Solid forms of Alpha-1062 gluconate

Abstract

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.

Claims

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.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention is demonstrated by way of the figures disclosed herein. The figures provide support for a description of potentially preferred, non-limiting embodiments of the invention.

(2) FIG. 1. Chemical Structure of Alpha-1062 Gluconate.

(3) FIG. 2. XRPD patterns of Alpha-1062 Gluconate Study Lots.

(4) FIG. 3. XRPD pattern comparison of Alpha-1062 Gluconate, lot QCL-PLC-I-96 with pure phases overlaid.

(5) FIG. 4. XRPD pattern comparison of Alpha-1062 Gluconate, lot QCL-PLC-I-96 with pure phases overlaid, expanded view.

(6) FIG. 5. Thermograms of Alpha-1062 Gluconate, lot QCL-PL-C-I-96, Forms A+B+D.

(7) FIG. 6. XRPD patterns.

(8) FIG. 7. Tentative indexing solution of Form A: Alpha-1062 Gluconate, lot CA19-1144.

(9) FIG. 8. Observed XRPD peaks of Form A: Alpha-1062 Gluconate, lot CA19-1144.

(10) FIG. 9. Overlay of Transmission and Reflectance XRPD patterns of Form A.

(11) FIG. 10. ATR FTIR Spectrum of Form A: Alpha-1062 Gluconate, lot 2455 RD-00017-002.

(12) FIG. 11. Thermograms of Form A: Alpha-1062 Gluconate, lot CA19-1144.

(13) FIG. 12. DVS isotherm of Form A: Alpha-1062 Gluconate, lot CA19-1144.

(14) FIG. 13. Tentative indexing solution of Form B: Alpha-1062 Gluconate, sample 8235-85-01.

(15) FIG. 14. Observed XRPD peaks of Form B: Alpha-1062 Gluconate, sample 8235-85-01.

(16) FIG. 15. ATR FTIR Spectrum of Form B: Alpha-1062 Gluconate, sample 8296-41-01.

(17) FIG. 16. Thermograms of Form B: Alpha-1062 Gluconate, sample 8235-82-08.

(18) FIG. 17. DVS isotherm of Form B: Alpha-1062 Gluconate, sample 8235-82-08.

(19) FIG. 18. DVS isotherm of Form B: Alpha-1062 Gluconate, sample 8235-82-08, corrected for water content.

(20) FIG. 19. Tentative indexing solution of Form C: Alpha-1062 Gluconate, sample 8235-87-02.

(21) FIG. 20. Observed XRPD peaks of Form C: Alpha-1062 Gluconate, sample 8235-87-02.

(22) FIG. 21. ATR FTIR Spectrum of Form C: Alpha-1062 Gluconate, lot 2455 RD-00049-001.

(23) FIG. 22. Thermograms of Form C: Alpha-1062 Gluconate, sample 8235-87-02.

(24) FIG. 23. DSC thermogram of Form C: Alpha-1062 Gluconate Form C, sample 8296-08-01.

(25) FIG. 24. DVS data of Form C: Alpha-1062 Gluconate, sample 8235-92-11.

(26) FIG. 25. DVS isotherm of Form C: Alpha-1062 Gluconate, sample 8235-92-11, corrected for water content.

(27) FIG. 26. XRPD pattern of Form D: Alpha-1062 Gluconate, sample 8235-86-01.

(28) FIG. 27. Tentative indexing solution of Form D: Alpha-1062 Gluconate, sample 8235-86-01.

(29) FIG. 28. Observed XRPD peaks of Form D: Alpha-1062 Gluconate, sample 8235-86-01.

(30) FIG. 29. ATR FTIR Spectrum of Form D: Alpha-1062 Gluconate, sample 8235-86-01.

(31) FIG. 30. XRPD pattern of Material E, sample 8235-76-04.

(32) FIG. 31. Thermograms of Material E, sample 8235-76-04.

(33) FIG. 32. XRPD pattern of Material F, sample 8235-76-07.

(34) FIG. 33. XRPD pattern of Material G, sample 8235-100-02.

(35) FIG. 34. XRPD pattern of amorphous Alpha-1062 Gluconate, sample 8235-92-10.

(36) FIG. 35. Cyclic DSC of amorphous Alpha-1062 Gluconate, sample 8235-92-10.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Examples

(37) The invention is demonstrated by way of the examples disclosed herein. The examples provide technical support for a detailed description of potentially preferred, non-limiting embodiments of the invention.

Study Materials

(38) Three lots of Alpha-1062 Gluconate (Galantamine Benzoylester Gluconate) were used to initiate these studies (Table 1). XRPD analyses (FIG. 2) indicate lots CA19-1144 and CA19-0673 are similar. Lot QCL-PLC-I-96 was found to have similar peaks, but also contained many additional peaks, indicative of a mixture of materials.

(39) Subsequent studies described below have determined lots CA19-1144 and CA19-0673 to be identified as Form A and determined lot QCL-PLC-I-96 to be a mixture of Forms A, B, and D (FIGS. 3 and 4). Thermal Analysis of the QCL-PLC-I-96 Material (FIG. 5) showed a weight loss of 3.6% up to 121° C. and exhibited a broad endotherm with an onset of 69° C. and a final endotherm with an onset at 119° C. Characterization details of the three lots are provided in Tables 0 through 4. For continuity, lot CA19-1144 is assumed representative of Form A and is discussed further below.

Polymorph Screening And Stability

(40) A polymorph screening study was initiated to investigate the presence and identity of various solid materials that may be possible for Alpha-1062 Gluconate. This study used lot CA19-1144 as the starting material and utilized various solvent systems and conditions to isolate and study the materials produced during the studies (Table 5). The various materials were analyzed by XRPD and the various solid forms identified as shown (FIG. 6).

(41) To investigate the stability of the four pure crystalline forms of Alpha-1062 Gluconate, water activity (a.sub.w) slurries using a variety of mixed aqueous/organic solvent systems (Table 6) along with relative humidity stressing (Table 7) were used to define the regions of stability for the given hydrates of Alpha-1062 Gluconate. Slurries of each sample in each solvent system were studied for a period of time to determine the interconversion to the most stable form.

(42) From these studies Form A (anhydrate) was found to be the most stable Form at low water activities of less than about 0.12 a.sub.w (12% RH). Above this water activity, up to about 0.5 a.sub.w, Form A Anhydrate converts to Form C (Monohydrate) which appears to be the stable Form. Above 0.5 a.sub.w, Form B (Tetrahydrate) is formed and is the most stable Form. Form D (Dihydrate) was only observed from exposure at about 75% RH or by drying. Form D does not appear stable at any of the conditions evaluated and readily converts to other dependent Forms dependent upon the storage humidity.

Characterization of the Materials

(43) Form A: Alpha-1062 Gluconate, lot CA19-1144 (Table 2). Form A is an anhydrous material. Form A was found to undergo conversion to hydrated forms in solvent systems with a water activity above 0.12 a.sub.w (12% RH). Regardless, Form A appears kinetically stable in the solid state at 43% RH (RT) and was sustained up to 5 days at that condition. XRPD (FIG. 7). The X-ray powder diffraction pattern of Form A was successfully indexed by a single primitive orthorhombic unit cell and provides a robust description of the crystalline form through tentative crystallographic unit cell parameters and strong evidence that the pattern is representative of a single crystalline phase. The formula unit volume of 688 Å.sup.3 calculated from the indexing results generates a calculated density of 1.419 g/cm.sup.3. Sugars are known to pack densely due to a large number of hydrogen bonding. Tabulation of the XRPD pattern (FIG. 8) for Form A lists the observed peak positions and intensities with the most prominent peaks shaded for emphasis. Due to the plate-like nature of the material, the use of a zero background mount in reflectance mode results in the presence of preferred orientation in Form A (FIG. 9) relative to a transmission mode pattern. Solution NMR spectrum is consistent with the chemical structure and contains 1 mol/mol of gluconic acid, consistent with a 1:1 stoichiometric salt. FTIR spectral analysis using an ATR collection mode for sample 2455_RD-00017-002 generates an FTIR spectrum (FIG. 10) consistent with the structure of anhydrous Form A Alpha-1062 Gluconate. Thermal Analyses (FIG. 11). The TGA thermogram exhibits a 0.17% weight loss up to 121° C. A single endotherm with an onset of 117° C. is observed in the DSC consistent with a melt. Based on the observed weight loss after the melt, decomposition is likely. Heating material to just beyond the melt (125° C.) and subsequent cooling resulted in an amorphous material. The dynamic vapor sorption (DVS) isotherm (FIG. 12) indicates Form A exhibits significant hygroscopicity above 75% RH. A 0.57% weight gain was observed from 5 to 75% RH. Weight significantly increased above 75% RH with 2.97% weight gained from 75 to 85% RH and an additional 8.7% weight gained from 85 to 95% RH. Hysteresis was observed on desorption with a stable plateau achieved, suggesting the material likely converted to a hydrated form. The weight achieved within the stable plateau is consistent with the gain of more than 3 mol/mol water and suggests that Form A converted to Form B when above 85% RH. The material recovered from the DVS experiment was identified as Form A+minor peaks of Form B; however, it should be noted that the material was held at 5% RH once the DVS experiment was completed and likely partially dehydrated back to Form A before recovery and testing was performed. Solubility Studies (Table 9) were performed on Form A in various solvents and the results are tabulated showing high aqueous solubility.

(44) Form B: Alpha-1062 Gluconate, Sample 8235-82-08 (Table 10). Form B is a tetrahydrate crystalline lattice. It appears that at least one of the four water sites in the crystal lattice is somewhat labile. DVS data suggests that Form B can contain approximately 3.6 to 3.9 mol/mol of water in the relative humidity range between 15 and 85% RH. Form B was observed in solvent systems with water activity above 0.52 a.sub.w (52% RH) and in equilibrium with Form C below 0.52 and above 0.31 a.sub.w (31% RH). XRPD (FIG. 13). The XRPD pattern was successfully indexed by a single primitive orthorhombic unit cell. The formula unit volume of 772 Å.sup.3 calculated from the indexing results is larger than Form A by 84 Å.sup.3. The excess volume, relative to Form A, is sufficient to accommodate up to 4 mol/mol of water and generates a calculated density of 1.420 g/cm.sup.3. Tabulation of the XRPD pattern (FIG. 14) for Form B lists the observed peak positions and intensities with the most prominent peaks shaded for emphasis. Form B (sample 8296-34-01) was held at 57% RH for four days and analyzed by XRPD and coulometric Karl Fischer (KF) titration. The resulting sample remained Form B and contained 10.2% water (equivalent to ˜3.7 mol/mol of water) and is consistent with the indexing results. Solution NMR spectrum is consistent with the chemical structure and contains 1 mol/mol of gluconic acid, consistent a 1:1 stoichiometric salt; residual organic solvents (such as MEK) were not observed. FTIR spectral analysis using an ATR collection mode for sample 8296-41-01 generates an FTIR spectrum (FIG. 15) consistent with the structure of Form B Alpha-1062 Gluconate. Thermal Analyses (FIG. 16). The TGA thermogram exhibits a 3.3% weight loss up to 114° C. and an additional 5.2% up to 147° C. A broad endotherm with an onset of 66° C. (concurrent with weight loss in the TGA) is observed in the DSC consistent with desolvation. A second endotherm with an onset of 115° C. is observed followed by a weak endotherm at 152° C. Heating of a sample of Form B at 40-75° C. over 10 minutes was analyzed by XRPD and resulted in partial dehydration and conversion to a mixture of Forms D and C (both purported hydrates, but each at a lower hydration state) and an additional peak. Form B was shown to dehydrate to Form A at 0% RH after 1 day (Table 7). The dynamic vapor sorption (DVS) isotherm (FIG. 17) was collected starting at 50% RH (to avoid conversion from loss of hydration prior to data acquisition). Form B exhibits limited hygroscopicity; with a 1.5% weight gain from 50-95% RH. Upon desorption, 1.8% weight loss from 95-15% RH followed by 6.8% weight loss from 15-5% RH was observed. The DVS data was corrected for water content measured by KF at 57% RH (FIG. 18). A stable plateau of between 3.6 and 3.9 mol/mol of water for Form B is evident between 15 and 85% RH. The material recovered from the DVS experiment was identified as anhydrous Form A.

(45) Form C: Alpha-1062 Gluconate, Sample 8235-87-02 (Table 11). Form C was determined to be a monohydrate crystal lattice occupied at only about 0.4 to 0.5 mol/mol of water. Form C was observed in solvent systems with a water activity between 0.12 and 0.31 a.sub.w (12 and 31% RH) and in equilibrium with Form B above 0.31 and below 0.52 a.sub.w (52% RH). XRPD (FIG. 19). The XRPD pattern was successfully indexed by a single primitive monoclinic unit cell. The formula unit volume of 706 Å.sup.3 calculated from the indexing results is larger than Form A by 18 Å.sup.3. The excess volume, relative to Form A, is sufficient to accommodate up to 1 mol/mol of water and generates a calculated density of 1.425 g/cm.sup.3. Tabulation of the XRPD pattern (FIG. 20) for Form C lists the observed peak positions and intensities with the most prominent peaks shaded for emphasis. Form C (sample 8296-34-02) was held at 11% RH for four days and analyzed by XRPD and coulometric Karl Fischer (KF) titration. The resulting sample remained Form C and contained 1.3% water (equivalent to ˜0.4 mol/mol of water). FTIR spectral analysis using an ATR collection mode for sample 2455_RD-00049-001 generates an FTIR spectrum (FIG. 21) consistent with the structure of Form C Alpha-1062 Gluconate. Thermal Analyses (FIG. 22). The TGA thermogram exhibits a 0.9% weight loss up to 121° C. An endotherm with an onset of 119° C. is observed in the DSC. Form C (sample 8235-92-04) was held at 11% RH for seven days and analyzed by XRPD and DSC for comparison (sample 8296-08-01). The resulting sample remained Form C and a single sharp endotherm with an onset of 129° C. is observed in the DSC (FIG. 23). Form C (sample 8235-93-02) was stored at 45° C. under a vacuum for three hours and was analyzed by XRPD. The resulting sample remained Form C with the presence of a minor amount of Form A. The dynamic vapor sorption (DVS) isotherm (FIG. 24, sample 8235-92-11) indicates that Form C exhibits significant hygroscopicity above 75% RH. The sample exhibited no significant weight gain from 5-75% RH but 4.6% weight gain was observed from 75-95%. Upon desorption, a 1.5% weight loss is observed from 95-75% RH. The DVS data was corrected for water content measured by KF at 11% RH (FIG. 25). The sample retained ˜1.4 mol/mol water. The material recovered from the DVS experiment was identified by XRPD as a mixture of Forms C and B.

(46) Form D: Alpha-1062 Gluconate, Sample 8235-86-01 (Table 12). Form D was determined to be a dihydrate crystal lattice that is not thermodynamically stable and will eventually convert to other more stable hydrates with time, dependent upon the RH conditions. Form D is formed by the exposure of Form A at about 75% RH. Attempts to generate pure Form D as a single crystalline phase resulted in mixtures contaminated with minor amounts of either Form A or Form B. XRPD (FIGS. 26-27). The XRPD pattern represents a mixture of Form D and minor peaks of Form A. Small peaks near 12.68, 18.43, and 20.91° (2θ) are consistent with Form A and were purposefully ignored during indexing. Form D was successfully indexed from the remaining peaks by a single primitive orthorhombic unit cell. The formula unit volume of 733 Å.sup.3 calculated from the indexing results is larger than Form A by 45 Å.sup.3. The excess volume, relative to Form A, is sufficient to accommodate up to 2 mol/mol of water and generates a calculated density of 1.413 g/cm.sup.3. Tabulation of the XRPD pattern (FIG. 28) for Form D lists the observed peak positions and intensities with the most prominent peaks shaded for emphasis. FTIR spectral analysis using an ATR collection mode for sample 8235-86-01 generates an FTIR spectrum (FIG. 29) consistent with the structure of Form D Alpha-1062 Gluconate. A sample of Form D and minor Form B (8235-34-03) was held at 75% RH for one day (to limit conversion) and analyzed by XRPD and Karl Fischer (KF) titration. The sample increased only slightly in Form B but, overall, remained similar to the initial composition. The sample contained 4.3% water or ˜1.5 mol/mol of water. Water activity slurries and relative humidity stressing studies (Tables 6-7) suggests that Form D is a metastable form at all conditions evaluated and eventually converts to Form B with extended exposure to relative humidity ≥52% RH or converts to Form C at relative humidity <52% RH.

(47) Material E: Sample 8235-76-04 (Table 13). The material generated from evaporation of a Dichloromethane (DCM) solution is not consistent with Alpha-1062 Gluconate. XRPD (FIG. 30). The XRPD pattern was indexed (not provided), but the volume is not sufficient to contain an Alpha-1062 Gluconate molecule suggesting this to be the free base or a decomposition product. Solution NMR spectrum contains a non-stoichiometric amount of gluconate. Two molecular species are present in the spectrum. Also, 0.6 mol/mol of DCM is observed. The NMR spectrum is not consistent with the salt. Thermal Analyses (FIG. 31). A 1.6% weight loss up to 101° C. was observed in the TGA. Multiple endothermic events are observed in the DSC.

(48) Material F: Sample 8235-76-07 (Table 14). A likely decomposition product generated from evaporation of a Dichloromethane (DCM) slurry. XRPD (FIG. 32). The XRPD pattern was indexed (not provided), but the volume is not sufficient to contain either Alpha-1062 free base or its salt suggesting this to be a simple Gluconate salt or a decomposition product.

(49) Material G: Alpha-1062 Gluconate, Samples 8235-87-01 and 8235-100-02 (Table 15). Material G has been observed from evaporative experiments of both 1,4-dioxane and THF. The material was waxy upon isolation but contained fine aciculars dispersed throughout. XRPD (FIG. 33) of sample 8235-100-02 shows much amorphous character due to its waxy nature. A reanalysis of 8235-87-01 after five weeks indicated the sample has partially converted to Form B (evidence of a minor amount of Form B was present in the initial pattern). Based on the spontaneous conversion, Material G is metastable with Form B at that condition. Material G was not observed during any of the water activity slurries or relative humidity work.

(50) Amorphous: Alpha-1062 Gluconate, sample 8235-76-13 (Table 16) has been observed from slow evaporation from methanol (Table 5). During Alpha-1062 Gluconate synthesis the material does not readily crystallize from solution and must be seeded. Typically, oils and tacky films are first generated which then nucleate over time. Sample 8235-76-13 spontaneously crystallized to a mixture of Forms B and C after 13 days. XRPD (FIG. 34) of an amorphous material generated via a melt quench was observed to remain amorphous after 5 weeks. No significant impurity increases were observed by .sup.1H NMR. Thermal Analysis (FIG. 35). A cyclic DSC was conducted to determine the glass transition (T.sub.g) temperature of the amorphous solid. The glass transition temperature was determined to be near 41° C. Decomposition was observed upon continued heating with no nucleation.

Tables

(51) TABLE-US-00005 TABLE 1 Study Materials (Alpha-1062 Gluconate) Lot No. Storage Quantity (g) CA19-1144 ambient 6.0 QCL-PLC-I-96 ambient 0.7 CA19-0673 ambient 0.5

(52) TABLE-US-00006 TABLE 2 Characterization for Alpha-1062 Gluconate, Lot CA19-1144 Technique Details Result XRPD indexed Form A .sup.1H NMR D.sub.2O consistent with structure FTIR ATR 2455_RD- consistent with structure 00017-002 TGA ambient to 0.17% wt. loss up to 121° C. 350° C. DSC −30 to endotherm with onset of 117° C. 250° C. DSC 120-125° C. @ amorphous glass upon cooling (8235- 1°/min 92-10) brittle, off white, NB DVS 5 to 95 to 5% 0.57% wt. gain from 5 to 75% RH RH 2.96% wt. gain from 75 to 85% RH 8.67% wt. gain from 85 to 95% RH 1.73% wt. loss from 95 to 85% RH 2.98% wt. loss from 85 to 5% RH hysteresis observed XRPD of 8118-78-01 Form A + B (trace) post DVS conversion occurred in instrument after run completed as sample held at 5% RH

(53) TABLE-US-00007 TABLE 3 Characterization for Alpha-1062 Gluconate Lot QCL-PLC-I-96 Technique Details Result XRPD — Form A + B + D TGA ambient to 3.6% wt. loss up to 121° C. 350° C. DSC −30 to broad endotherm onset at 69° C. 250° C. final endotherm onset at 119° C.

(54) TABLE-US-00008 TABLE 4 Characterization for Alpha-1062 Gluconate Lot CA19-0673 Technique Details Result XRPD — Form A

(55) TABLE-US-00009 TABLE 5 Polymorph Screen of Alpha-1062 Gluconate (using Lot CA19-1144 [Form A]) Solvent Method.sup.1 Observation.sup.2 Result Sample acetone slow cool, reflux 1. oiled — 8235-92-08 1. ambient 2. no changes 2. refrigerated, 1 d 3. waxy film, NB, no singles 3. freezer, 7 d slurry, ambient, 14 d white fines, B C + D 8235-76-01 ACN slurry, ambient, 14 d white fines, B C 8235-76-02 ACN/H.sub.2O cooling of solution fine blades, limited, too thin — 8296-02-01 97:03 v/v source: 8235-93-02 for single analysis filtrate + seed DCM 1. fast evaporation 1. film, NB E 8235-76-04 2. scratched 2. nucleated, fines, B slurry, ambient, 14 d fines, B F 8235-76-07 1,4-dioxane 1. fast evaporation 1. waxy film with limited G + B 8235-87-01 source: 8235-76-10 rosettes of fine aciculars solution # step 3 2. increased nucleation bulk 2. scratched, left waxy capped, 1 d slow cool, 53° C. 1. clear solution — 8235-76-10 1. refrigerated, 1 d 2. froze 2. freezer, hrs. 3. clear solution 3. warmed ambient solvent: anti-solvent flocculent formed — 8235-87-03 w/Et.sub.2O deliquesced upon isolation, source: 8235-76-10 36% RH solution # step 3 filtered solids slurry, ambient, 14 d fines, B A 8235-76-11 source: 8235-76-11 fines, B A 8235-100- sub sampled wet 03 EtOH 1. slow evaporation 1. tacky film, limited fines — 8235-76-05 2. scraped 2. no nucleation slow cool, reflux 1. tacky film in base 1. ambient 2. white solids, fines C + A 8235-76-15 2. refrigerated, 5 d aggregated minor slurry, ambient, 14 d white fines, B C + A 8235-76-06 EtOAc slurry, ambient, 14 d white fines, B A 8235-76-03 IPA slow cool, 53° C. 1. irregular masses, NB C + 8235-76-08 1. ambient 2. increase in solids diffuse 2. refrigerator, 1 d 3. irregular masses, fines, scatter 3. filtered, briefly damp, B dried under N.sub.2 8235-76-08 step 1 soft material, flowed — 8235-81-01 spotted on slide slurry, ambient, 14 d fines, B C 8235-76-09 IPA/H.sub.2O fast evaporation limited fine aciculars, thin amorph + 8296-02-03 96:04 v/v source: 8235-92-04 tacky film, bulk of materials C filtrate + seed (c) IPA/H.sub.2O cooling of solution film deposited, no singles, — 8296-02-02 97:03 v/v source: 8235-92-03 limited material filtrate MEK/H.sub.2O 1. heat to 55° C., 5 min. 1. partially dissolved C + B 8235-86-02 98:02 v/v 2. removed, cooled 2. turbid 0.42 a.sub.w briefly 3. slurry 3. sonicated 4. slurry 4. heat to 55° C., few 5. fine aciculars, B hrs. 5. cooled to ambient; left overnight solids wetted, left very fine aciculars, increased — 8235-92-15 at ambient, 22 d size, no singles MeOH slow evaporation film, soft, areas brittle amorph 8235-76-13.sup.3 scraped with pick 1. rotary evaporation 1. oil amorph + 8235-92-13 2. vacuum dried, 2. tacky film, NB C ambient, 1 d 3. solidified 3. treated with heptane 4. opaque solids, NB sonicated 4. filtered, N.sub.2 dried vapor diffusion 1. oil — 8235-79-01 w/Et.sub.2O 2. oil 1. ambient 3. opaque, oil 2. refrigerated, 1 d 4. oil 3. freezer, 7 d 4. slurry, ambient 34 d THF fast evaporation oily/waxy residue, fines and G 8235-100- source: 8235-76-14 limited wispy rosettes, B, 02 filtrate mixed slurry, ambient, 14 d fines, B A 8235-76-14 THF/H.sub.2O cooling of solution white fines, B B 8235-92-05 95:05 v/v refrigerated, 1 d 0.76 a.sub.w water 1. fast evaporation 1. film, zone of aciculars, B C + B 8235-76-12 2. mixed with pick 2. tacky, no nucleation 3. left at ambient 3. nucleated solvent: anti-solvent 1. white flocculent then amorph 8235-92-09 1. added to ACN clumped/dissolved 2. ambient, 1 d 2. oil droplets in base 3. refrigerated, 1 d 3. no changes 4. freezer, 7 d 4. off white solids, tacky film, NB solvent: anti-solvent 1. seed remained 1. ACN seeded with 2. turbid, seed retained C 8235-92-11 8235-87-02 (C) 3. opaque white, NB 2. water/API added 3. slurry, ambient, 4 d .sup.1Times and temperatures are approximate unless noted. .sup.2B = birefringent and NB = non birefringent when material viewed using polarized light microscopy. .sup.3Solutions treated with activated charcoal prior to evaporation. Yellow hue removed or reduced upon treatment.

(56) TABLE-US-00010 TABLE 6 Water Activity for Slurries of Alpha-1062 Gluconate Solvent Source Temp Time Result Sample ACN/H.sub.2O 8296-34-01: Form B ambient 13 d B 8296-39-07 88:12 v/v; 0.90 a.sub.w 8296-34-02: Form C 8296-34-03: Form D THF/H.sub.2O lot CA19-1144: Form A ambient 1 d B 8235-92-06 95:05 v/v; 0.76 a.sub.w 8296-34-01: Form B ambient 13 d B 8296-39-06 8296-34-02: Form C 8296-34-03: Form D MEK/H.sub.2O lot CA19-1144: Form A ambient 7 d B 8235-82-06.sup.1 93:07 v/v; 0.71 a.sub.w 1 d B 8235-85-01 MEK/H.sub.2O lot CA19-1144: Form A ambient 7 d B 8235-82-07 95:05 v/v; 0.64 a.sub.w 2 d B 8296-34-01 1 d B 8235-85-02 8296-34-01: Form B ambient 13 d B 8296-39-05 8296-34-02: Form C 8296-34-03: Form D MEK/H.sub.2O lot CA19-1144: Form A ambient 2 d B 8235-82-08 97:03 v/v; 0.52 a.sub.w 1 d B 8235-85-03 8235-82-03: Forms B + ambient 7 d B + C 8296-09-03 D 8296-34-01: Form B ambient 13 d B 8296-39-04 8296-34-02: Form C 8296-34-03: Form D ACN/H.sub.2O lot CA19-1144: Form A ambient 7 d C 8235-93-02 97:03 v/v; 0.50 a.sub.w 7 d C 8296-09-01 MEK/H.sub.2O lot CA19-1144: Form A ambient 2 d C + B 8235-82-09 98:02 v/v; 0.42 a.sub.w 1 d C + B 8235-85-04 8235-94-02: Form B ambient 7 d B 8296-09-02 8296-34-01: Form B ambient 13 d C + B 8296-39-03 8296-34-02: Form C 8296-34-03: Form D IPA/H.sub.2O lot CA19-1144: Form A ambient 7 d C 8235-92-04 96:04 v/v; 0.38 a.sub.w IPA/H.sub.2O lot CA19-1144: Form A ambient 7 d C 8235-92-03 97:03 v/v; 0.31 a.sub.w 2 d C 8235-34-02 8235-34-02 sub sample ambient 1 d C 8235-34-04 8235-82-03: Forms B + ambient 7 d B 8296-09-04 D 8296-34-01: Form B ambient 13 d C + B 8296-39-02 8296-34-02: Form C 8296-34-03: Form D MEK/H.sub.2O lot CA19-1144: Form A ambient 7 d C + A 8235-82-10 99:01 v/v; 0.27 a.sub.w 1 d A 8235-85-05 8235-82-10: Forms C + ambient 3 d C 8296-07-01 A IPA/H.sub.2O 8296-34-01: Form B ambient 13 d C + 8296-39-01 99:01 v/v; 0.12 a.sub.w 8296-34-02: Form C minor B 8296-34-03: Form D MEK lot CA19-1144: Form A ambient 7 d A 8235-92-14 ~0 a.sub.w 1 d A 8235-85-06 .sup.1Sample observed to dissolve to partially dissolve with oiling, nucleated with stirring.

(57) TABLE-US-00011 TABLE 7 Relative Humidity Stressing of Alpha-1062 Gluconate Samples Source Condition Result Sample Form A 75% RH, 1 d D + minor A 8235-86-01 lot CA19-1144 8235-92-12 75% RH, 2 d D + minor B 8235-34-03 43% RH, 5 d A 8235-92-07 Form B 0% RH, P.sub.2O.sub.5, 1 d A 8235-94-01 8235-82-08 43% RH, 5 d B 8235-94-02 Form B 57% RH, 4 d B 8296-41-01 8296-34-01 Form C 43% RH, 7 d C 8296-08-02 8235-92-04 11% RH, 7 d C 8296-08-01 Form C 11% RH, 4 d C 8296-41-02 8296-34-02 Form C 0% RH, P.sub.2O.sub.5, 1 d C + minor A 8296-03-01 8235-93-02 Form C + B 0% RH, P.sub.2O.sub.5, 1 d C + A 8235-97-01 8235-82-09 Form D + A 75% RH, 1 d D + minor A 8235-93-01 8235-86-01 Form D + A 75% RH, 4 d B + D 8235-98-01 8235-93-01 Form D + A 75% RH, 1 d D + B 8296-03-03 8235-92-12 Form D + B 75% RH, 1 d D + B 8296-43-01 8235-34-03

(58) TABLE-US-00012 TABLE 8 Overlay of XRPD Prominent Peaks of Alpha-1062 Gluconate, Forms A, B, C & D Exemplary Prominent Two Theta (2 theta) Peak positions for found Crystalline Forms Form A Form B Form C Form D 3.61 3.76 3.90 9.74 10.16 10.35 10.69 10.65 10.98 16.08 16.27 16.45 16.46 16.70 17.02 17.17 17.24 17.31 17.43 17.79 17.96 12.92 13.26 13.35 13.35 13.80 13.75 14.41 14.56 14.56 14.77 15.08 15.01 15.20 15.66 18.44 18.86 19.03 19.24 19.77 19.87 20.18 20.15 20.91 21.00 21.22 21.21 21.43 22.40 22.32

(59) TABLE-US-00013 TABLE 9 Approximate Ambient Solubility of Form A: Alpha-1062 Gluconate, Lot CA19-1144 Solubility Solvent (mg/mL) Sample acetone <3 8235-76-01 ACN (acetonitrile) <3 8235-76-02 DCM (dichloromethane) <3 8235-76-04 1,4-dioxane <3 8235-76-10 EtOH (ethanol) 3 8235-76-05 EtOAc (ethyl acetate) <2 8235-76-03 IPA (isopropanol) <2 8235-76-08 MeOH (methanol) 37 8235-76-13 MEK (methyl ethyl ketone) <4 8235-92-14 THF (tetrahydrofuran) <3 8235-76-14 water >123 8235-76-12

(60) TABLE-US-00014 TABLE 10 Characterization for Form B: Alpha-1062 Gluconate Technique Details Result Sample XRPD — Form B 8235-82-08 indexed 8235-85-01 held @ 57% RH; 4 d 8296-41-01 .sup.1H NMR D.sub.2O consistent with structure 8235-82-08 FTIR ATR consistent with structure 8296-41-01 TGA ambient-350° C. 3.3% wt. loss up to 113° 8235-82-08 C. + 5.2% wt. loss up to 147° C. DSC −30 to 250° C. broad endotherm onset of 8235-82-08 66° C. followed by endo- therm with onset of 115° C., weak endotherm with peak max of 152° C. DSC on 40-75° C., 10 min; Form D + C + peak 8235-94-03 8235-82-07 Analyzed by XRPD DVS 50-95-5% RH 1.5% wt. gain from 50-95% RH 8235-82-08 1.8% wt. loss from 95-15% RH 6.8% wet loss from 15-5% RH post DVS sample; Form A 8118-83-01 Analyzed by XRPD coulometric KF held @ 57% RH; 4 d 10.2% water content 8296-41-01

(61) TABLE-US-00015 TABLE 11 Characterization for Form C: Alpha-106 Gluconate Technique Details Result Sample XRPD indexed Form C 8235-87-02 held @ 11% RH; 4 d 8296-41-02 held @ 11% RH; 7 d 8296-08-01 FTIR ATR consistent with structure 2455_RD- 00049-01 TGA ambient-350° C. 0.9% wt. loss up to 121° C. 8235-87-02 DSC −30 to 250° C. broad endotherm, onset of 119° C. 8235-87-02 DSC held @ 11% RH; 7 d endotherm, onset of 129° C. 8296-08-01 XRPD — Form C 8235-92-11 DVS 5-95-5% RH 0% wt. gain from 5-65% RH 8235-92-11 4.6% wt. gain from 75-95% RH 1.5% wt. loss from 95-75% RH ~3% wt. retained from 75-5% RH hysteresis observed post DVS sample; Form C + B 8118-85-01 Analyzed by XRPD coulometric KF held @ 11% RH; 4 d 1.3% water content 8296-41-02 XRPD vacuum; 45° C.; 3 hrs C + minor A 8296-03-02

(62) TABLE-US-00016 TABLE 12 Characterization for Form D: Alpha-1062 Gluconate Technique Details Result Sample XRPD indexed Form D + minor A 8235-86-01 FTIR ATR consistent with structure 8235-86-01 XRPD held @ 75% Form D + minor B 8296-43-01 RH; 1 d coulometric KF held @ 75% 4.3% water content 8296-43-01 RH; 1 d

(63) TABLE-US-00017 TABLE 13 Characterization for Material E Technique Details Result XRPD indexed Material E indexing volume consistent with free form volume and not the salt .sup.1H NMR D.sub.2O non stoichiometric amount of gluconic acid present (evaporative experiment), two species present, and 0.6 mol/mol DCM TGA ambient-350° C. 1.5% weight loss up to 101° C. DSC −30 to 250° C. broad endotherm with peak max at 53° C. endotherm with peak max at 108° C. series of weak events above 120° C.

(64) TABLE-US-00018 TABLE 14 Characterization for Material F Technique Details Result XRPD indexed Material F indexing volume less than that of the API, likely a simple gluconate salt (Na, Ca, etc.)

(65) TABLE-US-00019 TABLE 15 Characterization for Material G Technique Details Result Sample XRPD — Material G 8235-100-02 reanalyzed, 5 weeks Material G + Form B 8235-87-01

(66) TABLE-US-00020 TABLE 16 Characterization for amorphous Alpha-1062 Gluconate Technique Details Result Sample XRPD — amorphous 8235-76-13 reanalyzed, 13 days Form B + C 8235-76-13 melt generated amorphous 8235-92-10 reanalyzed, 5 weeks amorphous 8235-92-10 1HNMR D.sub.2O consistent with structure, 8235-92-10 no significant increase in impurities DSC cyclic glass transition: 41° C. 8235-92-10 no crystallization upon further heating

(67) Re-Processing Alpha-1062 Gluconate

(68) Alpha-1062 gluconate (CA19-0673) was re-processed and assessed to determine if multiple, potentially insoluble, polymorph or pseudopolymorph forms could be produced.

Experiment 1

(69) The Alpha-1062 gluconate (CA19-0673) was re-slurried in MEK/H2O at 20° C. 5.6 g of Alpha-1062 gluconate was used in 19.3 g MEK+1.9 g H2O. The slurry was stirred for 30 min before washing of the filter cake with 4.1 g MEK, re-filtration and drying.

(70) The reaction mixture was yellow to orange. The suspension was initially relatively thin, then became thicker upon longer stirring. After 30 min a very thick paste-like suspension was obtained that was difficult to stir and transfer to filter. The suspension was deemed too thick and therefore unsuitable for production. The isolated material was slightly yellowish (white to pale yellow).

Experiment 2

(71) The Alpha-1062 gluconate (CA19-0673) was re-slurried in MEK/H2O at 20° C. 5.6 g of Alpha-1062 gluconate was used in 38.6 g MEK+3.8 g H2O. The slurry was stirred for 30 min before washing of the filter cake with 8.2 g MEK, re-filtration and drying. The reaction mixture was yellow to orange. The suspension was initially relatively thin, then became thicker upon longer stirring. After 30 min a suspension was obtained that was notably less thick than in experiment 1 and was able to be easily stirred and transferred to filter. The material was washed in MEK and dried in a rotator at 30° C./20 mbar for approx. 2 hours.

(72) The isolated material was comparable in color to batch CA19-0673. The relative retention time (RRT) in HPLC was consistent with earlier measurements and a recovery of approx. 90% was obtained. Powder X-Ray diffraction spectra were obtained by measuring the dried product. The pattern revealed a mixture of multiple Forms, including Form A and one or more of Forms B-D, likely a mixture of Forms A, B and C.

Experiment 3

(73) The Alpha-1062 gluconate (CA19-0673) was re-slurried in MEK at 20° C., without water. 5.6 g of Alpha-1062 gluconate was used in 38.6 g MEK. The slurry was stirred for 30 min before drying.

(74) The reaction mixture was lighter than the previous experiments, a light yellow. The suspension was of consistent viscosity upon stirring. After 30 min a suspension was obtained that was notably less thick than in experiment 1 and was able to be easily stirred and transferred to filter. The material was dried in a rotator at 30° C./20 mbar for approx. 2 hours.

(75) The isolated material was comparable in color to batch CA19-0673. The relative retention time (RRT) in HPLC was consistent with earlier measurements and a recovery of approx. 95% was obtained. Powder X-Ray diffraction spectra were obtained by measuring the dried product. The pattern corresponded to Form A, as shown in FIG. 8.

Synthesis of Alpha-1062 Gluconate

(76) The gluconate salt of Alpha-1062 was created according to the following previously established general scheme:

(77) ##STR00001##