Solid forms of α-1062 gluconate

Abstract

The present invention relates to a crystalline form of α-1062 gluconate (Scheme I(I)). In one aspect, the present invention relates to a crystalline solid form of α-1062 gluconate (Form A), which has prominent peaks at 3.61, 10.98, 14.41 and 18.44±0.2°2θ in the powder X-ray diffraction pattern. Furthermore, the present invention relates to methods for preparing the crystalline form and compositions comprising the crystalline form. TIFF2024503545000026.tif57153

Description

[Technical field]

[0001] The present invention relates to the field of pharmaceutical solid forms and preparation methods thereof. The present invention relates to a crystalline solid form of alpha-1062 gluconate. In one aspect, the present invention relates to a crystalline solid form of alpha-1062 gluconate (Form A), which has prominent peaks at 3.61, 10.98, 14.41 and 18.44±0.2°2θ in the X-ray powder diffraction pattern. Furthermore, the present invention also relates to a method for preparing the crystalline form and a composition comprising the crystalline form. [Background technology]

[0002] Alzheimer's disease (AD) is the most common type of dementia among the elderly. It is characterized by progressive memory loss, including impairments in attention, semantic memory, abstract thinking, and other cognitive functions. Several experimental treatments that may alleviate the disease are currently under investigation, most notably antibodies targeting the abnormal accumulation of proteins such as β-amyloid oligomers and plaques outside cells, and tau proteins inside cells. However, recent phase III clinical studies of antibody therapy targeting β-amyloid have failed to show sufficient therapeutic efficacy.

[0003] Another early marker of AD is the increasing loss of cholinergic neurons and the decrease in the density of nicotinic acetylcholine receptors (nAChRs) during the course of the disease. Therefore, cholinergic enhancement by enhancing cholinergic transmission is considered a symptomatic treatment to improve cognitive function. Drugs approved for this purpose are tacrine, donepezil, rivastigmine and galantamine; they are inhibitors of the enzymes acetylcholinesterase (AChE) and, to a lesser extent, butyrylcholinesterase (BuChE), which normally metabolize and thereby inactivate the cholinergic transmitter acetylcholine (ACh). The increase in cholinergic function in the brain, through the action of these drugs, leads to improved cognition and various behavioral aspects in AD conditions.

[0004] Galantamine is a tertiary amide and occurs naturally in some bulbous plants. In addition to inhibiting AChE, galantamine also enhances cholinergic activity by noncompetitive allosteric modulation of nAChRs. It was introduced as a drug for AD in 2000 and is now approved in over 70 countries. The labeling is generally for "mild to moderate Alzheimer's dementia." It is currently sold in the United States as Razadyne® and elsewhere as Reminyl®.

[0005] However, in contrast to rivastigmine and donepezil, galantamine does not significantly concentrate in the human brain compared to plasma because galantamine is a plant alkaloid and is less lipophilic than the other two cholinesterase inhibitors used in AD medicines, and therefore shows only a rather low brain-to-blood concentration ratio (BBCR<2) at steady state.

[0006] Like other cholinesterase inhibitors, galantamine has clinically significant levels of gastrointestinal (GI) side effects, including nausea, vomiting, and diarrhea. To accommodate patients, cholinesterase inhibitors are often initially administered at low (non-effective) doses and then titrated to what the patient experiences as a tolerable level of GI side effects, and it is likely that most, if not all, patients will not receive treatment at the most therapeutically effective level.

[0007] To increase the lipophilicity of acetylcholinesterase inhibitors such as galantamine and improve their passage through the blood-brain barrier, hydrophobic side chains have been added to the basic alkaloid structure, as described in EP1940817, WO2009 / 127218 and US2009 / 0253654.

[0008] Therefore, to increase the hydrophobicity of galantamine, the galantamine prodrug alpha-1062 (also known as GLN-1062 or Memogain®) was developed as a benzoic ester of galantamine. Alpha-1062 has virtually no pharmacological activity until it is cleaved by carboxylesterase to release galantamine. There is ample evidence from animal studies that intravenous, intranasal, buccal and sublingual administration of alpha-1062 achieves higher brain concentrations of alpha-1062 and galantamine more rapidly and has proportionally higher brain:blood concentration ratios than intravenous and oral administration of galantamine. Alpha-1062 improves the transport of galantamine to the brain and reduces GI side effects, thus providing advantages over other drugs currently available for AD.

[0009] WO2014 / 016430 discloses various formulations and salts of alpha-1062 (α-1062) including, for example, lactate, gluconate, maleate and saccharate salts, as well as transmucosal administration of alpha-1062 (α-1062) via intranasal, buccal and sublingual modes. WO2014 / 016430 also teaches two methods for producing the gluconate salt of α-1062 and provides powder X-ray diffraction patterns of the solid forms obtained from these methods.

[0010] The α-1062 gluconate salts described in WO2014 / 016430 exhibit a solubility in water of more than 10% weight per volume (w / v). Despite good solubility, these gluconates are metastable in solution, and a completely dissolved homogeneous solution can only be recovered by warming the aqueous mixture, for example to >50° C., until the precipitate disappears. Therefore, precautions must be taken to reduce or avoid precipitate seeding in such formulations.

[0011] Although solid forms and formulations of alpha-1062 are well known in the art, further development is needed into improved or more effective means of preparing and / or formulating alpha-1062 to provide soluble and / or stable forms for formulation and medical administration. Summary of the Invention

[0012] In light of the prior art, the technical problem underlying the present invention was to provide improved or alternative means for providing soluble and / or stable forms of alpha-1062.

[0013] This problem is solved by the features of the independent claims. Preferred embodiments of the invention are provided by the dependent claims.

[0014] Thus, in one aspect, the present invention relates to a crystalline solid form of alpha-1062 gluconate, designated Form A.

[0015] Alpha-1062 gluconate (Figure 1) has been developed and used as a pharmaceutical drug substance. Many organic drug substances can exist in solid forms such as polymorphs, pseudopolymorphs (hydrates / solvates) or amorphous forms, each with different physicochemical properties. These physicochemical properties of drug substances affect the solubility, dissolution, stability and bioavailability of the drug substance and are crucial for the development and performance of the drug substance. Therefore, a polymorphic study was performed on three lots of Alpha-1062 gluconate (Table 1) to investigate and identify its stable solid forms (polymorphs) and determine their relative relationship and interconversion with other proposed hydrates / solvates (pseudopolymorphs).

[0016] Of the wide variety of analytical techniques available for characterization of materials, some of the most critical are for the determination and elucidation of polymorphic forms of materials. These methods include X-ray diffraction (single crystal and powder diffraction [XRPD]); thermal analysis (thermogravimetric analysis [TGA] and differential scanning calorimetry [DSC]); and vibrational spectroscopy (infrared [FTIR], near infrared [FT-NIR], and Raman).

[0017] The preferred technique for determining polymorphism is X-ray diffraction. Therefore, identification and release of crystalline forms of α-1062 gluconate can be achieved using the prominent peaks at 2θ positions found in the XRPD pattern in transmission mode.

[0018] During the study of these polymorphs utilizing various solvents and crystallization conditions (Table 5) and subsequent XRPD analysis, seven unique crystalline materials were observed and isolated, designated Forms A, B, C, D and Materials E, F and G (Figure 6). Amorphous material has also been observed.

[0019] A detailed description of each of the identified solid forms is provided below. (For example, in Table 8, significant peak overlay is shown for Forms A-D.)

[0020] Along with relative humidity stress (Table 7), water activity (a w ) slurry (Table 6) was used to define the region of stability for the hydrate of α-1062 gluconate. The data are w At lower water activities, the most stable form is shown to be anhydrous form A. w When the water activity increases to about 0.5a, the most stable form is the monohydrate form C. w Above this temperature, the most stable form is the tetrahydrate form B. Form D does not appear to be stable at any of the conditions evaluated and readily converts to other dependent forms depending on storage humidity.

[0021] A summary of the morphologies identified is provided below: Form A is an anhydrous, crystalline material with a simultaneous melting / decomposition onset around 117°C. Form A appears to be kinetically stable in the solid state at 43% RH (RT) and has persisted at these conditions for up to 5 days. Form B forms a tetrahydrate crystal lattice. At least one of the lattice water sites is unstable and is not fully hydrated, usually with about 3.6 to 3.9 water molecules. Form C forms a monohydrate crystal lattice. The lattice water sites are unstable and are not fully hydrated, usually with about 0.4-0.5 water molecules. Form D forms a dihydrate crystal lattice that is not thermodynamically stable and readily transforms into other more stable hydrates depending on the storage RH conditions. Substances E and F are believed to be unidentified decomposition products and are formed when dichloromethane is used as a crystallization solvent. Substance G is an unknown but suspected metastable hydrate. Substance G can be isolated by evaporation from either THF or 1,4-dioxane. Upon storage, partial conversion to Form B was observed.

[0022] Based on the data discovered during these studies, anhydrous Form A, stored under appropriate temperature and humidity conditions to maintain its form and stability, appears to be optimal as a drug substance for use in the formulation and manufacture of pharmaceutical products. Thus, the present invention discloses multiple novel solid forms of α-1062 gluconate. Thus, the present invention is based in some embodiments on the discovery of hydrate forms of α-1062 gluconate, which in some embodiments are avoided due to their relatively lower solubility in water compared to anhydrous Form A. The present invention, in some embodiments, relates to the unexpected discovery of multiple solid forms of α-1062 gluconate, each having distinctive properties, and the identification of Form A, which appears to be optimal for drug development.

[0023] Form A: In one aspect, the present invention relates to a crystalline solid form of alpha-1062 gluconate (Form A), said crystalline form having prominent peaks at 3.61, 10.98, 14.41 and 18.44±0.2 degrees 2θ in a powder X-ray diffraction pattern.

[0024] These four peaks were selected from the prominent peak list presented below and do not appear to show sufficient overlap with prominent peaks in the XRPD patterns of Forms B-D or Substances E-G. Therefore, in one embodiment, Form A can be reliably distinguished using one or more prominent peaks upon comparison of the corresponding X-ray powder diffraction patterns, e.g., as described above or in Figure 8 or Table 8. In one embodiment, the presence of these peaks in the X-ray powder diffraction pattern can be used to identify and / or distinguish Form A from solid forms previously described in the art, e.g., as described in WO2014 / 016430.

[0025] In one embodiment, Form A has one or more additional prominent peaks in its powder X-ray diffraction pattern at 15.20, 17.31, 17.79, 22.77, 23.64, 24.88, and 34.31±0.2 degrees 2θ. These peaks were selected from a list of prominent peaks, as outlined below, that do not appear to show sufficient overlap with prominent peaks in the XRPD patterns of Forms B-D or Substances E-G.

[0026] In one embodiment, Form A has at least five prominent peaks selected from the list consisting of 3.61, 10.98, 13.80, 14.41, 14.56, 15.08, 15.20, 17.02, 17.31, 17.79, 18.44, 19.24, 20.18, 20.91, 21.22, and 22.40±0.2 degrees 2θ in an X-ray powder diffraction pattern.

[0027] This peak list represents a list of prominent peaks from Table 8 for Form A. Usually, not all peaks from this list need to be detected to determine the presence of Form A in any preparation. In accordance with the present invention, for example, in some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more peaks, preferably having relatively high signal intensity, can be used to determine any crystalline form. For example, the 4, 5, 6, 7, 8, 9 or 10 most intense peaks can be used to identify any crystalline form. In one embodiment, sufficient identification of any crystalline form, such as Form A, is achieved when the presence of at least 4 prominent peaks can be determined based on XRPD comparison.

[0028] Typically, the prominent XRPD peaks are the most intense, low angle, non-overlapping peaks observed in the XRPD pattern. In some embodiments, a "prominent peak" has a relative intensity of preferably ≧20%, preferably ≧30%, more preferably ≧40% in the powder X-ray diffraction pattern. However, the relative intensity values ​​may vary depending on the instrument or mode of analysis, and are not intended to be inherently limiting to the solid forms described herein.

[0029] In one embodiment, Form A has peaks at 7.25 and / or 12.67±0.2 degrees 2θ in its powder X-ray diffraction pattern. These peaks are of relatively low intensity compared to the peaks listed above as prominent peaks. However, the peaks at 7.25 and / or 12.67±0.2 degrees 2θ appear to be absent from all other patterns of Forms B-D or Substances E-G.

[0030] In one embodiment, the peaks are determined using powder X-ray diffraction analysis in transmission mode.

[0031] In one embodiment, Form A has at least three peaks in an X-ray powder diffraction pattern selected from the list consisting of 10.98, 14.41, 17.31, 18.44, and 22.40±0.2 degrees 2θ. In one embodiment, the three peaks are within the five peaks with the highest relative intensity in an X-ray powder diffraction pattern obtained using analysis in transmission mode. In one embodiment, these five peaks are the most intense peaks in an XRPD pattern using transmission mode, as outlined in the Examples below.

[0032] In one embodiment, the peaks are determined using powder X-ray diffraction analysis in reflection mode.

[0033] In one embodiment, Form A has at least three prominent peaks in an X-ray powder diffraction pattern selected from the list consisting of 3.61, 7.25, 10.98, 14.56, and 22.40±0.2°2θ. In one embodiment, the three peaks are within the five peaks with the highest relative intensity in an X-ray powder diffraction pattern obtained preferably using analysis in reflectance mode. In one embodiment, these five peaks are the most intense peaks in an XRPD pattern using reflectance mode, as outlined in the Examples below.

[0034] In one embodiment, Form A has one or more peaks in an X-ray powder diffraction pattern selected from the list consisting of 3.61, 7.25, 10.98, 14.56, and 22.40±0.2 degrees 2θ, which peaks are also observable from an XRPD pattern using reflection mode.

[0035] In one embodiment, Form A has one or more doublets in its X-ray powder diffraction pattern selected from the list consisting of 14.41 and 14.56, 15.08 and 15.20, and 24.88 and 25.09±0.2°2θ. These doublets can be used to identify Form A and optionally distinguish Form A from other forms.

[0036] Below is a table of typically observed XRPD patterns for Form A collected in transmission mode.

[0037] Peak List for Form A: The peak list was determined from the powder X-ray diffraction pattern of Form A according to Figure 8. The accuracy in degrees 2θ is provided to two decimal places and some batch or instrument dependent variations can be clearly appreciated. [Table 1] *In some embodiments, the peaks can be considered prominent peaks observed in an XRPD pattern.

[0038] In one embodiment, Form A exhibits an onset of melting at a temperature between 116-120°C, preferably at about 117°C, as assessed using differential scanning calorimetry (DSC).

[0039] In one embodiment, Form A exhibits a weight loss of <1%, preferably <0.5%, more preferably <0.3% or <0.2% before the onset of melting using DSC, as assessed using thermogravimetry (TGA).

[0040] As known to those skilled in the art, defined properties of melting temperature and weight loss can be used to identify a particular solid form. As described in detail below, DSC and TGA analyses were used to determine the distinct characteristics of the solid forms described herein.

[0041] In one embodiment, Form A exhibits a solubility in water of greater than 100 mg / ml, preferably greater than 120 mg / ml, more preferably about 123 mg / ml. Methods for determining solubility in water are known to those skilled in the art and can be performed without undue burden. Thus, Form A exhibits unexpectedly good water solubility.

[0042] In one embodiment, Form A is stable and does not convert or shows negligible conversion to any one of Forms B-D or Substances E-G when stored at relative humidity (RH) below 75%, preferably below 50%, and more preferably Form A is stable at a RH of about 43% or less.

[0043] As described in the Examples below, Form A exhibits hygroscopicity above about 75% RH. A weight increase of 0.57% was observed from 5 to 75% RH. The weight increased significantly above 75% RH, with a weight increase of 2.97% from 75 to 85% RH and an additional 8.7% weight increase from 85 to 95% RH. The data suggests that above 85% RH, Form A converted to Form B. Of note is that once the DVS experiment was completed and dehydrated, the material was retained at 5% back to Form A. Hence, Form A has low water absorption at RH values ​​below 75%.

[0044] Form A represents an advantageous form of α-1062 gluconate. w Due to its high stability when stored (at low water activity of less than 1000 mol / L) and good solubility in water, it represents an ideal form for the preparation of pharmaceutical products. Form A has improved solubility in water compared to forms B-D, but preferably, in some embodiments, forms B-D also have good solubility in water and can be suitable for formulation. The pseudopolymorphic hydrate forms B-D tend to convert to form A when stored at low humidity, thereby maintaining the unique polymorphic form, which is a crucial part of pharmaceutical drug preparation and formulation, is a reliable process, whereby form A appears to be the optimal form.

[0045] Form B: In another embodiment, the present invention relates to a crystalline solid form of alpha-1062 gluconate designated Form B.

[0046] Therefore, the present invention relates to a crystalline solid form of α-1062 gluconate (Form B), said crystalline form having prominent peaks at 10.69, 17.17, 21.00 and 24.67±0.2 degrees 2θ in a powder X-ray diffraction pattern.

[0047] These four peaks were selected from the list of prominent peaks presented below and do not appear to show sufficient overlap with prominent peaks in the XRPD patterns of Forms A, C, or D, or Substances E-G. Therefore, in one embodiment, Form B can be reliably distinguished using one or more prominent peaks when comparing the corresponding X-ray powder diffraction patterns, for example, as described above or in FIG. 14 or Table 8. In one embodiment, the presence of these peaks in the X-ray powder diffraction pattern can be used to distinguish Form B from solid forms previously described in the art, for example, in WO2014 / 016430.

[0048] In one embodiment, Form B has at least five prominent peaks selected from the list consisting of 10.69, 12.92, 13.26, 14.56, 16.45, 17.17, and 21.00±0.2 degrees 2θ in an X-ray powder diffraction pattern. This peak list represents the list of prominent peaks from Table 8 for Form B.

[0049] In one embodiment, Form B has at least three prominent peaks in a powder X-ray diffraction pattern selected from the list consisting of 10.69, 16.45, 17.17, 21.00 and 24.67±0.2 degrees 2θ. This peak list represents a list of the five most intense peaks from Table 8 for Form B.

[0050] Typically, it is not necessary for all peaks from this list to be detected in any preparation to determine the presence of Form B. In accordance with the present invention, for example, in some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more peaks, preferably having relatively high signal intensity, can be used to determine any crystalline form. For example, the 4, 5, 6, 7, 8, 9 or 10 most intense peaks can be used to identify any crystalline form. In one embodiment, sufficient identification of any crystalline form, such as Form B, is achieved when the presence of at least 4 prominent peaks can be determined based on XRPD comparison.

[0051] In one embodiment, Form B has peaks at 12.92 and / or 15.46±0.2 degrees 2θ in its powder X-ray diffraction pattern. These peaks are of relatively low intensity compared to the peaks listed above as prominent peaks. However, the peaks at 12.92 and / or 15.46±0.2 degrees 2θ do not appear to be present in any other patterns of Forms A, C, or D, or Materials E-G.

[0052] In one embodiment, Form B exhibits an onset of melting at a temperature between 60-70° C., preferably at about 66° C., when assessed using Differential Scanning Calorimetry (DSC). In one embodiment, Form B exhibits a second onset of melting at a temperature between 110-120° C., preferably at about 114° C., when assessed using Differential Scanning Calorimetry (DSC). In one embodiment, Form B exhibits a third onset of melting at a temperature between 148-156° C., preferably at about 152° C., when assessed using Differential Scanning Calorimetry (DSC).

[0053] In one embodiment, Form B exhibits a weight loss of 3-4%, more preferably about 3.3%, up to 114° C., as assessed using thermogravimetric analysis (TGA). In one embodiment, Form B exhibits a weight loss of 5-6%, more preferably about 5.2%, up to 147° C., as assessed using thermogravimetric analysis (TGA). In one embodiment, Form B has good solubility in water, making it suitable for pharmaceutical formulation and administration.

[0054] Peak List for Form B: The peak list was determined from the transmission X-ray powder diffraction pattern of Form B according to Figure 14. The accuracy in degrees 2θ is provided to two decimal places and some batch or instrument dependent variations can be clearly appreciated. [Table 2] *In some embodiments, the peaks can be considered prominent peaks observed in an XRPD pattern.

[0055] Form C: In another embodiment, the present invention relates to a crystalline solid form of alpha-1062 gluconate designated Form C.

[0056] Therefore, the present invention relates to a crystalline solid form of α-1062 gluconate (Form C), said crystalline form having prominent peaks at 3.90, 9.74, 10.35 and 21.43 (optionally also 15.66 and / or 23.90) ±0.2° 2θ in a powder X-ray diffraction pattern.

[0057] These four peaks were selected from the list of prominent peaks presented below and do not appear to show sufficient overlap with prominent peaks in the XRPD patterns of Forms A, B, or D, or Substances E-G. Therefore, in one embodiment, Form C can be reliably distinguished using one or more prominent peaks when comparing the corresponding X-ray powder diffraction patterns, for example, as described above or in Figure 20 or Table 8. In one embodiment, the presence of these peaks in the X-ray powder diffraction pattern can be used to distinguish Form C from solid forms previously described in the art, for example, in WO2014 / 016430.

[0058] In one embodiment, Form C has at least five prominent peaks selected from the list consisting of 3.90, 9.74, 10.35, 10.65, 13.35, 15.01, 15.66, 16.08, 16.46, 17.43, 19.77, 21.43, and 22.32±0.2 degrees 2θ in an X-ray powder diffraction pattern. This peak list represents the list of prominent peaks from Table 8 for Form C.

[0059] In one embodiment, Form C has at least three prominent peaks in a powder X-ray diffraction pattern selected from the list consisting of 10.35, 13.35, 15.01, 16.08, and 16.46±0.2 degrees 2θ. This peak list represents a list of the five most intense peaks from Table 8 for Form C.

[0060] Typically, it is not necessary for all peaks from this list to be detected in any preparation to determine the presence of Form C. In accordance with the present invention, for example, in some forms, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more peaks, preferably having relatively high signal intensity, can be used to determine any crystalline form. For example, the 4, 5, 6, 7, 8, 9 or 10 most intense peaks can be used to identify any crystalline form. In one embodiment, sufficient identification of any crystalline form, such as Form C, is achieved when the presence of at least 4 prominent peaks can be determined based on XRPD comparison.

[0061] In one embodiment, Form C has a peak at 7.85±0.2°2θ in its powder X-ray diffraction pattern. This peak is of relatively low intensity compared to the peaks listed above as prominent peaks. However, the 7.85±0.2°2θ peak does not appear to be present in any other patterns of Forms A, B, or D, or Materials E-G.

[0062] In one embodiment, Form C exhibits an onset of melting at a temperature between 115-125°C, preferably at about 119°C, as assessed using differential scanning calorimetry (DSC).

[0063] In one embodiment, Form C exhibits a weight loss of 0.5-1.5%, preferably about 0.9%, up to 121° C. as assessed using thermogravimetric analysis (TGA).

[0064] In one embodiment, Form C has good solubility in water and can be suitable for pharmaceutical formulation and administration.

[0065] Peak List for Form C: The peak list was determined from the transmission X-ray powder diffraction pattern of Form C according to Figure 20. The accuracy in degrees 2θ is provided to two decimal places and some batch or instrument dependent variations can be clearly appreciated. [Table 3] *In some embodiments, the peaks can be considered prominent peaks observed in an XRPD pattern.

[0066] Form D: In another embodiment, the present invention relates to a crystalline solid form of alpha-1062 gluconate designated Form D.

[0067] Therefore, the present invention relates to a crystalline solid form of α-1062 gluconate (form D), said crystalline form having prominent peaks at 3.76, 10.16, 14.77 and 19.03 (optionally also 17.96, 18.86 and / or 28.14) ±0.2° 2θ in a powder X-ray diffraction pattern.

[0068] These four peaks were selected from the list of prominent peaks presented below and do not appear to show sufficient overlap with the prominent peaks in the XRPD patterns of Forms A-C or Substances E-G. Therefore, in one embodiment, Form D can be reliably distinguished using one or more prominent peaks when comparing the corresponding X-ray powder diffraction patterns, for example, as described above or in Figure 28 or Table 8. In one embodiment, the presence of these peaks in the X-ray powder diffraction pattern can be used to distinguish Form D from solid forms previously described in the art, for example, in WO2014 / 016430.

[0069] In one embodiment, Form D has at least five prominent peaks selected from the list consisting of 3.76, 10.16, 13.35, 13.75, 14.77, 16.27, 16.70, 17.24, 17.96, 18.86, 19.03, 19.87, and 20.15, 21.21±0.2 degrees 2θ in an X-ray powder diffraction pattern. This peak list represents the list of prominent peaks from Table 8 for Form D.

[0070] In one embodiment, Form D has at least three prominent peaks selected from the list consisting of 3.76, 10.16, 13.35, 14.77, and 19.03±0.2 degrees 2θ in an X-ray powder diffraction pattern. This peak list represents a list of the five most intense peaks from Table 8 for Form D.

[0071] Typically, it is not necessary for all peaks from this list to be detected in any preparation to determine the presence of Form D. In accordance with the present invention, for example, in some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more peaks, preferably having relatively high signal intensity, can be used to determine any crystalline form. For example, the 4, 5, 6, 7, 8, 9 or 10 most intense peaks can be used to identify any crystalline form. In one embodiment, sufficient identification of any crystalline form, such as Form D, is achieved when the presence of at least 4 prominent peaks can be determined based on an XRPD comparison.

[0072] In one embodiment, Form D has peaks at 7.53 and / or 12.09±0.2 degrees 2θ in its powder X-ray diffraction pattern. These peaks are of relatively low intensity compared to the peaks listed above as prominent peaks. However, the peaks at 7.53 and / or 12.09±0.2 degrees 2θ appear to be absent from all other patterns of Forms A-C or Substances E-G.

[0073] In one embodiment, Form D is a metastable form. As illustrated in the Examples below, Form D will eventually convert to Form B upon prolonged exposure to relative humidity ≧52% RH, or to Form C upon exposure to relative humidity <52% RH. In one embodiment, Form D has good solubility in water and can be suitable for pharmaceutical formulation and administration.

[0074] Peak List for Form D: The peak list was determined from the transmission X-ray powder diffraction pattern of Form D according to Figure 28. The accuracy in degrees 2θ is provided to two decimal places and some batch or instrument dependent variations can be clearly appreciated. [Table 4] *In some embodiments, the peaks can be considered prominent peaks observed in an XRPD pattern.

[0075] Preparation: In another aspect, the present invention relates to a preparation comprising crystalline solid form A, as described herein, which is essentially free of or contains only trace levels of one or more additional crystalline solid forms of alpha-1062 gluconate (such as forms B, C and / or D or substances E-G).

[0076] In one embodiment, the preparation comprises: i. Form B, wherein said Form B preferably has prominent peaks at 10.69, 17.17, 21.00 and 24.67±0.2 degrees 2θ in a powder X-ray diffraction pattern, as described herein; ii. Form C, wherein said Form C preferably has prominent peaks at 3.90, 9.74, 10.35, and 21.43±0.2 degrees 2θ in a powder X-ray diffraction pattern, as described herein; and iii. Form D, wherein said Form D preferably has prominent peaks at 3.76, 10.16, 14.77, and 19.03±0.2 degrees 2θ in a powder X-ray diffraction pattern, as described herein; The composition is essentially free of, or contains only trace levels of, one or more additional crystalline solid forms selected from the group consisting of:

[0077] As described in detail in the Examples, Form A, when anhydrous and maintained under appropriate conditions, appears to be the most stable of Forms AD. Thus, Form A can be maintained in an essentially "pure" form or a form that is essentially free of, or contains only trace levels of, one or more additional crystalline solid forms B-D and / or substances E-G.

[0078] From the examples described herein, Form A (anhydrous) has a molecular weight of about 0.12a w It appears to be the most stable form at low water activities below (12% RH). Furthermore, Form A appears to be kinetically stable in the solid state at 43% RH (RT), persisting at these conditions for up to 5 days. Above this water activity, Form A is stable at approximately 0.5a w Up to 0.5a, form A transforms into form C (monohydrate). w Above 100° C., form B (tetrahydrate) is formed. Form D (dihydrate) has only been observed from exposure to approximately 75% RH or by drying. Form D does not appear to be stable at any of the conditions evaluated and readily converts to other forms depending on storage humidity.

[0079] Therefore, the present invention relates to the preparation of Form A which is free of Forms B-G or contains them at low or negligible levels, thereby including compositions of "pure" Form A or compositions which may transition depending on the moisture content. The most preferred form is a composition containing Form A in an essentially stable anhydrous form without (significant) conversion to pseudo-polymorphic hydrate forms.

[0080] method: In another aspect, the present invention relates to a process for preparing the crystalline solid form A, comprising contacting α-1062 gluconate with an organic solvent, preferably selected from the list consisting of methyl ethyl ketone (MEK), 1,4-dioxane, ethyl acetate (EtOAc) and tetrahydrofuran (THF), preferably forming a slurry, followed by filtering and / or drying the slurry to obtain the crystalline solid form.

[0081] In one embodiment, the method includes combining alpha-1062 gluconate with a solvent and inducing crystallization of the salt under suitable crystallization conditions.

[0082] In one embodiment, the crystallization conditions include contacting a gluconate salt of alpha-1062 with a solvent to form a slurry and / or suspension.

[0083] In one embodiment, alpha-1062 gluconate is provided in a solid form. A preferred method for preparing alpha-1062 gluconate is disclosed in the Examples below.

[0084] Preferably, the solid forms of α-1062 gluconate are mixed to create a slurry and / or suspension. Optionally, the slurry may be stirred and / or heated. In a preferred embodiment, the slurry is formed and stirred at a temperature of 15-25° C., more preferably between 18-22° C., such as about 20° C. In one embodiment, the slurry is formed and stirred at room temperature, e.g., under typical laboratory conditions.

[0085] In one embodiment, a method for forming Form A comprises using an organic solvent to form a suspension and / or slurry comprising alpha-1062 gluconate.

[0086] In one embodiment, the process for forming Form A comprises using an organic solvent without water to form a suspension and / or slurry.

[0087] In one embodiment, a method for forming Form A of alpha-1062 gluconate includes using methyl ethyl ketone (MEK), also known as butanone, as a solvent to form a suspension and / or slurry.

[0088] As described in the Examples below, the inventors observed that forming a slurry with α-1062 gluconate and MEK at 20° C. resulted in the formation of a yellowish, beige, or light orange suspension that maintained its visual characteristics and consistency throughout the stirring period. Filtration and drying of the solid form produced a light yellow / orange solid containing Form A, as defined by the powder X-ray diffraction pattern of Form A outlined above and in the Examples below.

[0089] Therefore, in one embodiment, the present invention relates to a method for preparing crystalline solid form A, comprising contacting alpha-1062 gluconate with MEK, forming a slurry, filtering and / or drying the slurry as described herein to obtain the crystalline solid form.

[0090] Therefore, in one embodiment, the present invention relates to a method of preparing crystalline solid Form A, comprising contacting α-1062 gluconate with MEK as described herein to form a slurry, stirring the slurry at a temperature between 15-25° C., preferably at about 20° C., filtering the slurry to remove MEK, optionally washing the solid form obtained via filtration with MEK, repeating the filtration, and drying the slurry to obtain Form A. In a preferred embodiment, the solvent used to form the slurry is MEK free of water.

[0091] Methods for producing the herein described pseudopolymorphic hydrate forms (Forms B-D) of α-1062 gluconate are also disclosed herein and include contacting α-1062 gluconate with MEK and water to form a slurry, filtering and / or drying the slurry, and obtaining a crystalline solid form.

[0092] As described in the Examples below, the inventors observed that when reslurried with α-1062 gluconate and MEK mixed with water at 20° C., a yellow or orange suspension formed that thickened over time with stirring. Filtration of the solid form was difficult and relatively time consuming. Drying the material produced an orange solid with hydrate forms defined by the powder X-ray diffraction patterns of Forms B-D outlined above and in the Examples below. Forms B-D can be produced by transitions between forms due to atmospheric moisture as described herein.

[0093] Form A exhibits properties that may, for example, in some embodiments, include greater thermodynamic stability, greater crystallinity, and / or greater solubility than the other forms, making it advantageous compared to forms B-D for many utilities.

[0094] Many factors affect the crystallization conditions, which are well known to those skilled in the art. Therefore, alternative means of crystallization may be used. Such factors include, for example, the concentration of salt in the solution (crystallization solution), optionally the difference between the initial and final temperatures of the crystallization solution, optionally the cooling rate, optionally the evaporation rate of the solution, potential seeding, potential supersaturation ratio, and / or optionally the presence of a precipitating agent. With guidance from the disclosure provided herein, one skilled in the art can select and / or adjust one or more appropriate factors to arrive at crystallization conditions to provide one of the forms A-D described herein without undue experimentation.

[0095] Pharmaceutical Compositions and Medical Uses: In another aspect, the present invention relates to a pharmaceutical composition comprising crystalline solid Form A as described herein and / or a preparation having Form A as described herein, said composition additionally comprising one or more pharma- ceutically acceptable excipients. Pharmaceutical excipients are known to those skilled in the art and can be selected, for example, depending on the medical indication, the patient, the route of administration, the dosage and the formulation.

[0096] In one embodiment, the pharmaceutical composition of the invention and / or the preparation of the invention comprises crystalline solid form A as described herein and is packaged to reduce atmospheric moisture in contact with said composition. Suitable packaging is known to those skilled in the art. In some embodiments, aluminium foil blister packaging (Alu-Alu), packaging with a polymeric film with an aluminium layer, and / or packaging with the use of a desiccant are used.

[0097] In one embodiment, the pharmaceutical composition is suitable for oral or transmucosal administration.

[0098] In one embodiment, the pharmaceutical composition is used in the treatment of a brain disease associated with cognitive dysfunction.Furthermore, the present invention relates to a method for treating a brain disease associated with cognitive dysfunction, comprising administering to a patient in need thereof a composition or preparation of the present invention.

[0099] In one embodiment, the brain disease is associated with a choline deficiency disorder. In one embodiment, the composition is used as or for use as a nicotinic acetylcholine receptor sensitizer.

[0100] In one embodiment, the brain disorder is selected from the group consisting of brain disorders including cholinergic disorders, Alzheimer's disease, Parkinson's disease, dementia, schizophrenia, epilepsy, stroke, polio, neuritis, myopathy, oxygen and nutrient deficiency in the brain following hypoxia, anoxia, asphyxiation, cardiac arrest, chronic fatigue syndrome, intoxication, anesthesia, spinal cord disorders, central inflammatory disorders, autism, Rett syndrome, post-operative delirium, neuropathic pain, alcohol and drug abuse, toxic alcohol and / or nicotine craving and the effects of radiation therapy.

[0101] A further aspect of the invention relates to a kit, or part of a kit, comprising the preparation of Form A and one or more other ingredients useful for preparing pharmaceutical compositions as described herein. Preferably, Form A is packaged and / or prepared to reduce atmospheric moisture in contact with said solid form.

[0102] In some embodiments, such kits may include one or more additional solvents, such as water, to prepare a solution or other formulation for administration of alpha-1062 gluconate to a patient.

[0103] In some embodiments, as described herein, Form A exhibits greater solubility in water and improved stability upon storage compared to other solid forms of alpha-1062 gluconate described in the art.

[0104] In one embodiment, Form A is prepared for formulation in solution, preferably for transmucosal administration, as described herein.

[0105] In one embodiment, Form A, as described herein, is prepared for formulation into a tablet for administration in the oral cavity, preferably for transmucosal administration, such as a sublingual or buccal tablet or film formulation.

[0106] Preferred, but non-limiting, modes of transmucosal administration are preferably selected from oral, intranasal, sublingual or buccal administration of a therapeutically effective amount of alpha-1062 gluconate. The improved solubility of Form A described herein represents a surprising and beneficial development. High solubility allows higher concentrations of the compound to be administered in smaller amounts, thereby further enhancing administration via, for example, transmucosal administration.

[0107] The preferred mucosal administration represents a beneficial mode of delivery due to a combination of factors. Improved solubility allows higher concentrations of alpha-1062 to be administered, thereby allowing a greater amount of the active substance (galantamine) to become active in the brain after cleavage. The transport of alpha-1062 is improved compared to galantamine (measured either by alpha-1062 itself in the brain or by galantamine levels in the brain after cleavage of the prodrug), thereby allowing galantamine to be delivered to the brain more effectively than previously possible. The prodrug properties of alpha-1062 are utilized and enhanced in a beneficial manner by the mucosal application of the gluconate salt. As described herein, Form A further enhances these modes of administration due to its high solubility.

[0108] Therefore, the present invention also relates to a method of treating a brain disease associated with cognitive impairment in a patient, the method comprising administering a therapeutically effective amount of alpha-1062 gluconate to a patient in need thereof.

[0109] In one embodiment, the gluconate salt of alpha-1062 is administered in a dosage of 0.1-200 mg, 1-100 mg, preferably 2-40 mg, preferably 1-3 times per day, more preferably twice per day, and even more preferably only once per day.

[0110] In one embodiment, the gluconate salt of alpha-1062 is administered intranasally, orally, or sublingually, preferably as a 2-40% weight per volume (w / v) solution, e.g., in a volume of 20-100 microliters, preferably in a single (intranasal or oral (sublingual / buccal)) spray event, e.g., 1-3 times daily.

[0111] In one embodiment, the brain disease being treated is Alzheimer's disease and α-1062 gluconate in crystalline form 1 or α-1062 gluconate derived from crystalline form 1 is administered intranasally, orally or sublingually as about a 10% weight per volume (w / v) solution in a volume of 20 to 100 microliters, for example about 50 microliters, 1 to 3 times, preferably twice daily in a single administration event.

[0112] In one embodiment, transmucosal application is performed by administering a therapeutically effective amount of α-1062 gluconate of crystalline form 1 or α-1062 gluconate derived from crystalline form 1 using an appropriate metered dose device such as an atomizer, sprayer, pump spray, dropper, squeeze tube, squeeze bottle, pipette, ampoule, nasal cannula, metered dose device, nasal spray inhaler, nasal continuous positive pressure device, and / or breath-actuated bidirectional delivery device.

[0113] In one embodiment, sublingual administration is performed by administering a therapeutically effective amount of α-1062 gluconate of Form A or α-1062 gluconate derived from Form A under the tongue, by placing one or more drops of a quantity of particulates in the form of a solution or lyophilized powder or emulsion under the tongue, or by using a sublingual tablet or film formulation and / or by spraying a preselected volume of a liquid composition containing α-1062 gluconate of Form A or α-1062 gluconate derived from Form A onto the underside of the tongue.

[0114] In one embodiment, buccal administration is performed by administering a therapeutically effective amount of α-1062 gluconate of Form A or α-1062 gluconate derived from Form A to the buccal cavity inside the mouth between the cheek and gums, such as via a powder or emulsion, or a tablet or film formulation, or an orally disintegrating or orally dispersible tablet (ODT).

[0115] Detailed Description of the Invention The present invention relates to a stable, crystalline form of gluconate salt of α-1062. Thus, the present invention relates to a crystalline solid form of α-1062 gluconate (Form A), which has prominent peaks at 3.61, 10.98, 14.41 and 18.44±0.2°2θ in its powder X-ray diffraction pattern.

[0116] Drug Substance: The pharmaceutical agent of the present invention is alpha-1062 (also known as Memogain®, GLN-1062, PubChem CID 44240142, galantamine benzoate, CAS:224169-27-1). The salt used in the present invention is the gluconate salt of alpha-1062. Figure 1 provides the chemical structure of alpha-1062 gluconate.

[0117] Chemical name (IUPAC, calculated by LexiChem 2.6.6): [(1S,12S,14R)-9-methoxy-4-methyl-11-oxa-4-azatetracyclo[8.6.1.01,12.06,17]hepradec-6(17),7,9,15-tetraen-14-yl]benzoate.

[0118] Molecular formula of free base: C 24 H 25 NO4; Molecular formula of gluconic acid: C6H 12 O7; molecular weight of free base: 391.47 g / mol; molecular weight of α-1062 gluconate: 587.61 g / mol; conversion factor: 1 mg base = 1.501 mg salt.

[0119] Three chiral centers are present in the galantamine benzyl ester cation and four chiral centers are present in the gluconate anion. The gluconate salt is a white to pale yellow powder.

[0120] There is ample evidence from preclinical studies in several animal species that intravenous, intranasal, sublingual or buccal administration of alpha-1062 achieves higher brain concentrations of galantamine more rapidly and has a proportionately higher brain:blood concentration ratio than oral administration of galantamine. Data generated in preclinical and clinical Phase 1 studies suggest that superior efficacy, including improved tolerability, may be achieved by administration of alpha-1062 compared to the established oral route of administration of galantamine.

[0121] The present invention now provides a novel, useful crystalline form of alpha-1062, suitable for pharmaceutical use.

[0122] Solid form: As used herein, amorphous refers to non-crystalline due to the disordered arrangement of drug substance molecules in the solid state.

[0123] As used herein, polymorphism is the existence of a drug substance in multiple crystalline forms that exhibit different arrangements / structures of molecules in the crystal lattice that can affect the solid state properties of the substance. For example, as described herein, Form A can be considered a polymorph of alpha-1062 gluconate.

[0124] As used herein, pseudopolymorphism refers to the existence of a drug substance in crystalline forms that include solvates / hydrates associated with the drug substance in the crystal lattice. For example, hydrate forms B-D can be considered pseudopolymorphs of α-1062 gluconate.

[0125] As used herein, hydrates are crystalline forms that contain water molecules in the crystal lattice. In addition to polymorphs and amorphous solids, other examples of possible solids are solvates and hydrates. Hydrates are frequently encountered solvates in pharmacology, since water is applied in many processing steps. APIs can form hydrates when exposed to water, and hydrates can lose their water under high temperature or low humidity.

[0126] As used herein, crystalline preferably refers to a material that has an ordered, long-range molecular structure. The crystallinity of a crystalline form can be determined by a number of techniques, including, for example, powder X-ray diffraction, moisture sorption, differential scanning calorimetry, solution calorimetry, and dissolution properties.

[0127] Crystalline organic compounds consist of a large number of atoms arranged in a periodic sequence in three-dimensional space. Structural periodicity usually manifests distinct physical properties such as sharp, well-defined spectral features by most spectroscopic probes (e.g., X-ray diffraction, infrared, and solid-state NMR). X-ray diffraction (XRD) is recognized as one of the most accurate methods for determining the crystallinity of solids. Crystals yield well-defined diffraction maxima that occur at specific angles that are consistent with lattice spacings, as predicted by Bragg's law. Amorphous materials, on the other hand, do not have long-range order. They, like liquids, frequently retain additional volume between molecules. Due to the lack of a repeating crystal lattice with long-range order, amorphous materials usually reveal featureless XRD patterns with broad, diffuse halos.

[0128] Crystalline forms are preferred in many pharmaceutical applications. Crystalline forms are generally more thermodynamically stable than amorphous forms of the same substance. This thermodynamic stability is preferably reflected in the improved physical stability of the crystalline form. The ordered packing of molecules in crystalline solids preferably rejects the incorporation of chemical impurities. Hence, crystalline substances generally possess higher chemical purity than their amorphous counterparts. The packaging in crystalline solids generally restricts the molecules to well-defined lattice point positions, reducing the molecular mobility that is a prerequisite for chemical reactions. Thus, crystalline solids are, with very few notable exceptions, more chemically stable than amorphous solids of nearly identical molecular composition. Preferably, the crystalline forms of alpha-1062 gluconate disclosed in the present application possess one or more advantageous chemical and / or physical properties disclosed herein.

[0129] As used herein, the term stable can refer to either chemical stability or polymorphic stability. Polymorphic stability refers to the ability of a polymorph to remain in its particular crystalline state under appropriate storage conditions. For example, a stable polymorph maintains at least about 95% by weight, preferably at least about 98% by weight, more preferably at least about 99% by weight or more of its crystalline form, i.e., after storage for a specified period of time under specified conditions, the form remains unchanged. In the context of the present invention, Form A of α-1062 gluconate can, for example, be maintained at room temperature and at about 43% RH, or at less than about 43%, or at less than 0.12a for multiple months. w Form A appears to exhibit good stability under conditions of storage at low water activity, such as less than 1000 gluconate / g ...

[0130] Powder X-ray diffraction (PXRD): Powder X-ray diffraction (PXRD) measures the diffraction pattern of a crystalline substance. Each active pharmaceutical ingredient (API) can produce a unique pattern that depends on the structure of its crystal lattice. Each polymorph, pseudopolymorph, polymorphic salt, or co-crystalline substance can have its own unique pattern. For this reason, PXRD of an API can be performed under controlled conditions to assess the presence or absence of crystalline material and any form transformations.

[0131] PXRD can also be used to determine the changes, if any, in the crystalline form in a formulation that occurred, for example, during storage or stability studies. Identification of the crystalline form therefore relies on the presence of detectable diffraction peaks for any crystalline form. Furthermore, the peaks of the API must be distinguishable from the peaks of any crystalline excipients, the composition should be evaluated after formulation. PXRD can also be used as a qualitative, and sometimes quantitative, assessment of the crystallinity of a pure API. One skilled in the art can, without undue effort, evaluate a PXRD pattern and identify the presence and / or absence of suitable peaks that can be used to characterize the properties of the crystalline form of any API.

[0132] In some embodiments, the peaks determined by PXRD analysis are essentially the same as those presented in the following examples. The term "essentially the same" in reference to PXRD means that the variability in peak positions and relative intensities of peaks is taken into account. For example, the typical accuracy of 2θ values ​​is within ±0.2°2θ.

[0133] As used herein, characteristic XRPD peaks are a representative subset of peaks from the XRPD pattern of a crystalline form of a substance that can be statistically proven to distinguish it from other crystalline forms of that substance. Not all crystalline polymorphs of a substance necessarily have characteristic peaks.

[0134] As used herein, prominent XRPD peaks are the most intense, low angle, non-overlapping peaks observed in an XRPD pattern. In some embodiments, a "prominent peak" has a relative intensity of preferably ≧20%, preferably ≧30%, more preferably ≧40% in an X-ray powder diffraction pattern.

[0135] As used herein, a representative XRPD peak is a peak from the XRPD pattern of a crystalline form of a material that statistically shows no bias from particle size / shape or preferred orientation during repeated samples and measurements.

[0136] As used herein, preferred orientation refers to a phenomenon observed in XRPD analysis where, depending on the particle size / shape and the pattern collection technique used, it is very difficult or impossible to randomly orient the particles of a material during collection and obtain a pattern with statistically consistent intensities.

[0137] With regard to the relative intensities and prominent peaks of the X-ray powder diffraction patterns described above, the relative intensity values ​​provided are intended to limit the identification of the prominent or characteristic peaks referred to. As known to those skilled in the art, relative peak intensities will account for some instrumental and batch-to-batch variability, as well as variability due to crystallinity, preferred orientation, and sample preparation, and as such are provided as an indication of the intensity of the peaks in the X-ray powder diffraction pattern and as a qualitative measure only, but not by way of a limiting definition.

[0138] Thus, the term "prominent peak" in the context of defining the present invention is not limited to the respective relative intensities provided above, and any one or more respective peaks can be determined as the prominent peak of any α-1062 gluconate form. Preferably, at least 1, 2, 3 or 4 prominent peaks can be used to characterize a crystalline form, and in other embodiments, at least 5, 6, 7, 8, 9 or 10 prominent peaks can be used. Thus, the prominent peaks are also not limited to peaks unique to any crystalline form, but rather a peak can be used to identify a crystalline form in any combination with multiple other peaks from the PXRD pattern. In the context of the present invention, crystalline forms A-D can share multiple prominent peaks, but also exhibit peaks that are distinct from each other that can be used to distinguish any two forms. In some embodiments, the prominent peaks referred to in the embodiments of the present invention can also be characteristic peaks and / or representative peaks.

[0139] Analytical techniques and terminology: As used herein, ATR (attenuated total reflectance) is an FTIR data collection technique in which a small amount of solid or liquid sample is placed in direct contact with an ATR crystal that allows an IR beam to be reflected internally through the sample generating an evanescent wave that is used to measure the spectrum of the sample.

[0140] As used herein, DSC (Differential Scanning Calorimetry) is a thermodynamic technique for the evaluation of the thermal energy changes that occur in a sample undergoing a physical or chemical change involving a controlled change in temperature.

[0141] As used herein, DVS (Dynamic Vapor Sorption) is a gravimetric method for measuring the rate and amount of solvent uptake by a sample under controlled conditions.

[0142] In this specification, FTIR (Fourier Transform Infrared Spectroscopy) is a simple and reliable technique that is widely used in the pharmaceutical industry for the identification and characterization of substances. Infrared spectra can be used for the identification of substances because the functional groups of the substances give rise to vibrational bands that are characteristic in both intensity and frequency.

[0143] As used herein, NMR (Nuclear Magnetic Resonance) is a technique in which a sample is placed in a strong magnetic field and NMR-active nuclei absorb electromagnetic radiation at a frequency characteristic of the sample. The most common types are proton (1H) NMR and carbon (13C) NMR.

[0144] As used herein, TGA (Thermogravimetric Analysis) is a thermogravimetric method that measures the change in mass of a sample as a function of time and / or temperature.

[0145] As used herein, XRPD (X-ray powder diffraction) is a technique for the identification and characterization of crystalline materials to ensure that the appropriate phase or polymorph is present. The technique can be used to measure samples in either transmission or reflectance mode for analysis.

[0146] As used herein, RH (relative humidity) refers to the ratio of the partial pressure of water vapor to the equilibrium vapor pressure of water at a given temperature. To determine RH, a hygrometer can be used to measure the humidity of air. Relative humidity is expressed as a percentage; a higher percentage means a more humid air-water mixture.

[0147] Composition and Administration: The term "active ingredient" or "API" herein refers to the relevant drug molecule (e.g., alpha-1062), as well as its pharma- ceutically acceptable and therapeutically effective salts, esters, amides, prodrugs, metabolites, enantiomers, polymorphs, analogs, etc., that induce the desired pharmacological or physiological effect. Terms such as "active," "active agent," and "active substance" can be used synonymously with "active ingredient." In the context of this application, alpha-1062 is considered an API, although it is not the active per se prior to enzymatic cleavage, it is the prodrug molecule that is prepared and / or formulated.

[0148] The terms "effective amount" or "therapeutically effective amount" are used interchangeably and are defined to mean the amount or quantity of a drug (e.g., alpha-1062) that is sufficient to elicit an appreciable biological response when administered to a patient. It is understood that the precise therapeutic dose will depend on the age and condition of the patient, the nature of the condition being treated, and is ultimately at the discretion of the attending physician.

[0149] A pharmaceutical composition may contain one or more pharma- ceutically acceptable carriers or excipients. The term "excipient" refers to pharmacologically inactive ingredients such as, for example, diluents, disintegrants, carriers, and pharmaceutical agents. Excipients useful in the preparation of pharmaceutical compositions are generally safe, non-toxic, and acceptable for veterinary, as well as human, pharmaceutical use. Reference to an excipient includes both one excipient and more than one excipient. In some embodiments, excipients are described herein according to "wt%", i.e., "weight percentage".

[0150] As used herein, "administering" or "administration" refers to the delivery of an API, e.g., in the form of a crystalline form of the present invention or a pharmaceutical composition thereof, to an organism for the purpose of preventing or treating a brain disease associated with cognitive impairment.

[0151] Suitable routes of administration include, but are not limited to, oral, rectal, transmucosal or intraintestinal administration, or intramuscular, subcutaneous, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreal, intraperitoneal, intranasal or intraocular injection. Preferred routes of administration are transmucosal or intravenous injection.

[0152] The pharmaceutical composition of the present invention can be prepared by processes well known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, mashing, emulsifying, encapsulating, encapsulating, dissolving or lyophilizing processes. The pharmaceutical composition for use according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of the crystals of the present invention into pharmaceutical preparations. The appropriate formulation depends on the selected route of administration.

[0153] For injection or transmucosal administration, the crystals of the present invention or pharmaceutical compositions thereof can be formulated in an aqueous solution, preferably in a physiologically compatible buffer such as Hanks' solution, Ringer's solution or physiological saline buffer. For transmucosal administration, a penetrant suitable for the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art.

[0154] For oral administration, the crystal of the present invention or its pharmaceutical composition can be formulated by combining the crystal of the present invention with pharma- ceutically acceptable carriers well known in the art. Such carriers allow the crystal of the present invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by patients. Oral medicaments can be produced by processing the mixture of granules, optionally grinding the resulting mixture with solid excipients, and optionally adding other suitable auxiliaries to obtain tablet or dragee cores. Useful excipients are in particular fillers such as sugar, starch and other substances. Disintegrants can be added if necessary.

[0155] For administration by inhalation, the crystals of the present invention or pharmaceutical compositions thereof are conveniently delivered in the form of an aerosol spray using a pressurized pack or nebulizer and a suitable propellant, such as, but not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide.In the case of a pressurized aerosol, the dosage unit can be controlled by providing a valve to deliver a metered amount.For example, gelatin capsules and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the crystals of the present invention or pharmaceutical compositions thereof and a suitable powder material, such as lactose or starch.

[0156] The crystals of the present invention or pharmaceutical compositions thereof can also be formulated for parenteral administration, for example, by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, for example, in ampoules or multi-dose containers, with the addition of preservatives. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory substances such as suspending, stabilizing and / or dispersing agents.

[0157] Pharmaceutical compositions for parenteral administration contain aqueous solutions of soluble forms of the crystals of the present invention or pharmaceutical compositions thereof. In addition, suspensions of the crystals of the present invention or pharmaceutical compositions thereof can be formulated in lipophilic carriers. Suitable lipophilic carriers include substances such as fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate and triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers and / or agents that increase the solubility of the crystals of the present invention or pharmaceutical compositions thereof to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, such as sterile, pyrogen-free water, before use.

[0158] The crystals of the present invention or pharmaceutical compositions thereof may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.

[0159] According to the present invention, the preferred mode of administration is transmucosal administration. The term "transmucosal administration" refers to It relates to the entry of pharmaceutical agents through or across mucous membranes. The mucosal routes of administration of the present invention are preferably intranasal, buccal and / or sublingual.

[0160] Nasal or intranasal administration refers to any form of application to the nasal cavity. The nasal cavity is covered by a thin mucous membrane that is well vascularized. Therefore, drug molecules can be rapidly transported across a single epithelial cell layer without first-pass hepatic and intestinal metabolism. Thus, intranasal administration is used as an alternative to oral administration of, for example, tablets or capsules, which leads to extensive degradation in the gut and / or liver.

[0161] Buccal administration refers to any form of application that results in absorption across the buccal mucosa, preferably on the inside of the cheek, on the surfaces of the teeth, or on the gums adjacent to the cheek. Sublingual administration refers to administration under the tongue, whereby the chemical comes into contact with and diffuses through the mucous membrane under the tongue.

[0162] Pharmaceutical compositions suitable for buccal and / or sublingual administration may contain additional pharma- ceutically acceptable carriers or excipients. The active agent may be physically combined with substances that are some or all of the types of ingredients that function as pH adjusters, preservatives, viscosity adjusters, absorption enhancers, stabilizers, solvents, and carrier vehicles. Such agents may be present in either solid or liquid form in the pharmaceutical composition.

[0163] Determination of a therapeutically effective amount and suitable modes of administration is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. The amount of a composition administered will, of course, depend on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

[0164] The composition can be presented in a pack or dispenser device, such as an FDA approved kit, which may include a dosage form containing the active ingredient, if desired. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container of a shape prescribed by a governmental agency regulating the manufacture, use, or sale of drugs, which notice reflects the form of the composition or the approval by the agency for human or veterinary administration. Such notice may be, for example, a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved insert. The composition comprising the crystals of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and labeled for the treatment of the indicated condition. A suitable condition is a brain disease associated with cognitive dysfunction; preferably one disclosed herein, particularly AD and PD.

[0165] method: Based on the disclosure provided herein, a person skilled in the art can prepare the crystalline form of the present invention without undue effort. In some embodiments, the method for preparing the crystalline solid form A includes contacting α-1062 gluconate with an organic solvent, preferably MEK, to form a slurry, and then stirring, filtering and drying the slurry to obtain the crystalline solid form.

[0166] An organic solvent is a type of volatile carbon-based chemical that can dissolve or disperse one or more other chemicals. Common organic solvents are classified as aliphatic, cyclic, aromatic, halogenated, ketones, amines, esters, alcohols, aldehydes, and ethers. Butanone, the preferred solvent for slurrying, is also known as methyl ethyl ketone (MEK) and is an organic compound with the formula CH3C(O)CH2CH3. MEK is a ketone with a pungent, sweet odor reminiscent of butterscotch and acetone. It is manufactured industrially on a large scale, dissolves in water, and is commonly used as an industrial solvent. 1,4-dioxane (dioxane), ethyl acetate (EtOAc), and tetrahydrofuran (THF) are also useful.

[0167] Methods for slurry preparation, filtering and drying which belong to standard techniques in the pharmaceutical industry are known to those skilled in the art and can be used on a laboratory or industrial scale.

[0168] The crystalline forms or polymorphs of the present invention can also be produced using alternative means as disclosed herein. Those skilled in the art can adjust the conditions to produce any crystalline form. Generally, the production of polymorphs is carried out by crystallizing the material from a single solvent or a mixture of solvents via cooling crystallization, evaporation or antisolvent crystallization. In addition, heating and cooling rates, crystallization temperature, evaporation rate, degree of supersaturation, stirring speed, pH of the medium are variables that can affect the crystallization process and thus the polymorph formed. After identifying the surprising crystalline forms described herein, those skilled in the art can adjust these factors to reproduce the forms described herein. [Brief description of the drawings]

[0169] figure The present invention is demonstrated by way of the figures disclosed herein, which provide support for the description of potentially preferred, non-limiting embodiments of the invention. [Figure 1] Chemical structure of α-1062 gluconate [Diagram 2] XRPD patterns of α-1062 gluconate research lots [Diagram 3] Comparison of XRPD patterns of α-1062 gluconate, lot QCL-PLC-I-96, with the overlaid pure phase [Figure 4] XRPD pattern comparison of α-1062 gluconate, lot QCL-PLC-I-96, with the pure phase overlaid in the enlarged view. [Diagram 5] Thermogram of α-1062 Gluconate, Lot QCL-PLC-I-96, Forms A+B+D [Figure 6] XRPD Pattern [Figure 7] Test indexing solution of Form A: α-1062 gluconate, Lot CA19-1144 [Figure 8] Observed XRPD peaks for Form A: α-1062 Gluconate, Lot CA19-1144 [Figure 9] Overlay of transmission and reflection XRPD patterns of Form A [Figure 10] ATR FTIR spectrum of Form A: α-1062 Gluconate, Lot 2455_RD-00017-002 [Figure 11] Thermogram of Form A: α-1062 Gluconate, Lot CA19-1144 [Figure 12] DVS Isotherm for Form A: α-1062 Gluconate, Lot CA19-1144 [Figure 13] Test indexing solution of Form B: α-1062 gluconate, sample 8235-85-01 [Figure 14] Observed XRPD peaks for Form B: α-1062 gluconate, sample 8235-85-01 [Figure 15] ATR FTIR spectrum of Form B: α-1062 gluconate, sample 8296-41-01 [Figure 16] Thermogram of Form B: α-1062 Gluconate, sample 8235-82-08 [Figure 17] DVS Isotherm of Form B: α-1062 Gluconate, Sample 8235-82-08 [Figure 18] DVS Isotherm of Form B: α-1062 Gluconate, corrected for moisture content, sample 8235-82-08 [Figure 19] Test indexing solution for Form C: α-1062 gluconate, sample 8235-87-02 [Figure 20] Observed XRPD peaks for Form C: α-1062 gluconate, sample 8235-87-02 [Figure 21] ATR FTIR spectrum of Form C: α-1062 Gluconate, Lot 2455_RD-00049-001 [Figure 22] Thermogram of Form C: α-1062 Gluconate, sample 8235-87-02 [Figure 23] DSC Thermogram of Form C: α-1062 Gluconate Form C, Sample 8296-08-01 [Figure 24]DVS Data for Form C: α-1062 Gluconate, Sample 8235-92-11 [Diagram 25] DVS Isotherm of Form C: α-1062 Gluconate, Corrected for Moisture Content, Sample 8235-92-11 [Figure 26] XRPD pattern of Form D: α-1062 gluconate, sample 8235-86-01 [Figure 27] Test indexing solution for Form D: α-1062 gluconate, sample 8235-86-01 [Figure 28] Observed XRPD peaks for Form D: α-1062 gluconate, sample 8235-86-01 [Figure 29] ATR FTIR spectrum of Form D: α-1062 gluconate, sample 8235-86-01 [Diagram 30] XRPD pattern of substance E, sample 8235-76-04 [Diagram 31] Thermogram of substance E, sample 8235-76-04 [Diagram 32] XRPD pattern of substance F, sample 8235-76-07 [Diagram 33] XRPD pattern of material G, sample 8235-100-02 [Diagram 34] XRPD pattern of amorphous α-1062 gluconate, sample 8235-92-10 [Diagram 35] Cyclic DSC of amorphous α-1062 gluconate, sample 8235-92-10 EXAMPLES

[0170] The invention is demonstrated by way of the examples disclosed herein, which provide technical support for the detailed description of potentially preferred, non-limiting embodiments of the invention.

[0171] Research materials: Three lots of α-1062 gluconate (galantamine benzyl ester gluconate) were used to initiate these studies (Table 1). XRPD analysis (Figure 2) shows that 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, indicating a mixture.

[0172] Subsequent studies described below determined that lots CA19-1144 and CA19-0673 were identified as Form A, and lot QCL-PLC-I-96 was determined to be a mixture of Forms A, B, and D (Figures 3 and 4). Thermal analysis of the QCL-PLC-I-96 material (Figure 5) showed a 3.6% weight loss to 121°C, a broad endotherm with an onset at 69°C, and a terminal endotherm with an onset at 119°C. Detailed properties of the three lots are provided in Tables 0 through 4. For consistency, lot CA19-1144 is assumed to be representative of Form A and is discussed further below.

[0173] Polymorph Screening and Stability: A polymorph screening study was initiated to investigate and identify the presence of various possible solid forms of α-1062 gluconate. This study used lot CA19-1144 as the starting material and utilized various solvent systems and conditions to isolate and study the material produced during the study (Table 5). The various materials were analyzed by XRPD and the various solid forms were identified as shown (Figure 6).

[0174] To investigate the stability of the four pure crystalline forms of α-1062 gluconate, we tested water activity (a) using various mixed aqueous / organic solvent systems (Table 6) along with relative humidity stress (Table 7). w ) slurries were used to define the region of stability of a given hydrate of α-1062 gluconate. Slurries of each sample in each solvent system were studied over a period of time to determine interconversion to the most stable form.

[0175] From these studies, Form A (anhydrous) was found to be approximately 0.12%w It was found that the most stable form is at low water activities below 12% RH. Above this water activity, approximately 0.5a w Up to 0.5a, form A, anhydrous, converts to form C (monohydrate), which appears to be the stable form. w Above 100°C, Form B (tetrahydrate) is formed and is the most stable form. Form D (dihydrate) was only observed after exposure to approximately 75% RH or upon drying. Form D does not appear to be stable under any of the conditions evaluated and readily converts to other dependent forms depending on the humidity of storage.

[0176] Material characterization: Form A: α-1062 gluconate, lot CA19-1144 (Table 2). Form A is anhydrous. Form A is 0.12a w It was found to convert to a hydrate form in solvent systems with water activities above (12% RH). Nevertheless, Form A appeared to be kinetically stable in the solid state at 43% RH (RT) and persisted in that state for up to 5 days. XRPD (Figure 7). The powder X-ray diffraction pattern of Form A is well indexed by a single primitive orthorhombic unit cell, providing a robust description of the crystal form with tentative crystal unit cell parameters and strong evidence that the pattern represents a single crystalline phase. The calculated 688 Å diffraction pattern from the index results. 3 The formula unit volume of is 1.419g / cm 3 The calculated density of saccharides is known to be densely packed due to the large number of hydrogen bonds. The XRPD pattern of Form A (Figure 8) is tabulated listing 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 reflection mode results in the presence of a preferred orientation in Form A compared to the transmission mode pattern (Figure 9). · The solution NMR spectrum is consistent with the chemical structure and is consistent with a 1:1 stoichiometric salt containing 1 mol / mol gluconic acid. - FTIR spectroscopic analysis using ATR acquisition mode of sample 2455_RD-00017-002 results in an FTIR spectrum (Figure 10) that is consistent with the structure of anhydrous Form A of α-1062 gluconate. Thermal Analysis (Figure 11). The TGA thermograph shows a weight loss of 0.17% up to 121°C. In the DSC a single endotherm was observed with an onset of 117°C, consistent with melting. Based on the weight loss observed after melting, decomposition is likely occurring. Heating the material just beyond the melt (125°C) and subsequent cooling resulted in an amorphous material. The dynamic vapor sorption (DVS) isotherm (Figure 12) indicates that Form A exhibits significant hygroscopicity above 75% RH. A weight increase of 0.57% was observed from 5 to 75% RH. Weight increased significantly above 75% RH, with a 2.97% weight increase from 75 to 85% RH and an additional 8.7% weight increase from 85 to 95% RH. Hysteresis was observed, including a stable plateau obtained upon desorption, suggesting that the material was likely converted to a hydrated form. Weights obtained within the stable plateau were consistent with an increase in water of more than 3 mol / mol, suggesting that Form A converted to Form B above 85% RH. The material recovered from the DVS experiment was identified as Form A + minor peaks of Form B; however, it is noteworthy that once the DVS experiment was completed, the material was held at 5% RH and was likely partially dehydrated back to Form A before recovery and testing was performed. Solubility studies (Table 9) were conducted on Form A in various solvents and tabulated the results showing high water solubility.

[0177] Form B: α-1062 gluconate, sample 8235-82-08 (Table 10). Form B is a tetrahydrate crystal lattice. At least one of the four water sites in the crystal lattice appears to be somewhat unstable. DVS data suggests that Form B can contain approximately 3.6-3.9 mol / mol of water at relative humidities ranging from 15-85% RH. Form B has a 0.52a w (52% RH), and 0.52a w (52% RH) or less and 0.31a w Above 31% RH, it was in equilibrium with Form C. -XRPD (Figure 13). The XRPD pattern was successfully indexed by a single simple orthorhombic unit cell. The calculated alignment of 772 Å from the indexing results. 3 The formula unit volume of Form A is 84 Å. 3 Compared to form A, the excess volume is sufficient to accommodate up to 4 mol / mol of water, which is 1.420 g / cm 3 yields the calculated density of The XRPD pattern of Form B (Figure 14) is tabulated, listing 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 4 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 water), consistent with the indicative results. The solution NMR spectrum was consistent with the chemical structure and a 1:1 stoichiometric salt containing 1 mol / mol gluconic acid; no residual organic solvents (e.g., MEK) were observed. · FTIR spectroscopic analysis using ATR acquisition mode of sample 8296-41-01 results in an FTIR spectrum (Figure 15) that is consistent with the structure of α-1062 gluconate form B. Thermal Analysis (Figure 16). The TGA thermograph shows a 3.3% weight loss up to 114°C, followed by an additional 5.2% weight loss up to 147°C. In the DSC, a broad endotherm with onset at 66°C (which coincides with the weight loss in the TGA) is observed, consistent with desolvation. A second endotherm with onset at 115°C is observed, followed by a weaker endotherm at 152°C. A sample of Form B heated for longer than 10 minutes between 40 and 75°C and analyzed by XRPD resulted in partial dehydration and conversion to a mixture of Forms D and C (both of which are said to be hydrates, but each in a lower state of hydration) and additional peaks. Form B was shown to dehydrate to Form A at 0% RH after 1 day (Table 7). Dynamic Vapor Sorption (DVS) isotherms (Figure 17) were collected starting at 50% RH (to avoid conversion due to loss of hydration prior to data acquisition). Form B showed limited hygroscopicity; with a weight increase of 1.5% from 50 to 90% RH. Upon desorption, a weight loss of 1.8% was observed from 95 to 15% RH, followed by a weight loss of 6.8% from 15 to 5% RH. The DVS data were corrected for water content measured by KF at 57% RH (Figure 18). A stable plateau of water between 3.6 and 3.9 mol / mol for Form B is evident between 15 and 85% RH. The material recovered from the DVS experiment was identified as anhydrous Form A.

[0178] Form C: α-1062 gluconate, sample 8235-87-02 (Table 11). Form C was determined to be a monohydrate crystal lattice occupied exclusively by water at approximately 0.4-0.5 mol / mol. Form C is a monohydrate with a water activity of 0.12-0.31 a w (12-31% RH), and above 0.31aw (31% RH) and 0.52a w (52% RH) and was in equilibrium with form B. -XRPD (Figure 19). The XRPD pattern was successfully indexed by a single simple monoclinic unit cell. The calculated alignment of 706 Å 3 The formula unit volume of is 18 Å from Form A. 3Compared to form A, the excess volume is sufficient to accommodate up to 1 mol / mol of water, which is 1.425 g / cm 3 yields the calculated density of The XRPD pattern of Form C (Figure 20) is tabulated, listing 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 4 days and analyzed by XRPD and coulometric Karl Fischer (KF) titration. The resulting sample remained as Form C and contained 1.3% water (equivalent to ~0.4 mol / mol water). - FTIR spectroscopic analysis using ATR acquisition mode of sample 2455_RD-00049-001 results in an FTIR spectrum (Figure 21) that is consistent with the structure of α-1062 gluconate form C. Thermal analysis (Figure 22). The TGA thermograph shows a weight loss of 0.9% up to 121°C. In the DSC an endotherm is observed with an onset at 119°C. Form C (sample 8235-93-04) was held at 11% RH for 7 days and analyzed by XRPD and DSC for comparison (sample 8296-08-01). The resulting sample remains Form C and exhibits a single sharp endotherm with an onset of 129° C. in the DSC (FIG. 23). Form C (sample 8235-93-02) was stored at 45°C under vacuum for 3 hours and analyzed by XRPD. The resulting sample remained Form C with a small amount of Form A present. Dynamic Vapor Sorption (DVS) isotherms (Figure 24, sample 8235-92-11) indicate that Form C exhibits significant hygroscopicity above 75% RH. The sample did not show significant weight gain from 5 to 75% RH, but a 4.6% weight gain was observed from 75 to 95% RH. Upon desorption, a 1.5% weight loss was observed from 95 to 75% RH. The DVS data was corrected for water content measured by KF at 11% RH (Figure 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.

[0179] Form D: α-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 over time to other more stable hydrates depending on the RH conditions. Form D is formed by exposure of Form A to approximately 75% RH. Attempts to produce pure Form D as a single crystalline phase have resulted in mixtures contaminated with small amounts of either Form A or Form B. -XRPD (Figures 26-27). The XRPD pattern shows a mixture of minor peaks for Form D and Form A. Small peaks around 12.68, 18.43 and 20.91° (2θ) are consistent with Form A and were intentionally ignored during indexing. Form D was successfully indexed from the remaining peaks with a single simple orthorhombic unit cell. The calculated 733 Å from the indexing results. 3 The formula unit volume of Form A is 45 Å. 3 Compared to Form A, the excess volume is sufficient to accommodate up to 2 mol / mol of water, which is 1.413 g / cm 3 yields the calculated density of · The XRPD pattern of Form D (Figure 28) is tabulated, listing the observed peak positions and intensities, with the most prominent peaks shaded for emphasis. - FTIR spectroscopic analysis using ATR acquisition mode of sample 8235-86-01 results in an FTIR spectrum (Figure 29) that is consistent with the structure of Form D of α-1062 gluconate. A sample of Form D and traces of Form B (8235-34-03) was held at 75% RH for 1 day (to limit conversion) and analyzed by XRPD and coulometric Karl Fischer (KF) titration. The sample remained generally similar to the initial composition with only a slight increase in Form B. The sample contained 4.3% water, i.e., ~1.5 mol / mol water. Water activity slurry and relative humidity stress studies (Tables 6-7) suggest that Form D is a metastable form under all conditions evaluated and will eventually convert to Form B upon prolonged exposure to relative humidity ≥ 52% RH or to Form C at relative humidity < 52% RH.

[0180] Material E: Sample 8235-76-04 (Table 13). The material produced from evaporation of the dichloromethane (DCM) solution is not consistent with α-1062 gluconate. - XRPD (Figure 30). The XRPD pattern was indexed (not provided) but the volume was not sufficient to contain the α-1062 gluconate molecule, suggesting that this is either the free base or a degradation product. The solution NMR spectrum contains a non-stoichiometric amount of gluconate. Two species are present in the spectrum. Also, 0.6 mol / mol DCM is observed. The NMR spectrum is not consistent with a salt. Thermal analysis (Figure 31). In TGA, a weight loss of 1.6% was observed up to 101°C. In DSC, multiple endothermic events were observed.

[0181] Material F: Sample 8235-76-07 (Table 14). Likely a decomposition product produced from evaporation of a dichloromethane (DCM) slurry. - XRPD (Figure 32). The XRPD pattern was indexed (not provided), but the volume was not sufficient to contain either the α-1062 free base or its salts, suggesting that this is a simple gluconate salt or a degradation product.

[0182] Material G: α-1062 gluconate, samples 8235-87-01 and 8235-100-02 (Table 15). Material G was observed from evaporation experiments in both 1,4-dioxane and THF. The material was waxy upon isolation but contained thin needles dispersed throughout. · The XRPD (Figure 33) of sample 8235-100-02 shows a lot of amorphous nature due to its waxy nature. Reanalysis of 8235-87-01 after 5 weeks showed the sample to partially convert to Form B (there was evidence of a small amount of Form B in the initial pattern). Based on the spontaneous conversion, material G is metastable with Form B under the conditions. Material G was not observed during any water activity slurry or relative humidity studies.

[0183] Amorphous: α-1062 gluconate. Sample 8235-76-13 (Table 16) has been observed from slow evaporation of methanol (Table 5). During the synthesis of α-1062 gluconate, the material does not easily crystallize from solution and must be seeded. Usually, an oily and sticky film is formed first, which then nucleates over time. Sample 8235-76-13 spontaneously crystallized into a mixture of forms B and C after 13 days. The XRPD of the amorphous material produced via melt quench (Figure 34) was observed to remain amorphous after 5 weeks. No significant impurity increase was observed. 1 Not observed by 1 H NMR. Thermal analysis (Figure 35). Glass transition (T g Cyclic DSC was performed to determine the glass transition temperature. The glass transition temperature was determined to be near 41° C. On continued heating, decomposition was observed without nucleation.

[0184] table: Table 1: Study materials (α-1062 gluconate) [Table 5]

[0185] Table 2: Characterization of α-1062 gluconate, lot CA19-1144 [Table 6]

[0186] Table 3: Characterization of α-1062 gluconate lot QCL-PLC-I-96 [Table 7]

[0187] Table 4: Characterization of α-1062 Gluconate Lot CA19-0673 [Table 8]

[0188] Table 5: Polymorphism Screen of α-1062 Gluconate (using Lot CA19-1144 [Form A]) [Table 9-1] [Table 9-2] [Table 9-3]

[0189] Table 6: Water activity of α-1062 gluconate slurries [Table 10-1] [Table 10-2]

[0190] Table 7: Relative humidity stress of α-1062 gluconate samples [Table 11]

[0191] Table 8: XRPD prominent peak overlays of α-1062 gluconate forms A, B, C and D, typical prominent two-theta (2θ) peak positions of the crystal forms found. [Table 12]

[0192] Table 9: Approximate ambient solubility of Form A: α-1062 gluconate, Lot CA19-1144 [Table 13]

[0193] Table 10: Characterization of Form B: α-1062 gluconate [Table 14]

[0194] Table 11: Characterization of Form C: α-1062 Gluconate [Table 15]

[0195] Table 12: Characterization of Form D: α-1062 Gluconate [Table 16]

[0196] Table 13: Characterization of substance E [Table 17]

[0197] Table 14: Characterization of substance F [Table 18]

[0198] Table 15: Characterization of substance G [Table 19]

[0199] Table 16: Characterization of amorphous α-1062 gluconate [Table 20]

[0200] Reprocessing of α-1062 Gluconate: Alpha-1062 gluconate (CA19-0673) was reprocessed and evaluated to determine whether multiple potentially insoluble polymorphs or pseudopolymorphs could be produced.

[0201] Test 1: Alpha-1062 gluconate (CA19-0673) was reslurried 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 minutes before washing the filter cake with 4.1 g MEK, refiltering, and drying.

[0202] The reaction mixture was yellow to orange in color. The suspension was relatively thin initially but then became more viscous with longer stirring. After 30 minutes, a very thick, pasty suspension was obtained that was difficult to stir and transfer to a filter. The suspension was deemed too viscous and therefore unsuitable for processing. The isolated material was slightly yellowish (white to pale yellow).

[0203] Test 2: α-1062 gluconate (CA19-0673) was reslurried in MEK / H2O at 20°C. 5.6g α-1062 gluconate was used in 38.6g MEK+3.8g H2O. The slurry was stirred for 30 minutes before washing the filter cake with 8.2g MEK, refiltering and drying. The reaction mixture was yellow to orange in colour. The suspension was relatively thin at first, but then thickened with prolonged stirring. After 30 minutes a suspension was obtained that was significantly less viscous than in experiment 1 and could be easily stirred and transferred to a filter. The material was washed in MEK and dried on a rotator at 30°C / 20mbar for approximately 2 hours.

[0204] The isolated material was of similar color to batch CA19-0673. The relative retention time (RRT) on HPLC was consistent with previous measurements, with approximately 90% recovery. A powder X-ray diffraction spectrum was obtained by measuring the dried product. The pattern revealed a mixture of forms including Form A and one or more of Forms B-D, possibly a mixture of Forms A, B and C.

[0205] Experiment 3 Alpha-1062 gluconate (CA19-0673) was reslurried in water-free MEK at 20° C. 5.6 g of Alpha-1062 gluconate was used in 38.6 g of MEK. The slurry was stirred for 30 minutes before being dried.

[0206] The reaction mixture was a lighter pale yellow than in the previous experiment. The suspension reached a certain viscosity upon stirring. After 30 min a suspension was obtained which was significantly less viscous than in experiment 1 and could be easily stirred and transferred to a filter. The material was dried on a rotor at 30° C. / 20 mbar for approximately 2 h.

[0207] The isolated material was of similar color to batch CA19-0673. The relative retention time (RRT) in HPLC was consistent with previous measurements, with approximately 95% recovery. A powder X-ray diffraction spectrum was obtained by measuring the dried product. The pattern corresponded to Form A, as shown in Figure 8.

[0208] Synthesis of α-1062 gluconate: The gluconate salt of α-1062 was produced according to the following previously established general scheme:

[0209] [ka]

Claims

1. A crystalline solid form of α-1062 gluconate (Form A), said crystalline solid form having prominent peaks at 3.61, 10.98, 14.41 and 18.44±0.2 degrees 2θ in an X-ray powder diffraction pattern.

2. 2. The crystalline solid form of claim 1, wherein the 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±0.2 degrees 2θ in a powder X-ray diffraction pattern.

3. 3. The crystalline solid form of any one of claims 1 or 2, wherein the crystalline form has at least five prominent peaks selected from the list consisting of 3.61, 10.98, 13.80, 14.41, 14.56, 15.08, 15.20, 17.02, 17.31, 17.79, 18.44, 19.24, 20.18, 20.91, 21.22 and 22.40±0.2 °2θ in an X-ray powder diffraction pattern.

4. 4. The crystalline solid form of any one of claims 1 to 3, wherein the crystalline form has peaks at 7.25 and / or 12.67±0.2 degrees 2θ in a powder X-ray diffraction pattern.

5. 5. The crystalline solid form of any one of claims 1 to 4, wherein the crystalline form has at least three prominent peaks selected from the list consisting of 10.98, 14.41, 17.31, 18.44 and 22.40±0.2°2θ, said three peaks being among the five peaks having the highest relative intensity in an X-ray powder diffraction pattern obtained using transmission mode of analysis.

6. 6. The crystalline solid form of any one of claims 1 to 5, wherein the crystalline form has at least three peaks selected from the list consisting of 3.61, 7.25, 10.98, 14.56 and 22.40±0.2 degrees 2θ, said three peaks being among the five peaks having the highest relative intensity in an X-ray powder diffraction pattern obtained using reflection mode analysis.

7. The crystalline solid form of any one of claims 1 to 5, wherein the peaks are determined using X-ray powder diffraction analysis in transmission mode.

8. 8. The crystalline solid form of any one of claims 1 to 7, wherein the crystalline form exhibits an onset of melting at a temperature between 116-120°C as assessed using Differential Scanning Calorimetry (DSC).

9. 9. The crystalline solid form of claim 8, wherein the crystalline form exhibits an onset of melting at a temperature of about 117°C.

10. 10. The crystalline solid form of any one of claims 1 to 9, wherein the crystalline form exhibits a loss of weight of <0.5% before the onset of melting using DSC when assessed using thermogravimetry (TGA).

11. 11. The crystalline solid form of claim 10, wherein the crystalline form exhibits a weight loss of <0.3% or <0.2% before the onset of melting using DSC.

12. A formulation comprising the crystalline solid form (form A) according to any one of claims 1 to 11, said formulation being essentially free or containing negligible levels of one or more additional crystalline solid forms of alpha-1062 gluconate selected from forms B, C and / or D, said additional crystalline solid forms being: a. Form B, wherein said Form B has prominent peaks at 10.69, 17.17, 21.00, and 24.67±0.2 degrees 2θ in a powder X-ray diffraction pattern; b. Form C, wherein said Form C has prominent peaks at 3.90, 9.74, 10.35, and 21.43±0.2 degrees 2θ in an X-ray powder diffraction pattern; and c. Form D, wherein said Form D has prominent peaks at 3.76, 10.16, 14.77, and 19.03±0.2 degrees 2θ in an X-ray powder diffraction pattern; The formulation is selected from the group consisting of:

13. A formulation comprising the crystalline solid form of any one of claims 1 to 11 (Form A), said formulation further comprising one or more additional crystalline solid forms of alpha-1062 gluconate selected from Forms B, C and / or D as defined in claim 12.

14. A pharmaceutical composition comprising the crystalline solid form (Form A) of any one of claims 1 to 11 and / or the formulation of any one of claims 12 or 13, said composition further comprising one or more pharma- ceutically acceptable excipients.

15. 15. The pharmaceutical composition of claim 14, wherein the composition is packaged to reduce atmospheric moisture in contact with the composition.

16. The pharmaceutical composition of claim 15, wherein the packaging is an aluminum foil blister pack (Alu-Alu), a polymeric film with an aluminum layer, and / or a desiccant packaging.

17. The pharmaceutical composition according to any one of claims 14 to 16, wherein the composition is suitable for oral or transmucosal administration.

18. A pharmaceutical composition according to any one of claims 14 to 17 for use as a medicament in the treatment of brain diseases associated with cognitive impairment and / or choline deficiency disorders.

19. 19. The composition for use according to claim 18, wherein the brain disease is selected from the group consisting of brain diseases including cholinergic disorders, Alzheimer's disease, Parkinson's disease, dementia, schizophrenia, epilepsy, stroke, polio, neuritis, myopathy, post-hypoxia cerebral oxygen and nutrient deficiency, anoxia, asphyxiation, cardiac arrest, chronic fatigue syndrome, intoxication, anesthesia, spinal cord disorders, central inflammatory disorders, autism, Rett syndrome, post-operative delirium, neuropathic pain, alcohol and drug abuse, toxic alcohol and / or nicotine craving, and effects of radiation therapy.

20. 12. A process for preparing the crystalline solid form of any one of claims 1 to 11, comprising contacting a gluconate salt of alpha-1062 with an organic solvent, forming a slurry, followed by filtering and / or drying the slurry, to obtain the crystalline solid form.

21. 21. The method of claim 20, wherein the organic solvent is selected from the list consisting of methyl ethyl ketone (MEK), 1,4-dioxane (dioxane), ethyl acetate (EtOAc) and tetrahydrofuran (THF).

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