WO2018162395A1 - Co-cristaux de chlorhydrate de vinpocétine - Google Patents

Co-cristaux de chlorhydrate de vinpocétine Download PDF

Info

Publication number
WO2018162395A1
WO2018162395A1 PCT/EP2018/055316 EP2018055316W WO2018162395A1 WO 2018162395 A1 WO2018162395 A1 WO 2018162395A1 EP 2018055316 W EP2018055316 W EP 2018055316W WO 2018162395 A1 WO2018162395 A1 WO 2018162395A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
theta
vinpocetine
hydrochloride
vinpocetine hydrochloride
Prior art date
Application number
PCT/EP2018/055316
Other languages
English (en)
Inventor
Barbara PACCHETTI
Andrea Mereu
Giuseppe Paladino
Original Assignee
Linnea Sa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Linnea Sa filed Critical Linnea Sa
Publication of WO2018162395A1 publication Critical patent/WO2018162395A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine

Definitions

  • the present invention relates to novel co-crystals of vinpocetine hydrochloride and different co-formers.
  • Vinpocetine is a derivative of the alkaloid vincamine.
  • Vincamine is found in the aerial part of Vinca minor plant and can also be derived from other plant sources such as the Voacanga and the Crioceras Longiflorus.
  • the Vinca minor plant is a creeping root plant which has a long history of use as a traditional tonic to refresh weariness, especially the type associated with advanced age, and also as an astringent, for excessive menses, bleeding gums and mouth sores.
  • Vinpocetine is the active ingredient of Cavinton and Intelectol. Vinpocetine is held to exhibit an activity on neuronal metabolism by favoring the aerobic glycolysis and promoting the redistribution of the blood flow towards ischemic areas. Vinpocetine is also reported to act to increase cerebral circulation and the use of oxygen.
  • Vinpocetine is commonly used as an aid to improving memory, as an aid in activities requiring highly focused attention and concentration such as technical writing or computer operation and to combat the symptoms of senile dementia. Vinpocetine has also been reported as showing promising results in the treatment of tinnitus or ringing in the ears as well as other causes of impaired hearing. Vinpocetine is also indicated in the treatment of strokes, menopausal symptoms and macular degeneration. Literature suggests vinpocetine may also act to improve conditions related to insufficient blood flow to the brain including vertigo and Meniere's disease, difficulty in sleeping, mood changes and depression. Vinpocetine is represented by the following formula (I).
  • vinpocetine is (3a,16a)-eburnamenine-14-carboxylic acid ethyl ester.
  • Apovincamine is the corresponding methyl ester of the (3a, 16a)- eburnamenine-14-carbox lic acid.
  • Active pharmaceutical ingredients which, like vinpocetine, are generally less water soluble and less bioavailable create huge problems for the pharmaceutical industry.
  • Some attempts to use such techniques with vinpocetine are described, for example, in EP0154756B1 and EP0689844A1 .
  • the salt and solid state form (i.e., the crystalline or amorphous form) of a drug candidate can be critical to its pharmacological properties and to its development as a viable API.
  • crystalline forms of API's have been used to alter the physicochemical properties of a particular API.
  • Each crystalline form of a drug candidate can have different solid state (physical and chemical) properties.
  • the differences in physical properties exhibited by a novel solid form of an API affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and solubility and dissolution rates (important factors in determining bioavailability).
  • Obtaining crystalline forms of an API is extremely useful in drug development. It permits better characterization of the drug candidate's chemical and physical properties. It is also possible to achieve desired properties of a particular API by forming a co-crystal of the API and a co- former. Crystalline forms often have better chemical and physical properties than the free base in its amorphous state. Such crystalline forms may, as with the co-crystals of the invention, possess more favorable pharmaceutical and pharmacological properties or be easier to process than known forms of the API itself. For example, a co-crystal may have different dissolution and solubility properties than the API itself and can be used to deliver APIs therapeutically. New drug formulations comprising co-crystals of a given API may have superior properties over its existing drug formulations.
  • Another potentially important solid state property of an API is its dissolution rate in aqueous fluid.
  • the rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it impacts the rate at which an orally administered active ingredient may reach the patient's bloodstream.
  • converting poorly water soluble APIs into the corresponding salts, such as hydrochlorides is a common way to enhance their solubility in water.
  • obtaining a co-crystal of such salt could afford a more stable final form of the desired API possessing physical and chemical properties more suitable for pharmaceutical application.
  • a co-crystal of an API is a distinct chemical composition of the API and co- former and generally possesses distinct crystallographic and spectroscopic properties when compared to those of the API and co-former individually. Crystallographic and spectroscopic properties of crystalline forms are typically measured by X-ray powder diffraction (XRPD) and single crystal X-ray crystallography, among other techniques. Co-crystals often also exhibit distinct thermal behavior, usually measured in the laboratory by differential scanning calorimetry (DSC). Stoichiometry of the API and co-former within the co- crystal can be confirmed by H NMR technique.
  • Co-crystals are generally defined as homogeneous crystalline structures comprising two or more components that can be atoms or molecules in a definite stoichiometric ratio. Contrary to salts, where the arrangement in the crystal lattice is based on ion pairing, the components of a co-crystal structure interact via non-ionic and also non-covalent weak intermolecular interactions such as hydrogen bonding, van der Waals forces and ⁇ -interactions.
  • the Applicant has faced the problem of finding stable co-crystalline forms of vinpocetine hydrochloride with the aim of improving the chemical and physical properties of vinpocetine.
  • a first aspect of the present invention consists in new co- crystalline forms of vinpocetine hydrochloride and a co-former selected from the group consisting of benzoic acid, gentisic acid, 4-aminobenzoic acid, vanillic acid, fumaric acid, and maleic acid.
  • the co-former was selected from the group consisting of gentisic acid, 4-aminobenzoic acid, vanillic acid, and maleic acid.
  • a new co-crystalline form of vinpocetine hydrochloride and benzoic acid was found having a molar ratio of vinpocetine hydrochloride to benzoic acid equal to 2:1.
  • a form according to the present invention will be referred to as "Form B".
  • a new co-crystalline form of vinpocetine hydrochloride and gentisic acid was found having a molar ratio of vinpocetine hydrochloride to gentisic acid equal to 2:1.
  • a form according to the present invention will be referred to as "Form C”.
  • a new co-crystalline form of vinpocetine hydrochloride and 4-aminobenzoic acid was found having a molar ratio of vinpocetine hydrochloride to 4-aminobenzoic acid equal to 2:1 .
  • a form according to the present invention will be referred to as "Form D”.
  • a new co-crystalline form of vinpocetine hydrochloride and vanillic acid was found having a molar ratio of vinpocetine hydrochloride to vanillic acid equal to 2:1 .
  • a form according to the present invention will be referred to as "Form E”.
  • a new co-crystalline form of vinpocetine hydrochloride and fumaric acid was found having a molar ratio of vinpocetine hydrochloride to fumaric acid equal to 2:1 .
  • a form according to the present invention will be referred to as "Form G”.
  • Form H a new co-crystalline form of vinpocetine hydrochloride and maleic acid was found having a molar ratio of vinpocetine hydrochloride to maleic acid equal to 1 :1.
  • the Form B can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 7.3°; 7.7°; 12.7°; 13.4°; 15.6°; 16.4°; 20.0°; and 20.6° (2-Theta, ⁇ 0.1 ).
  • the Form B can be characterized by a XRPD pattern substantially as depicted in Figure 1 .
  • the Form B shows a DSC profile having an endothermic peak at 198.08°C ⁇ 1 °C with an onset at 196.32°C ⁇ 1 °C. Furthermore, the Form B can be characterized by a DSC profile substantially as depicted in Figure 2.
  • Form B can be characterized by a 1 H NMR spectrum substantially as depicted in Figure 3.
  • the Form C can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 7.2°; 7.5°; 12.8°; 13.5°; 15.7°; 16.6°; and 19.6° (2-Theta, ⁇ 0.1 ). Furthermore, the Form C can be characterized by a XRPD pattern substantially as depicted in Figure 4.
  • the Form C shows a DSC profile having an endothermic peak at 152.83°C ⁇ 1 °C with an onset at 148.92°C ⁇ 1 °C followed by an endothermic peak at 224.17°C ⁇ 1 °C with an onset at 219.88°C ⁇ 1 °C. Furthermore, the Form C can be characterized by a DSC profile substantially as depicted in Figure 5.
  • Form C can be characterized by a 1 H NMR spectrum substantially as depicted in Figure 6.
  • the Form D can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 7.2°; 7.5°; 12.5°; 13.6°; 15.7°; 16.4°; 19.7°; 20.4°; and 24.2° (2-Theta, ⁇ 0.1 ). Furthermore, the Form D can be characterized by a XRPD pattern substantially as depicted in Figure 7.
  • the Form D shows a DSC profile having an endothermic peak at 189.12°C ⁇ 1 °C with an onset at 184.59°C ⁇ 1 °C. Furthermore, the Form D can be characterized by a DSC profile substantially as depicted in Figure 8.
  • the Form D can be characterized by a 1 H NMR spectrum substantially as depicted in Figure 9.
  • the Form E can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 7.2°; 7.5°; 7.6°; 12.7°; 13.1 °; 15.4°; 16.1 °; 20.0°; 20.4°; and 24.2° (2-Theta, ⁇ 0.1 ).
  • the Form E can be characterized by a XRPD pattern substantially as depicted in Figure 10.
  • the Form E shows a DSC profile having an endothermic peak at 205.06°C ⁇ 1 °C with an onset at 202.55°C ⁇ 1 °C.
  • the Form E can be characterized by a DSC profile substantially as depicted in Figure 1 1.
  • Form E can be characterized by a 1 H NMR spectrum substantially as depicted in Figure 12.
  • the Form G can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 10.3°; 15.5°; 20.3°; 20.6°; and 20.8° (2-Theta, ⁇ 0.1 ). Furthermore, the Form G can be characterized by a XRPD pattern substantially as depicted in Figure 13.
  • the Form G shows a DSC profile having a first endothermic peak at 151 .28°C ⁇ 1 °C with an onset at 145.56°C ⁇ 1 °C, followed by an exothermic peak at 162.40°C ⁇ 1 °C with an onset at 150.23°C ⁇ 1 °C, further followed by a last endothermic peak at 180.24°C ⁇ 1 °C with an onset at 175.15°C ⁇ 1 °C.
  • the Form G can be characterized by a DSC profile substantially as depicted in Figure 14.
  • the Form G can be characterized by a 1 H NMR spectrum substantially as depicted in Figure 15.
  • the Form H can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 6.7°; 9.8°; 13.5°; 13.8°; 16.8°; 19.1 °; 19.5°; and 21.7° (2-Theta, ⁇ 0.1 ). Furthermore, the Form H can be characterized by a XRPD pattern substantially as depicted in Figure 16.
  • the Form H shows a DSC profile having an endothermic peak at 174.89°C ⁇ 1 °C with an onset at 171.57°C ⁇ 1 °C. Furthermore, the Form H can be characterized by a DSC profile substantially as depicted in Figure 17. As a further alternative, the Form H can be characterized by a 1 H NMR spectrum substantially as depicted in Figure 18.
  • Figure 1 shows an XRPD pattern for the 2:1 vinpocetine hydrochloride and benzoic acid co-crystals (Form B).
  • Figure 2 shows a DSC profile for the 2:1 vinpocetine hydrochloride and benzoic acid co-crystals (Form B).
  • Figure 3 shows the 1 H NMR spectrum of 2:1 vinpocetine hydrochloride and benzoic acid co-crystals (Form B).
  • Figure 4 shows an XRPD pattern for the 2:1 vinpocetine hydrochloride and gentisic acid co-crystals (Form C).
  • Figure 5 shows a DSC profile for the 2:1 vinpocetine hydrochloride and gentisic acid co-crystals (Form C).
  • Figure 6 shows the 1 H NMR spectrum of 2:1 vinpocetine hydrochloride and gentisic acid co-crystals (Form C).
  • Figure 7 shows an XRPD pattern for the 2:1 vinpocetine hydrochloride and 4-aminobenzoic acid co-crystals (Form D).
  • Figure 8 shows a DSC profile for the 2:1 vinpocetine hydrochloride and 4- aminobenzoic acid co-crystals (Form D).
  • Figure 9 shows the 1 H NMR spectrum of 2:1 vinpocetine hydrochloride and 4-aminobenzoic acid co-crystals (Form D).
  • Figure 10 shows an XRPD pattern for the 2:1 vinpocetine hydrochloride and vanillic acid co-crystals (Form E).
  • Figure 1 1 shows a DSC profile for the 2:1 vinpocetine hydrochloride and vanillic acid co-crystals (Form E).
  • Figure 12 shows the 1 H NMR spectrum of 2:1 vinpocetine hydrochloride and vanillic acid co-crystals (Form E).
  • Figure 13 shows an XRPD pattern for the 2:1 vinpocetine hydrochloride and fumaric acid co-crystals (Form G).
  • Figure 14 shows a DSC profile for the 2:1 vinpocetine hydrochloride and fumaric acid co-crystals (Form G).
  • Figure 15 shows the 1 H NMR spectrum of 2:1 vinpocetine hydrochloride and fumaric acid co-crystals (Form G).
  • Figure 16 shows an XRPD pattern for the 1 :1 vinpocetine hydrochloride and maleic acid co-crystals (Form H).
  • Figure 17 shows a DSC profile for the 1 :1 vinpocetine hydrochloride and maleic acid co-crystals (Form H).
  • Figure 18 shows the 1 H NMR spectrum of 1 :1 vinpocetine hydrochloride and maleic acid co-crystals (Form H).
  • Figure 19 shows an XRPD pattern for the crystalline form of vinpocetine hydrochloride.
  • Figure 20 shows a DSC profile for the crystalline form of vinpocetine hydrochloride.
  • the Form B according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 7.3°; 7.7°; 12.7°; 13.4°; 15.6°; 16.4°; 20.0°; and 20.6° (2-Theta, ⁇ 0.1 ).
  • XRPD X-ray powder diffraction
  • the Form B according to the present invention can be further characterized by a XRPD pattern having one or more additional detectable peak(s) selected from the peaks at 21.3°; 22.4°; 24.4°; 24.9°; and 28.2° (2-Theta, ⁇ 0.1 ).
  • Form B according to the present invention can be further characterized by a XRPD pattern having one or more additional detectable peak(s) selected from the peaks at 12.3°; 18.1 °; 22.9°; and 27.0° (2-Theta, ⁇ 0.1 ).
  • Form B can be characterized by a XRPD pattern substantially as depicted in Figure 1.
  • the Form C according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 7.2°; 7.5°; 12.8°; 13.5°; 15.7°; 16.6°; and 19.6° (2-Theta, ⁇ 0.1 ).
  • XRPD X-ray powder diffraction
  • the Form C according to the present invention can be further characterized by a XRPD pattern having one or more additional detectable peak(s) selected from the peaks at 13.3°; 15.1 °; 20.2°; 20.7°; 21.2°; 22.6°; 24.1 °; 25.2°; and 28.6° (2-Theta, ⁇ 0.1 ).
  • the Form C according to the present invention can be further characterized by a XRPD pattern having one or more additional detectable peak(s) selected from the peaks at 18.0°; 23.0°; 25.5°; and 27.0° (2-Theta, ⁇ 0.1 ). Furthermore, the Form C can be characterized by a XRPD pattern substantially as depicted in Figure 4.
  • the Form D according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 7.2°; 7.5°; 12.5°; 13.6°; 15.7°; 16.4°; 19.7°; 20.4°; and 24.2° (2-Theta, ⁇ 0.1 ).
  • XRPD X-ray powder diffraction
  • the Form D according to the present invention can be further characterized by a XRPD pattern having one or more additional detectable peak(s) selected from the peaks at 13.1 °; 20.0°; 21.2°; 22.2°; 25.3°; and 28.5° (2-Theta, ⁇ 0.1 ).
  • Form D according to the present invention can be further characterized by a XRPD pattern having one or more additional detectable peak(s) selected from the peaks at 22.7°; 26.7°; and 31 .1 ° (2-Theta, ⁇ 0.1 ).
  • the Form D can be characterized by a XRPD pattern substantially as depicted in Figure 7.
  • the Form E according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 7.2°; 7.5°; 7.6°; 12.7°; 13.1 °; 15.4°; 16.1 °; 20.0°; 20.4°; and 24.2° (2-Theta, ⁇ 0.1 ).
  • XRPD X-ray powder diffraction
  • the Form E according to the present invention can be further characterized by a XRPD pattern having one or more additional detectable peak(s) selected from the peaks at 13.4°; 15.1 °; 21.1 °; 22.2°; and 27.8° (2-Theta, ⁇ 0.1 ).
  • Form E according to the present invention can be further characterized by a XRPD pattern having one or more additional detectable peak(s) selected from the peaks at 12.0°; 17.5°; 22.6°; and 22.8° (2-Theta, ⁇ 0.1 ).
  • Form E can be characterized by a XRPD pattern substantially as depicted in Figure 10.
  • the Form G according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 10.3°; 15.5°; 20.3°; 20.6°; and 20.8° (2-Theta, ⁇ 0.1 ).
  • XRPD X-ray powder diffraction
  • the Form G according to the present invention can be further characterized by a XRPD pattern having one or more additional detectable peak(s) selected from the peaks at 13.0°; 13.4°; 15.7°; and 26.9° (2-Theta, ⁇ 0.1 ).
  • Form G according to the present invention can be further characterized by a XRPD pattern having one or more additional detectable peak(s) selected from the peaks at 6.8°; 17.0°; 17.8°; 22.8°; 23.0°; 23.3°. 24.4°; and 28.7° (2-Theta, ⁇ 0.1 ).
  • Form G can be characterized by a XRPD pattern substantially as depicted in Figure 13.
  • the Form H according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 6.7°; 9.8°; 13.5°; 13.8°; 16.8°; 19.1 °; 19.5°; and 21.7° (2-Theta, ⁇ 0.1 ).
  • XRPD X-ray powder diffraction
  • the Form H according to the present invention can be further characterized by a XRPD pattern having one or more additional detectable peak(s) selected from the peaks at 1 1.8°; 18.4°; 22.8°; 24.4°; and 25.0° (2-Theta, ⁇ 0.1 ).
  • Form H according to the present invention can be further characterized by a XRPD pattern having one or more additional detectable peak(s) selected from the peaks at 14.7°; 15.3°; 21.0°; 24.2°; 25.3°; 26.6°; 27.9°; and 30.2° (2-Theta, ⁇ 0.1 ).
  • Form H can be characterized by a XRPD pattern substantially as depicted in Figure 16.
  • Diffraction measurement was performed at ambient conditions on a PANalytical X'Pert PRO ⁇ - ⁇ diffractometer of 240 mm of radius in reflection geometry, equipped with Cu Ka radiation and a PIXcel detector, operated at 45 kV and 40 mA.
  • the sample was mounted on a zero background silicon sample holder and allowed to spin at 0.25 rev/s during the data collection.
  • the measurement angular range was 3.0-40.0° (2 ⁇ ) with a step size of 0.013°.
  • the scanning speed was 0.0827s (40.8 s/step).
  • Form B of the present invention shows a DSC profile having an endothermic peak at 198.08°C ⁇ 1 °C with an onset at 196.32°C ⁇ 1 °C.
  • the whole DSC profile of the Form B is substantially as depicted in Figure 2.
  • Form C of the present invention shows a DSC profile having an endothermic peak at 152.83°C ⁇ 1 °C with an onset at 148.92°C ⁇ 1 °C, followed by an endothermic peak at 224.17°C ⁇ 1 °C with an onset at 219.88°C ⁇ 1 °C.
  • the whole DSC profile of the Form C is substantially as depicted in Figure 5.
  • Form D of the present invention shows a DSC profile having an endothermic peak at 189.12°C ⁇ 1 °C with an onset at 184.59°C ⁇ 1 °C.
  • the whole DSC profile of the Form D is substantially as depicted in Figure 8.
  • Form E of the present invention shows a DSC profile having an endothermic peak at 205.06°C ⁇ 1 °C with an onset at 202.55°C ⁇ 1 °C.
  • the whole DSC profile of the Form E is substantially as depicted in Figure 1 1 .
  • Form G of the present invention shows a DSC profile having a first endothermic peak at 151.28°C ⁇ 1 °C with an onset at 145.56°C ⁇ 1 °C, followed by an exothermic peak at 162.40°C ⁇ 1 °C with an onset at 150.23°C ⁇ 1 °C, followed by a last endothermic peak at 180.24°C ⁇ 1 °C with an onset at 175.15°C ⁇ 1 °C.
  • the whole DSC profile of the Form G is substantially as depicted in Figure 14.
  • Form H of the present invention shows a DSC profile having an endothermic peak at 174.89°C ⁇ 1 °C with an onset at 171.57°C ⁇ 1 °C.
  • the whole DSC profile of the Form H is substantially as depicted in Figure 17.
  • Form B of the invention can be characterized by a 1 H NMR spectrum substantially as depicted in Figure 3.
  • Form C of the invention can be characterized by a 1 H NMR spectrum substantially as depicted in Figure 6.
  • Form D of the invention can be characterized by a 1 H NMR spectrum substantially as depicted in Figure 9.
  • Form E of the invention can be characterized by a 1 H NMR spectrum substantially as depicted in Figure 12.
  • Form G of the invention can be characterized by a 1 H NMR spectrum substantially as depicted in Figure 15.
  • Form H of the invention can be characterized by a 1 H NMR spectrum substantially as depicted in Figure 18.
  • detecttable peak denotes that the peak in the XRPD pattern has a signal-to-noise (S/N) ratio equal or higher than 3.0.
  • Signal-to-noise ratio of a peak is a dimensionless parameter that is calculated by dividing the height of the peak by the baseline width of the diffraction plot, both expressed using the same length units (e.g. mm). The height of a peak is calculated by measuring the distance between peak's maximum and the baseline of the peak. Peak's maximum 2-theta values are identified by having a first-derivative value equal to zero, and a negative second-derivative value.
  • the baseline of the peak is obtained by tracing a straight line which is tangent to the diffraction plot at the closest 2-theta value which is lower than peak's maximum 2-theta value and has both first- and second-derivative values equal to zero, and also tangent to the diffraction plot at the closest 2-theta value which is higher than peak's maximum 2-theta value and has both first- and second-derivative values equal to zero.
  • the height of the peak is obtained by tracing a second straight line which is parallel to the previously obtained baseline of the peak and tangent to the diffraction plot at the peak's maximum
  • the baseline width of the diffraction plot is calculated by tracing two parallel lines to the X- 5 axis of the diffraction plot, the first line being tangent to the diffraction plot at its
  • hydrochloride co-crystalline Forms B, C, D, E, G, and H are summarized in Table 1. It is worth noting that vinpocetine hydrochloride co-crystalline Forms B, C, D, and E, obtained with aromatic co-formers, have identical vinpocetine hydrochloride to co-former
  • two crystals are said to be isostructural if they have the same structure, but not necessarily the same cell dimensions nor the same chemical composition, and with a 'comparable' variability in the atomic coordinates to that of the cell dimensions and chemical composition.
  • the Forms B and G according to the present invention showed good solubility, but showed a limited stability under storage at 40°C and 75% ⁇ 5%
  • the Forms B, C, D, E, G, and H are therefore suitable for the use in the pharmaceutical field, as well as in the non-pharmaceutical field, as supplement and/or nutraceutical.
  • the Forms C, D, E, and H are preferably selected from the pharmaceutical field, as well as in the non-pharmaceutical field, as supplement and/or nutraceutical.
  • the Forms C, D, E, and H are preferably selected from the pharmaceutical field, as well as in the non-pharmaceutical field, as supplement and/or nutraceutical.
  • the Forms C, D, E, and H are therefore suitable for the use in the pharmaceutical field, as well as in the non-pharmaceutical field, as supplement and/or nutraceutical.
  • the Forms C, D, E, and H are preferably selected from the pharmaceutical field, as well as in the non-pharmaceutical field, as supplement and/or nutraceutical.
  • the Forms C, D, E, and H are preferably selected from the pharmaceutical field, as
  • this invention further encompasses pharmaceutical compositions comprising any one of the Forms B, C, D, E, G, and H, as described above, and at least one pharmaceutically acceptable excipient, and a process for the preparation of such a pharmaceutical composition by
  • this invention further encompasses supplement and/or nutraceutical compositions comprising any one of the Forms B, C, D, E, G, and H, as described above, and at least one edible excipient.
  • excipients comprise without any particular limitations any material which is suitable for the preparation of a pharmaceutical composition which is to be administered to a living being.
  • excipients are classified into (i) filler excipients, (ii) production excipients, (iii) preservative excipients, and (iv) presentation excipients.
  • These materials are for example (i) diluents, absorbents, adsorbents, fillers and humectants, (ii) lubricants, binders, glidants, plasticizers and viscosity modifiers, (iii) preservatives, antimicrobials, antioxidants and chelating agents, and (iv) flavorings, sweeteners and coloring agents.
  • the Forms B, C, D, E, G, and H and the compositions containing any one of them can be used as a medicament, supplement or nutraceutical for example as an aid to improve memory, to combat the symptoms of senile dementia, and to improve conditions related to insufficient blood flow to the brain.
  • the DSC profile for the crystalline vinpocetine hydrochloride is shown in Figure 20.
  • DSC analysis showed an exothermic event with an onset at 130°C that should correspond to a polymorphic transition solid-solid followed by an endothermic event around 218°C which should correspond to the melting point of vinpocetine hydrochloride.
  • the DSC profile for the co-crystalline Form B is shown in Figure 2.
  • DSC analysis showed an endothermic event around 196°C which should correspond to the melting point of Form B.
  • the 1 H NMR spectrum of the co-crystalline Form B is shown in Figure 3.
  • the 1 H NMR spectrum shown in Figure 3 displayed resonance signals coherent with a 2:1 stoichiometry between vinpocetine hydrochloride and benzoic acid.
  • the DSC profile for the co-crystalline Form C is shown in Figure 5.
  • DSC analysis showed an endothermic event around 149°C which should correspond to a polymorphic transition solid-solid followed by an endothermic event around 220°C that should correspond to the melting point of the co- crystalline Form C. Therefore DSC analysis seems to indicate the presence of another polymorph of Form C.
  • the 1 H NMR spectrum of the co-crystalline Form C is shown in Figure 6.
  • the 1 H NMR spectrum shown in Figure 6 displayed resonance signals coherent with a 2:1 stoichiometry between vinpocetine hydrochloride and gentisic acid.
  • the XRPD pattern for the co-crystalline Form D is shown in Figure 7.
  • the DSC profile for the co-crystalline Form D is shown in Figure 8.
  • DSC analysis showed an endothermic event around 185°C which should correspond to the melting point of co-crystalline Form D.
  • the 1 H NMR spectrum of the co-crystalline Form D is shown in Figure 9.
  • the 1 H NMR spectrum shown in Figure 9 displayed resonance signals coherent with a 2:1 stoichiometry between vinpocetine hydrochloride and 4- aminobenzoic acid.
  • a scaled-up procedure for the preparation of co-crystalline Form E was optimized.
  • a mixture of vinpocetine hydrochloride (250.0 mg, 0.65 mmol), vanillic acid (104 mg, 0.62 mmol, 1 eq) and EtOAc (4.0 mL) was sonicated in a bath for 1 min.
  • the resulting white suspension was stirred for 20 h, then filtered and washed with EtOAc (1 .0 mL).
  • Pure co- crystalline Form E was obtained by evaporating to drying the resulting solution as white solid (yield 74 %).
  • the DSC profile for the co-crystalline Form E is shown in Figure 1 1 .
  • DSC analysis showed an endothermic event around 202°C which should correspond to the melting point of co-crystalline Form E.
  • the 1 H NMR spectrum of the co-crystalline Form E is shown in Figure 12.
  • the 1 H NMR spectrum shown in Figure 12 displayed resonance signals coherent with a 2:1 stoichiometry between vinpocetine hydrochloride and vanillic acid.
  • the DSC profile for the co-crystalline Form G is shown in Figure 14. DSC analysis showed an endothermic event around 145°C which should correspond to the melting point of co-crystalline Form G, an exothermic event around 150 °C which corresponds to a crystallization in other crystalline form and finally other exothermic event around 175°C which should correspond to the melting point of this new crystalline form.
  • the 1 H NMR spectrum of the co-crystalline Form G is shown in Figure 15.
  • the 1 H NMR spectrum shown in Figure 15 displayed resonance signals coherent with a 2:1 stoichiometry between vinpocetine hydrochloride and fumaric acid.
  • the DSC profile for the co-crystalline Form H is shown in Figure 17.
  • DSC analysis showed an endothermic event around 171°C which should correspond to the melting point of co-crystalline Form H.
  • the 1 H NMR spectrum of the co-crystalline Form H is shown in Figure 18.
  • the 1 H NMR spectrum shown in Figure 18 displayed resonance signals coherent with a 1 :1 stoichiometry between vinpocetine hydrochloride and maleic acid.
  • the stability of the new co-crystalline forms of vinpocetine hydrochloride Forms C, D, E, and H of the present invention was evaluated by exposure to atmosphere of a sample exposed on the XRPD sample holder under accelerated stability conditions according to ICH guidelines (75 ⁇ 5 RH %, 40°C). The sample was analyzed by XRPD at different times to observe if the crystalline phase was stable.
  • Form C remained stable at 40°C under 75 ⁇ 5% relative humidity for more than 21 days.
  • Form D remained stable at 40°C under 75 ⁇ 5% relative humidity for more than 14 days.
  • Form E remained stable at 40°C under 75 ⁇ 5% relative humidity for more than 21 days.
  • Form H Form H remained stable at 40°C under 75 ⁇ 5% relative humidity for more than 7 days.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des formes co-cristallines de chlorhydrate de vinpocétine et un co-agent sélectionné dans le groupe constitué par : l'acide benzoïque, l'acide gentisique, l'acide 4-aminobenzoïque, l'acide vanillique, l'acide fumarique et l'acide maléique, et des compositions de ceux-ci.
PCT/EP2018/055316 2017-03-07 2018-03-05 Co-cristaux de chlorhydrate de vinpocétine WO2018162395A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT102017000025306A IT201700025306A1 (it) 2017-03-07 2017-03-07 Co-cristalli di vinpocetina cloridrato
IT102017000025306 2017-03-07

Publications (1)

Publication Number Publication Date
WO2018162395A1 true WO2018162395A1 (fr) 2018-09-13

Family

ID=59409633

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2018/055316 WO2018162395A1 (fr) 2017-03-07 2018-03-05 Co-cristaux de chlorhydrate de vinpocétine

Country Status (2)

Country Link
IT (1) IT201700025306A1 (fr)
WO (1) WO2018162395A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0154756A1 (fr) * 1984-02-29 1985-09-18 Covex (S.A.) Citrate de vinpocetine et son procédé de préparation
EP0202051A2 (fr) * 1985-05-06 1986-11-20 American Home Products Corporation Compositions thérapeutiques pour administration orale
EP0689844A1 (fr) 1994-06-23 1996-01-03 Tecnimede-Sociedade Tecnico-Medicinal, S.A. Complexes de vinpocetine avec cyclodextrines, procédé pour leur préparation et compositions pharmaceutiques les contenant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0154756A1 (fr) * 1984-02-29 1985-09-18 Covex (S.A.) Citrate de vinpocetine et son procédé de préparation
EP0154756B1 (fr) 1984-02-29 1989-08-16 Covex (S.A.) Citrate de vinpocetine et son procédé de préparation
EP0202051A2 (fr) * 1985-05-06 1986-11-20 American Home Products Corporation Compositions thérapeutiques pour administration orale
EP0689844A1 (fr) 1994-06-23 1996-01-03 Tecnimede-Sociedade Tecnico-Medicinal, S.A. Complexes de vinpocetine avec cyclodextrines, procédé pour leur préparation et compositions pharmaceutiques les contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DRITAN HASA ET AL: "Enhanced Oral Bioavailability of Vinpocetine Through Mechanochemical Salt Formation: Physico-Chemical Characterization andStudies", PHARMACEUTICAL RESEARCH, KLUWER ACADEMIC PUBLISHERS-PLENUM PUBLISHERS, NL, vol. 28, no. 8, 19 March 2011 (2011-03-19), pages 1870 - 1883, XP019921751, ISSN: 1573-904X, DOI: 10.1007/S11095-011-0415-8 *

Also Published As

Publication number Publication date
IT201700025306A1 (it) 2018-09-07

Similar Documents

Publication Publication Date Title
ES2550771T3 (es) Sal de bismesilato etexilato de dabigatrán, formas en estado sólido y proceso para la preparación de las mismas
US6242460B1 (en) Zolpidem salt forms
US10150770B2 (en) Crystal form of bisulfate of JAK inhibitor and preparation method therefor
WO2013079007A1 (fr) Pamoate de donépezile, son procédé de préparation et son utilisation
JP2018501289A (ja) ネラチニブマレイン酸塩の新規な結晶形及びその製造方法
BR112019021447A2 (pt) sal fumarato, forma cristalina i do referido sal, métodos para preparação dos mesmos, composição farmacêutica compreendendo o sal e a forma cristalina i e uso do sal fumarato, da forma cristalina i e da composição farmacêutica
JP2020502190A (ja) Ｐ２ｘ３アンタゴニストの結晶塩および多形
WO2015176591A1 (fr) Sels de betrixaban, procede de preparation et utilisation de ceux-ci
JP2021014404A (ja) トリアゾロピラジン誘導体の塩及び結晶
US20230106064A1 (en) Crystalline form of fluvatinib or fluvatinib methanesulfonate and preparation method therefor
WO2018038255A1 (fr) Cristaux de dérivé d'amine cyclique et utilisation pharmaceutique associée
US8772488B2 (en) Crystals of prasugrel hydrobromate
EP2551257A1 (fr) Co-cristaux d'agomélatine avec formeurs de co-cristaux
WO2022105644A1 (fr) Sel de composé benzothiazole, forme cristalline et son utilisation
WO2018041112A1 (fr) Dérivé de sel de tétrahydroisoquinoléine et son cristallin, son procédé de préparation et son application
WO2018162395A1 (fr) Co-cristaux de chlorhydrate de vinpocétine
KR102514961B1 (ko) 에독사반 벤젠술폰산염 1 수화물 결정형 및 그 제조방법
US10815232B2 (en) Crystalline forms of viral-protein inhibitor drug VX-787, processes for preparation thereof and use thereof
JP5651271B2 (ja) デニブリン二塩酸塩
WO2018162394A1 (fr) Formes cristallines du chlorhydrate de vinpocétine
US9981912B2 (en) Cocrystal of lorcaserin, preparation methods, pharmaceutical compositions and uses thereof
WO2018162393A1 (fr) Co-cristaux de vinpocétine et leur procédé de préparation
EP3412661A1 (fr) Co-cristaux de bromhydrate vortioxetine et du résorcinol
EP1163241A1 (fr) Sels de zolpidem
WO2023143350A1 (fr) Forme cristalline et sel de composé de phénothiazine, son procédé de préparation et son utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18709532

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18709532

Country of ref document: EP

Kind code of ref document: A1