SALTS OF AN ANTIOXIDANT AND CRYSTALLINE FORMS THEREOF
20250388550 ยท 2025-12-25
Inventors
- Jan Trampota (Fairfield, NJ, US)
- Stephan D. Parent (West Lafayette, IN, US)
- Travis Lee HOUSTON (West Lafayette, IN, US)
Cpc classification
A61K31/4172
HUMAN NECESSITIES
C01P2002/72
CHEMISTRY; METALLURGY
International classification
A61K31/4172
HUMAN NECESSITIES
Abstract
The present disclosure is directed to salt forms of
Claims
1. An
2.
3. The
4. The crystalline
5. Co-crystal
6. The co-crystal of claim 5, characterized by an X-ray powder diffraction (XRPD) comprising peaks at 14.99, 18.68, 20.69, and 21.070.2 2.
7. The co-crystal of claim 6, characterized by an XRPD comprising peaks at 11.38, 14.99, 18.68, 20.69, 21.07, and 21.780.2 2.
8. The co-crystal of claim 7, characterized by an XRPD comprising peaks at 11.38, 14.99, 15.41, 18.68, 19.05, 19.82, 20.69, 21.07, 21.78, 24.38, 24.63, 25.17, 27.22, 27.73, 28.54, and 29.680.2 2.
9. The co-crystal of any one of claims 5-8, characterized by a differential scanning calorimetry (DSC) thermograph having two endotherms wherein the first has an endotherm maximum between about 75 C. and 85 C. and wherein the second an endotherm maximum between about 235 C. and 245 C.
10. The co-crystal of claim 9, wherein characterized by a DSC thermograph having two endotherms wherein the first endotherm a maximum at about 77 C. and wherein the second endotherm a maximum at about 241 C.
11. The co-crystal of any one of claims 5-8, characterized by a DSC thermograph substantially similar to that set forth in
12. The co-crystal of any one of claims 5-11, characterized by a weight loss in the range of about 1% and 5% when heated up to about 120 C. in a thermogravimetric analysis (TGA).
13. The co-crystal of claim 12, characterized by a weight loss of about 2.4% when heated up to about 117 C. in a TGA.
14. The co-crystal of any one of claims 5-11, characterized by TGA substantially similar to that set forth in
15. A pharmaceutical composition comprising the
16. A pharmaceutical composition comprising
17. The pharmaceutical composition of claim 15-16, in a dosage form suitable for topical administration.
18. A method for the purification of
19. The method of claim 18, further comprising mixing the
20. The method of claim 19, wherein the protic solvent is selected from the group consisting of methanol, ethanol, isopropanol, formic acid, acetic acid, and combinations thereof.
21. A crystalline form of
22. The crystalline form of claim 21, characterized by an XRPD comprising peaks at 11.17, 12.44, 12.77, 19.72, 19.96, and 22.720.2 2.
23. A crystalline form of
24. The crystalline form of claim 23, characterized by an XRPD comprising peaks at 11.17, 12.44, 12.77, 14.90, 15.26, 19.72, 19.96, 20.59, 21.16, 21.36, 22.72, 25.04, 26.88, 27.70, and 30.470.2 2.
25. The crystalline form of any one of claims 21-23, characterized by a differential scanning calorimetry (DSC) thermograph having an endotherm with an onset between about 260 C. and 270 C.
26. The crystalline form of claim 25, characterized by a differential scanning calorimetry (DSC) thermograph having an endotherm with an onset of about 265 C.
27. The crystalline form of any one of claims 21-23, characterized by a DSC thermograph substantially similar to that set forth in
28. The crystalline form of any one of claims 21-27, characterized by a weight loss in the range of 0% to about 1% when heated up to about 255 C. in a thermogravimetric analysis (TGA).
29. The crystalline form of claim 28, characterized by a weight loss of about 0.3% when heated up to about 250 C. in a TGA.
30. The crystalline form of any one of claims 21-27, characterized by TGA substantially similar to that set forth in
31. A crystalline form of
32. The crystalline form of claim 31, characterized by an XRPD comprising peaks at 5.30, 10.63, 12.52, 14.82, 15.83, 17.93, 18.35, 19.50, 20.84, 21.06, 21.91, 22.16, 23.40, 23.71, 24.73, 29.00, 30.05, and 30.530.2 2.
33. A crystalline form of
34. The crystalline form of claim 33, characterized by an XRPD comprising peaks at 4.20, 8.41, 12.55, 13.67, 14.34, 15.48, 17.13, 18.80, 19.95, 20.74, 22.56, 23.41, 24.08, 27.58, and 27.880.2 2.
35. A crystalline form of
36. The crystalline form of claim 35, characterized by an XRPD comprising peaks at 5.65, 11.32, 12.18, 14.27, 16.13, 17.98, 18.90, 19.27, 19.69, 21.51, 22.83, 23.56, 24.03, 24.57, and 26.120.2 2.
37. A crystalline form of
38. The crystalline form of claim 37, characterized by an XRPD comprising peaks at 12.10, 13.39, 14.13, 17.22, 17.52, 18.17, 18.91, 21.16, 24.17, 24.52, 25.37, and 28.970.2 2.
39. A crystalline form of
40. The crystalline form of claim 39, characterized by an XRPD comprising peaks at 5.83, 11.97, 14.52, 16.71, 18.60, 20.41, 21.09, 21.83, 22.65, and 28.040.2 2.
41. A crystalline form of
42. The crystalline form of claim 41, characterized by an XRPD comprising peaks at 5.55, 14.32, 15.53, 16.41, 18.10, 18.53, 18.85, 20.69, 26.56, and 26.920.2 2.
43. A crystalline form of
44. A pharmaceutical composition comprising the crystalline form of any one of claims 21-43 in a pharmaceutically acceptable carrier.
45. A method for the treatment of a disease or disorder caused by oxidative stress and/or inflammation comprising administering the crystalline form of any one of claims 21-43 or a pharmaceutical composition of claim 44.
Description
BRIEF DESCRIPTION OF FIGURES
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DETAILED DESCRIPTION
[0049] The present disclosure provides salts of
[0050] The present disclosure also provides a crystalline form of
[0051] The present disclosure also provides a crystalline form of
[0052] The present disclosure provides at least the following embodiments: [0053] a)
Definitions
[0065] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures known in the art that are described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art.
[0066] As used herein, the singular forms a, an, and the include the plural referents unless the context clearly indicates otherwise.
[0067] As used herein, the term about refers to the stated value plus or minus 10%, plus or minus 5%, or plus or minus 1%. For example, a value of about 10 can encompass a range of 9 to 11. For logarithmic scales, the term about refers to the stated value plus or minus 0.3 log units, or plus or minus 0.2 log units, or plus or minus 0.1 log units. For example, a value of about pH 4.6 can encompass a pH range of 4.5-4.7.
[0068] The term substantially free of or substantially in the absence of with respect to a composition refers to a composition that includes at least about 85 or 90% by weight, in certain embodiments at least about 95%, 98%, 99% or 100% by weight, of a designated enantiomer or stereoisomer of a compound. For example, substantially free of or substantially in the absence of with respect to a composition can refer to a composition that includes about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% by weight of a designated enantiomer or stereoisomer of a compound. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of other enantiomers or stereoisomers.
[0069] Similarly, the term isolated with respect to a composition refers to a composition that includes at least 85, 90%, 95%, 98%, and 99% to 100% by weight, of a designated compound, enantiomer, or stereoisomer, the remainder comprising other chemical species, enantiomers, or stereoisomers. For example, isolated with respect to a composition can refer to a composition that includes about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% by weight of a designated compound, enantiomer, or stereoisomer, the remainder comprising other chemical species, enantiomers, or stereoisomers.
[0070] As used herein, the terms subject and patient are used interchangeably herein. The terms subject and subjects refer to an animal, such as a mammal including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee and a human), and for example, a human. In another embodiment, the subject is a farm animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or a cat). In certain embodiments, the subject is a human.
[0071] Therapeutically effective amount refers to an amount of a compound or composition that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. A therapeutically effective amount can vary depending on, inter alia, the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
[0072] Treating or treatment of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject. In another embodiment, treating or treatment includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, treating or treatment includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, treating or treatment includes delaying the onset of the disease or disorder.
[0073] As used herein, the terms prophylactic agent and prophylactic agents as used refer to any agent(s) which can be used in the prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term prophylactic agent includes a compound provided herein. In certain other embodiments, the term prophylactic agent does not refer a compound provided herein. For example, a prophylactic agent is an agent which is known to be useful for, or has been or is currently being used to prevent or impede the onset, development, progression and/or severity of a disorder.
[0074] As used herein, the phrase prophylactically effective amount refers to the amount of a therapy (e.g., prophylactic agent) which is sufficient to result in the prevention or reduction of the development, recurrence or onset of one or more symptoms associated with a disorder (, or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent).
[0075] In one embodiment, provided herein is an isolated crystalline form of
[0076] In one embodiment, co-crystal
[0099] In one embodiment, co-crystal
[0100] In one embodiment, co-crystal
[0101] Co-crystal
[0102] In one embodiment, co-crystal
[0106] In one embodiment, the precipitate is allowed to stand for at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, or at least 24 hours in step (c).
[0107] In one embodiment, provided herein is an isolated crystalline form of
[0108] In one embodiment,
[0115] In one embodiment,
[0116] In one embodiment,
[0117] In one embodiment,
[0118] In one embodiment, provided herein is an isolated crystalline form of
[0119] In one embodiment,
[0126] In one embodiment,
[0127] In one embodiment,
[0128] In one embodiment, provided herein is an isolated form of
[0129] In one embodiment,
[0136] In one embodiment, provided herein is an isolated crystalline form of
[0137] In one embodiment,
[0144] In one embodiment,
[0145] In one embodiment,
[0146] In one embodiment, provided herein is an isolated crystalline form of
[0147] In one embodiment,
[0154] In one embodiment,
[0155] In one embodiment,
[0156] In one embodiment, provided herein is an isolated crystalline form of
[0157] In one embodiment,
[0164] In one embodiment,
[0165] In one embodiment,
[0166] In one embodiment, provided herein is an isolated crystalline form of
[0167] In one embodiment,
[0174] In one embodiment,
[0175] In one embodiment,
[0176]
[0177] In one embodiment, provided herein is an isolated crystalline form of the anhydrate free base
[0178] In one embodiment,
[0188] In one embodiment,
[0189] In one embodiment,
[0190] Substantially when describing XRPD patterns is meant that the reported peaks can vary by 0.2.
[0191] Substantially when describing differential scanning calorimetry (DSC) thermographs and a thermogravimetric analysis (TGA) is meant that the reported temperatures can vary by +0.5 C.
[0192] Also provided herein is a salt form of
[0193] In one embodiment, provided herein is a salt form of
[0194] In one embodiment, provided herein is a salt form of
[0195] The salt forms of
[0196] Unless described otherwise the salt forms are substantially
Pharmaceutical Compositions
[0197] The forms of
[0198] The methods provided herein encompass administering pharmaceutical or nutraceutical compositions containing at least one form of
[0199] The term nutraceutical has been used to refer to any substance that is a food or a part of a food and provides medical or health benefits, including the prevention and treatment of disease. Hence, compositions falling under the label nutraceutical may range from isolated nutrients, dietary supplements and specific diets to genetically engineered designer foods, herbal products, and processed foods such as cereals, soups and beverages. In a more technical sense, the term has been used to refer to a product isolated or purified from foods, and generally sold in medicinal forms not usually associated with food and demonstrated to have a physiological benefit or provide protection against chronic disease.
[0200] In pharmaceutical compositions, use may be made, as solid compositions for oral administration, of tablets, pills, hard gelatin capsules, powders or granules. In these compositions, the active product is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.
[0201] In clinical practice the compositions provided herein may be administered by any conventional route, in particular orally, parenterally, rectally or by inhalation (e.g. in the form of aerosols). In certain embodiments, the compositions provided herein are administered orally.
[0202] These compositions can comprise substances other than diluents, for example a lubricant, such as magnesium stearate, or a coating intended for controlled release.
[0203] In certain embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein, or other prophylactic or therapeutic agent), and a typically one or more pharmaceutically acceptable carriers or excipients. In a specific embodiment and in this context, the term pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term carrier includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E. W. Martin.
[0204] Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well-known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific active ingredients in the dosage form. The composition or single unit dosage form, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
[0205] Lactose free compositions provided herein can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) SP (XXI)/NF (XVI). In general, lactose free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.
[0206] Further encompassed herein are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long term storage in order to determine characteristics such as shelf life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379 80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
[0207] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
[0208] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
[0209] Generally, the ingredients of compositions are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
[0210] Typical dosage forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food. Particular dosage forms can have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active compound(s).
[0211] Further, the salt forms of
Topical and Mucosal Delivery
[0212] Also provided herein is a method of making a pharmaceutical composition comprising highly purified
[0213] In one embodiment, the pharmaceutical composition comprising highly purified
[0214] Topical and mucosal dosage forms include, but are not limited to, solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16.sup.th, 18.sup.th and 20.sup.th eds., Mack Publishing, Easton PA (1980, 1990 & 2000); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). In certain embodiments, the dosage form is selected from creams, lotions, gels, ointments, serum, face and body powder, foundation, color makeup, eyeliner, mascara, antiperspirant, deodorant, and micro-sponge.
[0215] The products may be designed to reduce inflammation of the skin, even skin tone, hydrate or moisturize the skin, reduce fine lines and wrinkles, improve skin and such.
[0216] Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are nontoxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16.sup.th, 18.sup.th and 20.sup.th (eds., Mack Publishing, Easton PA (1980, 1990 & 2000).
[0217] Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients provided. For example, penetration enhancers can be used to assist in delivering the active ingredients to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
[0218] The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery enhancing or penetration enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
Methods of Treatment
[0219] In one embodiment, a form of
[0220] Non-limiting examples of inflammatory diseases or disorders include Alzheimer's, arthritis, asthma, atherosclerosis, Crohn's disease, colitis, cystic fibrosis, dermatitis, diverticulitis, hepatitis, irritable bowel syndrome (IBS), lupus erythematous, muscular dystrophy, nephritis, Parkinson's, rheumatoid arthritis, shingles and ulcerative colitis. Inflammatory diseases also include, for example, stroke, cardiovascular disease, chronic obstructive pulmonary disease (COPD), bronchiectasis, chronic cholecystitis, tuberculosis, Hashimoto's thyroiditis, kidney fibrosis, sepsis, sarcoidosis, silicosis and other pneumoconioses.
EXAMPLES
Methods
[0221] In various embodiments, XRPD patterns were collected with a PANalytical XPert PRO MPD or a PANalytical Empyrean diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu K X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640f) was analyzed to verify that the observed position of the Si 111 peak was consistent with the NIST-certified position. A specimen of the sample was sandwiched between 3-m-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, and antiscatter knife edge were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (XCelerator) located 240 mm from the specimen and Data Collector software v. 5.5. The data acquisition parameters for each pattern are displayed above the appropriate FIG.
[0222] In other embodiments, the XRPD patterns were collected with a PANalytical XPert PRO MPD diffractometer using an incident beam of Cu K radiation produced using a long, fine-focus source and a nickel filter. The diffractometer was configured using the symmetric Bragg-Brentano geometry. Prior to the analysis, a silicon specimen (NIST SRM 640f) was analyzed to verify that the observed position of the Si 111 peak was consistent with the NIST-certified position. A specimen of the sample was prepared as a thin, circular layer centered on a silicon zero-background substrate. Antiscatter slits (SS) were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (XCelerator) located 240 mm from the sample and Data Collector software v. 5.5. The data acquisition parameters for each pattern are displayed above the appropriate FIG., including the divergence slit (DS) and the incident-beam SS.
[0223] DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. A tau lag adjustment was performed with indium, tin, and zinc. The temperature and enthalpy were adjusted with octane, phenyl salicylate, indium, tin and zinc. The adjustment was then verified with octane, phenyl salicylate, indium, tin, and zinc. The sample was placed into a hermetically sealed aluminium DSC pan, the weight was accurately recorded, and the sample was inserted into the DSC cell. A weighed aluminium pan configured as the sample pan was placed on the reference side of the cell. The pan lid was pierced prior to sample analysis. The samples were analysed from 25 C. to 250 C. at 10 C./min.
[0224] In other embodiments, DSC was performed using a TA Instruments model Q10 differential scanning calorimeter. The instrument was calibrated using indium. The sample was placed into a standard aluminum DSC pan, covered with a lid, and the weight was accurately recorded. An aluminum pan configured as the sample pan was placed on the reference side of the cell. The pan lid was crimped prior to sample analysis. Samples were analyzed in a single run from 25 to 300 C. at a heating rate of 10 or 20 C./min under nitrogen gas.
[0225] Thermogravimetric (TG) analyses were performed using a Mettler-Toledo TGA/DSC3+ analyzer. Temperature and enthalpy adjustments were performed using indium, tin, and zinc, and then verified with indium. The balance was verified with calcium oxalate. The sample was placed in an aluminum pan. The pan was hermetically sealed, the lid pierced, and the pan was then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference platform. The furnace was heated under nitrogen. Samples were analyzed from 25 C. to 350 C. at 10 C./min. Thermogravimetric analyses typically experience a period of equilibration at the start of each analysis, indicated by red parentheses on the thermograms. The starting temperature for relevant weight loss calculations is selected at a point beyond this region (typically above 35 C.) for accuracy. DSC analysis on this instrument is less sensitive than on the DSC3+ differential scanning calorimeter. Therefore, in certain embodiments, samples with sufficient solids were analyzed by both instruments and the TGA thermogram from Mettler-Toledo TGA/DSC3+ analyzer is reported below.
[0226] Moisture sorption/desorption data were collected on a VTI SGA-100 Vapor Sorption Analyzer. Samples were not dried prior to analysis. Sorption and desorption data were collected over a range from 5% to 95% RH at 10% RH increments under a dry air purge. The equilibrium criterion used for analysis was less than 0.0100% weight change in 5 minutes with a maximum equilibration time of 3 hours with a 2-minute data logging interval. Data were not corrected for the initial moisture content of the samples.
[0227] Ion chromatography analyses were performed using a Dionex ICS-5000.sup.+ series ion chromatograph. The ICS-5000.sup.+ consists of two chromatography systems that share an autosampler. The system used for anion detection was equipped with a gradient pump, an eluent generator module, a conductivity detector, and a suppressor (AERS 4 mm). A Dionex UTAC-ULP1 523 mm concentrator column was installed in place of the sample loop. A Dionex IonPac AG19 450 mm guard column and a Dionex IonPac AS19 4250 mm analytical column were installed. Water (18.2 M, dispensed from ELGA Purelab Flex 2) was used to fill the eluent reservoir, for standard preparations, and for autosampler flush. DMSO was used for sample preparation and associated blank injections.
[0228] For optical microscopy, samples were observed under a Motic or Wolfe optical microscope with crossed polarizers or under a Leica stereomicroscope with a first order red compensator with crossed polarizers.
[0229] The solution NMR spectra were acquired with an Avance 600 MHz spectrometer. The samples were prepared by dissolving approximately 5-10 mg of sample in DMSO-d6 containing TMS.
Example 1. Salt Studies of
[0230] A number of salt forms of
[0231] Two forms of
[0232] All salt forms discussed below were formed from a mixture of
TABLE-US-00001 TABLE 1 Coformers used in Salt Studies Wermuth Class pKa1 pKa2 pKa3 1 4.76 Acetic Acid 4.44 5.44 Adipic 1.88 3.65 9.6 L-Aspartic 3.13 4.76 6.40 Citric 3.03 4.38 Fumaric ~6.1 Hydrochloric 1.92 6.23 Maleic 1.96 7.12 12.32 Phosphoric 3 1.92 Sulfuric 3.02 4.36 (+)-L-Tartaric 2 4.19 Benzoic 2.17 (+)-Camphor-10- sulfonic 1.2 Methanesulfonic GRAS Calcium chloride
[0233] Unique crystalline materials were isolated from the acetate, benzoate, fumarate, hydrochloride, maleate, phosphate, sulfate, and tartrate salt/cocrystal study and from the ionic calcium chloride cocrystal study. The experimental conditions and characterization of the crystalline materials are discussed below.
[0234] The approximate solubility of the
TABLE-US-00002 TABLE 2 Solubility of L-Ergothioneine mixture used in salt studies Solvent Temperature Solubility (mg/mL)* Acetone RT <3 1,4-dioxane RT <3 Et.sub.2O RT <2 EtOAc RT <3 HFIPA RT 3 MeOH RT <2 60 C. <2 THF RT <21 *Solubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions used or a slow rate dissolution. Values are rounded to the nearest whole number. If dissolution did not occur as determined by visual assessment, the value is reported as <. If dissolution occurred as determined by the visual assessment after the addition of the first aliquot, the value is reported as >.
[0235]
TABLE-US-00003 TABLE 3 Studies for the Isolation of L-Ergothioneine Phosphoric Acid Cocrystal Form A Technique Result 1 1. L-Ergothioneine Form A/B contacted with Phosphate A + a molar eq. of acid in MeOH free form 2. slurry, RT, 5 d protected from light anhydrous 3. filtered, N.sub.2 dried 2 1. L-Ergothioneine Form A/B in acetic acid, Phosphate A 75 C. hot plate 2. water added 3. molar eq. of acid added, heat off 4. RT, overnight protected from light 5. filtered, N.sub.2 dried 3 Phosphate Form A from (2) above filtrate Phosphate A 1. fast evaporation partial 2. filtered, N.sub.2 dried B = birefringence and NB = no birefringence upon observation by polarized light microscopy.
[0236] A crystal of sufficient size and quality for single crystal structure elucidation was culled. The crystal system was monoclinic and the space group was C2. The cell parameters and calculated volume were: a=30.7749 (5) , b=6.01160 (10) , c=7.80400 (10) , =90, =95.7830 (10), =90, V=1436.44 (4) 3. The formula weight was 327.29 g mol.sup.1 with Z=4, resulting in a calculated density\\\ of 1.513 g cm.sup.3. Additional details of the crystal data and crystallographic data collection parameters are summarized in Table 4.
TABLE-US-00004 TABLE 4 Crystal Data and Data Collection Parameters for L-Ergothioneine Phosphoric Acid Cocrystal Form A Empirical formula C.sub.9H.sub.18N.sub.3O.sub.6PS Formula weight (g mol.sup.1) 327.29 Temperature (K) 299.77(10) Wavelength () 1.54184 Crystal system monoclinic Space group C2 Unit cell parameters a = 30.7749(5) a = 90 b = 6.01160(10) /3 = 95.7830(10) c = 7.80400(10) = 90 Unit cell volume (.sup.3) 1436.44(4) Cell formula units, Z 4 Calculated density (g cm.sup.3) 1.513 Absorption coefficient (mm.sup.1) 3.345 F(000) 688 Crystal size (mm.sup.3) 0.11 0.08 0.04 Reflections used for cell measurement 5366 O range for cell measurement 5.6890-75.5940 Total reflections collected 6274 Index ranges 37 h 38; 7 k 7; 9 l < 8 O range for data collection Omin = 5.698, Omax = 75.789 Completeness to Omax 99% Completeness to Ofull = 67.684 99.9% Absorption correction multi-scan Transmission coefficient range 0.838-1.000 Refinement method full matrix least-squares on F2 Independent reflections 2886 [Rint = 0.0159, R = 0.0206] Reflections [I > 2(I)] 2834 Reflections/restraints/parameters 2886/1/253 Goodness-of-fit on .sub.F2 S = 1.04 Final residuals [I > 2(I)] R = 0.0212, Rw = 0.0561 Final residuals [all reflections] R = 0.0216, Rw = 0.0564 Largest diff. peak and hole (e .sup.3) 0.167, 0.190 Max/mean shift/standard uncertainty 0.002/0.000 Absolute structure determination Flack parameter: 0.000(7)
[0237] An atomic displacement ellipsoid drawing of
[0238] Table 5 is a list of the XRPD peaks for the
TABLE-US-00005 TABLE 5 Peaks of the XRPD pattern of L-Ergothioneine Phosphoric Acid Cocrystal Form A 2 d space () Intensity (%) 5.77 0.20 15.312 0.550 4 11.38 0.20* 7.768 0.138 52 11.57 0.20 7.645 0.134 3 12.25 0.20 7.219 0.119 8 13.27 0.20 6.666 0.102 7 14.99 0.20* 5.905 0.079 100 15.41 0.20* 5.746 0.075 13 17.10 0.20 5.182 0.061 52 17.36 0.20 5.103 0.059 3 18.68 0.20* 4.745 0.051 87 19.05 0.20* 4.654 0.049 27 19.82 0.20* 4.476 0.045 29 20.09 0.20 4.417 0.044 6 20.69 0.20* 4.290 0.041 68 21.07 0.20* 4.212 0.040 71 21.78 0.20* 4.078 0.037 53 22.93 0.20 3.875 0.034 26 23.03 0.20 3.859 0.033 30 23.25 0.20 3.823 0.033 4 24.20 0.20 3.675 0.030 14 24.38 0.20* 3.648 0.030 48 24.63 0.20* 3.611 0.029 13 24.88 0.20 3.575 0.029 3 25.17 0.20* 3.535 0.028 12 26.82 0.20 3.321 0.024 19 27.22 0.20* 3.273 0.024 23 27.42 0.20 3.250 0.023 13 27.73 0.20* 3.215 0.023 15 27.98 0.20 3.187 0.022 9 28.54 0.20* 3.125 0.022 15 29.16 0.20 3.060 0.021 4 29.43 0.20 3.033 0.020 3 29.68 0.20* 3.007 0.020 22 29.91 0.20 2.984 0.020 4 30.27 0.20 2.951 0.019 35 *Prominent peaks
[0239] Solution .sup.1H NMR spectrum was consistent with the chemical structure of
[0240]
[0241] The XRPD pattern of acetate Form A is shown in
TABLE-US-00006 TABLE 6 Peaks of the XRPD pattern of L-Ergothioneine Acetate Form A 2 d space () Intensity (%) 5.30 0.20* 16.663 0.653 41 10.63 0.20* 8.316 0.159 11 12.52 0.20* 7.065 0.114 50 14.51 0.20 6.101 0.085 5 14.82 0.20* 5.971 0.081 11 15.83 0.20* 5.595 0.071 26 15.98 0.20 5.542 0.070 6 17.93 0.20* 4.942 0.055 15 18.35 0.20* 4.831 0.053 35 19.50 0.20* 4.548 0.047 100 20.84 0.20* 4.259 0.041 33 21.06 0.20* 4.215 0.040 18 21.34 0.20 4.160 0.039 9 21.91 0.20* 4.053 0.037 61 22.16 0.20* 4.008 0.036 48 22.65 0.20 3.923 0.035 9 23.40 0.20* 3.799 0.032 63 23.71 0.20* 3.749 0.031 35 24.73 0.20* 3.597 0.029 17 25.17 0.20 3.535 0.028 7 25.44 0.20 3.499 0.027 7 26.12 0.20 3.409 0.026 6 26.81 0.20 3.323 0.025 13 27.22 0.20 3.273 0.024 24 27.37 0.20 3.255 0.024 9 29.00 0.20* 3.077 0.021 28 29.35 0.20 3.041 0.020 5 29.63 0.20 3.012 0.020 7 30.05 0.20* 2.971 0.019 12 30.53 0.20* 2.925 0.019 14 *Prominent peaks
[0242] The solution .sup.1H NMR spectrum was consistent with the chemical structure of
[0243] The thermograms are provided in
[0244]
[0245] The XRPD pattern of
TABLE-US-00007 TABLE 7 Peaks of the XRPD pattern of L-Ergothioneine Benzoate Form A 2 d space () Intensity (%) 4.20 0.20* 21.040 1.053 100 8.41 0.20* 10.508 0.256 8 12.55 0.20* 7.046 0.114 35 12.80 0.20 6.909 0.109 4 13.67 0.20* 6.472 0.096 14 14.34 0.20* 6.172 0.087 13 15.48 0.20* 5.721 0.074 21 16.85 0.20 5.259 0.063 14 17.13 0.20* 5.172 0.061 9 18.80 0.20* 4.716 0.050 29 19.57 0.20 4.532 0.046 50 19.67 0.20 4.509 0.046 45 19.95 0.20* 4.446 0.045 22 20.29 0.20 4.373 0.043 3 20.74 0.20* 4.279 0.041 14 21.14 0.20 4.199 0.040 2 21.83 0.20 4.069 0.037 2 22.21 0.20 3.999 0.036 2 22.56 0.20* 3.938 0.035 59 23.41 0.20* 3.796 0.032 21 24.08 0.20* 3.692 0.030 26 24.99 0.20 3.561 0.028 10 25.39 0.20 3.506 0.027 4 25.84 0.20 3.445 0.026 7 25.94 0.20 3.432 0.026 9 26.10 0.20 3.411 0.026 4 26.82 0.20 3.321 0.024 6 27.06 0.20 3.293 0.024 2 27.58 0.20* 3.232 0.023 10 27.88 0.20* 3.198 0.023 12 29.38 0.20 3.038 0.020 9 *Prominent peaks
[0246] The solution .sup.1H NMR spectrum was consistent with the chemical structure of
[0247]
[0248] The XRPD pattern representing
TABLE-US-00008 TABLE 8 Peaks of the XRPD pattern of L-Ergothioneine Calcium Chloride Material A 2 d space () Intensity (%) 5.22 0.20 16.930 0.675 14 10.46 0.20 8.448 0.164 14 12.07 0.20* 7.328 0.123 51 14.41 0.20 6.143 0.086 21 15.09 0.20* 5.866 0.078 74 15.61 0.20 5.672 0.073 28 17.30 0.20 5.122 0.059 20 17.83 0.20* 4.970 0.056 46 18.65 0.20 4.754 0.051 44 18.80 0.20 4.716 0.050 100 19.32 0.20 4.591 0.048 25 19.85 0.20 4.468 0.045 24 20.26 0.20 4.381 0.043 25 21.01 0.20 4.225 0.040 29 21.19 0.20* 4.189 0.039 56 21.39 0.20 4.150 0.039 25 22.04 0.20* 4.029 0.036 84 22.83 0.20 3.892 0.034 24 23.06 0.20 3.853 0.033 31 23.23 0.20* 3.826 0.033 45 23.68 0.20 3.754 0.032 25 24.08 0.20 3.692 0.030 22 24.30 0.20 3.660 0.030 26 24.43 0.20* 3.640 0.030 42 25.39 0.20 3.506 0.027 20 26.14 0.20 3.407 0.026 27 26.47 0.20 3.364 0.025 26 26.62 0.20 3.346 0.025 32 27.66 0.20 3.223 0.023 33 28.03 0.20 3.181 0.022 26 28.31 0.20 3.150 0.022 34 28.51 0.20 3.128 0.022 28 29.65 0.20 3.011 0.020 27 *Prominent peaks
[0249]
[0250] The XRPD pattern of hemifumarate Form A is shown in
TABLE-US-00009 TABLE 9 Peaks of the XRPD pattern of L-Ergothioneine hemifumarate Form A 2 d space () Intensity (%) 5.65 0.20* 15.629 0.573 37 11.32 0.20* 7.814 0.140 11 12.18 0.20* 7.258 0.121 32 12.57 0.20 7.037 0.113 9 14.27 0.20* 6.200 0.088 38 15.09 0.20 5.866 0.078 3 15.26 0.20 5.802 0.077 3 16.13 0.20* 5.491 0.068 53 17.01 0.20 5.207 0.061 4 17.98 0.20* 4.929 0.055 65 18.90 0.20* 4.691 0.050 17 19.27 0.20* 4.602 0.048 100 19.45 0.20 4.559 0.047 25 19.69 0.20* 4.506 0.046 34 20.82 0.20 4.262 0.041 8 21.51 0.20* 4.128 0.038 76 22.56 0.20 3.938 0.035 9 22.83 0.20* 3.892 0.034 99 23.56 0.20* 3.772 0.032 24 24.03 0.20* 3.700 0.031 43 24.57 0.20* 3.621 0.029 60 25.35 0.20 3.510 0.027 3 26.12 0.20* 3.409 0.026 27 27.24 0.20 3.271 0.024 11 27.39 0.20 3.253 0.023 14 27.64 0.20 3.224 0.023 13 28.51 0.20 3.128 0.022 52 28.69 0.20 3.109 0.021 16 28.93 0.20 3.084 0.021 15 29.61 0.20 3.014 0.020 4 *Prominent peaks
[0251] The solution 1H NMR spectrum was consistent with the chemical structure of
[0252]
TABLE-US-00010 TABLE 10 Studies for the Isolation of L-Ergothioneine Hydrochloride Form A Technique Result 1. L-Ergothioneine Form A/B in a MeOH slurry HCl C + 2. a molar eq. acid added slowly HCl A 3. filtered 4. refrigerated, 4 d 5. fast evaporation partial 6. evaporation complete 1. L-Ergothioneine Form A/B in aMeOH slurry HCl A + 2. a molar eq. acid added HCl B 3. MeOH added 4. filtered 5. EtOAc added 6. 8609-44-01 seed added with EtOAc 7. refrigerated, 30 min 8. freezer, 1 d 9. filtered, N.sub.2 dried HCl C + HCl A filtrate HCl A 1. transferred to vial 2. N.sub.2 evaporation partial 3. EtOAc added 4. MeOH added 5. filtered, EtOAc rinse, N.sub.2 dried
[0253] The XRPD pattern of HCl Form A is shown in
[0254] Table 11 is a list of the XRPD peaks for the
TABLE-US-00011 TABLE 11 Peaks of the XRPD pattern of L-Ergothioneine Hydrochloride Form A 2 d space () Intensity (%) 12.10 0.20* 7.306 0.122 11 13.39 0.20* 6.607 0.100 25 14.03 0.20 6.309 0.091 18 14.13 0.20* 6.264 0.090 52 17.22 0.20* 5.146 0.060 29 17.52 0.20* 5.058 0.058 64 18.17 0.20* 4.878 0.054 13 18.64 0.20 4.757 0.051 12 18.91 0.20* 4.690 0.050 100 21.16 0.20* 4.195 0.040 56 22.58 0.20 3.934 0.035 6 22.85 0.20 3.889 0.034 5 23.92 0.20 3.717 0.031 6 24.17 0.20* 3.679 0.030 39 24.34 0.20 3.654 0.030 8 24.52 0.20* 3.627 0.029 24 24.69 0.20 3.603 0.029 8 25.37 0.20* 3.507 0.027 62 25.71 0.20 3.463 0.027 22 26.53 0.20 3.358 0.025 11 26.71 0.20 3.335 0.025 8 26.94 0.20 3.306 0.024 10 27.11 0.20 3.286 0.024 5 27.68 0.20 3.220 0.023 7 28.06 0.20 3.177 0.022 10 28.25 0.20 3.157 0.022 10 28.57 0.20 3.122 0.022 19 28.97 0.20* 3.080 0.021 36 29.48 0.20 3.027 0.020 12 *Prominent peaks
[0255] The solution .sup.1H NMR spectrum of the mixture substantially composed of
[0256] Thermograms of the mixture substantially composed of
[0257] A mixture of
[0258] The predominant component in the XRPD pattern exhibited by the mixture was visually similar to hemifumarate Form A (
[0259] A solution of 30.8 L sulfuric acid and 129.2 mg of
[0260] The XRPD pattern of sulfate Form A is shown in
[0261] Table 12 is a list of the XRPD peaks for the
TABLE-US-00012 TABLE 12 Peaks of the XRPD pattern of L-Ergothioneine Sulfate Form A 2 d space () Intensity (%) 5.83 0.20* 15.137 0.537 10 11.97 0.20* 7.390 0.125 10 13.02 0.20 6.794 0.106 3 14.52 0.20* 6.094 0.085 29 16.71 0.20* 5.300 0.064 72 17.55 0.20 5.050 0.058 5 18.42 0.20 4.813 0.052 22 18.60 0.20* 4.766 0.051 76 19.29 0.20 4.598 0.048 7 20.41 0.20* 4.349 0.043 100 21.09 0.20* 4.209 0.040 94 21.83 0.20* 4.069 0.037 63 22.65 0.20* 3.923 0.035 16 23.33 0.20 3.810 0.032 19 23.55 0.20 3.775 0.032 57 24.07 0.20 3.695 0.031 7 24.95 0.20 3.566 0.028 11 25.05 0.20 3.552 0.028 10 25.50 0.20 3.490 0.027 5 26.15 0.20 3.404 0.026 9 27.66 0.20 3.223 0.023 20 28.04 0.20* 3.179 0.022 25 28.64 0.20 3.114 0.021 13 29.01 0.20 3.075 0.021 6 29.50 0.20 3.026 0.020 7 29.98 0.20 2.978 0.020 17 *Prominent peaks
[0262] The TGA thermogram (
[0263] A slurry of 182.3 mg of
[0264] The XRPD pattern of hemitartrate Form A is shown as
[0265] Table 13 is a list of the XRPD peaks for the
TABLE-US-00013 TABLE 13 Peaks of the XRPD pattern of L-Ergothioneine Hemitartrate Form A 2 d space () Intensity (%) 5.55 0.20* 15.911 0.594 20 11.13 0.20 7.942 0.145 9 12.08 0.20 7.318 0.123 51 12.22 0.20 7.238 0.120 15 14.32 0.20* 6.179 0.087 65 14.64 0.20 6.045 0.083 9 14.97 0.20 5.911 0.080 13 15.53 0.20* 5.703 0.074 31 16.41 0.20* 5.397 0.066 32 18.10 0.20* 4.897 0.054 90 18.53 0.20* 4.783 0.052 100 18.85 0.20* 4.703 0.050 29 19.42 0.20 4.567 0.047 83 19.69 0.20 4.506 0.046 14 20.07 0.20 4.420 0.044 12 20.69 0.20* 4.290 0.041 26 21.33 0.20 4.163 0.039 47 21.56 0.20 4.119 0.038 83 22.65 0.20 3.923 0.035 22 23.18 0.20 3.834 0.033 91 23.77 0.20 3.741 0.031 16 24.50 0.20 3.630 0.029 46 26.10 0.20 3.411 0.026 58 26.56 0.20* 3.354 0.025 18 26.92 0.20* 3.309 0.024 23 27.69 0.20 3.219 0.023 20 28.09 0.20 3.174 0.022 30 28.46 0.20 3.134 0.022 28 28.88 0.20 3.089 0.021 14 29.18 0.20 3.058 0.021 12 29.56 0.20 3.019 0.020 12 *Prominent peaks
[0266] The material was difficult to filter and was isolated as a wet cake; the residual methanol is likely due to the inefficiency of the filtration process. The 1H NMR spectrum is consistent with the chemical structure of
Example 2. Characterization of
[0267]
[0268] The crystal system was orthorhombic and the space group was P2.sub.12.sub.12.sub.1. The cell parameters and calculated volume were: a=8.9959 (2) , b=10.8401 (2) , c=11.5979 (3) , =90, =90, =90, V=1130.99 (4) .sup.3. The molecular weight was 229.30 g mol.sup.1 with Z=4, resulting in a calculated density of 1.347 g cm.sup.3. Further details of the crystal data and crystallographic data collection parameters are summarized in Table 14.
TABLE-US-00014 TABLE 14 Crystal Data and Data Collection Parameters for L-Ergothioneine Form C Anhydrate Empirical formula C.sub.9H.sub.15N.sub.3O.sub.2S Formula weight (g mol.sup.1) 229.30 Temperature (K) 299.58(11) Wavelength () 1.54184 Crystal system orthorhombic Space group P212121 Unit cell parameters a = 8.9959(2) a = 90 b = 10.8401(2) /1 = 90 c = 11.5979(3) y = 90 Unit cell volume (.sup.3) 1130.99(4) Cell formula units, Z 4 Calculated density (g cm.sup.3) 1.347 Absorption coefficient (mm.sup.1) 2.446 F(000) 488 Crystal size (mm.sup.3) 0.1 0.07 0.06 Reflections used for cell measurement 3337 O range for cell measurement 5.5750-75.4900 Total reflections collected 4844 Index ranges 11 h 7; 13 k 13; 12 l 14 O range for data collection Omin = 5.586, Omax = 75.820 Completeness to Omax 97.7% Completeness to Ofull = 67.684 100% Absorption correction multi-scan Transmission coefficient range 0.707-1.000 Refinement method full matrix least-squares on F2 Independent reflections 2268 [Rint = 0.0360, R = 0.0422] Reflections [I > 2(I)] 2179 Reflections/restraints/parameters 2268/0/196 Goodness-of-fit on .sub.F2 S = 1.06 Final residuals [I > 2(I)] R = 0.0411, Rw = 0.1037 Final residuals [all reflections] R = 0.0423, Rw = 0.1047 Largest diff. peak and hole (e .sup.3) 0.486, 0.204 Max/mean shift/standard uncertainty 0.000/0.000 Absolute structure determination Flack parameter: 0.024(14)
[0269] An atomic displacement ellipsoid drawing of
TABLE-US-00015 TABLE 15 Peaks of the XRPD pattern of L-Ergothioneine Form C Anhydrate 2 d space () Intensity (%) 11.17 0.20* 7.916 0.144 12 12.44 0.20* 7.110 0.116 23 12.77 0.20* 6.925 0.110 51 14.90 0.20* 5.943 0.080 14 15.26 0.20* 5.800 0.077 16 16.35 0.20 5.417 0.067 3 17.32 0.20 5.116 0.059 4 18.05 0.20 4.910 0.055 18 18.19 0.20 4.874 0.054 39 19.09 0.20 4.645 0.049 3 19.72 0.20* 4.497 0.046 100 19.96 0.20* 4.445 0.045 72 20.59 0.20* 4.309 0.042 14 21.16 0.20* 4.195 0.040 13 21.36 0.20* 4.156 0.039 29 22.45 0.20 3.957 0.035 5 22.72 0.20* 3.911 0.034 19 24.55 0.20 3.622 0.029 21 25.04 0.20* 3.553 0.028 34 25.82 0.20 3.447 0.026 5 26.39 0.20 3.374 0.025 7 26.88 0.20* 3.314 0.024 16 27.70 0.20* 3.218 0.023 18 28.35 0.20 3.146 0.022 6 29.12 0.20 3.064 0.021 3 30.07 0.20 2.969 0.019 6 30.47 0.20* 2.931 0.019 12 *Prominent peaks
[0270] Two other forms of
[0271] The TGA and DSC thermograms for Form C Anhydrate are presented in
Example 3. Physical Stability of
[0272] The DVS isotherm indicated that Form A exhibits low hygroscopicity from 5 to 85% RH and significant hygroscopicity above 85% RH. Consistent with the DVS result, the critical water activity between the anhydrate and the dihydrate was tentatively determined to fall between 0.76 and 0.85 aw, above which hydration to Form B Dihydrate will occur. This is also consistent with the physical stability assessment at 33, 75, and 95% RH for 22 days; Form A Anhydrate remained Form A below the critical water activity, while hydration to Form B Dihydrate occurred above (Table 16).
TABLE-US-00016 TABLE 16 Physical Stability L-Ergothioneine Form A Anhydrate Condition Results 33% RH, RT, 22 days A 75% RH, RT, 22 days A 95% RH, RT, 22 days B
[0273] The physical stability assessment at 33, 75, and 95% RH for 22 days showed that Form B Dihydrate was sustained at 75% RH and above within the timeframe evaluated. The material did partially dehydrate to a small quantity of both Forms A and C Anhydrates at 33% RH.
[0274] Form C Anhydrate is monotropically related and thermodynamically metastable relative to Form A. Form C exhibits a congruent melt and decomposition onset near 265 C. as described in Example 2.
[0275] The DVS isotherm indicated that Form C exhibits limited hygroscopicity from 5 to 85% RH and significant hygroscopicity above 85% RH (
[0276] The physical stability assessment at 75 and 95% RH for 22 days is consistent the DVS results above; Form C remained at 75% RH, while hydration to Form B Dihydrate occurred at 95% RH (Table 17).
TABLE-US-00017 TABLE 17 Physical Stability for L-Ergothioneine Form C Anhydrate Condition Results 75% RH, RT, 22 days Form C 95% RH, RT, 22 days Form B
Example 4. Thermodynamic Stability
[0277] Phase transitions of solids can be thermodynamically reversible or irreversible. Crystalline forms which transform reversibly at a specific transition temperature are called enantiotropic polymorphs. If the crystalline forms are not interconvertible under these conditions, the system is monotropic (one thermodynamically stable form). Several rules help predict the relative thermodynamic stability of polymorphs and whether the relationship between the polymorphs is enantiotropic or monotropic. The density and heat of fusion rules, justified on a statistical mechanical basis, are used here for guidance of monotropy or enantiotropy.
[0278] The density rule, which is based on Kitagorodski's principle of closest packing for molecular crystals (Kitagorodski, A. I. Molecular Crystals and Molecules; Academic Press: New York, 1973), states that, for a non-hydrogen-bonded system at absolute zero, the most stable polymorph will have the highest density, because of stronger intermolecular van der Waals interactions. Thus, according to this rule, the crystal structure with the most efficient packing will also have the lowest free energy. This assumes that hydrogen bonding (long range effect) is not a major parameter in crystal packing. The densities determined from the indexing results of Form A (1.42 g cm.sup.3) and the single crystal structure of Form C (1.35 g cm.sup.3) suggest that, at absolute zero, Form A is more stable than Form C.
[0279] The melt onsets and heats of fusion, obtained from calorimetry data, are normally useful to estimate the relative physical stabilities of polymorphic pairs. Due to concomitant decomposition at the melt, the heats of fusion values for each form of
[0280] Interconversion slurry experiments are a solution-mediated process that provides a pathway for the less soluble (more stable) crystal to grow at the expense of the more soluble crystal form (Bernstein, J. Polymorphism in Molecular Crystals. Clarendon Press, Oxford, 2006; Polymorphism in Pharmaceutical Solids. Brittain, Harry G. ed. Marcek Dekker, Inc. New York. 1999). Outside the formation of a solvate or degradation, the resulting more stable polymorph from an interconversion experiment is independent of the solvent used because the more thermodynamically stable polymorph has a lower energy and therefore lower solubility. The choice of solvent affects the kinetics of polymorph conversion and not the thermodynamic relationship between polymorphic forms (Gu, CH., Young, V. Jr., Grant, DJ. J. Pharm. Sci 2001; 90 (11): 1878-1890). Competitive slurry experiments conducted in solvent systems that provide at least about 3 mg/mL (or about 8 mM) solubility should complete within a reasonable timeframe.
[0281] Finding a solvent system with adequate solubility that did not form solvates with
TABLE-US-00018 TABLE 18 Forms A and C Interconversion Experiments at Room Temperature and 75 C. Solvent Condition Result EtOH 75 C., 14 days A + C EtOH 75 C., 28 days A + C (minor) MeOH RT, 14 days A
[0282] Although the dihydrate of
TABLE-US-00019 TABLE 19 Trituration of Form C in Aqueous Methanol below the Critical Water Activity at Room Temperature v/v Solvent(s) a.sub.w Condition Result 20:80 water/MeOH 0.47 RT, 5 d A 15:85 water/MeOH 0.39 RT, 5 d A 10:90 water/MeOH 0.29 RT, 5 d A + C (minor) 3:97 water/MeOH 0.10 RT, 5 d C
[0283] The interconversion and trituration experiments confirm that Form A is the more thermodynamically stable form, relative to Form C, at the temperatures evaluated.
Example 5. Stability of the Hydrates
[0284] Water activity is related to relative humidity in that RH %=a.sub.w100. Therefore, it is possible to directly relate the stability of an anhydrous/hydrate system in slurry experiments to solid state stability. Literature suggests that the slurry technique at controlled water activities provides an accurate method of rapidly predicting the physically stable form in anhydrous/hydrate systems (Ticehurst M D, Storey R A, Claire W. Int J Pharm. 2002; 247:1-10; Sacchetti M. Int J Pharm. 2004; 273:195-202; Zhu H, Yuen C, Grant D J W. 1. Theophylline. Int J Pharm. 1996; 135:151-160; Zhu H, Grant D J W. 2. Ampicillin. Int J Pharm. 1996; 139:33-43).
[0285] The method is particularly valuable when slow kinetics of conversion in the solid state prevents reaching true equilibrium in a reasonable timeframe, since solvent-mediated transformation accelerates the conversion process.
[0286] The effect of relative humidity (RH) and water activity (aw) on the hydration state of
TABLE-US-00020 TABLE 20 Water Activity Experiments of Form A and Form C at RT v/v Solvent(s) a.sub.w Method Observation Result 70:30 water/MeOH 0.86 RT, 13 d Birefringent plates B (PO) 50:50 water/MeOH 0.76 RT, 13 d Birefringent plates, wet solids A A + B + anotherform A + B + anotherform A + B + anotherform A + B + anotherform A + B + anotherform 20:80 water/MeOH 0.47 RT, 8 d Small birefringent blades B + A + C 20:80 water/MeOH 0.47 RT, 14 d Unknown morphology, birefringent A + B 15:85 water/MeOH 0.39 RT, 8 d Small birefringent blades B + A + C + anotherform 15:85 water/MeOH 0.39 RT, 14 d Unknown morphology, birefringent A
Example 6. Characterization of
[0287]
TABLE-US-00021 TABLE 21 Crystal Data and Data Collection Parameters for DL-Ergothioneine Form A Space group P2.sub.1/C Cell Volume (.sup.3) 1319.51 a () 15.103 () 90 b () 6.059 () 77.12 c () 14.791 () 90 d.sub.samp (mm) 0.094 R.sub.wp 9.1% * * many minor peaks are not accounted for by this indexing solution, indicating the presence of an impurity: 12.5, 15.0, 15.8, 18.0, 21.2, 25.6, 27.9, 29.8, . . .
[0288] Molecular volumes are predicted according to Hofmann [0]:
[0289] The embodiments and examples described above are intended to be merely illustrative and non-limiting. Those skilled in the art will recognize or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials and procedures. All such equivalents are considered to be within the scope and are encompassed by the appended claims.