MXPA06007435A - Crystal form of quinoline compound and process for its production - Google Patents

Abstract

A method for producing a drug substance of crystalline pitavastatin calcium excellent in stability, is presented. In the production of a compound (pitavastatin calcium) 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

FORM OF CRYSTAL OF THE COMPOUND QUINOLINE AND PROCEDURE FOR ITS PRODUCTION TECHNICAL FIELD The present invention relates to a crystal form of pitavastatin calcica known by a chemical name bis [(3R, 5S, 6E) -7- (2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl) -3, 5-dihydroxy-6-heptenoate] monocalcium, which is useful for the treatment of hyperlipemia, as an HMG-CoA reductase inhibitor, to a process for its production and to a pharmaceutical composition comprising this compound and a pharmaceutically acceptable carrier. Particularly, it refers to crystallized pitavastatin in crystal form, which is characterized in that it contains from 5 to 15% (w / w) of water and which is useful as a drug substance for pharmaceutical products, from the point of view of stability, etc., to a process for its production and to a pharmaceutical composition that contains it.

PREVIOUS TECHNIQUE Calcium pitavastatin (see patent documents 1, 2 and 3) is commercially available as an antihyperlipidemic treatment agent, and has already been reported about its production method, optical resolution method employing optically active α-methylbenzylamine (cf. patent document 4 and non-patent document 1).

Known as methods for producing the compound of the formula (3) as the starting material are: • column chromatographic separation employing a column of optical isomer separation (see patent document 5), • asymmetric synthesis (see patent documents 6 and 7), • method of subjecting to chemical synthesis reduction a compound of formula (4) that can be produced using chiral synthon (see patent document 8) • method of subjecting a compound of formula (4) to reduction of biological synthesis (see patent document 9), and • optical resolution using an enzyme (see patent document 10) . wherein R is a C1-4 alkyl group. wherein R is an alkyl group of C -? - 4. Patent Document 1: JP-A-1 -279866 Patent Document 2: EP304063A Patent Document 3: US Patent. No. 5,011, 930 Patent Document 4: JP-A-5-148237 Patent Document 5: WO95 / 23125 Patent Document 6: WO03 / 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 BRIEF DESCRIPTION OF THE INVENTION A drug substance for pharmaceuticals having high quality and a stable crystal form is needed from the storage point of view and it is further required to be durable for large scale production. However, in the conventional method for producing calcitic pitavastatin, no reference has been made to the water content or the crystal form. It has been found that if the calcium pitavastatin (crystal form A) is subjected to drying in the usual manner, the crystallinity will decrease to a state close to the amorphous state, as shown in Figure 2, when the water content turns out to be a as much as 4%, even with one that shows X-ray diffraction through powder, as shown in figure 1, before drying. In addition, it has been found that calcium pitavastatin that has become amorphous has very poor stability during storage, as shown in table 1.

TABLE 1 Stability data of the drug substance (influence of water content) It is an object of the present invention to provide a crystalline pitavastatin crystalline drug substance, which is stable, even if it is not stored under special storage conditions and also to enable mass industrial production. The present inventors have carried out 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 the calcitic pitavastatin can be markedly improved., controlling the water content in the drug substance within a specific range. In addition, it has been found that there are three types of crystal form that have the same water content and, among them, the crystal (crystal form A) characterized by X-ray diffraction through powder, which is measured using lightning CuKa, is very preferred as a drug substance for pharmaceutical products. The present invention has been carried out on the basis of these discoveries. Specifically, the present invention provides: 1. The crystal (crystal form A) of a compound of the formula d): which contains 5 to 15% water and which shows, in its X-ray powder diffraction, which is measured using CuKa radiation, a peak that has a relative intensity of more than 25% at an angle of diffraction (2T) of 30.16 °. 2. A process for producing the crystal (crystal form A) as defined in article 1, which comprises adding a calcium compound to a compound of the formula (2): wherein M + represents an alkali metal ion, dissolved in water or in a C1-4 alcohol containing at least 60% water. 3. A method for producing a drug substance of the crystal (crystal form A) as defined in article 1, which comprises adjusting the water content to a level of 5 to 15%. 4. A pharmaceutical composition containing the crystal (crystal form A) as defined in article 1. The two types of crystal forms other than the crystal form A are represented by the crystal forms B and C, but none of them shows peaks at the diffraction angles of 10.40 °, 13.20 ° and 30.16 ° characteristic of the crystal form A, thus indicating that they are crystal polymorphs. It was evident that they are deficient in filtration capacity, require strict drying conditions (which are likely to experience a change in the crystal form during drying), are likely to include an inorganic substance, such as NaCl, and are not necessarily able to maintain the ability to reproduce in the control of the crystal form. Thus, there are many drawbacks from the point of view of the industrial production method and the crystal form A is the best as a drug substance for pharmaceutical products.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a powder X-ray diffraction pattern of the crystal form A, in which the water content is 8.78%. Figure 2 is a powder X-ray diffraction pattern; when the crystals are used in figure 1, they are dried to make the water content of 3.76%.

BEST MODE FOR CARRYING OUT THE INVENTION Now, the present invention will be described in detail. The crystallized pitavastatin, which is in the form of crystal A, is characterized by its powder X-ray diffraction pattern. Diffraction Angle (29) (") Grid distribution d Relative intensity (> 25%) 4.96 17.7999 35.9 6.72 13.1423 55.1 9.08 9.7314 33.3 10.40 8.4991 34.8 10.88 8.1248 27.3 13.20 6.7020 27.8 13.60 6.5053 48.8 13.96 6.3387 60.0 18.32 4.8386 56.7 20.68 4.2915 100.0 21.52 4.1259 57.4 23.64 3.7604 41.3 24.12 3.6866 45.0 27.00 3.2996 28.5 30.16 2.9607 30.6 Apparatus Powder X-ray diffraction measurement equipment: MXLabo (manufactured by MacScience) Light source: Cu, wavelength: 1.54056A, goniometer: vertical goniometer Monochrome: used, auxiliary means: None, X-ray tube voltage: 50.0 KV, tube current: 30.0 mA.

Measurement method Before the measurement, the alignment of the X-ray tube is tested, using silicon (usual substance). Approximately 100 mg of a sample is placed on a glass plate for the sample and flattened, followed by measurement under the following conditions. Data interval: from 3.0400 to 40.0000 degrees. Number of data points: 925. Scan axis: 2T / T, axis angle?: No adjustment. Sampling interval: 0.0400 degrees. Scan speed: 4,800 degrees / minute. The present invention also provides a production method for controlling the calcitic pitavastatin to have the crystal form A.

The starting material is an alkali metal salt of pitavastatin shown by formula (2) and the alkali metal can be, for example, lithium, sodium or potassium, preferably sodium. As the calcium compound, calcium chloride or calcium acetate may be preferred and its amount is within a range of 0.3 to 3 moles, preferably 0.5 to 2 moles, per mole of the compound of the formula (2). The alkaline metal salt of pitavastatin of the formula (2) should not necessarily be isolated. For example, the Ca salt can be produced, as a result of the hydrolyzing reaction, for example a compound of the formula (3).

As the solvent to be used, water or C1-4 alcohol containing at least 60% water is preferred. The alcohol of C -? - can be, for example, methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or tert-butyl alcohol. The amount of solvent to be used is usually within a range of 3 to 100 times by mass, preferably within the range of 5 to 30 times by mass, to the amount of the compound of formula (2). The crystallization temperature is not particularly limited, but is usually within a range of -10 to 70 ° C, preferably within a range of -5 to 40 ° C, more preferably within a range of 0 to 20 ° C. The crystallization time is not particularly limited, but a crystallization time of about 30 minutes to 15 hours is usually sufficient. As the crystallization method, there may be mentioned, for example, a method of carrying out crystallization in a state of rest or a method of carrying out crystallization with stirring. However, it is preferred to carry out the crystallization with stirring. In addition, seed crystals of the crystal form A can be used, as the case requires. Then the precipitated crystals will 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 15 to 40 ° C.

The water content is adjusted, so that it is finally within a range of 5 to 15% (w / w), preferably within a range of 7 to 15% (w / w), more preferably within a range of 7 to 13% (w / w), most preferably within a range of 9 to 13% (w / w). The obtained calcium pitavastatin will be pulverized and then used as a drug substance for pharmaceutical products. The administration of the compound of the present invention can be, for example, parenteral administration in the form of 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 drug in syrup, 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 compound, other pharmaceutically active compounds or those of veterinary medicine may be incorporated. The clinical dosage of the compound of the present invention may vary, depending for example on age, body weight, sensitivity of the patient or severity of the symptom: However, the effective dosage is usually at a level of 0.03 to 100 mg, preferably from 0.01 to 10 mg, per day for an adult. However, if necessary, a dosage outside this range can be used. The compound of the present invention can be formulated for administration according to a common method for the preparation of medicines. Specifically, tablets, capsules, granules or pills can be formulated for oral administration, using, for example, an excipient, such as sucrose, lactose, glucose, starch or mannitol; a binder, such as hydroxypropylcellulose, syrup, gum arabic, gelatin, sorbitol, tragacanth, methylcellulose or polyvinylpyrrolidone; a disintegrant, such as starch, carboxymethylcellulose, 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 or an aerosol drug can be prepared 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 a sorbitan fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene fatty acid ester, a polyoxyethylene ether of hydrogenated castor oil or lecithin; a suspending agent, such as carboxymethyl sodium salt, or a cellulose derivative, such as methylcellulose, tragacanth, a natural rubber, such as gum arabic; a preservative, such as p-hydroxybenzoate, benzalkonium chloride or a salt of sorbic acid.

For an ointment which is a percutaneous absorption type formulation, for example, white petrolatum, liquid paraffin, a higher alcohol, macrogol ointment, hydrophilic ointment or an aqueous gel base material can be used. A suppository can be prepared, using for example cocoa butter, polyethylene glycol, lanolin, fatty acid triglyceride, coconut oil or polysorbate. Now, the present invention will be described in greater detail with reference to an example. However, it should be understood that the present invention is not restricted in any way to the specific example. The compound (5) used in the example was prepared according to 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 that the solution was a uniform solution, 58.5 kg of water was added. After cooling to -3 to 3 ° C, 3.37 liters of an aqueous solution of sodium hydroxide at 2 moles / liter was added dropwise thereto, followed by stirring at the same temperature for 3 hours to complete the reaction hydrolytic In order to introduce the entire amount of the aqueous solution of sodium hydroxide 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 10 and up to 20 ° C. To the obtained concentrated solution was added dropwise an aqueous solution of calcium chloride prepared separately (95% CaCl 2 775 g / water 39.3 kg, 5.53 moles) over a period of 2 hours. In order to introduce the entire amount of the aqueous solution of calcium chloride into the reaction system, 4.70 kg of water was used. After completion of the dropwise addition, stirring was continued at the same temperature for 12 hours, after which the precipitated crystals were collected by filtration. The crystals were washed with 72.3 kg of water and then dried under reduced pressure in a dryer at 40 ° C, while paying attention to the temperature of the product, until the water content was converted to 10%, to obtain 2.80 kg (yield: 95%) of calcium pitavastatin as white crystals. X-ray diffraction was measured through powder to confirm that the crystals were of crystal form A.

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

Claims (4)

NOVELTY OF THE INVENTION CLAIMS

1. - A crystal (crystal form A) of a compound of the formula (1): which contains 5 to 15% water and which shows, in its X-ray powder diffraction, which is measured using CuKa radiation, a peak that has a relative intensity of more than 25% at an angle of diffraction (2T) of 30.16 °.

2. A process for producing a crystal (crystal form A) as claimed in claim 1, characterized in that it comprises adding a calcium compound to a compound of the formula (2): wherein M + represents an alkali metal ion, dissolved in water or a C1- alcohol containing at least 60% water.

3. A method for producing a drug substance of a crystal (crystal form A) as claimed in claim 1, characterized in that it comprises adjusting the water content at a level of 5 to 15%.

4. A pharmaceutical composition, characterized in that it contains a crystal (crystal form A) as claimed in claim 1.