WO2008037366A2

WO2008037366A2 - Solid state forms ab of acetyl salicylic acid

Info

Publication number: WO2008037366A2
Application number: PCT/EP2007/008054
Authority: WO
Inventors: Roland Boese; Andrew D. Bond; Gautam R. Desiraju; Sascha Redder
Original assignee: Sciconcept Gmbh
Priority date: 2006-09-26
Filing date: 2007-09-17
Publication date: 2008-04-03
Also published as: WO2008037366A3

Abstract

The invention relates to a new form of acetyl salicylic acid designated as Form AB as well as processes for their preparation and formulation comprising it. Also, the invention relates to solid state forms of acetyl salicylic acid Form AB, in particular Form AB-A, as well as processes for their preparation and formulation comprising them.

Description

Solid State Forms AB of Acetyl Salicylic Acid

Recently a second polymorph of Aspirin (acetyl salicylic acid, o-acetylsalicylic acid), ("Form II") 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, IR, 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". According to PZ crystals of Form Il convert to Form I under ambient conditions; however, they are relatively stable at 100 K.

It is noted that several anomalous indicators in the structure of PZ exist: (1 ) The data are truncated to 2Θ = 40° (MoKa); (2) The /7-factors are unacceptably large (FC\ [h>2σ(l)] = 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 L/_iso 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 '/2 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 II".

The data collected on an authentic sample of Form I of Aspirin can be treated readily to produce the "Form II" structure reported by PZ to their level of accuracy and precision. 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.

Acetyl salicylic acid was first synthesized in 1853 but up to now 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 ⁰C. 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 the claims.

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 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 terms mixed crystals or Mischkristalle as they were called in a prior application DE 10 2006 045 780.3. Such domains can be multiply interlaced to a different extend and different size, called as intergrowths of Form I and Form II. Therefore, Form AB comprises intergrowths of Form I and Form II, in particular intergrowths of Form I and Form Il in a single entity. This represents a rare case in solid state chemistry of organic material. A model illustrates the mechanism of the formation of acetyl salicylic acid Form AB, see Figure 1 a to d.

For the purpose of the present invention solid form of acetyl salicylic acid includes in particular pseudopolymorphs, solvates, polymorphs and/or solid solutions.

The cell dimensions of pure Form I and of the hypothetical pure Form Il have the different cell dimensions.

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

Form II: a = 12.09, b = 6.49, c = 11.32 A, β = 111.51 °

Form AB of the present invention as interlaced crystal can be indexed on the basis of both cell 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 A, β = 95.8° for Form I and a = 12.09, b = 6.49, c = 11.32 A, β = 111.51 ° for Form Il and wherein these values can vary by ±2 %. Measurements are usually performed at 180 K. For single crystal analysis see for example the general textbook, Werner Massa; Kristallstrukturbestimmung; 5^th edition 2007, 265 pages, 109 Tab.; Teubner B.G. GmbH I ISBN: 3835101137, or English editions of Werner Massa; Crystal Structure Determination; Verlag: Springer, Berlin; 2nd edition, 2004; ISBN-10: 3540206442; ISBN-13: 978-3540206446. The content of the whole textbook is incorporated by reference.

With the size and the ratio of the two crystal domains the overall ratio of the packing characteristics of Form I and Form Il can vary. Suitably, the proportion of the contents of Form Il to Form I can be larger than 10 % and is not expected be much more than 90 %, specifically the proportion is between 10 % to 20 %, 10 % to 30 % or most preferred 20 % to 30 % weight percent.

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 hypothetical pure Form Il is characterized by signals in the PXRD at 15.9°; 19.9°; and/or 25.6° (±0.2°) in the 2Theta range (Cu-radiation for Cu-K_αi-radiation, RT for room temperature) which have, in particular intensities at 19.9° (±0.2°) of 49 % (±5 %) and at 25.6° (±0.2°) of 51 % (±5 %), respectively in relation to the 100 % peak at 15.6° (±0.2°). Acetyl salicylic acid as Form AB can be characterized by additional signals in the PXRD compared to the pure Form I at 15.9°, 19.9° and/or 25,6° (± 0.2°) in the 2Theta range (Cu-radiation), in particular with intensities greater than 12 % and 13 %, respectively, of the 100 % signal at 15.6° (capillary technique, Laue technique, RT, Siemens D5000-Powder diffractometer with graphite monochromator, Cu-Ka₁, PSD-50M (MBraun), range 7° in 2Theta, capillary sample holder, capillary diameter 0.5 mm, 40 kV, 35 mA, data coll. time 240 min for complete scan range).

Accordingly, a powder with 50 % of Form Il in the domains exhibit intensities in the PXRD (capillary technique, Laue technique, RT) at 19.9° of 24.5 % and/or at 25.6° (± 0.2°) of 25.5 %, respectively in relation to the 100 % peak at 15.5°.

The acetyl salicylic acid as Form AB as interlaced crystals according to the invention can be characterized by at least one additional signal in the PXRD compared to pure Form I of acetyl salicylic acid at 15.9° and/or 19.9° and/or 25.6° (± 0.2°) in the 2Theta range (Cu-radiation), in particular by at least two additional signals at 15.9°, 19.9° and/or 25.6° (± 0.2°) in the 2Theta range (Cu-radiation).

Form AB can further be characterized by additional signals in the PXRD compared to the pure Form I at 15.9° and/or 19.9° and/or 25.6° (± 0.2°) in the 2Theta range (Cu- radiation), where the intensities are greater than 12 % and 13 %, respectively, of the 100 % signal at 15.6°, especially the intensities can be for both peaks up 24.5 % for peak 19.9° and 25.5 % for peak 25.6° (± 0.2°), most preferred are 29 % to 46 % for peak 19.9° and 30.5 % to 48.5 % for peak 25.6° (± 0.2°) respectively in relation to the 100 % peak at 15.6° measured with capillary technique (Laue technique, RT). Most preferred the acetyl salicylic acid as Form AB as interlaced crystals according to the invention can be characterized by three additional signals in the PXRD compared to pure Form I at 15.9°, 19.9° and/or 25.6° (± 0.2°) in the 2Theta range (Cu- Kααradiation, 22 ⁰C). Additional, but less preferred diagnostic peaks of Form Il in Form AB are peaks at 16.2°, 19.0°, and/or 28.6° (± 0.2°) in the 2Theta range (Cu- radiation, 22 ⁰C). All diagnostic peaks to prove Form I in Form AB which do not overlap with Form Il peaks are relatively weak, these are 17.0°, 17.7°, 27.6° and/or 28.9° (± 0.2°) in the 2Theta range (Cu-radiation, 22 ⁰C). An estimated detectable lower limit of Form I is at about 30 to 40 % of Form I in the presence of Form AB.

The acetyl salicylic acid as Form AB as interlaced crystals according to the invention can also be characterized by additional signals in the PXRD compared to the pure Form I at 15.9°, 20.16 ° and/or 26.0° (± 0.2°) in the 2Theta range (Cu-radiation, 180 K), 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 20.16° and 25.5 % for peak 25.6° (± 0.2°), most preferred are 29 % to 46 % for peak 20.16° and 30.5 % to 48.5 % for peak 26.0° (± 0.2°) at 180 K respectively in relation to the 100 % peak at 15.7° measured with capillary technique (Laue technique, 180 K)..

Single crystal analysis is a method to characterize the contents of the two different domains in the Form AB, in particular without detectable defects and/or without less ordered regions. Measurements are usually performed at 180 K.. 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. For single crystal analysis and odd I as Miller indices see for example the general textbook of Werner Massa mentioned above or Stout, Jensen "X-Ray structure Determination; A Practical Guide, Mac Millian Co. Ney York, N.Y. (1968).

The resulting crystallographic ft-value in the single crystal refinement of Form Il is suited to characterize the contents of the different domains in Form AB. The /^-values obtained for a refinement in Form I and Form II, respectively, are correlated according to Figure 2 and therefore represent the relative proportion of domains in the Form AB. This applies as long as no defects or less ordered regions occur at the boundaries of the domains. 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. Wherein the particle size of both forms is essentially the same. See Figure 31 and text on pages 25/26.

It is assumed that the improved dissolution rate is correlated with the efficiency of the solvent to cleave the boundaries between the domains of Form I and Form II. In this case the increase in dissolution rate is strongly dependent on the size of domains (Figure: 1d), and less on a particular ratio of domains of Form I and Form II. A model illustrates the mechanism of the formation of acetyl salicylic acid Form AB, see Figure 1 a to d.

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. Even, when Form AB is stored at 60 ⁰C and 75 % relative humidity (sample open in a desiccator at 60 ⁰C, 75 % RH) the PXRD measured prior to storage and form a sample after six months proved the stability.

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 3 and wherein the arrangement A of Figure 3 contains centrosymmetric C-H- O dimers, which are located between the slabs shown in the lower part of Figure 3, arrangement B contains C-H- O catemers, arranged along a twofold screw axis, as shown in the upper part of the Figure 3. 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-0 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 4.

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 5 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 acid from a saturated solution in acetonitrile, particularly at a temperature of 50 to 70 °C and rapid cooling to 0 to

25 ⁰C, typically from about 60 ⁰C to about 20 ⁰C 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 anhydride, keeping the mixture at elevated temperature (elevated temperature may be best 50 ⁰C but 40 ⁰C up to boiling point will also work) until the salicylic acid is dissolved, the reaction mixture is subsequently cooled, wherein subsequently cooled means directly cooled, and the precipitate is isolated directly, especially instantaneously recrystallized from water at boiling heat. By instantaneous recrystallization of the isolated precipitate, the ratio of Form Il domains can be increased.

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

This process 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 montmorillonit can also be used.

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 from 50 to 70 ⁰C down to 0 to 25 ⁰C, typically from 60 ⁰C to 25 ⁰C within 10 min or alternatively within 5 min. Rapid cooling is generally performed in a water bath, under running water or with an ice bath.

In a further alternative the isolated crystallized precipitate and/or the recrystallized 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 ⁰C to the boiling point of the mentioned solvents.

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 temperatures up to the boiling point of each solvent, followed by rapid cooling and immediate isolation (suck off) of the crystalline material. A crucial point of all crystallization and recrystallization steps is that the resulting precipitate is isolated or the 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 60 ⁰C 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, and/or in particular the dissolution rate of the obtained product in water is improved with respect to Form I. For the skilled person all parameters must be kept equal, in particular the same, for the determination of dissolution rates, especially temperature, pH, particle size, masses, stirring rates and/or procedures etc..

a) A process for producing acetyl salicylic acid as Form AB is to crystallize acetyl salicylic acid with or without addition of 1-10 % salicylic acid from a saturated solution in acetonitrile, particularly at a temperature of 50 to 70 ⁰C and rapid cooling to 0 to 25 °C, typically from about 60 ⁰C to about 20 ⁰C within 5 minutes.

Advantageously during the crystallization from acetonitrile in process a) any further additives to the saturated solution are omitted.

b) A process for producing acetyl salicylic acid as Form AB is to favourably adding salicylic acid to acetic acid anhydride, keeping the mixture at elevated temperature, particularly elevated temperature may be best 50 ⁰C but 40 ⁰C 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 Il domains can be increased and subsequent cooling is meant as rapid cooling from elevated temperature to 0 to 25 ⁰C within a short period of 5 to 10 minutes, in particular direct cooling. 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 montmorillonit 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 ⁰C down to 0 to 25 ⁰C, typically from 60 ⁰C 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) In a further alternative process the isolated crystallized precipitate and/or the recrystallized material is immediately recrystallized from water, alcohols, ethers or heterocyclic aromatic compounds, wherein the recrystallization 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 (e.g. Buchner filtration) 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 step is performed immediately, thus as fast as possible.

f) The isolated Form AB of acetyl salicylic acid from processes a) to e) is dried by evaporation of the solvent at elevated temperatures and/or at reduced pressure, typically at 60 ⁰C 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 applicable. I. Examples:

Example 1 : A typical process to produce acetyl salicylic acid Form AB with a content of 60 % domain Form Il comprises the following procedure: 9.6 grams of salicylic acid are added to 20 mL acetic acid anhydride as well as 16 drops of cone, sulphuric acid. The mixture 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 min. in an ice bath. The product crystallizes as a white powder, which can be filtered and dried in a desiccator above CaCI₂. 9.1 g of acetyl salicylic acid Form AB could be isolated.

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) Recrystallization from demineralized water: 9.1 g of Form AB of Example 1 are added to 5 ml water and the mixture is heated to 80 ⁰C for about 10 minutes. Cooling is performed in an ice bath, the resulting precipitate is immediately isolated (sucked off) and stored over water free CaCI₂ 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 anhydride (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 heated to 50 ⁰C under stirring for 10 min. The clear solution is poured into 25 mL of water (dist., RT). Crystallization starts at the boundary of an oily and the aqueous phase. Further 25 mL of water (dist., RT) are added and the mixture is cooled for 15 min in an ice bath. The crystalline product is filtered off and dried in a desiccator for 3 hours above dry CaCI₂. 9 grams of the dry powder are dissolved in 5 mL water at 80 ⁰C giving ca. 12 mL of a solution, kept 10 min at 80 ⁰C 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 content of Form AB is 60 % according to PXRD, single crystal structure analyses and ¹³C CP- MAS NMR. Relating to the above mentioned problem, further subjects of the present invention correspond to solid forms of Form AB of acetyl salicylic acid named as Form AB-A comprising interlaced crystals and at least one dopant, in particular containing at least one dopant, wherein containing means that the dopant is inside the interlaced crystals. The aforementioned problem is likewise solved by the solid forms of Form AB-A and the processes for production of the solid forms of Form AB-A as described in the claims. According to the invention a dopant is a substance which is introduced into the crystal lattice in a minor concentration, in particular in between layers and/or voids, most preferred in voids at the boundaries, which separate domains of different arrangements of Form I and Form II. An additive interferes in the nucleation step of the crystallization, wherein it enables to form the first outer layer of the growing crystals and will therefore not be found inside the crystals. Or in an alternative an additive blocks the crystallization or influences the crystallization of specific faces of the crystals.

Inter alia these solid forms can also be indexed on the basis of both cell dimensions. Likewise Form AB-A deduced from Form AB comprises one entity of arrangements of Form I and Form Il and a content of a dopant, and can be sketchily characterized as interlaced crystals having 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, c = 11.32 A, β = 111.51 ° for Form Il (both at 180 K) and wherein these values can vary by ±2 %. But they can also be indexed by multiple cell or supercell dimensions of Form I and Form II.

In the context of synthesising acetylsalicylic acid (further called AS) Form AB (further named AS Form AB) as specified above and in PCT application no. PCT/EP2006/010698, a variation of Form AB was found, further named AS Form AB-A because it is based on the presence of at least one dopant, in particular a dopant with similar structure and/or similar connectivity or intramolecular interactions, most preferred are dopants derived from acetyl salicylic acid, or a derivate thereof as acetylsalicylic acid anhydride, further named ASAN [CH₃C(O)O(C₆H₄)C(O)OC(O)(C₆H₄)OC(O)CH₃] or [Ci₈H₁₄O₇]:

ASAN

Additional dopants maybe salicylic acid or derivative thereof or mixtures thereof, purposeful the dopant may not be salicylic acid.

According to the invention Form AB of acetyl salicylic acid exists as Form AB-A comprising interlaced crystals of Form I and Form Il of acetyl salicylic acid and containing a content of at least one dopant, in particular the dopant is inside the interlaced crystals, wherein the dopant is acetyl salicylic acid anhydride.

Form AB of acetyl salicylic acid can further exist as Form AB-A comprising interlaced crystals of Form I and Form Il of acetyl salicylic acid and comprising a content of at least one dopant, in particular Form AB-A derived from Form AB comprising a content of a dopant, most preferred Form AB-A contains a content of a dopant, wherein the dopant may be acetyl salicylic acid anhydride and/or a derivative of acetyl salicylic acid or a reactant as dopant molecule, salicylic acid may be will also do, but purposeful the dopant may not be salicylic acid, in particular the dopant may not be levetiracetam and/or acetamide..

Further the interlaced crystals of Form AB-A comprise intergrowths of Form I and Form Il of acetyl salicylic acid. Form AB-A comprising, in particular containing, a content of acetyl salicylic acid anhydride is most preferred because the anhydride is easily rehydrated to acetyl salicylic acid. The content of the dopant in Form AB-A depends strongly to process of production and is limited to a certain small amount. Maybe between 0.00001 and 10 % (w/w), in particular 0.0001 to 5 % (w/w), preferred

0.001 to 2 % (w/w), most preferred 0.001 to 1.1 % (w/w) in Form AB-A.

It was found that the domain structure and the level of defects, which are presumably responsible for the enhanced solubility kinetics, can be further influenced by the presence of a dopant, as ASAN. Defects are sites in a crystal lattice which do not follow the regular pattern in all directions; they mostly consist of dislocated molecules, dopants or voids. A model illustrates the mechanism of the formation of AS Form AB and Form AB-A, which also leads to the understanding of the role of ASAN (Figure 1 , a to f).

Crystals with the Form I and Form Il structure types are different entities, each with a different unit cell that may be used to describe each type of arrangement completely (Figure 1 : Form I (a) and Form Il (b) structure type). By contrast, crystals of Form AB are single entities in which both the Form I and Form Il structure types or arrangements exist (Figure 1 : (d)). A shift of layers within Form I structure type leads to the Form Il structure type (Figure 1 : (c) shift of layers). If not all layers are shifted in an alternating fashion, a crystal develops, which has both structure types present. Such a crystal must be described using two unit cells simultaneously, both unit cells being required to describe the two different, but coexisting, domain types (Figure 1 : (d)). The arrangement depicted as Form AB, in the aforementioned invention, illustrates the ideal situation (Figure 1 : (d) Form AB). The X-ray diffraction pattern of such a Form AB crystal contains Bragg reflections attributed to each of the two different domain types, with their relative intensities dependent on the relative occurrence and size of the two domain types.

A simple additive nature for the X-ray diffraction pattern will be observed as long as the structural domains are large and well ordered - that is, as long as all regions of the crystal can be described completely using only the unit cells of the Form I and Form Il structure types.

If there exist regions of the crystal with a less ordered structure, the X-ray diffraction pattern will also contain regions of diffuse scattered intensity. Diffuse scattered intensity is the blurring in preferred directions of otherwise sharp spots of diffraction patterns.

In the context of examining AS Form AB, it has been observed that the Form AB arrangement is sensitive to produce defects, mainly as voids. A model is depicted in Figure 1 (Figure 1 : (e) Form AB with defects). It is assumed that the size and number of defects can be influenced by various crystallization parameters like solvents, stirring, temperature, and pressure.

Form AB with defects is expected to be rather unstable especially towards pressure: the structure changes to eliminate the voids, resulting in conversion of the crystal to the Form I structure type.

Molecules having the correct size, shape and attractive forces to the surrounding molecules in the crystal lattice might be introduced into the voids that exist within Form AB with defects (Figure 1 : (f) Form AB with defects and a doping molecule). For AS Form AB similar molecules can be derivatives of salicylic acid or AS, or anhydrides of both. The presence of such molecules can also be made to control the number and size of defects, and therefore also the distribution of the domains. A very small number of such molecules are usually needed, and the process of adding such molecules is called doping. Doping molecules usually do not have any regular translational arrangement in the crystal, which is why they do not generate their own X-ray pattern.

The doped solids exist as so-called 'solid solutions', in which the dopant molecules are irregularly distributed and therefore oriented similar to a solution. For such doping molecules, the environment will be very different throughout the crystal, which is why they will not be detected by CP/MAS NMR or diffraction techniques, which requires the surrounding of an atom to be the same within the crystal or powder, respectively. If doping molecules exceed a concentration which does not allow any more of them to be accepted into the crystal lattice, they start to crystallize with themselves, producing crystals with their own characteristic lattice and/or a solid phase with own characteristics, separated from the Form AB-A lattice. In such a case, they become visible to CP/MAS NMR and X-ray diffraction techniques.

Molecules in a different but regular environment have different neighbours which is why their atoms having contact to the surrounding changes from one arrangement to the other polymorphic arrangements. Such atoms are influenced with their vibrations in respect to the atoms they are chemically bound and this is why some details of the vibration spectra (IR, NIR, Raman) may also become visible.

Different lattices or lattices with defects or doped lattices will have different vibrations for the whole lattice, which will become detectable in Terra-Hertz Spectroscopy.

Although the presence of low-level dopant molecules is difficult to detect using diffraction or spectroscopic techniques, a doped crystal has different properties from the chemically pure crystal, including physical properties such as melting point, solubility or solubility kinetics such as dissolution rates.

According to the invention some dopants have the property to fit into the void of Form AB and generating Form AB-A. In particular ASAN has the property to fit into the voids of Form AB, and these dopants, in particular ASAN and/or derivatives of acetyl salicylic acid, can be used to control the ratio and the size of the domains through the defects. Wherein it is purposeful that salicylic acid may not be a dopant. There exist no facile methods to quantify the number and size of domains and the defects in AS Form AB-A. However, the presence of dopant, in particular ASAN, in single crystals of AS Form AB-A can be detected by dissolution of the crystals followed by analytical techniques such as NMR, Raman Spectroscopy, HPLC, GC and/or MS methods.

As a result of doping and/or depending on the process of production AS Form AB to yield AS Form AB-A the crystals display different solubility and dissolution rates.

AS Form AB-A of acetyl salicylic acid has a powder diffraction pattern that includes all peaks of the Form I structure type of acetyl salicylic acid and all peaks of the Form Il structure type of acetyl salicylic acid. The three most intense peaks of the Form Il structure type occur at 15.9±0.2°, 19.9±0.2° and 25.6±0.2° (derived from single crystal data, Cu-radiation, 22 ⁰C) and are not found in the PXRD pattern of the Form I structure type (Figure 36). The most intense peaks of the Form I structure type which are not found in the PXRD pattern of the Form Il structure type occur at 17.7±0.2°,

27.6±0.2° and 28.9±0.2° (derived from single crystal data at room temperature).

However, the characteristic peaks of the Form I structure type are relatively weak, so can be difficult to detect when the relative proportion of Form I domains is low, maybe below 30 % (w/w).

Variation in the positions of these peaks may increase with the contents of ASAN but will probably not exceed ±0.6° for peaks at about 15.9±0.6°, 19.9±0.6° and 25.6±0.6° for Form Il structure type. The variations for the most intense peaks of Form Il structure type are 15.86°, 19.95° and 25.62° 2Theta at room temperature derived from single crystal measurement; the 100 % peak of Form AB or Form AB-A can be found at 15.57°; the most intense peaks of Form Il structure type are at 15.7°, 19.8° and 25.5° 2 Theta at room temperature with Bragg-Brentano technique, wherein the 100 % peak of Form AB or Form AB-A is at about 15.4°; and from single crystal measurements at 180 K the most intense peaks of Form Il structure type are about 15.9°, 20.16° and 25.9° 2Theta, wherein the 100 % peak is at about 15.68° 2Theta.

Depending on the procedure and/or the amount of ASAN present and/or added, the characteristic peaks of crystalline ASAN at 11.1 ±0.2° and 14.8±0.2° will appear, indicating crystalline ASAN additional to that ASAN which is present within AS Form AB-A as dopant.

Following Procedure A, the lowest significant peaks of ASAN in the PXRD are found with acetic acid (AcOH), but diethylether (Et₂O) and methanol (MeOH) are also comparable, wherein these acronyms will be used as from now. THF (tetrahydrofurane) gives the most significant ASAN peaks with all other parameters kept nearly the same. This indicates that there can be a different uptake of ASAN in the acetyl salicylic acid crystals, presumably depending on the phase transfer agent. Details are given in the Examples Section.

Following Procedure B generally leads to a greater proportion of crystalline ASAN in the bulk sample compared to Procedure A. As an example, the PXRD for Example AST(B) is given in Figure 6 and 7, the HPLC is displayed in Figure 8. Further details are given in the Examples Section below. Following Procedure C, the lowest significant peaks of ASAN in the PXRD are found with acetic acid, followed by Et₂O, MeOH and THF as the most significant, with all other parameters kept the same. This indicates a different uptake of ASAN in acetyl salicylic acid crystals, depending on the solvent.

Following Procedure D, except of the ground mixture of ASF with 1 % (w/w) ASAN, all PXRD patterns do show the characteristic peaks for ASAN, albeit at the limit of detection (LOD). For the 2 % (w/w) and 4 % (w/w) mixtures, they appear expectedly more pronounced. The characteristic peak at 19.9° 2Theta is likewise hardly to detect, and it appears to be present for the ground mixtures with 2 % (w/w) and 4 % (w/w) ASAN, but amongst 2 % (w/w) the mixtures, ground with some drops of the solvents acetonitrile (MeCN), acetic acid (AcOH), methanol (MeOH) and tetrahydrofurane (THF), the most significant effect appears with THF.

AS Form AB-A has a single-crystal diffraction pattern that includes Bragg peaks from the Form I structure type of acetyl salicylic acid and Bragg peaks of the Form Il structure type of acetyl salicylic acid. However, for the reflections with odd I index (where hkt denotes the 'Miller indices' of the Bragg planes), diffuse streaking lies between the Bragg peaks. This is displayed in the reconstructed precession photograph from a single crystal Example ASE(C) (Figure 9).

Regarding background information of diffuse scattering see "Atlas of Opitical Transforms" G.Harburn, CA. Taylor, T. R. Welberry; Cornell University Press, Ithaca, New York, published 1975; see especially plate 18, second row; "Diffuse X-ray Scattering and Models of Disorder", by Thomas Richard Welberry; published 2004, Oxford University Press, ISBN 0198528582)

The reconstructed precession photograph from a single crystal Example ASE(C) in Figure 9 shows the section in the ( Mi) plane, where odd I rows exhibit Bragg peaks for the arrangement Form Il structure type and significant diffuse scattering (every second horizontal arrangement of spots is blurred out). The extent of the diffuse streaking increases as the structural arrangement becomes less well ordered. If the intensities of the Bragg peaks are assessed in the usual way (that is, by 'integration' of diffraction images only in the regions of the Bragg peaks), the relative intensities of the Bragg peaks with odd t index compared to the Bragg peaks with even I index can give an indication of the proportion of the single crystal with the Form I and Form Il structural domain types.

This procedure will be applicable for an idealised Form AB arrangement depicted in Figure 10, and the proportions derived for the Form I and Form Il of acetyl salicylic acid structure types should then sum to unity.

For Form AB, assessment of the Bragg intensity alone gives a good indication of the relative proportions of the domains with the Form I and Form Il structure types. For AS Form AB-A, however, the extent of diffuse scattering increases and procedures that consider only the Bragg intensity no longer operate.

The extent of diffuse scattering in the single-crystal X-ray diffraction pattern gives some indication of the extent of defects within the AS Form AB-A crystals. However, single-crystal X-ray diffraction cannot prove or disprove the presence of ASAN within the AS Form AB-A crystals.

The total amount of ASAN within the AS Form AB-A crystals can be traced by dissolving single crystals or a sample then applying analytical techniques such as NMR, HPLC, GC and/or GC/MS. For bulk samples produced by Procedures A or B, detected ASAN gives the total amount of ASAN in the sample, which may be internal or external to the AS Form AB-A crystals.

However, application of the procedures to single crystals which have been shown by X-ray diffraction to be AS Form AB-A and which have had their surfaces cleaned, can establish the presence of ASAN within the AS Form AB-A crystals. HPLC and ¹H NMR establishes the level of ASAN within AS Form AB-A crystals to be of the order of 1 % (w/w) (Figure 11 ).

In contrast, a single crystal produced from a batch synthesized according to Example 1 and recrystallization from MeCN as above, in priority application PCT/EP2006/010698, and allocated as Form AB, does not show any dopant, in particular ASAN, inside the crystal by HPLC (Figure 12).

These experiments prove the existence of Form AB without dopant, in particular without ASAN, and a quite low extend of defects (strikes in the single crystal reconstructed precession photograph) in contrast to approximately 1 % ASAN inside the single crystal of Form AB-A with a high extent of defects.

As for AS Form AB-A solid state ¹³C NMR Data were recorded, the details of measurements are listed below. The CP-MAS NMR method allows to discriminate carbon atoms in different environments in the solid state, the LOD is usually less than 1 %. The pure Form I of acetyl salicylic acid (ASF) is expected to exhibit only one signal for the carbon atom of the methyl group, which is found and shown in Figure 13, the spectral range around 20 ppm is enlarged and separated in the same Figure. ASAN has a different packing compared to acetyl salicylic acid Form I (ASF) and therefore a single ¹³C signal of the methyl group occurs at 19.4 ppm, as shown in Figure 14, the range around 20 ppm is enlarged and separated in the same Figure.

With two different arrangements according to Form I and Form Il in the solid state for Form AB-A, especially the methyl group is a meaningful probe for the ratio of both arrangements. However, molecules which may exist in many arrangements in a crystal lattice and which have a low concentration, will unlikely be detected. Additional external crystals with the lattice of ASAN are expected to show the ¹³C at 19.4 ppm signal in the spectrum. Following, the CP-MAS NMR spectra are listed for the compounds prepared according to Procedure A with MeOH, product ASM(A) (Figure 15), Et₂O, product ASD(A) (Figure 16), AcOH, product ASAc(A) (Figure 17), and THF. product AST(A) (Figure 18). In all cases and as expected, the signal at 19.9 ppm for Form I arrangement occurs, but also all of them exhibit a second signal at 20.5 ppm which is somewhat smaller for ASM(A), more pronounced for ASD(A) as well as for AsAc(A) and the lowest for AST.

For the compounds prepared according to Procedure B with MeOH, product ASM(B) (Figure 19), Et₂O, product ASD(A) (Figure 20), AcOH, product ASAc(A) (Figure 21 ), and THF. product AST(A) (Figure 22). In all cases and as expected, the signal at 19.9 ppm for Form I arrangement occurs, but also all of them exhibit a second signal at 20.5 ppm which is somewhat smaller for ASM(A), more pronounced for ASD(A) as well as for AsAc(A) and the lowest for AST.

In all cases, the signal for ASAN is not visible and indicates that the acetyl salicylic anhydride (Aspirin anhydride) molecules either have significantly less than 1 % content or they exist as solid solutions in the crystals. The signal of the ASAN methyl C-atoms will not be visible in the CP/MAS ¹³C-NMR if the direct surrounding of the methyl group adopts different orientations as assumed for the doped crystals.

Object of the invention is Form AB-A of acetyl salicylic acid which has 0,5 to 98 % domains with Form Il arrangements and domains with Form I arrangements ad 100 %, wherein it comprises further a content of a dopant and/or voids and/or any further defects. In particular Form AB-A of acetyl salicylic acid has 2 to 98 %, 5 to 98 %, 10 to 98 %, 15 to 98 %, 15 to 98 %, preferred 20 to 98%, 30 to 98 %, 40 to 98%, most preferred 50 to 98 %, 60 to 98 %, 70 to 98 %, 80 to 98% domains with Form Il arrangements and domains with Form I arrangements ad 100 %, wherein it comprises further a content of a dopant and/or voids and/or any further defects. Wherein the percentages of domains with Form Il arrangements and domains with Form I arrangements are determined by integration of the normalized CP/MAS ¹³C-NMR signals at 20.5 ppm (±0.5 ppm) for domains of Form Il and at 19.9 ppm (±0.5 ppm) for domains of Form I.

Regarding ¹³C and/or ¹H NMR in saturated solutions of d-MeCN, the methyl protons for acetyl salicylic acid (AS) resonate at 2.255 ppm, whereas those of ASAN show the methyl proton signal at 2.238 ppm. The aromatic protons are also well distinguishable and integration gives a content of 3-4 % ASAN for ASM, 0.2-0.3 % for ASD 0.3-1 %, 3-5 % ASAc, 1.4-1.7 % for AST products obtained from several executed procedures of Procedure A and B.

The total amount of a dopant, in particular ASAN, can be traced by dissolving crystals, crystals with cleaned surfaces and/or a powdery sample, in particular a washed powdery sample in order to clean the surfaces of the particles, in d-MeCN and record the ¹H-NMR spectra which can be integrated for quantitative evaluation, whereas the ¹³C-NMR spectra indicate the presence of a dopant qualitatively. In cases in which the quantitative amount of a dopant, in particular ASAN or a derivative of AS, is greater by integration of an ¹H-NMR spectrum of a dissolved sample than the measured amount of this dopant in this sample according to CP/MAS ¹³C-NMR and/or PXRD or to an analytical method which furnishes equal information, a form of a Form AB-A polymorph of acetyl salicylic acid can be verified.

No significant differences can be detected between compounds AS Form AB and AS Form AB-A with IR spectra. But also no difference is detected in the IR spectrum between ASF (Figure 23) and AS Form AB-A, exemplified by product (AST (B)) according to Procedure B which employs THF, see Figure 24. The doublet signal at 2361 cm^'1 is caused by to CO₂.

Regarding NIR spectroscopy no significant differences can be detected between compounds of acetylic salicylic acid Form AB and acetyl salicylic acid Form AB-A.

Usually Raman spectroscopy is a useful tool in determination for polymorphs or in general for different solid phases. In the current case, wherein only a few dopant molecules are present in the crystalline phase of Form AB-A, presumably in the voids and thus forming Form AB-A, the content of the dopant molecules with same the vibrational pattern appear to be below the detection limit of Raman spectroscopy.

For ASAN, two characteristic lines which do not have an overlap with acetyl salicylic acid Form I (ASF) or acetyl salicylic acid Form AB (AS-AB), wherein Form AB is without a dopant, are significant and occur at 1726^"1 and 1786 cm^"1. These are shown in the range 1700-1800 cm^"1 in comparison to ASF and AS-AB in Figure 25. The signal at 1751 cm^"1 for ASAN overlaps with the signal for ASF at 1750 cm^"1. The limit of detection (LOD) for ASAN in ASF is below 0.5 %, which is shown by the spectra in the range 1700-1800 cm^"1 for mixtures ASAN in ASF with 0.5 %, 1 %, 2 % (w/w). See

Figure 26. For the four products of AS Form AB-A made by Procedure A but with the different solvents (Methanol, Diethylether, Acetic Acid and THF) and named ASM(A), ASD(A)₁ ASAc(A) and AST(A), respectively, the significant signals at 1726 cm^"1 and 1786 cm^"1 are detectable except for one of AST(A) products, which obviously has a content of ASAN lower than 0.5 % as shown in Figure 27.

In the range 700-800 cm^"1 ASAN has three significant signals at 712 cm^"1(w), 748.7 cm^"1(s) and 785 cm^'1(m) whereas ASF exhibits three signals at 704 cm^"1(w), 750.6 cm^'1(s) and 785 cm^"1(w) in the same range, both can be distinguished by the first two signals at 704 cm^"1 and 712 cm^"1. This is demonstrated in Figure 28. For the four products, ASM(A), ASD(A), ASAc(A) and AST(A), the same signals occur in this range at 704 cm^"1(w), 750.6 cm^"1(s) and 785 cm^"1(m) as it is shown in Figure 29.

The Raman spectra of the compounds made according to Procedure B, named ASAc(B), ASD(B), ASAc(B) and AST(B) have the same features as those made by Procedure A (not shown here).

Therefore it can be concluded that Raman spectra allow to a) detect a dopant in principle; b) detect ASAN down to 0.5 % (w/w) in AS Form AB-A c) show that except for AST a significant amount of ASAN (>0.5 % w/w) is present in the samples, produced according to Procedure C, where the equal procedure is applied with MeOH (ASM), Et₂O (ASD), AcOH (AsAc) and THF (AST), d) ASAN can be present as crystalline material outside the AS Form AB-A crystals as well as inside the crystals, Raman spectroscopy does not distinguish the two situations.

The onset and peak max temperatures (°C) measured with DSC (differential scanning calometry) for the compounds coded as above are:

The compounds AS Form AB-A generally have a lower melting point than Form I (ASF) and those synthesized according to Procedure B have a slightly lower melting point than according to Procedure A except for the example AST, for which the melting point according to Procedure B is significantly higher. The series according to Procedure A is shown in Figure 30, together with ASF and AS Form AB, the product of Example 1a, recrystallized from MeCN, giving 60% Form Il estimated from PXRD intensities.

HPLC or other common liquid phase analytical methods are applicable to detect the qualitative amount of a dopant in crystalline material, single crystals and/or solid material after dissolution of theses samples, in particular in Form AB-A phases or samples comprising Form AB-A crystals. The best results are obtained when the surfaces of the crystals have been cleaned before dissolution or the sample has been carefully washed before dissolution. Other liquid phase analytical methods maybe ¹H- NMR, GC, UV-Vis etc. methods, wherein the skilled person is aware and used to do calibration work of the used method, when used to prove a qualitative amount of a dopant.

Object of the invention is therefore Form AB-A₁ with a content of a dopant in the interlaced crystals. Wherein the dopant influences the properties of the resulting Form AB-A, such as melting point, dissolution rate etc.. The detection of the dopant maybe performed by comparison of the quantitative amount of the dopant established by ¹³C CP-MAS NMR or PXRD measurements to liquid phase detection of the amount of the dopant. Wherein the amount of the dopant derived from liquid phase analytical methods is greater than the content of the dopant measured by solid state analytical methods such as PXRD and/or ¹³C CP-MAS NMR. Samples may comprise also additional external dopant, such as adhesive dopant or separately crystallized dopant. In the latter case the external dopant is visible in PXRD. Therefore it is preferred to carefully clean the surfaces of the crystal and/or to wash the material carefully before performing the measurements. Cleaning can be done by washing the crystal or the crystalline material with an appropriate solvent in a small amount. Cleaning or washing of Form AB, and Form AB-A, respectively, was adequate if the dopant cannot be detected anymore by PXRD or CP-MAS. For example if solid state analytical methods, such as PXRD or CP-MAS ¹³C-NMR show the existence of Form Il and no signals of the dopant, in particular no external ASAN, and at the same time liquid phase analytical data, such as HPLC, ¹H-NMR or GC, prove the existence of an amount of a dopant, it has to be concluded that the dopant is located inside the interlaced crystals or lattice of Form AB, and therefore Form AB constitutes Form AB- A. The amount of dopant detected by the liquid phase methods must exceed the LOD of the solid state methods.

Therefore it is a further object of the invention that the content and/or real qualitative amount of a dopant in the crystal lattice of Form AB-A, is detected by an analytical method after dissolution of a crystal or a crystalline material. Liquid phase analytical methods comprise but are not limited to HPLC, ¹H-NMR, GC/MS gas chromatography and mass spectroscopy or GC.

The dissolution rates and/or dissolution kinetics of the obtained or obtainable solid forms of Form AB-A were performed with conductometry. The dissolution of ASF achieves approximately 3.3 g/L in water at 25 ⁰C. For assessment of the dissolution rate, electrical conductivity measurements are appropriate and were performed with an apparatus described below in the section regarding execution examples. The dissolution rates in water depend on many factors such as particle size and surface, dispersion and stirring conditions, temperature and pH etc. The measurements of electrical conductivity of solutions furnishes relative values for a series of experiments which are suitable for the assessment of dissolution rates (Frenning G., Fichtner F., and Alderborn G.; Chem. Eng. Sci., Vol. 60, (2005) 3909).

All samples were sieved with sets of sieves and only samples were submitted to measurements which were collected on a sieve with a mash sizes of 60 μm sitting below a sieve with a mash size of 90 μm. Therefore 100 % of the crystals possessed a particle size in the range from 60 to 90 μm. All data were collected at 25 ⁰C in 200 g demineralised water (pH 6.7) and stirring conditions, such as stirring rates, agitator etc., were kept constant.

In order to assess the dissolution rates in g/L after a given period, in a first step four data sets were collected for which acetyl salicylic acid Form I (ASF Fluka) was dissolved completely in 200 ml_ water at 25 ⁰C for 0.0527, 0.1065 and 0.1607 g ASF. The conductivity measured was 1.5, 183, 280 and 354 μS/cm for 0.0527, 0.1065 and 0.1607 g ASF, respectively. These data (converted for g/L, namely for 0.266, 0.533 and 0.803 g/L) are introduced in Figure 31 (horizontal dotted lines). In a second step 0.522 g ASF were poured into 200 mL water (corresponding to 2.61 g/L) and the electrical conductivity was recorded every 15 sec. from 0 to 1800 sec (solid line). The conductivity versus time was introduced to the same graph. The same was done in further experiments for 0.508 g AS Form AB (dashed line) and 0.519 g AS Form AB-A (dotted line). The latter dissolution experiment reached saturation after 600 sec which is why no further data were collected. The sample AS Form AB was taken from an experiment Example 1a (recrystallized from MeCN) and contained about 60% Form Il arrangement, estimated from PXRD data.

Apparently, after one minute, the electrical conductivity of AS Form AB is the six-fold and 16-fold for AS Form AB-A (AST), respectively compared to AS Form I (ASF). Another estimate shows for Form I (ASF) (solid line) that a conductivity of 185 μS/cm corresponding to 0.266 g/L is reached after 5 min, 280 μS/cm corresponding to 0.533 g/L after 13 min, and for 354 μS/cm corresponding to 0.8 g/L is reached after 19 min for the given conditions.

Another estimation from the same graph tells that after 5 min 1 -1.5 g AS Form AB are dissolved while saturation has already been reached for Form AB-A (at least 3.2-3.5 g/L) after the same time. Further, related to AS Form I (ASF), this results in a factor of about 6 for Form AB and in a factor of 13 for Form AB-A after 5 min, provided that saturation is reached at 3.2 to 3.5 g/L. Object of the present invention are therefore solid forms of Form AB of acetyl salicylic acid, in particular without a dopant, wherein their dissolution rate in water at 25 ⁰C, in particular within the first and 5 minutes respectively, is increased by a factor of 2 to 6, preferred is a factor of 4 to 6, compared to Form I of acetyl salicylic acid, wherein the particle size of the crystalline material and/or the samples are comparable, in particular in the same range, namely between 60 to 90 μm.

A further object of the present invention are therefore solid forms of Form AB-A of acetyl salicylic acid with a dopant, wherein their dissolution rate in water at 25 ⁰C, in particular within the first and 5 minutes respectively, is increased by a factor of 2 to 13, in particular by a factor of 4 to 13, preferred is a factor of 6 to 13, compared to Form I of acetyl salicylic acid, wherein the particle size of the crystalline material and/or the samples are comparable, in particular in the same range, namely between 60 to 90 μm.

In order to assess the difference of dissolution rates for AS Form AB-A, the conductivity is plotted versus time for compounds synthesized according Procedure A based on various solvents. For Form I (ASF), solid line, Form AB-A (MeCN, ASCN(A)) (dashed line), Form AB-A (MeOH(ASM(A)) (dash-dotted line) and Form AB-A (THF(AST(A)) (dotted line), 1.515 g, 1.602 g, 1.547 g and 1.533 g, respectively, were added to 200 ml_ water (Figure 32). The result is that the solvent used during the process of making Form AS-A has a fundamental influence on the dissolution rates. The respective conductivities are increased by 20 %, 320 %, and 420 % compared to Form I for the Forms AB-A (MeCN), (MeOH), and (THF) after 5 min.. After 10 min, these values are approximately 30 %, 250 % and 320 %, respectively.

The conductivity plotted versus time for compounds synthesized according Procedure B based on various solvents is shown in Figure 33. For Form I (ASF), solid line, and the Forms AB-A: AcOH (ASAc(B)) (dashed line), EtOH (ASE(B)) (dash-two-dotted line), MeOH (ASM(B)) (dash-dotted line), and THF (AST(B)) (dotted line), 0.522 g, 1.512 g, 1.501 g, 1.500 g and 1.503 g, respectively, were added to 200 ml_ water. The result is that not only the solvent used during the process but the procedure (A or B) for making Form AB-A also has an influence on the dissolution rates. This is apparent with the two products based on the same solvents for the two processes: The MeOH product has an increase of the relative conductivity of for Procedure A by 320 % and for Procedure B by 460 % after 5 min and by 320 % and 300 %, respectively after 10 min.

For the THF product the increase in conductivity after 5 min for Procedure A is 420 % and for Procedure B by 600 % and after 10 min 320 % and 430 %, respectively.

Object of the present invention are therefore solid forms of Form AB-A of acetyl salicylic acid with a content of a dopant, wherein their dissolution rates and their solubility at a certain time, in particular at 5 and 10 minutes respectively, is increased by about 30 % to 600 %, in particular by about 300 to 600 %, preferred are about 400 to 600 %, in respect of Form I of acetyl salicylic acid, wherein the particle size of the crystalline material and/or the samples are comparable, in particular in the same range, namely between 60 to 90 μm. A further object of the invention is Form AB-A, wherein their dissolution rate and/or their solubility, measured as conductivity, in water at 25 °C after 1 minute, from start of dissolution and measurement, is increased by at least 50 % compared to acetyl salicylic acid Form I, in particular with comparable particle size of the crystalline material and/or the samples are comparable, in particular between 60 to 90 μm.

For THz Spectroscopy measurements pellets were pressed for the measurements for which 50 mg of each acetyl salicylic acid comprising sample, as Form I (ASF) and Form AB-A samples, the samples are ground with 100 mg PE (sample pellet) and 120 mg of polyethylene is used as reference (PE pellet).

The spectra for AS Form I (ASF) are displayed together with the products from Procedure A (ASM(A), ASE(A), AST(A), and ASAc(A)) in Figure 34. This Figure shows characteristic differences between Form I and Form AB-A. Form I has a significant peak at 55 cm^"1 which does not appear in the spectra of the products Form AB-A or is at least significantly less pronounced as for ASAc(A). Form I also has a significant peak maximum at 65 cm^"1, this maximum is shifted by 8-15 cm^'1 towards higher wave numbers for all Forms AB-A.

Regarding the stability of Form AB samples, a sample of 9 g synthesized according to Example 2 as described above was stored at 60 ⁰C and 75 % relative humidity (RH), wherein the sample was in direct contact with the humidity of 75 % (saturated solution of NaCI in water). The PXRD data recorded prior the storage and from a sample taken after six months did not show any significant change. Therefore Form AB is stable for at least six month under accelerated conditions such as 60 ⁰C and 75 % RH.

A sample of 9 g, synthesized according Procedure A with AcOH to produce ASAc(A) was stored under the same conditions (60 ⁰C and 75 % RH, open stored) for three weeks. Likewise, the PXRD did not show any changes. Therefore Form AB-A is stable for at least three weeks under accelerated conditions such as 60 ⁰C and 75 % RH. Under conditions like room temperature and 40 % RH, open stored, this Form AB-A was stable for 3 month. Further stability testing is ongoing. Object of the invention is therefore a Form AB-A with a stability of at least 3 month at 22 ⁰C and 40 % RH, open stored.

Several basic procedures to make AS Form AB-A are developed. In general suitable dopants maybe produced in situ or maybe added to the reaction mixtures to produce Form AB-A of acetyl salicylic acid. Suitable dopants are for example acetyl salicylic acid anhydride, derivatives of acetyl salicylic acid and/or starting materials to produce acetyl salicylic acid, wherein salicylic acid may be not a dopant. Further dopant may be suitable when the molecules fit into the voids and/or possess the appropriate functional groups. Wherein in all processes for producing Form AB-A, as well as Form AB-A solid forms obtainable by this processes, levetiracetam and acetamide are not regarded as dopants.

Object of the invention is that ASAN as a dopant molecule maybe produced in situ (Procedure A and B) or may be taken from an independent source e.g. purchased as a commercial product and added to acetyl salicylic acid (AS), for example as it is described for Procedure C and D, wherein the scope of the invention shall not be limited to the disclosed procedures. For the skilled person it is clear that any suitable dopant maybe crystallized from a solvent or solvent mixture or reacted via solid phase processes with acetyl salicylic acid to produce a solid form of Form AB-A.

Object of the invention is therefore a process for producing Form AB-A of acetyl salicylic acid, as well as Form AB-A solid forms obtainable by this process, wherein acetyl salicylic acid and acetic anhydride are stirred and if necessary heated to 30 ⁰C to 40 ⁰C or up to boiling point, in particular heated to 40 ⁰C to 60 ⁰C, preferred are about 50 ⁰C, an catalyst is added, wherein the catalyst maybe an acid as an acid catalyst, preferred in a small amount, preferred is a small amount of concentrated sulphuric acid, and during stirring - of the reaction mixture- at least one phase transfer agent and if applicable an antisolvent are present and/or a phase transfer agent and/or an antisolvent or a mixture thereof is added, wherein maybe the PTA is already present, in this case only the antisolvent has to be added, and/or a phase transfer agent and subsequently an antisolvent, or an antisolvent and subsequently a phase transfer agent, or a mixture of an antisolvent and a phase transfer agent are added, in particular it is essential to stir violently to make the mixture nearly homogenous in the presence of a phase transfer agent (PTA) and the antisolvent or after adding the PTA, antisolvent and/or a mixture thereof, first an emulsion is obtained by violent stirring, which becomes a dispersion during continuing stirring, the mixture is allowed to cool, in particular to room temperature 20-25 ⁰C, during stirring, in particular during violent stirring, wherein the formed emulsion becomes a dispersion by the crystallization of Form AB-A, the solid product is obtained.

Regarding the adding of the PTA and/or the antisolvent each of them or a mixture of them should be added rapidly, in particular at once, by pouring the PTA and/or antisolvent and/or a mixture thereof into the reaction mixture. The obtained product can be isolated by filtration or collection the material. The product maybe washed by shaking in ice water and is filtered again and left to dry in air, but in this case the yield decreases dramatically due to the good solubility of the Form AB-A. Normally the product is isolated by filtration and left to dry in air or in vacuum, maybe with increased temperature.

According to the invention water is used as an antisolvent. The catalyst may comprises an acid, in particular an usual inorganic or organic acid, preferred are sulphuric acid, nitric acid, phosphoric acid, formic acid and/or acetic acid as well as mixtures thereof. Further appropriate acids can be citric acid or sulfonic acid etc. According to the invention concentrated sulphuric acid is used as catalyst, in particular a small amount.

The preferred dopant acetyl salicylic acid anhydride is produced in situ after adding the catalyst. In alternatives a dopant is added before the antisolvent is present or added, wherein in particular the dopant is a derivative of acetylsalicylic acid.

Suitable phase transfer agents (PTA) are capable to dissolve acetyl salicylic acid and/or acetyl salicylic acid anhydride. The phase transfer agent may be an aprotic polar solvent, a protic polar solvent, or a mixture thereof. The PTA shall at least partially dissolve acetyl salicylic acid (AS) and/or the dopant, in particular acetyl salicylic acid anhydride (ASAN). According to the invention the phase transfer agent is suitable when the mixture of the antisolvent and the phase transfer agent is capable to dissolve acetyl salicylic acid and the dopant, in particular acetyl salicylic acid anhydride (ASAN). The agent shall at least partially dissolve AS or ASAN, in particular the mixture shall be capable to dissolve acetyl salicylic acid and acetyl salicylic acid anhydride at a reasonable or a comparable extent. Phase transfer agents according to the invention are carboxylic acids, alcohols, ethers, ketons, aldehyds, amides, amines, or N-containing molecules, preferred are acetic acid, acetonitrile, propionitrile, tetrahydrofuran, methanol, ethanol, propanol, diethylether, propanoic acid, butanoic acid or pentanoic acid and/or a mixture of two or more of these agents, most preferred are alcohols and/or THF.

Wherein it is preferred to use, in particular to add the phase transfer agent in 1 to 10 mol equivalent with regard to salicylic acid or acetyl salicylic acid, in particular 1 to 5 mol equivalent, preferred are 1 to 3 and most preferred are 1 to 2 mol equivalent.

Regarding stirring during the reaction, the addition of the PTA and/or the antisolvent and the following cooling - the crystallization step - it is crucial to stir to get the dopant in the crystalline material of forming Form AB-A. Therefore stirring should be as violent as possible. At least an emulsion, in particular a nearly homogeneous emulsion, should be formed in the presence of the PTA and the antisolvent, during crystallization the emulsion becomes a dispersion. To avoid crystallization of pure Form I the phase transfer agent and/or the antisolvent, or the phase transfer agent and/or subsequently an antisolvent or the antisolvent and subsequently the phase transfer agent or a mixture of the antisolvent and the phase transfer agent are added at once.

The resulting mixture is allowed to cool during intense stirring to form an emulsion and/or a dispersion, most preferred is violent stirring, wherein the solid product may be washed with little amount of ice water.

Procedure A; One procedure starting from commonly available AS (e.g. ASF, Aspirin Fluka grade) is to produce ASAN by adding an acid to a solution of AS in acetic anhydride. Violent stirring should be made to disperse the hydrophobic acetic anhydride phase (and with it the ASAN molecules) in an aqueous 'anti-solvent' phase (the water added), which then results in the crystallisation of AS Form AB-A in the aqueous phase. It seems to be important to get the hydrophobic phase dispersed in the aqueous phase, from where crystallisation takes place. To ensure adequate dispersion of the hydrophobic phase in the aqueous phase, aprotic polar solvents, in particular such as MeCN, EtCN, THF, Et₂θ, can also be applied. These solvents serve as 'phase transfer agents', ensuring that the AS crystallises together with ASAN in the aqueous phase. Addition of carboxylic acids or alcohols or any suitable protic polar solvents will also perform this role.

Object of the invention is also a process for producing Form AB-A of acetyl salicylic acid, as well as Form AB-A solid forms obtainable by this process, wherein salicylic acid in acetic anhydride is stirred and if necessary heated to 30 ⁰C to 40 ⁰C or up to boiling point, in particular heated to 40 ⁰C to 60 °C, preferred are about 50 ⁰C, an catalyst is added, wherein the catalyst maybe an acid as an acid catalyst, preferred in a small amount, preferred is a small amount of concentrated sulphuric acid, and during stirring - of the reaction mixture - at least one phase transfer agent and if applicable an antisolvent are present and/or a phase transfer agent and/or an antisolvent or a mixture thereof is added, wherein maybe the PTA is already present, in this case only the antisolvent has to be added, and/or a phase transfer agent and subsequently an antisolvent, or an antisolvent and subsequently a phase transfer agent, or a mixture of an antisolvent and a phase transfer agent are added, in particular it is essential to stir violently to make the mixture nearly homogenous in the presence of a phase transfer agent (PTA) and the antisolvent or after adding the PTA, antisolvent and/or a mixture thereof, first an emulsion is obtained by violent stirring, which becomes a dispersion during continuing stirring, the mixture is allowed to cool, in particular to room temperature 20-25 ⁰C, during stirring, in particular during violent stirring, wherein the formed emulsion becomes a dispersion by the crystallization of Form AB-A, the solid product is obtained.

Regarding the adding of the PTA and/or the antisolvent each of them or a mixture should be added rapidly, in particular at once, by pouring the PTA and/or antisolvent and/or a mixture thereof to the reaction mixture. The obtained product can be isolated by filtration or collection the material. The product maybe washed by shaking in ice water and is filtered again and left to dry in air, but in this case the yield decreases dramatically due to the good solubility of the Form AB-A. Normally the product is isolated by filtration and left to dry in air or in vacuum, maybe with increased temperature.

According to the invention water is used as antisolvent. The catalyst may comprise an acid, in particular an usual inorganic or organic acid, preferred are sulphuric acid, nitric acid, phosphoric acid, formic acid and/or acetic acid as well as mixtures thereof. Further appropriate acids can be citric acid or sulfonic acid etc. According to the invention concentrated sulphuric acid is used as catalyst, in particular a small amount.

Suitable phase transfer agents (PTA) are capable to dissolve acetyl salicylic acid and/or acetyl salicylic acid anhydride. The phase transfer agent may be an aprotic polar solvent, a protic polar solvent, or a mixture thereof. The PTA shall at least partially dissolve acetyl salicylic acid (AS) and/or the dopant, in particular acetyl salicylic acid anhydride (ASAN). According to the invention the phase transfer agent is suitable when the mixture of the antisolvent and the phase transfer agent is capable to dissolve acetyl salicylic acid (AS) and the dopant, in particular acetyl salicylic acid anhydride (ASAN). The agent shall be at least partially dissolves AS or ASAN, in particular the mixture shall be capable to dissolve acetyl salicylic acid and acetyl salicylic acid anhydride at a reasonable or a comparable extent. Phase transfer agents according to the invention are carboxylic acids, alcohols, amides, ethers, ketons, aldehyds amines, or N-containing molecules, preferred are acetic acid, acetonitrile, propionitrile, tetrahydrofuran, methanol, ethanol, propanol, diethylether, propanoic acid, butanoic acid or pentanoic acid and/or a mixture of two or more of these agents, preferred are alcohols and/or THF.

Wherein it is preferred to use, in particular to add the phase transfer agent in 1 to 10 mol equivalent with regard to salicylic acid, in particular 1 to 5 mol equivalent, preferred are 1 to 3 and most preferred are 1 to 2 mol equivalent. Wherein it is necessary for acetic acid as a PTA to be added in about 1 mol equivalent in addition to get Form AB-A.

Regarding the stirring during the reaction, the addition of the PTA and/or the antisolvent and following cooling, crystallization step it is crucial to stir to get the dopant in the crystalline material of forming Form AB-A. Therefore stirring should be as violent as possible. At least an emulsion should be formed in the presence of the PTA and the antisolvent, during crystallization the emulsion becomes a dispersion. To avoid crystallization of pure Form I the phase transfer agent and/or the antisolvent, or the phase transfer agent and/or subsequently an antisolvent or the antisolvent and subsequently the phase transfer agent or a mixture of the antisolvent and the phase transfer agent are added at once.

Object of the invention is Form AB-A of acetyl salicylic acid which has 0,5 to 98 % domains with Form Il arrangements and domains with Form I arrangements ad 100 %, wherein it comprises further a content of a dopant and/or voids and/or any further defects. In particular Form AB-A of acetyl salicylic acid has 2 to 98 %, 5 to 98 %, 10 to 98 %, 15 to 98 %, 15 to 98 %, preferred 20 to 98%, 30 to 98 %, 40 to 98%, most preferred 50 to 98 %, 60 to 98 %, 70 to 98 %, 80 to 98% domains with Form Il arrangements and domains with Form I arrangements ad 100 %, wherein it comprises further a content of a dopant and/or voids and/or any further defects. Wherein the percentages of domains with Form Il arrangements and domains with Form I arrangements are determined by integration of the normalized CP/MAS ¹³C-NMR signals at 20.5 ppm (±0.5 ppm) for domains of Form Il and at 19.9 ppm (±0.5 ppm) for domains of Form I. Procedure B: The common synthesis of AS usually starts with salicylic acid dissolved in acetic anhydride, giving AS and acetic acid. By providing an excess of acetic acid, it is possible to produce ASAN 'in situ' within the acetic anhydride phase. Violent stirring to disperse the hydrophobic acetic anhydride phase in an aqueous 'anti- solvent' phase can lead to crystallisation of AS Form AB-A in the aqueous phase as above. Again, acetic acid or other carboxylic acids, aprotic polar solvents such as MeCN, EtCN, THF₁ Et₂O, or alcohols can be added to assist dispersion of the hydrophobic acetic anhydride phase in the aqueous anti-solvent phase.

Object of the invention is therefore a process for producing Form AB-A of acetyl salicylic acid, as well as Form AB-A solid forms obtainable by this process, wherein acetyl salicylic acid and a dopant, most preferred acetyl salicylic acid anhydride, are dissolved in a solvent and Form AB-A is obtained. Suitable solvents comprise, but are not limited to, methanol, ethanol, acetic acid, acetonitrile, propionitrile, tetrahydrofuran, propanol, diethylether, propanoic acid, butanoic acid or pentanoic acid, or a mixture of two or more of these solvents. To avoid formation of Form I crystals it is most preferred to stir the formed solution, preferred is intense stirring, most preferred is violent stirring. To form crystals of Form AB-A it is preferred to remove the solvent, wherein it is most preferred to evaporate the solvent within 12 hours or in vacuum, e.g. with a rotary evaporator.

Procedure C: Dissolving both AS and ASAN in various organic solvents with subsequent evaporation of the solvent will produce AS Form AB-A if both components have a reasonable solubility in the solvent.

Object of the invention is also a process for producing Form AB-A of acetyl salicylic acid, as well as Form AB-A solid forms obtainable by this process, wherein acetyl salicylic acid and a dopant, most preferred acetyl salicylic acid anhydride, are co- ground, in particular in the presence of a small amount of a suitable solvent, e.g. solvent drop grinding. Wherein it is preferred that acetyl salicylic acid and acetyl salicylic acid anhydride are co-ground in a ball mill, in particular in a planetary ball mill, in which g force up to 47 g or even up to 95 g are developed. Procedure D: Co-grinding AS and ASAN can produce AS Form AB-A. This process is made more efficient by addition of a minute amount of a solvent (so-called 'solvent drop co-grinding').

The characterization of AS Form AB-A is described above, which is consistent with the assumed theoretical background given above.

Object of the invention is Form AB-A of acetyl salicylic acid obtainable by a process according to claim 52 or a process according to one of the claims 54 to 68 relating to claim 52. A further object of the invention is Form AB-A of acetyl salicylic acid obtainable by a process according to claim 53 or a process according to one of the claims 54 to 68 relating to claim 53. Wherein it is preferred to obtain Form AB-A by using the phase transfer agent acetic acid, tetrahydrofuran, an alcohol, as for example methanol or ethanol, or a mixture of two or more of these agents. In addition the Form AB-A obtainable by these processes possess an improved dissolution rate in water with respect to Form I of acetyl salicylic acid, in particular at a comparable particle size of the crystalline materials and at room temperature or at about 37 ⁰C. A comparable particle size means in a range of about ± 30 μm, in particular ± 15 μm. Further the products are stable at room temperature (22 ⁰C) for at least 3 month.

Also an object of the invention is Form AB-A of acetyl salicylic acid obtainable by a process according to claim 69 to 74. In addition an object of the invention is Form AB-

A of acetyl salicylic acid obtainable by a process according to claim 75 to 78. Wherein the Form AB-A obtainable by these processes possesses an improved dissolution rate in water with respect to Form I of acetyl salicylic acid, in particular at a comparable particle size of the crystalline materials and at room temperature or at about 37 °C. A comparable particle size means in a range of about ± 30 μm, in particular ± 15 μm. Further the products are stable at room temperature (22 ⁰C) for at least 3 month.

Form AB-A obtainable by the previous described processes has a content of at least a dopant, wherein in particular the dopant may not be salicylic acid.

Regarding the obtainable products of Form AB-A described above, it is a further object of the present invention that these solid forms of Form AB-A of acetyl salicylic acid with a content of a dopant, possess dissolution rates and solubilities at a certain time, in particular at 5 and 10 minutes respectively, are increased by about 30 % to 600 %, in particular by about 300 to 600 %, preferred are about 400 to 600 %, in respect of Form I of acetyl salicylic acid, wherein the particle size of the crystalline material and/or the samples are comparable, in particular in the same range, namely between 60 to 90 μm. A further object of the invention is Form AB-A, wherein their dissolution rate and their solubility, measured as conductivity in water at 25 ⁰C after 1 minute, from start of dissolution and measurement, is increased by at least 50 % compared to acetyl salicylic acid Form I, in particular with comparable particle size of the crystalline material and/or the samples are comparable, in particular between 60 to 90 μm.

A further aspect of the present invention is a pharmaceutical formulation comprising acetyl salicylic acid as Form AB-A. The pharmaceutical formulation may be in form of a tablet, a patch, injection or infusion formulation, 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. Preferred are formulations for immediate release, such as powders or disintegrating formulation permitting a fast dissolution of acetyl salicylic acid. In particular as migraine medication for a fast relief in a migraine attack, immediate release formulation, wherein normal Form I formulation can be regarded as slow release or delayed release formulation due to the dissolution rate of form I of acetyl salicylic acid.

Pharmaceutical formulation comprising acetyl salicylic acid as Form AB or Form AB- A, wherein these forms may be further stabilized by drying means, in particular by a drying agent, for example a paraffin coating. 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, lactose anhydride, polymeric film coating or other compounds that are able to bind water physically, chemically or to protect Form AB or Form AB-A from water to stabilize Form AB or AB-A by other means.

Use of acetyl salicylic acid as Form AB or Form AB-A for the production of a medicament to be used as means for headache, migraine, as analgesic agent, as antipyretic, anti-inflammatory, 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 or From AB-A 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 or Form AB-A 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. Formulation comprising Acetyl salicylic acid Form AB or Form AB-A produced for this purpose shall contain 75 or 81 mg. High doses of acetyl salicylic acid Form AB or Form AB-A 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 35 are described in more detail:

Figure 1 : Model for arrangement of molecules in Form AB and Form AB-A a) Form I structure type; b) Form Il structure type; c) Shift of layers; d) Form AB; e) Form AB with defects; f) Form AB-A with defects and a doping molecule. Figure 2: Fractional composition of acetyl salicylic acid Form AB domains Form I and Form Il in the single crystal; batch scale factor applied to odd I reflections x 100, derived from refined crystallographic l values.

Figure 3: 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 0-H-O hydrogen bonds are identical (O-H—O slab).

Figure 4: 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 II; 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 II. Figure 5: NIR-Spectrum of Form I (lower curve) and Form AB with 60 % content of Form Il domains (upper curve) in cm^"1.

Figure 6: PXRD of Example AST(B) on a linear scale for intensity Figure 7: PXRD of Example AST(B) on a square root scale for intensity. Figure 8: HPLC for Example AST(B).

Figure 9: Reconstructed precession photograph ( h K ) for a single crystal from Example ASE(C) based on arrangement Form I or Form II.

Figure 10: Reconstructed precession photograph for a single crystal from Example 1.

This section ( h1£ ) shows Form AB with a low extent of strikes in every second horizontal line.

Figure 1 1 : HPLC from a cleaned single crystal from a batch Example ASE(C), approximately 1 % ASAN is present inside the crystal.

Figure 12: HPLC from a cleaned single crystal from a batch Example 1 and recrystallized from MeCN. No detectable ASAN is present inside the crystal.

Figure 13: CP/MAS ¹³C NMR Spectrum of ASF with details of the methyl C-atom in the range 17.5-22.5 ppm.

Figure 14: CP/MAS ¹³C NMR Spectrum of ASAN with details of the methyl

C-atom in the range 17.5-22.5 ppm. Figure 15: CP/MAS ¹³C NMR Spectrum of ASM(A) with details of the methyl C-atom in the range 17.5-22.5 ppm; Figure 16: CP/MAS ¹³C NMR Spectrum of ASD(A) with details of the methyl C-atom in the range 17.5-22.5 ppm; Figure 17: CP/MAS ¹³C NMR Spectrum of ASAc(A) with details of the methyl C-atom in the range 17.5-22.5 ppm;

Figure 18: CP/MAS ¹³C NMR Spectrum of AST(A) with details of the methyl C- atom in the range 17.5-22.5 ppm;

Figure 19: CP/MAS ¹³C NMR Spectrum of ASM(B) with details of the methyl C-atom in the range 17.5-22.5 ppm; Figure 20: CP/MAS ¹³C NMR Spectrum of ASD(B) with details of the methyl C-atom in the range 17.5-22.5 ppm; Figure 21 : CP/MAS ¹³C NMR Spectrum of ASAc(B) with details of the methyl C-atom in the range 17.5-22.5 ppm; Figure 22: CP/MAS ¹³C NMR Spectrum of AST(B) with details of the methyl C-atom in the range 17.5-22.5 ppm;

Figure 23: IR Spectrum in the range 4000-600 cm^"1 for Form I (ASF); Figure 24: IR Spectrum in the range 4000-600 cm^"1 for Form AB-A (AST(B)); Figure 25: Raman spectra of ASAN, AS-AB (example 2, regarding process to from Form AB) and ASF in the range 1700-1800 cm^"1;

Figure 26: Raman spectra of mixtures ASF and ASAN with 0.5, 1 and 2 %(w/w) in the range 1700-1800 cm^"1; Figure 27: Raman spectra of ASM(A), ASD(A), ASAc(A) and AST(A) in the range

1700-1800 cm^"1; Figure 28: Raman spectra of ASAN and ASF in the range 700-800 cm^"1;

Figure 29: Raman spectra of ASM, ASD, ASAc, and AST in the range 700-800 cm^"1; Figure 30: DSC thermograms of ASF, ASAC, ASD, ASM, and AST according to

Procedure A, as well as compound acetyl salicylic acid Form AB (AS-AB) synthesised according to Example 2. Figure 31 : Relative conductivity versus iime (sec) for ASF, Form AB and Form AB-A for Aspirin with conductivity given for solutions at various concentrations, Figure 32: Relative conductivity versus time (sec) for ASF and different Forms AB-

A(A) of Aspirin synthesized according to Procedure A;

Figure 33: Relative conductivity versus time (sec) for ASF and different Forms AB-A(A) of Aspirin synthesized according to Procedure B;

Figure 34: THz Spectra for ASF, ASAc(A), AST(A), ASD(A), and ASM(A). Figure 35. Calibration Curve for HPLC Standards; Figure 36: Simulated PXRD of Form Il domains of Form AB-A (THF(A)) crystal, derived from single crystal measurements at room temperature, wherein simulated PXRD of Form I domains of Form AB-A crystal are not shown.

Those peaks which are not present in Form I arrangement are marked with an asterisk. II. Examples

ILa Instruments and chemicals specifications:

Chemicals: manu- factory purity

Compound grade facturer number (%) shortcut

Aspirin, acetyl salicylic acid AS

Aspirin, Form I p.a Fluka 1459 99 ASF

Acetanhydride p.a Fluka 45830 97 ASAc

Hydrochloric acid p.a Riedel 7102 37 HCI

Tetrahydrofuran p.a Fluka 87371 99.5 THF

Ethanol p.a Riedel 32205 99.8 EtOH

Methanol p.a Riedel 24229 99.7 MeOH

Acetyl salicylic acid anhydride p.a Fluka 1460 98 ASAN (Aspirin anhydride)

Acetonitrile p.a Fluka 700 99.5 MeCN

Salicylic acid p.a Fluka 84210 99 SA

Diethylether p.a Fluka 31690 99.8 Et2O

Sulfuric acid p.a Riedel 30743 95-97 H2SO4

Acetic acid p.a. Riedel 27221 99-100 AcOH

PXRD: Siemens D5000 powder X-ray diffractometer, Bragg-Brentano geometry, generator; 35 kV, 35 mA, Siemens ceramic Cu fine focus tube, wavelengths (λ): Kαi = 1.5406 A, Ka₂ = 1.5444 A, Intensity weighted average wavelength: 1.5418 A, monochromator: graphite, divergence slit (pre-sample): 0.2 mm, anti-scatter slit (post- sample): 0.2 mm, detector slit: 0.1 mm, beam width at sample; ca 10 mm, detector: scintillation counter

Scan details: step scans, step size 0.01 °, time per step 2 seconds, measurements were performed at room temperature.

Sample preparation: The sample is ground with an agate mortar and pestle for approximately 30 seconds. The powdered sample is transferred to an acrylic sample holder, with a circular well of diameter 25 mm and depth 1 mm, and compressed into the well using a glass microscope slide. The sample holder is static during data collection. Scan details: Step scans, step size 0.01 °, time per step 2 seconds. Calibration details for PXRD: Nine standard samples ASAN in ASF(w/w) were prepared at 1 , 2, 3, 4, 5, 10, 15, 20, and 30 %. The pure components were ground separately prior to weighing, and the mixed compound was shaken thoroughly. The mixed sample was ground further for 30 seconds in the course of preparing the PXRD samples.

Calibration patterns are shown only for the 1 and 2 %(w/w) mixtures in Figure 2 and 3 to demonstrate the Limit Of Detection (LOD), which at the 2 % level is hardly detectable with the linear presentation, and at the 1 % level only with the intensity plotted on a square root scale (not shown).

The conclusion from the calibration is that the lower limit for detection of a crystalline Aspirin anhydride phase in a bulk sample of crystalline Aspirin under the specified measurement conditions is below 1 % (w/w).

Single Crystal Diffractometry: Bruker-Nonius D8 APEX-II, 3-axis diffractometer, Siemens ceramic Mo fine focus tube, wavelength (λ): Kαi,₂ = 0.71069 A, graphite monochromator, generator 40 kV, 35 mA, scans with 10 sec. per frame and reconstruction of the precession image with APEX-II V2.1 -4 Siemens software. Measurements were operated at 180 K for the cell dimensions and at RT for simulation of PXRD data. For single crystal analysis see for example the general textbook, Werner Massa; Kristallstrukturbestimmung; 5^th edition 2007, 265 pages, 109 Tab.; Teubner B.G. GmbH | ISBN: 3835101137, or previous editions or Werner Massa; Crystal Structure Determination; Verlag: Springer, Berlin; 2nd edition, 2004; ISBN-10: 3540206442; ISBN-13: 978-3540206446. The content of the whole textbook is incorporated by reference. Literature for diffuse scattering see "Atlas of Opitical Transforms" G.Harburn, CA. Taylor, T. R. Welberry; Cornell University Press, Ithaca, New York, published 1975; see especially plate 18, second row. A second text book is "Diffuse X-ray Scattering and Models of Disorder", by Thomas Richard Welberry; published 2004, Oxford University Press, ISBN 0198528582.

CP-MAS NMR: ASX 400 (Bruker, Rheinstetten) spectrometer with a 7 mm double resonance probe. Between 240 and 300 mg were used, applying the cross- polarization method with a contact time of 5.0 ms and repeat time of 5.0 s. The MAS frequency was chosen 4.75 kHz, in order to avoid overlaps of the rotation side bands of the methyl group signals. The chemical shifts refer to TMS; the secondary reference was adamantane, which has signals at 29.5 and 38.5 according to "Solid state nmr II" Ed. P. Diehl et al., Springer Verlag, 1994; Earl and Vander Hart, J. Magn. Reson. 48 (1982), 35-54.

NMR: DRX500 (Bruker), measured frequencies: ¹H-NMR at 499.6 MHz and ¹³C-NMR at 125.7 MHz). The chemical shifts are given with δ-values relative to those of tetramethylsilane (0 ppm). As reference for the ¹H-NMR spectra, the non-deuterated proportion of the used solvent CD2HCN = 1.94 ppm and for the 13C-NMR spectra the signal of the solvent CD3CN = 1.39 ppm) was taken, data were recorded at 298K.

FT-IR: Varian 3100 FT-IR, Excalibur Series in diffuse reflection mode with KBr in a Pike-sample holder "EasiDiff", the samples were added to well ground KBr, then mixed and filled into the sample holder.

NIR: Perkin Elmer NIRA, manufacturer: PerkinElmerLAS (Germany) GmbH, Spectrum One NTS.

Raman: Bruker IFS66 Raman spectrometer (Raman modul FRA 106). The final Raman-spectra were obtained as an average spectrum of 500 scans. Laser: ADLAS DPY 321 (Diode Laser Pumped Nd: YAG laser) Laserpower; 100 %; Wavelength: 1064 nm, Detector: Bruker - D316/8.

DSC: DSC 204 Phoenix, manufacturer: NETZSCH Geratelabor GmbH, manufaction 2001 , temperature range 20-180 ⁰C₁ heating rate 5 °C/min, open Al crucible. Samples with weights between 3 and 6 mg were subjected to measurements.

HPLC: Instrument type: Dionex Ultimate 3000 (comprising Ultimate 3000 pump, Ultimate 3000 autosample, Ultimate 3000 variable wavelength detector), Solvent: 50 % MeCN, 50 % H₂O, Flow: 1 mL / min over 15 mins, Column: Dionex C18, 5 μm, 120 A, 4.6 x 150 mm (Prod. No. 059148, Serial No. 002540), UV Wavelength: 254 nm, Software: Dionex Chromeleon Version 6.80 SP1 Build 2238. HPLC Preparation: General sample preparation: Solid samples were dissolved in 1 :1 MeCN:H₂O (v/v) to a concentration of ca 2 mmol (typically 0.001 g sample in 3 ml_ solvent). Calibration: The same standard mixtures were used as outlined for the PXRD calibration. The whole sample was dissolved in 1 :1 MeCN:H₂O (v/v) with stirring, taking successive dilutions until the concentration reached ca 0.02 mmol. For example: 2.5 g (ca. 0.014 mol) was dissolved in 100 ml_ MeCN:H₂O with stirring to give a 0.14 mol/L solution. 1 ml_ of this solution was taken (containing 0.00014 mol in 1 ml_) and made up to 75 ml. to give a 1.85 mmol solution. Retention times are attributed to Aspirin (2.61 min), Aspirin anhydride (10.57 min), salicylic acid (3.3 min) and acetic acid (5-6 min).

Calibration curve: In the range 0-30 % Aspirin anhydride (w/w), the relative peak areas give the curve shown in Figure 35. The commercial sample of Aspirin (ASF) was subjected to HPLC analysis, the contents of ASAN was found to be less than 0.1 % which corresponds to literature data (J. C. Reepmeyer, R. D. Kirchhoefer, J Pharm. ScL, 68, 1167 (1979); A. L. DeWeck, Int. Arch. Allergy Appl. Immonol., 41 , 393 (1971)).

Conductometry: The electrical conductivity was recorded with a WTW (Wissenschaftlich-Technische Werkstetten, 82362 Weilheim, Germany) TetraCon 325 four-electrode system and a WTW lno lab controller, 250 mL beaker, temperature control at 25±0.2 ⁰C, Lauda Type: U3-S15/12, magnetic stirring by lkamag RET, stirring rate 300 rpm with a magnetic bar 40 mm x 4 mm.

THz Spectroscopy: The experimental set-up for the spectrometer is as follows: The pulse source of the THz TD spectrometer is a titanium-sapphire (Ti:Sa) femtosecond laser (fs laser) from KMLabs Inc. that is pumped by a 532 nm Verdi laser (from Coherent). The fs laser emits pulses at 800 nm, fwhm = 25 fs, repetition rate = 80 MHz, average output power = 600 mW. Because the coherent generation and detection of the THz pulse, the fs beam split in two parts: For emission, the fs beam is focused on the emitter (a low temperature grown gallium arsenide (LTG-GaAs) photoconductive antenna from Gigaoptics); this results in the generation of free charge carriers in the conduction band of the semiconductor and due to their acceleration THz radiation is emitted. For detection the free-space electro-optic sampling (EOS) is used; the principle is based on the Pockels effect that describes the change of optical properties of a nonlinear crystal (e.g. ZnTe) by applying an electric field to this medium; the nonlinear crystal gets birefringent when the THz pulse transmits; this results in a rotation of the polarization of the fs beam and this change is proportional to the electric field of the THz pulse. The THz setup: consists of the emitter, 4 parabolic mirrors, the sample and the nonlinear crystal for EOS; the setup is enclosed in a box and purged with dry air; the THz beam is focused on the sample by the 2nd parabolic mirror and focused on the ZnTe crystal by the 4th parabolic mirror. Details are also described in the references given, wherein the whole disclosure is incorporated by reference (C. A. Schmuttenmaer, Chem. Rev. 104, 1759 (2004)). Sample preparation: For THz Spectrocopy measurements pellets were pressed for the measurements for which 50 mg of each ASS sample is ground with 100 mg PE (sample pellet) and 120 mg of polyethylene is used as reference (PE pellet). The powders were pressed to two pellets: each at 3 tons for 3 min. Three measurements were made: an air scan, the PE pellet and the sample pellet and for each measurement 8 scans were taken and the mean average was used for further analysis. The humidity in the THz Box was 15 %, the temperature was 18°C. After the experiment the thickness of the pellets was determined. For data analysis the mean average of the data was Fourier transformed and the absorption coefficient α was calculated by Lambert Beer's law to get α(ASS): α(ASS)= α(sample pellet) - α(PE pellet). The frequency resolution of the spectra is 0.488 cm^"1.

Storage (stability testing): For maintaining a constant relative humidity, an open salt solution within a crystallization bowl is stored together with the open sample distributed in a watch glass in an exsiccator and placed in a drying oven. The oven is kept at a constant temperature (max ±0.5 ⁰C) with the temperature monitored electronically.

Ball Mill (Co-Grinding): Plenetary Micro Mill pulverisette 7 (Fritsch) with agate beaker and four agate balls, max 1100 rpm. II. b Examples: Procedure A:

Example ASAc(A): In a 500 mL round-bottom flask, ASF (10.00 g, 0.0556 mol) dispersed in acetic anhydride (20 mL) is heated to 50 °C in an oil bath with magnetic stirring at 300 rpm. ca. 0.15 mL of H₂SO4 (cone.) are added with continued stirring to give a clear, colourless solution. Acetic acid (3.33 g, 0.0556 mol) is added and the flask is removed from the oil bath with continued stirring. Distilled water (200 mL, 25 ⁰C) is poured into the mixture, which becomes milky and then clarifies so that oily drops remain visible, which are then dispersed through the solution by action of the stirring. The flask is left to cool gradually, still with stirring, and crystallisation occurs after ca. 30 min. After 1 hour, the flask is placed into a bath of iced water for 15 minutes with continued stirring. The solid is then removed by Buchner filtration to yield a white powder (9.0-9.5 g) that is left to dry in air at room temperature. HPLC indicates 1.0 % ASAN, in the PXRD the peaks at 11.1 ° and 14.8° attributed to ASAN are clearly visible and the peak at 19.9° attributed to arrangement Form Il has a 18 % relative height to the main peak at 15.5°.

Example ASD(A): The same procedure as for ASAc is followed, but instead of acetic acid, Et₂O (2.56 g, 0.0556 mol) is added. HPLC indicates 1.0 % ASAN, in the PXRD the peaks at 11.1° and 14.8° attributed to ASAN are clearly visible and the peak at 19.9° attributed to arrangement Form Il has a 17 % relative height to the main peak at 15.5°.

Example ASM(A): The same procedure as for ASAc is followed, but instead of acetic acid, MeOH (1.78 g, 0.0556 mol) is added.

HPLC indicates 1.0 % ASAN, in the PXRD the peaks at 11.1° and 14.8° attributed to

ASAN are clearly visible and the peak at 19.9° attributed to arrangement Form Il has a 12 % relative height to the main peak at 15.5°.

Example AST(A): The same procedure as for ASAc is followed, but instead of acetic acid, THF (4.00 g, 0.0556 mol) is added.

HPLC indicates 0.6 % ASAN plus 0.3 % acetic acid and 0.5 % salicylic acid; in the

PXRD the peaks at 11.1° and 14.8° attributed to ASAN are clearly visible and the peak at 19.9° attributed to arrangement Form Il has a 6 % relative height to the main peak at 15.5°.

Procedure B: Example ASAc(B): In a 500 ml_ round-bottom flask, salicylic acid (7.68 g, 0.0556 mol) in acetic anhydride is heated to 50 ⁰C with stirring (magnetic stirring at 300 rpm). Ca 0.15 ml_ of H₂SO₄ cone, are added and the solution is left to stir for 5 min. After this time, acetic acid (3.33 g, 0.0556 mol) is added and the flask is removed from the oil bath with continued stirring. Distilled water (200 ml_, 25°C) is poured into the mixture, which becomes milky, then clarifies so that oily drops remain visible, which are then dispersed through the solution by action of the stirring. The flask is left to cool naturally (still with stirring), and crystallisation occurs after ca. 30 min. After 1 hour, the flask is placed into a bath of iced water for 15 minutes with continued stirring. The solid is then removed by Buchner filtration to yield a white powder (9.0- 9.5 g) that is left to dry in air at room temperature.

HPLC indicates 0.7 % ASAN; in the PXRD the peaks at 11.1 ° and 14.8° attributed to ASAN are just visible and the peak at 19.9° attributed to arrangement Form Il has a 8 % relative height to the main peak at 15.5°.

Example ASD(B): The same procedure as for ASAc procedure B is followed, but instead of acetic acid, Et₂O (2.56 g, 0.0556 mol) is added.

HPLC indicates 1.0 % ASAN; in the PXRD the peaks at 11.1 ° and 14.8° attributed to ASAN are clearly visible and the peak at 19.9° attributed to arrangement Form Il has a 11 % relative height to the main peak at 15.5°.

Example ASM(B): The same procedure as for ASAc procedure B is followed, but instead of acetic acid, MeOH (1.78 g, 0.0556 mol) is added.

HPLC indicates 1.3 % ASAN; in the PXRD the peaks at 11.1 ° and 14.8° attributed to ASAN are clearly visible and the peak at 19.9° attributed to arrangement Form Il has a 9 % relative height to the main peak at 15.5°.

Example AST(B): The same procedure as for ASAc procedure B is followed, but instead of acetic acid, THF (4.00 g, 0.0556 mol) is added. HPLC indicates 2.2 % ASAN; in the PXRD the peaks at 11.1 ° and 14.8° attributed to ASAN are pronounced visible and the peak at 19.9° attributed to arrangement Form Il has a 12 % relative height to the main peak at 15.5°.

The PXRD with intensity on linear scale (Figure 4) and square root intensity (Figure 5) are exemplarily presented for AST(B), together with the HPLC pattern and attached table (Figure 6). Note that the estimate of 2.2 % ASAN is based on the calibration curve in Figure 31.

Procedure C; A mixture of 15.00 g of ASF and 2 % ASAN are dissolved in 15 mL of one of the solvents MeOH, EtOH, CH₃CN or in 25 mL of THF, Diethylether, or CH₃COOH. The solution is stirred for 30 min and the solvents are then allowed to evaporate within 12 hours or are removed in vacuo (ca. 10 mm Hg). The residual white powder is subjected to PXRD measurements. The amount of ASAN detectable by PXRD is estimated by comparison of the peak heights at 11.1 ° and 14.8° 2-Theta. A measure of the amount of arrangements Form-ll in the samples is estimated by the relative heights of the peak at 19.9° in comparison of the signal at 15.5°.

The same procedure is followed by adding 4 % ASAN instead of 2 %. For the percentages of ASAN given below, it should be noted that the estimates of 'free' ASAN (i.e. crystalline) with the powder diffraction method is very crude and made only by visual comparison of the peak heights in the PRXD patterns. This is why sometimes more free ASAN appears to be in the product than previously added. In all examples, the indicative peak at 19.9° in the PXRD for the arrangement Form Il is higher for the 2 %(w/w) ASAN solution than for the 4 %(w/w) solution.

Example AS2Ac(C): From a solution of ASF and 2 %(w/w) ASAN in acetic acid, after drying, estimated 2-5 % ASAN occurs in the PXRD and the relative height to the main peak at 15.5° is 8 %.

Example AS4Ac(C): From a solution of ASF and 4 %(w/w) ASAN in acetic acid, after drying, estimated <1 % ASAN occurs in the PXRD and the relative height to the main peak at 15.5° is not detectable. Example AS2M(C): From a solution of ASF and 2 %(w/w) ASAN in methanol, after drying, estimated 2-5 % ASAN occurs in the PXRD and the relative height of the 19.9° peak to the main peak at 15.5° is 10 %.

Example AS4M(C): From a solution of ASF and 4 %(w/w) ASAN in methanol, after drying, estimated <1 % ASAN occurs in the PXRD and the relative height of the 19.9° peak to the main peak at 15.5° is 1 %.

Example AS2T(C): From a solution of ASF and 2 %(w/w) ASAN in THF, after drying, estimated 2-5 % ASAN occurs in the PXRD and the relative height of the 19.9° peak to the main peak at 15.5° is 10 %.

Example AS4T(C): From a solution of ASF and 4 %(w/w) ASAN in THF, after drying, estimated <1 % ASAN occurs in the PXRD and the relative height of the 19.9° peak to the main peak at 15.5° is 3 %.

Example AS2CN(C): From a solution of ASF and 2 %(w/w) ASAN in acetonitrile, after drying, estimated <1 % ASAN (not detectable) occurs in the PXRD and the relative height of the 19.9° peak to the main peak at 15.5° is 10 %.

Example AS4CN(C): From a solution of ASF and 4 %(w/w) ASAN in acetonitrile, after drying, estimated 1-2 % ASAN occurs in the PXRD and the relative height of the 19.9° peak to the main peak at 15.5° is 5 %.

Example AS2D(C): From a solution of ASF and 2 %(w/w) ASAN in diethylether, after drying, estimated <1 % ASAN (not detectable) occurs in the PXRD and the relative height of the 19.9° peak to the main peak at 15.5° is 2 %.

Example AS4D(C): From a solution of ASF and 4 %(w/w) ASAN in diethylether, after drying, estimated 1-2 % ASAN occurs in the PXRD and the relative height of the 19.9° peak to the main peak at 15.5° is 1 %. Procedure D: The co-grinding of AS and ASAN as a neat powder. Example ASI (D): A mixture of 0.99 g ASF and 0.01 g ASAN is subjected to grinding in a ball mill for 1 min, the resulting powder showed no detectable ASAN but the relative height of the 19.9° peak to the main peak at 15.5° is 1 %.

Example AS2(D): A mixture of 0.98 g ASF and 0.02 g ASAN is subjected to grinding in a ball mill for 1 min, the resulting powder showed no detectable ASAN but the relative height of the 19.9° peak to the main peak at 15.5° is 2 %.

Example AS4(D): A mixture of 0.96 g ASF and 0.04 g ASAN is subjected to grinding in a ball mill for 1 min, the resulting powder showed 2 % ASAN but the relative height of the 19.9° peak to the main peak at 15.5° is 2 %.

Example AS2CN(D): A mixture of 0.98 g ASF and 0.02 g ASAN, together with 4 drops of MeCN is subjected to grinding in a ball mill for 1 min, the resulting powder shows no detectable ASAN but the relative height of the 19.9° peak to the main peak at 15.5° is 5 %.

Example AS2M(D): A mixture of 0.98 g ASF and 0.02 g ASAN, together with 4 drops of methanol is subjected to grinding in a ball mill for 1 min, the resulting powder shows no detectable ASAN but the relative height of the 19.9° peak to the main peak at 15.5° is 5 %.

Example AS2Ac(D): A mixture of 0.98 g ASF and 0.02 g ASAN, together with 4 drops of acetic acid is subjected to grinding in a ball mill for 1 min, the resulting powder shows no detectable ASAN but the relative height of the 19.9° peak to the main peak at 15.5° is 5 %.

Example AS2T(D): A mixture of 0.98 g ASF and 0.02 g ASAN, together with 4 drops of THF is subjected to grinding in a ball mill for 1 min, the resulting powder shows no detectable ASAN but the relative height of the 19.9° peak to the main peak at 15.5° is 5 %. Literature:

- Peterson, Zaworotko, and co-workers (J. Am. Chem. Soc. 2005, 127, 16802); -Werner Massa; Kristallstrukturbestimmung; 5^th edition 2007, 265 pages, 109 Tab.; Teubner B.G. GmbH, ISBN: 3835101137, or Werner Massa; Crystal Structure Determination; Verlag: Springer, Berlin; 2nd edition, 2004; ISBN-10: 3540206442; ISBN-13: 978-3540206446;

- Stout, Jensen "X-Ray structure Determination; A Practical Guide, Mac Millian Co. Ney York. N.Y. (1968); - "Atlas of Opitical Transforms" G.Harburn, CA. Taylor, T. R. Welberry; Cornell

University Press, Ithaca, New York, published 1975; see especially plate 18, second row;

- "Diffuse X-ray Scattering and Models of Disorder", by Thomas Richard Welberry; published 2004, Oxford University Press, ISBN 0198528582; - C. A. Schmuttenmaer, Chem. Rev. 104, 1759 (2004).

- J. C. Reepmeyer, R. D. Kirchhoefer, J Pharm. ScL, 68, 1167 (1979).

- A. L DeWeck, Int. Arch. Allergy Appl. Immonol., 41 , 393 (1971 );

-(Frenning G., Fichtner F., and Alderborn G.; Chem. Enq. ScL. Vol. 60, (2005) 3909).

Claims

Patent Claims

1. Acetyl salicylic acid as Form AB comprising interlaced 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 intergrowths of Form I and Form II.

3. Acetyl salicylic acid as Form AB according to claim 1 or 2, characterized 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, fc = 6.49, C = 11.32 A, β = 111.51 ° for Form Il and wherein these values can vary by ±2 %.

4. Acetyl salicylic acid as Form AB according to 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 more 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 larger than

50 % and not more than 90 %.

6. Form AB according to one of claims 1 to 5, characterized by at least one additional signal in the PXRD compared to pure Form I of acetyl salicylic acid at 15.9° and/or 19.9° and/or 25.6° (± 0.2°) in the 2Theta range (Cu-radiation).

7. Form AB according to one of claims 1 to 5, characterized by at least two additional signals in the PXRD compared to the pure Form I of acetyl salicylic acid at 15.9°, 19.9° and/or 25.6° (± 0.2°) in the 2Theta range (Cu-radiation).

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 I 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.

11. 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 3 and wherein the arrangement A of Figure 3 contains centrosymmetric C-H- O dimers, which are located between the slabs shown in the lower part of Figure 3, arrangement B contains C-H- O catemers, arranged along a twofold screw axis, as shown in the upper part of the Figure 3. The intermediate region in the central layer (Intergrowth region) is only for illustration, because all slabs with O-H-0 hydrogen bonds are identical (O-H-0 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. Acetyl salicylic acid as Form AB according to one of claims 1 to 18, characterized in consisting of interlaced crystals of Form I and Form Il comprising intergrowths of Form I and Form Il of acetyl salicylic acid.

20. Process for producing Form AB of acetyl salicylic acid as defined in one of claims 1 to 19, 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.

21. Process for producing Form AB of acetyl salicylic acid according to claim 20, 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.

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

23. Process for producing Form AB of acetyl salicylic acid according to one of the previous claims 1 to 19, wherein the process for producing acetyl salicylic acid in the

Form AB comprises adding salicylic acid to acetic acid anhydride, 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 boiling heat.

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

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

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

27. Process for producing Form AB of acetyl salicylic acid according to claim 25, wherein the saturated solution of acetonitrile is rapidly cooled from

60 ⁰C to about 25 ⁰C within 5 minutes.

28. Process for producing Form AB of acetyl salicylic acid according to one of the claims 23 or 24, wherein the isolated crystallized precipitate and/or the recrystallized material is immediately recrystallized from water, alcohols, ethers or heterocyclic aromatic solvents.

29. Process for producing Form AB of acetyl salicylic acid according to one of the claims 23 or 24, wherein the isolated crystallized precipitate and/or the recrystallized material is immediately recrystallized from any solvent in which acetyl salicylic acid can be solved.

30. Process for producing Form AB of acetyl salicylic acid according to one of the claims 23, 24, 28 or 29, wherein the isolated product is dried by evaporation of the solvent at elevated temperatures and/or at reduced pressure.

31. Acetyl salicylic acid as Form AB obtainable by one of the processes according to one of the claims 20 to 30, 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.

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

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

34. 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 rheumatic agent, as an antiplatelet agent and in long-term low-doses to prevent heart attacks and cancer.

35. Form AB of acetyl salicylic acid as Form AB-A comprising interlaced crystals of Form I and Form Il of acetyl salicylic acid and a content of at least one dopant.

36. Form AB-A according to claim 35, characterized by interlaced crystals of Form I and Form Il of acetyl salicylic acid and containing a content of at least one dopant.

37. Form AB-A according to claim 35 or 36, characterized by a content of acetyl salicylic acid anhydride and/or a derivative of acetyl salicylic acid as dopant molecule.

38. Form AB-A according to one of claims 35 to 37, wherein the interlaced crystals comprise intergrowths of Form I and Form II.

39. Form AB-A according to one of claims 35 to 38, characterized by at least one additional signal in the PXRD compared to the pure Form I at 15.9± 0.2°, 19.9± 0.2° and/or 25.6± 0.2° in the 2Theta range.

40. Form AB-A according to one of claims 35 to 39, characterized by at least two additional signals in the PXRD compared to the pure Form I selected from signals at 15.9 ± 0.2°, 19.9± 0.2° and 25.6± 0.2° in the 2Theta range.

41. From AB-A according to one of claims 35 to 40, characterized by at least one signal in the PXRD at 15.9± 0.2°, 19.9± 0.2° and/or 25.6± 0.2° for Form Il and at least one signal at 17.7± 0.2°, 27.6± 0.2° and/or 28.9± 0.2° for Form I in Form AB-A in the 2Theta range.

42. Form AB-A according to one of claims 35 to 41 , characterized by a signal in the ¹³C CPMAS NMR spectrum at 20.5 (±0.5 ppm) ppm.

43. Form AB-A according to one of claims 35 to 42, characterized by an additional signal in the ¹³C CPMAS NMR spectrum at 20.5 (±0.5 ppm) ppm compared to the spectrum of essentially pure Form I of acetyl salicylic acid.

44. Form AB-A according to one of claims 35 to 43, characterized 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, c = 11.32 A, β = 111.51° for Form Il and wherein these values can vary by ±2 % and/or supercells of these cell dimensions.

45. From AB-A according to one of claims 35 to 44, characterized by a content of a dopant, wherein the content of the dopant derived from liquid phase analytical methods is greater than the amount of the dopant measured by solid state analytical methods such as PXRD and/or ¹³C CPMAS NMR.

46. From AB-A according to one of claims 35 to 45, characterized by a content of a dopant in the crystal lattice of Form AB-A, wherein the dopant is detected by an analytical method after dissolution of the crystal.

47. Form AB-A according to one of claims 35 to 46, characterized in that it possesses an improved dissolution rate in water compared to Form I.

48. Form AB-A according to one of claims 35 to 47, characterized in that it possesses an improved dissolution rate in water compared to Form I₁ wherein the conductivity of water at 25 ⁰C is increased by at least 50 % after 1 minute compared to acetyl salicylic acid Form I.

49. Form AB-A according to one of claims 35 to 48, characterized by 0,5 to 98 % domains with Form Il arrangements and ad 100 % of domains with Form I arrangements.

50. Form AB-A according to one of claims 35 to 49, characterized in that it is stable at room temperature for at least 3 month at 22 ⁰C and 40 % relative humidity.

51. Form AB-A or Form AB according to one of claims 1 to 50, wherein a peak is shifted by 8 to 15 cm^'1 in the THz spectrum in respect of the corresponding peak of

Form I of acetyl salicylic acid at about 65 cm^"1.

52. Process for producing Form AB-A of acetyl salicylic acid, wherein acetyl salicylic acid and acetic anhydride are stirred and if necessary heated to 30 ⁰C or up to boiling point, a catalyst is added, and during stirring,

- at least one phase transfer agent and if applicable an antisolvent are present, or a phase transfer agent and/or an antisolvent or a mixture thereof is added,

- the mixture is allowed to cool during stirring, the solid product is obtained.

53. Process for producing Form AB-A of acetyl salicylic acid as defined in one of the previous claims 35 to 51 , wherein salicylic acid and acetic anhydride are stirred and if necessary heated to 30 ⁰C or up to boiling point, a catalyst is added, and during stirring,

54. Process as defined in claims 52 or 53, wherein the antisolvent is water.

55. Process as defined in one of claims 52 to 54, wherein the catalyst comprises an acid.

56. Process as defined in one of claims 51 to 55, wherein the catalyst is sulphuric acid, nitric acid, phosphoric acid, formic acid and/or acetic acid or a mixture thereof.

57. Process as defined in one of claims 52 to 56, wherein the acid is concentrated sulphuric acid.

58. Process as defined in one of claims 52 to 57, wherein the phase transfer agent is suitable when it is capable to dissolve acetyl salicylic acid and/or the dopant.

59. Process as defined in one of claims 52 to 58, wherein the phase transfer agent is suitable when it is capable to dissolve acetyl salicylic acid and/or acetyl salicylic acid anhydride.

60. Process as defined in one of claims 52 to 59, wherein the phase transfer agent is suitable when the mixture of the antisolvent and the phase transfer agent is capable to dissolve acetyl salicylic acid and the acetyl salicylic acid anhydride.

61. Process as defined in one of claims 52 to 60, wherein the phase transfer agent is acetic acid, acetonitrile, propionitrile, tetrahydrofuran, methanol, ethanol, propanol, Diethylether, propanoic acid, butanoic acid or pentanoic acid and/or a mixture of two or more of these agents.

62. Process as defined in one of claims 52 to 61 , wherein the phase transfer agent is used in 1 to 10 mol equivalent with regard to salicylic acid or acetyl salicylic acid.

63. Process as defined in one of claims 52 to 62, wherein the phase transfer agent is used in 1 to 2 mol equivalent with regard to salicylic acid or acetyl salicylic acid.

64. Process as defined in one of the previous claims 52 to 63, wherein during stirring,

- the phase transfer agent and subsequently an antisolvent or

- the antisolvent and subsequently the phase transfer agent or

- a mixture of the antisolvent and the phase transfer agent are added at once.

65. Process as defined in one of claims 52 to 64, wherein the mixture is allowed to cool during intense stirring to form an emulsion and/or a dispersion.

66. Process as defined in one of claims 52 to 65, wherein acetyl salicylic acid anhydride as dopant is produced by adding the catalyst.

67. Process as defined in one of claims 52 to 66, wherein a dopant is added before the antisolvent is present or added.

68. Process as defined in claim 67, wherein the dopant is a derivative of acetylsalicylic acid.

69. Process for producing Form AB-A of acetyl salicylic acid, wherein acetyl salicylic acid and a dopant are dissolved in a solvent and Form AB-A is obtained.

70. Process as defined in claim 69, wherein acetyl salicylic acid and acetyl salicylic acid anhydride are dissolved in a solvent and Form AB-A is obtained.

71. Process as defined in claim 69 or 70, wherein the solvent is methanol, ethanol, acetic acid, acetonitrile, propionitrile, tetrahydrofuran, propanol, diethylether, propanoic acid, butanoic acid or pentanoic acid, or a mixture of two or more of these solvents.

72. Process as defined in one of claims 69 to 71 , wherein the formed solution is stirred.

73. Process as defined in one of claims 69 to 72, wherein Form AB-A is obtained by removal of the solvent.

74. Process as defined in one of claims 69 to 73, wherein the solvent is evaporated within 12 hours or is removed in vacuum.

75. Process for producing Form AB-A of acetyl salicylic acid, wherein acetyl salicylic acid and a dopant are co-ground.

76. Process as defined in claim 75, wherein acetyl salicylic acid and acetyl salicylic acid anhydride are co-ground.

77. Process as defined in claim 75 or 76, wherein acetyl salicylic acid and acetyl salicylic acid anhydride are co-ground in the presence of a solvent.

78. Process as defined in one of claims 75 to 77, wherein acetyl salicylic acid and acetyl salicylic acid anhydride are co-ground in a ball mill.

79. Form AB-A of acetyl salicylic acid obtainable by a process according to claim

52 or a process according to one of the claims 54 to 68 relating to claim 52.

80. Form AB-A of acetyl salicylic acid obtainable by a process according to claim

53 or a process according to one of the claims 54 to 68 relating to claim 53.

81. Form AB-A as defined in claim 79 or 80, wherein it is obtained by using the phase transfer agent acetic acid, tetrahydrofuran, methanol or ethanol, or a mixture of two or more of these agents.

82. Form AB-A as defined in claim 79 or 80, wherein the dissolution rate of the obtained product in water is improved with respect to Form I of acetyl salicylic acid.

83. Form AB-A of acetyl salicylic acid obtainable by a process according to claims 69 to 74.

84. Form AB-A of acetyl salicylic acid obtainable by a process according to claims 75 to 78.

85. Form AB-A as defined in claim 83 or 84, wherein the dissolution rate of the obtained product in water is improved with respect to Form I of acetyl salicylic acid.

86. Pharmaceutical formulation comprising Form AB-A of acetyl salicylic acid according to one of the claims 35 to 85 and excipients for an immediate release formulation.

87. Use of Form AB-A according to one of the previous claims 35 to 85 for the production of a medicament.

88. Use of Form AB-A according to one of the previous claims 35 to 85 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.