WO2010062147A2

WO2010062147A2 - Crystal form of adefovir dipivoxil, preparation method thereof, and pharmaceutical composition containing the same

Info

Publication number: WO2010062147A2
Application number: PCT/KR2009/007068
Authority: WO
Inventors: 이기화; 전재일; 홍덕기; 우병영; 이영란
Original assignee: (주)아모레퍼시픽
Priority date: 2008-11-28
Filing date: 2009-11-30
Publication date: 2010-06-03
Also published as: KR20100061401A; WO2010062147A3

Abstract

A crystal form of Adefovir Dipivoxil according to the present invention is an ethyl alcohol solvated form. A method for preparing the crystal form of Adefovir Dipivoxil comprises the steps of: dissolving Adefovir Dipivoxil into an anhydrous ethyl alcohol, and cooling and stirring the Adefovir Dipivoxil solution obtained by the dissolving step to form crystals. The crystal form of Adefovir Dipivoxil according to the present invention has superior solubility and velocity of dissolution, and excellent biosafety, and can be widely used in medical fields.

Description

Crystalline Form of Adefober difficile, Preparation Method thereof, and Pharmaceutical Composition Comprising the Same

The present invention relates to a crystalline form of adefober difficile, a preparation method thereof, and a pharmaceutical composition comprising the same.

Adefober difficile is a bis-pivaloyloxy methyl ester of the parent compound 9- [2- (phosphonomethoxy) ethyl] adenine (PMEA) and is known to have antiviral activity against animals and humans. have:

Crystalline forms of Adefober difficile and methods for their preparation are mentioned in some prior art (Starettet et al., J. Med. Chem (1994) 37, pp 1857-1864). For example, Korean Patent No. 0618663 discloses a crystalline form of adefober difficile, an anhydrous crystalline form, a hydrate form (dihydrate of adefober difficile), a methyl alcohol solvent, a fumarate of adefober coated yarn, or The form of the composite is known. As another example, a crystalline form of a triclinic system is known.

As such, research on new crystalline forms of adefober difficile has been continued. The development of new crystalline forms with beneficial properties over conventionally known drugs is very important from a pharmaceutical point of view.

It is an object of one embodiment of the present invention to provide an ethyl alcohol solventized crystalline form of adefober difficile.

It is an object of another embodiment of the present invention to provide a method for preparing an ethyl alcohol solvent-ized crystalline form of adefober difficile.

It is an object of another embodiment of the present invention to provide a pharmaceutical composition for preventing and treating viral infections comprising ethyl alcohol solvated crystalline form of adefober difficile.

The crystalline form of adefober difficile according to the present invention is characterized by being an ethyl alcohol solvent-ized type. The method for producing a crystalline form of the adefober difficile includes a step of dissolving adefober difficile in anhydrous ethyl alcohol and a step of cooling and stirring the adefober difficile solution obtained by the dissolution step to form crystals. do. In addition, the pharmaceutical composition comprising the ethyl alcohol solvated crystalline form of Adefober difficile in the present invention can be used as an agent for preventing and treating viral infections.

Adefober difficile according to the present invention has high solubility and dissolution rate, and is excellent in biosafety.

1 is a graph showing an X-ray powder diffraction pattern (XRD) for the crystalline form of adefober difficile according to one embodiment;

Figure 2 is a graph showing the results of measuring the endothermic peak of the crystalline form of adefober difficile according to another embodiment;

Figure 3 is a graph showing the thermogravimetric analysis of the crystalline form of adefober difficile according to another embodiment.

Adefober difficile crystalline form according to an embodiment of the present invention is an ethyl alcohol solvent-ized crystalline form. In addition, the adefober difficile crystalline form relates to a new crystalline form of adefober difficile in the ethyl alcohol solvent-formed form, and specifically relates to the adefober difficile hemiethanol solvent-formed crystalline form.

The "solventized crystalline form" refers to a crystalline form according to the type of solvent used in the crystallization process, "ethyl alcohol solvent-ized crystalline form" means a form crystallized using ethyl alcohol as a crystallization solvent. In the present invention, ethyl alcohol was used as the crystallization solvent to obtain a new crystalline form for adefober difficile.

Adefober difficile according to an embodiment of the present invention is 9- [2-[{bis (pivaloyloxy) methoxy} phosphinyl] methoxy] ethyl] adenine, which can be represented by the following Chemical Formula 1. have.

Formula 1

In one embodiment, the adefober difficile crystal form has a diffraction of 2θ of at least 7.94, 8.54, 14.32, 16.22, 19.3, 20.82, 22.3, 23.5 + 0.2 in an X-ray powder diffraction pattern It is characterized by having a peak at an angle.

The present invention also provides a production method in which adefober difficile is dissolved in anhydrous ethyl alcohol to form a supersaturated adefober difficile solution, followed by cooling and stirring to generate crystals.

In another embodiment, it provides a pharmaceutical composition comprising adefober difficile crystalline form and a pharmaceutically acceptable carrier and the like according to the present invention, the pharmaceutical composition is useful as a composition for the prevention and treatment of viral infections It is possible.

Republic of Korea Patent No. 0624214 refers to the control of drying loss and the use of alkaline excipients in order to prevent stability deterioration due to hydrolysis of adefober difficile. However, in most embodiments disclosed in the patent, the formulation is made by a wet granulation process using water, and when formulated by the wet granulation process, the drug is inevitably exposed to moisture from the manufacturing stage. Since adefober difficile is sensitive to moisture, hydrolysis proceeds when exposed to moisture. Therefore, when the method disclosed in the patent, there is a problem that the formulation stability can not be secured. In addition, adefober difficile dissolved by moisture can be converted into an unintended crystalline form such as a hydrate during drying.

In terms of ensuring the flowability and uniformity of the content of the granules for compression, the wet granulation method is a very general manufacturing process, and the solvent used to form the wet granules is limited to water or ethyl alcohol. The use of water as a solvent can cause serious problems in physicochemical stability such as decomposition product formation and crystalline change by hydrolysis. In addition, even when ethyl alcohol is used as the solvent, a change in crystal form may be caused in the manufacturing process.

Adefober difficile crystalline form according to an embodiment of the present invention is characterized in that the solvent-soluble crystalline form after the process of dissolving in anhydrous ethyl alcohol. Therefore, even if the wet granulation method using ethyl alcohol in the manufacturing process of the therapeutic product can be maintained a very stable state does not cause physicochemical changes.

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

Adefober difficile crystalline form according to an embodiment of the present invention is a new crystalline form of the ethyl alcohol solvent-formed form.

In one embodiment, the ethyl alcohol solvated crystalline form of Adefober difficile (hereinafter referred to as "crystalline form P") contains about 0.3 to about 0.7 equivalents of ethyl alcohol in the crystal lattice. More specifically, the crystalline form P of the adefober difficile may contain about 0.5 equivalents of ethyl alcohol in the crystal lattice, which means that the adefober difficile crystalline form is (adefover difficile). (½EtOH) It exists in the form of (formular weight: 524.51). Theoretical value of the content of ethyl alcohol for Form P of Adefober difficile to contain 0.5 equivalent of ethyl alcohol is about 4.39%. Residual ethyl alcohol analysis and thermogravimetric analysis (TGA) yielded about 4.4% and 4.0%, respectively.

From these results, it can be seen that the crystalline form P of the adefober difficile is present in the form of (adefover difficile) · (½EtOH), which is essentially free of other detectable solvents or water. have.

Ethyl alcohol contained in the crystalline form P of the Adefober difficile is managed as a solvent of Class 3 by a process such as ICH guideline Q3C (Impurities: Guideline for residual solvents), and is classified as a solvent of Class 2 Higher biosafety than methyl alcohol. Therefore, crystalline form P of adefober difficile according to an embodiment of the present invention has an advantage of higher biostability than a conventional methyl alcohol-solvated form.

In one embodiment, the crystalline form P of the adefober difficile is at least 7.94, 8.54, 14.32, 16.22, 19.3, 20.82, 22.3, 23.5 + 0.2, as measured by X-ray powder diffraction using Cu-Kα radiation. Has a peak at a diffraction angle of 2θ. The measurement result by the specific X-ray powder diffraction method is shown in Figure 1 below.

In addition, it can be confirmed that the crystalline form P of the adefober difficile has a melting point at about 66 + 2.0 ° C. and about 78 + 2.0 ° C. when observing the endothermic transition property measured by the differential scanning calorimetry method. Specific measurement results of the endothermic transition characteristics by the differential scanning calorimetry is shown in Figure 2 below.

The present invention also provides a process for preparing Form P of adefober difficile.

In one embodiment, the preparation method includes a step of dissolving adefober difficile, and a step of forming crystals from the adefober difficile solution obtained in the step.

First, adefober difficile is dissolved in anhydrous ethyl alcohol. The amount of anhydrous ethyl alcohol used at this time is 1 or more, based on the weight to volume ratio of the dissolved adefober difficile [the weight of the anhydrous ethyl alcohol (ml) / adefober difficile (g)], specifically It may be 1.5 to 3.

In this dissolution process, adefober difficile may be warmed to an appropriate temperature, for example 25 to 40 ° C., in order to readily dissolve in anhydrous ethyl alcohol, and if there is an insoluble solid, it may be filtered.

Next, the adefober difficyl ethyl alcohol solution obtained in the dissolution step is cooled to form crystals. Cooling the adefober difficile ethylalcohol solution warmed to a temperature of about 25-40 ° C. in the dissolution process results in precipitation of the supersaturated adefober difficile, resulting in crystals. In one embodiment, to increase the yield of the resulting crystals, the solution can be cooled and stirred, for example, in the range of about 5 to -10 ° C.

Crystals obtained by the preparation method as described above have peaks at diffraction angles of at least 7.94, 8.54, 14.32, 16.22, 19.3, 20.82, 22.3, 23.5 + 0.2 when measured by X-ray powder diffraction method, and differential scanning Observing the endothermic transition properties measured by calorimetry, it has a melting point at about 66 + 2.0 ° C and about 78 + 2.0 ° C.

The present invention also provides a pharmaceutical composition containing Form P of the above adefober difficile. The pharmaceutical composition may include a pharmaceutically acceptable carrier, and may be used as an agent for preventing and treating viral infections, for example, for preventing and treating AIDS or hepatitis B.

The pharmaceutical composition according to the present invention may be administered via an appropriate route depending on the conditions prescribed. Suitable routes include oral, rectal, nasal, topical (eye, mouth and sublingual), vaginal and parenteral (subcutaneous, intramuscular, intravenous, intradermal, intradermal, intrathecal and dural) routes. Generally, the pharmaceutical composition is administered orally, but may be administered via any of the other routes mentioned above. Forms of oral administration can be, for example, tablets, capsules, granules, powders or solutions, and the like, specifically, tablets or capsules.

In one embodiment, for tablet formation or encapsulation by compression, a pharmaceutically acceptable carrier may be used in addition to the adefober difficile crystalline form of the present invention. In tablet formation, it can be compressed by direct compression after mixing the adefober difficile crystalline form and the carrier, it can be carried out dry or wet granulation process for the production of tableting granules. The pharmaceutically acceptable carriers are organic and inorganic compounds, and include those for preparing oral solid preparations, such as diluents, binders, disintegrants, lubricants and other additives.

Specific diluents include one or more selected from the group consisting of lactose (monohydrate or anhydride), dicalcium phosphate (dihydrate or anhydride), calcium carbonate, starch, cellulose, sucrose, dextrose, mannitol and sorbitol It includes. As a binder, gelatin, sugar (sucrose, glucose, dextrose, lactose), starch, acacia, sodium alginate, polyvinylpyrrolidone, celluloses (carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, Hydroxypropylmethylcellulose or polyethylene glycol, etc. Disintegrants include pregelatinized starch, microcrystalline cellulose, alginic acid, sodium starch glycolate, croscarmellose sodium or crosslinked polyvinylpyrrolidone (crospovidone). Glidants also include magnesium stearate, stearic acid, talc, sodium stearyl fumarate, glyceryl behenate, sodium lauryl sulfate.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the following Examples and the like are for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1 Preparation of Adefober difficile Crystalline Form P

30 g of adefober difficile was dissolved in 60 ml of anhydrous ethyl alcohol at 35 ° C. to obtain an adefober difficile solution. Insolubles were filtered off and stirred for 30 minutes in a salt-ice water bath (-5 ° C). The solid produced through stirring was filtered and washed with n-hexane. The reaction product was vacuum dried at 25 ° C. to obtain 28.3 g of adefober difficile crystals.

[Purity (HPLC method): 99.7%, purity analytical conditions-column: Waters Sperisorb C6, 250 × 4.6 mm, 5 μ; Mobile phase: 70% acetonitrile; Detector wavelength: 265 nm; Sample injection volume: 20 µl; Flow rate: 1.0 ml / min]

Example 2 Preparation of Adefober difficile Crystalline Form P

100 g of adefober difficile was dissolved in 200 ml of anhydrous ethyl alcohol at 37 ° C. to obtain an adefober difficile solution. The resulting solution was stirred at 1.5 ° C. for 2 hours. The resulting solid was filtered and dried in vacuo at 25 ° C. to yield 91 g of adefober difficile crystals.

Experimental Example 1 XRD and DSC Analysis

1-1. X-ray powder diffraction (XRD) analysis

XRD analysis was performed on the crystalline form of the adefober difficile obtained in Examples 1 and 2 by Rigaku, MiniFlex X-ray powder diffractometer. CuKα ₁ wire (λα ₁ = 1.54056 Hz) operated at 30 kV and 15 mA was used to measure the scan speed of 10.0 ^° per minute between 2θ values of 4 to 40 degrees. The XRD pattern of Example 1 is shown in Figure 1 as a representative drawing.

From Fig. 1, the crystalline form of the adefober difficile of Example 1 has a peak at a diffraction angle of at least 7.94, 8.54, 14.32, 16.22, 19.3, 20.82, 22.3, 23.5 + 0.2 in an X-ray powder diffraction pattern You can check it.

1-2. Differential Scanning Calorimetry (DSC) Analysis

The endothermic peak of the adefober difficile crystals obtained in Examples 1 and 2 was measured using a TA Instruments, DSC Q1000 differential scanning calorimeter. Measurement conditions were made into 20 degreeC of start temperature, 120 degreeC of end temperature, and a temperature increase rate of 10 degreeC / min. The DSC thermogram of Example 1 is shown in FIG. 2 as a representative figure.

From Figure 2 it can be seen that the crystalline form of the adefober difficile of Example 1 has a melting point at 66 + 2.0 ℃ and about 78 + 2.0 ℃.

Experimental Example 2 Analysis of Ethyl Alcohol Content in Form P of Adefober difficile

2-1. Thermogravimetry Analysis (TGA)

TA Instruments, TGA 2050 thermogravimetric analyzer was used to determine the weight change with temperature rise for the crystalline form of adefober difficile obtained in Examples 1 and 2. It measured at the start temperature of 35 degreeC, the end temperature of 200 degreeC, and a temperature increase rate: 5 degreeC / min. The TGA thermogravimetric diagram of Example 1 is shown in FIG. 3 as a representative drawing.

From Figure 3, the weight change was observed in the temperature range of about 40 ℃ to 60 ℃ adefober difficile crystal form of Example 1 and Example 2, the range was found to be about 4% weight loss.

2-2. Residual Ethyl Alcohol Analysis

Ethyl alcohol standard was weighed to 200,000 μg / ml, and placed in a 100 ml flask, filled with acetonitrile to the mark. 30 ml of this solution was taken and placed in a 50 ml flask to obtain a first standard solution. The first standard solution was diluted 10 and 100 times to obtain a second and third standard solution, respectively. A sample solution was prepared by dissolving 100 mg of crystalline form P of each adefober difficile obtained in Examples 1 and 2 in 10 ml of acetonitrile.

The ethyl alcohol content of the crystalline form of the adefober difficile obtained in Experimental Example 1 and 2 by gas chromatography (Gas Chromatography) analysis under the analysis conditions of Table 1 below. As a result of analysis, the ethyl alcohol content was measured in the range of 4.25 ~ 4.46%.

Table 1

column	Supelco wax ^tm -10 (30 mx 0.32 mm, 0.5 μm)
Inj	250 ° C, Det ,: 280 ° C (FID)
Flow rate	1 mL / min
Temperature Programming	35 (1 min) → 5 ° C / min temperature rise → 80 ° C (0 min) → 20 ° C / min temperature rise → 200 ° C

Through the weight change in FIG. 3 and the residual ethyl alcohol analysis of Table 1, it was confirmed that the crystalline forms of the adefober difficile compounds of Experimental Examples 1 and 2 exist in the form of (adefover difficile) · (½EtOH). have.

The adefober difficile crystal form according to the present invention has high solubility and dissolution rate, shows excellent biosafety, and can be widely used in medicine.

Claims

Crystalline form of Adefober difficile in ethyl alcohol solvent form.
The method of claim 1,

The crystalline form of the adefober difficile is a crystalline form of adefober difficile containing 0.3 to 0.7 equivalents of ethyl alcohol in the crystal lattice.
The method of claim 1,

The crystalline form of the adefober difficile is a crystalline form of adefober difficile, which is a hemiethanol solvent-formed crystalline form containing 0.5 equivalents of ethyl alcohol in the crystal lattice.
The method of claim 1,

The crystalline form of the adefove difficile is adefober difficile having a peak at a diffraction angle of 7.94, 8.54, 14.32, 16.22, 19.3, 20.82, 22.3, 23.5 + 0.2, when measured by X-ray powder diffraction method. Crystalline form.
The method of claim 1,

The crystalline form of the adefober difficile is a crystalline form of adefober difficile having melting points of 66 + 2 ° C. and 78 + 2 ° C.
Dissolving adefober difficile in anhydrous ethyl alcohol; And

A method for producing a crystalline form of adefober difficile, comprising a step of forming a crystal by cooling and stirring the adefober difficile solution obtained in the step.
The method of claim 6,

The amount of anhydrous ethyl alcohol of the dissolution step is 1.5 to 3, based on the volume ratio (volume of anhydrous ethyl alcohol (ml) / weight of adefober difficile (g)) of the weight of adefober difficile, adefo Method for producing crystalline form of buddycover.
The method of claim 6,

In the said crystal formation process, the temperature to carry out cooling stirring is 5 to -10 degreeC, The manufacturing method of the crystalline form of the adefober difficile chamber.
A pharmaceutical composition for preventing or treating a viral infection comprising the crystalline form of adefober difficile according to any one of claims 1 to 5 as an active ingredient.