Dichloromethane was evaporated and replaced with acetone. 4-hydroxybenzoic acid (61 g) was added and refluxed with stirring. The mixture was filtered and separated, and dried at 50 °C to obtain lamiditam 4-hydroxybenzoic acid product with a yield of 62.54% and an HPLC purity of 99.69%.

[0054] Comparative Example 2

[0055] A lamiditam free base ethanol solution (1.00 weight corrected, approximately 4.5 volumes, 183 g) was added to a clean reactor through an online filter. The reactor was rinsed online with ethanol (0.5 volumes, 0.4 weight, 91 mL), and then heated to 75-80°C under a nitrogen atmosphere. Succinic acid (0.16 parts, 0.53 parts, 29.3 g) and ethanol (3.0 parts, 2.4 parts, 550 mL) were added to a second container and stirred at 20-25°C for 40-50 minutes under a nitrogen atmosphere. After dissolution, the solution was added to the reactor containing the lamiditam ethanol solution. The reactor was maintained at 75-80°C and rinsed online with ethanol (1.0 volume, 0.8 weight, 183 mL). The reactor was cooled to 60-63°C, and the crystallization process in the reactor was visually inspected and the crystallization temperature was recorded. The reactor was stirred for 50-60 minutes. The contents of the reaction vessel were cooled to 20-25°C within 40-60 minutes (approximately 1°C / minute), stirred for 4-6 hours, the solid was collected, washed with ethanol, and dried under vacuum at 45°C to obtain lamiditam hemisuccinate crystal form A product with an HPLC purity of 99.44%.

[0056] Verification Example:

[0057] 1. Influencing Factors Experiment

[0058] To verify the stability of the crystal form of this invention, lamiditam crystal forms prepared in Example 1 and Comparative Examples 1-2 were used as test samples and accelerated tests were conducted under three conditions: light irradiation (4500 Lux), high temperature (60°C), and high humidity (90% relative humidity). Samples were taken on days 15 and 30 after storage, and purity was determined by HPLC. Simultaneously, XRPD analysis was performed on the test samples on day 30 to examine the retention ability of the specific crystal form under extreme conditions and whether crystal transformation occurred. The results are shown in Table 3.

[0059] Table 3. Experimental Results of Factors Affecting the Crystal Form of Lameditham

[0060] The results show that the lamiditam-phthalate crystal form obtained in this invention has high stability; in contrast, the crystal forms obtained in Comparative Examples 1-2 have poor stability. After being placed under light, high temperature and high humidity conditions, the total impurity content increases significantly, and crystal transformation occurs.

[0061] 2. Pharmacokinetic studies

[0062] One hundred healthy SPF-grade Kunming mice, half male and half female, weighing 18-25g, were randomly divided into two groups (n=50). Each group was given a single oral gavage administration of lamiditan crystal form (prepared as a solution before administration, dose 10 mg / kg) obtained in Example 1 and the relatively more stable comparative Example 2. At 10 min, 20 min, 30 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 8 h, 12 h, and 24 h post-administration, five mice from each group were sacrificed at each time point. Approximately 100 μL of blood was collected from the fundus venous plexus and placed in heparinized tubes. The plasma was separated by centrifugation, and the drug concentration in the plasma was determined by LC-MS / MS. The results are shown in Table 4.

[0063] Table 4. Pharmacokinetic Study Results of Lameditamine Crystal Forms

[0064] Pharmacokinetic studies showed that the lamidutane crystal form obtained in this invention effectively overcomes the deficiency of insufficient in vivo absorption in the prior art. Compared with the crystal form product of Comparative Example 2, the crystal form of this invention improves the bioavailability of lamidutane.

Claims

1. A lamivudine-o-phthalate salt crystalline form characterized by, The crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its 2θ X-ray diffraction pattern at 3.68±0.2°, 11.77±0.2°, 13.83±0.2°, 17.75±0.2°, 19.11±0.2°, 23.89±0.2°, 25.43±0.2°, and 26.87±0.2°.

2. The crystal form as described in claim 1, characterized in that, The crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 3.68±0.2°, 11.77±0.2°, 13.83±0.2°, 17.75±0.2°, 19.11±0.2°, 19.87±0.2°, 23.89±0.2°, 24.72±0.2°, 25.43±0.2°, 26.03±0.2°, 26.87±0.2°, and 42.91±0.2°.

3. The crystal form as described in claim 1, characterized in that, The crystal form was subjected to Cu-Kα radiation, and its characteristic peaks conformed to the X-ray powder diffraction pattern shown in Figure 1.

4. The crystal form as described in claim 1, characterized in that, The crystal of the described crystal form consists of two molecules of lamiditam and three molecules of phthalic acid as basic units.

5. The crystal form as described in claim 1, characterized in that, The crystallographic parameters of the crystal form are: monoclinic crystal system, space group P21 / c; cell parameters are: a = 7.9057(2) Å, b = 15.0937(6) Å, c = 48.9648(15) Å, α = 90.00°, β = 91.084(3) °, γ = 90.00°, z = 4, cell volume V = 5841.7(3) Å 3 .

6. A process for preparing the crystalline form of any one of claims 1-5, comprising, The method includes the following steps: adding lamiditam and phthalic acid to a mixture of a good solvent and water to form a suspension with a solid content of 10-27 mg / mL; heating and stirring the suspension until it is completely converted into lamiditam-phthalate crystal form; filtering; and vacuum drying to obtain lamiditam-phthalate crystal form.

7. The method of claim 6, wherein, The mass-to-volume ratio of lamiditan to the mixed solvent is 37.7:3~8, preferably 37.7:4~6; wherein the mass is expressed in mg and the volume in mL.

8. The method of claim 6, wherein, The mass-to-volume ratio of phthalic acid to the mixed solvent is 41.7:3~8, preferably 41.7:4~6; wherein the mass is expressed in mg and the volume in mL.

9. The method of claim 6, wherein, The benign solvent is selected from one or more of methanol, acetone, acetonitrile, and trifluoroethanol.

10. The method of claim 6, wherein, In the mixed solvent, the volume ratio of water to good solvent is 1:1~2.

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