Paliperidone cocrystal, and preparation and use thereof

Abstract

The present invention provides a paliperidone cocrystal, and a preparation method therefor and a use thereof. The cocrystal former of the paliperidone cocrystal is nicotinic acid. The paliperidone cocrystal is obtained by dissolving paliperidone and nicotinic acid in an aqueous organic solvent and then evaporating to dryness under reduced pressure. The paliperidone cocrystal of the present invention has high purity and stable quality, is suitable for commercial storage, has greatly improved solubility and dissolution rate, and is more suitable for the development of paliperidone preparations.

Description

A paliperidone cocrystal and its preparation and application Technical Field

[0001] The present invention relates to paliperidone cocrystals and preparation and application thereof, belonging to the field of medicinal chemistry. Background Art

[0002] Paliperidone (PLPT) is classified as a second-generation antipsychotic. It is derived from the metabolic conversion of risperidone and forms its active metabolite. This drug combines efficacy with minimal side effects, particularly with significantly fewer extrapyramidal side effects compared to first-generation antipsychotics. However, paliperidone has very low water solubility. According to results reported by the Japanese PMDA (Pharmaceuticals and Medical Devices Agency), the solubility of PLPT in pure water is only 0.03 mg / mL. This solubility increases to 15 mg / mL and 30 mg / mL in acetate buffer at pH 5.0 and hydrochloric acid at pH 2.0, respectively. However, at around pH 7, the solubility is similar to that in pure water, and solubility further decreases with increasing pH. The primary dissolution and absorption site of PLPT preparations is the intestinal tract, where the pH is approximately 6.8. This low solubility limits its oral absorption and bioavailability (reported bioavailability is approximately 28%).

[0003] To overcome the low water solubility of paliperidone, existing technologies have disclosed methods for improving its solubility and pharmaceutical properties through crystal engineering and cocrystallization techniques. Cocrystals are substances in which the active pharmaceutical ingredient (API) and the cocrystal ligand (CCF) are connected by non-covalent bonds to form a fixed stoichiometric ratio. Chinese patent documents CN102153552B and CN102584818A disclose paliperidone cocrystals, where the cocrystal ligands are p-hydroxybenzoic acid and p-aminobenzoic acid, respectively. While these paliperidone cocrystals have improved water solubility compared to paliperidone, their solubility remains limited. Summary of the Invention

[0004] The present invention aims to provide a novel paliperidone cocrystal and its preparation method and application. Compared with paliperidone, the paliperidone cocrystal of the present invention has significantly improved water solubility.

[0005] Technical solution of the present invention:

[0006] A paliperidone cocrystal, characterized in that the cocrystal ligand is niacin.

[0007] The paliperidone cocrystal of the present invention has paliperidone (PLPT) as its active ingredient, whose chemical name is (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, and its molecular formula is C 23 H 27 FN4O3, whose structural formula is shown in a. The eutectic ligand is niacin (or nicotinic acid, NA), whose chemical name is pyridine-3-carboxylic acid and belongs to the B vitamins. Its molecular formula is C6H5NO2, and its structural formula is shown in b.

[0008] The paliperidone cocrystal described above is characterized in that it is a solvate, and preferably, the solvent is water and / or methanol.

[0009] Preferably, the paliperidone cocrystal described above is characterized in that the basic structural unit consists of one paliperidone (PLPT) molecule, one niacin (NA) molecule and two water molecules, as shown in the following formula (I).

[0010] The paliperidone cocrystal described above is characterized in that the crystal belongs to the triclinic system with space group P1(2).

[0011] The above-mentioned paliperidone cocrystal is characterized in that the unit cell parameters of the crystal are: axis length a = 11.1548, b = 12.0939, c = 12.8245, axis angle α = 93.2920°, β = 91.9760°, γ = 115.8980°.

[0012] The paliperidone cocrystal described above is characterized in that its X-ray powder diffraction pattern has a characteristic peak at 2θ±0.2° (diffraction peak position), and the 2θ is selected from at least 3 of 6.8, 9.0, 11.0, 13.1, 13.9, 14.5, 15.0, 16.2, 18.6, 19.2, 20.0, 21.5, 22.0, 24.6, 25.0, 28.0, and 31.2, preferably at least 5, and more preferably at least 7.

[0013] The paliperidone cocrystal described above is characterized by having a molecular structure determined by X-ray single crystal diffraction as shown in Figure 1 of the specification.

[0014] The paliperidone cocrystals described above are characterized by having an X-ray powder diffraction pattern as shown in Figure 3 of the specification.

[0015] As another object of the present invention, a method for preparing the above-mentioned paliperidone cocrystal is provided, which is characterized by comprising the step of dissolving paliperidone (PLPT) and nicotinic acid (NA) in a mixed solvent of methanol and water to obtain the crystal.

[0016] In the above-described method, preferably, the paliperidone co-crystal is obtained by removing the solvent under reduced pressure.

[0017] As another object of the present invention, a method for preparing single crystals of the above-mentioned paliperidone cocrystal is provided, which is characterized by comprising the step of dissolving the paliperidone cocrystal in a solvent and naturally volatilizing and crystallizing to obtain single crystals of the paliperidone cocrystal.

[0018] In the above-mentioned method for preparing a single crystal, the solvent is preferably ethyl acetate.

[0019] In the paliperidone cocrystal of formula (I) above, the proton on the carboxyl group of NA is transferred to the N atom of the piperidine ring at the center of PLPT. Therefore, the PLPT cation and the NA anion are bound together by charge-assisted hydrogen bonds (N+-H…O-). Subsequently, one hydrogen atom on the first water molecule forms a hydrogen bond with the oxygen atom on the NA anion, while the other hydrogen atom interacts with the hydroxyl oxygen at the end of the PLPT cation. The first hydrogen atom on the second water molecule forms a hydrogen bond with the oxygen atom of the first water molecule, while the other hydrogen atom interacts with the carbonyl oxygen of the PLPT cation. In addition, hydrogen bonding occurs between the hydrogen atom on the hydroxyl group of the PLPT cation and the nitrogen atom at the hydroxyl position of the adjacent PLPT cation. In addition, adjacent PLPT cations at the end of the benzene ring form π…π interactions, but do not form an effective one-dimensional chain; instead, they are spaced apart. The interplanar distances of these π…π interactions are, respectively. and The displacement value is

[0020] Preferably, as one of the specific embodiments, the method for preparing the paliperidone cocrystal of the present invention is to add PLPT and NA into a glass flask, then add a mixed solvent of methanol and water, heat and stir to clarify, and then evaporate the solvent under reduced pressure to obtain a solid.

[0021] The molar ratio of PLPT to NA in the method is 1:1.

[0022] Wherein, the volume ratio of water to methanol in the above method is 0.5:99.5 to 10:90.

[0023] In the above method, the weight-to-volume ratio of PLPT to the solvent is 1:20-80, preferably 1:50.

[0024] Wherein, the heating temperature in the above-mentioned method is 40-65°C.

[0025] Wherein, the reduced pressure in the above-mentioned method is less than -0.09 MPa, and the temperature is 30 to 100°C, preferably 50 to 70°C.

[0026] Preferably, as one of the specific embodiments, a method for preparing a single crystal of the paliperidone cocrystal of the present invention is as follows: the solid compound of formula (I) is dissolved in a solvent at about 80° C. at a ratio of solid weight (W / g) to ethyl acetate (V / ml) ​​of 1: (100-300) to obtain a clear solution, which is filtered through a 0.45 μm filter into another clean round-bottom flask, covered with plastic wrap, pierced with a hole, and allowed to stand at 5-20° C. for slow natural evaporation and crystallization to obtain a single crystal of the compound of formula (I).

[0027] As another object of the present invention, provided is the use of the above-mentioned paliperidone cocrystal as a drug, for example, in the preparation of antipsychotic drugs.

[0028] Surprisingly, the present invention provides a paliperidone cocrystal using niacin as a cocrystal ligand, exhibiting excellent crystallinity, high purity, and long-term stability under moderate commercial storage conditions. While maintaining the therapeutic properties of traditional APIs, the solubility and dissolution rate of paliperidone are significantly improved, thereby potentially improving the low oral bioavailability of existing paliperidone preparations. The compound of formula (I) of the present invention is a novel paliperidone cocrystal, and a single crystal was obtained from the crystal. X-ray diffraction analysis of the single crystal yielded a molecular structure diagram ( FIG1 ). A crystal packing diagram ( FIG2 ) was simulated using computational software. An X-ray powder diffraction (XRPD) pattern of the crystal was also measured, and the simulated XRPD pattern using the single crystal diffraction data was compared with the actual measured XRPD pattern of the crystal ( FIG3 ). The comparison results demonstrate consistent crystal form and high purity.

[0029] In addition, the novel paliperidone cocrystal of the present invention and the cocrystal ligand niacin are mainly present in animal viscera and muscle tissue, and also exist in trace amounts in fruits and egg yolks. They are one of the 13 vitamins essential to the human body, an indispensable component for the growth and development of humans and animals, and an essential component beneficial to the human body. They can also form a complex with paliperidone to exert a synergistic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1: Molecular structure of the cocrystal of formula (I) determined by X-ray single crystal diffraction

[0031] Figure 2: Crystal packing diagram of the cocrystal of formula (I)

[0032] Figure 3: Comparison of the X-ray powder diffraction (XRPD) pattern simulated from the single crystal diffraction data of the cocrystal of formula (I) and the X-ray powder diffraction (XRPD) pattern actually measured from the crystal, where 1 is the measured pattern and 2 is the simulated pattern. Specific implementation method:

[0033] The following examples are provided to help understand the present invention, but are not intended to limit the present invention.

[0034] All raw materials and reagents used in the examples of the present invention are commercially available.

[0035] Example 1 Preparation of Compound (I):

[0036] PLPT (1 g, 2.35 mmol) and NA (0.29 g, 2.35 mmol) were weighed separately and placed in a 100 mL round-bottom flask. 49.5 mL of methanol and 0.5 mL of water were added. The mixture was heated to 60°C and stirred to clarify. The mixture was maintained for 1 hour. The solvent was removed by rotary evaporation under reduced pressure at 60°C to obtain 1.38 g of a white solid.

[0037] The X-ray powder diffraction pattern is shown in Figure 3, and the measurement conditions and data are as follows:

[0038] Instrument: Japan Rigaku D / MAX-2500 X-ray diffractometer

[0039] Target: Cu-Kα ray λ = 1.5405A

[0040] Pipe voltage: 40kv

[0041] Tube current: 100mA

[0042] Scanning range: 2θ = 2-50°

[0043] Among them, 2θ is the diffraction peak position: 6.8, 9.0, 11.0, 13.1, 13.9, 14.5, 15.0, 16.2, 18.6, 19.2, 20.0, 21.5, 22.0, 24.6, 25.0, 28.0, 31.2.

[0044] Example 2 Preparation of single crystal of compound (I):

[0045] Take 0.1 g of the solid prepared in Example 1 and put it into a 50 mL round-bottom flask. Add 20 mL of ethyl acetate, heat to clarify, filter through a 0.45 μm filter into another clean 50 mL round-bottom flask, cover with plastic wrap, poke 3 holes on it, and let it stand at about 15°C. After 20 days, block crystals appeared. Select single crystals that meet the standards for X-ray single crystal diffraction (SCXRD) analysis to determine their precise structure.

[0046] The X-ray single crystal diffraction pattern is shown in Figure 1, and the measurement conditions are as follows:

[0047] Instrument: Burke APEX II Duo

[0048] Target: Copper target

[0049] Temperature: 293K

[0050] A comparison of the X-ray powder diffraction (XRPD) pattern simulated from single crystal diffraction data of the crystalline form of the compound of formula (I) and the actual measured X-ray powder diffraction (XRPD) pattern of the crystal is shown in Figure 3. The comparison results show that the crystalline form is consistent and the material is very pure.

[0051] Example 3 Comparison of Saturation Solubility of the Compound of Formula (I) and Paliperidone (PLPT)

[0052] Weigh an excess of drug into a test tube, add 1 mL of medium (purified water, pH 1.2, pH 4.0, or pH 6.8 buffer), and shake at 75 rpm and 25°C for 24 hours (to ensure excess drug and any undissolved material). Filter the suspension to remove the precipitate, then remove the supernatant and filter through a 0.45 μm filter. After appropriate dilution of the filtrate, analyze all samples using high-performance liquid chromatography (HPLC) to determine the concentration of PLPT in the samples. The HPLC method follows the method outlined in the 2023 United States Pharmacopoeia (USP2023).

[0053] PH 1.2 medium: Take 7.0 mL of concentrated hydrochloric acid, dissolve it in water and dilute it to 1000 mL.

[0054] PH4.0 medium: Take 1.22g of sodium acetate trihydrate and 2.46g of acetic acid, dissolve them in water and dilute to 1000mL.

[0055] PH 6.8 medium: Take 6.805g of potassium dihydrogen phosphate and 0.896g of sodium hydroxide, dissolve them in water and dilute to 1000mL.

[0056] The determination results are shown in the table below. It can be seen from the results in the table that the saturated solubility of the compound of formula (I) in all media is much greater than that of the paliperidone raw material.

[0057] Comparison of saturated solubility in different media

[0058] Example 4 Comparison of dissolution of the compound of formula (I) and paliperidone (PLPT)

[0059] The compound powder (equivalent to approximately 6 mg of PLPT after conversion) was accurately weighed and placed into capsules. Dissolution studies were performed using the rotating basket method (37°C, 100 rpm). 5 mL of solution was taken at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, and 120 min, and 5 mL of medium was added to the dissolution apparatus. The 5 mL of solution was filtered through a 0.45 μm filter, and the filtrate was measured by high-performance liquid chromatography (HPLC). The dissolution test was carried out in a buffer medium at pH 6.8. The specific preparation of the buffer medium is shown in Example 3. The HPLC method is based on the method included in the 2023 United States Pharmacopoeia (USP2023).

[0060] The test results are shown in the table below. As can be seen from the results in the table, the compound of formula (I) was almost completely dissolved within 15 minutes in a pH 6.8 medium, while PLPT was only dissolved 17.8% in 15 minutes and was not completely dissolved even after 120 minutes.

[0061] Comparative dissolution results in pH 6.8 medium

[0062] Example 5 Comparison of Thermal Stability of the Compound of Formula (I) and Paliperidone (PLPT)

[0063] The compound of formula (I) and PLPT were tested using a DSC analyzer to evaluate the thermal properties of the drug. Alumina crucibles each held approximately 8 mg of sample. The test temperature range was 300 K to 800 K, the heating rate was 15 K / min, and the nitrogen flow rate was 20 mL / min.

[0064] The measurement results are shown in the table below. It can be seen from the results in the table that the thermal decomposition temperature of the compound of formula (I) is 40K higher than that of PLPT, indicating that the thermal stability is better than PLPT.

[0065] Thermal stability comparison results

[0066] Example 6 Comparison of saturated solubility of the compound of formula (I) and other cocrystals

[0067] PLPT-p-hydroxybenzoic acid cocrystal was prepared according to CN102153552B, and PLPT-p-aminobenzoic acid cocrystal was prepared according to CN102584818A.

[0068] Weigh an excess of drug into a test tube, add 1 mL of purified water, and shake at 75 rpm at 25°C for 24 hours (to ensure excess drug is present and any undissolved material is present). Filter the suspension to remove any precipitate, then remove the supernatant and filter through a 0.45 μm filter. After appropriate dilution of the filtrate, analyze all samples using high-performance liquid chromatography (HPLC) to determine the PLPT concentration. The HPLC method follows that outlined in the 2023 United States Pharmacopoeia (USP2023).

[0069] The measurement results are shown in the table below. It can be seen from the results in the table that the saturated solubility of the compound of formula (I) in pure water medium is much greater than that of PLPT-p-hydroxybenzoic acid cocrystal and PLPT-p-aminobenzoic acid cocrystal.

[0070] Comparison results of saturated solubility in pure water medium

Claims

1. A paliperidone cocrystal, characterized in that The cocrystal ligand is niacin.

2. The paliperidone cocrystal according to claim 1, characterized in that It is a solvate; preferably, the solvent is water and / or methanol.

3. The paliperidone cocrystal according to claim 1 or 2, characterized in that The basic structural unit of the co-crystal consists of one paliperidone (PLPT) molecule, one niacin (NA) molecule and two water molecules, as shown in the following formula (I).

4. The paliperidone cocrystal according to any one of claims 1 to 3, characterized in that The cocrystal belongs to the triclinic system with space group P1(2), axial lengths a=11.1548, b=12.0939, c=12.8245, axial angles α=93.2920°, β=91.9760°, γ=115.8980°.

5. The paliperidone cocrystal according to any one of claims 1 to 4, characterized in that The X-ray powder diffraction pattern has a characteristic peak at 2θ±0.2°, and the 2θ is selected from at least 3 of 6.8, 9.0, 11.0, 13.1, 13.9, 14.5, 15.0, 16.2, 18.6, 19.2, 20.0, 21.5, 22.0, 24.6, 25.0, 28.0, and 31.2, preferably at least 5, and more preferably at least 7.

6. The paliperidone cocrystal according to any one of claims 1 to 5, characterized in that The molecular structure is determined by X-ray single crystal diffraction as shown in Figure 1.

7. The paliperidone cocrystal according to any one of claims 1 to 6, characterized in that It has the X-ray powder diffraction pattern shown in Figure 3.

8. A method for preparing the paliperidone cocrystal according to any one of claims 1 to 7, characterized in that The method comprises the step of dissolving paliperidone and nicotinic acid in a mixed solvent of methanol and water to prepare the crystals.

9. A method for preparing a single crystal of the paliperidone cocrystal according to any one of claims 1 to 7, characterized in that The method comprises the steps of dissolving the paliperidone cocrystal in a solvent and allowing the solvent to evaporate and crystallize naturally to obtain a single crystal of the paliperidone cocrystal; preferably, the solvent is ethyl acetate.

10. Use of the paliperidone cocrystal according to any one of claims 1 to 7 in the preparation of antipsychotic drugs.

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