HK1184464A - New process for preparation of crystal modifications for use in preparation of esomeprazole sodium salt - Google Patents

Description

Novel process for the preparation of crystal modifications for the preparation of esomeprazole sodium salt

The present application is a divisional application of an invention patent application entitled "novel method for preparing crystal modifications for the preparation of esomeprazole sodium salt", filed on 20.6.2005, national application No. 200580020874.2(PCT/SE 2005/000954).

Technical Field

The present invention relates to a novel process for the preparation of crystal modifications for the preparation of esomeprazole sodium salt. Further, the invention also relates to the use of the novel crystal modifications for the treatment of gastrointestinal disorders, pharmaceutical compositions containing them, and crystal modifications and the like.

Background

Omeprazole, i.e. the compound 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl]Sulfinyl radical]-1H-benzimidazoles and their therapeutically acceptable salts are described in EP 5129. Some specific alkaline salts of omeprazole are disclosed in EP 124495.

Omeprazole is a sulfoxide and is a chiral compound in which the sulfur atom is the stereogenic center. Omeprazole is thus a racemic mixture of its two single enantiomers, the R-and S-enantiomers of omeprazole, the S-enantiomer having the generic name esomeprazole. Esomeprazole is recently marketed as a new generation of proton pump inhibitors, wherein the active pharmaceutical ingredient is the magnesium salt of esomeprazole. Esomeprazole shows an improvement in the treatment of GERD compared to previous drugs.

The absolute configuration of the enantiomer of omeprazole was determined by X-ray studies of N-alkylated derivatives of the (+) -enantiomer in non-salt form. The (+) -enantiomer in non-salt form and the (-) -enantiomer in non-salt form were found to have R and S configurations, respectively, and the (+) -enantiomer of magnesium salt and the (-) -enantiomer of magnesium salt were also found to have R and S configurations, respectively. The conditions for optical rotation measurements on each of these enantiomers are described in WO 94/27988.

Salts of the single enantiomers of omeprazole and their preparation are disclosed in WO 94/27988. These compounds have improved pharmacokinetic and metabolic properties and will result in an improved therapeutic profile, such as low inter-individual variability.

WO96/02535 discloses a process for the preparation of the single enantiomers of omeprazole and salts thereof, including the sodium salt.

WO98/54171 discloses a process for the preparation of magnesium salts of the S-enantiomer of omeprazole trihydrate, wherein the potassium salt of omeprazole is used as an intermediate.

WO00/44744 discloses the potassium salt of S-omeprazole without methanol.

WO03/089408(Sun Pharmaceutical Industries Limited) discloses alkali or alkaline earth metal salts of esomeprazole, including the sodium salt.

Disclosure of Invention

It has been unexpectedly found that during the preparation of esomeprazole sodium salt, a number of new crystal modifications are formed. Some of these new intermediates are stable and can therefore be isolated and characterized. Others are too short to characterize, others are crystalline but in a wet state, but convert to various anhydrous forms immediately after drying, and are therefore difficult to characterize. These modifications may be passed through many other forms with less crystalline content during the drying process. All crystal modifications can be obtained by the process of the invention.

The process of the present invention makes optimal use of the new crystal modifications and their properties by allowing them to be used in a more efficient and effective way to prepare esomeprazole sodium.

The present process is advantageous because it enables the preparation of esomeprazole sodium salt directly from the corresponding potassium salt in high yield and good quality using a crystal modification with good filtration characteristics. Other advantages are high reproducibility, good processing ability, including safety, and the use of one of the main solvent systems in the overall process, which preferably includes an oxidation step followed by steps and operations. More preferably, the same solvent system as used in the preparation of the potassium salt of esomeprazole is employed in the present invention.

The method of the invention essentially comprises the following steps:

i) in a suitable solvent S₁Dissolving esomeprazole neutral form;

ii) adding additional suitable solvent S₂；

iii) adding about 1 molar equivalent of a sodium salt of a suitable base B;

iv) crystallizing the esomeprazole sodium salt and isolating the salt formed.

Brief Description of Drawings

Figure 1 is an X-ray powder diffraction pattern of esomeprazole sodium salt modification C.

Fig. 2 is an enlarged version of fig. 1.

Figure 3 is an X-ray powder diffraction pattern of esomeprazole sodium salt modification E.

Fig. 4 is an enlarged version of fig. 3.

Figure 5 is an X-ray powder diffraction pattern of esomeprazole sodium salt modification H.

Detailed Description

In one embodiment of the invention, esomeprazole neutral form is prepared from the corresponding potassium salt of esomeprazole and is used more or less immediately in the subsequent steps defined above. If so, esomeprazole potassium salt can be prepared by any of the methods described in the prior art and then suspended in the solvent S₁In (1). The pH should be adjusted thereafter to prepare esomeprazole in a neutral form. The pH adjustment may be performed by adding about 1 molar equivalent of a suitable acid HA, preferably an aqueous HA solution. The acid isExamples of HA include, but are not limited to, all mineral acids that form water-soluble potassium salts, such as hydrochloric acid and acetic acid. The aqueous phase is thereafter discarded and the organic phase is optionally washed with water or brine. The esomeprazole neutral form can then be used more or less immediately in steps ii) -iv) as defined above.

In another embodiment of the invention, esomeprazole neutral form is prepared from the corresponding magnesium salt of esomeprazole and is used more or less immediately in the subsequent steps defined above.

In one embodiment of the invention, the solvent S₁Is toluene.

In one embodiment of the invention, the solvent S₂Is methanol.

In one embodiment of the invention, the solvent S₂Is ethanol.

In one embodiment of the invention, the solvent S₂Is isopropanol (isopyrosylkohol).

In one embodiment of the invention, the base B is a hydroxide.

In one embodiment of the invention, the base B is added as an aqueous solution.

In one embodiment of the invention, the crystallization of step iv) is initiated by addition of seed crystals.

In one embodiment of the present invention, step iii) above is performed before step ii).

The esomeprazole sodium salt isolated in step iv) will depend on which solvent S is used₂. The isolated esomeprazole sodium salt is thereafter dried and most of the solvent S is used during the drying process₂Together with some additional water. The isolated esomeprazole sodium salt according to the examples was crystalline, both in wet and wet state, but immediately transformed into various anhydrous forms after drying. The isolated crystal modification may be subjected to a plurality of crystal contents during the drying processLower, other forms.

All esomeprazole sodium salts obtainable by the process of the present invention can be suitably dried by conventional drying methods in order to convert them into various anhydrous forms. The drying process will slightly affect the position and intensity of the peaks in the X-ray diffraction pattern of esomeprazole sodium modification C, E and H. In order to reproduce the diffraction patterns of fig. 1-3 completely, it is important to carefully follow the procedure in the examples. Small deviations from this may affect the position and intensity of the peaks in the X-ray diffraction pattern.

Thus, the crystal modifications of the invention are most suitable for use as intermediates due to their good filtration properties. However, they can all be completely dried and formulated as pharmaceutical compositions for use in patients in need thereof.

When methanol is used as solvent S2, esomeprazole sodium salt modification C is an isolated crystal modification.

When ethanol is used as solvent S2, esomeprazole sodium salt modification E is an isolated crystal modification.

When isopropanol is used as solvent S2, esomeprazole sodium salt modification H is an isolated crystal modification.

For the avoidance of doubt, it is to be understood that where a process step or similar activity is defined by the term "hereinbefore defined", that step includes the first-occurring and broadest definition as well as each and every other definition of that step.

It is to be understood that the phrase "more or less immediately" as used in this specification means that the subsequent steps or activities should be carried out at a time to avoid degradation of the active compound. This subsequent step can therefore be carried out at a rather late time, provided care must be taken to avoid degradation of the active compound.

Suitable solvents S₁Including but not limited to toluene.

Suitable solvents S₂Including but not limited toIn methanol, ethanol and isopropanol.

Suitable bases B include, but are not limited to, hydroxides, methoxy and ethoxy metals, preferably added as an aqueous solution.

It is another object of the present invention to provide new stable crystal modifications of esomeprazole sodium salt. Esomeprazole sodium salt can exist in the form of more than one crystal modification. The crystal modifications or forms are hereinafter referred to as esomeprazole sodium salt modification C, E and H. The symbols C, E and H are related to the time at which the crystal modification is produced, and not to their relative thermodynamic stability.

One aspect of the present invention is to provide esomeprazole sodium salt modification C.

Esomeprazole sodium salt modification C, characterized by providing an X-ray powder diffraction pattern as shown in figure 1, essentially exhibiting major peaks with the following d-values and intensities;

the peaks identified by the d-values calculated from the bragg formula and intensity were refined from the diffractogram of esomeprazole sodium salt modification C. Only the most characteristic, significant, unique and/or reproducible main peaks are tabulated, but other peaks can be refined from the diffraction pattern by conventional methods. In most cases, the presence of these main peaks, which are reproducible and within the error limits, is sufficient to determine the presence of the crystal modification. The reliability of the relative intensity is low, the following definitions are adopted instead of numerical values;

the relative intensity is obtained from the diffraction pattern measured with an adjustable slit.

Another aspect of the present invention is to provide esomeprazole sodium salt modification E.

Esomeprazole sodium salt modification E, characterized by providing an X-ray powder diffraction pattern as shown in figure 3, essentially exhibiting major peaks with the following d-values and intensities;

the peaks identified by the d-values calculated from the bragg formula and intensity are refined from the diffractogram of esomeprazole sodium salt modification E. Only the most characteristic, significant, unique and/or reproducible main peaks are tabulated, but other peaks can be refined from the diffraction pattern by conventional methods. In most cases, the presence of these main peaks, which are reproducible and within the error limits, is sufficient to determine the presence of the crystal modification. The reliability of the relative intensity is low, the following definitions are adopted instead of numerical values;

the relative intensity is obtained from the diffraction pattern measured with an adjustable slit.

Another aspect of the present invention is to provide esomeprazole sodium salt modification H.

Esomeprazole sodium salt modification H, characterized by providing an X-ray powder diffraction pattern as shown in figure 5, essentially exhibiting major peaks with the following d-values and intensities;

the peaks identified by the d-values calculated from the bragg formula and intensity were refined from the diffractogram of esomeprazole sodium salt modification H. Only the most characteristic, significant, unique and/or reproducible main peaks are tabulated, but other peaks can be refined from the diffraction pattern by conventional methods. In most cases, the presence of these main peaks, which are reproducible and within the error limits, is sufficient to determine the presence of the crystal modification. The reliability of the relative intensity is low, the following definitions are adopted instead of numerical values;

the relative intensity is obtained from the diffraction pattern measured with an adjustable slit.

The crystallization of the crystal modification according to the invention from a suitable solvent system comprising a plurality of solvents can be achieved by achieving supersaturation in the solvent system by evaporation of the solvent, lowering the temperature and/or addition of an anti-solvent, i.e. a solvent in which the crystal modification is poorly soluble.

Whether the anhydrate or solvate crystallizes is related to the kinetics and equilibrium conditions of the individual crystal modifications under specific conditions. Thus, as can be appreciated by those skilled in the art, the resulting crystal modification is dependent on the kinetics and thermodynamics of the crystallization process. Under certain thermodynamic conditions (solvent system, temperature, pressure, and concentration of the compounds of the present invention), one crystal modification may be more stable than the other (or indeed any of the others). However, crystal modifications with relatively low thermodynamic stability may be kinetically favored. Thus, in addition, kinetic factors such as time, impurity profile, agitation, presence or absence of seed crystals, etc. may also influence which crystal modification will crystallize.

In order to ensure that a particular crystal modification is prepared substantially free of other crystal modifications, it is preferred to carry out the crystallization by adding a seed crystal of the desired crystal modification. This applies in particular to each of the specific crystal modifications described in the examples.

Esomeprazole sodium salt modification C, E and H that can be obtained according to the present invention are substantially free of other crystalline and amorphous forms of esomeprazole sodium salt. It is to be understood that the term "substantially free of other crystalline and amorphous forms of esomeprazole sodium salt form" means that the desired esomeprazole crystalline form contains less than 15%, preferably less than 10%, more preferably less than 5% of any other form of esomeprazole sodium salt form.

The crystal modification of the present invention is effective as a gastric acid secretion inhibitor and thus can be used as an antiulcer agent. More broadly, they may be used for the prevention and treatment of gastric acid related conditions in mammals, particularly humans, including, for example, reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. In addition, they may be used to treat other gastrointestinal disorders requiring gastric acid inhibitory effects, such as patients on NSAID therapy, patients with non-ulcer dyspepsia, patients with symptomatic gastro-esophageal reflux disease, and patients with gastrinomas. They may also be used in intensive care patients, patients with acute upper gastrointestinal bleeding, pre-and post-operative patients to prevent gastric acid aspiration, to prevent and treat stress ulcers and asthma, and to improve sleep. Furthermore, the crystal modifications of the present invention may be used for the treatment of psoriasis and for the treatment of helicobacter pylori infections and related diseases. The crystal modifications of the invention may also be used for the treatment of inflammatory conditions in mammals including humans.

Any suitable route of administration may be used to provide the patient with an effective dose of the crystal modification. For example, oral or parenteral formulations, including intravenous injection, and the like, may be used. Dosage forms include capsules, tablets, dispersions, suspensions, solutions, and the like.

Further provided are pharmaceutical compositions comprising as active ingredient a crystal modification according to the invention in combination with a pharmaceutically acceptable carrier, diluent or excipient, and optionally in combination with other active pharmaceutical ingredients. Compositions comprising other therapeutic ingredients are of interest in the treatment of the conditions listed above. The invention also provides the use of a crystal modification for the manufacture of a medicament for use in said condition, as well as a method of treating a gastric acid related condition, which method comprises administering a pharmaceutically effective amount of a crystal modification to a subject suffering from said condition.

The compositions of the present invention include compositions suitable for oral, intravenous or parenteral administration. The most preferred route is the intravenous route. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods of galenic pharmacy.

In the practice of the present invention, the most suitable route of administration and therapeutic dosage strength will depend on the nature and severity of the condition being treated. The dose and frequency of administration will also vary according to the age, weight and response of the individual patient. For patients with Zollinger-Ellison syndrome, special requirements may be required, such as higher doses than are required for typical patients. Children and liver disease patients will generally benefit from doses somewhat below the average. Thus, in certain conditions, it may be necessary to use dosages outside the ranges indicated below, for example, longer term treatment may require lower dosages. Such higher and lower dosages are within the scope of the present invention. The daily dose will vary from 5mg to 300 mg.

In general, suitable oral dosage forms of the compounds of the invention may cover a dosage range of 5mg to 300mg of total daily dose, administered in a single dose or in divided doses. The preferred dosage range is 10mg to 80 mg.

The compounds of the present invention may be intimately admixed as active ingredients with pharmaceutical carriers according to conventional techniques, such as oral dosage forms described in WO96/01623 and EP0247983, the contents of which are hereby incorporated by reference in their entirety.

Combination preparations comprising the compounds of the invention and other active ingredients may also be used. Examples of such active ingredients include, but are not limited to, antibacterial compounds, non-steroidal anti-inflammatory agents, antacids, alginates, and prokinetic agents.

The compounds of the invention may be further processed before being formulated into suitable pharmaceutical preparations. For example, the crystal modification may be milled or ground into smaller particles.

For the avoidance of doubt, "treatment" includes both therapeutic treatment and prophylaxis of the condition.

The presence of other substances in the sample, such as pharmaceutical excipients, will of course mask some of the small peaks in the crystal modification of any of the above characterizations when characterized by X-ray powder diffraction. This fact alone certainly does not prove the absence of crystal modifications in the sample. In such cases due care must be taken and the presence of substantially all of the main peaks in the X-ray powder diffraction pattern may be sufficient to characterize the crystal modification. Therefore, the crystal modification of the present invention is preferably analyzed in the absence of other substances.

The invention is illustrated by the following examples, but is not limited in any way.

Examples

General procedure

X-ray powder diffraction analysis (XRPD) was performed on samples prepared according to standard methods, such as those described in: giacovazzo, C.et al (1995), Fundamentals of Crystallography, Oxford University Press; jenkins, R.and Snyder, R.L. (1996), Introduction to X-Ray Powder diffraction, John Wiley & Sons, New York; bunn, C.W, (1948), chemical crystallography, Clarendon Press, London; or Klug, H.P. & Alexander, L.E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York. X-ray diffraction analysis was performed using Philips X' Pert MPD for 16 minutes, from 1-40 ℃ 2. theta. The sample is analyzed without an internal reference, as sample loading may affect the time it takes to prepare the sample, and thus the position and intensity in the X-ray diffraction pattern. The measured peak was adjusted based on previous experience (-0.05 ° 2 θ). The calculation of the d-value is then performed.

The XRPD distance values may vary in the range of ± 2 over the last decimal place.

Example 1.1

Preparation of Esomeprazole sodium salt modifier C

esomeprazole-K (11.89g) was dissolved in water (50ml) and toluene (80ml) was added. The pH was then adjusted to about 7 by the addition of acetic acid (5.89ml, 25% v/v). The two phases were mixed for 10 minutes and then allowed to separate. The aqueous phase was removed and the remaining organic phase was washed with aqueous NaCl (50ml, 10%). After phase separation, methanol (4.24ml) was added to the toluene phase followed by 1eq NaOH (1.52ml, aq, 45%). To the solution 25mg of Eso-Na seeds were added. The crystals were crystallized overnight with stirring, filtered under vacuum and washed rapidly twice with toluene (2 × 10 ml). The resulting wet cake is dried briefly in air, e.g., for 2-5 minutes, and then analyzed.

Example 1.2

Preparation of Esomeprazole sodium salt modifier E

esomeprazole-K (11.89g) was dissolved in water (50ml) and toluene (80m1) was added. The pH was then adjusted to about 7 by the addition of acetic acid (5.89ml, 25% v/v). The two phases were mixed for 10 minutes and then allowed to separate. The aqueous phase was removed and the remaining organic phase was washed with aqueous NaCl (50ml, 10%). After phase separation, ethanol (11.1ml) was added to the toluene phase followed by 1eq NaOH (1.52ml, aq, 45%). To the solution was added 55mg of Eso-Na seeds. The crystals were crystallized overnight with stirring, filtered under vacuum and washed rapidly twice with toluene (2 × 10 ml). The resulting wet cake is dried briefly in air, e.g., for 2-5 minutes, and then analyzed.

Example 1.3

Preparation of Esomeprazole sodium salt modifier H

esomeprazole-K (11.89g) was dissolved in water (50ml) and toluene (80ml) was added. The pH was then adjusted to about 7 by the addition of acetic acid (5.89ml, 25% v/v). The two phases were mixed for 10 minutes and then allowed to separate. The aqueous phase was removed and the remaining organic phase was washed with aqueous NaCl (50ml, 10%). After phase separation, 2-propanol (3.6ml) was added to the toluene phase followed by 1eq naoh (1.52ml, aq, 45%). 53mg of Eso-Na seeds were added to the solution. The crystals were crystallized overnight with stirring, filtered under vacuum and washed rapidly twice with toluene (2 × 10 ml). The resulting wet cake is dried briefly in air, e.g., for 2-5 minutes, and then analyzed.

Claims (1)

1. Esomeprazole sodium salt modification C characterized by an X-ray powder diffraction pattern having peaks with d-values of 15.7, 7.9, 6.1, 5.3, 4.56, 3.59, 3.49, 3.17 a.