WO2008037289A1

WO2008037289A1 - Form ab of acetyl salicyclic acid

Info

Publication number: WO2008037289A1
Application number: PCT/EP2006/010698
Authority: WO
Inventors: Roland Boese; Andrew D. Bond; Gautam R. Desiraju; Sascha Redder
Original assignee: Sciconcept Gmbh
Priority date: 2006-09-26
Filing date: 2006-11-08
Publication date: 2008-04-03
Also published as: DE102006045780A1

Abstract

The invention relates to a new form of acetyl salicylic acid designated as Form AB as well as processes for the preparation and formulation comprising it.

Description

Form AB of Acetyl Salicylic Acid

Recently a second polymorph of aspirin (acetyl salicylic acid, oacetylsalicylic acid), ("Form M") was reported by Peterson, Zaworotko, and co-workers (J. Am. Chem. Soc. 2005, 127, 16802), further referred to as PZ. This new form was obtained by crystallization of pure aspirin in the presence of either levetiracetam or acetamid from MeCN (Acetonitril), and it was claimed to be characterized by single-crystal X-ray diffraction. "Form II" was also "characterized by melting point, IR₁ DSC, and HPLC". It was stated that "there are clear differences between the unit-cell parameters" of Form I and Form II, and also that "the molecular geometry of aspirin molecules in Form Il is slightly different in terms of the torsion angle defined by the carboxylic acid and acetyl groups, although the centrosymmetric carboxylic acid dimer remains intact" .

It is noted that several anomalous indicators in the structure of PZ exist: (1) The data are truncated to 20= 40° (MoKa); (2) The f?-factors are unacceptably large (fl1[/>2σ(/)] = 0.162, ιvfl2(all data) = 0.308; (3) All atoms are refined isotropically, implying that anisotropic refinement was not possible; (4) Several of the refined U₁₅₀ values are zero or disturbingly close to zero. Most revealingly, the unit cell reported by PZ [a = 12.095(7), b = 6.491(4), c = 11.323(6) A, β = 111.509(9)°, V = 827.1(8) A³] can be transformed to the cell obtained for Form I, which is the well-known form of aspirin, with the metric transformation [1 0 Vz 0 -1 0 0 0 -1]. Likewise, an experimental Form I cell could be transformed to a cell having a = 12.084, b = 6.552, c = 11.274 A, β = 111.81°, V = 828.7 A³ which is remarkably close to the cell reported by PZ for "Form M".

The data collected on an authentic sample of Form I of aspirin can be treated readily to produce the "Form M" structure reported by PZ to their level of accuracy and precision. Since the main experimental evidence that they provided for the existence of "Form M" of aspirin was their single crystal X-ray structure determination, all of their claims must be re-evaluated with appropriate and additional experimental evidence before one is able to conclude that a new polymorph of aspirin has indeed been discovered. In the end, it is not clear if their "Form II" structure is an artifact of improper handling of data or a poor crystallographic result on a sub-optimal crystal. Nothing in the PZ paper helps one to select between these possibilities.

In conclusion, it must be stated that at the present time, and with the information given by PZ, it is not possible to determine if there is a second form of aspirin in the samples obtained by PZ, or whether any additive such as levetiracetam or acetamide would be needed to produce any such form. This is stated in a publication in Angewandte Chemie by A.D. Bond, R. Boese and Gautam R. Desiraju (in press). Subsequently the expression "Form II" will not be applied to a pure polymorphic form of acetyl salicylic acid instead of an arrangement of molecules as depicted in Figure 2 of the present invention.

Acetyl salicylic acid was first synthesized in 1853 but up to know no further crystalline second polymorphic form was established. Further it is well known form the state of the art that acetyl salicylic acid (Form I) possesses a poor solubility. For example it is not possible to solve essentially more than 4 grams of aspirin in 1000 mL of water at 20 °C. Accordingly the bioavailability of acetyl salicylic acid is relatively low. Therefore there is a desire of producing a polymorphic form with enhanced solubility in water or water containing solutions.

In respect of the aforementioned problems, the inventors of the present invention have sought to find a new form with enhanced solubility properties and stable characteristics at ambient temperature. This problem is solved by acetyl salicylic acid as disclosed in claim 1. According to the invention acetyl salicylic acid exists as Form AB comprising interlaced crystals of Form I and Form II. It is noted, that such interlaced crystals do not consist of a simple mixture of two polymorphic forms. Instead, each crystal has 5 domains of two molecular packing characteristics, described as Form I and Form II, where both forms are separated by distinct boundaries within the crystal. Such crystals also cannot be described as twins because of the different packing characteristics in the neighbouring domains. Wherein the term interlaced crystals is interchangeably used in this application with the terms10 mixed crystals or Mischkristalle as they were called in a prior application DE 10 2006045780.3.

Such domains can be multiply interlaced at a different extend and different size, called as intergrowths of Form I and Form II. Therefore, Form AS comprises intergrowths of Form I and Form II. 15 The cell dimensions of pure Form 5 and of the hypothetical pure Form II have the different cell dimensions.

Form I: a = 11.28, b = 6.55, c = 11.27 Å, β = 95.8°

Form II: a - 12.09, & = 6.49, O= 11.32 Å, β = 111.51°

Form A3 of the present invention as interlaced crystal can be indexed on the20 basis of both ceil dimensions. Form AB can therefore be sketchily characterized as interlaced crystals having the cell dimensions of a = 11.28, b = 6.55, c = 11.27 Å, β = 95.8° for Form I and a = 12.09, b = 6.49, c = 11.32 Å, β = 111.51° for Form II and wherein these values can vary by ±2%.

With the size and the ratio of the two crystal domains the overall ratio of the25 packing characteristics of Form i and Form JS can vary. Suitably, the proportion of the contents of Form ϋ to Form I can bo larger than 10% and is not expected he much more than 90%, specifically the proportion is between 10% to 20%, 10% to 30% or 20% to 30% weight percsnt Most preferred is acetyl salicylic acid as Form AB wherein the proportion of the contents of Form Il to Form I is larger than 50% and not more than 90%, specifically the proportion is between 60% to 90%, 60% to 95% or 60% to 99% weight percent. The contents of Form I and Form Il in the domains of interlaced or intergrowths crystals can be derived from X-ray and spectrum data (eg. NIR, CP-MAS ¹³C-NMR) where the accuracy of the relative intensities is in the range of ±7%.

The elusive and hypothetical pure Form Il is characterized by signals in the PXRD at 20,9° and 26,0° (±0,2°) in the 2Theta range (CuKα-radiation) which have intensities at 20,9° (±0,2°) of 49% (±5%) and at 26,0° (±0,2°) of 51% (±5%), respectively in relation to the 100% peak at 15,7° (±0,2°). Acetyl salicylic acid as Form AB can be characterized in that the two additional signals in the PXRD compared to the pure Form I at 20,9° and 26,0° (± 0,2°) in the 2Theta range (Cu-radiation), possess intensities greater than 12% and 13%, respectively, of the 100% signal at 15,7° (capillary technique, Laue technique).

Accordingly, a powder with 50% of Form Il in the domains exhibit intensities in the PXRD (capillary technique, Laue technique) at 20,9° of 24,5% and at 26,0° (± 0,2°) of 25,5%, respectively in relation to the 100% peak at 15,7°.

The acetyl salicylic acid as Form AB as interlaced crystals according to the invention can be characterized by two additional signals in the PXRD compared to the pure Form I at 20,9° and 26,0° (± 0,2°) in the 2Theta range (Cu-radiation), where the intensities are greater than 12% and 13%, respectively, of the 100% signal at 15,7°, especially the intensities can be for both peaks up 24,5 % for peak 20,9° and 25,5% for peak 26,0° (± 0,2°), most preferred are 29 % to 46% for peak 20,9° and 30,5% to 48,5% for peak 26,0° (± 0,2°) respectively in relation to the 100% peak at 15,7° measured with capillary technique (Laue technique).

Single crystal analysis is a method to characterize the contents of the two different domains in the Form AB. Refined batch scale factors, which are based on the reflections having odd / as Miller indices referring to the Form II, represent the proportion of the respective domains. A batch scale factor which represents 60 to 95% of Form Il in respect to that of Form I is preferred for Form AB.

The resulting crystallographic fl-value in the single crystal refinement of Form Il is suited to characterize the contents of the different domains in Form AB. The /7-values obtained for a refinement in Form I and Form II, respectively, are correlated according to Figure 1 and therefore represent the relative proportion of domains in the Form AB. A ratio of refined crystallographic f?-values which represent a proportion of 60 to 95% Form Il domains in Form AB is preferred.

Acetyl salicylic acid in pure Form I is soluble in water with about 3,5 g/L at 25 ⁰C. Acetyl salicylic acid as crystalline material according to the present invention possesses an improved solubility in water compared to Form I of acetyl salicylic acid.

Especially, Form AB possesses an improved dissolution rate in water compared to Form I, wherein known Form I is to be regarded as essential pure Form I. Depending on the contents of domain Form Il in respect of Form I, Form AB of acetyl salicylic has higher solubility properties in water at the same temperature. For example, 60% domain Form Il has a solubility which is increased by a factor of 2-10 and above.

The dissolution rate is one factor that defines speed of effectiveness of a drug, especially if it is the rate determining step. At 25 ⁰C for Form AB the dissolution rate is increased by a factor of 2 which improves the effectiveness of a drug by time after intake.

Typically, the solubility of Form AB with a content of domains Form Il in a range of 10-45% is increased at least by a factor of 2 in hot water at 80 ⁰C. The Form AB with a content of 60% domains Form Il dissolves up to 9 grams in 5 mL of hot water at 80 ⁰C. The factor of increased solubility in water can vary between 2 to 10 depending on the contents of domains Form Il in Form AB. Advantageously acetyl salicylic acid as Form AB is stable at room temperature. The stability at room temperature or even at higher temperatures is further improved by the contents of domain ratios Form I and Form Il when kept under dry conditions, typically by dry CaCI₂. Under these conditions Form AB does not show any significant variation of intensities of the characteristic signals in the CP-MAS ¹³C NMR experiment, the PXRD, the NIR spectrum or the single crystal experiments. Form AB is stable for several weeks and up to 6 months when kept under dry conditions at room temperature.

Acetyl salicylic acid as Form AB is characterized by comprising interlaced or intergrown crystals of Form I and Form II, wherein the molecules of acetyl salicylic acid are arranged according to the schematic drawing given in Figure 2 and wherein the arrangement A of Figure 1 contains centrosymmetric C-H- O dimers, which are located between the slabs shown in the lower part of Figure 2, arrangement B contains C-H- O catemers, arranged along a twofold screw axis, as shown in the upper part of the Figure 2. The intermediate region in the central layer (Intergrowth region) is only for illustration, because all slabs with

0-H—O hydrogen bonds are identical (O-H— O slab).

Acetyl salicylic acid as Form AB is characterized by a signal in the ¹³C CPMAS NMR spectrum at 20.5±0.5 ppm. This characteristic signal can exhibit an intensity that amounts for 10 to 90% of the signal at 19,8 ppm and has typically an intensity which is equal or higher than the 19,8(±0,5) ppm signal as shown in Figure 3.

Acetyl salicylic acid as Form AB is characterized by a brought signal in the NIR spectrum at about 5200 cm^"1, and a brought signal at about 6900 cm^"1. The first signal ranges from about 4800 to 5500 cm^"1 and the second from about 6500- 7200 cm^"1 as shown in Figure 4 for Form AB where the contents of Form Il in the domains is about 60%.

Acetyl salicylic acid as Form AB is characterized by a melting point of 125 to 128 ⁰C by thermal microscopy (heating rate 2 °C/min) wherein the Form AB comprises domains of Form Il of about 60%. A process for producing acetyl salicylic acid as Form AB is to crystallize acetyl salicylic acid with or without addition of 1-10% salicylic add from a saturated solution in acetonitrile, particularly at a temperature of 50 to 70 °C and rapid cooling to 0 to 25 °C, typically from about 60 °C to about 20 °C within 5 minutes. Advantageously during the crystallization from acetonitrile any further additives to the saturated solution is omitted. The synthesis of acetyl salicylic acid as Form AB employs crystallization from Form I by rapid cooling but without any further additive.

A second process for producing acetyl salicylic acid as Form AB is to favourably adding salicylic acid to acetic acid anhydrate, keeping the mixture at elevated temperature (elevated temperature may be best 50 °C but 40 °C up to bolling point will also work) until the salicylic acid is dissolved, the reaction mixture is subsequently cooled and the precipitate is isolated directly, especially instantaneously recrystallized from water at boiling heat. By instantaneous recrystaflizatlon of the isolated precipitate, the ratio of Form Il domains can be

Subsequent cooling Ia meant as rapid cooling from elevated temperature to 0 to 25 °C within a short period of 5 to 10 minutes. Generally the cooling takes place in a water bath, under running water or with an ice bath.

This process can bθ catalyzed by adding a proton donor, typically as an acid. Typical proton donors are organic or inorganic acids, especially mineral acids as hydrochloric acid, sulphuric acid, but proton donors as proton sponges or montmorlllonit can also be used.

Alternatively the precipitate and/or the recrystallized material is isolated and røcrystallisθd from a saturated solution of acetonitrile. Favourably it is recrystallized by rapid cooling of the saturated solution of acetonitrile from SO to 70 ^aC down to 0 to 25 ^aC, typically from SO ⁰C to 25 ⁰C within 10 min of alternatively within 5 min. Rapid cooling is generally performed in a wafer bath, under running water or with an ice bath. On a further alternative the isolated crystallized precipitate and/or the recrystailized material is immediately recrystallized from water, alcohols, ethers or heterocyclic aromatic compounds, wherein the recrystallization is performed from solutions at elevated temperature. Elevated temperatures are 40 °C to the boiling point of the mentioned solvents.

Likewise, the isolated crystallized precipitate and/or the recrystailized material is immediately recrystallized from any solvent in which acetyl salicylic acid can be solved. It is appropriate to solve the isolated crystallized precipitate and/or the recrystailized material of acetyl salicylic acid at elevated temperatures up to the boiling point of each solvent, followed by rapid cooling and immediate isolation

A crucial point of all crystallization and recrystaization steps is that the resulting precipitate is isolated or trie next recrystallization step is performed immediately, which is as fast as possible.

The Isolated Form AB of acetyl salicylic acid is dried by evaporation of the solvent at elevated temperatures and/or at reduced pressure, typically at 30 °C and/or 20 mbar.

Acetyl salicylic acid as Form AB obtainable by one of the processes according to one of the following processes a) to f) wherein the solubility of the obtained product in water is improved with respect to Form I and wherein the product is stable at room temperature.

a) A process for producing acetyl salicylic acid as Form AB 5s to crystallize acetyl salicylic acid with or without addition of 1-10% salicylic acid from a saturated solution in acβtonitrile, particularly at a temperature of SO to 70 ⁶C and rapid cooling to 0 to 25 ⁰C, typically from about 60 ⁰G Io about 20 ^flC within 5 minutes.

Advantageously during the crystallization from acetonitrilβ in process a) any further addotives to the saturated solution are omitted. b) A process for producing acetyl salicylic add as Form AB is to favourably adding salicylic acid to acetic acid anhydrate, keeping the mixture at elevated temperature, particularly elevated temperature may be best 50 °C but 40 °C up to boiling will also work, until the salicylic acid is dissolved, the reaction mixture is subsequently cooled and the precipitate is isolated directly, especially instantaneously recrystallized from water at boiling heat.

Whereby, by instantaneously recrystallization of isolated precipitate the ratio of Form II domains can be increased and subsequent cooling is meant as rapid cooling from elevated temperature to 0 to 25 °C within a short period of 5 to 10 minutes. Generally the cooling takes place in a water bath, under running water or with an ice bath.

Process b) can be catalyzed by adding a proton donor, typically as an acid.

Typical proton donors are organic or inorganic acids, especially mineral acids as hydrochloric acid, sulphuric acid, but proton donors as proton sponges or møntrnorlilonit can be also used.

c) Alternatively the precipitate and/or the recrystallized material is isolated and recrystallized from a saturated solution of acetonitrile. Favourably it is recrystallized by rapid cooling of the saturated solution of acetonitrile, particularly from 50 to 70 °C down to 0 to 25 °C, typically from 60 °C to 25 °C within 10 min or alternatively within 5 min.

Whereby, rapid cooling is generally performed in a water bath, under running water or with an ice bath.

d) Jn a further alternative process the isolated crystallized precipitate and/or the røcrystaϋisθc. material is immediately recrystailized from water, alcohols, ethers or heterocyclic aromatic compounds, wherein the recirysffallizatioπ is performed from solutions at elevated temperatures. Elevated temperatures are 40 ⁰C to boiling point of the mentioned solvents. e) Likewise, the isolated crystallized precipitate and/or the recrystallized material is immediately recrystallized from any solvent in which acetyl salicylic acid can be solved. It is appropriate to solve the isolated crystallized precipitate and/or the recrystallized material of acetyl salicylic acid at elevated temperature up to the boiling point of each solvent, followed by rapid cooling and immediate isolation (eg. suck off) of the crystalline material.

Regarding processes a) to e) a crucial point of all crystallization and recrystallization steps is that the resulting precipitate is isolated or the next recrystallization stop is performed immediately, thus as fast as possible.

f) The isolated Form AB of acetyl salicylic add from processes a) to Θ) is dried by evaporation of the solvent at elevated temperatures and/or at reduced pressure, typically at 60°C and/or 20 mbar.

Regarding the stability of Form AB of acetyl salicylic acid it is noted that it is stable for several, weeks and up to 6 months when kept under dry conditions. As for the higher solubility in water of Form AB the above mentioned solubility is

Erømpi® 1: A typical process to produce acetyl salicylfc acid Form AS with a content of 60% domain Form Il comprises the following procedure: 9,6 grams of $altcyiic acid are added to 20 mL acetic acid anhydrate as well as 16 drops of cone. Sulphuric acid. The mature is warmed to 50 ⁰C and kept at this temperature for 10 min. This mixture is added to 25 ml water (demineralised) at room temperature which causes an immediate crystallization and a second, viscous phase which is washed with 25 mL water and cooled 15 mm. in an ice bath. The product crystallines as a white powder, which can be filtered and dried in a desiccator above CaCl₂. 9.1 g of acetyl salicylic acid Form AB could be Alternatively the following two recrystallization steps can subsequently be performed to improve the ratio of domains Form Il in Form AB and to increase the stability of Form AB:

a) Recrystallization from ether, ethanol, methanol or acetonitrile as mentioned above.

b) Reerystaliizatlon from demineralized water: 9,1 g of Form AB of example 1 are added to 5 ml water and the mixture Js heated to 80 °C for about 10 minutes.

Cooling is performed in an ice bath, the resulting precipitate is immediately Isolated (sucked off) and storage over water free CaCIa or P₂O₅. Yield is 8 grams of from AB. Form AB derived from this recrystallization step is most stable.

Example 2: 9,6 g Salicylic acid (p.a.) is dissolved in 20 mL acetic acid anhydrate (p.a.) in a 100 mL Erlenmeyer flask to achieve a clear solution at room temperature. 16 drops of sulphuric acid (cone, p.a.) are added and the heated to 50 °C under stirring for 10 min. The clear solution is poured into 25 mL of water (dest., RT). Crystallization starts at the boundary of an oily and the aqueous phase. Further 25 mL of water (dost, RT) are added and the mixture is cooled for 15 min 5n an ice bath, The crystalline product is filtered off and dried in a desiccator for 3 hours above dry CaCIa. 9 grams of the dry powder is dissolved in 5 mL water at 80 °C giving ca. 12 mL of a solution, kept 10 min at 80 °C and then cooled in an ice bath. The crystallized product is again filtered off and dried in a desiccator for 3 hours above dry CaCI₂. The contents of Form AB ϊs 60% according to PXRD, single crystal structure analyses and ¹³C CP=MAS

A further aspect of the present invention is a pharmaceutical formulation comprising acetyl salicylic acid as form AB. The pharmaceutical formulation may be in form of a tablet, capsule, sachet, instant release formulation, controlled release formulation, sustained released formulation, delayed release formulation, powder, and compressed powder etcetera. The formulation further comprises common excipients.

Pharmaceutical formulation comprising acetyl salicylic acid as Form AB, wherein Form AB is stabilized by drying means, in particular by a drying agent. Wherein drying means are all compounds or package means that keep Form AB stable in the formulation and/or Form AB stable in a formulation in a package. Packages may be blister packages or vials. Drying agents may be water free CaCI₂ or other compounds that are able to bind water physically or chemically to stabilize Form AB by other means.

Use of acetyl salicylic acid as Form AB for the production of a medicament to be used as means for headache, migraine, as analgesic agent, as antipyretic, antiinflammatory, as an antiplatelet agent, as rheumatic agent and in long-term low- doses to prevent heart attacks and cancer.

Acetyl salicylic acid as Form AB is an analgesic (against minor pains and aches), antipyretic (against fever), and anti-inflammatory agent. It has also an antiplatelet ("blood-thinning") effect and is used in long-term low-doses to prevent heart attacks and cancer.

Low-dose long-term acetyl salicylic acid Form AB irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation, and this blood-thinning property makes it useful for reducing the incidence of heart attacks. Acetyl salicylic acid Form AB produced for this purpose shall contain 75 or 81 mg. High doses of acetyl salicylic acid Form AB is given immediately after an acute heart attack. These doses may also inhibit the synthesis of prothrombin and may therefore produce a second and different anticoagulant effect. Below, Figures 1 to 4 are described in more detail.

Figure 1 : Fractional composition of acetyl salicylic acid Form AB domains Form I and Form Il in the single crystal; batch scale factor applied to odd / reflections x 100, derived from refined crystallographic R values.

Figure 2: Schematic drawing of the packing of molecules in interlaced crystals in Form I and Form Il and wherein the arrangement A of the Figure contains centrosymmetric C-H- O dimers, which are located between the slabs shown in the lower part of the

Figure, arrangement B contains C-H -O catemers, arranged along a twofold screw axis, as shown in the upper part of the Figure. The intermediate region in the central layer (Intergrowth region) is only for illustration, because all slabs with O-H- O hydrogen bonds are identical (O-H- O slab).

Figure 3: ASS2 (middle curve) displays the signal of the methyl group in CP-MAS C¹³-NMR solid state spectrum of Form I in ppm.

ASS1 (lower curve) shows the signal of the methyl groups in CP-MAS C¹³-NMR solid state spectrum of Form AB with a low content of domains of Form Il in ppm.

ASS3 (upper curve) shows the signal of the methyl groups in CP-MAS C¹³-NMR solid state spectrum of

Form AB with 60% content of domains of Form Il in ppm. Figure 4: NIR-Spectrum of Form I (lower curve) and Form AB with 60% content of Form Il domains (upper curve) in cm^"1.

Claims

1. Acetyl salicylic acid as Form AB comprising interfaced crystals of Form I and Form II.

2. Acetyl salicylic acid as Form AB, characterized according to claim 1 , wherein the interlaced crystals comprises an Imtergrowths of Form I and FormII

3. Acetyl salicylic acid as Form AB according to claim 1 or 2, characterised in that the interlaced crystals have the cell dimensions of a = 11.28, b - 6.55, c = 11.27 A, β = 95.8° for Form I and a = 12.09, b - 6.49, e = 11.32 A, β = 111.51° for Form II and wherein these values can vary by ±2%,

4. Acetyl salicylic as Form AB according io one of the previous claims 1 to 3, characterized in that the proportion of the contents of Form Il to Form I is larger than 10% and not mors than 90%.

5. Acetyl salicylic acid as Form AB according to one of the previous claims 1 to 4, characterized in that the proportion of the contents of Form Il to

Form I is targer than 50% and not more than 90%.

6. Acetyl salicylic acid as Form AB according to on© of tho previous claims 1 to 5, characterised in that the interlaced crystals are characterized by two additional signals in the PXRD compared, to the pure Form i at 20,9" and

26,0° (± 0,2°) in the 2Theta range (Cu-radiation), where the intensities are greater than 12% and 13%, respectively, of the 100% signal at 15,7°.

7. Acetyl salicylic acid as Form AB according to one of the previous claims 1 to 5, characterized in that the interlaced crystals are characterized by two additional signals in the PXRD compared to the pure Form I at 20,9° and 26,0° (± 0,2°) in the 2Theta range (Cu-radiation), where the intensities are greater than 12% and 13%, respectively, of the 100% signal at 15,7° and not more than 29 % to 46% as for 20,9° and 30,5% to 48,5% for the 26,0° in 2Theta.

8. Acetyl salicylic acid as Form AB according to one of the previous claims 1 to 7, characterized by single crystal analysis, which employs the refined batch scale factors for odd / based on Form Il and derives the domain ratio of Form I and Form II, wherein the ratio results in 60 to 95% Form II.

9. Acetyl salicylic acid as Form AB according to one of the previous claims 1 to 8, characterized by single crystal analysis, which employs the refined crystallographic R values and derives the domain ratio of Form I and Form II, wherein the ratio results in 60 to 95% Form II.

10. Acetyl salicylic acid as crystalline material, wherein its solubility in water is improved compared to Form I.

1 1. Acetyl salicylic acid as Form AB according to one of the previous claims 1 to 10, characterized in that it possesses an improved dissolution rate in water compared to Form I.

12. Acetyl salicylic acid as Form AB according to one of the previous claims 1 to 10, characterized in that the solubility in water compared to Form I is increased by a factor of 10.

13. Acetyl salicylic acid as Form AB according to one of the previous claims 1 to 12, characterized in that it is stable at room temperature.

14. Acetyl salicylic acid as Form AB according to one of the previous claims 1 to 13, characterized by comprising interlaced crystals of Form I and Form II, wherein the molecules of acetyl salicylic acid are arranged according to the schematic drawing given in Figure 1 and wherein the arrangement A of Figure 2 contains centrosymmetric C-H- O dimers, which are located between the slabs shown in the lower part of Figure 2, arrangement B contains C-H- O catemers, arranged along a twofold screw axis, as shown in the upper part of the Figure 2. The intermediate region in the central layer (Intergrowth region) is only for illustration, because all slabs with O-H— O hydrogen bonds are identical (O-H -O slab).

15. Acetyl salicylic acid as Form AB according to one of the previous claims 1 to 14, characterized by a signal in the ¹³C CPMAS NMR spectrum at 20.5 (±0.5 ppm) ppm.

16. Acetyl salicylic acid as Form AB according to one of the previous claims 1 to 15, characterized by a signal in the ¹³C CPMAS NMR spectrum at 20.5 (±0.5 ppm) ppm, with an intensity at an equal or higher level than the signal at 19.8 (±0.5 ppm) ppm.

17. Acetyl salicylic acid as Form AB according to one of the previous claims 1 to 16, characterized by a brought signal in the NIR spectrum at about 5200 cm^"1, and a brought signal at about 6900 cm^'1.

18. Acetyl salicylic acid as Form AB according to one of the previous claims 1 to 17, characterized by a melting point of 125 to 128 ⁰C.

19. Process for producing Form AB of acetyl salicylic acid as defined in claim 1 , wherein acetyl salicylic acid is crystallized from a saturated solution in acetonitrile with or without addition of 1 to 10 % salicylic acid, particularly at a temperature of 50 to 70 ⁰C and rapid cooling to 0 to 25 ⁰C.

20. Process for producing Form AB of acetyl salicylic acid according to claim 19, wherein the cooling of the saturated solution of acetyl salicylic acid in acetonitrile from about 60 ⁰C to about 20 ⁰C is performed within 5 minutes.

21. Process for producing Form AB of acetyl salicylic acid according to one of the previous claims 19 to 20, wheroin any further additive to the saturated solution is omitted.

22. Process for producing Form AB of acetyl salicylic acid according to

5 one of the previous claims 1 to 14, wherein the process for producing acetyl salicylic acid in the Form A3 comprises adding salicylic acid to acetio acid anhydrate, keeping the mixture at elevated temperature until the salicylic acid is dissolved, the reaction mixture is subsequently cooled and the precipitate is isolated directly, especially instantaneously recrystallized from water at boiling10 heat.

23. Process for producing Form AB of acetyl salicylic acid according to claim 22, wherein the mixture contains a proton donor.

24. Process for producing Form AB of acetyl salicylic acid according to one of the claims 22 to 23, wherein the isolated crystallized precipitate and/or15 the recrystalllzed material is recrystailized from a saturated solution of acetonitrile.

25. Process for producing Form AB of acetyl salicylic acid according to claim 24, wherein the saturated solution of acetonitrile is rapidly cooled from 50 to 70 °C to 0 to 25 °C. 20 26, Process for producing Form AB of acetyl saiicyϋc acid according to claim 24 , wherein the saturated solution of acetonitsile is rapidly cooled from 60

⁰C to about Z§ ⁹Q within 5 minutes.

27 Process for producing Form A3 of acetyl salicylic acid according to one of the claims 22 or 23, wherein the isolated crystallised precipitate and/or25 the røcrystaliteΘd material is imnrrødϊafcΘly recrystallized from water, alcohols, ethers or heterocyclic aromatic solvents. ^" , 28 Process for producing Form AB of acetyl salicylic acid according to one of the claims 22 or 23, wherein the isolated crystallized precipitate and/or the recrystallized material is immediately recrystallized from any solvent in which acetyl salicylic acid can be solved.

29 Process for producing Form AB of acetyl salicylic acid according to one of the claims 22, 23, 27 or 28, wherein the isolated product is dried by evaporation of the solvent at elevated temperatures and/or at reduced pressure. 30 Acetyl salicylic acid as Form AS obtainable by one of the processes according to one of the claims 19 to 29, wherein the solubility of the obtained product in water is Improved with respect to Form I and wherein the product is stable at room temperature,

31 Pharmaceutical formulation comprising acetyl salicylic acid as Form AB according to one of claims 1 to 18,

32 Pharmaceutical formulation comprising acetyl salicylic acid as Form AB according to claim 31 , wherein Form AB is stabilised by drying means.

33 Use of acetyl salicylic acid as Form AB for the production of a medicament to be used as means for headache, migraine, as analgesic agent, as antipyretic, anti-inflammatory, as rheumatic agent, as an antiplatelet agent and in long-term low-doses to prevent heart attacks and cancer.