HK1169832B - Novel solid materials of {[2s,5r,8s,11s)-5-benzyl-11-(3-guanidino-propyl)-8-isopropyl-7-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid} and methods for obtaining them - Google Patents

Description

Novel solid substances of { [ (2S,5R,8S,11S) -5-benzyl-11- (3-guanidino-propyl) -8-isopropyl-7-methyl-3, 6,9,12, 15-pentaoxo-1, 4,7,10, 13-pentaaza-cyclopentadecan-2-yl ] -acetic acid } and process for obtaining them

The present invention relates to novel solid substances of { [ (2S,5R,8S,11S) -5-benzyl-11- (3-guanidino-propyl) -8-isopropyl-7-methyl-3, 6,9,12, 15-pentaoxo-1, 4,7,10, 13-pentaaza-cyclopentadecan-2-yl ] -acetic acid }, processes for their preparation and the use of said solid substances in medicine.

{ [ (2S,5R,8S,11S) -5-benzyl-11- (3-guanidino-propyl) -8-isopropyl-7-methyl-3, 6,9,12, 15-pentaoxo-1, 4,7,10, 13-pentaaza-cyclopentadecan-2-yl ] -acetic acid } or cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) was first described in the first published patent/patent applications US6,001,961 and EP 0770622 in 1997. Various salt forms of the compounds are described in the patent, such as the hydrochloride, acetate and mesylate salts. Later, an improved preparation of the inner salt leading to cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) was described in WO 00/53627. However, the solid obtained according to the process appears to be amorphous.

Pharmaceutical activity is of course a fundamental prerequisite for the achievement of a pharmaceutically active substance, a pharmaceutically active component or an Active Pharmaceutical Ingredient (API) before being approved as a drug on the market. However, pharmaceutically active substances must also comply with a number of further requirements. These requirements are based on various parameters relating to the nature of the active substance itself. Examples of such parameters are, without limitation, the stability of the active substance or active ingredient under various environmental conditions, its stability during the preparation of the pharmaceutical formulation and the stability of the active substance or active ingredient in the final pharmaceutical composition. The pharmaceutically active substance used for the preparation of the pharmaceutical composition should be as pure as possible and its stability in long-term storage must be ensured under various environmental conditions. This is absolutely necessary to prevent the use of pharmaceutical compositions which, in addition to the actual active substance, contain, for example, decomposition or degradation products thereof. In such cases, the content of active substance in the medicament may be lower than indicated and/or the quality control of the medicament may be unacceptable.

Technical factors such as the particle size or the uniform distribution of the active ingredient or active ingredients in the formulation can be critical factors, especially when the medicament is a combination formulation and/or the medicament must be administered at low doses. To achieve a compound formulation system and/or to ensure uniform distribution, the particle size of the active substance can be adjusted to a suitable level, for example by grinding. Since the decomposition of the pharmaceutically active substance as a side effect of process steps such as purification, dissolution, melting, grinding, micronization, mixing and/or extrusion has to be minimized, it is absolutely essential that the active substance is highly stable throughout said process steps, although strict conditions are required during said process steps. Only if the active substance is sufficiently stable during the working steps, it is possible to produce homogeneous pharmaceutical preparations which always meet the quality requirements and contain the indicated amounts of active substance in a reproducible manner.

Another problem that may arise in the milling operation used to prepare the intended pharmaceutical formulation is the energy and/or pressure input caused by the process steps, such as stress on the surface of the API particles, whether it is amorphous or crystalline. In some cases this may lead to polymorphic changes, changes in the amorphous configuration or lattice changes, depending on the solid substance or form employed in the working step. Since the pharmaceutical quality of pharmaceutical formulations requires that the active substance should always have the same morphology, preferably the same crystalline morphology, the stability and properties of solid APIs are also subject to stringent requirements from this point of view. Therefore, the stability of the API itself as well as the long shelf life is really important.

Many pharmaceutical solids can exist in different physical forms. Polymorphism is preferably characterized by the ability of a compound, such as a drug substance, to exist as two or more crystal modifications having different molecular arrangements and/or conformations in the crystal lattice (d.j.w.grant.the same and origin of Polymorphism. in "Polymorphism in pharmaceutical solutions" of h.g.britain (ed.), Marcel Dekker inc., new york, 1999, pages 1-34, the disclosure of which is incorporated herein by reference in its entirety). Amorphous solids consist of disordered arrangements of molecules and do not have a crystal lattice and/or long program. Solvates are crystalline solids containing a stoichiometric or non-stoichiometric amount of solvent incorporated within the crystal structure. If the solvent incorporated is water, the solvate is often also referred to as a hydrate. Polymorphism refers to the occurrence of different crystal modifications of the same compound or drug substance. Polymorphism in this annotation is as defined in International Conference on harmony (ICH) guidelines Q6A (International Conference on harmony Q6A guidelines: specificities for New Drug substructures: Chemical substructures, 10 1999, the disclosure of which is incorporated herein by reference in its entirety), including solvates and amorphous forms.

Stoichiometric solvates are preferably considered as molecular compounds. The term preferably means that the ratio of solvent to compound is fixed (although not necessarily an integer). The non-stoichiometric solvates are preferably a class of inclusion compounds. The most important feature of such solvates is that the structure is preserved, while the solvent content may take all values between 0 and up to a number of molar compound ratios, if possible. The amount of solvent in the structure depends on the partial pressure and temperature of the solvent in the environment of the solid (see U.J. Griesser, "the Import of solvents", in "Polymorphism in the pharmaceutical Industry" of R.Hilfiker (eds.), Wiley VCH, 2006, the disclosure of which is incorporated herein in its entirety).

Polymorphs and/or solvates of a pharmaceutical solid can have different chemical and physical properties, such as melting point, hygroscopicity, chemical reactivity, apparent solubility, dissolution rate, optical and electrical properties, vapor pressure, and/or density. These properties may have a direct impact on the processability of the drug substance and the quality/performance of the drug product, such as stability, dissolution and/or bioavailability. Metastable drug solid state forms may change crystalline structure or solvate/desolvate in response to changes in environmental conditions, handling, or over time.

The stability of the API is also important in pharmaceutical compositions to determine the shelf life of a particular agent; shelf life is the period of time within the approved specification that a pharmaceutical product is expected to be stored, provided that it is stored under specified conditions. The medicament can be administered without any risk to the patient during the prescribed shelf life. Thus, the high stability of the pharmaceutical agents in the above pharmaceutical compositions under various storage conditions is an additional advantage for both the patient and the manufacturer.

In addition to the requirements indicated above, it should generally be borne in mind: any change in the solid state form of a pharmaceutical composition that improves its physical and chemical stability yields significant advantages over the less stable form of the same agent.

It was therefore an object of the present invention to provide a new stable solid substance of the compound cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) which meets the stringent requirements imposed on pharmaceutically active substances as mentioned above. It is therefore an object of the present invention to provide new solid substances or forms of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) with improved solid state properties.

It has now been found that cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) and especially the inner salts thereof can be obtained as crystalline material as well as in a specific crystalline form. Surprisingly, a whole class of novel crystalline forms of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) of similar structural type (hereinafter also referred to as pseudopolymorphs, PP) have been found which actually show beneficial solid state properties and preferably also have an advantageous combination of beneficial solid state properties, e.g. of the known substances with the novel substances of the present invention.

Furthermore, it has surprisingly been found that: the different methods for obtaining the new crystalline material preferably result in different crystalline forms or modifications within the crystalline form class. These crystalline forms or variants of the compound cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) and especially the inner salts thereof and the process for preparing them are preferably the subject of the present application.

The novel solid materials and the crystalline forms or modifications exhibit valuable properties and advantages over previously known amorphous materials, including but not limited to higher thermodynamic stability, reduced hygroscopicity, higher crystallinity, improved handling properties, favorable solubility properties, and/or improved storage stability.

The compounds { [ (2S,5R,8S,11S) -5-benzyl-11- (3-guanidino-propyl) -8-isopropyl-7-methyl-3, 6,9,12, 15-pentaoxo-1, 4,7,10, 13-pentaaza-cyclopentadecan-2-yl ] -acetic acid } or cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) (also known under the international non-proprietary name as cilengitide) show advantageous biological activities, including but not limited to its integrin inhibitory activity, anti-angiogenic activity and radiotherapy enhancing activity, which are widely used as active ingredients in pharmaceutical applications.

Factors such as high purity, excellent handling properties, adequate stability and a reliable manufacturing process are critical for use as an active ingredient in pharmaceutical applications or simply as an API. Furthermore, for such peptide compounds having both a basic center or moiety and an acidic center or moiety, the precise stoichiometry in salt formation is another critical factor and therefore a task for preparing the API. The acid salt of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) has been found to be readily prepared, but has been found to be less stable due to acid-catalyzed degradation. It has been found that basic salts generally have undesirable dissolution and handling properties. The previously known and described amorphous form of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) has been found to have unfavorable hygroscopicity, which is a major disadvantage in the preparation of dosage forms and in the development of suitable pharmaceutical preparations.

Thus, solid forms having improved stability, improved handling, higher purity and/or higher purification rates of the API compared to known amorphous forms are often highly desirable and a real need for reliable technical large-scale preparation of the API. This is especially true if a solid dosage formulation or suspension formulation of the API must be provided.

The subject of the invention is therefore:

a solid substance of a compound of formula I,

cyclo- (Arg-Gly-Asp-DPhe-NMeVal) (I)

Wherein the solid substance comprises one or more crystalline forms of the compound of formula I characterized by a unit cell having the following lattice parameters:

and

the unit cell is preferably a crystallographic unit cell or a crystallographically defined unit cell.

In the unit cell, the angle α is preferably 90 ° ± 2 °, the angle β is preferably 90 ° ± 2 °, and/or the angle γ is preferably 90 ° ± 2 °.

The solid substance preferably comprises at least 10% by weight, more preferably at least 30% by weight, even more preferably 60% by weight, in particular at least 90% by weight or at least 95% by weight of one or more crystalline forms of the compound of formula I as defined above and/or below. For example, the solid substance comprises about 25, about 50, about 75, about 95, about 99 or about 100% by weight of one or more crystalline forms of the compound of formula I as defined above and/or below.

Particularly preferably, the solid substance comprises at least 10 mol%, more preferably at least 30 mol%, even more preferably 60 mol%, especially at least 90 mol% or at least 95 mol% of one or more crystalline forms of the compound of the formula I as defined above and/or below. For example, the solid substance comprises about 25, about 50, about 75, about 95, about 99 or about 100 mole% of one or more crystalline forms of the compound of formula I as defined above and/or below.

The weight percentages given for the solid substance of the invention preferably relate to the ratio between the weight of the crystalline form or forms as defined above/below contained in the solid substance and the total weight of the compound of formula I contained in the solid substance. In other words, the weight percentages given are preferably weight percentages of the total amount of the one or more crystalline forms as defined above and/or below, calculated on the total weight of the compound of formula I. Thus, the weight percentages given for the content of one or more crystalline forms in the solid substance of the invention are preferably independent of the amount or content of compounds or impurities other than the compound of formula I contained in the solid substance. Thus, the weight percentages given for the solid substance are preferably corrected for the solvent molecules contained, i.e. the weight percentages given for the solid substance are preferably calculated independently of the solvent molecules in the solid substance or in the absence of such solvent molecules.

The molar percentages (% moles) given for the solid substance of the invention preferably relate to the molar ratio between the one or more crystalline forms as defined above/below contained in the solid substance and the total molar amount of compound of formula I contained in the solid substance. In other words, the given mole percentages are preferably mole percentages calculated for the total amount of the one or more crystalline forms as defined above and/or below, based on the total molar amount of the compound of formula I. Thus, the molar percentages given for the content of one or more crystalline forms in the solid substance of the invention are preferably independent of the amount or content of compounds or impurities other than the compound of formula I contained in the solid substance. Therefore, the molar percentages given for the solid substance are preferably corrected for the solvent molecules contained, i.e. the molar percentages given for the solid substance (% moles) are preferably calculated independently of the solvent molecules in the solid substance or in the absence of such solvent molecules.

By one or more crystalline forms in respect of the solid substance is preferably meant that the solid substance comprises at least one or more crystalline forms or modifications of the compound of formula I having a unit cell within the lattice parameters as defined above and/or below, or that the solid substance comprises a mixture of two or more, for example two or three, crystalline forms or modifications of the compound of formula I, each having a unit cell within the lattice parameters as defined above and/or below.

Preferably, the solid substance comprises one, two, three or four crystalline forms of the compound of formula I as defined above and/or below.

More preferably, the solid substance comprises one or more, preferably one, two, three or four, even more preferably one or two, crystalline forms of the compound of formula I, each having a unit cell with a lattice parameter (ULP) selected from the group consisting of:

ULP1：

and

and

ULP2：

and

more preferably, the solid substance comprises one or more, preferably one, two, three or four, even more preferably one or two, crystalline forms of the compound of formula I, each having a unit cell with a lattice parameter (ULP) selected from the group consisting of:

ULP1：

and

and

ULP2：

and

in a unit cell with lattice parameters ULP1 and/or ULP2, the angle α is preferably 90 ° ± 2 °, the angle β is preferably 90 ° ± 2 ° and/or the angle γ is preferably 90 ° ± 2 °.

Preferably, the unit cell having the lattice parameter ULP1 may alternatively or additionally, preferably additionally, be characterized by a content of about 4 molecules of the compound of formula I contained within the unit cell.

In a unit cell with the lattice parameter ULP2, the angle α is preferably 90 ° ± 0.5 °, the angle β is preferably 90 ° ± 0.5 ° and/or the angle γ is preferably 90 ° ± 0.5 °. In a unit cell with the lattice parameter ULP2, the angles α, β and γ are more preferably 90 ° ± 0.1 °.

Preferably, the unit cell having the lattice parameter ULP2 may alternatively or additionally, preferably additionally, be characterized by a content of about 4 molecules of the compound of formula I contained within the unit cell.

More preferably, the solid substance comprises one or more, preferably one, two, three or four, even more preferably one or two, crystalline forms of the compound of formula I selected from:

crystalline form A1 to have a lattice parameterAndthe unit cell of (a) is characterized,

crystalline form S1 to have a lattice parameterAndthe unit cell of (a) is characterized,

crystalline form S2 to have a lattice parameterAnda unit cell of (A), and

crystalline form S3 to have a lattice parameterAndand (3) unit cell characterization.

More preferably, the solid substance comprises one or more, preferably one, two, three or four, even more preferably one or two, crystalline forms of the compound of formula I selected from:

crystalline form a1, characterized by a unit cell having the following lattice parameters:andpreferably, α ═ β ═ γ ═ 90 ° ± -1 ° and in particular α ═ β ═ γ ═ 90 °;

crystalline form S1, characterized by a unit cell having the following lattice parameters:andpreferably, α ═ β ═ γ ═ 90 ° ±.2 °, in particular α ═ 90 ° ±.1 °, β ═ 91 ° ±.1 °, γ ═ 90 ° ±.1 °, in particular α ═ 90 °, β ═ 91.2 °, γ ═ 90 °;

crystalline form S2, characterized by a unit cell having the following lattice parameters:andpreferably, α ═ β ═ γ ═ 90 ° ± -1 °, in particular α ═ β ═ γ ═ 90 °; and

crystalline form S3, characterized by a unit cell having the following lattice parameters:andpreferably, α ═ β ═ γ ═ 90 ° ±.1 ° and in particular α ═ β ═ γ ═ 90 °.

Preferably, crystalline forms S1, S2 and S3 may alternatively or additionally, preferably additionally, be characterized by a content of about 4 molecules of the compound of formula I in the unit cell.

Crystalline forms S1, S2, and S3 are preferably also characterized as solvates.

In the context of the present invention, solvates are preferably crystalline solid adducts containing stoichiometric or non-stoichiometric amounts of solvent incorporated within the crystalline structure, i.e. the solvent molecules preferably form part of the crystalline structure. If the solvent incorporated is water, the solvate is also commonly referred to as a hydrate.

Thus, the solvent in the solvate preferably forms part of the crystal structure and is therefore typically detectable by X-ray methods, preferably by X-ray methods as described herein.

Generally, for a given crystal structure, the amount of solvent incorporated into the structure has an upper limit (does not cause a transition to another crystal structure). However, in some cases it is possible to remove at least a portion of the incorporated solvent by physical manipulation of the crystalline structure, for example by a drying operation, for example by storage at elevated temperatures (but preferably below the melting point or other phase transition point) and/or reduced pressure, preferably including the application of a vacuum and reduced partial pressure. Typically in such cases, the solvent may be partially or completely removed from the crystalline structure, thereby introducing voids in the crystalline structure. The probability of phase and/or polymorphic transformations (e.g. into a different polymorph or especially into an amorphous form, a solvate or hydrate containing less solvent or water molecules or a dehydrated form) increases as the amount of solvent incorporated approaches zero.

In such cases, the solvent contained and/or the amount thereof, and thus the composition or solvate structure of each solvate, may preferably be altered by appropriate handling, including but not limited to conditioning and/or recrystallization. For example, a solvent may be partially or completely removed from such solvates, a solvent may be partially or completely replaced in such solvates by a different solvent, and/or the amount of solvent in such solvates may be increased or decreased. Thus, solvates containing a particular solvent can potentially be converted to solvates containing mixtures of solvents, and vice versa.

In this respect, the conditioning preferably involves physical handling, wherein the initial crystal structure of the respective solvate is substantially preserved. Methods and means and/or parameters suitable for adjusting the solvates are known in principle to the skilled worker. Examples of suitable conditioning methods are disclosed in the present application, preferably including but not limited to: exposure to solvent vapor, exposure to thermal conditions (e.g., by differential scanning calorimetry, thermogravimetric analysis, and/or storage at a particular temperature or temperature gradient), pulping (e.g., forming and/or handling a suspension of a solvate in a liquid comprising one or more solvents), exposure to variable partial pressures of one or more solvents, exposure to particular partial pressures of one or more solvents, and/or a particular partial pressure gradient, and combinations thereof. For example, pulping and/or exposure to variable partial pressures of one or more solvents may be achieved at specific temperatures or temperature gradients. Preferred forms of modification are solvation or desolvation. Slurries and operating techniques for slurries or pulping are known in the art, for example from Martyn d. ticerhurst, Richard a. storey, Claire Watt, International Journal of pharmaceuticals 247(2002)1-10, the disclosure of which is incorporated herein in its entirety.

Additionally or alternatively, the solvent contained and/or the amount thereof and thus the composition of the individual solvates or the solvate structure may also preferably be changed by recrystallization, in particular by recrystallization from a different solvent or solvent mixture, provided that the initial crystal structure of the solvate is reproduced or substantially reproduced.

In this respect, solvate preferably means a solvent molecule having a unit cell or crystallographic unit cell containing about the stoichiometric amount (whole or non-whole) of the solvent or solvents for each molecule of the compound of formula I contained in said unit cell. The approximate stoichiometry of solvent molecules in the unit cell for each molecule of the compound of formula I contained in the unit cell is preferably from about 0.01 solvent molecule to about 8 solvent molecules, more preferably from about 0.1 solvent molecule to about 7 solvent molecules, even more preferably from about 1.5 solvent molecules up to about 4.5 solvent molecules, for example about 0.1 solvent molecule, about 0.5 solvent molecule, about 1.5 solvent molecule, about 3 solvent molecules, about 4 solvent molecules, or about 7 solvent molecules, per molecule of the compound of formula I. Especially preferred are solvates with about 4 solvent molecules per molecule of the compound of formula I contained in the unit cell. A unit cell or crystallographic unit cell is preferably considered to be a tetrasolvate if it contains about 4 solvent molecules of one or more solvents per molecule of the compound of formula I contained in said unit cell; it is preferably considered to be a heptasolvate if it contains solvent molecules of about 7 one or more solvents per molecule of the compound of formula I contained in the unit cell.

In this respect, solvate preferably means a solvent molecule having a unit cell or crystallographic unit cell containing about the stoichiometric amount (preferably an integer or non-integer, more preferably about an integer) of one or more solvents per molecule of the compound of formula I contained in said unit cell. The approximate stoichiometry of solvent molecules in the unit cell for each molecule of the compound of formula I contained in the unit cell is preferably from about 0.5 solvent molecules to about 6 solvent molecules, more preferably from about 0.5 solvent molecules to about 4.5 solvent molecules, even more preferably from about 1.5 solvent molecules up to about 4 solvent molecules, for example about 0.5 solvent molecules, about 1.5 solvent molecules, about 4 solvent molecules, or about 6 solvent molecules, for each molecule of the compound of formula I contained in the unit cell. Especially preferred are solvates with about 4 solvent molecules per molecule of the compound of formula I contained in the unit cell. A unit cell or crystallographic unit cell is preferably considered to be a tetrasolvate if it contains about 4 solvent molecules of one or more solvents per molecule of the compound of formula I contained in said unit cell.

In this regard, preferred solvents or solvent molecules are selected from water and alcohols, more preferably from water, methanol and ethanol.

For example, if a unit cell of a crystalline form contains 1 molecule of the compound of formula I and about 4 molecules of a solvent, the form is preferably considered to be a tetrasolvate. If the unit cell of a crystalline form contains 2 molecules of the compound of the formula I and about 8 molecules of a solvent, said form is also preferably regarded as a tetrasolvate. If the unit cell of a crystalline form contains 4 molecules of the compound of the formula I and about 16 molecules of a solvent, said form is also preferably regarded as a tetrasolvate. The same is true if the unit cell in crystalline form contains 2 and 1/2 molecules of the compound of formula I and about 10 molecules of solvent.

Thus, a solvate more preferably means a solvent molecule in which each crystalline form contains about the stoichiometric amount (whole or non-whole) of one or more solvents per molecule of the compound of formula I. The approximate stoichiometry of the solvent molecule(s) in the solvate is preferably from about 0.1 solvent molecule to about 7 solvent molecules per molecule of the compound of formula I, more preferably from about 0.5 solvent molecule per molecule of the compound of formula I up to about 4.5 solvent molecules per molecule of the compound of formula I, even more preferably from about 1.5 solvent molecules per molecule of the compound of formula I up to about 4 solvent molecules per molecule of the compound of formula I, e.g., about 0.5 solvent molecule, about 1.5 solvent molecule, about 3 solvent molecules, about 4 solvent molecules, or about 7 solvent molecules per molecule of the compound of formula I contained in the unit cell. Especially preferred are solvates with about 4 solvent molecules per molecule of the compound of formula I.

Thus, a solvate more preferably means a solvent molecule in which the respective crystalline form contains about the stoichiometric amount of one or more solvents per molecule of the compound of formula I. The approximate stoichiometry of the solvent molecule(s) in the solvate is preferably from about 0.5 solvent molecule to about 6 solvent molecules per molecule of the compound of formula I, more preferably from about 0.5 solvent molecule up to about 4.5 solvent molecules per molecule of the compound of formula I, even more preferably from about 1.5 solvent molecules per molecule of the compound of formula I up to about 4 solvent molecules per molecule of the compound of formula I, e.g., about 0.5 solvent molecule, about 1.5 solvent molecule, about 4 solvent molecules, or about 6 solvent molecules per molecule of the compound of formula I. Especially preferred are solvates with about 4 solvent molecules per molecule of the compound of formula I.

A more preferred stoichiometry of the solvate is defined as depicted in the grey shaded area of the following figure (figure I):

in this figure, x is the number of water molecules (which may be an integer or non-integer) per molecule of the compound of formula I, and y is the number of molecules of an alcohol, preferably methanol or ethanol, or mixtures thereof, and may be an integer or non-integer. Thus, the number of alcohol molecules per molecule of the compound of formula I is preferably from 0 to about 4, preferably from 0.1 to 4, and the number of water molecules is from 0 to about 4, preferably from 0.1 to 4.

An even more preferred stoichiometry of the solvate is defined as depicted in the grey shaded area of the following figure (figure II):

in this figure, x is the number of water molecules (which may be an integer or non-integer) per molecule of the compound of formula I, and y is the number of molecules of an alcohol, preferably methanol or ethanol, or mixtures thereof, and may be an integer or non-integer. Thus, the number of alcohol molecules per molecule of the compound of formula I is preferably from 0 to about 2, preferably from 0.1 to 2, and the number of water molecules is from 0 to about 4, preferably from 0.1 to 4.

An even still more preferred stoichiometry of the solvate is defined as depicted in the grey shaded area of the following figure (figure III):

in this figure, x is the number of water molecules (which may be an integer or non-integer) per molecule of the compound of formula I, and y is the number of molecules of an alcohol, preferably methanol or ethanol, or mixtures thereof, and may be an integer or non-integer. Thus, the number of alcohol molecules per molecule of the compound of formula I is preferably from 0 to about 1, more preferably from 0.1 to 1, and the number of water molecules is from 0 to about 4, more preferably from 0.1 to 4.

In this respect, particularly preferred solvents or solvent molecules are selected from water and alcohols, more preferably from water, methanol and ethanol.

Solvates of the compounds of the formula I having the composition or stoichiometry as described in, and preferably as described in the paragraphs relating to, respectively, figure I, figure II and/or figure III are particularly preferred subjects of the present invention. For the solvates described with a composition or stoichiometry within the ranges as described in fig. I, fig. II and/or fig. III, the solvates described above and/or below are particularly preferred examples and thus also particularly preferred subjects of the present invention.

From the description given above and/or below and preferably also from the description of the solvate or crystalline form S1, S2 and/or S3, it is evident that: a solvate or crystalline form characterized by a unit cell having a unit cell parameter ULP1 may comprise from 0 to about 4 solvent molecules per molecule of the compound of formula I within the unit cell, more preferably from 0.01 to about 4 solvent molecules per molecule of the compound of formula I within the unit cell, especially from 0.5 to 4 solvent molecules per molecule of the compound of formula I within the unit cell.

Thus, a common feature or characteristic of a solvate or crystalline form characterized by a unit cell having the unit cell parameter ULP1 is that the upper limit of the solvent content is about 4 molecules of one or more solvents, preferably solvents as described herein, per molecule of the compound of formula I. Solvates or crystalline forms characterized by an upper limit of solvent content of about 4 molecules of one or more solvents per molecule of the compound of formula I in the unit cell are preferably referred to in the art as tetrasolvates.

However, as described in detail herein, the solvate or crystalline form characterized by a unit cell having the unit cell parameter ULP1 may be desolvated resulting in a solvent content of about 3 or less solvent molecules per molecule of the compound of formula I within the unit cell, a solvent content of about 2 or less solvent molecules per molecule of the compound of formula I within the unit cell, a solvent content of about 1 or less solvent molecules per molecule of the compound of formula I within the unit cell, or even a solvent content approaching 0.5, 0.1, or 0 solvent molecules per molecule of the compound of formula I within the unit cell. These desolvates in solvated or crystalline form characterized by a unit cell having the unit cell parameter ULP1 are also preferred subjects of the present invention.

As a result, the terms "tetra-solvate" and/or "tetrahydrate" as used herein preferably also include partially or fully desolvated forms of said tetra-solvate and/or tetrahydrate, preferably as long as the respective crystal structure of the original tetra-solvate or tetrahydrate is retained or substantially retained.

As a further consequence thereof, the term "tetra-solvate" as used herein preferably also includes alcoholic solvates (or alcoholates) or mixed hydro-alcoholic solvates, preferably including but not limited to dihydrate-dialcohols, dihydrate-alcoholates and dihydrate-monoalcohols and/or partially or completely desolvated forms thereof, preferably as long as the respective crystal structure of the initial tetra-solvate and especially preferably the initial crystal structure of the tetrahydrate S3 is retained or substantially retained.

As a further consequence thereof, the term "tetra-solvate" as used herein preferably also includes alcoholic solvates (or alcoholates) or mixed hydro-alcoholic solvates, preferably including but not limited to dihydrate-glycolides, dihydrate-alcoholates, dihydrate-monoolates and glycolides (preferably of formula (Cil)₁(alcohol)₂(H₂O)₀Given) and/or partially or completely desolvated forms thereof, preferably as long as the respective crystal structure of the initial tetrahydrate and especially preferably the initial crystal structure of the tetrahydrate S3 is retained or substantially retained. Thus, all crystalline forms within the unit cell parameters of ULP1 as defined herein are preferably considered to be the tetrasolvate of the present invention.

The dialcohols of the present invention are preferably regarded as tetrasolvents and/or desolvated versions thereof, which preferably contain about 2 alcohol molecules per molecule of the compound of formula I, but which preferably contain less than 1 molecule, more preferably less than 0.5 molecule, especially less than 0.1 water molecule per molecule of the compound of formula I. Thus, preferred dialdehydes of the invention contain about 4 molecules of the compound of formula I and about 8 molecules of an alcohol, but preferably less than 1 molecule of water, in the unit cell. The alcohol in the dialdehydes is preferably selected from methanol and ethanol and mixtures thereof. Thus, the dialdehydes of the present invention may also preferably be considered as desolvates or more specifically anhydrates of the dihydrate-dialdehydes of the present invention.

Crystalline form a1 is preferably also characterized as being anhydrous or solventless (ansolvate).

In this respect, anhydrous or solventless preferably means that the unit cell contains no or substantially no solvent molecules in about stoichiometric amounts of one or more solvents. In this respect, anhydrous or solvent-free more preferably means that the unit cell is substantially free of water molecules and solvent molecules. Substantially free of solvent molecules in this respect preferably means that the amount of solvent molecules in the unit cell is below 0.5, more preferably below 0.1, even more preferably below 0.01, especially below 0.001.

Since both the anhydrous and the solventless material are characterized by the absence of the respective solvent and thus by the absence of any solvent, the terms anhydrous and solventless material are preferably considered synonyms in the context of the present invention.

The amount of molecules in the unit cell can preferably be determined by crystallographic methods, more preferably by single crystal X-ray diffraction and/or powder X-ray diffraction.

Alternatively, the amount of the crystalline form, the solvate, and/or the solvent in each unit cell may be determined or estimated by elemental analysis, gas chromatography, or Karl-Fischer (Karl-Fischer) titration. In this context, substantially free of solvent molecules preferably means a solvent content of less than 5%, even more preferably less than 2%, even more preferably less than 1%, especially less than 0.1%, for example from 5% to 0.1% or from 2% to 0.01%. In this respect, the percentages (%) indicated are preferably selected from the group consisting of% mol and% wt, particularly preferably% wt.

Crystalline forms a1, S2, and/or S3 are also preferably characterized by orthorhombic unit cells.

Crystalline form S1 is also preferably characterized by a monoclinic unit cell.

The unit cell and lattice parameters (preferably including but not limited to a, b, c, α, β and/or γ) are crystallographic parameters known to those skilled in the art. Thus, they can be determined according to methods known in the art. This is also preferred for the orthorhombic and/or monoclinic form of the unit cell.

The unit cells given above and the lattice parameters associated therewith are preferably determined by X-ray diffraction, more preferably single crystal X-ray diffraction and/or powder X-ray diffraction according to standard methods, e.g. as described in the following documents: chapter 6, 2.9.33 of the European pharmacopoeia, 6 th edition, and/or RolfHilfiker, Polymorphism in the Pharmaceutical Industry ', Wiley-VCH, Weinheim2006 (chapter 6: X-ray diffraction) and/or H.G.Brittain, ' Polymorphism Pharmaceutical solutions ', volume 95, Marcel Dekker Inc., New York, 1999 (chapter 6 and references therein).

Alternatively, and preferably, the unit cell given above and the lattice parameters associated therewith can be obtained by single crystal X-ray, optionally together with additional structural data, preferably on the following instrument:

equipped with graphite monochromator and using Mo K_αAn XCalibur diffractometer from Oxford diffraction, preferably at a temperature of 298K + -5K, of a radioactive CCD detector; and/or

Equipped with graphite monochromator and using Mo K_αCAD4 four-circle diffractometer from Nonius, emitting scintillation counter, preferably at a temperature of 298K + -5K.

The unit cells given above and the lattice parameters associated therewith are preferably determined by X-ray diffraction, more preferably powder X-ray diffraction, according to standard methods, for example as described in the following documents: european pharmacopoeia 6 th edition, chapter 2.9.33, and/or Rolf Hilfiker, Polymorphism in the Pharmaceutical Industry ', Wiley-VCH.Weinheim2006 (chapter 6: X-ray diffraction) and/or H.G.Brittain, ' Polymorphism in Pharmaceutical Solids ', volume 95, Marcel Dekker Inc., New York, 1999 (chapter 6 and references therein).

Higher amounts of one or more crystalline forms as defined above and/or below in the solid substance as described above and/or below are generally preferred.

A solid substance as described above and/or below consisting essentially of one or more crystalline forms of a compound of formula I is characterized by a unit cell having the following lattice parameters:

and

in particular as described above and/or below.

By essentially consisting of one or more crystalline forms of the compound of formula I is preferably meant that the compound of formula I contained in the solid substance is essentially selected from the one or more crystalline forms of the compound of formula I, or in other words, that one or more crystalline forms in the solid form provides the necessary amount of the compound of formula I in the solid form. More specifically, in this respect, substantially preferably means that one or more of the crystalline forms in the solid form provides an amount of 90% or more, preferably 95% or more, even more preferably 99% or more, especially 99.9% or more of the compound of formula I in the solid form. In this respect, the percentages (%) indicated are preferably selected from% mol and% by weight, particularly preferably% mol.

The amount may be provided by one single crystalline form as described herein or by a mixture of two or more crystalline forms as described herein. The amount is preferably provided by one single crystalline form as described herein. More preferably, the amount is provided by a single crystalline form selected from the group consisting of crystalline form a1, crystalline form S1, crystalline form S2, and crystalline form S3 as described herein.

If the solid substance comprises two or more crystalline forms as described herein, one of these crystalline forms is preferably the predominant crystalline form, while one or more other crystalline forms present are present in minor amounts. The predominant crystalline form preferably provides 60% by weight or more, more preferably 75% or more, even more preferably 90% or more, especially 95% or 99% or more of the total amount of crystalline forms present. In this respect, the percentages (%) indicated are preferably selected from% mol and% by weight, particularly preferably% mol.

The percentages (or%) given herein for compounds and/or solvents are preferably weight or mole percentages, preferably mole percentages, unless otherwise indicated. Since the content of one or more crystalline forms in the solid substance of the invention and, if applicable, the proportion of two or more crystalline forms in the solid substance of the invention can advantageously be determined by methods, including but not limited to powder X-ray diffraction, raman spectroscopy and infrared spectroscopy, more preferably by powder X-ray diffraction, raman spectroscopy and/or infrared spectroscopy, the percentage values relating thereto are particularly preferably molar percentage values, if not explicitly stated otherwise.

Preferably, the percentages (or%) given herein in the following cases are preferably relative percentages (i.e. percentages of the respective maximum values), unless otherwise indicated:

i) spectral data, such as transmission, especially IR transmission, raman intensity;

ii) powder X-ray diffraction intensity (PXRD intensity); and/or

iii) analytical parameters such as relative humidity (rh or r.h), etc.

A preferred subject of the present invention is one or more of the crystalline forms of the compounds of formula I as described herein, in particular as described above and/or below.

The one or more crystalline forms of the compound of formula I are preferably selected from the crystalline forms as described above and/or below having a monoclinic unit cell or an orthorhombic unit cell.

The one or more crystalline forms of the compound of formula I are preferably selected from the group consisting of anhydrates or solvates and solvates.

The solvate is preferably selected from the group consisting of a hydrate, a methanolate (methanol solvate), and an ethanolate (ethanol solvate), and mixtures thereof. The mixture is preferably selected from the group consisting of mixed water-methanol solvate, mixed water-ethanol solvate, mixed methanol-ethanol solvate and mixed methanol-ethanol-water-solvate.

Preferably, the anhydrate or solvate-free, especially crystalline form a1 of the present invention can alternatively or additionally be characterized by a melting/decomposition temperature > 282 ℃, more preferably 288 ± 5 ℃ or higher, especially 288 ± 5 ℃.

The melting/decomposition temperatures and/or thermal behaviors described herein are preferably determined by DSC (differential scanning calorimetry) and TGA (thermogravimetric analysis). DSC and/or TGA methods, or generally thermal analysis methods and apparatus suitable for their determination, are known in the art, for example from chapter 2.02.34, "european pharmacopoeia, 6 th edition, in which suitable standard techniques are described. For melting/decomposition temperatures or behaviour and/or thermal analysis it is generally more preferred to use Mettler Toledo DSC 821 and/or Mettler Toledo TGA 851, preferably as described in chapter 2.02.34 of the European pharmacopoeia, 6 th edition.

Figures 1 and 2 show DSC and TGA measurements showing the thermal analysis (Mettler-Toledo DSC 821, 5K/min, nitrogen bleed 50 ml/min; Mettler-Toledo TGA 851, 5K/min, nitrogen bleed 50ml/min) and melting/decomposition temperatures given above.

Preferably, the anhydrate or solvate-free, especially crystalline form a1 of the present invention can alternatively or additionally be characterized by powder X-ray diffraction, more preferably by a powder X-ray diffraction pattern comprising one or more, more preferably 6 or more, even more preferably 8 or more, especially all, of the powder X-ray peaks given below:

a)

or more preferably

b)

Preferably, the anhydrate or solvate-free, especially crystalline form a1 of the present invention can alternatively or additionally be characterized by powder X-ray diffraction, more preferably by a powder X-ray diffraction pattern comprising the powder X-ray peaks given below:

a)

or more preferably

b)

Preferably, the anhydrate or solvate-free, especially crystalline form a1 of the present invention can alternatively or additionally be characterized by powder X-ray diffraction, more preferably by a powder X-ray diffraction pattern comprising one or more, more preferably 10 or more, even more preferably 12 or more, especially all, of the powder X-ray peaks given below:

a)

or more preferably

b)

The powder X-ray diffraction and more preferably the powder X-ray diffraction patterns are preferably carried out or determined as described herein, in particular by standard techniques as described in the 6 th edition European pharmacopoeia, chapter 2.9.33, even more preferably with the parameter Cu-Ka₁Radiation and/orPreferably on a Stoe StadiP 611KL diffractometer.

Fig. 3 shows a powder X-ray diffraction pattern of crystalline form a 1.

Preferably, the anhydrate or solvate-free, especially crystalline form a1 of the present invention can alternatively or additionally be characterized by single crystal X-ray structural data, such as single crystal X-ray structural data obtained under the following conditions: on a diffractometer preferably equipped with a graphite monochromator and a CCD detector, Mo K is preferably used_αIrradiation, preferably at a temperature of 298K + -5K, even more preferably at a temperature equipped with a graphite monochromator and a CCD detectorOn an XCalibur diffractometer from Oxford Diffraction, Mo K was used_αRadiation, at about 298K.

The anhydrate and especially crystalline form A1 of the compound of formula I have lattice parameters based on the obtained single crystal X-ray structural dataIs inclined space group P2₁2₁2₁The crystallization is carried out with a unit cell volume of preferably

As is clear from the single crystal structure, form a1 represents either an anhydrate or a solventless material.

FIG. 4 depicts a single crystal X-ray structure.

Preferably, the anhydrate and solvate-free and especially crystalline form a1 of the present invention can alternatively or additionally comprise one or more of the band positions (± 2 cm) given below^-1) More preferably 6 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably 9 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses: 3431cm^-1(s)，3339cm^-1(s)，3189cm^-1(s)，2962cm^-1(m)，2872cm^-1(m)，1676cm^-1(s)，1660cm^-1(s)，1617cm^-1(s)，1407cm^-1(s)，1316cm^-1(m)，1224cm^-1(m)，1186cm^-1(m)，711cm^-1(m).

More preferably, the anhydrate and solvate-free and especially crystalline form a1 of the present invention can alternatively or additionally comprise one or more of the band positions (± 2 cm) given below^-1) More preferably 9 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably 12 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses: 3431cm^-1(s)，3339cm^-1(s)，3189cm^-1(s)，3031cm^-1(m)，2962cm^-1(m)，2872cm^-1(m)，1676cm^-1(s)，1660cm^-1(s)，1617cm^-1(s)，1539cm^-1(s)，1493cm^-1(s)，1407cm^-1(s)，1358cm^-1(m)，1316cm^-1(m)，1247cm^-1(m)，1224cm^-1(m)，1186cm^-1(m)，994cm^-1(w)，921cm^-1(w)，711cm^-1(m)，599cm^-1(m).

The relative intensities given in parentheses are preferably defined as follows:

strong (transmittance preferably 50%) or less, "m" medium (transmittance preferably 50% < transmittance 70%),

"w" is weak (transmission is preferably > 70%).

Preferably, the IR or FT-IR spectra are obtained using a KBr chip as the sample preparation technique.

Preferably, the IR-spectroscopy data is obtained by FT-IR-spectroscopy. IR-spectroscopy data or FT-IR-spectroscopy data are preferably obtained by standard techniques as described in chapter 2.02.24, European pharmacopoeia, 6 th edition. For the determination of FT-IR spectroscopy, a Bruker Vector 22 spectrometer is preferably used. The FT-IR spectrum is preferably baseline corrected, preferably using Bruker OPUS software.

The FT-IR spectrum of the anhydrate of the invention and especially crystalline form a1 is given in figure 5.

Preferably, the anhydrate or solvate-free form of the present invention, especially crystalline form a1, can alternatively or additionally comprise one or more of the band positions given below (± 2 cm)^-1) More preferably 9 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably 9 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses: 3064cm^-1(w)，2976cm^-1(m)，2934cm^-1(m)，2912cm^-1(m)，2881cm^-1(m)，1603cm^-1(w)，1209cm^-1(w)，1029cm^-1(w)，1003cm^-1(m)，852cm^-1(w).

More preferably, the anhydrate or solvate-free form of the invention, especially crystalline form a1, may alternatively or additionally comprise one or more of the band positions given below (± 2 cm)^-1) More preferably 12 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably 18 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses: 3064cm^-1(w)，2976cm^-1(m)，2934cm^-1(m)，2912cm^-1(m)，2881cm^-1(m)，1677cm^-1(w)，1648cm^-1(w)，1603cm^-1(w)，1584cm^-1(w)，1465cm^-1(w)，1407cm^-1(w)，1314cm^-1(w)，1242cm^-1(w)，1209cm^-1(w)，1129cm^-1(w)，1029cm^-1(w)，1003cm^-1(m)，943cm^-1(w)，901cm^-1(w)，852cm^-1(w)，623cm^-1(w)，589cm^-1(w).

The relative intensities given in parentheses are preferably defined as follows:

"s" is strong (relative raman intensity is preferably ≥ 0.04), "m" is medium (preferably 0.04 > relative raman intensity ≥ 0.02), "w" is weak (relative raman intensity is preferably < 0.02).

Preferably, the raman or FT-raman spectra are obtained using an aluminium cup as the sample container for each solid substance.

Preferably, the raman spectroscopy data is obtained by FT-raman spectroscopy. Preferably, the Raman spectroscopy data or FT-Raman spectroscopy data is obtained by standard techniques as described in European pharmacopoeia, 6 th edition, chapter 2.02.48. For the determination of FT-Raman spectroscopy, a Bruker RFS100 spectrometer is preferably used. The FT-Raman spectra are preferably baseline corrected, preferably using Bruker OPUS software.

The FT-raman spectrum of the anhydrate of the invention and especially crystalline form a1 is given in figure 6.

Preferably, the anhydrate or solvate-free, especially crystalline form a1 of the present invention can alternatively or additionally be characterized by dynamic vapor absorption experiments. Results may be obtained by standard techniques as described in Rolf Hilfiker, Polymorphism in the Pharmaceutical Industry', Wiley-VCH.Weinheim2006 (Chapter 9: Water vapor absorption, and references therein). Water vapour absorption behaviour shows small water absorption levels up to 98% relative humidity (rh or r.h.) the anhydrate or solvate-free material of the invention, especially crystalline form a1, can be classified as non-hygroscopic according to the european pharmacopoeia criteria. No formation or conversion to hydrate was observed. The water vapor sorption isotherm (25 ℃) (SMS DVS Intrinsic) of crystalline form a1 is given in fig. 7.

The anhydrate or solvate-free, especially crystalline form a1, of the present invention exhibit one or more properties selected from the advantageous properties discussed above. More specifically, the anhydrate or solventless, especially crystalline form a1 of the present invention can exhibit thermodynamically stable unsolvated and/or thermodynamically stable forms and unexpectedly exhibits thermodynamically stable forms in the presence of water-based solvents (preferably including, but not limited to, suspensions and wetted materials), especially in substantially aqueous systems such as saline and the like (e.g., without limitation, suspensions and wetted materials), especially in such aqueous systems in the absence of methanol and/or ethanol. In this connection, the wetting substance is preferably a mixture of the individual anhydrates or solventless substances which contains at least 5% by weight, more preferably at least 10% by weight, in particular 20% by weight, of the respective aqueous system.

More specifically, the anhydrate or solvate-free, especially crystalline form a1 of the present invention can be shown to be thermodynamically stable in the unsolvated form and/or in the thermodynamically stable form and surprisingly even in the presence of high relative humidity.

Furthermore, the anhydrate of the present invention, especially crystalline form a1, showed better properties in terms of hygroscopic behavior, with the crystalline form being excellent in physical stability and/or crystallinity and thermal behavior throughout the relative humidity range (0-98%).

This results in good properties for processing (e.g. phase separation by filtration, drying, milling, micronisation) and storage and is thus good for the formulation of suspensions. The anhydrate or solvate-free, especially crystalline form a1 of the present invention exhibits superior properties for the purification of the compound of formula I, because structure-related impurities, ionic compounds and residual solvents can be easily reduced. Thus, purification can be achieved in one step, wherein solid forms such as amorphous forms prepared according to conventionally known methods and/or other polymorphic crystalline forms of non-anhydrates require significantly higher efforts to achieve GMP-compliant purity, e.g. three or more subsequent purification operations.

The compounds of formula I may also form a class of pseudopolymorphs which are incorporated in variable amounts and/or proportions, preferably in variable proportions, into different solvents and are thus solvates. As shown, for example by powder X-ray diffraction data, including indices of these forms, these solvates are structurally closely related, which results in a similar unit cell. Moreover, selected structural examples will be discussed in terms of single crystal structures and structural analyses based on powder data. Finally, a discussion will be given regarding the specific beneficial properties of this pseudopolymorph class.

3 preferred examples of pseudopolymorphs of the compound of formula I are described below:

s1 (preferably also referred to as methanol-water solvate and/or methanol solvate),

s2 (preferably also referred to as ethanol-water solvate and/or ethanol solvate), and

s3 (preferably also referred to as hydrate and/or tetrahydrate). These preferred examples may also be described as tetrasolvates.

Thus, the solid crystalline form having a unit cell with a lattice parameter of ULP1 as defined above is preferably also characterized herein as a solvate, more preferably also as a tetrasolvate. The solvate and/or tetrasolvate preferably comprises one or more crystalline forms selected from S1, S2 and S3 as defined herein, preferably also mixtures thereof.

Crystalline forms S1, S2, and/or S3 are preferably also characterized as solvates, especially also as tetrasolvates, i.e., they preferably exhibit about a stoichiometric amount of solvent molecules in the respective unit cell, which stoichiometric amount is about up to 4 solvent molecules per molecule of the compound of formula I per unit cell.

In these solvates and more preferably in these tetra-solvates, the solvent molecules are preferably selected from molecules of water and alcohols, more preferably from molecules of water, methanol and ethanol and mixtures thereof.

Thus, the solvate may preferably also be characterized as a hydrate, an alcohol solvate (or alcoholate) or a mixed water-alcohol solvate, more preferably as a hydrate, a methanol solvate (or methanolate), an ethanol solvate (or ethanolate), a mixed water-methanol solvate, a mixed water-ethanol solvate or a mixed water-methanol-ethanol solvate. More specifically, mixed solvates may be obtained if the solvate is prepared from or contacted with a solvent mixture, for example by recrystallization from or conditioning with a solvent mixture. Particularly preferably, mixed hydroalcoholic solvates and in particular mixed hydromethanol solvates, mixed hydroethanol solvates and/or mixed water-methanol-ethanol solvates may thus be obtained. Furthermore, solvent molecules within one solvate may be partially or fully interchanged with solvent molecules of another solvent. It is thus clear that solvates, more preferably tetra-solvates, in particular crystalline forms S1, S2 and S3 all belong to a specific class of solid crystalline forms.

Preferably, the tetra-solvate of the invention, more preferably the tetrahydrate of the invention, especially crystalline form S3 may alternatively or additionally be characterized by a melting/decomposition temperature > 210 ℃, more preferably 217 ± 5 ℃ melting/decomposing or higher, especially 217 ± 5 ℃ melting/decomposing. Preferably, the melting/decomposition temperature obtained for the tetra-solvate of the invention, more preferably the tetrahydrate of the invention, especially obtained for crystalline form S3, is < 250 ℃.

The melting/decomposition temperatures and/or thermal behaviors described herein are preferably determined by DSC (differential scanning calorimetry) and TGA (thermogravimetric analysis). DSC and/or TGA methods, or generally thermal analysis methods and apparatus suitable for their determination, are known in the art, for example from chapter 2.02.34, "european pharmacopoeia, 6 th edition, in which suitable standard techniques are described. For melting/decomposition temperatures or behaviour and/or thermal analysis it is generally more preferred to use Mettler Toledo DSC 821 and/or Mettler Toledo TGA 851, preferably as described in chapter 2.02.34 of the European pharmacopoeia, 6 th edition.

Figures 23 and 24 show DSC and TGA measurements showing the thermal analysis (Mettler-Toledo DSC 821, 5K/min, nitrogen bleed 50 ml/min; Mettler-Toledo TGA 851, 5K/min, nitrogen bleed 50ml/min) and melting/decomposition temperatures given above.

Preferably, the tetra-solvate of the invention, more preferably the tetrahydrate of the invention, especially crystalline form S3, may alternatively or additionally be characterized by a powder X-ray diffraction pattern, more preferably comprising one or more, more preferably 3 or more, even more preferably 6 or more, especially all, of the powder X-ray peaks given below:

a)

or more preferably

b)

Preferably, the tetra-solvate of the invention, more preferably the tetrahydrate of the invention, especially crystalline form S3, may alternatively or additionally be characterized by a powder X-ray diffraction pattern, more preferably comprising one or more, more preferably 9 or more, even more preferably 12 or more, especially all, of the powder X-ray peaks given below:

a)

or more preferably

b)

Preferably, the tetra-solvate of the invention, more preferably the tetrahydrate of the invention, especially crystalline form S3, may alternatively or additionally be characterized by a powder X-ray diffraction pattern, more preferably comprising one or more, more preferably 10 or more, even more preferably 13 or more, especially all, of the powder X-ray peaks given below:

a)

or more preferably

b)

Fig. 25 shows a powder X-ray diffraction pattern of crystalline form S3.

The powder X-ray diffraction and more preferably the powder X-ray diffraction patterns are preferably carried out or determined as described herein, in particular by standard techniques as described in the 6 th edition European pharmacopoeia, chapter 2.9.33, even more preferably with the parameter Cu-Ka₁Radiation and/orPreferably on a Stoe StadiP 611KL diffractometer.

Preferably, the tetrasolvate of the invention, more preferably the tetrahydrate of the invention, especially crystalline form S3, may alternatively or additionally be represented by single crystal X-ray structural data, e.g. as followsSingle crystal X-ray structural data obtained under conditions to characterize: on a diffractometer preferably equipped with a graphite monochromator and a CCD detector, Mo K is preferably used_αIrradiation, preferably at a temperature of 298K + -5K, even more preferably on an XCalibur diffractometer from Oxford Diffraction equipped with a graphite monochromator and a CCD detector, using Mo K_αRadiation, at about 298K.

Based on the single-crystal X-ray structural data obtained, the tetrahydrate and especially the crystalline form S3 of the compound of formula I according to the invention has a lattice parameterIs inclined space group P2₁2₁2₁The crystallization is carried out with a unit cell volume of preferablyAs is clear from the single crystal structure, form S3 represents a tetrasolvate, more particularly a tetrahydrate.

FIG. 26 depicts a single crystal X-ray structure. Additional structural information based on the single crystal X-ray structural data is given in fig. 26a, 26b and 26 c.

Preferably, the tetrasolvate of the invention, more preferably the tetrahydrate of the invention, especially crystalline form S3, may alternatively or additionally comprise one or more of the band positions given below (± 2 cm)^-1) More preferably 3 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably comprises 6 or more of the band positions (. + -. 2 cm) given below^-1) In particular all bands given belowPosition (+/-2 cm)^-1) And preferably together with the relative intensities given in parentheses:

3319cm^-1(s)，3067cm^-1(s)，2966cm^-1(s)，1668cm^-1(s)，1541cm^-1(s)，1395cm^-1(s)，704cm^-1(m)

more preferably, the tetrasolvate of the invention, more preferably the tetrahydrate of the invention, especially crystalline form S3, may alternatively or additionally comprise one or more of the band positions given below (± 2 cm)^-1) More preferably 6 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably 9 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses:

3428cm^-1(s)，3319cm^-1(s)，3067cm^-1(s)，2966cm^-1(s)，2874cm^-1(m)，1668cm^-1(s)，1541cm^-1(s)，1455cm^-1(s)，1395cm^-1(s)，1232cm^-1(m)，704cm^-1(m)

the relative intensities given in parentheses are preferably defined as follows: "s" ═ strong (transmission preferably 50%) or less, "m" ═ medium (transmission preferably 50% < transmission 70%) or "w" ═ weak (transmission preferably > 70%).

Preferably, the IR or FT-IR spectra are obtained using a KBr chip as the sample preparation technique.

Preferably, the IR-spectroscopy data is obtained by FT-IR-spectroscopy. Preferably, the IR-spectroscopy data or FT-IR-spectroscopy data is obtained by standard techniques as described in European pharmacopoeia 6 th edition, chapter 2.02.24. For the determination of FT-IR spectroscopy, a Bruker Vector 22 spectrometer is preferably used. The FT-IR spectrum is preferably baseline corrected, preferably using Bruker OPUS software.

The FT-IR spectrum of the tetrahydrate of the invention, more preferably the tetrahydrate of the invention, especially crystalline form S3 is given in figure 27.

Preferably, the tetrasolvate of the invention, more preferably the tetrahydrate of the invention, especially crystalline form S3, may alternatively or additionally comprise one or more of the band positions given below (± 2 cm)^-1) More preferably 4 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably 7 or more band positions (. + -. 2 cm) as given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses:

3069cm^-1(m)，2931cm^-1(s)，1666cm^-1(m)，1607cm^-1(w)，1443cm^-1(w)，1339cm^-1(w)，1205cm^-1(w)，1004cm^-1(s)，911cm^-1(m).

more preferably, the tetrasolvate of the invention, more preferably the tetrahydrate of the invention, especially crystalline form S3, may alternatively or additionally comprise one or more of the band positions given below (± 2 cm)^-1) More preferably 9 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably 12 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses:

3069cm^-1(m)，2931cm^-1(s)，1666cm^-1(m)，1607cm^-1(w)，1585cm^-1(w)，1443cm^-1(w)，1339cm^-1(w)，1205cm^-1(w)，1122cm^-1(w)，1033cm^-1(w)，1004cm^-1(s)，936cm^-1(w)，911cm^-1(m)，825cm^-1(w)，624cm^-1(w)，519cm^-1(w)，

the relative intensities given in parentheses are preferably defined as follows: "s" is strong (relative raman intensity is preferably ≥ 0.04), "m" is medium (preferably 0.04 > relative raman intensity ≥ 0.02), "w" is weak (relative raman intensity is preferably < 0.02).

Preferably, the raman or FT-raman spectra are obtained using an aluminium cup as the sample container for each solid substance.

Preferably, the raman spectroscopy data is obtained by FT-raman spectroscopy. Preferably, the Raman spectroscopy data or FT-Raman spectroscopy data is obtained by standard techniques as described in chapter 2.02.24 and/or 2.02.48, 6 th edition (European pharmacopoeia). For the determination of FT-Raman spectroscopy, a Bruker RFS100 spectrometer is preferably used. The FT-Raman spectra are preferably baseline corrected, preferably using Bruker OPUS software.

The FT-raman spectrum of the tetrasolvate of the invention, in particular of crystalline form S3, is given in fig. 28.

Preferably, the tetra-solvate of the invention, more preferably the tetrahydrate of the invention, especially crystalline form S3, may alternatively or additionally be characterised by dynamic vapour absorption experiments. Results may be obtained by standard techniques as described in Rolf Hilfiker, Polymorphism in the Pharmaceutical Industry', Wiley-VCH.Weinheim2006 (Chapter 9: Water vapor absorption, and references therein).

The water vapor absorption behavior showed a loss of water molecules (about 9% by weight) during the initial drying step (0% relative humidity (rh)). During the water absorption cycle, aggregation of water molecules in the crystal lattice (about 10% by weight) can be shown at elevated relative humidity (rh). This amount of water loss can be shown in the second desorption cycle. The water vapor absorption isotherm (25 ℃) of form S3 is shown in fig. 29.

In general, the thermal analysis data presented herein confirm the tetrahydrate structure, which is observed to be fully dehydrated at elevated temperatures in TGA (calculated water content of 10.9 wt% for the tetrahydrate). The water vapor absorption data show that only-9 wt% of the water is separated out even under dry conditions (0% rh) at 25 ℃, indicating that complete dehydration of the structure preferably does not occur. The water vapor sorption isotherm (25 ℃) of crystalline form S3 (SMS DVS Intrinsic) is given in fig. 29.

Surprisingly, it has been found that water molecules within the hydrates of the present invention, in particular water molecules within the tetrahydrate of the present invention, may be partially or completely replaced by alcohol molecules, preferably selected from the following: monohydric, dihydric or trihydric alcohols having 1 to 6 carbon atoms, more preferably monohydric alcohols having 1 to 4 carbon atoms, in particular monohydric alcohols selected from the group consisting of methanol and ethanol, and mixtures thereof.

Experimental methods such as dynamic vapor absorption/desorption experiments, single crystal X-ray experiments and/or powder X-ray experiments show that: starting from, for example, the tetrahydrate characterized as crystalline form S3, the water molecules of the tetrahydrate may be partially and/or approximately completely removed from the tetrahydrate and/or replaced by methanol and/or ethanol.

For example, dynamic vapour absorption/desorption experiments (preferably with vapours of organic solvents and/or water, preferably organic solvents and/or vapours of water selected from one or more alcohols, preferably alcohols as defined herein, especially vapours of methanol, ethanol and/or water) show that water molecules from the tetrahydrate can be successively replaced by alcohol molecules, especially methanol and/or ethanol molecules, possibly until a tetraol solvate or a mixed alcohol-water solvate or a tetrahydrate is formed.

As another example, adjusting a) the amorphous material of the compound of formula I or b) the hydrate form under a mixed water-alcohol atmosphere (preferably a water-ethanol atmosphere) representing different water and alcohol partial pressures, in both cases results in crystalline solvates with different stoichiometries, such as tetrahydrate S3(4 water molecules) or diethanolate S2(2 ethanol molecules, see e.g. fig. 31), the stoichiometries being at most 4 water molecules or at most 2 ethanol molecules per molecule of the compound of formula I, depending on the respective conditions used. Fig. 30 depicts the stoichiometry as determined by karl-fischer titration for water and HS-GC for ethanol. Also depicted in this figure are points representing the stoichiometry of 4 or more water molecules per molecule of the compound of formula I. Since there is no space in the crystal lattice of the tetrahydrate to accommodate more than 4 water molecules, an excess of more than 4 water molecules represents absorbed moisture.

The results (see also example 13) show that: as the vapor pressure of ethanol increases, hydrate form S3 floatingly converts to mixed water-ethanol or anhydrous ethanol solvate form S2. All solvates (including hydrates) have similar lattice parameters, which increase only slightly with aggregation of the ethanol molecules.

As another example, conditioning an amorphous or hydrated form of a compound of formula I under a methanol atmosphere produces a crystalline solvate with 2 molecules of methanol per molecule of the compound of formula I.

Thus, crystalline forms may be obtained that may be characterized as tetrasolvates, having a solvent content of between up to about 100% water (meaning 4 water molecules per molecule of the compound of formula I, i.e. the tetrahydrate) and a solvent content of up to about 100% alcohol (meaning 4 alcohol molecules per molecule of the compound of formula I, i.e. the tetraalcoholate), with intermediate values between them being preferred.

The results are discussed further above and/or below, especially in tables 1 and 2 given below. For example, metastable crystalline solvates may be obtained and discussed in detail above and/or below, which are mixed dihydrate-glycolides (referring to 2 water molecules and 2 alcohol molecules per molecule of the compound of formula I), and are characterized in detail hereinafter as dihydrate-dimethanolate and crystalline form S1 and dihydrate-diethanolate and crystalline form S2, respectively. These stoichiometries are derived and/or derived from the dynamic vapor absorption experiments described herein. Novel X-ray experiments have shown that metastable crystalline solvates may also exist as mixed dihydrate-alcoholates or more specifically as dihydrate-monoolate (meaning 2 water molecules and 1 alcohol molecule per molecule of the compound of formula I) and as other manifestations of these non-stoichiometric classes of pseudopolymorphs, which are hereinafter detailed characterized in detail as other manifestations of dihydrate-methanolate, dihydrate-monomethanolate and/or crystalline form S1 and as other manifestations of dihydrate-ethanolate, dihydrate-monoethanolate and/or crystalline form S2, respectively, metastable crystalline solvates may be obtained and discussed in detail above and/or below,

in this respect reference is made in particular to tables 1 and 2 given below and the paragraphs relating thereto.

The table below shows the calculated water and/or methanol weight content for each of the tetra-solvates ranging from the tetrahydrate to the tetraalcoholate; in this calculation, integer increments have been used in the solvate stoichiometry based on 1 molecule of the compound of formula I in the tetrasolvate and a total of 4 molecules of each solvent or solvent mixture. This can be preferably represented by the following formula:

[ Cyclo- (Arg-Gly-Asp-DPhe-NMe-Val)]Alcohol (C)]_x·[H₂O]_(y)(0. ltoreq. x.ltoreq.4 and 0. ltoreq. y.ltoreq.4), more specifically:

[ Cyclo- (Arg-Gly-Asp-DPhe-NMe-Val)]Alcohol (C)]_x·[H₂O]_(4-x)(0. ltoreq. x. ltoreq.4) (for interconversion between tetrahydrate and tetraalcoholate),

or

[ Cyclo- (Arg-Gly-Asp-DPhe-NMe-Val)]Alcohol (C)]_x·[H₂O]_(y)(0. ltoreq. y.ltoreq.4 and x. ltoreq.2-0.5. xy and x. ltoreq.1) (for interconversion between tetrahydrate and dihydrate-alcoholate or more particularly dihydrate-monoalcohol). ("# ═ multiplier)

Table 1: (Water/methanol exchange)

Table 2: (Water/ethanol exchange)

A mass gain of 9% has been obtained in the respective dynamic vapor absorption experiments discussed in more detail herein, which were conducted at 25 ℃ with methanol vapor at 98% relative saturation for dihydrate-dimethanol/crystalline form S1. This is in good agreement with the results shown above for the tetramethylalcoholate (calculated 108.5%, i.e. an 8.5% increase in mass).

A mass gain of 17% has been obtained in the respective dynamic vapour absorption experiments discussed in more detail herein, which were carried out at 25 ℃ with ethanol vapour at 98% relative saturation for dihydrate-diethanolate/crystalline form S2. This is in good agreement with the results shown above for the tetraalkoxide (calculated 117.0%, i.e. a 17.0% mass increase).

As indicated above and/or below, the tetrasolvates of the invention are preferably convertible, more preferably convertible between a substantially pure tetrahydrate and a substantially pure tetraalcoholate, and all possible intermediate forms between them, preferably their desolvates (exhibiting a lower water and/or alcohol content), preferably exemplified in the following form:

a mixed dihydrate-diol compound as discussed in detail above and/or below, and

dihydrate-alcoholate or dihydrate-monoolate (e.g. by the formula [ cyclo- (Arg-Gly-Asp-DPhe-NMe-Val)]Alcohol (C)]_x·[H₂O]_(y)(0. ltoreq. y.ltoreq.4 and x. ltoreq.2-0.5. xy and x. ltoreq.1), more specifically S1 and/or S2.

Since those tetra-solvates have very similar structural characteristics such as crystallographic parameters, analytical data and/or physical properties and are otherwise transformable, it is clear that the tetra-solvates form one or a subset of the crystalline forms of the present invention and/or the solid materials of the present invention.

The tetrasolvate is therefore a preferred subject of the present invention, according to which the tetrasolvate as characterized herein is preferred.

For reasons of clarity, a tetrasolvate containing 3 or more equivalents of water (i.e. having a water content > 75% mole, calculated on the total amount of solvent contained in each crystalline form) and containing less than 1 equivalent of one or more solvents other than water, preferably less than 1 equivalent of one or more alcohols (preferably selected from methanol and ethanol), is preferably referred to as hydrate, hydrate of the invention or hydrate-tetrasolvate.

For reasons of clarity, a tetrahydrate comprising approximately 4 equivalents of water (i.e. having a water content of > 90 mol%, preferably > 95 mol%, calculated on the total amount of solvent contained in the respective crystalline form) is preferably referred to as the tetrahydrate or the tetrahydrate of the invention.

For reasons of clarity, a tetrasolvate containing one or more equivalents of alcohol (i.e. having an alcohol content of 25% by moles or more, calculated on the total amount of solvent contained in each crystalline form) is preferably referred to as an alkoxide, an alkoxide according to the invention or an alkoxide-tetrasolvate. Examples of such alcoholates or alcoholate-tetrasolvates are the methanolate and/or ethanolate (or methanolate-tetrasolvate and/or ethanolate-tetrasolvate) of the present invention.

For reasons of clarity, a tetrasolvate containing close to 4 equivalents of one or more alcohols (i.e. having a total alcohol content of > 90 mol%, preferably > 95 mol%, calculated on the total amount of solvent contained in each crystalline form) is preferably referred to as a tetraolate or a tetraolate of the invention. Examples of such tetraols are the tetramethylalcoholates and/or the tetraethanolates or the tetramethylalcoholates and/or the tetraethanolates of the invention.

Two additional tetrasolvates are described below that can be described as alcohol solvates, alkoxide-tetrasolvates or desolvates thereof or more preferably as dihydrate-diols, dihydrate-alkoxides or dihydrate-monoolates:

preferably, the tetrasolvate, more preferably the dihydrate-dimethanolate, dihydrate-methanolate, dihydrate-monoethanolate, dimethanolate and/or desolvated forms thereof, especially crystalline form S1, of the present invention may alternatively or additionally be characterized by a melting/decomposition temperature > 205 ℃, more preferably 210 ± 5 ℃ melting/decomposition ℃ or higher, especially 210 ± 5 ℃ melting/decomposition. Preferably, said melting/decomposition temperature obtained for the tetrahydrate of the invention, more preferably obtained for the dihydrate-dimethanolate, dihydrate-methanolate, dihydrate-monoethanolate, dimethanolate and/or desolvated forms thereof, especially obtained for crystalline form S1, is < 250 ℃.

The melting/decomposition temperatures and/or thermal behaviors described herein are preferably determined by DSC (differential scanning calorimetry) and TGA (thermogravimetric analysis). DSC and/or TGA methods, or generally thermal analysis methods and apparatus suitable for their determination, are known in the art, for example from the 6 th edition european pharmacopoeia, chapter 2.02.34, in which suitable standard techniques are described. For melting/decomposition temperatures or behaviour and/or thermal analysis it is generally more preferred to use Mettler Toledo DSC 821 and/or Mettler Toledo TGA 851, preferably as described in the European pharmacopoeia 6 th edition, chapter 2.02.34.

Figures 8 and 9 show DSC and TGA measurements showing the thermal analysis (Mettler-Toledo DSC 821, 5K/min, nitrogen bleed 50 ml/min; Mettler-Toledo TGA 851, 5K/min, nitrogen bleed 50ml/min) and melting/decomposition temperatures given above.

Preferably, the tetrahydrate, more preferably the dihydrate-dimethanolate, dihydrate-methoxide, dihydrate-monoethanolate, dimethanolate and/or desolvated forms thereof, especially crystalline form S1, of the present invention may alternatively or additionally be characterized by a powder X-ray diffraction pattern, more preferably comprising one or more, more preferably 6 or more, even more preferably 9 or more, especially all, of the powder X-ray peaks given below:

preferably, the tetrahydrate, more preferably the dihydrate-dimethanolate, dihydrate-methoxide, dihydrate-monoethanolate, dimethanolate and/or desolvated forms thereof, especially crystalline form S1, of the present invention may alternatively or additionally be characterized by a powder X-ray diffraction pattern, more preferably by a powder X-ray diffraction pattern comprising one or more, more preferably 8 or more, even more preferably 12 or more, especially all, of the powder X-ray peaks given below:

preferably, the tetrahydrate, more preferably the dihydrate-dimethanolate, dihydrate-methoxide, dihydrate-monoethanolate, dimethanolate and/or desolvated forms thereof, especially crystalline form S1, of the present invention may alternatively or additionally be characterized by a powder X-ray diffraction pattern, more preferably by a powder X-ray diffraction pattern comprising one or more, more preferably 10 or more, even more preferably 12 or more, especially all, of the powder X-ray peaks given below:

a powder X-ray diffraction pattern of crystalline form S1 is shown in figure 10.

A PXRD pattern with the following monoclinic cell (space group P21) can be successfully indexed:β＝91.2°(±0.1)，

the powder X-ray diffraction and more preferably the powder X-ray diffraction patterns are preferably carried out or determined as described herein, in particular by standard techniques as described in the 6 th edition European pharmacopoeia, chapter 2.9.33, even more preferably with the parameter Cu-Ka₁Radiation and/orPreferably on a Stoe StadiP 611KL diffractometer.

Preferably, the inventive tetrahydrate, more preferably the dihydrate-dimethanolate, dihydrate-methoxide, dihydrate-monoethanolate, dimethanolate and/or desolvated forms thereof, especially crystalline form S1, may alternatively or additionally be characterized by single crystal X-ray structural data, for example single crystal X-ray structural data obtained under the following conditions: in the preferred installationOn a diffractometer equipped with a graphite monochromator and a CCD detector, Mo K is preferably used_αIrradiation, preferably at a temperature of 298K + -5K, even more preferably on an XCalibur diffractometer from Oxford diffraction equipped with a graphite monochromator and a CCD detector, using Mo K_αRadiation, at about 298K.

Preferably, the tetrasolvate, more preferably the dihydrate-dimethanolate, dihydrate-methanolate, dihydrate-monoethanolate, dimethanolate and/or desolvated forms thereof, especially crystalline form S1 of the present invention may alternatively or additionally comprise one or more of the band positions given below (± 2 cm)^-1) More preferably 3 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably comprises 6 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses:

3311cm^-1(s)，2965cm^-1(m)，2875cm^-1(w)，1668cm^-1(s)，1542cm^-1(s)，1396cm^-1(m)，1028cm^-1(w)，707cm^-1(m)

more preferably, the tetrasolvate, more preferably the dihydrate-dimethanolate, dihydrate-methanolate, dihydrate-monoethanolate, dimethanolate and/or desolvated forms thereof, especially crystalline form S1 of the present invention may alternatively or additionally comprise one or more of the band positions given below (± 2 cm)^-1) More preferably 6 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably 9 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses:

3311cm^-1(s)，3067cm^-1(m)，2965cm^-1(m)，2937cm^-1(m)，2875cm^-1(w)，1668cm^-1(s)，1542cm^-1(s)，1456cm^-1(m)，1396cm^-1(m)，1028cm^-1(w)，707cm^-1(m)

the relative intensities given in parentheses are preferably defined as follows: "s" ═ strong (transmission preferably 50%) or less, "m" ═ medium (transmission preferably 50% < transmission 70%) or "w" ═ weak (transmission preferably > 70%).

Preferably, the IR or FT-IR spectra are obtained using a KBr chip as the sample preparation technique.

Preferably, the IR-spectroscopy data is obtained by FT-IR-spectroscopy. Preferably, the IR-spectroscopy data or FT-IR-spectroscopy data is obtained by standard techniques as described in European pharmacopoeia 6 th edition, chapter 2.02.24. For the determination of FT-IR spectroscopy, a Bruker Vector 22 spectrometer is preferably used. The FT-IR spectrum is preferably baseline corrected, preferably using Bruker OPUS software.

The FT-IR spectrum of the tetrahydrate, more preferably the dihydrate-dimethanolate, dihydrate-methanolate, dihydrate-monoethanolate, dimethanolate and/or desolvated forms thereof, especially crystalline form S1, of the present invention is given in figure 11.

Preferably, the tetrasolvate, more preferably the dihydrate-dimethanolate, dihydrate-methanolate, dihydrate-monoethanolate, dimethanolate and/or desolvated forms thereof, especially crystalline form S1 of the present invention may alternatively or additionally comprise one or more of the band positions given below (± 2 cm)^-1) More preferably 5 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably 8 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses:

3067cm^-1(w)，2936cm^-1(s)，1668cm^-1(m)，1606cm^-1(w)，1446cm^-1(w)，1338cm^-1(w)，1203cm^-1(w)，1033cm^-1(w)，1004cm^-1(s)，904cm^-1(m)，624cm^-1(w).

more preferably, the tetrasolvate, more preferably the dihydrate-dimethanolate, dihydrate-methanolate, dihydrate-monoethanolate, dimethanolate and/or desolvated forms thereof, especially crystalline form S1 of the present invention may alternatively or additionally comprise one or more of the band positions given below (± 2 cm)^-1) More preferably 9 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably 12 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses:

3067cm^-1(w)，2936cm^-1(s)，1668cm^-1(m)，1606cm^-1(w)，1585cm^-1(w)，1446cm^-1(w)，1338cm^-1(w)，1203cm^-1(w)，1123cm^-1(w)，1033cm^-1(w)，1004cm^-1(s)，904cm^-1(m)，824cm^-1(w)，624cm^-1(w)，523cm^-1(w).

the relative intensities given in parentheses are preferably defined as follows: "s" is strong (relative raman intensity is preferably ≥ 0.04), "m" is medium (preferably 0.04 > relative raman intensity ≥ 0.02), "w" is weak (relative raman intensity is preferably < 0.02).

Preferably, the raman or FT-raman spectra are obtained using an aluminium cup as the sample container for each solid substance.

Preferably, the raman spectroscopy data is obtained by FT-raman spectroscopy. Preferably, the Raman spectroscopy data or FT-Raman spectroscopy data is obtained by standard techniques as described in European pharmacopoeia, 6 th edition, chapter 2.02.48. For the determination of FT-Raman spectroscopy, a Bruker RFS100 spectrometer is preferably used. The FT-Raman spectra are preferably baseline corrected, preferably using Bruker OPUS software.

The FT-raman spectrum of the tetrasolvate of the invention, in particular of crystalline form S1, is given in fig. 12.

Preferably, the inventive tetrahydrate, more preferably the dihydrate-dimethanolate, dihydrate-methoxide, dihydrate-monoethanolate, dimethanolate and/or desolvated forms thereof, especially crystalline form S1, may alternatively or additionally be characterized by dynamic vapor experiments with water vapor and/or methanol vapor. Results may be obtained by standard techniques as described in Rolf Hilfiker, Polymorphism in the pharmaceutical Industry', Wiley-VCH.Weinheim2006 (Chapter 9: Water vapour absorption, and references therein).

The water vapor absorption behavior of the inventive tetrahydrate, more preferably the dihydrate-dimethanolate, dihydrate-methoxide, dihydrate-monoethanolate, dimethanolate and/or desolvated forms thereof, especially crystalline form S1, showed a mass loss of about 8 wt% in the first desorption cycle (which is slightly lower than the mass increase in methanol observed in the methanol vapor absorption experiment). Upon water vapor absorption, aggregation of water molecules in the crystal lattice was observed, with a maximum weight gain of about 8 wt% at elevated relative humidity (rh). In the second desorption cycle, a total mass loss of about 9.9 wt% was observed. For the dihydrate dimethanol compound of the compound of formula I, the calculated methanol content is equal to 9.3 wt%. Form S1 may prove to be a thermodynamically stable form in an atmosphere of 100% methanol vapor. The water vapor sorption isotherm (25 ℃) of crystalline form S1 (SMS DVS Intrinsic) is given in fig. 13. The methanol vapor sorption isotherms (25 ℃) of the hydrate form to form S1 (SMS DVS Advantage) are given in fig. 14.

Thus, crystalline form S1 is a crystalline methanol solvate form or a mixed water/methanol solvate form, preferably selected from the group consisting of dihydrate-methanolate, dihydrate-monoethanolate, dimethanolate and/or desolvates thereof, which may be obtained, for example, by methanol vapor absorption, preferably by methanol vapor absorption starting with a hydrate structure such as the hydrate of the invention and especially the tetrahydrate of the invention (i.e. crystalline form S3). As can be seen from the methanol vapor absorption curve shown in fig. 13 and discussed above, about 9 wt% of the methanol was absorbed by the sample at the elevated partial pressure of methanol.

Preferably, the tetrasolvate, more preferably the dihydrate-diethanolate, dihydrate-ethanolate, dihydrate-monoethanolate, diethanolate and/or desolvated, especially crystalline form S2 of the present invention may alternatively or additionally be characterized by a melting/decomposition temperature > 205 ℃, more preferably 210 ± 5 ℃ melting/decomposition ℃ or higher, especially 210 ± 5 ℃ melting/decomposition. Preferably, said melting/decomposition temperature obtained for the tetra-solvate, more preferably dihydrate-diethanolate, dihydrate-ethanolate, dihydrate-monoethanolate, diethanolate and/or desolvated forms thereof of the present invention, in particular obtained for crystalline form S2, is < 250 ℃.

The melting/decomposition temperatures and/or thermal behaviors described herein are preferably determined by DSC (differential scanning calorimetry) and TGA (thermogravimetric analysis). DSC and/or TGA methods, or generally thermal analysis methods and apparatus suitable for their determination, are known in the art, for example from chapter 2.02.34, "european pharmacopoeia, 6 th edition, in which suitable standard techniques are described. For melting/decomposition temperatures or behaviour and/or thermal analysis it is generally more preferred to use Mettler Toledo DSC 821 and/or Mettler Toledo TGA 851, preferably as described in chapter 2.02.34 of the European pharmacopoeia, 6 th edition.

Figures 15 and 16 show DSC and TGA measurements showing the thermal analysis (Mettler-Toledo DSC 821, 5K/min, nitrogen bleed 50 ml/min; Mettler-Toledo TGA 851, 5K/min, nitrogen bleed 50ml/min) and melting/decomposition temperatures given above.

Preferably, the inventive tetrahydrate, more preferably the dihydrate-diethanolate, the dihydrate-ethanolate, the dihydrate-monoethanolate, the diethanolate and/or the desolvated, especially crystalline form S2, may alternatively or additionally be characterized by a powder X-ray diffraction pattern, more preferably by a powder X-ray diffraction pattern comprising one or more, more preferably 3 or more, even more preferably 5 or more, especially all, of the powder X-ray peaks given below:

a)

or more preferably

b)

Preferably, the inventive tetrahydrate, more preferably the dihydrate-diethanolate, the dihydrate-ethanolate, the dihydrate-monoethanolate, the diethanolate and/or the desolvated, especially crystalline form S2, may alternatively or additionally be characterized by a powder X-ray diffraction pattern, more preferably by a powder X-ray diffraction pattern comprising one or more, more preferably 4 or more, even more preferably 6 or more, especially all, of the powder X-ray peaks given below:

a)

or more preferably

b)

Preferably, the inventive tetrasolvate, more preferably the dihydrate-diethanolate, dihydrate-ethanolate, dihydrate-monoethanolate, diethanolate and/or desolvated, especially crystalline form S2, may alternatively or additionally be diffracted by powder X-rays, more preferably by powder X-ray diffraction comprising one or more, more preferably 10 or more, even more preferably 12 or more, powder X-ray peaks as given below,

In particular a powder X-ray diffraction pattern comprising all the powder X-ray peaks given below:

a)

or more preferably

b)

A powder X-ray diffraction pattern of crystalline form S2 is shown in fig. 17.

Can be successfully indexed to have the following orthorhombic unit cell (space group P2)₁2₁2₁) PXRD pattern of (a):

the powder X-ray diffraction and more preferably the powder X-ray diffraction patterns are preferably carried out or determined as described herein, in particular by standard techniques as described in the 6 th edition European pharmacopoeia, chapter 2.9.33, even more preferably with the parameter Cu-Ka₁Radiation and/orPreferably on a Stoe StadiP 611KL diffractometer.

Preferably, the inventive tetra-solvate, more preferably the dihydrate-diethanolate, dihydrate-ethanolate, dihydrate-monoethanolate, diethanolate and/or desolvated, especially crystalline form S2, may alternatively or additionally be characterized by single crystal X-ray structural data, for example single crystal X-ray structural data obtained under the following conditions: on a diffractometer preferably equipped with a graphite monochromator and a CCD detector, Mo K is preferably used_αIrradiation, preferably at a temperature of 298K + -5K, even more preferably on an XCalibur diffractometer from Oxford diffraction equipped with a graphite monochromator and a CCD detector, using Mo K_αRadiation, at about 298K.

According to the single crystal X-ray structural data obtained, the inventive tetra-solvate, more preferably the dihydrate-diethanolate, dihydrate-ethanolate, diethanolate and/or desolvated form thereof, in particular the crystalline form S2, is such as to have a lattice parameterIs inclined space group P2₁2₁2₁The crystallization is carried out with a unit cell volume of preferably

As is clear from the single crystal structure, form S2 represents the inventive tetra-solvate, more specifically a mixed ethanol-water solvate, even more specifically a dihydrate-monoethanol.

FIG. 32 depicts a single crystal X-ray structure.

Preferably, the tetrasolvate, more preferably the dihydrate-diethanolate, dihydrate-ethanolate, dihydrate-monoethanolate, diethanolate and/or desolvated forms thereof, especially crystalline form S2, of the present invention may alternatively or additionally comprise one or more of the band positions given below (± 2 cm)^-1) More preferably 3 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably comprises 6 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses:

3306cm^-1(s)，2968cm^-1(m)，1668cm^-1(s)，1546cm^-1(s)，1395cm^-1(m)，1223cm^-1(w)，1049cm^-1(w)，705cm^-1(w).

more preferably, the tetrasolvate, more preferably the dihydrate-diethanolate, dihydrate-ethanolate, dihydrate-monoethanolate, diethanolate and/or desolvated, in particularIt is crystalline form S2 that may alternatively or additionally comprise one or more of the band positions (± 2 cm) given below^-1) More preferably 6 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably 9 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses:

3306cm^-1(s)，2968cm^-1(m)，2872cm^-1(m)，1668cm^-1(s)，1546cm^-1(s)，1452cm^-1(w)，1395cm^-1(m)，1223cm^-1(w)，1086cm^-1(w)，1049cm^-1(w)，746cm^-1(w)，705cm^-1(w).

the relative intensities given in parentheses are preferably defined as follows: "s" ═ strong (transmission preferably 50%) or less, "m" ═ medium (transmission preferably 50% < transmission 70%) or "w" ═ weak (transmission preferably > 70%).

Preferably, the IR or FT-IR spectra are obtained using a KBr chip as the sample preparation technique.

Preferably, the IR-spectroscopy data is obtained by FT-IR-spectroscopy. Preferably, the IR-spectroscopy data or FT-IR-spectroscopy data is obtained by standard techniques as described in European pharmacopoeia 6 th edition, chapter 2.02.24. For the determination of FT-IR spectroscopy, a Bruker Vector 22 spectrometer is preferably used. The FT-IR spectrum is preferably baseline corrected, preferably using Bruker OPUS software.

The FT-IR spectrum of the inventive tetrasolvate, especially crystalline form S2, is given in fig. 18.

Preferably, the tetrasolvate, more preferably the dihydrate-diethanolate, dihydrate-ethanolate, dihydrate-monoethanolate, diethanolate and/or desolvated forms thereof, especially crystalline form S2, of the present invention may alternatively or additionally comprise one or more of the band positions given below (± 2 cm)^-1)、More preferably 5 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably 8 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses:

3068cm^-1(w)，2934cm^-1(s)，1668cm^-1(w)，1606cm^-1(w)，1449cm^-1(w)，1337cm^-1(w)，1204cm^-1(w)，1120cm^-1(w)，1004cm^-1(m)，904cm^-1(w)，825cm^-1(w)，624cm^-1(w)，521cm^-1(w).

more preferably, the tetrasolvate, more preferably the dihydrate-diethanolate, dihydrate-ethanolate, dihydrate-monoethanolate, diethanolate and/or desolvated forms thereof, especially crystalline form S2, of the present invention may alternatively or additionally comprise one or more of the band positions given below (± 2 cm)^-1) More preferably 9 or more of the band positions (. + -. 2 cm) given below^-1) Even more preferably 12 or more of the band positions (. + -. 2 cm) given below^-1) In particular comprising all the band positions (. + -. 2 cm) given below^-1) And preferably together with the relative intensities given in parentheses:

3068cm^-1(w)，2934cm^-1(s)，1668cm^-1(w)，1606cm^-1(w)，1586cm^-1(w)，1449cm^-1(w)，1337cm^-1(w)，1204cm^-1(w)，1120cm^-1(w)，1033cm^-1(w)，1004cm^-1(m)，904cm^-1(w)，825cm^-1(w)，624cm^-1(w)，521cm^-1(w).

the relative intensities given in parentheses are preferably defined as follows: "s" is strong (relative raman intensity is preferably ≥ 0.04), "m" is medium (preferably 0.04 > relative raman intensity ≥ 0.02), "w" is weak (relative raman intensity is preferably < 0.02).

Preferably, the raman or FT-raman spectra are obtained using an aluminium cup as the sample container for each solid substance.

Preferably, the raman spectroscopy data is obtained by FT-raman spectroscopy. Preferably, the Raman spectroscopy data or FT-Raman spectroscopy data is obtained by standard techniques as described in European pharmacopoeia, 6 th edition, chapter 2.02.48. For the determination of FT-Raman spectroscopy, a Bruker RFS100 spectrometer is preferably used. The FT-Raman spectra are preferably baseline corrected, preferably using Bruker OPUS software.

The FT-raman spectrum of the tetrahydrate, more preferably the dihydrate-diethanolate, dihydrate-ethanolate, dihydrate-monoethanolate, diethanolate and/or desolvated form thereof, especially crystalline form S2, of the present invention is given in fig. 19.

Preferably, the inventive tetra-solvate, more preferably dihydrate-diethanolate, dihydrate-ethanolate, dihydrate-monoethanolate, diethanolate and/or desolvated forms thereof, especially crystalline form S2, may alternatively or additionally be characterized by dynamic vapor experiments with water vapor and/or methanol vapor. Results may be obtained by standard techniques as described in Rolf Hilfiker, Polymorphism in the pharmaceutical Industry', Wiley-VCH.Weinheim2006 (Chapter 9: Water vapour absorption, and references therein).

The water vapor absorption behavior of the inventive tetrasolvate, more preferably the dihydrate-diethanolate, dihydrate-ethanolate, dihydrate-monoethanolate, diethanolate and/or desolvated forms thereof, especially crystalline form S2, showed a mass loss of about 6.5 wt% in the first desorption cycle (which is lower than the increase in ethanol mass observed in ethanol vapor absorption experiments). Upon water vapor absorption, water molecules are observed to aggregate in the crystal lattice, with a maximum weight gain of about 6.4 wt% at elevated relative humidity (rh). In the second desorption cycle, a total mass loss of about 9.2 wt% was observed. For the dihydrate diethanolate of the compound of formula I, the calculated ethanol content is equal to 12.5% by weight. Form S2 may prove to be a thermodynamically stable form in an atmosphere of 100% ethanol vapor. The water vapor sorption isotherm (25 ℃) of crystalline form S2 (SMS DVS Intrinsic) is given in fig. 20. The ethanol vapor sorption isotherms (25 ℃) of the hydrate form to form S2 (SMS DVS Advantage) are given in fig. 21.

Thus, crystalline form S2 is a crystalline ethanol solvate form or a mixed water/ethanol solvate form, preferably selected from the group consisting of dihydrate-ethanolate, dihydrate-monoethanollate, diethanolate and/or desolvates thereof, which may be obtained, for example, by ethanol vapor absorption, preferably by ethanol vapor absorption starting with a hydrate structure such as the hydrate of the invention and especially the tetrahydrate of the invention (i.e. crystalline form S3). As can be seen from the ethanol vapor absorption curves shown in fig. 21 and discussed above, approximately 17 wt% ethanol was absorbed by the sample at the elevated ethanol partial pressure.

As can be seen from the data given and discussed herein, solvates, especially the tetrasolvates, of the compounds of formula I form a new class of crystalline forms based on the same structural type (otherwise also referred to as pseudopolymorphs or abbreviated PP) that have highly similar physical properties, are readily convertible, preferably all converted forms are potentially derivable, especially all converted forms between the pseudopolymorphs described herein.

The similarity of the structure types is additionally shown by the overlay of the PXRD patterns given in figure 22 for the three selected pseudopolymorphs S1, S2 and S3. It can be seen that all three selected pseudopolymorphs show very similar PXRD patterns and produce essentially identical unit cells, since the replacement of water by methanol or ethanol only slightly enlarges the unit cell and thus slightly increases the unit cell volume. This is more pronounced for the ethanol solvate than for the methanol solvate, as expected from the molar volume of the solvent.

Interconversion within pseudopolymorph types (including solvates of the invention, especially the tetra-solvates) readily occurs in the presence of alcohols, preferably methanol and/or ethanol and/or water, present at different concentrations or partial pressures. Since alcohols, preferably methanol and/or ethanol, are useful solvents in the preparation process, the use of pseudopolymorphs is preferably beneficial to obtain compounds of formula I in a crystalline solid state modification that shows advantageously high solubility and good crystallinity.

The solvates, especially the tetrasolvates, within the pseudopolymorph form or system are crystalline and preferably exhibit favorable solid state stability without loss of the bulk structure of the cilengitide as compared to the amorphous solid materials previously described. Pseudopolymorphs of the type described herein exhibit unexpectedly high solubility, particularly in aqueous media, which makes them particularly useful for preparing liquid formulations. Furthermore, polymorphs of this type also exhibit advantageously reduced hygroscopicity compared to previously known amorphous materials.

Solubility of the tetrahydrate form S3 in different solvents:

the reduced hygroscopicity, good solubility and good crystallinity combine to give superior properties compared to the amorphous phase. In contrast, purification, handling and processing of amorphous materials is very difficult due to, for example, the very high hygroscopicity and low stability of amorphous solid materials.

Furthermore, the pseudopolymorph and/or anhydrate or solvate-free form of the present invention exhibits improved physical and/or chemical stability compared to the amorphous phase, which preferably results in reduced formation of degradation products (e.g., by hydrolysis) during storage. This improved hydrolytic stability of the solid material of the invention, particularly the crystalline form of the invention, is believed to result from the reduction of trace ionic impurities that are typically present in the amorphous materials of the prior art.

As a result, all of those factors discussed herein are believed to explain why the solid state stability of the solid materials of the present invention, the crystalline forms of the present invention, and particularly the solvates and/or anhydrates or solvates of the present invention, is advantageously improved.

Furthermore, all those factors discussed herein are also believed to explain the advantageous improvement of the stability of the medicament of the present invention comprising the solid substance of the present invention, preferably the crystalline form of the present invention, especially the solvate and/or anhydrate or solvate-free substance of the present invention, which leads e.g. to a longer shelf-life due to higher thermal and/or storage stability,

a preferred subject matter of the present invention is a solid substance as described above and/or below for use in the treatment of disorders.

The disorder in this respect is preferably selected from the group consisting of cancerous disorders, angiogenic or angiogenic disorders, autoimmune disorders, inflammatory disorders and ocular disorders, more preferably from the group consisting of brain cancer, lung cancer, head and neck cancer, breast cancer and prostate cancer and metastases thereof, arthritis, rheumatoid arthritis, psoriasis, retinopathy, diabetic retinopathy, atherosclerosis, macular degeneration and age-related macular degeneration.

Especially preferred are solid substances as described above and/or below for use in the treatment of a disorder selected from cancerous disorders.

Especially preferred is a solid substance as described above and/or below for use in the treatment of a cancerous disorder, wherein the cancerous disorder is selected from the group consisting of brain cancer, lung cancer, head and neck cancer, breast cancer and prostate cancer and metastases thereof.

A preferred subject of the present invention is a method for treating a cancerous disorder in a patient, which method comprises administering to said patient a solid substance as described above and/or below.

Especially preferred is a method as described above, wherein the cancerous disorder is selected from one or more of the group of disorders described above.

A preferred subject matter of the present invention is the use of the solid substances according to the invention for the preparation of a medicament for the treatment of disorders. Preferably, the disorder is selected from one or more of the above mentioned group of disorders.

Thus, a preferred subject of the present invention is the use of a solid substance consisting essentially of or consisting of one or more of the crystalline forms of the present invention for the preparation of a medicament for the treatment of a disorder, preferably a disorder as described herein.

An even more preferred subject matter of the present invention is the use of a solid substance consisting essentially of or consisting of one or more crystalline forms selected from crystalline form a1, crystalline form S1, crystalline form S2 and crystalline form S3 and mixtures thereof for the manufacture of a medicament for the treatment of a disorder, preferably a disorder as described herein.

A particularly preferred subject matter of the present invention is the use of a solid substance consisting essentially of or consisting of crystalline form a1 or crystalline form S3 or a mixture thereof for the preparation of a medicament for the treatment of a disorder, preferably a disorder as described herein.

Surprisingly, the solid substances according to the invention, in particular one or more of the crystalline forms according to the invention, can be prepared by contacting a compound of the formula I with a solvent or solvent mixture, preferably a polar and/or protic solvent or solvent mixture.

A preferred subject matter of the present invention is therefore a process for producing or preparing the solid substance according to the invention, in particular one or more of the crystalline forms according to the invention, which comprises contacting a compound of the formula I with a solvent or solvent mixture, preferably a polar and/or protic solvent or solvent mixture, and separating the solid substance according to the invention obtained by said contacting from said solvent or solvent mixture.

Said separation from said solvent or solvents is preferably effected by:

i) crystallizing and/or precipitating the solid substance of the invention from the solvent or solvent mixture, and/or

ii) separating the solid material of the invention from the solvent, preferably by physical means such as filtration or centrifugation or alternatively by sedimentation and/or decantation.

However, a variety of separation techniques are known in the art for achieving solid/liquid separation. Preferably, any of them can be successfully applied to the separation.

Preferably, the solid substance according to the invention, in particular one or more of the crystalline forms according to the invention, can be prepared as follows: starting with a solid substance which is substantially free or preferably free of one or more of the compounds of the invention in crystalline form, and then by contacting it with a solvent or solvent mixture, preferably a polar and/or protic solvent or solvent mixture.

Alternatively, the solid substance according to the invention, in particular one or more of the crystalline forms according to the invention, can be prepared as follows: starting with a solution which is substantially free or preferably free of one or more of the crystalline forms of the compound of the formula I according to the invention and then transferring said solution which is substantially free or preferably free of one or more of the crystalline forms of the compound of the formula I according to the invention into a solvent or solvent mixture, preferably a polar and/or protic solvent or solvent mixture, by bringing it into contact with said solvent or solvent mixture, preferably a polar and/or protic solvent or solvent mixture.

Typically, in order to obtain the solid form of the invention and/or one or more crystalline forms of the invention, a separation step is performed after contact with said solvent or solvent mixture, preferably said polar and/or protic solvent or solvent mixture, or with said solvent or solvent mixture, preferably said polar and/or protic solvent or solvent mixture, wherein the solid substance of the invention and/or one or more crystalline forms of the invention are obtained in solid form.

In this respect, contact preferably means contact in the broadest sense, e.g. "in the presence of …". Thus, examples of contacting with the solvent or solvent mixture include, but are not limited to: dissolved or partially dissolved in the solvent or solvent mixture, suspended in the solvent or solvent mixture, stirred in the presence of the solvent or solvent mixture, triturated with or in the presence of the solvent or solvent mixture, placed in the presence of the solvent or solvent mixture, heated in the presence of the solvent or solvent mixture, cooled in the presence of the solvent or solvent mixture, crystallized or recrystallized from the solvent or solvent mixture, and/or precipitated from the solvent or solvent mixture.

In this respect, preferred contact means are preferably selected from: dissolved or partially dissolved in the solvent or solvent mixture, stirred in the presence of the solvent or solvent mixture, triturated with or in the presence of the solvent or solvent mixture, heated or cooled, preferably heated, in the presence of the solvent or solvent mixture, crystallized or recrystallized from the solvent or solvent mixture, and/or precipitated from the solvent or solvent mixture.

In this respect, particularly preferred contact means include: the starting material compounds of formula I and/or salts thereof are dissolved, substantially dissolved or suspended in a (first) polar and/or protic solvent or solvent mixture, preferably followed by recrystallization, crystallization and/or precipitation of the formed product from said solvent or solvent mixture, wherein the formed product is preferably a solid material according to the invention. Preferably, the recrystallization, crystallization and/or precipitation of the formed product is initiated or promoted by cooling and/or adding a further (or second) solvent or solvent mixture, preferably a further solvent or solvent mixture having a different polarity, more preferably having a lower polarity than the (first) solvent or solvent mixture.

In this respect, another particularly preferred contact pattern comprises: forming a slurry of a starting material such as a compound of formula I as hereinbefore and/or hereinafter described with a polar and/or protic solvent or solvent mixture, stirring and/or agitating the slurry, preferably for a reaction time as herein described, the reaction temperature or the treatment temperature being as herein described. This is preferably also referred to as "slurry conversion".

Solvents and solvent mixtures suitable for use in the methods and/or processes of the present invention are known in the art. Preferred solvents and solvent mixtures are preferably selected from the group consisting of organic solvents, water, saline, buffered solutions and mixtures thereof. The term "polar and/or protic solvent or solvent mixture" is known and clear to the person skilled in the art.

Examples of polar and/or protic solvents include, but are not limited to, water, saline or physiological NaCl solution, phosphate buffer solution, lower alcohols such as monohydric, dihydric or trihydric alcohols having 1 to 6 carbon atoms, lower ketones such as acetone or methyl ethyl ketone, acetonitrile, propionitrile, DMF, DMSO, and the like. Preferred polar and/or protic solvents are selected from the group consisting of water, brine, methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, propionitrile, DMF and DMSO.

Examples of polar and/or protic solvent mixtures include, but are not limited to, mixtures of the polar and/or protic solvents given above, more preferably mixtures of water with one or more polar and/or protic solvents other than water given above, saline or physiological NaCl solution or phosphate buffer solution with one or more polar and/or protic solvents given above.

Preferred polar and/or protic solvent mixtures are selected from: mixtures of water with methanol, ethanol and/or isopropanol, mixtures of acetone with water and/or acetonitrile, mixtures of methanol with acetone, acetonitrile and/or water, and mixtures of ethanol with acetone, acetonitrile, are also preferably selected from the mixtures given above, wherein water is used instead of saline, physiological NaCl solution or phosphate buffer solution. Preference is given to mixtures which comprise all of the solvents mentioned, preferably consisting essentially of 2, 3 or 4 of the solvents mentioned. Especially preferred in the mixture is a mixture comprising at least 5%, especially at least 10%, of the respective solvents contained in the mixture.

In this respect, examples of preferred solvents and/or solvent mixtures are selected from water, methanol, ethanol, isopropanol and mixtures thereof, more preferably from water, methanol, ethanol and mixtures thereof.

In the process for preparing the solid substance according to the invention, the starting substance, the compound of formula I, is preferably selected from:

a) an amorphous or substantially amorphous material of a compound of formula I,

b) acid addition salts or base addition salts of compounds of formula I,

c) an amorphous solid or substantially amorphous solid of an acid addition salt or a base addition salt of a compound of formula I, and

b) solutions of the crude compounds of formula I and/or their acid addition salts or base addition salts, preferably such as those obtained by the synthesis of said compounds and/or their salts,

and mixtures thereof.

Furthermore, it has surprisingly been found that: one first crystalline form of the invention may be converted to one or more other crystalline forms of the invention, preferably reversibly. It was also found that: a first mixture of one or more crystalline forms of the invention can be converted to a second mixture of crystalline forms of the invention different from the first mixture, or to a pure or substantially pure single crystalline form of the invention.

Thus, the present invention also provides a process for converting a first solid substance of the invention (comprising one or more first crystalline forms) into a second solid substance of the invention (comprising one or more second crystalline forms). The process can preferably be carried out in the same manner and preferably with the same solvents and/or solvent mixtures as the preparation process described above and/or below, but using the first solid substance according to the invention as starting material for the process.

A preferred subject matter of the present invention is therefore a process for preparing or converting, preferably preparing, the solid substance of the invention, which comprises:

a) contacting cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or an acid addition salt or a base addition salt thereof with a solvent or solvent mixture, preferably a polar and/or protic solvent or solvent mixture,

b) precipitating and/or crystallizing the inner salt of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) from a polar and/or protic solvent or solvent mixture, and

c) optionally isolating the solid material of the invention.

In the conversion process, the starting material used in step a) is preferably a (first) solid form according to the invention containing cyclo- (Arg-Gly-Asp-DPhe-NMeVal) as inner salt, and the solid substance according to the invention obtained in step b) and optionally isolated according to step c) is a (second) different solid substance according to the invention. Preferably, the difference between a first inventive solid substance and a second, different inventive solid substance is the amount of crystalline form contained in said second solid form, the choice of crystalline form contained in said solid form or the proportion of crystalline form contained in said solid form.

In the preparation process, the starting materials used in step a) are preferably selected from:

i) solid forms of the compounds of formula I other than the solid forms of the present invention,

ii) a solution of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or an acid addition salt or a base addition salt thereof, wherein the solution is preferably a crude solution or obtained, more preferably directly, from the synthesis of cyclo- (Arg-Gly-Asp-DPhe-NMeVal), and/or

iii) by dissolving a solid form of the compound of formula I other than the solid form of the invention.

A preferred subject matter of the present invention is therefore a process for preparing the solid substance according to the invention, which comprises:

a) contacting an acid addition salt or a base addition salt of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) with a polar and/or protic solvent or solvent mixture,

b) precipitating and/or crystallizing the inner salt of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) from a polar and/or protic solvent or solvent mixture, and

c) optionally isolating the solid material of the invention.

In the preparation and/or conversion process, steps a), b) and/or c) are preferably carried out at a pH of from 5.5 to 8, more preferably at a pH of from 6 to 7.5, more preferably at a pH of from 6.5 to 7.2, in particular at a pH of from 6.7 to 6.9, for example at a pH of about 6.8. More preferably, two or more steps selected from a), b) and c) are performed at the pH values given above, in particular steps a), b) and c) are all performed at the pH values given above. Performing one or more steps selected from a), b) and c) at the pH values given above facilitates the conversion of an acid-or base-addition salt of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) into an inner salt of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) or facilitates the maintenance or stabilization of an inner salt of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) within the process.

In the preparation and/or conversion process, steps a), b) and/or c) are preferably carried out under about isoelectric conditions. More preferably, two or more steps selected from a), b) and c) are performed at about isoelectric conditions, in particular all steps a), b) and c) are performed at about isoelectric conditions. Performing one or more steps selected from a), b) and c) under about isoelectric conditions further facilitates the conversion of an acid-or base-addition salt of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) to an inner salt of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) or facilitates the maintenance or stabilization of an inner salt of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) within the process.

In the preparation and/or conversion process, steps a), b) and/or c) are preferably carried out at a temperature of from-20 ℃ to +200 ℃, more preferably from-5 ℃ to +150 ℃, even more preferably from +5 ℃ to +110 ℃, especially from +10 ℃ to +100 ℃, for example at about room temperature (about 25 ℃), about 50 ℃ or about 75 ℃ or about 100 ℃.

Generally, higher temperatures tend to accelerate the production process and/or the conversion process as described herein.

Generally, temperatures at the higher end of a given temperature range tend to promote the formation of the anhydrate or solvate of the invention.

Generally, temperatures at the lower end of a given temperature range tend to promote the formation of the solvates of the present invention.

In the process for preparing the solid substance of the invention and/or in the process for converting or converting the solid substance of the invention and/or crystallizing the form of the invention, the treatment time or "reaction time", i.e. the time during which the contacting, precipitation, crystallization and/or separation preferably takes place, is generally from 5 minutes to 4 weeks. The treatment time as described is preferably not a very critical factor for the process of the invention, since there is very little or no decomposition of the compound of formula I during the time as given above, in particular very little or no decomposition of the compound of formula I within the preferred process parameters or process conditions as described herein. Furthermore, the product of the process, i.e. the solid material of the invention, is generally stable under the conditions under which it is formed.

Therefore, the treatment time is preferably 10 minutes to 3 weeks, more preferably 15 minutes to 1 week, more preferably 30 minutes to 72 hours, particularly 1 hour to 48 hours.

The treatment time for the formation or transformation, preferably the formation, of the anhydrate or solvate-free of the invention, especially the formation of crystalline form a1, is preferably from 1 hour to 3 weeks, more preferably from 1 hour to 2 weeks, especially from 1 hour to 72 hours.

The formation or conversion, preferably the treatment time of the formation, especially the treatment time of the formation of the crystalline form S1, of the solvate according to the invention, more preferably the tetrasolvate according to the invention, even more preferably one or more crystalline forms S1, S2 and/or S3 is preferably from 5 minutes to 3 weeks, more preferably from 5 minutes to 1 week, even more preferably from 5 minutes to 48 hours, especially from 10 minutes to 24 hours.

Generally, as is known in the art, lower temperatures during the process result in longer processing times.

In general, water, methanol and/or ethanol and mixtures thereof are preferred polar and/or protic solvents or solvent mixtures for steps a), b) and/or c), especially for steps a), b) and c).

In the preparation and/or conversion process, the solvent of steps a), b) and/or c), preferably the solvents of a), b) and c), consists essentially of water, methanol or ethanol.

Preferably, identical or substantially identical solvents or solvent mixtures, preferably polar and/or protic solvents or solvent mixtures, are used in process steps a), b) and c).

In general, the formation of the solvates according to the invention is promoted in steps a), b) and/or c) by using a solvent or solvent mixture comprising at least 5% by weight, more preferably at least 10% by weight, especially at least 20% by weight, of one or more alcohols, preferably selected from methanol, ethanol and isopropanol, more preferably from methanol and ethanol.

More specifically, the use of a solvent mixture comprising the following components in steps a), b) and/or c) preferably promotes the formation of the solvates of the invention:

i) from 5 to 90% by weight of at least one alcohol selected from methanol and ethanol, and

ii)10 to 95% by weight of water.

Even more specifically, the use of a solvent mixture comprising the following ingredients in steps a), b) and/or c) preferably promotes the formation of the solvates of the invention:

i) from 5 to 50% by weight, in particular from 10 to 60% by weight, of at least one alcohol, preferably selected from methanol and ethanol, and

ii) from 50 to 95% by weight, in particular from 40 to 90% by weight, of water.

Thus, a process as described above and/or below for the preparation of a solid substance according to the invention, preferably a solvate according to the invention, especially one or more of a tetrasolvate according to the invention, is preferred, wherein the solvent or solvent mixture of steps a), b) and/or c) comprises:

i) from 5 to 90% by weight, preferably from 5 to 50% by weight, of at least one alcohol selected from methanol and ethanol, and

ii)10 to 95% by weight, preferably 50 to 95% by weight, of water.

Thus, processes as described above and/or below for the solid material according to the invention, preferably the anhydrate or solvate-free material according to the invention, especially crystalline form a1, are preferred, wherein the solvent of step a), b) and/or c) consists essentially of water, methanol and ethanol, more preferably essentially of water.

Therefore, a process as described above and/or below for the preparation of the solid material of the invention, preferably the anhydrate or solvate-free, especially crystalline form a1 of the invention is preferred, wherein steps a), b) and/or c) are carried out at a temperature above +40 ℃, more preferably at a temperature of +50 ° or higher, especially at a temperature of +60 ° or higher.

In the preferred process parameters for the formation of solvates, especially the tetrasolvates, of the invention, the alcohol content at the lower end of the given range and/or the water content at the upper end of the given range promotes the formation of the hydrates of the invention. Alternatively, alcohol content at the upper end of a given range and/or water content at the lower end of a given range promotes alcohol solvate formation.

In this respect, especially preferred solvates are the tetrasolvates, preferably selected from the group consisting of the tetrahydrate, the methanol solvate and the ethanol solvate and mixed forms thereof, even more preferably selected from the group consisting of the tetrahydrate, the methanol solvate S1 and the ethanol solvate S2 and especially the tetrahydrate S3.

Thus, a preferred method for preparing the solid substance of the invention comprises or preferably consists essentially of the following steps:

i) crystallizing or recrystallizing an amorphous or substantially amorphous material of a compound of formula I from a solvent or solvent mixture, preferably a polar and/or protic solvent or solvent mixture, preferably a polar and/or protic solvent or solvent mixture as described herein, and optionally

ii) separating the thus obtained solid substance of the invention from said solvent or solvent mixture by a solid/liquid separation technique, preferably a solid/liquid separation technique as described herein, in particular by filtration.

Thus, a preferred method for converting a first solid substance of the invention into a second solid substance of the invention comprises or preferably consists essentially of:

a) precipitating, crystallizing or recrystallizing a first solid substance according to the invention from a solvent or solvent mixture, preferably a polar and/or protic solvent or solvent mixture, preferably a solvent or solvent mixture as described herein, preferably a polar and/or protic solvent or solvent mixture, and optionally

b) The second solid substance of the invention thus obtained is separated from the solvent or solvent mixture by a solid/liquid separation technique, preferably a solid/liquid separation technique as described herein, in particular by filtration.

In the synthesis of the compound cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the end or crude product of the synthesis is in many cases an acid addition salt or a base addition salt of the compound cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), preferably an acid addition salt of the compound cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), for example the hydrochloride of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) ((cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) × HCl), cyclo- (jg-Gly-Asp-DPhe-NMe-Val) x HCl)(Arg-Gly-Asp-DPhe-NMe-Val) trifluoroacetate (cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) × TFA), cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) sulfate (cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) × SO)₄More specifically cyclo- (Arg-Gly-Asp-DPhe-NMe-Val). times.0.5 SO₄) Or mixtures thereof.

Thus, a preferred example of a process for preparing the solid substance of the invention starts with said crude product in the form of an acid addition salt or a base addition salt, preferably an acid addition salt.

A preferred subject matter of the present invention is therefore a process for preparing the solid substance according to the invention, which comprises:

a) contacting an acid-addition salt or a base-addition salt, preferably an acid-addition salt, of the compound cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) with a polar and/or protic solvent or solvent mixture, preferably as defined herein, preferably by dissolving and/or suspending said salt in said solvent,

b) converting said salt into the free base or preferably the inner salt of the compound cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), preferably by adjusting the pH, and

c) the solid substance of the invention thus obtained is crystallized and/or precipitated from the solvent or solvent mixture and optionally isolated.

A more preferred subject of the invention is therefore a process for preparing the solid substance according to the invention, which comprises:

a) contacting an acid-addition salt or a base-addition salt, preferably an acid-addition salt, of the compound cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) with a solvent or solvent mixture consisting essentially of or consisting of water, preferably a polar and/or protic solvent or solvent mixture, preferably by dissolving and/or suspending said salt in said solvent,

b) converting said salt into the free base or preferably the inner salt of the compound cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), preferably by adjusting the pH, and

c) preferably, the solid substance of the invention thus obtained is crystallized and/or precipitated from the solvent or solvent mixture and optionally isolated.

This process facilitates the preparation of the solid substance of the invention which consists essentially of or preferably consists of the anhydrate or solvate-free substance of the invention, especially consists essentially of or preferably consists of crystalline form a 1.

Thus, another more preferred subject of the invention is a process for preparing the solid substance of the invention, which comprises:

a) contacting an acid-addition salt or a base-addition salt, preferably an acid-addition salt, of the compound cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) with a polar and/or protic solvent or solvent mixture, wherein said solvent or solvent mixture is selected from water and a mixture of 60 to 99.9% by weight water and 0.1 to 40% by weight of at least one alcohol, wherein said alcohol is preferably selected from methanol and ethanol, more preferably wherein said solvent or solvent mixture is water, preferably by dissolving and/or suspending said salt in said solvent or solvent mixture,

b) converting said salt into the free base or preferably the inner salt of the compound cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), preferably by adjusting the pH, and

c) the thus obtained solid substance of the invention is crystallized and/or precipitated, preferably by adding an alcohol, preferably methanol and/or ethanol, to the solvent or solvent mixture until the weight ratio between water and alcohol in the resulting solvent mixture is from about 1: 1 to about 1: 9, and optionally separating the solid substance from the resulting solvent mixture.

The process facilitates the preparation of a solid substance of the invention consisting essentially of or preferably consisting of a solvate of the invention, especially consisting essentially of or preferably consisting of one or more of crystalline forms S1, S2 and S3, preferably comprising mixed-hydro-alcoholic solvates with different chemical dosages.

Preferred solvents or solvent mixtures, preferably polar and/or protic solvents or solvent mixtures, the pH to be adjusted and the temperatures to be used in the above-described process are given and discussed herein.

Preferred examples or embodiments of method steps a), b) and/or c) include the adjustment as described herein. More preferably, the contacting and/or converting step may be viewed as a modulating or modulating step as described herein.

Preferred forms of the method as described above comprise an adjustment or one or more adjustment steps as described herein.

A preferred form of the method as described above consists essentially of the conditioning or one or more conditioning steps as described herein.

The results of subsequent slurry conversion experiments, depicted graphically below, present preferred parameters for the process for preparing the solids of the invention or for converting to one or more of the crystalline forms of the invention.

The first two panels given below show the parameters and results of a competitive slurry in MeOH/water-mixture at room temperature (25 ℃) as a function of the methanol content in each mixture and of the treatment time, i.e. after one day and after three weeks:

according to additional PXRD studies, it has been demonstrated that the residue obtained from the competitive slurry represents a solvate comprising water and methanol. Thus, the residue has been designated hereinafter as S1 (shown in the second panel) instead of S3 (shown in the first panel).

The second set of two graphs given below shows the parameters and results of a competitive slurry in an EtOH/water-mixture at room temperature (25 ℃) as a function of the ethanol content in each mixture and of the treatment time, i.e. after one day and after three weeks:

according to additional PXRD studies, it has been demonstrated that the residue obtained from the competitive slurry represents a solvate comprising water and ethanol. Thus, the residue has been designated hereinafter as S2 (shown in the second panel) instead of S3 (shown in the first panel).

Particularly preferred preparation methods, conversion or transformation methods and additionally preferred temperatures, solvents, solvent mixtures, reaction times, starting materials and/or additional process parameters are given in the examples. Thus, the examples, together with the description and/or claims of the invention, provide sufficient guidance to practice the invention within its full scope. However, methods and particularly method parameters outside of the examples can be taken, alone and in combination with one or more of those methods and/or parameters, and used with the disclosure and/or claims of this specification.

In addition, higher order crystalline solvate forms containing up to about 7 solvent molecules per molecule of the compound of formula I in each unit cell, preferably desolvated versions thereof, may be obtained. These higher order crystalline solvate forms are preferably referred to as heptasolvates. The unit cell of these heptasolvates preferably contains about 4 molecules of the compound of formula I. The solvent molecules contained in these heptasolvates are preferably selected from water and alcohols, more preferably from water, methanol and ethanol and mixtures thereof. It is particularly preferred that the solvent molecules in the heptasolvate consist essentially of water.

These higher order crystalline solvate forms are therefore preferably referred to as heptasolvates (of the invention), more preferably as heptahydrates (of the invention) and their desolvates, especially as crystalline form H1. The heptasolvates of the present invention are preferably characterized by a unit cell comprising about 4 molecules of the compound of formula I and up to about 7 molecules of solvent per molecule of the compound of formula I. The heptasolvates of the present invention are more preferably represented by a unit cell comprising or preferably consisting essentially of about 4 molecules of the compound of formula I and an upper limit of about 7 solvent molecules per molecule of the compound of formula I. The heptasolvate or heptahydrate of the present invention is also preferably a desolvated compound thereof, as long as the initial crystal structure of each heptasolvate is substantially retained.

Preferably, the heptasolvates of the invention, more preferably the heptahydrates of the invention and their desolvates, especially crystalline form H1, are alternatively or additionally characterized by a unit cell having the following unit cell lattice parameter (ULP) ULP 3:

and

more preferably characterized by a unit cell having the following unit cell lattice parameter (ULP) ULP 3:

and

in particular, characterized by a unit cell having the following unit cell lattice parameter (ULP) ULP 3:

and

in a unit cell with the lattice parameter ULP3, the angle α is preferably 90 ° ± 2 °, the angle β is preferably 90 ° ± 2 °, and/or the angle γ is preferably 90 ° ± 2 °.

Preferably, the unit cell having the lattice parameter ULP3 may alternatively or additionally, preferably additionally, be characterized by a content of about 4 molecules of the compound of formula I contained within the unit cell.

Preferably, a unit cell having the lattice parameter ULP3 may alternatively or additionally, preferably additionally, be characterized by an upper limit of the content of solvent molecules, preferably water molecules, of about 7 solvent molecules, preferably water molecules, for each molecule of the compound of formula I within the unit cell.

Thus, preferably, the unit cell can alternatively or additionally be characterized by a total content of about 4 molecules of the compound of the formula I and a total content or upper limit of 28 molecules of the solvent, preferably water molecules.

In a unit cell with the lattice parameter ULP3, angle α is preferably 90 ° ± 0.5 °, angle β is preferably 90 ° ± 0.5 °, and/or angle γ is preferably 90 ° ± 0.5 °. In a unit cell with the lattice parameter ULP3, the angles α, β and γ are more preferably 90 ° ± 0.1 °.

The heptasolvates of the invention, more preferably the heptahydrates of the invention and their desolvates, especially crystalline form H1, may alternatively or additionally be characterized by a melting/decomposition temperature.

The melting/decomposition temperature and/or thermal behaviour can preferably be determined by DSC (differential scanning calorimetry) and TGA (thermogravimetric analysis). DSC and/or TGA methods, or generally thermal analysis methods and apparatus suitable for their determination, are known in the art, for example from the 6 th edition european pharmacopoeia, chapter 2.02.34, in which suitable standard techniques are described. For melting/decomposition temperatures or behaviour and/or thermal analysis it is generally more preferred to use a Mettler Toledo DSC 821 and/or a Mettler Toledo TGA 851, preferably as described in the European pharmacopoeia 6 th edition, chapter 2.02.34.

Preferably, the heptasolvates of the invention, more preferably the heptahydrates of the invention and their desolvates, especially crystalline form H1, may alternatively or additionally be characterized by single crystal X-ray structural data, such as obtained under the following conditions: on a diffractometer preferably equipped with a graphite monochromator and a CCD detector, Mo K is preferably used_αIrradiation, preferably at a temperature of 302K + -5K, even more preferably on an XCalibur diffractometer from Oxford Diffraction equipped with a graphite monochromator and a CCD detector, using Mo K_αRadiation, at about 302K.

According to the single crystal X-ray structural data obtained, the heptasolvates of the invention, more preferably the heptahydrates of the invention and their desolvates, especially the crystalline form H1, are such as to have a lattice parameterIs inclined space group P2₁2₁2₁The crystallization is carried out with a unit cell volume of preferably

Even more preferably still, the first and second substrates are,and

as is clear from the single crystal structure, form H1 represents a heptasolvate, more specifically a heptahydrate.

FIG. 33 depicts a single crystal X-ray structure.

The heptasolvates of the invention, more preferably the heptahydrates of the invention and their desolvates, especially crystalline form H1, may alternatively or additionally be characterized by powder X-ray diffraction.

Preferably, the heptasolvates of the invention, more preferably the heptahydrates of the invention and their desolvates, especially crystalline form H1, may alternatively or additionally be characterized by a powder X-ray diffraction pattern, more preferably comprising one or more, more preferably 3 or more, even more preferably 6 or more, especially all, of the powder X-ray peaks given below:

more preferably, the heptasolvate according to the invention, more preferably the heptahydrate according to the invention and its desolvated form, especially crystalline form H1, may alternatively or additionally be characterized by a powder X-ray diffraction pattern, more preferably comprising one or more of the powder X-ray peaks given below, more preferably comprising 5 or more of the powder X-ray peaks given below, even more preferably 9 or more of the powder X-ray peaks given below, especially comprising all of the powder X-ray peaks given below:

even more preferably, the heptasolvate according to the invention, more preferably the heptahydrate according to the invention and its desolvated form, especially crystalline form H1, may alternatively or additionally be characterized by a powder X-ray diffraction pattern, more preferably by a powder X-ray diffraction pattern comprising one or more of the powder X-ray peaks given below, more preferably comprising 8 or more of the powder X-ray peaks given below, even more preferably 10 or more of the powder X-ray peaks given below, especially comprising all 12 single crystal X-ray peaks given below:

the powder X-ray diffraction and more preferably the powder X-ray diffraction patterns may preferably be performed or determined as described herein, especially byIs carried out or determined by standard techniques described in European pharmacopoeia, 6 th edition, chapter 2.9.33, even more preferably using the parameter Cu-Ka₁Radiation and/orPreferably on a Stoe StadiP 611KL diffractometer.

Preferably, the heptasolvates of the present invention, more preferably the heptahydrates of the present invention and their desolvates, especially crystalline form H1, may alternatively or additionally be characterized by infrared spectroscopy data. IR-spectroscopy data may preferably be obtained by FT-IR-spectroscopy. IR-spectroscopy data or FT-IR-spectroscopy data may preferably be obtained by standard techniques as described in European pharmacopoeia 6 th edition, chapter 2.02.24. For the determination of FT-IR spectroscopy, a Bruker Vector 22 spectrometer can preferably be used. The FT-IR spectrum is preferably baseline corrected, preferably using Bruker OPUS software.

Preferably, the heptasolvates of the invention, more preferably the heptahydrates of the invention and their desolvates, especially crystalline form H1, may alternatively or additionally be characterized by raman spectroscopy data.

Preferably, the raman or FT-raman spectra are obtained using an aluminium cup as the sample container for each solid substance.

Preferably, the raman spectroscopy data is obtained by FT-raman spectroscopy. Preferably, the Raman spectroscopy data or FT-Raman spectroscopy data is obtained by standard techniques as described in European pharmacopoeia, 6 th edition, chapter 2.02.48. For the determination of FT-Raman spectroscopy, a Bruker RFS100 spectrometer can preferably be used. The FT-Raman spectra are preferably baseline corrected, preferably using Bruker OPUS software.

Preferably, the heptasolvates of the invention, more preferably the heptahydrates of the invention and their desolvates, especially crystalline form H1, may alternatively or additionally be characterized by dynamic vapor absorption experiments. Results may be obtained by standard techniques as described in Rolf Hilfiker, Polymorphism in the pharmaceutical industry', Wiley-VCH.Weinheim2006 (Chapter 9: Water vapour absorption, and references therein).

A preferred subject matter of the present invention is therefore solid substances of the compounds of the formula I,

cyclo- (Arg-Gly-Asp-DPhe-NMeVal) (I)

Wherein the solid substance comprises one or more crystalline forms of the compound of formula I characterized by a unit cell having the following lattice parameter (ULP) ULP 3:

and

more preferably characterized by a unit cell having the following unit cell lattice parameter (ULP) ULP 3:

and

in particular, characterized by a unit cell having the following unit cell lattice parameter (ULP) ULP 3:

and

the unit cell is preferably a crystallographic unit cell or a crystallographically defined unit cell.

In the unit cell, the angle α is preferably 90 ° ± 2 °, the angle β is preferably 90 ° ± 2 °, and/or the angle γ is preferably 90 ° ± 2 °.

The solid substance preferably comprises at least 10% by weight, more preferably at least 30% by weight, even more preferably 60% by weight, in particular at least 90% by weight or at least 95% by weight of one or more crystalline forms of the compound of formula I as defined above and/or below. For example, the solid substance comprises about 25, about 50, about 75, about 95, about 99 or about 100% by weight of one or more crystalline forms of the compound of formula I as defined above and/or below.

Particularly preferably, the solid substance comprises at least 10 mol%, more preferably at least 30 mol%, even more preferably 60 mol%, especially at least 90 mol% or at least 95 mol% of one or more crystalline forms of the compound of the formula I as defined above and/or below. For example, the solid substance comprises about 25, about 50, about 75, about 95, about 99 or about 100 mole% of one or more crystalline forms of the compound of formula I as defined above and/or below.

Especially preferred is a solid substance as defined above comprising crystalline form H1 or a desolvated form thereof, wherein crystalline form H1 is characterized by one or more of the parameters given herein, preferably including the unit cell parameter ULP3 as given herein.

Especially preferred is a solid substance as defined above consisting essentially of crystalline form H1 or a desolvated form thereof, wherein crystalline form H1 is characterized by one or more of the parameters given herein, preferably including the unit cell parameter ULP3 as given herein.

Thus, another preferred subject matter of the present invention is a solid substance comprising one or more, preferably one, two, three or four, even more preferably one or two, crystalline forms of a compound of formula I, wherein each of said crystalline forms has a unit cell with a lattice parameter (ULP) selected from the group consisting of:

ULP1：

and

ULP2：

and

and

ULP3：

and

more preferably, the solid substance comprises one or more, preferably one, two, three or four, even more preferably one or two, crystalline forms of the compound of formula I, each having a unit cell with a lattice parameter (ULP) selected from the group consisting of:

ULP1：

and

ULP2：

and

and

ULP3：

and

in a unit cell with the lattice parameters ULP1, ULP2 and/or ULP3, the angle α is preferably 90 ° ± 2 °, the angle β is preferably 90 ° ± 2 ° and/or the angle γ is preferably 90 ° ± 2 °.

Preferably, the unit cell having lattice parameters ULP1, ULP2 and/or ULP3 may alternatively or additionally, preferably additionally, be characterized by a content of about 4 molecules of the compound of formula I contained within the unit cell.

In a unit cell with the lattice parameters ULP2 and/or ULP3, the angle α is preferably 90 ° ± 0.5 °, the angle β is preferably 90 ° ± 0.5 ° and/or the angle γ is preferably 90 ° ± 0.5 °. In a unit cell with lattice parameters ULP2 and/or ULP3, the angles α, β and γ are more preferably 90 ° ± 0.1 °.

Preferably, the unit cell having lattice parameters ULP1, ULP2 and/or ULP3 may alternatively or additionally, preferably additionally, be characterized by a content of about 4 molecules of the compound of formula I contained within the unit cell.

Preferably, the unit cell having the lattice parameter ULP3 may alternatively or additionally, preferably additionally, be characterized by a content of about 4 molecules of the compound of formula I contained within the unit cell.

More preferably, the solid substance comprises one or more, preferably one, two, three or four, even more preferably one or two, crystalline forms of the compound of formula I selected from:

crystalline form A1 to have a lattice parameterAndthe unit cell of (a) is characterized,

crystalline form S1 to have a lattice parameterAndthe unit cell of (a) is characterized,

crystalline form S2 to have a lattice parameterAndthe unit cell of (a) is characterized,

crystalline form S3 to have a lattice parameterAnda unit cell of (A), and

crystalline form H1 to have a lattice parameterAndand (3) unit cell characterization.

More preferably, the solid substance comprises one or more, preferably one, two, three or four, even more preferably one or two, crystalline forms of the compound of formula I selected from:

crystalline form a1, characterized by a unit cell having the following lattice parameters:andpreferably, α ═ β ═ γ ═ 90 ° ± -1 ° and in particular α ═ β ═ γ ═ 90 °;

crystalline form S1, characterized by a unit cell having the following lattice parameters:andpreferably, α ═ β ═ γ ═ 90 ° ±.2 °, in particular α ═ 90 ° ±.1 °, β ═ 91 ° ±.1 °, γ ═ 90 ° ±.1 °, in particular α ═ 90 °, β ═ 91.2 °, γ ═ 90 °;

crystalline form S2, characterized by a unit cell having the following lattice parameters:andpreferably, α ═ β ═ γ ═ 90 ° ± -1 °, in particular α ═ β ═ γ ═ 90 °;and

crystalline form S3, characterized by a unit cell having the following lattice parameters:andpreferably, α ═ β ═ γ ═ 90 ° ± -1 °, in particular α ═ β ═ γ ═ 90 °; and

crystalline form H1, characterized by a unit cell having the following lattice parameters:andpreferably, α ═ β ═ γ ═ 90 ° ± -1 °, in particular α ═ β ═ γ ═ 90 °.

Preferably, crystalline forms S1, S2, S3 and/or H1 may alternatively or additionally, preferably additionally, be characterized by a content of about 4 molecules of the compound of formula I in the unit cell.

Crystalline forms S1, S2, S3 and/or H1 are preferably also characterized as solvates.

More preferably, crystalline form H1 is also characterized as a heptasolvate.

In the context of the present invention, the solvate and/or heptasolvate is preferably a crystalline solid adduct containing a stoichiometric or non-stoichiometric amount of solvent incorporated within the crystalline structure, i.e. the solvent molecules preferably form part of the crystalline structure. If the solvent incorporated is water, the solvate is also commonly referred to as a hydrate.

Thus, the solvent in the solvate preferably forms part of the crystal structure and is therefore typically detectable by X-ray methods, preferably by X-ray methods as described herein.

Preferably, one or more of claims 3 to 8 in respect of solid matter and the disclosure relating thereto as described herein for solid matter comprising one or more crystalline forms as described herein in addition to crystalline form H1 are preferably also applicable to crystalline form H1 and/or solid matter comprising crystalline form H1. In this respect, particularly preferred solid substances are the subject matter of claims 3 to 8 in the present application, preferably including the preferred embodiments given in the description of this aspect.

Preferably, the one or more methods of disposal and the disclosure relating thereto as described herein for a solid substance comprising one or more crystalline forms as described herein other than crystalline form H1 are preferably also applicable to crystalline form H1 and/or a solid substance comprising crystalline form H1. In this respect, particularly preferred disposal methods are the subject matter of the disposal method claims in the present application, preferably including the preferred embodiments given in the description of this aspect.

Preferably, the one or more methods and the disclosure related thereto as described herein for solid materials comprising one or more crystalline forms as described herein in addition to crystalline form H1 are preferably also applicable to crystalline form H1 and/or solid materials comprising crystalline form H1. In this respect, particularly preferred methods are the subject matter of the method claims in the present application, preferably including the preferred embodiments given in the description of this aspect.

Preferably, the one or more uses and the disclosure relating thereto as described herein for a solid substance comprising one or more crystalline forms as described herein other than crystalline form H1 are preferably also applicable to crystalline form H1 and/or a solid substance comprising crystalline form H1. A particularly preferred use in this respect is the subject matter of the claims for use in this application, preferably including the preferred embodiments given in the description of this aspect.

For compounds of formula I (cyclo- (Arg-Gly-Asp-DPhe-NMeVal)), the following written names of the classes are preferably considered equivalents:

cyclo- (Arg-Gly-Asp-DPhe- [ NMe ] Val) ═ cyclo- (Arg-Gly-Asp-DPhe- [ NMe ] -Val) ═ cyclo- (Arg-Gly-Asp-DPhe-NMeVal) ═ cyclo (Arg-Gly-Asp-DPhe-NMe-Val) ═ crgdfmev ═ c (rggdnmev).

Preferably cyclo- (Arg-Gly-Asp-DPhe-NMeVal) is also referred to as cilengitide, which is the INN (international non-proprietary name) of the compound.

In this context cyclo- (Arg-Gly-Asp-DPhe-NMeVal) is preferably used as a pharmaceutically acceptable salt, more preferably a pharmacologically acceptable hydrochloride salt, especially preferably as an inner salt, which is the compound cyclo- (Arg-Gly-Asp-DPhe-NMeVal) itself.

Unless otherwise indicated, reference to a compound of formula I preferably denotes the reference to the compound cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) itself, which is preferably the inner salt of said compound. Thus, cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) preferably also means the inner salt of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), unless otherwise indicated.

Especially preferred according to the present invention are the subject-matters as described herein, wherein features of two or more preferred, more preferred and/or especially preferred embodiments, aspects and/or subject-matters are combined into one embodiment, aspect and/or subject-matter.

The term "about" as used herein with respect to numbers, ranges and/or amounts preferably means "about" and/or "approximately". The meaning of those terms is well known in the art and preferably includes differences, deviations and/or variability of the respective numbers, ranges and/or amounts plus/minus 15%, especially plus/minus 10%.

The present invention is explained in more detail below by way of examples. The invention may be carried out in the full scope of the claims and is not limited to the examples given herein.

Furthermore, the following examples are given to aid the skilled person in a better understanding of the present invention by way of example. The examples are not intended to limit the scope of protection afforded by the claims. The exemplified features, properties and advantages of the compounds, compositions, methods and/or uses defined in the examples may be given to other compounds, compositions, methods and/or uses not specifically described and/or defined in the examples, but falling within the scope as defined in the claims.

Preferably, the exemplified features, properties and advantages of the compounds, compositions, methods and/or uses defined in the examples and/or claims may be given to other compounds, compositions, methods and/or uses not specifically described and/or defined in the examples and/or claims, but falling within the scope specified in the description and/or claims.

Experiment of

Analytical method

IR-spectroscopy:

FT-IR spectra are preferably obtained on a Bruker Vector 22 spectrometer at room temperature. Therefore, it is preferred to use standard techniques as described in the 6 th edition of the European pharmacopoeia, chapter 2.02.24. FT-IR spectra are preferably obtained using KBr tablets as sample preparation technique. Thus, about 3mg of the sample was ground, mixed with KBr, and the mixture was subsequently ground in a mortar. Selecting 2cm^-1And 32 scans gave spectra. Baseline correction of the FT-IR spectra is preferably performed using Bruker OPUS software.

Raman spectroscopy:

FT-Raman spectra are preferably obtained on a Bruker RFS100 spectrometer equipped with an NdYAG laser (wavelength 1064nm) at room temperature. Therefore, it is preferred to use standard techniques as described in the 6 th edition of the European pharmacopoeia, chapter 2.02.48. The FT-raman spectrum is preferably obtained using an aluminum cup as the sample container. About 5mg of sample was mechanically filled into the sample container. Preferably 1cm^-1Or 2cm^-1The raman-spectrum was obtained with a spectral resolution of 500 scans and a laser power of 500 mW.

TG or TGA:

preferably, the TG assay is performed on Mettler Toledo TG 851. Preferably, the determination is effected by standard techniques as described in the European pharmacopoeia 6 th edition, chapter 2.02.34. Preferably, about 10-20mg of each sample is prepared in a 100 μ L aluminum pan without a lid. The measurement is preferably carried out in a nitrogen atmosphere (50mL/min) at a heating rate of 5K/min.

DSC：

Preferably, the DSC measurement is carried out on a Mettler Toledo DSC 821. Preferably, the determination is effected by standard techniques as described in the European pharmacopoeia 6 th edition, chapter 2.02.34. Preferably, about 2-10mg of each sample is prepared in a 40 μ L aluminum pan with a perforated lid. The measurement is preferably carried out in a nitrogen atmosphere (50mL/min) at a heating rate of 5K/min.

XRD：

The powder X-ray diffraction patterns are preferably obtained at room temperature on a Stoe StadiP 611KL equipped with a linear PSD detector, preferably by standard techniques as described in the european pharmacopoeia 6 th edition, chapter 2.9.33. Therefore, it is preferable to use a composition havingAndc of wavelengthu-Ka1 or Co-Ka 1. Preferably, about 30mg of sample is prepared in the capillary. The scanning is preferably performed from 5 ° to 72 ° with a step size of 0.02 ° and an integration time of 150 s.

DVS：

Dynamic vapor absorption assays are preferably obtained on the SMS DVS Intrinsic system. The results are preferably obtained by standard techniques as described by Rolf Hilfiker, "Polymorphism in the Pharmaceutical Industry", Wiley-VCH. Weinheim2006 (Chapter 9: Water vapor absorption, and references therein). Preferably, about 2-10mg of sample is weighed into a 100 μ L aluminum pan and placed in the sample incubator of a DVS instrument with a microbalance. Humidification is preferably performed using a total nitrogen flow rate (combined dry and wet gas flow) of 200 mL/min. The water vapor absorption isotherm is preferably obtained at 25 ℃ in the range of 0% relative humidity to 98% relative humidity, typically in 10% relative humidity increments. For all relative humidity increases, preferably equilibrium conditions are used in which dm/dt ≦ 0.0005 wt%/min, with a minimum relative humidity increase time of 10 minutes and a maximum relative humidity increase time of 360 minutes, which is preferably used as a time-out if the above-mentioned dm/dt criterion has not been reached.

Example A) crystallization of the inner salt from the hydrochloride

1.25g cyclo- (Arg-Gly-Asp-DPhe-NMeVal). times.HCl was dissolved in 10ml water. The pH was adjusted to 6.8 by using concentrated ammonia. After standing overnight at 4 ℃, crystals appeared which were isolated by filtration, washed with ice cold water and air dried. The mother liquor was concentrated to yield additional crystalline product.

Example B) crystallization of inner salt from trifluoroacetate

1.41g cyclo- (Arg-Gly-Asp-DPhe-NMeVal). times.TFA was dissolved in 10ml water. The pH was adjusted to 6.8 by using concentrated ammonia. After standing overnight at ambient temperature, crystals appeared which were isolated by filtration, washed with ice cold water and air dried. The mother liquor was concentrated to yield additional crystalline product.

Example C) inner salt for chromatography

5.04g cyclo- (Arg-Gly-Asp-DPhe-NMeVal). times.TFA were dissolved in 100ml water with 25% NH₃The aqueous solution adjusted the pH to 7.0. The solution was transferred by means of pump A onto a 2-pump gradient system RP-HPLC column (Lichrosorb RP8(10um) 50X 250 mm). Firstly, the column is eluted with water and secondly, the chromatographic purification of the compound is carried out by elution with a gradient of a solution of 15-25% 2-propanol in water at 20ml/min over 2 hours. Detection was at 215/254 nm. Fractions were collected and pooled. During evaporation of 2-propanol from the pool, crystalline inner salts of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) precipitated and were collected by filtration. The mother liquor was concentrated to yield additional crystalline product.

Example D) preparation of crystals of the inner salt from the cosolvent mixture

1g of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) was dissolved in 20ml of water/2-propanol (8: 2 vol) at 40 ℃. After 2 days at room temperature (25 ℃), a crystalline compound had precipitated.

Example E) X-ray structural determination of the inner salt

Crystals of crystalline form S3 were selected for X-ray analysis. The correct peptide covalent structure and compound conformation in the crystalline solid state indicates the presence of the tetrahydrate with 4 molecules of formula 1 per unit cell.

Example F) X-ray structural determination of anhydrate

Crystals of crystalline form a1 were selected for X-ray analysis. The correct peptide covalent structure and compound conformation in the crystalline solid state indicates the presence of 4 anhydrates of formula 1 per unit cell.

Example G) X-ray structural determination of dihydrate-monoethanol compound

Crystals of the crystalline form representing a specific example of form S2 were selected for X-ray analysis. The correct peptide covalent structure and compound conformation in the crystalline solid state indicates the presence of the dihydrate-monoethanol compound having 4 molecules of formula 1 per unit cell.

Example H) preparation of crystalline form H1

Crystalline form H1 was obtained as follows: crystalline form S2 was dissolved in 0.9% saline until a clear solution of the compound of formula I at a concentration of 15mg/mL was obtained. The solution was stored at +5 ℃ for 4 to 9 weeks with continuous shaking, whereby small rod-like crystals precipitated. The crystal thus obtained was confirmed to be crystalline form H1 by single crystal X-ray diffraction.

Example I) X-ray structural determination of crystalline form H1

Crystals of crystalline form H1 were selected for X-ray analysis. The correct peptide covalent structure and product conformation in the crystalline solid state indicates that heptahydrate has been formed with 4 cyclic peptides per crystalline unit.

1. Method for obtaining pseudopolymorphs by stirring in methanol/water and ethanol/water mixtures

a) The crystalline tetrasolvates of the invention, in particular crystalline forms S1 and S2, can be obtained by slurry conversion from form A1 in a methanol/water mixture (70 v%: 30 v%) with stirring at 25 ℃ for 2 days and in an ethanol/water mixture (60 v%: 40 v%) with stirring at 25 ℃ for 18 days, respectively.

The general method comprises the following steps:

about 500mg of form a1 of cilengitide was dispersed in 5ml of solvent at room temperature. The dispersion was stirred by a magnetic stirrer for the mentioned time and finally filtered.

b) In addition, the crystalline tetrasolvates of the invention, in particular crystalline forms S1 and S2, can also be prepared by competitive slurry conversion experiments at different temperatures with mixtures (1: 1) of pseudopolymorphs (e.g. S1, S2, S3 or mixtures thereof) and form a1 in water/methanol and water/ethanol mixtures with different alcohol contents, respectively.

The general method comprises the following steps:

about 20mg of pseudopolymorph of cilengitide (e.g. S1, S2, S3 or mixtures thereof) and 20mg of form a1 were dispersed in 300 μ l of water/alcohol mixture at 0 ℃ or room temperature (25 ℃). The dispersion was stirred at room temperature (25 ℃) for 24 hours by means of a magnetic stirrer, for a further 3 weeks (long-term experiment) and finally filtered.

The experimental conditions for producing each of the four solvates of the invention are set forth in the following table:

i)S1：

ii)S2：

c) in contrast thereto, no pseudopolymorph could be obtained under the following conditions, but rather the substantially pure anhydrate/solvate-free a1 was formed.

About 20mg of pseudopolymorph of cilengitide (e.g. S1, S2, S3 or mixtures thereof) and 20mg of form a1 were dispersed in 300 μ l of water/alcohol mixture at 50 ℃. The dispersion was stirred by magnetic stirrer for 24 hours and finally filtered.

The experimental conditions for producing form a1 are listed in the table below:

water "added to 100 v%" preferably means that water is added to the previously specified amount of solvent (volume percent (v%)) other than water in an amount to make up 100 v% of each solvent/water mixture.

2. Method for obtaining form S1 by carrying out conditioning experiments in a desiccator under a methanol atmosphere

About 1g of pseudopolymorph (e.g. S2, S3 or a mixture thereof) is dried on silica gel in a desiccator. The material was then stored in a desiccator with an atmosphere of 100% methanol vapor for 5 days.

3. Method for obtaining form S2 by carrying out conditioning experiments in a desiccator under an ethanol atmosphere

About 1g of pseudopolymorph (e.g. S3, S1 or a mixture thereof) is dried on silica gel in a desiccator. The material was then stored in a desiccator with an atmosphere of 100% ethanol vapor for 5 days.

4. Process for converting the A1/S3 polymorphic mixture to S2 by stirring in an ethanol/water mixture

Cilengitide (mixture of polymorphic forms a1 and S3, 275,5g) was suspended in a mixture of deionised water (700ml) and ethanol (700 ml). The suspension was stirred at room temperature for 24 hours and then cooled to 5 ℃. The product was isolated by suction filtration and washed with cold ethanol. Drying at 60 ℃ for 72 h under vacuum yielded 270g of cilengitide (crystalline form S2, 3.6% EtOH, HPLC purity: 99.9%).

5. Preparation of crystalline form a1 by slurry conversion

Form a1 of cilengitide can be obtained by slurry transformation from pseudopolymorphs (e.g. S1, S2, S3 or mixtures thereof) in water at 25 ℃. The conversion to form a1 was accelerated by elevated temperature (50 ℃).

About 10g of a pseudopolymorph of cilengitide (e.g., S1, S2, S3, or a mixture thereof) was dispersed in 50ml of deionized water at room temperature. The dispersion was stirred by magnetic stirrer for 24 hours and finally filtered.

6. Preparation of crystalline form a1 by competitive slurry conversion

Furthermore, form A1 can be prepared in pure form by competitive slurry conversion experiments at room temperature (25 ℃), mixtures (1: 1) of pseudopolymorphs (e.g., S1, S2, S3 or mixtures thereof) and A1 used in acetone, acetonitrile, isopropanol, physiological NaCl solutions, phosphate buffer (pH7.4), and in a 1: 1 (v: v) mixture of acetone, acetonitrile, isopropanol and water.

About 20mg of pseudopolymorph of cilengitide (e.g. S1, S2, S3 or mixtures thereof) and 20mg of form a1 were dispersed in 200-700 μ l of solvent at room temperature. The dispersion was stirred at room temperature (25 ℃) for 5 days by means of a magnetic stirrer, for a further 26 days (long-term experiment) and finally filtered.

7. Competitive slurry conversion

In addition, form a1 can also be prepared by competitive slurry conversion experiments at different temperatures using mixtures (1: 1) of pseudopolymorphs (e.g., S1, S2, S3 or mixtures thereof) and a1 in water/methanol and water/ethanol mixtures with different alcohol contents. The experimental conditions to produce pure form a1 are listed in the table below.

About 20mg of pseudopolymorph of cilengitide (e.g. S1, S2, S3 or mixtures thereof) and 20mg of form a1 were dispersed in 300 μ l of water/alcohol mixture at 0 ℃, room temperature and 50 ℃. The dispersion was stirred at room temperature (25 ℃) for 24 hours by means of a magnetic stirrer, for a further 3 weeks (long-term experiment) and finally filtered.

8. Process for obtaining crystalline form S2 comprising crystallization from an ethanol/water mixture

Cyclo- (Arg-Gly-Asp-DPhe-NMeVal) x TFA XH₂SO₄(400g) Dissolved in water (1600ml) at 59 ℃. Ammonia (30%) was added to adjust the pH to 6.8. Methanol (9600ml) was added to the solution over 3 hours. The resulting mixture was cooled to 23 ℃ over 3 hours and stirred at this temperature overnight. The mixture was then cooled to 5 ℃ and stirred for an additional 2 hours. Is separated by suction filtrationThe precipitated crude product was isolated and washed with cold methanol. Drying at 50 ℃ for 48 hours under vacuum yielded 335g of cilengitide (crystalline form S2, HPLC: 99.8%).

The crude material (335g) was dissolved in 58 ℃ water (1507 g). Methanol (8040ml) was added to the solution over 3 hours. The suspension thus formed was then cooled to 23 ℃ over 3 hours, stirred at this temperature overnight. The suspension was then cooled to 5 ℃ and stirred for an additional 3 hours. The product was isolated by suction filtration and washed with methanol. Drying at 60 ℃ under vacuum for 48 hours gave 309g of cilengitide (crystalline form S1, HPLC: 99.9%, 3.8% MeOH, IC: < 0.1% Cl^-0.0007% TFA and 10.3% SO₄ ^2-)。

150g of the above-obtained material was dissolved in 56 ℃ water (600ml) and ethanol (600 ml). The mixture was cooled to 23 ℃ over 3 hours and stirred overnight. The mixture (suspension) was cooled to 5 ℃ and stirred at this temperature for 2 hours. The product was isolated by suction filtration and washed with cold water. Drying under vacuum at 60 deg.C for 48 hours yielded 115.4g of cilengitide (crystalline form S2,. ltoreq.0.05% methanol, 5.3% EtOH IC: < 0.01% Cl^-，＜0.0011％TFA，0.34％SO₄ ^2-)。

9. Preparation of crystalline form A1 by crystallization from water

The preferred and very efficient method to obtain a1 is by crystallization from water starting from a crude material of cilengitide, since it is deduced from the following preparation method:

crude cilengitide (300g, amorphous material, form S1 (. The solution was cooled to 23 ℃ over 3 hours and stirred at this temperature overnight. The suspension was then cooled to 5 ℃ and stirred at this temperature for 2 hours. The product was isolated by suction filtration and washed with cold deionized water. Drying at 50 ℃ under vacuum for 48 hours yielded about 230g of cilengitide (crystalline form A1, < 0.001% TFA, 0.22% S0₄ ^2-0.06% ammonium, 99% HPLC purity,0.027% water).

10. Dynamic vapor absorption experiment of crystalline form S3

Dynamic vapor experiments on crystalline form S3 were performed using the SMS DVS I system. Results have been obtained by standard techniques as described in Rolf Hilfiker, Polymorphism in the Pharmaceutical Industry', Wiley-VCH.Weinheim2006 (Chapter 9: Water vapor absorption, and references therein). The water vapor absorption behavior showed a loss of water molecules (about 9 wt%) during the initial drying step (0% rh). During the water absorption cycle, water molecules are shown to aggregate in the crystal lattice (about 10 wt%) at elevated relative humidity (rh). In the second desorption cycle, there is a loss of this amount of water. The water vapor absorption isotherm (25 ℃) of form S3 is shown in fig. 29.

11. Dynamic vapor absorption experiment of crystalline form S1

Dynamic vapor experiments were performed using SMS DVS Intrinsic. Results were obtained by standard techniques as described in Rolf Hilfiker, Polymorphism in the Pharmaceutical Industry', Wiley-VCH.Weinheim2006 (Chapter 9: Water vapor absorption, and references therein). The water vapor absorption behavior showed a mass loss of about 8 wt% in the first desorption cycle, which is slightly lower than the methanol mass increase observed in the methanol vapor absorption experiment. Upon water vapor absorption, aggregation of water molecules in the crystal lattice was observed, with a maximum weight gain of about 8 wt% at elevated relative humidity (rh). In the second desorption cycle, a total mass loss of about 9.9 wt% was observed. For the cilengitide dihydrate-dimethanol compound, the calculated methanol content is equal to 9.3% by weight. The water vapor absorption isotherm (25 ℃) of form S1 is given in fig. 13.

12. Dynamic vapor absorption experiment of crystalline form S2

Dynamic vapor experiments were performed using SMS DVS Intrinsic. Results were obtained by standard techniques as described in Rolf Hilfiker, Polymorphism in the Pharmaceutical Industry', Wiley-VCH.Weinheim2006 (Chapter 9: Water vapor absorption, and references therein). The water vapor absorption behavior showed a mass loss of about 6.5 wt% in the first desorption cycle, which is lower than the ethanol mass increase observed in the ethanol vapor absorption experiment. Upon water vapor absorption, water molecules are observed to aggregate in the crystal lattice, with a maximum weight gain of about 6.4 wt% at elevated relative humidity (rh). In the second desorption cycle, a total mass loss of about 9.2 wt% was observed. For the cilengitide dihydrate-diethanolate, the calculated ethanol content is equal to 12.5% by weight. The water vapor absorption isotherm (25 ℃) of form S2 is given in fig. 20.

13. Regulation experiment

a)

Conditioning amorphous cilengitide (abbreviated Cil; cilengitide ═ cyclo- (Arg-Gly-Asp-DPhe-NMeVal)) under mixed water-ethanol atmospheres representing different water and alcohol partial pressures (adjusted with different EtOH content (vol%, v%) in the liquid phase) yields solvates exhibiting different stoichiometries with up to 4 water molecules and up to 2 ethanol molecules per molecule of cilengitide. Table 3 depicts the stoichiometry as determined by karl-fischer titration (KF) for quantifying water and gas chromatography over liquid (HS-GC) (and nuclear magnetic resonance spectroscopy (NMR)) for quantifying ethanol. Also seen in this table are points representing the stoichiometry of more than 4 water molecules per molecule of cilengitide. Since there is no space in the crystal lattice to accommodate more than 4 water molecules, an excess of more than 4 water molecules represents absorbed moisture.

The variations and lattice parameters from the diffraction pattern indices are also compiled in table 3.

Table 3:

table 3 shows: as the vapor pressure of ethanol increases, hydrate form S3 floatingly converts to mixed water-ethanol or anhydrous ethanol solvate form S2. From the X-ray data obtained for each solvate, all solvates (including hydrates) had similar lattice parameters, which increased only slightly and continuously as the ethanol molecules aggregated.

b)

Conditioning of amorphous cilengitide (abbreviated Cil; cilengitide ═ cyclo- (Arg-Gly-Asp-DPhe-NMeVal) in a methanol atmosphere produced solvates with 2 molecules of methanol per molecule of cilengitide.

Claims (18)

1. Solid substances of the inner salts of the compounds of the formula I,

cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) (I)

Wherein the solid substance comprises one or more crystalline forms of the compound of formula I characterized by a unit cell having the following lattice parameters:

and

and wherein the unit cells are monoclinic or orthorhombic.

2. Solid matter according to claim 1, comprising at least 95% by weight of one or more crystalline forms of the compound of formula I characterized by a unit cell with the following lattice parameters:

and

3. solid substance according to claim 1 or 2, wherein the one or more crystalline forms of the compound of formula I are selected from the group consisting of solvates and solvates.

4. Solid substance according to claim 1 or 2, wherein the one or more crystalline forms of the compound of formula I are selected from anhydrates.

5. Solid matter according to claim 3, wherein the solvate is selected from the group consisting of hydrates, methanolates and ethanolates and/or mixed water-methanol solvates, mixed water-ethanol solvates, mixed water-methanol-ethanol solvates and mixtures thereof.

6. Use of a solid substance according to any one of claims 1-5 in the manufacture of a medicament for the treatment of a disorder, wherein the disorder is selected from the group consisting of cancerous disorders, autoimmune disorders, inflammatory disorders, and ocular disorders.

7. Use according to claim 6, wherein the disorder is selected from cancerous disorders.

8. Use according to claim 7, wherein the cancerous disorder is selected from the group consisting of brain cancer, lung cancer, head and neck cancer, breast cancer and prostate cancer and metastases thereof.

9. A process for preparing the solid substance of any one of claims 1 to 5, which process comprises:

a) contacting cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) and/or an acid addition salt or a base addition salt thereof with a solvent or a mixture of solvents,

b) precipitating and/or crystallizing the inner salt of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) from said solvent or solvent mixture,

thereby obtaining a solid substance according to any one of claims 1 to 5.

10. The method of claim 9, further comprising:

c) separating the solid substance according to any one of claims 1 to 5 from the solvent or solvent mixture.

11. A process according to claim 9 or 10, wherein the solvent or solvent mixture is a polar and/or protic solvent or solvent mixture.

12. The process according to claim 9 or 10, wherein said steps a), b) and/or c) are carried out at a pH value of 5.5 to 8.

13. The method according to claim 9 or 10, wherein said steps a), b) and/or c) are performed under isoelectric conditions.

14. The process according to claim 9 or 10, wherein said steps a), b) and/or c) are carried out at a temperature of-50 ℃ to +200 ℃.

15. The process according to claim 9 or 10, wherein the solvent or solvent mixture of steps a), b) and/or c) is selected from the group consisting of water, methanol and ethanol and mixtures thereof.

16. The process according to claim 9 or 10 for the preparation of a solid substance according to any one of claims 1 to 5, wherein the solvent or solvent mixture of steps a), b) and/or c) comprises:

i) from 5 to 90% by weight of at least one alcohol selected from methanol and ethanol, and

ii)10 to 95% by weight of water.

17. The process according to claim 9 or 10 for the preparation of a solid substance according to any one of claims 1 to 4, wherein the solvent of step a), b) and/or c) consists of water, methanol and ethanol.

18. The process according to claim 9 or 10 for the preparation of a solid substance according to any one of claims 1-4 comprising at least 95% by weight of the anhydrate, wherein steps a), b) and/or c) are carried out at a temperature above +60 ℃.