Paliperidone co-crystal and preparation method thereof

Abstract

The invention relates to a paliperidone co-crystal and a preparation method thereof, and the method comprises the following steps: dissolving paliperidone and nicotinic acid in a water-containing organic solvent, and drying by distillation under reduced pressure to obtain the paliperidone co-crystal. The obtained crystal is high in purity, stable in quality and suitable for commercial storage, the solubility and the dissolution rate are greatly improved, and the crystal is more suitable for development of paliperidone solid preparations.

Description

Technical Field

[0001] The present invention relates to a paliperidone cocrystal and its preparation. Specifically, it relates to a cocrystal of the antipsychotic drug paliperidone with niacin and water and its preparation method. The invention belongs to the field of pharmaceutical chemistry. Background Art

[0002] Paliperidone (PLPT) is classified as a second-generation antipsychotic. It is derived from the metabolic conversion of risperidone to its active metabolite. This drug combines efficacy with low 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, the solubility of PLPT in pure water is only 0.03 mg / mL. This solubility increases to 15 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 the solubility decreases further with increasing pH. The primary dissolution and absorption site of PLPT preparations is the intestinal tract, where the pH is approximately 6.8. Therefore, this low solubility of PLPT likely limits its oral absorption and bioavailability (reported bioavailability is approximately 28%). Therefore, molecular-level studies are of great interest. To overcome this problem, researchers have focused on improving its solubility and drug performance through crystal engineering and co-crystallization technology. For example, CN102153552B and CN102584818A respectively disclosed PLPT drug co-crystals, which showed significant improvements in solubility, stability and bioavailability.

[0003] The preparation, characterization, and research of new solid-state drug forms have profound implications for the pharmaceutical industry. Different crystalline forms of the same drug often exhibit significant differences in stability, solubility, bioavailability, and toxic side effects. With the widespread application of drug cocrystals in drug development, drug cocrystal screening has become an essential step in pre-formulation research. Summary of the Invention

[0004] One of the objects of the present invention is to provide a novel co-crystal of paliperidone and a preparation method thereof.

[0005] Another object of the present invention is to provide a method for preparing a single crystal of the novel co-crystal of paliperidone.

[0006] The active pharmaceutical ingredient of the present invention is paliperidone (PLPT), 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 H27 FN4O3, its structural formula is shown in a. The organic co-ligand of the present invention is nicotinic acid (NA), chemically known as pyridine-3-carboxylic acid, which belongs to the B vitamins, with a molecular formula of C6H5NO2, and its structural formula is shown in b.

[0007]

[0008] As one of the objects of the present invention, a paliperidone cocrystal is provided, 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).

[0009]

[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 cocrystals described above are characterized by having characteristic peaks at 2θ (diffraction peak positions) of approximately 6.8, 9, 11, 13.1, 13.9, 14.5, 15, 16.2, 18.6, 19.2, 20, 21.5, 22, 24.6, 25, 28, and 31.2 in their X-ray powder diffraction pattern.

[0013] The above-mentioned paliperidone cocrystal is characterized by having Figure 1 The molecular structure determined by single crystal X-ray diffraction is shown.

[0014] 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 PLPT and NA in a mixed solvent of methanol and water to obtain the crystal.

[0015] In the above-described method, preferably, the solid compound of formula (I) is obtained by removing the solvent under reduced pressure.

[0016] 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 steps of dissolving the solid compound of formula (I) in a solvent and allowing it to evaporate and crystallize naturally to obtain single crystals of the compound of formula (I).

[0017] In the above-mentioned method for preparing a single crystal, the solvent is preferably ethyl acetate.

[0018] In the paliperidone cocrystals of the present invention, the proton on the NA carboxyl group is transferred to the N atom of the central piperidine ring 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 crystal plane distances of these π…π interactions are, respectively. and The displacement value is

[0019] 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.

[0020] The molar ratio of PLPT to NA in the method is 1:1.

[0021] Wherein, the volume ratio of water to methanol in the above method is 0.5:99.5 to 10:90.

[0022] Wherein, in the above-mentioned method, the weight-to-volume ratio of PLPT to the solvent is 1:20-80, preferably 1:50.

[0023] Wherein, the heating temperature in the above method is 40-65°C.

[0024] 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.

[0025] Preferably, as one of the specific embodiments, a method for preparing a single crystal of the paliperidone cocrystal of the present invention is provided, wherein the solid compound of formula (I) is dissolved in a solvent at a ratio of solid weight (W / g) to ethyl acetate (V / ml) ​​of 1:(100-300) at about 80°C 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).

[0026] 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.

[0027] The present invention surprisingly found that the compound of formula (I) prepared by the present invention is a new type of PLPT cocrystal, and a single crystal was obtained from the crystal. The single crystal was subjected to X-ray single crystal diffraction measurement to obtain its molecular structure diagram ( Figure 1 ), and the crystal stacking diagram was simulated using computational software ( Figure 2 ), and the X-ray powder diffraction (XRPD) pattern of the crystal was measured, and the X-ray powder diffraction (XRPD) pattern simulated by the single crystal diffraction data was compared with the X-ray powder diffraction (XRPD) pattern actually measured for the crystal ( Figure 3 ), the comparison results demonstrate consistent crystal forms and high purity. The compound of formula (I) of the present invention exhibits excellent crystallinity, high purity, and long-term stability under moderate commercial storage conditions. While maintaining the therapeutic properties of traditional APIs, it significantly improves the solubility and dissolution rate of PLPT, potentially improving the low oral bioavailability of existing paliperidone formulations.

[0028] In addition, the novel PLPT cocrystal of the present invention, and its organic co-compound niacin, are mainly found in animal viscera and muscle tissue, and are also present in trace amounts in fruits and egg yolks. They are one of the 13 vitamins essential to the human body and are indispensable for the growth and development of humans and animals. They are also essential and beneficial to the human body. They can also form a complex with paliperidone to exert a synergistic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 :Molecular structure diagram of the compound of formula (I) determined by X-ray single crystal diffraction

[0030] Figure 2 : Crystal packing diagram of compound of formula (I)

[0031] Figure 3 : Comparison of the X-ray powder diffraction (XRPD) pattern simulated from the single crystal diffraction data of the compound of formula (I) with the X-ray powder diffraction (XRPD) pattern actually measured from the crystal, where 1 is the measured pattern and 2 is the simulated pattern. DETAILED DESCRIPTION

[0032] The following examples are provided to help understand the present invention, but are not intended to limit the present invention.

[0033] All raw materials and reagents used in the examples of the present invention are commercially available.

[0034] Example 1 Preparation of Compound (I):

[0035] 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.

[0036] X-ray powder diffraction pattern see Figure 3 , the measurement conditions and measurement data are as follows:

[0037] Instrument: Japan Rigaku D / MAX-2500 X-ray diffractometer

[0038] Target: Cu-Kα ray λ = 1.5405A

[0039] Pipe voltage: 40kv

[0040] Tube current: 100mA

[0041] Scanning range: 2θ = 2-50°

[0042] Among them, 2θ is the diffraction peak position: 6.8, 9, 11, 13.1, 13.9, 14.5, 15, 16.2, 18.6, 19.2, 20, 21.5, 22, 24.6, 25, 28, 31.2.

[0043] Example 2 Preparation of single crystal of compound (I):

[0044] 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 and 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 appear. Select single crystals that meet the standards for SCXRD detection and analysis to determine their precise structure.

[0045] X-ray single crystal diffraction pattern see Figure 1 , and its determination conditions are as follows:

[0046] Instrument: Burke APEX II Duo

[0047] Target: Copper target

[0048] Temperature: 293K

[0049] A comparison of the X-ray powder diffraction (XRPD) pattern simulated from the single crystal diffraction data of the crystalline form of the compound of formula (I) and the X-ray powder diffraction (XRPD) pattern actually measured on the crystal is shown in FIG. Figure 3 The comparison results show that the crystal forms are consistent and the substances are very pure.

[0050] Example 3 Comparison of saturated solubility of the compound of formula (I) and PLPT

[0051] An excess of drug was weighed into a test tube. 1 mL of medium (purified water, pH 1.2, pH 4.0, or pH 6.8 buffer) was added. The suspension was shaken at 75 rpm and 25°C for 24 hours to ensure excess drug and any undissolved material. The suspension was filtered to remove the precipitate, and the supernatant was removed and filtered through a 0.45 μm filter. The filtrate was appropriately diluted, and all samples were analyzed by high-performance liquid chromatography (HPLC) to determine the PLPT concentration in the samples.

[0052] PH 1.2 medium: Take 7.0mL of concentrated hydrochloric acid, dissolve it in water and dilute it to 1000mL.

[0053] PH4.0 medium: Take 1.22g of sodium acetate trihydrate and 2.46g of acetic acid, dissolve them in water and dilute to 1000mL.

[0054] 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.

[0055] 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.

[0056] Comparison of saturated solubility in different media

[0057] medium Compound of formula (I) PLPT purified water 65.4mg / ml 0.074mg / ml pH 1.2 213.5mg / ml 33.5mg / ml pH 4.0 69.8mg / ml 13.5mg / ml pH 6.8 58.3mg / ml 0.35mg / ml

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

[0059] Accurately weighed compound powder (equivalent to approximately 6 mg of PLPT) was loaded into capsules and dissolution was studied using a rotating basket method (37°C, 100 rpm). 5 mL of solution was withdrawn at 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes, 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 analyzed by high-performance liquid chromatography (HPLC). Dissolution testing was conducted in a pH 6.8 buffer medium. The specific preparation of the buffer medium is shown in Example 3.

[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]

[0063] Example 5 Comparison of thermal stability of the compound of formula (I) and PLPT

[0064] 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.

[0065] 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.

[0066] Thermal stability comparison results

[0067] Thermal decomposition temperature (K) Formula (I) 528 PLPT 488

[0068] Example 6 Comparison of saturated solubility of the compound of formula (I) and other cocrystals

[0069] PLPT-p-hydroxybenzoic acid cocrystal was prepared according to CN102153552B, and PLPT-p-aminobenzoic acid cocrystal was prepared according to CN102584818A.

[0070] 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.

[0071] 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.

[0072] Comparison results of saturated solubility in pure water medium

[0073] Compound Medium: Purified water Compound of formula (I) 65.4mg / ml PLPT-parahydroxybenzoic acid 6.78mg / ml PLPT-para-aminobenzoic acid 16.37mg / ml

Claims

1. A paliperidone cocrystal, 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).

2. The paliperidone cocrystal according to claim 1, characterized in that The crystals belong to the triclinic system with space group P1(2).

3. The paliperidone cocrystal according to claim 2, 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°.

4. The paliperidone cocrystal according to claim 1-3, characterized in that The 2θ (diffraction peak position) of the X-ray powder diffraction pattern has characteristic peaks at approximately 6.8, 9, 11, 13.1, 13.9, 14.5, 15, 16.2, 18.6, 19.2, 20, 21.5, 22, 24.6, 25, 28, and 31.

2.

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

6. A method for preparing the paliperidone cocrystal according to claims 1 to 5, characterized in that The method comprises the steps of dissolving PLPT and NA in a mixed solvent of methanol and water to prepare the crystals.

7. The method according to claim 6, wherein the solid compound of formula (I) is obtained by removing the solvent under reduced pressure.

8. A method for preparing a single crystal of the paliperidone cocrystal according to claims 1 to 5, characterized in that The method comprises the steps of dissolving the solid compound of formula (I) in a solvent and allowing the solid compound to evaporate and crystallize naturally to obtain a single crystal of the compound of formula (I).

9. The method according to claim 8, wherein the solvent is preferably ethyl acetate.

10. Use of the paliperidone cocrystal according to claims 1 to 5 in the preparation of antipsychotic drugs.

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