CN116410134A

CN116410134A - Roflumilast hydrate crystal and preparation method and application thereof

Info

Publication number: CN116410134A
Application number: CN202111671449.7A
Authority: CN
Inventors: 胡卫东; 龚俊波; 王梦薇; 吴送姑; 李沛怡
Original assignee: Beijing Jimeitang Medicine Research Co ltd
Current assignee: Beijing Jimeitang Medicine Research Co ltd
Priority date: 2021-12-31
Filing date: 2021-12-31
Publication date: 2023-07-11

Abstract

The invention belongs to a crystal of roflumilast, and relates to a crystal of a hydrate of roflumilast, a preparation method and application thereof; the molecular formula of the Luo Shasi He hydrate crystal is C ₁₉ H ₁₆ N ₂ O ₅ ·1.5H ₂ O; in an X-ray powder diffraction spectrum of the Luo Shasi hydrate crystal, characteristic diffraction peaks are arranged at the diffraction angles of 2 theta of 3.021 +/-0.2 degrees, 6.179+/-0.2 degrees, 9.699 +/-0.2 degrees, 10.133 +/-0.2 degrees, 11.536 +/-0.2 degrees, 12.478 +/-0.2 degrees, 13.438 +/-0.2 degrees, 15.740 +/-0.2 degrees, 18.460 +/-0.2 degrees and 23.340 +/-0.2 degrees; luo Shasi the hydrate crystal has higher solubility and better stability, and is easy to store; in the preparation process, the roflumilast hydrate crystal is obtained through the selection of a specific type of polymer and a buffer solution, the adjustment of pH and the control of the crystallization process.

Description

Roflumilast hydrate crystal and preparation method and application thereof

Technical Field

The invention belongs to a crystal of roflumilast, and relates to a crystal of a hydrate of roflumilast, a preparation method and application thereof.

The invention relates to a preparation method for preparing a solid pharmaceutical composition by adopting hydrate crystal form roflumilast.

Background

Luo Shasi he (Roxadurat), chemical name [ [ (4-hydroxy-1-7-phenoxy-isoquinoline-3-) carbonyl ] -amino ] -acetic acid. Roflumilast is an oral hypoxia-inducible prolyl hydroxylase inhibitor (HIF-PHI) that stimulates erythropoiesis and is used to treat anemia arising from Chronic Kidney Disease (CKD) in patients undergoing dialysis treatment. As HIF-PHI, luo Shasi, he effectively promotes erythropoiesis by promoting endogenous erythropoietin production, improving iron absorption and utilization, reducing hepcidin, and not being negatively affected by inflammation on hemoglobin and erythropoiesis. Among multiple sub-populations of chronic kidney disease patients, luo Shasi is able to maintain erythropoietin levels at or near normal physiological ranges, thereby increasing red blood cell numbers while not being affected by inflammatory conditions and also avoiding venous iron supplementation.

Compared with the traditional renal anemia drugs, the traditional Chinese medicine has smaller side effects and further improves the treatment target of renal anemia. Luo Shasi he (trade name: orezepine) is approved for the treatment of anemia in dialysis patients with Chronic Kidney Disease (CKD). In 2019, 8 months, the medicine is used for treating anemia of non-dialysis dependent chronic kidney disease (NDD-CKD) in new indications.

WO2013013609a discloses Luo Shasi its forms I, II, III, IV, V, VI, VII. WO2014014835a discloses Luo Shasi its forms a, B, C, D and various salts. WO2019042485a discloses Luo Shasi his potassium, lithium, iron and the like salts. WO2020135058A discloses Luo Shasi its crystalline form ARZ-A, ARZ-B, ARZ-C, ARZ-D, ARZ-F, ARZ-F, ARZ-G, ARZ-H, ARZ-I, ARZ-J, ARZ-K, ARZ-L. Many of the crystalline forms disclosed above are solvates and are not suitable for use in commercial processes. The crystal form on the market is roflumilast A crystal form, the water solubility is very poor, and the solubility in pure water is only 71 mug/mL (measured in WO2020/135058A 1).

Therefore, there is a strong need in the art for a new crystalline form of roflumilast with excellent solubility and stability to be suitable for the industrial preparation of formulations and to meet various performance requirements of the formulations.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a roflumilast hydrate crystal, a preparation method and application thereof, wherein Luo Shasi other hydrate crystals have higher solubility and better stability and are easy to store; the Luo Shasi hydrate crystal has the advantages of simple preparation method, easily obtained raw materials, low price and easy realization; in the preparation process, the roflumilast hydrate crystal with good stability and high solubility is obtained through the selection of a specific type of polymer and a buffer solution, the adjustment of pH and the control of the crystallization process; the roflumilast hydrate crystal provides a new choice for preparing the roflumilast medicament, has important significance for developing medicaments, and is better used for clinical treatment.

In order to achieve the aim of the invention, the invention adopts the following technical scheme:

one of the purposes of the present invention is to provide a crystal of roflumilast hydrate, wherein the molecular formula of the crystal of Luo Shasi he hydrate is C ₁₉ H ₁₆ N ₂ O ₅ ·1.5H ₂ O；

In the X-ray powder diffraction spectrum of the Luo Shasi hydrate crystal, characteristic diffraction peaks are arranged at the diffraction angles of 2 theta of 3.021 +/-0.2 degrees, 6.179+/-0.2 degrees, 9.699 +/-0.2 degrees, 10.133 +/-0.2 degrees, 11.536 +/-0.2 degrees, 12.478 +/-0.2 degrees, 13.438 +/-0.2 degrees, 15.740 +/-0.2 degrees, 18.460 +/-0.2 degrees and 23.340 +/-0.2 degrees.

The roflumilast hydrate crystal provided by the invention has higher solubility and better stability, is easy to store, provides a new choice for preparing the roflumilast medicament, and has important significance for developing medicaments.

In the present invention, the solubility of Luo Shasi his hydrate crystals was 0.664.+ -. 0.05mg/mL, 8.35 times higher than the solubility of commercial form A (71. Mu.g/mL), 3.34 times higher than the solubility of roflumilast monohydrate form ARZ-A disclosed in WO 2020135058A. The high solubility is beneficial to improving the bioavailability and has important significance for the development of medicines.

In the invention, luo Shasi hydrate crystal is placed in 40 ℃/75% RH environment for 0 days, 5 days, 15 days and 30 days, sampling detection is carried out, and no change of crystal form and crystallinity is found, thus indicating that the crystal has better stability.

Preferably, the Luo Shasi his hydrate crystals begin to lose weight at 50±5 ℃, the loss weight being 6.68-7.45%, such as 6.68%, 6.70%, 6.80%, 6.90%, 7.00%, 7.10%, 7.20%, 7.24%, 7.45% and so on, wherein loss of weight means heating a substance to gradually volatilize and decompose the substance, and the change in mass is measured as a function of temperature.

Preferably, the Luo Shasi hydrate crystal has a DSC profile with a characteristic endothermic peak in the range of 50-126 ℃, a characteristic endothermic peak in the range of 163-211 ℃, and starts to decompose at 220+ -2 ℃.

Another object of the present invention is to provide a method for preparing a crystal of roflumilast hydrate according to one of the objects, comprising the steps of:

(1) Mixing roflumilast and a polymer in an organic solvent to obtain a compound;

(2) And (3) dissolving the compound obtained in the step (1) in a phosphate buffer solution, and crystallizing to obtain the Luo Shasi He hydrate crystal.

The preparation method of the Luo Shasi hydrate crystal is simple, raw materials are easy to obtain, the price is low, the method is easy to realize, the method is green and environment-friendly, and the method can be applied to large-scale industrial production.

Preferably, the mass ratio of Luo Shasi to polymer in step (1) is from 1:1 to 1:9, e.g., 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, etc.

Preferably, the polymer of step (1) is a water-soluble polymer.

Preferably, the water-soluble polymer is a water-soluble polymer containing any one or a combination of at least two of carbonyl, hydroxyl or carboxyl groups.

Preferably, the water soluble polymer is any one or a combination of at least two of PVP, HPMC, HPMCP, HPMCAS, PVPVA, or Eudragit EPO, preferably PVP.

In the present invention, by controlling mixing of roflumilast with a water-soluble polymer, a complex containing roflumilast in an amorphous state and a polymer can be obtained.

Preferably, the solvent comprises any one or a combination of at least two of dichloromethane, acetone or methanol.

Preferably, the solvent is a mixture of dichloromethane and acetone.

In the present invention, luo Shasi he is mixed with the polymer in a solvent, which has the advantage of allowing the roflumilast to be dispersed sufficiently by the polymer, and a mixture of methylene chloride and acetone is preferred because of good solubility of the roflumilast and the polymer and low boiling point of the solvent for easy separation.

Preferably, the volume of dichloromethane and acetone in the solvent is 1:1-1:2, e.g., 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc.

Preferably, the means of separation comprises rotary evaporation.

Preferably, the buffer solution in step (2) is a phosphate buffer solution.

Preferably, the pH of the buffer solution of step (2) is between 5 and 7, e.g. 5, 5.2, 5.5, 5.8, 6, 6.2, 6.5, 6.7, 7, etc.

Preferably, the buffer solution of step (2) is added in an amount of 80 to 120mL, for example 80mL, 90mL, 100mL, 110mL, 120mL, etc., based on 1g of the complex.

Preferably, the temperature of the dissolution in step (2) is 37-50 ℃, for example 37 ℃, 38 ℃, 39 ℃, 40 ℃, 41 ℃, 42 ℃, 43 ℃, 44 ℃, 45 ℃, 46 ℃, 47 ℃, 48 ℃, 49 ℃, 50 ℃, etc.

Preferably, the dissolution of step (2) is performed under stirring conditions at a rate of 350.+ -.50 rpm, e.g, 300rpm, 330rpm, 350rpm, 380rpm, 400rpm, etc.

Preferably, the crystallization of step (2) is a cooling crystallization.

Preferably, the temperature of the cooling crystallization is-4 to 25 ℃, for example-4 ℃, 0 ℃,5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, etc.

Preferably, the step (2) further comprises separating, washing and drying the mixture obtained after crystallization in sequence.

Preferably, the separating comprises filtering.

Preferably, the washing comprises washing 3-5 times, such as 3 times, 4 times or 5 times, with deionized water.

Preferably, the drying is an atmospheric drying at a temperature of 25-40 ℃, e.g., 25 ℃, 27 ℃, 30 ℃, 32 ℃, 35 ℃, 37 ℃, 40 ℃, etc., for a time of 6-24 hours, e.g., 6 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, etc.

It is a further object of the present invention to provide amorphous Luo Shasi he, said amorphous roflumilast being obtained by drying of crystalline roflumilast hydrate according to one of the objects.

Preferably, the drying temperature is 125-150deg.C, such as 125 deg.C, 130 deg.C, 135 deg.C, 140 deg.C, 145 deg.C, 150 deg.C, etc.

Preferably, the drying time is 1-3min, such as 1min, 2min, 3min, etc.

In the invention, amorphous roflumilast has the advantage of high solubility.

The fourth object of the invention is the use of the crystalline roflumilast hydrate according to one of the objects or the amorphous Luo Shasi according to the third object for the preparation of an anemic medicament.

The fifth purpose of the present invention is to prepare a solid pharmaceutical composition by using the crystal of roflumilast hydrate according to one of the purposes, and the solid pharmaceutical composition further comprises pharmaceutically acceptable excipients: filler, binder, disintegrating agent and lubricant.

The filler is lactose monohydrate or microcrystalline cellulose.

The adhesive is any one of povidone and hypromellose.

The disintegrating agent is any one of croscarmellose sodium and crospovidone.

The lubricant is magnesium stearate.

The solid pharmaceutical composition comprises a tablet and a capsule.

Compared with the prior art, the invention has the following beneficial effects:

the roflumilast hydrate crystal has higher solubility and better stability, and is easy to store; the Luo Shasi hydrate crystal has the advantages of simple preparation method, easily obtained raw materials, low price and easy realization, and is suitable for industrial mass production and application; in the preparation process, the roflumilast hydrate crystal with good stability and high solubility is obtained through the selection of specific polymers and buffer solutions, the adjustment of pH and the control of crystallization process.

The national institutes office issues opinion about developing the consistency evaluation of the quality and the curative effect of the imitated drugs, and the consistency evaluation core is equivalent to the original research agent-the judgment standard is bioequivalence test (BE), namely, the imitated drugs are consistent with the pharmacokinetics parameters of the original research agent in human bodies, and the drug effect of the imitated drugs is identical with that of the original research agent, so that the imitated drugs with lower price and consistent drug effect can BE selected to replace the original research agent, the burden of patients is reduced, the expenditure of the national medical department is greatly reduced, and the social stability is facilitated. The quality of the preparation product prepared by the crystal of the roflumilast hydrate is not inferior to that of the original preparation (the product is prepared from the ASLIKANG and has the trade name of cabomt) and is equivalent in vivo. Provides a new choice for the preparation of the roflumilast medicament, has important significance for the development of medicaments and is better used for clinical treatment.

Drawings

FIG. 1 is an X-ray diffraction pattern of crystalline roflumilast hydrate in example 1 of the present invention;

FIG. 2 is a thermal weight loss TGA plot of crystalline roflumilast hydrate of example 1 of the present invention;

FIG. 3 is a differential scanning calorimetric DSC of a crystal of roflumilast hydrate in example 1 of the present invention;

fig. 4 is a graph comparing stability test patterns of roflumilast hydrate crystals in example 1 of the present invention at 40 ℃/75% rh.

Detailed Description

The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.

In the X-ray powder diffraction spectrum, a diffraction pattern obtained from a crystalline compound tends to be characteristic for a specific crystal form, in which the relative intensities of characteristic peaks may vary due to the dominant orientation effect caused by differences in crystallization conditions, particle size, and other measurement conditions. Thus, the relative intensities of the diffraction peaks are not characteristic for the crystals aimed at. It is determined whether or not the relative positions of peaks, rather than their relative intensities, are concurrent with the known crystalline phases. Furthermore, for any given crystal, the position of the peak may deviate somewhat due to equipment and operating conditions, and a characteristic peak within the error range may be considered to be the same characteristic peak, as is also well known in the field of crystallography. For example, the position of the peak may be shifted due to a change in temperature at the time of analyzing the sample, a sample shift, calibration of the instrument, or the like, and a measurement error of the 2θ value may be about ±0.2°. Therefore, this error should be taken into account when determining each crystalline structure. For the isomorphous crystallization of the same compound, the peak positions of the XPRD spectra have similarity as a whole, and the relative intensity errors may be large.

The roflumilast is obtained by referring to the preparation method of the roflumilast in the embodiment 10 of the patent CN 103539735B.

(1) XRPD testing instrument: an X-ray powder diffractometer;

instrument model: japanese Rigaku D/max-2500;

the testing method comprises the following steps: the Cu target Ka has the voltage of 40KV, the current of 100mA, the test angle of 2-40 DEG, the step length of 8 DEG/min, the exposure time of 0.2s, the slit width of a light pipe of 1mm and the slit width of a detector of 2.7mm.

(2) TGA test instrument: a thermogravimetric analyzer;

instrument model: metrehler-tolidol company Mettler Toledo TGA/DSC 1/SF;

the testing method comprises the following steps: the temperature rising rate is 10 ℃/min, and the flow rate of the shielding gas nitrogen is 20mL/min.

(3) DSC test apparatus: differential calorimeter scanner

Instrument model: metrehler-tolidol company Mettler Toledo DSC/500

The testing method comprises the following steps: the temperature rising rate is 10 ℃/min, and the flow rate of the protective gas nitrogen is 50mL/min.

(4)HPLC

Instrument model: waters 2695 series high performance liquid chromatography system

The testing method comprises the following steps: the mobile phase was 0.1% aqueous trifluoroacetic acid-acetonitrile (40:60) and the detection wavelength was 260nm. The chromatographic column used was a Ultimate X8C 8 (250 mm. Times.4.6 mm,5 μm) column.

Example 1

And (3) physically and uniformly mixing 250 mg of roflumilast and PVP according to a mass ratio of 1:4, dissolving a mixed solution of dichloromethane and acetone (1:1.5; V: V) until the mixed solution is clear, and carrying out rotary evaporation on the solution to obtain dry powder of the roflumilast and PVP compound. 200mg of the roflumilast and PVP compound powder is added into 20ml of phosphate buffer solution with pH of 6.8, and the mixture is stirred for 24 hours at 37 ℃ until the mixture is completely dissolved. Subsequently, the clear solution was left to crystallize under cooling at-4℃to give white crystals. Air drying at 35deg.C for 24 hr to obtain white powder.

FIG. 1 is a powder X-ray diffraction pattern of the white powder product prepared in example 1, and it is understood from FIG. 1 that characteristic peaks at 3.021 °, 6.179 °, 9.699 °, 10.133 °, 11.536 °, 12.478 °, 13.438 °, 15.740 °, 18.460 ° and 23.340 ° are represented by diffraction angles 2θ.

FIG. 2 is a TGA spectrum of the white powder product prepared in example 1, which, as can be seen from FIG. 2, starts to lose weight at 45℃and is 7.21%; and the moisture content of the obtained product is measured by adopting a Karl Fischer method (a testing instrument: metrefoil Tokay Karl Fischer moisture meter C20S), so that the moisture content in the hydrate crystal is 7.35 percent and is similar to the theoretical moisture content of 7.12 percent, and the obtained product can be determined to contain 1.5 crystal waters.

Fig. 3 is a DSC diagram of the white powder product prepared in example 1, and it can be seen from fig. 3 that the roflumilast hydrate first dehydrates in the range of 45-115 ℃ with temperature, then recrystallizes in the range of 163-211 ℃ and then starts to decompose at 220 ℃.

The obtained product was subjected to solubility test: 200mg of the product was taken and placed in 200mL of distilled water, stirred at 37℃for 24 hours, and then filtered, and the solubility of the product in water was determined to be 0.664mg/mL by liquid chromatography.

And (3) testing the stability of the obtained product: taking 5g of the product, placing under the condition of 40 ℃/75% RH, measuring the physical stability of the product after being placed for 0 day, 5 days, 15 days and 30 days, and comparing test results with a graph in FIG. 4, wherein the obtained crystal of the roflumilast hydrate can exist stably as can be seen from the graph in FIG. 4; in fig. 4, the effect graphs are set for 0 day, 5 days, 15 days, and 30 days in order from bottom to top.

Example 2

And (3) physically and uniformly mixing 250 mg of roflumilast and PVP according to a mass ratio of 1:9, dissolving the mixed solution of dichloromethane and acetone (1:1.5; V: V) until the mixed solution is clear, and steaming the solution to obtain dry powder of the roflumilast and PVP compound. 200mg of the roflumilast and PVP composite powder is added into 20ml of phosphate buffer solution with pH of 6.8, and the mixture is stirred for 24 hours at 37 ℃. Subsequently, the solution was left to crystallize upon cooling at-4℃to give white crystals. After filtration, the mixture was air-dried at 35℃for 24 hours to give a white powdery product.

The product obtained in this example was tested by the same test method as in example 1, and it was found that:

the powder X-ray diffraction pattern of the product shows characteristic peaks at 3.020 degrees, 6.160 degrees, 9.660 degrees, 10.217 degrees, 11.502 degrees, 12.403 degrees, 13.438 degrees, 15.740 degrees, 18.718 degrees and 23.282 degrees by diffraction angles 2 theta.

The product starts to lose weight at 45 ℃, the weight loss is 7.22%, and the DSC decomposition temperature is 220 ℃; the karl fischer-tropsch assay showed a moisture content of 7.40% indicating that the product was Luo Shasi and 1.5 crystalline hydrate crystals.

The solubility of the product was 0.609mg/mL.

The product is placed for 0 days, 5 days, 15 days and 30 days under the condition of 40 ℃/75% RH, and the HPLC determination shows that the obtained roflumilast hydrate crystal can exist stably.

Example 3

And (3) physically and uniformly mixing 250 mg of roflumilast and PVPVA according to a mass ratio of 1:3, dissolving in acetone and ethanol (1:1.5; V: V) until the mixture is clarified, and performing rotary evaporation on the clarified solution to obtain dry powder of the roflumilast and PVPVA compound. 200mg of the roflumilast and PVPVA composite powder were taken in 20ml of phosphate buffer solution with pH6.5 and stirred at 37℃for 15h. Subsequently, the solution was left to crystallize upon cooling at-4℃to give white crystals. After filtration, the mixture was air-dried at 35℃for 24 hours to give a white powdery product.

the powder X-ray diffraction pattern of the product shows characteristic peaks at 3.021 degrees, 6.161 degrees, 9.670 degrees, 10.219 degrees, 11.522 degrees, 12.503 degrees, 13.435 degrees, 15.735 degrees, 18.618 degrees and 23.382 degrees by diffraction angles 2 theta.

The product starts to lose weight at 46 ℃, the loss of weight is 6.68%, and the DSC decomposition temperature is 220 ℃; the karl fischer-tropsch assay showed a moisture content of 7.17% indicating that the product was Luo Shasi and 1.5 crystalline hydrate crystals.

The solubility of the product was 0.672mg/mL.

The product is placed for 0 days, 5 days, 15 days and 30 days under the condition of 40 ℃/75% RH, the product is placed for 0 days, 5 days, 15 days and 30 days under the condition of 40 ℃/75% RH by adopting HPLC, and the obtained roflumilast hydrate crystal can exist stably by adopting HPLC.

Example 4

250 mg of roflumilast was combined with Eudragit EPO according to 1:3, dissolving in acetone and ethanol (1:1.5; V: V) until the mixture is clarified, and steaming the clarified solution to obtain dry powder of the roflumilast and Eudragit EPO compound. 200mg of the roflumilast and Eudragit EPO complex powder are taken in 20ml of phosphate buffer at pH5.0 and stirred at 37℃for 15h. Subsequently, the solution was left to crystallize upon cooling at 15 ℃ to give white crystals. Air drying at 35 ℃ for 24 hours after filtering to obtain white powdery products.

the powder X-ray diffraction pattern of the product has characteristic peaks at 3.020 degrees, 6.179 degrees, 9.699 degrees, 10.133 degrees, 11.536 degrees, 12.478 degrees, 13.438 degrees, 15.740 degrees, 18.460 degrees and 23.340 degrees expressed in terms of diffraction angle 2 theta.

The product starts to lose weight at 43 ℃, the weight loss is 7.24%, and the DSC decomposition temperature is 221 ℃; the karl fischer-tropsch assay showed a moisture content of 7.45% indicating that the product was Luo Shasi and 1.5 crystalline hydrate crystals.

The solubility of the product was 0.660mg/mL.

Example 5

And (3) physically and uniformly mixing 250 mg of roflumilast with PVP (polyvinyl alcohol) according to the mass ratio of 1:2:1, dissolving in acetone and ethanol (1:1.5; V: V) until the mixture is clarified, and rotationally steaming the clarified solution to obtain dry powder of the roflumilast-PVP-PVPVA compound. 200mg of the powder of the PVPVA-PVPVA complex and roflumilast were taken in 20ml of phosphate buffer solution with pH 7.0 and stirred at 37℃for 20h. Subsequently, the solution was left to crystallize upon cooling at 15 ℃ to give white crystals. Air drying at 35 ℃ for 24 hours after filtering to obtain white powdery products.

the powder X-ray diffraction pattern of the product shows characteristic peaks at 3.078 degrees, 6.223 degrees, 9.840 degrees, 10.133 degrees, 11.678 degrees, 12.478 degrees, 13.438 degrees, 15.740 degrees, 18.460 degrees and 23.340 degrees by diffraction angles 2 theta.

The product starts to lose weight at 46 ℃, the weight loss is 7.01%, and the DSC decomposition temperature is 220 ℃; the karl fischer-tropsch assay showed a moisture content of 7.13% indicating that the product was Luo Shasi and 1.5 crystalline hydrate crystals.

The solubility of the product was 0.643mg/mL.

Example 6

And (3) uniformly and physically mixing 250 mg of roflumilast with PVP according to the mass ratio of 1:2:1, dissolving the mixture in acetone and ethanol (1:1.5; V: V) until the mixture is clarified, and performing rotary evaporation on the clarified solution to obtain dry powder of the roflumilast, PVP and HPMCP compound. 200mg of the HPMCP complex powder of roflumilast and PVP were stirred in 20ml of phosphate buffer solution at pH6.8 at 37℃for 20h. Subsequently, the solution was left to crystallize upon cooling at 10 ℃ to give white crystals. Air drying at 35 ℃ for 24 hours after filtering to obtain white powdery products.

The product starts to lose weight at 43 ℃, the weight loss is 7.21%, and the DSC decomposition temperature is 220 ℃; the karl fischer-tropsch assay showed a moisture content of 7.44% indicating that the product was Luo Shasi and 1.5 crystalline hydrate crystals.

The solubility of the product was 0.656mg/mL.

Example 7

And (3) uniformly and physically mixing 250 mg of roflumilast with PVP (polyvinyl pyrrolidone) according to the mass ratio of 1:2:1, dissolving the mixture in acetone and ethanol (1:1.5; V: V) until the mixture is clarified, and performing rotary evaporation on the clarified solution to obtain dry powder of the roflumilast-PVP-HPMC compound. 200mg of the roflumilast and PVP HPMC composite powder is taken in 20ml of phosphate buffer solution with pH of 6.8 and stirred for 20h at 37 ℃. Subsequently, the solution was left to crystallize upon cooling at 10 ℃ to give white crystals. Air drying at 35 ℃ for 24 hours after filtering to obtain white powdery products.

the powder X-ray diffraction pattern of the product has characteristic peaks at 3.021 degrees, 6.179 degrees, 9.699 degrees, 10.133 degrees, 11.536 degrees, 12.478 degrees, 13.438 degrees, 15.740 degrees, 18.460 degrees and 23.340 degrees expressed in terms of diffraction angle 2 theta.

The product starts to lose weight at 45 ℃, the loss of weight is 6.69%, and the DSC decomposition temperature is 220 ℃; the karl fischer-tropsch assay showed a moisture content of 7.21% indicating that the product was Luo Shasi and 1.5 crystalline hydrate crystals.

The solubility of the product was 0.662mg/mL.

Example 8

And (3) physically and uniformly mixing 250 mg of roflumilast with PVPVA, and dissolving HPMCAS in dichloromethane and ethanol (1:1.5; V: V) according to a mass ratio of 1:2:2 until the mixture is clarified, and performing rotary evaporation on the clarified solution to obtain dry powder of the roflumilast-PVPVA, HPMCAS compound. 200mg of the HPMCAS complex powder was mixed with PVPVA in 20ml of phosphate buffer solution at pH6.8 and stirred at 37℃for 20h. Subsequently, the solution was left to crystallize upon cooling at-4℃to give white crystals. Air drying at 35 ℃ for 24 hours after filtering to obtain white powdery products.

the powder X-ray diffraction pattern of the product has characteristic peaks at diffraction angles 2 theta of 2.197 DEG, 6.199 DEG, 9.801 DEG, 10.233 DEG, 11.436 DEG, 12.498 DEG, 13.423 DEG, 15.755 DEG, 18.506 DEG and 23.325 deg.

The product starts to lose weight at 46 ℃, the weight loss is 7.10%, and the DSC decomposition temperature is 220 ℃; the moisture content measured by the karl fischer method is 7.19%, which indicates that the product is roflumilast sesquihydrate crystal.

The solubility of the product was 0.634mg/mL.

Example 9

Mixing 250 mg of roflumilast and PVPVA, PVP, HPMCP according to the mass ratio of 1:1:1:1, dissolving in dichloromethane and ethanol (1:1.5; V: V) until the mixture is clarified, and steaming the clarified solution in a rotary manner to obtain dry powder of the roflumilast and PVPVA, PVP, HPMCP compound. 200mg of the roflumilast and PVPVA, PVP, HPMCP composite powder was taken in 20ml of phosphate buffer at pH6.8 and stirred at 37℃for 20h. Subsequently, the solution was left to crystallize upon cooling at-4℃to give white crystals. Air drying at 35 ℃ for 24 hours after filtering to obtain white powdery products.

the powder X-ray diffraction pattern of the product shows characteristic peaks at 3.020 degrees, 6.166 degrees, 9.660 degrees, 10.217 degrees, 11.502 degrees, 12.403 degrees, 13.438 degrees, 15.740 degrees, 18.718 degrees and 23.282 degrees by diffraction angles 2 theta.

The product starts to lose weight at 45 ℃, the loss of weight is 6.96%, and the DSC decomposition temperature is 220 ℃; the karl fischer-tropsch assay showed a moisture content of 7.30% indicating that the product was Luo Shasi and 1.5 crystalline hydrate crystals.

The solubility of the product was 0.632mg/mL.

Example 10

The roflumilast hydrate crystal prepared by adopting the embodiment is prepared into capsules by adopting the following prescription composition and process:

the auxiliary materials comprise: microcrystalline cellulose, lactose monohydrate, povidone K30, croscarmellose sodium and magnesium stearate.

The preparation process comprises the following steps:

1) Pretreatment of materials: sieving roflumilast and excipient with 80 mesh sieve respectively;

2) Granulating: 1. placing the raw materials and auxiliary materials except magnesium stearate into a wet granulator to be uniformly mixed; 2. adding purified water into a wet granulator under stirring and shearing to prepare a soft material, granulating, drying and finishing;

3) Mixing: uniformly mixing the dried granules with magnesium stearate by adopting a mixing granulator;

5) And (3) filling: filling the mixed particles by a capsule filling machine;

example 11

The crystal of roflumilast hydrate was prepared using the above examples and tablets were prepared using the following formulation and process:

the auxiliary materials comprise: microcrystalline cellulose, lactose monohydrate, hypromellose E6, crospovidone, and magnesium stearate.

The preparation process comprises the following steps:

5) Tabletting: tabletting the mixed particles by adopting a rotary tablet press;

the product prepared in the example 11 and the example 12 is packaged and then is synchronously placed for 1, 2, 3 and 6 months under the condition of 40 ℃/75% RH, the quality standard is met according to the quality standard detection result, the quality is not inferior to that of the original preparation, the crystal form is synchronously sent for inspection, and Luo Shasi hydrate crystals can stably exist in the stability process (accelerated for 6 months).

The products prepared in the examples 11 and 12 and the original developer have been subjected to BE clinical tests, wherein 90% confidence intervals of Cmax, AUC (0- ≡), AUC (0-t) data are all within the range of 80% -125%, which shows that the products are bioequivalent to the original developer, and the clinical substitution requirements are met.

Comparative example 1

Luo Shasi he form a (CN 103539735B).

The product from this comparative example was subjected to the same solubility and stability tests as in example 1, as follows: luo Shasi the solubility of form A in water was 83 μg/mL, keeping the original form unchanged during the 30 day stability test period.

As can be seen from the comparison of the example 1 and the comparative example 1, the crystalline form of the roflumilast hydrate obtained by the patent has higher solubility.

Comparative example 2

Luo Shasi he crystalline form ARZ-A (CN 109369525A).

The product from this comparative example was subjected to the same solubility and stability tests as in example 1, as follows: the solubility of the crystal form ARZ-A in water is 162 mug/mL, and the original crystal form is still unchanged in the stability test period of 30 days.

As can be seen from the comparison of the example 1 and the comparative example 2, the crystal form of the roflumilast hydrate obtained by the patent has higher solubility and good stability.

Comparative example 3

The only difference from example 1 is that the crystalline form of roflumilast hydrate described in this patent could not be obtained by replacing the polymer in example 1 with the water insoluble polymer PVAc.

Comparative example 4

The difference from example 1 is only that the crystalline form of roflumilast hydrate described in this patent cannot be obtained by directly dissolving and crystallizing roflumilast during the preparation process, i.e. without mixing roflumilast with the polymer.

Comparative example 5

The difference from example 1 is only that in the preparation process, the roflumilast and the water-soluble polymer are directly dissolved and crystallized, i.e. the mixing of the roflumilast and the polymer is not included, and the crystal form of the roflumilast hydrate can not be obtained.

Comparative example 6

The difference from example 1 is only that the crystalline form of roflumilast hydrate described in this patent could not be obtained by mixing roflumilast with a polymer and then dissolving in an aqueous solution at ph=1.2.

Application example 1

Drying the roflumilast hydrate crystals obtained in examples 1-9 at 120 ℃ for 5min to obtain a dried product.

The powder X-ray diffraction test is carried out on the dried product, so that the obtained product is amorphous roflumilast.

The applicant declares that the above is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be apparent to those skilled in the art that any changes or substitutions that are easily conceivable within the technical scope of the present invention disclosed by the present invention fall within the scope of the present invention and the disclosure.

Claims

1. A crystal of roflumilast hydrate is characterized in that the molecular formula of the crystal of Luo Shasi Talc hydrate is C ₁₉ H ₁₆ N ₂ O ₅ ·1.5H ₂ O；

2. A crystalline roflumilast hydrate according to claim 1, characterised in that the crystalline Luo Shasi hydrate starts to lose weight at 50 ± 5 ℃, the loss of weight being 6.68-7.45%; the DSC spectrum of the Luo Shasi hydrate crystal has a characteristic endothermic peak in the range of 50-126 ℃, a characteristic endothermic peak in the range of 163-211 ℃ and starts to decompose at 220+/-2 ℃.

3. A method for preparing crystalline roflumilast hydrate according to claim 1 or 2, characterized in that the method comprises the steps of:

(1) Mixing roflumilast with a polymer, and separating to obtain a compound;

(2) And (3) dissolving the compound obtained in the step (1) in a buffer solution, and crystallizing to obtain the Luo Shasi He hydrate crystal.

4. A process according to claim 3, wherein,

the mass ratio of Luo Shasi to the polymer in the step (1) is 1:1-1:9;

the polymer in the step (1) is a water-soluble polymer; the water-soluble polymer is a water-soluble polymer containing any one or a combination of at least two of carbonyl, hydroxyl and carboxyl.

5. A method of preparation according to claim 3, wherein the mixing in step (1) is solvent mixing;

the solvent mixing includes: mixing roflumilast and a polymer in a solvent, and separating to obtain the compound;

the solvent comprises any one or a combination of at least two of dichloromethane, acetone or methanol;

the separation mode comprises rotary steaming.

6. A process according to claim 3, wherein,

the water-soluble polymer in the step (1) is any one or at least two of PVP, HPMC, HPMCP, HPMCAS, PVPVA or Eudragit EPO;

the solvent in the step (1) is a mixture of dichloromethane and acetone; the volume of the methylene dichloride and the acetone is 1:1-1:2

The buffer solution in the step (2) is phosphate buffer solution;

the pH of the buffer solution in the step (2) is 5-7;

the addition volume of the buffer solution in the step (2) is 80-120mL based on the addition amount of the complex of 1 g;

the dissolution temperature in the step (2) is 37-50 ℃;

the dissolution in the step (2) is carried out under stirring conditions;

the crystallization in the step (2) is cooling crystallization;

the temperature of the cooling crystallization is-4-25 ℃;

the step (2) further comprises separating, cleaning and drying the mixture obtained after crystallization in sequence;

the separating comprises filtering;

the cleaning comprises the steps of cleaning 3-5 times by deionized water;

the drying is normal pressure drying, the drying temperature is 25-40 ℃, and the drying time is 6-24 h.

7. An amorphous form Luo Shasi he, characterized in that it is obtained by drying the crystalline form of roflumilast hydrate according to claim 1 or 2;

the drying temperature is 125-150 ℃;

the drying time is 1-3min.

8. Use of crystalline roflumilast hydrate according to claim 1 or 2 or amorphous Luo Shasi according to claim 7 for the preparation of a medicament for the treatment of anemia.

9. A pharmaceutical composition characterized by: the pharmaceutical composition comprises the hydrate crystal form of claim 1, and further comprises pharmaceutically acceptable excipients: filler, binder, disintegrating agent and lubricant.

10. The pharmaceutical composition according to claim 9, characterized in that the filler is lactose monohydrate, microcrystalline cellulose; the adhesive is any one of povidone and hypromellose; the disintegrating agent is any one of croscarmellose sodium and crospovidone; the lubricant is magnesium stearate.