KR101089620B1 - Anhydrate form of Adefovir Dipivoxil and its Method using inoic liquid - Google Patents

Abstract

The present invention relates to a new type of anhydrous crystalline adefovir difficile (hereinafter referred to as AD) and a method for preparing the same, which are prepared by aggregating crystallization using an ionic liquid as a solvent and an organic or inorganic solvent as a half solvent.

According to the present invention, the crystallization of AD through the agitation crystallization method using the unique properties of the ionic liquid, such as thermal stability, non-volatility, low vapor pressure and the ability not to solvate, results in a new anhydrous AD, i. It is possible to produce a crystal form with more physicochemical and pharmacological stability.

Adefovir difficile, ionic liquid, molten crystallization

Description

Anhydrate form of Adefovir Dipivoxil and its Method using inoic liquid}

The present invention relates to an anhydrous crystalline adefovir difficile and a method for preparing the same using an ionic liquid. More specifically, the present invention relates to a physical and chemical process using a crystalline liquid crystallization method using an ionic liquid as a solvent and an organic or inorganic solvent as a half solvent. And a method for preparing a new anhydrous crystalline adefovir difficile having excellent pharmacological stability.

The antiviral drug adefovir difficile (hereinafter referred to as AD. FIG. 1) is 9- [2- [bis (pivaloyloxy) -methoxy] phosphinyl] methoxy] ethyl] adenine (9) in compound nomenclature. -[2- [bis (pivaloyloxy) -methoxy] phosphinyl] methoxy] ethyl] adenine) and as a nucleotide reverse transcriptase inhibitor, it shows excellent in vivo antiviral activity against HIV and hepatitis B (HBV).

Such AD is known to have two forms in its natural state, amorphous and crystal. WO 2000/035460 "Drug Preparation" includes anhydrous crystalline AD, dihydrate crystalline AD and alkaline excipient. Pharmaceutical formulations of more stable ADs are disclosed, and other WO 1999/04774 discloses compositions comprising one or more crystalline ADs, including anhydrous crystalline forms, hydrate forms, solvated forms, and salts. It includes a crystalline form, and WO 2004/043972 discloses obtaining one new anhydrous crystalline AD using a spray drying method, and WO 2009/015892 discloses one water. Crystal forms in monohydrate form in which molecules are bound are disclosed.

In the above-described method disclosed in WO 1999/04774, the yield is reduced, impurities are increased, and stability is lowered at a crystallization temperature of 50 ° C. or higher.

Accordingly, the present inventors have diligently researched to obtain a new form of AD crystals that are more stable than AD by the methods of the prior arts, and as a result, the unique characteristics of the ionic liquid are not thermally stable, nonvolatile, low vapor pressure and solvate. In the case of crystallizing AD through the calcification method using the ability, etc., it is possible to crystallize AD at a high temperature, thereby confirming that it is possible to prepare a new anhydrous crystalline AD which is physicochemically and pharmacologically stable and completes the present invention. It became.

Therefore, the main object of the present invention is to provide a method for preparing new anhydrous crystalline AD which is physicochemical and pharmacologically stable.

According to one aspect of the present invention, the present invention provides a method for preparing anhydrous crystalline adefovir difficile using a crystalline crystallization method using an ionic liquid as a solvent and an organic or inorganic solvent as a half solvent.

In the method for preparing anhydrous crystalline AD of the present invention, it is preferable to use an ionic liquid based on imidazolium, have a cation, and a liquid at room temperature, more preferably 1-allyl- It is preferred to use 3-ethylimidazolium tetrafluoroborate (1-allyl-3-ethylimidazolium tetrafluoroborate, AEImBF ₄ , FIG. 2).

In the method for producing the anhydrous crystalline AD of the present invention, it is preferable to use water as the inorganic solvent.

In the method for producing the anhydrous crystalline AD of the present invention, by heating to 85 to 95 ℃ by the molten crystallization method to increase the affinity of the ionic liquid and water to use the method dissolved in the ionic liquid crystallized It is desirable to.

According to another aspect of the present invention, the present invention provides anhydrous crystalline AD prepared by the above method.

The anhydrous crystalline AD of the present invention has a characteristic peak represented by 2 ?? in the powder X-ray diffraction pattern with 2.3 to 2.8, 4 to 4.5, 8 to 8.5, 12.5 to 12.9, 17 to 17.3, 21.4 to 21.5, 25.8 to 25.9 and 30.2 to 30.3, characterized by having an endothermic transition peak of 55 ° C. to 59 ° C. and an exothermic transition peak of 54 ° C. to 58 ° C. in a DSC heat graph, and a Fourier transform infrared spectroscopy spectrum (FT-IR). ) 3390 to 3340 cm ^-1 , 3113 to 3110 cm ^-1 , 3060 to 3050 cm ^-1 , 2980 to 2950 cm ^-1 , 2940 to 2920 cm ^-1 , 1750 to 1740 cm ^-1 , 1710 to 1700 cm ^-1 , 1600 to 1590 cm ^-1 and It is characterized by having a peak at 1100 to 1060cm ^-1 .

Hereinafter, the present invention will be described in more detail step by step.

Ionic liquid used in the present invention is a generic term for melting salts below 100 ℃, characterized by high thermal stability, non-volatile low vapor pressure, high solvation ability for organic and inorganic materials, the ability not to solvate, 400 It has unique characteristics such as a wide liquid range up to ℃. The biggest feature of ionic liquids is that the unique properties of the aforementioned ionic liquids depend on the size and structure of the cations and anions. In other words, an appropriate ionic liquid can be designed depending on the intended use. For example, the larger the size of the anion and cation, the lower the melting point of the ionic liquid, and the higher the symmetry and crosslinking degree of the cation, the higher the melting point. In addition, as the size of the cation increases, the density of the ionic liquid decreases, and as the mass of the anion increases, the density increases. In this sense, ionic liquids are called "Designer Solvent". Ionic liquids can be categorized according to their melting point.The ionic liquids that exist as liquids at room temperature can be classified into room temperature ionic liquids, and the ionic liquids that exist as liquid below room temperature can be classified as low temperature ionic liquids. Ionic liquids) and ionic liquids can be designed according to various research purposes. These are called task specific ionic liquids (TSILs).

Of the ionic liquids described above, the ionic liquid to be used in the method for producing anhydrous crystalline AD of the present invention should have good affinity with water and be capable of dissolving AD first. As such an ionic liquid, those based on imidazolium and having a cation can be selected, and it is preferable to select a room temperature ionic liquid whose melting point is also liquid at room temperature. Among them, 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF ₄ ) has a low melting point and is present as a liquid at room temperature, and has low viscosity, good thermal stability, and low temperature. It has a vapor pressure, it can exist as a liquid at a temperature range of 300 ℃, has a high affinity with water, and has a high solvation ability, so it can dissolve organic and inorganic substances well. Preferred for crystallization.

Drowning-out crystallization is the separation by addition of a third material that produces a separation effect, which is more sensitive to heat than other crystallization techniques that rely on evaporation or temperature changes, but whose solubility is not significantly dependent on temperature. Particularly suitable for separation, it is one of the widely used methods in the fine chemical, food, pharmaceutical and biochemical industries. The external components in the crystallization are gases, liquids, supercritical fluids or solids, which are used as antisolvents, diluents, drowning-out agents, precipitants, salting-outs, solventing-outs or watering-out agents. In general, the organic solvent, such as alcohol (alcohol) is well dissolved in water, using a property that the solubility is significantly reduced, the process of precipitating separation by adding an external substance alcohol to the crystallization target solution.

In the present invention, it is preferable to use an ionic liquid, especially 1-allyl-3-ethylimidazolium tetrafluoroborate, as a solvent of the crystallization target material in order to apply the above-mentioned molten crystallization method. It is preferable to use water as a semi-solvent, and it is necessary to maintain it until it is crystallized by heating it to 85-95 ° C. In this case, the heating device used is programmed to control the temperature and to confirm the temperature. A suitable method is to put water in the reactor and put a container with AD solution in it to maintain the temperature, ie, bath.

Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectrometry (FT-IR), Thermogravimetric Analysis (TGA) and X- X-Ray Diffraction (XRD) was used, and according to the present invention the characteristic peaks represented by 2θ in the powder X-ray diffraction pattern were about 2.5, about 4.27, about 8.56, about 12.83, about 17.15, about 21.48, about 25.86, and appears at about 30.27, DSC column in the graph has a heat transition peak of the endothermic transition peak at about 58 ℃ to 59 ℃ and 55 ℃ to 57 ℃, about 3390cm in the Fourier transform infrared spectrum (FT-IR) ^{- 1} , about 3113cm ^-1 , about 3058cm ^-1 , about 2970cm ^-1 , about 2930cm ^-1 , about 1746cm ^-1 , about 1702cm ^-1 , about 1599cm ^-1 and about 1070cm ^-1 .

Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for illustrating the present invention, and thus the scope of the present invention is not construed as being limited by these embodiments.

Example 1 Preparation of Anhydrous Crystalline AD Using Ionic Liquid

AD, a raw material of this example, was prepared by the preparation method of AD anhydrous crystalline Form 1 (C ₂₀ , H ₃₂ , N ₅ , O ₈ , P) described in WO 1999/04774. Anhydrous crystalline AD was prepared by mixing with a semi solvent water at a crystallization temperature of 90 ° C. using the unique properties of the ionic liquids according to the following method.

In a 5 ml Bayer bottle, 32 mg of AD was dissolved in 0.5 ml of ionic liquid 1-Allyl-3-ethylimidazolium tetrafluoroborate (AEImBF ₄ ), and 0.5 mg of water was mixed to prepare a total solution of 32 mg / ml.

After raising the reactor on a temperature controlled heating device, 100 ml of water was filled in the reactor, and the Bayer bottle was fixed thereon and held at 90 ° C. for at least 12 hours. The precipitated crystals were then collected.

At this time, the temperature of the heating device was maintained at 85 ℃ to 90 ℃ state, the Bayer bottle containing AD was firmly fixed so that water does not escape using the Teflon tape.

Example 2 Determination of Purity of the Novel Anhydrous AD of the Present Invention by HPLC

To determine the purity of the crystal obtained in Example 1 (anhydrous crystalline AD of the present invention) was analyzed using HPLC. For analysis, 5 mg of the crystal obtained in Example 1 was dissolved in 10 ml of HPLC mobile phase to prepare an analytical sample.

Analysis conditions of AD using HPLC are as follows.

Mobile phase: Dissolve 20 g of KH ₂ PO _{4 in} 1 L of H ₂ O and adjust the pH to prepare a calcium phosphate buffer at pH 6, then mix the buffer with acetonitrile at a ratio of 60:40. The resulting mobile phase is filtered and washed using an ultrasonic cleaner.

Flow rate: 1.2 ml / min

-Holding time: 30min

Temperature: room temperature

-Detector: ultraviolet absorbance photometer (wavelength: 254nm)

-Stationary phase: A column filled with octysilylated silica gel for liquid check chromatography of 5 µm in a stainless tube having an inner diameter of about 4.6 mm and a length of about 250 mm.

Analytical sample injection volume: 50 μl

As a result of analyzing the crystal obtained in Example 1 under the above conditions, it was confirmed that the crystal was an AD crystal having a purity of 97%.

Example 3 Characterization of the Inventive New Anhydrous Crystalline AD

Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectrometry (FT-IR), Thermogravimetric Analysis (TGA) to analyze the characteristics of the AD crystal of the present invention prepared in Example 1 ) And X-ray diffraction (X-Ray Diffraction, XRD) were used.

As a result, the endothermic transition temperature was 58 ℃ to 59 ℃ in the DSC heat graph, the crystallization temperature was 57 ℃ when heating-cooling-heating (Fig. 3 and 4). In the TGA, the mass loss intervals appearing in the hydrate and solvate were not identified, and only the mass loss intervals appearing when decomposed after 110 ° C. were observed (FIG. 5), and when the XRD pattern was expressed as 2θ, about 2.5, 4.27, 8.56, 12.83, 17.15, 21.48, a peak was found at 25.86 and 30.27 (6), the Fourier transform infrared spectrum (FT-IR) was about ^{3390cm -1, 3113cm -1, 3058cm -1} , 2970cm -1, 2930cm ^{-1, 1746cm -1, 1702cm -1,} 1599cm -1, a peak appeared at 1070cm ^-1 position (FIG. 7).

This means that the new AD crystal of the present invention is in anhydrous crystalline form different from the existing AD crystal.

As described above, the crystallization of AD through the agitation crystallization method using the thermal stability, non-volatility, low vapor pressure and the ability not to solvate, which are unique characteristics of the ionic liquid according to the present invention, results in a new anhydrous crystalline AD, In other words, it is possible to prepare a crystal form having superior physicochemical and pharmacological stability than existing crystal forms.

1 is a diagram showing the molecular structure of AD.

2 is a diagram showing the molecular structure of 1-Allyl-3-ethylimidazolium Tetrafluoroborate (AEImBF ₄ ) used as an ionic liquid in an embodiment of the present invention.

3 is an endothermic, exothermic transition graph of heat-cooling-heating of DSC for anhydrous crystalline AD according to the present invention.

4 is a thermal graph of DSC for anhydrous AD according to the present invention.

5 is a graph of mass loss of TGA for anhydrous AD according to the present invention.

6 is an X-ray diffraction pattern graph of the anhydrous crystalline AD according to the present invention.

7 is a Fourier transform spectrum for anhydrous AD according to the present invention.

8 is a photograph of an anhydrous crystalline AD according to the present invention under a microscope.

Claims (9)

delete delete delete delete A process for preparing anhydrous crystalline adefovir difficile using agolite crystallization using 1-allyl-3-ethylimidazolium tetrafluoroborate as a solvent and water as a half solvent. delete delete delete The method of claim 5, wherein the calcined crystallization method is heated to 85 to 95 ℃ to increase the affinity of 1-allyl-3-ethylimidazolium tetrafluoroborate and water 1-allyl-3-ethylimidazolium tetra A method for producing anhydrous crystalline adefovir difficile, wherein the adefovir difficile dissolved in fluoroborate is crystallized.

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