CN104496972A - Novel pharmaceutical tegafur co-crystal and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical eutectics, and specifically relates to a new eutectic of tegafur and a preparation method thereof, in particular to a new eutectic of tegafur and 4-hydroxybenzamide composed of organic matter. The co-crystal uses tegafur as the pharmaceutical active ingredient (API), and the selected co-crystal former is 4-hydroxybenzamide, and tegafur is connected to it through hydrogen bonding and π-π stacking. The metering ratio (molar ratio) is 1:1. The method adopted in the preparation of the eutectic in the present invention is the cooling crystallization method, which is simple and easy to operate; the solvents used are low-boiling and cheap organic solvents such as acetonitrile and ketones, which are convenient for industrialized production.

Description

A kind of novel tegafur pharmaceutical co-crystal and preparation method thereof

technical field

The invention belongs to the technical field of organic drug co-crystals, and in particular relates to a new co-crystal of tegafur and a preparation method of the new co-crystal.

Background technique

Tegafur is the second-generation fluorouracil drug for anti-metabolic tumor chemotherapy, which was successfully synthesized in 1968 by Dr. Hiller, a former Soviet scientist. Tegafur is an inactive precursor of 5-FU, which is degraded by liver drug-metabolizing enzymes and cytochrome P-450 system in vivo, and gradually transforms into 5-FU to work. Its anti-tumor mechanism is the same as that of 5-FU. Tegafur has the advantages of high fat solubility, oral administration, rapid gastrointestinal absorption, and long half-life. Its side effects are one-seventh of that of 5-FU, and its curative effect index is twice as high.

Tegafur is widely used in the treatment of intestinal cancer and metastatic intestinal cancer, but because tegafur has certain toxicity, there are relatively serious bone marrow suppression, gastrointestinal reactions and liver and kidney damage, etc., so reduce its toxicity or improve Its bioavailability has become a research hotspot. For example, it is described in Belgian Patent No.855121 that there are 2'R and 2'S racemic isomers in tegafur, but studies such as Yasumoto M have shown that the two isomers have the same biological activity and the same toxicity (YasumotoM.et al .,"J.Med.Chem.", 1977, vol.41, No.9, 1632-1635); Later, Uchida T et al. studied the crystal form of tegafur and obtained its α, β, Four crystal forms of γ and δ ("Chem.Pharm.Bull.", Vol.41, No.9, 1623-1625). Dissolve tegafur in hot acetone and crystallize at low temperature to obtain the α crystal form; the saturated tegafur methanol solution can obtain the β crystal form after rotary evaporation; heat the β crystal form to 130°C to obtain the γ crystal form; Recrystallization from methanol solution and slow evaporation at room temperature gave the delta crystal form. There is no significant difference in the therapeutic effect of the above crystal forms.

From the above description, it is known that the efficacy of tegafur or the toxicity of tegafur cannot be improved or reduced through configuration or crystal form screening, so finding a compound that has a synergistic effect with tegafur is a current research hotspot. For example, KagawaY. etc. confirmed that tegafur and uracil can effectively improve the curative effect of tegafur after being mixed with uracil at a molar ratio of 1:4 ("Cancer Investigation", Vol.13, No.5, 470-474.); Sanchiz F et al. A compound consisting of tegafur, folic acid and uracil ("Jpn.Journal Clin. Oncol.", 1994, vol.24, No.6, 322-326) was used to improve the bioavailability of tegafur. Because uracil itself has certain toxicity, Fujita H et al. pointed out that the toxicity reduction of tegafur is more obvious when it is used in combination with thymine, adenosine, thymidine, etc. (Experimental and Clinical Pharmacotherapy, Issue 12, Riga, 1983, p.205). US Patent No. 6,538,001 reported that the solubility and bioavailability of tegafur can be improved when tegafur and methyluracil form a molecular complex (i.e. co-crystal) at a ratio of 1:2 or 1:1. In summary, combination therapy is an effective way to improve the bioavailability of tegafur.

Pharmaceutical co-crystals are crystals in which active pharmaceutical ingredients (active pharmaceutical ingredient, API) and other physiologically acceptable molecules are combined in the same crystal lattice according to a certain stoichiometric ratio in the form of hydrogen bonds and other non-covalent bonds according to the principles of crystal engineering. . Rationally designed drug co-crystals can significantly improve the physicochemical properties, solubility, dissolution rate, and stability of drugs, thereby increasing the bioavailability of drugs. In November 2011, the FDA issued the "Guidance for Industry: Regulatory Classification of Pharmaceutical Cocrystals", pointing out that when a drug forms a cocrystal with an excipient, the drug cocrystal can be used as a "preparation intermediate" to Management and control, so the co-crystal does not need to be registered as a drug alone. Therefore, it is of great practical significance to obtain more novel, practical and creative drug co-crystals, especially for some water-insoluble drugs. In recent years, the study of pharmaceutical co-crystals has attracted more and more attention. At this stage, foreign research on drug co-crystals has gradually increased and deepened; while domestic research on it is still relatively small. For generic drugs, the study of drug co-crystals can also break the patent protection of drug crystal forms by original drug companies, which is conducive to the introduction of generic drugs to the market.

The design of pharmaceutical co-crystals is a prerequisite for the successful preparation of co-crystals. The design of supramolecular structures by using the principles of supramolecular chemistry and self-assembly is the characteristic of co-crystals prepared by crystal engineering. Co-crystallization experiments were designed to assess the strength of potential intermolecular interactions and to consider hydrogen bonding principles. At present, the co-crystal formation types can be divided into the following categories from the structure: amide drug co-crystal, carboxylic acid drug co-crystal, alcohol-phenol drug co-crystal, heterocyclic drug co-crystal. Among them, amide drugs are a kind of drug active ingredients involved in drug co-crystal research. The carbonyl O atom in the molecule is a proton acceptor, and the amino N atom is a proton donor, which can be combined with the proton acceptor or The donor forms a variety of intermolecular hydrogen bonds. From the structural analysis of tegafur, it also belongs to amide drugs, and its structure is simple, so it is easier to form co-crystals with other drugs or pharmaceutical excipients. The present invention finds that tegafur can form a cocrystal with 4-hydroxybenzamide as a cocrystal former (CCF), which provides a basis for us to select drug-drug cocrystals in the future.

Contents of the invention

The purpose of the present invention is to improve the deficiencies of the prior art, provide a co-crystal of tegafur drug and its preparation method, and carry out characterization research on its structure. It provides a way for improving the bioavailability of tegafur and reducing the toxic and side effects.

The present invention is achieved through the following technical solutions:

A kind of tegafur medicine eutectic, eutectic is made up of tegafur (I) and 4-hydroxybenzamide (II), described tegafur (I) and 4-hydroxybenzamide (II) ) has the following structural formula:

As a further improvement, the present invention uses tegafur as the pharmaceutical active ingredient, and 4-hydroxybenzamide as the co-crystal former; a tegafur molecule and a 4-hydroxybenzamide molecule constitute the basic structural unit of the co-crystal, Its crystallographic parameters are: monoclinic system, P 21/n space group, unit cell parameters: b= α=90.000°, β=36.304(3)9°, γ=90.000° unit cell volume Z=4, molecular formula: C ₈ H ₉ FN ₂ O ₃ ·C ₇ H ₇ NO ₂ .

As a further improvement, the co-crystal of the present invention has an X-ray powder diffraction pattern as shown in Figure 3, expressed as: 4.30°, 4.88°, 9.75°, 10.99°, 11.78° in terms of diffraction angle 2θ°±0.1 , 12.99°, 14.65°, 16.27°, 18.19°, 19.59°, 20.54°, 20.88°, 21.67°, 22.10°, 22.78°, 23.20°, 23.46°, 23.85°, 24.47°, 24.794°, 25.89°, 26.16 °, 28.06°, 28.48°, 29.19°, 29.60°, 29.93°, etc.

The invention also discloses a preparation method of tegafur drug co-crystal, which is characterized in that:

Feed tegafur and the eutectic former in an equimolar ratio in an organic solvent, the ratio of the weight g of tegafur to the volume ml of the solvent is 1:5-1:30, reflux and stir in a high-temperature water bath until the solution is clear And continue to stir for a certain period of time, quickly put the above clear solution into an ice-water bath for cooling and crystallization, and overnight, the obtained precipitate is filtered and dried to obtain the tegafur eutectic.

As a further improvement, the organic solvents described in the present invention are acetone and acetonitrile.

At the same time, the present invention also discloses the application of a tegafur drug co-crystal, which can be applied to the treatment of gastrointestinal tumors or the treatment of breast cancer or bronchial lung cancer or liver cancer, and the gastrointestinal tumor is gastric cancer or colon cancer or rectal cancer or pancreatic cancer.

The beneficial effects of the present invention are as follows:

Tegafur is a derivative of fluorouracil, which is gradually transformed into fluorouracil in the body through liver activation to play an anti-tumor effect. It interferes and blocks DNA, RNA and protein synthesis in the body. It is an anti-pyrimidine drug and a cell cycle-specific drug. The chemotherapy index is twice that of fluorouracil, and the toxicity is only 1/4 to 1/7 of that of fluorouracil.

The co-crystal prepared by the invention inherits the pharmacological activity of tegafur itself, and has certain improvements in stability and bioavailability. The results of thermal analysis showed that the starting temperature of eutectic decomposition was 207.4°C, while that of tegafur API was 185.69°C, which indicated that the thermal stability of tegafur and 4-hydroxybenzamide was improved after forming a eutectic. Significantly improved. The crystal structure analysis of the eutectic prepared by the present invention shows that there is a rich hydrogen bond network between tegafur and 4-hydroxybenzamide in the eutectic, and the intramolecular and intermolecular hydrogen bonds form the eutectic molecule into an infinitely extended Helical molecular chain, this molecular chain extends infinitely along the b direction, the helical chain is structurally similar to a chain in the double helix structure of DNA, from a biological point of view, this structure may be beneficial to tegafur to block the synthesis of DNA , thereby improving the activity of tegafur as an anti-pyrimidine drug.

Description of drawings

Fig. 1 is the crystal structure diagram of the organic drug cocrystal of tegafur and 4-hydroxybenzamide;

Fig. 2 is the hydrogen bonding diagram of the organic drug cocrystal of tegafur and 4-hydroxybenzamide;

Fig. 3 is the X-ray powder diffraction (XRD) pattern of the organic drug cocrystal of tegafur and 4-hydroxybenzamide;

Fig. 4 is the thermogravimetric analysis (TG) figure of the organic medicine eutectic of tegafur and 4-hydroxybenzamide;

Fig. 5 is a differential scanning analysis (DSC) diagram of an organic drug cocrystal of tegafur and 4-hydroxybenzamide.

Detailed ways

The invention provides a drug co-crystal of tegafur and a preparation method thereof. The active ingredient (API) of the selected drug is tegafur, and the co-crystal former (CCF) is 4-hydroxybenzamide. A Co-crystals of novel structures.

Tegafur (Tegafur), as the pharmaceutical active ingredient of the present invention, has a chemical name of 1-(tetrahydro-2-furyl)-5-fluoro-2,4(1H,3H)-pyrimidinedione, and its molecular formula is C ₈ H ₉ FN ₂ O ₃ , its structure is shown in Figure 1, which is the crystal structure diagram of the organic drug cocrystal of tegafur and 4-hydroxybenzamide.

The co-crystal former (CCF) that the present invention selects is 4-hydroxybenzamide, and molecular formula C ₇ H ₇ NO _The structure is as shown in Figure II the hydrogen bond connection diagram of the organic drug cocrystal of tegafur and 4-hydroxybenzamide .

Tegafur drug cocrystal of the present invention is composed of a tegafur molecule and a 4-hydroxybenzamide molecule tegafur drug cocrystal (Fig. 1), belongs to monoclinic system, P21/n space group , the crystallographic parameters are shown in Table 1, and the atomic coordinates and temperature factors are shown in Table 2. The hydroxyl group on the 4-hydroxybenzamide acts as a hydrogen bond donor to form a hydrogen bond with the carbonyl group on the pyrimidinone of tegafur, and the carbonyl group on the tegafur pyrimidone has a strong bond with the hydroxyl group of the 4-hydroxybenzamide The hydrogen bonding effect of intramolecular and intermolecular hydrogen bonds forms an infinitely extending helical molecular chain (Figure 2), and the molecular chain extends infinitely along the b direction. The X-ray powder diffraction (XRD) pattern of the eutectic (Fig. 3), the X-ray characteristic diffraction line is represented by the diffraction angle 2θ (2θ, ±0.1°) as: 4.30°, 4.88°, 9.75°, 10.99°, 11.78 °, 12.99°, 14.65°, 16.27°, 18.19°, 19.59°, 20.54°, 20.88°, 21.67°, 22.10°, 22.78°, 23.20°, 23.46°, 23.85°, 24.47°, 24.794°, 25.89°, 26.16°, 28.06°, 28.48°, 29.19°, 29.60°, 29.93. The results of thermogravimetric (TG) analysis of the cocrystal showed no weight loss from room temperature to 150 °C, indicating that cocrystal 1 did not contain crystal water and solvent (Figure 4), and differential thermal analysis (DSC) showed that it was at 145.4 °C (peak value ) has an endothermic peak, indicating that the melting point (peak top value) of the eutectic is 145.4°C (Fig. 5).

Crystallographic parameters of table 1 Tegafur-4-hydroxybenzamide cocrystal

Atomic coordinates and temperature factors of each atom (non-hydrogen atom) in the cocrystal of tegafur-4-hydroxybenzamide in table 2

atom x Y Z Ueq C1 0.4166(8) 0.3702(6) 0.07429(12) 0.0464(11) C2 0.5316(11) 0.2202(8) 0.09098(17) 0.0823(18) C3 0.6229(11) 0.1289(8) 0.05732(19) 0.0817(15) C4 0.4246(10) 0.1745(6) 0.02841(15) 0.0621(14) C5 0.6017(7) 0.6032(5) 0.10857(10) 0.0344(9) C6 0.9646(7) 0.7670(5) 0.08608(10) 0.0337(9) C7 0.9434(7) 0.6652(5) 0.05380(10) 0.0381(10) C8 0.7709(8) 0.5453(5) 0.04984(11) 0.0400(10) C9 0.5220(7) 0.9200(5) 0.19087(10) 0.0352(9) C10 0.5074(6) 0.9221(5) 0.23150(10) 0.0323(9) C11 0.6910(7) 0.8374(5) 0.25351(11) 0.0389(10) C12 0.6793(7) 0.8316(6) 0.29111(11) 0.0419(10) C13 0.4820(7) 0.9165(5) 0.30808(10) 0.0363(9) C14 0.3015(7) 1.0053(5) 0.28680(11) 0.0387(10) C15 0.3129(7) 1.0083(5) 0.24866(11) 0.0376(9) F1 1.1100(5) 0.6990(4) 0.02700(7) 0.0613(8) N1 0.6017(6) 0.5122(4) 0.07711(8) 0.0375(8) N3 0.3014(6) 0.9428(5) 0.17083(9) 0.0465(10) O1 0.3538(6) 0.3379(4) 0.03746(8) 0.0536(8) O2 0.4474(5) 0.5798(4) 0.13276(8) 0.0493(8) O3 1.1231(5) 0.8782(4) 0.09103(8) 0.0468(8) O4 0.7368(5) 0.8967(4) 0.17628(8) 0.0472(8) O5 0.4717(5) 0.9055(4) 0.34531(7) 0.0527(9)

The instrument that detects drug eutectic structure among the present invention is as follows:

Single crystal diffraction: Rigaku R-AXIS-RAPID single crystal diffractometer, using MoKα Rays, structure analysis and correction with SHELXS97 and SHELXL97. Structural maps were obtained using Diamond and Mercury software.

Powder X-ray diffraction (XRD) characterization: Instrument: Rigaku D/Max-2550PC, CuKα radiation, power 40kV×250mA, scanning range 2θ3～40°, step width 0.02°, scanning speed 5°/min.

Thermogravimetric analysis (TG) characterization: Instrument: TA company SDT Q600, purge gas: nitrogen 120ml/min, heating rate: 10°C/min, temperature range: room temperature to 380°C.

Differential scanning calorimetry (DSC) characterization: Instrument: TA company DSC Q100, purge gas: nitrogen 50ml/min, heating rate: 10°C/min, temperature range: room temperature to 200°C.

The technical scheme of the present invention will be further described by specific examples below:

Example 1

Take 0.40g of tegafur and 0.27g of 4-hydroxybenzamide, add 2ml of acetonitrile solution, heat to reflux at 60°C, stir to dissolve, continue to reflux for 20-30 minutes, quickly put it in an ice-water bath, and slowly precipitate white After 24 hours, the crystals were filtered to obtain a white tegafur organic drug co-crystal.

Example 2

Take 0.40g of tegafur and 0.27g of 4-hydroxybenzamide, add 4ml of acetonitrile solution, heat to reflux at 60°C, stir to dissolve, continue to reflux for 20-30 minutes, quickly put it in an ice-water bath, and slowly precipitate white After 24 hours, the crystals were filtered to obtain a white tegafur organic drug co-crystal.

Example 3

Take 0.80g of tegafur and 0.54g of 4-hydroxybenzamide, add 5ml of acetonitrile solution, heat to reflux at 60°C, stir to dissolve, continue to reflux for 20-30 minutes, quickly put it in an ice-water bath, and slowly precipitate white After 24 hours, the crystals were filtered to obtain a white tegafur organic drug co-crystal.

Example 4

Take 0.40g of tegafur and 0.27g of 4-hydroxybenzamide, add 4ml of acetone solution, heat to reflux at 60°C, stir to dissolve, continue to reflux for 20-30 minutes, quickly put it in an ice-water bath, and slowly precipitate white crystals After 24 hours, it was filtered to obtain a white tegafur organic drug eutectic.

Example 5

Take 4.0g of tegafur and 2.7g of 4-hydroxybenzamide, add 50ml of acetone solution, heat to 60°C and reflux, stir to dissolve, continue to reflux for 20-30 minutes, quickly put it in an ice-water bath, and slowly precipitate white crystals After 24 hours, it was filtered to obtain a white tegafur organic pharmaceutical eutectic, which weighed 5.2 g.

The powder that embodiment 1-5 obtains is measured with X-ray powder diffraction, and its diffraction pattern is consistent, with interplanar spacing d, diffraction angle 2θ (expressed in ° ± 0.2) and relative intensity (expressed as relative to the strongest spectral line expressed as a percentage).

Finally, it should be noted that the above examples are only some specific examples and comparative examples of the present invention. Obviously, the present invention is not limited to the above embodiments, and many variations are possible. All deformations that can be directly derived or associated by those skilled in the art from the content disclosed in the present invention should be considered as the protection scope of the present invention.

Claims (7)

1. a Tegafur pharmaceutical co-crystals, it is characterized in that, described eutectic is made up of Tegafur (I) and 4-hydroxybenzamide (II), and described Tegafur (I) is as follows with the structural formula of 4-hydroxybenzamide (II):

2. a Tegafur pharmaceutical co-crystals according to claim 1, is characterized in that, take Tegafur as active constituents of medicine, and 4-hydroxybenzamide is eutectic formation; The basic structural unit of a Tegafur molecule and a 4-hydroxybenzamide molecular composition eutectic, its crystallographic parameters is: oblique system, P 21/n spacer, unit cell parameters: α=90.000 °, (3) 9 °, β=36.304, γ=90.000 ° unit cell volume z=4, molecular formula: C ₈h ₉fN ₂o ₃c ₇h ₇nO ₂.

3. a Tegafur pharmaceutical co-crystals according to claim 2, it is characterized in that, described eutectic has X-ray powder diffraction pattern as shown in Figure 3, be expressed as with diffraction angle 2 θ ° ± 0.1: 4.30 °, 4.88 °, 9.75 °, 10.99 °, 11.78 °, 12.99 °, 14.65 °, 16.27 °, 18.19 °, 19.59 °, 20.54 °, 20.88 °, 21.67 °, 22.10 °, 22.78 °, 23.20 °, 23.46 °, 23.85 °, 24.47 °, 24.794 °, 25.89 °, 26.16 °, 28.06 °, 28.48 °, 29.19 °, 29.60 °, 29.93 ° etc.

4. a preparation method for the Tegafur pharmaceutical co-crystals as described in claim 1 or 2 or 3, is characterised in that:

In organic solvent Tegafur and eutectic formation are fed intake according to equimolar ratio, the weight g of Tegafur and the volume ml of solvent are than being 1:5 ~ 1:30, under high temperature bath condition, backflow is stirred to solution clarification and Keep agitation certain hour, above-mentioned settled solution is put into ice-water bath cooling crystallization fast, spend the night, the throw out obtained, filter, drying obtains described Tegafur eutectic.

5. a preparation method for Tegafur pharmaceutical co-crystals according to claim 4, is characterized in that, described organic solvent is acetone and acetonitrile.

6. an application for the Tegafur pharmaceutical co-crystals as described in 1 or 2 or 3, is characterized in that, described eutectic can be applicable to treatment digestive tract tumor or treatment mammary cancer or lung bronchogenic carcinoma or liver cancer.

7. the application of Tegafur pharmaceutical co-crystals according to claim 6, is characterized in that, described digestive tract tumor is cancer of the stomach or colorectal carcinoma or rectum or carcinoma of the pancreas.