Patent Application
20230303572
The present invention relates to compositions of salts and polymorphs of 18-methoxycoronaridine.
18-methoxycoronaridine (18-MC) is a derivative of ibogaine with the chemical formula of C22H28N2O3. The freebase 18-MC is a synthetic coronaridine congener and a specific negative allosteric modulator (antagonist) of α3β4 nicotinic cholinergic receptors; it indirectly modulates the dopaminergic mesolimbic pathway via blockade of α3β4 nicotinic receptors in the habenulo-interpeduncular pathway and the basolateral amygdala (Glick et al., 2008). Animal studies have demonstrated that 18-MC significantly reduces drug self-administration in a number of substance use models (nicotine, alcohol, morphine, cocaine and methamphetamine) at dosages as low as 10 mg/kg i.p. (Glick et al., 1994; Rezvani et al., 1995; Glick et al., 1996; Glick et al., 1998; Glick et al., 2000a). More recently, 18-MC has been shown in an animal model to attenuate effects of the environmental cues responsible for stimulating cocaine-seeking or “craving” behaviors (Polston et al., 2012, and U.S. Pat. Application No. 14/387,339 to Glick, et al.). This property of 18-MC could potentially help address the craving component of human addictive behaviors.
U.S. Pat. Application No. 14/387,339 to Glick, et al. discloses methods of preventing drug relapse, especially during cue inducement, by administering an effective amount of an α3β4 nicotinic antagonist (18- Methoxycoronaridine) to a mammal, after an initial period of drug use, and preventing a relapse of drug use. It was shown that rats conditioned with a musical cue show increased drug-seeking behaviors with cocaine when compared to control groups. Pharmaceutically acceptable HCl salts of 18-MC are mentioned, however, polymorphism is not disclosed. Preparation of the 18-MC HCl salt has been briefly described in the literature (Acta Crystallographica Section E, Structure Reports, ISSN 1600-5368, Acta Cryst. (2012). E68, o1041). However, few details are provided and conflicting information is provided regarding the solvent system. Understanding and control of polymorphism is required in order to develop a robust and scalable API manufacturing process resulting in a stable material that is suitable for drug product manufacturing.
Therefore, there remains a need for salts and polymorphs of 18-MC.
The present invention provides for a composition including a salt of 18-MC, wherein the salt is chosen from gentisate, hydrobromide, besylate, napadisylate, hydrochloride, sulfate, oxalate, maleate, mesylate, and tosylate.
The present invention provides for a composition including a polymorph of 18-MC, wherein the polymorph is chosen from HCl salt Type A, HCl salt Type B, HCl salt Type C, HCl salt Type D, HCl salt Type E, HCl salt Type F, HCl salt Type G, HCl salt Type H, HCl salt Type I, HCl salt Type J, HCl salt Type K, HCl salt Type L, HCl salt Type M, HCl salt Type N, HCl salt Type O, HCl salt Type P, HCl salt Type Q, HCl salt Type R, HCl salt Type S, HCl salt Type T, HCl salt Type U, HCl salt Type V, sulfate salt Type A, sulfate salt Type B, sulfate salt Type C, sulfate salt Type D, sulfate salt Type E, sulfate salt Type F, oxalate salt Type A, oxalate salt Type B, maleate salt Type A, mesylate salt Type A, mesylate salt Type B, mesylate salt Type C, HBr salt Type A, HBr salt Type B, HBr salt Type C, HBr salt Type D, tosylate salt Type A, tosylate salt Type B, tosylate salt Type C, tosylate salt Type D, tosylate salt Type E, tosylate salt Type F, tosylate salt Type G, tosylate salt Type H, tosylate salt Type I, besylate salt Type A, besylate salt Type B, besylate salt Type C, napadisylate salt Type A, napadisylate salt Type B, napadisylate salt Type C, napadisylate salt Type D, and gentisate salt Type A.
Other advantages of the present invention are readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:
The present invention provides for salts and polymorphs of 18-MC. The polymorphs can be crystalline or amorphous.
The salts can include gentisate, hydrobromide, besylate, napadisylate, hydrochloride, sulfate, oxalate, maleate, mesylate, and tosylate.
The polymorphs can include HCl salt Type A, HCl salt Type B, HCl salt Type C, HCl salt Type D, HCl salt Type E, HCl salt Type F, HCl salt Type G, HCl salt Type H, HCl salt Type I, HCl salt Type J, HCl salt Type K, HCl salt Type L, HCl salt Type M, HCl salt Type N, HCl salt Type O, HCl salt Type P, HCl salt Type Q, HCl salt Type R, HCl salt Type S, HCl salt Type T, HCl salt Type U, HCl salt Type V, sulfate salt Type A, sulfate salt Type B, sulfate salt Type C, sulfate salt Type D, sulfate salt Type E, sulfate salt Type F, oxalate salt Type A, oxalate salt Type B, maleate salt Type A, mesylate salt Type A, mesylate salt Type B, mesylate salt Type C, HBr salt Type A, HBr salt Type B, HBr salt Type C, HBr salt Type D, tosylate salt Type A, tosylate salt Type B, tosylate salt Type C, tosylate salt Type D, tosylate salt Type E, tosylate salt Type F, tosylate salt Type G, tosylate salt Type H, tosylate salt Type I, besylate salt Type A, besylate salt Type B, besylate salt Type C, napadisylate salt Type A, napadisylate salt Type B, napadisylate salt Type C, napadisylate salt Type D, and gentisate salt Type A.
Crystalline gentisate salt Type A can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 10.3, about 11.1, about 16.3, about 20.6, about 21.0, and about 27.8. Crystalline HBr salt Type A can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 8.6, about 13.1, about 19.1, about 19.9, about 26.1, and about 26.3. Crystalline HBr salt Type B can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 7.5, about 15.0, about 21.2, about 21.9, about 24.1, and about 30.3. Crystalline besylate salt Type A can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 7.4, about 8.1, about 14.3, about 14.7, about 19.7, and about 22.7. Crystalline besylate salt Type B can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 8.3, about 9.8, about 16.6, about 17.7, about 18.4, and about 18.7. Crystalline napadisylate salt Type A can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 7.6, about 8.1, about 12.2, about 12.7, about 14.6, and about 17.5.
Crystalline napadisylate salt Type B can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 8.2, about 10.6, about 17.8, about 19.3, about 20.0, and about 21.3. Crystalline napadisylate salt Type C can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 7.3, about 9.6, about 15.2, about 18.4, about 19.1, and about 24.5. Crystalline napadisylate salt Type D can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 7.3, about 7.5, about 15.0, about 17.8, about 18.0, and about 22.5. Crystalline HCl salt Type A and is characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 8.8, about 11.0, about 13.4, about 16.2, about 16.5, and about 16.8. Crystalline sulfate salt Type A can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 5.2, about 10.5, about 13.8, about 15.7, about 18.3, and about 20.4.
Crystalline maleate salt Type A can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 7.9, about 14.3, about 14.7, about 15.9, about 18.3, and about 19.1. Crystalline tosylate salt Type A can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 8.6, about 10.4, about 11.8, about 17.9, about 18.2, and about 21.0. Crystalline tosylate salt Type B can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 7.4, about 7.6, about 9.6, about 11.6, about 14.9, and about 15.3. Crystalline mesylate salt Type A can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 8.1, about 9.2, about 13.0, about 16.9, about 18.2, and about 21.1. Crystalline oxalate salt Type A can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 6.0, about 9.1, about 13.6, about 15.8, about 18.2, and about 21.8. Crystalline oxalate salt Type B can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 7.7, about 11.8, about 13.7, about 16.7, about 17.7, and about 18.9. The freebase can be characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 11.0, about 11.7, about 14.0, about 15.5, about 18.3, and about 21.3.
A formal, broad salt and polymorph screen was conducted resulting in at least 10 pharmaceutically relevant salts. Most of these exhibit polymorphism that was further characterized as described in the EXAMPLES below. The hydrochloride salt exhibits at least 22 different forms. Form A is the most thermodynamically stable form. Unexpectedly, however, Form J was isolated on up to ~100 g scale when isolated from HCl/EtOAc. Thus, appropriate control of the manufacturing process is critical to obtain the desired salt and polymorph.
The current standard process for making 18-MC (isolation from dioxane/HCI) ensures the controlled isolation of Form A.
The invention is further described in detail by reference to the following experimental examples. These examples are provided for the purpose of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.
Applicant performed an extended salt screening and collected data of alternative salts.
18-MC Freebase was first isolated from 18-MC HCl salt and then used for salt screening. In the screening, a total of 100 experiments were performed using 20 acids and 5 solvents. Resulting solids were characterized by X-ray powder diffraction (XRPD). Based on XRPD comparison results, new forms were then characterized by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), proton nuclear magnetic resonance (1H NMR) high-performance liquid chromatography (HPLC) and/or ion chromatography (IC). As the results showed, a total of 16 salt forms were discovered from screening and form re-preparation, including gentisate Type A, HBr salt Types A and B, besylate Types A and B and napadisylate Types A, B, C′ and D. XRPD patterns are shown in
To summarize, a total of 16 new salt forms were found and fully characterized in the extended salt screening.
Three batches of starting material of 18-MC HCl salt were characterized by XRPD, TGA, DSC and HPLC/IC. Characterization results are summarized in TABLE 2A and displayed from
As shown in
As shown in
As shown in
A detailed procedure for the preparation of 18-MC Freebase from 18-MC HCl Salt can be found below, and characterization results of prepared freebase batches are summarized in TABLE 2F. Additional data are shown in
For freebase Type A (824509-03-A), the Cl- contents was determined to be less than 0.24%. TGA/DSC curves from
For freebase Type A (824509-21-A), the Cl- contents was determined to be less than 0.15%. TGA/DSC curves from
For freebase Type A (824509-24-A), no Cl- residual in the sample was detected. TGA/DSC curves from
Using prepared freebase Type A (batch 824509-03-A and 824509-24-A) as starting material, a total of 100 experiments of salt screening were conducted with 20 acids and different solvent systems. For the CHCl3 system, a stock solution of freebase was first prepared by dissolving ~150 mg of freebase Type A sample in 3.75 mL of CHCl3. Then the corresponding acids (charge molar ratio of acid/freebase=1:1) were added in 0.5 mL of stock solutions and slurried at RT. For the remaining solvent systems (IPAc, MIBK, 1,4-dioxane, IPA, DCM/EtOAc (1:1, v/v), acetone/H20 (9:1, v/v) and ACN/THF (3:1, v/v)), about 20 mg of freebase Type A sample was weighed into each HPLC vial and mixed with corresponding solid acids (charge molar ratio of acid/freebase=1:1). About 0.5 mL of solvents were added into the vial and the mixture was transferred to slurry at RT. Liquid acids were first diluted with 0.25 mL solvent and then added into freebase solution (freebase in 0.25 mL solvent). After slurry for about 5 days, precipitates were separated by centrifugation and the resulting solids were vacuum-dried at RT overnight (4 to 15 hours). If oil or gel-like samples were obtained after slurry, the samples were transferred to temperature cycling (one cycle: ramp to 50° C. at a rate of 4.5° C./min, keep the temperature at 50° C. for 30 min; cool down to 5° C. at a rate of 0.1° C./min and keep the temperature at 5° C. for 30 min. 4 cycles were conducted). If clear solution was obtained, it was transferred to slurry at 5° C. If it was still clear, the solution was transferred to slurry at -20° C. If there was still no precipitate, the clear solution was transferred to evaporation at RT or anti-solvent addition to induce precipitation. After vacuum drying at RT, all the resulting dry solids were tested by XRPD.
As the XRPD comparison results in TABLE 3A and TABLE 3B shows, a total of 9 salt forms were discovered, including gentisate Type A, HBr salt Types A and B, besylate Types A and B and napadisylate Types A, B, C, and D. XRPD overlay was displayed in
Gentisate Type A (824511-01-C9) was obtained by stirring 8.3 mg gentisic acid in 0.5 mL stock solution of freebase (40 mg/mL, charge molar ratio of acid to freebase was 1:1) in CHCl3 at RT for about 5 days. Resulting solids were isolated by centrifugation and vacuum dried at RT overnight. The XRPD pattern was displayed in
HBr salt Type A (824511-01-E10) was obtained by diluting 11.0 µL HBr (~40% aqueous solution) in 0.25 mL IPA and suspending 19.8 mg freebase in 0.25 mL IPA at RT, then adding acid solution to freebase suspension (charge molar ratio of acid to freebase was 1:1) and slurry at RT for about 5 days. Resulting solids were isolated by centrifugation and vacuum dried at RT overnight. The XRPD pattern was displayed in
HBr salt Type B (824511-01-D10) was obtained by diluting 11.0 µL HBr (~40% aqueous solution) in 0.25 mL 1,4-dioxane and suspending 20.1 mg freebase in 0.25 mL 1,4-dioxane at RT, then adding acid solution to freebase suspension (charge molar ratio of acid to freebase was 1:1) and slurry at RT for about one week. Resulting solids were isolated by centrifugation and vacuum dried at RT overnight. Another batch of HBr salt Type B (824511-10-A1) was prepared using the same method, and the XRPD overlay was displayed in
Napadisylate Type A (824511-30-B7) was obtained by slurry ~20.0 mg freebase and 16.2 mg naphthalene-1,5-disulfonic acid (charge molar ratio of acid to freebase was 1:1) in 0.5 mL acetone/H2O (9:1, v/v) at RT for about one week. Resulting solids were isolated by centrifugation and vacuum drying at RT overnight. The XRPD pattern was displayed in
Napadisylate Type B (824511-36-A7) was obtained by slurry ~20.0 mg freebase and 16.1 mg naphthalene-1,5-disulfonic acid (charge molar ratio 1:1) in 0.5 mL IPA at RT for about 3 days and then transfer to slurry at 50° C. for about 4 days. Resulting solids were isolated by centrifugation and vacuum drying at RT overnight. The XRPD pattern was displayed in
Napadisylate Type C (824511-36-B7) was obtained by slurry ~20.0 mg freebase and 16.1 mg naphthalene-1,5-disulfonic acid (charge molar ratio of acid to freebase was 1:1) in 0.5 mL 1,4-dioxane for about 3 days and then transfer to slurry at 50° C. for about 4 days. Resulting solids were isolated by centrifugation and vacuum drying at RT overnight. The XRPD overlay was displayed in
Napadisylate Type D (824511-44-B1) was discovered in the re-preparation trial of napadisylate Type C by slurry 20.2 mg freebase and 16.0 mg naphthalene-1,5-disulfonic acid (charge molar ratio of acid to freebase was 1:1) in 0.5 mL 1,4-dioxane at RT for 8 days. Resulting solids were isolated by centrifugation and vacuum drying at RT overnight. The XRPD overlay was displayed in
Besylate Type A (824511-30-A10) was obtained by slurry ~20.0 mg freebase and 8.9 mg benzenesulfonic acid (charge molar ratio of acid to freebase was 1:1) in 0.5 mL DCM/EtOAc (1:1, v/v) at RT for about 4 days and transferred to stir at 50° C. for about 1 day, then transferred to stir at -20° C. for about 3 days. Resulting solids were isolated by centrifugation and vacuum drying at RT overnight. Another batch of besylate Type A (824511-35-A1) was prepared using the same method and characterized. The XRPD overlay was displayed in
Besylate Type B (824511-36-A10) was obtained by slurry ~20.0 mg freebase and 8.7 mg benzenesulfonic acid (charge molar ratio of acid to freebase was 1:1) in 0.5 mL IPA at RT overnight and then transferred to slurry at 50° C. for about 4 days. Resulting solids were isolated by centrifugation and vacuum drying at RT overnight. The XRPD result was displayed in
Detailed procedure of freebase isolation is summarized in TABLE 5A.
TABLE 5B summarizes the salts and salt forms produced and the corresponding reports with additional details.
For XRPD analysis, a PANalytical Empyrean and X′ Pert3 X-ray powder diffract meter was used. The XRPD parameters used are listed in TABLE 5C.
TGA data was collected using a TA Q5000/Discovery TGA 5500 from TA Instruments. DSC was performed using a Discovery DSC 2500 from TA Instruments. Detailed parameters used are listed in TABLE 5D.
Agilent 1260 with DAD detector was utilized and detailed chromatographic condition is listed in TABLE 5E.
Time (min)
%B
Thermo Scientific™ Dionex™ Aquion™ Ion Chromatography (IC) System 1100 with conductivity detector was utilized and detailed chromatographic condition is listed in TABLE 5F.
Solution 1H NMR was collected on a Bruker 400 MHz NMR Spectrometer using DMSO-d6 as the solvent.
An extended salt screening was performed for compound 18-MC using prepared freebase material. As the results showed, a total of 9 salt forms were found and characterized, including gentisate Type A, HBr salt Types A and B, besylate Types A and B and napadisylate Types A, B, C, and D.
Starting from HCl salt materials with different forms, a total of 100 polymorph screening experiments was performed using different crystallization methods including salt formation by liquid vapor diffusion/slurry at elevated temperature, evaporation at RT/high temperatures, slurry and reverse anti-solvent addition at different temperatures, slow/crash cooling, polymer induced crystallization and grinding. All the resulting solids were isolated for XRPD test, and new forms were further characterized by TGA, DSC, 1H NMR and HPLC/ IC. As the results showed, 11 new forms (HCl salt Types L to V) were discovered. Further identification results showed that HCl salt Types M, P, Q, R, S, T, and U were solvates (which converted to HCl salt Type A after desolvation), HCl salt Types L, N, O,, and V were metastable forms (which converted to HCl salt Type A after air drying or room temperature (RT) storage). Characterization results of different HCl salt forms were summarized in TABLE 6A to 6C. Inter-conversion relationship among different forms were displayed in
To summarize, an additional polymorph screening was performed for 18-MC HCl salt. As the results showed, 11 new forms were obtained. Among the forms obtained, HCl salt Type A was thermodynamically more stable than other anhydrates at RT.
&: Acid to freebase.
#: Exposure to ambient conditions (~50%RH).
&: Acid to freebase.
#: RT storage.
Using freebase Type A (824509-03-A), HCl salt Type A (824509-01-A and 824509-11-B), the low crystallinity HCl salt (824509-12-E) and amorphous (824509-20-A) as the starting material, a total of 100 polymorph screening experiments were conducted via various crystallization methods. Results of polymorph screening is summarized in TABLE 7A, TABLE 7B and TABLE 7C. XRPD results showed that a total of 11 forms (HCl salt Types L to V) were obtained in polymorph screening and characterization. The screening details are further detailed below.
HCl salt Type M (824509-05-A4) was obtained by salt formation through liquid vapor diffusion in 1,4-dioxane/MTBE. The detailed procedure was as follows: dissolve 20.0 mg freebase in 1.0 mL 1,4-dioxane at RT in a 4-mL vial. Dilute 1 mL HCŀEtOAc solution (conc. of HCl was 2 mol/L) by 3 mL MTBE in a 20-mL vial. Put the uncapped 4-mL vial into the 20-mL vial and keep the capped 20-mL vial at RT for about 4 days. Solids were isolated by air dried for characterization. The XRPD result is displayed in
In
HCl salt Type P (824509-10-A3) was obtained by adding 1.0 mL 2,2,2-trifluoroethanol solution (conc. of HCl salt was ~20 mg/mL) in 9.0 mL MIBK directly at RT and stir at RT for 4 days. Since no solids precipitated after RT stirring, the clear solution was transferred to stir at 5° C. overnight, -20° C. overnight and evaporation at RT for about 3 weeks. The resulting solids were centrifuged and air dried for characterization. The XRPD result is displayed in
The VT-XRPD result in
HCl salt Type Q (824509-16-A4) was obtained by slurrying 20.3 mg HCl salt Type A (824509-12-E) in 0.5 mL isopentanol at 60° C. for about 4 days. Resulting solids were isolated by centrifugation and air drying. HCl salt Type R (824509-16-A3) was obtained from 2-BuOH via the same method. XRPD results were shown in
For HCl salt Type Q (824509-16-A4), TGA/DSC results in
For HCl salt Type R (824509-16-A3), TGA/DSC results in
HCl salt Type S (824509-25-A2) was obtained by slurrying 19.7 mg amorphous HCl salt in 0.5 mL cyclohexanone at -20° C. for about 4 days. The resulting solids were isolated by centrifugation and the wet cake was tested by XRPD. The Type S sample turned to be gel like after air drying at RT It was re-prepared (824509-29-A3) by slurrying amorphous HCl salt in cyclohexanone at -20° C. for 7 days, and vacuum drying at RT for ~4 hours. The XRPD results are displayed in
XRPD results in
HCl salt Type T (824509-39-A1) was obtained by slurrying 40 mg HCl salt amorphous in 0.5 mL propionic acid at -20° C. for 4 days and drying at RT with silica gel. The XRPD results are displayed in
XRPD results in
HCl salt Type U (824509-29-B4) was obtained by slurry 40 mg HCl salt amorphous in 0.5 mL benzylalcohol/methyl acetate (1:1, v/v) at -20° C. for 3 days, and isolated by centrifugation and vacuum dried at 50° C. ~3 hrs, and this sample was used for characterization. The XRPD results were displayed in
XRPD results in
HCl salt Type V (824509-25-A4) was obtained by slurry 20.0 mg HCl salt amorphous in 0.5 mL trifluoroethanol/m-xylene (1:1, v/v) at -20° C. overnight, then the clear solution was transferred to anti-solvent addition (EtOAc, 4.5 mL) at RT and stir at 5 and -20° C. to produce more solids for 5 days. Resulting solids were isolated by centrifugation and air dried in desiccator at RT with silica gel for ~3 hrs. The XRPD overlay of the wet sample was displayed in
Sample (824509-05-A1,
XRPD pattern in
HCl salt Type A+N (824509-10-A1,
HCl salt Type A+O (824509-10-A2,
A summary of information about HCl salt Type A to K is shown in TABLE 15.
An additional polymorph screening was performed for 18-MC HCl salt. As the characterization results showed, 11 new forms were obtained. Among the forms obtained, HCl salt Type A was still the most thermodynamically stable form at RT based on desolvation and physical form conversion data.
18-MC sulfate Type A was first obtained as described in Example 1. Polymorph screening of 18-MC sulfate was performed to better understand polymorphism of the salt.
Sulfate material was first prepared using 18-MC freebase and used as starting material for polymorph screening. In the screening, different crystallization methods including temperature cycling and slurry conversion at different temperatures were used, and a total of 30 experiments were conducted. Solids from screening were isolated for XRPD. New forms were further characterized by TGA, DSC and HPLC/IC. As the characterization and identification results showed, five new forms (sulfate Type B-F) were discovered. Identification results indicated that sulfate Type A and Type F were anhydrates, Type D was a hydrate, Type E was a hydrate or anhydrate, Type B was an ACN solvate (converted to sulfate Type E after storage) and Type C was a metastable form (converted to sulfate Type A after air drying). Characterization results are summarized in TABLE 15 and XRPD patterns of different forms are displayed in
To summarize, a brief polymorph screen was performed and a total of six forms of the sulfate were discovered.
#: Determined by HPLC/IC.
&: Identified in Example 1.
&&: No further identification was performed due to the failure of re-preparation.
The preparation procedure of sulfate Type A (824511-04-A) was as follows: 2 g of freebase Type A (824509-01-A was weighed, 20 mL of EtOAc was added to prepare a suspension. 1.36 mL of 4 M H2SO4 was diluted by 20 mL of EtOAc. The diluted H2SO4 solution was added into the suspension under magnetic stirring dropwise. The sample was transferred to temperature cycling (50° C.~5° C., 3 cycles, one cycle: heat to 50° C. at 4.5° C./min, isothermal at 50° C. for 30 min; cool to 5° C. at 0.1° C./min, isothermal at 5° C. for 30 min; keep slurry at 5° C. at last). After XRPD confirmation, the solids were isolated by vacuum filtration and vacuum dried at RT for one day. As a result, about 1.77 g of sulfate Type A (824511-04-A) was obtained.
The XRPD pattern of prepared sulfate Type A in
VT-XRPD results in
Approximate solubility values of sulfate Type A (824511-04-A) were estimated in 10 solvents to guide the solvent selection in the polymorph screening, with results summarized in TABLE 16B.
XPRD data for sulfate Type A is in TABLE 16C.
Using prepared sulfate Type A (824511-04-A, anhydrate) as the starting material, a total of 30 polymorph screening experiments were conducted via various crystallization methods. Results of polymorph screening is summarized in TABLE 17A. Results showed that a total of 6 forms (sulfate Type A~F) were obtained in the polymorph screening, including 2 anhydrates (sulfate Type A/F), 1 hydrate (sulfate Type D), 1 solvate (sulfate Type B), and 1 metastable form (sulfate Type C). Sulfate Type E was a hydrate or anhydrate, while no further identification was conducted due to the failure of re-preparation trials. Characterization data of obtained forms was summarized in TABLE 15 and the XRPD overlays of these forms were displayed in
Sulfate Type D (824511-12-A17) was obtained by slurrying 20.3 mg sulfate Type A (824511-04-A) in THF/H2O (981:19, v/v, aw≈0.2) at RT for about one week and isolating solids by centrifugation and air drying. The XRPD result is displayed in
Sulfate Type E (824511-11-A3-0315) was obtained by storing sulfate Type B (824511-11-A3) at RT in a sealed vial for ~12 days. The XRPD result was displayed in
Sulfate Type B (824511-11-A3) was obtained by slurrying sulfate Type A (824511-04-A) in ACN with temperature cycling (suspend 20.3 mg sulfate in 0.5 mL ACN at RT and then transfer to temperature cycling (3 cycle): ramp to 50° C. at a rate of 1° C./min, isothermal for 120 min, cool to 5° C. at a rate of 0.1° C./min, isothermal for 120 min). Resulting solids were isolated by centrifugation and air drying. The XRPD result is displayed in
Sulfate Type C (824511-11-A4) was obtained by slurrying sulfate Type A (824511-04-A) in 1,4-dioxane with temperature cycling (suspend 20.3 mg sulfate in 0.5 mL 1,4-dioxane at RT and then transfer to temperature cycling (3 cycle): ramp to 50° C. at a rate of 1° C./min, isothermal for 120 min, cool to 5° C. at a rate of 0.1° C./min, isothermal for 120 min). Resulting solids were isolated by centrifugation and air drying. The XRPD result is displayed in
A brief polymorph screening of 18-MC sulfate was performed and a total of six salt forms were obtained.
18-MC oxalate Type A was first obtained as described in Example 1. Polymorph screening of 18-MC oxalate was performed to better understand polymorphism of the salt.
Oxalate material was prepared using 18-MC freebase and used as starting material for polymorph screening. X-ray powder diffraction (XRPD) result showed that the prepared oxalate displayed a different XRPD pattern from oxalate Type A, which was assigned as oxalate Type B, and further characterized by TGA, DSC and HPLCIC. Based on the limited weight loss in TGA and neat DSC before decomposition, both oxalate Type A and oxalate Type B were speculated as anhydrates.
Using prepared oxalate Type B as the starting material, a total of 30 polymorph screening experiments were conducted with different crystallization methods including temperature cycling and slurry conversion at different temperatures. Solids from the screening experiments were isolated for XRPD testing. As the results showed, only oxalate Type B was obtained. Characterization results of oxalate Type A and B were summarized in TABLE 18 and XRPD patterns of the two forms were displayed in
To summarize, a brief polymorph screening experiments were performed and only oxalate Type B was observed.
#: Determined by HPLC/IC.
Preparation procedure of oxalate was as follows: weigh 2.0 g of freebase Type A (824509-03-A) and 0.7 g of oxalic acid dihydrate into 500 mL of EtOAc and transfer the suspension to slurry at RT for ~5 days. Resulting solids were isolated by vacuum filtration and vacuum drying at RT overnight. About 2.4 g of oxalate sample (824511-04-C) was obtained. XRPD comparison results in
Approximate solubility of oxalate Type B (824511-04-C) was estimated in 10 solvents to guide the solvent selection in polymorph screening of oxalate, and the results were summarized in TABLE 19C.
Procedure: weigh ~2 mg solids into each 3-mL glass vial, add in corresponding solvent stepwise and sonicate or oscillate to see if solids dissolved completely. Stop adding solvent till the solids dissolves or total volume reaches 1.0 mL. Calculate the approximate solubility based on solvent volume.
Using oxalate Type B (824511-04-C) as the starting material, a total of 30 experiments were conducted using different crystallization methods. XRPD results showed that oxalate Type B was the only form obtained from the screen. The results of polymorph screening are summarized in TABLE 20A, and only oxalate Type B was observed.
Temperature cycling experiments were conducted in 5 solvent systems. About 20 mg of starting material (824511-04-C) was suspended in an HPLC vial with 0.5 mL of corresponding solvents listed in TABLE 20B. Cycling procedure: ramped to 50° C. at a rate of 4.5° C./min, kept the temperature at 50° C. for 30 min; cooled down to 5° C. at a rate of 0.1° C./min and kept the temperature at 5° C. for 30 min. After three cycles, the obtained solids were isolated by centrifugation and air dried for XRPD analysis. Results were summarized in TABLE 20B, and only oxalate Type B was observed.
Slurry conversion experiments were conducted at RT in 20 different solvent systems. About 20 mg of starting material (824511-04-C) was suspended in an HPLC vial with 0.5 mL of corresponding solvents listed in TABLE 20C. If the solid dissolved then more solids were added until a suspension was obtained. The suspensions were stirred at RT using magnetic stirring with a speed of ~750 rpm. After about 5 days, the remaining solids were isolated by centrifugation and air dried for XRPD analysis. If a clear solution was obtained, the sample was cooled to 5° C. If it was still clear, the solution was cooled to -20° C. If there was still no precipitate, the solution was allowed to evaporate in an open vial at RT to obtain solids. Results are summarized in TABLE 20C, and only oxalate Type B was observed.
Slurry conversion experiments were conducted at 50° C. in 5 solvent systems. About 20 mg of starting material (824511-04-C) was suspended in an HPLC glass vial with 0.5 mL of corresponding solvents listed in TABLE 20D. Samples were stirred at 50° C. for 5 days. If there was no solid after the slurry, the sample was cooled to 5° C. Resulting solids were isolated by centrifugation and air dried for XRPD analysis. Results are summarized in TABLE 20D, and only oxalate Type B was observed.
XPRD data for oxalate Type A is shown in TABLE 20E.
A brief polymorph screening of 18-MC oxalate was performed and one new form was obtained.
18-MC mesylate Type A was first obtained as described in Example 1. Polymorph screening of 18-MC mesylate was performed to better understand polymorphism of the salt.
Mesylate material was first prepared using 18-MC freebase and used as starting material for polymorph screening. In the screening, different crystallization methods including temperature cycling and slurry conversion at different temperatures were used, and a total of 30 experiments were conducted. Solids from the screening were isolated for XRPD testing. As the results showed, two new forms, assigned as mesylate Types B and C, with weak crystallinity were observed. Attempts were made to reprepare the two new forms for further characterization. However, they were not found to be physically stable at ambient conditions and easily converted to gels/oils. Additional data were not collected. XRPD patterns of different forms are displayed in
To summarize, brief polymorph screening experiments were performed and a total of three forms of mesylate were discovered.
#: Calculation based on 1 H NMR result.
Mesylate Type A (824511-23-B) was prepared as follows: 1.0 g of freebase (824509-21-A) was weighed into a 20-mL glass vial. Approximately 5 mL of EtOAc was added to prepare a suspension. Methanesulfonic acid (264.6 mg) was mixed with 5 mL of EtOAc, and the acid solution was added to the freebase suspension dropwise while stirring with a magnetic stirrer. The sample became gel like, which was then stirred at RT for 3 days. The sample was then used for a temperature cycling experiment to improve crystallinity (50° C.~5° C., 2 cycles, one cycle: heat to 50° C. at 4.5° C./min, isothermal at 50° C. for 30 min; cool to 5° C. at 0.1° C./min, isothermal at 5° C. for 30 min). After XRPD confirmation on a slurry sample, the sample was centrifuged and vacuum dried at RT overnight. As a result, 1.11 g of mesylate Type A (824511-23-B) was obtained. The XRPD pattern of prepared mesylate Type A and reference is shown in
VT-XRPD results in
The approximate solubility of mesylate Type A (824511-23-B) was estimated in 10 solvents to guide the solvent selection in polymorph screening of the mesylate, with results summarized in TABLE 22C.
Using mesylate Type A (8245511-23-B) as the starting material, a total of 30 experiments of polymorph screening were conducted using different methods. Characterization results showed that a total of 3 forms (mesylate Types A, B, and C) were obtained, including one anhydrate (mesylate Type A) and two metastable forms (mesylate Types B and C). Since mesylate Types B and C were metastable forms and could not be re-prepared, additional data could not be collected. Results of the screening experiments are summarized in TABLE 23A. Characterization data of obtained forms was summarized in TABLE 21 and the XRPD overlays of these forms were displayed in
Temperature cycling experiments were conducted in 5 solvent systems. About 20 mg of starting material (824511-23-B) was suspended in an HPLC vial with 0.5 mL of corresponding solvents listed in TABLE 23B. Cycling procedure: ramped to 50° C. at a rate of 4.5° C./min, kept the temperature at 50° C. for 30 min; cooled down to 5° C. at a rate of 0.1 C/min and kept the temperature at 5° C. for 30 min. After three cycles, store the samples at 5° C. before isolation by centrifugation and air drying for XRPD analysis. Results are summarized in TABLE 23B. Results showed that mesylate Type A and amorphous were obtained.
#: Solid was obtained after -20° C. stirring and it dissolved quickly during solid isolation for XRPD test at RT.
Slurry conversion experiments were conducted at RT in 20 different solvent systems. About 20 mg of starting material (824511-23-B) was suspended in an HPLC vial with 0.5 mL of corresponding solvents listed in TABLE 23C. If the solid was dissolved then more solids were added until a suspension was obtained. The suspension was slurried at RT using magnetic stirring with the speed of ~750 rpm. After ~5 days, the remaining solids were isolated by centrifugation and air dried for XRPD analysis. If a clear solution were obtained, the sample was slurried at 5° C. If it remained clear, the sample was slurried at -20° C. If there was still no precipitate, the solution was evaporated in an open vial at RT. Results are summarized in TABLE 23C. Results showed that mesylate Type A, Type B, Type C, amorphous, gel and oil were obtained.
Slurry conversion experiments were conducted at 50° C. in 5 solvent systems. About 20 mg of starting material (824511-23-B) was suspended in an HPLC glass vial with 0.5 mL of corresponding solvents listed in TABLE 23D and stirred at 50° C. If there was no solid observed, the sample was slurried at 5° C. The resulting solids were isolated by centrifugation and air dried for XRPD analysis. Results are summarized in TABLE 23D. Results showed that mesylate Type A, amorphous, oil/gel were obtained.
#: Solid was obtained after -20° C. stirring and it dissolved quickly during solid isolation for XRPD test at RT.
The detailed procedures and the results of re-preparation trials of mesylate are summarized in TABLE 23E.
A brief polymorph screening of 18-MC mesylate was performed and a total of three salt forms were obtained.
18-MC HBr salt Type A and Type B were obtained as described in Example 1. Polymorph screening of 18-MC HBr salt was performed to have better understand polymorphism of the salt.
The HBr salt was prepared using 18-MC freebase and used as the starting material for polymorph screening. In the screening, different crystallization methods including temperature cycling and slurry conversion at different temperatures were used, and a total of 30 experiments were conducted. Solids from screening were isolated for XRPD testing. New forms were further characterized by TGA, DSC, 1H NMR and HPLC/IC. As the characterization results showed, two new forms (HBr salt Types C and D) were discovered. Identification results indicated that HBr salt Type A was an anhydrate, HBr salt Type B was a hydrate or solvate, HBr salt Type C was a hydrate or anhydrate and HBr salt Type D was a solvate. HBr salt Types B, C, and D could convert to HBr salt Type A after storage or heating experiments. Characterization results are summarized in TABLE 24 and XRPD patterns of different forms are displayed in
To summarize, a brief polymorph screening experiments were performed and a total of four forms of HBr salt were discovered.
#: Exothermic signal.
&: Determined by HPLC/IC.
Preparation procedure of HBr salt (824511-29-B) was as follows: 1.0 g of freebase (824509-24-A) was weighed into a 20-mL glass vial, and 7 mL of IPA were added to prepare a suspension. 554.8 mg of 40% HBr was added to 5 mL of IPA. The acid solution was added to the freebase suspension dropwise while stirring with a magnetic stirrer. The clear solution was slurried at RT for 3 days. The resulting sample was centrifuged and vacuum dried at RT overnight. About 1.08 g of HBr salt (824511-29-B) was obtained and it was consistent with HBr salt Type A reference (824511-01-E10), described in EXAMPLE 1. The XRPD result is shown in
Approximate solubility of HBr salt Type A (824511-29-B) was estimated in 10 solvents to guide the solvent selection in polymorph screening of HBr salt, with data summarized in TABLE 25B.
Using HBr salt Type A (824511-29-B) as the starting material, a total of 30 polymorph screening experiments were conducted via various crystallization methods. Results of the polymorph screening are summarized in TABLE 25C. The XRPD results showed that two new forms (HBr salt Types C and D) were obtained. Characterization data of the forms are summarized in TABLE 24 and the XRPD overlay of these forms are displayed in
HBr salt Type A was identified as an anhydrate. Characterization data on Type A reference was shown above.
HBr salt Type B (824511-01-D10) was obtained as described in Example 1 by slurring freebase and HBr (charge molar ratio 1:1) in 1,4-dioxane at RT. Another batch of HBr salt Type B (824511-10-A1) was prepared using the same method for characterization, and the XRPD results are displayed in
HBr salt Type C (824511-39-A3) was obtained by slurrying 20.3 mg HBr salt Type A (824511-29-B) in 0.5 mL DCM at RT overnight. Since no solids precipitated, the clear solution was transferred to stir at 5° C. for about two weeks and then transferred to evaporation to dryness in desiccator at RT with silica gel. The XRPD result is displayed in
XRPD results in
HBr salt Type D (824511-39-A12) was obtained by slurrying 20.0 mg HBr salt Type A (824511-29-B) in 0.5 mL THF:H2O (924:76, v/v, aw≈0.6) at RT overnight. Since no solids precipitated, the clear solution was transferred to stir at 5° C. for about two weeks and then transferred to evaporation to dryness in desiccator at RT with silica gel. The XRPD result is displayed in
XRPD results in
A brief polymorph screening of 18-MC HBr salt was performed and a total of four salt forms were obtained.
18-MC tosylate Type A and Type B were first obtained as described in Example 1. Polymorph screening of 18-MC tosylate was performed to better understand polymorphism of the salt.
Tosylate material was first prepared using 18-MC freebase and used as the starting material for the polymorph screening. In the screening, different crystallization methods including temperature cycling and slurry conversion at different temperatures were used, and a total of 30 experiments were conducted. Solids from screening were isolated for XRPD testing. New forms were further characterized by TGA, DSC, 1H NMR and HPLC. As the characterization and identification results showed, seven new forms (tosylate Types C, D, E, F, G, H, and I) were discovered. Results indicated that tosylate Types A, B, and C were hydrates, Types D and I were anhydrates, Types E, F, and G were solvates and Type H was a metastable form. Characterization results are summarized in TABLE 26 and XRPD patterns of different forms are displayed in
To summarize, a brief polymorph screen was performed and a total of nine forms of the tosylate salt were discovered.
#: Determined based on 1H NMR data.
Preparation procedure of tosylate sample was as follows: 1.0 g of freebase (824509-21-A) was weighed into a 20-mL glass vial. 4 mL of THF was added to prepare a suspension. 527.5 mg of p-toluenesulfonic acid was dissolved in 4 mL of THF. The acid solution was added into the freebase suspension dropwise with stirring. The resulting clear solution was allowed to stir at 5° C. for 4 days. Solids were isolated from suspension by centrifugation and vacuum dried at RT overnight. As a result, about 1.23 g of tosylate (824511-23-A) was obtained and it showed different XRPD pattern from tosylate Type A or B, and was assigned as tosylate Type C. After storing tosylate Type C (824511-23-A) at RT for about 2.5 month, a form change to tosylate Type B (renamed as 824511-23-A-0628) was observed (
Approximate solubility of tosylate Type B (824511-23-A-0628) was estimated in 40 solvents to guide the solvent selection in polymorph screening of tosylate, with data summarized in TABLE 27B.
&: little solid in the vial. Procedure: weigh ~2 mg solids into each 3-mL glass vial, add in corresponding solvent stepwise and sonicate or oscillate to see if solids dissolved completely. Stop adding solvent till the solids dissolves or total volume reaches 1.0 mL. The above procedure was conducted at corresponding temperature. Calculate the approximate solubility based on solvent volume.
Using tosylate Type B (824511-23-A-0628) as the starting material, a total of 30 polymorph screening experiments were conducted via various crystallization methods. Results of polymorph screening are summarized in TABLE 27C. XRPD results showed that a total of nine forms (tosylate Types A to I) were obtained from the polymorph screening and characterization, including three hydrates (tosylate Types A, B, and C), two anhydrate (tosylate Types D and I), three solvates (tosylate Types E, F, and G) and one metastable form (tosylate Type H). Characterization data of obtained forms is summarized in TABLE 26 and the XRPD overlays of these forms are displayed in
Tosylate Type A was first obtained in a previous experiment. For batch 824528-06-A3-0809, it was obtained by air drying of tosylate Type H (824528-06-A3, slurry 40.2 mg tosylate (824511-23-A-0628) in 0.5 mL IPA/EtOAc (1:4, v/v) at 50° C. for 3 days) at RT for ~3 hours. The XRPD result is displayed in
VT-XRPD results in
XRPD results in
Tosylate Type C (824511-23-A) was obtained by slurrying 1.0 g freebase and 527.5 mg p-toluenesulfonic acid (charge molar ratio 1:1) in 8 mL THF at 5° C. for ~4 days. Resulting solids were isolated by centrifugation and vacuum drying at RT overnight. The XRPD result is displayed in
VT-XRPD result in
XRPD result in
Tosylate Type E (824528-05-A9) was obtained by slurrying 19.9 mg tosylate Type B (824511-23-A-0618) in 0.5 mL 1,4-dioxane/n-heptane (9:1, v/v) at 50° C. for ~4 days. Resulting solids were isolated by centrifugation and air drying. The XRPD result is displayed in
XRPD results in
Tosylate Type F (824528-06-B1) was prepared by slurrying 40.3 mg tosylate Type B (824511-23-A-0618) in 0.5 mL CHCl3/n-hexane (1:1, v/v) at 50° C. for ~6 days. Resulting solids were isolated by centrifugation and air drying. The XRPD results are displayed in
XRPD results in
Tosylate Type G (824528-06-A1) was obtained by slurrying 50.2 mg tosylate Type B (824511-23-A-0618) in 0.5 mL anisole at 50° C. for ~3 days. Resulting solids were isolated by centrifugation and air drying. The XRPD results are displayed in
XRPD results in
Tosylate Type H (824528-05-A12) was obtained by slurrying 23.5 mg tosylate Type B (824511-23-A-0618) in 0.5 mL IPA/EtOAc (1:4, v/v) at 50° C. for ~4 days. Resulting solids were isolated by centrifugation and air drying. The XRPD result is displayed in
A brief polymorph screening of 18-MC tosylate was performed and a total of nine salt forms were obtained.
18-MC besylate Type A and Type B were obtained as described in Example 1. Polymorph screening of 18-MC besylate was performed to better understand polymorphism of the salt.
The besylate material was first prepared using 18-MC freebase and then used as starting material for polymorph screening. In the screen, different crystallization methods, including temperature cycling and slurry conversion at different temperatures, were used, and a total of 30 experiments were conducted. Solids from screening were isolated for X-ray powder diffraction (XRPD) testing. From the results of characterization and form identification, a total of three besylate forms were obtained, including two anhydrates, besylate Types B and C, and one hydrate, besylate Type A. Characterization results are summarized in TABLE 30 and XRPD patterns of different forms are displayed in
To summarize, a brief polymorph screen was performed and a total of three forms of besylate were discovered.
#: Calculation based on 1H NMR result.
Preparation procedure of the besylate (824511-44-C2) was as follows: 1.0 g of freebase (824509-24-A) was weighed into a 20-mL glass vial along with 436.6 mg of benzenesulfonic acid. Then, 6 mL of IPA was added to the vial to produce a suspension which was slurried at RT for ~7 days. The resulting sample was centrifuged and vacuum dried at RT for 6 hours. As the results (FIGURE ) showed, about 1.15 g of besylate Type B (824511-44-C2) was obtained.
Approximate solubility of besylate Type B (824511-44-C2) was estimated in 38 solvents to guide the solvent selection in polymorph screening of besylate, with results shown in TABLE 31.
Using besylate Type B (824511-44-C2) as the starting material, a total of 30 polymorph screening experiments were conducted via various crystallization methods. Results of polymorph screening is summarized in TABLE 32A. XRPD results showed that a total of 3 forms (besylate Types A, B, and C) were obtained from the screening and characterization studies, including two anhydrates (besylate Types B and C) and one hydrate (besylate Type A). Characterization data of obtained forms is summarized in TABLE 30 and the XRPD overlays of these forms are displayed in
Besylate Type A (824511-35-A1) was obtained by slurrying 40.2 mg freebase and 17.4 mg benzenesulfonic acid (charge molar ratio of acid to freebase was 1:1) in 0.5 mL DCM/EtOAc (1:1, v/v) at RT for ~2 days. Resulting solids were isolated by centrifugation and vacuum drying at RT overnight. The XRPD results are displayed in
VT-XRPD test was performed using another batch of besylate Type A (824529-04-A5). As the results displayed in
Besylate Type B (824511-44-C2) was prepared by slurrying 1.0 g freebase and 436.6 mg benzenesulfonic acid (charge molar ratio of acid to freebase was 1:1) in 6.0 mL IPA at RT for ~7 days. Resulting solids were isolated by centrifugation and vacuum drying at RT for about 6 hrs. The XRPD result of besylate Type B (824511-44-C2) is shown in
VT-XRPD results in
A brief polymorph screen of 18-MC besylate was performed and a total of three polymorphs were obtained.
Throughout this application, various publications, including United States patents, are referenced by author and year and patents by number. Full citations for the publications are listed below. The disclosures of these publications and patents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
The invention has been described in an illustrative manner, and it is to be understood that the terminology, which has been used is intended to be in the nature of words of description rather than of limitation.
Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention can be practiced otherwise than as specifically described.
| Number | Date | Country | |
|---|---|---|---|
| 63317632 | Mar 2022 | US |
