VINPOCETINE HYDROCHLORIDE CO-CRYSTALS

FIELD OF THE INVENTION

The present invention relates to novel co-crystals of vinpocetine hydrochloride and different co-formers.

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.

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, 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. 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. For example, converting poorly water soluble APIs into the corresponding salts, such as hydrochlorides, is a common way to enhance their solubility in water. Furthermore, 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 ττ-interactions.

SUMMARY OF THE INVENTION

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.

After extensive investigation, the Applicant has found stable co-crystalline forms of vinpocetine hydrochloride with a selection of co-formers.

Accordingly, 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. Preferably, the co-former was selected from the group consisting of gentisic acid, 4-aminobenzoic acid, vanillic acid, and maleic acid.

Advantageously, 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. For sake of clarity, for the purpose of the present description and appended claims, such a form according to the present invention will be referred to as "Form B".

Advantageously, 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. For sake of clarity, for the purpose of the present description and appended claims, such a form according to the present invention will be referred to as "Form C".

Advantageously, 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 . For sake of clarity, for the purpose of the present description and appended claims, such a form according to the present invention will be referred to as "Form D".

Advantageously, 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 . For sake of clarity, for the purpose of the present description and appended claims, such a form according to the present invention will be referred to as "Form E".

Advantageously, 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 . For sake of clarity, for the purpose of the present description and appended claims, such a form according to the present invention will be referred to as "Form G".

Finally, 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. For sake of clarity, for the purpose of the present description and appended claims, such a form according to the present invention will be referred to as "Form H". 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 ). Furthermore, 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.

As a further alternative, the 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.

As a further alternative, the 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.

As a further alternative, 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 ). Furthermore, 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. Furthermore, the Form E can be characterized by a DSC profile substantially as depicted in Figure 1 1.

As a further alternative, the 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. Furthermore, the Form G can be characterized by a DSC profile substantially as depicted in Figure 14. As a further alternative, 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.

BRIEF DESCRIPTION OF THE FIGURES

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.

DETAILED DESCRIPTION OF THE INVENTION

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 ).

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 ).

Furthermore, 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 12.3°; 18.1 °; 22.9°; and 27.0° (2-Theta, ±0.1 ).

Furthermore, the 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 ).

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 ).

Furthermore, 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 ).

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 ).

Furthermore, 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 22.7°; 26.7°; and 31 .1 ° (2-Theta, ±0.1 ).

Furthermore, 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 ).

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 ).

Furthermore, 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 12.0°; 17.5°; 22.6°; and 22.8° (2-Theta, ±0.1 ).

Furthermore, the 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 ).

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 ).

Furthermore, 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 6.8°; 17.0°; 17.8°; 22.8°; 23.0°; 23.3°. 24.4°; and 28.7° (2-Theta, ±0.1 ).

Furthermore, the 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 ).

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 ).

Furthermore, 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 14.7°; 15.3°; 21.0°; 24.2°; 25.3°; 26.6°; 27.9°; and 30.2° (2-Theta, ±0.1 ).

Furthermore, the 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 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).

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.

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.. Preferably, Form B of the invention can be characterized by a ¹ H NMR spectrum substantially as depicted in Figure 3.

Preferably, Form C of the invention can be characterized by a ¹ H NMR spectrum substantially as depicted in Figure 6.

Preferably, Form D of the invention can be characterized by a ¹ H NMR spectrum substantially as depicted in Figure 9.

Preferably, Form E of the invention can be characterized by a ¹ H NMR spectrum substantially as depicted in Figure 12.

Preferably, Form G of the invention can be characterized by a ¹ H NMR spectrum substantially as depicted in Figure 15. Preferably, Form H of the invention can be characterized by a ¹ H NMR spectrum substantially as depicted in Figure 18.

Proton nuclear magnetic resonance analysis was recorded in deuterated methanol (CD ₃ OD) in a Varian Mercury 400 spectrometer, equipped with a broadband probe ATB ¹ H/ ¹⁹ F/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 20 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 20)" 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- 5 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.

10 Conveniently, the most relevant features of the newly obtained vinpocetine

hydrochloride co-crystalline Forms B, C, D, E, G, and H according to the present invention 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

15 ratio (2:1 ), and show similar XRPD patterns indicating isostructurality. As

known to those skilled in the art, 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.

20 TABLE 1

Ratio

Melting Selected XRPD peaks (°2-

Form Co-former (vinpocetine- HCI/co- (onset DSC;°C) Theta, ±0.1 ) former)

7.3; 7.6; 12.7; 13.4; 15.6;

Form B Benzoic acid 2:1 196

16.4; 20.0; 20.6

7.2; 7.5; 12.8; 13.5; 15.7;

Form C Gentisic acid 2:1 220 ^*

16.5; 19.6

4-aminobenzoic 7.2; 7.5; 12.5; 13.6; 15.7;

Form D 2:1 185

acid 16.4; 19.7; 20.4; 24.2 7.2; 7.5; 7.6; 12.7; 13.1 ;

Form E Vanillic acid 2:1 202

15.4; 16.1 ; 19.9; 20.4; 24.2

Form G Fumaric acid 2:1 145 ^** 10.3; 15.5; 20.3; 20.6; 20.8

6.7; 9.8; 13.5; 13.8; 16.8;

Form H Maleic acid 1 :1 172

19.1 ; 19.5

^* A possible transition solid-solid is also observed

^** Other thermal events occurred after the melting

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%

5 relative humidity (RH). Advantageously, the Forms C, D, E, and H according

to the present invention showed excellent stability and solubility.

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. Preferably, the Forms C, D, E, and H are

10 particularly suitable for the use in the pharmaceutical field.

Accordingly, 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

15 combining any one of the Forms B, C, D, E, G, and H, as described above,

and at least one pharmaceutically acceptable excipient.

At the same time, 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.

20 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 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.

For better illustrating the invention the following non-limiting examples are now given.

EXAMPLE 1 - PREPARATIVE TESTS

Preparation of crystalline vinpocetine hydrochloride 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. Crystalline vinpocetine hydrochloride was obtained by evaporating to drying the resulting solution.

The XRPD pattern for the crystalline vinpocetine hydrochloride is shown in Figure 19.

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.

Crystalline vinpocetine hydrochloride, as obtained as described above, and different co-formers were subjected to extensive co-crystallization studies. Several experiments with six different solvents (ethyl acetate, methanol, ethanol, toluene, chloroform, dimethylformamide), different stoichiometry between vinpocetine hydrochloride and co-former (1 :1 , 1 :2, and 1 :5), and different techniques (slurrying and wet grinding) were conducted in order to identify new co-crystalline forms of vinpocetine hydrochloride with different co- formers, as listed in the following Table 2.

TABLE 2

EtOAc : Ethyl acetate

MeOH : Methanol

EtOH : Ethanol DMF : Dimethylformamide

The results of such an extensive experimentation provided the conclusion that vinpocetine hydrochloride did not form a co-crystal in any solvent, with any technique and stoichiometry with any of the co-formers L-tartaric acid, L- malic acid, glutaric acid, succinic acid, oxalic acid, and citric acid. Advantageously, both techniques listed in the above Table 2 afforded co- crystalline forms of vinpocetine hydrochloride with any of the co-formers benzoic acid, gentisic acid, 4-aminobenzoic acid, vanillic acid, fumaric acid, and maleic acid.

Preparation of a co-crystalline form of vinpocetine hydrochloride and benzoic acid (Form B)

A mixture of vinpocetine hydrochloride (25.0 mg, 0.06 mmol), benzoic acid (39.3 mg, 0.32 mmol, 5 eq.) and EtOAc (0.4 mL) was sonicated in a bath for 1 min. The resulting white suspension was stirred for 19 h, then filtered and washed with EtOAc (0.1 mL). Pure co-crystalline Form B was obtained by evaporating to drying the resulting solution as white solid (yield 38 %).

The XRPD pattern for the co-crystalline Form B is shown in Figure 1.

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.

Preparation of a co-crystalline form of vinpocetine hydrochloride and gentisic acid (Form C)

A mixture of vinpocetine hydrochloride (25.0 mg, 0.06 mmol), gentisic acid (50.0 mg, 0.32 mmol, 5 eq.) and EtOAc (0.4 mL) was sonicated in a bath for 1 min. The resulting white suspension was stirred for 19 h, then filtered and washed with EtOAc (0.1 mL). Pure co-crystalline Form C was obtained by evaporating to drying the resulting solution as white solid (yield 68 %). The XRPD pattern for the co-crystalline Form C is shown in Figure 4.

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.

Preparation of a co-crystalline form of vinpocetine hydrochloride and 4- aminobenzoic acid (Form D)

A mixture of vinpocetine hydrochloride (25.5 mg, 0.06 mmol), 4- aminobenzoic acid (45.0 mg, 0.32 mmol, 5 eq.) and EtOAc (0.4 mL) was sonicated in a bath for 1 min. The resulting white suspension was cooled to 5°C and stirred at this temperature for 19 h, then filtered and washed with EtOAc (0.1 mL). Pure co-crystalline Form D was obtained by evaporating to drying the resulting solution as white solid (yield 29 %).

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.

Preparation of a co-crystalline form of vinpocetine hydrochloride and vanillic acid (Form E)

A mixture of vinpocetine hydrochloride (25.9 mg, 0.06 mmol), vanillic acid (10.4 mg, 0.32 mmol, 1 eq.) and EtOAc (0.4 mL) was sonicated in a bath for 1 min. The resulting white suspension was stirred for 19 h, then filtered and washed with EtOAc (0.1 mL). Pure co-crystalline Form E was obtained by evaporating to drying the resulting solution as white solid (yield 69 %).

Conveniently, a scaled-up procedure for the preparation of co-crystalline Form E was optimized. In particular, 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 XRPD pattern for the co-crystalline Form E is shown in Figure 10.

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.

Preparation of a co-crystalline form of vinpocetine hydrochloride and fumaric acid (Form G)

A mixture of vinpocetine hydrochloride (26.2 mg, 0.06 mmol), fumaric acid (7.8 mg, 0.32 mmol, 1 eq.) and EtOAc (0.4 mL) was sonicated in a bath for 1 min. The resulting white suspension was stirred for 19 h, then filtered and washed with EtOAc (0.1 mL). Pure co-crystalline Form G was obtained by evaporating to drying the resulting solution as white solid (yield 69 %). Conveniently, a scaled-up procedure for the preparation of co-crystalline Form G was optimized. In particular, a mixture of vinpocetine hydrochloride (250.0 mg, 0.65 mmol), fumaric acid (78 mg, 0.67 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 G was obtained by evaporating to drying the resulting solution as white solid (yield 57.8 %).

The XRPD pattern for the co-crystalline Form G is shown in Figure 13.

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.

Preparation of a co-crystalline form of vinpocetine hydrochloride and maleic acid (Form H) A mixture of vinpocetine hydrochloride (25.2 mg, 0.06 mmol), maleic acid (15.1 mg, 0.32 mmol, 2 eq.) and EtOAc (0.4 mL) was sonicated in a bath for 1 min. The resulting white suspension was stirred for 19 h, then filtered and washed with EtOAc (0.1 mL). Pure co-crystalline Form H was obtained by evaporating to drying the resulting solution as white solid (yield 70 %).

The XRPD pattern for the co-crystalline Form H is shown in Figure 16.

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.

EXAMPLE 2 - STABILITY TESTS

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

Form C remained stable at 40°C under 75 ± 5% relative humidity for more than 21 days. Form D

Form D remained stable at 40°C under 75 ± 5% relative humidity for more than 14 days.

Form E

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.

The stability tests, summarized in the below Table 3, demonstrated that vinpocetine hydrochloride co-crystalline Forms C and E were stable at 40°C under 75 ± 5% relative humidity for more than 21 days. Under the same conditions co-crystalline Form D was stable for 14 days, Form H for 7 days. Furthermore, co-crystalline Form H was formed with a co-former very soluble in water.