CN107721902A - Cocrystallization of Apremilast and niacinamide and its preparation method and application - Google Patents

Abstract

The present invention relates to cocrystallization of Apremilast and niacinamide and preparation method thereof.Comprehensive sign has been carried out to cocrystallization with means such as X ray powder diffraction analysis, thermogravimetic analysis (TGA), differential scanning calorimetric analysis, it is found that the cocrystallization has more excellent physical chemistry and patent medicine performance compared with Apremilast.The preparation method of the cocrystallization of the Apremilast and niacinamide is simple, is easily controlled, favorable reproducibility, can stablize the cocrystallization for obtaining Apremilast and niacinamide.

Description

Co-crystallization of apremilast and nicotinamide and its preparation method and application

technical field

The invention belongs to the technical field of medicinal chemistry and crystallization technology, and specifically relates to the co-crystallization of apremilast and nicotinamide and its preparation method and application.

Background technique

Drug co-crystallization (co-crystal) refers to the interaction between active pharmaceutical ingredient (API) molecules and other physiologically acceptable acids, bases, salts, non-ionic compound molecules through hydrogen bonding, π-π stacking, van der Waals forces and other non-covalent interactions. bonded together in the same crystal lattice. The greatest application value of co-crystals in drugs is that they can introduce new components without changing the covalent structure of drugs, greatly improving the physical and chemical properties of drugs, such as stability, melting point, solubility, dissolution rate, bioavailability, etc., and Since there are many types of ligands (CCF), the properties of the drug can also be regulated to varying degrees. The differences in physical properties exhibited by each new solid form of an active pharmaceutical ingredient affect storage stability, compressibility and density as well as solubility and dissolution rate.

Compared with other solid forms such as salts and solvates, co-crystals have greater advantages in drug development. First of all, for solvates, because the types of solvents acceptable in pharmacy are limited, and solvates often undergo desolvation (water) phenomenon during the preparation process, transforming into unstable amorphous or less soluble crystals. type. Secondly, compared to salts, since the formation of salt requires at least one ionization center for the drug substance, and each component in the drug co-crystal can be a neutral molecule, the drug co-crystal can cover all APIs, including acids, Alkali and non-ionic compounds; and, there are many molecules that are potentially used to form co-crystals with API, these substances may include food additives, preservatives, pharmaceutical excipients, minerals, vitamins, amino acids and other active molecules, and can even be Other APIs. In general, co-crystal is a solid form with broad application prospects, which has a profound impact on the pre-prescription research and dosage form design of drugs.

A co-crystal may have unique properties due to its specific crystal morphology as well as its specific chemical composition. For example, compared with API, co-crystal has better pharmacological and pharmaceutical properties, and is easier to process; co-crystal has more advantageous dissolution rate and solubility, which can make the human body more effectively use the active ingredients of the drug, so it has better Bioavailability; co-crystals have better storage stability. In conclusion, co-crystals may possess other favorable properties besides therapeutic effects.

The chemical name of Apremilast is: S-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline -1,3-diketone}, its chemical structure is as follows:

Apremilast is an inhibitor of phosphodiesterase-4 (PDE-4). Clinically indicated for the treatment of adults with active psoriatic arthritis and moderate to severe plaque psoriasis with phototherapy and systemic therapy. Due to the poor solubility of apremilast in water, its bioavailability in vivo is low. So far, no co-crystallization of apremilast has been reported.

Nicotinamide, also known as Nicotinamide, English name: Nicotinamide. Chemical formula: C ₆ H ₆ N ₂ O, its chemical structure is as follows:

In view of the above-mentioned deficiencies in the prior art, one of the technical problems to be solved by the present invention is to provide a nicotinamide co-crystal of apremilast. On the basis of the unique hydrogen bond synthon design, the present invention obtains the co-crystallization of apremilast and nicotinamide. The study found that the co-crystallization of apremilast and nicotinamide has high crystallinity, low hygroscopicity, regular crystal shape, and significantly enhanced water solubility, which is conducive to the improvement of drug process and physical and chemical properties, and improves the drug performance .

Contents of the invention

One of the objects of the present invention is to provide a co-crystal of apremilast and nicotinamide.

The second object of the present invention is to provide a method for preparing co-crystals of apremilast and nicotinamide.

The third object of the present invention is to provide a pharmaceutical composition, which comprises the above-mentioned co-crystal of apremilast and nicotinamide and a pharmaceutically acceptable carrier.

The fourth object of the present invention is to provide a co-crystal of apremilast and nicotinamide used in the preparation of moderate to severe plaque psoriasis for the treatment of active psoriatic arthritis and phototherapy or systemic therapy in the application.

According to the first aspect of the present invention, a co-crystal of apremilast and nicotinamide is provided, in the co-crystal, the molar ratio of apremilil and nicotinamide is 2:1.

The 2θ angles in the X-ray powder diffraction pattern of the co-crystallization of Apremilast and nicotinamide are about: 7.39°±0.2°, 9.59°±0.2°, 11.25°±0.2°, 19.25°±0.2°, There are characteristic peaks at 22.39°±0.2°, 26.26°±0.2°, and 28.93°±0.2°.

Preferably, in the X-ray powder diffraction pattern of the co-crystal of apremilast and nicotinamide, the 2θ angle is about 15.20°±0.2°, 16.35°±0.2°, 17.67°±0.2°, 20.19° ±0.2°, 20.72°±0.2°, 21.33°±0.2°, 22.74°±0.2°, 23.38°±0.2°, 24.75°±0.2°, 25.36°±0.2°, 25.88°±0.2°, 27.46°±0.2 °, 27.92°±0.2°, 29.66°±0.2°, 34.37°±0.2° have characteristic peaks.

In particular, the X-ray powder spectrum of the co-crystal of apremilast and nicotinamide has an XRPD spectrum substantially as shown in FIG. 1 .

Due to different measurement conditions, the 2θ angle and relative intensity of each peak on the XRPD diffraction pattern will change. Generally, the 2θ angle changes within ±0.2°, but it can also slightly exceed this range. Those skilled in the art should understand that the relative intensity of diffraction Intensity may depend, for example, on the sample preparation or the equipment used.

The co-crystal of apremilast and nicotinamide is a tetragonal crystal system, the space group is P4 ₁ 2 ₁ 2, and the unit cell parameters are: α=90°, β=90°, γ=90°, the unit cell volume is

The thermogravimetric analysis of the co-crystal of Apremilast and nicotinamide begins to lose weight at about 147±1°C, and there is no weight loss phenomenon before decomposition; in particular, the co-crystal of Apremilast and nicotinamide has The thermogravimetric analysis (TG) spectrum shown in Figure 2 is basically.

The differential scanning calorimetry analysis of the co-crystal of Apremilast and nicotinamide has a characteristic endothermic peak at about 144.9±0.2°C; The differential scanning calorimetry (DSC) spectrum shown.

The infrared spectrum of the co-crystal of apremilast and nicotinamide is at least about 3367cm ^-1 , 3008cm ^-1 , 2983cm ^-1 , 2947cm ^-1 , 2841cm ^-1 , 1763cm ^-1 , 1699cm ^-1 , ^1618cm -1 ¹ , 1525cm ^-1 , 1479cm ^-1 , 1396cm ^-1 , 1365cm ^-1 , 1300cm ^-1 , 1173cm ^-1 , 1138cm ^-1 , 1101cm ^-1 , 1026cm ^-1 , 872cm ^-1 , 754cm ^-1 , 656cm ^-1 , There are characteristic peaks at 592cm ^-1 , 486cm ^-1 and 455cm ^-1 .

The hygroscopicity of the co-crystal of apremilast and nicotinamide is less than 0.6% in a relative humidity range of 0-95% in a dynamic moisture adsorption test.

The co-crystallization of apremilast and nicotinamide has higher equilibrium solubility than apremilast itself, and has a better dissolution rate, which is more than 5 times that of apremilast.

The co-crystallization of apremilast and nicotinamide has better stability, greater solubility in water, and improved dissolution rate, which is beneficial to the absorption and utilization of the drug by the human body.

According to the second aspect of the present invention, there is provided a method for preparing the co-crystallization of said apremilast and nicotinamide, said method being one of the following methods:

method one:

Add apremilast and nicotinamide into an organic solvent, dissolve completely, and volatilize slowly to obtain co-crystals of apremilast and nicotinamide;

Method Two:

Dissolve excess nicotinamide in an organic solvent, add a little excess of apremilast to the supernatant, stir until a large amount of white solids are precipitated; dry the solid part to obtain co-crystals of apremilast and nicotinamide.

in,

The organic solvent includes all organic solvents that have a certain solubility to the raw materials and do not cause deterioration of the raw materials, and can be: one or a combination of organic solvents such as alcohols, ketones, esters, alkanes, aromatic hydrocarbons or halogenated alkanes , preferably, the organic solvent is a mixture of one or more of methanol, ethanol, ethyl acetate, acetone, dichloromethane;

The temperature for preparing the co-crystallization of apremilast and nicotinamide is from room temperature to 50°C, preferably room temperature.

Preferably,

In method one, the molar ratio of apremilast to nicotinamide is about 4:1 to 1:4; preferably, the molar ratio of apremilil to nicotinamide is about 2:1;

The weight-to-volume ratio of said Apremilast to the organic solvent is about (2-50) mg: 1 mL; more preferably about (4-30) mg: 1 mL;

In method 2, the weight-to-volume ratio of the nicotinamide to the organic solvent is about (10-40) mg: 1 mL; more preferably about (20-30) mg: 1 mL;

The weight-to-volume ratio of said apremilast to the organic solvent is about (10-100) mg: 1 mL; more preferably about (40-70) mg: 1 mL;

The stirring time is more than 24 hours;

Described drying is drying in vacuum oven.

The preparation method involved in the invention is simple to operate, easy to control the crystallization process, high in crystallinity and good in reproducibility, and can stably obtain co-crystallization of apremilast and nicotinamide.

The third aspect of the present invention relates to a pharmaceutical composition, which comprises the co-crystal of apremilast and nicotinamide and a pharmaceutically acceptable carrier.

The fourth aspect of the present invention relates to the co-crystallization of apremilast and nicotinamide and/or the pharmaceutical composition as described above in the preparation of moderate to severe plaques for the treatment of active psoriatic arthritis and phototherapy or systemic therapy Drug use in massive psoriasis.

Description of drawings

Fig. 1 is the X-ray powder diffraction (XRPD) pattern of the co-crystal of Apremilast and nicotinamide of embodiment 1;

Fig. 2 is the thermogravimetric analysis (TG) figure of the co-crystallization of apremilast and nicotinamide of embodiment 1;

Fig. 3 is the differential scanning calorimetry (DSC) figure of the co-crystallization of apremilast and nicotinamide of embodiment 1;

Fig. 4 is the infrared spectrum (IR) figure of the co-crystallization of apremilast and nicotinamide of embodiment 1;

Fig. 5 is the Raman spectrum (Raman) figure of the co-crystallization of apremilast and nicotinamide of embodiment 1;

Fig. 6 is the dynamic water adsorption (DVS) figure of the co-crystallization of apremilast and nicotinamide in embodiment 1;

Fig. 7 is the equilibrium solubility diagram at different pHs of the co-crystallization of apremilast and nicotinamide in Example 1;

Fig. 8 is the equilibrium solubility diagram of different polymer media for the co-crystallization of apremilast and nicotinamide in Example 1;

Fig. 9 is the dissolution rate curve chart of the co-crystallization of apremilast and nicotinamide in embodiment 1;

Fig. 10 is the X-ray single crystal diffraction of the co-crystal of apremilast and nicotinamide in Example 1.

detailed description

The present invention will be further described below in conjunction with specific examples, but the present invention is not limited.

Testing instruments and methods:

The instrument used for X-ray single crystal diffraction (SCXRD) is a Bruker SmartApex II type X-ray single crystal diffractometer from Bruker Instruments Co., Ltd. The measurement conditions are graphite monochromator, Mo–Kα rays Test at room temperature with a test voltage of 50kV and a current of 30mA. The data reduction and structure analysis of all single crystal structures were completed by the SAINT-5.0 and SHELXTL-2014 programs, respectively, and the absorption correction was completed by the SADABS program. The coordinates of non-hydrogen atoms are obtained by the difference function method and the least square method, and the hydrogen atoms are added to the appropriate positions through theoretical calculations.

X-ray powder diffraction method, instrument model: Bruker D8advance, target: Cu Kα (40kV, 40mA), the instrument uses the standard sample that comes with the instrument to correct the peak position before use. The acquisition software is Diffrac Plus XRD Commander, and the analysis software is MDI Jade 6.0. The samples are tested at room temperature, and the samples to be tested are placed on organic glass slides. Distance from sample to detector: 30cm, scanning range: 3°～40°(2θ value), scanning step: 0.02°, step length: 0.1 second/step.

Thermogravimetric analysis method, instrument model: Netzsch TG 209F3, instrument control software is NETZSCH-Proteus-6, analysis software is Proteus Analysis. Under the protection of 50mL/min dry nitrogen at a heating rate of 10°C/min, the temperature range: 30-400°C, scan rate: 10K/min, purge gas: 25mL/min, protective gas: 15mL/min.

Differential scanning calorimetry analysis method, instrument model: TADSC Q2000, temperature range: 50-200°C, scan rate: 10°C/min, nitrogen flow rate: 50mL/min.

Infrared spectrum method, Nicolet FTIR 6700 infrared spectrometer analyzer at room temperature detection, infrared shift: 4000-400cm ^-1 .

Raman spectroscopy method, instrument model: Thermo DXR micro-Raman spectrometer, Raman shift: 3200-300cm ^-1 .

Dynamic moisture adsorption, instrument model: SMS DVS Intrinsic, 0-95% RH, temperature: 25°C.

Liquid phase conditions: instrument: Agilent 1260, mobile phase: water: acetonitrile = 60:40 (0 ~ 2min), 40:60 (2 ~ 9min), 20:80 (9 ~ 12min), 60:40 (12 ~ 15min ), column temperature: 30°C, flow rate: 1.0mL/min.

Reagents such as methanol were of analytical grade and provided by Sinopharm Chemical Reagent Co., Ltd. The reagents and solvents used were not specially treated unless otherwise specified. The bulk drug of Apremilast was purchased from Shanghai Demo Pharmaceutical Technology Co., Ltd., and the bulk drug of nicotinamide was purchased from Bailingwei Technology Co., Ltd., with a purity greater than 99%. All temperatures are expressed in °C (degrees Celsius), and room temperature means 20-25 °C.

Example 1

At room temperature, Apremilast (0.02mmol) and nicotinamide (0.01mmol) were added into methanol (2mL) according to the stoichiometric ratio of 2:1, and after being completely dissolved by ultrasonic oscillation, they were slowly evaporated at room temperature to obtain Apremilast and Niacinamide (0.01mmol). Co-crystallization of niacinamide. The prepared co-crystal was characterized by X-ray single crystal diffraction. The X-ray single crystal diffraction structure diagram of the co-crystal of Apremilast and nicotinamide is shown in Figure 10. The results of X-ray single crystal diffraction show that Apremilast The molar ratio of Prester and Niacinamide is 2:1. The co-crystal of apremilast and nicotinamide is a tetragonal crystal system, the space group is P4 ₁ 2 ₁ 2, and the unit cell parameters are: α=90°, β=90°, γ=90°, the unit cell volume is

X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), differential scanning calorimetry (DSC), Raman spectrum (Raman), hygroscopicity Analytical (DVS) as well as solid-state methods such as infrared (IR) spectroscopy were analyzed.

See accompanying drawing 1 for X-ray powder diffraction analysis results, see accompanying drawing 2 for thermogravimetric analysis results, see accompanying drawing 3 for differential scanning calorimetric analysis results, see accompanying drawing 4 for infrared analysis results, and refer to accompanying drawing 5 for Raman analysis results, The results of Dynamic Water Sorption (DVS) analysis are shown in Figure 6.

Example 2

At room temperature, Apremilast (0.1mmol) and nicotinamide (0.05mmol) were added into ethyl acetate (2mL) according to the stoichiometric ratio of 2:1, and after being completely dissolved by ultrasonic oscillation, slowly volatilized at room temperature to obtain Apremilast Special co-crystallization with niacinamide.

Example 3

At room temperature, add apremilast (0.1mmol) and nicotinamide (0.05mmol) into a mixed solvent of methanol and ethyl acetate (1:1, each 1mL) at a stoichiometric ratio of 2:1, and dissolve completely by ultrasonic oscillation Afterwards, slowly volatilize at room temperature to obtain co-crystals of apremilast and nicotinamide.

Example 4

At room temperature, Apremilast (0.1mmol) and nicotinamide (0.05mmol) were added into acetone (2mL) according to the stoichiometric ratio of 2:1, and after being completely dissolved by ultrasonic oscillation, slowly volatilized at room temperature to obtain Apremilast and Co-crystallization of niacinamide.

Example 5

At room temperature, Apremilast (0.1mmol) and nicotinamide (0.05mmol) were added into dichloromethane (2mL) according to the stoichiometric ratio of 2:1. Special co-crystallization with niacinamide.

Example 6

Dissolve excess nicotinamide (40mg) in methanol (2mL) at room temperature, keep the supersaturated state of the ligand during the stirring equilibrium process; filter the suspension, take the supernatant and add a little excess apremilast (80mg ), stirred at room temperature for more than 24 hours until a large amount of white solids were precipitated; filtered, and the solid part was dried in a vacuum oven to obtain a co-crystallized powder of apremilast and nicotinamide.

The co-crystals of Apremilast and nicotinamide prepared in Examples 2 to 6 were analyzed by X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), differential scanning calorimetry (DSC) and infrared (IR ) spectrum and other solid chemical methods, the results were basically consistent with the co-crystals of apremilast and nicotinamide prepared in Example 1.

test case 1

Equilibrium solubility experiment at different pH of the co-crystal of apremilast and nicotinamide, the source of the sample received: the co-crystal of apremilast nicotinamide was prepared by the above method. Experimental method: take excess co-crystal powder of apremilast and nicotinamide and add pH 2.0 glycine-hydrochloric acid buffer solution (1mL), pH 4.6 disodium hydrogen phosphate-citric acid buffer solution (1mL), pH 6.8 dihydrogen phosphate Sodium-citric acid buffer solution (1 mL), suspending at room temperature for more than 24 hours and filtering the filtrate to measure the concentration by high performance liquid phase. The analysis results are shown in Figure 7.

test case 2

The co-crystallization of apremilast and nicotinamide in different polymer medium equilibrium solubility experiments, the source of the sample received: the co-crystallization of apremilast and nicotinamide was prepared by the above method. Experimental method: Take excess co-crystallized powder of Apremilast and nicotinamide and add different solubilizers (polyethylene glycol PEG2000, hydroxypropyl cellulose HPC, polyvinylpyrrolidone PVP, Tween80Tween80, four Butylammonium bromide (TBAB) in a pH 2.0 glycine-hydrochloric acid buffer solution (1 mL), suspended at room temperature for more than 24 hours and filtered to obtain the filtrate to measure the concentration by high performance liquid phase. The analysis results are shown in Figure 8.

Test case 3

Intrinsic dissolution rate experiment of the co-crystal of apremilast and nicotinamide, the source of the sample received: the co-crystal of apremilast and nicotinamide was prepared by the above-mentioned Example 1. Experimental method: Take the co-crystallized powder of Apremilast and nicotinamide and press into tablets in 10 ml of dissolution medium, take 0.2 ml of the solution at intervals, monitor the concentration of the solution at each time point with high performance liquid phase, and finally obtain Apremilast Dissolution rate profile of co-crystallization of Tetracycline with niacinamide.

Dissolution conditions: Instrument: micro dissolution apparatus, dissolution medium: pH 2.0 glycine-hydrochloric acid buffer solution of 1wt.% hydroxypropyl cellulose HPC, stirring speed: 75rpm, dissolution temperature: 37°C, sampling time: 10, 20, 30, 45, 60 minutes. The analysis results are shown in Figure 9.

The above is only a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto, and any person skilled in the art may, within the technical scope disclosed in the present invention, not think of changes or changes through creative work. Replacement should be covered within the protection scope of the present invention.

Claims (10)

1. A co-crystal of apremilast and nicotinamide, characterized in that the molar ratio of apremilast to nicotinamide in the co-crystal of apremilast and nicotinamide is 2: 1.

2. A co-crystal of apremilast and nicotinamide, characterized in that the co-crystal of apremilast and nicotinamide has characteristic peaks at an X-ray powder diffraction pattern at 2 theta angles of about 7.39 ° ± 0.2 °, 9.59 ° ± 0.2 °, 11.25 ° ± 0.2 °, 19.25 ° ± 0.2 °, 22.39 ° ± 0.2 °, 26.26 ° ± 0.2 °, 28.93 ° ± 0.2 °.

3. An apremilast and nicotinamide co-crystal according to claim 1 or 2, characterized in that the apremilast and nicotinamide co-crystal has an X-ray powder diffraction pattern with peaks at 2 Θ angles of about 7.39 ° ± 0.2 °, 9.59 ° ± 0.2 °, 11.25 ° ± 0.2 °, 15.20 ° ± 0.2 °, 16.35 ° ± 0.2 °, 17.67 ° ± 0.2 °, 19.25 ° ± 0.2 °, 20.19 ° ± 0.2 °, 20.72 ° ± 0.2 °, 21.33 ° ± 0.2 °, 22.39 ° ± 0.2 °, 22.74 ° ± 0.2 °, 23.38 ° ± 0.2 °, 24.75 ° ± 0.2 °, 25.36 ° ± 0.2 °, 25.88 ° ± 0.2 °, 26.26 ° ± 0.2 27.46 ° ± 0.2 °, 3.2 ° ± 0.3 ° ± 0.2 ° ± 0.34 ° ± 0.2 °.

4. The co-crystal of apremilast and nicotinamide according to claim 1 or 2, characterized in that the X-ray diffraction pattern of the co-crystal of apremilast and nicotinamide has an X-ray powder diffraction pattern substantially as shown in figure 1.

5. The co-crystal of apremilast and nicotinamide as claimed in claim 1 or 2, wherein the co-crystal of apremilast and nicotinamide has a Differential Scanning Calorimetry (DSC) spectrum with a characteristic endothermic peak at about 144.9 ± 0.2 ℃.

6. A process for preparing a co-crystal of apremilast and nicotinamide according to any of claims 1-5, characterized in that said process is one of the following:

the method comprises the following steps:

adding apremilast and nicotinamide into an organic solvent, and slowly volatilizing after completely dissolving to obtain a co-crystal of apremilast and nicotinamide;

the second method comprises the following steps:

dissolving excessive nicotinamide in organic solvent, taking supernatant, adding a little excessive apremilast, and stirring until a large amount of white solid is separated out; drying the solid part to obtain the co-crystal of apremilast and nicotinamide.

7. The process for the preparation of a co-crystal of apremilast and nicotinamide according to claim 6, characterized in that:

the organic solvent comprises all organic solvents which have certain solubility on the raw materials and do not cause deterioration of the raw materials, and is selected from one or a combination of more of organic solvents such as alcohols, ketones, esters, alkanes, aromatic hydrocarbons or halogenated alkanes; preferably, the organic solvent is one or more of methanol, ethanol, ethyl acetate, acetone and dichloromethane.

8. The process for the preparation of a co-crystal of apremilast and nicotinamide according to claim 6, characterized in that:

in the first method, the mole ratio of apremilast to nicotinamide is about 4: 1-1: 4; preferably, the mole ratio of apremilast to nicotinamide is about 2: 1;

the weight volume ratio of the apremilast to the organic solvent is about 2-50 mg:1 mL; more preferably about 4 to 30 mg/1 mL;

in the second method, the weight-volume ratio of the nicotinamide to the organic solvent is about 10-40 mg:1 mL; more preferably about 20-30 mg:1 mL;

the weight volume ratio of the apremilast to the organic solvent is about 10-100 mg:1 mL; more preferably about 40-70 mg:1 mL;

the stirring time is more than 24 hours;

the drying is drying in a vacuum drying oven.

9. A pharmaceutical composition comprising the co-crystal of apremilast and nicotinamide of any one of claims 1-5 and a pharmaceutically acceptable carrier.

10. Use of a co-crystal of apremilast and nicotinamide according to any of claims 1-5 or a pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment of active psoriatic arthritis and moderate to severe plaque psoriasis in phototherapy or systemic therapy.