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WO2008037289A1 - Forme ab de l'acide acétyl-salicylique - Google Patents

Forme ab de l'acide acétyl-salicylique Download PDF

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Publication number
WO2008037289A1
WO2008037289A1 PCT/EP2006/010698 EP2006010698W WO2008037289A1 WO 2008037289 A1 WO2008037289 A1 WO 2008037289A1 EP 2006010698 W EP2006010698 W EP 2006010698W WO 2008037289 A1 WO2008037289 A1 WO 2008037289A1
Authority
WO
WIPO (PCT)
Prior art keywords
salicylic acid
acetyl salicylic
previous
acetyl
producing
Prior art date
Application number
PCT/EP2006/010698
Other languages
English (en)
Inventor
Roland Boese
Andrew D. Bond
Gautam R. Desiraju
Sascha Redder
Original Assignee
Sciconcept Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sciconcept Gmbh filed Critical Sciconcept Gmbh
Priority to PCT/EP2007/008054 priority Critical patent/WO2008037366A2/fr
Publication of WO2008037289A1 publication Critical patent/WO2008037289A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds
    • C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
    • C07C69/157—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to a new form of acetyl salicylic acid designated as Form AB as well as processes for the preparation and formulation comprising it.
  • Acetyl salicylic acid was first synthesized in 1853 but up to know no further crystalline second polymorphic form was established. Further it is well known form the state of the art that acetyl salicylic acid (Form I) possesses a poor solubility. For example it is not possible to solve essentially more than 4 grams of aspirin in 1000 mL of water at 20 °C. Accordingly the bioavailability of acetyl salicylic acid is relatively low. Therefore there is a desire of producing a polymorphic form with enhanced solubility in water or water containing solutions.
  • acetyl salicylic acid exists as Form AB comprising interlaced crystals of Form I and Form II. It is noted, that such interlaced crystals do not consist of a simple mixture of two polymorphic forms. Instead, each crystal has 5 domains of two molecular packing characteristics, described as Form I and Form II, where both forms are separated by distinct boundaries within the crystal. Such crystals also cannot be described as twins because of the different packing characteristics in the neighbouring domains.
  • interlaced crystals is interchangeably used in this application with the terms10 mixed crystals or Mischkristalle as they were called in a prior application DE 10 2006045780.3.
  • Form AS comprises intergrowths of Form I and Form II.
  • the cell dimensions of pure Form 5 and of the hypothetical pure Form II have the different cell dimensions.
  • Form A3 of the present invention as interlaced crystal can be indexed on the20 basis of both ceil dimensions.
  • the proportion of the contents of Form ⁇ to Form I can bo larger than 10% and is not expected he much more than 90%, specifically the proportion is between 10% to 20%, 10% to 30% or 20% to 30% weight percsnt
  • 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 13 C-NMR) where the accuracy of the relative intensities is in the range of ⁇ 7%.
  • the elusive and hypothetical pure Form Il is characterized by signals in the PXRD at 20,9° and 26,0° ( ⁇ 0,2°) in the 2Theta range (CuK ⁇ -radiation) which have intensities at 20,9° ( ⁇ 0,2°) of 49% ( ⁇ 5%) and at 26,0° ( ⁇ 0,2°) of 51% ( ⁇ 5%), respectively in relation to the 100% peak at 15,7° ( ⁇ 0,2°).
  • Acetyl salicylic acid as Form AB can be characterized in that the two additional signals in the PXRD compared to the pure Form I at 20,9° and 26,0° ( ⁇ 0,2°) in the 2Theta range (Cu-radiation), possess intensities greater than 12% and 13%, respectively, of the 100% signal at 15,7° (capillary technique, Laue technique).
  • a powder with 50% of Form Il in the domains exhibit intensities in the PXRD (capillary technique, Laue technique) at 20,9° of 24,5% and at 26,0° ( ⁇ 0,2°) of 25,5%, respectively in relation to the 100% peak at 15,7°.
  • the acetyl salicylic acid as Form AB as interlaced crystals according to the invention can be characterized by two additional signals in the PXRD compared to the pure Form I at 20,9° and 26,0° ( ⁇ 0,2°) in the 2Theta range (Cu-radiation), where the intensities are greater than 12% and 13%, respectively, of the 100% signal at 15,7°, especially the intensities can be for both peaks up 24,5 % for peak 20,9° and 25,5% for peak 26,0° ( ⁇ 0,2°), most preferred are 29 % to 46% for peak 20,9° and 30,5% to 48,5% for peak 26,0° ( ⁇ 0,2°) respectively in relation to the 100% peak at 15,7° measured with capillary technique (Laue technique).
  • Single crystal analysis is a method to characterize the contents of the two different domains in the Form AB.
  • Refined batch scale factors which are based on the reflections having odd / as Miller indices referring to the Form II, represent the proportion of the respective domains.
  • a batch scale factor which represents 60 to 95% of Form Il in respect to that of Form I is preferred for Form AB.
  • the resulting crystallographic fl-value in the single crystal refinement of Form Il is suited to characterize the contents of the different domains in Form AB.
  • the /7-values obtained for a refinement in Form I and Form II, respectively, are correlated according to Figure 1 and therefore represent the relative proportion of domains in the Form AB.
  • a ratio of refined crystallographic f?-values which represent a proportion of 60 to 95% Form Il domains in Form AB is preferred.
  • Acetyl salicylic acid in pure Form I is soluble in water with about 3,5 g/L at 25 0 C.
  • 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.
  • 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.
  • Form AB of acetyl salicylic has higher solubility properties in water at the same temperature.
  • 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 0 C for Form AB the dissolution rate is increased by a factor of 2 which improves the effectiveness of a drug by time after intake.
  • 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 0 C.
  • the Form AB with a content of 60% domains Form Il dissolves up to 9 grams in 5 mL of hot water at 80 0 C.
  • 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 CaCI 2 .
  • Form AB does not show any significant variation of intensities of the characteristic signals in the CP-MAS 13 C NMR experiment, the PXRD, the NIR spectrum or the single crystal experiments. Form AB is stable for several weeks and up to 6 months when kept under dry conditions at room temperature.
  • Acetyl salicylic acid as Form AB is characterized by comprising interlaced or intergrown crystals of Form I and Form II, wherein the molecules of acetyl salicylic acid are arranged according to the schematic drawing given in Figure 2 and wherein the arrangement A of Figure 1 contains centrosymmetric C-H- O dimers, which are located between the slabs shown in the lower part of Figure 2, arrangement B contains C-H- O catemers, arranged along a twofold screw axis, as shown in the upper part of the Figure 2.
  • the intermediate region in the central layer (Intergrowth region) is only for illustration, because all slabs with
  • Acetyl salicylic acid as Form AB is characterized by a signal in the 13 C CPMAS NMR spectrum at 20.5 ⁇ 0.5 ppm. This characteristic signal can exhibit an intensity that amounts for 10 to 90% of the signal at 19,8 ppm and has typically an intensity which is equal or higher than the 19,8( ⁇ 0,5) ppm signal as shown in Figure 3.
  • Acetyl salicylic acid as Form AB is characterized by a brought signal in the NIR spectrum at about 5200 cm “1 , and a brought signal at about 6900 cm “1 .
  • the first signal ranges from about 4800 to 5500 cm “1 and the second from about 6500- 7200 cm “1 as shown in Figure 4 for Form AB where the contents of Form Il in the domains is about 60%.
  • Acetyl salicylic acid as Form AB is characterized by a melting point of 125 to 128 0 C by thermal microscopy (heating rate 2 °C/min) wherein the Form AB comprises domains of Form Il of about 60%.
  • a process for producing acetyl salicylic acid as Form AB is to crystallize acetyl salicylic acid with or without addition of 1-10% salicylic add from a saturated solution in acetonitrile, particularly at a temperature of 50 to 70 °C and rapid cooling to 0 to 25 °C, typically from about 60 °C to about 20 °C within 5 minutes.
  • any further additives to the saturated solution is omitted.
  • the synthesis of acetyl salicylic acid as Form AB employs crystallization from Form I by rapid cooling but without any further additive.
  • a second process for producing acetyl salicylic acid as Form AB is to favourably adding salicylic acid to acetic acid anhydrate, keeping the mixture at elevated temperature (elevated temperature may be best 50 °C but 40 °C up to bolling point will also work) until the salicylic acid is dissolved, the reaction mixture is subsequently cooled and the precipitate is isolated directly, especially instantaneously recrystallized from water at boiling heat.
  • elevated temperature may be best 50 °C but 40 °C up to bolling point will also work
  • Subsequent cooling Ia meant as rapid cooling from elevated temperature to 0 to 25 °C within a short period of 5 to 10 minutes. Generally the cooling takes place in a water bath, under running water or with an ice bath.
  • This process can b ⁇ catalyzed by adding a proton donor, typically as an acid.
  • a proton donor typically as an acid.
  • Typical proton donors are organic or inorganic acids, especially mineral acids as hydrochloric acid, sulphuric acid, but proton donors as proton sponges or montmorlllonit can also be used.
  • the precipitate and/or the recrystallized material is isolated and r ⁇ crystallis ⁇ d from a saturated solution of acetonitrile. Favourably it is recrystallized by rapid cooling of the saturated solution of acetonitrile from SO to 70 a C down to 0 to 25 a C, typically from SO 0 C to 25 0 C within 10 min of alternatively within 5 min. Rapid cooling is generally performed in a wafer bath, under running water or with an ice bath.
  • the isolated crystallized precipitate and/or the recrystailized material is immediately recrystallized from water, alcohols, ethers or heterocyclic aromatic compounds, wherein the recrystallization is performed from solutions at elevated temperature. Elevated temperatures are 40 °C to the boiling point of the mentioned solvents.
  • the isolated crystallized precipitate and/or the recrystailized material is immediately recrystallized from any solvent in which acetyl salicylic acid can be solved. It is appropriate to solve the isolated crystallized precipitate and/or the recrystailized material of acetyl salicylic acid at elevated temperatures up to the boiling point of each solvent, followed by rapid cooling and immediate isolation
  • a crucial point of all crystallization and recrystaization steps is that the resulting precipitate is isolated or trie next recrystallization step is performed immediately, which is as fast as possible.
  • the Isolated Form AB of acetyl salicylic acid is dried by evaporation of the solvent at elevated temperatures and/or at reduced pressure, typically at 30 °C and/or 20 mbar.
  • Acetyl salicylic acid as Form AB obtainable by one of the processes according to one of the following processes a) to f) wherein the solubility of the obtained product in water is improved with respect to Form I and wherein the product is stable at room temperature.
  • any further addotives to the saturated solution are omitted.
  • a process for producing acetyl salicylic add as Form AB is to favourably adding salicylic acid to acetic acid anhydrate, keeping the mixture at elevated temperature, particularly elevated temperature may be best 50 °C but 40 °C up to boiling will also work, until the salicylic acid is dissolved, the reaction mixture is subsequently cooled and the precipitate is isolated directly, especially instantaneously recrystallized from water at boiling heat.
  • the ratio of Form II domains can be increased and subsequent cooling is meant as rapid cooling from elevated temperature to 0 to 25 °C within a short period of 5 to 10 minutes.
  • 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 m ⁇ ntrnorlilonit can be also used.
  • the precipitate and/or the recrystallized material is isolated and recrystallized from a saturated solution of acetonitrile. Favourably it is recrystallized by rapid cooling of the saturated solution of acetonitrile, particularly from 50 to 70 °C down to 0 to 25 °C, typically from 60 °C to 25 °C within 10 min or alternatively within 5 min.
  • rapid cooling is generally performed in a water bath, under running water or with an ice bath.
  • a typical process to produce acetyl salicylfc acid Form AS with a content of 60% domain Form Il comprises the following procedure: 9,6 grams of $altcyiic acid are added to 20 mL acetic acid anhydrate as well as 16 drops of cone. Sulphuric acid. The mature is warmed to 50 0 C and kept at this temperature for 10 min. This mixture is added to 25 ml water (demineralised) at room temperature which causes an immediate crystallization and a second, viscous phase which is washed with 25 mL water and cooled 15 mm. in an ice bath. The product crystallines as a white powder, which can be filtered and dried in a desiccator above CaCl 2 . 9.1 g of acetyl salicylic acid Form AB could be Alternatively the following two recrystallization steps can subsequently be performed to improve the ratio of domains Form Il in Form AB and to increase the stability of Form AB:
  • Example 2 9,6 g Salicylic acid (p.a.) is dissolved in 20 mL acetic acid anhydrate (p.a.) in a 100 mL Erlenmeyer flask to achieve a clear solution at room temperature. 16 drops of sulphuric acid (cone, p.a.) are added and the heated to 50 °C under stirring for 10 min. The clear solution is poured into 25 mL of water (dest., RT). Crystallization starts at the boundary of an oily and the aqueous phase.
  • sulphuric acid cone, p.a.
  • a further aspect of the present invention is a pharmaceutical formulation comprising acetyl salicylic acid as form AB.
  • the pharmaceutical formulation may be in form of a tablet, capsule, sachet, instant release formulation, controlled release formulation, sustained released formulation, delayed release formulation, powder, and compressed powder etcetera.
  • the formulation further comprises common excipients.
  • 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 CaCI 2 or other compounds that are able to bind water physically or chemically to stabilize Form AB by other means.
  • acetyl salicylic acid as Form AB for the production of a medicament to be used as means for headache, migraine, as analgesic agent, as antipyretic, antiinflammatory, as an antiplatelet agent, as rheumatic agent and in long-term low- doses to prevent heart attacks and cancer.
  • Acetyl salicylic acid as Form AB is an analgesic (against minor pains and aches), antipyretic (against fever), and anti-inflammatory agent. It has also an antiplatelet ("blood-thinning") effect and is used in long-term low-doses to prevent heart attacks and cancer.
  • acetyl salicylic acid Form AB irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation, and this blood-thinning property makes it useful for reducing the incidence of heart attacks.
  • Acetyl salicylic acid Form AB produced for this purpose shall contain 75 or 81 mg.
  • High doses of acetyl salicylic acid Form AB is given immediately after an acute heart attack. These doses may also inhibit the synthesis of prothrombin and may therefore produce a second and different anticoagulant effect.
  • Figure 1 Fractional composition of acetyl salicylic acid Form AB domains Form I and Form Il in the single crystal; batch scale factor applied to odd / reflections x 100, derived from refined crystallographic R values.
  • FIG. 1 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
  • arrangement B contains C-H -O catemers, arranged along a twofold screw axis, as shown in the upper part of the Figure.
  • the intermediate region in the central layer (Intergrowth region) is only for illustration, because all slabs with O-H- O hydrogen bonds are identical (O-H- O slab).
  • FIG. 3 ASS2 (middle curve) displays the signal of the methyl group in CP-MAS C 13 -NMR solid state spectrum of Form I in ppm.
  • ASS1 shows the signal of the methyl groups in CP-MAS C 13 -NMR solid state spectrum of Form AB with a low content of domains of Form Il in ppm.
  • ASS3 (upper curve) shows the signal of the methyl groups in CP-MAS C 13 -NMR solid state spectrum of
  • Figure 4 NIR-Spectrum of Form I (lower curve) and Form AB with 60% content of Form Il domains (upper curve) in cm "1 .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne une nouvelle forme de l'acide acétyl-salicylique désignée sous la forme AB, ainsi que des procédés pour sa préparation et une formulation la comportant.
PCT/EP2006/010698 2006-09-26 2006-11-08 Forme ab de l'acide acétyl-salicylique WO2008037289A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2007/008054 WO2008037366A2 (fr) 2006-09-26 2007-09-17 Formes ab a l'etat solide d'acide acetyl salicylique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006045780.3 2006-09-26
DE200610045780 DE102006045780A1 (de) 2006-09-26 2006-09-26 Mischkristalle der Form I und Form II der Acetylsalicylsäure

Publications (1)

Publication Number Publication Date
WO2008037289A1 true WO2008037289A1 (fr) 2008-04-03

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PCT/EP2006/010698 WO2008037289A1 (fr) 2006-09-26 2006-11-08 Forme ab de l'acide acétyl-salicylique

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DE (1) DE102006045780A1 (fr)
WO (1) WO2008037289A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104151163A (zh) * 2014-07-14 2014-11-19 西安交通大学 一种阿司匹林的晶型及其制备方法和应用

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BOND, ANDREW D. ET AL: "On the polymorphism of aspirin: crystalline aspirin as intergrowths of two "polymorphic" domains", ANGEWANDTE CHEMIE, INTERNATIONAL EDITION, vol. 46, no. 4, 2007, pages 618 - 622, XP002438564 *
BOND, ANDREW D. ET AL: "On the polymorphism of aspirin: crystalline aspirin as intergrowths of two "polymorphic" domains", ANGEWANDTE CHEMIE, INTERNATIONAL EDITION, vol. 46, no. 4, 2007, pages S1 - S12, XP002438565 *
VISHWESHWAR, PEDDY ET AL: "The Predictably Elusive Form II of Aspirin", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 127, no. 48, 2005, pages 16802 - 16803, XP002438562 *
VISHWESHWAR, PEDDY ET AL: "The Predictably Elusive Form II of Aspirin", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 127, no. 48, 2005, pages S1 - S6, XP002438563 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104151163A (zh) * 2014-07-14 2014-11-19 西安交通大学 一种阿司匹林的晶型及其制备方法和应用
CN104151163B (zh) * 2014-07-14 2016-08-24 西安交通大学 一种阿司匹林的晶型及其制备方法和应用

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