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EP1155033A1 - Procede de preparation d'un amide n- n- n-(4-piperidin- 4-yl)butanoyl)- n-ethylglycyl]- (l)-aspartyl]-(l)- $g(b)-cyclohexylalanine cristallin non hygroscopique stable - Google Patents

Procede de preparation d'un amide n- n- n-(4-piperidin- 4-yl)butanoyl)- n-ethylglycyl]- (l)-aspartyl]-(l)- $g(b)-cyclohexylalanine cristallin non hygroscopique stable

Info

Publication number
EP1155033A1
EP1155033A1 EP99969282A EP99969282A EP1155033A1 EP 1155033 A1 EP1155033 A1 EP 1155033A1 EP 99969282 A EP99969282 A EP 99969282A EP 99969282 A EP99969282 A EP 99969282A EP 1155033 A1 EP1155033 A1 EP 1155033A1
Authority
EP
European Patent Office
Prior art keywords
piperdin
butanoyl
aspartyl
ethylglycyl
hygroscopic
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99969282A
Other languages
German (de)
English (en)
Inventor
Jean Rene Authelin
Alain Thouzery
Fabrice Mangin
Pierre Bailly
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharmaceuticals Inc
Original Assignee
Aventis Pharmaceuticals Inc
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 Aventis Pharmaceuticals Inc filed Critical Aventis Pharmaceuticals Inc
Publication of EP1155033A1 publication Critical patent/EP1155033A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala

Definitions

  • This invention is directed to a process for preparing a non-hygroscopic stable crystalline polymo ⁇ h of -[ -[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)- ⁇ -cyclohexyl- alanine amide.
  • this invention is directed to a method of converting the hygroscopic polymorph ofN-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)- ⁇ -cyclohexyl- alanine amide to its stable, non-hygroscopic crystal form.
  • N- N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)- ⁇ -cyclohexyl-alanine amide possesses antithrombotic activity, including the inhibition of platelet aggregation and thrombus formation in mammals, and is useful in the prevention and treatment of thrombosis associated with disease states such as myocardial infarction, stroke, peripheral arterial disease and disseminated intravascular coagulation.
  • N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)- ⁇ -cyclohexylalanine amide and general conditions for converting the hygroscopic polymo ⁇ h to the non-hygroscopic crystal form under static and dynamic conditions are described in WO 98/07696.
  • the static procedure involves exposing the hygroscopic polymorph to temperatures of from about 40 °C to about 80 °C and relative humidity (RH) of about 65% to about 80% in a non-moving vessel.
  • the dynamic procedure involves agitating the hygroscopic polymorph, for example by tumbling in a rapidly rotating rotary evaporation flask or by propeller agitation in a cylindrical vessel, under the humidity and temperature levels described for the static model.
  • the temperature and humidity levels are achieved by injecting humidified air into a sealed chamber at the desired temperature or by introduction of water vapor under vacuum into a sealed chamber or into a conversion apparatus such as the heated flask of a rotary evaporator.
  • this invention is directed to a method of preparing non-hygroscopic, crystalline N- [N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)- ⁇ -cyclohexylalanine amide comprising
  • the non hygroscopic, crystal form of N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycyl]-(L)-aspartyl]-(L)- ⁇ -cyclohexylalanine amide prepared as described herein has advantageous properties which render is especially suitable for subsequent formulation.
  • this invention is directed to the non hygroscopic, crystalline N-[N-[N-(4-piperdin-4-yl)butanoyl)- N-ethylglycyl]-(L)-aspartyl]-(L)- ⁇ -cyclohexylalanine amide prepared according to the method described herein.
  • N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)- ⁇ - cyclohexylalanine amide means any crystalline polymo ⁇ h of N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethyIglycyl]-(L)-aspartyl]-(L)- ⁇ -cyclohexylalanine amide, or mixtures thereof.
  • N-[N-[N-(4- piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-(3-cyclohexylalanine amide for use in the process described herein is the hygroscopic crystalline polymorph prepared as described in PCT Patent Application Publication Nos. WO 95/10295 and WO 98/07696 and U.S. Patent Application Ser. No. 60/061 ,719, inco ⁇ orated herein by reference.
  • the relative humidity required for converting N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycyl]-(L)-aspartyl]-(L)- ⁇ -cyclohexylalanine amide to its non-hygroscopic crystal form is achieved by injecting humidified air into a chamber such as a humidity oven as described in WO 98/07696, or into a sealed reaction vessel such as a fluidized bed dryer, or preferably, by injecting water vapor into a reaction vessel under vacuum.
  • this invention is directed to a method of preparing non- hygroscopic N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspa ⁇ yl]-(L)- ⁇ -cyclohexylalanine amide comprising:
  • Preferred conditions of temperature and relative humidity for the crystal form conversion are a relative humidity of about 65% to about 80% and a temperature of about 55 °C to about 100 °C. More preferred conditions of temperature and relative humidity are a relative humidity of about 75% and a temperature of about 60 °C to about 80 °C.
  • RH Relative humidity
  • P H20 and P S H20 are the partial pressure of water and the pressure of saturated water vapor, respectively, at the temperature in question.
  • the partial pressure of the water vapor equals the total pressure; therefore, the relative humidity can be readily controlled by regulating the total pressure in the chamber.
  • the necessary condition is that the chamber, except for the introduction of the water vapor, be completely air and water tight so that the entry of ambient air does not dilute the water vapor.
  • the chamber must remain at constant temperature, otherwise unless the water pressure is homogeneous, the pressure of saturated vapor and also the relative humidity will change locally.
  • the saturating pressure and the partial pressures corresponding to relative humidities ranging from 60 to 100%> for temperatures between 55 and 65 °C are given in Table 1.
  • Table 1 For example, if the chamber is equilibrated at 159 mbar, which corresponds to 80%) RH at 60 °C, a cold point at 55 °C will cause the appearance of condensation. A cold point at 57 °C will be exposed to a RH of about 90%, so that there is a risk of product in this area deliquescing.
  • the form conversion is accomplished in any reaction vessel capable of maintaining uniform temperature throughout with no cold points and no pressure gradient.
  • Preferred reaction vessels for the form conversion are bicone dryers, such as the bicone dryers available from Italvacuum Company. Bicones from the Italvacuum Company have an internal system of knives called "crushers" designed for coarse grinding of the powder therein (analogous equipment exists in other drying systems such as Guedu dryers, Inox Maurer stirring ovens, etc.). The parts of the bicone exposed to water vapor are double-walled and insulated.
  • the conversion is typically accomplished over about 4 to about 36 hours, depending on the quantity ofN-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)- ⁇ -cyclohexylalanine amide to be converted, temperature and relative humidity. In general, conversion is slower at lower temperatures or lower relative humidity. As discussed herein, the product should be removed from humidification as soon as conversion is complete. The progress of the conversion is monitored by removing samples from the reaction vessel for analysis, for example by x-ray crystallography.
  • the N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycyl]-(L)-aspartyl]-(L)- ⁇ -cyclohexylalanine amide starting material is optionally milled prior to undergoing conversion to the non-hygroscopic crystal form.
  • Milling or grinding refers to physically breaking up the large particles or aggregates of particles contained in the N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)- ⁇ - cyclohexylalanine amide starting material using methods and apparatus well known in the art for particle size reduction of powders.
  • the grinding is preferably performed on a conical-screen grinding mill such as a Quadro Comill grinding mill or C.M.A. grinding mill.
  • the material is forced to pass through the screen by a moving body in the shape of an anchor.
  • Preferred screens have round holes with a diameter of about 610 ⁇ m to about 630 ⁇ m.
  • Rotation under humidification also tends to increase the population of large particles or aggregates of particles.
  • These large particles or aggregates of particles can be broken up using the internal crushers of the bicone.
  • the population of these large particles or aggregates is more advantageously controlled by reducing their formation by minimizing the period of rotation under humidification. rather than through use of the internal crushers. Accordingly, in a preferred aspect of this process, the conversion is accomplished with the internal crushers turned off.
  • the non-hygroscopic crystalline N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)- aspartyl]-(L)- ⁇ -cyclohexylalanine amide prepared as described above is optionally sieved to remove coarse particles. "Sieving” or “screening” refers to the operation of sorting particles by size. "Passes" means particles which pass through the screen and "waste” means the coarse particles which are left behind.
  • the coarse particles are recycled by recrystallization as described in WO 95/10295, WO 98/07696 and U.S. Patent Application Ser. No. 60/061.719 to form hygroscopic N-[N-[N-(4-piperdin-4- yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)- ⁇ -cyclohexyl-alanine amide, which is then converted to the non-hygroscopic crystal form as described above.
  • Crystalline hygroscopic N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)- ⁇ - cyclohexylalanine amide (41.54 kg) is introduced in the screw feeder and milled at a mass flow of 40 kg/hour in a conical-screen grinding mill (100 mm, 630 ⁇ m opening grid) equipped with a double screw feeder, type K-Tron, T35.
  • the milled product is stored in Polyethylene bags.
  • Water vapor is generated by introducing purified water into a 50-liter stainless tank, the double walls of which are heated at 68 °C with a bank of heaters. Water vapor is transported toward the bicone through a double-walled pipe heated to 60 °C.
  • the temperature regulation system of the pipe is the same as that of the vacuum arm (not heat-insulated in Italvacuum's standard 350-liter pilot plant).
  • a manual control valve made it possible to control the flow rate of the water vapor.
  • the vapor In the bicone, the vapor is guided toward the chamber through a pipe concentric with the vacuum pipe.
  • the piping is designed to admit a vapor flow rate on the order of 5 kg/h, i.e. it permits the quantity to be added equivalent to that needed for the transformation (about 4%> of the weight, or 1.2 kg) in less than one hour.
  • the vacuum system contains first a cyclone topped with a bag filter followed by a safety gauntlet, then a condenser cooled to 5 °C with a cooling battery.
  • the condenser is efficient enough to condense almost all the vapor.
  • the vacuum is ensured by a pump with a liquid ring.
  • the vacuum is regulated by aspirating air at the level of the vacuum pump.
  • a pressure probe is placed in the aspiration arm of the vacuum.
  • a RH probe also located in the aspiration arm, makes it possible to confirm the data indicated by the pressure probe. During operation, the operator confirms that the pressure data and data from the RH probe agree by using a table of equivalents.
  • the vacuum is broken by adding filtered nitrogen. To prevent a countercurrent of nitrogen from returning dust deposited in the arm of the dryer to the tank, nitrogen is introduced through the same pipe as the water vapor. Water vapor can be substituted for nitrogen by turning the valve.
  • the milled product is placed in a bicone dryer (Italvacuum, 350 L).
  • the jacket of the bicone has been previously heated to 60 °C.
  • the product is heated to 57 °C in the bicone (rotation 0.5 rpm) over 65 minutes.
  • the bicone is then put carefully under vacuum (60 mbar) in 10 minutes. Vapor coming from the boiler is introduced in the bicone.
  • the pressure is increased up to 150mbar within 35 minutes.
  • Rotation is maintained during 1.5 hours, after which the bicone is rotated during 5 minutes each hour.
  • the pressure is maintained at 150mbar (+/- lmbar) for 26 hours.
  • Crystalline hygroscopic N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)- ⁇ - cyclohexylalanine amide (68.68 kg) is introduced in the screw feeder and milled at a mass flow of 51.6 kg/hour in a conical-screen grinding mill (200 mm, 630 ⁇ m opening grid) equipped with a double screw feeder, type K-Tron, T35. The milled product falls directly into the bicone.
  • Water vapor is generated as described above by introducing purified water into a 150-liter stainless tank, the double walls of which are heated at 65 °C with a bank of heaters. The jacket of the pipe between the boiler and the bicone is heated at 60 °C.
  • the milled product is placed in a bicone dryer (Italvacuum, 600 L).
  • the jacket of the bicone has been previously heated to 61 °C.
  • the product is heated to 59 °C in the bicone (rotation 0.3 ⁇ m) over 165 minutes.
  • the rotation speed is decreased to 0.17 ⁇ m and the bicone is put carefully under vacuum (44 mbar) in 20 minutes.
  • Vapor coming from the boiler is introduced in the bicone and the pressure is increased up to 153 mbar within 25 minutes. Rotation is maintained for 40 minutes, then the bicone is rotated during 6 minutes each 2 hours.
  • the pressure is maintained at 154mbar (+/- lmbar) for 27.5 hours.
  • Water vapor is generated as described above by introducing purified water into a 150-liter stainless tank, the double walls of which are heated at 75 °C with a bank of heaters. The jacket of the pipe between the boiler and the bicone is heated at 75 °C.
  • the milled product is placed in a bicone dryer (Italvacuum. 600 L).
  • the jacket of the bicone has been previously heated to about 72°C.
  • the product is heated to about 72 °C in the bicone (rotation 0.34 rpm) over 3 hours.
  • the bicone is then put carefully under vacuum (231 mbar). Water vapor coming from the boiler is introduced in the bicone and the bicone is rotated at 0.34 ⁇ m for 5 hours. The rotation is then stopped and heating under vacuum is continued for an additional 8 hours.
  • the bicone is then emptied and the material is sieved on a 2 mm sieve. Yield: 172.5 kg (96%) (including samples for analysis and research pu ⁇ ose). Large particles (more than 2 mm in diameter): 2.1 kg. Lost product: 6.0 kg.
  • Carr index and density are measured following European Pharmacopoeia.
  • a 250 ml test tube is filled with powder up to ca. 220 ml.
  • the mass of the sample as well as the exact volume that it occupies (v 0) are determined.
  • the test tube is placed on an Engelsmann STAV 2003 volume meter, and the volume is determined after 0, 10, 50, 100, 250, and 500 blows.
  • the Carr Index is equal to:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne un procédé permettant de transformer le polymorphe hygroscopique de l'amide N-[N-[N- (4-pipéridin- 4-yl)butanoyl)- N-éthylglycyl]- (L)-aspartyl]-(L)- β-cyclohexylalanine en un polymorphe cristallin non hygroscopique stable.
EP99969282A 1998-12-30 1999-12-15 Procede de preparation d'un amide n- n- n-(4-piperidin- 4-yl)butanoyl)- n-ethylglycyl]- (l)-aspartyl]-(l)- $g(b)-cyclohexylalanine cristallin non hygroscopique stable Withdrawn EP1155033A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US11428998P 1998-12-30 1998-12-30
US114289P 1998-12-30
PCT/US1999/029969 WO2000040601A1 (fr) 1998-12-30 1999-12-15 Procede de preparation d'un amide n-[n- [n-(4-piperidin- 4-yl)butanoyl)- n-ethylglycyl]- (l)-aspartyl]-(l)- $g(b)-cyclohexylalanine cristallin non hygroscopique stable

Publications (1)

Publication Number Publication Date
EP1155033A1 true EP1155033A1 (fr) 2001-11-21

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP99969282A Withdrawn EP1155033A1 (fr) 1998-12-30 1999-12-15 Procede de preparation d'un amide n- n- n-(4-piperidin- 4-yl)butanoyl)- n-ethylglycyl]- (l)-aspartyl]-(l)- $g(b)-cyclohexylalanine cristallin non hygroscopique stable

Country Status (3)

Country Link
EP (1) EP1155033A1 (fr)
AU (1) AU2844800A (fr)
WO (1) WO2000040601A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1569912B1 (fr) 2002-12-03 2015-04-29 Pharmacyclics, Inc. Derives de 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine utilises en tant qu'inhibiteurs du facteur viia

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2890881B2 (ja) * 1990-06-27 1999-05-17 味の素株式会社 アミノ酸又は核酸の晶析法
US5780590A (en) * 1993-10-15 1998-07-14 Rhone-Poulenc Rorer Pharmaceuticals Inc. Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides
NZ275948A (en) * 1993-10-15 1997-02-24 Rhone Poulenc Rorer Pharma Antithrombotic azacycloalkylalkanoyl peptides
AP9901462A0 (en) * 1996-08-21 1999-03-31 Aventis Pharmaceuticals Products Inc Stable non-hygroscopic crystalline form of N-[N-N-(4-(Piperidin-4-YL)Butanoyl)-N-Ethylglycyl] amide.
EP0826660B1 (fr) * 1996-08-27 2002-04-03 Showa Denko Kabushiki Kaisha Cristaux non hygroscopiques d'acide p-aminométhylbenzoique et procédé pour leur préparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0040601A1 *

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Publication number Publication date
WO2000040601A1 (fr) 2000-07-13
AU2844800A (en) 2000-07-24

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Free format text: PROCESS FOR PREPARING A STABLE NON-HYGROSCOPIC CRYSTALLINE N-??N-??N-(PIPERDIN-4-YL)BUTANOYL)-N-ETHYLGLYCYL -(L)-ASPARTYL -SS-CYCLOHEXYLALANINE AMIDE