Patent Description:
The present invention relates to a novel process for preparing a hydrated form of perindopril L-arginine with improved process properties.

The process according to the invention includes a crystallisation process for the formation of a product, a hydrated form of perindopril L-arginine, wherein a suspension of the hydrated form of perindopril L-arginine formed in one of the steps of the process has excellent processing properties, which is achieved by precisely controlling and regulating the amount of water present in the process. The formed suspension of the hydrated form of perindopril L-arginine is stable and has a short filtration time, and the process according to the invention at the same time has a high molar yield comparable to the yields of the processes known in the prior art. The product obtained has high chromatographic purity and adequate stability under storage conditions at room temperature.

The process according to the invention is transferable to a large scale and is suitable for use on an industrial scale and provides an efficient, economical and reproducible process for the production of a hydrated form of perindopril L-arginine using materials that can be readily regenerated with a minimal environmental footprint.

Angiotensin-converting enzyme inhibitors (ACE inhibitors) are used to treat high blood pressure and certain types of cardiovascular diseases. Perindopril, with the chemical name (<NUM>)-<NUM>-[(<NUM>)-<NUM>-carbethoxybutylamino]-<NUM>-oxopropyl-(<NUM>, 3aS, 7aS)-perhydroindole-<NUM>-carboxylic acid, is a potent ACE inhibitor.

The prior art literature contains several descriptions of anhydrous and hydrated forms of perindopril L-arginine and of a process for preparing perindopril L-arginine, but nowhere is there a description of a process with a high molar yield and an industrially applicable process with good isolation properties for the production of a hydrated form of perindopril L-arginine.

The anhydrous forms of perindopril L-arginine (beta and delta) can be produced in high yield and with good filtration properties. The hydrated polymorphic forms (alpha, gamma) of perindopril L-arginine can also be produced in high yield, but always with slower filtration of the product, which makes efficient and rapid production on an industrial scale difficult. For example, when rapid filtration of a suspension of the product is described and when the amount of water in the suspension is lower than the molar equivalent based on the amount of peridopril L-arginine, the observed molar yields of the crystallisation processes are significantly lower. The prior art literature does not describe a reproducible crystallisation process for preparing a hydrated form of perindopril L-arginine with high molar yield and good filtration properties.

<CIT> describes perindopril and its pharmaceutically acceptable salts, where a pharmaceutically acceptable salt is selected from the group consisting of salts of mineral or organic acids or bases, such as sodium salt or maleate salt.

Perindopril L-arginine, its hydrates, a pharmaceutical composition and a treatment process were first described in <CIT>.

The alpha and beta forms of perindopril L-arginine are described in <CIT> and <CIT>. The forms were prepared by crystallisation from a mixture of several solvents.

The gamma hydrated form of perindopril L-arginine is described in <CIT>, where it was produced by spray-drying, freeze-drying, suspension or various crystallisation processes. In cases where high molar yields of the process are reported, the isolation properties of the suspension are poor - long filtration times of the product, the hydrated form of perindopril L-arginine.

Improved isolation properties of the crystallisation process are described in patent application <CIT>. In the examples <NUM>-<NUM> described herein, the molar yield of conversion to perindopril L-arginine from perindopril tert-butylamine was <NUM>-<NUM> %.

High molar yields of conversion from perindopril tert-butylamine to perindopril L-arginine are described in patent application <CIT>.

High molar yields of the crystallisation process of perindopril L-arginine gamma form with rapid filtration properties are described in patent application <CIT>.

The delta form of perindopril L-arginine is described in <CIT>, where the filtration properties of the isolated product were investigated in detail. The thermal stability of the product under stress conditions has been studied and described in detail. The delta form has been shown to be more stable under stress conditions compared to the hydrated or amorphous form.

There is a market need for a process for preparing a hydrated form of perindopril L-arginine with a high molar yield that is cost-competitive and that can be readily used in multi-purpose production equipment.

In the context of the invention, the hydrated form of perindopril L-arginine is understood to mean the hydrated polymorphic form of perindopril L-arginine.

It has been found that in the process for the production of a hydrated form of perindopril L-arginine, by controlling and regulating the amount of water in the crystallisation solution comprising perindopril L-arginine, the isolation properties of the suspension of the hydrated form of perindopril L-arginine formed in the process are improved, i.e. the stability time of the obtained suspension is prolonged, the filtration time of the suspension is shortened and the amount of solvent and antisolvent in the final product - an isolated wet filter cake of the hydrated form of perindopril L-arginine - is reduced, wherein the wet filter cake has a high dry residue value after drying and wherein the hydrated form of perindopril L-arginine with a high molar yield is obtained.

The term 'dry residue after drying', expressed as a %, as used throughout the present patent application, is defined as the % (w/w) of the dry fraction of the product of the hydrated form of perindopril L-arginine in the total weight of the isolated wet filter cake. The term 'paste strength' is also used in the art, e.g. as described in <CIT>.

The term relative mother liquor flow rate, as used throughout the present patent application to estimate the filtration rate of the hydrated form of perindopril L-arginine, is defined as the mass flow rate of solvent and antisolvent per unit area (kg/h/m<NUM>). This parameter quantifies the filtration rate of a suspension of the hydrated form of perindopril L-arginine.

The molar yield of the process according to the present invention, expressed as a %, is understood as the molar yield of conversion from perindopril tert-butylamine or perindopril to the hydrated form of perindopril L-arginine.

In the process for preparing a hydrated form of perindopril L-arginine according to the invention, perindopril or a perindopril salt may be used as a starting material. Preferably perindopril or perindopril tert-butylamine is used as a starting material.

The subject of the present invention is therefore a novel process for preparing a hydrated form of perindopril L-arginine, wherein perindopril or a perindopril salt is used as a starting material and wherein the process comprises:.

to obtain a product, a wet filter cake of the hydrated form of perindopril L-arginine, having a dry residue value after drying in the range of <NUM>-<NUM>%.

The process according to the invention is characterised by a high molar yield, the molar yield of the process being <NUM>-<NUM>%, preferably the molar yield of the process being <NUM>-<NUM>%.

The suspension formed in the step of forming a suspension of the hydrated form of perindopril L-arginine has good filtration properties and has a relative mother liquor flow rate in the range of <NUM>-<NUM>/h/m<NUM>.

In one embodiment, the present invention relates to a process for preparing a hydrated form of perindopril L-arginine, wherein perindopril tert-butylamine is used as a starting material and wherein the process comprises:.

In a further embodiment, the present invention relates to a process for preparing a hydrated form of perindopril L-arginine, wherein perindopril is used as a starting material and wherein the process comprises:.

to obtain a product, a wet filter cake of the hydrated form of perindopril L-arginine, having a dry residue value after drying in the range of <NUM>-<NUM>% and the molar yield of the process after drying is <NUM>-<NUM>%.

A yet further embodiment of the process according to the invention is a preparation of a hydrated form of perindopril L-arginine, from perindopril as a starting material, wherein perindopril is dissolved in ethanol at <NUM>. L-arginine is added to this solution and stirred at <NUM> for <NUM>-<NUM> minutes or until a clear solution is formed. The solvent is partially removed using techniques such as vacuum or atmospheric distillation. To the resulting clear solution, an antisolvent ethyl acetate at room temperature, is added, then the crystallisation solution is seeded while stirred and the amount of water is adjusted to give a suspension of the hydrated form of perindopril L-arginine, which is filtered and dried.

In the process according to the invention ethyl acetate isused as an antisolvent.

The amount of water in the resulting crystallisation solution is controlled and adjusted by adding such an amount of water to the crystallisation solution that the amount of water in the crystallisation solution is adjusted to <NUM>-<NUM> molar equivalents of water, calculated with respect to perindopril L-arginine, preferably <NUM>-<NUM> molar equivalents of water.

Less than <NUM> molar equivalent of water, calculated with respect to perindopril L-arginine, in the crystallisation solution results in a lower yield of the hydrated form of perindopril L-arginine.

Prior art processes for the crystallisation of the hydrated polymorphic form of perindopril L-arginine invariably use a large excess of water or a crystallisation mixture with less than <NUM> molar equivalent of water, resulting in a low yield of the isolated hydrated form of perindopril L-arginine.

If the amount of water in the crystallisation solution exceeds <NUM> molar equivalents, calculated per perindopril L-arginine, the filtration time of the resulting suspension after <NUM> hours at the final crystallisation temperature is longer or the relative flow rate of the mother liquor is reduced, moreover the amount of solvent and antisolvent in the isolated wet filter cake is also higher.

If the amount of water in the process is not controlled and water is added to the crystallisation solution in larger quantities, e.g. more than <NUM> molar equivalents, calculated per perindopril L-arginine, after <NUM>-<NUM> hours of stirring at the final crystallisation temperature, a gel-like suspension is formed and the filtration time of the resulting suspension of the hydrated form of perindopril L-arginine is considerably prolonged, or the relative flow rate of the mother liquor is reduced. In this case, the isolated wet filter cake contains a significantly lower proportion of dry matter.

In the step of adding a seeding material, the hydrated form of perindopril L-arginine is added as a seeding material in an amount of <NUM>-<NUM>% by weight relative to perindopril L-arginine.

In the process according to the invention, a stable suspension of the hydrated form of perindopril L-arginine with improved filtration properties is formed which, when stirred, retains unchanged filtration properties for a period of up to <NUM> hours after the suspension has been formed.

The crystallisation suspension of the hydrated form of perindopril L-arginine formed in the process according to the invention has a filtration time more than <NUM> times shorter compared to the processes described in the prior art, e.g. in <CIT>. For example, in an experiment where <NUM> of perindopril was used, the filtration time of the suspension of the hydrated form of perindopril L-arginine obtained by the process according to the invention was <NUM> minute and the relative mother liquor flow rate was <NUM>/h/m<NUM> (Example <NUM>, given hereafter) and in an experiment where <NUM> of perindopril tert-butylamine was used, the filtration time of the suspension of the hydrated form of perindopril L-arginine obtained by the process according to the invention was <NUM> minutes, and the relative mother liquor flow rate was <NUM>/h/m<NUM> (Example <NUM>, given hereafter).

Therefore, the process according to the invention is suitable for efficient and easy application on an industrial scale.

The wet filter cake of the hydrated form of perindopril L-arginine, isolated by the process according to the invention, has a dry residue value after drying in the range of <NUM>-<NUM>%. This means that <NUM>-<NUM>% (w/w) of the hydrated form of perindopril L-arginine is present in the resulting wet filter cake, the remainder being the solvent and the antisolvent. A higher dry residue value after drying means less solvent and antisolvent in the final isolated wet filter cake and vice versa. Due to the lower amount of solvent and antisolvent in the wet cake isolated by the process according to the invention, the wet product has a shorter drying time.

The correlation between the amount of water in the crystallisation solution and the isolation properties, i.e. the filtration time of the suspension of the hydrated form of perindopril L-arginine and the dry residue after drying, is shown in Table <NUM> which is presented in the present patent application hereinafter.

The hydrated form of perindopril L-arginine obtained after drying the filter cake obtained by the process according to the invention has high chromatographic purity and adequate stability under storage conditions at room temperature. The resulting hydrated form of perindopril L-arginine is stable under normal storage conditions at room temperature.

The hydrated form of perindopril L-arginine obtained by the process according to the invention is physically stable, with no observed tendency in the X-ray diffraction profile of the sample, and is chemically stable, with no observed tendency of degradation in the chromatographic profile.

The following apparatus were used in the processes and examples described below:
X-ray diffraction was performed on a PANalytical - XPert Pro MPD apparatus.

The chromatographic analysis was carried out using a Hitachi Primaide system apparatus. The results were given as a percentage of peak area or as an area percentage of the total area of the integrated peaks - area %.

The water content was determined on a Metrohm Karl-Fisher titrator (Model: <NUM> Basic Titrino), sample weight ranging from <NUM> to <NUM>.

The correlation between the stirring time of the suspension of the hydrated form of perindopril L-arginine at a final crystallisation temperature of <NUM> and the filtration time of the suspension is presented in Table <NUM> which is given in the present patent application hereinafter. The term stirring time, as used in the present application, means the stability time of the resulting suspension that is stirred.

Table <NUM> shows the correlation between the filtration time of the suspension at the final crystallisation temperature and the isolation properties of the product. Stirring the suspension of the hydrated form of perindopril L-arginine for more than <NUM> hours at the final crystallisation temperature has a negative impact on the filtration properties of the resulting suspension. If the suspension is stirred for more than <NUM> hours, the suspension becomes immiscible and has the properties of a gel.

When perindopril tert-butylamine is used as the starting material in the process according to the present invention, isolation of solid perindopril as an intermediate is not required.

The process according to the invention is advantageous in that it provides a simple and robust crystallisation process in which, by controlling and adjusting the appropriate amount of water in the crystallisation solution, a suspension of a hydrated form of perindopril L-arginine with excellent filtration properties is obtained, and which results in a high molar yield of conversion from perindopril tert-butylamine or perindopril to perindopril L-arginine.

The process according to the invention is cost-effective and suitable for being transferred to industrial scale for the routine production of a hydrated form of perindopril L-arginine.

The hydrated form of perindopril L-arginine obtained after drying the filter cake obtained by the process according to the invention is suitable for further use in the pharmaceutical industry, for example for the preparation of pharmaceutical dosage forms, preferably for the preparation of tablets.

The equivalents (equiv. ) mentioned in the text of the present application are molar equivalents.

The following embodiments are given for the purpose of illustrating an embodiment of the invention and do not limit the invention in any way.

Disodium hydrogen phosphate (<NUM>) was added to water (<NUM>), the resulting mixture was stirred and heated at <NUM>-<NUM> to obtain a clear solution. The clear solution was cooled to <NUM>-<NUM> and dichloromethane (<NUM>) and N-[(S)-<NUM>-carbethoxy-<NUM>-butyl]-(S)-alanine (<NUM>) were added while stirring and cooling to <NUM>-<NUM>. A solution of triphosgene (<NUM>) dissolved in dichloromethane (<NUM>) was slowly added to the reaction mixture at <NUM>-<NUM>. After the addition, the mixture was stirred for <NUM> minutes. Pyridine (<NUM>) was added to the reaction mixture and stirred for a further <NUM> hour. The organic phase was separated and washed first with 2N hydrochloric acid solution (<NUM>) and then with water (<NUM>). The organic phase was filtered and dichloromethane was distilled off under reduced pressure to give a pale-yellow oily residue, perindopril N-carboxy anhydride, weighing <NUM>. The dry residue value after distillation of perindopril N-carboxy anhydride is <NUM>%.

(<NUM>,3aS,7aS)-octahydro-<NUM>-indole-<NUM>-carboxylic acid (<NUM>), dichloromethane (DCM) (<NUM>) and triethylamine (<NUM>) were added to a reaction flask and stirred for <NUM>-<NUM> minutes at room temperature. The perindopril N-carboxy anhydride oily residue with a dry matter content of <NUM>% (<NUM>-<NUM>) - obtained by the above process - and dichloromethane (<NUM>) were added slowly at room temperature. After the addition, the reaction mixture was stirred for <NUM> hour. Water (<NUM>) was added and the reaction mixture was cooled to <NUM>-<NUM>, the pH of the reaction mixture was adjusted to pH <NUM>-<NUM> using a 2N hydrochloric acid solution. After pH adjustment, the layers were separated and the aqueous layer was washed twice with dichloromethane (<NUM>). The organic phases were combined and distilled at reduced pressure and at a temperature below <NUM> to give the oily residue, pure (<NUM>,3aS,7aS)-<NUM>-ethoxy-<NUM>-<NUM>-<NUM>-oxopentan-<NUM>-yl)-L-alanyl) octahydro-<NUM>-indol-<NUM>-carboxylic acid (perindopril) weighing <NUM>.

To <NUM> of the oily residue, containing pure (<NUM>,3aS,7aS)-<NUM>-ethoxy-<NUM>-<NUM>-oxopentan-<NUM>-yl)-L-alanyl) octahydro-<NUM>-indol-<NUM>-carboxylic acid obtained by the above process for preparing perindopril, ethyl acetate (<NUM>) was added and stirred for <NUM> minutes at <NUM>-<NUM>. If necessary, filtering was carried out to remove undissolved particles. Tert-butylamine (<NUM>) was added and stirred for <NUM> minutes at <NUM>. The resulting suspension was heated to reflux temperature and stirred until completely dissolved, but not more than <NUM> minutes. The resulting solution was then cooled to <NUM> in a period of <NUM> hours and stirred for <NUM> hours at a final temperature of <NUM>. The suspension was filtered and washed with ethyl acetate (<NUM>) to give a wet product, crude perindopril tert-butylamine, weighing <NUM>. The dry residue value after drying of perindopril tert-butylamine is <NUM>%.

To a wet filter cake of perindopril tert-butylamine (<NUM>) obtained by the above process for preparing crude perindopril tert-butylamine, ethyl acetate (<NUM>) and <NUM> of tert-butylamine were added and stirred for <NUM> at <NUM>. The suspension was heated to reflux temperature and stirred until completely dissolved, but not more than <NUM> minutes. The resulting solution was then cooled to <NUM> in a period of <NUM> hours and stirred for <NUM> hours at a final temperature of <NUM>. The suspension was filtered and washed with ethyl acetate (<NUM>). The resulting material, perindopril tert-butylamine, was dried in a dryer for <NUM> hours at <NUM> and a pressure of <NUM> mbar. The weight of the dried perindopril tert-butylamine is <NUM>.

Perindopril tert-butylamine (<NUM>) obtained by the above process was added to a reaction vessel and water (<NUM>) and dichloromethane (<NUM>) were added. The mixture was cooled to <NUM> and hydrochloric acid (<NUM>% solution) was added to adjust the pH to <NUM>. It was stirred for <NUM> minutes and then left to stand to allow the phases to separate. The aqueous layer was washed with dichloromethane (<NUM>), stirred for <NUM> minutes and then stirring was discontinued for the phases to separate. The combined dichloromethane phases were evaporated under vacuum at <NUM>. After evaporation, N-heptane (<NUM>) was added to the resulting oily residue and stirred at <NUM> for <NUM> hours. The obtained material was filtered and dried for <NUM> hours at <NUM> and a pressure of <NUM> mbar in a dryer to obtain <NUM> of (<NUM>,3aS,7aS)-<NUM>-ethoxy-<NUM>-<NUM>-oxopentan-<NUM>-yl)-L-alanyl)octahydro-<NUM>-indole-<NUM>-carboxylic acid.

Perindopril obtained by the above process (<NUM>, calculated as per <NUM>% perindopril content) was dissolved in ethanol (<NUM>) at <NUM>. L-arginine (<NUM>, <NUM> equiv. ) was added to the solution and stirred until completely dissolved. If necessary, the resulting solution (<NUM>) was filtered through a GF/B filter to obtain a completely clear solution. The solvent (<NUM> of ethanol solvent) was distilled off the resulting solution using a vacuum at <NUM>. The partially evaporated solution weighing <NUM> was cooled to <NUM>. Ethyl acetate (<NUM>, water content < <NUM>% by weight) was added to the solution at <NUM>. The solution was stirred for a few minutes and the water content was measured and then adjusted to <NUM> equivalents, calculated with respect to perindopril L-arginine - the total amount of water in the crystallisation solution was <NUM>. After adding water, the seeding material, the hydrated form of perindopril L-arginine (<NUM>), was added and the resulting suspension was stirred for <NUM> hours at <NUM>. The isolation technique of vacuum filtration was used and the resulting wet filter cake was dried for <NUM> hours at <NUM> and a pressure of <NUM> mbar.

The molar yield of the process was <NUM> %, the filtration time of the product, the hydrated form of perindopril L-arginine, was <NUM> minute, the relative mother liquor flow rate was <NUM>/h/m<NUM>, and the wet filter cake had a dry residue value after drying of <NUM>%.

The resulting solid after drying was identified as the hydrated form of perindopril L-arginine with a water content of <NUM>% by weight.

The sample was packed in double <NUM> polyethylene bags with silica gel and stored in an aluminium heat-sealed bag.

Process for preparing a hydrated form of perindopril (L)-arginine from perindopril tert-butylamine as a starting material.

Perindopril tert-butylamine (<NUM>, calculated to <NUM>% perindopril tert-butylamine content) was dissolved in water (<NUM>) and dichloromethane (<NUM>) was added at <NUM>. Hydrochloric acid solution (<NUM>% solution) was added dropwise to the reaction mixture until the pH reached <NUM>. The layers were separated and the aqueous layer was washed with dichloromethane (<NUM>), and the organic phase was collected. The organic phases were combined and ethanol (<NUM>) was added to the organic phase and the solvent mixture was distilled off. On completion of distillation, a solution weighing <NUM> was obtained, the water content in this solution had to be ≤ <NUM>% by weight (water content less than <NUM> equiv. with respect to perindopril). If the criterion was not met, ethanol (<NUM>) was added and the solvent mixture distilled off (<NUM>), or the addition of ethanol was repeated (<NUM>) and then distilled off (<NUM>) until the water content in the solution weighing <NUM> of ≤ <NUM>% by weight was achieved. L-arginine (<NUM>, <NUM> molar equiv. ) was added to the solution and stirred until completely dissolved at <NUM>. If necessary, the solution was filtered through a GF/B filter to obtain a completely clear solution. The solvent was distilled off the resulting solution using vacuum evaporation at <NUM>. The partially evaporated solution weighing <NUM> was cooled to <NUM>. Ethyl acetate (<NUM>, water content < <NUM>% by weight) was added to the solution at <NUM>. The resulting crystallisation solution of perindopril L-arginine was stirred for a few minutes, the water content was controlled and adjusted to <NUM> molar equivalents, calculated with respect to perindopril L-arginine - the total amount of water in the crystallisation mixture was <NUM>. After adding water, the seeding material, the hydrated form of perindopril L-arginine (<NUM>), was added and the resulting suspension was stirred for <NUM> hours at the final crystallisation temperature of <NUM>. The vacuum filtration was used as the isolation technique and the obtained wet filter cake was dried for <NUM> hours at <NUM> and a pressure of <NUM> mbar.

The molar yield of the process was <NUM> %, the filtration time of the product, the hydrated form of perindopril L-arginine, was <NUM> minute, the relative mother liquor flow rate was <NUM>/h/m<NUM>, and the wet cake had a dry residue value after drying of <NUM>%.

The obtained solid after drying was identified as the hydrated form of perindopril L-arginine with a water content of <NUM>% by weight.

The sample was packed in double <NUM> polyethylene (PE) bags with silica gel and stored in an aluminium heat-sealed bag.

Following the process described in Example <NUM> above, a hydrated form of perindopril L-arginine was prepared from perindopril tert-butylamine as a starting material, wherein various amounts or molar equivalents of water, calculated with respect to perindopril L-arginine, were added to the crystallisation solution during the process.

The results represented in Table <NUM> below show the correlation between the amount of water in the crystallisation solution of perindopril L-arginine and the isolation properties of the suspension of the hydrated form of perindopril L-arginine, resulting from the process. If the amount of water in the crystallisation solution exceeded <NUM> molar equivalents, calculated with respect to perindopril L-arginine, the filtration time of the suspension of the hydrated form of perindopril L-arginine resulting from the process was considerably longer and the amount of solvent and antisolvent in the isolated wet filter cake was also higher.

If the amount of water in the process was not controlled and water was added to the crystallisation solution of perindopril L-arginine in larger quantities, e.g. more than <NUM> molar equivalents, calculated with respect to perindopril L-arginine, after <NUM>-<NUM> hours of stirring the suspension of the hydrated form of perindopril L-arginine at the final crystallisation temperature, a gel-like suspension was formed and the filtration time of the resulting suspension was considerably prolonged.

Less than <NUM> molar equivalent of water in the crystallisation solution, calculated with respect to perindopril L-arginine, resulted in a lower yield of the hydrated form of perindopril L-arginine.

Following the process described in Example <NUM> above, a hydrated form of perindopril L-arginine was prepared from perindopril tert-butylamine as a starting material, wherein the stirring time of the suspension of the hydrated form of perindopril L-arginine formed in the process was changed at the final crystallisation temperature of <NUM>.

Table <NUM> shows the correlation between the stirring time at the final crystallisation temperature and the filtration time of the suspension. Stirring longer than <NUM> hours at the final crystallisation temperature had a negative impact on the filtration properties. The suspension became immiscible and gel-like if stirred for more than <NUM> hours.

The hydrated form of perindopril L-arginine, prepared according to the process described in Example <NUM> above, was exposed to storage conditions at <NUM> and <NUM>% relative humidity for <NUM> months.

The hydrated form of perindopril L-arginine was found to be chemically and physically stable at storage conditions of <NUM> and <NUM>% relative humidity after <NUM> months with a chromatographic purity of more than <NUM>%. The samples were packed in double polyethylene bags to prevent moisture absorption on the product and to control the water content of the packed sample to be below <NUM> % by weight. Silica gel was used as a drying agent. A precisely measured amount of water in the crystallisation solution ensures that the sample does not contain additional non-crystal-bound water after drying.

The hydrated form of perindopril L-arginine obtained by the process according to the invention is physically stable, with no observed tendency in the diffraction pattern of the sample, and chemically stable, with no observed degradation in the chromatographic profile.

The investigation of the stability of the samples or the observation of the degradation of the samples was mainly focused on the investigation of the tendency of two impurities: impurity B (Imp. B, <NUM>,3aS,7aS)-<NUM>-[(<NUM>)-<NUM>-[[[(<NUM>)-<NUM>-carboxybutyl]-amino]propanoyl]octahydro-<NUM>-indole-<NUM>-carboxylic acid) and Impurity F (Imp. F, ethyl (<NUM>)-<NUM>-[(<NUM>,5aS,9aS,10aS)-<NUM>-methyl-<NUM>,<NUM>-dioxodecahydropyrazino-[<NUM>,<NUM>-a]indol-<NUM>(<NUM>)-yl]pentanoate) according to the analytical procedure described in the European Pharmacopoeia PhEur <NUM>. Impurity B and impurity F are typical impurities of perindopril degradation due to the hydrolytic mechanism, usually caused by exposure to water, temperature and time.

Table <NUM> presents the stability samples of the hydrated form of perindopril L-arginine prepared according to the process described in Example <NUM> above, wherein the amount of L-arginine in the salt formation reaction was varied.

The samples were packed in double <NUM> polyethylene bags with silica gel and stored in an aluminium heat-sealed bag to protect the samples against moisture ingress.

The parameter investigated was the amount of L-arginine added to the crystallisation solution, which influences the L-arginine content in the isolated material. The results show that a slight excess of L-arginine molar equivalent must be used for salt formation to effectively control the low level of impurity F when tested under storage conditions at <NUM> and <NUM>% relative humidity for <NUM> months. The diffraction pattern of the hydrated sample remains identical after <NUM> months at storage conditions of <NUM> and <NUM>% relative humidity compared to the initial sample.

The results presented in Table <NUM> show the correlation between stability under conditions at <NUM> and <NUM>% relative humidity. Table <NUM> shows that an increase in the water content in the storage of the material - the hydrated form of perindopril L-arginine - leads to an increase in the amount of impurity B. It is essential that the water content in the stored material is controlled to be below <NUM> % by weight during storage/storage conditions at <NUM> and <NUM>% relative humidity for <NUM> months, resulting in an impurity content at an appropriately low level.

The investigated material, the hydrated form of perindopril L-arginine, is hygroscopic when exposed to relative humidity > <NUM>% at room temperature.

Table <NUM> shows the results of stress conditions at a temperature of <NUM> and <NUM>% relative humidity. A comparison experiment with a water content of <NUM> % by weight after <NUM> days shows that impurity B (Imp. B) content increased up to <NUM> times faster compared to the sample in which the water content was controlled and no increase in the water content of the sample was observed after <NUM> days.

Perindopril tert-butylamine (<NUM>, calculated with respect to <NUM>% perindopril tert-butylamine content) was dissolved in water (<NUM>) and dichloromethane (<NUM>) at <NUM>. A hydrochloric acid solution (<NUM>% solution) was slowly added to the reaction vessel until the pH <NUM> was reached. The layers were separated and the aqueous phase was washed with dichloromethane (<NUM>), the organic phase was collected. Ethanol (<NUM>) was added to the combined organic phase (perindopril formation yield is <NUM>%) and the solvent mixture was distilled off. On completion of distillation, a solution weighing <NUM> was obtained, the water content of this solution had to be ≤ <NUM>% by weight (water content less than <NUM> equiv. with respect to perindopril). If the criterion is not met, ethanol (<NUM>) is added and the solvent mixture (<NUM>) distilled off until the water content of ≤ <NUM>% by weight is reached or the addition of ethanol is repeated (<NUM>) and then distilled off (<NUM>) until the water content in the solution weighing <NUM> of ≤ <NUM>% by weight is achieved. L-arginine (<NUM>, <NUM> equiv. ) was added to the solution and stirred until completely dissolved at <NUM>. If necessary, the solution was filtered through a GF/B filter to obtain a completely clear solution. The solvent was distilled off the resulting solution using a vacuum at <NUM>. The partially evaporated solution weighing <NUM> was cooled to <NUM>. Ethyl acetate (<NUM>, water content < <NUM>% by weight) was added to the solution at <NUM>. The solution was stirred for a few minutes, the water content was adjusted to <NUM> molar equivalents, calculated with respect to equiv. of perindopril L-arginine - the total amount of water in the crystallisation mixture was <NUM>. After having added water, the seeding material, the hydrated form of perindopril L-arginine (<NUM>), was added and the suspension was stirred for <NUM> hours at <NUM>. The vacuum filtration was used as the isolation technique and the wet filter cake was dried in a dryer for <NUM> hours at <NUM> and a pressure of <NUM> mbar.

The molar yield was <NUM> %, the filtration time of the product, the hydrated form of perindopril L-arginine, was <NUM> minutes, the relative mother liquor flow rate was <NUM>/h/m<NUM>, and the wet cake had a dry residue value after drying of <NUM>%.

The hydrated form of perindopril L-arginine was prepared according to the process described in <CIT>, Example <NUM>.

Water (<NUM>), perindopril (<NUM>) and L-arginine (<NUM>) were introduced into a reaction vessel at room temperature while stirring. When a clear solution was formed, methylcyclohexane (<NUM>) was added and then dimethyl sulfoxide (<NUM>) was slowly added. The mixture was stirred until the temperature of the heterogeneous mixture stabilised at about <NUM>, after which the mixture was vacuum filtered and the obtained solid was washed and dried.

The molar yield was <NUM>%, the filtration time of the product, the hydrated form of perindopril L-arginine, was <NUM>, the relative mother liquor flow rate was <NUM>/h/m<NUM>, and the wet cake had a dry residue value after drying of <NUM>%.

Perindopril (<NUM>), L-arginine (<NUM>) and water (<NUM>) were introduced into a reaction vessel equipped with a water separator (Dean-Stark trap) at room temperature while stirring. Once a clear solution was formed, cyclohexane (<NUM>) was added and the mixture was stirred at reflux temperature until no more water separation was observed - water separation was complete and water was no longer removed from the reaction mixture. The reactor temperature was cooled to <NUM> and stirred for <NUM> hour. The suspension was filtered and the resulting wet cake was dried.

Claim 1:
A process for preparing a hydrated form of perindopril L-arginine, characterized in that perindopril or a perindopril salt is used as a starting material and in that the process comprises:
- forming a crystallisation solution comprising perindopril L-arginine, wherein forming the crystallisation solution comprises at least:
- forming a perindopril solution, wherein ethanol is used as a solvent and ethyl acetate is used as an antisolvent, and wherein the perindopril solution formed contains less than <NUM> mol. equiv. of water with respect to perindopril,
- adding L-arginine to the perindopril solution,
to form a crystallisation solution comprising perindopril L-arginine,
- measuring the amount of water in the obtained crystallisation solution comprising perindopril L-arginine,
- adjusting the amount of water in the obtained crystallisation solution by adding such an amount of water to the crystallisation solution that the amount of water in the crystallisation solution is adjusted to <NUM>-<NUM> molar equivalents of water, preferably <NUM>-<NUM> molar equivalents of water, calculated with respect to perindopril L-arginine,
- adding a seeding material to the obtained crystallisation solution, wherein the seeding material is the hydrated form of perindopril L-arginine,
- forming a suspension of the hydrated form of perindopril L-arginine, having a relative mother liquor flow rate in the range of <NUM>-<NUM>/h/m<NUM>,
- filtering the obtained suspension of the hydrated form of perindopril L-arginine,
to obtain a final product, a wet filter cake of the hydrated form of perindopril L-arginine, having a dry residue value after drying in the range of <NUM>-<NUM>%.