ANDRE VANIA MAFALDA DE OLIVEIRA (PT)
SILVA LUIS MANUEL CUNHA (PT)
SANTOS PEDRO PAULO DE LACERDA E OLIVEIRA (PT)
EMPIS JOSE MANUEL ABECASSIS (PT)
DUARTE MARIA TERESA NOGUEIRA LEAL DA SILVA (PT)
ANDRE VANIA MAFALDA DE OLIVEIRA (PT)
SILVA LUIS MANUEL CUNHA (PT)
SANTOS PEDRO PAULO DE LACERDA E OLIVEIRA (PT)
EMPIS JOSE MANUEL ABECASSIS (PT)
WO2007017894A2 | 2007-02-15 | |||
WO2008050185A2 | 2008-05-02 | |||
WO2007092758A2 | 2007-08-16 | |||
WO2008114270A1 | 2008-09-25 | |||
WO2007017893A2 | 2007-02-15 | |||
WO2005037788A1 | 2005-04-28 | |||
WO2005068425A1 | 2005-07-28 | |||
WO2007020009A1 | 2007-02-22 | |||
WO2001087835A1 | 2001-11-22 | |||
WO2005059609A1 | 2005-06-30 | |||
WO2005108365A1 | 2005-11-17 |
EP1647547A1 | 2006-04-19 | |||
EP1296947B1 | 2004-02-04 | |||
EP1676839A2 | 2006-07-05 | |||
EP1296948A2 | 2003-04-02 | |||
EP0049658A1 | 1982-04-14 | |||
US4508729A | 1985-04-02 | |||
PT73755A | 1981-11-01 | |||
EP0308341A1 | 1989-03-22 | |||
PT88527A | 1988-10-01 | |||
EP1296947A1 | 2003-04-02 | |||
EP1294689A1 | 2003-03-26 | |||
EP1676839A2 | 2006-07-05 | |||
EP1296948A2 | 2003-04-02 | |||
EP1636185A1 | 2006-03-22 | |||
EP1647547A1 | 2006-04-19 |
CLAIMS 1. Crystalline hydrated form of perindopril erbumine (I) characterized in that it has a stoichiometry of 1:1:1.25 between the perindopril anion, the erbumine cation and the water molecules, it crystallizes in the triclinic soace group PI with the cell parameters a=6.578(1) A, b=12.104(1) A, c=16.729(4) A, a=97.919 (4) °, β=9 .762 ( 4 ) ° , γ=91.321(4)° and it presents a X-ray powder diffraction pattern with peaks at 9.51, 15.32 and 21.68 ± 0.02 degrees in 2Θ. 2. Crystalline hydrated form of perindopril erbumine (I), according to claim 1, characterized in that it displays a X-ray powder diffraction pattern with peaks at 9.51, 15.32, 15.50, 15.68, 16.10, 21.06, 21.43, 21.68 ± 0.02 degrees in 2Θ. 3. Crystalline hydrated form of perindopril erbumine (I) according to the previous claims, characterized in that it crystallizes in the triclinic system and it has its molecular structure determined by single crystal X-ray diffraction. 4. Preparation process of the crystalline hydrated form of perindopril erbumine as defined in any of the previous claims, characterized in that it dissolves any of the polymorphic forms of perindopril erbumine in ethanol, or other alcohol containing between one to four carbon atoms, and let the solvent evaporate at room temperature (20-25°C) . 5. Preparation process of the crystalline hydrated form of perindopril erbumine as defined in claims 1, 2 or 3 characterized in that it dissolves a polymorphic form of perindopril erbumine in ethanol, or other alcohol containing between one to four carbon atoms, and crystallize by removal of the solvents or by distillation, or by changing the temperature, or by the addition of a non-solvent, or by seeding, or by the combination of any of the techniques described. 6. Preparation process of the crystalline hydrated form of perindopril erbumine as defined in claims 1 to 3 characterized in that it obtains the new form by grinding of the alpha, beta and gamma polymorphic forms of perindopril erbumine. 7. Preparation process of the crystalline hydrated form of perindopril erbumine as defined in claims 1 to 3 characterized in that it obtains the new form by crystallization from slurrying perindopril erbumine in ethanol, or other alcohol containing between one to four carbon atoms, for 48 hours, obtaining the thermodynamically most stable form. 8. Pharmaceutical composition containing the crystalline hydrated form of perindopril erbumine as defined in claims 1 to 3 characterized in that it comprises one or more pharmaceutically acceptable excipients. 9. Pharmaceutical composition containing the crystalline hydrated form of perindopril erbumine as defined in claims 1 to 3, and according to claim 7, characterized in that it equally comprises a diuretic. 10. Use of the crystalline hydrated form of perindopril erbumine as defined in claims 1 to 3, characterized in that is used in the production of drugs for the treatment or prevention of cardiovascular diseases. Date: September 23 , 2011 |
A NEW HYDRATED CRYSTALLINE FORM OF PERINDOPRIL ERBUMINE, METHODS FOR ITS PREPARATION AND ITS USE IN PHARMACEUTICAL PREPARATIONS
Field of invention Technical field
The invention concerns a new hydrated form of perindopril erbumine, as well as its preparation and its use in pharmaceutical preparations.
The invention is a new form of perindopril erbumine with formula I .
Prior art
Perindopril, with the chemical designation 2-methylpropane- 2-amine- ( 2 S , 3aS-7aS) -1- [ (2S) -2- [ [ (IS) -1-ethoxycarbonyl ) - butyl] amino] propanoyl] octahydro-lff-indole-2-carboxylic acid and of the formula II, is an important ACE (angiotensine conversion enzyme) inhibitor that is used as a successful drug for the treatment of hypertension.
Perindopril was first synthesised in 1981 and disclosed in EP49,658, US4,508,729 and PT73755. The synthesis is complex and a stereoisomer mixture is formed, which must be separated. The coupling reagent involved in the formation of the peptide bond is DCC, N, N' -dicyclohexylcarbodiimide . The substance as a pure (S,S,S,S,S) isomer is claimed therein as well as its acceptable pharmaceutical salts.
Perindopril is commercially available as a tertbutylamine (erbumine) salt of formula III that was described for the first time in 1988 in patents EP308,341 and PT88, 527. Both claim the synthesis of perindopril and its tertbutylamine (erbumine) salt.
Perindopril erbumine is usually commercialized in combination with a diuretic for the treatment of high blood pressure.
In recent years, several crystalline forms of perindopril erbumine have been successfully prepared and patents applied. X- Ray powder diffraction is the technique most widely used in the characterization and identification of the different polymorphic forms . EPl, 296, 947, EPl, 294, 689/EPl, 676, 839, EP1,296, 948, WO2007/017894 and WO2008/050185 disclose processes of preparation of forms alpha, beta, gamma, eta and theta, respectively. Other polymorphic forms are disclosed in EPl, 636, 185, WO2007/092758 and WO2008/114270.
EPl, 647, 547 discloses new crystalline forms of perindopril erbumine monohydrate, perindopril erbumine sesquihydrate and perindopril erbumine anhydrous and a process for their preparation thereof by dissolving perindopril erbumine in water or in water under the addition of a volatile water-miscible polar organic solvent, freezing and lyophilising. WO2007/017893 discloses a new process for the preparation of the monohydrated form of perindopril erbumine. O2005037788A1, O2005068425A1, WO2007020009A1 and WO2007092758 report other forms of perindopril erbumine.
Summary of the invention
The object of this invention is a new hydrated form of perindopril erbumine (1:1:1.25) characterized by different techniques, including powder and single crystal X-ray diffraction (PXRD and SCXRD, respectively) , being useful in the preparation of pharmaceutical products. This new form may be obtained by crystallization from an alcoholic solution or directly by grinding other forms. All the processes described lead to the new form starting from any polymorphic form of perindopril erbumine. Detailed description of the invention
According to the present invention, the novel process for preparing this new crystalline form of perindopril erbumine hydrate is advantageous as a highly pure product is obtained whose crystal structure is determined by single-crystal X-ray diffraction data and with characteristic 2Θ values in the X-ray powder diffractogram.
The final product is not hygroscopic and it is easy to use, facilitating its formulation. All the preparation steps are easy to execute, namely drying and filtration. Very high yields are achieved, close to 100%, occurring losses of product only in the materials used during the process. The new hydrate of perindopril erbumine is obtained from grinding of forms alpha, beta or gamma of perindopril erbumine.
The powder X-Ray diffractogram of this novel perindopril erbumine hydrate form was measured under the following experimental conditions: the instrument used was a D8 Advance Bruker AXS Θ-2Θ diffractometer, with a copper radiation (Cu Kcc, λ=1.5406 A) and a secondary monochromator, operated at 40kV and 30mA; measurement temperature was 20 °C; the measurement range of 2Θ was 3-38° and step size was 0.01 in 2Θ; scan type was continuous. Single-crystal X-ray structure of the new hydrated form of perindopril erbumine was determined at 150K on a Bruker AXS-KAPPA APEX II diffractometer with graphite-monochromated radiation (Mo Κα, λ=0.71069 A). The X-ray generator was operated at 50 kV and 30 mA; the X-ray data collection was monitored by SMART program (Bruker, 2003) . All the data were corrected for Lorentzian, polarization and absorption effects using SAINT and SADABS (Bruker, 2003) programs. SIR97 was used for structure solution and SHELXL-97 was used for full matrix least-squares refinement on Έ 2 . All non-hydrogen atoms were refined anisotropically . H atoms were added in calculated positions and refined riding on their host atoms. From this analysis the bond distances and angles of perindopril anions and erbumine cations are determined as well as their conformations. All the chiral centers of perindopril anion were confirmed.
The present invention as disclosed herein relates to a novel process that leads to the formation of a new hydrated form of the perindopril erbumine salt. The water is in a 1.25 to 1 proportion relatively to the perindopril anion and erbumine cation.
This new form is prepared by perindopril erbumine form alpha commercially available or obtainable, for example through the techniques described in patent WO 01/87835 or in patent applications WO 2005/059609 and WO 2005/108365, by dissolution in alcohols containing between one and four carbon atoms. The use of other perindopril erbumine polymorphic forms to synthesize the novel hydrate is also possible. The alcoholic solution of any of these forms is stirred for a few minutes for complete dissolution and left to crystallize by slow evaporation in an open vessel, at room temperature. Crystals are formed after one day.
The crystallization process can also be performed by partial removal of the crystallization solvent or by distillation, or by variable temperature, or by addition of a non-solvent, or by seeding or by the combination of any of the techniques mentioned. Alternatively, the new form can be synthesized by mechanochemistry starting from different perindopril erbumine polymorphic forms. echanochemical synthesis consists of grinding perindopril erbumine form a, in the presence of small amounts of ethanol, to obtain the pure new form in a fast and quantitative way. This experimental technique was successfully used in the synthesis of the new hydrated form starting from other crystalline forms.
The novel hydrate of perindopril erbumine hydrate thus obtained by the different synthetic pathways previously described exhibits characteristic XRPD pattern with the main peaks observed at the following angles 2Θ: 9.508, 15.315, 15.497, 15.676, 16.102, 21.064, 21.429, 21.677° (only main peaks with intensity higher than 30% are listed) .
The peaks at 9.508 (the most intense), 15.315 and 21.677° are the ones that better distinguish this form from all the others reported in the literature.
Single crystal structure of this novel hydrated form was determined, with the following crystallographic data: C19H31N2O5. C4H12 1.1.25H 2 0, M r =466.60, triclinic symmetry, space group PI, unit cell parameters: a=6.578(1) A, b=12.104(1) A, c=16.729(4) A, a=97.919 (4) °, β=94.762 ( 4 ) ° , γ=91.321 (4) 0 , V=1313.9 A 3 ; Z=l, D c =l.167g/cm 3 , μ=0.084 mm "1 , 0 min =2.79°, 0 max =25.85 o , Rint=0.0760, R x (wR 2 ) =0.0661 (0.140 ) .
The asymmetric unit is represented in Figure 2, depicting the relative positioning of the atoms. The determination of the number of hydration water was done by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and confirmed by SCXRD.
Vibrational spectroscopy studies (Attenuated Total Reflection Fourier Transform Infrared, ATR-FT-IR, spectrum, in the range 3600-250 cm "1 , measured on a Matson 7000 FT-IR spectrometer equipped with a Specac Golden Gate Mk II ATR accessory having a diamond top-plate and KRS-5 focusing lenses; and Fourier Transform Raman, FT-Raman, spectrum, in the range 4000-300 cm "1 , recorded on a Bruker RFS 100 spectrometer with a Nd:YAG coherent laser, λ = 1064 nra) support the structural features unveiled by single crystal X-ray diffraction data which are reflected in the spectra through a number of diagnostic bands.
In particular the strong bands in the range of 3200-2600 cm "1 are attributed to the u s (C-H) and u s (N-H) stretching vibrational modes diagnosting the presence of NH and NH 3 + groups in the perindopril anion and erbumine cation, respectively.
The strong bands at 1642, 1569 cm -1 and 1387 cm -1 are assigned to the u s (COO " ) and u as (COO " ) respectively, confirming the deprotonation of the carboxylic acid group. ATR-FT-IR spectrum is represented in Figure 3 and FT-Raman is represented in Figure .
The thermal analysis were performed in different devices: thermogravimetric analysis (TGA) was carried out using a Shimadzu TGA 50 apparatus, from room temperature to ca . 300 °C, with a heating rate of 2°C/min, under a continuous nitrogen stream with a flow rate of 20 cm 3 /min; differential scanning calorimetry (DSC) study was performed in a Shimadzu DSC 50 equipment between the room temperature and ca . 160 °C, and using a heating rate of 2°C/min; hot-stage microscopy (HSM) experiments were carried out using a Linkam TP94 device connected to a Linkam LTS350 platinum plate.
Figures 5, 6 and 7 represent the DSC, TGA and HSM results, respectively.
TGA (Figure 6) shows a loss of approximately 5% in the range of 60-120°C and thus the ratio of 1 mol of salt to 1.25 mol of water is confirmed. The release of the crystallization water molecules can be verified in Figure 7 where water starts releasing at 84°C.
The combination of the three thermal analyses indicates that this novel hydrated form suffers simultaneous melting and decomposition at 120°C.
Stability tests to the form claimed here were performed using slurry techniques with ethanol. After 48 hours the product was identical to the starting material as verified by comparing both powder patterns. The same tests were performed to polymorphic forms alpha, beta and gamma and after 48 hours the product obtained was the new hydrated form claimed here (1:1:1.25), that remained unchangeable after 48 hours.
Shelf stability tests were performed proving that the product claimed is stable on shelf for 12 months as can be seen in Figure 9. The present invention is illustrated by the following Examples, but not limited by them.
Figures description
Figure 1 represents the XRPD diffractogram of the claimed perindopril erbumine hydrated form.
Figure 2 represents the molecular diagram of the claimed perindopril erbumine hydrated form (stoichiometry 1:1:1.25), obtained from SCXRD.
Figure 3 represents ATR-FT-IR spectra of the claimed perindopril erbumine hydrated form. Figure 4 represents the Raman-FT spectra of the claimed perindopril erbumine hydrated form.
Figure 5 represents the DSC data for the claimed perindopril erbumine hydrated form.
Figure 6 represents the TGA data for the claimed perindopril erbumine hydrated form. Figure 7 represents the HSM images for the claimed perindopril erbumine hydrated form.
Figure 8 represents the diffractograms obtained before (a) and after (b) of the slurry experiments using the new hydrated form of perindopril erbumine.
Figure 9 represents the powder patterns of the new hydrated of perindopril erbumine after the synthesis (a) and after 12 months in the shelf (b) .
Figure 10 represents the perindopril erbumine hydrated form.
Examples
Example 1:
0.0634 g (0.1436 mmol) of perindopril erbumine form alpha were dissolved in 3 mL of ethanol and stirred until dissolution. Solution was left standing at room temperature to crystallize by slow evaporation. Colourless plate-like crystals were formed. The XRPD pattern of the crystals formed contains the following peaks, in 2 Θ values: 9.51, 15.32, 15.50, 15.68, 16.10, 21.06, 21.43, 21.68° (±0.02) , characteristic of the new hydrated form. Example 2 :
0.1341 g (0.3036 mmol) of perindopril erbumine form alpha were dissolved in 6 mL of ethanol and stirred until dissolution. Solution was left standing at room temperature to crystallize by slow evaporation. Colourless plate-like crystals were formed, showing the XRPD pattern characteristic of the new hydrated form, mentioned in example 1.
Example 3:
15.4 g (34.09 mmol) of perindopril erbumine form alpha were dissolved in 150 mL de of ethanol and stirred until dissolution. Solution was left standing at room temperature to crystallize by slow evaporation. Colourless plate-like crystals were formed, showing the XRPD pattern characteristic of the new hydrated form, mentioned in example 1.
Example 4 :
0.3319 g (0.7516 mmol) of perindopril erbumine form alpha were dissolved in 6 mL of ethanol and stirred until dissolution. Stirring was maintained during the crystallization process by slow evaporation at room temperature. White powder was formed with the XRPD pattern characteristic of the new hydrated form, mentioned in example 1.
Example 5 :
0.1163 g (0.2633 mmol) of perindopril erbumine form alpha were dissolved in 2 mL of methanol and stirred until dissolution. Solution was left standing at room temperature to crystallize by slow evaporation. Colourless plate-like crystals were formed, showing the XRPD pattern characteristic of the new hydrated form, mentioned in example 1. Example 6:
0.0773 g (0.1750 mmol) of perindopril erbumine form beta were dissolved in 7 mL of ethanol and stirred until dissolution. Stirring was maintained during the crystallization process by slow evaporation at room temperature. White powder was formed with the XRPD pattern characteristic of the new hydrated form, mentioned in example 1.
Example 7 :
0.0484 g (0.1096 mmol) of perindopril erbumine form gamma were dissolved in 4 mL of ethanol and stirred until dissolution. Stirring was maintained during the crystallization process by slow evaporation at room temperature. White powder was formed with the XRPD pattern characteristic of the new hydrated form, mentioned in example 1.
Example 8 :
0.2578 g (0.5838 mmol) of perindopril erbumine form alpha were manually ground using an agate mortar and pestle for 30 minutes in the presence of a few drops of ethanol used to keep the powder slightly wet. The white powder obtained displays the XRPD pattern characteristic of the new hydrated form, mentioned in example 1.
Example 9:
0.3653 g (0.8298 mmol) of perindopril erbumine form beta were manually ground using an agate mortar and pestle for 30 minutes in the presence of a few drops of ethanol used to keep the powder slightly wet. The white powder obtained displays the XRPD pattern characteristic of the new hydrated form, mentioned in example 1. Example 10:
0.3832 g (0.8704 mmol) of perindopril erbumine form gamma were manually ground using an agate mortar and pestle for 30 minutes in the presence of a few drops of ethanol used to keep the powder slightly wet. The white powder obtained displays the XRPD pattern characteristic of the new hydrated form, mentioned in example 1.
Date: September 23 th , 2011