Solid forms of Alpha-1062 gluconate
The invention relates to crystalline forms of Alpha-1062 gluconate. In one aspect, the invention relates to a crystalline solid form of Alpha-1062 gluconate (Form A), wherein said crystalline form has prominent peaks at 3.61, 10.98, 14.41 and 18.44 degrees 2-theta (±0.2) in a powder X-ray diffraction pattern. The invention further relates to methods for manufacturing crystalline forms and compositions comprising said crystalline forms.
1. A crystalline solid form of Alpha-1062 gluconate (Form A), wherein said crystalline form has prominent peaks at 3.61, 10.98, 14.41 and 18.44 degrees 2-theta (±0.2) in a powder X-ray diffraction pattern.
2. The crystalline solid form according to claim 1 , wherein said crystalline form has one or more additional prominent peaks at 15.20, 17.31, 17.79, 22.77, 23.64, 24.88 and 34.31 degrees 2-theta (±0.2) in a powder X-ray diffraction pattern.
3. The crystalline solid form according to claim 1 , wherein said crystalline form further has at least another prominent peak selected from the group consisting of 13.80, 14.56, 15.08, 15.20, 17.02, 17.31, 17.79, 19.24, 20.18, 20.91, 21.22 and 22.40 degrees 2-theta (±0.2) in a powder X-ray diffraction pattern.
4. The crystalline solid form according to claim 1 , wherein said crystalline form further has additional peak(s) at 7.25 and/or 12.67 degrees 2-theta (±0.2) in a powder X-ray diffraction pattern.
5. The crystalline solid form according to claim 1 , wherein said crystalline form further has prominent peaks at 17.31 and 22.40 degrees 2-theta (±0.2).
6. The crystalline solid form according to claim 5 , wherein said prominent peaks are the five peaks with the highest relative intensity in a powder X-ray diffraction pattern obtained using analysis in transmission mode.
7. The crystalline solid form according to claim 1 , wherein said crystalline form further has peaks at 7.25, 14.56 and 22.40 degrees 2-theta (±0.2).
8. The crystalline solid form according to claim 7 , wherein said peaks are the five peaks with the highest relative intensity in a powder X-ray diffraction pattern obtained using analysis in reflectance mode.
9. The crystalline solid form according to claim 1 , wherein the peaks are determined using powder X-ray diffraction analysis in transmission mode.
10. The crystalline solid form according to claim 1 , wherein said crystalline form exhibits an onset of melting at a temperature of 116-120° C. when assessed using differential scanning calorimetry (DSC).
11. The crystalline solid form according to claim 10 , wherein said crystalline form exhibits an onset of melting at a temperature of 117° C.
12. The crystalline solid form according to claim 1 , wherein said crystalline form exhibits a weight loss prior to the onset of melt using DSC of <0.5% when assessed using Thermo-Gravimetric Analysis (TGA).
13. The crystalline solid form according to claim 12 , wherein said crystalline form exhibits a weight loss prior to the onset of melt using DSC of <0.3%, or <0.2%.
14. A preparation comprising the crystalline solid form (Form A) according to claim 1 , wherein said preparation is free of one or more additional crystalline solid forms of Alpha-1062 gluconate (Forms B, C and/or D), wherein said additional crystalline solid forms are selected from the group consisting of:
Form B, wherein said Form B has prominent peaks at 10.69, 17.17, 21.00 and 24.67 degrees 2-theta (±0.2) in a powder X-ray diffraction pattern,
Form C, wherein said Form C has prominent peaks at 3.90, 9.74, 10.35 and 21.43 degrees 2-theta (±0.2) in a powder X-ray diffraction pattern, and
Form D, wherein said Form D has prominent peaks at 3.76, 10.16, 14.77 and 19.03 degrees 2-theta (±0.2) in a powder X-ray diffraction pattern.
15. A preparation comprising the crystalline solid form (Form A) according to claim 1 , wherein said preparation comprises additionally one or more additional crystalline solid forms of Alpha-1062 gluconate according to Forms B, C and/or D, wherein said additional crystalline solid forms are selected from the group consisting of:
Form B, wherein said Form B has prominent peaks at 10.69, 17.17, 21.00 and 24.67 degrees 2-theta (±0.2) in a powder X-ray diffraction pattern,
Form C, wherein said Form C has prominent peaks at 3.90, 9.74, 10.35 and 21.43 degrees 2-theta (±0.2) in a powder X-ray diffraction pattern, and
Form D, wherein said Form D has prominent peaks at 3.76, 10.16, 14.77 and 19.03 degrees 2-theta (±0.2) in a powder X-ray diffraction pattern.
16. A pharmaceutical composition in solid form comprising the crystalline solid form according to claim 1 (Form A), wherein said composition additionally comprises one or more pharmaceutically acceptable excipients.
17. The pharmaceutical composition according to claim 16 , wherein the composition is packaged to reduce atmospheric moisture in contact with said composition.
18. The pharmaceutical composition according to claim 17 , wherein the packaging is aluminium foil blister packaging (Alu-Alu), packaging with polymeric films with aluminium layers(s) and/or by using a desiccant.
19. The pharmaceutical composition according to claim 16 , wherein the composition is suitable for oral or transmucosal administration.
20. A method of treating a brain disease associated with cognitive impairment and/or with a cholinergic deficit in a subject, comprising administering the pharmaceutical composition according to claim 16 to a subject in need thereof.
21. The method according to claim 20 , wherein the brain disease is selected from the group consisting of a brain disease with a cholinergic deficit, Alzheimer's disease, Parkinson's disease, dementia, schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy, oxygen and nutrient deficiencies in the brain after hypoxia, anoxia, asphyxia, cardiac arrest, chronic fatigue syndrome, poisoning, anaesthesia, spinal cord disorders, central inflammatory disorders, autism, Rett's syndrome, postoperative delirium, neuropathic pain, abuse of alcohol and drugs, addictive alcohol and/or nicotine craving, and effects of radiotherapy.
22. A method for preparing the crystalline solid form according to claim 1 , comprising contacting an Alpha-1062 gluconate salt with an organic solvent, forming a slurry and subsequently filtering and/or drying the slurry, obtaining a crystalline solid form, wherein the organic solvent is selected from the group consisting of methyl ethyl ketone (MEK), 1,4-dioxane (dioxane), ethyl acetate (EtOAc) and tetrahydrofuran (THF).
23. A pharmaceutical composition in solid form comprising the preparation according to claim 14 , wherein said composition additionally comprises one or more pharmaceutically acceptable excipients.