SI21848A - Preparation of sesquihydrate hydrochloride salt of tetrazole derivative - Google Patents

Abstract

The submitted invention refers to a sesquihydrate hydrochloride salt of irbesartan. Irbesartan, applied as a starting material for the preparation of the described sesquihydrate of irbesartan hydrochloride, may be in any form, e.g. it can be used when contained in a reaction solution, in a raw form, in a filtrate in the presence of various solvents or in an anhydrous or any solvated or hydrated form, in amorphous or any of known crystal forms or in a mixture thereof.

Description

The present invention relates to the field of organic chemistry and relates to a new form of 2-butyl-1 [2 '- (1 H -tetrazol-5-yl) biphenyl-4-yl-methyl] spiro [2-imidazoline-4.r -cyclopentan] -5-one (hereinafter referred to as its generic name irbesartan) and the process for its preparation.

TECHNICAL PROBLEM

Irbesartan or 2-butyl-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl-methyl] spiro [2-imidazolin-4. Cyclopentan] -5-one is an angiotensin II receptor antagonist, or so. AT-1 and AT-2 receptors. By binding irbesartan to these receptors instead of angiotensin II, vasoconstrictive action of angiotensin II is prevented, therefore irbesartan acts as an antihypertensive agent. The compound, prepared in the prior art in the form of polymorphic Form A, crystallizes in the form of stable and non-hygroscopic needles, which can be stored and incorporated into pharmaceutical formulations without disintegration. However, they have the disadvantage that great care is needed when preparing pharmaceutical formulations, since Form A of irbesartan is very electrostatic and likes to accumulate on the walls of containers in which it is located, e.g. on sieves, in tablets or in mills.

In part, the problem of electrostatics was solved in WO 99/67236 and EP 1089994, respectively, which protects irbesartan with a special morphological form of crystals having changed properties. The length to width ratio of irbesartan crystals of this morphological form of crystals is between 1: 1 to 10: 1, preferably 1: 1 to 5: 1, and its capacitance is 0 to -10 nC / g. The process for its preparation is characterized by subjecting the suspension of Form A crystals to temperature oscillation or mechanical shear, which is a complex, difficult to control and poorly reproducible process in the pharmaceutical industry.

Therefore, there is still a need for an improved process for the preparation of low-electrostatic irbesartan, to avoid the disadvantages mentioned above, and for the preparation of pure and electrostatic-grade irbesartan, which would make it highly suitable for the preparation of pharmaceutical formulations on an industrial scale.

These problems are solved by the present invention.

BACKGROUND OF THE INVENTION

The synthesis of irbesartan is described in EP 0 454 511 BI. In EP application 0 708 103 as well as in article Bernhart, C. A; Perreaut, P. M., Ferrari, B. P. et al .: "A new series of imidazolones: Highly specific and potent nonpeptide ATI angiotensin II receptor antagonists", J. Med. Chem. 1993, 36, p. 3371-80, mention that they prepare Form A according to the procedure of EP 0 454 511 BI.

EP 0 708 103 protects the process for the preparation of both crystalline forms of irbesartan, A and B, crystalline form B and the pharmaceutical compositions containing it. In the prior art, crystals of Form A of the parent patent or article are said to be needle-shaped, non-hygroscopic and not to decay. However, they mention big problems because they are very electrostatic and therefore like to accumulate on the walls of vessels and appliances. If a solvent containing less than 10% water is used to crystallize irbesartan, Form A is formed ^{in the} case of a solvent system containing more than 10% water, Form B. The latter is found to exhibit less electrostaticity and to give an equally stable form A and does not go into the first. They state that the pH should not be less than 2-3, otherwise irbesartan B does not drop. Form B is a tautomeric form of irbesartan where the hydrogen atom in the tetrazole ring is located on the N2 atom. This is also confirmed in the article Acta Cryst., 1998, C54, p. 808-810, where they published the X-ray structure.

In an article by J. Chem. Soc., Perkin Trans. 2, 1998, p. 475-481 have announced that suspension of irbesartan form A in aqueous HCl solution at pH = 2 after 36 hours at room temperature transforms to form B. Form A converts in water to form B at pH 2 to 8. At higher pH to the dissolution of irbesartan and the formation of salt. The reverse process, the conversion of Form B to Form A does not expire.

WO 99/67236 or EP 1089994 protects irbesartan of a particular morphological form of crystals having modified properties, wherein the ratio of the length to width of the crystals is between 1: 1 to 10: 1, preferably 1: 1 to 5: 1, and its capacitance is 0 to -10 nC per gram of irbesartan. In addition to the specific morphological form of crystals, it protects the method for its preparation and the pharmaceutical compositions containing it. The method is characterized by subjecting the suspension of Form A crystals to temperature oscillation or mechanical shear, which is a complex and poorly reproducible process in the pharmaceutical industry. This results in a transition to a particular morphological form of crystals, which has the above-mentioned modified properties.

WO 03/050110 describes the preparation of a novel amorphous form of irbesartan and a process for its preparation involving the dissolution of crystalline forms A or B in a solvent mixture consisting of halogenated alkanes and alcohols at room temperature followed by evaporation of the solvents to dry, amorphous irbesartan .

US 5,541,209 describes the use of irbesartan for the treatment and prevention of cardiac arrhythmia and for the preparation of irbesartan sodium and potassium salts from basic solutions. As possible pharmaceutically acceptable salts, in addition to basic salts such as sodium or potassium salts, it also mentions amine salts, e.g. trometamol, amino acids such as arginic and lysine and addition salts with acids such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methylsulfate, maleate, fumarate and naphthalene-2-sulfonate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffractogram of the sesquihydrate hydrochloride salt of irbesartan

MAIN CONTENT OF THE INVENTION

The present invention relates to a novel and well-defined hydrate form of irbesartan hydrochloride, characterized by an X-ray powder diffractogram and an infrared spectrum containing 3 water molecules and 2 hydrochloride molecules per irbesartan molecule. The sesquihydrate hydrochloride salt of irbesartan is prepared from aqueous suspensions or irbesartan solutions with a pH below 1.2, preferably in the pH range between 1 and 0.5.

Irbesartan used as starting material may be in any form, e.g. it may be in the reaction solution, in the crude form, in the filtrate, anhydrous, solvated or hydrated, amorphous or any of the known crystalline forms, or in the form of mixtures thereof.

It was unexpectedly found that the sesquihydrate hydrochloride salt of irbesartan falls out of the aqueous suspension or solution acidified to a pH below 1.2. The preparation of this salt avoids the disruptive electrostatic properties of irbesartan in an economical and easy way that is very suitable for industrial use, but the new form is extremely stable and does not decompose even at prolonged heating at elevated temperatures.

The preferred embodiments of the process are described below.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel and well-defined sesquihydrate form of irbesartan hydrochloride, characterized by an X-ray powder diffractogram and an infrared spectrum containing 3 water molecules and 2 hydrochloride molecules per irbesartan molecule. The irbesartan hydrochloride sesquihydrate is prepared from aqueous suspensions or irbesartan solutions acidified to a pH below 1.2, preferably in the pH range between 1 and 0.5.

X-ray powder diffraction patterns were recorded with a Phillips PW3040 / 60 X'Pert PRO diffractometer; CuK _a radiation 0.1541874 nm.

As used herein, the following abbreviated terms are used: m refers to a strong relative intensity of 30 to 100% and s refers to a mean relative intensity of 10 to 30%.

The 2-butyl-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl-methyl] spiro [2-imidazolin-4''-cyclopentane] -5-hydrochloride hydrochloride form is characterized by the following data:

A typical X-ray powder diffractogram is represented by the following 2-theta values, which are accompanied by intensity labels:

Table 1:

[° 2Th.] Label intensity 6.98 s 7.47 s 8.24 m 11.01 m 12.87 m 13.18 m 13.97 m 14.81 m 14.96 m 15.33 m 16.30 m 17.39 m 17.78 m 18.30 s 19.06 s 20.06 m 21.02 m 21.57 s

22.12 m 22.53 m 22.94 m 23.39 m 23.59 m 24.67 s 26.54 m 26,97 m 27.52 s 28,47 s 28,90 s 29.43 s

The preferred sesquihydrate form of 2-butyl-1- [2 '- (1 H -tetrazol-5-yl) biphenyl-4-ylmethyl] spiro [2-imidazolin-4'-cyclopentane] -5-one hydrochloride is characterized by the following 2- theta values: 7.47, 8.24, 11.01, 15.33, 17.39, 22.53, 23.39.

IR spectra were recorded on a PERKIN ELMER FT-IR Spectrometer SPECTRUM 1000.

Irbesartan used as starting material for the preparation of the described sesquihydrate hydrochloride salt of irbesartan may be in any form, e.g. it may be used if contained in the reaction solution, in crude form, in filtrate with various solvents present, or in anhydrous or any solvated or hydrated form, in amorphous or any of the known crystalline forms, or in a mixture thereof.

The sesquihydrate hydrochloride salt of irbesartan, prepared and described in accordance with the present invention, can also be used to prepare other polymorphic or amorphous forms of irbesartan, or mixtures thereof.

Irbesartan, of any known form, or salt thereof, is suspended or dissolved in water in any ratio, preferably in a ratio of 1: 5 to 1:15 (m: m). The process can be performed at temperatures between 0 ° C and reflux temperature, preferably at room temperature. Compounds that reduce surface tension may be added to achieve a more homogeneous suspension, preferably auxiliary solvents such as alcohols or other water-soluble organic solvents may be added, preferably in amounts not exceeding 10% of the total volume.

The suspension or solution of irbesartan is acidified to a pH below 1.2, preferably in the pH range between 1 and 0.5, with HCl, preferably in its aqueous solution. The hydrochloric acid concentration must be high enough to reach such a pH. At the above pH, the suspension is preferably stirred for up to 5 hours at a temperature of from 0 to 50 ° C, preferably at room temperature. The filtered product was dried in vacuo for 1-5 hours at temperatures between 50 ° C and room temperature.

The amount of water that can be bound to the irbesartan molecule can be from 5.5 to 7.0%, preferably 6.2 to 6.4%, of water.

The sesquihydrate hydrochloride salt of irbesartan of the present invention can be used to prepare pharmaceutical compositions together with pharmaceutically acceptable carriers, diluents, excipients, additives, fillers, lubricants, binders, stabilizers, solvents or solvates.

The pharmaceutical composition may be in the form of tablets, capsules, lozenges, powders, syrups, solutions, suspensions, ointments or dragees and the like, and may contain artificial flavors, sweeteners and the like, in suitable solid or liquid carriers or diluents, or in sterile media for preparation of injectable solutions or suspensions.

The present invention is illustrated by the following example, but not limited thereto.

Example 1

1.5 g of irbesartan were suspended at room temperature in 15 ml of water and 1.5 ml of methanol were added. The suspension was then acidified with IM HCl to pH 0.8. 6.8 ml of this solution was consumed. The suspension was stirred for 2 h at room temperature and then the precipitate was filtered off. The product was dried in a vacuum oven at 50 ° C for 1 h and 1.58 g of the sesquihydrate hydrochloride salt of irbesartan was isolated.

IR (characteristic peaks): 1760, 1639, 1513, 1323, 943, 741

NMR: Corresponds to irbesartan

Water (KF) 6.25%

Elemental analysis for the sesquihydrate hydrochloride salt of irbesartan:

Calculated for irbesartan * HCl * 1.5 H ₂ O:

61.03% C, 6.56% H, 17.08% N

Specified.

60.79% C, 6.70% H, 17.02% N

Claims (13)

A sesquihydrate hydrochloride salt of irbesartan containing 2 molecules of hydrochloride and 3 molecules of water per 2 molecules of irbesartan. 2. The sesquihydrate hydrochloride salt of irbesartan, characterized by the X-ray powder diffractogram of Figure 1. 3. The sesquihydrate hydrochloride salt of irbesartan, characterized by the following 2-theta values in X-ray powder diffractograms: 6.98, 7.47, 8.24, 11.01, 12.87, 13.18, 13.97, 14.81, 14.96, 15.33, 16.30, 17.39, 17.78, 18.30, 19.06, 20.06, 21.02, 21.57, 22.12, 22.53, 22.94, 23.39, 23.59, 24.67, 26.54, 26.97, 27.52, 28.47, 28.90 and 29.43. The sesquihydrate hydrochloride salt of irbesartan of claim 3, which is preferably characterized by the following 2-theta values: 7.47, 8.24, 11.01, 15.33, 17.39, 22.53, 23.39. 5. The sesquihydrate hydrochloride salt of irbesartan, characterized by characteristic peaks in the IR spectrum at 1760, 1639, 1513, 1323, 943, 741cm ^-1 . 6. The sesquihydrate hydrochloride salt of irbesartan, which according to the Karl-Fischer method of determination contains from 5.5 to 7.0%, preferably 6.2 to 6.4% water. Process for the preparation of the sesquihydrate hydrochloride salt of irbesartan according to claims 1 to 6, characterized in that the suspension or solution of irbesartan in water is acidified with HCl to a pH below 1.2 and stirred until the sesquihydrate hydrochloride of irbesartan is eliminated. Process for the preparation of the sesquihydrate hydrochloride salt of irbesartan according to claim 7, characterized in that a compound which reduces the surface tension of water is added to the aqueous solution or suspension of irbesartan in water and acidified with HCl to a pH below 1.2, preferably in The pH is between 1 and 0.5, and is stirred for several hours at temperatures between 0 ° C and reflux, preferably at room temperature, until the sesquihydrate hydrochloride salt of irbesartan is eliminated. Process for the preparation of the sesquihydrate hydrochloride salt of irbesartan according to claim 7, characterized in that the precipitated sesquihydrate hydrochloride salt of irbesartan is dried in vacuo for 1-5 hours at temperatures between 50 ° C and room temperature. A pharmaceutical composition comprising the sesquihydrate hydrochloride salt of irbesartan of claims 1 to 6 and pharmaceutically acceptable carriers, diluents, excipients, additives, fillers, lubricants, binders, stabilizers, solvents or solvates. The pharmaceutical composition of claim 10, in the form of tablets, capsules, lozenges, powders, syrups, solutions, suspensions, ointments or dragees. The pharmaceutical composition of claims 10 and 11 for the treatment of hypertension and heart failure. Use of the sesquihydrate hydrochloride salt of claims 1 to 6 or the pharmaceutical composition of claims 10 or 11 for the preparation of a medicament for the treatment of hypertension or heart failure.