CN108117570A - A kind of crystallization of tenofovir alafenamide hemifumarate and its preparation method - Google Patents

Abstract

The invention relates to the field of medicines, and discloses a tenofovir alafenamide hemifumarate crystal and a preparation method thereof, wherein the X-ray powder diffraction of the crystal has characteristic peaks at the following 2 theta angle positions: 7.02 °, 8.62 °, 11.02 °, 12.12 °, 13.90 °, 15.86 °, 16.30 °, 17.62 °, 18.32 °, 20.26 °, 20.82 °, 23.16 °, 26.60 ° and 27.84 °. The tenofovir alafenamide hemifumarate prepared by the invention has good crystal fluidity, small hygroscopicity and stable crystal form, and is particularly suitable for pharmaceutical preparations.

Description

A kind of crystallization of tenofovir alafenamide hemifumarate and its preparation method

technical field

The invention belongs to the technical field of medicine, and in particular relates to a crystallization of tenofovir alafenamide hemifumarate and a preparation method thereof.

Background technique

Tenofovir alafenamide hemifumarate has a structure shown in formula (I), and its chemical name is N-[(S)-[[(1R)-2-(6-amino-9H-purine- 9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-L-alanine 1-methylethyl ester hemifumarate.

Tenofovir alafenamide is a nucleoside reverse transcriptase inhibitor being developed by Gilead Sciences and is a prodrug of tenofovir for oral treatment of chronic hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infection.

Tenofovir alafenamide hemifumarate was first disclosed in WO2013025788. The crystals obtained in this patent application were obtained by reacting tenofovir alafenamide and hemifumaric acid in an acetonitrile solution, and by means of selective crystallization Carry out purification and resolution. CN104558036 discloses another crystal form of tenofovir alafenamide hemifumarate, which is obtained by crystallizing tenofovir alafenamide hemifumarate in a solvent system such as ether or acetonitrile.

Changes in the crystal form of pharmaceutical compounds usually lead to compounds with different melting points, solubility, stability, biological activity, etc., which are important factors that affect the ease of drug preparation, storage stability, preparation, and bioavailability. When a compound exists in polymorphic forms, since specific polymorphic forms have specific thermodynamic properties and stability, it is important to understand the crystalline form of the compound used in each dosage form during the preparation process to ensure that the production process Apply the drug in the same form. Therefore, it is necessary to ensure that the compound is a single crystalline form or a known mixture of several crystalline forms.

In judging which polymorph is preferred, their many properties must be compared and the preferred polymorph is selected based on a number of physical properties. It is entirely possible that a polymorphic form is preferred where certain aspects such as ease of preparation, stability etc. are considered critical. In other cases, a different polymorph may be preferred for greater solubility or superior pharmacokinetics.

The discovery of new polymorphs of pharmaceutical compounds provides an opportunity to improve the physical properties of drugs, that is, to expand the overall properties of substances, so as to better guide the research of compounds and their preparations. When a drug is found to exist in several polymorphic forms, the conditions under which each crystalline form is formed must be carefully studied. In this way, certain crystallization conditions can be maintained between batches to ensure that raw materials and pharmaceutical preparations have uniform and consistent crystal forms. Changes in the solvent used for recrystallization, the rate of crystallization, or other factors may lead to a phenomenon in which one crystal form predominates.

Contents of the invention

On the one hand, the present application provides a crystal of tenofovir alafenamide hemifumarate, using Cu-Kα radiation, the X-ray powder diffraction of the crystal has a diffraction peak at the following 2θ angle position: 7.02° , 8.62°, 11.02°, 12.12°, 13.90°, 15.86°, 16.30°, 17.62°, 18.32°, 20.26°, 20.82°, 23.16°, 26.60°, and 27.84°.

Further preferably, the crystal has diffraction peaks at the following 2θ angle positions: 7.02°, 8.62°, 11.02°, 12.12°, 13.90°, 14.90°, 15.86°, 16.30°, 17.62°, 18.32°, 18.68°, 19.60 , 20.26°, 20.82°, 21.22°, 21.36°, 22.50°, 23.16°, 24.08°, 25.08°, 26.60°, 27.84°, 28.76°, and 31.60°.

In some embodiments of the present application, the crystallization of tenofovir alafenamide hemifumarate has no diffraction peak at a 2θ angle of 9.7±0.2° using Cu-Kα radiation.

In another aspect of the present application, a method for preparing the above tenofovir alafenamide hemifumarate crystals is provided, including:

a) dissolving tenofovir alafenamide free base and fumaric acid in an organic solvent;

b) adding a small amount of seed crystals to the solution obtained in step a);

c) crystallization, filtration, and drying under reduced pressure to obtain crystals of tenofovir alafenamide hemifumarate.

Wherein, the organic solvent in step a) is selected from one or more mixtures of the solvents selected from C ₁ -C ₄ alkyl alcohols, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, 1,4-dioxane , wherein the C ₁ -C ₄ alkyl alcohol is selected from methanol, ethanol, isopropanol, n-butanol; in some embodiments, the solvent is acetone; in some embodiments, the solvent It is a mixture of isopropanol and ethanol, and the volume ratio of the mixed solvent is 9:1-1:1, preferably, the volume ratio of the mixed solvent is 3:1.

Wherein, step a) is dissolved under heating conditions, and the heating temperature is 40°C-70°C; in some embodiments, the heating temperature is 50°C-60°C.

Wherein, the preparation method of tenofovir alafenamide hemifumarate seed crystals in step b) is: adding the first organic solvent, tenofovir alafenamide, fumaric acid in sequence, heating to reflux to dissolve, Filtrate, evaporate the solvent under reduced pressure, add a second organic solvent, crystallize at room temperature, and dry under reduced pressure to obtain the seed crystal.

Wherein, in step b), the first organic solvent and the second organic solvent are independently selected from one of C ₁ -C ₄ alkyl alcohol, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, 1,4-dioxane or Several mixtures; In some embodiments, the first organic solvent is acetonitrile, the second organic solvent is a mixture of isopropanol and ethanol, and the volume ratio of the mixed solvent is 3:1; In some embodiments, the step The time for crystallization when preparing the seed crystals in b) is 20-30 hours; in some embodiments, the time for crystallization when preparing the seed crystals in step b) is 24 hours.

Wherein, the crystallization temperature in step c) is 0° C. to 30° C., preferably room temperature, and the crystallization time is 6 to 24 hours. In some embodiments, the crystallization temperature is 25±5° C., and the crystallization time is 6 hours. The drying temperature does not exceed 60°C; in some embodiments, the drying temperature is 50°C.

Another aspect of the present application also provides a crystalline composition containing the above-mentioned crystals, wherein the above-mentioned crystals in the composition account for more than 50% by weight of the composition, preferably more than 70%, more preferably more than 90%, most preferably 95% Above, the composition may contain small amounts of other crystalline or amorphous substances.

In another aspect, the present application provides a pharmaceutical composition comprising the above-mentioned crystalline or crystalline composition. The pharmaceutical composition also includes one or more pharmaceutical excipients and, if necessary, other therapeutically active ingredients.

The pharmaceutical composition is preferably administered orally. Pharmaceutical compositions suitable for oral administration include tablets, capsules, powders, granules, dripping pills, pastes, powders, tinctures, etc., preferably tablets and capsules. Wherein the tablet can be ordinary tablet, dispersible tablet, effervescent tablet, sustained-release tablet, controlled-release tablet or enteric-coated tablet, and the capsule can be ordinary capsule, sustained-release capsule, controlled-release capsule or enteric-coated capsule.

The pharmaceutical composition of the present application can be prepared by conventional methods using conventional pharmaceutical excipients known in the art. Conventional pharmaceutical excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc. Fillers include starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, magnesium oxide, etc.; wetting agents include water, ethanol, etc.; binders include hypromellose cellulose, povidone, microcrystalline cellulose, etc.; disintegrants include croscarmellose sodium, crospovidone, surfactants, low-substituted hydroxypropyl cellulose, etc.; lubricants include stearic acid Magnesium, talc, polyethylene glycol, magnesium lauryl sulfate, micronized silica gel, talc, etc. Pharmaceutical excipients also include colorants, sweeteners, etc.

In another aspect, the present application provides the use of the above-mentioned crystals, crystal compositions, and pharmaceutical compositions in the preparation of antiviral drugs for treatment. Wherein said virus is chronic hepatitis B virus (HBV) or human immunodeficiency virus (HIV).

It should be noted that in X-ray diffraction spectroscopy (XRD), the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystal, where the relative intensities of the bands may vary depending on crystallization conditions, particle size, and other factors. The effect of dominance orientation varies with the difference in assay conditions. Therefore, the relative intensities of the diffraction peaks are not characteristic of the crystal in question, and more attention should be paid to the relative positions of the peaks rather than their relative intensities when judging whether it is the same as a known crystal. Furthermore, for any given crystal, there may be slight errors in the position of the peaks, as is well known in the art of crystallography. For example, due to temperature changes, sample movement, or instrument calibration when analyzing samples, the position of the peak can move, and the measurement error of the 2θ value is sometimes about ±0.2°. Therefore, this error should be taken into account when determining each crystal structure. In the XRD spectrum, the 2θ angle or the crystal plane distance d is usually used to represent the peak position, and there is a simple conversion relationship between the two: d=λ/2sinθ, where d represents the crystal plane distance, λ represents the wavelength of the incident X-ray, and θ is Diffraction angle.

The tenofovir alafenamide hemifumarate crystals prepared by the present application have the advantages of high purity, high crystallinity, good stability, low moisture absorption, and good fluidity; meanwhile, the tenofovir alafenamide provided by the invention The preparation method of the crystalline fovir alafenamide hemifumarate is simple, has high yield, mild crystallization conditions, is suitable for industrial production, and can better meet the needs of the pharmaceutical industry.

Description of drawings

The X-ray powder diffraction (XRD) figure of Fig. 1 tenofovir alafenamide hemifumarate crystallization

Fig. 2 thermogravimetric analysis (TGA) diagram of tenofovir alafenamide hemifumarate crystallization

Detailed ways

The technical solution of the present invention is illustrated with specific examples, but the protection scope of the present invention is not limited to the scope of the following examples. The reagents used are all commercially available products.

Instruments and methods used to collect data:

X-ray powder diffraction spectrum (XRD) was measured under the following conditions, instrument and its model: D/Max-RA Japan Rigaku XMiniFlex II X-ray powder diffractometer; ray: monochromatic Cu-Ka ray Scanning mode: θ/2θ, scanning range: 0～40°, voltage: 30Kv, current 15mA; testing environment conditions: temperature: 23.9°C, humidity: 38.6%.

Thermogravimetric analysis (TGA) was measured under the following conditions, instrument and its model: TG 209F3 thermogravimetric analyzer; scanning rate: l0°C/min; scanning range: 30°C-300°C; protective gas: nitrogen.

The preparation of embodiment 1 tenofovir alafenamide

Add 20kg of (R)-(+)-9-[2-(hydroxyphenoxyphosphorylmethoxy)propyl]adenine into the reaction kettle, add 140L of ethylene glycol dimethyl ether, 13.2kg of chlorinated Sulfoxide, heated to about 70-80°C, reacted for 24 hours, evaporated the solvent under reduced pressure, added 100L of toluene to obtain an acid chloride toluene solution. Add 28kg L-alanine isopropyl ester hydrochloride and 115kg dichloromethane into the reaction kettle, cool down to 0°C, add 20kg triethylamine under stirring, stir for 3 hours under nitrogen protection, filter, add 4A molecular sieve to the filtrate Dry overnight, filter, add 5.6kg of triethylamine, nitrogen protection, cool down to -20～-30°C, add acid chloride toluene solution dropwise, rise to room temperature for 30min reaction, use 100L×3 10% sodium dihydrogen phosphate solution Wash 3 times, wash 1 time with 100L 15% KHCO ₃ , wash 1 time with 100L water, dry the organic phase with anhydrous sodium sulfate, filter and evaporate to dryness. Add 50L of toluene and acetonitrile mixed solution (toluene/acetonitrile = 4:1), after dissolving, add 500g of activated carbon, decolorize for 10min, filter, cool down to 0-10°C for crystallization for 5 hours, filter, and vacuum dry at 50°C for 5 hours to obtain Off-white solid 13kg.

Example 2 Preparation of tenofovir alafenamide hemifumarate seed crystals

Add 100mL of acetonitrile, 10g of tenofovir alafenamide, and 1.3g of fumaric acid into the reaction flask, heat to reflux to dissolve, filter, evaporate the solvent under reduced pressure, add 75mL of isopropanol and 25mL of ethanol, and crystallize at room temperature for 24 hours , dried under reduced pressure at 50°C for 4 hours to obtain 1.5 g of off-white solid.

Example 3 Preparation of tenofovir alafenamide hemifumarate crystals

Add 750ml of isopropanol, 250ml of ethanol, 100g of tenofovir alafenamide, and 13g of fumaric acid into the reaction flask, heat to 50-60°C to dissolve, filter, add a small amount of seed crystals, crystallize at room temperature for 6 hours, and filter , dried under reduced pressure at 50°C for 4 hours to obtain 103 g of off-white solid. Using Cu-Kα radiation, its X-ray powder diffraction data are shown in Table 1, and its XRD pattern is shown in Figure 1.

Table 1

Its thermogravimetric analysis (TGA) diagram is shown in Figure 2.

Example 4 Preparation of tenofovir alafenamide hemifumarate crystals

Add 10L of acetone and 1kg of tenofovir alafenamide into the reaction kettle, heat to reflux to dissolve, add 130g of fumaric acid, dissolve and filter, add a small amount of seed crystals, crystallize at room temperature for 6 hours, filter, and decompose at 50°C. After pressing and drying for 4 hours, 1.05 kg of off-white solid was obtained, which had the X-ray powder diffraction pattern shown in FIG. 1 .

Example 5 The stability of tenofovir alafenamide hemifumarate crystals

The stability test of the crystal in Example 3 herein was tested with reference to the method described in Appendix XIX C of Part Two of the Chinese Pharmacopoeia 2010 Edition, and the results are shown in Table 2.

Table 2

From the experimental results under high temperature, strong light and high humidity conditions, it can be seen that the tenofovir alafenamide hemifumarate of the present application has high crystalline purity, low moisture absorption, stable thermodynamics, and X-ray powder Diffraction measurements showed unchanged crystallization and are therefore particularly suitable for pharmaceutical formulations.

Claims (10)

1. the tenofovir Chinese mugwort shown in formula (I) draws the crystallization of phenol amine hemifumarate,

It is characterized in that, being radiated using Cu-K α, the X-ray powder diffraction of the crystallization has diffraction in following 2 θ angle positions Peak：7.02°、8.62°、11.02°、12.12°、13.90°、15.86°、16.30°、17.62°、18.32°、20.26°、 20.82 °, 23.16 °, 26.60 ° and 27.84 °.

2. tenofovir Chinese mugwort as described in claim 1 draws the crystallization of phenol amine hemifumarate, it is characterised in that the crystallization exists 2 θ angle positions have diffraction maximum below：7.02°、8.62°、11.02°、12.12°、13.90°、14.90°、15.86°、 16.30°、17.62°、18.32°、18.68°、19.60、20.26°、20.82°、21.22°、21.36°、22.50°、23.16°、 24.08 °, 25.08 °, 26.60 °, 27.84 °, 28.76 ° and 31.60 °.

3. tenofovir Chinese mugwort as described in claim 1 draws the crystallization of phenol amine hemifumarate, have substantially as shown in Figure 1 X-ray powder diffraction collection.

4. a kind of prepare the method for according to the tenofovir Chinese mugwort described in claim 1,2 or 3 phenol amine hemifumarate being drawn to crystallize, Comprise the following steps：

A) tenofovir ends draws phenol amine free alkali and fumaric acid to be dissolved with organic solvent；

B) a small amount of crystal seed is added in the solution obtained to step a)；

C) crystallization, filtering, is dried under reduced pressure, and obtains the crystallization that tenofovir Chinese mugwort draws phenol amine hemifumarate.

5. according to the method described in claim 4, solvent is selected from the solvent selected from C in wherein step a)₁-C₄Alkylol, third Ketone, tetrahydrofuran, acetonitrile, ethyl acetate, one or more of mixtures of Isosorbide-5-Nitrae-dioxane, preferably acetone, isopropanol and The mixture of ethyl alcohol, more preferable isopropanol and ethyl alcohol.

6. according to the method described in claim 4, tenofovir Chinese mugwort draws the system of phenol amine hemifumarate crystal seed in wherein step b) Preparation Method is：The first organic solvent, tenofovir Chinese mugwort drawing phenol amine, fumaric acid are sequentially added, is heated to reflux dissolving, filter, decompression Solvent is evaporated off, adds in the second organic solvent, room temperature crystallization is dried under reduced pressure, and obtains the crystal seed.

7. according to the method described in claim 6, the first organic solvent and the second organic solvent are independently selected from C₁-C₄Alkylol, third The mixture of one or more of ketone, tetrahydrofuran, acetonitrile, ethyl acetate, 1,4- dioxane；First organic solvent is preferred The mixture of acetonitrile, the preferred isopropanol of the second organic solvent and ethyl alcohol, the volume ratio of mixed solvent is 3:1.

8. according to the method any one of claim 4-7, recrystallization temperature is 0 DEG C~30 DEG C in wherein step c), preferably Room temperature, when the crystallization time is 6~24 small；Drying temperature is no more than 60 DEG C, preferably 50 DEG C.

9. a kind of crystal composition, the tenofovir Chinese mugwort wherein any one of claim 1-3 draws phenol amine hemifumarate Crystallization accounts for more than the 50% of composition weight, preferably more than 70%, more preferably more than 90%, most preferably more than 95%.

10. a kind of pharmaceutical composition, the Chinese mugwort containing with good grounds claim 1-3 any one of them tenofovir draws half rich horse of phenol amine The crystal composition and one or more pharmaceutically acceptable carriers of hydrochlorate crystallization or claim 9.