LSD salt crystal morphology

Abstract

The present invention provides polymorphs of lysergic acid diethylamide (LSD) in crystalline salt form, and pharmaceutical formulations of polymorphs of crystalline salt form LSD containing pharmaceutically acceptable excipients. [Solution] A crystalline form of LSD containing a D-LSD free base or a D-LSD free base and an acid is provided.

Description

[Technical Field]

[0001] Background of the Invention 1. Technical field This invention relates to a composition in the form of a salt crystal ((crystal form)) of lysergic acid diethylamide (LSD Regarding ) [Background technology]

[0002] 2.Background technology Lysergic acid diethylamide (LSD) was synthesized by Albert Hofmann in 1938. It is a hallucinogenic drug. LSD is generally thought to cause alterations in the serotonin system in users. It has the effect of altering thoughts, emotions, and awareness of the environment. LSD is 5-HT1A. Shadow on 5-HT2A, 5-HT2B, 5-HT2c, 5-HT5A, and 5-HT6 receptors It can have an effect, which may increase glutamate release in the cerebral cortex. LSD It can be manufactured in crystalline form, but is then converted into a liquid, or into tablets, capsules, gelatin, etc. It is formed in gelatin squares or absorbed into paper.

[0003] LSD is used as a safe therapeutic treatment for overcoming anxiety, depression, and addiction. It is being used to improve an individual's mental health and help them overcome their problems. It can be useful in enabling a view of the overall picture. For example, one study, LSD disrupts rigid thought patterns and personal feelings such as frankness, optimism, and mood. We discovered that the increase in emotion can be altered.

[0004] The crystal structure of LSD bound to 5-HT2B was recently discovered. Wacker, et al. (Cell, January 26, 2018) showed that there was conformational rearrangement in the receptor to accommodate LSD. Furthermore, we demonstrated conformational selectivity for the major diethylamide moiety of LSD.

[0005] In some cases, a single drug exists in one or more distinct crystalline forms (polymorphs). It may exist. Certain crystalline forms of drugs provide stability and good handling during processing. This may become desirable. Vippangunta, et al. (Adv Drug Deliv Rev. 2001 May 16;48(1):3-2 6.) From phase transitions such as polymorphic interconversion, desolvation of solvates, hydrate formation, and crystallization Conversion to an amorphous form can occur during various compounding processes, affecting the dissolution rate of the drug and It states that transport characteristics can be altered. Specifically, various polymorphic forms of pharmaceuticals are, for example, For example, particle size, filtration rate, hygroscopicity, ability to pulverize into fine powder, stability, dissolution rate, dispersibility in powder, and Polymorph screening can have various properties related to bioavailability. This can facilitate the identification of drug polymorphs with the most favorable solid state and pharmacological profile. This is because the polymorphic morphology profile can differ from that of the free base to various solid crystalline salt forms. Therefore, it is especially important. Furthermore, the crystalline form is ex vivo and in This can affect vivo stability, targeting, solubility, dissolution rate, and bioavailability. The selection of the optimal polymorph is based on factors such as low water solubility, slow dissolution in gastrointestinal media, low permeability, and initial It is possible to improve the in-body performance of compounds that have inherent barriers to drug delivery, such as multi-pass metabolism, within the body. (Yadav, et al. Indian J Pharm Sci, 2009, 71 (4): 359-370).

[0006] As LSD is gaining momentum as a useful therapeutic agent for the treatment of psychiatric health indications , various formulations are being developed for indication-appropriate administration. Since various polymorphic forms of the LSD salt form have not been evaluated, the formulations currently under development may not be optimal for their intended usage. Therefore, there is still a need for the identification and characterization of LSD polymorphic forms and the identification of polymorphic forms of the crystalline salt form of LSD . SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0007] Summary of the Invention The present invention provides polymorphic forms of lysergic acid diethylamide (LSD) in crystalline salt form .

[0008] The present invention also provides pharmaceutical formulations of polymorphic forms of LSD in crystalline salt form, including pharmaceutically acceptable excipients .

[0009] In one embodiment, the present invention provides polymorphic forms of LSD free base

[0010] In one embodiment, the present invention provides polymorphic forms of the salt form of LSD

[0011] In one embodiment, the salt form of LSD is a salt formed from LSD and 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid , 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid , D-ascorbic acid, L-aspartic acid, D-aspartic acid, benzenesulfonic acid , benzoic acid, (+)-borneolic acid, (-)-borneolic acid, (+)-camphor-[[]] ​​10-sulfonic acid, (-)-camphor-10-sulfonic acid, capric acid (decanoic acid), Caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, citric acid, citric acid Cramic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, Fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, L-glucoheptonic acid D-gluconic acid, L-gluconic acid, D-glucuronic acid, L-glucuronic acid, L-gluta Minic acid, D-glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, bromide Hydrogen acid, hydrochloric acid, isobutyric acid, D,L-lactic acid, D-lactic acid, L-lactic acid, lactobionic acid, Lauric acid, maleic acid, L-malic acid, D-malic acid, malonic acid, D,L-mandelic acid D-mandelic acid, L-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid Nitric acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid Tincture, pamoic acid, phosphoric acid, proprionic acid, L-pyroglutamic acid D-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, L -Tartaric acid, D-Tartaric acid, Mesotartaric acid, Thiocyanic acid, Paratoluenesulfonic acid, Undecyl It contains an acid selected from lentic acid and xinafoic acid.

[0012] Description of the drawing Other advantages of the present invention, when considered in conjunction with the accompanying drawings, refer to the detailed description below. It is therefore better understood and easily recognized. [Brief explanation of the drawing]

[0013] [Figure 1] This is an XPRD diffractogram of D-LSD naphthalene-2-sulfonate. [Figure 2]This is an XRPD diffractogram of D-LSD tartaric acid (+L) hemisalt. [Figure 3] This is an XRPD diffractogram of D-LSD maleate form A. [Figure 4] This is an XRPD diffractogram of D-LSD maleate form B. [Figure 5] This is an XRPD diffractogram of D-LSD xinafoate form A. [Figure 6] This is an XRPD diffractogram of D-LSD xinafoate form A'. [Figure 7] This is an XRPD diffractogram of D-LSD phosphate form A. [Figure 8] This is the XRPD diffractogram of D-LSD naphthalene-1,5-disulfonic acid hemisalt. [Figure 9] This is an XRPD diffractogram of D-LSD oxalate form A. [Figure 10] This is an XRPD diffractogram of D-LSD benzoate form A. [Figure 11] This is an XRPD diffractogram of D-LSD benzoate form B. [Figure 12] This is an XRPD diffractogram of D-LSD fumarate. [Figure 13] This is an XRPD diffractogram of D-LSD fumarate hemisalt. [Figure 14] This is an XRPD diffractogram of D-LSD ascorbic acid (L) salt form A. [Figure 15] This is an XRPD diffractogram of D-LSD ascorbic acid (L) salt form B. [Figure 16] This is an XRPD diffractogram of D-LSD D-tartrate. [Figure 17] This is an XRPD diffractogram of D-LSD hydrochloride form A. [Figure 18] This is an XRPD diffractogram of D-LSD hydrochloride form A'. [Figure 19]This is an XRPD diffractogram of D-LSD hydrochloride form B. [Figure 20] This is an XRPD diffractogram of D-LSD hydrochloride form C. [Figure 21] This is an XRPD diffractogram of D-LSD hydrochloride form D. [Figure 22] This is an XRPD diffractogram of D-LSD hydrochloride form E. [Figure 23] These are XRPD diffractograms of D-LSD free base morphology A (bottom panel) and morphology B (top panel). [Figure 24] This is the molecular structure of D-LSD (free base). [Figure 25] DSC and TGA thermographs of D-LSD benzoate pattern A are shown. [Figure 26] DSC and TGA thermographs of D-LSD benzoate pattern A' are shown. [Figure 27] This is the NMR spectrum of D-LSD free base form B. [Figure 28] These are DSC and TGA thermographs of D-LSD tartrate. [Figure 29] These are DSC and TGA thermographs of D-LSD phosphate form B. [Figure 30] This is the 1H NMR spectrum of D-LSD phosphate form B. [Figure 31] This is the 1H NMR spectrum of D-LSD D-tartrate. [Figure 32] DSC and TGA thermographs of D-LSD phosphate form A are shown. [Figure 33] DSC and TGA thermographs of D-LSD maleate form A are shown. [Figure 34] DSC and TGA thermographs of D-LSD maleate form A (peak at 145°C) and form B (peak at 199°C) are shown. [Figure 35] This is the DVS profile of D-LSD D-tartrate. [Figure 36]This is a DSC thermogram of D-LSD phosphate pattern C. [Figure 37] This is an overlay of the XRPD pattern on the D-LSD phosphate pattern C. [Figure 38] DSC and TGA thermographs of amorphous D-LSD oxalate are shown. [Figure 39] This shows the XRPD pattern of amorphous D-LSD oxalate. [Figure 40] This is a DSC thermogram of D-LSD oxalate pattern B. [Figure 41] This is a DSC thermogram of D-LSD oxalate pattern C. [Figure 42] This is a TGA thermogram of D-LSD oxalate pattern C. [Figure 43] This is a DSC thermogram of D-LSD oxalate pattern E. [Figure 44] This is a TGA thermogram of D-LSD oxalate pattern E. [Figure 45] This is a DSC thermogram of D-LSD oxalate pattern G. [Figure 46] This is a TGA thermogram of D-LSD oxalate pattern G. [Figure 47] The XRPD patterns of D-LSD oxalate are shown in patterns A (bottom), B, C, D, E, F, and G (top). [Figure 48] This is the XRPD pattern of amorphous D-LSD phosphate. [Figure 49] This is a DSC thermogram of amorphous D-LSD phosphate. [Figure 50] This is a DSC thermogram of D-LSD phosphate pattern D. [Figure 51] This is a TGA thermogram of D-LSD phosphate pattern D. [Figure 52] This is the 1H NMR spectrum of the D-LSD phosphate pattern D. [Figure 53]This is a DSC thermogram of D-LSD phosphate pattern B. [Figure 54] The XRPD patterns of D-LSD HBr pattern A (bottom), D-LSD HBr pattern B (middle), and D-LSD HBr pattern C (top) are shown. [Figure 55] This is a DSC / TGA thermogram of D-LSD HBr salt pattern C. [Figure 56] This is the 1H NMR spectrum of the D-LSD HBr salt pattern C. [Figure 57] The images show the XRPD patterns of D-LSD hydrobromide pattern A starting material (bottom panel) and after stress at 40°C / 75RH (top panel). [Figure 58] These are XRPD overlays of D-LSD phosphate patterns A (bottom), B (second), C (third), D (fourth), and E (top). [Figure 59] The DSC / TGA thermogram of D-LSD phosphate pattern E is shown. [Figure 60] This is the 1H NMR spectrum of the D-LSD phosphate pattern E. [Figure 61] This is the XRPD pattern of the D-LSD sulfate amorphous salt. [Figure 62] This is a DSC thermogram of D-LSD sulfate amorphous salt. [Figure 63] This is the 1H NMR spectrum of D-LSD sulfate. [Figure 64] This is the 1H NMR overlap of D-LSD free base (bottom panel) and D-LSD sulfate (top panel). [Figure 65] This is the XRPD pattern of D-LSD hydrobromide amorphous salt. [Figure 66] This is the 1H NMR spectrum of D-LSD hydrobromide. [Figure 67] This is the 1H NMR overlap of D-LSD free base (bottom panel) and D-LSD hydrobromide (top panel). [Figure 68] This is the DVS profile of D-LSD oxalate pattern B. [Figure 69] This is the XRPD pattern of (e.g.) D-LSD oxalate pattern B, investigated after DVS equilibrium at 0% RH (middle trace) and 90% RH (upper trace), compared to the Pattern B standard (lower trace). [Figure 70] The XRPD patterns of D-LSD oxalate pattern B after storage at 40°C / 75%RH (top panel) are shown compared to the initial state (bottom panel). [Figure 71] The XRPD patterns of D-LSD phosphate pattern C after storage at 40°C / 75%RH (top panel) are shown compared to the initial state (bottom panel). [Figure 72] The XRPD pattern of amorphous D-LSD sulfate is shown. [Figure 73] This is a DSC thermogram of D-LSD HBr salt. [Figure 74] The XRPD pattern of D-LSD HBr pattern A relative to D-LSD free base (bottom panel) is shown. [Figure 75] The XRPD patterns of D-LSD free base pattern B (bottom), D-LSD HBr pattern A (middle), and D-LSD HBr pattern B isolated from toluene (top) are shown. [Figure 76] The DSC / TGA thermogram of D-LSD HBr pattern B is shown. [Figure 77] The 1H NMR spectrum of D-LSD HBr pattern B is shown. [Figure 78] The DSC / TGA thermogram of D-LSD sulfate is shown. [Figure 79] The DSC / TGA thermogram of D-LSD HBr amorphous salt is shown. [Figure 80] This is a DSC / TGA thermogram of D-LSD sulfate pattern A. [Figure 81] This is the 1H NMR spectrum of D-LSD sulfate pattern A. [Figure 82] The DSC / TGA thermogram of D-LSD HBr pattern A salt is shown. [Figure 83]The XRPD pattern of D-LSD sulfate pattern A obtained after the mixed solvent cooling crystallization experiment is shown. [Modes for carrying out the invention]

[0014] Detailed description of the invention This invention provides polymorphic forms of lysergic acid diethylamide (LSD) in crystalline salt form. .

[0015] The crystalline salt form optionally contains a free base LSD, which is a basic amine, along with an acid.

[0016] The crystalline form may be anhydrous, hydrate, or solvate. The hydrate is approximately 0.25 to approximately It has a molecular ratio of water to LSD of 10. The solvates are methanol, ethanol, iso Propanol, tetrahydrofuran, dioxane, ethyl acetate, hexane, benzene, Luene, xylene, tert-butyl methyl ether, diethyl ether, dibutyl ether Tel, acetone, anisole, isopropyl acetate, methyl ethyl ketone, 1-propano It may contain organic solvents such as tert-butyl methyl ether. Its form may be amorphous. could be.

[0017] The acids are 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, and 2-hydroxyethyl acetate. Sulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid Acids, acetic acid, adipic acid, L-ascorbic acid, D-ascorbic acid, L-aspartic acid D-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (-) -Campanulate, (+)-camphor-10-sulfonic acid, (-)-camphor-10- Sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octa) (Citrate), Carbonic acid, Cinnamic acid, Citric acid, Cyclamic acid, Dodecyl sulfate, Ethane-1,2-diphosphate Sulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-g Glucoheptonic acid, L-glucoheptonic acid, D-gluconic acid, L-gluconic acid, D-gluc L-glucuronic acid, L-glucuronic acid, L-glutamic acid, D-glutamic acid, glutaric acid, glycerin Lophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, D,L-lactic acid, D-lactic acid, L-lactic acid, lactobionic acid, lauric acid, maleic acid, L-malic acid, D-L Mangoic acid, malonic acid, D,L-mandelic acid, D-mandelic acid, L-mandelic acid, methanesulfate Naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid Nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propriolic acid, L- Pyroglutamic acid, D-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, co Sulfuric acid, L-tartaric acid, D-tartaric acid, mesotartaric acid, thiocyanate, paratoluenesulfuric acid The acid may be, but is not limited to, phonic acid, undecylenic acid, and xinafoic acid. A variety of stereoisomers, i.e., (L) or (D) or (D,L), (+) or (-), and (meso) may also be used. Salt stoichiometry is tartaric acid or citric acid or other dihydrogen. - or tri-carboxylic acid, di- or tri-sulfonic acid, or generally known to those skilled in the art. It can be used with other acids, such as 1:0.5, 1:1, 2:1, 3:1, etc. LSD (an acid).

[0018] It will be understood by those skilled in the art that other acids are useful for preparing salt forms of LSD. Those skilled in the art will further understand that the aforementioned salt form may exist in numerous polymorphic forms.

[0019] Our research has shown that LSD can exist in salt forms as anhydrous, hydrate, solvate, and cocrystal. It is understood by the person that the hydrate, solvate, and cocrystal may exist in numerous polymorphic forms. This will be further understood by those skilled in the art. The salt is the molecular weight of the acid relative to approximately 0.25 to approximately 3 LSD. It may have a ratio.

[0020] The salt form of LSD, along with various stoichiometric ratios of the free base of LSD and the acid component of the salt form of LSD. Those skilled in the art will understand that this can exist. Those skilled in the art will understand that this property is present in the acid unit. You will notice that it does not necessarily depend on the number of sex residues. For example, a monoacid is a monosalt, hemisalt, or These can form alternative free base / acid combinations. Similarly, diacids can form hemisalts, monosalts, or alternatives. It can form free base / acid combinations. Salt forms with different stoichiometric ratios of free base and acid component. Those skilled in the art will further understand that the state is a unique salt form and can exist in different polymorphic forms. It can be done.

[0021] LSD crystalline salt morphology is determined by X-ray powder diffraction (XPRD) signal, melting point, and differential scanning calorimetry. (DSC), thermogravimetric analysis (TGA), infrared spectroscopy (IR), or other methods known to those skilled in the art. It can be characterized and identified by the method.

[0022] The crystalline salt form of LSD is not limited to slurry at room temperature, and solid vapor diffusion (where LSD is soluble). (Diffusion of vapors of non-volatile solvents into the solvent containing the sample to be crystallized), temperature cycle (Continuous heating-cooling cycle for dissolution and recrystallization), slow steaming at different temperatures Crystallization induced by vapor diffusion, polymer-induced crystallization, and addition of poor solvents (in a new mixed solvent) Addition of a solvent that reduces LSD solubility and a miscible liquid, grinding, or using methods known to those skilled in the art. It can be manufactured by various methods, including other methods.

[0023] In one embodiment, the present invention relates to lysergic acid diethylamide (LSD) in crystalline salt form. It provides polymorphic forms of LSD. In some embodiments, the polymorphic forms of LSD It may be a free base, a hydrate of LSD free base, or a solvate of LSD free base. In one embodiment, the polymorph of LSD is the hydrate of LSD. In this state, the polymorph of LSD is the solvate of LSD. Therefore, the polymorph of LSD is the free base of LSD.

[0024] In one embodiment, the present invention provides polymorphic forms of salts of LSD. Several embodiments In terms of form, the polymorphic form of the salt form of LSD is the salt form of LSD, and the water form of the salt form of LSD. A solvate of LSD in salt form, or a cocrystal of LSD containing LSD free base and acid. It is possible. In some embodiments, the polymorphs of the salt form of LSD are the salt form of LSD It is a hydrate. In some embodiments, the polymorph of the salt form of LSD is the salt of LSD It is a solvate of the form. In some embodiments, the polymorph of LSD is LSD free. This is a cocrystal of LSD containing a base and an acid.

[0025] The following examples show several different polymorphs. D-LSD phosphate is pattern A, It is pattern B, pattern C, pattern D, pattern E, pattern F, or pattern G. Obtain. D-LSD oxalate is available in patterns A, B, C, D, and P It may be turn E, pattern F, pattern G, or pattern H. D-LSD sulfate is It could be pattern A. D-LSD HBr salt is pattern A, pattern B, or pattern It could be C.

[0026] In one embodiment, the salt form of LSD is LSD and 1-hydroxy-2-naphthoate Acids, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-Acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid Ascorbic acid, D-ascorbic acid, L-aspartic acid, D-aspartic acid, benzenesulfonate Camphor acid, benzoic acid, (+)-camphor acid, (-)-camphor acid, (+)-camphor- 10-sulfonic acid, (-)-camphor-10-sulfonic acid, capric acid (decanoic acid), Caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, citric acid, citric acid Cramic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, Fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, L-glucoheptonic acid D-gluconic acid, L-gluconic acid, D-glucuronic acid, L-glucuronic acid, L-gluta Minic acid, D-glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, bromide Hydrogen acid, hydrochloric acid, isobutyric acid, D,L-lactic acid, D-lactic acid, L-lactic acid, lactobionic acid, Lauric acid, maleic acid, L-malic acid, D-malic acid, malonic acid, D,L-mandelic acid D-mandelic acid, L-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid Nitric acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid Tincture, pamoic acid, phosphoric acid, proprionic acid, L-pyroglutamic acid, D-pyroglutamine Acids, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, D-tartaric acid Mesotartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and xinafoic acid It includes an acid selected from the following.

[0027] In preferred embodiments, the salt form of LSD is LSD along with acetic acid, hydrochloric acid, meta Sulfonic acid, maleic acid, L-malic acid, D-malic acid, mesotartaric acid, L-tartaric acid, D - Tartaric acid, citric acid, succinic acid, paratoluenesulfonic acid, sulfuric acid, phosphoric acid, benzenesulfonic acid Honic acid, xinafoic acid, hydrobromic acid, oxalic acid, L-aspartic acid, D-aspartic acid Naphthalene-1,5-disulfonic acid, L-glutamic acid, D-glutamic acid, malonic acid Fumaric acid, D-glucuronic acid, D-gluconic acid, glycolic acid, L-ascorbic acid, Selected from naphthalene-2-sulfonic acid, benzoic acid, and ethane-1,2-disulfonic acid. It contains acid.

[0028] In a more preferred embodiment, the salt form of LSD is LSD and hydrochloric acid, methane Sulfonic acid, maleic acid, mesotartaric acid, L-tartaric acid, D-tartaric acid, phosphoric acid, benzenesulfonic acid Honic acid, xinafoic acid, hydrobromic acid, oxalic acid, naphthalene-1,5-disulfonic acid, fuma Malic acid, L-ascorbic acid, naphthalene-2-sulfonic acid, benzoic acid, L-malic acid, It contains an acid selected from enoic acid, malonic acid, and sulfuric acid.

[0029] In the most preferred embodiment, the salt form of LSD is LSD and maleic acid, L-alcohol Calcium carbonate, D-tartaric acid, phosphoric acid, xinafoic acid, oxalic acid, naphthalene-1,5-disulfonic acid Selected from naphthalene-2-sulfonic acid, L-ascorbic acid, fumaric acid, and benzoic acid. It contains an acid. In some embodiments, the salt form of LSD is LSD and L-tartaric acid. It includes. In some embodiments, the salt form of LSD comprises LSD and D-tartaric acid. In some embodiments, the salt form of LSD comprises LSD and phosphate. In some embodiments, the salt form of LSD comprises LSD and xinafoic acid. In terms of form, the salt form of LSD contains LSD and oxalic acid. In some embodiments... The salt form of LSD contains LSD and naphthalene-1,5-disulfonic acid. In one embodiment, the salt form of LSD comprises LSD and fumaric acid. Several embodiments In terms of form, the salt form of LSD contains LSD and naphthalene-2-sulfonic acid. In several embodiments, the salt form of LSD comprises LSD and L-ascorbic acid. In some embodiments, the salt form of LSD comprises LSD and benzoic acid.

[0030] The naphthalene-2-sulfonate in D-LSD is approximately 5.0, approximately 6.1, approximately 11.5, and approximately Irradiation by Cu KαX rays has peaks represented as 2θ at 17.3 and approximately 18.9. The material is characterized by the X-ray powder diffraction pattern obtained by irradiation (Figure 1).

[0031] The L-tartrate hemisalt of D-LSD has 2θ values ​​of approximately 9.6, 11, 20.8, and 24.7. X-ray powder diffraction obtained by irradiation with Cu KαX-rays, which has a peak represented as follows: The characteristics are defined by the pattern (Figure 2).

[0032] The maleate form A of D-LSD is approximately 8.8, 16.2, 17.4, and 18.8. Cu KαX-rays have peaks represented as 2θ at approximately 20.1 and 25.0. The material is characterized by the X-ray powder diffraction pattern obtained by irradiation (Figure 3).

[0033] The maleate form B of D-LSD is approximately 8.4, 14.7, 15.1, and 17.4. And, due to irradiation with Cu KαX rays, which has a peak expressed as 2θ of approximately 22.1 The resulting X-ray powder diffraction pattern is used for characterization (Figure 4).

[0034] The xinafoate form A of D-LSD is approximately 10.2, 11.6, 13.3, and 15. Irradiation with Cu KαX rays has peaks represented as 6 and 2θ of approximately 21.6 The properties are characterized by the X-ray powder diffraction pattern obtained (Figure 5).

[0035] The xinafoate form A' of D-LSD is approximately 14.7, approximately 15.6, approximately 21.5, and approximately 2 Obtained by irradiation with Cu KαX rays, having a peak represented as 2θ of 6.6. The pattern is characterized by X-ray powder diffraction (Figure 6).

[0036] The phosphate form A of D-LSD is approximately 7.2, approximately 13.5, approximately 16.9, approximately 23.0 and Obtained by irradiation with Cu KαX-rays, having a peak expressed as 2θ at approximately 24.5. The properties are characterized by the X-ray powder diffraction pattern (Figure 7).

[0037] The naphthalene-1,5-disulfonic acid hemisodium salt of D-LSD is approximately 10.1, approximately 14.4, and approximately The 2θ values ​​are 16.7, approximately 23.5, approximately 24.5, approximately 21.9, and approximately 22.6. The X-ray powder diffraction pattern obtained by irradiation with Cu KαX-rays has a distinctive characteristic. It becomes sexualized (Figure 8).

[0038] The oxalate form A of D-LSD is approximately 8.2, 10.4, 17.7, and 19.2. Obtained by irradiation with Cu KαX rays, which has a peak expressed as 2θ of approximately 21.9. The properties are characterized by the resulting X-ray powder diffraction pattern (Figure 9).

[0039] The benzoate form A of D-LSD is approximately 8.5, approximately 14.6, approximately 16.6, and approximately 18.5. Obtained by irradiation with Cu KαX-rays, which has a peak expressed as 2θ of approximately 19.0. The properties are characterized by the X-ray powder diffraction pattern (Figure 10).

[0040] The benzoate form B of D-LSD is approximately 17.3, 19.8, 20.4, and 25. X-rays obtained by irradiation with Cu Kα X-rays, having a peak expressed as 2θ of 2. The properties are characterized by powder diffraction patterns (Figure 11).

[0041] The fumarate content of D-LSD is approximately 11.2, 18.4, 19.7, and 22.1. X-ray powder obtained by irradiation with Cu KαX-rays has a peak represented as θ. The characteristics are determined by the folding pattern (Figure 12).

[0042] The fumarate hemisalts of D-LSD are approximately 7.5, 21.3, 22.7, and 24.7. X-ray powder obtained by irradiation with Cu KαX-rays has a peak represented as θ. The characteristics are determined by the folding pattern (Figure 13).

[0043] The L-ascorbate form A of D-LSD is approximately 7.2, approximately 16.3, approximately 19.8 and Obtained by irradiation with Cu KαX-rays, having a peak expressed as 2θ of approximately 28.2 The properties are characterized by the X-ray powder diffraction pattern (Figure 14).

[0044] The L-ascorbate form B of D-LSD is approximately 7.1, approximately 17.5, approximately 26.8 and Obtained by irradiation with Cu KαX-rays, having a peak expressed as 2θ of approximately 30.2 The properties are characterized by the X-ray powder diffraction pattern (Figure 15).

[0045] The D-tartrate in D-LSD is approximately 9.7, approximately 15.5, approximately 17.5, approximately 20.4, and approximately Obtained by irradiation with Cu KαX rays, having a peak represented as 2θ of 23.4. The properties are characterized by the X-ray powder diffraction pattern (Figure 16).

[0046] The hydrochloride form A of D-LSD is approximately 7.3, 12.5, 15.0, and 16.3. And, due to irradiation with Cu KαX rays, which has a peak expressed as 2θ of approximately 24.3 The resulting X-ray powder diffraction pattern is used for characterization (Figure 17).

[0047] The hydrochloride form A' of D-LSD is approximately 7.3, 8.9, 12.5, and 15.0. And, due to irradiation with Cu KαX rays, which has a peak expressed as 2θ of approximately 24.3 The resulting X-ray powder diffraction pattern is used for characterization (Figure 18).

[0048] The hydrochloride form B of D-LSD is approximately 6.7, approximately 7.2, approximately 9.7, approximately 14.8 and Obtained by irradiation with Cu KαX-rays, having a peak expressed as 2θ of approximately 24.6. The properties are characterized by the X-ray powder diffraction pattern (Figure 19).

[0049] The hydrochloride form C of D-LSD is approximately 5.8, 6.7, 15.4, 18.8, and Obtained by irradiation with Cu KαX rays, which has a peak expressed as 2θ of approximately 24.4. The properties are characterized by the X-ray powder diffraction pattern (Figure 20).

[0050] The hydrochloride form D of D-LSD is approximately 7.3, 12.4, 15.0, and 18.0. And, by irradiation with Cu KαX rays, which has a peak expressed as 2θ of approximately 24.2 The resulting X-ray powder diffraction pattern is used for characterization (Figure 21).

[0051] The hydrochloride form E of D-LSD is approximately 7.3, 12.4, 15.0, and 19.7. And, due to irradiation with Cu KαX rays, which has a peak expressed as 2θ of approximately 24.3 The resulting X-ray powder diffraction pattern is used for characterization (Figure 22).

[0052] LSD crystalline salts can be stored as is, or manufactured as a liquid, gel, or solid for pharmaceutical purposes. It can also be prepared as a formulation. Therefore, the present invention relates to one or more pharmaceutically acceptable excipients. The present invention provides pharmaceutical formulations in the form of LSD salt crystals, including the agent.

[0053] The crystalline form of LSD and the crystalline salt form of LSD differ depending on the salt used in the formulation. It may have stability and dissolution rate. This is because it can improve the quality of the active pharmaceutical ingredient and its conversion to the desired formulation. This may affect performance / absorption rate when delivered orally.

[0054] In one embodiment, the polymorphic forms of LSD are oral, IV, sublingual, topical, transdermal, subcutaneous, and intramuscular. It is formulated as a pharmaceutical composition for intramuscular, intranasal, or rectal administration. Several embodiments In some embodiments, the polymorphs of LSD are formulated for oral administration. Therefore, polymorphic forms of LSD are formulated for IV administration. In some embodiments, L The polymorphic forms of SD are formulated for sublingual administration. In some embodiments, LSD Polymorphic forms are formulated for topical administration. In some embodiments, polymorphic forms of LSD The form is formulated for transdermal administration. In some embodiments, the polymorphic form of LSD is administered transdermally. It is formulated for intramuscular administration. In some embodiments, polymorphs of LSD are administered intramuscularly. It is formulated for administration. In some embodiments, polymorphs of LSD are used for rectal administration. It is formulated for this purpose.

[0055] In one embodiment, the polymorphic forms of the salt form of LSD are administered orally, IV, sublingually, topically, transdermally, It is formulated as a pharmaceutical composition for subcutaneous, intramuscular, or rectal administration. Several embodiments In this context, polymorphic forms of the salt form of LSD are formulated for oral administration. Several implementations In this context, polymorphic forms of the salt form of LSD are formulated for intravenous administration. Several practices In terms of form, the polymorphic forms of the salt form of LSD are formulated for sublingual administration. In terms of application forms, polymorphic forms of LSD salts are formulated for topical administration. In some embodiments, polymorphic forms of the salt form of LSD are formulated for transdermal administration. In one embodiment, polymorphic forms of the salt form of LSD are formulated for subcutaneous administration. In that embodiment, polymorphic forms of the salt form of LSD are formulated for intramuscular administration. In some embodiments, polymorphic forms of the salt form of LSD are formulated for rectal administration.

[0056] The compositions of the present invention are based on the clinical condition of individual patients, the site and method of administration, the administration schedule, and the patient. Taking into consideration the patient's age, sex, weight, and other factors known to the practicing physician, in accordance with the standards of appropriate medical care. It is administered and prescribed. Therefore, the pharmaceutically effective amount for the purposes of this specification is It is determined by considerations that are publicly known in the technical field. The amount is determined by the improved survival rate or A more rapid recovery, or improvement or disappearance of symptoms, and a measure of appropriateness selected by those skilled in the art. It must be effective in achieving improvements that include, but are not limited to, other factors. stomach.

[0057] In one embodiment, the composition of the present invention is administered to a subject requiring treatment at a dose of approximately 1 ug per unit. It is administered to deliver approximately 1 mg of LSD free base equivalent. In some embodiments The composition of the present invention is administered to a subject requiring treatment in an amount of approximately 1 ug to approximately 10 ug per dose. In some embodiments, the present invention is administered to deliver SD free base equivalents. The composition contains approximately 3 ug to 6 ug of LSD free base equivalent per dose for subjects requiring treatment. It is administered to deliver. In some embodiments, the compositions of the present invention provide treatment To deliver approximately 5ug to 20ug of LSD free base equivalent per dose to the target population. It is administered to the subject. In some embodiments, the compositions of the present invention are used to treat the subject It is administered to deliver approximately 15ug to 50ug of free base equivalents of LSD per dose. In some embodiments, the compositions of the present invention are administered in doses to subjects requiring treatment. It is administered to deliver approximately 40ug to 100ug of free base equivalent of LSD. In one embodiment, the composition of the present invention is administered to a subject requiring treatment at a dose of approximately 100 µg per unit area. The LSD is administered in such a manner that it delivers approximately 1 mg of free base equivalent. The compound of the present invention can be administered by various methods. It can be administered as a compound, alone or As an active ingredient in combination with pharmaceutically acceptable carriers, diluents, adjuvants, and vehicles It should be noted that the compound can be administered orally, subcutaneously, or intravenously or intra-arterially. , including intramuscular, intraperitoneal, intratonsillar, and intranasal administration, as well as parenteral administration including intrathecal and infusion techniques. It can be administered. Implants of the compound are also useful. Patients being treated are warm-blooded animals, especially Mammals, including humans. Pharmaceutically acceptable carriers, diluents, adjuvants, and vehicles. Furthermore, implant carriers are generally inert and non-toxic, and do not react with the active ingredients of the present invention. This refers to solid or liquid fillers, diluents, or encapsulating materials.

[0058] Administration can be a single dose or multiple doses over a period of several days. Treatment is generally Specifically, it has a length that is proportional to the length of the disease course, the effectiveness of the drug, and the race of the patient being treated. .

[0059] In one embodiment, the composition of the present invention is administered to human subjects 1 to 4 times a day. In several embodiments, the composition of the present invention is administered to human subjects once daily. In some embodiments, the composition of the present invention is administered to human subjects twice daily. In the administration model, the composition of the present invention is administered to human subjects three times a day. Several implementation models In this configuration, the composition of the present invention is administered to human subjects four times a day.

[0060] In one embodiment, the duration of treatment for human subjects is daily, daily for 7 days, or daily for 14 days. The duration of treatment for a human subject is either between sessions or daily for 30 days. In some embodiments, the duration of treatment for a human subject is... This is daily. In some embodiments, the duration of treatment for human subjects is 7 days daily. In some embodiments, the duration of treatment for human subjects is 14 days daily. In some embodiments, the duration of treatment for human subjects is 30 days, daily.

[0061] When the composition of the present invention is administered orally, it is generally available in the form of a liquid, suspension, emulsion, or tablet. It will be formulated in unit dosage forms selected from a list including capsules.

[0062] When the composition of the present invention is administered sublingually, it is generally in the form of a tablet that dissolves rapidly. It will be formulated in a unit dosage form selected from a list that includes bi-strips.

[0063] When the composition of the present invention is administered topically, it is generally selected from creams and ointments. It will be formulated in the selected unit dosage form.

[0064] When the composition of the present invention is administered transdermally, it is generally prepared in a unit dosage form including a patch. They will be drugged.

[0065] When the composition of the present invention is administered rectally, it is generally selected from a list including suppositories. It will be formulated in a single dosage form.

[0066] When the composition of the present invention is administered intranasally, it is generally in the form of a dry powder, a liquid, and It will be formulated in a dosage form selected from a list including emulsions. Those skilled in the art will know that intranasal administration is, Generally, a delivery device calibrated for the delivery of the specified dose per use. They will realize that they need it.

[0067] When the composition of the present invention is administered by injection (IV, subcutaneous, intramuscular), it is generally It will be formulated in unit dosage forms selected from a list including liquids, suspensions, and emulsions. Suitable pharmaceutical formulations for injection include sterile aqueous solutions or dispersions and sterile injectable solutions or dispersions. Contains sterile powder for reconstitution into liquid. The carrier is, for example, water, ethanol, polio (For example, glycerol, propylene glycol, liquid polyethylene glycol, etc.) ), a suitable mixture thereof, and a solvent or dispersion medium containing vegetable oil.

[0068] The sterile injectable solution contains the composition used in carrying out the present invention in the required amount It can be prepared by incorporating various other components as desired into a suitable solvent.

[0069] The present invention will be further described in detail with reference to the following experimental examples. These examples are These are provided for explanatory purposes only and are not limited unless otherwise specified. The present invention should not be construed as being limited to the following embodiments, but rather, the present invention It can be interpreted as encompassing all possible variants, as revealed as a result of the instruction provided in the detailed document. It should be explained. [Examples]

[0070] Example 1: General preparation of the D-LSD salt form A solution of acid dissolved in ethanol is mixed with a tetrahydrofuran solution of D-LSD free base. The combined material was recovered by filtration and then subjected to a crystallization test to determine its crystalline form. This was produced. If the solid form could not be isolated, dichloromethane, ethyl acetate, acetone Alternative solvents, including cetones and acetonitrile, were evaluated.

[0071] Example 2 - General preparation of D-LSD salt crystalline form The solid salt form of D-LSD is mediated by a solvent-mediated equilibrium and crystalline form mediated by a poor solvent. Standard processes including crystallization, mixed solvent recrystallization, solvent-vapor diffusion crystallization, and compression and grinding of solid salt forms. The product was subjected to various crystallization methods. The isolated solid salt form was obtained by DVS, DSC, TGA, and XRP. The crystalline morphology was characterized by evaluation using D.

[0072] Example 3: Naphthalene-2-sulfonate The crystalline form of the D-LSD salt with naphthalene-2-sulfonic acid was shown in Example 1 and Example 2. It was prepared as described. The crystalline form was approximately 5.0, 6.1, 11.5, and 17.3. Obtained by irradiation with Cu KαX rays, which has a peak expressed as 2θ of approximately 18.9. The X-ray powder diffraction pattern was used to characterize the material.

[0073] Example 4 - L-tartrate hemisalt The crystalline form of the D-LSD hemisalt with L-tartaric acid was determined as described in Examples 1 and 2. It was prepared. The crystalline form is expressed as 2θ of approximately 9.6, approximately 11, approximately 20.8, and approximately 24.7. The X-ray powder diffraction pattern obtained by irradiation with Cu KαX-rays has a peak that is It became more specialized.

[0074] Example 5 - Maleate Form A The crystalline form of the D-LSD salt with maleic acid was prepared as described in Examples 1 and 2. The crystalline form was approximately 8.8, approximately 16.2, approximately 17.4, approximately 18.8, approximately 20.1 and Obtained by irradiation with Cu KαX-rays, having a peak expressed as 2θ at approximately 25.0. The X-ray powder diffraction patterns were characterized (Figure 3). The crystalline morphology was determined using DSC and TGA. Further characterization was achieved (Figure 33). The solid DSC thermograph showed the main endothermic melting at 145°C. I showed it.

[0075] Example 6 - Maleate Form B The crystalline form of the D-LSD salt with maleic acid was prepared as described in Examples 1 and 2. The crystalline form was determined to be approximately 8.4, 14.7, 15.1, 17.4, and 22.1. X-ray powder obtained by irradiation with Cu KαX-rays, having a peak represented as 2θ. The diffraction pattern was used to characterize the material (Figure 4). The crystalline morphology was characterized by DSC and TGA. (Figure 34). The DSC thermograph of the solid showed the major endothermic melting at 199°C. It is a preferred maleate.

[0076] Example 7 - Xinafoate Form A The crystalline form of LSD was prepared as described in the above method. The acid was xinafoic acid, and The crystalline morphology is defined by 2θ of approximately 10.2, 11.6, 13.3, 15.6, and 21.6. X-ray powder diffraction pattern obtained by irradiation with Cu KαX-rays, having a peak represented as shown. It was characterized by the turn.

[0077] Example 8 - Xinafoate Form A' The crystalline form of LSD was prepared as described in the above method. The acid was xinafoic acid, and The crystalline morphology is expressed as 2θ of approximately 14.8, 15.6, 21.5, and 26.6. X-ray powder diffraction patterns obtained by irradiation with Cu KαX-rays, which have peaks, It was characterized.

[0078] Example 9 - Phosphate Form A The crystalline form of LSD was prepared as described in the above method. The acid was phosphoric acid, and the crystalline form was The shapes are approximately 7.2, 13.5, 14.8, 16.9, 24.2, and 24.5. X-ray powder obtained by irradiation with Cu KαX-rays, having a peak represented as 2θ. The pattern was characterized by diffraction. Figure 7 shows the XRPD pattern of LSD phosphate pattern A. Yes. The material was characterized by DSC and TGA (Figure 32). DSC / TGA analysis is T g was subjected to a reaction at 122°C (half Cp), followed by an exothermic reaction at 165°C, and then a fusion endothermic reaction at 233°C. The values ​​are shown in °C. A weight loss of 0.2% w / w was observed between 27 and 136°C, followed by 0 A second minor weight loss of 0.37% w / w was observed.

[0079] Example 10: Naphthalene-1,5-disulfonate hemisulfate The crystalline form of LSD was prepared as described in the above method. The acid was naphthalene-1,5- It is a disulfonic acid, and its crystalline form is approximately 10.1, 14.4, 16.7, and 23.5. Cu has peaks represented as 2θ of approximately 24.5, approximately 21.9, and approximately 22.6. The data was characterized by the X-ray powder diffraction pattern obtained by irradiation with Kα X-rays.

[0080] Example 11 - Oxalate Form A The crystalline form of LSD was prepared as described in the above method. The acid was oxalic acid, and the crystals The sexual morphology is set to 2θ of approximately 8.2, 10.4, 17.7, 19.2, and 21.9. X-ray powder diffraction pattern obtained by irradiation with Cu KαX-rays, having the represented peak. It was characterized by [something].

[0081] Example 12 - Benzoate Form A The crystalline form of the D-LSD salt with benzoic acid was prepared as described in Examples 1 and 2. The crystalline form was approximately 8.5, 14.6, 16.6, 18.5, and 19.0. X-ray powder obtained by irradiation with Cu KαX-rays has a peak represented as θ. The material was characterized by its folding pattern (Figure 10). The material was characterized by DSC and TGA (Figure 10). 25). DSC showed an endothermic peak at 148°C. TGA showed a 1.0% mass loss at 25. The results were obtained at temperatures between ℃ and 130℃. This represents the preferred benzoate form.

[0082] Example 13 - Benzoate Form B The crystalline form of the D-LSD salt with benzoic acid was prepared as described in Examples 1 and 2. The crystalline form was expressed as 2θ of approximately 17.3, 19.8, 20.4, and 25.2. X-ray powder diffraction pattern obtained by irradiation with Cu KαX-rays, having a peak. The material was characterized by (Figure 11). The material was characterized by DSC and TGA (Figure 26). D SC showed an endothermic peak at 149°C. TGA showed a 0.6% mass loss from 25°C to 130°C. As shown.

[0083] Example 14 - Fumarate The crystalline form of LSD was prepared as described in the above method. The acid was fumaric acid, and the crystals The sexual morphology is expressed as 2θ of approximately 11.2, 18.4, 19.7, and 22.1. The X-ray powder diffraction pattern obtained by irradiation with Cu KαX-rays has a distinctive characteristic. It became sexualized (Figure 12).

[0084] Example 15 - Fumarate hemisalt The crystalline form of LSD was prepared as described in the above method. The acid was fumaric acid, and the crystals The sexual morphology is expressed as 2θ of approximately 7.5, 21.3, 22.7, and 24.7. The X-ray powder diffraction pattern obtained by irradiation with Cu KαX-rays has properties It transformed (Figure 12).

[0085] Example 16-L-ascorbate form A The crystalline form of LSD was prepared as described in the above method. The acid used was L-ascorbic acid. Yes, the crystalline form is expressed as 2θ of approximately 7.2, 16.3, 19.8, and 28.2. X-ray powder diffraction pattern obtained by irradiation with Cu KαX-rays, having a peak. This was then characterized (Figure 14).

[0086] Example 17-L-ascorbate form B The crystalline form of LSD was prepared as described in the above method. The acid used was L-ascorbic acid. Yes, the crystalline form is expressed as 2θ of approximately 7.1, 17.5, 26.8, and 30.2. X-ray powder diffraction pattern obtained by irradiation with Cu KαX-rays, having a peak. This was then characterized (Figure 15).

[0087] Example 18-D-Tartrate The crystalline form of the D-LSD salt with D-tartaric acid was prepared as described in Examples 1 and 2. The crystalline morphology was characterized by XRPD, DSC, TGA, and DVS. Cu The X-ray powder diffraction patterns obtained by irradiation with KαX rays were approximately 9.7, approximately 15.5, and approximately It has peaks represented as 2θ at 17.5, approximately 20.4, and approximately 23.4 (Figure 16). The materials were characterized by DSC and TGA (Figure 28). The DSC thermograph was taken at 203°C. It contains major endothermic melting, and the corresponding TGA thermograph does not show weight loss until decomposition. 1 The 1H NMR spectrum (Figure 31) shows a tartrate peak (2H) at 4.2 ppm. Confirm the monostoichiometry of salts. DVS profiling of D-LSD D-tartrate pattern A. The diagram is shown in Figure 35. During the initial desorption cycle, the solid is 0.6 wt% at 50%RH~0%R It lost H and did not achieve an anhydrous state. During the subsequent sorption cycle, the solid remained at 80% RH. It absorbed 0.65% water. This increased to 1% at 90% RH. DVS Profile This water absorption is reversible as the relative humidity decreases, and shows slight hysteresis. Confirm that only this has been done. Solvent exclusion is suggested as the cycle progresses, The final detachment is completed, resulting in a dry, solid state.

[0088] Example 19 - Hydrochloride Form A The crystalline form of the D-LSD salt with hydrochloric acid was prepared as described in Examples 1 and 2. The crystalline form was determined to be approximately 7.3, 12.5, 15.0, 16.3, and 24.3. X-ray powder obtained by irradiation with Cu KαX-rays, having a peak represented as 2θ. The diffraction pattern was used to characterize the product (Figure 17).

[0089] Example 20 - Hydrochloride Form A' The crystalline form of the D-LSD salt with hydrochloric acid was prepared as described in Examples 1 and 2. The crystalline form was determined to be approximately 7.3, 8.9, 12.5, 15.0, and 24.3. X-ray powder obtained by irradiation with Cu KαX-rays has a peak represented as θ. The characteristics were determined by the folding pattern (Figure 18).

[0090] Example 21 - Hydrochloride Form B The crystalline form of the D-LSD salt with hydrochloric acid was prepared as described in Examples 1 and 2. The crystalline form was determined to have 2θ values ​​of approximately 6.7, 7.2, 9.7, 14.8, and 24.6. X-ray powder diffraction obtained by irradiation with Cu KαX-rays, which has a peak represented as follows: The patterns were characterized (Figure 19).

[0091] Example 22 - Hydrochloride Form C The crystalline form of the D-LSD salt with hydrochloric acid was prepared as described in Examples 1 and 2. The crystalline form was determined to be approximately 5.8, 6.7, 15.4, 18.8, and 24.4. X-ray powder obtained by irradiation with Cu KαX-rays has a peak represented as θ. The characteristics were determined by the folding pattern (Figure 20).

[0092] Example 23 - Hydrochloride Form D The crystalline form of the D-LSD salt with hydrochloric acid was prepared as described in Examples 1 and 2. The crystalline form was determined to be approximately 7.3, 12.4, 15.0, 18.0, and 24.2. X-ray powder obtained by irradiation with Cu KαX-rays, having a peak represented as 2θ. The diffraction pattern was used to characterize the product (Figure 21).

[0093] Example 24 - Hydrochloride Form E The crystalline form of the D-LSD salt with hydrochloric acid was prepared as described in Examples 1 and 2. The crystalline form was determined to be approximately 7.3, 12.4, 15.0, 19.7, and 24.3. X-ray powder obtained by irradiation with Cu KαX-rays, having a peak represented as 2θ. The diffraction pattern was used to characterize the product (Figure 22).

[0094] Example 25 - Free base form A The crystalline form of D-LSD free base was prepared by crystallization from ethyl acetate. The morphology is approximately 10.2, 12.0, 16.2, 17.2, 20.0, and 23.1. X-ray powder obtained by irradiation with Cu KαX-rays, having a peak expressed as 2θ. The final diffraction pattern was used to characterize the sample (Figure 23, bottom panel).

[0095] Example 26 - Free base form B The crystalline morphology of D-LSD free base was determined by a post-treatment incorporating 1M NaOH washing. It was prepared. The crystalline form was obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ of about 8.5, about 8.6, about 17.1, about 18.1, about 18.7 and characterized by an X-ray powder diffraction pattern. Thermal analysis was collected for Pattern B solid . The DSC thermogram included a first endotherm with an onset at 71 °C and a second endotherm at 108 °C. The corresponding TGA thermogram showed a weight loss of 4.12% w / w from 32 to 222 °C (Figure 23, upper panel).

[0096] Example 27 - Phosphate Form B The D-LSD free base (Pattern A, 2.02 g) was placed in a round-bottom flask (V = 50 mL) and dissolved in EtOH (10 V). The solution was heated to 50 °C at 300 rpm for 30 minutes. Then, a stock solution of phosphoric acid (1 M, 6.25 mL) prepared in EtOH was added slowly. The system was equilibrated for 15 minutes and the temperature was lowered to 25 °C overnight. A suspension was observed and filtered to isolate the solid. The recovered solid was placed in a vacuum oven at 45 °C for 48 hours. Yield 82%. The material was analyzed by XRPD, DSC / TGA, and proton NMR. The crystalline form was characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as about 6.8, about 7.5, about 7.9, about 13.8, about 16.7 and about 17 .3 (Figure 58, second from the bottom). The Pattern B form of D-LSD phosphate was characterized by DSC / TGA as a crystalline monoethanol solvent <00—0904>ate solid having a melting temperature of 223 °C (Figure 29). The DSC / TGA thermogram showed a first endotherm onset at 105 °C, a second endotherm at 182 °C, followed by a melting endotherm at 233 °C [[ID=3—]] ​​This major melting corresponds to pattern A. 9.4% w at 29-171°C. A weight loss of / w (approximately 1 molar equivalent of EtOH) was observed in the TGA thermogram. There was a small weight loss of 0.3% w / w at 174-223°C.

[0097] Example 28 - Phosphate Form C As an alternative crystalline form of LSD phosphate, as shown in Table 1, is LSD phosphate form B or It was prepared by maturation using a thermal cycle.

[0098] [Table 1]

[0099] The crystalline form is approximately 7.8, 8.5, 12.8, 15.0, 15.1 and 21 X-ray powder diffraction obtained by irradiation with Cu KαX-rays, exhibiting a peak represented as 0.1. Characterized by pattern. This is a preferred phosphate form. Figure 36 shows LSD phosphate. This is a DSC thermogram of salt acid pattern C. Figure 37 shows the X of LSD phosphate pattern C. This is an RPD pattern.

[0100] Example 29 - Oxalate Form B The crystalline form of LSD was prepared as described in the above method. The acid was phosphoric acid, and the crystalline form was The morphology is approximately 13.0, 15.4, 17.9, 19.8, 21.5, and 23.1. X-ray powder diffraction pattern obtained by irradiation with Cu KαX-rays, having a peak represented as Characterized by [a specific compound]. This is the preferred oxalate form.

[0101] Example 30 - Hydrobromide Form A The crystalline form of LSD was prepared as described in the above method. The acid was hydrobromic acid, and The crystalline morphology is approximately 6.6, 9.6, 14.7, 24.2, 24.5, and 25.6. X-ray powder diffraction pattern obtained by irradiation with Cu KαX-rays, having a peak represented as Characterized by [method / method]. Figure 57 shows the D-LSD hydrobromide pattern A starting material (bottom panel). The image also shows the XRPD pattern after stress at 40°C / 75RH (top panel).

[0102] Example 31 - Amorphous oxalate Place D-LSD free base (pattern A, 1.97g) into a round-bottom flask (V=50mL). The solution was placed and dissolved in EtOH(10V). The solution was heated at 300 rpm for 30 minutes at 50°C. It was heated. Then, a stock solution of oxalic acid prepared in EtOH (1M, 6.03mL) was added. The solution was slowly added. The system was allowed to equilibrate for 15 minutes, and the temperature was allowed to decrease to 25°C overnight. The material was observed and dried under vacuum using a rotor vaporizer. The material was weighed, and the yield was 98%. That was the case.

[0103] The recovered powder was analyzed by XRPD, DSC / TGA, and proton NMR.

[0104] XRPD analysis showed the formation of D-LSD oxalate as an amorphous solid. DSC / The TGA thermogram showed a first endothermic onset at 52°C, followed by a fusion endothermic onset at 19°C. This was shown at 3°C. This melting temperature is for a salt with a melting temperature of 213°C, during salt screening. It was lower than that of the crystalline version of the identified oxalate. 3.6% w / w weight A decrease in volume (0.83 molar equivalents of water) was observed at 45-161°C. NMR analysis revealed that this was the case. This suggests a link to the loss of absorbed ethanol, but the level is normal for a single solvent. It is insufficient for the object. The NMR spectrum of the proton was consistent with the molecular structure. Figure 38 shows DSC and TGA thermographs of the D-LSD oxalate amorphous material are shown.

[0105] Compression Experiment: D-LSD amorphous oxalate (Lot: DC1134, about 50 mg) was compressed with a force of 10 5 N for approximately 24 hours. Then, the solid was removed from the press for analysis by XRPD. After the compression experiment, the LSD amorphous oxalate remained an amorphous solid. Figure 39 shows the XRPD patterns of the solid isolated after compression, the D-LSD amorphous oxalate standard (lower panel), and the LSD amorphous oxalate isolated after the compression experiment (upper panel).

[0106] Example 32 - Aging of D-LSD oxalate (DC1108) by thermal cycling The amorphous oxalate was subjected to aging by thermal cycling in various solvents.

[0107] Experiment: Amorphous D-LSD oxalate (Lot: DC1135; 24 × 50 mg) was weighed into a crystallization tube, a solvent (various volume fillings) was added, and the mixture was equilibrated at 25 °C for about 15 minutes. Then, the solvent was added, the temperature was raised and evaluated for dissolution, and a series of aging / recrystallization was given by systematically increasing the temperature to 70 °C and 20 volumes.

[0108] The mixture was thermally cycled between 70 °C and 25 °C for 48 hours with a minimum of 5 hours at the temperature during the heating period. The solid was isolated at two temperatures, at 25 °C during the last cycle and also at high temperature. The solvent with a lower boiling point was equilibrated to 45 °C. Each solution was clarified and transferred to a clean hot tube.

[0109] Place in a container to induce unbiased recrystallization, followed by cooling or slow evaporation. It was isolated by [method / tool].

[0110] The entire solid was isolated by filtration, and the liquid was analyzed by HPLC to determine its concentration relative to a known standard. Solubility measurements were obtained. The solid was selected for purity evaluation to remove impurities and / or potential impurities. I informed them about the stability issues.

[0111] Prior to analysis, the entire solid was dried in a vacuum at 45°C.

[0112] Table 2 shows the form fate of the solid after equilibrium.

[0113] [Table 2]

[0114] API is prepared at 25°C by adding 200 ml of the following solvents and solvent mixtures: EtOH and MeOH. It was shown to have excellent solubility exceeding g / ml.

[0115] The majority of solids isolated from the screen at both 25°C and high temperatures are referred to as Pattern B. We addressed a new pattern of detection. Pattern A was isolated after maturation in chlorobenzene. Pattern E was isolated once after maturation in DCM. Pattern D material was subjected to a solvent at 70°C. The powder was isolated from ripening in nitromethane and patterned using the same solvent at 25°C. Converted to G.

[0116] A representative sample of pattern B (lot: DC1136-18) was analyzed by DSC. The thermograms showed endothermic onset at 176 and 204°C, respectively.

[0117] D-LSD oxalate pattern C (lot: DC1136-11) is used in DSC and TG Characterized by A. The DSC thermogram showed a first broad endothermic onset of 41°C. The second endothermic onset was represented at 137°C, and the third endothermic onset at 200°C. TGA corresponds to the first endothermic reaction in DSC, with a 0.6% w / w rating at 25-75°C. It showed weight loss and a second weight loss of 0.6% w / w at 75-210°C.

[0118] D-LSD oxalate pattern E material was characterized by DSC and TGA. The omogram shows a poor thermal profile with two endothermic onsets at 44°C and 207°C. This was shown. The corresponding TGA represented a weight loss of 2.4% w / w at 80-150°C.

[0119] D-LSD oxalate pattern G material was characterized by DSC and TGA. - The omogram shows the first endothermic onset at 119°C, followed by the fusion endothermic onset at 204°C. The TGA showed a weight loss of 1.38% w / w at 80-160°C.

[0120] Figure 40 shows the DSC thermogram of D-LSD oxalate pattern B. Figure 41 shows Figure 42 shows the DSC thermogram of D-LSD oxalate pattern C. Figure 43 shows the TGA thermogram of oxalate pattern C. Figure 44 shows the DSC thermogram of pattern E. Figure 44 shows the TG of D-LSD oxalate pattern E. A thermogram is shown. Figure 45 is a DSC thermogram of D-LSD oxalate pattern G. Figure 46 shows the TGA thermogram of D-LSD oxalate pattern G. 47 shows patterns A (bottom row), B, C, and pattern isolated after the maturation experiment. XRPD pattern overlap of pattern D, pattern E, pattern F and pattern G (upper row) It indicates a point.

[0121] Example 33 - Amorphous Phosphate Preparation of amorphous phosphates The amorphous phase of a solid is often metastable, readily reconfiguring into a thermodynamically more stable crystalline form. Since it is a high-energy phase, its evaluation (accessing) is performed in polymorph screening. It is very useful.

[0122] We attempted to produce amorphous D-LSD phosphate using a freeze-drying method starting from water.

[0123] The recovered material was analyzed by XRPD and DSC. The amorphous phase was shown in Figure 48. It was well generated. Thermal analysis showed a relatively complex thermal profile (Figure 49). Ill is characteristic of amorphous solids and can be observed by DSC at 43, 134, 158 and 212°C. It exhibited four distinct thermal events with corresponding endothermic properties.

[0124] Example 34 D-LSD phosphate polymorphic screen Solvent aging of amorphous D-LSD phosphate (DC1139) The amorphous phase of D-LSD phosphate exhibits a series of solvent-mediated equilibrium reactions depending on temperature amplitude. provided.

[0125] Experiment: Crystallization of amorphous D-LSD phosphate (DC1139-2) (20 x 30 mg) The mixture was weighed into a tube, 20 volumes of solvent were added, and the mixture was equilibrated at 25°C for approximately 15 minutes. The mixture was subjected to a thermal cycle between 50°C and 25°C for 48 hours. The solid was then subjected to a thermal cycle between 50°C and 25°C. Isolation by filtration at °C and 25°C, drying in vacuum at 45°C for 18 hours, and then data I collected them.

[0126] The recovered solid was analyzed by XRPD, and pattern C was primarily isolated.

[0127] A new pattern, pattern D, was isolated from nitromethane at both 50°C and 25°C. Thermal analysis of pattern D (Figure 50) shows an exothermic onset at approximately 176°C, followed by melting. Onset was shown at 225°C. Analysis by TGA (Figure 51) showed minor changes between 40 and 210°C. It showed a weight reduction of 0.12% w / w. 1 The 1H NMR spectrum matches the molecular structure. And no residual solvent was observed. Figure 5 shows pattern A reference (bottom 1st trace); pattern Pattern B standard (2nd trace); Pattern C standard (3rd trace); Nitromethane at 50°C Pattern D (4th trace) isolated after maturation in nitromethane at 25°C. This shows pattern D (5th trace) isolated after maturation.

[0128] Pattern D recrystallizes to become pattern C, as shown in the solid DSC thermogram. This represents the anhydrous phase which may occur. Figure 52 shows pattern D. 1 This is an H NMR spectrum.

[0129] Poor solvent-mediated crystallization of D-LSD phosphate (DC1145) Crystallization mediated by poor solvents is useful for identifying new forms or versions of solids. The reason for this method is that once dissolved, APIs do not retain morphological memory, and bias This is because it can be recrystallized. The solubility evaluation of the API during the initial solvent maturation experiment is done using all Several solvents and poor solvents had been identified.

[0130] Experiment: D-LSD phosphate stock solution, material (200 mg, DC1134) It was prepared by dissolving it in a certain amount of water and DMSO. Then the stock solution was clarified. The sample was placed in a clean sample vial. 16 aliquots (25 mg API) of the stock solution were added. It was placed in the crystallization tube and preheated to 50°C (30°C for DCM). Then, 5 Add the poor solvent, preheated to 0°C, in packing amounts of 2 volumes, until a cloudy solution is observed, or 2 The solution was then added until it reached a volume equal to zero of the poor solvent. The solution was then cooled and equilibrated at 25°C for 24 hours. I transformed it.

[0131] The results and observations are shown in Table 3.

[0132] XRPD analysis revealed that pattern C was mainly isolated, while pattern B was obtained from water and nitromethane. This demonstrated that pattern B was obtained from the reaction crystallization of salts in ethanol. The solution was isolated after equilibrium in IPA / water under pattern B. The resulting solution was placed in a refrigerator. We will observe them again in a week.

[0133] [Table 3]

[0134] Pattern B material was analyzed by XRPD, DSC, and proton NMR.

[0135] The XRPD pattern of pattern B isolated from IPA / water shows scale-up in EtOH. It was similar to pattern B, which was isolated after the initial phase. The phase is an isostructural solvate. Scale up Later isolated pattern B was an ethanol solvate, but pattern B isolated from IPA / water Substance B was an IPA solvate.

[0136] Thermal analysis of pattern B isolated from water / IPA showed that the first endothermic onset was at 145°C. Subsequently, the endothermic onset of fusion was shown at 234°C (Figure 53). Proton NMR spectrum The Toll molecule corresponds to the molecular structure, and the presence of IPA was confirmed (approximately 0.5 molar equivalents).

[0137] Solvent vapor diffusion of amorphous D-LSD phosphate (DC1140) To investigate the tendency of amorphous D-LSD phosphate to become polymorphic, use amorphous input. The experiment was carried out using solvent vapor diffusion techniques. This technique is suitable for systems with low forcing (less f Using an orcing system, the API regulates itself through surface interactions with the solvent, inducing crystallization. It makes it possible to guide.

[0138] Experiment: In the solvent vapor chamber, pour the solvent (3 ml, Table 4) into a glass vial. A dosing was prepared. In this vapor chamber, amorphous API (30 mg, DC1134) was added. A smaller glass vial was placed to accommodate the contents. The chamber was sealed for observation and XRP. Prior to D analysis, the samples were allowed to stabilize quietly for two weeks. The results and observations are shown in Table 4.

[0139] We primarily recovered D-LSD phosphate pattern C salt, but a new pattern we named pattern E also recovered. The element was isolated. This material was analyzed using XRPD (Figure 58), DSC, TGA, and proton NMR. Characterized by the following. The DSC thermogram (Figure 59) shows the first endothermic onset at 42°C. , a second endothermic onset occurred at 178°C, followed by two endothermic fusion onsets. The results were obtained at 18°C. TGA analysis showed a 4.9% weight loss (0.25 molar equivalents of MTBE). The temperature range shown was 29-149°C.1 The 1H NMR spectrum matches the molecular structure, indicating the presence of MTBE. This was observed (approximately 0.1 molar equivalent). Figure 60 shows the D-LSD phosphate pattern E. 1 H This is an NMR spectrum.

[0140] [Table 4]

[0141] Crystallization of D-LSD phosphate (DC1149) under mixed solvent cooling The investigation revealed that various solvents and APIs can be used to provide various modes of crystallization. Poor solvents were identified. The morphological behavior of D-LSD oxalate was observed in a series of mixed solvent cooling crystallizations. I appreciated it even more.

[0142] Experiment: Amorphous D-LSD phosphate (DC1135, 8 x 25 mg) is placed in a crystallization tube. The solution was weighed out and suspended in the relevant poor solvent (detailed in Table 5) (10 volumes). The temperature was raised to 50°C. The solvent was added in small amounts until a solution was obtained. The solution was cooled and allowed to equilibrate at room temperature for 16 hours. The solid was isolated by filtration, dried in a vacuum at 40°C for 18 hours, and then processed. I collected them.

[0143] Results and observations are shown in Table 5.

[0144] The recovered suspension was filtered and analyzed by XRPD. Pattern B was obtained from EtOH / water. Separated. Pattern C was obtained from MeOH / water, 1,4-dioxane / water and MeCN / water. The sample was released. The resulting solution was slowly evaporated, and the gel sample was recovered.

[0145] [Table 5]

[0146] Example 35: Polymorphic screen of D-LSD oxalate Crystallization of D-LSD oxalate (DC1143) under mixed solvent cooling The investigations conducted during the work plan can be used to give various crystallization modes. Various solvents and poor solvents of I were identified. The morphological behavior of D-LSD oxalate was observed in a series of mixtures. Further evaluation was performed by solvent-cooled crystallization.

[0147] Experiment: Crystallization tube of amorphous D-LSD oxalate (DC1135, 8 x 25 mg) The mixture was weighed and suspended in the relevant poor solvent (detailed in Table 6) (10 volumes). The temperature was raised to 50°C. The solvent was added in small amounts until a solution was obtained. The solution was cooled and allowed to equilibrate at room temperature for 16 hours. The solid was isolated by filtration, dried in a vacuum at 40°C for 18 hours, and then processed. I collected them.

[0148] The results and observations are shown in Table 6.

[0149] [Table 6]

[0150] Example 36 D-LSD sulfate polymorph screen Slurry experiment (DC1162) A sufficient amount of D-LSD sulfate (lot: DC1151) is dissolved in the undissolved solid until it reaches the desired temperature (2 The mixture was added to the given solvent until it remained at 5°C. The crystallization tube was sealed, and the slurry was selected. The mixture was maintained at a constant temperature and stirred by magnetic stirring for 3 days. The solid was then processed using a 0.45 μm PTFE filter. The sample was isolated by filtration using a router and then analyzed by XRPD. The results are shown in Table 7. Gel We mainly obtained samples.

[0151] [Table 7]

[0152] Example 37 D-LSD HBr salt polymorph screen Slurry experiment A sufficient amount of D-LSD HBr salt (lot: DC1152) is added, and the undissolved solid reaches the desired temperature. The mixture was added to the given solvent until it remained at (25°C). The crystallization tube was sealed, and the slurry was selected. The mixture was maintained at the specified temperature and stirred by magnetic stirring for 3 days. The solid was then processed using 0.45 μm PTFE. The samples were isolated by filtration and then analyzed by XRPD. The results are shown in Table 8. A new pattern, named D-LSD HBr pattern C, was isolated and analyzed using DSC, TGA and Beauty 1 The data was characterized by 1H NMR.

[0153] XRPD results showed that the material exhibited low crystallinity (Figure 54). DSC and TG Analysis A showed a weight loss of 0.42% (w / w) at 46-189°C and melting at approximately 197°C. The set is shown (Figure 55). 1 The 1H NMR spectrum matches the molecular structure, indicating trace amounts of impurities. An object was detected (Figure 56).

[0154] [Table 8]

[0155] Water mixture solvent cooling crystallization (DC1164) Morphological behavior of D-LSD HBr salt (lot: DC1152) under a series of water-mixed solvent cooling Further evaluation was performed through crystallization.

[0156] Experiment: Crystallization of D-LSD HBr salt (lot: DC1152, 6 x approximately 25 mg) Place in a bowl and suspend in 5-10 volumes of a suitable poor solvent. Heat the mixture to 50°C and stir. The mixture was then equilibrated at 50°C for approximately 30 minutes, then cooled to 25°C and equilibrated for approximately 20 hours. The mixture, which had returned to a suspension at room temperature, was isolated under vacuum, and the solid was incubated at 45°C for 20 hours prior to characterization. It was left to dry for a while.

[0157] The results are summarized in Table 9. D-LSD HBr pattern A was primarily recovered.

[0158] [Table 9]

[0159] Crash precipitation of D-LSD HBr salt (DC1167) Crushing precipitation of API solutions into various poor solvents reveals a potential metastable form of crystalline solids. This is a method for evaluating [something].

[0160] Experiment: Weigh D-LSD HBr salt (DC1152) into a COC vial and dissolve appropriately. It was then dissolved in a medium (EtOH, 10 volumes at 50°C). Next, a transparent solution free of visible particles was used. To obtain the solution, it was clarified and placed in a clean tube. Then, approximately 25 mg of To ensure that each aliquot contained the material, the solution was divided into eight aliquots per solvent. Then, using the aliquots as a single packing, a crystallization tube containing 10 volumes of a suitable poor solvent was prepared. Transfer to a container and pre-cool to 0°C. Equilibrate the mixture at 0°C for up to 30 minutes. The given entry was isolated, and the solid was dried at 45°C for approximately 20 hours prior to characterization. Amorphous The qualitative material was primarily recovered, and pattern A was isolated from EtOH / heptane (Table 10).

[0161]

Table 10

[0162] Example 38 Preparation and Characterization of Amorphous D-LSD Sulfate The D-LSD free base (Pattern A, 5.01 g) was placed in a round-bottom flask (V = 200 mL) and dissolved in EtOH (10V). The solution was stirred at 300 rpm for 30 minutes at 25 °C and then a stock solution of sulfuric acid in EtOH (1 M, 15.49 mL) was slowly added. The reaction was carried out overnight at 25 °C. The solution was observed and reduced in vacuo to give a solid The recovered material was analyzed by XRPD, DSC, TGA and 1H NMR 1 yield = 97.5% (6.35 g)

[0163] The XRPD analysis showed the formation of an amorphous salt of D-LSD sulfate (Figure 61). Figure 62 is the DSC thermogram of the amorphous salt of D-LSD sulfate.

[0164] The amorphous D-LSD sulfate (Lot: DC1151) was characterized by DSC and TGA. The DSC analysis showed a possible glass transition at 120 °C (half Cp), followed by an endothermic onset at 177 °C and an exothermic onset at 210 °C. The TGA analysis showed a weight loss of 5.7% (w / w) from 24 to 163 °C. Figure 78 shows the DSC / TGA thermogram of D-LSD sulfate.

[0165] The 1H NMR spectrum of the amorphous D-LSD sulfate was consistent with the molecular structure and showed trace amounts of impurities

[0166] of 1 D-LSD sulfate ​​​​​​The collected DSC profiles are shown along with the appropriate solvent content (Figure 63). D-LSD release. Base and D-LSD sulfate 1 The overlapping 1H NMR spectra illustrate salt formation. The expected shift was shown (Figure 64).

[0167] Example 39 Preparation of D-LSD hydrobromic acid amorphous salt Place D-LSD free base (pattern A, 2.53 g) in a round-bottom flask (V=100 mL). The solution was placed in a container and dissolved in EtOH (10V). The solution was heated at 300 rpm for 30 minutes at 25°C. Stirring intermittently, slowly add the stock solution of HBr in EtOH (48%) (1M, 7.8mL) The mixture was added. The reaction was carried out overnight at 25°C. The solution was observed and reduced in a vacuum, and the solid was removed. The materials were then processed using XRPD, DSC, and 1 Analysis was performed by 1H NMR.

[0168] Yield = 93% (2.95g)

[0169] XRPD analysis showed the formation of amorphous D-LSD hydrobromic acid salt (Figure 65).

[0170] D-LSD HBr salt 1 The 1H NMR spectrum matches the molecular structure, indicating trace levels of dissolution. A medium was present (approximately 2 wt% EtOH, Figure 66). D-LSD (lot; ASH65) 7) and D-LSD HBr salt 1 The 1H NMR spectrum overlap is due to a salt formed by a strong acid. This shows the expected shift induced by the formation (Figure 67).

[0171] Example 40 Hierarchical study of D-LSD phosphate patterns A, C, and D (DC1150) API; Further details on the relationship between the three types of anhydrous forms: Pattern A, Pattern C, and Pattern D. To elucidate and identify a thermodynamically preferred version of D-LSD phosphate, a hierarchical approach was adopted. The test was conducted. Equal amounts of patterns A, C, and D were used at three different temperatures of 25°C. The solid was competitively equilibrated in different solvents and solvent mixtures. After 7 days, the solid was isolated and XRPD was applied. We investigated and evaluated their forms.

[0172] Experiment: D-LSD phosphate pattern A (lot: DC1137-19), D-LSD Phosphate pattern C (Lot: DC1137-23) and D-LSD phosphate pattern D ( Lot: DC1140-12) (10 mg each, 1:1:1) in a crystallization tube The sample was weighed, the solvent (detailed in Table 11) was added, and the sample was stirred (25°C, 7 days). The sample was then decomposed. Prior to the analysis, the samples were dried in a vacuum (40°C, 20 hours).

[0173] The results are shown in Table 11.

[0174] Complete conversion to pattern C is THF:water (95:5 v / v), 1,4-dioxane And observed in THF. Instead, a mixture of pattern A and pattern C was observed in EtOH. It was done.

[0175] [Table 11]

[0176] Example 41 Accelerated preservation of D-LSD phosphate pattern C and D-LSD oxalate pattern B D-LSD phosphate pattern C (lot: DC1137-9) and D-LSD oxalate Salt pattern B (lot: DC1144-4) under controlled conditions of 40°C / 75%RH The samples were placed in an unsealed vial in a cabinet for 14 days. Visual observation was performed, and after stress, physical stability was assessed by XRPD, and HPLC was performed. Further analysis was conducted regarding chemical stability. Figure 68 shows the DV of D-LSD oxalate pattern B. This is the S profile. Figure 69 shows the 0%RH profile compared to the Pattern B reference (lower trace). DL investigated after DVS equilibrium at (intermediate trace) and 90% RH (upper trace) This is an XRPD pattern of SD oxalate pattern B.

[0177] Error! Reference source not found. Table 12 is This summarizes the XRPD and HPLC data collected from each solid.

[0178] D-LSD oxalate pattern B and D-LSD ri after stress at 40℃ / 75RH Sodium salt pattern C did not show any morphological changes (Figures 70 and 71).

[0179] [Table 12]

[0180] Example 42 Aging and initial solubility evaluation of D-LSD sulfate amorphous salt by thermal cycling (DC1153) Experiment: Place D-LSD sulfate (lot: DC151; 24 x 25 mg) into a crystallization tube. The mixture was weighed out, solvent (various volume packing amounts) was added, and the mixture was equilibrated at 25°C for approximately 15 minutes. Next, the solvent is added, the temperature is raised, and the dissolution is evaluated, systematically increasing the volume to 70°C and 30°C. A series of maturation / recrystallization processes were carried out while the material was being added.

[0181] The mixture was heated for a minimum of 5 hours at 70°C and 25°C for 48 hours. The solid was subjected to a thermal cycle between two temperatures, 25°C between the last cycle and also high. It was isolated using warm water.

[0182] The solvent with the lower boiling point was equilibrated at 45°C.

[0183] Each solution is clarified and placed in a clean, hot tube to ensure unbiased recrystallization. It was isolated after cooling or by slow evaporation.

[0184] Most of the samples observed at room temperature were gels.

[0185] The solid recovered from the solution by slow evaporation was analyzed by XRPD to observe the amorphous material. (Figure 72).

[0186] API has a solubility of over 200 mg / mL in MeOH at 25°C, and solubility of over 200 mg / mL in EtOH at 25°C. Solubility exceeding 100 mg / mL, and solubility at 40°C with iPrOAc / water (98:2) and IPA It had a solubility of over 100 mg / mL in water (95:5).

[0187] Example 43 Thermal characterization of amorphous D-LSD HBr salts The DSC thermogram of amorphous D-LSD HBr salt (lot: DC1152) shows exothermic The onset temperature was shown as 220°C.

[0188] Thermal cycling experiments were conducted on amorphous D-LSD HBr salt. A small sample of this material ( Place approximately 5 mg of the sample in a TGA pan and heat at 40°C / min to 190°C, then add the sample to -2 The system was cooled to 0°C. The cycle was repeated twice. The thermogram showed no exothermic or endothermic events whatsoever. It was not shown. Figure 73 shows the DSC thermogram of D-LSD HBr salt.

[0189] Example 44 D-LSD Aging of HBr amorphous salt by thermal cycling and evaluation of initial solubility (DC115 4) Thermal cycling maturation is used to evaluate material behavior across a wide range of solvent species and mixed solvents. This is a practical method. Such experimental modulations represent solvent vs. poor solvent and temperature-solubility effects. Furthermore, it also indicates potential morphological changes induced from the input based on the type of solvent. The seed bed can be maintained from the input form, but the dissolved material obtained through purification The liquid provides unbiased recrystallization, along with the potential to introduce new phases for evaluation.

[0190] Experiment: Crystallization of D-LSD HBr salt (lot: DC1152; 24 x 25 mg) Weigh the mixture into a bowl, add solvent (various volume packing amounts), and equilibrate the mixture at 25°C for approximately 15 minutes. Next, the solvent was added, the temperature was raised, and the dissolution was evaluated at 70°C and 30 volumes. A series of maturation / recrystallization processes were subjected to systematic increases until the desired level was reached.

[0191] The mixture was heated for a minimum of 5 hours at 70°C and 25°C for 48 hours. The solid was subjected to a thermal cycle between two temperatures, 25°C between the last cycle and also high. It was isolated using warm water.

[0192] The solvent with the lower boiling point was equilibrated to 45°C.

[0193] Each solution is clarified and placed in a clean, hot tube to ensure unbiased recrystallization. It was isolated after cooling or by slow evaporation.

[0194] The entire solid was isolated by filtration, and the liquid was analyzed by HPLC to determine its concentration relative to a known standard. Solubility measurements were obtained. A solid was selected for purity evaluation to remove impurities and / or potential impurities. They reported a stability issue.

[0195] Prior to analysis, the entire solid was dried in a vacuum at 45°C.

[0196] API is 200 mg / mL in MeOH, THF / water (95:5 v / v) at 25°C. It possessed extremely high solubility.

[0197] Solubility of over 100 mg / mL in EtOH, MEK, and nitromethane at 25°C.

[0198] At 40℃, 1,4-dioxane, iPrOAc / water (98:2 v / v), IPA / water ( Solubility greater than 100 mg / mL in a 95:5 v / v solution.

[0199] Table 13 shows the morphological behavior of D-LSD amorphous HBr after equilibrium in various solvents under thermal modulation. And a summary of solubility is shown.

[0200] [Table 13]

[0201] The majority of the solids isolated from the screen were amorphous materials. This is called Pattern A. A new pattern was isolated from alkyl and MeCN. Pattern B was isolated in toluene. It was isolated once after maturation.

[0202] The D-LSD HBr pattern A sample was characterized by XRPD (Figure 74, top).

[0203] D-LSD HBr pattern isolated by poor solvent cooling crystallization from MeOH / MTBE Samples of ¹A salt (lot: DC1159-10) were characterized by DSC and TGA (Figure) 82). DSC analysis showed melting onset at 184°C. TGA thermogram showed 4% The weight loss (w / w) was expressed at 23-172°C, indicating that the material is a monohydrate salt.

[0204] D-LSD HBr pattern B was obtained using XRPD (Figure 75) and DSC / TGA (Figure 76). Characterized by DSC analysis, the exothermic peak at 210°C was identified by the instrument. A small bump due to a defect is shown at approximately 160°C. The thermogram shows no endothermic events observed at all. It is unique because it is not done. The TGA thermogram shows a slight weight loss of 0.21% (w / w). The small amount was observed at 35-202°C. The significant lack of energy processes in this salt version is due to the crystallization. This may be related to the degree of chemical change or other contents that give it such behavior. 1 H NMR spectrum (Figure 77) shows a molecular structure consistent with the detection of trace amounts of impurities / solvent.

[0205] Example 45 Characterization of D-LSD HBr amorphous salts Amorphous D-LSD HBr salt (Lot: DC1152) was characterized by DSC and TGA. DSC analysis showed a fever onset at 220°C. TGA analysis showed 4.0% ( The weight loss (w / w) was shown at 22–207°C. Figure 79 shows the DSC of D-LSD HBr salt. The TGA thermogram is shown.

[0206] Example 46 Solvent vapor diffusion of amorphous D-LSD sulfate (DC1155) An investigation into the polymorphism tendency of amorphous D-LSD sulfates using solvent vapor with amorphous input. The experiment was conducted using a diffusion technique. This technique uses a low-forcing system and allows the API to dissolve. This allows the material to orient itself through surface interactions with the medium, thereby inducing crystallization.

[0207] Experiment: In the solvent vapor chamber, pour the solvent (3 ml, Table 14) into a glass vial. It was prepared by the following. In this steam chamber, amorphous API (30 mg, DC1151) A smaller glass vial containing the contents was placed inside. The chamber was sealed, and observation and X-rays were performed. Prior to the RPD analysis, the samples were allowed to quietly equilibrate for two weeks.

[0208] The results and observations are shown in Table 14, but most of the recovered material was gel. D- LSD sulfate pattern A was isolated once from cyclohexane (Lot: DC1155- 16) This material is XRPD, DSC, TGA and 1 The data was characterized by 1H NMR.

[0209] DSC analysis showed an endothermic onset of approximately 118°C, followed by two other endothermic onsets. The temperature was shown at 172 and 199°C. The TGA thermogram showed a weight loss of 5.1% (w / w). The small values ​​are expressed as 25-142°C. Stoichiometrically, 1 molar equivalent of water is 4.1% w / w. This shows the monohydrate salt. 1 The 1H NMR spectrum (Figure 81) matches the molecular structure, and traces Trace amounts of heptane were detected (0.006 molar equivalents). Figure 80 shows the D-LSD sulfate pattern. The DSC / TGA thermogram of plane A is shown.

[0210] [Table 14]

[0211] Crystallization mediated by the poor solvent of D-LSD sulfate (DC1158) Experiment: Prepare the minimum amount of material (200 mg, DC1151) in D-LSD sulfate stock solution. It was prepared by dissolving it in MeOH and EtOH. Then, the stock solution was clarified. Then, it was placed in a clean sample vial. An aliquot (25 mg API) of the stock solution was added. Next, the mixture was placed in 14 crystallization tubes and preheated to 50°C (30°C for DCM). Then, the poor solvent, preheated to 50°C, is added in 2-volume packing amounts until a cloudy solution is observed. Alternatively, add until 20 volumes of poor solvent have been added. Then, cool the solution and leave it at 25°C for 24 hours. The system was brought into equilibrium.

[0212] The results and observations are shown in Table 15. The solution and amorphous material were recovered. The solution was then subjected to ambient conditions. The gel was then evaporated and mainly isolated.

[0213] [Table 15]

[0214] D-LSD HBr salt polymorph screen Solvent vapor diffusion of amorphous D-LSD HBr salt (DC1156) An investigation into the polymorphism tendency of amorphous D-LSD hydrobromide was conducted using amorphous input. The process was carried out using a vapor diffusion technique. This technique uses a low-forcing system and AP I is able to orient itself through surface interactions with the solvent, thereby inducing crystallization.

[0215] Experiment: In the solvent vapor chamber, pour the solvent (3 ml, Table 16) into a glass vial. It was prepared by the following. In this steam chamber, amorphous API (30 mg, DC1152) A smaller glass vial containing the contents was placed inside. The chamber was sealed, and observation and X-rays were performed. Prior to the RPD analysis, the samples were allowed to quietly equilibrate for two weeks.

[0216] The results and observations are shown in Table 16. Amorphous material was mainly recovered, and the D-LSD HBr pattern Line A was isolated twice from MeCN and cyclohexane.

[0217] [Table 16]

[0218] Poor solvent-mediated crystallization of D-LSD HBr salt (DC1159) Crystallization mediated by poor solvents is useful for identifying new forms or versions of solids. The reason for this method is that once dissolved, APIs do not retain morphological memory, and bias This is because it can be recrystallized. For evaluating the solubility of APIs during initial solvent aging experiments, use Several solvents and poor solvents were identified that should be used.

[0219] Experiment: D-LSD HBr salt stock solution was used with the material (200 mg, DC1152) It was prepared by dissolving it in small amounts of MeOH and EtOH. Then, the stock solution was prepared. The solution was clarified and placed in a clean sample vial. An aliquot of the stock solution (25 mg API) was then added. The ) was placed in 16 crystallization tubes and preheated to 50°C (30°C for DCM). Next Then, add the poor solvent, preheated to 50°C, in 2-volume packing amounts, until a cloudy solution is observed. or until 20 volumes of poor solvent have been added. Then the solution was cooled and left to stand at 25°C for 24 hours. Time equilibration was performed.

[0220] The results and observations are shown in Table 17. XRPD analysis revealed that pattern A was primarily isolated. This was shown. The solution recovered after the poor solvent cooling crystallization experiment was slowly evaporated. The gel was the main component. It was isolated.

[0221] [Table 17]

[0222] Example 47 D-LSD sulfate polymorph screen Crystallization of amorphous D-LSD sulfate (DC1160) by cooling in a mixed solvent. The investigations conducted during the work plan can be used to provide various modes of crystallization. Various solvents and poor solvents for the API were identified. D-LSD sulfate (Lot: DC1151) The morphological behavior was further evaluated by a series of mixed solvent cooling crystallization processes.

[0223] Experiment: Amorphous D-LSD sulfate (DC1151, 21 × 25 mg) is placed in a crystallization tube. The solution was weighed out and suspended in the appropriate poor solvent (Table 18). The temperature was raised to 50°C to obtain the solution. The solvent was added in small amounts until the solution was fully cooled and equilibrated at room temperature for 16 hours. The sample was isolated by filtration, dried in a vacuum at 40°C for 18 hours, and then data was collected. If solutions are observed, place them in a refrigerator at 0°C for 24 hours and collect the suspension. The solution was filtered and analyzed by XRPD. After cooling, the recovered solution was evaporated under ambient conditions. The observed solids were analyzed by XRPD. Gel samples and amorphous materials were collected.

[0224] [Table 18]

[0225] D-LSD HBr salt polymorph screen Crystallization of amorphous D-LSD HBr salt (DC1161) by cooling in a mixed solvent. The investigations conducted during the work plan can be used to provide various modes of crystallization. Various solvents and poor solvents for API were identified. D-LSD HBr salt (Lot: DC115) The morphological behavior of (2) was further evaluated by a series of mixed solvent cooling crystallization processes.

[0226] Experiment: Crystallization tube of amorphous D-LSD HBr (DC1152, 17 × 25 mg) The mixture was weighed out and suspended in the relevant poor solvent (detailed in Table 19) (10 volumes). The temperature was set to 50°C. The mixture was then heated, and the solvent (detailed in Table 19) was added little by little until a solution was obtained. The solution was then cooled. The mixture was allowed to equilibrate at room temperature for 16 hours. The solid was isolated by filtration and dried in a vacuum at 40°C for 18 hours. After drying, data was collected. If any solution was observed, it was placed in a refrigerator at 0°C for 2 minutes. The suspension was left to stand for 4 hours, then filtered and analyzed by XRPD. After cooling, the collected suspension was recovered. The solution was evaporated under ambient conditions, and the observed solid was analyzed by XRPD.

[0227] Results and observations are shown in Table 19. Gel samples and amorphous materials were mainly recovered. D- LSD sulfate pattern A, EtOH / TBME, EtOH / IPAC, EtOH / Hept Isolated from tan and MeOH / MIBK. Isolated D-LSD sulfate pattern A solid. The XRPD pattern is shown in Figure 83.

[0228] [Table 19]

[0229] Through this application, various publications, including U.S. patents, are listed by author and year, and the patents are numbered. References are made for each issue. A complete list of citations of these publications and patents is provided below. The overall disclosure is provided for reference in order to more fully describe the state of the art to which the present invention relates. It will be incorporated more into this application.

[0230] This invention is described illustratively, and the terminology used is descriptive rather than restrictive. It should be understood that this is something that falls within the properties of the material.

[0231] Clearly, many improvements and modifications of the present invention are possible in light of the above disclosure. Therefore, the present invention is not specifically described within the scope of the attached claims. It should be understood that this can be done by law.

Claims

1. A crystalline form of D-LSD free base or LSD containing D-LSD free base and acid.

2. A D-LSD free base is selected from the group consisting of anhydrous, hydrate, solvate, and cocrystal. The crystalline form of the LSD according to claim 1.

3. Claim 2, wherein the hydrate has a water molecular ratio of about 0.25 to about 10 LSD. The crystalline form of the LSD described.

4. The solvates include methanol, ethanol, isopropanol, tetrahydrofuran, Dioxane, ethyl acetate, hexane, benzene, toluene, xylene, tert-butyl Methyl ether, diethyl ether, dibutyl ether, acetone, anisole, acetate Sopropyl, methyl ethyl ketone, 1-propanol, and tert-butylmethyl ester The crystalline form of the LSD according to claim 2, comprising an organic solvent selected from the group consisting of tel.

5. The crystalline form comprises an LSD free base and an acid, wherein the acid is 1-hydroxy-2-naphth Toe acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutal Acids, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid Rubic acid, D-ascorbic acid, L-aspartic acid, D-aspartic acid, benzene Sulfonic acid, benzoic acid, (+)-camphoric acid, (-)-camphoric acid, (+)-camphor -10-sulfonic acid, (-)-camphor-10-sulfonic acid, capric acid (decanoic acid) ), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, gy Acids, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, L-glucoheptonic acid D-gluconic acid, L-gluconic acid, D-glucuronic acid, L-glucuronic acid, L-gluc Glutamic acid, D-glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, Hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, D-lactic acid, L-lactic acid, lactobionic acid Lauric acid, maleic acid, L-malic acid, D-malic acid, malonic acid, D,L-mandel acid Acids, D-mandelic acid, L-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfate Nitric acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, pal Mitic acid, pamoic acid, phosphoric acid, proprionic acid, L-pyroglutamic acid, D-pyroglutamic acid Acids, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, D-tartaric acid Acids, mesotartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and xina A crystalline form of the LSD according to claim 1, selected from folic acid.

6. The crystalline form of the LSD according to claim 5, which is a salt or a cocrystal.

7. The salt has a molecular weight ratio of acid to LSD of about 0.25 to about 3, as described in claim 6. Crystalline form of LSD.

8. Claim 7, wherein the salt is selected from the group consisting of anhydrous, hydrate, solvate, and cocrystal. The crystalline form of LSD as described.

9. Claim 8, wherein the hydrate has a water molecular ratio of about 0.25 to about 10 LSD. The crystalline form of the LSD described.

10. The solvates include methanol, ethanol, isopropanol, tetrahydrofuran, Dioxane, ethyl acetate, hexane, benzene, toluene, xylene, tert-butyl Methyl ether, diethyl ether, dibutyl ether, acetone, anisole, acetate Sopropyl, methyl ethyl ketone, 1-propanol, and tert-butylmethyl ester The crystalline form of the LSD according to claim 8, comprising an organic solvent selected from the group consisting of tel.

11. The acid is naphthalene-2-sulfonic acid, and the crystalline form is approximately 5.0, approximately 6.

1. Cu has peaks represented as 2θ of approximately 11.5, 17.3, and 18.

9. Characterized by an X-ray powder diffraction pattern obtained by irradiation with KαX rays, claim 5 The crystalline form of LSD as described.

12. The acid is L-tartaric acid, and the crystalline form is about 9.6, about 11, about 20.8 and about Obtained by irradiation with Cu KαX rays, having a peak represented as 2θ of 24.

7. The crystalline morphology of the LSD according to claim 5, characterized by an X-ray powder diffraction pattern.

13. The crystalline form according to claim 12, wherein the salt is a hemisalt.

14. The acid is maleic acid, and the crystalline form is approximately 8.9, approximately 16.3, approximately 17.

4. Cu K has peaks represented as 2θ of approximately 18.8, 20.2, and 25.

0. The characteristics are determined by the X-ray powder diffraction pattern obtained by irradiation with αX rays, as per claim 5. The crystalline form of the LSD described.

15. The acid is maleic acid, and the crystalline form is approximately 8.4, approximately 14.7, approximately 15.

1. Cu KαX-rays have peaks represented as 2θ at approximately 17.4 and 22.

1. The LSD according to claim 5, characterized by the X-ray powder diffraction pattern obtained by irradiation. The crystalline form of.

16. The acid is xinafoic acid, and the crystalline form is approximately 10.2, approximately 11.6, and approximately 13.

3. Cu KαX rays have peaks represented as 2θ of approximately 15.6 and 21.

6. The LS according to claim 5 is characterized by the X-ray powder diffraction pattern obtained by irradiation. The crystalline form of D.

17. The acid is xinafoic acid, and the crystalline form is approximately 14.7, approximately 15.6, and approximately 21.

5. And, by irradiation with Cu KαX rays, which has a peak expressed as 2θ of approximately 26.6 The crystalline form of the LSD according to claim 5 is characterized by the obtained X-ray powder diffraction pattern. Status.

18. The acid is in phosphoric acid form A, and the crystalline form is approximately 7.2, approximately 13.5, and approximately 14.

8. Cu has peaks represented as 2θ of approximately 16.9, 24.2, and 24.

5. Characterized by an X-ray powder diffraction pattern obtained by irradiation with KαX rays, claim 5 The crystalline form of LSD as described.

19. The acid is naphthalene-1,5-disulfonic acid, and the crystalline form is about 10.

1. 2θ values ​​of approximately 14.4, 16.7, 23.5, 24.5, 21.9, and 22.6 X-ray powder diffraction pattern obtained by irradiation with Cu KαX-rays, having a peak represented as shown. The crystalline form of the LSD according to claim 5, characterized by turning.

20. The crystalline form according to claim 19, wherein the salt is a hemisalt.

21. The acid is oxalic acid, and the crystalline form A is approximately 8.2, approximately 10.4, approximately 17.

7. Cu KαX-rays have peaks represented as 2θ of approximately 19.2 and 21.

9. The LSD according to claim 5, characterized by the X-ray powder diffraction pattern obtained by irradiation. The crystalline form of.

22. The acid is benzoic acid, and the crystalline form A is approximately 8.5, approximately 14.6, approximately 16.

6. Cu KαX-rays have peaks represented as 2θ at approximately 18.5 and 19.

0. The LSD according to claim 5, characterized by the X-ray powder diffraction pattern obtained by irradiation. The crystalline form of.

23. The acid is benzoic acid, and the crystalline form B is approximately 17.3, approximately 19.8, and approximately 20.4 And, by irradiation with Cu KαX rays, which has a peak expressed as 2θ of approximately 25.2 The crystalline form of the LSD according to claim 5 is characterized by the obtained X-ray powder diffraction pattern. Status.

24. The acid is fumaric acid, and the crystalline form is approximately 11.2, approximately 18.4, approximately 19.7 and Obtained by irradiation with Cu KαX rays, which has a peak expressed as 2θ of approximately 22.

1. The crystalline morphology of the LSD according to claim 5, characterized by the X-ray powder diffraction pattern obtained. 。

25. The acid is fumaric acid, and the crystalline form is about 7.5, about 21.3, about 22.7 and Obtained by irradiation with Cu KαX rays, having a peak expressed as 2θ of approximately 24.

7. The crystalline morphology of the LSD according to claim 5, characterized by the X-ray powder diffraction pattern.

26. The crystalline form according to claim 25, wherein the salt is a hemisalt.

27. The acid is L-ascorbic acid, and the crystalline form is approximately 7.2, approximately 16.3, approximately 1 Irradiation with Cu KαX rays exhibits peaks represented as 9.8 and approximately 28.2°. The LSD according to claim 5 is characterized by the X-ray powder diffraction pattern obtained Crystalline form.

28. The acid is L-ascorbic acid, and the crystalline form is approximately 7.1, approximately 17.5, and approximately 2 Irradiation with Cu KαX rays exhibits peaks represented as 6.8 and approximately 30.2 degrees 2θ. The LSD according to claim 5 is characterized by the X-ray powder diffraction pattern obtained Crystalline form.

29. The acid is D-tartaric acid, and the crystalline form is approximately 9.7, approximately 15.5, approximately 17.

5. Cu KαX-rays have peaks represented as 2θ at approximately 20.4 and 23.

4. The LSD according to claim 5, characterized by the X-ray powder diffraction pattern obtained by irradiation. The crystalline form of.

30. The acid is hydrochloric acid, and the crystalline form is approximately 7.3, approximately 12.5, approximately 15.

0. Cu KαX-rays have peaks represented as 2θ at approximately 16.3 and 24.

3. The LSD according to claim 5, characterized by the X-ray powder diffraction pattern obtained by irradiation. The crystalline form of.

31. The acid is hydrochloric acid, and the crystalline form is approximately 7.3, approximately 8.9, approximately 12.5, approximately Irradiation by Cu KαX rays has peaks expressed as 15.0 and approximately 24.3 θ. The LSD according to claim 5 is characterized by the X-ray powder diffraction pattern obtained by irradiation. Crystalline form.

32. The acid is hydrochloric acid, and the crystalline form is approximately 6.7, approximately 7.2, approximately 9.7, and approximately 1 Irradiation with Cu KαX rays, exhibiting peaks represented as 4.8 and approximately 24.6 degrees 2θ. The LSD according to claim 5 is characterized by the X-ray powder diffraction pattern obtained Crystalline form.

33. The acid is hydrochloric acid, and the crystalline form is approximately 5.8, approximately 6.7, approximately 15.4, approximately Irradiation by Cu KαX rays has peaks represented as 18.8 and approximately 24.4 θ. The LSD according to claim 5 is characterized by the X-ray powder diffraction pattern obtained by irradiation. Crystalline form.

34. The acid is hydrochloric acid, and the crystalline form is approximately 7.3, approximately 12.4, approximately 15.

0. Cu KαX-rays have peaks represented as 2θ at approximately 18.0 and 24.

2. The LSD according to claim 5, characterized by the X-ray powder diffraction pattern obtained by irradiation. The crystalline form of.

35. The acid is hydrochloric acid, and the crystalline form is approximately 7.3, approximately 12.4, approximately 15.

0. Cu KαX-rays have peaks represented as 2θ at approximately 19.7 and 24.

3. The LSD according to claim 5, characterized by the X-ray powder diffraction pattern obtained by irradiation. The crystalline form of.

36. Amorphous form of LSD containing free base or free base and acid.

37. A free LSD base is included and selected from the group consisting of anhydrous, hydrate, and solvate. The amorphous form of the LSD described in item 36.

38. Claim 37, wherein the hydrate has a water molecular ratio to LSD of about 0.25 to about 10. The amorphous form of LSD as described.

39. Methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetic acid Ethyl, hexane, benzene, toluene, xylene, tert-butyl methyl ether, Solvation with an organic solvent selected from the group consisting of diethyl ether and dibutyl ether. The amorphous form of the LSD described in claim 37, which is a material.

40. The amorphous form comprises LSD free base and acid, wherein the acid is 1-hydroxy-2-naphth Toe acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutal Acids, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid Rubic acid, D-ascorbic acid, L-aspartic acid, D-aspartic acid, benzene Sulfonic acid, benzoic acid, (+)-camphoric acid, (-)-camphoric acid, (+)-camphor -10-sulfonic acid, (-)-camphor-10-sulfonic acid, capric acid (decanoic acid) ), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, gy Acids, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, L-glucoheptonic acid D-gluconic acid, L-gluconic acid, D-glucuronic acid, L-glucuronic acid, L-gluc Glutamic acid, D-glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, Hydrobromic acid, hydrochloric acid, isobutyric acid, D,L-lactic acid, D-lactic acid, L-lactic acid, lactobion Acids, lauric acid, maleic acid, L-malic acid, D-malic acid, malonic acid, D,L-mandextrin Mandelic acid, D-mandelic acid, L-mandelic acid, methanesulfonic acid, naphthalene-1,5-disyl Sulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, Lumitic acid, pamoic acid, phosphoric acid, proprionic acid, L-pyroglutamic acid, D-pyroglutamic acid Minic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, D-alcohol Calcium carbonate, mesotartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and xylyl acid An amorphous form of the LSD according to claim 36, selected from naphoic acid.

41. The amorphous form of the LSD according to claim 36, which is a salt.

42. The salt has a molecular weight ratio of acid to LSD of about 0.25 to about 3, as described in claim 41. The amorphous form of LSD.

43. The salt is selected from the group consisting of anhydrous, hydrate, and solvate, as described in claim 41. The amorphous form of the LSD shown.

44. Claim 43, wherein the hydrate has a water molecular ratio to LSD of about 0.25 to about 10. The amorphous form of LSD as described.

45. The solvates include methanol, ethanol, isopropanol, tetrahydrofuran, Dioxane, ethyl acetate, hexane, benzene, toluene, xylene, tert-butyl Methyl ether, diethyl ether, dibutyl ether, acetone, anisole, acetate Sopropyl, methyl ethyl ketone, 1-propanol, and tert-butylmethyl ester An amorphous form of the LSD according to claim 43, comprising an organic solvent selected from tel.

46. Free base form A, approximately 10.2, 12.0, 16.2, 17.2, and 20. Irradiation with Cu KαX rays has peaks represented as 0 and approximately 23.1 θ The crystallinity of the LSD according to claim 2 is characterized by the X-ray powder diffraction pattern obtained. form.

47. Free base form B, approximately 8.5, approximately 8.6, approximately 17.1, approximately 18.1, approximately 18.7 and Obtained by irradiation with Cu KαX rays, which has a peak expressed as 2θ of approximately 25.

0. The crystalline morphology of the LSD according to claim 2, characterized by the X-ray powder diffraction pattern obtained. 。

48. The acid is phosphoric acid, and the crystalline form B is approximately 6.8, approximately 7.5, approximately 7.9, and approximately 13 8. Cu KαX rays, having peaks represented as 2θ at approximately 16.7 and 17.

3. Characterized by an X-ray powder diffraction pattern obtained by irradiation with the method described in claim 5. Crystalline form of LSD.

49. The acid is phosphoric acid, and the crystalline form C is approximately 7.8, approximately 8.5, approximately 12.8, approximately 1 Cu KαX has peaks represented as 2θ at 5.0, approximately 15.1, and approximately 21.

1. Characterized by an X-ray powder diffraction pattern obtained by irradiation with a line, as described in claim 5. The crystalline form of LSD.

50. The acid is oxalic acid, and the crystalline form B is approximately 13.0, approximately 15.4, and approximately 17.9 Cu has peaks represented as 2θ of approximately 19.8, 21.5, and 23.

1. Characterized by an X-ray powder diffraction pattern obtained by irradiation with KαX rays, claim 5 The crystalline form of LSD as described.

51. The acid is hydrobromic acid, and the crystalline form is approximately 6.6, approximately 9.6, approximately 14.7, approximately Cu Kα has peaks expressed as 2θ at 24.2, approximately 24.5, and approximately 25.

6. Characterized by an X-ray powder diffraction pattern obtained by X-ray irradiation, as described in claim 5. Crystalline morphology of the LSD shown.

52. Crystalline form of D-LSD free base or LSD of D-LSD free base and acid, and pharmaceutical A pharmaceutical preparation containing an acceptable excipient.

Images