KR20050045436A - Pharmaceutical composition comprising crystalline raloxifene phosphate monohydrate - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating osteoporosis, which comprises a novel crystalline raloxifene phosphate monohydrate of the formula (2). The crystalline raloxifene phosphate monohydrate according to the present invention has a much higher solubility than the conventional raloxifene hydrochloride anhydride, and can be prepared without using an organic solvent due to the high solubility, and thus there is no problem of residual organic solvent. It is also stable against moisture and heat and can be usefully used as an active ingredient in pharmaceutical compositions.

<Formula 2>

Description

Pharmaceutical composition containing crystalline raloxifene phosphate monohydrate {PHARMACEUTICAL COMPOSITION COMPRISING CRYSTALLINE RALOXIFENE PHOSPHATE MONOHYDRATE}

The present invention relates to a pharmaceutical composition for preventing or treating osteoporosis, and more particularly to a pharmaceutical composition comprising a raloxifene acid-addition crystalline monohydrate.

Raloxifene, ie [6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methane The structure of an on is as shown in formula (1).

Raloxifene has the effect of inhibiting the growth of breast tumors (see US Pat. No. 4,133,814), breast cancer, fibrocystic disease, prostate cancer or benign prostatic hyperplasia with anti-estrogen and anti-androgen efficacy prostatic hypertrophy) and the like are known to be used (see US Patent No. 4,418,068).

In addition, a series of benzothiophene derivatives including raloxifene are known to treat or prevent osteoporosis (see US Patent No. 5,457,117 and Korean Patent Registration No. 161,300).

However, since such raloxifene is a poorly soluble substance that is difficult to handle in pharmaceuticals, it has been required to convert it into an acid-addition salt form.

Therefore, raloxifene hydrochloride has been developed as an acid-addition salt of high solubility raloxifene (see US Pat. No. 5,393,763). The development of such raloxifene hydrochloride makes it possible to use raloxifene in medicine.

However, raloxifene hydrochloride is also slightly soluble compared to raloxifene but is still poorly soluble (see Physicians' Desk Reference, 54ed, 2000). Specifically, the solubility of raloxifene hydrochloride in water is 0.3 mg / ml at 25 ° C., the solubility in simulated gastric fluid (US Pharmacopeia) is 0.003 mg / ml at 37 ° C. and simulated intestinal fluid (US Pharmacopeia). The solubility in) is known to be 0.002 mg / ml at 37 ° C.

On the other hand, in order to solve such a problem of poor solubility of raloxifene, U.S. Patent No. 5,624,940 discloses an inclusion complex in which raloxifene hydrochloride is combined with a water-soluble cyclodextrin, but such an inclusion complex has a large molecular weight. Because of the increase, the dosage of the drug is also increased, which reduces the medication compliance with the drug of the patient, and also has the disadvantage that the price is very high.

In addition, International Patent Publication No. WO 98/08513 and Korean Patent Publication No. 2000-0035941 disclose that raloxifene hydrochloride may be prepared in an amorphous form to increase solubility, but such amorphous form of raloxifene hydrochloride may be used to improve product quality. And maintenance of the amorphous form may not be ensured, and organic solvents used during the manufacturing process may remain.

Furthermore, WO 97/35571 and US Pat. No. 6,458,811 disclose methods of increasing the solubility and dissolution rate by micronizing the particle size of raloxifene hydrochloride to 5-20 μm, but such methods It is difficult to always produce particles with the desired particle distribution uniformly, the physicochemical properties may change during the grinding process, and the bulk density of the micronized particles is greatly increased, resulting in a large number of capsule filling or tablet manufacturing processes. Cause problems.

Evista (registered trademark) of Eli Lilly, USA, which is available as a treatment / prevention agent for osteoporosis in postmenopausal women, has increased the dissolution rate by micronizing poorly soluble raloxifene hydrochloride. However, in order to maximize the elution of micronized raloxifene hydrochloride, it is known to use surfactants such as polysorbate 80 during the tablet manufacturing process (see US Pat. Nos. 5,972,383 and 5,811,120).

On the other hand, the poor solubility of raloxifene causes a problem of residual organic solvent used during the manufacturing process in addition to the problem of bioavailability. Methods for preparing raloxifene and its hydrochloride salts are described in US Pat. Nos. 4,418,068 and 5,750,688, and WO 96/09045, WO 97/34888, WO 98/49156 and WO 01/23369. The raloxifene and its hydrochloride are typically a final process in which the protecting group is removed from a precursor protected by two phenolic hydroxy groups with a reagent such as sodium hydroxide, ethanethiol or boron trichloride and subsequently treated as shown in Scheme 1 below. It is prepared by performing.

Deprotection of a hydroxy group-protected raloxifene precursor as shown in Scheme 1 according to the method disclosed in US Pat. No. 4,418,068 yields raloxifene or its hydrochloride having different melting points depending on the solvent used. The reason for this is obtained because of the solvent remaining therein. Korean Patent Publication No. 1985-1881 discloses that 0.5% of methanol remains when methanol is used as a solvent. The residual amount of methanol 0.5% is below the threshold for solvent residue recommended by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), but it is obvious that it is not desirable for long-term administration as a therapeutic. Residual solvent used in the preparation of raloxifene or its hydrochloride is inevitable because raloxifene or its hydrochloride has affinity with an organic solvent and cannot be easily removed by conventional drying means.

In addition, WO 96/09045, WO 97/34888 and WO 98/08513 disclose that pure raloxifene can be purified using this affinity between raloxifene hydrochloride and an organic solvent. That is, 1,2-dichloroethane or chlorobenzene solvate of raloxifene hydrochloride is prepared purely using 1,2-dichloroethane or chlorobenzene as an organic solvent, and then the solvate is desolvated in methanol solution. To prepare raloxifene hydrochloride free of 1,2-dichloroethane or chlorobenzene. However, even in this case, methanol remains, and there is a possibility that 1,2-dichloroethane or chlorobenzene, which is defined as a residual solvent to be more strictly regulated in the ICH due to the risk of carcinogenicity and the like, may remain. Therefore, the remainder of methanol and 1,2-dichloroethane or chlorobenzene is inevitable in the preparation of hydrochloric acid of high purity raloxifene.

As described above, raloxifene and its hydrochloride salts, despite the therapeutic utility, have many limitations due to poor solubility problems. Nevertheless, many of the prior art known so far with respect to raloxifene describe only various common pharmaceutically acceptable acid-addition salts, including hydrochloride, and specific acid-addition salts other than hydrochloride. Of course, there are no known preparations, physicochemical properties, or pharmaceutical effects, especially for hydrates of acid-addition salts.

The present inventors have completed the present invention by finding crystalline raloxifene phosphate monohydrate that is sufficiently stable against moisture and heat and at the same time improved solubility.

It is an object of the present invention to provide a pharmaceutical composition for preventing or treating osteoporosis, which comprises as an active ingredient a hydrate of raloxifene acid-addition salt having a high solubility and is stable against moisture and heat.

Another object of the present invention is to provide a hydrate of raloxifene acid-addition salt and a method for preparing the same.

In accordance with the above object, the present invention provides a pharmaceutical composition comprising a novel crystalline raloxifene phosphate monohydrate of formula (2), which is stable against moisture and heat and has high solubility.

According to another object of the present invention, the present invention provides a crystalline raloxifene phosphate monohydrate of the formula (2) and a preparation method thereof.

The term "raloxifene phosphate monohydrate" used in the present invention is an aggregate consisting of one molecule of raloxifene phosphate and one molecule of water, and means a kind of crystal water.

The expression "hazardous residual solvent" used in the present invention means a hazardous residual solvent other than water or ethanol.

Hereinafter, the present invention will be described in detail.

The crystalline raloxifene phosphate monohydrate of the formula (2) according to the present invention has improved the solubility in water while at the same time meeting the stability and non-hygroscopicity of water and heat required as active ingredients of the pharmaceutical composition.

Specifically, the crystalline raloxifene phosphate monohydrate of Formula 2 has a peak value of 2θ when I / I _o ≥50 in X-ray diffraction analysis of 4.6 ± 0.2, 9.2 ± 0.2, 10.9 ± 0.2, 11.3 ± 0.2, 12.5 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 17.8 ± 0.2, 18.2 ± 0.2, 18.8 ± 0.2, 19.4 ± 0.2, 19.9 ± 0.2, 20.9 ± 0.2, 21.9 ± 0.2, 22.7 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 25.3 ± 0.2, 26.5 ± 0.2, 26.8 ± 0.2, 27.7 ± 0.2, 29.5 ± 0.2, 30.0 ± 0.2, 30.5 ± 0.2, 31.7 ± 0.2 and 32.8 ± 0.2.

The method for preparing the crystalline raloxifene phosphate monohydrate of Formula 2 is as follows.

Raloxifene of Formula 1 is reacted with phosphoric acid in water or a mixed solvent of water and ethanol to prepare crystalline raloxifene phosphate monohydrate of Formula 2.

<Formula 1>

Raloxifene, a starting material for use in the present invention, can be prepared according to known literature ( J. Med. Chem. , 27 , 1057-1066 (1986), US Pat. Nos. 4,418,068 and 5,750,688, and International Patent Publications). See WO 96/09045, WO 97/34888, WO 98/49156 and WO 01/23369.

In the above method, the amount of phosphoric acid may be used in a ratio of 1.0 to 2.0 molar equivalents, preferably 1.1 to 1.3 molar equivalents, relative to 1.0 molar equivalent of raloxifene. Phosphoric acid is usually added dropwise into a neat or a solution dissolved in the solvent (water or a mixed solvent of water and ethanol). The reaction temperature is from 0 deg. C to the boiling point of the solvent, preferably from 20 to 40 deg.

The reaction is carried out for 0.5 to 24 hours, preferably 3 to 7 hours. When the reaction is finished, the reaction solution is cooled to 0 ° C. to room temperature to filter the resulting solid.

When a mixed solvent of water and ethanol is used as the solvent, it is preferable to mix water and ethanol in a weight ratio of 99: 1 to 5:95. The amount of the solvent is used in a proportion of 3 to 30 ml, preferably 5 to 15 ml with respect to 1 g of raloxifene.

The crystals thus formed are subjected to lacquer filtration or centrifugal filtration under reduced pressure and sufficiently washed with the solvent used for the reaction. The filtered crystals are dried using an inert gas such as air or nitrogen at a temperature of 50 to 80 ° C., under atmospheric pressure or reduced pressure.

The crystalline raloxifene phosphate monohydrate of Formula 2 according to the present invention can be usefully used as an active ingredient of the pharmaceutical composition because it has improved solubility and is stable against heat and moisture.

In pharmaceutical compositions comprising the crystalline raloxifene phosphate monohydrate according to the invention as an active ingredient, the preferred dosage form is oral administration, and such means of administration include tablets or capsules.

Tablets may be prepared by mixing the active ingredient with a carrier, diluent or excipient and the like followed by tableting, examples of suitable carriers, diluents or excipients used include disintegrants such as starch, sugars and mannitol; Fillers and extenders such as calcium phosphate and silicic acid derivatives; Binders such as carboxymethyl cellulose and other cellulose derivatives, gelatin, and polyvinyl pyrrolidone; Talc, calcium stearate and magnesium stearate, and lubricants such as solid polyethylene glycols, surfactants such as polysorbate, cetyl alcohol, and glycerol monostearate, and the like. Hard or soft gelatin capsules containing the active ingredient without or with additives such as carriers, diluents or excipients may also be prepared according to conventional methods.

In this case, it is preferable that the crystalline raloxifene phosphate monohydrate of Formula 2 as the active ingredient of the pharmaceutical composition contains 5 to 150 parts by weight based on 250 parts by weight of the pharmaceutical composition. For example, 60 mg of crystalline raloxifene phosphate monohydrate of Formula 2, 7.5 mg of microcrystalline cellulose, 120 mg of anhydrous lactose, 20 mg of lactose monohydrate, as active ingredients in the preparation of the pharmaceutical composition according to the present invention with a total weight of 250 mg, 5 mg of silicon dioxide and 5 mg of magnesium stearate, 15 mg of crospovidone, 15 mg of povidone, and 2.5 mg of polysorbate may be prepared, but the composition ratio of such an active ingredient and a carrier, diluent or excipient is one example, and thus the present invention The scope of is not limited thereto.

Hereinafter, the crystalline raloxifene phosphate monohydrate of Formula 2 according to the present invention and a preparation method thereof will be described in more detail with reference to the following examples, which are only intended to help the understanding and construction of the present invention. The range of is not limited by these.

Example 1 Preparation of Raloxifene

J. Med. Chem. , 27 , 1057 to 1066 (1986)] was added 100 g of raloxifene hydrochloride to a mixed solution of 700 ml of isopropanol and 200 ml of water, and 200 ml of 1N sodium hydroxide solution was slowly added at room temperature to Was adjusted to about 9.0. Then, after stirring for 5 hours at room temperature, the resulting solid was filtered and washed sequentially with a mixed solution of 100 ml of isopropanol and 100 ml of water, and 200 ml of water. The washed solid was dried at 60 ° C. to give 96 g of raloxifene as a yellow solid as isopropanol solvate in a 0.5 molar equivalent ratio.

Melting point 125 to 130 ° C;

¹ H-NMR (DMSO-d6): δ9.75 (bs, 2H), 7.63 (d, 2H), 7.32 (s, 1H), 7.23 (d, 1H), 7.15 (d, 2H), 6.90 (d , 2H), 6.84 (d, 1H), 6.66 (d, 2H), 4.05 (t, 2H), 2.59 (t, 2H), 2.35 (m, 4H), 1.43 (m, 4H), 1.33 (m, 2H).

Example 2 Preparation of Crystalline Raloxifene Phosphate Monohydrate 1

10.6 g of isopropanol solvate relative to raloxifene in 0.5 molar equivalent ratio prepared in Example 1 was suspended in 150 ml of water, and 2.5 g of phosphoric acid was added dropwise at 40 ° C, followed by stirring for 1 hour. After cooling the reaction solution to room temperature and stirring for 5 hours, the resulting solid was filtered and washed with 40 ml of ice water. Drying at temperature of 60 ° C. gave 11.0 g of the title compound as an off white solid.

Melting point 230 ° C. (decomposition, observation of dehydration at 160 ° C.);

Moisture content 3.10% (theoretical 3.06%);

¹ H-NMR (DMSO-d6): δ 7.72 (d, 2H), 7.41 (s, 1H), 7.33 (s, 1H), 7.21 (d, 2H), 7.00 (d, 2H), 6.92 (d , 1H), 6.74 (d, 2H), 4.26 (m, 2H), 2.99 (m, 2H), 2.78 (m, 4H), 1.64 (m, 4H), 1.47 (m, 2H).

Example 3 Preparation of Crystalline Raloxifene Phosphate Monohydrate 2

11.1 g of the off-white title compound was obtained in the same manner as in Example 2, except that a mixed solvent of 120 mL of water and 30 mL of ethanol was used instead of 150 mL of water. The water content obtained was 3.09% (theoretical value 3.06%), the melting point and the ¹ H-NMR data were the same as in Example 2.

Example 4 Preparation of Crystalline Raloxifene Phosphate Monohydrate 3

The same procedure as in Example 2 was carried out, except that 75 ml of water and 75 ml of ethanol were used instead of 150 ml of water, to obtain 10.5 g of a pale white title compound. The moisture content obtained was 3.05% (theoretical value 3.06%), the melting point and the ¹ H-NMR data were the same as in Example 2.

Example 5 Preparation of Crystalline Raloxifene Phosphate Monohydrate 4

The same procedure as in Example 2 was carried out, except that 200 ml of 95% ethanol mixed solvent was used instead of 150 ml of water, to obtain 11.5 g of a pale white title compound. The moisture content obtained was 3.05% (theoretical value 3.06%), the melting point and the ¹ H-NMR data were the same as in Example 2.

Example 6: Qualitative Identification of Crystalline Raloxifene Phosphate Monohydrate Structure

Crystalline raloxifene phosphate monohydrate prepared in Examples 2 to 5 qualitatively confirmed the structure through nuclear magnetic resonance spectrum ( ¹ H-NMR) and infrared spectroscopy (IR), the water content is Karl-Fischer ( Kaal-Fisher) was measured with a moisture meter. The crystal state of raloxifene phosphate monohydrate was measured by powder X-ray diffraction spectroscopy (see FIG. 1), and as a result, it was confirmed that the crystalline raloxifene monohydrate was a crystal having a characteristic diffraction angle as shown in Table 1 below.

Powder X-ray diffraction analysis for raloxifene phosphate monohydrate shows the case where I / I _o ≥50 among the characteristic peaks shown in the spectrum, where “2θ” is the diffraction angle and “d”. Is the distance between crystal faces and "I / I _o " is the relative strength of the peak.

2θ (± 0.2) d I / I _o 2θ (± 0.2) d I / I _o 4.69.210.911.312.514.615.717.818.218.819.419.920.9 19.199.608.147.857.056.075.644.974.884.734.584.474.24 16454575512511561178067100016537862 21.922.723.324.025.326.526.827.729.530.030.531.732.8 4.053.913.813.713.523.363.313.213.032.972.932.822.72 1452221367926955109949183696050

Example 7: Solubility Measurement

The crystalline raloxifene phosphate monohydrate prepared in Examples 2 to 5 and J. Med. Chem. , 27 , 1057 to 1066 (1986)], each of the raloxifene hydrochlorides prepared in accordance with the Korean Pharmacopoeia Disintegration Test Method for pH 1.2 hydrochloric acid solution and pH 6.8 solution corresponding to the first and second solutions, respectively. After dissolving to reach saturation in, and non-ionized water, the solution was taken and analyzed by high performance liquid chromatography (HPLC) to measure the amount dissolved based on the raloxifene free base, and the results are shown in Table 2 below.

Solubility (mg / ml) Raloxifene Hydrochloride Raloxifene Phosphate Monohydrate According to the Invention Non-ionized water 0.303 0.557 pH 1.2 0.004 0.184 pH 6.8 0.003 0.007

As shown in Table 2, the crystalline raloxifene phosphate monohydrate according to the present invention has about 2 times improved solubility in non-ionized water and pH 6.8 solution and 45 times higher solubility in pH 1.2 solution than known raloxifene hydrochloride. Indicated.

Example 8: Stability Test

The thermal stability of the active ingredient used in the pharmaceutical composition is a very important factor in the long-term storage of the product as well as in the manufacturing process of products such as tablets and capsules, and therefore the crystalline raloxifene phosphate monohydrate according to the present invention under high temperature and literature [ J. Med. Chem. , 27 , 1057-1066 (1986)] and compared the stability over time of the raloxifene hydrochloride prepared according to. Specifically, after leaving each compound at a temperature of 100 ℃ for 3 days, the residual stability was measured by high performance liquid chromatography (HPLC) relative to the initial active ingredient value was compared to compare the results in Table 3 Indicated.

Active ingredient Metric Early 3 days later Raloxifene Hydrochloride content (%) 99.7 99.7 moisture (%) 0.20 0.19 Residual Methanol (%) 0.50 0.40 Raloxifene Phosphate Monohydrate According to the Invention content (%) 99.8 99.8 moisture (%) 3.10 3.08 Residual Methanol (%) 0 0

As shown in Table 3, raloxifene phosphate monohydrate maintained its content and moisture similar to raloxifene hydrochloride even at high temperatures. On the other hand, the raloxifene phosphate monohydrate did not use methanol during the manufacturing process, but methanol did not remain. However, the methanol used during the preparation of the raloxifene hydrochloride remained in the raloxifene hydrochloride, and such residual methanol was not completely removed even at high temperatures.

Example 9: Nonhygroscopic Test

Crystalline raloxifene phosphate monohydrate prepared in Examples 2 to 5 and J. Med. Chem. , Raloxifene hydrochloride, and raloxifene phosphate anhydride, prepared according to the method described in the followings, 27 , 1057 to 1066 (1986). After 7 days of continuous exposure under the temperature of and a reduced pressure of 10mmHg, each moisture content was measured by a Kahl-Fisher moisture meter, the results are shown in Table 4 below. Table 4 below shows the water content (% by weight) of the water contained in the active ingredient after the initial and 7 days.

Water content (% by weight) compound     Condition Early 7 days later Raloxifene Hydrochloride 25 ℃, 60% Humidity 0.20 0.22 40 ℃, 75% humidity 0.20 0.37 80 ℃, 10mmHg 0.20 0.12 Raloxifene Phosphate Monohydrate According to the Invention 25 ℃, 60% Humidity 3.10 3.10 40 ℃, 75% humidity 3.10 3.12 80 ℃, 10mmHg 3.10 3.08 Raloxifene Phosphate Anhydride 25 ℃, in air 0.55 1.51 40 ℃, 75% humidity 0.55 2.11

As shown in Table 4, the raloxifene phosphate monohydrate according to the present invention is a non-hygroscopic, which does not absorb moisture similarly to known raloxifene hydrochloride even in high humidity conditions, and furthermore, it is confirmed that it is a hydrate that is not easily dehydrated even under high temperature and reduced pressure conditions. It was. Therefore, the crystalline raloxifene phosphate monohydrate has excellent solubility and is stable against heat and moisture, and thus can be usefully used as an active ingredient of the pharmaceutical composition.

Example 10: Osteoporosis Therapeutic Effect Test of Raloxifene Phosphate Monohydrate

The ovaries of female SD rats (Biogenomeics Co., Ltd.) were excised and fed low-calcium diets (Low Calcium Diet, Harlan TEKLAD), each to 1.5% carboxymethyl cellulose and 1.5% carboxymethyl cellulose once daily. Dissolved raloxifene phosphate monohydrate prepared in Examples 2-5 and J. Med. Chem. , 27 , 1057-1066 (1986)] was administered for 8 weeks. On the other hand, 1.5% carboxymethyl cellulose was administered to the female SD rats without ovarian resection in the same manner as above. After 8 weeks, the femoral bones of the rats were separated, and bone mineral density (BMD), maximum force to break bone (Maximum Load), and bone strength (Stiffness) were measured, and the results are shown in Table 5.

Test group Medication Drug Dose (mg / kg) BMD (mg / cm 2) Maximum force to break a goal (N) Bone Strength (N / mm) Ovarian abscession group Vehicle ⁽¹⁾ - 198.22 ± 11.54 94.40 ± 8.90 117.92 ± 34.84 Ovariectomy group Vehicle ⁽¹⁾ - 78.01 ± 8.86 21.91 ± 3.35 29.78 ± 10.51 Raloxifene Phosphate Monohydrate 6.93 ⁽²⁾ 93.76 ± 6.22 32.09 ± 4.37 38.64 ± 15.25 Raloxifene Hydrochloride 6.00 ⁽²⁾ 92.04 ± 6.94 32.75 ± 5.14 42.51 ± 11.33 ⁽¹⁾ Vehicle: 1.5% carboxymethyl cellulose ⁽²⁾ Raloxifene free base, 5.6 mg / kg

 As shown in Table 5, the raloxifene phosphate monohydrate according to the present invention was found to have a similar osteoporosis treatment effect as known raloxifene hydrochloride.

The crystalline raloxifene phosphate monohydrate according to the present invention, compared to the known raloxifene hydrochloride, has a very good solubility and does not require the use of an organic solvent in the manufacturing process due to this improved solubility, so that there is no problem of harmful residual solvent, Since it is the same or superior in stability and non-hygroscopicity, it can be usefully used to prevent or treat osteoporosis by preparing a pharmaceutical composition comprising a therapeutic or prophylactically effective amount.

Figure 1 shows the powder X-ray Diffraction Spectrum of the crystalline raloxifene phosphate monohydrate according to the present invention.

Figure 2 shows the powder X-ray diffraction spectroscopy of raloxifene phosphate.

Figure 3 shows the powder X-ray diffraction spectroscopy of raloxifene hydrochloride.

Figure 4 shows a differential scanning calorimeter thermogram of the crystalline raloxifene phosphate monohydrate according to the present invention.

Claims (11)

A pharmaceutical composition for preventing or treating osteoporosis, comprising the crystalline raloxifene phosphate monohydrate of Formula 2 below. <Formula 2> The method of claim 1, In the X-ray diffraction analysis, the crystalline raloxifene phosphate monohydrate showed peak values of 2θ in the X-ray diffraction analysis of 4.6 ± 0.2, 9.2 ± 0.2, 10.9 ± 0.2, 11.3 ± 0.2, 12.5 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 17.8 ± 0.2, 18.2 ± 0.2, 18.8 ± 0.2, 19.4 ± 0.2, 19.9 ± 0.2, 20.9 ± 0.2, 21.9 ± 0.2, 22.7 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 25.3 ± 0.2, 26.5 ± 0.2, 26.8 ± 0.2, 27.7 ± 0.2, 29.5 ± 0.2, 30.0 ± 0.2, 30.5 ± 0.2, 31.7 ± 0.2, and 32.8 ± 0.2. The method according to claim 1 or 2, A composition further comprising a pharmaceutically acceptable carrier, diluent or excipient. The method according to claim 1 or 2, 5 to 150 parts by weight of crystalline raloxifene phosphate monohydrate based on 250 parts by weight of the composition. Crystalline raloxifene phosphate monohydrate of formula (2). <Formula 2> The method of claim 5, wherein In X-ray diffraction analysis, the peak values of 2θ are 4.6 ± 0.2, 9.2 ± 0.2, 10.9 ± 0.2, 11.3 ± 0.2, 12.5 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 17.8 ± 0.2, 18.2 ± 0.2, 18.8 ± 0.2 , 19.4 ± 0.2, 19.9 ± 0.2, 20.9 ± 0.2, 21.9 ± 0.2, 22.7 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 25.3 ± 0.2, 26.5 ± 0.2, 26.8 ± 0.2, 27.7 ± 0.2, 29.5 ± 0.2, 30.0 Crystalline raloxifene phosphate monohydrate, characterized in that ± 0.2, 30.5 ± 0.2, 31.7 ± 0.2 and 32.8 ± 0.2. A process for producing the crystalline raloxifene phosphate monohydrate according to claim 5 or 6 by reacting raloxifene with phosphoric acid in water or a mixed solvent of water and ethanol. The method of claim 7, wherein 1.0 molar equivalent to 1.0 molar equivalent of raloxifene. The method of claim 7, wherein Using water as a solvent. The method of claim 7, wherein A method characterized by using a mixed solvent of water and ethanol as a solvent. The method of claim 10, Using a mixed solvent in which water and ethanol are mixed in a weight ratio of 99: 1 to 5:95.