WO2011098258A1 - Salts of aliskiren - Google Patents

Abstract

The present invention relates to new salts of the renin inhibitor Aliskiren in a crystalline or amorphous form, processes for the manufacture of the new Aliskiren salts in a crystalline form, and a process for forming salts of Aliskiren by freeze-drying and/or spray-drying.

Description

Salts of Aliskiren

Background

The present invention relates to new salts of the renin inhibitor Aliskiren in a crystalline or amorphous form, processes for the manufacture of the new Aliskiren salts in a crystalline form, and a process for forming salts of Aliskiren by freeze drying, trituration/precipitation and/or spray drying.

In the art Aliskiren is currently employed as a medicament for arterial hypertension.

As known from prior art Aliskiren is the INN name of the free base compound with the chemical name:

2(S),4(S),5(S),7(S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-di(1-methylethyl)-4- hydroxy-5-amino-8-[4-methoxy-3-(3-methoxy-propoxy)phenyl]-octanamide.

The Aliskiren free base compound is reported to have the following structure:

The Aliskiren free base is reported to have one basic amino group in position 5, which has a pKb of 4.21. The amino group is a relatively strong base. It is therefore possible to form salts of this basic functionality with a corresponding acid. The hydrochloride salts of Aliskiren have been disclosed in EP 0 678 503 B1. A common salt is also the hemifumarate salt of Aliskiren, which is known in the art and has been employed for the development of anti-hypertensive agents. The HCI salt is apparently difficult to handle and does not crystallize well. On the other hand, while the hemifumarate salt does form crystals, which are at least partially crystalline, it is said to be difficult to formulate.

Furthermore, Aliskiren allegedly has a very poor oral resorption rate. The bioavailability is consequently low. Higher drug loads are not easily accessible, because the produced tablets tend to become friable or instable. In order to improve the bioavailability of the active ingredient, new formulations and Aliskiren compositions are therefore required.

In particular, the new Aliskiren compositions should have an improved stability. This is important in view of the high hygroscopicity of Aliskiren. The absorption of water into the formulation impedes the storage stability and processability of Aliskiren medicaments.

An effective method to improve the stability is to achieve a higher degree of crystallinity of the salt product, which is thus generally desirable.

In addition, a good flowability and uniformity of the product is essential for drug substance quality. The wetting susceptibility, tackiness, bulk density and particle size distribution all contribute to these properties.

In order to achieve uniform dosage tablets or formulation dosage units, the addition of water must be controlled in such a manner that it is minimized or at least held constant. In addition, the formulations must be physically and chemically stable. Summary of the invention

Unexpectedly, the above described objects have been solved by new salts of Aliskiren.

Therefore, subject of the present invention are salts of the Aliskiren free base compound, with one or more acid compounds of the Formula H_mX, wherein H is a dissociable hydrogen atom, X is a pharmaceutically acceptable residue and m is a natural number, but wherein X is not a fumarate, hemifumarate, nitrate, chloride, sulphate or orotate, showed improved properties.

The salts of Aliskiren with fumaric acid, nitric acid, hydrochloric acid, sulphuric acid, or orotic acid each suffer from particular disadvantages.

Specifically, these salts do not crystallize well under rapid drying conditions and therefore tend to afford poor formulations. This disadvantage is more pronounced when the purification method of spray and/or freeze drying according to the invention is performed. In this case, the fumarate, hemifumarate, nitrate, chloride, sulphate or orotate salts show poor crystallization and purification results. Therefore, the salts of Aliskiren with these acids cannot be prepared as well using the rapid drying methods as described herein. Surprisingly, it was further found that the above problems can be solved particularly well by a salt of the Aliskiren free base compound, with one or more acid compounds of the Formula H_mX, wherein H is a dissociable hydrogen atom, X is a pharmaceutically acceptable residue and m is a natural number, wherein the acid compound or the acid compounds have a melting point of between 5 °C and 275 °C.

Detailed description of the invention

In the following the invention and preferred embodiments thereof are illustrated. In a preferred embodiment, the above acid compound has a melting point of between 15 °C and 275 °C. In this range, the effects as described below can be achieved particularly well. Preferably, in the above inventive salts m is a number from 1 to 8, more preferably 1 , 2, 3 or 4. In general, a dissociable hydrogen atom is considered to have a pK_a of between -6 and 14. It is also preferred that the acid compound has a melting point of between 30 °C and 250 °C, more preferably between 100 °C and 180 °C.

The salts achieved under the above conditions have been found to achieve a higher degree of stability, in particular in drug formulations. It appears that very hard mineral acids with low melting points do not form good stable salts with Aliskiren. These salts tend not to crystallize well and are difficult to handle. On the other hand, high melting point acids are not well suited for stable salt formation either.

Furthermore, the salts of these acids have a higher degree of crystallinity and lower hygroscopicity. Hard mineral acid salts of Aliskiren tend to attract water and do not inhibit the water-pulling properties of the Aliskiren free base molecule main body, which contains a number of polar groups.

On the other hand, while larger complementary acid molecules can prevent water attraction in the formed salt, they should not themselves have too high enthalpic stability, so as not to preclude the stability of the formed salt.

In a preferred aspect of the invention, the salt is formed from an acid compound, which is preferably an organic acid. In a particularly preferred development of the invention, the acid comprises two or more acidic protons, which each have a pK_a of between 0.1 and 13.0. Preferably, the pK_ai value of the acid is between 1.0 and 10.0, more preferably between 1.1 and 8.0, even more preferably greater than 1.8, but superior effects are achieved if the pK_ai value of the acid is less than 3.5. Hence, a subject of the present invention is a salt of the Aliskiren free base compound, with one or more acid compounds of the Formula H_mX, wherein H is a dissociable hydrogen atom having a pK_a of between 0.1 and 13.0, preferably between 1.0 and 10.0, more preferably between 1.1 and 8.0, and X is a pharmaceutically acceptable residue and m is a natural number.

In a further alternative embodiment, the pK_a value can be as low as up to -8, but preferably more than or equal to -6.

In an even more preferred embodiment of the invention, the acid of the salt is such that the difference in the acidic strengths of the first and second acidic functionalities i.e. pK₃2 - p _ai is greater or equal to 0.5, but less than or equal to 5.5.

More preferably the delta pK_a, pK_a2 - pK_ai , of the acid compound is between 1.0 and 5.1 , even more preferably less than 4.5, and more preferably greater or equal to 1.35, most preferably greater or equal to 1.50. In an alternative aspect, a high difference can be preferable of pK_a2 - pK_a1 between 7.0 and 8.0.

In an alternative preferred embodiment, the acid has one acidic proton with a pK_a of between 1.0 and 8.0, more preferably between 1.5 and 7.0.

The acid dissociation constant, K_a (also known in the art as acidity constant, or acid ionization constant), is a quantitative measure of the strength of an acid in solution, preferably in water, more preferably in pure water. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions. The equilibrium can be written symbolically as:

where HX is an acid which dissociates by splitting into A^", known as the conjugate base of the acid, and the hydrogen ion or proton, H⁺, which, in the case of aqueous solutions, exists as a solvated hydronium ion.

The dissociation constant is usually written as a quotient of the equilibrium concentrations, denoted by [HA], [A^~] and [H⁺]:

[A-][H+]

[HA] Due to the many orders of magnitude spanned by K_a values, a logarithmic measure to the basis 10 of the acid dissociation constant is more commonly used in practice. pK_a, which is equal to -logio _a, may also be referred to as an acid dissociation constant: pK_* = - logic K_*

The larger the value of pK_a, the smaller the extent of dissociation. An acid having a pK_a value in the approximate range of -2 to 12 in water can be regarded as "weak acid". An acid with a pK_a value of less than about -2 can be regarded as "strong acid". If an acid comprises more than one dissociable protons the term "pK_a " refers to the dissociation constant of the proton dissociating first, "pK_a2" refers to the dissociation constant of the proton dissociating second and so on.

Generally, the pK_a value is determined at 25 °C by potentiometric titration or by Capillary electrophoresis (CE; capillary zone electrophoresis = CZE).

A summary of the melting points of the acid compounds forming the salts and the corresponding pK_a values is shown in Table 1.

Table 1

The hardness and softness of the acid function also appears to play a role. Generally, the Lewis acid strength of the acidic function should not be too soft so as to be incompatible with the free base amino function. On the other hand, very hard mineral acids are found to be less suitable also.

The above features afford more stable forms of Aliskiren, which are even easier to manage in the drying, filtration or granulation processes that general form part of the compound manufacturing process.

The acidic strength ranges presented above lead to an improved crystallinity of the compound, which facilitates the preparation of pharmaceutical formulations as explained above.

In a further aspect of the invention, the invention pertains to a salt, wherein the acid compound is an organic acid with between 1 and 13 carbon atoms.

Preferably, the organic acid has between 2 and 8 carbon atoms, more preferably 4 carbon atoms.

The salts thus generated display a reduced hygroscopicity. Since these salts do not pull water as strongly as comparative salts in the art, such as the hemifumarate salt of Aliskiren, they have advantages in galenic formulations. In particular, the combination of the above described factors improves the standard tablet manufacturing process. The water content stability enables more uniform dosage units and an improved long-term shelf life of the formulations.

Good salts can be achieved with the following acids: formic acid, dichloroacetic acid, glyoxylic acid, oxalic acid, acetic acid, glycolic acid, malonic acid, propanoic acid, lactic acid, maleic acid, succinic acid, malic acid, L- tartaric acid, L-aspartic acid, butanoic acid, glutaric acid, 2-oxoglutaric acid, L-glutamic acid, hippuric acid, 2-methylbutanoic acid, 3-methylbutanoic acid, pentanoic acid, picolinic acid, 3-pyridinecarboxylic acid, 4-pyridinecarboxylic acid, benzenesulfonic acid, L-ascorbic acid, citric acid, adipic acid, 3-methylglutaric acid, benzoic acid, 4-acet- amidobenzoic acid, hydroxy benzoic acid, dihydroxybenzoic acid, dihydroxymalic acid, gallic acid, 2,4,6-trihydroxybenzoic acid, aminobenzoic acid, heptanoic acid, D- or L- mandelic acid, octanoic acid, cinnamic acid, methylcinnamic acid,

The inventive salt preferably comprises an acid compound, which is one or more selected from the following list: oxalic acid, maleic acid, malic acid, alpha-tartaric acid, preferably alpha-L-tartaric acid, succinic acid, ascorbic acid, citric acid, adipic acid, D or L-mandelic acid, acetic acid, D- or L-aspartic acid.

Hence, a further subject of the present invention is a salt of the Aliskiren free base compound with one or more acid compounds selected from oxalic acid, maleic acid, malic acid, alpha-tartaric acid, alpha-L-tartaric acid, succinic acid, ascorbic acid, citric acid, adipic acid, D or L-mandelic acid, acetic acid, D- or L-aspartic acid or mixtures thereof.

More preferred acid compounds are acetic acid, aspartic acid, succinic acid, oxalic acid, maleic acid, malic acid and/or alpha-tartaric acid and even more preferred are maleic acid and/or tartaric acid.

These acids afford very stable Aliskiren salts. XRD measurements show the high crystallinity.

In particular, the salt should not be formed of a fumaric acid, which has a relatively low melting point combined with a high hygroscopicity as well as readily undergoing multiple polymorphic transitions, which impede stable galenic formulations. Preferably, the acid compound in the salt is therefore not a fumaric acid.

Preferred organic ions for X are ascorbate, succinate, oxalate, mandelate, adipate, ethanesulfonate, naphthalene-1 ,5-disulfonate, naphthalene-1 -sulfonate, naphthalene- 2-sulfonate, L-aspartate, 4-acetamidobenzoate, (+) camphorate, (+) camphor-10- sulfonate, decanoate, hexanoate, octanoate, cinnamate, dodecylsulfate, ethane-1 ,2- disulfonate, 2-hydroxyethanesulfonate, glutarate, D or L-lactate, 1-hydroxy-2- naphthoate, laureate, salicylate, tartrate or mixtures thereof.

In an alternative variant of the invention, the anionic counter ion in the salt can be an inorganic anion. Preferable, the anion X is carbonate, hydrogencarbonate, phosphate, hydrogenphosphate, dihydrogenphosphate, diphosphate, silicate, hydrogensilicate, bromide, fluoride and/or iodide. More preferable are the phosphate ions, in particular dihydrogenphosphate.

The counter ion should generally be pharmaceutically acceptable. In a further aspect of the invention, the acid compound to free base compound ratio in the salt is from 1 :3.2 to 2.1 :1. Preferably the ratio is from 1 :3 to 1 :1.

In particular, the ratio of acid compound to free base compound is preferably set that all dissociable hydrogen atoms of the acid compound can react with the respective equivalent of free base compound. Therefore for an acid compound with one dissociable hydrogen, such as acetic acid, the preferred ratio would be 1 :1. For an acid compound with two dissociable hydrogen atoms, such as tartaric acid or succinic acid, the preferred ratio would be 1 :2. Further for an acid compound with three possible dissociable hydrogen atoms, such as citric acid, the preferred ratio would be 1 :3.

The stability of Aliskiren salts may be related to the ratio of acid compound to free Aliskiren. This seems to be especially important when polyfunctional acids and acids with multiple acid groups are involved. Polyfunctional acids and acids with multiple acid groups are able to form Aliskiren salts with different ratios of acid compound to free base compound. The preferably set ratio as above can lead to a significant enhanced stability. This can be due to the fact that for an example a 1 :2 ratio of tartaric acid to Aliskiren leads to a neutral salt. In contrast a 1 :1 ratio of tartaric acid to free Aliskiren would result in an acidic salt and the presence of excess acid can lead to higher degradation.

In alternative embodiments, the invention relates to the hydrate or solvate forms of the inventive salts. The salts according to the invention, their solvates and polymorphous forms exhibit the improved properties. Preferably the inventive salts are in a crystalline form, or at least in a partly crystalline form. The higher degree of crystallinity, leads to more stable salts. In addition, these salts display an improved flowability and formulation processability. Highly crystalline salts are less tacky and can be tabletted with high drug load uniformity. These salts are generally superior to the amorphous salts, such as those of Aliskiren hemifumarate, which show little stability and which tend to form hard foams, waxes or oils.

The high degree of crystallinity can be seen in XRD measurements and from the DCS graphs. Preferably the degree of crystallinity is more than or equal to 40 wt.%.

It is also preferred that the water content is less than 0.1 to 5 wt.%, more preferably from 0.5 to 3 wt.%. The water content is determined as described below in the experimental section. The salts according to the present invention have high purity and a low residual solvent content. In cases where the solvent is not water preferably the solvent content is less than 1500 ppm, more preferably of less than 500 ppm, particularly less than 200 ppm. Solvates and also hydrates of the salts according to the invention may be present, for example, as hemi-, mono-, di-, tri-, tetra-, penta-, hexa-solvates or hydrates, respectively. Solvents used for crystallisation, such acetonitrile, alcohols, especially methanol, ethanol, aldehydes, ketones, especially acetone, esters, e.g. ethyl acetate, or alkanes, especially pentane, hexane, heptane or cyclohexane, may be embedded in the crystal grating.

The salts according to the invention preferably exist in isolated and essentially pure form, for example in a degree of purity of >95 wt.%, preferably >98 wt.%, more preferably >99 wt.%. The enantiomer purity of the salts according to the invention is >98 wt.%, preferably >99 wt.%. Usually, pharmaceutically acceptable salts of Aliskiren are obtained in crystalline form. Depending on the acidic compound, pharmaceutically acceptable salts of Aliskiren may, however, be obtained in different polymorphic forms. In crystalline solids with an identical chemical composition, the appearance of different resulting crystal gratings is termed polymorphism. When the salts are subjected to differential scanning calorimetry, (DSC) the endothermic peaks indicate molecular rearrangements or transformations. Moreover, none of the peaks in the figures shown below is related to residual solvents or other impurities.

The invention thus also relates to the polymorphous forms of the salts. Depending on the respective salt, the polymorphic forms show different properties with regard to flowability and storage stability. The inventive Aliskiren salts preferably are present in particulate form. Usually the particles have a volume mean particle size (D50) of 1 to 250 pm, preferably of 2 to 200 μητι, more preferably of 5 to 150 pm, further more preferably of 10 to 120 pm, most preferably of 15 to 90 pm. The mean particle size is determined as described below in the experimental section. The Aliskiren salts of the invention preferably possess Hausner ratios in the range of 1.01 to 1.5 or 1.05 to 1.4, preferably of 1.06 to 1.3, more preferably between 1.08 to 1.25. The Hausner ratio is the ratio of tapped density to bulk density. Tapped and bulk density preferably are determined according to Ph. Eur. 6.0, 2.2.42. In an alternatively preferred embodiment, the salts of the invention are formed in an amorphous state or form.

For the present application, the term "amorphous" usually relates to the condition of solid-state compounds, for which the constituents (atoms, ions or molecules) do not show a periodic arrangement over a larger scale (long-range order). However, in amorphous substances, the constituents are typically not completely stationary and are not in a purely statistical arrangement, but are instead distributed in such a way that they display a certain regularity and similarity to the crystalline condition with regard to the distance and orientation to their immediate neighbours (short range order). Amorphous substances thus generally display a short-range order, but no long-range order.

In contrast to anisotropic crystals, solid amorphous substances are isotropic. They typically do not have any well-defined melting point, but instead slowly change into the fluid state by gradual softening. Amorphous substances can be distinguished from crystalline substances with the aid of X-ray diffraction, for which no sharp, but instead normally only few non-descript interferences at small diffraction angles are achieved.

Surprisingly, the generally less preferred amorphous state has a number of advantages. Due to the higher initial water content, the later uptake of water can be reduced. In addition, the bioequivalence/bioavailability is comparable to prior-art compositions or formulations. In a preferred alternative, the salt is therefore more than or equal to 50 wt.% amorphous. Thus, in some cases a more uniform or stable formulation can be achieved when the salt is in an amorphous state.

Therefore, both the crystalline and the amorphous salts according to the invention are less hygroscopic than the hemifumarate salt. The salts according to the invention have proved to be physically more stable. Improved physicochemical properties are of importance when these salts are produced in the form of pharmaceutically active substances and when producing, storing and applying the galenic preparation. Due to an improved constancy of the physical parameters, an even higher quality of the formulations can be guaranteed.

Further, it was an object of the present invention to provide an improved process for producing Aliskiren in the form of different pharmaceutically acceptable salts, which show a constant dissolution profile before and after storage. In addition, the salts should be highly crystalline and exhibit a greater stability than those generated by conventional methods such as those employed to afford the hemifumarate salt.

The present invention surprisingly affords a process for the manufacture of the inventive salt as described above in a form, which is at least partially crystalline, characterized in that: (i) the free base compound and/or the corresponding acid compound is dissolved in an organic solvent,

(ii) the solution or solutions of (i) are mixed with each other, or alternatively with the other compound of either the free base compound or the corresponding acid compound, whichever was not originally dissolved in step (i), (iii) optionally, the solution of (ii) is stirred, preferably for at least 5 minutes,

(iv) the solution is kept without stirring under conditions acceptable for salt crystallization, such as at RTP, with or without heating, cooling, reduced pressure, and/or vacuum, preferably for at least 1 hour, but more preferably for at least 1 day, (v) the salt precipitate is extracted, for example by decantation of the supernatant or filtration, followed by drying, optionally under vacuum, (vi) the salt is collected.

The term "RTP" stands for ambient room temperature and pressure and preferably refers to 23 °C and 1013 mbar.

This above process can be carried out to afford a high yield and enables a large-scale production. The obtained salts have a high degree of purity and a low residual solvent content.

Most notably the salts obtained in this way are highly crystalline. This can be confirmed by XRD measurements. The high crystal regularity is confirmed by sharp melting/rearrangement peaks in the DSC and by appearance of additional IR bands.

In particular, it is preferred that step (iv) is conducted for at least 1 day, more preferably for 10 days, even more preferably for 18 days or more, up to advantageously 100 days. This long period for step (iv) in the inventive process affords very pure crystals that have a high crystallinity and stability.

Another subject of the present invention is a trituration process. That means, the present invention relates to a process for the manufacture of a salt which can be least partially amorphous, characterized in that: (I) dissolving free base compound and/or the corresponding acid compound in an organic solvent,

(II) mixing the solution or solutions of (I) with each other, or alternatively with the other compound of either the free base compound or the corresponding acid compound, whichever was not originally dissolved in step (I), (III) concentrating the mixture (II),

(IV) triturating the residue of (III) optionally repeatedly with a suitable solvent,

(V) optionally collecting and drying the solid.

The above process can be carried out to enable a large-scale production with reasonable yields. The obtained salts can have a high degree of purity and a low residual solvent content.

In a preferred embodiment of the invention concentrating the mixture (II) can be preferably carried out by evaporating the solvent, e.g. at 25 °C, more preferably under reduced pressure, e.g. at 0.01 to 0.9 bar, more preferably at 0.05 to 0.5 bar.

In another preferred embodiment of the invention triturating the residue of (III) optionally repeatedly with a suitable solvent can comprise adding the suitable solvent, triturating, preferably with mechanical forces, for example stirring, removing the above standing liquid and repeating the procedure by starting adding fresh solvent, wherein preferably not more than four cycles are carried out. A suitable solvent can be preferably an organic solvent, in which the solubility of the Aliskiren salt at 25 °C is lower than 100 mg/ml, preferably lower than 10 mg/ml, more preferably lower than 5 mg/ml, most preferably lower than 1 mg/ml.

In another embodiment drying of the solid (V) can be carried out in two steps. Preferably the first step may remove solvent, e.g. at 25 °C, preferably under reduced pressure, e.g. at 0.01 to 0.9 bar, more preferaby at 0.05 to 0.5 bar. Subsequently, the solid can be dried, e.g. at 50 °C in a drying gun (Buchi).

Measurements of the FT infrared absorption spectrum of the salts of Aliskiren show the significant bands expressed on a reciprocal scale in wave numbers (cm^"1) as indicated in Table 2.

The intensities of the absorption bands were classified as follows: (w) = weak; (m) = medium; and (st) = strong intensity. The error margin for the absorption bands is ± 2 cm^"1.

The weaker bands are not indicated in Table 2.

Table 2

Generally, Aliskiren salts show typical bands at 2960 cm^"1, which correspond to a C-H absorption. Absorptions due to amide C=0 or aromatic C=C vibrations around 1650 cm^'1 or an amid band at 1516 cm^"1 are also generally present. However, surprisingly when comparing standard amorphous salt preparations with the inventive crystallization process as described above, it was possible to achieve crystals with high regularity and stability. This is demonstrated by the additional bands between 3000 cm^"1 and 3500 cm^"1. Therefore, the invention also relates to Aliskiren salts, wherein the IR Spectrum graph of the salt product shows at least one peak between 3000 to 3500 cm^"1, preferably between 3100 and 3490 cm^"1, more preferably between 3200 and 3480 cm^"1, even more preferably between 3380 and 3470 cm^"1, most preferably between 3400 and 3460 cm^"1. The above peaks are not due to solvents or water in the crystal. Such peaks are classified as distinct when they belong to the category "m" or "st".

The peaks in this range are more pronounced, when the salt precipitation duration in step (iv) is longer. Hydrogen bridges in the salt could be responsible for the new bands.

In the dissolving process (i), the organic solvent employed is advantageously an alcohol, such as ethanol or isopropanol, or an alkylnitrile, especially acetonitrile, and/or water. The solvent may be warmed to above room temperature to e.g. 25 to 60 °C, more preferably 30 to 50 °C, most preferably 40 to 45 °C.

The use of solvents, having undesirable toxic effects, is thus avoided.

In the process step (ii), the aqueous solution employed is advantageously a 10 to 30 wt.%, more preferably a 15 to 25 wt.%, such as a 20 wt.% solution of the acid compound. Preferably, the molarity of the solution is from 0.5 to 1.5 M.

The stirring step can be preferably from 5 to 60 minutes, more preferably it is from 7 to 15 minutes.

In the process step (iv), the solution is advantageously left standing so as to slowly evaporate off the solvent. This is preferably conducted by cooling to room temperature or below, more preferably cooling to -10 to +25 °C, still more preferably -5 to +10 °C, most preferably 0 to 5 °C. The concentration of the solution can also take place by warming to above room temperature, e.g. to greater than 25 to 100 °C, more preferably 30 to 70 °C. In the process step (v), the drying is preferably effected at elevated temperatures, more preferably 20 to 50 °C most preferably 30 to 42 °C. This step is preferably conducted under vacuum. The term "vacuum" usually indicates that the pressure is preferably selected to be 1 to 100 mbar, preferably 10 to 50 mbar, more preferably 20 to 40 mbar, such as 30 mbar. The drying typically takes place until a constant mass is obtained. Depending on the drying conditions, the drying may take from 1 to 48 h, preferably 1.5 to 24 h, such as 2 to 10 h.

In a preferred variant, the crystallisation may be optimized, e.g. accelerated, by adding at least one seed crystal.

A further object of the invention is a process for forming salts of Aliskiren by rapid drying methods.

The starting material solid salt, prepared in any other way from the method described above can be obtained by mixing the free base compound with the corresponding acid and evaporating/removing the solvent from the precipitate quickly, e.g. by rotary evaporation. This quick method frequently provides amorphous crystals or can even afford solid dispersions. These products are suitable for certain intended Aliskiren salt pharmaceutical formulations.

Surprisingly, it was found that the properties of the salt can, however, generally be improved by an additional processing step, which includes a rapid drying method.

Rapid drying methods include spray-drying or freeze-drying. Freeze-drying is preferred. Thus, the invention affords a process for the generation of the inventive salts, in a form, which is at least partly crystalline and/or at least partly amorphous, obtained by:

(a) dissolving the solid salt according to any of the preceding claims in a solvent, such as alcohol and/or water,

(β) freeze-drying and/or spray drying the solution to obtain a final solid product. Preferably, the salt is (preferably completely) dissolved in water and/or an organic solvent. Suitable solvents are alcohols, e.g. ethanol. Preferably, water or a water/ethanol mixture is used.

Freeze-drying can be done, using a VirTis^® Bench top K Freeze dryer. Generally, the freeze-drying process (β) might comprise two stages:

Stage 1 : Freezing the solution resulting from step (a) and reducing the pressure.

Preferably, the pressure is reduced below the triple point of the solution resulting from step (a) ;

Stage 2: Raising the temperature, preferably to the sublimation curve, in order to allow latent heat of sublimation. In a preferred embodiment, stage 1 is carried out at temperatures between - 40 °C and - 60 °C, more preferably between - 50 °C and - 52 °C. Preferably, the pressure ranges from 1 to 50 Pa, more preferably from 5 to 10 Pa. Stage 1 might take 1 to 40 hours, preferably 10 to 25 hours.

In a preferred embodiment, stage 2 is carried out at temperatures between 10 °C and 60 °C, more preferably between 35 °C and 40 °C. Preferably the pressure ranges from 1 to 50 Pa, more preferably from 5 to 10 Pa. Stage 2 might take 5 to 50 hours, preferably 25 to 35 hours.

The products obtained by rapid drying processes of the inventive salts, preferably generated from organic acid compounds, achieve a unique balance between the amorphous and crystalline phase. They display a reduced hygroscopicity.

These effects are particularly good for the salts as described above, more preferably for organic acid salts and most preferably Aliskiren oxalates, Aliskiren maleates and Aliskiren tartrates.

The achieved final products display a higher crystal regularity and are more crystalline than the starting solids.

This can be seen in the DSC graphs of the final products. Example 2 affords a relatively amorphous solid product of Aliskiren oxalate. By treating the solid with the above method according to example 3 a final product can be achieved with unique properties.

As can be seen in the DSC the graph is more specifically structured including sharper peaks, rather than broad bands. Thus, the invention also includes a salt prepared by one of the above described methods, wherein the differential scanning calorimetry (DSC) graph of the salt product shows at least one endothermic peak between 100 °C to 300 °C. Preferably, the peaks are between 130 °C and 240 °C.

In addition, the IR spectra show similar bands in the rapidly dried state as compared to the original material.

Unexpectedly, the above process particularly affects the flowability properties in a positive way. The resulting product usually has a superior bulk density when compared to original amorphous form prior to freeze-drying.

The thus prepared salts are more readily processable in the preparation of pharmaceutical formulations, in particular when being compared to Aliskiren hydrochloride or the hemifumarate or fumarate salt thereof.

Alternatively, spray-drying (β) can preferably be used. Spray-drying is particularly preferred if the resulting salt should be provided in form of an oral dosage form. The spray-drying can be performed with or without additives. As additives e.g. sorbitol, xylitol, polyethylene glycol, dextrose or lactose can be used.

Generally, spray-drying can be carried out, using an inlet temperature of 120 to 220 °C, preferably about 180 °C, and an outlet temperature of about 70 to 120 °C, preferably of about 95 °C. For example, spray-drying can be carried out by using a Biichi^® Lab Niro spray-drier. The spray-dried products are more stable and have a more defined crystal structure.

Freeze drying may be combined with spray drying to afford a spray-freeze drying method, which is particularly advantageous.

The invention also relates in particular to a pharmaceutical composition, especially in a solid dosage unit, comprising an inventive Aliskiren salt as described above, preferably for oral administration, optionally together with one or more pharmaceutically acceptable carriers, excipients and/or additives.

Brief Description of the Table and Figures:

Table 1 shows a table comparing the melting points and pK_a values of the comparative example acid compounds fumaric acid with a number of the inventive example acids. Table 2 shows a table of the major IR bands of the inventive Aliskiren salts.

Table 3 shows a table of the melting points and major DSC major peak values of the comparative example acid compounds Aliskiren fumarate and a number of the inventive example acids. Exothermic peaks are indicated by "ex". Sharp peaks are denoted by "s". Figure 1 : DSC thermogram of Aliskiren oxalate Example 1

Figure 2: IR spectrum of Aliskiren oxalate Example 1

Figure 3: DSC thermogram of Aliskiren oxalate Example 2

Figure 4: IR spectrum of Aliskiren oxalate Example 2

Figure 5: DSC thermogram of Aliskiren oxalate Example 3 Figure 6: IR spectrum of Aliskiren oxalate Example 3 Figure 7: DSC thermogram of Aliskiren oxalate Example 4

Figure 8: IR spectrum of Aliskiren oxalate Example 4

Figure 9: DSC thermogram of Aliskiren malate Example 5

Figure 10: IR spectrum of Aliskiren malate Example 5

Figure 11 : DSC thermogram of Aliskiren maleate Example 6

Figure 12: IR spectrum of Aliskiren maleate Example 6

Figure 13: DSC thermogram of Aliskiren tartrate Example 7

Figure 14: IR spectrum of Aliskiren tartrate Example 7

Figure 15: DSC thermogram of Aliskiren phosphate Example 8 Figure 16: IR spectrum of Aliskiren phosphate Example 8

Figure 17: DSC thermogram of Aliskiren phosphate Example 9

Figure 18: DSC thermogram of Aliskiren acetate Example 10

Figure 19: DSC thermogram of Aliskiren succinate Example 1 1

Figure 20: IR spectrum of Aliskiren succinate Example 11 Figure 21 : DSC thermogram of Aliskiren maleate Example 12

Figure 22: IR spectrum of Aliskiren maleate Example 12

Figure 23: DSC thermogram of Aliskiren malate Example 13

Figure 24: IR spectrum of Aliskiren malate Example 13

Figure 25: DSC thermogram of Aliskiren aspartate Example 14 Figure 26: IR spectrum of Aliskiren aspartate Example 14

Figure 27: DSC thermogram of Aliskiren tartrate Example 15

Figure 28: IR spectrum of Aliskiren tartrate Example 15

Figure 29: DSC thermogram of Aliskiren citrate Example 16

Figure 30: IR spectrum of Aliskiren citrate Example 16 Figure 31 : DSC thermogram of Aliskiren phosphate Example 17 Figure 32: IR spectrum of Aliskiren phosphate Example 17 Figure 33: DSC thermogram of Aliskiren oxalate Example 18 Figure 34: IR spectrum of Aliskiren oxalate Example 18 Figure 35: X-ray powder diffractogram of Aliskiren maleate Example 12 Figure 36: X-ray powder diffractogram of Aliskiren malate Example 13 Figure 37: X-ray powder diffractogram of Aliskiren aspartate Example 14 Figure 38: X-ray powder diffractogram of Aliskiren tartrate Example 15 Figure 39: X-ray powder diffractogram of Aliskiren citrate Example 16 Figure 40: X-ray powder diffractogram of Aliskiren phosphate Example 17 Figure 41 : X-ray powder diffractogram of Aliskiren oxalate Example 18

The invention shall be illustrated by the following examples.

EXAMPLES List of Equipment:

Freeze-drying: VirTis^® Bench top K Freeze dryer. The VirTis^® glass bottle of 40 ml capacity, condenser temperature is from -53 °C to -105 °C, particularly -104 °C, and the vacuum is 15 mT (2 Pa).

Residual water content: determined according to the Karl Fischer method as described in Ph. Eur. 6^th edition, 2008, section 2.5.12.. The determination is done using Mettler Toledo DL31 Karl Fischer titrator. Usually, a sample of 50 to 100 mg of the salt is analyzed.

IR: Perkin Elmer model Spectrum One FT IR in diffuse reflectance mode

DSC: Mettler Toledo Model DSC 822; heating range for the samples 30 to 300 deg C; heating rate = 10 deg C / min; purge gas = nitrogen 50 ml / min; 40 micron aluminum crucible;

Melting point: Lab India Visual melting range apparatus; Particle sizes: the volume mean particle size (D50) is determined by the light scattering method, using a Mastersizer 2000 apparatus made by Malvern Instruments (wet measurement, 2000 rpm, ultrasonic waves for 60 sec, data interpretation via Fraunhofer method).

Example 1

Aliskiren Oxalate

1.00 g (1.81 mmol) Aliskiren free base was dissolved in 20 ml acetonitrile by stirring at ambient temperature under nitrogen atmosphere for 10 min. To this solution, a clear solution of 0.163 g (1.81 mmol) anhydrous oxalic acid in 10 ml acetonitrile was added. The reaction mixture was stirred at ambient temperature for 1 h and left without stirring for 18 days. The solid was isolated by decanting out the supernatant and dried under vacuum at 40 °C for 2 h. DSC shows a minor endotherm at 144.4, followed by a major endotherm at 153.5 and another broad endotherm at 215.0 °C.

Melting point = 147.9 to 149.8 °C.

IR shows bands at 3405, 3201 , 2960, 1721 and 1666 cm ¹. Example 2

Aliskiren Oxalate

A solution of 0.023 g (0.254 mmol) oxalic acid anhydrous was prepared in 1 .5 ml ethanol and added to 0.14 g (0.254 mmol) Aliskiren free base at ambient temperature. The solution obtained was stirred for 10 min and then evaporated on a rotary evaporator at ambient temperature and high vacuum to obtain 0.14 g product.

Melting point = 65 °C to 71 °C.

DSC does not show any distinct peaks.

IR shows bands at 2960.26, 1654.19 and 1515.84 cm^"1.

Example 3 Aliskiren Oxalate

75 mg of the Aliskiren oxalate, obtained above in Example 2, were dissolved in 1 ml of Milli Q water. The solution was freeze-dried to yield 66 mg of the product as a white solid.

DSC shows broad endothermic peaks at 161.5, 196.1 and 212.8 °C. IR shows bands at 2960.2, 1654.7, 1515.72 and 1261 .3 cm-¹. Example 4 Aliskiren Oxalate

0.1 17 g (0.2 1 mmol) Aliskiren free base was dissolved in 1.5 ml ethyl acetate by stirring at ambient temperature under nitrogen atmosphere for 10 min. A solution of 0.019 g (0.21 1 mmol) oxalic acid anhydrous in 1.0 ml ethyl acetate was prepared by warming in a water bath at 45 °C for 5 min and then added. The reaction mixture was stirred at ambient temperature for 1 h and left without stirring for 38 days. The solid was separated by decanting out the supernatant and was dried under vacuum at 40 °C for 2 h to yield 8.2 mg of a white solid. DSC shows a broad endotherm at 113.53, followed by a sharp endotherm at 153.87 °C.

Melting point = 151.2 °C to 152.2 °C.

IR shows bands at 3407.3, 2959.5, 1742.5, 1621.8, 1219.7, 1 102, 1025, 718 and 516.42 cm ¹.

Example 5

Aliskiren L-Malate

1 .5 ml acetonitrile was added to 0.10 g (0.181 mmol) Aliskiren free base and stirred at room temperature under nitrogen atmosphere for 10 min to obtain a clear solution. A solution of 0.024 g (0.181 mmol) L-malic acid in 1 ml acetonitrile was added to the solution of Aliskiren free base in acetonitrile. The reaction mixture was stirred at room temperature for 1 h and then kept aside for crystallization for 10 days. The solvent was decanted off and the precipitate was dried under vacuum at 40 °C for 2 h.

The filtrate was kept for further crystallization. DSC shows an endotherm at 63.1 °C, followed by an exotherm at 88.5 °C.

Melting point = 51 °C to 55 °C.

IR shows bands at 3176, 2957, 1730, 1666, 1516.4, 1389.4, 1370.9, 1262.5, 1086.9 and 1026 cm^"1.

Example 6 Aliskiren Maleate

5 ml dichloromethane were added to 0.556 g (1.0 mmol) of Aliskiren free base and stirred at room temperature for 10 min under nitrogen atmosphere to give a clear solution. A solution of 0.116 g (1.0 mmol) maleic acid in 1 ml ethanol was added and stirred at room temperature for 10 min. The reaction mixture was cooled to 10 °C for 15 min. The solvent was distilled out on a rotary evaporator at ambient temperature resulting in an oily residue, which became a foamy solid on drying under high vacuum. The foamy solid was dissolved in 5 ml dichloromethane to give a clear solution. 5 ml petroleum ether was added which was followed by slow addition of 20 ml dry diethyl ether resulting in a turbid solution. This solution was kept at -18 °C for 5 days. The crystallized solid was separated by decanting out the supernatant solution and then dried at 40 °C under high vacuum for 3 h to yield 0.515 g of a white solid.

DSC shows a sharp endotherm at 77.3 °C and a broad endothermic peak at 185.44 °C. Melting point = 65.4 °C to 69.9 °C.

IR shows bands at 2959.8, 1667.9, 1642.3, 1515.6, 1470.3, 1355, 1259.7, 1026.4 and 865.6 cm^"1.

Example 7 Aliskiren L-Tartrate

0.113 g (0.205 mmol) Aliskiren free base was dissolved in 1 ml isopropanol by stirring at ambient temperature for 10 min under nitrogen atmosphere. A clear solution of 0.031 g (0.205 mmol) L-(+)-tartaric acid in 1 ml isopropanol (dissolved by warming in a water bath at 43 °C and subsequent sonication) was added to the solution of Aliskiren free base. The reaction mixture was stirred at ambient temperature for 1 h and left without stirring for 38 days to crystallize. The supernatant was decanted out and the solid was dried at 40 °C under vacuum for 2 h to yield 6.8 mg of a solid.

DSC shows a broad endotherm at 253.71 °C.

IR: 3451 .5, 2955.1 , 1764.8, 1634.24, 1516.1 , 1399, 1 134.7, 1070.9 and 703 crrf . Example 8

Aliskiren Phosphate

A solution of 0.043 g (0.375 mmol) 85% phosphoric acid in 1 ml ethanol was added to 0.212 g (0.384 mmol) of Aliskiren free base. The reaction mixture was stirred at ambient temperature to obtain a clear solution. The solvent was evaporated on a rotary evaporator to give an oil, which was dried under high vacuum to give a solid.

DSC shows a small and broad endotherm at 126 °C, exotherm at 185 °C.

IR: 2960.2, 1654.4, 1515.7, 1470.7, 1369.4, 1263, 1236.6 crrf¹.

Example 9

Aliskiren Phosphate 89 mg Aliskiren phosphate from Example 8 was dissolved in 1 ml Milli Q water. The solution was freeze-dried to obtain 77 mg of a solid.

DSC shows a broad endotherm at 160 °C and broad exotherm at 186 °C. Example 10

Aliskiren Acetate

A solution of 48.9 mg (0.8155 mmol) of acetic acid in 4 ml water was added to 450 mg (0.8155 mmol) of Aliskiren free base and the resulting mixture was shaken well for 30 min to obtain a milky solution. This was frozen using liquid nitrogen and was lyophilized for 3 h to yield 400 mg (65%) of a white solid.

Melting point: 48 °C - 67 °C.

DSC shows a broad endotherm at 159.6 °C and 215.2 °C.

Example 11 Aliskiren Succinate

A solution of 97.4 mg (0.8390 mmol) of succinic acid in 4 ml water was added to 463 mg (0.839 mmol) of Aliskiren free base and the mixture was shaken well at room temperature for 45 min resulting in a slight turbid solution. This solution was frozen, using liquid nitrogen, and was lyophilized for 4 h to yield 467 mg (83.3 %) of a white solid.

DSC shows broad endotherms at 164.7, 183.4 and 192.9 °C.

Melting point: 45 °C - 65 °C.

LCMS purity: 99.76 %.

IR: 2959.8, 2875, 1716.4, 1661 .9, 1587.9, 1555.6,, 1515.9, 1473.7 cm ¹ Example 12

Aliskiren Maleate

A solution of 1 13.5 mg (0. 9786 mmol) of maleic acid in 4 ml water was added to 540 mg (0. 979 mmol) Aliskiren free base and the resulting mixture was shaken well at room temperature for 45 min resulting in a milky solution. This was frozen, using liquid nitrogen, and was lyophilized for 4 h to yield 575 mg (88 %) of a white solid.

LCMS purity: 99.5 %.

Melting point: 61 °C - 71 °C.

DSC shows a broad endotherm at 197.9 °C.

IR: 2960, 2875.7, 1708.4, 1660.1 , 1585.9, 1516, 1475.1 cm^"1. Example 13

Aliskiren Malate

A solution of 109.8 mg (0. 8192 mmol) L-malic acid in 2 ml water was added to 452 mg (0.819 mmol) Aliskiren free base and the resulting mixture was shaken well for 30 min resulting in a milky solution. This was frozen, using liquid nitrogen, and was lyophilized for 3 h to yield 356 mg (63.3 %) of a white solid.

LCMS purity: 99.51 %. Melting point: 63 °C - 69 °C.

DSC shows a very broad endotherm at 177.6 and 193.8 °C.

IR: 2959.9, 2874.6, 1720.1 , 1659.3, 1588.7, 1516.1 and 1474.3 cm ¹. Example 14

Aliskiren Aspartate

A solution of 37.8 mg (0.285 mmol) L-aspartic acid in 7 ml water was added to 157 mg (0.2845 mmol) Aliskiren free base and the resulting mixture was shaken well for 30 min at room temperature resulting in a slightly turbid solution. This was frozen, using liquid nitrogen, and was lyophilized for 3 h to yield 161 mg (82.6 %) white solid.

LCMS purity: 99.79 %.

Melting point: 65 °C -69 °C.

DSC shows a broad endotherms at 189 and 211 .4 °C

IR: 2959.1 , 2874.5, 2835.1 , 1655.2, 1588.7, 1516.2 and 1475.2 cm^"1. Example 15

Aliskiren L -Tart rate

A solution of 91 mg (0. 6067 mmol) of L-tartaric acid in 4 ml water was added to 335 mg (0. 6071 mmol) of Aliskiren free base was added and was shaken well for 30 min at room temperature resulting in a slight turbid solution. This was frozen, using liquid nitrogen, and was lyophilized for 4 h to yield 357 mg (83.8 %) white solid.

LCMS purity: 98.45 %.

IR: 2959.7, 2875.1 , 2835.8, 1730.4, 1659, 1589.8, 1516.3, 1474.4, 1371.9, 1262.6 cm^"1.

DSC shows a broad endotherm at 200.7 °C.

Melting point = 70 °C - 79.6 °C. Example 16 Aliskiren Citrate

A solution of 188 mg (0. 9786 mmol) of citric acid in 4 ml water was added to 540 mg (0.9786 mmol) of Aliskiren free base and was shaken well for 45 min at room temperature, resulting in a turbid solution. This was frozen, using liquid nitrogen, and was lyophilized for 3 h to yield 646 mg (88.7 %) white solid.

LCMS purity: 99.38 %.

DSC shows a broad endotherm at 178.1 °C.

IR: 2960.3, 1721 .2, 1658.6, 1589.3, 1515.9, 1473.8, 1443.3, 1261 .3 cm^"1. Example 17

Aliskiren Phosphate

A solution of 28.78 mg (0.2878 mmol) of 85 % phosphoric acid in 1 ml water was added to 142 mg (0.2573 mmol) of Aliskiren free base and was shaken well for 30 min at room temperature to obtain a slightly turbid solution. This solution was frozen, using liquid nitrogen, and was lyophilized for 3 h to obtain 121 mg (70.8 %) white solid.

LCMS purity : 99.80 %.

DSC shows a broad endotherm at 163.4 °C followed by an exotherm at 186 °C.

IR: 2959, 2874.4, 2835.1 , 1659.3, 1589.6, 1516.2, 1473.9, 1262.1 cm^"1. Example 18

Aliskiren Oxalate

A solution of 70 mg (0.7793 mmol) of oxalic acid in 3 ml water was added to 430 mg (0.7793 mmol) of Aliskiren free base and was shaken well for 30 min at room temperature to obtain a turbid solution. This was frozen, using liquid nitrogen, into a thin film and lyophilized for 3 h to yield 434 mg (87. 2 %) white solid.

LCMS purity: 99.59 %.

DSC does not show a distinct peak.

Melting point = 45 °C - 67 °C.

IR: 2960, 2875.3, 1725.7, 1658.6, 1516, 1473.7, 1371 .2, 1261.6, 1235.7 cm^"1.

MP and DSC-data of Examples 1 to 18 are summarized in Table 3. Table 3

Endo- Endo- Endo-

Mpt

Example DSC therm 1 therm 2 therm 3

(^eC)

CO CO CO

Aliskiren hemifumarate

Comp. 96.6

WO 2007/098503 A2

Aliskiren oxalate

Expl. 1 147.9-149.8 144.4 153.5 s 215.0

(crystalline)

Expl. 2 Aliskiren oxalate (amorph)

Aliskiren oxalate (amorph

Expl. 3 161 .5 196.1 212.8 freeze-dried)

Aliskiren oxalate

Expl. 4 151 .2-152.2 1 13.5 153.8 s

(crystalline)

Expl. 5 Aliskiren malate 51 -55 63.1 88.5

Expl. 6 Aliskiren maleate 65.4-69.9 77.3 s 185.4

Expl. 7 Aliskiren tartrate 253.7 s

Aliskiren phosphate

Expl. 8 42.35 126 185 ex

(amorph)

Aliskiren phosphate

Expl. 9 160 186 ex

(freeze dried)

Aliskiren acetate

Expl. 10 48-67 159.6 215.2

(freeze dried)

Aliskiren succinate

Expl. 11 45-65 164.7 183.4 192.9

(freeze dried)

Aliskiren maleate

Expl. 12 61-71 197.9

(freeze dried)

Aliskiren malate

Expl. 13 63-69 177.6 193.8

(freeze dried)

Aliskiren aspartate

Expl. 14 65-69 189 21 1 .4

(freeze dried)

Expl. 15 Aliskiren tartrate 70-79.6 200.7

Expl. 16 Aliskiren citrate 178.1

Expl. 17 Aliskiren phosphate 163.4 186 ex Aliskiren oxalate 45-67 -

Expl. 18

Example 19

Comparative Example (Aliskiren Fumarate 2:1 ), Prior Art

Aliskiren fumarate 2:1 according to prior art was provided and analyzed. DSC: Broad endotherm at 102.43 °C along with small endotherms at 76.3 and 209.4 °C and a small exotherm at 174 °C.

IR (cm^-1): 3194.8, 2959.1 , 2874.9, 1662.7, 1562.9, 1515.9, 1467.6 and 1425.

The following three examples are produced by a trituration/precipitation process.

Example 20 Alskiren Citrate (3:1 )

A solution of 5.24 g (9.5 mmol) Aliskiren free base was prepared in 25 ml MeCN by stirring at ambient temperature for 2 min. A solution of 0.61 g (3.1 mmol) citric acid in 8 ml EtOH (prepared by warming on the water bath at 50 °C for 5 min) was added to a solution of Aliskiren free base and stirred at RT for 5 min. The reaction mixture was concentrated using a rotary evaporator at room temperature for 30 min to obtain a viscous oil. To this oil 100 ml diethyl ether was added and stirred for 30 min. The ether layer was decanted off, fresh diethyl ether was added and the mixture was stirred for 30 min. The ether layer was decanted off to obtain a white powder. The powder was dried using a rotary evaporator at room temperature under high vacuum for 3 h to obtain a solid.

Yield = 1 .0 g (17.1 %). This solid was further dried under vacuum at 50 °C for 16 h, using a drying gun (Buchi).

DSC showed a broad endotherm at 191 .5 °C. XRPD showed amorphous nature of the product.

IR (cm ): 3195.5, 2958.6, 2873.9, 1668.2 and 1515.4. HPLC purity = 99.7%. Example 21 Aliskiren Malate (2:1 )

A solution of 5.1 g (9.2 mmol) Aliskiren free base was prepared in 25 ml MeCN by stirring for 15 min. A solution of 0.64 g (4.6 mmol) L-malic acid in 8 ml EtOH was added and the mixture was stirred at room temperature for 20 min. The reaction mixture was concentrated using a rotary evaporator at room temperature for 30 min to obtain a viscous residue. To this 100 ml diethyl ether was added and the mixture was stirred for 30 min. The ether layer was decanted off and this process was repeated once more with 00 ml diethyl ether and the ether layer was decanted off to obtain a white powder. The powder was dried on a rotary evaporator at room temperature under high vacuum for 3 h to obtain a solid (3.68 g, 64.5 %). This solid was further dried at 50 °C, using a drying gun (Biichi) under vacuum for 16 h.

DSC showed two very broad endothermic peaks at 139.1 and 194.5 °C.

XRD showed the amorphous nature of the product.

IR (cm ¹): 3185.8, 2958.9, 2875.2, 1667.2, 1515.4 and 1471 .8.

HPLC purity = 99.73%.

Water content = 1.63 %. Residual solvent: Diethyl ether = 433 ppm.

Example 22 Aliskiren L-Tartrate (2:1 )

A solution of 5.2 g (9.4 mmol) Aliskiren free base in 25 ml MeCN was prepared by stirring for 5 min. A solution of 0.7 g (4.7 mmol) L-tartaric acid in 1 1 ml EtOH was added dropwise to a solution of Aliskiren free base and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated using a rotary evaporator at room temperature under vacuum for 30 min to obtain a viscous residue. Diethyl ether (100 ml) was added to the viscous residue and the mixture was stirred for 30 min. The ether layer was decanted off and this process was repeated twice with 100 ml diethyl ether each to obtain a white solid. This was dried, using a rotary evaporator at room temperature under high vacuum for 3 h. Yield = 4.28 g (72.85%). This solid was further dried using a drying gun (Biichi) at 50 °C under vacuum for 16 h.

DSC showed a broad endothermic peak at 184.3 and an exothermic peak at 223.6 °C. IR (cm ¹): 3195, 2958.9, 2874.5, 1661 .8, 1590.8 and 1515.5.

Example 23: Stability Tests

Solid state stability results of Aliskiren salts prepared by trituration/precipation process

The impurities were measured by HPLC after treating the Aliskiren salts for 2 weeks and for 4 weeks in closed bottles at 60°C. Table 4

As shown in Table 4, the Aliskiren salts according to the present invention contain significant less impurities after storing the samples under stress conditions for both two and four weeks, when being compared with the hemifumarate salt known from prior art. The stability increase led to unexpected superior shelf-life properties in pharmaceutical formulations.

The following examples are produced by using lyophilisation.

Example 24 Aliskiren Citrate 3 : 1

A solution of 131 mg (0. 9786 mmol) citric acid in 15 ml water was added to 1 132 mg (2.051 mmol) Aliskiren free base and was stirred slowly for 30 min to obtain a turbid solution. By swirling the flask and freezing at -40°C (using a Julabo chiller), the solution was converted into a thin film and subsequently the flask was connected to a freeze drier (conditions: vacuum: 18 mTorr, condenser temperature -104.2 °C) for 4 h to obtain a solid.

Yield = 1.167 g (92.37 %).

DSC showed two broad endothermic peaks at 56.5 and 190.9 °C.

HPLC= purity 100 %. Example 25

Aliskiren L-Malate 2 : 1

A solution of 0.127 g (0.951 mmol) L-malic acid in 15 ml water was added to 1.05 g (1.903 mmol) Aliskiren free base and stirred slowly for 30 min to obtain a turbid solution. By swirling the flask and freezing at -40°C (using a Julabo chiller), the solution was converted into a thin film and subsequently the flask was connected to a freeze drier (conditions: vacuum: 18 mTorr, condenser temperature -104.2 °C) for 4 h to obtain solid. Yield = 1 .08 g (91.7 %).

DSC showed two merging endothermic peaks at 49.1 , 53.96 (due to water) and a broad endothermic peak at 178.6 °C.

Example 26 Aliskiren Oxalate 2 : 1

A solution of 94.6 mg (1 .05 mmol) anhydrous oxalic acid in 15 ml water was added to 1.160 g (2.102 mmol) Aliskiren free base and stirred slowly for 20 min to obtain a turbid solution. By swirling the flask and freezing at -40°C (using a Julabo chiller), the solution was converted into a thin film and subsequently the flask was connected to a freeze drier (conditions: vacuum 18 mTorr, condenser temperature 104.2 °C) for 4 h to obtain solid.

Yield = 1.163 g (93.36 %).

DSC showed a broad endotherm at 180.8 °C. XRPD confirmed the amorphous nature.

Example 27

Aliskiren Succinate 2:1

A solution of 0.122 g (1.036 mmol) succinic acid in 15 ml water was added to 1.143 g (2.071 mmol) Aliskiren free base and stirred slowly for 15 min to obtain a turbid solution. By swirling the flask and freezing at 40 °C (using a Julabo chiller), the solution was converted into a thin film and subsequently the flask was connected to a freeze drier (Conditions: vacuum 18 mTorr, temperature -104.2 °C) for 4 h to obtain a solid.

Yield = 1.172 g (92.6 %).

DSC showed a small endotherm at 43.8 °C.

XRPD confirmed amorphous the nature.

Example 28

Aliskiren D-Tartrate 2:1 A solution of 0.148 g (0.99 mmol) D-tartaric acid in 12 ml water was added to 1 .093 g (1.981 mmol) Aliskiren free base and stirred slowly for 30 min to obtain a turbid solution. By swirling the flask and freezing at -40°C (using a Julabo chiller), the solution was converted into a thin film and subsequently the flask was connected to a freeze drier (conditions: vacuum 18 mTorr, condenser temperature -104.2 °C) for 4 h to obtain a solid. DSC showed a broad endothermic peak at 184.7 °C.

XRPD confirmed the amorphous nature.

Example 29 Aliskiren L -Tart rate 2:1

A solution of 0.137 g (0.914 mmol) L-tartaric acid in 12 ml water was added to 1 .01 g (1.828 mmol) Aliskiren free base and stirred slowly for 30 min to obtain a turbid solution. By swirling the flask and freezing at -40°C (using a Julabo chiller), the solution was converted into a thin film and subsequently the flask was connected to a freeze drier (conditions: vacuum 18 mTorr, condenser temperature -104.2 °C) for 4 h to obtain a solid.

DSC showed a broad endotherm at 184.3 °C.

XRPD confirmed the amorphous nature.

IR (cm^" ):3087.9, 2959.6, 2875.1 , 2835.8, 1730.4, 1659, 1589.8, and 1516.3.

Example 30: Stability Tests Solid state stability results of Aliskiren salts prepared by lyophilisation process

The impurities were measured by HPLC after treating the Aliskiren salts for 2 weeks and for 4 weeks in closed bottles at 60 °C.

Table 5

As shown in Table 5 the Aliskiren salt according to the prior art (Aliskiren fumarate 2 :1) shows significantly more impurities under stressed storage conditions than the above mentioned inventive Aliskiren salts. Especially under long term stressed condition this feature is even more emphasized. Thus, the stability of the Aliskiren salts according to the present invention is significantly enhanced, leading to unexpected superior shelf life.

Example 30

Water Content of Aliskiren Salts The water content of the salts is determined by the method of Karl Fisher described above.

Table 6

As shown in Table 6, the water content of all Aliskiren salts according the present invention shows a significantly lower water content than the prior art salt.

Claims

Claims

1. A salt of the Aliskiren free base compound,

with one or more acid compounds of the Formula H_mX,

wherein H is a dissociable hydrogen atom, X is a pharmaceutically acceptable residue and m is a natural number,

and wherein X is not a fumarate, hemifumarate, chloride, nitrate, sulphate or orotate.

2. A salt of the Aliskiren free base compound according to claim 1 , with one or more acid compounds of the Formula H_mX, wherein H is a dissociable hydrogen atom, X is a pharmaceutically acceptable residue and m is a natural number, wherein the acid compound or the acid compounds have a melting point of between 5 °C and 275 °C, preferably of between 15 °C and 275 °C.

3. A salt according to claim 1 or 2, wherein the acid compound comprises two or more acidic protons, which each have a pK_a of between 0.1 and 13.0.

4. A salt according to claims 1 to 3, wherein pK_a2 - p _ai is greater or equal to 0.5 but less than or equal to 5.5.

5. A salt according to any of the preceding claims, wherein the acid compound is an organic acid with between 1 and 3 carbon atoms.

6. A salt according to any of the preceding claims, wherein the acid compound is one or more selected from oxalic acid, maleic acid, L-malic acid, alpha-tartaric acid, alpha-L-tartaric acid, succinic acid, ascorbic acid, citric acid, adipic acid, D or L- mandelic acid, acetic acid, D- or L-aspartic acid.

7. A salt according to claim 1 or 2, wherein X is carbonate, hydrogencarbonate, phosphate, hydrogenphosphate, dihydrogenphosphate, diphosphate, silicate, hydrogensilicate, bromide, fluoride and/or iodide.

8. A salt according to any of the preceding claims, wherein the acid compound to free base compound ratio in the salt is from 1 :3.2 to 2.1 :1.

9. A salt according to any of the preceding claims, in the form of a hydrate or a solvate.

10. A salt according to any of the preceding claims, in a crystalline form, a partly crystalline form, an amorphous form or a polymorphous form.

11. A process for the manufacture of a salt according to any of the claims 1 to 9 in a form, which is at least partially crystalline, characterized in that: (i) the free base compound and/or the corresponding acid compound is dissolved in an organic solvent,

(ii) the solution or solutions of (i) are mixed with each other,

or alternatively with the other compound of either the free base compound or the corresponding acid compound, whichever was not originally dissolved in step (i), (iii) optionally, the solution of (ii) is stirred,

(iv) the solution is kept without stirring under conditions acceptable for salt crystallization,

(v) the salt precipitate is filtered, followed by drying,

(vi) the salt is collected.

12. A process for the manufacture of a salt according to any one of the claims 1 to 9, in a form which is at least partially amorphous characterized in that:

(I) dissolving the Aliskiren free base compound and/or the corresponding acid compound in an organic solvent,

(II) mixing the solution or solutions of (i) with each other, or alternatively with the other compound of either the free base compound or the corresponding acid compound,

(III) preferably concentrating the mixture of (II),

(IV) triturating the residue of (III), optionally repeatedly, with a suitable solvent,

(V) optionally collecting and drying the solid.

13. A salt prepared according to claim 1 or 12, wherein the IR Spectrum graph of the salt product shows at least one peak between 3000 to 3500 cm^"1.

14. A salt according to claims 1 to 10, in a form, which is at least partly crystalline and/or at least partly amorphous, obtained by:

(a) dissolving the solid salt according to any of the preceding claims in a solvent or in water,

or alternatively dissolving Aliskiren freebase in an aqueous solution of acid,

(β) freeze-drying and/or spray-drying the solution to obtain a final solid product.

15. The salt according to claim 14, wherein the differential scanning calorimetry graph of the salt product shows at least one endothermic peak between 100 °C to 300 °C.

16. A pharmaceutical composition, comprising the salt according to any of the claims 1 to 10, 13, 14 or 15, wherein optionally the composition further comprises one or more pharmaceutically acceptable carriers, excipients and/or additives.