WO2017060290A1 - Chlorhydrate d'encenicline cristallin - Google Patents

Chlorhydrate d'encenicline cristallin Download PDF

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Publication number
WO2017060290A1
WO2017060290A1 PCT/EP2016/073777 EP2016073777W WO2017060290A1 WO 2017060290 A1 WO2017060290 A1 WO 2017060290A1 EP 2016073777 W EP2016073777 W EP 2016073777W WO 2017060290 A1 WO2017060290 A1 WO 2017060290A1
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Prior art keywords
crystalline form
encenicline hydrochloride
encenicline
hydrochloride
crystalline
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PCT/EP2016/073777
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English (en)
Inventor
Verena Adamer
Ramona METZ
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Sandoz Ag
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Priority claimed from EP15188651.2A external-priority patent/EP3153513A1/fr
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of WO2017060290A1 publication Critical patent/WO2017060290A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • the present invention relates to a crystalline forms of encenicline hydrochloride and a process for their preparations.
  • the invention also concerns a pharmaceutical compositions comprising an effective amount of the crystalline forms of encenicline hydrochloride and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical compositions of the present invention can be used as medicament, in particular for treatment and/or prevention of CNS disorders associated with cognitive deficits such as Alzheimer's disease and Schizophrenia.
  • Encenicline hydrochloride chemically also designated (i?)-7-chloro-N-(quinuclidin-3- yl)benzo[3 ⁇ 4]thiophene-2-carboxamide hydrochloride can be represented by the following chemical structure according to formula (A):
  • nAChR nicotinic acetylcholine receptor
  • WO 201 1/14651 1 Al describes three crystalline forms of encenicline hydrochloride.
  • Form I and form II are both monohydrates and form X is a form of low crystal linity, which may appear temporally during form I production.
  • a representative powder X-ray diffractogram of form X is displayed in figure 2 of WO 201 1/14651 1 Al .
  • the existence of broad and indistinct peaks as well as the low intensity of the reflections clearly indicate that form X is of low crystal linity.
  • form X is less stable than form I regardless of temperature.
  • form X seems to be no viable form of encenicline hydrochloride for the use in a pharmaceutical formulation.
  • the two monohydrates, form I and II of WO 2011/146511 Al suffer from certain drawbacks, in particular they are both sensitive to temperature stress, which can become critical as particular processing steps, such as milling or drying, usually involve the evolution of heat.
  • CN105601629 discloses crystalline forms of encenicline hydrochloride designated form A and form B. While form A is said to be an anhydrous form, the nature of form B is not further commented. Although the nature of form B is not further disclosed this form seems to be a hydrate or solvate which is also readily losing its solvent at moderate temperature as indicated by the TGA curve provided in figure 6 of CN105601629A.
  • the inventors of the present invention observed that the anhydrous form A of CN 105601629 A transforms to hydrate form I of WO 201 1/14651 1 A 1 , when subjecting it to ambient conditions of 25 °C/40% RH, rendering both pharmaceutical processing and storage of form A demanding.
  • an objective of the present invention was the provision of an improved form of encenicline Hydrochloride, which is suitable for pharmaceutical applications.
  • an objective of the present invention was the provision of an improved form of encenicline Hydrochloride, which is physically and chemically stable, i.e. which does not chemically degrade and/or convert to other solid forms during pharmaceutical processing and/or upon storage.
  • Another objective of the present invention was the provision of an improved form of encenicline Hydrochloride which is more robust during pharmaceutical processing where the generation of heat and/or moisture can be expected.
  • it was an objective to provide a solid pharmaceutical composition comprising an improved form of encenicline hydrochloride, wherein encenicline hydrochloride is chemically and physically stable upon storage under various conditions e.g. at elevated temperature and/or relative humidity.
  • the present invention relates to a new crystalline form of encenicline hydrochloride and a process for its preparation.
  • the crystalline form of the invention is characterized by an extraordinary high melting point and high stability against temperature stress. It is therefore a physical form of encenicline hydrochloride with superior properties during pharmaceutical processing steps where the generation of heat can be expected.
  • the crystalline form of encenicline hydrochloride of the present invention has the additional advantage that it enables the preparation of finished dosage forms comprising crystalline encenicline hydrochloride in the absence of amorphous encenicline hydrochloride, wherein the finished dosage form was prepared by a process including a process step where heat generation occurs.
  • the present invention relates to a crystalline form of encenicline Hydrochloride characterized by having a PXRD comprising reflections at 2-theta angles of (1 1.7 ⁇ 0.2)°, (13.5 ⁇ 0.2)° and (13.6 ⁇ 0.2)°.
  • the present invention also relates to an anhydrous crystalline form of encenicline hydrochloride and solves one or more of the aforementioned problems.
  • the anhydrous crystalline form of encenicline hydrochloride in contrast to the known hydrates/solvates, is very stable against temperature stress.
  • the anhydrous crystalline form of the present invention is more stable against humidity.
  • the anhydrous form of the present invention is an especially suitable form of encenicline Hydrochloride for pharmaceutical application, e.g. for the preparation of a pharmaceutical composition, where the evolution of heat and the presence of moisture can be expected.
  • the anhydrous form of the present invention is also an especially suitable form for storage, either as neat active pharmaceutical ingredient or present in a composition, such as a pharmaceutical composition. Therefore, in one aspect the present invention relates to a crystalline form of encenicline Hydrochloride characterized by having a PXRD comprising reflections at 2-theta angles of (8.1 ⁇ 0.2)°, (1 1.2 ⁇ 0.2)° and (19.6 ⁇ 0.2)°, when measured at a RH of 45% or less with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the present invention also relates to a process for the preparation of said anhydrous crystalline form, which comprises the desolvation of a particular species of isostructural solvates of encenicline Hydrochloride. Having these isostructural solvates in hands made the novel anhydrous crystalline form of the present invention accessible for the first time, therefore said solvates are also subject-matter of the present invention.
  • the invention further concerns a pharmaceutical composition
  • a pharmaceutical composition comprising an effective and/or predetermined amount of the anhydrous crystalline form of encenicline Hydrochloride of the present invention and one or more pharmaceutically acceptable excipient(s).
  • the invention relates to said pharmaceutical composition for use as medicament, in particular for treatment and/or prevention of CNS disorders associated with cognitive deficits such as Alzheimer's disease and Schizophrenia.
  • encenicline hydrochloride refers to (i?)-7-chloro-N-(quinuclidin-3- yl)benzo[3 ⁇ 4]thiophene-2-carboxamide hydrochloride represented by the chemical structure according to formula A herein.
  • encenicline Hydrochloride is characterized by having a molar ratio of encenicline and hydrochloric acid in the range of from 1.0: 0.8 to 1.2, preferably from 1.0: 0.9 to 1.1 and most preferably the molar ratio is 1.0: 1.0.
  • the terms "encenicline hydrochloride”, “encenicline hydrochloride” and “encenicline monohydrochloride” may be used interchangeably herein.
  • form I refers to the crystalline monohydrate of encenicline hydrochloride disclosed in WO 201 1/14651 1 Al which is characterized by having a PXRD comprising reflections at 2-Theta angles of (4.5 ⁇ 0.2)°, (14.2 ⁇ 0.2)°, (15.1 ⁇ 0.2)°, (19.5 ⁇ 0.2)° and (25.5 ⁇ 0.2)°, when measured at room temperature with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • form ⁇ refers to the crystalline monohydrate of encenicline hydrochloride disclosed in WO 201 1/14651 1 Al which is characterized by having a PXRD comprising reflections at 2-Theta angles of (4.5 ⁇ 0.2)°, (14.3 ⁇ 0.2)°, (21.2 ⁇ 0.2)°, (21.4 ⁇ 0.2)° and (25.0 ⁇ 0.2)°, when measured at room temperature with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • anhydrous when talking about a solid form of encenicline hydrochloride the term "anhydrous” as used herein relates to a solid form of encenicline hydrochloride comprising water in an amount of 2.0 weight% or less, preferably 1.0 weight% or less, more preferably 0.5 weight% or less based on the weight of the solid form of encenicline hydrochloride.
  • amorphous refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern with reflections.
  • polymorph refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.
  • solvate refers to a crystalline form of a molecule, atom, and/or ions that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a non- ordered arrangement.
  • the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
  • a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate.
  • the solvate When the solvent is water, the solvate is often referred to as a "hydrate". When the solvent is present in stoichiometric amount, the solvate may be referred to by adding greek numeral prefixes. For example, a hydrate may be referred to as monohydrate, dihydrate, trihydrate etc., depending on the water/encenicline monohydrochloride stoichiometry.
  • the solvent content can be measured, for example, by GC, ⁇ -NMR or Karl-Fischer (KF) titration.
  • room temperature refers to temperatures in the range of from 20 to 30 °C.
  • melting point refers to the temperature at which a crystalline solid changes state from a solid to liquid.
  • substantially pure with reference to a particular polymorphic form means that the polymorphic form includes less than 20%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2%, most preferably less than 1% by weight of any other solid forms of the compound.
  • reflection with regards to powder X-ray diffraction as used herein, means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order.
  • a solid material is classified as crystalline material, whereas amorphous material is defined as solid material, which lacks long-range order and only displays short-range order, thus resulting in broad scattering.
  • long-range order e.g.
  • the term "essentially the same" with reference to powder X-ray diffraction means that variabilities in peak positions and relative intensities of the peaks are to be taken into account.
  • a typical precision of the 2-theta values is in the range of ⁇ 0.2° 2-theta.
  • a diffraction peak that usually appears at 16.7° 2-theta for example can appear between 16.5° and 16.9° 2-theta on most X-ray diffractometers under standard conditions.
  • relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.
  • Crystalline encenicline hydrochloride may be referred to herein as being characterized by graphical data "as shown in" a figure.
  • Such data include, for example, powder X-ray diffractograms (PXRDs) and differential scanning calorimetry (DSC) thermograms.
  • PXRDs powder X-ray diffractograms
  • DSC differential scanning calorimetry
  • the person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration and sample purity may lead to small variations for such data when presented in graphical form, for example variations relating to the exact peak positions and intensities.
  • a comparison of the graphical data in the figures herein with the graphical data generated for an unknown solid form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art.
  • solid form refers to any crystalline and/or amorphous phase of a compound.
  • about means within 5%, more typically within 1% and most typically within 0.5% of the indicated value or range.
  • isostructural solvates refers to solvates having the same crystal structure but comprising one or more different solvent molecule(s) in the crystal structure.
  • Crystalline encenicline hydrochloride may be referred to herein as being characterized by a PXRD "essentially the same as displayed in” a figure meaning that variabilities in peak positions and relative intensities of the peaks are to be taken into account.
  • a typical precision of the 2-theta values is in the range of ⁇ 0.2° 2-theta.
  • a diffraction peak that usually appears at 19.6° 2-theta for example can appear between 19.4° and 19.8° 2-theta on most X-ray diffractometers under standard conditions.
  • predetermined amount refers to the amount of the anhydrous crystalline form of encenicline hydrochloride which is present in a composition, e.g. a pharmaceutical composition, at the time of preparing said composition.
  • anhydrous crystalline form of encenicline hydrochloride of the present invention means an amount of the anhydrous crystalline form of encenicline hydrochloride sufficient to provide a therapeutic benefit in the treatment of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder.
  • non-solvated as used herein when talking about a crystalline solid means that no organic solvent and water is coordinated in or accommodated by the crystal structure. Non- solvated forms may still contain traces of residual organic solvents, e.g. solvents adsorbed on the surface but are not part of the crystal structure.
  • the x-axis shows the position in °2-Theta
  • the y-axis shows the number of counts in the detection unit of the diffractometer.
  • Unit cell of the crystalline form of encenicline hydrochloride of the invention The atoms of the main component are drawn in capped-sticks style and the chloride ions are drawn as spheres.
  • Figure 6 Representative PXRD of the crystalline anhydrous form of encenicline hydrochloride of the present invention.
  • the x-axis shows the scattering angle in
  • the y-axis the intensity of the scattered X-ray beam in counts of detected photons.
  • Figure 7 Representative DSC curve of the crystalline anhydrous form of encenicline hydrochloride of the present invention.
  • the x-axis shows the temperature in degree Celsius (°C)
  • the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.
  • Figure 8 illustrates a comparison of representative PXRDs of the isostructural solvates of encenicline hydrochloride of the present invention.
  • the overlay displays from top to bottom the PXRDs of the isopropanol solvate, the isobutanol solvate and the chloroform solvate.
  • the reflections at (6.7 ⁇ 0.2)° and (8.0 ⁇ 0.2)°, which represent common characteristic reflections for this species of isostructural solvates, are highlighted.
  • the x-axis shows the scattering angle in ° 2-Theta.
  • the diffractograms were shifted along the y-axis to separate them for clarity reason. The y-axis is therefore arbitrary and was not labeled.
  • Figure 9 illustrates a comparison of representative GMS isotherms of encenicline hydrochloride form A of CN105601629A (solid line with triangles) and the crystalline anhydrous form of encenicline hydrochloride of the present invention (solid line with squares) during the sorption cycle from 0 - 45% RH.
  • the x-axis displays the RH in percent (%) measured at a temperature of (25.0 ⁇ 0.1) °C
  • the y-axis displays the equilibrium mass change in percent (%). The values are displayed as uncorrected values.
  • Figure 10 illustrates a comparisons of the dynamic course of representative GMS isotherms of encenicline hydrochloride form A of CN 105601629 A (round dotted line) and the crystalline anhydrous form of encenicline hydrochloride of the present invention (thick solid line) during the sorption cycle from 0 - 45% RH (stair- like black line).
  • the x-axis displays the stay time of the samples at respective RHs in hours.
  • the left y-axis displays the equilibrium mass change of the encenicline hydrochloride samples in percent (%>, uncorrected values).
  • the right y-axis displays the RH in percent (%) measured at a temperature of (25.0 ⁇ 0.1) °C.
  • Figure 11 illustrates a comparison of representative DSC curves of encenicline hydrochloride monohydrates form I (top) and form II (middle) of WO 201 1/14651 1 Al with the crystalline anhydrous form of the present invention (bottom).
  • the x-axis shows the temperature in degree Celsius (°C).
  • the thermograms were shifted along the y-axis to separate them for clarity reason. The y-axis is therefore arbitrary and was not labeled. Endothermic peaks are going up.
  • Figure 12 illustrates a PXRD of amorphous encenicline hydrochloride obtained from the reference example herein.
  • the x-axis shows the scattering angle in °2-Theta, the y-axis the intensity of the scattered X-ray beam in counts of detected photons.
  • the present invention relates to a new crystalline forms of encenicline hydrochloride. Surprisingly, it has been found that crystalline encenicline hydrochloride of the present invention has an extraordinary high melting points. This property makes the crystalline encenicline hydrochloride of the present invention particularly useful for the preparation of such pharmaceutical formulations, where the preparation process involves a process step where heat is generated.
  • the invention relates to a crystalline form of encenicline hydrochloride, in particular to a crystalline form of encenicline monohydrochloride having higher melting point and anhydrous encenicline hydrochloride.
  • the crystalline form of encenicline monohydrochloride of the present invention is characterized by having a molar ratio of encenicline and hydrochloric acid in the range of from about 1.0: 0.8 to 1.2, preferably from about 1.0: 0.9 to 1.1 and most preferably the molar ratio is about 1.0: 1.0.
  • the crystalline form of encenicline hydrochloride of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction, single crystal X-ray diffraction and differential scanning calorimetry. It may be characterized by one of the aforementioned methods or by combining two or more of them.
  • the crystalline encenicline hydrochloride, such as the crystalline monohydrochloride, of the present invention may be characterized by one of the following embodiments or by combining two or more of the following embodiments.
  • the crystalline form of the present invention can be clearly distinguished from form X of WO 201 1/14651 1 Al for example by its characteristic powder X-ray diffractogram.
  • the diffractogram of form X displayed in figure 2 of WO 201 1/14651 1 Al shows no reflections in the range of from about 10.0 to 14.0 ° 2-theta, whereas the crystalline form of the present invention inter alia exhibits reflections at 2-theta angles of (1 1.7 ⁇ 0.2)°, (13.5 ⁇ 0.2)° and (13.6 ⁇ 0.2)°.
  • the powder X-ray diffractogram of the crystalline form of the present invention is also significantly different from the diffracto grams of form I and II disclosed in figures 5 and 6 of WO 201 1/14651 1 Al respectively.
  • the diffractogram of the crystalline form of the present invention for example shows reflections at 2-theta angles of (8.2 ⁇ 0.2)°, (9.6 ⁇ 0.2)° and (1 1.7 ⁇ 0.2)° .
  • a comparison of the powder X-ray reflections of the crystalline form of the present invention, form I and form II in the range of from 2.0 to 20.0° 2-theta is displayed in table 1 :
  • Table 1 Powder X-ray reflection comparison of the different crystalline forms in the range of from 2.0 to 20.0° 2-theta
  • the invention refers to a crystalline form of encenicline hydrochloride characterized by having a powder X-ray diffractogram comprising reflections at 2-theta angles of (13.6 ⁇ 0.2)°, (16.7 ⁇ 0.2)° and (19.9 ⁇ 0.2)°, when measured at room temperature with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention refers to a crystalline form of encenicline hydrochloride characterized by having a powder X-ray diffractogram comprising reflections at 2-theta angles of (13.5 ⁇ 0.2)°, (13.6 ⁇ 0.2)°, (16.7 ⁇ 0.2)° and (19.9 ⁇ 0.2)°, when measured at room temperature with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention refers to a crystalline form of encenicline hydrochloride characterized by having a powder X-ray diffractogram comprising reflections at 2-theta angles of (13.5 ⁇ 0.2)°, (13.6 ⁇ 0.2)°, (16.7 ⁇ 0.2)°, (19.2 ⁇ 0.2)° and (19.9 ⁇ 0.2)°, when measured at room temperature with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention refers to a crystalline form of encenicline hydrochloride characterized by having a powder X-ray diffractogram comprising reflections at 2-theta angles of (1 1.7 ⁇ 0.2)°, (13.5 ⁇ 0.2)°, (13.6 ⁇ 0.2)° (16.7 ⁇ 0.2)°, (19.2 ⁇ 0.2)° and (19.9 ⁇ 0.2)°, when measured at room temperature Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention refers to a crystalline form of encenicline hydrochloride characterized by having a powder X-ray diffractogram comprising reflections at 2-theta angles of (8.2 ⁇ 0.2)°, (11.7 ⁇ 0.2)°, (13.5 ⁇ 0.2)°, (13.6 ⁇ 0.2)°, (16.7 ⁇ 0.2)°, (19.2 ⁇ 0.2)° and (19.9 ⁇ 0.2)°, when measured room temperature with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention refers to a crystalline form of encenicline hydrochloride characterized by having a powder X-ray diffractogram comprising reflections at 2-theta angles of (8.2 ⁇ 0.2)°, (9.6 ⁇ 0.2)°, (11.7 ⁇ 0.2)°, (13.5 ⁇ 0.2)°, (13.6 ⁇ 0.2)° (16.7 ⁇ 0.2)°, (19.2 ⁇ 0.2)°and (19.9 ⁇ 0.2)°, when measured at room temperature with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention refers to a crystalline form of encenicline hydrochloride characterized by having a powder X-ray diffractogram essentially the same as the one displayed in figure 1 of the present invention, when measured at room temperature with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention relates to a crystalline form of encenicline hydrochloride characterized by having a differential scanning calorimetry curve showing a single endothermic signal, when measured at a heating rate of 10 K/min and starting from room temperature, wherein the single endothermic signal is at a temperature above about 200 °C, preferably above about 220 °C and most preferably above about 240 °C.
  • the invention relates to a crystalline form of encenicline hydrochloride characterized by exhibiting a single melting point with an onset temperature above about 200 °C, preferably above about 220 °C and most preferably above about 240 °C, when measured with differential scanning calorimetry at a heating rate of 10 K/min and starting at room temperature.
  • the invention relates to the crystalline form of encenicline hydrochloride of the present invention comprising less than 20 weight%, preferably less than 10 weight%, more preferably less than 5 weight% and most preferably less than 2 weight% of any other solid form of encenicline hydrochloride.
  • the invention relates to a process for the preparation of the crystalline form of encenicline hydrochloride of the present invention comprising: (i) providing a solid form of encenicline hydrochloride,
  • encenicline hydrochloride examples include form I and form II of WO 201 1/14651 1 Al , which may be prepared according to the procedures disclosed in example 2 and example 3 of the same application respectively. Due to their low melting points form I and form II are especially suitable crystalline forms of encenicline hydrochloride for the production of the crystalline form of the present invention. Alternatively, amorphous encenicline hydrochloride can be used.
  • step (ii) Melting in step (ii) is performed by, for example, heating form I and/or form II and/or amorphous encenicline hydrochloride for example above about 140 °C, preferably above about 160 °C, more preferably above about 180 °C and most preferably above about 200 °C for a period sufficient to receive a melt.
  • the obtained melt is annealed at a temperature in the range of from about 210 to 250 °C, preferably from about 220 to 250 °C, more preferably from about 230 to 250 °C and most preferably from about 240 to 250 °C for a period sufficient to receive crystals.
  • crystals are obtained within a few minutes, for example within about 1 to 10 minutes. Once crystals are obtained they may optionally be cooled to room temperature.
  • the crystalline form of the present invention exhibits an extraordinary high melting point and is thus especially stable against temperature stress.
  • Table 2 summarizes the melting point onset temperatures of the different crystalline forms of encenicline hydrochloride determined by differential scanning calorimetry at a heating rate of 10 K/min.
  • Table 2 Comparison of melting point onsets of the different crystalline forms at a heating rate of l OK/min As can be seen from table 2 the crystalline form of the present invention clearly shows the highest melting point onset temperature. In addition, the differential scanning calorimetry curve of the crystalline form of the present invention shows no thermal event up to the melting point and therefore can be considered the most stable form of encenicline hydrochloride against temperature stress.
  • the crystals obtained according to the aforementioned procedure may be used as seed crystals, for example they may be added to a melt of encenicline hydrochloride or to a saturated solution of encenicline hydrochloride in a suitable solvent in order to promote crystallization of the crystalline form of the present invention.
  • the present invention relates to the use of the crystalline form of encenicline hydrochloride of the present invention as seed crystals in a process for the preparation of the crystalline form of encenicline hydrochloride of the present invention.
  • the present invention also relates to a crystalline anhydrous form of encenicline Hydrochloride, which may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction, differential scanning calorimetry and gravimetric moisture sorption.
  • the crystalline form of encenicline hydrochloride of the present invention may be characterized by one of the aforementioned methods or by combining two or more of them.
  • This invention further relates to the crystalline anhydrous form of a unique PXRD and therefore can be easily distinguished from encenicline hydrochloride form X, form I and form II of WO 201 1/14651 1 Al as well as from form A and form B of CN105601629A.
  • a very characteristic reflection which is unique for the crystalline form of the present invention, appears for example in the range of from (1 1.2 ⁇ 0.2)° 2-Theta. None of the aforementioned crystalline forms of encenicline Hydrochloride possesses a reflection in this area.
  • the invention relates to a crystalline form of encenicline hydrochloride characterized by having a PXRD comprising reflections at 2-theta angles of:
  • the invention refers to a crystalline form of encenicline hydrochloride characterized by having a PXRD essentially the same as the one displayed in figure 6 of the present invention, when measured at a RH of 45% or less with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention relates to a crystalline form of encenicline hydrochloride characterized by exhibiting a melting point with an onset temperature of 193 °C, when measured with DSC at a heating rate of 10 K/min.
  • the invention in another embodiment relates to a crystalline form of encenicline hydrochloride characterized by exhibiting a melting point with a peak temperature of 201 °C, when measured with DSC at a heating rate of 10 K/min.
  • the present invention relates to a crystalline form of encenicline hydrochloride as defined above being present in anhydrous form.
  • the present invention relates to a crystalline form of encenicline hydrochloride as defined above being present in non-solvated form.
  • the invention relates to a composition, preferably a pharmaceutical composition comprising the anhydrous crystalline form of encenicline hydrochloride of the present invention as defined before and less than 20 weight%>, preferably less than 10 weight%>, more preferably less than 5 weight% and most preferably less than 2 weight% of any other solid form of encenicline hydrochloride, based on the weight of the composition.
  • the any other solid form of encenicline hydrochloride is a solvate as defined hereinafter.
  • the any other solid form of encenicline hydrochloride is the monohydrate form I of WO 201 1/14651 1 Al .
  • Such a composition may be prepared by blending predetermined amounts of the anhydrous crystalline form of encenicline hydrochloride of the present invention and one or more of any other solid form(s) of encenicline hydrochloride.
  • the monohydrates form I and II disclosed in WO 201 1/14651 1 Al readily lose their water below 100 °C, the dehydration process going along with disruption of the crystal scaffold.
  • form B of CN 105601629 A is not described in detail this form seems to be a hydrate or solvate, which is indicated by the typical shape of the TGA curve displayed in figure 6 of said application.
  • the main solvent loss already occurs at a temperature well below 100 °C, thus indicating that this form is temperature sensitive as well.
  • the anhydrous form of the present invention is highly stable against temperature stress, which is indicated by its high melting point with an onset temperature of about 193 °C and a peak temperature of about 201 °C (see also DSC curve in figure 7 herein).
  • Table 3 summarizes the first thermal events, detected with DSC and TGA respectively.
  • Figure 6 herein displays an overlay of the corresponding DSC curves of the anhydrous crystalline form of the present invention, and the monohydrates form I and II of WO 201 1/14651 1 Al .
  • anhydrous crystalline form of the present invention is significantly more stable against moisture compared to the anhydrous form A of CN105601629A.
  • a GMS experiment performed with both anhydrates at a temperature of (25.0 ⁇ 0.1) °C revealed that form A of CN105601629A already starts to take up significant amounts of water at RHs between 35% and 40%, which is indicated by an increase of the slope (see figure 9).
  • a further, more dramatic increase of the slope can then be observed above 40% RH, which goes along with hydration to the monohydrate form I of WO 201 1/14651 1 Al , as confirmed by PXRD performed after the GMS measurement.
  • the crystalline anhydrous form of the present invention shows no increase of the slope in the range of from 0 to 45% RH (see figure 9) and preserves its crystal structure, which was confirmed by PXRD performed after the GMS measurement.
  • the crystalline form of the present invention is the preferred form to be used for pharmaceutical purposes e.g. for the preparation and storage of a pharmaceutical composition comprising encenicline hydrochloride.
  • the invention relates to a process for the preparation of the anhydrous crystalline form of encenicline hydrochloride as defined above comprising:
  • step (i) providing a solvate of encenicline hydrochloride as defined hereinafter; and (ii) subjecting the solvate provided in step (i) to an atmosphere having a relative humidity of 10% or less and/or a temperature in the range of from 120 to 150 °C, preferably from 135 to 150 °C;
  • the solvate provided in step (i) may be prepared according to the procedures disclosed hereinafter.
  • Desolvation in step (ii) may be performed by heating the encenicline hydrochloride solvate provided in step (i) to a temperature in the range of from about 120 to 150 °C, preferably from about 135 to 150 °C. Heating may be performed at ambient or reduced pressure e.g. under vacuum, preferably, heating is performed under vacuum for example at about 100 mbar or less, such as about 50 mbar or less or about 20 mbar or less. The material may be kept at the applied temperature for a period in the range of from about 5 to 60 minutes, for example from about 15 to 45 minutes.
  • desolvation may be monitored by taking a sample and investigating it by means of powder X- ray diffraction. Once, the desolvation is complete the crystals may be cooled to room temperature. Alternatively, desolvation may be accomplished by subjecting the encenicline hydrochloride solvate provided in step (i) to a dry atmosphere having a relative humidity of about 10% or less, preferably of about 0%. The material may be subjected to the the dry atmosphere for a period in the range of from about 1 to 30 days, preferably from about 1 to 14 days, more preferably from about 3 to 7 days. Completeness of the desolvation process may be monitored by taking a sample and investigating it by means of powder X- ray diffraction.
  • the process for the preparation of the preferred anhydrous crystalline form of the present invention comprises the desolvation of particular isostructural solvates, such as the 2-propanol, isobutanol and chloroform solvate of encenicline hydrochloride.
  • isostructural solvates such as the 2-propanol, isobutanol and chloroform solvate of encenicline hydrochloride.
  • a common technical feature which all these isostructural solvates share is a PXRD with characteristic reflections at 2-Theta angles of (6.7 ⁇ 0.2)° and (8.0 ⁇ 0.2)°, in particular of (6.7 ⁇ 0.2)°, (8.0 ⁇ 0.2)°, (15.5 ⁇ 0.2)°, (18.2 ⁇ 0.2)° and (18.9 ⁇ 0.2)°.
  • the invention refers to a solvate of encenicline hydrochloride characterized by having a PXRD comprising reflections at 2-theta angles of (6.7 ⁇ 0.2)° and (8.0 ⁇ 0.2)°, when measured at room temperature with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention refers to a solvate of encenicline hydrochloride characterized by having a PXRD comprising reflections at 2-theta angles of (6.7 ⁇ 0.2)°, (8.0 ⁇ 0.2)°, (15.5 ⁇ 0.2)°, (18.2 ⁇ 0.2)° and (18.9 ⁇ 0.2)°, when measured at room temperature with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the invention refers to a solvate of encenicline hydrochloride as defined above characterized in that the solvent incorporated into the crystal structure is selected from the group consisting of isopropanol, isobutanol and chloroform.
  • the solvates of the present invention are indispensable intermediates for the preparation of the anhydrous crystalline form of the present invention.
  • the present invention relates to the use of the crystalline solvate of encenicline hydrochloride as defined herein for the preparation of the anhydrous crystalline form of encenicline hydrochloride as defined above.
  • the invention relates to a process for the preparation of the solvate of the present invention as defined above comprising at least one of the following steps:
  • step (iv) optionally recovering the crystals obtained in any one of steps (i), (ii) and (iii);
  • the solid form of the starting material employed in step (i) and (ii) is not critical.
  • any crystalline or amorphous form or mixtures of crystalline and amorphous forms may be used as starting material.
  • Suitable crystalline forms are for example the monohydrates form I and II of WO 201 1/14651 1 Al , forms A and B of CN 105601629 A or any mixtures thereof.
  • the concentration of the suspension in step (i) is preferably in the range of from about 25 to 75 g/L, more preferably from about 40 to 60 g/L and most preferably the concentration is about 50 g/L.
  • the initial concentration in step (ii) is preferably in the range of from about 5 to 25 g/L, more preferably from about 5 to 20 g/L and most preferably the concentration is about 10 g/L.
  • the solvent which may be applied comprises, preferably consists of isopropanol, isobutanol and/or chloroform.
  • step (i) the slurry is kept at a temperature, where no complete dissolution occurs but a suspension is maintained.
  • the suspension is slurried typically at room temperature until the conversion to the desired solvate is complete, which may be monitored by taking a sample and investigating it by means of PXRD.
  • Slurrying encompasses agitation, mechanical agitation and stirring.
  • Agitation as used in this context of the present invention relates to any motion of a macroscopic constituent of the suspension comprising encenicline hydrochloride which is induced from outside, relative to another macroscopic constituent of the suspension.
  • Mechanical agitation as used in this context of the present invention relates to any motion of a macroscopic constituent of the suspension comprising encenicline hydrochloride which is induced from outside via a device, such as shaking or stirring or sonication, relative to another macroscopic constituent of the suspension.
  • Stirring as used in this context of the present invention relates to any motion of a macroscopic constituent of the suspension comprising encenicline hydrochloride which is induced from outside via a stirring device, relative to another macroscopic constituent of the solution.
  • the conversion is complete within 1 hour to 7 days, preferably within 6 hours to 3 days and most preferably within 12 to 24 hours.
  • step (ii) the solid starting material is completely dissolved, which is accomplished by increasing the temperature of the initial suspension.
  • the initial suspension is heated between about reflux temperature and 10 °C below reflux temperature.
  • a solution is obtained, it may optionally be filtrated in order to remove any undissolved particles.
  • the solution is cooled to room temperature, whereat the cooling rate is not critical and may be in the range of from about 0.01 to 10 K/min, preferably of from about 0.1 to 5 K/min and most preferably in the range of from 0.1 to 1 K min.
  • the desired crystals typically crystallize spontaneously upon cooling.
  • the solution may be seeded in order to initiate crystallization and/or to control crystal growth.
  • the crystals obtained in step (i) and step (ii) may be recovered.
  • at least a part of the crystals are separated from their mother liquor. Separation may be accomplished by any conventional means such as filtration, centrifugation, evaporation and/or decantation of the solvent.
  • the desired solvates may also be prepared by subjecting encenicline hydrochloride form A of CN105601629A to a solvent vapor comprising, preferably consisting of isopropanol, isobutanol and chloroform.
  • a solvent vapor comprising, preferably consisting of isopropanol, isobutanol and chloroform.
  • form A is equilibrated at 0% relative humidity before contacting it with the respective solvent vapor.
  • Form A and the respective solvent may then be placed into a containment and the containment may then be sealed.
  • the desired solvate is obtained within 1 to 30 days, preferably within 2 to 14 days and most preferably within 3 to 7 days.
  • the invention relates to the use of the anhydrous crystalline form of encenicline hydrochloride of the present invention as defined above for the preparation of a pharmaceutical composition.
  • An additional aspect of the present invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising an effective and/or predetermined amount of the anhydrous crystalline form of encenicline hydrochloride as defined hereinabove and one or more pharmaceutically acceptable excipient(s).
  • the one or more pharmaceutically acceptable excipient(s) may be selected from the group consisting of binders, diluents, disintegrants, glidants and lubricants.
  • microcrystalline cellulose can be used as a diluent and binder, anhydrous calcium hydrogen phosphate as a diluent, croscarmellose sodium as a disintegrant, anhydrous colloidal silica as a glidant and magnesium stearate as a lubricant in the pharmaceutical composition of the present invention.
  • the anhydrous crystalline form of encenicline hydrochloride of the present invention as defined hereinabove is preferably administered once a day at a dosage of 1 mg to 2 mg.
  • the pharmaceutical composition comprising an effective and/ or predetermined amount of the anhydrous crystalline form of encenicline hydrochloride as defined above is characterized by having an equilibrium relative humidity of about 45% or less, preferably of about 40%> or less, more preferably of about 35% or less.
  • the equilibrium relative humidity of the pharmaceutical composition is about 30%) or less, 25% or less, 20%> or less, 15% or less, 10%> or less, 5% or less or 0% or less.
  • the invention relates to the pharmaceutical composition as defined above for use as medicament.
  • the invention relates to a pharmaceutical composition as defined above for use in the treatment and/or prevention of cognitive disorders.
  • the cognitive disorders are selected from the group consisting of Alzheimer's disease, Cognition disorders, Schizoaffective disorder, Schizophrenia and/or Smoking withdrawal, preferably in the treatment of Alzheimer's disease and/or Schizophrenia.
  • a crystalline form of encenicline hydrochloride characterized by having a powder X- ray diffractogram comprising reflections at 2-theta angles of:
  • a crystalline form of encenicline hydrochloride characterized by having a powder X- ray diffractogram comprising reflections at 2-theta angles of:
  • a crystalline form of encenicline hydrochloride characterized by having a powder X- ray diffractogram comprising reflections at 2-theta angles of: (8.2 ⁇ 0.2)°, (9.6 ⁇ 0.2)°, (11.7 ⁇ 0.2)°, (13.5 ⁇ 0.2)°, (13.6 ⁇ 0.2)° (16.7 ⁇ 0.2)°,
  • the crystalline form according to any one of items 1 to 13 comprising less than 20 weight% of any other solid form of encenicline hydrochloride based on the weight of the crystalline form as defined in any one of items 1 to 13.
  • the crystalline form according to any one of items 1 to 14 comprising less than 10 weight% of any other solid form of encenicline hydrochloride based on the weight of the crystalline form as defined in any one of items 1 to 13.
  • the crystalline form according to any one of items 1 to 15 comprising less than 5 weight% of any other solid form of encenicline hydrochloride based on the weight of the crystalline form as defined in any one of items 1 to 13.
  • the crystalline form according to any one of items 1 to 16 comprising less than 2 weight% of any other solid form of encenicline hydrochloride based on the weight of the crystalline form as defined in any one of items 1 to 13.
  • the crystalline form according to any one of items 1 to 17 comprising less than 2 weight% of amorphous encenicline hydrochloride.
  • a process for the preparation of crystalline encenicline hydrochloride according to any one of items 1 to 18 comprising:
  • the pharmaceutical composition according to item 26 for use in the treatment of Alzheimer's disease, Cognition disorders, Schizoaffective disorder, Schizophrenia and/or Smoking withdrawal is a crystalline form of encenicline hydrochloride characterized by having a powder X- ray diffractogram comprising reflections at 2-theta angles of (8.1 ⁇ 0.2)°, (11.2 ⁇ 0.2)° and (19.6 ⁇ 0.2)°, when measured at a relative humidity of 45% or less with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the crystalline form of encenicline hydrochloride of item 30 characterized by having a powder X-ray diffractogram comprising reflections at 2-theta angles of (8.1 ⁇ 0.2)°, (8.7 ⁇ 0.2)°, (11.2 ⁇ 0.2)°, (16.0 ⁇ 0.2)° and (19.6 ⁇ 0.2)°, when measured at a relative humidity of 45% or less with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • composition comprising the crystalline form of encenicline hydrochloride of items 30 or 31 and less than 20 weight%, less than 10 weight%, less than 5 weight% or less than
  • composition of item 32, wherein the any other solid form of encenicline hydrochloride is the monohydrate form I, which is characterized by having a PXRD comprising reflections at 2-Theta angles of (4.5 ⁇ 0.2)°, (14.2 ⁇ 0.2)°, (15.1 ⁇ 0.2)°,
  • a process for the preparation of the crystalline form as defined in item 30 or 31 comprising:
  • step (ii) subjecting the solvate provided in step (i) to an atmosphere having a relative humidity of 10% or less and/or a temperature in the range of from 120 to 150 °C;
  • a solvate of encenicline hydrochloride characterized by having a powder X-ray diffractogram comprising reflections at 2-theta angles of (6.7 ⁇ 0.2)° and (8.0 ⁇ 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • a pharmaceutical composition comprising an effective and/or predetermined amount of the crystalline form of encenicline hydrochloride as defined in item 30 or 31 and one or more pharmaceutically acceptable excipient(s).
  • composition according to item 43 wherein the cognitive disorders are selected from the group consisting of Alzheimer's disease, Cognition disorders, Schizoaffective disorder, Schizophrenia and/or Smoking withdrawal.
  • Powder X-ray diffraction was performed with a PANalytical X'Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphai,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector.
  • Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-theta with 40s per step (255 channels) in the angular range of 2° to 40° 2-theta at ambient conditions.
  • a typical precision of the 2-theta values is in the range of ⁇ 0.2° 2-theta.
  • the diffraction peak of form A that appears for example at 16.7° 2-theta can appear between 16.5 and 16.9° 2-theta on most X-ray diffractometers under standard conditions.
  • Intensity data for the crystal structure were collected with Cu-Kalphai,2 radiation (wavelength: 0.15419 nm) on an Oxford Diffraction Gemini-R Ultra diffractometer at 173 K.
  • the structure was solved using the direct methods procedure in SHELXS97 and refined by full-matrix least squares on F 2 using SHELXL97.
  • DSC was performed on a Mettler Polymer DSC R instrument.
  • the samples (3.34 mg crystalline form of the present invention, 2.47 mg form I of WO 201 1/14651 1 Al , 1.52 mg form II of WO 201 1/14651 1 Al) were heated in a 40 microL aluminum pan with pierced aluminum lid either from 25 to 350 °C (in case of form A and form II) or from 25 to 300 °C (in case of form I) at a rate of 10 K/min. Nitrogen (purge rate 50 mL/min) was used as purge gas.
  • Example 1 Preparation of the crystalline form of encenicline hydrochloride of the present invention starting from form I of WO 2011/146511 Al
  • Encenicline hydrochloride form I (53 mg, prepared according to the procedure disclosed in example 2 of WO 201 1/14651 1 Al) was heated on a Kofler microscope at 30 K/min to a temperature of about 240 °C. The resulting melt was annealed at 240 °C until crystallization occurred (approximately 5 minutes). Finally, the crystals were allowed to cool to room temperature and scratched from the microscope slide. Differential scanning calorimetry (10 K/min): single melting endotherm with an onset temperature of about 278 °C;
  • the powder X-ray diffractogram of the obtained material is displayed in figure 1 and a list of reflections and the corresponding relative intensities are provided in table 4. Powder X-ray diffraction confirmed the receipt of the crystalline form of the present invention.
  • Table 4 Reflection list and relative intensities in the range of from 2.0 to 30.0° 2-theta of the crystalline form of encenicline hydrochloride of the present invention prepared according to example 1
  • Example 2 Preparation of the crystalline form of encenicline hydrochloride of the present invention starting from form II of WO 2011/146511 Al
  • Encenicline hydrochloride form II (25 mg, prepared according to the procedure disclosed in example 3 of WO 201 1/14651 1 Al) was heated on a Kofler microscope at 30 K/min to a temperature of about 240 °C. The resulting melt was annealed at 240 °C until crystallization occured (approximately 5 minutes). Finally, the crystals were allowed to cool to room temperature and scratched from the microscope slide. Powder X-ray diffraction confirmed the receipt of the crystalline form of the present invention.
  • Example 3 Preparation of the anhydrous crystalline form of encenicline Hydrochloride of the present invention.
  • Encenicline hydrochloride isobutanol solvate (80 mg, prepared according to the procedure disclosed in example 4.1 herein) was dried in a vacuum oven at a temperature of 120 °C and a vacuum of 45 mbar for 45 minutes.
  • the powder X-ray diffractogram of the obtained material is displayed in figure 6 and a list of reflections and the corresponding relative intensities are provided in table 5.
  • Encenicline hydrochloride isobutanol solvate (4.35 mg, prepared according to the procedure disclosed in example 4.1 herein) was heated in a TGA aluminum pan at a rate of 10 K/min to 150 °C.
  • Encenicline hydrochloride isobutanol solvate (50 mg, prepared according to the procedure disclosed in example 4.1 herein) was stored at room temperature in a desiccator over P2O5 having a relative humidity of about 0% for 6 days.
  • Encenicline hydrochloride isopropanol solvate (30 mg, prepared according to the procedure disclosed in example 2.2 herein) was heated on a hot stage microscope at a rate of 10 K/min to 135 °C and kept at this temperature for 5 minutes.
  • Encenicline hydrochloride isopropanol solvate (50 mg, prepared according to the procedure disclosed in example 4.2 herein) was stored at room temperature in a desiccator over P2O5 having a relative humidity of about 0% for 4 days.
  • Encenicline hydrochloride form I 250 mg, prepared according to the procedure disclosed in example 2 of WO 201 1/14651 1 Al was suspended in isobutanol (5 mL) and stirred with the aid of a magnetic stirring bar for 18 hours at room temperature. Finally, the crystals were collected by filtration and sucked dry on the filter.
  • the powder X-ray diffractogram of the obtained material is displayed in figure 8 (middle) and a list of reflections and the corresponding relative intensities are provided in table 6.
  • Encenicline Hydrochloride form I 250 mg, prepared according to the procedure disclosed in example 2 of WO 201 1/146511 Al was suspended in isopropanol (5 mL) and stirred with the aid of a magnetic stirring bar for 18 hours at room temperature. Finally, the crystals were collected by filtration and sucked dry on the filter.
  • the powder X-ray diffractogram of the obtained material is displayed in figure 8 (top) and a list of reflections and the corresponding relative intensities are provided in table 7.
  • Encenicline hydrochloride form A (20 mg, prepared according to example 1 of
  • Encenicline hydrochloride form I (50 mg, prepared according to the procedure disclosed in example 2 of WO 201 1/14651 1 Al) was dissolved in isobutanol (5 mL) upon heating to reflux temperature for 2 hours. The clear solution was allowed to cool to room temperature, the obtained crystals were collected by filtration and sucked dry on the filter.
  • Encenicline hydrochloride form I (50 mg, prepared according to the procedure disclosed in example 2 of WO 201 1/14651 1 Al) was dissolved in isopropanol (5 mL) upon heating to reflux temperature for 2 hours. The clear solution was allowed to cool to room temperature, the obtained crystals were collected by filtration and sucked dry on the filter.
  • FIG. 9 The anhydrous crystalline form of the present invention and form A of CN 105601629 A were both subjected to a GMS experiment using an SPSx- ⁇ moisture sorption analyzer (ProUmid, Ulm).
  • Figures 9 and 10 herein display the results of the sorption cycle from 0 to 45% relative humidity, which was performed in 5% steps.
  • the time per step was set to a minimum of 2 hours and a maximum of 6 hours. If an equilibrium condition with a constant mass of ⁇ 0.01% within 1 hour was reached before the maximum time for all examined samples the sequential humidity step was applied before the maximum time of 6 hours. If no equilibrium was achieved the consecutive humidity step was applied after the maximum time of 6 hours.
  • the temperature was (25 ⁇ 0.1) °C.
  • Encenicline hydrochloride monohydrate form I (175 mg, prepared according to the procedure disclosed in example 2 of WO 201 1/14651 1 Al) was dissolved in water (7 mL) upon slight heating. The solution was filtered through a Milipore syringe filter (0.45 microm) into a crystallization dish and lyophilized using a Christ Alpha 2-4 LSC Plus Lyophilizer. The solution was first frozen by cooling it to a temperature of -30 °C in 35 min. The main drying was performed at a vacuum of 0.12 mbar, whereat the temperature was stepwise increased, first in 3 hours to -20 °C, then in 5 hours to 0 °C and finally in 2 hours to 30 °C.
  • the final drying was performed by applying a vacuum of 0.001 mbar at a temperature of 30 °C for a period of 25 hours.
  • PXRD of the obtained material confirmed that amorphous encenicline hydrochloride was obtained (see figure 12 herein).

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Abstract

La présente invention concerne des formes cristallines de chlorhydrate d'encenicline et un procédé permettant leur préparation. L'invention concerne également une composition pharmaceutique comprenant une quantité efficace de la forme cristalline du chlorhydrate d'encenicline et au moins un excipient pharmaceutiquement acceptable. La composition pharmaceutique de la présente invention peut être utilisée en tant que médicament, en particulier dans le traitement et/ou la prévention de troubles du système nerveux central (SNC) associés à des déficiences cognitives telles que la maladie d'Alzheimer et la schizophrénie.
PCT/EP2016/073777 2015-10-06 2016-10-05 Chlorhydrate d'encenicline cristallin WO2017060290A1 (fr)

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EP15188651.2 2015-10-06
EP15188651.2A EP3153513A1 (fr) 2015-10-06 2015-10-06 Encenicline hydrochlorique crystallin
EP16186845 2016-09-01
EP16186845.0 2016-09-01

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003055878A1 (fr) 2001-12-27 2003-07-10 Bayer Healthcare Ag Amides d'acide 2-heteroarylcarboxylique
WO2011146511A1 (fr) 2010-05-17 2011-11-24 Envivo Pharmaceuticals, Inc. Forme cristalline de monohydrate d'hydrochlorure de (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
WO2013169646A1 (fr) * 2012-05-08 2013-11-14 Envivo Pharmaceuticals, Inc. Procédés de maintien, de traitement ou d'amélioration de la fonction cognitive
EP2727604A1 (fr) * 2011-06-30 2014-05-07 Toray Industries, Inc. Agent antiprurigineux
CN105601629A (zh) 2015-02-02 2016-05-25 苏州晶云药物科技有限公司 (R)-7-氯-N-(奎宁环-3-基)苯并[b]噻吩-2-甲酰胺的盐酸盐的新晶型

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003055878A1 (fr) 2001-12-27 2003-07-10 Bayer Healthcare Ag Amides d'acide 2-heteroarylcarboxylique
WO2011146511A1 (fr) 2010-05-17 2011-11-24 Envivo Pharmaceuticals, Inc. Forme cristalline de monohydrate d'hydrochlorure de (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
EP2727604A1 (fr) * 2011-06-30 2014-05-07 Toray Industries, Inc. Agent antiprurigineux
WO2013169646A1 (fr) * 2012-05-08 2013-11-14 Envivo Pharmaceuticals, Inc. Procédés de maintien, de traitement ou d'amélioration de la fonction cognitive
CN105601629A (zh) 2015-02-02 2016-05-25 苏州晶云药物科技有限公司 (R)-7-氯-N-(奎宁环-3-基)苯并[b]噻吩-2-甲酰胺的盐酸盐的新晶型

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Title
BARBIER, ANN J. ET AL: "Pharmacodynamics, Pharmacokinetics, Safety, and Tolerability of Encenicline, a Selective .alpha.7 Nicotinic Receptor Partial Agonist, in Single Ascending-Dose and Bioavailability Studies", CLINICAL THERAPEUTICS, vol. 37, no. 2, 2015, pages 311 - 324, XP002750548, ISSN: 0149-2918, DOI: 10.1016/J.CLINTHERA.2014.09.013 *
VITALIJ K. PECHARSKY; PETER Y. ZAVALIJ: "Fundamentals of Powder Diffraction and Structural Characterization of Materials", 2003, KLUWER ACADEMIC PUBLISHERS, pages: 3

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