WO2018162394A1 - Vinpocetine hydrochloride crystalline forms - Google Patents

Vinpocetine hydrochloride crystalline forms Download PDF

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Publication number
WO2018162394A1
WO2018162394A1 PCT/EP2018/055315 EP2018055315W WO2018162394A1 WO 2018162394 A1 WO2018162394 A1 WO 2018162394A1 EP 2018055315 W EP2018055315 W EP 2018055315W WO 2018162394 A1 WO2018162394 A1 WO 2018162394A1
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vinpocetine
vinpocetine hydrochloride
theta
peak
crystalline form
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PCT/EP2018/055315
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French (fr)
Inventor
Barbara PACCHETTI
Andrea Mereu
Giuseppe Paladino
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Linnea Sa
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    • 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 vinpocetine hydrochloride crystalline forms, and compositions thereof.
  • 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).
  • 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 possess more favorable pharmaceutical and pharmacological properties or be easier to process than known forms of the API itself. For example, a crystalline form may have different dissolution and solubility properties than the API itself and can be used to deliver APIs therapeutically. New drug formulations comprising crystalline forms of a given API may have superior properties over its existing drug formulations. They may also have better storage stability.
  • 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.
  • 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. Crystalline forms often also exhibit distinct thermal behavior, usually measured in the laboratory by differential scanning calorimetry (DSC). Stoichiometry of the API can be confirmed by H NMR technique.
  • the Applicant has faced the problem of finding stable crystalline forms of vinpocetine hydrochloride with the aim of improving the chemical and physical properties of vinpocetine. After extensive investigation, the Applicant has found stable crystalline forms of vinpocetine hydrochloride.
  • a first aspect of the present invention consists in crystalline forms of vinpocetine hydrochloride selected from the group consisting of (i) vinpocetine hydrochloride Form I having the X-ray powder diffraction pattern having detectable peak(s) at 7.4°; 7.6°; 8.2°; 12.5°; and 16.4° (2-Theta, ⁇ 0.1 ), (ii) vinpocetine hydrochloride Form II having the X-ray powder diffraction pattern having detectable peak(s) at 6.8°; 10.0°; 10.2°; 10.3°; and 20.5° (2- Theta, ⁇ 0.1 ), (iii) vinpocetine hydrochloride Form III having the X-ray powder diffraction pattern having detectable peak(s) at 10.3°; 13.4°; 14.3°; 15.6°; 20.0°; and 20.3° (2-Theta, ⁇ 0.1 ), (iv) vinpocetine hydrochloride Form III' having the X-ray powder
  • the Form I can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 7.4°; 7.6°; 8.2°; 12.5°; and 16.4° (2-Theta, ⁇ 0.1 ). Furthermore, the Form I can be characterized by a XRPD pattern substantially as depicted in Figure 1.
  • the Form I shows a DSC profile having an exothermic peak at 135.72°C ⁇ 1 °C with an onset at 130.01 °C ⁇ 1 °C followed by an endothermic peak at 222.20°C ⁇ 1 °C with an onset at 218.29°C ⁇ 1 °C.
  • the whole DSC profile of Form I is substantially as depicted in Figure 6.
  • the Form II can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 6.8°; 10.0°; 10.2°; 10.3°; and 20.5° (2-Theta, ⁇ 0.1 ). Furthermore, the Form II can be characterized by a XRPD pattern substantially as depicted in Figure 2.
  • the Form III can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 10.3°; 13.4°; 14.3°; 15.6°; 20.0°; and 20.3° (2- Theta, ⁇ 0.1 ). Furthermore, the Form III can be characterized by a XRPD pattern substantially as depicted in Figure 3.
  • the Form III shows a DSC profile having an endothermic peak at 222.44°C ⁇ 1 °C with an onset at 217.62°C ⁇ 1 °C.
  • the whole DSC profile of Form III is substantially as depicted in Figure 7.
  • the Form I II' can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 10.3°; 13.0°; 15.5°; 20.3°; 20.6°; and 26.9° (2- Theta, ⁇ 0.1 ). Furthermore, the Form III' can be characterized by a XRPD pattern substantially as depicted in Figure 4.
  • the Form I II' shows a DSC profile having an endothermic peak at 216.97°C ⁇ 1 °C with an onset at 21 1 .19°C ⁇ 1 °C.
  • the whole DSC profile of Form III' is substantially as depicted in Figure 8.
  • the Form IV can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 10.1 °; 10.8°; 12.0°; 13.1 °; and 24.3° (2-Theta, ⁇ 0.1 ). Furthermore, the Form IV can be characterized by a XRPD pattern substantially as depicted in Figure 5.
  • the Form IV shows a DSC profile having an endothermic peak at 64.33°C ⁇ rc with an onset at 61 .20°C ⁇ 1 °C followed by an endothermic peak at 221 .00°C ⁇ rc with an onset at 216.71 °C ⁇ 1 °C.
  • the whole DSC profile of Form IV is substantially as depicted in Figure 9.
  • Figure 1 shows the XRPD pattern for the vinpocetine hydrochloride crystalline Form I.
  • Figure 2 shows the XRPD pattern for the vinpocetine hydrochloride crystalline Form II.
  • Figure 3 shows the XRPD pattern for the vinpocetine hydrochloride crystalline Form III.
  • Figure 4 shows the XRPD pattern for the vinpocetine hydrochloride crystalline Form III'.
  • Figure 5 shows the XRPD pattern for the vinpocetine hydrochloride crystalline Form IV.
  • Figure 6 shows the DSC profile for the vinpocetine hydrochloride crystalline Form I.
  • Figure 7 shows the DSC profile for the vinpocetine hydrochloride crystalline Form III.
  • Figure 8 shows the DSC profile for the vinpocetine hydrochloride crystalline Form III'.
  • Figure 9 shows the DSC profile for the vinpocetine hydrochloride crystalline Form IV.
  • Figure 10 shows the 1 H NMR spectrum of the vinpocetine hydrochloride crystalline Form I.
  • Figure 1 1 shows the 1 H NMR spectrum of the vinpocetine hydrochloride crystalline Form III.
  • Figure 12 shows the 1 H NMR spectrum of the vinpocetine.
  • Figure 13 shows the XRPD pattern for the vinpocetine.
  • the vinpocetine hydrochloride crystalline Form I according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 7.4°; 7.6°; 8.2°; 12.5°; and 16.4° (2-Theta, ⁇ 0.1 ).
  • the vinpocetine hydrochloride crystalline Form I 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 10.3°; 20.9°; 22.2°; and 22.4° (2-Theta, ⁇ 0.1 ).
  • the vinpocetine hydrochloride crystalline Form I 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 14.9°; 19.9°; 25.3°; and 28.5° (2-Theta, ⁇ 0.1 ).
  • vinpocetine hydrochloride crystalline Form I can be characterized by a XRPD pattern substantially as depicted in Figure 1 .
  • the vinpocetine hydrochloride crystalline Form II according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 6.8°; 10.0°; 10.2°; 10.3°; and 20.5° (2-Theta, ⁇ 0.1 ).
  • the vinpocetine hydrochloride crystalline Form II 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°; 13.6°; 15.6°; 17.0°; and 20.8° (2-Theta, ⁇ 0.1 ).
  • the vinpocetine hydrochloride crystalline Form II 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 15.2°; 21.9°; and 27.4° (2-Theta, ⁇ 0.1 ).
  • the vinpocetine hydrochloride crystalline Form II can be characterized by a XRPD pattern substantially as depicted in Figure 2.
  • the vinpocetine hydrochloride crystalline Form III according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 10.3°; 13.4°; 14.3°; 15.6°; 20.0°; and 20.3° (2- Theta, ⁇ 0.1 ).
  • the vinpocetine hydrochloride crystalline Form III 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°; 16.2°; 17.0°; 17.4°; 19.8°; and 20.9° (2-Theta, ⁇ 0.1 ). Furthermore, the vinpocetine hydrochloride crystalline Form III 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 14.6°; 21.6°; 22.8°; 24.2°; and 24.6° (2-Theta, ⁇ 0.1 ).
  • vinpocetine hydrochloride crystalline Form III can be characterized by a XRPD pattern substantially as depicted in Figure 3.
  • the vinpocetine hydrochloride crystalline Form III' according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 10.3°; 13.0°; 15.5°; 20.3°; 20.6°; and 26.9° (2- Theta, ⁇ 0.1 ).
  • the vinpocetine hydrochloride crystalline Form III' 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 13.5°; 15.7°; 15.9°; and 17.8° (2-Theta, ⁇ 0.1 ).
  • the vinpocetine hydrochloride crystalline Form III' 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 17.00°; 21.9°; 22.3°; 23.0°; 23.3°; and 24.4° (2-Theta, ⁇ 0.1 ).
  • the vinpocetine hydrochloride crystalline Form III' can be characterized by a XRPD pattern substantially as depicted in Figure 4.
  • the vinpocetine hydrochloride crystalline Form IV according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 10.1 °; 10.8°; 12.0°; 13.1 °; and 24.3° (2-Theta, ⁇ 0.1 ).
  • the vinpocetine hydrochloride crystalline Form IV 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 8.9°; 18.4°; 22.8°; and 23.5° (2-Theta, ⁇ 0.1 ).
  • the vinpocetine hydrochloride crystalline Form IV 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 13.6°; 20.1 °; 21.7°; and 25.2° (2-Theta, ⁇ 0.1 ).
  • vinpocetine hydrochloride crystalline Form IV can be characterized by a XRPD pattern substantially as depicted in Figure 5.
  • 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).
  • the vinpocetine hydrochloride crystalline Form I shows a DSC profile having an exothermic peak at 135.72°C ⁇ 1 °C with an onset at 130.01 °C ⁇ 1 °C followed by an endothermic peak at 222.20°C ⁇ 1 °C with an onset at 218.29°C ⁇ 1 °C.
  • the whole DSC profile of vinpocetine hydrochloride crystalline Form I is substantially as depicted in Figure 6.
  • the vinpocetine hydrochloride crystalline Form III shows a DSC profile having an endothermic peak at 222.44°C ⁇ 1 °C with an onset at 217.62°C ⁇ 1 °C.
  • the whole DSC profile of vinpocetine hydrochloride crystalline Form III is substantially as depicted in Figure 7.
  • the vinpocetine hydrochloride crystalline Form III' shows a DSC profile having an endothermic peak at 216.97°C ⁇ 1 °C with an onset at 21 1.19°C ⁇ 1 °C.
  • the whole DSC profile of vinpocetine hydrochloride crystalline Form III' is substantially as depicted in Figure 8.
  • the vinpocetine hydrochloride crystalline Form IV shows a DSC profile having an endothermic peak at 64.33°C ⁇ 1 °C with an onset at 61 .20°C ⁇ 1 °C followed by an endothermic peak at 221.00°C ⁇ 1 °C with an onset at 216.71 °C ⁇ 1 °C.
  • the whole DSC profile of vinpocetine hydrochloride crystalline Form IV is substantially as depicted in Figure 9.
  • DSC analysis was performed with a Mettler-Toledo TGA DSC-2 Thermogravimetric Analyzer equipped with STAR e software version 13.00.
  • the sample under examination was heated at 10°C/min from 25 to 300°C under a nitrogen flow of 50 mL/min..
  • the vinpocetine hydrochloride crystalline Form I shows a 1 H NMR spectrum substantially as depicted in Figure 10.
  • the vinpocetine hydrochloride crystalline Form III shows a 1 H NMR substantially as depicted in Figure 1 1.
  • Figures 1 to 13 are generally influenced by factors such as variations in sample preparation and purity and variations in instrument response, which may result in small variations of peak intensities and peak positions. Nevertheless, the person skilled in the art would be readily capable of evaluating whether two sets of data are identifying the same crystal form or two different forms by comparing the graphical data disclosed herein with graphical data generated for a comparison sample. Therefore, the term "substantially as depicted in Figure 1 (or from 2 to 13)" includes crystalline forms characterized by graphical data with small variations well known to the skilled person.
  • 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 2-theta value, and measuring the distance (perpendicularly to the X-axis of the diffraction plot) between both parallel lines.
  • the baseline width of the diffraction plot is calculated by tracing two parallel lines to the X- axis of the diffraction plot, the first line being tangent to the diffraction plot at its maximum value in the range between 45° and 50° (2-theta), and the second line being tangent to the diffraction plot at its minimum value in the same range between 45° and 50° (2-theta), and measuring the perpendicular distance between both parallel lines.
  • vinpocetine hydrochloride crystalline forms according to the present invention show superior stability and solubility. ln particular, vinpocetine hydrochloride crystalline Form III', stored at 25°C ⁇ 2°C and 60 % ⁇ 5% relative humidity (RH), remained stable for up to 18 months.
  • Vinpocetine hydrochloride crystalline Form III' proved to be at least 75 times more soluble than crystalline vinpocetine free base.
  • Vinpocetine hydrochloride crystalline Form IV proved to be at least 30 times more soluble than crystalline vinpocetine free base.
  • vinpocetine hydrochloride crystalline forms are therefore particularly suitable for the use in the pharmaceutical field, as well as in the non- pharmaceutical field, as supplement and/or nutraceutical.
  • this invention further encompasses a pharmaceutical composition comprising the vinpocetine hydrochloride crystalline forms, as described above, and at least one pharmaceutically acceptable excipient, and a process for the preparation of such a pharmaceutical composition by combining the vinpocetine hydrochloride crystalline forms, as described above, and at least one pharmaceutically acceptable excipient.
  • this invention further encompasses supplement and/or nutraceutical compositions comprising the vinpocetine hydrochloride crystalline forms, as described above, and at least one edible excipient.
  • pharmaceutically acceptable excipient is understood to 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 vinpocetine hydrochloride crystalline forms and the pharmaceutical composition containing them can be used as a medicament, 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.
  • Vinpocetine free base was dissolved in toluene (17 vol.) and mixed with a solution of hydrochloric acid in ethanol (1 .25 M). A slight excess of hydrochloric acid (1.1 -1.2 equivalent) was used. Crystallization was not observed either by cooling to 0°C or by adding an anti-solvent like heptane.
  • Vinpocetine hydrochloride Form I was obtained by evaporating to dryness the resulting solution. HPLC assay: 100.3%. The XRPD pattern for the vinpocetine hydrochloride crystalline Form I is shown in Figure 1.
  • the DSC profile for the vinpocetine hydrochloride crystalline Form I is shown in Figure 6.
  • 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 1 H NMR spectrum of the vinpocetine hydrochloride crystalline Form I is shown in Figure 10.
  • the 1 H NMR spectrum shown in Figure 10 displayed resonance signals coherent with a structure of vinpocetine hydrochloride and different from the 1 H NMR spectrum of vinpocetine base (see Figure 12) indicating that the hydrochloride salt was formed.
  • Vinpocetine hydrochloride Form II Vinpocetine free base was dissolved in ethanol (17 vol.) and mixed with a solution of hydrochloric acid in ethanol (1 .25 M). A slight excess of hydrochloric acid (1.1 -1.2 equivalent) was used. Crystallization was not observed either by cooling to 0°C or by adding an anti-solvent like heptane. Vinpocetine hydrochloride Form II was obtained by evaporating to dryness the resulting solution.
  • the XRPD pattern for the vinpocetine hydrochloride crystalline Form II is shown in Figure 2.
  • the 1 H NMR spectrum of the vinpocetine hydrochloride crystalline Form II is very similar to that of Form I, but it has showed a high amount of residual ethanol (about 0.3 equivalent), which suggested the formation of a solvate.
  • Vinpocetine hydrochloride Form III was first obtained by exposing for 24 hours a sample of vinpocetine hydrochloride Form I to normal atmosphere at 40°C and 75% ⁇ 5% relative humidity.
  • Vinpocetine hydrochloride Form III was also obtained by slurrying from vinpocetine hydrochloride Form I in cyclohexane at room temperature. 25 mg of vinpocetine hydrochloride Form I were added to 5 volumes of cyclohexane at room temperature and stirred overnight, so obtaining the crystallization of vinpocetine hydrochloride Form III. Form III is then more stable than Form I.
  • XRPD pattern for the vinpocetine hydrochloride crystalline Form III is shown in Figure 3.
  • XRPD pattern of Form III contains all crystalline peaks of Form III', with a few additional minor crystalline peaks.
  • DSC profile for the vinpocetine hydrochloride crystalline Form III is shown in Figure 7.
  • DSC analysis showed an endothermic event around 217°C which should correspond to the melting point of vinpocetine hydrochloride Form III.
  • Form III is then considered a pure form distinct from Form III'.
  • the 1 H NMR spectrum of the vinpocetine hydrochloride crystalline Form III is shown in Figure 1 1 .
  • the 1 H NMR spectrum shown in Figure 1 1 is similar to that of Figure 10 without showing any chemical transformation or the presence of significant amount of residual solvent, so confirming that Form III was a distinct form of vinpocetine hydrochloride.
  • Vinpocetine free base 50 mg was dissolved in 10 mL of several solvents, showed in the following Table 1 , and mixed with a solution of hydrochloric acid in ethanol (1.25 M). A slight excess of hydrochloric acid (1.1 equivalent) was used. The resulting solution was stirred for 2.5 hours at room temperature and overnight at about 0°-5°C.
  • Vinpocetine hydrochloride Form III' was only obtained by crystallization from MTBE and HEP, and from cHEX after adding MTBE as antisolvent.
  • vinpocetine free base was suspended in cyclohexane (5 vol.) and mixed at room temperature with a solution of hydrochloric acid in ethanol (1.25 M). A slight excess of hydrochloric acid (1.1 equivalent) was used. Crystallization was not observed even after 2 h at room temperature.
  • MTBE was thus used as antisolvent, and the precipitation of vinpocetine hydrochloride started immediately upon addition of MTBE (3 vol.) at room temperature, without seeding with Form III'.
  • Pure vinpocetine hydrochloride Form III' was obtained by evaporating to dryness the resulting mixture, after 3 h of stirring at room temperature for 3 h and washing with MTBE (1 vol.). Vinpocetine hydrochloride Form III' was also obtained by evaporating to dryness the solution resulting from any solvent.
  • Vinpocetine hydrochloride Form III' can also be obtained by slurrying from vinpocetine hydrochloride Form I in some solvents at room temperature. Form III' is then more stable than Form I. In particular, 25 mg of vinpocetine hydrochloride Form I were added to 5 volumes of different solvents at room temperature and stirred overnight. Vinpocetine hydrochloride Form III' was obtained when using EtOAc, THF, MTBE, XYL, or acetone. No solid was obtained when using ACN, methanol, isopropyl alcohol or dioxane.
  • the XRPD pattern for the vinpocetine hydrochloride crystalline Form III' is shown in Figure 4. XRPD pattern of Form III' is very similar to XRPD pattern of Form III, but missing a few minor crystalline peaks.
  • the DSC profile for the vinpocetine hydrochloride crystalline Form III' is shown in Figure 8. DSC analysis showed an endothermic event around 21 1°C which should correspond to the melting point of vinpocetine hydrochloride Form III'. Form III' is then considered a pure form distinct from Form III.
  • Vinpocetine hydrochloride Form IV was first obtained by exposing for 24 hours a sample of vinpocetine hydrochloride Form I to normal atmosphere at 25°C and 90% ⁇ 5% relative humidity.
  • the DSC profile for the vinpocetine hydrochloride crystalline Form IV is shown in Figure 9.
  • DSC profile of Form IV showed a first endothermic event around 61 °C, which should come from a dehydration, and a second endothermic event around 216°C that corresponds to the melting point of vinpocetine hydrochloride Form III. Therefore, vinpocetine hydrochloride Form IV should be a hydrated form of vinpocetine hydrochloride.
  • the stability of vinpocetine hydrochloride crystalline forms 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.
  • thermodynamic stability relationship between both crystalline Forms III and III' was performed by a competitive slurrying in different solvents and temperatures.
  • a mixture of vinpocetine hydrochloride Form III and Form III' 1 :1 w/w was suspended in 10 volumes of the corresponding solvent at the indicated temperature and was stirred overnight.
  • the solids were recovered by filtration through a sinter funnel and dried under vacuum until were analyzed by XRPD. The results are summarized in the Table 2 below.
  • Form III' prevailing with minor amounts of Form III Form III to Form III' ratio equal to about 1 :1
  • Form III' remained stable under accelerated stability conditions according to ICH guidelines (75 ⁇ 5% RH, 40 °C) for at least two weeks.
  • the sample of vinpocetine hydrochloride crystalline Form III' was then stored at 25°C ⁇ 2°C and 60% RH ⁇ 5% RH for long term stability studies according to ICH guideline.
  • the sample was analysed at release and after 3, 6 and 12 months.
  • the crystalline form III' was found stable as XRDP remained unchanged over time.
  • the product was also analysed by HPLC purity and assay, KF water and GC solvent content, resulting chemically stable after 18 months storage.
  • the HPLC assay changed from 98.7% to 99.1 %.
  • Form IV remained stable at room temperature under 90% relative humidity for more than 21 days. Form IV dehydrated after 5 hours at 50°C under vacuum (4 mbar) providing an amorphous form.
  • Form III' was the most stable anhydrate form of vinpocetine hydrochloride. Furthermore, a solubility test showed that vinpocetine hydrochloride crystalline Form III' and Form IV had an excellent water solubility.
  • the solubility test was performed with 500 mg of vinpocetine hydrochloride Form III' and Form IV in a test tube with screw cap and magnetic stirring.
  • the water was added at room temperature in small portions of 0.5 mL, and the mixture magnetically stirred until a clear solution was obtained. After each addition, the sample was stirred for 2-5 minutes to reach equilibrium.
  • a batch of vinpocetine hydrochloride crystalline Form III' at 250 mg scale was prepared by reacting vinpocetine free base with 1.1 equivalents of HCI in ethanol (1.25 M) in MTBE (10 vol.). After the addition of HCI in ethanol (1.25 M), the resulting solution was seeded with vinpocetine hydrochloride crystalline Form III' and in a few minutes an abundant white solid precipitated. Finally, the resulting suspension was filtered through a sinter funnel (porosity n° 3), washed with 2 x 1 vol. of MTBE and dried under vacuum at room temperature obtaining vinpocetine hydrochloride crystalline Form III' as a white solid (199 mg, yield 73%). This preparation method was successfully reproduced even when it was seeded with vinpocetine hydrochloride crystalline Form III. Crystalline Form III' thus obtained was characterized through XRPD and DSC analysis as described above in example 1 .
  • a batch of vinpocetine hydrochloride crystalline Form I II' at 20 g scale was prepared by reacting vinpocetine free base (57.06 mmol) with 1.1 equivalents of HCI in ethanol (1 .25 M - 50.2 mL) in cyclohexane (5 vol., 100 ml_). After the addition of HCI in ethanol, the resulting clear solution did not crystallize even after 2 h at room temperature. MTBE (3 vol., 60 mL) was therefore added at room temperature and the precipitation of vinpocetine hydrochloride started immediately, without seeding with Form III'. The resulting mixture was stirred at room temperature for 3 h. Finally, the crystallized solid was filtered, washed with 2 x 1 vol. of MTBE and dried under vacuum at room temperature affording vinpocetine hydrochloride Form III' as a white solid (16.3 g, yield 74%). HPLC assay: 98.7%.
  • Crystalline Form III' thus obtained was characterized through XRPD and DSC analysis as described above in example 1 .

Abstract

The present invention relates to vinpocetine hydrochloride crystalline forms, and compositions thereof.

Description

VINPOCETINE HYDROCHLORIDE CRYSTALLINE FORMS
FIELD OF THE INVENTION
The present invention relates to vinpocetine hydrochloride crystalline forms, and compositions thereof.
BACKGROUND OF THE INVENTION
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). The chemical name of 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.
Figure imgf000003_0001
Active pharmaceutical ingredients (API's) which, like vinpocetine, are generally less water soluble and less bioavailable create huge problems for the pharmaceutical industry. Research has shown that some drug candidates fail in the clinical phase due to poor human bioavailability and problems with the formulation. Traditional methods to address these problems, without completely redesigning the molecule, include salt selection, producing amorphous material, particle size reduction, pro-drugs, and different formulation approaches. Some attempts to use such techniques with vinpocetine are described, for example, in EP0154756B1 and EP0689844A1 . Although therapeutic efficacy is the primary concern for an API, 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. Recently, 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 (such as a co-crystal or polymorph of the original therapeutic compound) 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). Because these practical physical properties are influenced by the solid state properties of the crystalline form of the API, they can significantly impact the selection of a compound as an API, the ultimate pharmaceutical dosage form, the optimization of manufacturing processes, and absorption in the body. Moreover, finding the most adequate solid state form for further drug development can reduce the time and the cost of that development.
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 possess more favorable pharmaceutical and pharmacological properties or be easier to process than known forms of the API itself. For example, a crystalline form may have different dissolution and solubility properties than the API itself and can be used to deliver APIs therapeutically. New drug formulations comprising crystalline forms of a given API may have superior properties over its existing drug formulations. They may also have better storage stability.
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.
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. Crystalline forms often also exhibit distinct thermal behavior, usually measured in the laboratory by differential scanning calorimetry (DSC). Stoichiometry of the API can be confirmed by H NMR technique. SUMMARY OF THE INVENTION
The Applicant has faced the problem of finding stable crystalline forms of vinpocetine hydrochloride with the aim of improving the chemical and physical properties of vinpocetine. After extensive investigation, the Applicant has found stable crystalline forms of vinpocetine hydrochloride.
Accordingly, a first aspect of the present invention consists in crystalline forms of vinpocetine hydrochloride selected from the group consisting of (i) vinpocetine hydrochloride Form I having the X-ray powder diffraction pattern having detectable peak(s) at 7.4°; 7.6°; 8.2°; 12.5°; and 16.4° (2-Theta, ±0.1 ), (ii) vinpocetine hydrochloride Form II having the X-ray powder diffraction pattern having detectable peak(s) at 6.8°; 10.0°; 10.2°; 10.3°; and 20.5° (2- Theta, ±0.1 ), (iii) vinpocetine hydrochloride Form III having the X-ray powder diffraction pattern having detectable peak(s) at 10.3°; 13.4°; 14.3°; 15.6°; 20.0°; and 20.3° (2-Theta, ±0.1 ), (iv) vinpocetine hydrochloride Form III' having the X-ray powder diffraction pattern having detectable peak(s) at 10.3°; 13.0°; 15.5°; 20.3°; 20.6°; and 26.9° (2-Theta, ±0.1 ), and (v) vinpocetine hydrochloride Form IV having the X-ray powder diffraction pattern having detectable peak(s) at 10.1 °; 10.8°; 12.0°; 13.1 °; and 24.3° (2-Theta, ±0.1 ). The Form I can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 7.4°; 7.6°; 8.2°; 12.5°; and 16.4° (2-Theta, ±0.1 ). Furthermore, the Form I can be characterized by a XRPD pattern substantially as depicted in Figure 1.
The Form I shows a DSC profile having an exothermic peak at 135.72°C ± 1 °C with an onset at 130.01 °C ± 1 °C followed by an endothermic peak at 222.20°C ± 1 °C with an onset at 218.29°C ± 1 °C. The whole DSC profile of Form I is substantially as depicted in Figure 6.
The Form II can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 6.8°; 10.0°; 10.2°; 10.3°; and 20.5° (2-Theta, ±0.1 ). Furthermore, the Form II can be characterized by a XRPD pattern substantially as depicted in Figure 2.
The Form III can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 10.3°; 13.4°; 14.3°; 15.6°; 20.0°; and 20.3° (2- Theta, ±0.1 ). Furthermore, the Form III can be characterized by a XRPD pattern substantially as depicted in Figure 3.
The Form III shows a DSC profile having an endothermic peak at 222.44°C ± 1 °C with an onset at 217.62°C ± 1 °C. The whole DSC profile of Form III is substantially as depicted in Figure 7.
The Form I II' can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 10.3°; 13.0°; 15.5°; 20.3°; 20.6°; and 26.9° (2- Theta, ±0.1 ). Furthermore, the Form III' can be characterized by a XRPD pattern substantially as depicted in Figure 4. The Form I II' shows a DSC profile having an endothermic peak at 216.97°C ± 1 °C with an onset at 21 1 .19°C ± 1 °C. The whole DSC profile of Form III' is substantially as depicted in Figure 8.
The Form IV can be characterized by a X-ray powder diffraction pattern having detectable peak(s) at 10.1 °; 10.8°; 12.0°; 13.1 °; and 24.3° (2-Theta, ±0.1 ). Furthermore, the Form IV can be characterized by a XRPD pattern substantially as depicted in Figure 5.
The Form IV shows a DSC profile having an endothermic peak at 64.33°C ± rc with an onset at 61 .20°C ± 1 °C followed by an endothermic peak at 221 .00°C ± rc with an onset at 216.71 °C ± 1 °C. The whole DSC profile of Form IV is substantially as depicted in Figure 9.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the XRPD pattern for the vinpocetine hydrochloride crystalline Form I. Figure 2 shows the XRPD pattern for the vinpocetine hydrochloride crystalline Form II.
Figure 3 shows the XRPD pattern for the vinpocetine hydrochloride crystalline Form III. Figure 4 shows the XRPD pattern for the vinpocetine hydrochloride crystalline Form III'.
Figure 5 shows the XRPD pattern for the vinpocetine hydrochloride crystalline Form IV.
Figure 6 shows the DSC profile for the vinpocetine hydrochloride crystalline Form I.
Figure 7 shows the DSC profile for the vinpocetine hydrochloride crystalline Form III.
Figure 8 shows the DSC profile for the vinpocetine hydrochloride crystalline Form III'. Figure 9 shows the DSC profile for the vinpocetine hydrochloride crystalline Form IV.
Figure 10 shows the 1H NMR spectrum of the vinpocetine hydrochloride crystalline Form I.
Figure 1 1 shows the 1H NMR spectrum of the vinpocetine hydrochloride crystalline Form III.
Figure 12 shows the 1H NMR spectrum of the vinpocetine.
Figure 13 shows the XRPD pattern for the vinpocetine.
DETAILED DESCRIPTION OF THE INVENTION
The vinpocetine hydrochloride crystalline Form I according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 7.4°; 7.6°; 8.2°; 12.5°; and 16.4° (2-Theta, ±0.1 ). The vinpocetine hydrochloride crystalline Form I 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 10.3°; 20.9°; 22.2°; and 22.4° (2-Theta, ±0.1 ). Furthermore, the vinpocetine hydrochloride crystalline Form I 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 14.9°; 19.9°; 25.3°; and 28.5° (2-Theta, ±0.1 ).
Finally, the vinpocetine hydrochloride crystalline Form I can be characterized by a XRPD pattern substantially as depicted in Figure 1 .
The vinpocetine hydrochloride crystalline Form II according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 6.8°; 10.0°; 10.2°; 10.3°; and 20.5° (2-Theta, ±0.1 ). The vinpocetine hydrochloride crystalline Form II 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°; 13.6°; 15.6°; 17.0°; and 20.8° (2-Theta, ±0.1 ).
Furthermore, the vinpocetine hydrochloride crystalline Form II 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 15.2°; 21.9°; and 27.4° (2-Theta, ±0.1 ).
Finally, the vinpocetine hydrochloride crystalline Form II can be characterized by a XRPD pattern substantially as depicted in Figure 2. The vinpocetine hydrochloride crystalline Form III according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 10.3°; 13.4°; 14.3°; 15.6°; 20.0°; and 20.3° (2- Theta, ±0.1 ). The vinpocetine hydrochloride crystalline Form III 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°; 16.2°; 17.0°; 17.4°; 19.8°; and 20.9° (2-Theta, ±0.1 ). Furthermore, the vinpocetine hydrochloride crystalline Form III 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 14.6°; 21.6°; 22.8°; 24.2°; and 24.6° (2-Theta, ±0.1 ).
Finally, the vinpocetine hydrochloride crystalline Form III can be characterized by a XRPD pattern substantially as depicted in Figure 3.
The vinpocetine hydrochloride crystalline Form III' according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 10.3°; 13.0°; 15.5°; 20.3°; 20.6°; and 26.9° (2- Theta, ±0.1 ). The vinpocetine hydrochloride crystalline Form III' 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 13.5°; 15.7°; 15.9°; and 17.8° (2-Theta, ±0.1 ).
Furthermore, the vinpocetine hydrochloride crystalline Form III' 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 17.00°; 21.9°; 22.3°; 23.0°; 23.3°; and 24.4° (2-Theta, ±0.1 ).
Finally, the vinpocetine hydrochloride crystalline Form III' can be characterized by a XRPD pattern substantially as depicted in Figure 4. The vinpocetine hydrochloride crystalline Form IV according to the present invention can be characterized by a X-ray powder diffraction (XRPD) pattern having detectable peak(s) at 10.1 °; 10.8°; 12.0°; 13.1 °; and 24.3° (2-Theta, ±0.1 ). The vinpocetine hydrochloride crystalline Form IV 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 8.9°; 18.4°; 22.8°; and 23.5° (2-Theta, ±0.1 ). Furthermore, the vinpocetine hydrochloride crystalline Form IV 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 13.6°; 20.1 °; 21.7°; and 25.2° (2-Theta, ±0.1 ).
Finally, the vinpocetine hydrochloride crystalline Form IV can be characterized by a XRPD pattern substantially as depicted in Figure 5.
Diffraction measurement was performed at ambient conditions on a PANalytical X'Pert PRO Θ-Θ 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° (2Θ) with a step size of 0.013°. The scanning speed was 0.0827s (40.8 s/step).
The vinpocetine hydrochloride crystalline Form I shows a DSC profile having an exothermic peak at 135.72°C ± 1 °C with an onset at 130.01 °C ± 1 °C followed by an endothermic peak at 222.20°C ± 1 °C with an onset at 218.29°C ± 1 °C. The whole DSC profile of vinpocetine hydrochloride crystalline Form I is substantially as depicted in Figure 6.
The vinpocetine hydrochloride crystalline Form III shows a DSC profile having an endothermic peak at 222.44°C ± 1 °C with an onset at 217.62°C ± 1 °C. The whole DSC profile of vinpocetine hydrochloride crystalline Form III is substantially as depicted in Figure 7.
The vinpocetine hydrochloride crystalline Form III' shows a DSC profile having an endothermic peak at 216.97°C ± 1 °C with an onset at 21 1.19°C ± 1 °C. The whole DSC profile of vinpocetine hydrochloride crystalline Form III' is substantially as depicted in Figure 8.
The vinpocetine hydrochloride crystalline Form IV shows a DSC profile having an endothermic peak at 64.33°C ± 1 °C with an onset at 61 .20°C ± 1 °C followed by an endothermic peak at 221.00°C ± 1 °C with an onset at 216.71 °C ± 1 °C. The whole DSC profile of vinpocetine hydrochloride crystalline Form IV is substantially as depicted in Figure 9.
DSC analysis was performed with a Mettler-Toledo TGA DSC-2 Thermogravimetric Analyzer equipped with STARe software version 13.00. The sample under examination was heated at 10°C/min from 25 to 300°C under a nitrogen flow of 50 mL/min..
The vinpocetine hydrochloride crystalline Form I shows a 1H NMR spectrum substantially as depicted in Figure 10.
The vinpocetine hydrochloride crystalline Form III shows a 1H NMR substantially as depicted in Figure 1 1.
Proton nuclear magnetic resonance analysis was recorded in deuterated methanol (CD3OD) in a Varian Mercury 400 spectrometer, equipped with a broadband probe ATB 1 H/19F/X of 5 mm. The spectrum was acquired dissolving 5 mg of the sample under examination in 0.6 mL of the deuterated solvent.
The skilled person will understand that the graphical representations of Figures 1 to 13 are generally influenced by factors such as variations in sample preparation and purity and variations in instrument response, which may result in small variations of peak intensities and peak positions. Nevertheless, the person skilled in the art would be readily capable of evaluating whether two sets of data are identifying the same crystal form or two different forms by comparing the graphical data disclosed herein with graphical data generated for a comparison sample. Therefore, the term "substantially as depicted in Figure 1 (or from 2 to 13)" includes crystalline forms characterized by graphical data with small variations well known to the skilled person.
The term "detectable peak", as used herein, 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 2-theta value, and measuring the distance (perpendicularly to the X-axis of the diffraction plot) between both parallel lines. On the other hand, the baseline width of the diffraction plot is calculated by tracing two parallel lines to the X- axis of the diffraction plot, the first line being tangent to the diffraction plot at its maximum value in the range between 45° and 50° (2-theta), and the second line being tangent to the diffraction plot at its minimum value in the same range between 45° and 50° (2-theta), and measuring the perpendicular distance between both parallel lines.
The vinpocetine hydrochloride crystalline forms according to the present invention show superior stability and solubility. ln particular, vinpocetine hydrochloride crystalline Form III', stored at 25°C ± 2°C and 60 % ± 5% relative humidity (RH), remained stable for up to 18 months.
Vinpocetine hydrochloride crystalline Form III' proved to be at least 75 times more soluble than crystalline vinpocetine free base. Vinpocetine hydrochloride crystalline Form IV proved to be at least 30 times more soluble than crystalline vinpocetine free base.
The vinpocetine hydrochloride crystalline forms are therefore particularly suitable for the use in the pharmaceutical field, as well as in the non- pharmaceutical field, as supplement and/or nutraceutical.
Accordingly, this invention further encompasses a pharmaceutical composition comprising the vinpocetine hydrochloride crystalline forms, as described above, and at least one pharmaceutically acceptable excipient, and a process for the preparation of such a pharmaceutical composition by combining the vinpocetine hydrochloride crystalline forms, as described above, and at least one pharmaceutically acceptable excipient.
At the same time, this invention further encompasses supplement and/or nutraceutical compositions comprising the vinpocetine hydrochloride crystalline forms, as described above, and at least one edible excipient. The term "pharmaceutically acceptable excipient" is understood to 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. Depending upon the role performed, excipients are classified into (i) filler excipients, (ii) production excipients, (iii) preservative excipients, and (iv) presentation excipients. These materials, which are known in the art, 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 vinpocetine hydrochloride crystalline forms and the pharmaceutical composition containing them can be used as a medicament, 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.
For better illustrating the invention the following non-limiting examples are now given.
EXAMPLE 1 - PREPARATIVE TESTS
Preparation of vinpocetine hydrochloride Form I
Vinpocetine free base was dissolved in toluene (17 vol.) and mixed with a solution of hydrochloric acid in ethanol (1 .25 M). A slight excess of hydrochloric acid (1.1 -1.2 equivalent) was used. Crystallization was not observed either by cooling to 0°C or by adding an anti-solvent like heptane.
Vinpocetine hydrochloride Form I was obtained by evaporating to dryness the resulting solution. HPLC assay: 100.3%. The XRPD pattern for the vinpocetine hydrochloride crystalline Form I is shown in Figure 1.
The DSC profile for the vinpocetine hydrochloride crystalline Form I is shown in Figure 6. 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 1H NMR spectrum of the vinpocetine hydrochloride crystalline Form I is shown in Figure 10. The 1H NMR spectrum shown in Figure 10 displayed resonance signals coherent with a structure of vinpocetine hydrochloride and different from the 1H NMR spectrum of vinpocetine base (see Figure 12) indicating that the hydrochloride salt was formed.
Preparation of vinpocetine hydrochloride Form II Vinpocetine free base was dissolved in ethanol (17 vol.) and mixed with a solution of hydrochloric acid in ethanol (1 .25 M). A slight excess of hydrochloric acid (1.1 -1.2 equivalent) was used. Crystallization was not observed either by cooling to 0°C or by adding an anti-solvent like heptane. Vinpocetine hydrochloride Form II was obtained by evaporating to dryness the resulting solution.
The XRPD pattern for the vinpocetine hydrochloride crystalline Form II is shown in Figure 2. The 1H NMR spectrum of the vinpocetine hydrochloride crystalline Form II is very similar to that of Form I, but it has showed a high amount of residual ethanol (about 0.3 equivalent), which suggested the formation of a solvate.
Preparation of vinpocetine hydrochloride Form III
Vinpocetine hydrochloride Form III was first obtained by exposing for 24 hours a sample of vinpocetine hydrochloride Form I to normal atmosphere at 40°C and 75%±5% relative humidity.
Vinpocetine hydrochloride Form III was also obtained by slurrying from vinpocetine hydrochloride Form I in cyclohexane at room temperature. 25 mg of vinpocetine hydrochloride Form I were added to 5 volumes of cyclohexane at room temperature and stirred overnight, so obtaining the crystallization of vinpocetine hydrochloride Form III. Form III is then more stable than Form I.
The XRPD pattern for the vinpocetine hydrochloride crystalline Form III is shown in Figure 3. XRPD pattern of Form III contains all crystalline peaks of Form III', with a few additional minor crystalline peaks.
The DSC profile for the vinpocetine hydrochloride crystalline Form III is shown in Figure 7. DSC analysis showed an endothermic event around 217°C which should correspond to the melting point of vinpocetine hydrochloride Form III. Form III is then considered a pure form distinct from Form III'.
The 1H NMR spectrum of the vinpocetine hydrochloride crystalline Form III is shown in Figure 1 1 . The 1H NMR spectrum shown in Figure 1 1 is similar to that of Figure 10 without showing any chemical transformation or the presence of significant amount of residual solvent, so confirming that Form III was a distinct form of vinpocetine hydrochloride. Preparation of vinpocetine hydrochloride Form III'
Vinpocetine free base (50 mg) was dissolved in 10 mL of several solvents, showed in the following Table 1 , and mixed with a solution of hydrochloric acid in ethanol (1.25 M). A slight excess of hydrochloric acid (1.1 equivalent) was used. The resulting solution was stirred for 2.5 hours at room temperature and overnight at about 0°-5°C.
Table 1
Figure imgf000016_0001
Vinpocetine hydrochloride Form III' was only obtained by crystallization from MTBE and HEP, and from cHEX after adding MTBE as antisolvent.
In particular, vinpocetine free base was suspended in cyclohexane (5 vol.) and mixed at room temperature with a solution of hydrochloric acid in ethanol (1.25 M). A slight excess of hydrochloric acid (1.1 equivalent) was used. Crystallization was not observed even after 2 h at room temperature. MTBE was thus used as antisolvent, and the precipitation of vinpocetine hydrochloride started immediately upon addition of MTBE (3 vol.) at room temperature, without seeding with Form III'. Pure vinpocetine hydrochloride Form III' was obtained by evaporating to dryness the resulting mixture, after 3 h of stirring at room temperature for 3 h and washing with MTBE (1 vol.). Vinpocetine hydrochloride Form III' was also obtained by evaporating to dryness the solution resulting from any solvent.
Vinpocetine hydrochloride Form III' can also be obtained by slurrying from vinpocetine hydrochloride Form I in some solvents at room temperature. Form III' is then more stable than Form I. In particular, 25 mg of vinpocetine hydrochloride Form I were added to 5 volumes of different solvents at room temperature and stirred overnight. Vinpocetine hydrochloride Form III' was obtained when using EtOAc, THF, MTBE, XYL, or acetone. No solid was obtained when using ACN, methanol, isopropyl alcohol or dioxane. The XRPD pattern for the vinpocetine hydrochloride crystalline Form III' is shown in Figure 4. XRPD pattern of Form III' is very similar to XRPD pattern of Form III, but missing a few minor crystalline peaks.
The DSC profile for the vinpocetine hydrochloride crystalline Form III' is shown in Figure 8. DSC analysis showed an endothermic event around 21 1°C which should correspond to the melting point of vinpocetine hydrochloride Form III'. Form III' is then considered a pure form distinct from Form III.
Preparation of vinpocetine hydrochloride Form IV
Vinpocetine hydrochloride Form IV was first obtained by exposing for 24 hours a sample of vinpocetine hydrochloride Form I to normal atmosphere at 25°C and 90%±5% relative humidity.
The XRPD pattern for the vinpocetine hydrochloride crystalline Form IV is shown in Figure 5.
The DSC profile for the vinpocetine hydrochloride crystalline Form IV is shown in Figure 9. DSC profile of Form IV showed a first endothermic event around 61 °C, which should come from a dehydration, and a second endothermic event around 216°C that corresponds to the melting point of vinpocetine hydrochloride Form III. Therefore, vinpocetine hydrochloride Form IV should be a hydrated form of vinpocetine hydrochloride.
EXAMPLE 2 - STABILITY TESTS
The stability of vinpocetine hydrochloride crystalline forms 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 I
After only one day vinpocetine hydrochloride crystalline Form I transformed into Form III . Form II
After only one day of exposition, this form became amorphous. The 1H NMR analysis indicates the loss of ethanol. The exposure of Form II to 75%±5% relative humidity at 40°C led to a desolvation providing an amorphous form. Form III and III'
The thermodynamic stability relationship between both crystalline Forms III and III' was performed by a competitive slurrying in different solvents and temperatures. A mixture of vinpocetine hydrochloride Form III and Form III' 1 :1 w/w was suspended in 10 volumes of the corresponding solvent at the indicated temperature and was stirred overnight. The solids were recovered by filtration through a sinter funnel and dried under vacuum until were analyzed by XRPD. The results are summarized in the Table 2 below.
Table 2 Test Solvent Temperature XRPD
A MI K 0°C Form III'
B MTBE 0°C Form III + Form III' (1)
C HEP 0°C Form III + Form III' (2)
D MIK 25°C Form III'
E MTBE 25°C Form III'
F HEP 25°C Form III + Form III' (1)
G MIK Reflux (1 17°C) Form III'
H MTBE Reflux (55°C) Form III'
I HEP Reflux (98°C) Form III'
Form III' prevailing with minor amounts of Form III Form III to Form III' ratio equal to about 1 :1
The results confirmed better stability of Form III' between 0°C and 1 17°C
Additionally, Form III' remained stable under accelerated stability conditions according to ICH guidelines (75±5% RH, 40 °C) for at least two weeks.
The sample of vinpocetine hydrochloride crystalline Form III' was then stored at 25°C ± 2°C and 60% RH ± 5% RH for long term stability studies according to ICH guideline.
The sample was analysed at release and after 3, 6 and 12 months. The crystalline form III' was found stable as XRDP remained unchanged over time.
The product was also analysed by HPLC purity and assay, KF water and GC solvent content, resulting chemically stable after 18 months storage. The HPLC assay changed from 98.7% to 99.1 %.
Form IV Form IV remained stable at room temperature under 90% relative humidity for more than 21 days. Form IV dehydrated after 5 hours at 50°C under vacuum (4 mbar) providing an amorphous form.
The stability tests demonstrated that Form III' was the most stable anhydrate form of vinpocetine hydrochloride. Furthermore, a solubility test showed that vinpocetine hydrochloride crystalline Form III' and Form IV had an excellent water solubility.
The solubility of vinpocetine hydrochloride crystalline Form III' and Form IV was assessed and compared to the solubility of vinpocetine free base crystals (VNP). These experiments were performed at 25°C by slowly adding ultrapure water under magnetically stirring until complete solubilisation was obtained.
The solubility test was performed with 500 mg of vinpocetine hydrochloride Form III' and Form IV in a test tube with screw cap and magnetic stirring. The water was added at room temperature in small portions of 0.5 mL, and the mixture magnetically stirred until a clear solution was obtained. After each addition, the sample was stirred for 2-5 minutes to reach equilibrium.
Complete solubilisation was obtained adding 4 volumes (2 ml) of water to the sample of Form III', and 10 volumes (5 ml) of water to the sample of Form IV.
On the other hand, a sample of 100 mg of vinpocetine free base crystals remained insoluble even using 300 volumes of water (30 ml).
EXAMPLE 3 - INDUSTRIAL PREPARATION A
A batch of vinpocetine hydrochloride crystalline Form III' at 250 mg scale was prepared by reacting vinpocetine free base with 1.1 equivalents of HCI in ethanol (1.25 M) in MTBE (10 vol.). After the addition of HCI in ethanol (1.25 M), the resulting solution was seeded with vinpocetine hydrochloride crystalline Form III' and in a few minutes an abundant white solid precipitated. Finally, the resulting suspension was filtered through a sinter funnel (porosity n° 3), washed with 2 x 1 vol. of MTBE and dried under vacuum at room temperature obtaining vinpocetine hydrochloride crystalline Form III' as a white solid (199 mg, yield 73%). This preparation method was successfully reproduced even when it was seeded with vinpocetine hydrochloride crystalline Form III. Crystalline Form III' thus obtained was characterized through XRPD and DSC analysis as described above in example 1 .
EXAMPLE 4 - INDUSTRIAL PREPARATION B
A batch of vinpocetine hydrochloride crystalline Form I II' at 20 g scale was prepared by reacting vinpocetine free base (57.06 mmol) with 1.1 equivalents of HCI in ethanol (1 .25 M - 50.2 mL) in cyclohexane (5 vol., 100 ml_). After the addition of HCI in ethanol, the resulting clear solution did not crystallize even after 2 h at room temperature. MTBE (3 vol., 60 mL) was therefore added at room temperature and the precipitation of vinpocetine hydrochloride started immediately, without seeding with Form III'. The resulting mixture was stirred at room temperature for 3 h. Finally, the crystallized solid was filtered, washed with 2 x 1 vol. of MTBE and dried under vacuum at room temperature affording vinpocetine hydrochloride Form III' as a white solid (16.3 g, yield 74%). HPLC assay: 98.7%.
Crystalline Form III' thus obtained was characterized through XRPD and DSC analysis as described above in example 1 .
EXAMPLE 5 - INDUSTRIAL PREPARATION C
10.1 g of vinpocetine hydrochloride Form I, obtained as described in Example 1 , were exposed at 25°C and 90%±5% relative humidity for 48 hours to obtain 10.6 g of vinpocetine hydrochloride Form IV. HPLC assay: 98.3%. Crystalline Form IV thus obtained was characterized through XRPD and DSC analysis as described above in example 1 .

Claims

1. A crystalline form of vinpocetine hydrochloride selected from the group consisting of (i) vinpocetine hydrochloride Form I having the X-ray powder diffraction pattern having detectable peak(s) at 7.4°; 7.6°; 8.2°; 12.5°; and 16.4° (2-Theta, ±0.1 ), (ii) vinpocetine hydrochloride Form II having the X-ray powder diffraction pattern having detectable peak(s) at 6.8°; 10.0°; 10.2°; 10.3°; and 20.5° (2-Theta, ±0.1 ), (iii) vinpocetine hydrochloride Form III having the X-ray powder diffraction pattern having detectable peak(s) at 10.3°; 13.4°; 14.3°; 15.5°; 20.0°; and 20.3° (2-Theta, ±0.1 ), (iv) vinpocetine hydrochloride Form III' having the X-ray powder diffraction pattern having detectable peak(s) at 10.3°; 13.0°; 15.6°; 20.3°; 20.6°; and 26.9° (2-Theta, ±0.1 ), and (v) vinpocetine hydrochloride Form IV having the X-ray powder diffraction pattern having detectable peak(s) at 10.1 °; 10.8°; 12.0°; 13.1 °; and 24.3° (2-Theta, ±0.1 ).
2. The vinpocetine hydrochloride crystalline Form I according to claim 1 , characterized by a X-ray powder diffraction (XRPD) pattern having one or more additional detectable peak(s) selected from the peaks at 10.3°; 20.9°; 22.2°; and 22.4° (2-Theta, ±0.1 ), and preferably having one or more additional detectable peak(s) selected from the peaks at 14.9°; 19.9°; 25.3°; and 28.5° (2-Theta, ±0.1 ).
3. The vinpocetine hydrochloride crystalline Form II according to claim 1 , characterized by a X-ray powder diffraction (XRPD) pattern having one or more additional detectable peak(s) selected from the peaks at 13.0°; 13.6°; 15.6°; 17.0°; and 20.8° (2-Theta, ±0.1 ), and preferably having one or more additional detectable peak(s) selected from the peaks at 15.2°; 21.9°; and 27.4° (2-Theta, ±0.1 ).
4. The vinpocetine hydrochloride crystalline Form II I according to claim 1 , characterized by a X-ray powder diffraction (XRPD) pattern having one or more additional detectable peak(s) selected from the peaks at 13.0°; 16.2°;
17.0°; 17.4°; 19.8°; and 20.9° (2-Theta, ±0.1 ), and preferably having one or more additional detectable peak(s) selected from the peaks at 14.6°; 21 .6°; 22.8°; 24.2°; and 24.6° (2-Theta, ±0.1 ).
5. The vinpocetine hydrochloride crystalline Form III' according to claim 1 , characterized by a X-ray powder diffraction (XRPD) pattern having one or more additional detectable peak(s) selected from the peaks at 13.5°; 15.7°; 15.9°; and 17.8° (2-Theta, ±0.1 ), and preferably having one or more additional detectable peak(s) selected from the peaks at 17.0°; 21.9°; 22.3°; 23.0°; 23.3°; and 24.4° (2-Theta, ±0.1 ). 6. The vinpocetine hydrochloride crystalline Form IV according to claim 1 , characterized by a X-ray powder diffraction (XRPD) pattern having one or more additional detectable peak(s) selected from the peaks at 8.9°; 18.4°; 22.8°; and 23.5° (2-Theta, ±0.1 ), and preferably having one or more additional detectable peak(s) selected from the peaks at 13.6°; 20.1 °; 21 .7°; and 25.2° (2-Theta, ±0.1 ).
7. The vinpocetine hydrochloride crystalline Form I according to claim 1 , characterized by a DSC profile having an exothermic peak at 135.72°C ± 1 °C with an onset at 130.01 °C ± 1 °C followed by an endothermic peak at 222.20°C ± 1 °C with an onset at 218.29°C ± 1 °C, and preferably substantially as depicted in Figure 6.
8. The vinpocetine hydrochloride crystalline Form II I according to claim 1 , characterized by a DSC profile having an endothermic peak at 222.44°C ± 1 °C with an onset at 217.62°C ± 1 °C, and preferably substantially as depicted in Figure 7. 9. The vinpocetine hydrochloride crystalline Form III' according to claim 1 , characterized by a DSC profile having an endothermic peak at 216.97°C ± 1 °C with an onset at 21 1 .19°C ± 1 °C, and preferably substantially as depicted in Figure 8. 10 The vinpocetine hydrochloride crystalline Form IV according to claim 1 , characterized by a DSC profile having an endothermic peak at 64.33°C ± 1 °C with an onset at 61.20°C ± 1 °C followed by an endothermic peak at 221.00°C ± 1 °C with an onset at 216.71 °C ± 1 °C, and preferably substantially as depicted in Figure 9.
1 1. A pharmaceutical composition comprising a crystalline form of vinpocetine hydrochloride selected from the group consisting of Form I, Form I I, Form III, Form III', and Form IV, as described in any one of the preceding claims 1 to 10, and at least one pharmaceutically acceptable excipient.
12. A supplement or nutraceutical composition comprising a crystalline form of vinpocetine hydrochloride selected from the group consisting of Form I, Form II, Form III, Form III', and Form IV, as described in any one of the preceding claims 1 to 10, and at least one edible excipient.
PCT/EP2018/055315 2017-03-07 2018-03-05 Vinpocetine hydrochloride crystalline forms WO2018162394A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0154756A1 (en) * 1984-02-29 1985-09-18 Covex (S.A.) Citrate of vinpocetine, and process for its preparation
EP0202051A2 (en) * 1985-05-06 1986-11-20 American Home Products Corporation Therapeutic compositions for oral administration
EP0689844A1 (en) 1994-06-23 1996-01-03 Tecnimede-Sociedade Tecnico-Medicinal, S.A. Complexes of vinpocetine formed with cyclodextrins, process for their preparation and pharmaceutical compositions containing them
EP0760240A1 (en) * 1995-04-12 1997-03-05 Decox, S.L. Novel composition stimulating the cerebral activity and based on alcaloids having an eburnamenine nucleus, and preparation methods

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0154756A1 (en) * 1984-02-29 1985-09-18 Covex (S.A.) Citrate of vinpocetine, and process for its preparation
EP0154756B1 (en) 1984-02-29 1989-08-16 Covex (S.A.) Citrate of vinpocetine, and process for its preparation
EP0202051A2 (en) * 1985-05-06 1986-11-20 American Home Products Corporation Therapeutic compositions for oral administration
EP0689844A1 (en) 1994-06-23 1996-01-03 Tecnimede-Sociedade Tecnico-Medicinal, S.A. Complexes of vinpocetine formed with cyclodextrins, process for their preparation and pharmaceutical compositions containing them
EP0760240A1 (en) * 1995-04-12 1997-03-05 Decox, S.L. Novel composition stimulating the cerebral activity and based on alcaloids having an eburnamenine nucleus, and preparation methods

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