KR100837843B1 - Crystalline form of nateglinide, process for the preparation thereof, and pharmaceutical composition comprising the same - Google Patents

Abstract

A crystal form I of nateglinide, a method for preparing the crystal form I, and a composition for treating diabetes containing the crystal form I are provided to improve fluidity and stability and to reduce volume density. A crystal form I of nateglinide is such that it has a peak at a 2theta diffraction angle of at least 7.54, 10.5, 13.5, 15.1, 15.7, 16.1, 18.6, 19.2, 19.8, 20.9 and 22.4±0.2 in X-ray powder diffraction pattern. Preferably the crystal form I of nateglinide has a melting point of 130-132 deg.C. The crystal form I of nateglinide is prepared by adding a nateglinide solution in isopropanol to water drop by drop at 10-25 deg.C to form crystal, wherein the amount of isopropanol is 15-20 vol% to the total amount of isopropanol and water.

Description

Crystalline form of nateglinide, process for the preparation conjugate, and pharmaceutical composition comprising the same

1 is an XRD diffraction pattern of nateglinide crystalline Form I according to the present invention.

2 is a DSC curve of nateglinide crystalline Form I according to the present invention.

3 is a spectrum of IR of nateglinide crystalline Form I according to the present invention.

4 is an XRD diffraction pattern of nateglinide crystalline Form II according to the present invention.

5 is a DSC curve of nateglinide crystalline Form II according to the present invention.

6 is a spectrum of IR of nateglinide crystalline Form II according to the present invention.

The present invention comprises a novel crystalline form of nateglinide ((-)-N-[(trans-4-isopropylcyclohexane) carbonyl] -D-phenylalanine) of formula (I), a preparation method thereof, and an active ingredient thereof It relates to a pharmaceutical composition.

Nateglinide is a drug of the meglitinide class and is developed for the purpose of controlling blood sugar in type II diabetic patients and improving hypoglycemia, a side effect of long-term use of sulfonyl urea-based drugs. Nateglinide represents a mechanism by which tissues selectively inhibit K ⁺ channels in the β-cells of the pancreas to promote insulin secretion and regulate blood glucose levels.

Nateglinide is used in low to high doses, such as 30, 90 and 120 mg, and is currently marketed under the trade names FASTIC® and STARLIX®. Nateglinide has a very short half-life and is used primarily to prevent blood sugar levels from rising after eating. Nateglinide is well soluble in organic solvents such as methanol, ethanol and chloroform, and has little solubility in water.

Nateglinide is known for a wide variety of crystal forms, for example, crystal forms A, C, D, F, G, I, J, K, L, M, N, O, P, Q, R, T, U, V , Y, α, β, γ, δ, ε, σ, and θ forms are known, and the characteristics and preparation methods of these crystalline forms are exemplified in various patent documents (US Patent Publication 2004/0116526, 2004/0181089, 2005/0014949, 2005/0075400, 2005/0090552). The crystalline forms of each nateglinide differ in physical properties, and examples of physical properties here include flowability of solids, dissolution in aqueous solution, stability, and bulk density. have.

U.S. Patent 4,816,484 discloses a process for crystallizing nateglinide from a mixture of water and methanol, wherein the crystals obtained can be prepared as a hydrate or methanol solvate after drying, where the hydrate is Form Z and the methanol solvate is Form E Dried crystals are defined as Form B.

U.S. Patents 5,463,116 and 5,488,150 describe the preparation of nateglinide Form B and Form H and their features. The nateglinide crystalline Form B has a melting point of 129 to 130 ° C, and the nateglinide crystalline Form H is 136 to 142 ° C. The X-ray powder diffraction pattern of nateglinide crystalline Form H has peaks at 2θ diffraction angles of 8.1, 13.1, 19.6, and 19.9 ± 0.2 °, and is characterized by having particularly strong diffraction at 15 ° and 17 °. On the other hand, the X-ray powder diffraction pattern of nateglinide crystalline Form B is characterized by weak peak intensity and especially weak diffraction at 15 ° and 17 °.

U.S. Patent 5,488,150 describes that nateglinide crystalline Form H is more stable than Form B, in particular, that crushed nateglinide crystalline Form H is more stable than Form B, which is determined by differential scanning calorimetry (DSC) analysis. Proved. That is, DSC of nateglinide crystalline Form B showed a strong endothermic pattern at 131.4 ° C., but after crushing, a new endothermic peak appeared at 138.2 ° C., whereas nateglinide crystalline Form H had no change in DSC pattern before and after grinding. This nateglinide crystalline H is currently used as an active ingredient of STARLIX®, which is marketed by Novartis.

However, the nateglinide crystalline form H has a static electricity, it is difficult to handle in the formulation process due to poor fluidity, and the filtration time is not very good filtration time is very long, and the washing after filtration is not easy to increase the process time when mass production There are disadvantages.

International Patent Publication WO 03/022251 discloses nateglinide crystalline AL and a method for preparing the same. The nateglinide crystalline AL has a melting point of 174-178 ° C. and the X-ray powder diffraction pattern has peaks at diffraction angles of 2θ of 7.5, 15.5, 19.8, and 20.2 ± 0.2 °, and 1711.5, 1646.5, 1538.7, 1238.8 in IR analysis. , 1215.1, characterized in that it has an absorption band at 700.5cm ^-1 . The nateglinide crystalline AL is obtained from acetonitrile solution in a specific temperature range.

As mentioned above, research on the development of new crystalline forms of nateglinide continues to be made. Developing new crystalline forms with beneficial properties over conventionally known drugs is important in terms of formulation.

Accordingly, the present inventors have completed the present invention as a result of research to develop a new crystalline form of nateglinide that is very fluid and excellent bulk density (bulk density).

Accordingly, it is an object of the present invention to provide a novel crystalline form of nateglinide with high fluidity, low bulk density and high stability.

It is also an object of the present invention to provide a process for preparing nateglinide of the new crystalline form.

It is also an object of the present invention to provide a composition for treating diabetes comprising the new crystalline form of nateglinide.

In order to achieve the above object, the present invention provides a 2θ of at least 7.54, 10.5, 13.5, 15.1, 15.7, 16.1, 18.6, 19.2, 19.8, 20.9, 22.4 ± 0.2 in an X-ray powder diffraction pattern. Provides nateglinide crystalline Form I having a peak at a diffraction angle of.

The present invention also provides nateglinide crystalline Form II having a peak at a diffraction angle of at least 9.4, 9.9, 14.3, 15.2, 16.3, 19.1, 20.2 ± 0.2 in a 2θ in an X-ray powder diffraction pattern. do.

The present invention also includes dropping a solution of nateglinide in isopropanol to water at 10 to 25 ° C, wherein isopropanol is used at 15 to 20% by volume based on isopropanol and water as a whole. Provided are methods for preparing glinide crystalline Form I.

The present invention also includes dropping a solution of nateglinide in isopropanol to water at 10 to 25 ° C, wherein isopropanol is used at 40 to 45% by volume based on isopropanol and water as a whole. Provided are methods for preparing glinide crystalline Form II.

The present invention also provides a composition for treating diabetes comprising the nateglinide crystalline Form I or the nateglinide crystalline Form II and a pharmaceutically acceptable carrier.

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

The present invention relates to a novel crystalline form of nateglinide with good flowability and low bulk density and high stability, and the present invention provides nateglinide crystalline Form I and Form II.

Nateglinide crystalline Form I has a diffraction of 2θ of at least 7.54, 10.5, 13.5, 15.1, 15.7, 16.1, 18.6, 19.2, 19.8, 20.9, 22.4 ± 0.2 as measured by X-ray powder diffraction method Characterized by having a peak at an angle, it may have an X-ray powder diffraction pattern of FIG. In addition, the nateglinide crystal Form I may have a melting point of 130 to 132 ° C. when measured by differential scanning calorimeter (DSC), and may have an IR spectrum as shown in FIG. have.

In addition, nateglinide crystal Form II provided by the present invention has a diffraction angle of at least 9.4, 9.9, 14.3, 15.2, 16.3, 19.1, 20.2 ± 0.2, as measured by X-ray powder diffraction method. It may be characterized by having a peak at, and may have an X-ray powder diffraction pattern of FIG. In addition, the nateglinide crystal Form II may have a melting point of 127 to 129 ° C. when measured by differential scanning calorimeter (DSC), and may have an IR spectrum as shown in FIG. 6 in infrared spectroscopy. have.

As described previously, nateglinide crystalline form H used in commercially available STARLIX® is electrostatically impaired and poor in fluidity, making it difficult to handle in the formulation process, poor filtration, long filtration time, and poor cleaning after filtration. In contrast, the process time is increased, but the nateglinide crystalline form I and crystalline form II according to the present invention have no static electricity compared to crystalline form H, which has excellent fluidity and low volume density, making it easy to apply during formulation and filtration. It is an excellent crystalline form that can greatly shorten the process time due to the excellent.

The nateglinide crystal Form I and Crystal Form II provided by the present invention can be obtained by using a mixed solvent of isopropanol and water in a specific ratio as a crystallization solvent in a specific temperature range. Specifically, nateglinide crystalline Form I and Form II may be prepared by a method comprising dropping a solution of nateglinide in isopropanol in water at 10 to 25 ° C. to form crystals, wherein isopropanol used herein Nateglinide crystalline Form I can be prepared when isopropanol and water as a whole, that is, 15 to 20% by volume based on the entire crystallization solvent, and when the isopropanol is 40 to 45% by volume based on the total crystallization solvent Naed crystalline Form II can be prepared.

More specifically, the nateglinide crystalline Form I is

Preparing a solution of nateglinide in isopropanol;

Dropping the nateglinide solution in water at 10 to 25 ° C. and stirring to precipitate nateglinide crystals;

Filtering the precipitated nateglinide crystals; And

Washing the nateglinide crystals with a mixture of water and isopropanol in the same ratio as the ratio of water and isopropanol used in the crystallization, and isopropanol used in the preparation of the nateglinide solution is crystallization of the nateglinide It can be prepared by a method of 15 to 20% by volume based on the isopropanol and water used in the.

In addition, the nateglinide crystalline form II is

Preparing a solution of nateglinide in isopropanol;

Dropping the nateglinide solution in water at 10 to 25 ° C. and stirring to precipitate nateglinide crystals;

Filtering the precipitated nateglinide crystals; And

And washing the nateglinide crystals with a mixture of water and isopropanol in the same ratio as the ratio of water and isopropanol used in the crystallization, and isopropanol used in the preparation of the nateglinide solution is formed by the formation of the nateglinide. It can be prepared by a method of 40 to 45% by volume based on the total isopropanol and water used for clarification.

The total amount of the solvent of isopropanol and water used in the preparation method of nateglinide crystalline Form I and Form II may be used in an amount of 5 to 20 times the weight of the nateglinide used, and the solvent of isopropanol and water as described above. The volume ratio of isopropanol to the total amount of is determined whether the resulting nateglinide crystalline form is Form I or Form II.

The manufacturing method will be described in more detail according to one embodiment of the present invention.

First, nateglinide is added to isopropanol and completely dissolved. At this time, the amount of isopropanol used is all isopropanol corresponding to the ratio of isopropanol to the total water and isopropanol used for crystallization of nateglinide. Then, a solution of nateglinide in the prepared isopropanol is added dropwise while adjusting the water corresponding to the volume calculated from the ratio to a specific temperature of 10 to 25 ° C. and maintaining the temperature. At this time, the dropping time may be performed for 10 to 60 minutes. It is possible to produce the nateglinide crystals of Form I or II according to the present invention in a higher yield in the dropping time range.

Then, stirring is performed at the same temperature as the dropping temperature to precipitate the crystals. Agitation can be carried out for 1 to 5 hours. The precipitated crystals are filtered by a conventional method and washed with the same mixed solvent as the mixed solvent of isopropanol and water used in the crystallization, and the washing mixed solvent used at this time is nateglinide used above. It can be used in a volume of 1 to 5 times the weight of. It can then be washed with the same volume of water as the wash mixed solvent. After the crystals have been washed, drying can be carried out by conventional methods known in the art.

By the method of the present invention as described above, nateglinide novel crystalline Form I and Form II can be prepared in high yield of 90% or more.

The present invention also provides a composition for treating diabetes comprising the nateglinide novel crystalline form I or II.

The composition of the present invention may be formulated into parenteral formulations such as oral preparations such as granules, powders, solutions, tablets, capsules, or dry syrups, or injections, but is not limited thereto. Preferably the compositions of the present invention may be in the form of tablets or capsules or in the form of solutions or injections.

As the pharmaceutically acceptable diluent or carrier used in the composition of the present invention, one or two or more of conventional excipients, disintegrants, binders, lubricants, and the like may be selectively used. For example, when the composition of the present invention is prepared in a solid form such as tablets or capsules, microcrystalline cellulose, lactose, low-substituted hydroxycellulose, etc. may be used as excipients, sodium starch glycolate, phosphoric anhydride as a disintegrant. Calcium hydrogen, and the like can be used. As the binder, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose and the like can be used, and the lubricant can be selected from magnesium stearate, silicon dioxide, talc and the like.

It is also possible to use additives that give gloss to tablets, such as anhydrous dibasic calcium phosphate, and to prevent moisture in the air from penetrating into the tablets by coating them with a water insoluble substance. At this time, the coating base should have a dense molecular structure and is not easily dissolved in an aqueous solution. As such a coating base, high molecular materials, such as methacrylic acid copolymer, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl alcohol, can be used. These polymeric materials may be used alone or in combination for coating. In addition, the coating may include additives, such as plasticizers, preservatives, colorants, light-shielding agents, etc. that can be added to the coating base conventionally in the art.

The compositions of the present invention may be in the form of solutions and injectables, such as sterile aqueous solutions, and may contain, if necessary, 10-40% propylene glycol and a sufficient amount (eg, about 1%) of sodium chloride to prevent hemolysis.

Nateglinide may be contained in an amount of 20 to 30% by weight based on the total weight of the composition of the present invention, when the composition of the present invention is prepared as a tablet at least 30 mg, specifically 60, 90, 120, or It may be contained at 180 mg.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, this is for illustrating the present invention, and the present invention is not limited by these examples.

<Example>

Example 1

Preparation of New Crystalline Form I of nateglinide

15 g of nateglinide was added to 40.5 mL of isopropanol to dissolve, and added dropwise to 229.5 mL of water at room temperature (22 to 25 ° C) for 20 minutes. After stirring for 4 hours at room temperature, the mixture was filtered, washed with 30 mL of 15% isopropanol aqueous solution, washed with 30 mL of water, and dried at 60 ° C. As a result, 14.7 g of nateglinide crystals were obtained (yield: 98%). The obtained nateglinide crystals were measured by X-ray powder diffraction, differential scanning calorimetry, and infrared spectroscopy. The XRD diffraction pattern by X-ray powder diffraction method is shown in FIG. 1, the DSC curve by differential scanning calorimetry is shown in FIG. 2, and the IR spectrum by infrared spectroscopy is shown in FIG.

Example 2

Preparation of Novel Crystalline I of Nateglinide

15 g of nateglinide was added to 54 mL of isopropanol to dissolve, and added dropwise to 216 mL of water at 10 ° C. for 20 minutes. After stirring for 3 hours at 10 ℃ filtered and washed with 30 mL of 20% isopropanol aqueous solution, washed with 30 mL of water and dried at 60 ℃. As a result, 14.85 g of nateglinide crystals were obtained (yield: 99%).

m.p: 131 ℃

Example 3

Preparation of Novel Crystalline II of Nateglinide

15 g of nateglinide was added to 121.5 mL of isopropanol to dissolve, and added dropwise to 148.5 mL of water at room temperature for 20 minutes. After stirring for 4 hours at room temperature, the mixture was filtered, washed with 30 mL of 45% isopropanol aqueous solution, washed with 30 mL of water, and dried at 60 ° C. As a result, 14.2 g of nateglinide crystals were obtained (yield: 94.9%).

m.p: 129 ℃

The obtained nateglinide crystals were measured by X-ray powder diffraction, differential scanning calorimetry, and infrared spectroscopy. The XRD diffraction pattern by X-ray powder diffraction method is shown in FIG. 4, the DSC curve by differential scanning calorimetry is shown in FIG. 5, and the IR spectrum by infrared spectroscopy is shown in FIG. 6, respectively.

Example 4

The novel crystalline Form I and the novel crystalline Form II obtained in Examples 1 and 3 were subjected to an accelerated test at 60 ° C. with nateglinide crystalline Form H prepared according to Example B1 of US Pat. No. 5,463,116.

<HPLC Analysis Conditions>

Detector: UV absorbance (wavelength 210 nm)

Column: octadecyl silica gel C18 (4.6mm x 150mm, 5μm),

Mobile phase: Sodium dihydrogen phosphate (0.2M): Acetonitrile = 55:45 (volume)

Flow rate: 1.0ml / min

The results are shown in Table 1.

TABLE 1

Early 1 week 2 weeks 4 Weeks Example 1 99.85% 99.85% 99.84% 99.84% Example 3 99.84% 99.84% 99.83% 99.82% Nateglinide H type 99.79% 99.79% 99.76% 99.73%

As shown in Table 1, the nateglinide novel crystalline Forms I and II of the present invention had little content change in the accelerated test at 60 ℃. However, it can be seen that the H type is relatively inferior in stability, and thus the new crystalline forms I and II are superior in thermal stability to H type.

As described above, according to the present invention, it is possible to provide a novel crystalline form of nateglinide having excellent fluidity and low bulk density and high stability.

Claims (15)

Nateglinide with peaks at diffraction angles of at least 7.54, 10.5, 13.5, 15.1, 15.7, 16.1, 18.6, 19.2, 19.8, 20.9, 22.4 ± 0.2 in an X-ray powder diffraction pattern Form I. delete The nateglinide crystalline Form I of claim 1, having an IR spectrum of 3357, 3295, 2937, 1742, 1648, 1602, 1541, 1498, 1210, 609 cm ⁻¹ . The nateglinide crystalline Form I according to claim 1, wherein the melting point is 130 to 132 캜. delete delete delete delete A solution of nateglinide in isopropanol is added dropwise to water at 10-25 ° C. to form crystals, wherein isopropanol is used at 15-20% by volume relative to isopropanol and water as a whole. Method for preparing nateglinide crystalline Form I according to the present invention. The method of claim 9, Preparing a solution of nateglinide in isopropanol; Dropping the nateglinide solution in water at 10 to 25 ° C. and stirring to precipitate nateglinide crystals; Filtering the precipitated nateglinide crystals; And And washing the nateglinide crystals with a mixture of water and isopropanol in the same ratio as the ratio of water and isopropanol used in the crystallization. delete delete 10. The method of claim 9, wherein the solution of nateglinide in the isopropanol is added dropwise to water for 10 to 60 minutes. A composition for treating diabetes comprising nateglinide crystalline Form I according to any one of claims 1, 3 and 4 and a pharmaceutically acceptable carrier. delete

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