KR20200085441A - Novel Crystal form of Ibandronate and the method of preparing the same - Google Patents

Abstract

A novel crystal form of ibandronate according to the present invention is remarkably excellent in stability, hygroscopicity and solubility. In addition, according to a method for producing the novel crystal form of ibandronate of the present invention, mass production of ibandronate sodium salt monohydrate with high yield and purity under mild conditions is possible.

Description

Novel Crystal form of Ibandronate and the method of preparing the same}

The present invention relates to a crystalline form of Ibandronate and a method for manufacturing the same.

Bones, like other organs, continue to change throughout their lives. Old bones are living tissues that repeat the process of reshaping, which breaks down and creates new bones. About 15% of all bones are absorbed and reformed in a year. do. Reconstruction of these bones appears differently depending on the age group.Bones in growing adolescents have a large amount of remodeling, so their size and strength increase, so that they continue to grow, but in adulthood and middle age, absorption and formation are similar, resulting in large changes in bone size. There is no. However, after the 40s, the amount of absorption is gradually increased than the amount of formation, and the bone mass decreases. Particularly in women, bone density decreases rapidly during the first 5-10 years due to a decrease in estrogen secretion after menopause, so the risk of stooping, kyphosis and fracture is significantly greater than in men. In men, bone loss decreases as aging progresses and sex hormone secretion decreases slowly. Osteoporosis is a disease in which the balance between bone resorption and bone formation appears to be broken, and as a result, bone mass decreases due to microscopic degeneration of the skeleton, resulting in bone weakness and fractures. That is, it refers to a disease in which there is no change in the chemical composition of the bone, and the bone mass in the unit volume decreases, thereby easily causing a fracture even in a light shock.

Patients with chronic inflammatory diseases such as rheumatoid arthritis often suffer from osteoporosis as a complication, and in addition to estrogen deficiency and aging, accelerates osteoporosis by chronic administration of steroids and thyroid hormones, alcoholism, calciumuria, smoking, etc. can do. Therefore, osteoporosis is an inevitable pathological phenomenon for both men and women, and is a disease in which the importance of treatment and prevention is highlighted along with the aging of humanity.

Recently, as molecular biological studies have been actively conducted for the treatment of osteoporotic diseases including osteoporosis, bone formation promoting factors and osteoclast inhibitors have been developed, and one of them is bisphosphonates.

Bisphosphonates are well-known chemical compounds used as a medicament for the prevention or treatment of metabolic osteopathies, such as metabolic diseases of some bones, such as osteoporosis, cancer metastasis, and osteopathies associated with rheumatoid arthritis.

Bisphosphonates are powerful agents for bone resorption and are currently used most frequently as a treatment for osteoporosis. Bisphosphonate has a very high binding capacity with calcium, and has two functions that inhibit osteoclast function. In order to be used as a therapeutic agent for osteoporosis, it should be weak to suppress mineralization by suppressing the function of osteoclasts and weakening the binding force with calcium. Bisphosphonates have a structure similar to pyrophosphate. That is, the P-O-P structure of pyrophosphoric acid has a P-C-P structure in which oxygen is converted to carbon, and the difference in efficacy depends on what two side chains (R1, R2) that bind to the carbon element are.

Depending on when bisphosphonate began to be used and the degree of bone resorption inhibitory effect, it can be divided into first-generation, second-generation, and third-generation, and can be divided into formulations that do not contain nitrogen and formulations that contain nitrogen. Specifically, the first generation bisphosphonates include etidronate and clodronate and do not contain nitrogen (see Table 1). Second generation bisphosphonates include alendronate (Alendronate) and pamidronate (Pamidronate), and nitrogen (amino group) was added to increase the bone resorption inhibitory effect by 100 to 1,000 times compared to etidronate (see Table 2). Third generation bisphosphonates include rizdronate, ibandronate and zoledronate, and have a drug effect of 1,000 to 10,000 times (see Table 3).

[Table 1]

[Table 2]

[Table 3]

Bisphosphonates have a very strong ability to bind calcium, so they strongly bind to hydroxyl apatite on the bone surface. In addition, bisphosphonates are not metabolized in the body, and bisphosphonates remaining in the blood are excreted in the kidneys. Once bound bisphosphonates do not separate well, the half life of alendronate is considered to be 10 years. In the process of osteoclast resorption, bisphosphonates are released, and then re-enter into osteoclasts, and bone resorption is reduced by inhibiting function in osteoclasts. As described above, the effect of bisphosphonates is determined according to the degree of binding of hydroxyapatite of bone tissue and the function of osteoclasts in osteoclasts.

The mechanism by which bisphosphonates act in osteoclasts differs from those containing nitrogen and those that do not. Bisphosphonates containing nitrogen block osteoclasts by blocking the activity of farnesyl pyrophosphatase during 3-hydroxy-3-methylglutaryl CoA reductase. The bone resorption function is reduced, leading to death. On the other hand, bisphosphonates that do not contain nitrogen form cytotoxic ATP derivatives in osteoclasts to suppress the function of osteoclasts and increase apoptosis, but are less effective than bisphosphonates containing nitrogen. It is not clear whether bisphosphonates act on cells other than osteoclasts.

Meanwhile, sodium hydrogen (1-hydroxy-3-(methyl(pentyl)amino)-1-phosphonopropyl)phosphonate hydrate or 3-(N-methyl) represented by the following [Formula 1], which is a third-generation bisphosphonate. -N-Pentyl)amino-1-hydroxypropane-1,1-isophosphonic monosodium salt monohydrate is called Ibandronate, which reduces the function of osteoclasts and reduces the number of bone destruction It is being used as a treatment for osteoporosis to prevent the disease.

[Formula 1]

However, there is a continuing need for new crystal forms that can be used for commercial production and obtain formulation and therapeutic efficiency. Some polymorphs of a drug substance have crystals that are converted to other crystalline forms upon storage, resulting in changes in drug physical form and shape, as well as a related change in distinct physical properties. In general, molecules want to be converted to a more thermodynamically stable form, which, when converted to a low solubility form, can sometimes result in reduced or below bioavailability for oral administration.

Therefore, in order to solve the above problems, it is necessary to research and develop new crystal forms of ibandronate.

U.S. Patent No. 4,927,814 International Publication Patent No. 2003-097655 International Publication Patent No. 2006-002348 Korean Registered Patent No. 0908529 Korean Registered Patent No. 0908530

It is an object of the present invention to provide a novel crystalline form of Ibandronate that has the strength of a crystalline form, has improved solubility, and is capable of providing a thermodynamically stable form with rapid onset of action.

Another object of the present invention is to provide a method for preparing a new crystalline form of ibandronate, which has the strength of a crystalline form, has improved solubility, and is capable of providing a thermodynamically stable form with a rapid onset of action.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of bone metabolic disease comprising a new crystalline form of ibandronate.

Another object of the present invention is to prevent a metabolic disease comprising the step of administering a pharmaceutical composition for the prevention or treatment of a bone metabolic disease comprising a new crystalline form of ibandronate to a mammal, including a human, in a therapeutically effective amount. Or to provide a method of treatment.

Another object of the present invention is to provide a use for the prevention or treatment of a bone metabolic disease of a pharmaceutical composition for the prevention or treatment of a bone metabolic disease comprising a new crystalline form of ibandronate.

Another object of the present invention is to provide a use for the manufacture of a medicament for the prophylaxis or treatment of a bone metabolic disease of a pharmaceutical composition for the prevention or treatment of a bone metabolic disease comprising a new crystalline form of Ivandronate.

In order to solve the above problems, a new crystalline form of Ivandronate and a method for manufacturing the same were developed.

The novel crystalline form of Ivandronate of the present invention has high purity, is safe, and has excellent stability against heat, light, and humidity, so that it can be stably maintained without a change in content in the long term. Therefore, the preparation of the formulation using the novel crystal form of the Ivandronate of the present invention, or even after the preparation of the formulation containing the same, the uniformity of the content of the formulation can be stably maintained for a long period of time, so that it is easy to mass-produce Can be applied. In addition, the novel crystalline form of ibandronate of the present invention exhibits high solubility, and can exhibit excellent pharmacological effects, such as osteoporosis, paget disease, periodontal disease, and bone metastasis ( Metastatic cancer) or rheumatoid arthiritis (rheumatoid arthiritis) can be effectively used as a new active ingredient of a pharmaceutical composition capable of treating a bone metabolic disease, and the novel crystalline form of the ibandronate of the present invention has high bioavailability upon oral administration. As shown, even when a small amount is taken, excellent therapeutic effect can be exhibited, thereby significantly improving the patient's medication convenience. In addition, the novel crystalline form of the ibandronate of the present invention has a rapid onset of action, has a thermodynamically stable form, and the new crystalline form of the ibandronate of the present invention exhibits low hygroscopicity in the range of relative humidity, so It is very advantageous for processing and storage, so it is easy to formulate, and the formulation is prepared using the novel crystalline form of Ibandronate of the present invention, or it remains in the same state even after preparation of the formulation containing the same, so that the content uniformity of the formulation for a long time It can be stably maintained for a while, so it can be easily applied to mass production.

In addition, the morphology (habit) of the crystalline form does not exhibit a needle shape or can be minimized to become a needle shape, and as a result, bulk density, fluidity, compressibility, etc. can be improved to increase drug loading rate. Additionally, the novel crystalline form of Ibandronate according to the present invention may have beneficial packaging properties, thermodynamics, kinetics, surface properties, mechanical properties, filterability or high chemical purity.

In addition, in the case of the novel crystalline form of the ibandronate of the present invention, mass production is possible with high yield and purity at low cost. The new crystalline form of ibandronate produced thereby exhibits excellent effects in terms of acceleration, stability according to severe storage conditions, light stability, thermal stability, stability with pH, and solubility.

Hereinafter, the present invention will be described in detail.

Ivandronate Sodium salt Monohydrate Crystalline Form I

The present invention is an ibandronate sodium salt hydrate crystal form represented by the following [Formula 1], the powder X-ray diffraction spectrum measured using CuKa radiation is 9.59 °, 10.95 °, 14.92 °, 15.16 °, 17.09 °, 18.30 Ibandronate sodium salt monohydrate crystal form I, which shows diffraction peaks at 2θ (±0.2°) values of °, 19.49°, 19.93°, 20.59°, 23.54°, 24.63°, 25.79°, 28.77° and 30.86° to provide.

[Formula 1]

Ibandronate sodium salt monohydrate crystal form I represented by the following formula (1) of the present invention has a spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG. 1.

[Formula 1]

The ibandronate sodium salt monohydrate crystal form I of the present invention is composed of a single crystal form, has stable good physical properties, and does not contain impurities such as metals, and is highly pure and safe.

The ibandronate sodium salt monohydrate crystal form I of the present invention has high purity, is safe, and has excellent stability against heat, light, and humidity, so that it can be stably maintained without a change in content in the long term. Therefore, the preparation of the formulation using the ibandronate sodium salt monohydrate crystal form I of the present invention, or even after the preparation of the formulation containing the same, the content uniformity of the formulation can be stably maintained for a long period of time, thereby making it possible for mass production. It can be easily applied. In addition, the ibandronate sodium salt monohydrate crystal form I of the present invention exhibits high solubility and may exhibit excellent pharmacological effects, such as osteoporosis, paget disease, periodontal disease, and bone metastasis. It can be effectively used as a new active ingredient of a pharmaceutical composition capable of treating bone metabolic diseases such as cancer (metastatic cancer) or rheumatoid arthiritis, and the ibandronate sodium salt monohydrate crystal form I of the present invention is administered orally. Since it shows a high bioavailability, even when a small amount is taken, an excellent therapeutic effect can be exhibited, thereby significantly improving patient medication convenience. In addition, the form of Ibandronate sodium salt monohydrate crystal form I has a rapid onset of action, has a thermodynamically stable form, and the form of Ibandronate sodium salt monohydrate crystal form I of the present invention exhibits low hygroscopicity in the range of relative humidity. Therefore, it is very advantageous in the processing and storage of pharmaceuticals, so it is easy to formulate, and the formulation is prepared using the ibandronate sodium salt monohydrate crystal form I of the present invention, or the formulation is maintained after preparation of a formulation containing the same The content uniformity of can be stably maintained for a long period of time, so it can be easily applied to mass production.

In addition, the morphology (habit) of the crystalline form does not exhibit a needle shape or can be minimized to become a needle shape, and as a result, bulk density, fluidity, compressibility, etc. can be improved to increase drug loading rate. Additionally, the ibandronate sodium salt monohydrate crystal form I according to the present invention may have advantageous packaging properties, thermodynamics, kinetics, surface properties, mechanical properties, filterability or high chemical purity.

Ivandronate Sodium salt Monohydrate Method for preparing crystalline form I

The present invention is a step of preparing an aqueous solution by dissolving the sodium salt of ibandronate or its hydrate in water; And the aqueous solution of isopropyl alcohol, isopropyl alcohol and tetrahydrofuran, a mixed solvent of isopropyl alcohol and isopropyl ether, a mixed solvent of isopropyl alcohol and methyl tert-butyl ether, a mixed solvent of isopropyl alcohol and methanol, iso 15 to 25°C with a mixed solvent of propyl alcohol and ethanol aqueous solution or a mixed solvent of isopropyl alcohol and acetonitrile It provides a method for producing a crystal form I of sodium ibandronate salt comprising the step of crystallization by mixing in.

The method of preparing the ibandronate sodium salt monohydrate crystal form I according to the present invention is capable of mass production of the novel ibandronate sodium salt monohydrate crystal form I with high yield and purity under mild conditions.

In one embodiment of the present invention, it may be prepared by mixing 2 parts by weight to 16 parts by weight of water with respect to 1 part by weight of the sodium salt of ibandronate or its hydrate. Specifically, 2 to 10 parts by weight or 3 to 5 parts by weight of water with respect to 1 part by weight of ibandronate may be prepared, but is not limited thereto.

In one embodiment of the present invention, the aqueous solution is mixed with 2 parts by weight to 16 parts by weight of water with respect to 1 part by weight of the sodium salt of ibandronate or its hydrate, and then ibandronate at 20 to 80°C or 30 to 50°C. It can be prepared by dissolving sodium salt or a hydrate thereof.

In one embodiment of the present invention, the mixed solvent of isopropyl alcohol and isopropyl ether may be mixed in a ratio of 1.5 to 3.5:1 (w/w), but is not limited thereto.

In one embodiment of the present invention, the mixed solvent of isopropyl alcohol and methyl tert-butyl ether may be mixed in a ratio of 1.5 to 3.5:1 (w/w), but is not limited thereto.

In one embodiment of the present invention, the mixed solvent of isopropyl alcohol and methanol may be mixed at a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w), but is not limited thereto.

In one embodiment of the present invention, the mixed solvent of the isopropyl alcohol and ethanol aqueous solution may be mixed in a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w), but is not limited thereto. At this time, the ethanol aqueous solution may be 50 to 99% ethanol aqueous solution (w/w), but is not limited thereto.

In one embodiment of the present invention, when the aqueous solution in which the sodium salt of ibandronate or a hydrate thereof is mixed is mixed with a mixed solvent of an aqueous solution of isopropyl alcohol and ethanol, the aqueous solution is 1 part by weight of sodium ibandronate salt or a hydrate thereof With respect to water, 3 parts by weight to 6 parts by weight of the mixture may be prepared by dissolving the sodium salt of ibandronate or its hydrate.

In one embodiment of the present invention, the mixed solvent of isopropyl alcohol and acetonitrile may be mixed at a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w), but is not limited thereto.

In one embodiment of the present invention, the aqueous solution and any one organic solvent may be mixed at 15 to 25°C when mixing, and after mixing is completed, the mixture is crystallized and stirred at 15 to 25°C for 15 to 120 minutes. The dronate may crystallize, but is not limited thereto.

In one embodiment of the present invention, the aqueous solution and the organic solvent may be mixed at a ratio of 1: 0.1 to 5 (w/w), but is not limited thereto.

In one embodiment of the present invention, the method may further include a step of drying at 60 to 80 ℃, as an example, the method at 2 to 50 mmHg conditions for 4 to 20 hours at 60 to 80 ℃ It may further include the step of drying under reduced pressure, but is not limited thereto.

Ivandronate Sodium salt Monohydrate Crystal form Ⅱ

As the crystal form of ibandronate sodium salt hydrate represented by the following [Formula 1] of the present invention, the powder X-ray diffraction spectrum measured using CuKa radiation is 9.67°, 12.20°, 14.09°, 14.82°, 16.62°, 17.04° , 18.01°, 18.35°, 19.43°, 20.08°, 21.30°, 23.52°, 23.99°, 24.86°, 26.48°, 28.35°, 28.90°, 30.16°, 30.78°, 34.01°, 35.60° and 36.26° 2θ Provides the sodium form of ibandronate sodium salt monohydrate, which shows a diffraction peak at a value of (± 0.2°).

[Formula 1]

The ibandronate sodium salt monohydrate crystal form II represented by the following formula 1 of the present invention has a spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG. 2.

[Formula 1]

The ibandronate sodium salt monohydrate crystal form II of the present invention is composed of a single crystal form, has stable good physical properties, and does not contain impurities such as metals, and is high in purity and safe.

The ibandronate sodium salt monohydrate crystal form II of the present invention has high purity, is safe, and has excellent stability against heat, light, and humidity, so that it can be stably maintained without a change in content in the long term. Therefore, the preparation of the formulation using the sodium form of ibandronate sodium monohydrate of the present invention or the preparation of a formulation containing the same can be maintained in the same state, so that the uniformity of the content of the formulation can be stably maintained for a long period of time. It can be easily applied. In addition, the ibandronate sodium salt monohydrate crystalline form II of the present invention exhibits high solubility, and can exhibit excellent pharmacological effects, such as osteoporosis, paget disease, periodontal disease, and bone metastasis. It can be effectively used as a new active ingredient of a pharmaceutical composition capable of treating bone metabolic diseases such as cancer (metastatic cancer) or rheumatoid arthiritis, and the ibandronate sodium salt monohydrate crystal form II of the present invention is administered orally. Since it shows a high bioavailability, even when a small amount is taken, an excellent therapeutic effect can be exhibited, thereby significantly improving patient medication convenience. In addition, the ibandronate sodium salt monohydrate crystal form II of the present invention has a rapid onset of action, has a thermodynamically stable form, and the ibandronate sodium salt monohydrate crystal form II of the present invention exhibits low hygroscopicity in the range of relative humidity. Therefore, it is very advantageous in the processing and storage of pharmaceuticals, so it is easy to formulate, and the formulation is prepared using the ibandronate sodium salt monohydrate crystal form II of the present invention, or the formulation is maintained even after preparation of a formulation containing the same The content uniformity of can be stably maintained for a long period of time, so it can be easily applied to mass production.

In addition, the morphology (habit) of the crystalline form does not exhibit a needle shape or can be minimized to become a needle shape, and as a result, bulk density, fluidity, compressibility, etc. can be improved to increase drug loading rate. Additionally, the ibandronate sodium salt monohydrate crystal form II according to the present invention may have advantageous packaging properties, thermodynamics, kinetics, surface properties, mechanical properties, filterability or high chemical purity.

Ivandronate Sodium salt Monohydrate Manufacturing method of crystal form Ⅱ

The present invention is a step of preparing an aqueous solution by dissolving the sodium salt of ibandronate or its hydrate in water; And the aqueous solution of tetrahydrofuran, acetonitrile, mixed solvent of methanol and ethanol aqueous solution, mixed solvent of methanol and methylene chloride, mixed solvent of methanol and acetonitrile, mixed solvent of methanol and toluene, mixed solvent of isopropyl alcohol and acetone Preparation of ibandronate sodium salt monohydrate crystal form II comprising the step of crystallization by mixing at 15 to 25°C with an organic solvent of a mixed solvent of an isopropyl alcohol and an ethanol aqueous solution and a mixed solvent of an ethyl acetate and an ethanol aqueous solution. Provides a method.

The production method of the ibandronate sodium salt monohydrate crystal form II according to the present invention is capable of mass production of the novel ibandronate sodium salt monohydrate crystal form II with high yield and purity under mild conditions.

In one embodiment of the present invention, it may be prepared by mixing 2 parts by weight to 16 parts by weight of water with respect to 1 part by weight of the sodium salt of ibandronate or its hydrate. Specifically, 2 to 10 parts by weight or 3 to 5 parts by weight of water with respect to 1 part by weight of ibandronate may be prepared, but is not limited thereto.

In one embodiment of the present invention, the aqueous solution is mixed with 2 parts by weight to 16 parts by weight of water with respect to 1 part by weight of the sodium salt of ibandronate or its hydrate, and then ibandronate at 20 to 80°C or 30 to 50°C. It can be prepared by dissolving sodium salt or a hydrate thereof.

In one embodiment of the present invention, the mixed solvent of the methanol and ethanol aqueous solution may be mixed at a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w), but is not limited thereto. At this time, the ethanol aqueous solution may be 50 to 99% ethanol aqueous solution (w/w), but is not limited thereto.

In one embodiment of the present invention, the mixed solvent of methanol and methylene chloride may be mixed at a ratio of 1.5 to 3.5:1 (w/w), but is not limited thereto.

In one embodiment of the present invention, the mixed solvent of methanol and acetonitrile may be mixed at a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w), but is not limited thereto.

In one embodiment of the present invention, the mixed solvent of methanol and toluene may be mixed at a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w), but is not limited thereto.

In one embodiment of the present invention, the mixed solvent of isopropyl alcohol and acetone may be mixed at a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w), but is not limited thereto.

In one embodiment of the present invention, the mixed solvent of the isopropyl alcohol and ethanol aqueous solution may be mixed at a ratio of 1: 1.5 to 3.5 (w/w), but is not limited thereto. At this time, the ethanol aqueous solution may be 50 to 99% ethanol aqueous solution (w/w), but is not limited thereto.

In one embodiment of the present invention, when the aqueous solution in which the sodium salt of ibandronate or a hydrate thereof is mixed is mixed with a mixed solvent of an aqueous solution of isopropyl alcohol and ethanol, the aqueous solution is 1 part by weight of sodium ibandronate salt or a hydrate thereof With respect to water, 5 parts by weight to 10 parts by weight of the mixture may be prepared by dissolving sodium ibandronate or a hydrate thereof.

In one embodiment of the present invention, the mixed solvent of the ethyl acetate and ethanol aqueous solution may be mixed at a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w), but is not limited thereto. At this time, the ethanol aqueous solution may be 50 to 99% ethanol aqueous solution (w/w), but is not limited thereto.

In one embodiment of the present invention, the aqueous solution and any one organic solvent may be mixed at 15 to 25°C when mixing, and after mixing is completed, the mixture is crystallized and stirred at 15 to 25°C for 15 to 120 minutes. The dronate may crystallize, but is not limited thereto.

In one embodiment of the present invention, the aqueous solution and the organic solvent may be mixed at a ratio of 1: 0.1 to 2 (w/w), but is not limited thereto.

In one embodiment of the present invention, the method may further include a step of drying at 60 to 80 ℃, as an example, the method at 2 to 50 mmHg conditions for 4 to 20 hours at 60 to 80 ℃ It may further include a step of drying under reduced pressure, but is not limited thereto.

Ivandronate Sodium salt Monohydrate Crystalline Ⅲ

The present invention is an ibandronate sodium salt hydrate crystal form represented by the following [Formula 1], the powder X-ray diffraction spectrum measured using CuKa radiation 14.21 °, 17.21 °, 18.60 °, 20.07 °, 24.99 °, 26.00 Ibandronate sodium salt monohydrate crystalline Form III is provided that exhibits diffraction peaks at 2θ (±0.2°) values of °, 28.79°, 30.58°, 30.94°, 31.28° and 36.54°.

[Formula 1]

The ibandronate sodium salt monohydrate crystal form III represented by the following Chemical Formula 1 of the present invention has a spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG. 3.

[Formula 1]

The ibandronate sodium salt monohydrate crystal form III of the present invention is composed of a single crystal form, has stable good physical properties, and does not contain impurities such as metals, and is high in purity and safe.

The ibandronate sodium salt monohydrate crystal form III of the present invention has high purity, is safe, and has excellent stability against heat, light, and humidity, so that it can be stably maintained without a change in content in the long term. Therefore, the preparation of the formulation using the ibandronate sodium salt monohydrate crystal form III of the present invention or the same state can be maintained even after preparation of a formulation containing the same, so that the uniformity of the content of the formulation can be stably maintained for a long period of time. It can be easily applied. In addition, the ibandronate sodium salt monohydrate crystalline form III exhibits high solubility, and can exhibit excellent pharmacological effects, such as osteoporosis, paget disease, periodontal disease, and bone metastasis. It can be effectively used as a new active ingredient of a pharmaceutical composition capable of treating bone metabolic diseases such as cancer (metastatic cancer) or rheumatoid arthiritis, and the ibandronate sodium salt monohydrate crystal form III of the present invention is administered orally. Since it shows a high bioavailability, even when a small amount is taken, an excellent therapeutic effect can be exhibited, thereby significantly improving the patient's medication convenience. In addition, the ibandronate sodium salt monohydrate crystalline form III has a rapid onset of action, has a thermodynamically stable form, and the ibandronate sodium salt monohydrate crystalline form III of the present invention exhibits low hygroscopicity in the range of relative humidity. Therefore, it is very advantageous in the processing and storage of pharmaceuticals, so it is easy to formulate, and the formulation is prepared by using the ibandronate sodium salt monohydrate crystal form III of the present invention, or the formulation is maintained even after preparation of a formulation containing the same The content uniformity of can be stably maintained for a long period of time, so it can be easily applied to mass production.

In addition, the morphology (habit) of the crystalline form does not exhibit a needle shape or can be minimized to become a needle shape, and as a result, bulk density, fluidity, compressibility, etc. can be improved to increase drug loading rate. Additionally, the ibandronate sodium salt monohydrate crystal form III according to the present invention may have beneficial packaging properties, thermodynamics, kinetics, surface properties, mechanical properties, filterability or high chemical purity.

Ivandronate Sodium salt Monohydrate Manufacturing method of crystal form Ⅲ

The present invention is a step of preparing an aqueous solution by dissolving the sodium salt of ibandronate or its hydrate in water; And a mixed solvent of isopropyl alcohol, isopropyl alcohol and isopropyl ether, a mixed solvent of isopropyl alcohol and methyl tert-butyl ether, a mixed solvent of isopropyl alcohol and methanol, and a mixed solvent of isopropyl alcohol and ethanol aqueous solution. Or it provides a method for producing sodium bromide sodium salt monohydrate crystalline form III comprising the step of crystallizing by mixing with any one of the organic solvent of isopropyl alcohol and acetonitrile at 30 to 40 ℃.

The method of preparing the ibandronate sodium salt monohydrate crystalline form III according to the present invention enables mass production of the novel ibandronate sodium salt monohydrate crystalline form III with high yield and purity under mild conditions.

In one embodiment of the present invention, the organic solvent may be a mixed solvent of an aqueous solution of isopropyl alcohol and ethanol.

In one embodiment of the present invention, the mixed solvent of the isopropyl alcohol and ethanol aqueous solution may be mixed in a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w), but is not limited thereto. In this case, the ethanol aqueous solution may be 50 to 99% ethanol aqueous solution (w/w), but is not limited thereto.

In one embodiment of the present invention, it may be prepared by mixing 2 parts by weight to 16 parts by weight of water with respect to 1 part by weight of the sodium salt of ibandronate or its hydrate. Specifically, 2 to 10 parts by weight or 3 to 5 parts by weight of water with respect to 1 part by weight of ibandronate may be prepared, but is not limited thereto.

In one embodiment of the present invention, the aqueous solution is mixed with 2 parts by weight to 16 parts by weight of water with respect to 1 part by weight of the sodium salt of ibandronate or its hydrate, and then ibandronate at 20 to 80°C or 30 to 50°C. It can be prepared by dissolving sodium salt or a hydrate thereof.

In one embodiment of the present invention, when mixing the aqueous solution and any one of the organic solvent may be mixed at a temperature of 30 to 40 ℃, after the mixing is completed through crystallization stirring at 30 to 40 ℃ for 15 to 120 minutes Ibandronate may crystallize, but is not limited thereto.

In one embodiment of the present invention, the method may further include a step of drying at 60 to 80 ℃, as an example, the method at 2 to 50 mmHg conditions for 4 to 20 hours at 60 to 80 ℃ It may further include the step of drying under reduced pressure, but is not limited thereto.

Ivandronate Sodium salt Monohydrate Crystalline Ⅳ

The present invention is an ibandronate sodium salt hydrate crystal form represented by the following [Formula 1], the X-ray diffraction spectrum is 9.87 °, 14.03 °, 18.56 °, 19.87 °, 23.79 °, 24.90 °, 25.94 °, 26.47 °, Provided is ibandronate sodium salt monohydrate crystalline Form IV, which shows diffraction peaks at 2θ (±0.2°) values of 30.26°, 31.28° and 41.32°.

[Formula 1]

The ibandronate sodium salt monohydrate crystal form IV represented by the following Chemical Formula 1 of the present invention has a spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG. 4.

[Formula 1]

The ibandronate sodium salt monohydrate crystal form IV of the present invention is composed of a single crystal form, has stable and good physical properties, and does not contain impurities such as metals, and thus has high purity and safety.

The ibandronate sodium salt monohydrate crystal form IV of the present invention has high purity, is safe, and has excellent stability against heat, light, and humidity, so that it can be stably maintained without a change in content in the long term. Therefore, the preparation of the formulation using the ibandronate sodium salt monohydrate crystal form IV of the present invention, or even after preparation of a formulation containing the same, maintains the same state, so that the uniformity of the content of the formulation can be stably maintained for a long period of time. It can be easily applied. In addition, the ibandronate sodium salt monohydrate crystalline form IV of the present invention exhibits high solubility, and can exhibit excellent pharmacological effects, such as osteoporosis, paget disease, periodontal disease, and bone metastasis. It can be effectively used as a new active ingredient of a pharmaceutical composition capable of treating bone metabolic diseases such as cancer (metastatic cancer) or rheumatoid arthiritis, and the ibandronate sodium salt monohydrate crystal form IV of the present invention is administered orally. Since it shows a high bioavailability, even when a small amount is taken, an excellent therapeutic effect can be exhibited, thereby significantly improving the patient's medication convenience. In addition, the ibandronate sodium salt monohydrate crystalline form IV has a rapid onset of action, has a thermodynamically stable form, and the ibandronate sodium salt monohydrate crystalline form IV of the present invention exhibits low hygroscopicity in the range of relative humidity. Therefore, it is very advantageous in the processing and storage of pharmaceuticals, so it is easy to formulate, and the formulation is prepared using the ibandronate sodium salt monohydrate crystal form IV of the present invention, or the formulation is maintained even after preparation of a formulation containing the same The content uniformity of can be stably maintained for a long period of time, so it can be easily applied to mass production.

In addition, the morphology (habit) of the crystalline form does not exhibit a needle shape or can be minimized to become a needle shape, and as a result, bulk density, fluidity, compressibility, etc. can be improved to increase drug loading rate. Additionally, the ibandronate sodium salt monohydrate crystal form IV according to the present invention may have beneficial packaging properties, thermodynamics, kinetics, surface properties, mechanical properties, filterability or high chemical purity.

Ivandronate Sodium salt Monohydrate Method for preparing crystalline form IV

The present invention is a step of preparing an aqueous solution by dissolving the sodium salt of ibandronate or its hydrate in water; And a mixed solvent of isopropyl alcohol, isopropyl alcohol and isopropyl ether, a mixed solvent of isopropyl alcohol and methyl tert-butyl ether, a mixed solvent of isopropyl alcohol and methanol, and a mixed solvent of isopropyl alcohol and ethanol aqueous solution. Or a mixture of isopropyl alcohol and acetonitrile and an organic solvent of any one of 50 to 70 ℃ to provide a method for producing sodium bromide crystal form IV containing sodium bromide.

The method of preparing the ibandronate sodium monohydrate crystalline form IV according to the present invention is capable of mass production of the novel ibandronate sodium salt monohydrate crystalline form IV with high yield and purity under mild conditions.

In one embodiment of the present invention, the organic solvent may be isopropyl alcohol.

In one embodiment of the present invention, it may be prepared by mixing 2 parts by weight to 16 parts by weight of water with respect to 1 part by weight of the sodium salt of ibandronate or its hydrate. Specifically, 2 to 10 parts by weight or 3 to 5 parts by weight of water with respect to 1 part by weight of ibandronate may be prepared, but is not limited thereto.

In one embodiment of the present invention, the aqueous solution is mixed with 2 parts by weight to 16 parts by weight of water with respect to 1 part by weight of the sodium salt of ibandronate or its hydrate, and then ibandronate at 20 to 80°C or 30 to 50°C. It can be prepared by dissolving sodium salt or a hydrate thereof.

In one embodiment of the present invention, when mixing the aqueous solution and any one of the organic solvent may be mixed at a temperature of 50 to 70 ℃, after the mixing is completed through crystallization stirring at 50 to 70 ℃ for 15 to 120 minutes Ibandronate may crystallize, but is not limited thereto.

In one embodiment of the present invention, the method may further include a step of drying at 60 to 80 ℃, as an example, the method at 2 to 50 mmHg conditions for 4 to 20 hours at 60 to 80 ℃ It may further include the step of drying under reduced pressure, but is not limited thereto.

Ivandronate Sodium salt Monohydrate Containing the new crystalline form Bone metabolism Pharmaceutical composition for prevention or treatment of disease

The pharmaceutical composition for preventing or treating osteoporosis of the present invention includes novel crystalline forms I, II, III, IV, or mixtures of sodium ibandronate salt monohydrate.

The novel crystalline form of sodium ibandronate monohydrate has the strength of a crystalline form, has improved solubility, has a rapid onset of action, has a thermodynamically stable form of an improved bioavailability drug substance, has a small particle size Uniform and excellent workability. In addition, the novel crystalline form of the sodium iandrondrate monohydrate of the present invention consists of a single crystalline form, has stable good physical properties, and does not contain impurities such as metals.

In the present invention, the term "prevention" means to suppress or delay the onset of disease, disorder or disease. Prevention can be considered complete if the onset of the disease, disorder or condition is inhibited or delayed for a predetermined period of time.

The term "treatment" in the present invention, partially or completely relieves, ameliorates, alleviates, inhibits or delays the symptoms associated with a specific disease, disorder, and/or disease or condition, reduces severity, or reduces one or more symptoms or characteristics. It means reducing the occurrence of.

In one embodiment of the present invention, the pharmaceutical composition of the present invention is formulated by using a pharmaceutically acceptable carrier according to a method that can be easily carried out by those skilled in the art to which the present invention pertains. It can be made in unit dose form or can be made by incorporating into a multi-dose container.

In the present invention, the term "carrier" means a compound that facilitates the addition of a compound into cells or tissues, and the term "pharmaceutically acceptable", when physiologically acceptable and administered to a human, is usually gastrointestinal. Refers to a composition that does not cause an allergic reaction such as a disorder or dizziness or a similar reaction.

The pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl Pyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like, but is not limited thereto.

The pharmaceutical composition of the present invention may further include additives such as fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, and preservatives in addition to the above components. In the present invention, the content of the additives contained in the pharmaceutical composition is not particularly limited, and can be appropriately adjusted within the content range used for conventional formulation.

The pharmaceutical composition of the present invention may be for oral administration. In the present invention, the term "oral administration" means that the active substance is administered to a substance prepared to be digested, that is, the gastrointestinal tract for absorption. Non-limiting examples of the formulation for oral administration include tablets, troches, lozenges, aqueous suspensions, oily suspensions, preparation powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs, etc. Can be heard. In order to formulate the pharmaceutical composition of the present invention for oral administration, a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin, etc.; Excipients such as dicalcium phosphate; Disintegrants such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax can be used, and sweeteners, fragrances, syrups and the like can also be used. Furthermore, in the case of capsules, in addition to the above-mentioned substances, a liquid carrier such as fatty oil, etc. may be additionally used.

In the present invention, the term "excipient" means any substance that is not a therapeutic agent, and is used as a carrier or medium for delivery of the therapeutic agent or means added to a pharmaceutical composition. This will improve handling and storage properties or allow and promote the formation of unit doses of the composition.

The composition of the present invention is an oral formulation such as liquid, suspension, powder, granule, tablet, capsule, pill, ex-emulsion, emulsion, syrup, aerosol, sterile injectable solution according to a conventional method according to each use purpose It can be formulated and used in various forms, such as oral administration or intravenous, intraperitoneal, subcutaneous, rectal, and topical administration.

In the present invention, the term "liquid" refers to a drug that is taken in the form of a medicine dissolved in water or an organic solvent. The liquid formulation has a more effective advantage of drug absorption into the systemic circulatory system in the intestinal tract than the suspension or solid formulation, and the liquid formulation may contain additional solutes in addition to pharmaceuticals, giving color, odor, sweetness or stability. Additives may also be included.

The term "suspending agent" in the present invention refers to any agent capable of providing the desired solubility and/or dispersibility of the alginate-containing composition, ie, providing a substantially transparent, sedimentation and lump-free aqueous formulation. it means.

In the present invention, the term "powder" means a finely divided drug, a chemical, or a mixture of both. Since the powder as a dosage form is in a crushed state, when administered orally, there is a disadvantage in that the unpleasant taste of the drug can be strongly felt. Therefore, when using the extract of Hwangnyeon without a separate treatment, the strong bitter taste of Hwangnyeon causes discomfort to the patient.

In the present invention, the term "granule" means a mixture of pharmaceutical or pharmaceutical products in the form of granules, and usually refers to a range that passes through a sieve of 4.76 to 20 mm. Granules are generally produced by soaking a powder, or powder mixture, and passing the mass through a sieve or granulator of suitable mesh size depending on the size of the granules required. Since granules, like powders, are in the form of particles, the degree to which the drug touches the tongue is large, and when a drug having a bitter taste is used in the form of granules, it may cause discomfort to patients, especially children or the elderly.

The term "tablet" in the present invention means that the powdered medicine is easily compressed and compressed into a small disk shape. Tablets may include uncoated tablets, film coated tablets, dragee tablets, multilayer tablets, nucleated tablets, inner core tablets, oral disintegrating tablets, chewable tablets, foamed tablets, dispersed tablets, dissolved tablets, and the like.

The term "capsule" in the present invention means that the medicine is filled into capsules in the form of liquid, suspension, water, powder, granule, mini-tablets or pellets or encapsulated with a capsule base.

In the present invention, the term "pill" is meant to encompass a small, round solid dosage form comprising composite particles mixed with a binder and other excipients.

In the present invention, the term "ex-agent", the medicinal active ingredients in vegetable or animal herbal medicines are leached using a suitable leaching agent, concentrated to a prescribed concentration by evaporating the solvent, and the content of the excipient is added when the content of the main ingredient is specified. It means a semi-solid or solid preparation made by adjusting.

In the present invention, the term "syrup agent" refers to a thick homemade sugar or a sugar substitute. In the present invention, the syrup agent is a medicine that has an unpleasant taste, such as a bitter taste, as a liquid and is easy to take, and is particularly suitable for children to take. In the present invention, the syrup may include, but not limited to, purified water and extracts of hwangryeon, a sugar substitute, or a substitute drug of a sugar used to impart sweetness and viscosity, an antimicrobial preservative, a flavoring agent flavor, or a colorant. Examples of sweeteners that may be included in such syrup agents include, but are not limited to, white sugar, mannitol, sorbitol, xylitol, aspartame, stevioside, fructose, lactose, sucralose, saccharin, or menthol.

Preferred dosages of the pharmaceutical compositions of the present invention are the patient's condition and weight, age, sex, health status, diet constitution specificity, the nature of the formulation, the degree of disease, the time of administration of the composition, the method of administration, the duration or interval of excretion, excretion The range may vary depending on the rate and the drug form, and may be appropriately selected by those skilled in the art. For example, it can range from about 0.1 to 1,000 mg/kg, from about 1 to 800 mg/kg, from about 5 to 600 mg/kg, or from about 10 to 400 mg/kg, preferably about It may be in the range of 50 to 500 mg/kg, but is not limited thereto, and may be administered once a month.

As used herein, the term "effective dosage of a pharmaceutical composition" means the amount of the active ingredient composition sufficient to treat a particular symptom. It may vary depending on the method of formulating the pharmaceutical composition, the method of administration, the administration time and/or the route of administration, and the type and extent of the reaction to be achieved by administration of the pharmaceutical composition, the type of the subject to be administered, age, weight, It can vary according to a number of factors, including general health conditions, the severity or severity of the disease, sex, diet, excretion, components of drugs or other compositions used simultaneously or simultaneously with the subject, and similar factors well known in the pharmaceutical arts. , Those skilled in the art can readily determine and prescribe a dose effective for the desired treatment.

Administration of the pharmaceutical composition of the present invention may be administered once a day, it may be divided into several times. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. Considering all of the above factors, it can be administered in an amount that can obtain the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art to which the present invention pertains.

In one embodiment of the present invention, the bone metabolic disease may be osteoporosis, paget disease, periodontal disease, metastatic cancer or rheumatoid arthiritis, , But is not limited thereto.

Bone metabolism How to prevent or treat a disease

The present invention is a method for preventing or treating a bone metabolic disease comprising the step of administering a pharmaceutical composition for the prevention or treatment of a bone metabolic disease comprising a new crystalline form of Ivandronate to a mammal, including a human, in a therapeutically effective amount. Gives

In one embodiment of the present invention, mammals, including humans, include mammals such as humans, monkeys, cattle, horses, dogs, cats, rabbits, rats, and mice.

The term "therapeutically effective amount" in the present invention is an amount effective for the treatment of a bone metabolic disease, for example, an amount of a composition administered to a subject to be treated, to prevent the occurrence or recurrence of a bone metabolic disease, or to relieve symptoms. It can include all amounts of a composition that inhibits, direct or indirect pathological consequences, prevents metastasis, reduces the rate of progression, alleviates or temporarily relieves the condition, or improves prognosis. That is, the therapeutically effective amount may be interpreted to encompass all doses in which symptoms of bone metabolic disease are improved or cured by the composition.

The prophylactic or therapeutic methods of the present invention include not only treating the disease itself prior to the manifestation of the manifestation, but also inhibiting or avoiding the manifestation thereof, by administering the composition. In the management of a disease, the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route the active ingredient is administered. The dose and frequency of dose will vary depending on the age, weight and response of the individual patient. Suitable dosage regimens can be readily selected by those of ordinary skill in the art taking these factors into account. In addition, the treatment method of the present invention may further include administration of a therapeutically effective amount of an additional active agent conducive to the treatment of a disease with the composition, and an additional active agent may be synergistic or additive with the composition. Can represent.

Bone metabolism Use for preventing or treating disease

The present invention provides a use for preventing or treating a bone metabolic disease of a pharmaceutical composition for the prevention or treatment of a bone metabolic disease comprising the new crystalline form of ibandronate.

Bone metabolism For the prevention or treatment of diseases Pharmaceutical manufacturing For

The present invention provides a use for the manufacture of a medicament for the prevention or treatment of a bone metabolic disease of a pharmaceutical composition for the prevention or treatment of a bone metabolic disease comprising a new crystalline form of ibandronate.

The composition of the present invention for the manufacture of a medicament may mix an acceptable carrier and the like, and may further include other agents.

The matters mentioned in the compositions, treatment methods and uses of the present invention apply equally unless contradictory to each other.

The novel crystalline form of the sodium iandronate sodium monohydrate of the present invention consists of a single crystalline form, has stable good physical properties, and does not contain impurities such as metals, and is highly pure and safe.

The novel crystal form of the sodium salt of ibandronate monohydrate of the present invention is excellent in stability against heat, light, and humidity, so that it can be stably maintained without a change in content in the long term.

The new crystalline form of the ibandronate sodium salt monohydrate of the present invention has the strength of the crystalline form.

The novel crystalline form of the ibandronate sodium salt monohydrate of the present invention has a thermodynamically stable form of a drug substance with rapid onset of action and improved bioavailability.

The novel crystalline form of the sodium salt of ibandronate sodium hydrate of the present invention has excellent particle size and uniformity and excellent workability.

Preparation of the formulation using the new crystalline form of the sodium salt of ibandronate of the present invention, or maintaining the same state after preparation of the formulation containing the same, so that the uniformity of the content of the formulation can be stably maintained for a long period of time for mass production. It can be easily applied.

The novel crystalline form of the sodium salt of ibandronate of the present invention exhibits high solubility, and thus can exhibit excellent pharmacological effects.

The method for producing a new crystalline form of the ibandronate sodium salt monohydrate according to the present invention is capable of mass production of a new crystalline form of the new ibandronate sodium salt monohydrate with high yield and purity under mild conditions.

1 is a powder X-ray diffraction spectrum for the ibandronate sodium salt monohydrate crystal form I represented by Formula 1 obtained in Examples 1 to 6.
FIG. 2 is a powder X-ray diffraction spectrum of the ibandronate sodium salt monohydrate crystal form II represented by Chemical Formula 1 obtained in Examples 7 to 13.
FIG. 3 is a powder X-ray diffraction spectrum of the ibandronate sodium salt monohydrate crystal form III represented by Chemical Formula 1 obtained in Example 14.
FIG. 4 is a powder X-ray diffraction spectrum of the ibandronate sodium salt monohydrate crystal form VI represented by Chemical Formula 1 obtained in Examples 15 and 16.

Hereinafter, examples will be described in detail to help understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

In addition, the reagents and solvents mentioned below were purchased from Sigma-Aldrich, unless otherwise specified, and the ibandronate sodium salt monohydrate was obtained from Gador S.A. It was purchased from the Active Pharmaceutical Ingredients Division and used.

The powder X-ray diffraction apparatus used MXLabo (manufactured by MacScience), the source was Cu, the wavelength was 1.54056A, the goniometer was used as a vertical goniometer, and the measurement method was performed by placing a 100 mg sample on a sample glass plate and flattening it. , Measured under the following conditions.

Data range: 3.040 to 40.000 deg,

Number of data points: 925

Scanning axis: 2θ/θ

Sample spacing: 0.0400 deg,

Scanning speed: 4.800 deg/min

<KF (Karl Fischer moisture measurement) equipment and conditions>

Manufacturer: METROHM

Model Name: METROHM 870KF Titrino

Analysis method: Direct titration analysis using Karl Fischer's solution

Data: 4% to 6% moisture.

< Example 1> Ivandronate Sodium salt Monohydrate Preparation of Form I

0.5 g of ibandronate sodium salt monohydrate was added to 2.0 g of purified water and dissolved at 40-50°C. In another reactor, 1.5 g of isopropyl alcohol (IPA) was added and stirred at 15-20°C. Then, the aqueous solution of ibandronate was slowly added dropwise to a reactor containing isopropyl alcohol (IPA) at 15-20°C, and then stirred at room temperature (20°C) for 1 hour to form crystals. The crystals were filtered and washed with 0.5 g of isopropyl alcohol (IPA). Thereafter, the wet body was dried in a vacuum oven at 60° C. for 5 to 10 mmHg for 12 hours to obtain Ibandronate sodium salt monohydrate crystalline Form I.

Yield: 96%, Moisture: 4.8%

The powder X-ray diffraction spectrum is as shown in Figure 1, with characteristic peaks of 9.59°, 10.95°, 14.92°, 15.16°, 17.09°, 18.30°, 19.49°, 19.93°, 20.59°, 23.54°, 24.63. °, 25.79°, 28.77° and 30.86°.

< Example 2> Ivandronate Sodium salt Monohydrate Preparation of Form I

0.5 g of ibandronate sodium salt monohydrate was added to 2.0 g of purified water and dissolved at 40-50°C. To the mixed solvent of 3.2 g of isopropyl alcohol (IPA) and 1.5 g of isopropyl ether (IPE), the aqueous solution of ibandronate was slowly added dropwise and stirred at room temperature (20° C.) for 1 hour to form crystals. The crystals were filtered and washed with 0.5 g of isopropyl alcohol (IPA) and isopropyl ether (IPE) mixed solvent (2:1 w/w). Thereafter, the wet body was dried in a vacuum oven at 60° C. for 5 to 10 mmHg for 12 hours to remove the solvent, thereby obtaining Ibandronate sodium salt monohydrate crystalline Form I.

Yield: 96%, Moisture: 5.2%

The powder X-ray diffraction spectrum was substantially the same as the crystal form of Example 1.

< Example 3> Ivandronate Sodium salt Monohydrate Preparation of Form I

0.5 g of ibandronate sodium salt monohydrate was added to 2.0 g of purified water and dissolved at 40-50°C. To the mixed solvent of 3.2 g of isopropyl alcohol (IPA) and 1.5 g of methyl tert-butyl ether (MTBE), the aqueous solution of ibandronate was slowly added dropwise and stirred at 15 to 20°C for 1 hour to form crystals. The crystals were filtered and washed with 0.5 g of isopropyl alcohol (IPA) and methyl tert-butyl ether (MTBE) mixed solvent (2:1, w/w). Thereafter, the wet body was dried in a vacuum oven at 60° C. for 5 to 10 mmHg for 12 hours to remove the solvent, thereby obtaining Ibandronate sodium salt monohydrate crystalline Form I.

Yield: 86%, moisture 5.1%

The powder X-ray diffraction spectrum was substantially the same as the crystal form of Example 1.

< Example 4> Ivandronate Sodium salt Monohydrate Preparation of Form I

0.5 g of ibandronate sodium salt monohydrate was added to 4.0 g of purified water and dissolved at 40-50°C. Into another reactor, 1.0 g of isopropyl alcohol (IPA) and 1.0 g of methanol (MeOH) were added and mixed by stirring at 15-20°C. Then, the aqueous solution of ibandronate was slowly added dropwise to a reactor containing methanol (MeOH) and isopropyl alcohol (IPA) mixed solvent, followed by stirring at 15-20°C for 1 hour to form crystals. The crystals were filtered and washed with 0.5 g of a mixed solvent of isopropyl alcohol (IPA) and methanol (MeOH) (1:1, w/w). Ibandronate sodium salt monohydrate crystalline Form I was obtained by drying the wetted body at 60° C. under a reduced pressure oven of 5 to 10 mmHg for 12 hours to remove the solvent.

Yield: 86%, moisture 4.7%

The powder X-ray diffraction spectrum was substantially the same as the crystal form of Example 1.

< Example 5> Ivandronate Sodium salt Monohydrate Preparation of Form I

0.5 g of ibandronate sodium salt monohydrate was added to 4.0 g of purified water and dissolved at 40-50°C. Into another reactor, 1.0 g of isopropyl alcohol (IPA) and 1.0 g of 95% ethanol (EtOH) aqueous solution (w/w) were added and mixed by stirring at room temperature (20° C.). Subsequently, the aqueous solution of ibandronate was slowly added dropwise to a reactor containing a mixed solvent of isopropyl alcohol (IPA) and a 95% ethanol (EtOH) aqueous solution (w/w), followed by stirring at 15-20°C for 1 hour to generate crystals. Did. The crystals were filtered and washed with 0.5 g of a mixed solvent (1:1, w/w) of isopropyl alcohol (IPA) and 95% ethanol (EtOH) aqueous solution (w/w). Ibandronate sodium salt monohydrate crystalline Form I was obtained by drying the wetted body at 60° C. under a reduced pressure oven of 5 to 10 mmHg for 12 hours to remove the solvent.

Yield: 87%, Moisture: 5.0%

The powder X-ray diffraction spectrum was substantially the same as the crystal form of Example 1.

< Example 6> Ivandronate Sodium salt Monohydrate Preparation of Form I

0.5 g of ibandronate sodium salt monohydrate was added to 4.0 g of purified water and dissolved at 40-50°C. Into another reactor, 1.0 g of isopropyl alcohol (IPA) and 1.0 g of acetonitrile (ACN) were added and mixed by stirring at room temperature (20° C.). Then, the aqueous solution of ibandronate was slowly added dropwise to a reactor containing isopropyl alcohol (IPA) and acetonitrile (ACN) mixed solvent, followed by stirring at 15-20° C. for 1 hour to form crystals. The crystals were filtered and washed with 0.5 g of a mixed solvent (1:1, w/w) of isopropyl alcohol (IPA) and acetonitrile (ACN). Ibandronate sodium salt monohydrate crystalline Form I was obtained by drying the wetted body at 60° C. under a reduced pressure oven of 5 to 10 mmHg for 12 hours to remove the solvent.

Yield: 92%, Moisture: 5.3%

The powder X-ray diffraction spectrum was substantially the same as the crystal form of Example 1.

< Example 7> Ivandronate Sodium salt Monohydrate Preparation of Form II

0.5 g of ibandronate sodium salt monohydrate was added to 4.0 g of purified water and dissolved at 40-50°C. In another reactor, 1.5 g of methanol (MeOH) and 1.5 g of 95% ethanol (EtOH) aqueous solution were added and stirred at 15-20° C.) to mix. Then, the aqueous solution of ibandronate was slowly added dropwise to a reactor containing a mixed solvent of methanol (MeOH) and 95% ethanol (EtOH), and then stirred at 15-20° C. for 30 minutes to form crystals. The crystals were filtered and washed with 1 g of a mixed solvent of methanol (MeOH) and 95% ethanol (EtOH) aqueous solution (1:1, w/w). The wet body was dried in a vacuum oven at 60° C. under a pressure of 5 to 10 mmHg for 12 hours to remove the solvent to obtain ibandronate sodium salt monohydrate crystalline form II.

Yield: 88%, moisture 5.1%

The powder X-ray diffraction spectrum is as shown in FIG. 2, and the characteristic peaks are 9.67°, 12.20°, 14.09°, 14.82°, 16.62°, 17.04°, 18.01°, 18.35°, 19.43°, 20.08°, 21.30 °, 23.52°, 23.99°, 24.86°, 26.48°, 28.35°, 28.90°, 30.16°, 30.78°, 34.01°, 35.60° and 36.26°.

< Example 8> Ivandronate Sodium salt Monohydrate Preparation of Form II

0.5 g of ibandronate sodium salt monohydrate was added to 4.0 g of purified water and dissolved at 40-50°C. In another reactor, 3.0 g of methanol (MeOH) and 1.5 g of methylene chloride (MC) were added and mixed by stirring at 15-20°C. Subsequently, the aqueous solution of ibandronate was slowly added dropwise to a reactor containing a mixed solvent of methanol (MeOH) and methylene chloride (MC), and then stirred at 15-20° C. for 1 hour to form crystals. The crystals were filtered and washed with methanol (MeOH) and methylene chloride (MC) mixed solvent (1:2, w/w) 0.5 g. Ibandronate sodium salt monohydrate crystalline form II was obtained by removing the solvent by drying the wet body under reduced pressure in a 60° C. reduced pressure oven at 5 to 10 mmHg for 12 hours.

Yield: 90%, moisture 5.1%

The powder X-ray diffraction spectrum was substantially the same as the crystal form of Example 7.

< Example 9> Ivandronate Sodium salt Monohydrate Preparation of Form II

0.5 g of ibandronate sodium salt monohydrate was added to 4.0 g of purified water and dissolved at 40-50°C. Into another reactor, 1.0 g of methanol (MeOH) and 1.0 g of acetonitrile (ACN) were added and mixed by stirring at 15-20°C. The aqueous solution of ibandronate was slowly added dropwise to a reactor containing methanol (MeOH) and acetonitrile (ACN) mixed solvent, followed by stirring at 15-20° C. for 1 hour to form crystals. The crystals were filtered and washed with methanol (MeOH) and acetonitrile (ACN) mixed solvent (1:1, w/w) 0.5 g. Ibandronate sodium salt monohydrate crystalline form II was obtained by removing the solvent by drying the wet body under reduced pressure in a 60° C. reduced pressure oven at 5 to 10 mmHg for 12 hours.

Yield: 86%, Moisture: 5.5%

The powder X-ray diffraction spectrum was substantially the same as the crystal form of Example 7.

< Example 10> Ivandronate Sodium salt Monohydrate Preparation of Form II

0.5 g of ibandronate sodium salt monohydrate was added to 4.0 g of purified water and dissolved at 40-50°C. In another reactor, 1.0 g of methanol (MeOH) and 1.0 g of toluene were added and mixed by stirring at 15-20°C. The aqueous solution of ibandronate was slowly added dropwise to a reactor containing a mixed solvent of toluene and methanol (MeOH), followed by stirring at 15-20° C. for 1 hour to form crystals. The crystals were filtered and washed with methanol (MeOH) and toluene mixed solvent (1:1, w/w) 0.5 g. The wetted body was dried under reduced pressure in a 5 to 10 mmHg vacuum oven at 60° C. for 12 hours to remove the solvent. By doing so, ibandronate sodium salt monohydrate crystal form II was obtained.

Yield: 72%, moisture 4.7%

The powder X-ray diffraction spectrum was substantially the same as the crystal form of Example 7.

< Example 11> Ivandronate Sodium salt Monohydrate Preparation of Form II

1.0 g of ibandronate sodium salt monohydrate was added to 4.0 g of purified water and dissolved at 40-50°C. In another reactor, 2.0 g of isopropyl alcohol (IPA) and 2.0 g of acetone were added, and the mixture was stirred and stirred at 15 to 20°C. To the reactor containing isopropyl alcohol (IPA) and acetone (Acetone) mixed solvent was slowly added dropwise the aqueous solution of ibandronate, and stirred at 15-20° C. for 1 hour to form crystals. The crystals were filtered and washed with 0.5 g of isopropyl alcohol (IPA) and acetone mixed solvent (1:1, w/w). Ibandronate sodium salt monohydrate crystalline form II was obtained by removing the solvent by drying the wet body under reduced pressure in a 60° C. reduced pressure oven at 5 to 10 mmHg for 12 hours.

Yield: 97%, Moisture: 5.5%

The powder X-ray diffraction spectrum was substantially the same as the crystal form of Example 7.

< Example 12> Ivandronate Sodium salt Monohydrate Preparation of Form II

1.0 g of ibandronate sodium salt monohydrate was added to 4.0 g of purified water and dissolved at 40-50°C. In another reactor, 2.0 g of isopropyl alcohol (IPA) and 4.0 g of 95% ethanol (EtOH) aqueous solution (w/w) were added and mixed by stirring at 15-20°C. To the reactor containing a mixed solvent of isopropyl alcohol (IPA) and 95% ethanol (EtOH) aqueous solution (w/w), the aqueous solution of ibandronate was slowly added dropwise, and stirred at 15-20°C for 1 hour to form crystals. Did. The crystals were filtered and washed with 0.5 g of isopropyl alcohol (IPA) and 95% ethanol (EtOH) aqueous solution (w/w) mixed solvent (1:2, w/w). Ibandronate sodium salt monohydrate crystalline form II was obtained by removing the solvent by drying the wet body under reduced pressure in a 60° C. reduced pressure oven at 5 to 10 mmHg for 12 hours.

Yield: 98%, moisture 5.6%

The powder X-ray diffraction spectrum was substantially the same as the crystal form of Example 7.

< Example 13> Ivandronate Sodium salt Monohydrate Preparation of Form II

1.0 g of ibandronate sodium salt monohydrate was added to 4.0 g of purified water and dissolved at 40-50°C. In another reactor, 2.0 g of ethyl acetate (EA) and 2.0 g of 95% ethanol (EtOH) aqueous solution were added and mixed by stirring at 15-20°C. To the reactor containing a mixed solvent of ethyl acetate (EA) and 95% ethanol (EtOH) aqueous solution, the aqueous solution of ibandronate was slowly added dropwise, followed by stirring at 15-20°C for 1 hour to form crystals. The crystals were filtered and washed with 0.5 g of a mixed solvent of ethyl acetate (EA) and 95% ethanol (EtOH) aqueous solution (1:1, w/w). Ibandronate sodium salt monohydrate crystalline form II was obtained by removing the solvent by drying the wet body under reduced pressure in a 60° C. reduced pressure oven at 5 to 10 mmHg for 12 hours.

Yield: 88%, moisture 5.3%

The powder X-ray diffraction spectrum was substantially the same as the crystal form of Example 7.

< Example 14> Ivandronate Sodium salt Monohydrate Preparation of Crystalline Form III

7.0 g of ibandronate sodium salt monohydrate was added to 28.0 g of purified water and dissolved at 40-50°C. In another reactor, 21.0 g of isopropyl alcohol (IPA) and 21.0 g of an aqueous 95% ethanol (EtOH) solution were added and mixed at 30-40°C. The aqueous solution of ibandronate was added dropwise to the reactor containing isopropyl alcohol (IPA) and 95% ethanol (EtOH) solution for 30 minutes at 30-40°C, followed by stirring at 30-40°C for 1 hour to produce crystals. . The crystals were filtered and washed with 2.0 g of isopropyl alcohol (IPA) and 2.0 g of an aqueous solution of 95% ethanol (EtOH) (1:1, w/w). Ibandronate sodium salt monohydrate crystalline Form III was obtained by removing the solvent by drying the wetted body under reduced pressure in a 60° C. vacuum oven at 5 to 10 mmHg for 12 hours.

Yield: 80%, Moisture: 5.2%

The powder X-ray diffraction spectrum is as shown in Figure 3, with characteristic peaks 14.21°, 17.21°, 18.60°, 20.07°, 24.99°, 26.00°, 28.79°, 30.58°, 30.94°, 31.28° and 36.54. °.

< Example 15> Ivandronate Sodium salt Monohydrate Preparation of Form IV

0.5 g of ibandronate sodium salt monohydrate was added to 2.0 g of purified water and dissolved at 40-50°C. 2.5 g of isopropyl alcohol (IPA) was added to another reactor, and the aqueous solution of ibandronate was added dropwise to a reactor containing isopropyl alcohol (IPA) for 30 minutes at 50 to 60°C, followed by 1 hour at 50 to 60°C. Stir to produce crystals. The crystals were filtered and washed with 0.5 g of isopropyl alcohol (IPA). Ibandronate sodium salt monohydrate crystalline Form IV was obtained by removing the solvent by drying the wetted body under reduced pressure in a 5° C. oven at 60° C. for 12 hours under reduced pressure for 12 hours.

Yield: 95%, Moisture: 5.1%

The powder X-ray diffraction spectrum is as shown in Figure 4, with characteristic peaks of 9.87°, 14.03°, 18.56°, 19.87°, 23.79°, 24.90°, 25.94°, 26.47°, 30.26°, 31.28° and 41.32. °.

< Example 16> Ivandronate Sodium salt Monohydrate Preparation of Form IV

0.5 g of ibandronate sodium salt monohydrate was added to 2.0 g of purified water and dissolved at 40-50°C. 2.5 g of isopropyl alcohol (IPA) was added to another reactor, and the aqueous solution of ibandronate was added dropwise to a reactor containing isopropyl alcohol (IPA) at 60 to 70°C for 30 minutes, and then at 60 to 70°C for 1 hour. Stir to produce crystals. The crystals were filtered and washed with 0.5 g of isopropyl alcohol (IPA). Ibandronate sodium salt monohydrate crystalline Form IV was obtained by removing the solvent by drying the wet body under reduced pressure in a 60° C. vacuum oven at 5 to 10 mmHg for 12 hours.

Yield: 98%, Moisture: 5.0%

The powder X-ray diffraction spectrum was substantially the same as the crystal form of Example 15.

Since the specific parts of the present invention have been described in detail above, for those skilled in the art, it is obvious that this specific technique is only a preferred embodiment, and the scope of the present invention is not limited thereby. something to do. Therefore, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (37)

As an ibandronate sodium salt hydrate crystal form represented by the following [Formula 1], the powder X-ray diffraction spectrum measured using CuKa radiation is 9.59°, 10.95°, 14.92°, 15.16°, 17.09°, 18.30°, 19.49 Ibandronate sodium salt monohydrate crystalline Form I, which shows diffraction peaks at 2θ (±0.2°) values of °, 19.93°, 20.59°, 23.54°, 24.63°, 25.79°, 28.77° and 30.86°:
[Formula 1]

The ibandronate sodium salt monohydrate crystal form I according to claim 1, which shows a peak of the powder X-ray diffraction spectrum of [Fig. 1]. As an ibandronate sodium salt hydrate crystal form represented by the following [Formula 1], the powder X-ray diffraction spectrum measured using CuKa radiation is 9.67°, 12.20°, 14.09°, 14.82°, 16.62°, 17.04°, 18.01 °, 18.35°, 19.43°, 20.08°, 21.30°, 23.52°, 23.99°, 24.86°, 26.48°, 28.35°, 28.90°, 30.16°, 30.78°, 34.01°, 35.60° and 36.26° 2θ (± 0.2°) Ibandronate sodium salt monohydrate crystal form II showing a diffraction peak at a value:
[Formula 1]

The ibandronate sodium salt monohydrate crystal form II according to claim 3, which shows a peak of the powder X-ray diffraction spectrum of [Fig. 2]. As an ibandronate sodium salt hydrate crystal form represented by the following [Formula 1], the powder X-ray diffraction spectrum measured using CuKa radiation is 14.21°, 17.21°, 18.60°, 20.07°, 24.99°, 26.00°, 28.79 Ibandronate sodium salt monohydrate crystalline form III showing diffraction peaks at 2θ (±0.2°) values of °, 30.58°, 30.94°, 31.28° and 36.54°:
[Formula 1]

The ibandronate sodium salt monohydrate crystal form III according to claim 5, which shows a peak of the powder X-ray diffraction spectrum of [Fig. 3]. As an ibandronate sodium salt hydrate crystal form represented by the following [Formula 1], X-ray diffraction spectra are 9.87°, 14.03°, 18.56°, 19.87°, 23.79°, 24.90°, 25.94°, 26.47°, 30.26°, Ibandronate sodium salt monohydrate crystal form IV showing diffraction peaks at 2θ (±0.2°) values of 31.28° and 41.32°:
[Formula 1]

The ibandronate sodium salt monohydrate crystal form IV according to claim 7, which shows a peak of the powder X-ray diffraction spectrum of [Fig. 4]. Preparing an aqueous solution by dissolving an ibandronate sodium salt or a hydrate thereof in water; And
The aqueous solution is mixed solvent of isopropyl alcohol, isopropyl alcohol and isopropyl ether, mixed solvent of isopropyl alcohol and tetrahydrofuran, mixed solvent of isopropyl alcohol and methyl tert-butyl ether, mixed solvent of isopropyl alcohol and methanol , Mixing and crystallizing at 15 to 25 °C with an organic solvent of either a mixed solvent of an isopropyl alcohol and an ethanol aqueous solution or a mixed solvent of isopropyl alcohol and acetonitrile, crystallizing Ivandronate sodium salt monohydrate Manufacturing method. 10. The method according to claim 9, which is prepared by mixing 2 parts by weight to 16 parts by weight of water with respect to 1 part by weight of the sodium salt of ibandronate or its hydrate. 10. The method according to claim 9, wherein the mixed solvent of isopropyl alcohol and isopropyl ether is mixed at a ratio of 1.5 to 3.5:1 (w/w). 10. The method according to claim 9, wherein the mixed solvent of isopropyl alcohol and methyl tert-butyl ether is mixed in a ratio of 1.5 to 3.5:1 (w/w). 10. The method of claim 9, wherein the mixed solvent of isopropyl alcohol and methanol is mixed in a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w). 10. The method of claim 9, wherein the mixed solvent of the aqueous solution of isopropyl alcohol and ethanol is mixed in a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w). 10. The method according to claim 9, wherein the mixed solvent of isopropyl alcohol and acetonitrile is mixed in a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w). 10. The method according to claim 9, wherein the aqueous solution and the organic solvent are mixed in a ratio of 1: 0.1 to 5 (w/w). 10. The method of claim 9, wherein the method further comprises drying at a temperature of 60 to 80°C. Preparing an aqueous solution by dissolving an ibandronate sodium salt or a hydrate thereof in water; And
The aqueous solution is tetrahydrofuran, acetonitrile, a mixed solvent of methanol and ethanol aqueous solutions, a mixed solvent of methanol and methylene chloride, a mixed solvent of methanol and acetonitrile, a mixed solvent of methanol and toluene, a mixed solvent of isopropyl alcohol and acetone, Method for producing sodium bromide crystalline form II comprising mixing and crystallizing at 15 to 25°C with an organic solvent of a mixed solvent of an isopropyl alcohol and ethanol aqueous solution and a mixed solvent of ethyl acetate and ethanol aqueous solution. . 19. The method according to claim 18, which is prepared by mixing 2 parts by weight to 16 parts by weight of water with respect to 1 part by weight of the sodium salt of ibandronate or its hydrate. 19. The method of claim 18, wherein the mixed solvent of the aqueous solution of methanol and ethanol is mixed in a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w). The method of claim 18, wherein the mixed solvent of methanol and methylene chloride is mixed in a ratio of 1.5 to 3.5:1 (w/w). 19. The method of claim 18, wherein the mixed solvent of methanol and acetonitrile is mixed at a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w). The method of claim 18, wherein the mixed solvent of methanol and toluene is mixed in a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w). The method of claim 18, wherein the mixed solvent of isopropyl alcohol and acetone is mixed in a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w). The method of claim 18, wherein the mixed solvent of the aqueous solution of isopropyl alcohol and ethanol is mixed at a ratio of 1:1.5 to 3.5 (w/w). The method of claim 18, wherein the mixed solvent of the ethyl acetate and ethanol aqueous solution is mixed in a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w). The method of claim 18, wherein the aqueous solution and the organic solvent are mixed in a ratio of 1:0.1-2 (w/w). 19. The method of claim 18, wherein the method further comprises drying at a temperature of 60 to 80°C. Preparing an aqueous solution by dissolving an ibandronate sodium salt or a hydrate thereof in water; And
The aqueous solution is a mixed solvent of isopropyl alcohol, isopropyl alcohol and isopropyl ether, a mixed solvent of isopropyl alcohol and methyl tert-butyl ether, a mixed solvent of isopropyl alcohol and methanol, a mixed solvent of isopropyl alcohol and ethanol aqueous solution, or A method of preparing ibandronate sodium salt monohydrate crystalline form III comprising the step of crystallizing by mixing with an organic solvent of any one of a mixed solvent of isopropyl alcohol and acetonitrile at 30-40°C. 30. The method according to claim 29, wherein the organic solvent is a mixed solvent of an aqueous solution of isopropyl alcohol and ethanol. 30. The method according to claim 29, which is prepared by mixing 2 parts by weight to 16 parts by weight of water with respect to 1 part by weight of the sodium salt of ibandronate or its hydrate. 30. The method according to claim 29, wherein the mixed solvent of the aqueous solution of isopropyl alcohol and ethanol is mixed at a ratio of 0.5 to 1.5: 0.5 to 1.5 (w/w). 30. The method of claim 29, wherein the method further comprises drying at a temperature of 60 to 80 °C. Preparing an aqueous solution by dissolving an ibandronate sodium salt or a hydrate thereof in water; And
The aqueous solution is a mixed solvent of isopropyl alcohol, isopropyl alcohol and isopropyl ether, a mixed solvent of isopropyl alcohol and methyl tert-butyl ether, a mixed solvent of isopropyl alcohol and methanol, a mixed solvent of isopropyl alcohol and ethanol aqueous solution, or A method for preparing ibandronate sodium salt monohydrate crystalline Form IV comprising the step of crystallizing by mixing with an organic solvent of any one of a mixed solvent of isopropyl alcohol and acetonitrile at 50 to 70°C. 35. The method of claim 34, wherein the organic solvent is isopropyl alcohol. The method of claim 34, wherein the ibandronate sodium salt or hydrate thereof is prepared by mixing 2 parts by weight to 16 parts by weight of water. 35. The method of claim 34, wherein the method further comprises drying at a temperature of 60 to 80 °C.

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