AU2013204129C1

AU2013204129C1 - Crystal Form of Quinoline Compound and Process for its Production

Info

Publication number: AU2013204129C1
Application number: AU2013204129A
Authority: AU
Inventors: Hiroo Matsumoto; Yoshio Ohara; Yasutaka Takada; Akihiro Yoshida
Original assignee: Nissan Chemical Corp
Current assignee: Nissan Chemical Corp
Priority date: 2003-12-26
Filing date: 2013-04-12
Publication date: 2017-03-02
Anticipated expiration: 2024-12-17
Also published as: AU2013204129B2; AU2013204129A1

Abstract

H:\dr\lntenvovn\NRPortbl\DCC\RBR\5067473_ .DOC- 1/04/2013 A method for producing a drug substance of crystalline pitavastatin calcium excellent in stability, is presented. In the production of a compound (pitavastatin calcium) 5 represented by the formula (1): The water content is adjusted to a level of from 5 to 15%, and the crystal form is controlled to be crystal form A, thereby to obtain a drug substance excellent in stability.

Description

DESCRIPTION

CRYSTAL FORM OF QUINOLINE COMPOUND AND PROCESS FOR ITS

PRODUCTION

This application is a divisional of Australian Patent Application No. 2011213742, the entire content of which is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a crystal form of pitavastatin calcium known by a chemical name monocalcium bis[(3R,5S,6E)-7-(2-cyclopropyl-4-(4-fluorophenyl)-3--quinolyl)-3,5-dihydroxy-6-heptenoate] , which is useful for treatment of hyperlipemia, as a HMG-CoA reductase inhibitor, a process for its production, and a pharmaceutical composition comprising this compound and a pharmaceutically acceptable carrier.

Particularly, it relates to pitavastatin calcium in a crystal form, which is characterized by containing from 5 to 15% (W/W) of water and which is useful as a drug substance for pharmaceuticals, from the viewpoint of the stability, etc., a process for its production, and a pharmaceutical composition containing it.

BACKGROUND ART

Pitavastatin calcium (see Patents Documents 1, 2 and 3) is commercially available as an antihyperlipemic treating agent, and as its production method, a method of optical resolution employing optically active a-methylbenzylamine has already been reported (see Patent Document 4 and Nonpatent Document 1).

Known as methods for producing the compound of the formula (3) as the starting material, are: •column chromatographic separation employing an optical isomer separation column (see Patent Document 5), •asymmetric synthesis (see Patent Documents 6 and 7), method of subjecting to chemical syn reduction a compound of the formula (4) which may be produced by using chiral synthon (see Patent Document 8) , method of subjecting to a biological syn reduction a compound of the formula (4) (see Patent Document 9), and •optical resolution employing an enzyme (see Patent Document 10).

(3) wherein R is a Ci_4 alkyl group.

(4) wherein R is a Ci_4 alkyl group.

Patent Document 1: JP-A-1-279866

Patent Document 2: EP304063A

Patent Document 3: U.S. Patent No. 5,011,930 Patent Document 4: JP-A-5-148237 Patent Document 5: W095/23125

Patent Document 6: W003/042180

Patent Document 7: JP-A-8-092217

Patent Document 8: JP-A-8-127585

Patent Document 9: JP-A-2002-300897

Patent Document 10: JP-A-13-352996

Non-patent Document 1: Bioorganic & Medicinal Chemistry Letters, 9 (1999), p. 2977

DISCLOSURE OF THE INVENTION A drug substance for pharmaceuticals is desired to have high quality and a stable crystal form from the viewpoint of the storage and is further required to be durable for the production in a large scale. However, in the conventional method for producing pitavastatin calcium, there has been no disclosure relating to the water content or the crystal form. It has been found that if pitavastatin calcium (crystal form A) is subjected to drying in a usual manner, the crystallinity will decrease to a state close to an amorphous state as shown in Fig. 2 when the water content becomes to be at most 4%, even with one which shows the powder X-ray diffraction as shown in Fig. 1 prior to the drying.

Further, it has been found that the pitavastatin calcium which has become amorphous, has very poor stability during the storage, as shown in Table 1. TABLE 1: Stability data of drug substance (influence of the water content)

The present invention advantageously provides a crystalline drug substance of pitavastatin caldium which is stable even if it is not stored under a special storage condition and further advantageously makes industrial mass production possible.

The present inventors have conducted an extensive study on the interrelation between the moisture and the stability of the drug substance and as a result, have found that the stability of pitavastatin calcium can be remarkably improved by controlling the water content in the drug substance within a specific range. Further, it has been found that there are three types of crystal forms having the same water content, and among them, crystal (crystal form A) characterized by the powder X-ray diffraction measured by using CuKa rays, is most preferred as a drug substance for pharmaceuticals. The present invention has been accomplished on the basis of these discoveries.

In some aspects, the present invention provides a method of storing a pitavastatin calcium salt, comprising: maintaining a water content of the pitavastatin calcium salt at greater than 4% (w/w); wherein: the pitavastatin calcium salt is a compound according to formula (1):

( 1 ) ; and an X-ray powder diffraction pattern of the pitavastatin calcium salt, as measured using CuKa radiation, exhibits peaks at diffraction angles (2Θ) of 10.40°, 13.20°, and 30.16°.

In other aspects, the present invention provides a method of storing a pitavastatin calcium salt, comprising: maintaining a water content of the pitavastatin calcium salt at greater than 4% (w/w) and at most 15% (w/w); wherein: the pitavastatin calcium salt is a compound according to formula (1): i ( 1 )

; and an X-ray powder diffraction pattern of the pitavastatin calcium salt, as measured using CuKa radiation, exhibits peaks at diffraction angles (2Θ) of 4.96°, 6.12°, 9.08°, 10.40°, 10.88°, 13.20°, 13.60°, 13.96°, 18.32°, 20.68°, 21.52°, 23.64°, 24.12°, 27.00°, and 30.16°; and the water content of the pitavastatin calcium salt at an initial stage is from 7% (w/w) to 13% (w/w).

In further aspects, the present invention provides:

Crystal (crystal form A) of a compound of the formula (1):

( 1 ) ; and which contains from 5 to 15% of water and which shows, in its X-ray powder diffraction as measured by using CuKa radiation, a peak having a relative intensity of more than 25% at a diffraction angle (2Θ) of 30.16°.

In other aspect, the present invention provides a process for producing the crystal (crystal form A), which comprises adding a calcium compound to a compound of the formula (2):

(2) wherein M+ represents an alkali metal ion, dissolved in water or in a C1-4 alcohol containing at least 60% of water.

In still further aspects, the present invention provides a method for producing a drug substance of the crystal (crystal form A) and pharmaceutical compositions comprising a crystal (crystal form A), wherein the method comprises adjusting the water content to a level of from 5 to 15%.

In other aspects, the present invention provides a pharmaceutical composition comprising a crystal (crystal form A) of a compound of the formula (1):

(1) which contains from 5 to 15% of water and which shows, in its X-ray powder diffraction as measured by using CuKa radiation, a peak having a relative intensity of more than 25% at a diffraction angle (2Θ) of 30.16°.

In further aspects, the present invention provides a pharmaceutical composition which contains the crystal (crystal form A).

The two types of crystal forms other than crystal form A are represented by crystal forms B and C, but neither of them shows peaks at diffraction angles 10.40°, 13.20° and

Fig. 2 is a powder X-ray diffraction pattern, when the crystals used in Fig. 1 are dried to bring the water content to be 3.76%.

BEST MODE FOR CARRYING OUT THE INVENTION

Now, the present invention will be described in detail.

Pitavastatin calcium having crystal form A is characterized by its powder X-ray diffraction pattern.

Apparatus:

Powder X-ray diffraction measuring apparatus: MXLabo (manufactured by MacScience)

Ray source: Cu, wavelength: 1.54056A, Goniometer: Vertical Goniometer

Monochrometer: Used, Auxiliary means: Nil, X-ray tube voltage: 50.0 Kv, Tube current: 30.0 mA

Measuring method:

Prior to the measurement, X-ray tube alignment is tested by using silicon (standard substance) .

About 100 mg of a sample is put on a glass plate for the sample and flattened, followed by measurement under the following conditions.

Range of data: from 3.0400 to 40.0000 deg, Number of data points: 925

Scanning axis: 2Θ/Θ, Θ axis angle: No setting Sampling interval: 0.0400 deg,

Scanning speed: 4.800 deg/min

The present invention also provides a production process to control pitavastatin calcium to have crystal form A.

The starting material is an alkali metal salt of pitavastatin shown by the formula (2) , and' the alkali metal may, for example, be lithium, sodium or potassium, preferably sodium.

As the calcium compound, calcium chloride or calcium acetate may, for example, be preferred, and its amount is within a range of from 0.3 to 3 mols, preferably from 0.5 to 2 mols, per mol of the compound of the formula (2) .

The alkali metal salt of pitavastatin of the formula t (2) may not necessarily be isolated. For example, the Ca salt may be produced as continued from the reaction of hydrolyzing e.g. a compound of the formula (3) .

As a solvent to be used, water or a Ci_4 alcohol containing at least 60% of water, is preferred. The Ci_4 alcohol may, for example, be methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or tert-butyl alcohol.

The amount of the solvent to be used, is usually within a range of from 3 to 100 times by mass, preferably within a range of from 5 to 3 0 times by mass, to the amount of the compound of the formula (2) .

The crystallization temperature is not particularly limited, but it is usually within a range of from -10 to 7 0°C, preferably within a range of from -5 to 40°C, more preferably within a range of from 0 to 20°C.

The crystallization time is not particularly limited, but a crystallization time of from about 30 minutes to 15 hours, is usually sufficient.

As a method for crystallization, a method of carrying out the crystallization in a standing still state, or a method of carrying out the crystallization with stirring, may, for example, be mentioned. However, it is preferred to carry out the crystallization with stirring.

Further, seed crystals of crystal form A may be used as the case requires.

Precipitated crystals will then be filtered and dried. In the present invention, it is very important to adjust the water content. The drying temperature is not particularly limited, but is preferably within a range of from 15 to 40°C.

The water content is adjusted so that it will finally be within a range of from 5 to 15% (W/W), preferably within a range of from 7 to 15% (W/W), more preferably within a range of from 7 to 13% (W/W), most preferably within a range of from 9 to 13% (W/W) .

The obtained pitavastatin calcium will be pulverized and then used as a drug substance for pharmaceuticals.

Administration of the compound of the present invention may, for example, be parenteral administration in the form of an injection drug (subcutaneous, intravenous, intramuscular or intraperitoneal injection), an ointment, a suppository, an aerosol or the like, or oral administration in the form of tablets, capsules, granules, pills, a syrup drug, a liquid drug, an emulsion drug or a suspension drug. A pharmaceutical or veterinary medicine composition containing the compound of the present invention, contains from about 0.001 to 30%, preferably from about 0.01 to 10% of the compound of the present invention, based on the weight of the total composition.

In addition to the compound of the present invention or the composition containing such a compound, other pharmaceutically or veterinary medicinary active compound may be incorporated.

The clinical dosage of the compound of the present invention may vary depending upon e.g. the age, the body | weight, the sensitivity of the patient or the degree of symptom. However, the effective dosage is usually at a level of from 0.003 to 100 mg, preferably from 0.01 to 10 mg, per day for an adult. However, if necessary, a dosage outside this range may be employed.

The compound of the present invention may be formulated for administration in accordance with a , common method for preparation of medicines. Namely, tablets, capsules, granules or pills for oral administration may be formulated by using, for example, an excipient, such as sucrose, lactose, glucose, starch or mannitol; a binder, such as hydroxypropyl cellulose, syrup, gum arabic, gelatin, sorbitol, tragacanth, methyl cellulose or polyvinylpyrrolidone; a disintegrant, such as starch, carboxymethyl cellulose or its calcium salt, fine crystal cellulose, or polyethylene glycol; a lubricant, such as talc, magnesium or calcium stearate, or silica; a lubricating agent, such as sodium laurate or glycerol.

An injection drug, a liquid drug, an emulsion drug, a suspension drug, a syrup drug and an aerosol drug may be prepared by using, for example, a solvent for the active ingredient, such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol or polyethylene glycol; a surfactant, such as sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil, or lecithin; a suspending agent, such as carboxymethyl sodium salt, or a cellulose derivative such as methyl cellulose, tragacanth, a natural rubber such as gum arabic; a preservative, such as a p-hydroxybenzoate, benzalkonium chloride or a sorbic acid salt.

For an ointment which is a percutaneous absorption type formulation, white petrolatum, liquid paraffin, a higher alcohol, macrogol ointment, hydrophilic ointment or an aqueous gel base material may, for example, be used. A suppository may be prepared by using e.g. cacao butter, polyethylene glycol, lanolin, fatty acid triglyceride, coconut oil or polysorbate.

Now, the present invention will be described in further detail with reference to Example. However, it should be understood that the present invention is by no means restricted to such a specific Example.

The compound (5) used in the Example was prepared in accordance with the method disclosed in W095/23125. EXAMPLE 1

2.71 kg (6.03 mol) of the compound (5) was dissolved in 50 kg of ethanol with stirring, and after confirming the solution to be a uniform solution, 58.5 kg of water was added. After cooling it to from -3 to 3°C, 3.37 liters of a 2 mol/liter sodium hydroxide aqueous solution was dropwise added thereto, followed by stirring at the same temperature for 3 hours to complete the hydrolytic reaction. In order to introduce the entire amount of the sodium hydroxide aqueous solution to the reaction system, 4.70 kg of water was used.

The reaction mixture was distilled under reduced pressure to remove the solvent, and after removing 52.2 kg of ethanol/water, the internal temperature was adjusted to from 10 to 20°C. Into the obtained concentrated solution, a separately prepared calcium chloride aqueous solution (95% CaCl2 775 g/water 39.3 kg, 6.63 mol) was dropwise added over a period of 2 hours.

In order to introduce the entire amount of the calcium chloride aqueous solution into the reaction system, 4.70 kg of water was used. After completion of the dropwise addition, stirring at the same temperature was continued for 12 hours, whereupon precipitated crystals were collected by filtration· The crystals were washed with 72.3 kg of water and then dried under reduced pressure in a drier at 40°C while paying an attention to the product temperature until the water content became 10%, to obtain 2.80 kg (yield: 95%) of pitavastatin calcium as white crystals.

The powder X-ray diffraction was measured to confirm the crystals to be crystal form A.

INDUSTRIAL APPLICABILITY

According to the present invention, an industrial method for producing· a crystalline drug substance of pitavastatin calcium excellent in stability, has been established.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (or information derived from it) , or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A method of storing a pitavastatin calcium salt, comprising: maintaining a water content of the pitavastatin calcium salt at greater than 4% (w/w); wherein: the pitavastatin calcium salt is a compound according to formula (1):

{ 1 ) ; and an X-ray powder diffraction pattern of the pitavastatin calcium salt, as measured using CuKa radiation, exhibits peaks at diffraction angles (2Θ) of 10.40°, 13.20°, and 30.16°.
2. The method according to claim 1, comprising maintaining the water content of the pitavastatin calcium salt at 5% (w/w) or greater.
3. The method according to claim 1, comprising maintaining the water content of the pitavastatin calcium salt at 5 to 15% (w/w).
4. The method according to claim 1, comprising maintaining the water content of the pitavastatin calcium salt at 7% (w/w) or greater.
5. The method according to claim 1, comprising maintaining the water content of the pitavastatin calcium salt at 7 to 13% (w/w).
6. The method according to claim 1, comprising maintaining the water content of the pitavastatin calcium salt at 7 to 15% (w/w).
7. The method according to claim 1, comprising maintaining the water content of the pitavastatin calcium salt at 9% (w/w) or greater.
8. The method according to claim 1, comprising maintaining the water content of the pitavastatin calcium salt at 9 to 13% (w/w).
9. The method according to claim 1, wherein the pitavastatin calcium salt is produced by:

adding a calcium compound to a solution comprising a compound according to formula (2): (2) wherein M+ represents an alkali metal ion, dissolved in water or in a C1-4 alcohol comprising at least 60% of water; filtering precipitated crystals; and drying the crystals so that a water content of the crystals is greater than 4% (w/w).
10. The method according to claim 2, wherein the pitavastatin calcium salt is produced by: adding a calcium compound to a solution comprising a compound according to formula (2):

¢2) wherein M+ represents an alkali metal ion, dissolved in water or in a Cm alcohol comprising at least 60% of water; filtering precipitated crystals; and drying the crystals so that a water content of the crystals is 5% (w/w) or greater.
11. The method according to claim 3, wherein the pitavastatin calcium salt is produced by: adding a calcium compound to a solution comprising a compound according to formula (2):

(2) wherein M+ represents an alkali metal ion, dissolved in water or in a Cm alcohol comprising at least 60% of water; filtering precipitated crystals; and drying the crystals so that a water content of the crystals is 5 to 15% (w/w).
12. The method according to claim 4, wherein the pitavastatin calcium salt is produced by: adding a calcium compound to a solution comprising a compound according to formula (2):

(2) wherein M+ represents an alkali metal ion, dissolved in water or in a Q_4 alcohol comprising at least 60% of water; filtering precipitated crystals; and drying the crystals so that a water content of the crystals is 7% (w/w) or greater.
13. The method according to claim 5, wherein the pitavastatin calcium salt is produced by: adding a calcium compound to a solution comprising a compound according to formula (2):

¢2} wherein M+ represents an alkali metal ion, dissolved in water or in a Ci_4 alcohol comprising at least 60% of water; filtering precipitated crystals; and drying the crystals so that a water content of the crystals is 7 to 13% (w/w).
14. The method according to claim 6, wherein the pitavastatin calcium salt is produced by: adding a calcium compound to a solution comprising a compound according to formula (2):

(2} wherein M+ represents an alkali metal ion, dissolved in water or in a Cm alcohol comprising at least 60% of water; filtering precipitated crystals; and drying the crystals so that a water content of the crystals is 7 to 15% (w/w).
15. The method according to claim 7, wherein the pitavastatin calcium salt is produced by:

adding a calcium compound to a solution comprising a compound according to formula (2): (2) wherein M+ represents an alkali metal ion, dissolved in water or in a Cm alcohol comprising at least 60% of water; filtering precipitated crystals; and drying the crystals so that a water content of the crystals is 9% (w/w) or greater.
16. The method according to claim 8, wherein the pitavastatin calcium salt is produced by: adding a calcium compound to a solution comprising a compound according to formula (2):

¢2) wherein M+ represents an alkali metal ion, dissolved in water or in a Ci_4 alcohol comprising at least 60% of water; filtering precipitated crystals; and drying the crystals so that a water content of the crystals is 9 to 13% (w/w).
17. The method according to claim 9, wherein drying the crystals comprises drying under reduced pressure.
18. The method according claim 9, wherein drying the crystals comprises drying at a temperature of from 15 to 40°C.
19. The method according to claim 1, wherein maintaining the water content of the pitavastatin calcium salt comprises storing under air tight conditions.
20. The method according to claim 1, wherein the X-ray powder diffraction pattern of the pitavastatin calcium salt, as measured using CuKa radiation, exhibits peaks at diffraction angles (20) of 4.96°, 6.72°, 9.08°, 10.40°, 10.88°, 13.20°, 13.60°, 13.96°, 18.32°, 20.68°, 21.52°, 23.64°, 24.12°, 27.00°, and 30.16°.
21. A pharmaceutical or veterinary medicine composition, comprising a pitavastatin calcium salt stored by the method according to claim 1.
22. A method of storing a pitavastatin calcium salt, comprising: maintaining a water content of the pitavastatin calcium salt at greater than 4% (w/w) and at most 15% (w/w); { 1 ) wherein: the pitavastatin calcium salt is a compound according to formula (1):

; and an X-ray powder diffraction pattern of the pitavastatin calcium salt, as measured using CuKa radiation, exhibits peaks at diffraction angles (2Θ) of 4.96°, 6.72°, 9.08°, 10.40°, 10.88°, 13.20°, 13.60°, 13.96°, 18.32°, 20.68°, 21.52°, 23.64°, 24.12°, 27.00°, and 30.16°; and a water content of the pitavastatin calcium salt at an initial stage is from 7% (w/w) to 13% (w/w).
23. The method according to claim 22, comprising maintaining the water content of the pitavastatin calcium salt at 5 to 15% (w/w).
24. The method according to claim 22, comprising maintaining the water content of the pitavastatin calcium salt at 7 to 15% (w/w).
25. The method according to claim 22, comprising maintaining the water content of the pitavastatin calcium salt at 9 to 15% (w/w).
26. The method according to claim 22, wherein maintaining the water content of the pitavastatin calcium salt comprises storing under air tight conditions.
27. A pharmaceutical composition comprising a crystal (crystal form A) of a compound of the formula (1):

(1) which contains from 5 to 15% of water and which shows, in its X-ray powder diffraction as measured by using CuKa radiation, a peak having a relative intensity of more than 25% at a diffraction angle (2Θ) of 30.16°.
28. A method for producing a pharmaceutical composition comprising a crystal (crystal form A) as defined in claim 27, which comprises adding a calcium compound to a compound of the formula (2):

(2) wherein M+ represents an alkali metal ion, dissolved in water or in a Cm alcohol containing at least 50% of water.
29. A method for producing a pharmaceutical composition as defined in claim 27, which comprises the step of adjusting the water content of a crystal (crystal form A) to a level of from 5 to 15%.
30. A pharmaceutical composition comprising a crystal (crystal form A) as defined in claim 27, wherein the crystal (crystal form A) shows, in its X-ray powder diffraction as measured by using CuKa radiation, a peak at a diffraction angle (2Θ) of 10.40°, 13.20° and 30.16°.
31. A pharmaceutical composition comprising a crystal (crystal form A) as defined in claim 27, wherein the crystal (crystal form A) shows, in its X-ray powder diffraction as measured by using CuKa radiation, a peak at a diffraction angle (2Θ) of 6.72°, 10.40°, 13.20°, 13.96°, 18.32°, 20.68°, 21.52°, and 30.16°.
32. A pharmaceutical composition comprising a crystal (crystal form A) as defined in claim 27, wherein the crystal (crystal form A) shows, in its X-ray powder diffraction as measured by using CuKa radiation, a peak at a diffraction angle (2Θ) of 4.96°, 6.72°, 9.08°, 10.40°, 10.88°, 13.20°, 13.60°, 13.96°, 18.32°, 20.68°, 21.52°, 23.64°, 24.12°, 27.00° and 30.16°.
33. A pharmaceutical composition which contains the crystal (crystal form A) as defined in any one of claims 27 and 30 to 32.
34. The method as defined in any one of claims 1, 22, 28 and 29 substantially as hereinbefore described with reference to any one of the Examples and/or Figures.
35. A crystal (crystal form A) as defined in claim 27 substantially as hereinbefore described with reference to any one of the Examples and/or Figures.