WO2015048937A1 - A solid form of ivabradine hydrochloride and (s)-mandelic acid and a pharmaceutical composition thereof - Google Patents

A solid form of ivabradine hydrochloride and (s)-mandelic acid and a pharmaceutical composition thereof Download PDF

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Publication number
WO2015048937A1
WO2015048937A1 PCT/CZ2014/000108 CZ2014000108W WO2015048937A1 WO 2015048937 A1 WO2015048937 A1 WO 2015048937A1 CZ 2014000108 W CZ2014000108 W CZ 2014000108W WO 2015048937 A1 WO2015048937 A1 WO 2015048937A1
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WO
WIPO (PCT)
Prior art keywords
cocrystal
mandelic acid
ivabradine hydrochloride
accordance
hydrochloride
Prior art date
Application number
PCT/CZ2014/000108
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English (en)
French (fr)
Inventor
Ondrej Dammer
Veronika SLADKOVA
Eliska SKOREPOVA
Gregor Sedmak
Original Assignee
Zentiva, K.S.
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.)
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Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2015048937A1 publication Critical patent/WO2015048937A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to a new solid form of ivabradine hydrochloride and (S)- mandelic acid, methods of its preparation and a physically stable pharmaceutical composition containing this solid form.
  • (I) is present in its hydrochloride form in medicinal products (original product Procorolan 5 mg; 7.5 mg). It is a representative of a newly constituted group referred to as the sinus node inhibitors or bradines.
  • the mechanism of action of ivabradine consists in inhibition of spontaneous depolarization of the sinus node cells by blocking the specific potassium channel If. Ivabradine efficiently reduces the heart rate and consequently the oxygen consumption by the myocardium. Ivabradine is used for symptomatic treatment of angina pectoris.
  • ivabradine and its salts are described in the patent EP 0 534 859.
  • a number of polymorphic forms of ivabradine hydrochloride are known. Servier have described the following polymorphs: alpha (EP 1 589 005), beta (EP 1 695 965), beta-d (EP 1 695 710), gamma (EP 1 707 562), gamma-d (EP 1 695 709), delta and delta d (WO2007042656 and WO2007042657).
  • Cocrystals are stoichiometric multi-component compounds composed of two or more molecular or ionic compounds that are in the solid state at the room temperature. Pharmaceutical cocrystals most frequently consist of a molecule of the active compound and a molecule of the cocrystallization partner (inactive molecule). The cocrystallization partner must meet the condition of pharmaceutical acceptability. Cocrystals are subject to intensive studying in pharmacology as they represent another numerous group of solid forms besides polymorphs, hydrates, solvates and salts. Cocrystals exhibit different physical-chemical properties, e.g. solubility or dissolution rate, which are directly related to the bioavailability of the active substances. Cocrystals of ivabradine, or ivabradine hydrochloride have not been described in the literature yet.
  • the invention provides methods for the preparation of a cocrystal of ivabradine hydrochloride and (S)-mandelic acid (IC1SM), its characterization and preparation of a pharmaceutical composition containing said cocrystal.
  • the prepared cocrystal manifests a high physical stability and thus it appears to be a suitable form of ivabradine hydrochloride useful in a pharmaceutical composition.
  • the high physical stability of the crystalline form exhibited a conversion rate of less than 3% molar after three months at 40°C and 75% RH.
  • the cocrystal is prepared by mixing of ivabradine hydrochloride, (S)-mandelic acid and a solvent, the solvent being selected from the group of C1-C4 alcohols, esters, ketones, ethers and dimethyl sulfoxide.
  • a convenient solvent is methanol, ethanol, ethyl acetate, acetone, dioxan.
  • Another possible preparation method is grinding of ivabradine hydrochloride and (S)- mandelic acid.
  • Another embodiment of the invention comprises a polymorphically stable pharmaceutical composition, comprising a cocrystal of ivabradine hydrochloride and (5)-mandelic acid. Still another embodiment of the invention comprises a granulate, composed of a cocrystal of ivabradine hydrochloride and (S -mandelic acid and at least one pharmaceutically acceptable excipient, said components being in an intimate contact with each other.
  • Fig. 1 X-ray powder pattern of a cocrystal.
  • Fig. 2. X-ray powder pattern of an ICISM cocrystal (top pattern). Diffraction patterns of the starting form of ivabradine hydrochloride (delta-d form; middle) and (S)- mandelic acid (bottom) are also given.
  • Fig. 3. ssNMR spectrum of am ICISM cocrystal (bottom) and comparison to the spectra of both the input components: (5)-mandelic acid at the top, delta d form of ivabradine hydrochloride in the middle.
  • Fig. 7 Raman spectrum of an ICISM cocrystal, comparison to the spectra of both the input components. Dashed line - spectrum of the delta d form of ivabradine hydrochloride, dotted line - spectrum of (S)-mandelic acid.
  • Fig. 8 Infrared spectrum of an ICISM cocrystal.
  • Fig. 9 Infrared spectrum of an ICISM cocrystal, comparison to the spectra of both the input components. Dashed line - spectrum of the delta d form of ivabradine hydrochloride, dotted line - spectrum of (5)-mandelic acid.
  • Fig. 10 DVS curve of an ICISM cocrystal.
  • the invention provides a new solid form of ivabradine hydrochloride, its cocrystal with (5 -mandelic acid with physical-chemical properties suitable for pharmaceutical use. It is especially the high physical stability of this solid form that makes it possible to obtain a stable pharmaceutical composition.
  • the invention describes preparation methods of a cocrystal of ivabradine hydrochloride with (5)-mandelic acid: (i) slow evaporation of the solvent (ethanol) from a solution containing ivabradine hydrochloride and ( ⁇ S)-mandelic acid; (ii) suspending the mixture of ivabradine hydrochloride and (S)-mandelic acid in a small amount of a solvent and subsequent agitation of the suspension in a shaker, (iii) kneading the mixture of ivabradine hydrochloride and (S)- mandelic acid in a ball grinder in the presence of a few drops of a solvent, (iv) slow and (v) abrupt cooling of the hot saturated solution containing ivabradine hydrochloride and (5)- mandelic acid.
  • Another possible preparation method may comprise (vi) spray drying of a solution of ivabradine hydrochloride and (5 ⁇ -mandelic acid in ethanol.
  • the thus prepared cocrystal of ivabradine hydrochloride with (S)-mandelic acid which has not been described in the literature, has been characterized by the following analytic methods: X- ray Powder Diffraction (XRPD), Single Crystal X-ray Diffraction (SXRD), Differential Scanning Calorimetry (DSC), Raman spectroscopy, IR spectroscopy, NMR spectroscopy and Dynamic Vapour Sorption (DVS).
  • XRPD X- ray Powder Diffraction
  • SXRD Single Crystal X-ray Diffraction
  • DSC Differential Scanning Calorimetry
  • Raman spectroscopy Raman spectroscopy
  • IR spectroscopy IR spectroscopy
  • NMR spectroscopy Dynamic Vapour Sorption
  • the crystalline form of the ICISM cocrystal in accordance with this invention is characterized by the reflections presented in Table 1.
  • Table 1 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of the ICISM cocrystal in accordance with this invention are: 11.0; 17.2; 17.9; 20.9; 24.5; 25.9° ⁇ 0.2° 2-theta.
  • the X- ray powder pattern is shown in Fig. 1.
  • Figure 2 shows the X-ray powder patterns of the ICISM cocrystal and those of the components from which the cocrystal has been prepared: the delta-d form of ivabradine hydrochloride (middle diffraction pattern) and (S)-mandelic acid (bottom diffraction pattern).
  • the stoichiometry of the cocrystal was evaluated using the NMR spectroscopy. It has been determined that the stoichiometric ratio in the cocrystal is 1:1; there is one molecule of (S)- mandelic acid per one molecule of ivabradine hydrochloride.
  • the crystalline structure of the ICISM cocrystal was determined using the single crystal X-ray diffraction.
  • the clear colourless crystal used was obtained by crystallization by cooling from a solution of ivabradine hydrochloride and (S)-mandelic acid in ethanol.
  • the structure was evaluated by direct methods (SIR92 program) and specified in the CRYSTALS 14.40b program. All non-hydrogen atoms were specified with thermal oscillations. The structure did not contain any traces of disorder or solvent presence.
  • Table 2 summarizes the cry stallo graphic data of the ICISM cocrystal.
  • the Raman spectrum of the ICISM cocrystal is shown in Figure 6.
  • the measured spectrum of the cocrystal is not a mere sum of the input components and thus this is not a mere physical mixture, as shown in Figure 7.
  • the observed changes in the cocrystal spectrum can be ascribed to the newly created interactions between ivabradine hydrochloride and (S)-mandelic acid. The most significant is a shift of the vibration of the (>S)-mandelic acid carbonyl by 30 cm "1 towards higher values of the wave number and changes of C-H vibrations in the vicinity of quaternary nitrogen. The observed changes are related to the occurrence of a new phase.
  • Fig. 9 shows the IR spectrum of the ICISM cocrystal and the spectra of the starting components. Neither the IR spectrum of the cocrystal is a mere sum of the input components, similarly to the Raman spectrum. Changes of (S ⁇ mandelic acid are observed: shift of the carbonyl band of the carboxylic group by 30 cm “1 to higher wave numbers and (ii) a drop of vibration intensity at 3500 cm "1 pertinent to the secondary alcohol. Further, the vibration intensity of the N-H* functional group of the hydrochloride at 2500 cm "1 changes, which corresponds to the newly formed interaction between ivabradine hydrochloride and (S)-mandelic acid.
  • the ICISM was further characterized with the dynamic vapour sorption.
  • the sample was loaded with two cycles of 0 - 90 - 0% relative humidity (RH). At 90% RH the sample increased its weight by 1.1% due to water sorption. During the subsequent desorption all the absorbed water was lost. The whole process appears to be reversible. The first cycle is identical to the second one.
  • the ICISM cocrystal is weakly hygroscopic.
  • the physical stability of the ICISM cocrystal was tested under two different conditions: 25°C/60% RH and 40°C/75% RH.
  • the samples were collected after 2 weeks, 1 and 3 months and analyzed using the X-ray diffraction method.
  • the X-ray patterns of the samples for both the stability conditions (25/60 and 40/75) at all the three time points of sampling were identical and were equal to the pattern measured before the stability testing.
  • the crystalline form of the ICISM cocrystal has not changed.
  • Table 3 contains the results of the stability testing of the crystalline form of the cocrystal and the starting crystalline form of ivabradine hydrochloride - delta-d form. While the cocrystal form has not changed, the delta-d form manifested transformation after one month of stability testing at the conditions of 25°C/60% RH already.
  • the invention further provides a pharmaceutical composition, comprising the above mentioned cocrystal and at least one pharmaceutically acceptable substance.
  • the composition may be prepared either with the use of the prepared cocrystal by means of common pharmaceutical processes (dry granulation, wet granulation, direct compression), or the cocrystal may be produced in-situ in the course of the preparation process of the composition by one of the above mentioned processes.
  • the resulting product has the form of a granulate consisting of the cocrystal and at least one pharmaceutically acceptable substance, which are in an intimate contact.
  • ivabradine hydrochloride was weighed into HPLC vials 50 mg (0.1 mmol) each and mixed with an equimolar amount of (5)-mandelic acid. The mixture was suspended in 0.5 ml of a solvent The solvents were selected from the group of C1-C4 alcohols (preferably ethanol and methanol), esters (preferably ethyl acetate), ketones (preferably acetone), ethers (preferably dioxan) and dimethyl sulfoxide. The vials were placed in an HLC shaker and shaken at 500 rpm at the room temperature for 3 days. The resulting crystalline product was isolated by filtration, dried at the room temperature and further described as a cocrystal of ivabradine hydrochloride and (S -mandelic acid.
  • the solvents were selected from the group of C1-C4 alcohols (preferably ethanol and methanol), esters (preferably ethyl acetate), ketones (preferably acetone), ethers (preferably dioxan) and dimethyl sulfoxide.
  • the final product was identified as a cocrystal of ivabradine hydrochloride and ( ⁇ -mandelic acid.
  • magnesium stearate (12 g) was added and the mixture was homogenized at 20 rpm for another 3 min.
  • the tableting blend produced in the above mentioned way was compressed in a rotary tableting machine and used for the production of tablets with the weight of 135 mg and average hardness of 60 N.
  • a 10mm mask and a 1/4° fixed anti- dispersion slit were used.
  • the irradiated area of the sample is 10 mm, programmable divergence slits were used.
  • For the correction of the secondary array 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used.
  • the records were measured with a DSC Pyris 1 device from Perkin Elmer.
  • the sample charge in a standard Al pot was 2.7 - 3.9 mg and the heating rate was 10°C/min.
  • the temperature program that was used consists of lmin stabilization of the sample at 20°C and then of heating up to 220°C at the rate of 10°C/min.
  • As the carrier gas 4.0 N2 was used at the flow rate of 20 ml/min.
  • the samples were measured in glass HPLC vials with a FT-Raman RFS100/S spectrometer, with a germanium detector (Bruker Optics, Germany), at the wavelength of a Nd:YAG laser 1064 nm, in the measurement range from 4000 to -2000 cm “1 , with the spectral differentiation of 4.0 cm " .
  • the data were obtained at 64 spectrum accumulations.
  • the OMNIC software was used to process the spectra.
  • ATR (ZnSe - single reflection) infrared spectra of the powder samples were measured with an infrared spectrometer ( icolet Nexus, Thermo, USA) equipped with a DTGS KBr detector, in the measurement range of 600-4000 cm “1 and the spectral resolution of 2.0 cm “1 .
  • the data were obtained at 12 spectrum accumulations.
  • the OMNIC 6.2 software was used to process the spectra.
  • the dynamic vapour sorption (DVS) records were measures with a DVS Advantage 1 instrument from Surface Measurement Systems.
  • the sample charge in a quartz pot was 19-22 mg and the temperature in the device was 25.6 °C.
  • the analysis was conducted at the temperature of 120 K using the Xcalibur, Atlas, Gemini ultra diffractometer with a mirror monochromator and a CCD detector, CuK ⁇ radiation with the wavelength of 1.5418 A.
  • the data were collected and reduced by the CrysAlisPro program by Agilent Technologies, version 1.171.36.28.
  • the SCALE3 ABSPAC scaling algorithm was used for empirical correction to absorption.

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PCT/CZ2014/000108 2013-10-02 2014-10-01 A solid form of ivabradine hydrochloride and (s)-mandelic acid and a pharmaceutical composition thereof WO2015048937A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2013-767A CZ305096B6 (cs) 2013-10-02 2013-10-02 Pevná forma Ivabradin hydrochloridu a (S)-mandlové kyseliny a její farmaceutická kompozice
CZPV2013-767 2013-10-02

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016004911A1 (en) * 2014-07-10 2016-01-14 Zentiva, K.S. A cocrystal of ivabradine hydrochloride and (r)-mandelic acid and its pharmaceutical composition
WO2020092288A1 (en) * 2018-10-30 2020-05-07 Amgen Inc. Process of making ivabradine hydrochloride drug product

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0534859A1 (fr) 1991-09-27 1993-03-31 Adir Et Compagnie 3-Benzazépin-zones substituées par un groupe benzocyclobutyl- ou indanyl-alkyl-amino-alkyle, utiles dans le traitement des affections cardiovasculaires
EP1589005A1 (fr) 2004-04-13 2005-10-26 Les Laboratoires Servier Procédé de synthèse de l'ivabradine et de ses sels d'addition à un acide pharmaceutiquement acceptable
EP1695709A1 (fr) 2005-02-28 2006-08-30 Les Laboratoires Servier Forme cristalline gamma-d du chlorhydrate del'ivabradine, son procédé de préparation, et les compositions pharmaceutiques qui la contiennent
EP1695710A1 (fr) 2005-02-28 2006-08-30 Les Laboratoires Servier Forme cristalline beta-d du chlorhydrate de l'ivabradine, son procéde de préparation, et les compositions pharmaceutiques qui la contiennent
EP1695965A1 (fr) 2005-02-28 2006-08-30 Les Laboratoires Servier Forme cristalline beta du chlorhydrate de l'ivabradine, son procédé de préparation, et les compositions pharmaceutiques qui la contiennent
EP1707562A1 (fr) 2005-02-28 2006-10-04 Les Laboratoires Servier Forme cristalline gamma du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutique qui la contiennent
EP1775287A1 (fr) * 2005-10-11 2007-04-18 Les Laboratoires Servier Forme cristalline delta d du chlorhydrate de l'ivabradine, son procédé de préparation, et les compositions pharmaceutiques qui la contiennent
WO2007042656A1 (fr) 2005-10-11 2007-04-19 Les Laboratoires Servier Forme cristalline delta du chlorhydrate de l ' ivabradine , son procede de preparation, et les compositions pharmaceutiques qui la contiennent
WO2008065681A2 (en) 2006-11-30 2008-06-05 Cadila Healthcare Limited Process for preparation of ivabradine hydrochloride
WO2008146308A2 (en) 2007-05-30 2008-12-04 Ind-Swift Laboratories Limited Process for the preparation of ivabradine hydrochloride and polymorph thereof
WO2010081342A1 (zh) 2009-01-13 2010-07-22 江苏恒瑞医药股份有限公司 硫酸伊伐布雷定及其i型结晶的制备方法
WO2011098582A2 (en) 2010-02-12 2011-08-18 Krka, D.D., Novo Mesto Novel forms of ivabradine hydrochloride
WO2011157720A2 (en) * 2010-06-14 2011-12-22 Ratiopharm Gmbh Ivabradine-containing pharmaceutical composition with modified release
WO2013064307A1 (en) 2011-11-04 2013-05-10 Urquima, S. A. Ivabradine hydrochloride form iv

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011104723A2 (en) * 2010-02-23 2011-09-01 Ind-Swift Laboratories Limited Acid addition salts of ivabradine and preparation thereof

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0534859A1 (fr) 1991-09-27 1993-03-31 Adir Et Compagnie 3-Benzazépin-zones substituées par un groupe benzocyclobutyl- ou indanyl-alkyl-amino-alkyle, utiles dans le traitement des affections cardiovasculaires
EP1589005A1 (fr) 2004-04-13 2005-10-26 Les Laboratoires Servier Procédé de synthèse de l'ivabradine et de ses sels d'addition à un acide pharmaceutiquement acceptable
EP1695709A1 (fr) 2005-02-28 2006-08-30 Les Laboratoires Servier Forme cristalline gamma-d du chlorhydrate del'ivabradine, son procédé de préparation, et les compositions pharmaceutiques qui la contiennent
EP1695710A1 (fr) 2005-02-28 2006-08-30 Les Laboratoires Servier Forme cristalline beta-d du chlorhydrate de l'ivabradine, son procéde de préparation, et les compositions pharmaceutiques qui la contiennent
EP1695965A1 (fr) 2005-02-28 2006-08-30 Les Laboratoires Servier Forme cristalline beta du chlorhydrate de l'ivabradine, son procédé de préparation, et les compositions pharmaceutiques qui la contiennent
EP1707562A1 (fr) 2005-02-28 2006-10-04 Les Laboratoires Servier Forme cristalline gamma du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutique qui la contiennent
EP1775287A1 (fr) * 2005-10-11 2007-04-18 Les Laboratoires Servier Forme cristalline delta d du chlorhydrate de l'ivabradine, son procédé de préparation, et les compositions pharmaceutiques qui la contiennent
WO2007042656A1 (fr) 2005-10-11 2007-04-19 Les Laboratoires Servier Forme cristalline delta du chlorhydrate de l ' ivabradine , son procede de preparation, et les compositions pharmaceutiques qui la contiennent
WO2007042657A1 (fr) 2005-10-11 2007-04-19 Les Laboratoires Servier FORME CRISTALLINE δd DU CHLORHYDRATE DE L'IVABRADINE, SON PROCEDE DE PREPARATION, ET LES COMPOSITIONS PHARMACEUTIQUES QUI LA CONTIENNENT
WO2008065681A2 (en) 2006-11-30 2008-06-05 Cadila Healthcare Limited Process for preparation of ivabradine hydrochloride
WO2008146308A2 (en) 2007-05-30 2008-12-04 Ind-Swift Laboratories Limited Process for the preparation of ivabradine hydrochloride and polymorph thereof
WO2010081342A1 (zh) 2009-01-13 2010-07-22 江苏恒瑞医药股份有限公司 硫酸伊伐布雷定及其i型结晶的制备方法
WO2011098582A2 (en) 2010-02-12 2011-08-18 Krka, D.D., Novo Mesto Novel forms of ivabradine hydrochloride
WO2011157720A2 (en) * 2010-06-14 2011-12-22 Ratiopharm Gmbh Ivabradine-containing pharmaceutical composition with modified release
WO2013064307A1 (en) 2011-11-04 2013-05-10 Urquima, S. A. Ivabradine hydrochloride form iv

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016004911A1 (en) * 2014-07-10 2016-01-14 Zentiva, K.S. A cocrystal of ivabradine hydrochloride and (r)-mandelic acid and its pharmaceutical composition
WO2020092288A1 (en) * 2018-10-30 2020-05-07 Amgen Inc. Process of making ivabradine hydrochloride drug product

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