Methods for treating a fatty liver disease

Abstract

The present disclosure provides a method of treating a fatty liver disease (e.g., non-alcoholic steatohepatitis (NASH)) in a human subject (e.g., an adult human subject) in need of such treatment (e.g., NASH / improving liver fibrosis) with 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (resmetirom) or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method of improving liver fibrosis in a human subject (e.g., an adult human subject) in need of such treatment (e.g., NASH / improving liver fibrosis) with 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (resmetirom) or a pharmaceutically acceptable salt thereof.

Description

Ways Treatment illness liver fatty Reference to relevant requests

[0001] This priority application is based on U.S. Patent Application No. 19 / 045,070, filed on February 4, 2025, and U.S. Provisional Patent Application Nos. 63 / 550,201, filed on February 6, 2024, 63 / 564,803, filed on March 13, 2024, 63 / 655,870, filed on June 4, 2024, 63 / 719,257, filed on November 12, 2024, 63 / 720,725, filed on November 14, 2024, and 63 / 721,474, filed on November 16, 2024, disclosures of which are all included herein for reference in their entirety. The technical field of invention

[0002] The current finding relates to the treatment of fatty liver disease, such as, for example, non-alcoholic steatohepatitis (NASH) (e.g., non-fibrotic NASH with moderate to advanced cirrhosis consistent with stages F2 and F3 fibrosis). Specifically, the finding concerns a method for the effective treatment of fatty liver disease (e.g., NASH) using the thyroid hormone receptor agonist (THR-beta) resmeterum or a pharmaceutically acceptable salt thereof. Additionally, the current finding relates to the treatment of stage F2 and F3 cirrhosis associated with fatty liver disease. Specifically, the finding concerns a method for the effective treatment of stage F2 and F3 cirrhosis associated with fatty liver disease, with an improvement in cirrhosis of up to one or two stages, using resmeterum or a pharmaceutically acceptable salt thereof. Technical background of the invention

[0003] Thyroid hormones are crucial for normal growth and development and for maintaining metabolic stasis. Circulatory thyroid hormone levels are tightly regulated by feedback mechanisms in the hypothalamic-pituitary-thyroid (HPT) axis. Thyroid dysfunction, leading to hypothyroidism or hyperthyroidism, clearly demonstrates that thyroid hormones exert profound effects on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone and muscle mass, and behavior.

[0004] The development of thyroid hormone analogs that avoid the unfavorable effects of hypothyroidism and hyperthyroidism while preserving the beneficial effects of thyroid hormones opens up new entry points for the potential treatment of patients with metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other disorders and diseases such as fatty liver and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer, thyroid diseases, thyroid hormone resistance and related disorders and diseases.

[0005] Nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease in the United States. NASH is a fatty inflammation of the liver and a leading cause of fibrosis, cirrhosis, and liver failure. The disease is progressive, beginning with fatty liver or nonalcoholic fatty liver disease (NAFLD), progressing to inflammatory fatty liver (NASH), and eventually leading to fibrosis and cirrhosis. The disease is generally asymptomatic until acute liver failure occurs.

[0006] Human patients undergoing treatment for NASH may experience elevated liver volumes, possibly due to increased liver fat and fluid retention resulting from inflammatory processes in NASH. As NASH progresses to cirrhosis, liver fat decreases as the liver becomes increasingly fibrotic. Liver volume remains elevated in human patients undergoing treatment for cirrhosis due to ongoing inflammation and venous congestion associated with hepatic portal hypertension. Reducing liver volume in non-alcoholic steatohepatitis with moderate to advanced cirrhosis, consistent with fibrosis in human patients at stages F2 and F3, is important for maintaining liver perfusion and reversing disease progression to cirrhosis. Liver volume reduction in both NASH and cirrhosis is associated with histological improvement in the liver.

[0007] The prevalence of NAFLD in the US population is approximately 20–23%, and can reach as high as 33%, while the prevalence of NASH in the US population is approximately 2–3%. Some patients with NASH progress to a late-stage disease: approximately 15–50% of NASH patients progress to severe fibrosis, and approximately 7–16% progress to cirrhosis. The liver mortality rate in NASH cirrhosis is approximately 10% per nodule.

[0008] Obesity is a common feature of both NASH and cirrhosis. Due to insufficient weight loss through diet and lifestyle modifications, this patient group is usually prescribed interventional surgical procedures (e.g., bariatric surgery). There is a trend toward significantly reducing liver size immediately prior to surgery to improve surgical access to the stomach. Invention Disclosure

[0009] Resmeter has previously been mentioned in conjunction with the treatment of fatty liver disease, such as NASH. However, it has now been surprisingly found that a 100 mg dose results in better outcomes than an 80 mg dose in human subjects weighing at least 100 kg. An 80 mg dose is optimal for human subjects weighing less than 100 kg to achieve better outcomes, and discontinuation rates are based on adverse outcomes in similar placebo-controlled clinical trials. These weight-based dosing was recognized by the Food and Drug Administration (FDA) in the REZDIFFRA™ (resmeter) approval, as reflected in the drug information leaflet (https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2024 / 217785s000lbl.pdf, included herein for reference in its entirety) and also illustrated in Figure 46.

[0010] The present invention reveals a method for treating or improving fatty liver disease, such as, for example, non-alcoholic steatohepatitis (NASH) (for example, non-alcoholic fibrotic steatohepatitis with moderate to advanced cirrhosis consistent with fibrosis in stages F2 and F3) in a human subject (for example, an adult human subject) who may be in need of such treatment or improvement.

[0011] Specifically, the present invention reveals a method for treating NASH. The method involves: determining the weight of a human subject undergoing treatment; and, based on the determination of the human subject's weight, administering to the human subject an oral solid dosage form containing: (1) Rismeterum or a pharmaceutically acceptable salt thereof at a dose of 100 mg per day, if it is determined that the human subject to treatment weighs 100 kg or more; or (2) Resmetrium or the pharmaceutically acceptable salt thereof at a dose of 80 mg per day, if it is determined that the human subject to treatment weighs less than 100 kg.

[0012] In some incarnations, it is specified that the human subject to treatment weighs 100 kg or more and is given the solid oral dosage form which includes rhizometrum or the pharmaceutically acceptable salt thereof at a dose of 100 mg per day.

[0013] In some incarnations, it is specified that the human subject under treatment weighs less than 100 kg and is given the solid oral dosage form which includes rhizometrum or the pharmaceutically acceptable salt thereof at a dose of 80 mg per day.

[0014] In some incarnations, the method for treating non-alcoholic non-fibrotic fatty liver disease with moderate to advanced cirrhosis is consistent with stages F2 to F3.

[0015] In some incarnations, the method for treating non-alcoholic non-fibrotic fatty liver disease with moderate to advanced cirrhosis is consistent with stage F1.

[0016] In some incarnations, the method is to improve non-alcoholic non-fibrotic fatty liver disease.

[0017] In some incarnations, the image of the solid oral dose includes resmeteorum.

[0018] In some incarnations, the image of the solid oral dose is a tablet.

[0019] In some incarnations, the human being being treated is an adult human being being treated.

[0020] The present invention also reveals a method for treating or improving liver fibrosis associated with fatty liver disease (e.g., NASH) in a human patient (e.g., an adult human patient) who may need such treatment or improvement.

[0021] Specifically, the present invention reveals a method for treating liver cirrhosis. The method involves: determining the weight of a human subject undergoing treatment; and, based on the determination of the human subject's weight, administering to the human subject an oral solid dosage form containing: (1) Rismeterum or a pharmaceutically acceptable salt thereof at a dose of 100 mg per day, if it is determined that the human subject to treatment weighs 100 kg or more; or (2) Rismeterum or the pharmaceutically acceptable salt thereof at a dose of 80 mg per day, if it is determined that the human subject to treatment weighs less than 100 kg; and Where the human patient undergoing treatment has cirrhosis associated with non-alcoholic steatohepatitis (NASH).

[0022] In some incarnations, the method is to improve liver fibrosis.

[0023] In some incarnations, the human subject undergoing treatment has liver cirrhosis that is classified as stage F1 cirrhosis.

[0024] In some incarnations, the human subject undergoing treatment has liver cirrhosis that is classified as stage F2 cirrhosis.

[0025] In some incarnations, the human subject undergoing treatment has liver cirrhosis that is classified as stage F3 cirrhosis.

[0026] In some incarnations, the method is to improve one stage of liver fibrosis in the human subject undergoing treatment.

[0027] In some incarnations, the method is to improve two-stage liver fibrosis in the human subject undergoing treatment.

[0028] In some incarnations, it is specified that the human subject to treatment weighs 100 kg or more and is given the solid oral dosage form which includes rhizometrum or the pharmaceutically acceptable salt thereof at a dose of 100 mg per day.

[0029] In some incarnations, it is specified that the human subject under treatment weighs less than 100 kg and is given the oral solid dosage form which includes rhizometrum or the pharmaceutically acceptable salt thereof at a dose of 80 mg per day.

[0030] In some incarnations, the image of the solid oral dose includes resmeteorum.

[0031] In some incarnations, the image of the solid oral dose is a tablet.

[0032] In some incarnations, the human being being treated is an adult human being being treated.

[0033] The present invention also reveals a method for treating or improving fatty liver disease (e.g., NASH) in a human patient (e.g., an adult human patient) who may require such treatment or improvement and who may also be on an intermediate CYP2C8 inhibitor regimen. In this case, the human patient is given resmeterum or a pharmaceutically acceptable salt thereof at a dose 20 mg / day lower than that given to the same human patient if treatment were based on a factor other than weight. If the human patient is already taking resmeterum or a pharmaceutically acceptable salt thereof prior to the use of an intermediate CYP2C8 inhibitor, the dose given to the human patient, as determined based on the human patient's weight, is reduced by 20 mg / day to the lower dose during concomitant use of the intermediate CYP2C8 inhibitor.If the human patient has not taken resmetrium or the pharmaceutically acceptable salt thereof prior to the use of an intermediate CYP2C8 inhibitor, the human patient shall start on the low dose and continue to take the low dose, as determined based on the human patient’s weight, during concomitant use of the intermediate CYP2C8 inhibitor.

[0034] Specifically, the present invention reveals a method for treating NASH, which includes: determining the weight of a human subject undergoing treatment; and, based on the determination of the human subject's weight, administering to the human subject an oral solid dosage form containing: (1) Resmeter or a pharmaceutically acceptable salt thereof at a low dose of 80 mg per day, if it is determined that the human subject under treatment weighs 100 kg or more and is using an intermediate CYP2C8 inhibitor; or (2) Resmetrium or the pharmaceutically acceptable salt thereof at a low dose of 60 mg per day, if it is determined that the human subject under treatment weighs less than 100 kg and the human subject under treatment is using an intermediate CYP2C8 inhibitor.

[0035] In some incarnations, it is specified that the human subject to treatment weighs 100 kg or more and is given the solid oral dosage form which includes resmeterum or the pharmaceutically acceptable salt thereof at a low dose of 80 mg per day.

[0036] In some incarnations, it is specified that the human subject under treatment weighs less than 100 kg and is given the solid oral dosage form which includes rhizometrum or the pharmaceutically acceptable salt thereof at a low dose of 60 mg per day.

[0037] In some incarnations, the human subject under treatment had used resmetrium or the pharmaceutically accepted salt thereof at an oral dose of 100 mg the day prior to starting the use of the intermediate CYP2C8 inhibitor, and the oral dose was reduced from 100 mg per day to a low dose of 80 mg per day.

[0038] In some incarnations, the human subject under treatment had used resmetrium or the pharmaceutically accepted salt thereof at an oral dose of 80 mg the day prior to starting the use of the intermediate CYP2C8 inhibitor, and the oral dose of 80 mg per day was reduced to a low dose of 60 mg per day.

[0039] In some incarnations, an intermediate CYP2C8 inhibitor is selected from the group consisting of rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, cresaborol, nabilone, bexarotene, ritonavir, nicardipine, loratadine, eltrombopag, diltiazem, enzalutamide, ketoconazole, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate, spironolactone, amlodipine, saquinavir, abiraterone, genistein, linvatinib, pioglitazone, clotrimazole, nilotinib, teriflunomide, topiroxostate, lovastatin, troglitazone, amitriptyline, pertopretinib, pilenostat, bezafibrate, candesartan, cholecalciferol; Cimetidine, colchicine, dabrafenib, deferasirox, diethylstilbestrol, enasidinib, erlotinib, ethinylestradiol, fenofibrate, gemfibrozil, edelalisib, isoniazid, ketoprofen, letromovir, lomacaftor, mefenamic acid, midostaurin, montelukast, nilutamide, opicabon, phenelzine, piroxicam, pyrimethamine, quercetin, raloxifene, repaglinide, rifampicin, rofecoxib, salmeterol, sorafenib, sulfaphenazolTegaserod, terbinafine, terfenadine, thiazolidine diones, ticlopidine, trametinib, triazolam, troleandomycin, valproic acid, verapamil, vismodegib, clopidogrel, and zafirlukast.

[0040] In some incarnations, the intermediate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and / or pioglitazone.

[0041] In some incarnations, the method for treating non-alcoholic non-fibrotic fatty liver disease with moderate to advanced cirrhosis is consistent with stages F2 to F3.

[0042] In some incarnations, the method for treating non-alcoholic non-fibrotic fatty liver disease with mild cirrhosis is consistent with stage F1.

[0043] In some incarnations, the method is to improve non-alcoholic non-fibrotic fatty liver disease.

[0044] In some incarnations, the image of the solid oral dose includes resmeteorum.

[0045] In some incarnations, the image of the solid oral dose is a tablet.

[0046] In some incarnations, the human being being treated is an adult human being being treated.

[0047] The present invention also reveals a method for treating or improving liver fibrosis associated with fatty liver disease (e.g., NASH) in a human patient (e.g., an adult human patient) who may need such treatment or improvement and who may also be following an intermediate CYP2C8 inhibitor regimen.

[0048] Specifically, the present invention reveals a method for treating liver cirrhosis, which includes: determining the weight of a human subject undergoing treatment; and, based on the determination of the human subject's weight, administering to the human subject an oral solid dosage form containing: (1) Resmeter or a pharmaceutically acceptable salt thereof at a low dose of 80 mg per day, if it is determined that the human subject under treatment weighs 100 kg or more and is using an intermediate CYP2C8 inhibitor; or (2) Resmeter or the pharmaceutically acceptable salt thereof at a low dose of 60 mg per day, if it is determined that the human subject under treatment weighs less than 100 kg and is using an intermediate CYP2C8 inhibitor; and Where the human patient undergoing treatment has cirrhosis associated with non-alcoholic steatohepatitis (NASH).

[0049] In some incarnations, it is specified that the human subject to treatment weighs 100 kg or more and is given the solid oral dosage form which includes resmeterum or a pharmaceutically acceptable salt thereof at a low dose of 80 mg per day.

[0050] In some incarnations, it is specified that the human subject under treatment weighs less than 100 kg and is given the solid oral dosage form which includes rhizometrum or the pharmaceutically acceptable salt thereof at a low dose of 60 mg per day.

[0051] In some incarnations, the human subject under treatment had used resmetrium or the pharmaceutically accepted salt thereof at an oral dose of 100 mg the day prior to starting the use of the intermediate CYP2C8 inhibitor, and the oral dose was reduced from 100 mg per day to a low dose of 80 mg per day.

[0052] In some incarnations, the human subject under treatment had used resmetrium or the pharmaceutically accepted salt thereof at an oral dose of 80 mg the day prior to starting the use of the intermediate CYP2C8 inhibitor, and the oral dose of 80 mg per day was reduced to a low dose of 60 mg per day.

[0053] In some incarnations, the method is to improve liver fibrosis.

[0054] In some incarnations, the human subject undergoing treatment has liver cirrhosis that is classified as stage F1 cirrhosis.

[0055] In some incarnations, the human subject undergoing treatment has liver cirrhosis that is classified as stage F2 cirrhosis.

[0056] In some incarnations, the human subject undergoing treatment has liver cirrhosis classified as stage F3 cirrhosis.

[0057] In some incarnations, the method is to improve one stage of liver fibrosis in the human subject undergoing treatment.

[0058] In some incarnations, the method is to improve two-stage liver fibrosis in the human subject undergoing treatment.

[0059] In some incarnations, an intermediate CYP2C8 inhibitor is selected from the group consisting of rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, cresaborol, nabilone, bexarotene, ritonavir, nicardipine, loratadine, eltrombopag, diltiazem, enzalutamide, ketoconazole, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate, spironolactone, amlodipine, saquinavir, abiraterone, genistein, linvatinib, pioglitazone, clotrimazole, nilotinib, teriflunomide, topiroxostate, lovastatin, troglitazone, amitriptyline, pertopretinib, pilenostat, bezafibrate, candesartan, cholecalciferol; Cimetidine, colchicine, dabrafenib, deferasirox, diethylstilbestrol, enasidinib, erlotinib, ethinylestradiol, fenofibrate, gemfibrozil, edelalisib, isoniazid, ketoprofen, letromovir, lomacaftor, mefenamic acid, midostaurin, montelukast, nilutamide, opicabon, phenelzine, piroxicam, pyrimethamine, quercetin, raloxifene, repaglinide, rifampicin, rofecoxib, salmeterol, sorafenib, sulfaphenazolTegaserod, terbinafine, terfenadine, thiazolidine diones, ticlopidine, trametinib, triazolam, troleandomycin, valproic acid, verapamil, vismodegib, clopidogrel, and zafirlukast.

[0060] In some incarnations, the intermediate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and / or pioglitazone.

[0061] In some incarnations, the image of the solid oral dose includes resmeteorum.

[0062] In some incarnations, the image of the solid oral dose is a tablet.

[0063] In some incarnations, the human being being treated is an adult human being being treated.

[0064] The present invention also reveals resmetrium or a pharmaceutically acceptable salt thereof for use in a method for the treatment of non-alcoholic steatohepatitis (NASH). The method involves: determining the weight of a human subject being treated; and, based on the determination of the human subject being treated's weight, administering to the human subject being an oral solid dosage form containing: (1) Resmeter or the pharmaceutically acceptable salt thereof at a dose of 100 mg per day, if it is determined that the human subject to treatment weighs 100 kg or more; or (2) Resmetrium or the pharmaceutically acceptable salt thereof at a dose of 80 mg per day, if it is determined that the human subject to treatment weighs less than 100 kg.

[0065] In some incarnations, the method for treating non-alcoholic non-fibrotic fatty liver disease with moderate to advanced cirrhosis is consistent with stages F2 to F3.

[0066] In some incarnations, the method for treating non-alcoholic non-fibrotic fatty liver disease with moderate to advanced cirrhosis is consistent with stage F1.

[0067] In some incarnations, the method is to improve non-alcoholic non-fibrotic fatty liver disease.

[0068] The present invention also reveals resmeteorum or a pharmaceutically acceptable salt thereof for use in a method for treating cirrhosis of the liver. The method involves: determining the weight of a human subject under treatment; and, based on the determination of the human subject under treatment's weight, administering to the human subject under treatment orally a solid oral dose form comprising: (1) Resmeter or the pharmaceutically acceptable salt thereof at a dose of 100 mg per day, if it is determined that the human subject to treatment weighs 100 kg or more; or (2) Rismeterum or the pharmaceutically acceptable salt thereof at a dose of 80 mg per day, if it is determined that the human subject to treatment weighs less than 100 kg; and Where the human patient undergoing treatment has cirrhosis associated with non-alcoholic steatohepatitis (NASH).

[0069] In some incarnations, the method is to improve liver fibrosis.

[0070] In some incarnations, the human subject undergoing treatment has liver cirrhosis that is classified as stage F1 cirrhosis.

[0071] In some incarnations, the human subject undergoing treatment has liver cirrhosis that is classified as stage F2 cirrhosis.

[0072] In some incarnations, the human subject undergoing treatment has liver cirrhosis that is classified as stage F3 cirrhosis.

[0073] In some incarnations, the method is to improve one stage of liver fibrosis in the human subject undergoing treatment.

[0074] In some incarnations, the method is to improve two-stage liver fibrosis in the human subject undergoing treatment.

[0075] In some incarnations, it is specified that the human subject to treatment weighs 100 kg or more and is given the solid oral dosage form which includes rhizometrum or the pharmaceutically acceptable salt thereof at a dose of 100 mg per day.

[0076] In some incarnations, it is specified that the human subject under treatment weighs less than 100 kg and is given the oral solid dosage form which includes rhizometrum or the pharmaceutically acceptable salt thereof at a dose of 80 mg per day.

[0077] In some incarnations, the image of the solid oral dose is a tablet.

[0078] In some incarnations, the human being being treated is an adult human being being treated.

[0079] The present invention also reveals resmetrium or a pharmaceutically acceptable salt thereof for use in a method for the treatment of non-alcoholic non-fibrotic fatty liver disease (NASH). The method involves: determining the weight of a human subject under treatment; and, based on the determination of the human subject under treatment's weight, administering to the human subject under treatment orally a solid oral dose form comprising: (1) Resmeter or a pharmaceutically acceptable salt thereof at a low dose of 80 mg per day, if it is determined that the human subject under treatment weighs 100 kg or more and is using an intermediate CYP2C8 inhibitor; or (2) Resmetrium or the pharmaceutically acceptable salt thereof at a low dose of 60 mg per day, if it is determined that the human subject under treatment weighs less than 100 kg and the human subject under treatment is using an intermediate CYP2C8 inhibitor.

[0080] In some incarnations, the method for treating non-alcoholic non-fibrotic fatty liver disease with moderate to advanced cirrhosis is consistent with stages F2 to F3.

[0081] In some incarnations, the method for treating non-alcoholic non-fibrotic fatty liver disease with moderate to advanced cirrhosis is consistent with stage F1.

[0082] In some incarnations, the method is to improve non-alcoholic non-fibrotic fatty liver disease.

[0083] The present invention also reveals resmeteorum or a pharmaceutically acceptable salt thereof for use in a method for treating cirrhosis of the liver. The method includes: (1) Resmeter or a pharmaceutically acceptable salt thereof at a low dose of 80 mg per day, if it is determined that the human subject under treatment weighs 100 kg or more and is using an intermediate CYP2C8 inhibitor; or (2) Resmeter or the pharmaceutically acceptable salt thereof at a low dose of 60 mg per day, if it is determined that the human subject under treatment weighs less than 100 kg and is using an intermediate CYP2C8 inhibitor; and Where the human patient undergoing treatment has cirrhosis associated with non-alcoholic steatohepatitis (NASH).

[0084] In some incarnations, the method is to improve liver fibrosis.

[0085] In some incarnations, the human subject undergoing treatment has liver cirrhosis that is classified as stage F1 cirrhosis.

[0086] In some incarnations, the human subject undergoing treatment has liver cirrhosis that is classified as stage F2 cirrhosis.

[0087] In some incarnations, the human subject undergoing treatment has liver cirrhosis classified as stage F3 cirrhosis.

[0088] In some incarnations, the method is to improve one stage of liver fibrosis in the human subject undergoing treatment.

[0089] In some incarnations, the method is to improve two-stage liver fibrosis in the human subject undergoing treatment.

[0090] In some incarnations, it is specified that the human subject to treatment weighs 100 kg or more and is given the oral solid dosage form which includes resmeterum or the pharmaceutically acceptable salt thereof at a dose of 80 mg per day.

[0091] In some incarnations, it is specified that the human subject under treatment weighs less than 100 kg and is given the solid oral dosage form which includes resmeterum or the pharmaceutically acceptable salt thereof at a dose of 60 mg per day.

[0092] In some incarnations, the human subject under treatment had used resmetrium or the pharmaceutically accepted salt thereof at an oral dose of 100 mg the day prior to starting the use of the intermediate CYP2C8 inhibitor, and the oral dose was reduced from 100 mg per day to a low dose of 80 mg per day.

[0093] In some incarnations, the human subject under treatment had used resmetrium or the pharmaceutically accepted salt thereof at an oral dose of 80 mg the day prior to starting the use of the intermediate CYP2C8 inhibitor, and the oral dose of 80 mg per day was reduced to a low dose of 60 mg per day.

[0094] In some incarnations, an intermediate CYP2C8 inhibitor is selected from the group consisting of rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, cresaborol, nabilone, bexarotene, ritonavir, nicardipine, loratadine, eltrombopag, diltiazem, enzalutamide, ketoconazole, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate, spironolactone, amlodipine, saquinavir, abiraterone, genistein, linvatinib, pioglitazone, clotrimazole, nilotinib, teriflunomide, topiroxostate, lovastatin, troglitazone, amitriptyline, pertopretinib, pilenostat, bezafibrate, candesartan, cholecalciferol; Cimetidine, colchicine, dabrafenib, deferasirox, diethylstilbestrol, enasidinib, erlotinib, ethinylestradiol, fenofibrate, gemfibrozil, edelalisib, isoniazid, ketoprofen, letromovir, lomacaftor, mefenamic acid, midostaurin, montelukast, nilutamide, opicabon, phenelzine, piroxicam, pyrimethamine, quercetin, raloxifene, repaglinide, rifampicin, rofecoxib, salmeterol, sorafenib, sulfaphenazolTegaserod, terbinafine, terfenadine, thiazolidine diones, ticlopidine, trametinib, triazolam, troleandomycin, valproic acid, verapamil, vismodegib, clopidogrel, and zafirlukast.

[0095] In some incarnations, the intermediate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and / or pioglitazone.

[0096] In some incarnations, the image of the solid oral dose includes resmeteorum.

[0097] In some incarnations, the image of the solid oral dose is a tablet.

[0098] In some incarnations, the human being being treated is an adult human being being treated. Brief description of the drawings

[0099] The above features and more features can be more clearly understood from the following detailed description when considered in conjunction with the accompanying figures.

[00100] Figure 1 is a graphic representation showing the correlation between reduced liver volume and reduced protonated liver fat percentage (PDFF) in patients treated with placebo and resmetrium after 12 weeks in Example 1. “PBO” represents placebo patients and “RES” represents patients treated with resmetrium.

[00101] Figure 2 is a graphical representation showing the change in MRI-PDFF (magnetic resonance imaging-PDFF) in several subgroups of patients treated with 100 mg of resmetrium, once daily, for 52 weeks in Example 1. “High SHBG” corresponds to 2 / 3 of the study patients with the highest increase from baseline in sex hormone-binding globulin (SHBG), a biomarker of liver exposure to resmetrium.

[00102] Figure 3 is a graphical representation showing the change in liver volume in several subgroups of patients treated with 100 mg of resmetrium, once daily, for 52 weeks in Example 1. The “high SHBG” 2 / 3 study patients corresponded to the highest increase from baseline in SHBG, a biomarker of liver exposure to resmetrium.

[00103] Figure 4 is a graphic representation showing the changes that resmeteorum contributes to MRI-PDFF and liver (LV) volume at week 52 in Example 1.

[00104] Figure 5 is a graphical representation showing the percentage of patients at week 52 with a 10% decrease or 10% increase in splenic volume (SV) in Example 1.

[00105] Figure 6 is a graph showing the correlation between the change in liver size after 52 weeks and the change in spleen size in patients who entered the study with a baseline PDFF <8% in Example 1.

[00106] Figure 7 is a graphical representation illustrating the study setup in Example 2. CAP: Controlled attenuation variable; LDL-C: Low-density lipoprotein cholesterol; MRE: Magnetic resonance imaging of liver stiffness; MRI-PDFF: Magnetic resonance imaging of liver fat-proton ratio; VCTE: Transient vibration-controlled tissue stiffness measurement.

[00107] Figure 8 is a diagram illustrating the statistical testing process for major primary and secondary endpoints at week 52 in Example 2. LDL-C: Low-density lipoprotein cholesterol.

[00108] Figure 9 is a diagram illustrating patient readiness in Example 2. AE: Side effect; LTFU: Loss of follow-up. The main reasons for biopsy failure include withdrawal of consent, MRI-PDFF <8%, and HbA1c >9. The F1 research group included F1A / F1C patients at baseline (n = 84) who were considered only for research efficacy and safety analyses. These patients received treatment but, as previously defined in the statistical analysis plan, were not included in the main analysis group.

[00109] Figures 10A–10C illustrate the major and major secondary endpoints in Example 2. The two major endpoints at week 52 were achieving treatment for non-alcoholic steatohepatitis (NASH) without worsening fibrosis (List A, Figure 10A) and improvement (reduction) in fibrosis by at least one stage without worsening NAFLD activity scores (List B, Figure 10B). The major secondary endpoint was the percentage change from baseline in low-density lipoprotein (LDL) cholesterol levels at week 24 (List C, Figure 10C). NAFLD activity scores are assessed on a scale of 0 to 8, with higher scores indicating more severe disease; the components of this measure are hepatic fat accumulation (assessed on a scale of 0 to 3), hepatitis (assessed on a scale of 0 to 3), and hepatocellular edema (assessed on a scale of 0 to 2). Treatment of NASH was defined as achieving a hepatocellular bulge score of 0, a lobar inflammatory score of 0 or 1, and a reduction in NAFLD activity score of at least 2. Fibrosis stages ranged from F0 (no fibrosis) to F4 (cirrhosis).A total of 11 patients had a delay in their 52-week biopsy due to closure of the biopsy site associated with COVID-19-related disease or other related causes and were removed from the main analysis group for liver biopsy analysis.

[00110] Figures 11A-11D are graphical representations illustrating subgroup analyses of the dual major endpoints at week 52 in Example 2: reaching cure for non-alcoholic fatty liver disease (NAFLD) (Figure 11A and Figure 11C) and improving fibrosis (Figure 11B and Figure 11D). Data were determined for the main analysis cohort (n=955, after removing COVID-affected biopsies outside the week 60 window). Eleven patients had delayed week 52 biopsies due to biopsy site closure caused by COVID-19 or related reasons and were removed from the analysis. Reaching cure for NAFLD was defined as achieving swelling scores of 0, inflammation scores of 0 or 1, and a ≥2-point decrease in NAFLD activity scores without worsening fibrosis. Improvement in fibrosis was defined as achieving a ≥1-stage decrease in fibrosis without worsening NAFLD activity scores. A one-point improvement in fibrosis is a change to F1A or F1C from F2 (a change from F2 to F1B is not considered a one-point improvement). Forest diagrams include predefined subsets with minor modifications.Body weight subgroups based on ≥200, >200 lb or BMI (body mass index) ≥35, >35 did not contain much information. The reduction in PDFF in the Resmeter groups was compared to all placebo patients with any PDFF at week 52; SHBG CFB% in the Resmeter groups was compared to all placebo patients with SHBG at week 52. A subsequent subgroup of ≥100 kg, >100 kg, shown in Table 21, also includes subgroups for ≥30% PDFF at week 16, region (US-outside the US), weight gain ≥5% F2 / F3, F1B. Subgroup analyses using statin and NAFLD activity scores (NAS) were subsequent analyses. Confidence intervals were not adjusted for multiplexing and cannot be used for hypothesis testing.

[00111] Figure 12 is a graphical representation showing the percentage of patients who were F1B or F2 at baseline with a worse fibrosis stage (progressed to ≥F3), stable (no change), or improved at week 52 based on the liver biopsy in Example 2. Inpatients with valid baseline and week 52 biopsies (80 mg, 100 mg: resmeteorum). My pathological assessment was similar, and the approach was to produce a single output.

[00112] Figure 13 is a graphical representation showing the percentage of patients with worse, stable (no change), or improved single components of non-alcoholic fatty liver disease activity points (bloating, inflammation, liver fat accumulation) in Example 2. Inpatients with a biopsy at baseline and valid at week 52 are shown. My pathological assessment was similar and the approach was used to produce a single output.

[00113] Figure 14 is a graphical representation showing the percentage change from baseline in lipids and lipoproteins at weeks 24 and 52 in Example 2. ApoB: lipid-free protein B; ApoCIII: lipid-free protein CIII; LDL-C: low-density lipoprotein cholesterol; Lp(a): lipoprotein a; non-HDL-C: non-high-density lipoprotein cholesterol. (80 mg, 100 mg: resmeteorum)

[00114] Figures 15A and 15B are graphic representations showing the percentage change from baseline in hepatic fat as measured by MRI-resolution protonated liver fat percentage at weeks 16 and 52 (Figure 15A), and hepatic fat accumulation as measured by controlled attenuation variable FibroScan at week 52 (Figure 15B) in Example 2 (80 mg, 100 mg: Resmeter). Based on the observed data, patients have been assessed at baseline and week 52.

[00115] Figure 16 is a graphical representation showing the percentage of patients who achieved ≥25% reduction from baseline in liver stiffness as measured by FibroScan transient vibration-controlled tissue stiffness measurement at week 52 in Example 2. Based on the observed data, patients have an assessment at baseline and week 52.

[00116] Figure 17 is a graphic representation showing the improvement or deterioration from baseline in liver stiffness as measured by magnetic resonance imaging of liver stiffness at week 52 in Example 2. (80 mg, 100 mg: resmeteorum) Based on the observed data, patients have an assessment at baseline and week 52.

[00117] Figures 18A and 18B are graphic representations showing the percentage change from baseline in liver volume (Figure 18A) and spleen volume (Figure 18B) at weeks 16 and 52 in Example 2. (80 mg, 100 mg: Resmeter) Based on observed data, patients have an assessment at baseline and week 52.

[00118] Figures 19A-19C are graphic representations illustrating the change from the baseline in improved liver fibrosis points (Figure 19A), TIMP-1 (Figure 19B), and P3NP (Figure 19C) in Example 2. (80 mg, 100 mg: resmeteorum) based on observed data.

[00119] Figure 20 is a graphic representation showing the time taken until the onset of the first gastrointestinal side effect in Example 2.

[00120] Figure 21 is a graphic representation illustrating the diarrhea period: the diarrhea period determined in the first 12 weeks of randomization in Example 2.

[00121] Figure 22 is a diagram illustrating the pre-screening and the sequence of screening in Example 2.

[00122] Figure 23 is a diagram illustrating the methods for evaluating the central pathology of liver biopsies in Example 2.

[00123] Figure 24A is a graphical representation showing the percentage of patients who achieved ≥120% increase in SHBG at week 52 in the Resmetrium 80 mg and Resmetrium 100 mg weight-based groups in Example 2. Figure 24B is a graphical representation showing the percentage of patients who achieved ≥30% decrease in MRI-PDFF at week 52 in the Resmetrium 80 mg and Resmetrium 100 mg weight-based groups in Example 2.

[00124] Figure 25A is a graphical representation showing the percentage of patients who achieved NASH treatment (bulking score = 0, inflammation score = 0 / 1, and ≥2 point reduction in NAS without worsening fibrosis) in the Resmetrium 80 mg and Resmetrium 100 mg weight groups in Example 2. Figure 25B is a graphical representation showing the percentage of patients who achieved fibrosis improvement (≥1 stage improvement in fibrosis without worsening NAS) in the Resmetrium 80 mg and Resmetrium 100 mg weight groups in Example 2.

[00125] Figure 26A is a graphical representation showing the percentage of patients who achieved NASH treatment (bulking score = 0, inflammation score = 0 / 1, and ≥2 point decrease in NAS without fibrosis worsening) in the Resmetrium 80 mg and Resmetrium 100 mg groups based on BMI in Example 2. Figure 26B is a graphical representation showing the percentage of patients who achieved fibrosis improvement (≥1 stage improvement in fibrosis without NAS worsening) in the Resmetrium 80 mg and Resmetrium 100 mg groups based on BMI in Example 2.

[00126] Figure 27 is a graphical representation showing the percentage of biopsy response to fibrosis improvement and NASH treatment in all patients treated with resemmeter (80 mg and 100 mg combined) and patients in the placebo group based on the percentage change from baseline PDFF at week 52 in Example 2. The graph shows that the greater the decrease in PDFF at week 52, the greater the likelihood of fibrosis and NASH responses with resemmeter treatment.

[00127] Figure 28 is a graphical representation showing the change over time from baseline to week 48 in SHBG in the placebo, resmetrium 80 mg, and resmetrium 100 mg groups in the MAESTRO-NASH master analysis group at week 52 in Example 2.

[00128] Figure 29A is a graphical representation showing the ALT response at week 48 in all patients randomly assigned to the placebo, resmetrium 80 mg, and resmetrium 100 mg groups in the MAESTRO-NASH master analysis group at week 52 in Example 2. Figure 29B is a graphical representation showing the ALT response at week 48 where the dose is aligned with the dose suggested in the drug leaflet for patients in the placebo, resmetrium 80 mg, and resmetrium 100 mg groups in the MAESTRO-NASH master analysis group at week 52 in Example 2.

[00129] Figure 30A is a graphical representation showing the change over time in VCTE from baseline to year 3 in patients in the placebo group, resmetrium 80 mg, and resmetrium 100 mg in Example 2. Figure 30B is a graphical representation showing the change over time in CAP (dB / m) from baseline to year 3 in patients in the placebo groups, resmetrium 80 mg, and resmetrium 100 mg in Example 2.

[00130] Figure 31 is a graphical representation showing the VCTE response analyses at years 1-3 in patients in the placebo, resmetrium 80 mg, and resmetrium 100 mg groups in the MAESTRO-NASH group in Example 2.

[00131] Figure 32A is a graphical representation showing the percentage of patients in the placebo, resmetrium 80 mg, and resmetrium 100 mg treatment groups who achieved ≥one stage improvement in fibrosis as determined by quantitative fibrosis and pathologists in Example 2. Figure 32B is a graphical representation showing the percentage of patients in the placebo, resmetrium 80 mg, and resmetrium 100 mg treatment groups who experienced progression in fibrosis as determined by quantitative fibrosis and pathologists in Example 2.

[00132] Figure 33A is a graphic representation showing the cross-sectional change of the portal canal from the baseline in the placebo and Resmetrum groups (80 mg and 100 mg combined) in phases F2 and F3 in Example 2. Figure 33B is a graphic representation showing the combined change in portal canal chain length from the baseline in the placebo and Resmetrum groups (80 mg and 100 mg combined) in phases F2 and F3 in Example 2.

[00133] Figure 34A is a graphic representation showing the cross-sectional change of the portal canal from baseline in responders and non-responders to the degree of fibrosis according to the pathology in the palliative and Resmetrum (80 mg and 100 mg combined) groups in stages F2 and F3 in Example 2. Figure 34B is a graphic representation showing the combined change in portal canal chain length from baseline in responders and non-responders to the degree of fibrosis according to the pathology in the palliative and Resmetrum (80 mg and 100 mg combined) groups in stages F2 and F3 in Example 2.

[00134] Figure 35A is a graphical representation showing the change from the baseline in the number of long-chain portal tracts in responders and non-responders in the placebo and Resmetrum (80 mg and 100 mg combined) groups in phases F2 and F3 in Example 2. Figure 35B is a graphical representation showing the change from the baseline in the number of short-chain zone 2 in responders and non-responders in the placebo and Resmetrum (80 mg and 100 mg combined) groups in phases F2 and F3 in Example 2.

[00135] Figure 36 is a graphical representation showing the percentage change from baseline in ALT at week 48 compared to the percentage of biopsy response in patients who achieved NASH treatment with prismmeterum, fibrosis improvement with prismmeterum, NASH treatment with placebo, and fibrosis improvement with placebo in Example 2.

[00136] Figure 37 is a graphical representation showing the change in CAP over time from baseline to year 3 in patients in the placebo, resmetrium 80 mg, and resmetrium 100 mg treatment groups in Example 2.

[00137] Figure 38 is a graphical representation showing the percentage change from baseline in CAP at week 52 compared to the percentage of biopsy response in patients who achieved NASH treatment with prismmeterum, fibrosis improvement with prismmeterum, NASH treatment with placebo, and fibrosis improvement with placebo in Example 2.

[00138] Figure 39 is a graph showing the percentage change from baseline in PDFF at week 52 compared to the percentage of biopsy response in patients who achieved NASH treatment with prismmeterum, fibrosis improvement with prismmeterum, NASH treatment with placebo, and fibrosis improvement with placebo in Example 2.

[00139] Figure 40 is a graphical representation showing the change in VCTE over time from baseline to year 3 in patients in the placebo, resmetrium 80 mg, and resmetrium 100 mg treatment groups in Example 2.

[00140] Figure 41 is a graphical representation showing the percentage change from baseline in VCTE at week 52 compared to the percentage of biopsy response in patients who achieved NASH treatment with prismmeterum, fibrosis improvement with prismmeterum, NASH treatment with placebo, and fibrosis improvement with placebo in Example 2.

[00141] Figure 42 is a graphical representation illustrating the importance of various response indices for the treatment response to NASH Prismeterum based on week 52 data in Example 2.

[00142] Figure 43 is a graphic representation illustrating the importance of various biopsy response indicators for improvement in prismmeter fibrosis based on week 52 data in Example 2.

[00143] Figure 44 is a graphical representation showing the change in P3NP versus the change in PRO-C3 at week 52 in patients in the placebo, resmetrium 80 mg, and resmetrium 100 mg treatment groups in Example 2.

[00144] Figure 45 is a graphical representation showing the change in ELF versus the change in PRO-C3 at week 52 in patients in the placebo, resmetrium 80 mg, and resmetrium 100 mg treatment groups in Example 2.

[00145] Figure 46 is an abbreviated version of the REZDIFFRA™ (rismetrum) drug leaflet.

[00146] Figure 47 is the powder X-ray diffraction pattern (XRPD) of image I of Resmeterum.

[00147] Figure 48 is a differential temperature testing (DSC) diagram for image I of Resmetrum.

[00148] Figure 49 is an XRPD pattern of the λ image of Resmetrium.

[00149] Figure 50 is an XRPD pattern of the F image of Resmetrium.

[00150] Figure 51 is an XRPD pattern of the image L of Resmetrium.

[00151] Figure 52 is an XRPD pattern of the CSIV crystallized image of Resmetrium.

[00152] Figure 53 is a thermal differential analysis (TGA) plot of the CSIV crystalline image of Resmetrium.

[00153] Figure 54 is a DSC plot of the CSIV crystallized image of Resmetrium.

[00154] Figure 55 is an XRPD pattern of the R3-A image of Resmetrium.

[00155] Figure 56 is a spectrum 13 C NMR solid-state image of Resmetrium R3-A (full range 200-0 ppm).

[00156] Figure 57 is a spectrum 13 C NMR in the solid state for the R3-A image of Resmetrium (200-100 ppm).

[00157] Figure 58 is a spectrum 13 C NMR solid-state image of Resmetrium R3-A (100-0 ppm).

[00158] Figure 59 is an XRPD pattern of Rismetrum:Nicotineamide (Image RC1-A).

[00159] Figure 60 is a spectrum 13 ¹¹C NMR solid-state rhymetimer:nicotinamide (image RC1-A) (full range 200-0 ppm).

[00160] Figure 61 is a spectrum 13 C NMR in the solid state of rhesmetrum:nicotinamide (image RC1-A) (200-100 ppm).

[00161] Figure 62 is a spectrum 13 C NMR in the solid state of rhesmetrum:nicotinamide (image RC1-A) (100-0 ppm).

[00162] Figure 63 is an XRPD pattern of Rismetrium:Caffeine (image RC2-A).

[00163] Figure 64 is a spectrum 13 ¹¹C NMR in the solid state of rhesmetrum:caffeine (image RC2-A) (full range 200-0 ppm).

[00164] Figure 65 is a spectrum 13 C NMR in the solid state of rhesmetrum:caffeine (image RC2-A) (200-100 ppm).

[00165] Figure 66 is a spectrum 13 C NMR in the solid state of rhesmetrum:caffeine (image RC2-A) (100-0 ppm).

[00166] Figure 67 is an XRPD pattern of Rismetrum:Caffeine (image RC2-B).

[00167] Figure 68 is a spectrum 13 ¹¹C NMR in the solid state of rhesmetrum:caffeine (image RC2-B) (full range 200-0 ppm).

[00168] Figure 69 is a spectrum 13 C NMR in the solid state of rhesmetrum:caffeine (image RC2-B) (200-100 ppm).

[00169] Figure 70 is a spectrum 13 C NMR in the solid state of rhesmetrum:caffeine (image RC2-B) (100-0 ppm).

[00170] Figure 71 is an XRPD pattern of rhizometrum:2-picolinenic acid (image RC3-A).

[00171] Figure 72 is an XRPD pattern of rhizometrum:urea (image RC4-A).

[00172] Figure 73 is an XRPD pattern of rhizometrum: N-methylmorpholene salt (image R1-A).

[00173] Figure 74 is an XRPD pattern of rhizometrum:piperazine salt (image R2-A).

[00174] Figure 75 is a spectrum 13 ¹¹C NMR in the solid state of rhysmetrum:piperazine salt (image R2-A) (full range 200-0 ppm).

[00175] Figure 76 is a spectrum 13 C NMR in the solid state of rhesmetrum:piperazine salt (image R2-A) (200-100 ppm).

[00176] Figure 77 is a spectrum 13 C NMR in the solid state of rhysmetrum:piperazine salt (image R2-A) (100-0 ppm).

[00177] Figure 78 is an XRPD pattern of rhizometrum:benzathen salt (image R4-A).

[00178] Figure 79 is a graph illustrating weight loss in conjunction with the effect of resmeteorum treatment on biopsy endpoints in the MAESTRO-NASH study.

[00179] Figure 80 is a graph illustrating weight loss in conjunction with the effect of resemmeter treatment on MRI-PDFF results in the MAESTRO-NASH study.

[00180] Figure 81 is an XRPD pattern of the N8 image of Resmetrium.

[00181] Figure 82 ghost 1 H NMR of the N8 image of Resmeterum.

[00182] Figure 83 DSC and TGA combined heat map of Resmetrium image N8.

[00183] Figure 84 is an XRPD pattern of image 3 for Resmetrum.

[00184] Figure 85 is an XRPD pattern of image 9 for Resmetrum.

[00185] Figure 86 is an XRPD pattern of a CSV image of Resmetrium.

[00186] Figure 87 is a TGA histogram of the CSV image of Resmetrum.

[00187] Figure 88 is an XRPD pattern of image 2 for Resmetrum.

[00188] Figure 89 is an XRPD pattern of image 4 for Resmetrum.

[00189] Figure 90 is an XRPD pattern of image 6 for Resmetrum.

[00190] Figure 91 is an XRPD pattern of image 7 for Resmetrum.

[00191] Figure 92 is an XRPD pattern of image 8 for Resmetrum.

[00192] Figure 93 is an XRPD pattern of image 10 for Resmetrum.

[00193] Figure 94 is an XRPD pattern of Resmetrum image 11.

[00194] Figure 95 is an XRPD pattern of image 13 of Resmetrum.

[00195] Figure 96 is an XRPD pattern of image 14 of Resmetrum.

[00196] Figure 97 is an XRPD pattern of image 15 for Resmetrum.

[00197] Figure 98 is an XRPD pattern of image 16 for Resmetrum.

[00198] Figure 99 is an XRPD pattern of image 17 of Resmetrum.

[00199] Figure 100 is an XRPD pattern of image 19 for Resmetrum.

[00200] Figure 101 is an XRPD pattern of image 20 for Resmetrum.

[00201] Figure 102 is an XRPD pattern of Resmetrium Image 21.

[00202] Figure 103 is an XRPD pattern of image 22 for Resmetrum.

[00203] Figure 104 is a spectrum 13 C NMR in the solid state of image 20 of Resmetrium (full range 200-0 ppm).

[00204] Figure 105 is a spectrum 13 C NMR in the solid state for image 20 of Resmetrium (200-100 ppm).

[00205] Figure 106 is a spectrum 13 C NMR in the solid state of image 20 for Resmetrium (100-0 ppm).

[00206] Figure 107 is an XRPD pattern of the CSVI image of Resmetrum.

[00207] Figure 108 is a TGA histogram of the CSVI image of Resmetrium.

[00208] Figure 109 is an XRPD pattern of the CSVI image of Resmetrum.

[00209] Figure 110 is an XRPD pattern of the E1 and / or E2 image of an amorphous rhizometrum.

[00210] Figure 111 is an XRPD pattern of an amorphous solid dispersion of rhizometrum with copovidone image E3 and / or E4.

[00211] Figure 112 is an XRPD pattern of image 3A for Resmetrum.

[00212] Figure 113 is a TGA histogram of Resmetrum's 3A image.

[00213] Figure 114 is a DSC histogram of Resmetrum image 3A.

[00214] Figure 115 is a Fourier transform infrared (FT-IR) plot of image 3A of Resmetrum.

[00215] Figure 116 is an XRPD pattern of the CSVII image of Resmetrum.

[00216] Figure 117 is a TGA histogram of the CSVII image of Resmetrum.

[00217] Figure 118 is a DSC histogram of the CSVII image of Resmetrum.

[00218] Figure 119 is an XRPD pattern of the K65 type image of Resmeterum.

[00219] Figure 120 is a K65 type Resmeter XRPD image pattern.

[00220] Figure 121 is an XRPD pattern of the K65 type image melting product of Resmeterum.

[00221] Figure 122 is an XRPD pattern of image 4A for Resmetrum.

[00222] Figure 123 is a TGA histogram of Resmetrum's 4A image.

[00223] Figure 124 is a spectrum 1 H NMR of image 4A of Resmetrium.

[00224] Figure 125 is an XRPD pattern of image 7A for Resmetrum.

[00225] Figure 126 is a TGA histogram of Resmetrum image 7A.

[00226] Figure 127 is a spectrum 1 H NMR of image 7A of Resmeterum.

[00227] Figure 128 is an XRPD pattern of image 9A for Resmetrum.

[00228] Figure 129 is a TGA histogram of Resmetrum image 9A.

[00229] Figure 130 is a spectrum 1 H NMR of image 9A of Resmetrium.

[00230] Figure 131 is an XRPD pattern of the BSI image of Resmetrium.

[00231] Figure 132 is a DSC histogram of the BSI image of Resmetrium.

[00232] Figure 133 is a TGA histogram of the BSI image of Resmetrium.

[00233] Figure 134 is an XRPD pattern of the R1 image of Resmetrium.

[00234] Figure 135 is an XRPD pattern of the R2 image of Resmetrium.

[00235] Figure 136 is an XRPD pattern of the R3 image of Resmetrium.

[00236] Figure 137 is an XRPD pattern of the R4 image of Resmetrium.

[00237] Figure 138 is an XRPD pattern of the R5 image of Resmetrium.

[00238] Figure 139 is an XRPD pattern of a rhizometrum amorphous solid dispersion with eudragit.

[00239] Figure 140 is an XRPD pattern of an amorphous image of rhizometrum designated in IN202241066042A.

[00240] Figure 141 is an XRPD pattern of the RL image of Resmetrium.

[00241] Figure 142 is an XRPD pattern of the M1 image of Resmetrium.

[00242] Figure 143 is an XRPD pattern of the M2 image of Resmetrium.

[00243] Figure 144 is an XRPD pattern of the M3 image of Resmetrium.

[00244] Figure 145 is an XRPD pattern of the M4 image of Resmetrum.

[00245] Figure 146 is an XRPD pattern of the M5 image of Resmetrium.

[00246] Figure 147 is an XRPD pattern of the M6 ​​image of Resmetrum.

[00247] Figure 148 is an XRPD pattern of the M7 image of Resmetrum.

[00248] Figure 149 is an XRPD pattern of the U1 image of Resmetrium.

[00249] Figure 150 is a combined DSC and TGA heat map of the U1 image of Resmetrium.

[00250] Figure 151 is an XRPD pattern of the U2 image of Resmetrium.

[00251] Figure 152 is a combined DSC and TGA heat map of the U2 image of Resmetrium.

[00252] Figure 153 is an XRPD pattern of the U3 image of Resmetrium.

[00253] Figure 154 is a combined DSC and TGA heat map of the U3 image of Resmetrium.

[00254] Figure 155 is an XRPD pattern of the U4 image of Resmetrium.

[00255] Figure 156 is an XRPD pattern of the U5 image of Resmetrium.

[00256] Figure 157 is an XRPD pattern of the U6 image of Resmetrium.

[00257] Figure 158 is a combined DSC and TGA heat map of the U6 image of Resmeterum.

[00258] Figure 159 is an XRPD pattern of the U7 image of Resmetrium.

[00259] Figure 160 is a combined DSC and TGA heat map of the U7 image of Resmeterum.

[00260] Figure 161 is an XRPD pattern of the U8 image of Resmetrium.

[00261] Figure 162 is a combined DSC and TGA heat map of the U8 image of Resmeterum.

[00262] Figure 163 is an XRPD pattern of the U9 image of Resmetrium.

[00263] Figure 164 is a combined DSC and TGA heat map of the U9 image of Resmetrum.

[00264] Figure 165 is an XRPD pattern of the C1 image of Resmetrium.

[00265] Figure 166 is a ghost 1 H NMR of the C1 image of Resmetrium.

[00266] Figure 167 is a combined DSC and TGA heat map of the C1 image of Resmetrium.

[00267] Figure 168 is the FTIR spectrum of image C1 of Resmetrium (below) compared to the FTIR spectrum of image I of Resmetrium (top).

[00268] Figure 169 is the Raman spectrum of image C1 of Rismetrium (below) compared to the Raman spectrum of image I of Rismetrium (top).

[00269] Figure 170 is an XRPD pattern of the C2 image of Resmetrium.

[00270] Figure 171 is a ghost 1 1H NMR C2 image of rhesmeter

[00271] Figure 172 is a combined DSC and TGA heat map of the C2 image of Resmetrium.

[00272] Figure 173 is the FTIR spectrum of the C2 image of Resmetrium (below) compared to the FTIR spectrum of the I image of Resmetrium (top).

[00273] Figure 174 is the Raman spectrum of image C2 of Rismetrium (below) compared to the Raman spectrum of image I of Rismetrium (top).

[00274] Figure 175 is an XRPD pattern of the C3 image of Resmetrium.

[00275] Figure 176 is an XRPD pattern of the C4 image of Resmetrium.

[00276] Figure 177 is a spectrum 1 1H NMR C4 image of rheismetrum

[00277] Figure 178 is a combined DSC and TGA heat map of the C4 image of Resmetrum.

[00278] Figure 179 is an XRPD pattern of the C5 image of Resmetrum.

[00279] Figure 180 is a spectrum 1 H NMR of the C5 image of Resmetrium.

[00280] Figure 181 is a combined DSC and TGA heat map of the C5 image of Resmetrum.

[00281] Figure 182 is the FTIR spectrum of the C5 image of Resmetrium (below) compared to the FTIR spectrum of the I image of Resmetrium (top).

[00282] Figure 183 is the Raman spectrum of image C5 of Rismetrium (below) compared to the Raman spectrum of image I of Rismetrium (top).

[00283] Figure 184 is an XRPD pattern of the C6 image of Resmetrium.

[00284] Figure 185 is an XRPD pattern of the rhizometrum salt 4-aminopyridine (Image C7).

[00285] Figure 186 is a spectrum 1 H NMR of the salt of resmeterom 4-aminopyridine (image C7).

[00286] Figure 187 is a combined DSC and TGA heat diagram for the rhizometrum salt 4-aminopyridine (Figure C7).

[00287] Figure 188 is the FTIR spectrum of the rhizometrum salt 4-aminopyridine (Image C7) (below) compared to the FTIR spectrum of Image I of rhizometrum (top).

[00288] Figure 189 is the Raman spectrum of rhizometrum salt 4-aminopyridine (Figure C7) (below) compared to the Raman spectrum of Figure I of rhizometrum (top).

[00289] Figure 190 is an XRPD pattern of resmetrium imidazole salt (Image C8).

[00290] Figure 191 is a spectrum 1 H NMR of resmetrium imidazole salt (image C8).

[00291] Figure 192 is a combined DSC and TGA heat diagram for the rismetromimidazole salt (Figure C8).

[00292] Figure 193 is the FTIR spectrum of the rhizometrum imidazole salt (image C8) (below) compared to the FTIR spectrum of image I of rhizometrum (top).

[00293] Figure 194 is the Raman spectrum of the rhizometrum imidazole salt (image C8) (below) compared to the Raman spectrum of image I of rhizometrum (top).

[00294] Figure 195 is an XRPD pattern of ristimetrum tromethamine salt (Image C9).

[00295] Figure 196 is a spectrum 1 H NMR for rismetrum tromethamine salt (image C9).

[00296] Figure 197 is a combined DSC and TGA heat diagram of tromethamine salt rhymetimer (Image C9).

[00297] Figure 198 is an XRPD pattern of the N1 image of Resmetrium.

[00298] Figure 199 is a spectrum 1 H NMR of the N1 image of Resmetrium.

[00299] Figure 200 is an XRPD pattern of the N2 image of Resmetrium.

[00300] Figure 201 is a spectrum 1 H NMR for the N2 image of Resmetrium.

[00301] Figure 202 is a combined DSC and TGA heat map of the N2 image of Resmetrum.

[00302] Figure 203 is an XRPD pattern of the N3 image of Resmetrium.

[00303] Figure 204 is a spectrum 1 H NMR for the N3 image of Resmetrium.

[00304] Figure 205 is an XRPD pattern of the N4 image of Resmetrium.

[00305] Figure 206 is a spectrum 1 H NMR of the N4 image of Resmetrium.

[00306] Figure 207 is a combined DSC and TGA heat map of the N4 image of Resmetrum.

[00307] Figure 208 is an XRPD pattern of the N6 image of Resmetrium.

[00308] Figure 209 is a spectrum 1 H NMR of the N6 image of Resmeterum.

[00309] Figure 210 is an XRPD pattern of the N7 image of Resmetrium.

[00310] Figure 211 is a spectrum 1 H NMR of the N7 image of Resmetrium.

[00311] Figure 212 is a combined DSC and TGA heat map of the N7 image of Resmetrum.

[00312] Figure 213 is an XRPD pattern of the N9 image of Resmetrium. Detailed description of the invention

[00313] Unless otherwise defined, all technical and scientific expressions used herein shall have the same meaning commonly understood by a person of ordinary skill in the field to which the present discovery belongs. The terms used in the description are intended to describe specific instances only and are not meant to be exhaustive of the scope of the invention.

[00314] As used here, the following expressions have the meanings explained, unless specifically stated otherwise in the context. Unless otherwise defined here, all technical expressions used here have the same meaning commonly understood by someone with ordinary skill in the field to which the current disclosure belongs.

[00315] As used here, the term "MRI-PDFF" describes the percentage of liver fat peritoneum as determined by magnetic resonance imaging (MRI). MRI-PDFF is a biomarker for MRI-based diagnostic imaging of the liver. It is a measure for assessing liver fat content and has been proposed as a non-invasive screening strategy for adults with clinical signs or risk factors suggestive of fatty liver disease, for example, non-alcoholic steatohepatitis (NASH) with moderate to advanced fibrosis consistent with stages F2 and F3. MRI-PDFF is also used as a monitoring tool to demonstrate the effectiveness and decline of NASH over time. It is a biomarker for accurate quantitative imaging with high reproducibility and yield, and it provides results from validation and testing datasets using MRI-PDFF compared to liver tissue analysis to demonstrate that MRI-PDFF sections are ideal for minimizing the number of unnecessary biopsies.

[00316] As used here, the term "portal hypertension" refers to an increase in pressure within the portal vein (the vein that carries blood from the digestive organs (large and small intestines, stomach, pancreas, spleen) to the liver). The increase in pressure results from a blockage in blood flow through the liver.

[00317] As used here, the term "cirrhosis" refers to a late stage of scarring (fibrosis) of the liver resulting from various forms of liver disease and conditions, such as hepatitis and chronic alcoholism. Liver fat in a treated human with cirrhosis (e.g., as measured by MRI-PDFF) does not exceed 5%.

[00318] As used here, “to administer” or “to be administered” refers to prescribing a drug to a human subject under treatment, instructing others to administer a drug to a human subject under treatment, instructing a human subject under treatment to self-administer a drug, and / or to physically ingest a drug. This may include administering a drug containing resmeterum (or a pharmaceutically acceptable salt of resmeterum) as its active pharmaceutical ingredient, by a physician or other medical professional who can prescribe a drug(s) or otherwise instructs a patient to self-administer a prescription, and / or by a human subject under treatment who ingests the drug, and / or by a caregiver who administers the drug to a human subject under treatment.

[00319] As used here, the expression “prevention” or “prevents” describes reducing or eliminating the onset of symptoms or complications of this disease, condition or disorder.

[00320] As used here, the expression "daily" means every day, where each day is defined by a 24-hour period. To avoid ambiguity, the 24-hour period that defines "daily" can span two calendar days, for example, Sunday-Monday; Monday-Tuesday; Tuesday-Wednesday; and so on.

[00321] As used here, the expression “dosage”, “titration” or “daily dose” refers to the weight of an active ingredient (for example, resmeteorum).

[00322] As used here, the expression "low dose" refers to a dose of resmeterum or the pharmaceutically acceptable salt thereof that is lower than the dose otherwise given to the human subject under treatment based on the determination of the human subject under treatment's weight due to concomitant use of an intermediate CYP2C8 inhibitor.

[00323] In some incarnations, the human patient receiving resmeter or its pharmacologically accepted salt concomitantly follows a moderate CYP2C8 inhibitor regimen. This human patient receives a lower daily dose of resmeter or its pharmacologically accepted salt compared to the daily dose given otherwise if the human patient is not on a moderate CYP2C8 inhibitor regimen.

[00324] In some incarnations, the human subject being treated is already taking an intermediate CYP2C8 inhibitor before being given resmeterum or the pharmaceutically acceptable salt of it.

[00325] As used here, the term "pharmaceuticalally acceptable excipient" means an excipient useful in preparing a formulation that is generally safe, non-toxic, and not biologically unfavorable or otherwise objectionable, and includes an excipient acceptable for veterinary use as well as for human pharmaceutical use. "Pharmaceuticalally acceptable excipient" as used in the specification and safeguards includes one or more such excipients.

[00326] As used here, the expression “under human treatment” refers to an adult or adolescent undergoing human treatment.

[00327] As used here, “adult human subject to treatment” refers to a human subject to treatment who is 18 years of age or older.

[00328] As used here, "adult human subject under treatment" refers to a human subject under treatment aged 12 years or older and younger than 18 years of age. A physician's prescription in conjunction with treatment and / or improvement as disclosed herein to a human subject under 18 years of age is considered treatment prescribed for a disease for which it is not intended.

[00329] As used here, the expression “human subject in need of treatment” refers to a human subject in need of treatment who has a disease (to be treated) or has an increased risk of developing a disease (to be prevented). A human subject in need of treatment may be someone who has already been diagnosed or identified as having a disease or disorder identified here. A human subject in need of treatment may also be someone who has (for example, suffers from) a disease or disorder identified here. Alternatively, a human subject in need of treatment may be someone who has an increased risk of developing this disease or disorder relative to the group as a whole (i.e., a human subject at risk of developing this disorder relative to the group as a whole). A human subject in need of treatment may have a resistant or unresponsive disease or disorder identified here (i.e., a disease or disorder identified here that does not respond or has not responded to treatment). A human subject in need of treatment may be resistant at the start of treatment or may become resistant during treatment.In some incarnations, the human subject in need of treatment has received and failed at all known effective treatments for the disease or disorder revealed here. In other incarnations, the human subject in need of treatment has received at least one previous treatment.

[00330] As used here, the term “salt” or “pharmaceuticalally acceptable salt” refers to a derivative of the present detection compound where the original compound is modified by the preparation of acid or base salts from it. Examples of pharmaceuticalally acceptable salts include, but are not limited to, mineral or organic acid salts of basic structural units such as amines, alkaloids, or organic salts of acid structural units such as carboxylic acids, etc. Pharmaceuticalally acceptable salts include conventional non-toxic salts and quaternary ammonium salts of the original compound formed, for example, from non-toxic organic or inorganic acids.For example, these conventional non-toxic salts include, but are not limited to, those derived from selected inorganic and organic acids such as 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolyl arsenic acid, hexylresorcinic acid, hydrapamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymalic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsilic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, and phenyl sulfonic acid. Acetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, hypoacetic, succinic, sulfamic, sulfanilic, sulfric, tannic, tartaric, toluene sulfonic, and commonly occurring amino acids, for example, glycine, alanine, phenylalanine, arginine, etc.Other examples of pharmaceutically acceptable salts include those derived from hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2,2,2]-oct-2-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tributylacetic acid, myoconic acid, and so on. Other examples of pharmaceutically acceptable salts include caffeine, urea, 2-picolinenic acid, N-methylmorpholine, piperazine, benzathine, and L-proline salts. The current investigation also includes salts formed when an acidic proton in the existing compound is replaced by either a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or by an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamamine, etc. In the form of a salt, it is understood that the ratio of the compound to the cation or anion of the salt may be 1:1, or any other ratio, for example, 3:1, 2:1, 1:2, or 1:3.It is understood that all references to pharmacologically acceptable salts include solvent-added forms (solutes), crystalline forms (polymorphs), or co-crystals, as defined here, of the same salt. Some pharmacologically acceptable salts of rhizometrum—and their methods of preparation—are specified in US Patent Applications Nos. 2021 / 0122740 and 2023 / 0364099, both of which are included here for reference in their entirety.

[00331] As used here, the expression “treat” or “treat” describes the control and care of a patient for the purpose of calming a disease, condition, or disorder and includes administering a compound with the current detection to relieve the symptoms or complications of a disease, condition, or disorder, or to rule out the disease, condition, or disorder. That is, it involves the "treatment" or "curing" of a condition, disorder, or situation, however: (1) delaying the onset of clinical symptoms of the developing condition, disorder, or situation in a person who may have the condition, disorder, or situation but has not experienced or is not exhibiting any clinical or subclinical symptoms of the condition, disorder, or situation; (2) inhibiting the condition, disorder, or situation, i.e. suppressing or reducing the progression or relapse of the disease (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof; or (3) alleviating or attenuating the disease, i.e. causing the condition, disorder, or situation to regress or at least one of its clinical or subclinical symptoms to subside.

[00332] As used here, "solute" refers to a crystalline form that includes a solvent (e.g., an organic solvent) that is chemically included with the parent molecule in fractional or whole molar ratios.

[00333] As used here, "hydrate" refers to a crystalline form that includes water chemically included with the parent molecule in various fractional or whole molar ratios.

[00334] As used here, a "co-crystal" refers to a crystalline material that includes at least two, different molecules in the same crystal matrix held together by non-ionic and / or non-covalent bonds in a defined stoichiometric ratio. In some incarnations, a co-crystal includes two molecules in their natural state. As used here, at least one of these other molecules is referred to as a "co-crystal forming agent." For example, a co-crystal might be a rhizometrum with at least one co-crystal forming agent in a defined stoichiometric ratio.

[00335] As used here, the symbol "resmeterum:nicotineamide" refers to a distinct molecular family that includes resmeterum and nicotineamide. Resmeterum:nicotine may be a co-crystal of resmeterum and nicotineamide. Alternatively, resmeterum:nicotine may be a salt.

[00336] As used here, the symbol "Rismeterum:Caffeine" refers to a distinct molecular family that includes rismeterum and caffeine. Rismeterum:Caffeine may be a co-crystal of rismeterum and caffeine. Alternatively, rismeterum:caffeine may be a salt.

[00337] As used here, the symbol "Rismeterum:2-piculenic acid" refers to a distinct molecular family that includes rismeterum and 2-piculenic acid. Rismeterum:2-piculenic acid may be a co-crystal of rismeterum and 2-piculenic acid. Alternatively, rismeterum:2-piculenic acid may be a salt.

[00338] As used here, the symbol "Rysmetrium:urea" refers to a distinct molecular family that includes rysmetrium and urea. Rysmetrium:urea may be a co-crystal of rysmetrium and urea. Alternatively, rysmetrium:urea may be a salt.

[00339] As used here, the symbol "Rysmetearm:N-methyl-morpholine salt" refers to a distinct molecular family that includes rysmetearm and N-methyl-morpholine. Rysmetearm:N-methyl-morpholine salt may be a co-crystal of rysmetearm and N-methyl-morpholine salt. Alternatively, rysmetearm:N-methyl-morpholine salt may be a salt.

[00340] As used here, the symbol "Rysmetirum:piperazine salt" refers to a distinct molecular family that includes rysmetirum and piperazine salt. Rysmetirum:piperazine salt may be a co-crystal of rysmetirum and piperazine salt. Alternatively, rysmetirum:piperazine salt may be a salt.

[00341] As used here, the symbol "Rysmetrium:benzathen salt" refers to a distinct molecular family that includes rysmetrium and benzathine salt. Rysmetrium:benzathen salt may be a co-crystal of rysmetrium and benzathine salt. Alternatively, rysmetrium:benzathen salt may be a salt.

[00342] As used here, the symbol "Rysmetrium:L-proline" refers to a distinct molecular family that includes rysmetrium and L-proline. Rysmetrium:L-proline may be a co-crystal of rysmetrium and L-proline. Alternatively, rysmetrium:L-proline may be a salt.

[00343] As used here, “amorphous image” refers to an amorphous material that lacks long-range order in its structure.

[00344] Unless the context dictates otherwise, all percentages and ratios used here are weighted. Other features and advantages of current detection are evident from the various examples. The examples provided illustrate different components and methods useful in current detection practice. The examples do not limit the detection to be protected. Based on current detection, a skilled practitioner can define and use other components and methods useful in current detection practice.

[00345] All patent notices and documents cited herein are included by reference as if each one had been specifically and individually cited as being included herein by reference. The inclusion of patent notices and documents is not intended to be an endorsement that any of them is a relevant prior art, nor does it constitute an endorsement of their contents or date. Having now described the invention in writing, it is understood by those skilled in the field that the invention may be exercised in a variety of embodiments and that the preceding description and the following examples are for illustrative purposes and not exhaustive of the following protections.

[00346] Rismeterum is a compound with the chemical name 2-(3,5-Dichloro-4-((5-Isopropyl-6-oxo-1,6-Dihydropyridazine-3-yl)oxy)phenyl)-3,5-Dioxo-2,3,4,5-Tetrahydro-1,2,4-Triazine-6-carbonitrile. Rismeterum has the following chemical structure: .

[00347] It is understood that rhizomethorphan or its pharmacologically acceptable salt may exist in crystalline or amorphous form. It is also understood that rhizomethorphan or its pharmacologically acceptable salt may exist as a hydrate, soluble, or co-crystalline.

[00348] Various forms of resmetrium or the pharmaceutically acceptable salt thereof—and processes for their preparation—are determined in the following patents, applications, and / or publications, all of which are included herein for reference as a whole: US Patent No. 9,266,861 US Patent No. 10,376,517 US Patent Application Bulletin No. 2021 / 0122740 US Patent Application Notice No. 2023 / 0416234 International Order No. WO 2022 / 171200 International Order No. WO 2025 / 011259 International Order No. WO 2021 / 063367 Chinese patent number CN 115124515A Indian Patent No. IN 202241066042A US Patent Application Bulletin No. 2024 / 0423993 Chinese patent number CN 118772117A MSN Laboratories Private Limited, R&D Center, et al, “Solid-state forms of Resmetirom and processes for preparation thereof,” located at https: / / www.tdcommons.org / cgi / viewcontent.cgi?article=8898&context=dpubs_series US Patent Application Bulletin No. 2022 / 0372021 US Patent Application Bulletin No. 2023 / 0364099

[00349] It is understood that rhizomethorphan or its pharmacologically accepted salt may be identified as different chemical isomers. It should also be understood that when compounds have chemical isomers, all chemical isomers are intended to be included in the current detection range, and the naming of the compounds does not exclude any chemical isomer. It is understood that some chemical isomers may have a higher level of activity than others.

[00350] In some incarnations, the rhizosphere exists in a crystalline form.

[00351] In some incarnations, the rhizosphere exists in an amorphous form.

[00352] In some incarnations, the rhizomatous is in the form of a solute.

[00353] In some incarnations, the solubility is chosen from 1,1,1-trichloroethane, 1,1,2-trichloroethene, 1,1-dichloroethene, 1,2-dichloroethane, 1,2-dichloroethene, 1,2-dimethoxyethane, 1,3-dioxolan, 1,4-dioxane, 1-butanol, 1-pentanol, 1-propanol, 2,2,2-trifluoroethanol, 2-butanol, 2-ethoxyethanol, 2-methoxyethanol, 2-methyl-1-propanol, 2-propanol, 3-methyl-1-butanol, acetic acid, acetone, acetonitrile, acetylacetone, anisole, benzene, benzyl alcohol; Butyl acetate, carbon tetrachloride, chlorobenzene, chloroform, cumene, cyclohexane, cyclohexanone, cyclopentyl methyl ether, die(ethylene glycol) ethyl ether, dibutyl ether, dichloromethane, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, ethylene glycol, formamide, formic acid, heptane, hexafluoroisopropanol, hexane, isobutyl acetate, isopropyl acetate, methanol, methyl acetate, methyl tetrahydrofuran, methyl butyl ketone, methyl cyclohexane, methyl ethyl ketone, methyl isobutyl ketone, MIPK, N,N-dimethylFormamide, N,N-Dimethylacetamide, Nitrobenzene, Nitromethane, N-Methylpyrrolidone, Pentane, Propionic Acid, Propionitrile, Propyl Acetate, Pyridine, Sulfolane, Tert-Butanol, Tert-Butyl Methyl Ether, Tetrahydrofuran, Tetraline, Toluene, Triethylamine, Trifluorotoluene, Tween 2.1% by weight, and Xylene.

[00354] In some incarnations, the solute is 2,2,2-trifluoroethanol, cyclohexanone, methyl acetate, methyl ethyl ketone, N,N-dimethylformamide, nitromethane, N-methylpyrrolidone, tert-butanol, or xylene.

[00355] In some incarnations, rhizomethorp is in the form of hydrates.

[00356] In some incarnations, rhizometrum is in the form of a co-crystal alongside a co-crystal-forming agent as part of the co-crystal.

[00357] In some incarnations, the co-crystalline agent is chosen from 1-(2-hydroxyethyl)pyrrolidine, 1-hydroxy-2-naphthoic acid, 4-(2-hydroxyethyl)morpholene, acesulfame, acesulfame potassium, 4-acetamidobenzoic acid, acetic acid, acetoin, acetylsalicylic acid, aconitic acid, adenine, adipic acid, alanine, aletam, alpha-tocopherol, aluminum, 4-aminobenzoic acid, 4-aminopyridine, 4-aminosalicylic acid, ammonia, ammonium chloride, anethole, arginine, ascorbic acid, ascorbyl palmitate, asparagine, aspartame, aspartic acid, benzathine, benzaldehyde, benzamide, benzenesulfonic acid, benzoic acid, beta-cyclodextrin, betaine; Betaine HCl, butylated hydroxyanisole, butylated hydroxytoluene, caffeine, calcium, calcium bromide, calcium chloride, camphoric acid, capric acid (decanoic acid), caprylic acid (octanoic acid), carbonic acid, carvone, cholic acid, choline, chrysin choline chloride, cinnamic acid, citric acid, p-coumaric acid, creatine, creatinine, cyclamic acid, cysteine, cytosine, dianol, dehydroacetic acid, acetyl, 2,2-dieChloroacetic acid, diethanamine, diethylamine, 2-diethylaminoethanol, 3,4-dihydroxybenzoic acid, dimethylglycine, 2-dimethylaminoethanol, erythritol, ethane-1,2-disulfonic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid, ethanolamine, ethylmaltol, ethylparaben, ethyl vanillin, ethylenediamine, eugenol, ferric chloride, folic acid, folinic acid, formic acid, fructose, fumaric acid, gallic acid, genistein, gentisic acid, glucohaptonic acid, gluconic acid, glucosamine, glucosamine hydrochloride, glucose, D-glucuronic acid, glutamic acid, L-glutamine, glutaric acid, glycerol / glycerol, glycine, glycolic acid, guanine, HCl Hippuric acid, L-Histidine, 4-hydroxybenzoic acid, Hypoxanthine, 1H-Imidazole, Inositol, D-Isoascorbic acid, Isobutyric acid, Isoleucine, Isonicotinamide, Ketoglutaric acid, Lactic acid, Lactitol, Lactobionic acid, Lactose, Lauric acid, L-Carnitine, Leucine, Linoleic acid, Lithium, Lysine, Magnesium, Magnesium bromide, Magnesium chloride, Maleic acid, Malonic acidMaltitol, Maltol, Maltose, Mandelic Acid, Manganese Chloride, Mannitol, Meglumine, Methanesulfonic Acid, Methionine, Methylanthranilate, Methylparaben, Monosodium Glutamate (MSG), Mucic Acid (Galactaric Acid), Naphthalene-1,5-Disulfonic Acid, 2-Naphthalenesulfonic Acid, n-Butyric Acid, Neotame, Nicotinamide, Nicotinic Acid, Oleic Acid, Orotic Acid, Oxalic Acid, Palmitic Acid, Pamoic Acid, Pantothenic Acid, Phenylalanine, Phosphoric Acid, Picolinic Acid, Piperazine, Piperonal, Potassium, Proline, Propionic Acid, Propyl Gallate, Propylparaben, Propylene Glycol, Pyridoxine, Pyruvate, Glutamic Acid, Quercetin, Resveratrol, Retinol, Riboflavin Saccharin, Sarcosin (N-methylglycine), Salicylic acid, Sebacic acid, Serine, Sodium, Sodium chloride, Sodium lauryl sulfate, Sorbic acid, Sorbitol, Tin chloride, Stearic acid, Succinic acid, Sucralose, Sucrose, Sulphric acid, Tagatose, L-Tartaric acid, Taurine, Theanine, Theobromine, Theophylline, Thiamine chloride, Thiamine nitrate, Thiocyanic acid, Threonine, Thiamine, p-Toluene sulfonic acid, Triacetin, Tribuirene, TriethanolamineTriethyl citrate, triethylamine, tromethamine, tromethamine hydrochloride, L-tryptophan, tyrosine, uracil, urea, valeric acid, valine, vanillic acid, vanillin, xanthine, xylitol, xylose, zinc, and zinc chloride.

[00358] In some incarnations, the co-crystal-forming agent is 4-aminopyridine, cytosine, 2,2-dichloroacetic acid, diethylamine, dimethylglycine, 1H-imidazole, pantothenic acid (calcium pantothenate), triethyl citrate, or tromethamine.

[00359] In some incarnations, the co-crystal-forming agent is L-proline, caffeine, or 2-picolinenic acid.

[00360] In some incarnations, racemeterum is present in a co-crystal or salt form that includes racemeterum:nicotineamide, racemeterum:caffeine, racemeterum:2-picolinenic acid, racemeterum:urea, racemeterum:N-methyl-morpholine salt, racemeterum:piperazine salt, racemeterum:benzathen salt, or racemeterum:L-proline.

[00361] All dosages or titrations mentioned herein for risemeterum or its pharmacologically accepted salt are based on the molecular weight of the compound itself, and not the molecular weight of its pharmacologically accepted salt, hydrate, solute, co-crystal, or any excipients in the formulation, unless otherwise stated. For example, administering risemeterum or its pharmacologically accepted salt at a dose of 100 mg per day means administering the equivalent of 100 mg of the compound itself per day, and not 100 mg of its pharmacologically accepted salt, hydrate, solute, or co-crystal, per day.

[00362] Resmeterum is described, for example, in examples 4 and 5 of US Patent No. 9,266,861 and International Application No. WO 2014 / 043706. One aspect of the present disclosure relates to methods of treatment or improvement as disclosed herein (for example, for NASH and / or cirrhosis) and contains a solid dosage form given to a human patient (for example, an adult human patient) who may need such treatment or improvement on resmeterum or a pharmaceutically acceptable salt thereof, present in a morphological form (for example, amorphous, crystalline, soluble, or hydrated) or a mixture of morphological forms.

[00363] In some incarnations, resmeteorum is present in image I. Image I is described in US Patent No. 9,266,861 and International Application No. WO 2014 / 043706 and can be synthesized as shown, for example, in examples 6 and 7 of US Patent No. 9,266,861 and International Application No. WO 2014 / 043706.

[00364] Example 6 of US Patent No. 9,266,861 and International Application No. WO 2014 / 043706 describes the conversion of Resmeterum to Image I:

[00365] Purified rhesometrum (4802 g) as a 1:1 MIBK solute obtained from intermediate compound 8, as described in Example 5 of US Patent No. 9,266,861 and International Application No. WO 2014 / 043706 above, was added to a 100-liter reactor, coated with 24 liters of ethanol. The resulting slurry was heated to 80 ± 5 °C (thermal rebound) for 1 hour and 25 minutes; the mixture was stirred at that temperature for 4 hours and 25 minutes. Analysis of the filtered solids after 2 hours and 55 minutes showed that the image transformation was complete, and the XRPD spectra were consistent with Figure I. The mixture was cooled to 20 ± 5 °C for 45 minutes and stirred at that temperature for 15 minutes. The slurry was filtered, and the filtrate paste was washed twice with previously filtered ethanol (2 × 4.8 L). The wet paste (4.28 kg) was dried under vacuum at 40 ± 5 °C for 118 hours to obtain 3390 g of Resmetrum 310.

[00366] X-ray diffraction (XRD) was performed on different sections of the morphological image I of the resmetrium produced by the previously described process. XRD after micron-scale conversion confirms the image I.

[00367] Data for image I are provided in the following table and diffraction measurements for image I are provided as in Figure 43.

[00368] Schedule 11 of US Patent No. 9,266,861 and International Application No. WO 2014 / 043706 2θ (angle) Value of d (angstroms) Intensity (counts) Intensity % (%) 3.0288 29.17117 1925.62 15.89 3.4596 25.5397 832.08 4.58 3.6702 24.07429 707.65 3.89 4.0027 22.07529 410.45 6.78 4.4466 19.87232 432.4 2.38 4.5794 19.29632 429.89 4.73 5.2533 16.82257 320.41 5.29 5.8566 15.09082 335.71 1.85 6.05 14.60887 224.56 9.89 6.8068 12.98624 287.97 3.17 7.2152 12.25213 293.93 4.04 7.6426 11.56781 239.85 2.64 8.2256 10.74918 1637.27 13.51 8.8542 9.98745 309.91 3.41 9.115 9.70221 244.6 2.02 9.576 9.23622 255.43 2.11 10.5373 8.39569 9763.54 100 11.1868 7.9096 2398.13 24.56 13.0814 6.76802 164.19 3.36 13.9013 6.37063 197.28 1.52 14.3022 6.19296 290.11 2.23 14.7284 6.01469 94.1 0.96 15.7399 5.63037 1305.28 16.71 16.4002 5.40513 804.24 10.3 16.732 5.2987 173.26 2.22 17.3055 5.12435 145.15 2.97 17.6872 5.01461 1400.39 17.93 18.3399 4.83761 1233.01 9.47 18.6986 4.7456 9825.6 100 18.9598 4.6808 572.69 3.5 19.3018 4.59864 278.53 1.7 19.6643 4.51468 97.55 0.4 2θ (angle) Value of d (angstroms) Intensity (counts) Intensity % (%) 20.0939 4.41912 64.71 2.63 21.0604 4.21845 333.65 2.72 22.2097 4.00268 833.43 8.48 22.6128 3.93224 1304.95 10.62 22.8964 3.88417 3375.42 34.35 23.066 3.856 976.63 5.96 23.5742 3.77401 3115.33 38.05 23.8662 3.72849 571.62 4.65 24.1 3.69284 572.34 6.99 24.5243 3.62991 1097.27 6.7 24.6502 3.61166 1580.95 16.09 25.4993 3.49329 225.6 2.76 26.4933 3.36443 506.03 5.15 26.7528 3.33239 244.51 1.99 27.1244 3.28756 130.69 1.06 27.4354 3.251 546.35 4.45 27.8382 3.20487 213.44 2.17 28.5208 3.12971 158.82 1.29 28.9064 3.08883 436.59 2.67 29.1352 3.06509 710.53 5.79 29.5077 3.02724 416.16 4.24 30.0267 2.97608 1470.29 17.96 30.3658 2.94361 260.89 1.59 30.6326 2.91858 132.13 0.54 31.316 2.85644 177.78 1.45 31.6013 2.83129 397.61 5.67 31.9237 2.80343 514.26 4.19 32.2125 2.77895 1293.04 18.42 32.8721 2.72469 434.37 2.65 33.3755 2.68474 295.36 2.4 33.8232 2.65022 358.99 3.65 34.8364 2.57542 140.57 1.72 35.1838 2.55079 739.55 7.53 35.7301 2.51303 98.13 1.2 36.0084 2.49424 110.57 1.35 36.4676 2.46389 316.07 2.57 37.2747 2.41237 199.99 4.07 38.3543 2.34691 34.08 0.42 39.1941 2.29854 63.88 1.3 39.9663 2.25589 211.73 1.29 40.6489 2.21957 96.61 0.59 41.194 2.19145 167.45 1.36 42.0276 2.14989 47.01 0.57 2θ (angle) Value of d (angstroms) Intensity (counts) Intensity % (%) 42.4477 2.12958 290.42 1.77 42.8091 2.11244 200.71 1.63 43.6289 2.07463 171.28 2.09

[00369] It was discovered that image I has a melting start at about 321°C, then disintegration after melting by DSC (Figure 44).

[00370] Example 7 of US Patent No. 9,266,861 and International Application No. WO 2014 / 043706 describes the preparation of image I for resmetrium: conversion of a resmetrium solute to image I:

[00371] A 50-liter, sealed glass vessel was filled with N2 solute-packed with MIBK resmetrum (2.72 kg) of Example 5 of US Patent No. 9,266,861 and International Application No. WO 2014 / 043706 above, and ethanol (13.6 L). Stirring was initiated, and the batch temperature was adjusted from 16.8°C to 79.4°C within 1.3 hours. The batch was held at 79.5°C for 2 hours and collected for XRPD analysis. The XRPD showed Figure 1, and the batch was cooled to 24.9°C within 1 hour and 10 minutes. An 18-inch Nutsche filter with tightly woven polypropylene fabric (0.67 ft / min) was fitted, and the batch was filtered. The filtration took 4 minutes. Ethanol (2.8 L) was added to the vessel and transferred to the filter paste. The slurry was manually resuspended and the liquids were vacuum-extracted. Ethanol (2.80 L) was added to the filtrate slurry, and the slurry was manually resuspended. The liquids were vacuum-extracted, and the slurry was vacuum-treated with nitrogen for 1 hour. The filtrate slurry was then transferred to drying vessels and dried at 45°C and 28 inHg for 1 day to produce an 89% yield (1).96 kg) of resmeteorum as a light yellow solid. HPLC analysis shows a purity of 99.6%. XRPD analysis is consistent with Figure I. Micronization of 300 g of this material on a 2-inch jet mill yields 284 g (95% yield) of micronized resmeteorum. XRPD analysis confirms that it remains micronized resmeteorum as in Figure I.

[00372] The solute of resemitterium DMAC, via the dihydrate and the solute of MIBK, can be converted to form I as described in Example 7 of US Patent No. 9,266,861 and International Application No. WO 2014 / 043706. Alternatively, the solute of DMAC was directly converted to form I with a yield of 75% (the yield was calculated from intermediate compound 8) by heating it with 8 volumes of ethanol to 80 °C for 2 hours, then cooling to room temperature and filtering. In another reaction, a sample of resemitterium, which was a mixture of the solute of DMAC and the dihydrate, was converted to form I with a yield of 69% by heating it with 8 volumes of MIBK to 80 °C and then cooling to room temperature.

[00373] In some embodiments, the I image of Resmeterum features a powder X-ray diffraction (XRPD) pattern that includes signals (e.g., peaks) at 10.5° ± 0.2°, 18.7° ± 0.2°, 22.9° ± 0.2°, 23.6° ± 0.2°, and 24.7° ± 0.2° 2θ. In some embodiments, the XRPD pattern also includes one or more signals (e.g., peaks) at 8.2° ± 0.2°, 11.2° ± 0.2°, 15.7° ± 0.2°, 16.4° ± 0.2°, 17.7° ± 0.2°, 30.0° ± 0.2°, and 32.2° ± 0.2° 2θ. The XRPD pattern of image I for 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (rismeterum), for example, is described in Table 11 of US Patent No. 9,266,861 and International Application No. WO 2014 / 043706 and Figure 43.

[00374] In some embodiments, the I-image of Resmeteorum features a differential heat sink (DSC) diagram with an absorption peak at 329 °C. In some embodiments, the I-image of Resmeteorum also features an initial melting temperature of 321 °C. The DSC diagram of the I-image of Resmeteorum is described, for example, in Example 6 of US Patent No. 9,266,861 and International Application No. WO 2014 / 043706 and Figure 44.

[00375] In some embodiments, rhizomethorphan or a pharmaceutically acceptable salt thereof is present in a morphological form (e.g., a crystalline form), as described in the Bulletin of U.S. Patent Application No. 2021 / 0122740 and International Application No. WO 2020 / 010068 (included herein for reference in their entirety).

[00376] In some incarnations, resmeteorum is the image λ, which was described in the Bulletin of U.S. Patent Application No. 2021 / 0122740 and International Application No. WO 2020 / 010068.

[00377] The image λ can be produced as described in US Patent Application Bulletin No. 2021 / 0122740 and International Application No. WO 2020 / 010068:

[00378] A suspension of resmeterium and isopropyl acetate was stirred for two days and then filtered. Heating to 100 °C for one hour produced the solute product. (Image λ, Figure 45).

[00379] In some embodiments, the λ image of Resmetrum features a powder X-ray diffraction pattern that includes peaks at 10.6° ± 0.2°, 12.0° ± 0.2°, 14.3° ± 0.2°, 16.2° ± 0.2°, 17.6° ± 0.2°, 18.0° ± 0.2°, and 24.3° ± 0.2° 2θ, where the powder X-ray diffraction pattern is obtained using a CuKα radiation source (1.54 angstroms). In some embodiments, the powder X-ray diffraction pattern of the λ image may also include one or more peaks from Table 29 of US Patent Application Bulletin No. 2021 / 0122740 and International Application No. WO 2020 / 010068. In some representations, the image λ has an X-diffraction pattern very similar to that shown in Figure 45.

[00380] Table 29 of the US Patent Application Bulletin No. 2021 / 0122740 and International Application No. WO 2020 / 010068 provides the following data: 2-θ d (angstrom) Height (counters) Relative intensity, % 8.85 9.97936 57 6 10.64 8.30722 834 94 11.24 7.86653 227 26 12.01 7.36601 291 33 14.33 6.1747 271 30 15.59 5.67972 261 29 16.20 5.46571 704 79 17.31 5.11846 206 23 17.60 5.03393 333 37 18.01 4.92036 528 59 19.56 4.53532 82 9 20.10 4.41393 151 17 22.34 3.97569 262 29 22.81 3.89618 50 6 24.26 3.66562 889 100 26.78 3.32625 117 13 27.68 3.22066 76 9 28.75 3.10234 183 21

[00381] In some incarnations, Resmeteorum is the F image, which was described in the Bulletin of U.S. Patent Application No. 2021 / 0122740 and International Application No. WO 2020 / 010068.

[00382] Image F can be produced as described in US Patent Application Bulletin No. 2021 / 0122740 and International Application No. WO 2020 / 010068:

[00383] A suspension of resmeteorum and ethyl acetate was stirred for two days and then filtered. Heating to 100 °C for one hour produced the solute (Picture F, Figure 46).

[00384] In some incarnations, the F image of Resmetrum features an X-ray diffraction pattern in the powder that includes peaks at 10.1° ± 0.2°, 10.4° ± 0.2°, 11.4° ± 0.2°, 13.9° ± 0.2°, 16.2° ± 0.2°, 16.4° ± 0.2°, 17.1° ± 0.2°, 22.0° ± 0.2°, 23.8° ± 0.2°, and 29.5° ± 0.2° 2θ, where the X-ray diffraction pattern in the powder is obtained using a CuKα radiation source (1.54 angstroms). In some representations, the powder X-ray diffraction pattern of image F may also include one or more peaks from Table 8 of US Patent Application No. 2021 / 0122740 and International Application No. WO 2020 / 010068. In some representations, image F has an X-ray diffraction pattern very similar to that shown in Figure 46.

[00385] Table 8 of the US Patent Application Bulletin No. 2021 / 0122740 and International Application No. WO 2020 / 010068 provides the following data: XRPD peak positions of image F 2-θ d (angstrom) Height (counters) Relative intensity, % 7.28 12.13064 156 13 10.12 8.73306 925 78 10.41 8.4933 920 78 11.37 7.77672 292 25 13.91 6.36341 1179 100 16.20 5.46847 262 22 16.38 5.40798 331 28 17.05 5.19679 456 39 18.41 4.81512 162 14 18.90 4.69209 77 7 19.27 4.60216 129 11 20.94 4.23938 107 9 22.00 4.03681 396 34 22.51 3.94607 226 19 23.21 3.82963 73 6 23.81 3.73378 424 36 25.30 3.51739 74 6 25.85 3.44375 81 7 27.97 3.18771 227 19 29.53 3.02271 676 57 29.87 2.98899 83 7

[00386] In some incarnations, resmeteorum is the image L, which was described in the Bulletin of U.S. Patent Application No. 2021 / 0122740 and International Application No. WO 2020 / 010068.

[00387] Image L can be produced as described in US Patent Application Bulletin No. 2021 / 0122740 and International Application No. WO 2020 / 010068:

[00388] A suspension of resmetriol and acetonitrile was stirred for two days and then filtered. XRPD analysis revealed the formation of an acetonitrile solute (Figure L, Figure 47).

[00389] In some incarnations, the L-image of Resmeterum features an X-ray diffraction pattern in the powder that includes peaks at 10.5° ± 0.2°, 11.5° ± 0.2°, 11.9° ± 0.2°, 15.2° ± 0.2°, 15.7° ± 0.2°, 16.0° ± 0.2°, 16.9° ± 0.2°, 17.1° ± 0.2°, 18.4° ± 0.2°, 18.7° ± 0.2°, 22.0° ± 0.2°, 22.8° ± 0.2°, 23.5° ± 0.2°, and 26.4° ± 0.2° 2θ, where the powder X-ray diffraction pattern is obtained using The CuKα radiation source is 1.54 angstroms. In some representations, the powder X-ray diffraction pattern of image L may also include one or more peaks from Table 13 of US Patent Application No. 2021 / 0122740 and International Application No. WO 2020 / 010068. In some representations, image L has an X-ray diffraction pattern very similar to that shown in Figure 47.

[00390] Table 13 of the US Patent Application Bulletin No. 2021 / 0122740 and International Application No. WO 2020 / 010068 provides the following data: 2-θ d (angstrom) Height (counters) Relative intensity, % 8.11 10.88728 170 12 10.53 8.39548 319 23 11.49 7.6921 904 64 11.87 7.45234 1402 100 12.27 7.20569 141 10 15.21 5.82222 794 57 15.65 5.6584 470 34 16.04 5.52206 591 42 16.88 5.24756 455 32 17.10 5.18216 849 61 17.70 5.00658 143 10 18.43 4.81125 278 20 18.71 4.73921 332 24 21.32 4.16467 128 9 22.04 4.02938 413 29 22.81 3.89506 695 50 23.45 3.79117 422 30 24.08 3.69229 206 15 24.72 3.59921 266 19 26.37 3.37757 328 23 29.03 3.07381 91 6 29.49 3.02679 70 5

[00391] A number of images of Resmetrum were determined to be in the field.

[00392] For example, one of the images is the CSIV image set out in the US Patent Application Bulletin No. 2022 / 0372021 and International Application No. WO 2021 / 129465.

[00393] A CSIV image can be characterized, for example, by a powder X-ray diffraction pattern that includes characteristic peaks at 2-theta values ​​of 6.3° ± 0.2°, 18.1° ± 0.2°, and 25.3° ± 0.2° using CuKα radiation. The powder X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 10.4° ± 0.2°, 14.5° ± 0.2°, 20.6° ± 0.2°, 24.6° ± 0.2°, and 28.6° ± 0.2° 2-theta.

[00394] Example 1 of US Patent Application No. 2022 / 0372021 and International Application No. WO 2021 / 129465 describes the preparation of the CSIV crystallized image of Resmetrum:

[00395] 145.2 mg of resmetrium was weighed into a glass vial. 1.5 mL of acetonitrile was added, and the mixture was stirred at room temperature for three days to form a suspension. The suspension was centrifuged to obtain a solid. The resulting solid was dried under vacuum at 100 °C for 3.5 hours to obtain the CSIV crystalline form of resmetrium.

[00396] The XRPD pattern of the CSIV crystallized image of Resmetrium obtained in this example is illustrated in Figure 48, and the XRPD data are listed in Table 2 of the US Patent Application Bulletin No. 2022 / 0372021 and International Application No. WO 2021 / 129465.

[00397] Table 2 of the US Patent Application No. 2022 / 0372021 and International Application No. WO 2021 / 129465 provides the following data: 2θ (degrees) Intermediate distance d (angstroms) Relative intensity % 6.26 14.13 15.68 7.88 11.21 3.93 10.40 8.50 6.46 14.48 6.12 19.94 14.57 6.08 18.19 15.32 5.78 7.55 15.51 5.72 8.63 16.39 5.41 2.88 17.08 5.19 3.69 18.10 4.90 71.67 19.65 4.52 13.55 20.60 4.31 17.34 20.98 4.23 10.25 23.21 3.83 20.11 23.85 3.73 16.01 24.58 3.62 74.11 25.31 3.52 100.00 26.08 3.42 7.51 27.11 3.29 4.29 28.55 3.13 21.78 30.05 2.97 14.73 31.02 2.88 6.02 31.67 2.83 10.20 32.94 2.72 14.56 34.03 2.63 7.50 34.76 2.58 5.80 35.50 2.53 5.77 36.76 2.45 2.33 37.43 2.40 2.42 38.80 2.32 5.18

[00398] The TGA curve of the CSIV crystalline image of rhizometrum is substantial as shown in Figure 49, indicating approximately 0.1% weight loss upon heating to 200°C.

[00399] The DSC curve of the CSIV crystalline form of rhysmetrium is substantial, as shown in Figure 50, and illustrates both an exothermic peak and an endothermic peak. The peak at approximately 245 °C (the onset temperature) is the exothermic peak of crystallization, and the endothermic peak at approximately 334 °C (the onset temperature) corresponds to the melting peak.

[00400] be Data 1 1H NMR of the CSIV crystalline image of Resmetrium: 1 H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 12.24 (s, 1H), 7.78 (s, 2H), 7.45 (s, 1H), 3.05 (m, 1H), 1.20 (d, J=6.9 Hz, 6H).

[00401] As described in Example 2 of US Patent Application No. 2022 / 0372021 and International Application No. WO 2021 / 129465, preparation of the CSIV crystallized image of Resmetrum:

[00402] A specified amount of resmetearum solid was placed in 30 mL of acetonitrile and stirred at −20 °C for approximately 37.5 hours. The resulting solid separated and was dried under vacuum at 50 °C for approximately 23.5 hours to obtain the CSIV crystalline image of resmetearum.

[00403] For example, one of the images is the CSV image specified in international request number WO 2021 / 129465.

[00404] The CSV image may be characterized, for example, by a powder X-ray diffraction pattern that includes characteristic peaks at 2-theta values ​​of 11.9° ± 0.2°, 13.8° ± 0.2°, and 17.3° ± 0.2° using CuKα radiation. The powder X-ray diffraction pattern may have any one, two, three, four, five, or six additional peaks selected from 19.9° ± 0.2°, 20.8° ± 0.2°, 21.2° ± 0.2°, 24.5° ± 0.2°, 26.2° ± 0.2°, and 27.0° ± 0.2° 2-theta.

[00405] Example 3 of US Patent Application No. 2022 / 0372021 and International Application No. WO 2021 / 129465 describes the preparation of a CSV crystallized image of Resmetrium:

[00406] 2.0742 g of resmetearum solid was weighed into a glass vial, 30 mL of dimethyl carbonate was added, and the mixture was stirred at 5 °C for 19 h to form a suspension. The suspension was centrifuged, and the separated solid was dried under vacuum at 50 °C for 4 h to obtain a dry solid. 54.9 mg of the dry solid was weighed into a glass vial, 1 mL of isopropyl alcohol was added, and the mixture was stirred at 5 °C for 1.5 h to obtain the CSV crystalline image of resmetearum.

[00407] The XRPD pattern of the CSV crystallized image of Resmetrium obtained in this example is illustrated in Figure 86, and the XRPD data are listed in Table 3 of the US Patent Application Bulletin No. 2022 / 0372021 and International Application No. WO 2021 / 129465.

[00408] Table 3 of the US Patent Application No. 2022 / 0372021 and International Application No. WO 2021 / 129465 provides the following data: 2θ (degrees) Intermediate distance d (angstroms) Relative intensity % 10.61 8.34 13.46 11.88 7.45 100.00 12.47 7.10 8.14 13.03 6.79 5.05 13.83 6.41 22.15 16.63 5.33 3.82 17.27 5.13 20.20 18.61 4.77 2.21 19.59 4.53 9.14 19.94 4.45 10.80 20.85 4.26 11.12 21.20 4.19 16.07 22.15 4.01 8.96 22.97 3.87 12.28 23.77 3.74 8.66 24.06 3.70 13.65 24.49 3.64 10.51 24.92 3.57 8.42 25.82 3.45 7.83 26.24 3.40 11.66 26.64 3.35 4.46 27.05 3.30 6.36 27.41 3.25 2.39 27.91 3.20 4.26 28.50 3.13 12.48 29.10 3.07 3.56 29.36 3.04 4.07 30.38 2.94 4.99 31.07 2.88 2.13 32.33 2.77 6.22 33.25 2.69 4.77 34.24 2.62 2.21 36.17 2.48 3.66 37.13 2.42 2.11 37.96 2.37 1.65 39.54 2.28 3.02

[00409] The TGA curve of the CSV crystalline image of Resmetrium is substantial as shown in Figure 87, indicating approximately 0.1% weight loss upon heating to 200°C.

[00410] data 1 The 1H NMR CSV image of Resmetrium is: 1 H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 12.25 (s, 1H), 7.79 (s, 2H), 7.45 (s, 1H), 3.05 (m, 1H), 1.20 (d, J=6.9 Hz, 6H).

[00411] For example, one of the images is the CSVI image specified in the US Patent Application Bulletin No. 2023 / 0416234 and International Application No. WO 2022 / 052822.

[00412] A CSVI image can be characterized, for example, by a powder X-ray diffraction pattern that includes characteristic peaks at 2-theta values ​​of 9.6° ± 0.2°, 10.1° ± 0.2°, and 18.9° ± 0.2° using CuKα radiation. The powder X-ray diffraction pattern may have any one, two, three, four, five, or six additional peaks selected from 11.6° ± 0.2°, 13.7° ± 0.2°, 19.5° ± 0.2°, 20.6° ± 0.2°, 23.3° ± 0.2°, and 31.9° ± 0.2° 2-theta.

[00413] Example 1 of US Patent Application No. 2023 / 0416234 and International Application No. WO 2022 / 052822 describes the preparation of a CSVI crystallized image of Resmetrium:

[00414] 1.5801 g of resmetrium was weighed into a vial, followed by the addition of 25 mL of acetonitrile, and then stirred at room temperature for 4 days. The resulting solid was separated by filtration, and then the solid was blown dry at 40 °C for 15.5 hours to obtain the CSVI crystalline image of resmetrium.

[00415] The XRPD pattern of the CSVI crystallized image of Resmetrium obtained in this example is illustrated in Figure 107, and the XRPD data are listed in Table 3 of the US Patent Application Bulletin No. 2023 / 0416234 and International Application No. WO 2022 / 052822.

[00416] Table 3 of the US Patent Application No. 2023 / 0416234 and International Application No. WO 2022 / 052822 provides the following data: 2θ (degrees) Intermediate distance d (angstroms) Relative intensity (%) 6.49 13.62 2.06 9.57 9.25 65.84 10.11 8.75 100.00 11.58 7.65 7.89 12.77 6.93 0.88 13.68 6.48 3.39 13.98 6.33 0.91 14.75 6.00 2.41 16.19 5.48 4.32 17.64 5.03 1.13 18.10 4.90 2.23 18.94 4.68 10.63 19.50 4.55 19.67 19.81 4.48 4.75 20.33 4.37 1.63 20.61 4.31 7.02 21.62 4.11 2.74 21.86 4.07 2.96 22.66 3.92 4.89 22.91 3.88 2.66 23.29 3.82 8.60 23.72 3.75 1.44 24.14 3.69 0.98 24.80 3.59 3.03 24.98 3.57 4.96 25.69 3.47 1.87 26.12 3.41 3.40 26.75 3.33 4.17 27.31 3.27 2.57 27.57 3.24 1.94 28.01 3.19 1.85 29.19 3.06 1.72 29.79 3.00 2.09 31.13 2.87 1.30 31.90 2.81 4.91 32.68 2.74 1.98 33.48 2.68 1.87 33.77 2.65 1.24 34.37 2.61 1.29 35.45 2.53 1.92 36.44 2.47 1.70 38.27 2.35 1.43 39.14 2.30 3.36

[00417] The TGA curve of the CSVI crystalline image of Resmetrum is substantial as shown in Figure 108, indicating approximately 0.2% weight loss when heated to 250°C.

[00418] be Data 1 The 1H NMR CSVI image of Resmetrium is: 1 H NMR (400MHz, DMSO-d6) δ13.28(s, 1H), 12.23(s, 1H), 7.79(s, 2H), 7.44(d, J=0.8Hz, 1H), 3.04 (dq, J=13.5, 6.8 Hz, 1H), 1.20 (d, J=6.9 Hz, 6H).

[00419] Example 2 of US Patent Application No. 2023 / 0416234 and International Application No. WO 2022 / 052822 describes the preparation of a CSVI crystallized image of Resmetrium:

[00420] 22.0 mg of resmetrium was weighed into a vial, followed by the addition of 2.0 mL of a solvent mixture of acetonitrile and water (95:5, v:v), dissolution at 50 °C, and filtration. The filtrate was then stirred at −20 °C for 4 hours. The resulting solid was separated by filtration and then dried at 25 °C under vacuum for 2 hours to obtain the CSVI crystalline image of resmetrium.

[00421] The XRPD pattern of the CSVI crystallized image of Resmetrium obtained in this example is illustrated in Figure 109, and the XRPD data are listed in Table 4 of the Bulletin of US Patent Application No. 2023 / 0416234 and International Application No. WO 2022 / 052822.

[00422] Table 4 of the US Patent Application No. 2023 / 0416234 and International Application No. WO 2022 / 052822 provides the following data: 2θ (degrees) Intermediate distance d (angstroms) Relative intensity (%) 6.48 13.65 9.15 9.55 9.26 51.51 10.09 8.76 100.00 11.56 7.65 10.22 13.00 6.81 1.45 13.67 6.48 6.38 13.97 6.34 1.56 14.71 6.02 2.42 16.18 5.48 9.37 17.61 5.04 0.98 18.11 4.90 1.81 18.93 4.69 22.10 19.49 4.56 18.39 19.82 4.48 2.83 20.61 4.31 4.81 21.61 4.11 3.08 21.84 4.07 7.91 22.64 3.93 4.23 22.88 3.89 3.26 23.27 3.82 12.36 24.97 3.57 3.66 25.62 3.48 1.81 26.11 3.41 3.28 26.73 3.34 3.74 27.28 3.27 2.52 27.59 3.23 2.25 27.96 3.19 5.37 29.20 3.06 1.70 29.76 3.00 1.82 31.13 2.87 3.79 31.91 2.81 5.06 32.69 2.74 2.33 33.43 2.68 3.01 34.36 2.61 2.57 35.41 2.53 1.64 36.43 2.47 1.33 38.18 2.36 1.33 39.15 2.30 2.37

[00423] For example, one of the images is the CSVII image specified in international application number WO 2025 / 011259.

[00424] The CSVII image can be characterized, for example, by a powder X-ray diffraction pattern that includes characteristic peaks at 2-theta values ​​of 6.5° ± 0.2°, 7.7° ± 0.2°, and 23.4° ± 0.2° using CuKα radiation. The powder X-ray diffraction pattern may have any one, two, three, four, five, or six additional peaks selected from 12.2° ± 0.2°, 19.7° ± 0.2°, 21.1° ± 0.2°, 22.7° ± 0.2°, 24.2° ± 0.2°, and 25.4° ± 0.2° 2-theta.

[00425] Example 1 of International Order No. WO 2025 / 011259 describes the preparation of the CSVII crystallized image for Resmetrium:

[00426] 527.6 mg of resmetrium was weighed into a bottle, followed by the addition of 15 mL of methyl tert-butyl ether, and then stirred at room temperature for 1 day. The resulting solid was separated by filtration and then dried under vacuum at 25°C for 0.5 hours to obtain a partially dried solid. The partially dried solid was heated to 140°C at 10°C / min under nitrogen protection and held warm for 60 minutes, then cooled to room temperature to obtain the CSVII crystalline form of resmetrium.

[00427] The XRPD pattern of the CSVII crystallized image of Resmetrium obtained in this example is illustrated in Figure 116, and the XRPD data are listed in Table 2 of International Order No. WO 2025 / 011259.

[00428] Table 2 of International Order No. WO 2025 / 011259 provides the following data: Diffraction angle 2θ value d severity % 5.1 17.2 2.5 6.5 13.7 13.1 7.7 11.4 100 12.2 7.3 2.9 14.2 6.2 1.1 17.1 5.2 1.2 19.7 4.5 3.5 21.1 4.2 1.1 22.7 3.9 1.7 23.4 3.8 6.2 24.2 3.7 3.8 25.4 3.5 2.3 26.6 3.3 2.1

[00429] The TGA curve of the CSVII crystalline image of rhizometrum is substantial as shown in Figure 117, indicating approximately 0.5% weight loss upon heating to 100°C.

[00430] The DSC curve of the CSVII crystalline image of Resmetrium is substantial, as shown in Figure 118, and shows a heat expulsion peak close to 264 °C and a heat absorption peak close to 333 °C.

[00431] be Data 1 1H NMR of the CSVII crystalline image of Resmetrium: 1 H NMR (400MHz, DMSO-d6) δ12.24(s, 1H), 7.79(s, 2H), 7.44(d, J=0.7Hz, 1H), 3.13-2.97 (m, 1H), 1.19 (d, J=6.9 Hz, 6H).

[00432] For example, one of the images is the K65 type image specified in international application number WO 2025 / 011259.

[00433] Example 4 of International Order No. WO 2025 / 011259 describes the preparation of a K65 crystallized image for Resmetrium:

[00434] 51.2 mg of resmetrium was weighed into a vial, and a mixed solvent (7:1 volume ratio) of 1.0 mL of acetonitrile and methanol was added. The mixture was suspended and stirred overnight at room temperature, and centrifuged to obtain the K65 crystalline form of resmetrium.

[00435] The XRPD pattern of the K65 crystalline image of resmetrium obtained in this example is illustrated in Figure 119, and the XRPD data are listed in Table 5 of International Order No. WO 2025 / 011259.

[00436] Table 5 of International Order No. WO 2025 / 011259 provides the following data: Diffraction angle 2θ value d severity % 6.5 13.6 3.8 7.6 11.7 100.0 8.2 10.7 56.9 10.0 8.8 13.3 13.4 6.6 4.3 14.3 6.2 7.8 15.1 5.9 7.7 16.3 5.4 4.0 18.0 4.9 15.8 19.1 4.7 4.8 19.5 4.6 10.9 20.1 4.4 6.1 21.0 4.2 4.5 22.4 4.0 7.3 23.1 3.8 10.7 24.4 3.6 5.8 24.7 3.6 6.6 26.0 3.4 5.7 26.4 3.4 8.8 27.3 3.3 4.2 27.9 3.2 3.0 31.1 2.9 1.7 31.4 2.9 2.9 32.3 2.8 1.6 32.6 2.7 1.5 35.5 2.5 1.7 38.6 2.3 1.2

[00437] Example 5 of International Order No. WO 2025 / 011259 describes the preparation of a K65 crystallized image for Resmeterum:

[00438] 10.1 mg of resmetrium was weighed into a vial, 0.2 mL of acetonitrile was added, and the vial was sonicated at room temperature for about 1 minute. It was then centrifuged to obtain the K65 crystalline image of resmetrium.

[00439] The XRPD pattern of the K65 crystalline image of Resmetrium obtained in this example is illustrated in Figure 120, and the XRPD data are listed in Table 6 of International Order No. WO 2025 / 011259.

[00440] Table 6 of International Order No. WO 2025 / 011259 provides the following data: Diffraction angle 2θ value d severity % 6.5 13.6 0.7 7.6 11.7 100.0 8.3 10.7 26.9 10.0 8.8 3.5 13.8 6.4 1.7 15.2 5.8 3.3 18.1 4.9 5.3 19.5 4.6 4.2 20.2 4.4 2.3 22.4 4.0 3.5 22.9 3.9 5.6 23.1 3.8 8.4 24.7 3.6 1.5 26.0 3.4 3.2 26.4 3.4 4.3 27.8 3.2 1.2 31.4 2.8 2.0 32.3 2.8 1.3 33.5 2.7 0.8 35.6 2.5 0.9 36.8 2.4 0.4 38.7 2.3 1.3

[00441] For example, one of the images is the K65 type melting product image specified in International Order No. WO 2025 / 011259.

[00442] Example 6 of International Order No. WO 2025 / 011259 describes the preparation of the K65 crystalline image melting product of Resmetrium:

[00443] The K65 crystalline image obtained in Example 4 was placed in a room temperature environment for approximately 5 hours.

[00444] The XRPD pattern of the K65 crystalline image melt product of Resmetrium obtained in this example is illustrated in Figure 120, and the XRPD data are listed in Table 6 of International Order No. WO 2025 / 011259.

[00445] Table 6 of International Order No. WO 2025 / 011259 provides the following data: Diffraction angle 2θ value d severity % 6.5 13.6 8.5 7.7 11.5 19.1 8.3 10.6 9.0 9.6 9.2 65.8 10.1 8.7 100.0 11.6 7.6 9.3 12.8 6.9 4.5 13.7 6.5 11.9 14.0 6.3 11.3 14.7 6.0 10.1 16.2 5.5 10.5 18.1 4.9 10.9 19.0 4.7 23.7 19.5 4.5 26.5 20.7 4.3 12.8 21.9 4.1 12.1 22.7 3.9 12.2 23.3 3.8 16.0 24.2 3.7 6.7 24.9 3.6 10.7 26.2 3.4 8.4 26.7 3.3 9.8 27.3 3.3 8.4 28.0 3.2 6.0 29.2 3.1 3.1 29.9 3.0 3.3 31.1 2.9 3.2 31.9 2.8 4.5 32.7 2.7 2.7 33.5 2.7 2.1 34.4 2.6 1.6 35.5 2.5 1.5 36.4 2.5 1.6 38.3 2.3 0.9 39.2 2.3 2.2

[00446] For example, one of the images is the R3-A image set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00447] The R3-A crystalline image can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern is strongly as shown in Figure 55; the powder's X-ray diffraction pattern has peaks at 8.6° ± 0.2°, 9.3° ± 0.2°, 10.3° ± 0.2°, 16.9° ± 0.2°, and 18.3° ± 0.2°; 2-theta spectrum 13 1C NMR solid-state with characteristic peaks at 161.7 ± 0.2, 152.4 ± 0.2, 135.1 ± 0.2, 60.8 ± 0.2 and 46.5 ± 0.2 ppm; spectrum 13 1C NMR solid-state and has the following absolute differences for chemical shift from a reference peak at 174.7 ppm ± 1 ppm: 13.0 ± 0.1, 22.3 ± 0.1, 39.6 ± 0.1, 114.0 ± 0.1 and 128.3 ± 0.1 ppm; spectrum 13 1C NMR of the solid state is extensively shown in Figures 56, 57, or 58; and combinations of those data. The X-ray diffraction pattern of the powder may have any one, two, three, four, or five additional peaks selected from 16.4° ± 0.2°, 20.1° ± 0.2°, 21.9° ± 0.2°, 24.8° ± 0.2°, and 25.8° ± 0.2° 2-theta.

[00448] Example 22 of US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of the R3-A image for resmetrium (resmetrium: L-proline image R3-A):

[00449] Procedure A

[00450] 2-methoxyethanol (3.5 mL, 26 v) was added to L-proline (132 mg, 1.15 mmol) to produce a slurry. The slurry was magnetically stirred at 80 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. Then, resmeterum (500 mg, 1.15 mmol) was added to the hot clear solution, which had been magnetically stirred at 80 °C, to produce another slurry. This slurry was then magnetically stirred at 80 °C to produce a clear solution, and precipitation occurred after 15 minutes. The resulting slurry was then cooled to room temperature and magnetically stirred for 18 hours. The solid was then filtered by Buchner and dried in a vacuum oven at 45 °C for 18 hours. The solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 53.

[00451] Procedure B

[00452] 2-methoxyethanol (0.66 mL, 55 v / s) was added to L-proline (12 mg, 0.11 mmol) to produce a slurry. The slurry was magnetically stirred at 80 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. The clear solution was then transferred to a 4 mL flask. Subsequently, in another 4 mL flask, 2-methoxyethanol (0.21 mL, 7 v / s) was added to resmeterum (30 mg, 0.07 mmol) to produce a slurry. This slurry was magnetically stirred at 80 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. The hot resmeterum solution was then added to the 4 mL flask containing the hot L-proline solution, and the reaction was magnetically stirred at 80 °C for 15 minutes. The purified solution was then concentrated using a rotary evaporator. The resulting solid was analyzed by X-ray diffraction of the powder and identified as L-proline resmeteorum salt (image R3-A).

[00453] For example, one of the images is RC1-A (rismetrum: nicotinamide) set out in US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00454] The RC1-A crystalline image of rhizometrum:nicotinamide can be classified by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial, as shown in Figure 59; the X-ray diffraction pattern in the powder has peaks at 8.7° ± 0.2°, 18.6° ± 0.2°, 21.1° ± 0.2°, 25.3° ± 0.2°, and 26.4° ± 0.2°; 2-theta spectrum 13 1C NMR solid-state with characteristic peaks at 159.9 ± 0.2, 153.4 ± 0.2, 136.2 ± 0.2, 134.9 ± 0.2 and 119.1 ± 0.2 ppm; spectrum 13 1C NMR solid-state and has the following absolute differences for chemical displacement from a reference peak at 170.2 ppm ± 1 ppm: 10.3 ± 0.1, 16.8 ± 0.1, 34.0 ± 0.1, 35.3 ± 0.1 and 51.0 ± 0.1 ppm; spectrum 13 1C NMR of the solid state is extensively shown in Figures 60, 61, or 62; and combinations of those data. The X-ray diffraction pattern of the powder may have any one, two, three, four, or five additional peaks selected from 11.5° ± 0.2°, 12.6° ± 0.2°, 13.9° ± 0.2°, 20.1° ± 0.2°, and 22.0° ± 0.2° 2-theta.

[00455] Example 24 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of the RC1-A image (rismetrum:nicotineamide).

[00456] Procedure A

[00457] Resmetrium (200 mg, 0.46 mmol) was ground with a mortar and pestle with nicotinamide (56.2 mg, 0.46 mmol, 1 equator) for 1 minute. Dichloromethane was added to 50 mg of the resmetrium-nicotinamide grinding mixture to produce a slurry. The resulting slurry was induced to crystallize using 0.1–0.5% RC1-A resmetrium:nicotinamide (prepared according to procedure B or C) and magnetically stirred at room temperature for 18 hours. The solid was then separated by centrifugation and dried in a vacuum oven at 45 °C for 18 hours. The resulting solid was analyzed by X-ray diffraction of the powder, and the XRPD pattern is shown in Figure 59.

[00458] Procedure B

[00459] 2-methoxyethanol (0.25 mL, 5 volumes) was added to resmeterum (50 mg, 0.115 mmol) to produce a slurry. The resulting slurry was stirred at 80 °C for 30 minutes until the solids were completely dissolved. Subsequently, nicotinamide (14.05 mg, 0.115 mmol, 1 equator) was added to the resulting hot clear solution to produce another slurry. This slurry was then magnetically stirred at 80 °C for 30 minutes until the solids were completely dissolved. The mixture was then dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. Finally, dichloromethane (0.512 mL, 8 volumes) was added to produce a slurry. This slurry was magnetically stirred at 25 °C for 18 hours. The solid was then separated by centrifugation and dried in a vacuum oven at 45°C for 18 hours. The solid was analyzed by X-ray diffraction of the powder and characterized as the RC1-A image of rhizometrum:nicotinamide.

[00460] Procedure C

[00461] Resmetrium (50 mg, 0.115 mmol) was ground with a mortar and pestle with nicotinamide (14.05 mg, 0.115 mmol, 1 equator) for 1 minute. The resulting solid mixture was heated in a 1.7 mL glass flask at 140 °C (10 °C above the melting point of the co-forming agent) for 2 hours. The flask was then cooled to 120 °C and heated at this temperature for 1 hour. Finally, the flask was cooled to room temperature. The resulting solid was analyzed and characterized as the RC1-A image of resmetrium:nicotinamide.

[00462] Procedure D

[00463] Dichloromethane (0.48 mL, 8 volumes) was added to resmetrium methyltetrahydrofuran solute (50 mg, 0.115 mmol) to produce a slurry. Nicotinamide (14 mg, 0.115 mmol, 1.0 Eq) was then added to the resulting slurry. The slurry was then magnetically stirred at room temperature, and crystallization was induced using 0.1–0.5% resmetrium RC1-A. The slurry was then magnetically stirred at room temperature for 4 days. The precipitate was separated by centrifugation and subsequently dried in a vacuum oven at 45 °C for 18 hours. The resulting solid was analyzed by X-ray diffraction of the powder and identified as resmetrium RC1-A:nicotineamide.

[00464] Procedure E

[00465] Dichloromethane (0.48 mL, 8 volumes) was added to resmetrium methyl ethyl ketone solute (50 mg, 0.115 mmol) to produce a slurry. Nicotinamide (14 mg, 0.115 mmol, 1.0 Eq) was then added to the resulting slurry. The slurry was then magnetically stirred at room temperature, and crystallization was induced using 0.1–0.5% resmetrium RC1-A. The slurry was then magnetically stirred at room temperature for 3 days. The precipitate was separated by centrifugation and subsequently dried in a vacuum oven at 45 °C for 18 h. The resulting solid was analyzed by X-ray diffraction of the powder and identified as resmetrium RC1-A:nicotineamide.

[00466] For example, one of the images is RC2-A (Resmetrum:Caffeine) set out in US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00467] The RC2-A crystalline image of Rismeterum:Caffeine can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial, as shown in Figure 63; the X-ray diffraction pattern in the powder has peaks at 6.0° ± 0.2°, 6.8° ± 0.2°, 10.4° ± 0.2°, 11.2° ± 0.2°, and 16.4° ± 0.2°; 2-theta spectrum 13 1C NMR solid-state with characteristic peaks at 139.5 ± 0.2, 118.8 ± 0.2, 106.7 ± 0.2, 34.0 ± 0.2 and 29.6 ± 0.2 ppm; spectrum 13 1C NMR solid-state and has the following absolute differences for chemical displacement from a reference peak at 161.0 ppm ± 1 ppm: 21.4 ± 0.1, 42.2 ± 0.1, 54.3 ± 0.1, 127.0 ± 0.1 and 131.4 ± 0.1 ppm; spectrum 13 1C NMR of the solid state is extensively shown in Figures 64, 65, or 66; and combinations of those data. The X-ray diffraction pattern of the powder may have any one, two, three, four, or five additional peaks selected from 14.6° ± 0.2°, 15.6° ± 0.2°, 17.8° ± 0.2°, 19.5° ± 0.2°, and 26.9° ± 0.2° 2-theta.

[00468] Example 25 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of the RC2-A image (Rismetrum:Caffeine).

[00469] Procedure A

[00470] 2-methoxyethanol (0.2 mL, 6.7 v) was added to resmeterum (30 mg, 0.07 mmol) to produce a slurry. The resulting slurry was stirred at 80 °C for 30 minutes until the solids were completely dissolved. Subsequently, caffeine (13.4 mg, 0.07 mmol, 1 Eq) was added to the resulting hot clear solution to produce a slurry. Then, ethanol (0.2 mL, 6.7 v) was added to the resulting slurry and magnetically stirred at 80 °C for 30 minutes until the solids were completely dissolved. The mixture was dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. Finally, isopropanol (0.18 mL, 4 v) was added to produce a slurry. The resulting slurry was magnetically stirred at 25°C for 18 hours. The solid was then separated by centrifugation and dried in a vacuum oven at 45°C for 18 hours. The solid was analyzed by X-ray diffraction of the powder, and the XRPD pattern is shown in Figure 63.

[00471] Procedure B

[00472] Isopropyl alcohol (0.45 mL, 6 volumes) was added to a resmetrium methyltetrahydrofuran solute (50 mg, 0.115 mmol) to produce a slurry. Caffeine (24.2 mg, 0.126 mmol, 1.1 Eq) was then added to the resulting slurry. The slurry was then magnetically stirred at room temperature, and crystallization was induced using 0.1–0.5% resmetrium RC2-A. The slurry was then magnetically stirred at room temperature for 4 days. The precipitate was separated by centrifugation and subsequently dried in a vacuum oven at 45 °C for 18 hours. The resulting solid was analyzed by X-ray diffraction of the powder and identified as resmetrium RC2-A:caffeine crystallized.

[00473] Procedure C

[00474] Isopropyl alcohol (0.45 mL, 6 volumes) was added to a resmetrium methyl ethyl ketone solute (50 mg, 0.115 mmol) to produce a slurry. Caffeine (24.2 mg, 0.126 mmol, 1.1 equiv) was then added to the resulting slurry. The slurry was then magnetically stirred at room temperature, and crystallization was induced using 0.1–0.5% resmetrium RC2-A. The slurry was then magnetically stirred at room temperature for 3 days. The precipitate was separated by centrifugation and subsequently dried in a vacuum oven at 45 °C for 18 hours. The resulting solid was analyzed by X-ray diffraction of the powder and identified as resmetrium RC2-A:caffeine crystallized.

[00475] For example, one of the images is RC2-B (Resmetrum:Caffeine) as determined in the Bulletin of the U.S. Patent Application No. 2023 / 0364099 and the International Application No. WO 2022 / 086894.

[00476] The RC2-B crystalline image of Rismeterum:Caffeine can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial, as shown in Figure 67; the X-ray diffraction pattern in the powder has peaks at 8.9° ± 0.2°, 10.6° ± 0.2°, 11.2° ± 0.2°, 14.5° ± 0.2°, and 17.1° ± 0.2°; 2-theta spectrum 13 1C NMR solid-state with characteristic peaks at 145.9 ± 0.2, 142.7 ± 0.2, 108.7 ± 0.2, 33.5 ± 0.2 and 28.1 ± 0.2 ppm; spectrum 13 1C NMR solid-state and has the following absolute differences for chemical shift from a reference peak at 161.1 ppm ± 1 ppm: 15.2 ± 0.1, 18.45 ± 0.1, 52.4 ± 0.1, 127.6 ± 0.1 and 133.0 ± 0.1 ppm; spectrum 13 1C NMR of the solid state is extensively shown in Figures 68, 69, or 70; and combinations of those data. The X-ray diffraction pattern of the powder may have any one, two, three, four, or five additional peaks selected from 14.9° ± 0.2°, 20.0° ± 0.2°, 21.9° ± 0.2°, 24.5° ± 0.2°, and 28.2° ± 0.2° 2-theta.

[00477] Example 26 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of the RC2-B image (Rismetrum:Caffeine).

[00478] Procedure A

[00479] 2-methoxyethanol (0.2 mL, 6.7 v) was added to resmeterum (30 mg, 0.07 mmol) to produce a slurry. The resulting slurry was stirred at 80 °C for 30 minutes until the solids were completely dissolved. Caffeine (13.4 mg, 0.07 mmol, 1 Eq) was then added to the resulting hot clear solution to produce a slurry. Ethanol (0.2 mL, 6.7 v) was then added to the resulting slurry and magnetically stirred at 80 °C for 30 minutes until the solids were completely dissolved. The mixture was then dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. Finally, toluene (0.18 mL, 4 v) was added to produce a slurry. The resulting slurry was magnetically stirred at 25°C for 18 hours. The solid was then separated by centrifugation and dried in a vacuum oven at 45°C for 18 hours. The solid was analyzed by X-ray diffraction of the powder, and the XRPD pattern is shown in Figure 67.

[00480] Procedure B

[00481] Resmetrium (200 mg, 0.46 mmol) was ground with a mortar and pestle along with caffeine (89 mg, 0.46 mmol, 1 equator) for 1 minute. Toluene (4 V) was added to 250 mg of the ground resmetrium and caffeine mixture to produce a slurry. The resulting slurry was induced to crystallize using 0.1–0.5% RC2-B resmetrium:caffeine (prepared according to the procedure in Example 26, Procedure A) and magnetically stirred at 25 °C for 48 h. The solid was then separated by centrifugation and dried in a vacuum oven at 45 °C for 72 h. The solid was analyzed by X-ray diffraction of the powder and identified as RC2-B.

[00482] Procedure C

[00483] Toluene (0.30 mL, 4 volumes) was added to resmetrium methyltetrahydrofuran solute (50 mg, 0.115 mmol) to produce a slurry. Caffeine (24.2 mg, 0.126 mmol, 1.1 Eq) was then added to the resulting slurry. The slurry was then magnetically stirred at room temperature, and crystallization was induced using 0.1–0.5% resmetrium:caffeine RC2-B. The slurry was then magnetically stirred at room temperature for 4 days. The precipitate was separated by centrifugation and subsequently dried in a vacuum oven at 45 °C for 18 h. The resulting solid was analyzed by X-ray diffraction of the powder and identified as the crystalline RC2-B resmetrium:caffeine.

[00484] Procedure D

[00485] Toluene (0.30 mL, 4 volumes) was added to resmetrium methyl ethyl ketone solute (50 mg, 0.115 mmol) to produce a slurry. Caffeine (24.2 mg, 0.126 mmol, 1.1 Eq) was then added to the resulting slurry. The slurry was then magnetically stirred at room temperature, and crystallization was induced using 0.1–0.5% resmetrium:caffeine RC2-B. The slurry was then magnetically stirred at room temperature for 3 days. The precipitate was separated by centrifugation and subsequently dried in a vacuum oven at 45 °C for 18 h. The resulting solid was analyzed by X-ray diffraction of the powder and identified as the crystalline RC2-B resmetrium:caffeine.

[00486] For example, one of the images is RC3-A (Rismetrum: 2-picolinenic acid) as determined in the Bulletin of U.S. Patent Application No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00487] The RC3-A crystalline image of rhizometrum:2-picolinenic acid can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 71; the X-ray diffraction pattern in the powder has peaks at 6.0° ± 0.2°, 6.8° ± 0.2°, 12.9° ± 0.2°, 15.6° ± 0.2° and 26.9° ± 0.2° 2-theta; and combinations of those data. The powder's X-ray diffraction pattern may have any one, two, three, four or five additional peaks selected from 10.4° ± 0.2°, 14.8° ± 0.2°, 18.0° ± 0.2°, 18.5° ± 0.2° and 24.7° ± 0.2° 2-theta.

[00488] Example 27 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of the RC3-A image (Rismetrum: 2-picolinenic acid).

[00489] Procedure A

[00490] 2-methoxyethanol (0.375 mL, 7.5 v) was added to resmeterum (50 mg, 0.115 mmol) to produce a slurry. The resulting slurry was stirred at 80 °C for 30 minutes until the solids were completely dissolved. Subsequently, 2-picolinic acid (14.6 mg, 0.115 mmol, 1 equator) was added to the resulting hot clear solution to produce another slurry. This slurry was then magnetically stirred at 80 °C for 30 minutes until the solids were completely dissolved. The mixture was then dried in a vacuum oven at 45 °C for 18 hours to obtain a yellow solid. The solid was analyzed by X-ray diffraction of the powder, and the XRPD pattern is shown in Figure 71.

[00491] Procedure B

[00492] Dichloromethane (0.5 mL, 8 volumes) was added to resmetrium methyltetrahydrofuran solute (50 mg, 0.115 mmol) to produce a slurry. Subsequently, 2-piculenic acid (15.62 mg, 0.126 mmol, 1.1 Eq) was added to the resulting slurry. The slurry was then magnetically stirred at room temperature, and crystallization was induced using 0.1–0.5% resmetrium RC3-A. The slurry was then magnetically stirred at room temperature for 4 days. The precipitate was separated by centrifugation and subsequently dried in a vacuum oven at 45 °C for 18 hours. The resulting solid was analyzed by X-ray diffraction of the powder and identified as the crystalline RC3-A of resmetrium:2-piculenic acid.

[00493] Procedure C

[00494] Dichloromethane (0.5 mL, 8 volumes) was added to resmetrium methyltetrahydrofuran solute (50 mg, 0.115 mmol) to produce a slurry. Subsequently, 2-piculenic acid (15.62 mg, 0.126 mmol, 1.1 Eq) was added to the resulting slurry. The slurry was then magnetically stirred at room temperature, and crystallization was induced using 0.1–0.5% resmetrium RC3-A. The slurry was then magnetically stirred at room temperature for 3 days. The precipitate was separated by centrifugation and subsequently dried in a vacuum oven at 45 °C for 18 hours. The resulting solid was analyzed by X-ray diffraction of the powder and identified as the crystalline RC3-A of resmetrium:2-piculenic acid.

[00495] For example, one of the images is RC4-A (rismeterum:urea) as determined in the Bulletin of US Patent Application No. 2023 / 0364099 and International Application No. WO 2022 / 086894. In some embodiments, the molar ratio of rismeterum and urea is approximately 1:1.

[00496] The RC4-A crystalline image of rhesmetrum:urea can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 72; the X-ray diffraction pattern in the powder has peaks at 7.6° ± 0.2°, 12.6° ± 0.2°, 15.7° ± 0.2°, 16.4° ± 0.2° and 16.9° ± 0.2° 2-theta; and combinations of those data. The powder's X-ray diffraction pattern may have any one, two, three, four or five additional peaks selected from 15.2° ± 0.2°, 19.1° ± 0.2°, 19.6° ± 0.2°, 22.0° ± 0.2° and 23.6° ± 0.2° 2-theta.

[00497] Example 28 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of the RC4-A image (Rismetrum: Urea).

[00498] Procedure A

[00499] Resmeterum (100 mg, 0.23 mmol) and urea (14 mg, 0.23 mmol) were dissolved in 2-methoxyethanol (0.57 mL, 5.7 v) at 80 °C for 30 min. The resulting solution was dried in a vacuum oven at 50 °C for 18 h to produce a solid, and then dried in a vacuum oven at 80 °C for 18 h. The resulting solid was characterized by X-ray diffraction of the powder as the RC4-A crystalline image of resmeterum:urea (Figure 72).

[00500] Procedure B

[00501] Dichloromethane (0.48 mL, 8 volumes) was added to resmetrium Me-THF solute (50 mg, 0.115 mmol) to produce a slurry. Urea (7.7 mg, 0.128 mmol, 1.1 Eq) was then added to the resulting slurry. The slurry was then magnetically stirred at room temperature, and crystallization was induced using 0.1–0.5% resmetrium RC4-A. The slurry was magnetically stirred at room temperature for 4 days. The precipitate was separated by centrifugation and subsequently dried in a vacuum oven at 45 °C for 18 hours. The resulting solid was analyzed by X-ray diffraction of the powder and identified as resmetrium RC4-A:urea crystallized.

[00502] Procedure C

[00503] Dichloromethane (0.46 mL, 8 volumes) was added to resmetrium methyl ethyl ketone solute (50 mg, 0.115 mmol) to produce a slurry. Urea (7.7 mg, 0.128 mmol, 1.1 Eq) was then added to the resulting slurry. The slurry was then magnetically stirred at room temperature, and crystallization was induced using 0.1–0.5% resmetrium RC4-A. This slurry was then magnetically stirred at room temperature for 3 days. The precipitate was separated by centrifugation and subsequently dried in a vacuum oven at 45 °C for 18 hours. The resulting solid was analyzed by X-ray diffraction of the powder and identified as resmetrium RC4-A crystalline urea.

[00504] For example, one of the images is R1-A (Rismetrum: N-methylmorpholine salt) set out in the Bulletin of U.S. Patent Application No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00505] The R1-A crystalline image of rhysmetrum:N-methylmorpholine salt can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 73; the X-ray diffraction pattern in the powder has peaks at 8.2° ± 0.2°, 16.5° ± 0.2°, 17.8° ± 0.2°, 18.6° ± 0.2° and 21.5° ± 0.2° 2-theta; and combinations of those data. The powder's X-ray diffraction pattern may have any one, two, three, four or five additional peaks selected from 10.0° ± 0.2°, 14.5° ± 0.2°, 20.2° ± 0.2°, 22.4° ± 0.2° and 27.4° ± 0.2° 2-theta.

[00506] Example 20 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of the image R1-A (Rismetrum: N-methylmorpholine salt).

[00507] Procedure A

[00508] N-methylmorpholine [4-methylmorpholine] (4.0 mL, 20 v) was added to resmeterum (200 mg, 0.26 mmol) to obtain a slurry. The slurry was magnetically stirred at room temperature for 48 hours. The solid was then separated by centrifugation and dried in a vacuum oven at 45 °C for 18 hours. The powder was then analyzed by X-ray diffraction, and the resulting XRPD pattern is shown in Figure 73.

[00509] For example, one of the images is R2-A (rismetrum: piperazine salt) as determined in the Bulletin of the U.S. Patent Application No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00510] The R2-A crystalline image of rhysmetrum:piperazine salt can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is strongly indicated as shown in Figure 74; the X-ray diffraction pattern in the powder has peaks at 10.7° ± 0.2°, 15.7° ± 0.2°, 19.5° ± 0.2°, 22.0° ± 0.2° and 23.9° ± 0.2°; 2-theta spectrum 13 1C NMR solid-state with characteristic peaks at 161.1 ± 0.2, 152.0 ± 0.2, 138.0 ± 0.2, 40.9 ± 0.2 and 39.9 ± 0.2 ppm; spectrum 13 1C NMR solid-state and has the following absolute differences for chemical shift from a reference peak at 164.6 ppm ± 1 ppm: 3.5 ± 0.1, 12.6 ± 0.1, 26.6 ± 0.1, 123.7 ± 0.1 and 124.7 ± 0.1 ppm; spectrum 13 1C NMR of the solid state is extensively shown in Figures 75, 76, or 77; and combinations of those data. The X-ray diffraction pattern of the powder may have any one, two, three, four, or five additional peaks selected from 12.0° ± 0.2°, 12.3° ± 0.2°, 12.6° ± 0.2°, 17.1° ± 0.2°, and 21.5° ± 0.2° 2-theta.

[00511] Example 21 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of the R2-A image (rismetrum: piperazine salt).

[00512] Procedure A

[00513] 2-methoxyethanol (4.2 mL, 35.3 v) was added to piperazine (119 mg, 1.38 mmol) to produce a slurry. The slurry was magnetically stirred at 80 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. Then, resmeterum (600 mg, 1.38 mmol) was added to the clear solution, which had been magnetically stirred at 80 °C, to produce another slurry. This slurry was then magnetically stirred at 80 °C to produce a clear solution, and after 15 minutes, a solid precipitated. The resulting slurry was then cooled to room temperature and magnetically stirred at room temperature for 18 hours. The solid material obtained was then separated by centrifugation, dried in a vacuum oven at 45°C for 18 hours, and analyzed by X-ray diffraction of the powder. The XRPD pattern obtained is presented in Figure 74.

[00514] Procedure B

[00515] 2-methoxyethanol (0.42 mL, 70 v) was added to piperazine (6 mg, 0.07 mmol) to produce a slurry. The slurry was magnetically stirred at 80 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. The clear solution was then transferred to a 4 mL flask. Subsequently, in another 4 mL flask, 2-methoxyethanol (0.25 mL, 8.3 v) was added to resmeterium (30 mg, 0.07 mmol) to produce a slurry. This slurry was magnetically stirred at 80 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. The hot resmeterium solution was then added to a 4 mL flask containing the hot piperazine solution, and the reaction was magnetically stirred at 80 °C for 15 minutes. The purified solution was then concentrated in a vacuum oven at 45°C for 24 hours. The resulting solid was analyzed by X-ray diffraction of the powder and identified as the R2-A image of rhizometrum:piperazine salt.

[00516] For example, one of the images is R4-A (Rismetrum:benzathen salt) as determined in the Bulletin of the U.S. Patent Application No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00517] The R4-A crystalline image of rhysmetrum:benzathen salt can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 78; the X-ray diffraction pattern in the powder has peaks at 8.8° ± 0.2°, 13.0° ± 0.2°, 17.6° ± 0.2°, 20.7° ± 0.2°, 22.3° ± 0.2° 2-theta; and combinations of those data. The powder's X-ray diffraction pattern may have any one, two, three, four or five additional peaks selected from 11.1° ± 0.2°, 11.4° ± 0.2°, 17.1° ± 0.2°, 18.7° ± 0.2° and 23.7° ± 0.2° 2-theta.

[00518] Example 23 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of the image R2-A (Rismetrum:benzathen salt).

[00519] Procedure A

[00520] Ethanol (45 mL, 75 v) was added to resmeterum (0.6 g, 1.38 mmol) to produce a slurry. The resulting slurry was heated to 75 °C and magnetically stirred at this temperature for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. Benzathen (0.663 mL, 2.76 mmol) was then added by distillation to the filtrated solution at 75 °C while magnetic stirring continued. The resulting clear mixture was then cooled to room temperature to produce a slurry and stirred at room temperature for 18 hours. The resulting solid was filtered by Buchner and then dried in a vacuum oven at 45 °C for 18 hours. The solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 78.

[00521] For example, one of the images is Image 2 set out in the Bulletin of U.S. Patent Application No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00522] The crystalline image 2 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 88; the powder's X-ray diffraction pattern with peaks at 6.9° ± 0.2°, 10.0° ± 0.2°, 14.1° ± 0.2°, 19.1° ± 0.2°, and 21.9° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.0° ± 0.2°, 15.7° ± 0.2°, 22.7° ± 0.2°, 23.3° ± 0.2°, and 25.2° ± 0.2° 2-theta.

[00523] Example 2 of the publication of US Patent Application No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of Image 2.

[00524] Procedure A

[00525] Methyl isopropyl ketone (MIPK) (1.25 mL, 50 v) was added to resmeterum (25 mg, 0.06 mmol) to obtain a slurry. The slurry was heated to 80 °C and magnetically stirred at 80 °C for 30 minutes to achieve complete dissolution, followed by hot mechanical filtration. Diethyl ether (5.6 mL) was then added as an antisolvent by distillation to the clear solution, which was stirred at 80 °C. The resulting clear solution was stirred at 80 °C for 1 hour and then cooled to room temperature. The solution was then magnetically stirred at room temperature for 48 hours to obtain a solid precipitate. The solid was then separated by centrifugation and analyzed by X-ray diffraction of the powder. The XRPD pattern is shown in Figure 88.

[00526] Procedure B

[00527] Methylisopropyl ketone (MIPK) (4.0 mL, 20 v) was added to resmetrium (200 mg, 0.46 mmol) to produce a slurry. The resulting slurry was heated to 80 °C and stirred at 80 °C for 48 h. The slurry was then cooled to room temperature and separated by centrifugation. The resulting solid was subsequently dried in a vacuum oven at 25 °C for 2 h and analyzed by X-ray diffraction of the powder, identified as crystalline image 2 of resmetrium.

[00528] For example, one of the images is Image 3 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00529] The crystalline image 3 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 84; the powder's X-ray diffraction pattern with peaks at 6.9° ± 0.2°, 13.8° ± 0.2°, 15.0° ± 0.2°, 20.0° ± 0.2°, and 20.8° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.1° ± 0.2°, 17.4° ± 0.2°, 17.8° ± 0.2°, 19.0° ± 0.2°, and 23.6° ± 0.2° 2-theta.

[00530] Example 3 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of Image 3.

[00531] Procedure A

[00532] Dioxane (1.7 mL, 57 v) was added to resmeterum (30 mg, 0.07 mmol) to obtain a slurry. The slurry was heated to 70 °C and magnetically stirred at 70 °C for 30 minutes to achieve complete dissolution, followed by hot mechanical filtration. Diethyl ether (6.8 mL) was then added as an antisolvent by distillation to the clear solution, which was stirred at 80 °C to obtain a solid precipitate. The resulting slurry was magnetically stirred at 80 °C for 1 hour and then cooled to room temperature with stirring. The slurry was then magnetically stirred at room temperature for 18 hours. The solid was subsequently separated by centrifugation and analyzed by XRPD. The resulting XRPD pattern is shown in Figure 84.

[00533] Procedure B

[00534] Dioxane (2.0 mL, 10 volumes) was added to resmetrium (200 mg, 0.46 mmol) to produce a slurry. The resulting slurry was heated to 80 °C and magnetically stirred at 80 °C for 48 hours. Afterward, the slurry was cooled to room temperature and separated by centrifugation. The resulting solid was dried in a vacuum oven at 25 °C for 2 hours. The solid was analyzed by X-ray diffraction of the powder and identified as crystalline image 3 of resmetrium.

[00535] For example, one of the images is Image 4 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00536] The crystalline image 4 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 89; the powder's X-ray diffraction pattern with peaks at 11.5° ± 0.2°, 14.2° ± 0.2°, 18.0° ± 0.2°, 22.0° ± 0.2°, and 25.4° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.1° ± 0.2°, 12.5° ± 0.2°, 15.2° ± 0.2°, 21.0° ± 0.2°, and 23.0° ± 0.2° 2-theta.

[00537] Example 4 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of Image 4.

[00538] Procedure A

[00539] Anisole (4.0 mL, 20 v) was added to resmeterum (200 mg, 0.46 mmol) to obtain a slurry. The slurry was heated to 80 °C and stirred at 80 °C for 48 h. The slurry was then separated by centrifugation. The resulting solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 89.

[00540] For example, one of the images is Image 6 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00541] The crystalline image 6 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 90; the powder's X-ray diffraction pattern with peaks at 5.4° ± 0.2°, 8.5° ± 0.2°, 10.9° ± 0.2°, 16.4° ± 0.2°, and 23.9° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 19.1° ± 0.2°, 19.9° ± 0.2°, 21.1° ± 0.2°, 22.3° ± 0.2°, and 25.7° ± 0.2° 2-theta.

[00542] Example 5 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of image 6.

[00543] Procedure A

[00544] N,N-dimethylformamide (DMF) (1.3 mL, 4.3 v) was added to resmeterum (30 mg, 0.07 mmol) to obtain a slurry. The slurry was heated to 80 °C and magnetically stirred at 80 °C for 30 min to achieve complete dissolution, followed by hot mechanical filtration. Water (2.6 mL) was then added as an antisolvent by distillation to the clear solution, which was stirred at 80 °C to obtain a solid precipitate. The resulting slurry was stirred at 80 °C for 1 h and cooled to room temperature. It was then magnetically stirred at room temperature for 18 h. The solid was subsequently separated by centrifugation and dried in a vacuum oven at 25 °C for 18 h. The solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 90.

[00545] For example, one of the images is Image 7 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00546] The crystalline image 7 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 91; the powder's X-ray diffraction pattern with peaks at 6.1° ± 0.2°, 11.8° ± 0.2°, 14.6° ± 0.2°, 19.1° ± 0.2°, and 26.6° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 11.0° ± 0.2°, 20.6° ± 0.2°, 21.2° ± 0.2°, 23.2° ± 0.2°, and 25.7° ± 0.2° 2-theta.

[00547] Example 6 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of image 7.

[00548] Procedure A

[00549] Acetylacetone (0.85 mL, 30 v) was added to resmeterum (30 mg, 0.07 mmol) to obtain a slurry. The slurry was heated to 80 °C and magnetically stirred at 80 °C for 30 minutes to achieve complete dissolution, followed by hot mechanical filtration. Subsequently, hexane (2.55 mL) was added as an antisolvent by distillation to the clear solution, which was stirred at 80 °C to obtain a solid precipitate. The resulting slurry was stirred at 80 °C for 1 hour and cooled to room temperature. It was then magnetically stirred at room temperature for 18 hours. The solid was subsequently separated by centrifugation and analyzed by X-ray diffraction of the powder. The resulting XRPD pattern is shown in Figure 91.

[00550] Procedure B

[00551] Acetylacetone (4.0 mL, 20 v) was added to resmetrium (200 mg, 0.46 mmol) to produce a slurry. The resulting slurry was stirred at room temperature for 48 hours. It was then centrifuged and dried in a vacuum oven at 25 °C for 2 hours. The solid was analyzed by XRPD and identified as crystalline form 7 of resmetrium.

[00552] For example, one of the images is Image 8 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00553] The crystalline image 8 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 92; the powder's X-ray diffraction pattern with peaks at 11.0° ± 0.2°, 12.2° ± 0.2°, 17.5° ± 0.2°, 20.7° ± 0.2°, and 22.0° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 10.3° ± 0.2°, 14.1° ± 0.2°, 15.4° ± 0.2°, 23.9° ± 0.2°, and 25.4° ± 0.2° 2-theta.

[00554] Example 7 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of image 8.

[00555] Procedure A

[00556] Acetylacetone (0.85 mL, 30 v) was added to resmetrium (30 mg, 0.07 mmol) to obtain a slurry. The slurry was heated to 80 °C and magnetically stirred at 80 °C for 30 minutes to achieve complete dissolution, followed by hot mechanical filtration. Propionitrile (3.4 mL) was then added as an antisolvent by distillation to the clear solution, which was stirred at 80 °C to obtain a solid precipitate. The resulting slurry was magnetically stirred at 80 °C for 1 hour and then cooled to room temperature. The slurry was then magnetically stirred at room temperature for 18 hours. The solid was subsequently separated by centrifugation and analyzed by X-ray diffraction of the powder, identifying it as crystalline image 8 of resmetrium.

[00557] Procedure B

[00558] Propioninitrile (0.80 mL, 20 v) was added to resmeterum (40 mg, 0.09 mmol) to produce a slurry. The resulting slurry was heated to 80 °C and stirred at 80 °C for 48 hours. Afterward, the slurry was allowed to cool to room temperature, separated by centrifugation, and dried in a vacuum oven at 25 °C for 2 hours. The solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 92.

[00559] For example, one of the images is Image 9 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00560] The crystalline image 9 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 85; the powder's X-ray diffraction pattern with peaks at 8.7° ± 0.2°, 13.4° ± 0.2°, 14.8° ± 0.2°, 15.5° ± 0.2°, and 22.8° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 11.1° ± 0.2°, 19.8° ± 0.2°, 20.3° ± 0.2°, 21.5° ± 0.2°, and 24.4° ± 0.2° 2-theta.

[00561] Example 8 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of image 9.

[00562] Procedure A

[00563] Nitrobenzene (2.0 mL, 10 volumes) was added to resmeterum (200 mg, 0.46 mmol) to produce a slurry. The resulting slurry was heated to 80 °C and stirred at 80 °C for 48 hours. Afterward, the slurry was allowed to cool to room temperature, separated by centrifugation, and dried in a vacuum oven at 25 °C for 2 hours. The solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 85.

[00564] For example, one of the images is Image 10 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00565] The crystalline image 10 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 93; the powder's X-ray diffraction pattern with peaks at 12.5° ± 0.2°, 14.9° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, and 23.4° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 7.4° ± 0.2°, 13.4° ± 0.2°, 16.0° ± 0.2°, 22.5° ± 0.2°, and 24.8° ± 0.2° 2-theta.

[00566] Example 9 of the publication of US Patent Application No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of image 10.

[00567] Procedure A

[00568] Diethylene glycol ethyl ether (2.0 mL, 10 volumes) was added to resmeterum (200 mg, 0.46 mmol) to produce a slurry. The resulting slurry was stirred at room temperature for 48 hours. Subsequently, the slurry was separated by centrifugation, and the powder was analyzed by X-ray diffraction. The resulting XRPD pattern is shown in Figure 93.

[00569] For example, one of the images is Image 11 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00570] The crystalline image 11 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 94; the powder's X-ray diffraction pattern with peaks at 5.9° ± 0.2°, 10.1° ± 0.2°, 11.8° ± 0.2°, 19.7° ± 0.2°, and 25.1° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.5° ± 0.2°, 16.4° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, and 22.2° ± 0.2° 2-theta.

[00571] Example 10 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of Image 11.

[00572] Procedure A

[00573] 1,3-Dioxolan (1 mL, 33.3 v) was added to resmeterum (30 mg, 0.07 mmol) and stirred at room temperature to produce a clear solution. The clear solution was mechanically filtered and left to evaporate slowly at room temperature for 4 days. The resulting solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 94.

[00574] For example, one of the images is Image 13 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00575] The crystalline image 13 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 95; the powder's X-ray diffraction pattern with peaks at 14.4° ± 0.2°, 17.0° ± 0.2°, 20.0° ± 0.2°, 22.7° ± 0.2°, and 24.5° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 7.3° ± 0.2°, 13.0° ± 0.2°, 17.9° ± 0.2°, 18.7° ± 0.2°, and 19.0° ± 0.2° 2-theta.

[00576] Example 11 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of Image 13.

[00577] Procedure A

[00578] Methyl ethyl ketone (3.33 mL, 33.3 v) was added to resmeterum (100 mg, 0.23 mmol) to obtain a slurry. The slurry was heated to 60 °C and magnetically stirred at 60 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. Dichloroethane (10 mL) was then added as an antisolvent by distillation to the clear solution, which was stirred at 60 °C to obtain a solid precipitate. The resulting slurry was stirred at 60 °C for 1 hour and cooled to room temperature. It was then magnetically stirred at room temperature for 18 hours. The solid was subsequently separated by centrifugation and dried in a vacuum oven at 25 °C for 2 hours. The solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 95.

[00579] Procedure B

[00580] 2-methoxyethanol (0.15 mL, 5 volumes) was added to resmetrium (30 mg, 0.07 mmol) to obtain a slurry. The slurry was heated to 80 °C and magnetically stirred at 80 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. Dichloroethane (0.6 mL) was then added as an antisolvent by distillation to the clear solution, which was stirred at 80 °C to obtain a solid precipitate. The resulting slurry was stirred at 80 °C for 1 hour and cooled to room temperature. It was then magnetically stirred at room temperature for 18 hours and subsequently separated by centrifugation. The solid was analyzed by X-ray diffraction of the powder and identified as crystalline image 13 of resmetrium.

[00581] For example, one of the images is Image 14 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00582] The crystalline image 14 can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 96; the X-ray diffraction pattern in the powder has peaks at 9.8° ± 0.2°, 11.1° ± 0.2°, and 23.2° ± 0.2° 2-theta; and combinations of those data.

[00583] Example 12 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of Image 14.

[00584] Procedure A

[00585] Methyl tetrahydrofuran (3.3 mL, 10 volumes) was added to resmeterum (100 mg, 0.23 mmol) to produce a slurry. The resulting slurry was stirred at 75 °C for 30 minutes until the solids were completely dissolved, followed by hot mechanical filtration. The clear solution was then magnetically filtered and stirred at 4 °C for 18 hours to obtain a solid precipitate. The solids were then separated by centrifugation and dried in a vacuum oven at 25 °C for 3 hours. The solids were analyzed by X-ray diffraction of the powder, and the resulting pattern is shown in Figure 96.

[00586] Procedure B

[00587] Methyl tetrahydrofuran (5 mL, 10 volumes) was added to resmetrium (500 mg, 0.15 mmol) to produce a slurry. The resulting slurry was heated to 60 °C and magnetically stirred at this temperature for 48 hours. The slurry was then cooled to room temperature and separated by centrifugation. The solid was dried in a vacuum oven at 25 °C for 3 hours. The solid was analyzed by X-ray diffraction of the powder and identified as crystalline image 14 of resmetrium.

[00588] For example, one of the images is Image 15 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00589] The crystalline image 15 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 97; the powder's X-ray diffraction pattern with peaks at 10.0° ± 0.2°, 11.6° ± 0.2°, 13.0° ± 0.2°, 18.6° ± 0.2°, and 23.8° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 10.7° ± 0.2°, 17.0° ± 0.2°, 18.2° ± 0.2°, 22.0° ± 0.2°, and 23.3° ± 0.2° 2-theta.

[00590] Example 13 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of Image 15.

[00591] Procedure A

[00592] Propionic acid (15 mL, 50 v) was added to resmeterum (300 mg, 0.7 mmol) to form a slurry. The slurry was magnetically stirred at 80 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. The clear, magnetically filtered solution was then stirred at 4 °C for 72 hours to obtain a solid precipitate. The solid was subsequently separated by centrifugation and dried in a vacuum oven at 25 °C for 3 hours. The solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 97.

[00593] For example, one of the images is Image 16 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00594] The crystalline image 16 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 98; the powder's X-ray diffraction pattern with peaks at 8.7° ± 0.2°, 11.5° ± 0.2°, 13.3° ± 0.2°, 14.7° ± 0.2°, and 26.0° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 10.2° ± 0.2°, 12.8° ± 0.2°, 19.5° ± 0.2°, 25.3° ± 0.2°, and 26.4° ± 0.2° 2-theta.

[00595] Example 14 of the publication of US Patent Application No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of Image 16.

[00596] Procedure A

[00597] Propionic acid (15 mL, 50 v) was added to resmeterum (300 mg, 0.7 mmol) to form a slurry. The slurry was magnetically stirred at 80 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. The clear, magnetically filtered solution was then stirred at 4 °C for 72 hours to obtain a solid precipitate. The saturated solution was then centrifuged and concentrated by slow evaporation of the solvent at 80 °C for 48 hours to yield a solid. The solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 99.

[00598] For example, one of the images is Image 17 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00599] The crystalline image 17 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 99; the powder's X-ray diffraction pattern with peaks at 6.8° ± 0.2°, 8.7° ± 0.2°, 11.4° ± 0.2°, 14.5° ± 0.2°, and 29.7° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 10.1° ± 0.2°, 15.0° ± 0.2°, 15.4° ± 0.2°, 19.7° ± 0.2°, and 20.0° ± 0.2° 2-theta.

[00600] Example 15 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of Image 17.

[00601] Procedure A

[00602] Methyl ethyl ketone (2 mL, 20 v) was added to resmeterum (100 mg, 0.23 mmol) to form a slurry. The slurry was magnetically stirred at 72 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. The clear solution was then magnetically filtered at 4 °C for 18 hours to obtain a solid precipitate. The solid was subsequently separated by centrifugation and dried in a vacuum oven at 25 °C for 2 hours. The solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 99.

[00603] Procedure B

[00604] Methyl ethyl ketone (20 mL, 20 v) was added to resmetrium (1000 mg, 2.3 mmol) to form a slurry. The slurry was magnetically stirred at 72 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. The clear, filtered solution was then concentrated by a rotary evaporator to produce a solid. The solid was dried in a vacuum oven at 25 °C for 18 hours. The solid was analyzed by X-ray diffraction of the powder and identified as crystalline image 17 of resmetrium.

[00605] For example, one of the images is Image 19 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00606] The crystalline image 19 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 100; the powder's X-ray diffraction pattern with peaks at 8.5° ± 0.2°, 9.1° ± 0.2°, 12.6° ± 0.2°, 14.5° ± 0.2°, and 15.2° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.1° ± 0.2°, 15.7° ± 0.2°, 20.8° ± 0.2°, 21.1° ± 0.2°, and 25.4° ± 0.2° 2-theta.

[00607] Example 16 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of image 19.

[00608] Procedure A

[00609] Methyl ethyl ketone (2.0 mL, 20 v) was added to resmeterum (100 mg, 0.23 mmol) to obtain a slurry. The slurry was magnetically stirred at 70 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. Toluene (8 mL) was then added as an antisolvent by distillation to the stirred clear solution at 70 °C to obtain a solid precipitate. The resulting slurry was stirred at 70 °C for 1 hour and cooled to room temperature. It was then magnetically stirred at room temperature for 18 hours. The solid was subsequently separated by centrifugation and dried in a vacuum oven at 25 °C for 3 hours. The solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 100.

[00610] Procedure B

[00611] Dimethylacetamide (DMAc) (2.5 mL, 5 volumes) was added to resmeterum (500 mg, 1.15 mmol) to obtain a slurry. The slurry was heated to 80 °C and magnetically stirred at 80 °C for 30 minutes to obtain complete dissolution, followed by hot mechanical filtration. Isopropyl alcohol (IPA) (10 mL) was then added distillate to the clear solution, which was stirred at 80 °C. The resulting clear solution was stirred at 80 °C for 1 hour and then cooled to room temperature. The solution was then magnetically stirred at room temperature for 18 hours to obtain a solid precipitate. The solid was then separated by centrifugation and dried in a vacuum oven at 25 °C for 18 hours.

[00612] Toluene (2.0 mL, 20 v) was added to the above-prepared resmetrium (100 mg, 0.23 mmol) to produce a slurry. The resulting slurry was stirred at 80 °C for 18 hours. It was then cooled to room temperature, filtered by centrifugation, dried in a vacuum oven at 45 °C for 18 hours, and analyzed by X-ray diffraction of the powder, identified as crystalline resmetrium 19.

[00613] For example, one of the images is Image 20 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00614] The crystalline image 20 can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder, as shown in Figure 101; the X-ray diffraction pattern in the powder, which has peaks at 6.5° ± 0.2°, 9.6° ± 0.2°, 10.1° ± 0.2°, 19.0° ± 0.2°, and 23.3° ± 0.2° 2-theta; and combinations of such data; spectrum 13 1C NMR solid-state with characteristic peaks at 161.0 ± 0.2, 155.0 ± 0.2, 151.1 ± 0.2, 145.3 ± 0.2, and 121.8 ± 0.2 ppm; spectrum 13 1C NMR solid-state and has the following absolute differences for chemical shift from a reference peak at 162.4 ± 1 ppm: 1.4 ± 0.1, 7.5 ± 0.1, 11.3 ± 0.1, 17.1 ± 0.1, and 40.6 ± 0.1 ppm; spectrum 13 1C NMR of the solid state is shown in Figures 104, 105, or 106; and combinations of those data. The X-ray diffraction pattern of the powder may have any one, two, three, four, or five additional peaks selected from 11.6° ± 0.2°, 16.2° ± 0.2°, 19.5° ± 0.2°, 21.8° ± 0.2°, and 24.9° ± 0.2° 2-theta.

[00615] Example 17 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of image 20.

[00616] Procedure A

[00617] Acetonitrile (66 mL, 132 V) was added to resmeterum (500 mg, 1.15 mmol) to form a slurry. The slurry was magnetically stirred at 80 °C for 30 minutes to obtain a dusty solution, followed by hot mechanical filtration. The clear, magnetically filtered solution was then stirred at room temperature for 18 hours to obtain a solid precipitate. The solid was subsequently separated by Buchner scaffolding and dried in a vacuum oven at 45 °C for 72 hours. The solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 101.

[00618] For example, one of the images is Image 21 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00619] The crystalline image 21 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 102; the powder's X-ray diffraction pattern with peaks at 7.0° ± 0.2°, 14.1° ± 0.2°, 15.9° ± 0.2°, 20.2° ± 0.2°, and 28.4° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.4° ± 0.2°, 17.0° ± 0.2°, 25.1° ± 0.2°, 25.8° ± 0.2°, and 29.3° ± 0.2° 2-theta.

[00620] Example 18 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of image 21.

[00621] Procedure A

[00622] Acetonitrile (10.8 mL, 120 v) was added to resmeterum (100 mg, 0.23 mmol) to form a slurry. The slurry was magnetically stirred at 80 °C for 30 minutes to obtain a clear solution, followed by hot mechanical filtration. The clear, filtered solution was then concentrated by a rotary evaporator to produce a solid. The solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 102.

[00623] For example, one of the images is Image 22 set out in the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894.

[00624] The crystalline image 22 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 103; the powder's X-ray diffraction pattern with peaks at 5.6° ± 0.2°, 15.0° ± 0.2°, 16.6° ± 0.2°, 17.4° ± 0.2°, and 23.0° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 11.5° ± 0.2°, 23.3° ± 0.2°, 26.1° ± 0.2°, 27.6° ± 0.2°, and 28.9° ± 0.2° 2-theta.

[00625] Example 18 of the US Patent Application Bulletin No. 2023 / 0364099 and International Application No. WO 2022 / 086894 describes the preparation of image 22.

[00626] Procedure A

[00627] Ethylene glycol (10 mL, 20 v) was added to resmeterum (500 mg, 1.15 mmol) to produce a slurry. The resulting slurry was stirred at room temperature for 48 hours. Subsequently, the solid material was separated by centrifugation and dried in a vacuum oven at 45 °C for 18 hours. The solid was analyzed by X-ray diffraction of the powder, and the resulting XRPD pattern is shown in Figure 103.

[00628] Resmetrium crystallized images 2, 3, 5 and 20 can also be used to prepare the crystallized image 22 for Resmetrium.

[00629] For example, one of the images is an amorphous E1 image as defined in the US Patent Application Bulletin No. 2024 / 0423993.

[00630] The amorphous image E1 can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 110.

[00631] Example-1 of US Patent Application Bulletin No. 2024 / 0423993 describes the preparation of the amorphous image E1.

[00632] Methanol (3000 mL) and rhizometrum (100 g) were added to an RB flask at 25°C to 35°C, and the reaction mass was stirred for 15 to 20 minutes to obtain a clear solution. The reaction mass was collected in a spray dryer. The reaction mass was spray dried under the following conditions. The product was collected from a conical separator and further dried at 40°C to 50°C under vacuum for 4 hours to obtain the amorphous form of rhizometrum.

[00633] For example, one of the images is an amorphous E2 image as defined in the US Patent Application Bulletin No. 2024 / 0423993.

[00634] The amorphous image E2 can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 110.

[00635] Example-2 of the US Patent Application Bulletin No. 2024 / 0423993 describes the preparation of the amorphous image E2.

[00636] Methanol (300 mL) and rhizometrum (100 g) were added at 25°C to 35°C. The reaction mass was stirred for 10 to 15 minutes to obtain a clear solution. The methanol was distilled under vacuum at less than 45°C from the previous reaction mass. n-heptane (500 mL) was added to the residue at 25°C to 35°C. The reaction mass was stirred for 15 to 20 minutes, and the mixture was filtered and washed with n-heptane (100 mL) to obtain the amorphous form of rhizometrum.

[00637] For example, one of the images is image E3 of a non-crystalline solid dispersion material specified in the US Patent Application Bulletin No. 2024 / 0423993.

[00638] The E3 image of the amorphous solid dispersion material can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 111.

[00639] Example-3 of US Patent Application Bulletin No. 2024 / 0423993 describes the preparation of image E3 of an amorphous solid dispersion material.

[00640] Methanol (3000 mL), resmetrium (100 g), and copovidone (Kollidone VA 64) (100 g) were added to an RB flask at 25°C to 35°C. The reaction mass was stirred for 15 to 20 minutes to obtain a clear solution. The reaction mass was collected in a spray dryer. The reaction mass was spray dried under the following conditions: The product was collected from a conical separator and further dried at 40°C to 50°C under vacuum for 4 hours to obtain an amorphous solid dispersion of resmetrium.

[00641] For example, one of the images is image E4 of a solid amorphous dispersion material specified in the US Patent Application Bulletin No. 2024 / 0423993.

[00642] Image E4 can be distinguished as a non-crystalline solid dispersion material by data selected from one or more of the following: X-ray diffraction pattern in the powder, as shown in Figure 111.

[00643] Example-4 of US Patent Application Bulletin No. 2024 / 0423993 describes the preparation of image E4 of a non-crystalline solid dispersion material.

[00644] Methanol (3000 mL) and rhizometrum (100 g) were added at 25°C to 35°C. The reaction mass was stirred for 15 to 20 minutes to obtain a clear solution. Copovidone (Kollidone VA 64) (100 g) was added to the reaction mass and stirred for 15 to 20 minutes, after which the reaction mass was filtered. The methanol was distilled at below 50°C from the previous reaction mass. Cyclohexane (400 mL) was added to the residue at 25°C to 35°C. The reaction mass was stirred for 15 to 20 minutes, filtered, and washed with cyclohexane (100 mL) to obtain an amorphous solid dispersion of rhizometrum.

[00645] For example, one of the images is image 3A as specified in international application number WO 2022 / 171200.

[00646] The crystalline image 3A can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder, as shown in Figure 112; the X-ray diffraction pattern in the powder with peaks at 10.7 ± 0.2°, 16.2 ± 0.2°, 18.0 ± 0.2°, 24.1 ± 0.2°, and 24.3 ± 0.2° 2-theta; and combinations of these data; the FT-IR spectrum, as shown in Figure 115; and the FT-IR spectrum with characteristic peaks at 1718 cm⁻¹. -1 ± 2 cm -1 1190 centimeters -1 ± 2 cm -1 1180 centimeters -1 ± 2 cm -1 908 centimeters -1 ± 2 cm -1 and 896 centimeters -1 ± 2 cm -1 FT-IR spectrum with characteristic peaks at 1603 cm -1 ± 2 cm -1 1461 centimeters -1 ± 2 cm -1 1406 centimeters -1 ± 2 cm -1 1337 centimeters -1 ± 2 cm -1 1230 centimeters -1 ± 2 cm -1 952 centimeters -1 ± 2 cm -1 908 centimeters -1 ± 2 cm -1 and 896 centimeters -1 ± 2 cm -1 ; and combinations of those data. The X-ray diffraction pattern in the powder may have any one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve additional peaks selected from 11.3 ± 0.2°, 12.0 ± 0.2°, 14.4 ± 0.2°, 15.6 ± 0.2°, 17.3 ± 0.2°, 17.6 ± 0.2°, 19.5 ± 0.2°, 20.0 ± 0.2°, 22.4 ± 0.2°, 26.7 ± 0.2°, 26.9 ± 0.2° and 28.7 ± 0.2° 2-theta.

[00647] International application number WO 2022 / 171200 provides the following data: 2θ Intensity % 8±0.2 degrees 5.2 10.7±0.2 degrees 83.2 11.3±0.2 degrees 13.8 12±0.2 degrees 56 12.6±0.2 degrees 14.2 13.9±0.2 degrees 29.8 14.4±0.2 degrees 20.7 15.6±0.2 degrees 21.2 16.2±0.2 degrees 63.7 16.8±0.2 degrees 4.5 17.3±0.2 degrees 32.5 17.6±0.2 degrees 33.1 18±0.2 degrees 48.4 19.5±0.2 degrees 12.5 20±0.2 degrees 20.9 20.9±0.2 degrees 8.6 21.3±0.2 degrees 13.1 22.4±0.2 degrees 34.5 23±0.2 degrees 12.3 23.4±0.2 degrees 49 24.1±0.2 degrees 100 24.3±0.2 degrees 93.8 25±0.2 degrees 13.2 25.9±0.2 degrees 11.1 26.3±0.2 degrees 6.3 26.7±0.2 degrees 17.5 26.9±0.2 degrees 14.9 27.6±0.2 degrees 10.8 28.1±0.2 degrees 3.4 28.7±0.2 degrees 34.6 29.3±0.2 degrees 11.7 30.4±0.2 degrees 21.6 31.1±0.2 degrees 6.9 32.2±0.2 degrees 9 32.7±0.2 degrees 6.5 33.3±0.2 degrees 3.6 33.7±0.2 degrees 5.1 34.2±0.2 degrees 20.3 35.8±0.2 degrees 3.1 36.3±0.2 degrees 12.7 39±0.2 degrees 4.1

[00648] The TGA pattern of this crystalline 3A image is largely as shown in Figure 113, with a weight loss of 0.3% before 100°C, and a decomposition temperature of 320°C.

[00649] The DSC pattern of the crystalline image 3A is very large as shown in Figure 114, and the melting point is 324 degrees Celsius.

[00650] Example 1-1 of International Order No. WO 2022 / 171200 describes the preparation of the crystallized image 3A.

[00651] 20 mg of resmeteorum is taken to form a suspension in 0.5 mL of n-propanol. After 5 days of crystallization at room temperature, the slurry is centrifuged and dried under vacuum at room temperature for 24 hours to obtain the crystalline 3A form.

[00652] Example 1-2 of International Order No. WO 2022 / 171200 describes the preparation of the crystallized image 3A.

[00653] 51.80 mg of resmeteorum is taken to form a suspension in 1.0 mL of n-propanol. After conversion to a slurry at room temperature for two days, it is centrifuged and dried under vacuum at room temperature for 24 hours to obtain the crystalline 3A form.

[00654] Example 1-3 of International Order No. WO 2022 / 171200 describes the preparation of the crystallized image 3A.

[00655] 200 mg of resmeteorum was taken to 3 ml of n-propanol to form a suspension, and after 3 days of crystallization at room temperature, the slurry was centrifuged and dried under vacuum at room temperature for 24 hours to obtain the crystalline 3A image.

[00656] Example 1-4 of International Order No. WO 2022 / 171200 describes the preparation of the crystallized image 3A.

[00657] 500 mg of resmeteorum is taken, a suspension is formed in 3.5 ml of n-propanol, converted to a slurry at room temperature for 16 hours, filtered, and dried under vacuum at room temperature for 67 hours to obtain the crystalline image 3A.

[00658] Example 2-1 of International Order No. WO 2022 / 171200 describes the preparation of the crystallized image 3A.

[00659] 20.15 mg of resmeteorum is dissolved in 2 mL of n-propanol at 60°C, filtered, and 3 mg of crystalline form 3, prepared in Example 1 as a crystallization induction seed, is added. The mixture is stirred at 4°C for 1 day, then centrifuged. Vacuum drying at room temperature for 24 hours yields crystalline form 3A.

[00660] Example 3-1 of International Order No. WO 2022 / 171200 describes the preparation of this crystallized image 3A.

[00661] 20.92 mg of resmeteorum was dissolved in 7 mL of n-propanol by sonication, filtered, and 3 mg of crystalline form 3 prepared in Example 1 was added as a crystallization inducer seed. After two days of evaporating the material in an open system at room temperature, crystalline form 3A was obtained.

[00662] For example, one of the images is image 4A as defined in Chinese patent No. CN115124515A.

[00663] The crystalline image 4A can be distinguished by data selected from one or more of the following: the powder X-ray diffraction pattern, as shown in Figure 122; the powder X-ray diffraction pattern with peaks at 7.2 ± 0.2°, 12.4 ± 0.2°, 13.3 ± 0.2°, 15.0 ± 0.2°, and 23.1 ± 0.2° 2-theta; and combinations of these data. The powder X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 8.6 ± 0.2°, 13.9 ± 0.2°, 19.6 ± 0.2°, 22.5 ± 0.2°, and 26.2 ± 0.2° 2-theta.

[00664] Chinese patent number CN115124515A provides the following data: 2θ Intensity % 7.2 100 7.9 8.5 8.6 21.1 10.8 4.8 12.4 28.6 13.3 42.9 13.9 25.5 14.3 15.1 15.0 43.9 15.9 6.5 17.3 15.5 17.7 16.9 18.0 19.4 18.6 15.3 19.6 26.2 20.5 4.8 20.8 5.1 21.5 7 21.8 3.5 22.5 21.7 22.8 18.5 23.1 55.1 24.0 16.1 24.4 4.1 24.9 16.5 25.4 5.9 25.8 12.2 26.2 24.4 29.4 6.1 29.8 16.4 29.9 9.9 30.3 11.5 30.8 3.4 31.4 3.6 31.8 6.2 32.1 7.7 33.0 3.4 34.0 3 34.7 2.9 35.1 5.9 35.5 5.5 35.7 5.8 38.0 4.3 39.1 3.

[00665] The TGA pattern of the crystalline image 4A is largely as shown in Figure 123, with a weight loss of 10.5% before 150 °C, and a decomposition temperature of 327.11 °C.

[00666] The spectrum 1 H NMR of the crystalline image 4A is shown in large detail in Figure 124.

[00667] Example 1 of Chinese Patent No. CN115124515A describes the preparation of this crystalline image 4A.

[00668] Approximately 20 mg of resmeteorum was sonicated in 2 ml of acetone, filtered, and 5.4 ml of n-heptane was added with stirring to the resulting suspension, which was stirred at room temperature for 3 hours, centrifuged, and dried under vacuum at room temperature for 24 hours to obtain the crystalline 4A.

[00669] For example, one of the images is image 7A as defined in Chinese patent No. CN115124515A.

[00670] The crystalline image 7A can be distinguished by data selected from one or more of the following: the powder X-ray diffraction pattern, as shown in Figure 125; the powder X-ray diffraction pattern with peaks at 6.9 ± 0.2°, 13.9 ± 0.2°, 15.0 ± 0.2°, 17.8 ± 0.2°, and 20.0 ± 0.2° 2-theta; and combinations of these data. The powder X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.2 ± 0.2°, 16.0 ± 0.2°, 20.9 ± 0.2°, 22.6 ± 0.2°, and 24.8 ± 0.2° 2-theta.

[00671] Chinese patent number CN115124515A provides the following data: 2θ Intensity % 6.9 100 10.0 10.4 10.6 21.7 11.8 18.2 12.2 52 13.9 86.1 15.0 86.7 15.5 22.4 16.0 46.2 16.3 10.6 17.4 41 17.8 78.1 19.1 23.2 20.0 85.3 20.9 52.2 21.4 27.7 22.3 29.4 22.6 46.6 23.0 27.7 23.7 28.4 24.4 28.2 24.8 63.8 25.6 8.7 25.8 7.9 26.4 34.8 27.5 14.3 28.1 17.4 29.0 15.9 30.4 36.2 31.1 7.5 32.2 16.1 33.2 10.8 33.6 13.7 34.5 7.7 34.9 8.5 37.2 6.2 37.7 8.5.

[00672] The TGA pattern of the crystalline image 7A is largely as shown in Figure 126, with a weight loss of 19% before 150°C, and a decomposition temperature of 327°C.

[00673] The spectrum 1 H NMR of the crystalline image 7A is shown in large detail in Figure 127.

[00674] Example 2 of Chinese patent No. CN115124515A describes the preparation of the crystallized image 7A.

[00675] Approximately 20 mg of resmeteorum was suspended in 0.6 mL of 1,4-dioxane / isopropyl ether (v:v 2:1) and stirred at 40°C for 5 days to obtain the crystalline 7A image.

[00676] Example 3 of Chinese patent No. CN115124515A describes the preparation of the crystallized image 7A.

[00677] Approximately 20 mg of resmeteorum was suspended in 0.5 mL of 1,4-dioxane / n-heptane (v:v 4:1) and stirred at 40°C for 5 days to obtain the crystalline 7A image.

[00678] Example 4 of Chinese patent No. CN115124515A describes the preparation of the crystallized image 7A.

[00679] Approximately 20 mg of resmeteorum was dissolved in 1.8 mL of 1,4-dioxane / water (v:v 2:1) mixed solvent at 60 °C, filtered, transferred to 4 °C and stirred to obtain the crystalline image 7A.

[00680] For example, one of the images is image 9A as defined in Chinese patent No. CN115124515A.

[00681] The crystalline image 9A can be distinguished by data selected from one or more of the following: the powder X-ray diffraction pattern is substantial as shown in Figure 128; the powder X-ray diffraction pattern has peaks at 14.5 ± 0.2°, 19.7 ± 0.2°, 22.2 ± 0.2°, 22.4 ± 0.2° and 23.9 ± 0.2° 2-theta; and combinations of those data, the powder X-ray diffraction pattern may have any one, two, three, four, or five additional peaks selected from 6.9 ± 0.2°, 10.6 ± 0.2°, 12.1 ± 0.2°, 22.9 ± 0.2° and 25.0 ± 0.2° 2-theta.

[00682] Chinese patent number CN115124515A provides the following data: 2θ Intensity % 6.9 22.0 8.7 9.9 9.7 5.6 10.0 15.1 10.6 27.5 11.4 20.0 12.1 22.9 13.7 5.7 14.5 100.0 15.0 5.5 15.8 14.2 17.5 17.3 18.7 15.9 19.7 36.7 20.0 15.8 20.7 13.1 21.4 6.7 22.2 32.7 22.4 30.1 22.7 20.7 22.9 26.7 23.5 4.1 23.9 35.3 24.3 4.8 24.5 7.3 25.0 29.7 25.3 4.2 25.8 17.0 26.3 4.4 27.0 8.0 27.5 7.4 27.8 5.6 28.9 7.1 29.3 11.1 29.8 18.8 30.6 4.3 31.2 8.5 31.5 8.8 31.8 6.5 32.6 12.4 34.8 3.5 35.5 5.4 36.9 4.3.

[00683] The TGA pattern of the crystalline image 9A is largely as shown in Figure 129, with a weight loss of 13.2% before 160°C, and a decomposition temperature of 340°C.

[00684] The spectrum 1 H NMR of the crystalline image 9A is shown in large detail in Figure 130.

[00685] Example 5 of Chinese patent No. CN115124515A describes the preparation of the crystallized image 7A.

[00686] Approximately 20 mg of resmeteorum was suspended in 0.5 mL of butanone and stirred at room temperature for 6 days to obtain the crystalline 9A image.

[00687] For example, one of the images is the BSI image specified in Chinese patent No. CN118772117A.

[00688] The crystalline BSI image can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 131; The X-ray diffraction pattern in the powder has peaks at 6.6 ± 0.2°, 7.8 ± 0.2°, 9.7 ± 0.2°, 10.2 ± 0.2°, 13.7 ± 0.2°, 16.3 ± 0.2°, 17.8 ± 0.2°, 18.2 ± 0.2°, 19.0 ± 0.2°, 19.6 ± 0.2°, 20.7 ± 0.2°, 22.0 ± 0.2°, 23.4 ± 0.2°, 24.9 ± 0.2°, 25.8 ± 0.2°, 26.8 ± 0.2°, 27.5 ± 0.2°, 28.0 ± 0.2°, 30.0 ± 0.2 degrees, 31.2 ± 0.2 degrees, 32.0 ± 0.2 degrees, 34.5 ± 0.2 degrees, 36.5 ± 0.2 degrees, 38.3 ± 0.2 degrees, and 42.4 ± 0.2 degrees 2-theta; and combinations of those data.

[00689] The DSC curve of the crystalline BSI image is large as shown in Figure 132, and shows a heat absorption peak approaching 334°C and a heat ejection peak approaching 238°C, which is the heat ejection peak for a crystal transition.

[00690] The TGA pattern of the crystalline BSI image is very large as shown in Figure 133, with a decomposition temperature of 340°C.

[00691] Example 1 of Chinese Patent No. CN118772117A describes the preparation of the BSI image.

[00692] Take 1 gram of resmetrium, add 5 milliliters of acetonitrile and 5 milliliters of toluene, stir to form a suspension, stir at room temperature for 3 days, filter, and dry in a vacuum oven (90-100°C) for 6 hours to obtain 0.88 grams of BSI crystalline resmetrium.

[00693] Example 2 of Chinese Patent No. CN118772117A describes the preparation of the BSI image.

[00694] Take 1 gram of resmetrium, add 5 milliliters of acetonitrile and 5 milliliters of cyclohexane, stir to form a suspension, stir at room temperature for 4 days, filter, and dry in a vacuum oven (90-100°C) for 6 hours to obtain 0.93 grams of BSI crystalline resmetrium.

[00695] Example 3 of Chinese Patent No. CN118772117A describes the preparation of the BSI image.

[00696] Take 1 gram of resmetrium, add 5 milliliters of acetonitrile and 5 milliliters of n-hexane, stir to form a suspension, stir at room temperature for 3 days, filter, and dry in a vacuum oven (90-100°C) for 6 hours to obtain 0.90 grams of BSI crystalline resmetrium.

[00697] Example 4 of Chinese Patent No. CN118772117A describes the preparation of the BSI image.

[00698] Take 1 gram of resmetrium, add 4 milliliters of acetonitrile, 3 milliliters of toluene and 3 milliliters of cyclohexane, stir to form a suspension, stir at room temperature for 3 days, filter, and dry in a vacuum oven (100-110°C) for 7 hours to obtain 0.87 grams of BSI crystalline resmetrium.

[00699] For example, one of the images is image R1 scheduled in IN202241066042A.

[00700] The crystalline image R1 can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 134; the X-ray diffraction pattern in the powder has peaks at 11.18° ± 0.2°, 12.48° ± 0.2°, 13.8° ± 0.2°, 15.02° ± 0.2°, 16.49° ± 0.2°, and 20.6° ± 0.2° 2-theta; and combinations of those data. The powder's X-ray diffraction pattern may have any one, two, three, four, five, or six additional peaks selected from 5.59° ± 0.2°, 10.56° ± 0.2°, 22° ± 0.2°, 22.76° ± 0.2°, 26.69° ± 0.2°, and 27.78° ± 0.2° 2-theta.

[00701] Example 1 of Indian Patent No. IN202241066042A describes the preparation of image R1.

[00702] A mixture of resmeterum (1 g) and formic acid (5 mL) was stirred for 3 days at room temperature. The resulting mixture was dried at room temperature for 2.5 hours, followed by drying under a VTD dryer for 1 day at 50°C to obtain the crystalline form R1.

[00703] For example, one of the images is the R2 image set out in Indian Patent No. IN202241066042A.

[00704] The R2 crystalline image can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 135; the powder's X-ray diffraction pattern with peaks at 9.04° ± 0.2°, 22.56° ± 0.2°, and 25.5° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, or three additional peaks selected from 9.6° ± 0.2°, 15.9° ± 0.2°, and 26.4° ± 0.2° 2-theta.

[00705] Example 2 of Indian Patent No. IN202241066042A describes the preparation of image R2.

[00706] A mixture of rhizometrum (1 g) and hexanoic acid (2 mL) was stirred for 20 hours at room temperature. Diisopropyl ether (25 mL) was added to the mixture and stirred for 2 hours at the same temperature. The solid was filtered under vacuum in a nitrogen atmosphere. The resulting solid was dried at room temperature for 2.5 hours, followed by drying at 50 °C for 12 hours using a VTD dryer to obtain the R2 crystalline form.

[00707] For example, one of the images is the R3 image set out in Indian Patent No. IN202241066042A.

[00708] The R3 crystalline image can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 136; the powder's X-ray diffraction pattern with peaks at 13.18° ± 0.2°, 27.2° ± 0.2°, 30° ± 0.2°, and 31.6° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, or three additional peaks selected from 9.68° ± 0.2°, 16.99° ± 0.2°, and 20.57° ± 0.2° 2-theta.

[00709] Example 3 of Indian Patent No. IN202241066042A describes the preparation of image R3.

[00710] A mixture of resmeter (1 g) and sulfonamide (2 mL) was stirred for 20 hours at room temperature. Water (25 mL) was added to the mixture and stirred for 1 hour at the same temperature. The reaction mixture was filtered under vacuum in a nitrogen atmosphere. The resulting solid was dried at room temperature for 2.5 hours, followed by drying at 50 °C for 12 hours using a VTD dryer to obtain the R3 crystalline form.

[00711] For example, one of the images is the R4 image specified in Indian Patent No. IN202241066042A.

[00712] The R4 crystalline image can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 137; the powder's X-ray diffraction pattern with peaks at 7.02° ± 0.2°, 8.9° ± 0.2°, 9.35° ± 0.2°, and 14.09° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one, two, or three additional peaks selected from 16.88° ± 0.2°, 22.56° ± 0.2°, and 28.77° ± 0.2° 2-theta.

[00713] Example 4 of Indian Patent No. IN202241066042A describes the preparation of image R4.

[00714] A mixture of rhizometrum (1 g) and butyric acid (5 mL) was stirred for two days at room temperature. Heptane (25 mL) was added to the mixture and stirred for two hours at the same temperature. The reaction mixture was filtered under vacuum in a nitrogen atmosphere. The resulting solid was dried at room temperature for 2.5 hours, followed by drying at 50 °C for 12 hours using a VTD dryer to obtain the R4 crystalline form.

[00715] For example, one of the images is the R5 image set out in Indian Patent No. IN202241066042A.

[00716] The crystalline R5 image can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 138; the X-ray diffraction pattern in the powder has peaks at 12.0° ± 0.2°, 14.28° ± 0.2°, 15.5° ± 0.2°, and 22.43° ± 0.2° 2-theta; and combinations of those data. The powder's X-ray diffraction pattern may have any one, two, three, four, five, or six additional peaks selected from 5.7° ± 0.2°, 10.6° ± 0.2°, 20.2° ± 0.2°, 21.09° ± 0.2°, 21.44° ± 0.2°, and 28.82° ± 0.2° 2-theta.

[00717] Example 5 of Indian Patent No. IN202241066042A describes the preparation of image R5.

[00718] A mixture of resmeteorum (1 g) and 1,2-dimethoxyethane (2.5 mL) was stirred for 24 hours at 40 °C. After 24 hours of stirring at 40 °C, the reaction mixture was cooled to 25 °C. The solid was filtered and dried under a VTD dryer for two days at 50 °C to obtain the R5 crystalline form.

[00719] For example, one of the images is a solid amorphous dispersion of rhizometrum and yodragite (1:2) as described in Indian Patent No. IN202241066042A.

[00720] The amorphous solid dispersion of rhizometrum and eudragit can be distinguished by the X-ray diffraction pattern in the powder, as shown in Figure 139.

[00721] Example 6 of Indian Patent No. IN202241066042A describes the preparation of an amorphous solid dispersion material for rhizometrum and yodragite.

[00722] A mixture of resmetrium (1.5 g) and eudragit (3 g) was heated in methanol (500 mL) at 50 °C and stirred for 1 hour. The mixture was filtered, and the resulting clear solution was spray-dried at 70 °C. The resulting solid was further dried at 40 °C under a VTD dryer for 18 hours to obtain an amorphous solid dispersion of resmetrium and eudragit.

[00723] For example, one of the images is an amorphous image of rhesmetrum as defined in Indian Patent No. IN202241066042A.

[00724] This amorphous image of rhesmetrum can be distinguished by the X-ray diffraction pattern in the powder, as shown in Figure 140.

[00725] Example 7 of Indian Patent No. IN202241066042A describes the preparation of this amorphous image of rhizometrum.

[00726] A mixture of rhizometrum (3 g) and acetone (300 mL) was stirred for 2 hours at 40 °C. The mixture was filtered, and the resulting clear solution was spray-dried at 65 °C to obtain this amorphous form of rhizometrum.

[00727] For example, one of the images is the RL image established in Indian Patent No. IN202241066042A.

[00728] The crystalline RL image can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern, as shown in Figure 141; the powder's X-ray diffraction pattern with peaks at 18.42° ± 0.2°, 19.09° ± 0.2°, and 20.49° ± 0.2° 2-theta; and combinations of these data. The powder's X-ray diffraction pattern may have any one or two additional peaks selected from 11.24° ± 0.2° and 17.12° ± 0.2° 2-theta.

[00729] Example 8 of Indian Patent No. IN202241066042A describes the preparation of the RL image.

[00730] A mixture of resmeteorum (1.7 g) and lysine (0.58 g) was stirred in acetone (15 mL) for two days at room temperature. The resulting solid was filtered and dried under a VTD dryer for three hours at room temperature to obtain the RL crystalline form.

[00731] For example, one of the images is the M1 image prescribed in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof".

[00732] The crystalline image M1 can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 142; the X-ray diffraction pattern in the powder has peaks at 10.6° ± 0.2°, 11.0° ± 0.2°, and 12.7° ± 0.2° 2-theta; and combinations of those data. The powder's X-ray diffraction pattern may have any one, two, three, four, five, six, or seven additional peaks selected from 10.2° ± 0.2°, 11.5° ± 0.2°, 16.9° ± 0.2°, 18.8° ± 0.2°, 21.1° ± 0.2°, 22.4° ± 0.2°, and 24.2° ± 0.2° 2-theta.

[00733] ​​Example 1 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof" describes the preparation of image M1.

[00734] A solution of rhizometrum (0.5 g) in a mixture of acetic acid (12 mL) and ethyl acetate (18 mL) at 40–50 °C is heated. The resulting solution is then cooled to 25–30 °C and stirred at the same temperature. The precipitated solid is filtered and dried to obtain the desired compound, crystalline form M1.

[00735] For example, one of the images is the M2 image prescribed in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof".

[00736] The crystalline M2 image can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 143; the X-ray diffraction pattern in the powder has peaks at 5.0° ± 0.2°, 6.4° ± 0.2°, 7.7° ± 0.2°, 15.1° ± 0.2°, and 23.7° ± 0.2° 2-theta; and combinations of those data. The powder's X-ray diffraction pattern may have any one, two, three, four, five, or six additional peaks selected from 10.1° ± 0.2°, 12.1° ± 0.2°, 14.3° ± 0.2°, 17.8° ± 0.2°, 19.6° ± 0.2°, and 21.8° ± 0.2° 2-theta.

[00737] Example 2 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof" describes the preparation of the M2 image.

[00738] Resmeterum (0.5 g) was dissolved in cyclohexanol (45 mL) at 60–70 °C and filtered to remove particles. The resulting filtrate was added to tert-methyl butyl ether (80 mL) at 25–30 °C and stirred at the same temperature. Cyclohexane (100 mL) was added to the mixture at 25–30 °C and stirred at the same temperature. The precipitated solid was filtered and dried to obtain the M2 crystalline form.

[00739] For example, one of the images is the M3 image prescribed in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof".

[00740] The crystalline image M3 can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 144; the X-ray diffraction pattern in the powder has peaks at 6.9° ± 0.2°, 8.6° ± 0.2°, 11.5° ± 0.2°, 13.9° ± 0.2°, 24.7° ± 0.2°, and 30.2° ± 0.2° 2-theta; and combinations of those data. The powder's X-ray diffraction pattern may have any one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve additional peaks selected from 9.8° ± 0.2°, 10.3° ± 0.2°, 10.7° ± 0.2°, 12.2° ± 0.2°, 15.7° ± 0.2°, 17.4° ± 0.2°, 17.9° ± 0.2°, 18.7° ± 0.2°, 21.6° ± 0.2°, 22.7° ± 0.2°, 26.7° ± 0.2°, and 28.5° ± 0.2° 2-theta.

[00741] Example 3 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof" describes the preparation of the M3 image.

[00742] Resmeterium solution (0.5 g) is dissolved in cyclohexanol (45 mL) at 60–70 °C. The resulting solution is then cooled to 25–30 °C and filtered to remove particles. The resulting filtrate is added to cyclohexane (80 mL) at 25–30 °C and stirred at the same temperature. The solid is then filtered and dried to obtain the crystalline form M3.

[00743] For example, one of the images is the M4 image prescribed in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof".

[00744] The crystalline M4 image can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern is substantial as shown in Figure 145; the powder's X-ray diffraction pattern has peaks at 3.9° ± 0.2°, 18.3° ± 0.2°, and 19.0° ± 0.2° 2-theta; and combinations of those data. The X-ray diffraction pattern in the powder may have any one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen additional peaks selected from 9.6° ± 0.2°, 11.9° ± 0.2°, 13.2° ± 0.2°, 14.9° ± 0.2°, 15.2° ± 0.2°, 16.9° ± 0.2°, 17.6° ± 0.2°, 19.7° ± 0.2°, 21.8° ± 0.2°, 23.9° ± 0.2°, 25.2° ± 0.2°, 25.7° ± 0.2°, 29.8° ± 0.2°, and 36.9° ± 0.2° 0.2 degrees 2-theta.

[00745] Example 4 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof" describes the preparation of the M4 image.

[00746] Resmeter (0.5 g) was dissolved in acetic acid (7 mL) at 70–80 °C. The resulting solution was added to cyclohexane (60 mL) at 25–30 °C and stirred. The mixture was cooled to 0–5 °C and stirred again at the same temperature. The mixture was then heated to 35–40 °C and stirred. The solid was filtered and dried to obtain the M4 crystalline form.

[00747] For example, one of the images is the M5 image prescribed in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof".

[00748] The crystalline M5 image can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern is substantial as shown in Figure 146; the powder's X-ray diffraction pattern has peaks at 6.4° ± 0.2°, 7.5° ± 0.2°, 8.2° ± 0.2°, and 9.5° ± 0.2° 2-theta; and combinations of those data. The powder's X-ray diffraction pattern may have any one, two, three, four, five, six, seven, eight, nine, or ten additional peaks selected from 10.0° ± 0.2°, 11.5° ± 0.2°, 16.1° ± 0.2°, 18.8° ± 0.2°, 19.4° ± 0.2°, 20.5° ± 0.2°, 21.7° ± 0.2°, 23.2° ± 0.2°, 24.7° ± 0.2°, and 27.2° ± 0.2° 2-theta.

[00749] Example 5 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof" describes the preparation of image M5.

[00750] Resmeter (0.5 g) and isonicotineamide (0.286 g) were dissolved in acetonitrile (12 mL) at 75–85 °C and filtered to remove particles at the same temperature. The resulting filtrate was cooled to 25–30 °C and stirred at the same temperature. The precipitated solid was filtered and dried to obtain the M5 crystalline form.

[00751] For example, one of the images is the M6 ​​image prescribed in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof".

[00752] The crystalline M6 image can be distinguished by data selected from one or more of the following: the X-ray diffraction pattern in the powder is substantial as shown in Figure 147; the X-ray diffraction pattern in the powder has peaks at 6.9° ± 0.2°, 8.5° ± 0.2°, 11.2° ± 0.2°, and 14.5° ± 0.2° 2-theta; and combinations of those data. The X-ray diffraction pattern in the powder may have any one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen additional peaks selected from 10.6° ± 0.2°, 12.1° ± 0.2°, 13.9° ± 0.2°, 15.3° ± 0.2°, 15.9° ± 0.2°, 16.4° ± 0.2°, 17.2° ± 0.2°, 17.9° ± 0.2°, 19.6° ± 0.2°, 19.9° ± 0.2°, 21.4° ± 0.2°, 22.4° ± 0.2°, 25.1° ± 0.2°, 27.5° ± 0.2°, 29.9° ± 0.2°, and 32.4° ± 0.2° 2-theta.

[00753] Example 6 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof" describes image preparation M6.

[00754] Resmeter (0.3 g) was dissolved in a (1:1) mixture of acetonitrile and tetrahydrofuran (6.0 mL) at 55–65 °C and filtered to remove particles at the same temperature. The resulting filtrate was cooled to 25–30 °C and stirred at the same temperature. The solid was then filtered and dried to obtain the M6 ​​crystalline form.

[00755] For example, one of the images is the M7 image prescribed in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof".

[00756] The crystalline image M7 can be distinguished by data selected from one or more of the following: the powder's X-ray diffraction pattern is substantial as shown in Figure 148; the powder's X-ray diffraction pattern has peaks at 9.1° ± 0.2°, 9.5° ± 0.2°, 10.5° ± 0.2°, 10.8° ± 0.2°, and 23.0° ± 0.2° 2-theta; and combinations of those data. The powder's X-ray diffraction pattern may have any one, two, three, four, five, six, seven, eight, or nine additional peaks selected from 11.9° ± 0.2°, 15.7° ± 0.2°, 17.3° ± 0.2°, 18.8° ± 0.2°, 19.5° ± 0.2°, 21.5° ± 0.2°, 24.3° ± 0.2°, 24.9° ± 0.2°, and 28.8° ± 0.2° 2-theta.

[00757] Example 7 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof" describes image preparation M7.

[00758] A mixture of isobutyl acetate (15.0 mL) and rhizometrum (0.3 g) was stirred at 25–30 °C. The solid was filtered and dried to obtain the crystalline form M7.

[00759] The current discovery also provides previously unknown morphological images, new common crystals, and salts of rhisometrum, along with methods for their preparation.

[00760] All XRPD patterns and peak lists of the new images described here are based on the Cu-Kα radiation wavelength (1.54 angstroms). The Rigaku Smart Lab X-ray biometer was configured in Bragg–Brentano reflection configuration with a beam deflector and knife edge to minimize incident beam and air scattering. Data acquisition variables are detailed in the following table: variable Value variable Value geometric shape Bragg–Brentano Receiving slot 1 (mm) 18 tube anode Cu Receiving slot 2 (mm) 20.1 Tube type Long microfocal focus Starting angle 2θ (degrees) 2 Tube voltage (kilovolts) 40 End angle 2 θ (degree) 40 Tube current (mA) 44 Step size (degrees) 0.02 Detector HyPix-3000 Scanning speed (degrees / minute) 6 Monochromatic color analyzer Ni Cu Kβ wafer filter Rotation (revolutions per minute) 11 Falling crack (degree) 1 / 3 Sample holder Si low-background

[00761] All DSC analyses of the new images described here were performed using a TA Instruments Q2000 Discovery Series instrument. Instrument temperature calibrations were performed using indium. The DSC cell was maintained under nitrogen purging at approximately 50 mL / min during analysis. Each sample was placed in a standardized, pressurized aluminum vessel and heated from approximately -30°C to 250 / 300°C or -30°C to 350 / 400°C at a rate of 10°C / min.

[00762] All thermogravimetric (TGA) analyses were performed using a TA Instruments Q5500 Discovery Series instrument. The instrument was balanced using Class M weights, and temperature calibration was performed using an alumel. Nitrogen purging was approximately 10 mL / min at equilibrium and approximately 25 mL / min at the furnace. The sample was placed in a pre-evacuated platinum vessel and heated from approximately 25 °C to 400 °C at a rate of 10 °C / min.

[00763] All infrared (IR) spectroscopic analyses of the new images described here were performed using a Thermo Scientific iS50 Fourier transform IR spectrophotometer (FT) equipped with a deuterium-treated triglyceride sulfate detector (DTGS), a potassium bromide beam splitter (KBr), and a Polaris™ long-life IR source. An amplitude-reflection diamond (ATR) sample collection aid with a 4000 cm⁻¹ spectral range was used. -1 Up to 400 centimeters -1 For ATR analysis, the SpectraTech drifts (Diffuse Infrared Fourier Transform Spectroscopy for Reflectance, DRIFTS) sample collection aid with a 4000 cm spectral range was used. -1 Up to 400 centimeters -1 For DRIFTS analysis, each spectrum was the result of 128 combined scans obtained when analyzing 2 cm. -1 A single-beam background scan of the air was obtained prior to the sample scan, enabling spectra to be presented in log1 / R units. Wavelength calibration was performed using polystyrene. The OMNIC v9.11 software package (Thermo-Nicolet) was used to acquire, process, and evaluate the spectral data.

[00764] All spectra were obtained 1 1H NMR images of the new images described here were obtained on a Bruker Avance NEO 400 MHz spectrometer. Samples were prepared by dissolving the material in DMSO-d6. The solutions were placed in single 5 mm NMR tubes for the following spectral acquisition. Each spectrum was processed using TopSpin version 4.1.4 and referenced to the chemical offset of the lagging DMSO-d6 peak (2.5 ppm).

[00765] All Raman spectroscopic analyses of the new images described here were performed using a Nicolet iS50 Raman module equipped with a 1064 nm near-infrared laser. The system was initialized with an indium gallium arsenic (InGaAs) detector and a calcium fluoride (CaF2) beam splitter. Each sample was placed on an automated XYZ stage, and the analysis was performed using a laser power tuned to optimize signal intensity while sparing the sample. Raman spectra were collected using 256 signal-approach scans with 2 cm⁻¹ analysis in the 3700 cm⁻¹ spectral range. -1 up to 100 centimeters -1 The data was acquired and processed using OMNIC v9.11 software.

[00766] Methods for synthesizing resmetrium can be found in U.S. Patents No. 7,452,882 and 9,266,861. Form I of resmetrium can be prepared according to the methods in U.S. Patent No. 9,266,861. Form D of resmetrium (acetone solubility) can be prepared according to the methods disclosed in U.S. Patent Application Bulletin No. 2021 / 0122740 A1. The contents of each of the following are included herein for reference in their entirety.

[00767] One aspect of the current detection relates to a morphological image, image U1, of rhymetime. Image U1 is a methyl ethyl ketone (MEK) solute. In some embodiments, image U1 exhibits an XRPD pattern that includes peaks at 10.0° ± 0.2°, 10.7° ± 0.2°, 13.8° ± 0.2°, 23.5° ± 0.2°, and 24.5° ± 0.2° 2-theta. In some embodiments, image U1 exhibits an XRPD pattern that includes any three, four, or five peaks selected from 10.0° ± 0.2°, 10.7° ± 0.2°, 13.8° ± 0.2°, 23.5° ± 0.2°, and 24.5° ± 0.2° 2-theta. In some representations, the XRPD pattern of image U1 also includes one or more additional peaks from Table U1 less than ±0.2° 2-theta. In other representations, image U1 is also or alternatively characterized by an XRPD pattern very similar to that shown in Figure 149. In still other representations, image U1 is or alternatively characterized by an XRPD pattern with peaks very similar to those presented in Table U1 less than ±0.2° 2-theta. Table U1 Number 2 theta (degree) d (angstrom) Relative intensity I 1 3.3317 26.49745 4.64 2 3.5531 24.84711 2.36 3 6.668 13.24523 8.67 4 7.1212 12.4033 1.6 5 9.9779 8.85771 100 6 10.6615 8.29121 86.33 7 10.8591 8.14081 48.91 8 11.7777 7.50785 1.03 9 12.1375 7.28608 9.53 10 13.7755 6.42318 38.35 11 14.235 6.21683 3.99 12 14.536 6.08877 3.6 13 16.236 5.45489 3.45 14 17.2717 5.13004 8.23 15 17.8018 4.97847 4.68 16 18.3525 4.83029 4.24 17 21.3924 4.15028 10.58 18 21.8783 4.05918 7.12 19 23.4542 3.7899 45.25 20 24.0996 3.68983 36.58 21 24.4903 3.63185 47.96 22 26.4943 3.3615 5.34 23 26.8229 3.32106 8.54 24 27.8691 3.19873 16.26 25 29.3368 3.04195 30.14 26 30.2886 2.94849 7.75 27 31.4065 2.84604 4.82 28 32.3727 2.76327 24.16 29 32.4526 2.75666 9.87 30 33.0847 2.70541 2.9 31 33.8123 2.64884 1.02 32 34.6542 2.58639 1.21 33 35.4358 2.53112 2.64

[00768] In other representations, image U1 is also or alternatively characterized by a DSC thermometer very similar to that shown in Figure 150. In other representations, image U1 is also or alternatively characterized by a TGA thermometer very similar to that shown in Figure 150. In other representations, image U1 is also or alternatively characterized by TGA and DSC thermometers very similar to those shown in Figure 150. In other representations, image U1 is also or alternatively characterized by a TGA thermometer that includes a 7.9% weight loss after heating to approximately 200 °C. In other representations, image U1 is also or alternatively characterized by a DSC thermometer that includes an endothermic event at approximately 150 °C and approximately 334 °C.

[00769] Another aspect of the current detection relates to a morphological image, the U2 image, of rhizometrum. The U2 image is a t-butanol solute. In some embodiments, the U2 image exhibits an XRPD pattern that includes peaks at 12.9° ± 0.2°, 13.7° ± 0.2°, 16.9° ± 0.2°, 23.6° ± 0.2°, and 29.3° ± 0.2° 2-theta. In some embodiments, the U2 image exhibits an XRPD pattern that includes any three, four, or five peaks selected from 12.9° ± 0.2°, 13.7° ± 0.2°, 16.9° ± 0.2°, 23.6° ± 0.2°, and 29.3° ± 0.2° 2-theta. In some representations, the XRPD pattern of image U2 also includes one or more additional peaks from Table U2 less than ±0.2° 2-theta. In other representations, image U2 also or alternatively features an XRPD pattern very similar to that shown in Figure 151. In still other representations, image U2 also or alternatively features an XRPD pattern with peaks very similar to those presented in Table U2 less than ±0.2° 2-theta. Table U2 Number 2 theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 10.024 8.81707 2258.11 27.95 2 10.3407 8.54768 1448.4 28.58 3 10.7052 8.25745 954.45 14.59 4 11.7874 7.50165 981.1 9.64 5 12.8873 6.8638 3089.65 36.31 6 13.7178 6.45006 4456.4 85.52 7 16.1154 5.49544 1247.37 27.01 8 16.9335 5.23173 3796.48 49.29 9 17.8294 4.97081 488.35 5.96 10 19.165 4.6273 1274.94 9.47 11 21.0246 4.22205 712.07 5.8 12 21.6724 4.09729 1133.4 42.01 13 23.6398 3.76055 4090.96 100 14 27.7625 3.21077 1875.32 41.19 15 29.3737 3.03821 4153.83 83.48 16 32.0425 2.79099 711.74 16.84 17 33.7973 2.64998 199.23 2.71 18 34.6434 2.58717 193.36 4.36

[00770] In other representations, image U2 also or alternatively features a DSC thermometer very similar to that shown in Figure 152. In other representations, image U2 also or alternatively features a TGA thermometer very similar to that shown in Figure 152. In other representations, image U2 also or alternatively features TGA and DSC thermometers very similar to those shown in Figure 152. In other representations, image U2 also or alternatively features a TGA thermometer that exhibits approximately 5.7% weight loss after heating to approximately 200°C. In other representations, image U2 also or alternatively features a DSC thermometer that exhibits an endothermic event at approximately 136°C and approximately 328°C.

[00771] Another aspect of the current detection relates to a morphological image, image U3, of rhysmetrum. Image U3 is an N-methylpyrrolidone solute. In some embodiments, image U3 is characterized by an XRPD pattern that includes peaks at 10.5° ± 0.2°, 11.2° ± 0.2°, 16.4° ± 0.2°, 22.7° ± 0.2°, and 23.2° ± 0.2° 2-theta. In some embodiments, image U3 is characterized by an XRPD pattern that includes any three, four, or five peaks selected from 10.5° ± 0.2°, 11.2° ± 0.2°, 16.4° ± 0.2°, 22.7° ± 0.2°, and 23.2° ± 0.2° 2-theta. In some representations, the XRPD pattern of image U3 also includes one or more additional peaks from Table U3 less than ±0.2° 2-theta. In other representations, image U3 is also or alternatively characterized by an XRPD pattern very similar to that shown in Figure 153. In still other representations, image U3 is also or alternatively characterized by an XRPD pattern with peaks very similar to those presented in Table U3 less than ±0.2° 2-theta. Table U3 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 8.166 10.81854 437.49 3.53 2 8.6549 10.20845 1324.3 10.61 3 9.037 9.77769 1061.32 7.21 4 9.6583 9.15005 702.38 7.88 5 10.5353 8.39028 3681.53 26.44 6 11.2411 7.865 8477.05 88.53 7 12.5458 7.04984 2260.49 15.04 8 12.822 6.8986 607.32 6.63 9 13.1418 6.73144 1308.89 9.03 10 13.3994 6.60262 492.71 4.59 11 14.973 5.91204 1763.05 13.56 12 16.0276 5.52533 2332.87 28.75 13 16.1275 5.49134 4171.44 19.54 14 16.4378 5.38837 8985.84 100 15 16.7728 5.2815 3388.24 23.22 16 16.9806 5.21734 2507.91 15.42 17 17.3758 5.09955 1663.92 13.71 18 17.6663 5.01633 1535.01 27.44 19 18.1516 4.8833 1438.72 8.22 20 18.3921 4.81999 1587.36 16.64 21 19.1134 4.63969 624.46 4.28 22 19.3672 4.57946 2303.43 13.68 23 19.712 4.50012 1769.3 13.45 24 19.9106 4.45567 1429.51 11.11 25 20.4248 4.34464 1194.18 15.67 26 22.7744 3.90146 4551.75 73.04 27 23.214 3.82856 6676.84 54.38 28 23.6511 3.75878 2756.85 14.99 29 23.877 3.72372 913.22 13.7 30 24.4476 3.6381 3377.94 23.01 31 24.9267 3.56924 6051.85 42.54 32 25.5169 3.48801 1443.75 13.35 33 25.7931 3.45128 3659.82 52.49 34 26.5991 3.3485 672.38 8.17 35 26.9009 3.31162 1963.75 12.85 36 27.5064 3.24007 3096.59 27.81 37 28.12 3.17075 1575.39 23.11 38 28.6236 3.1161 838.12 6.66 39 28.8312 3.09414 606.01 6.74 40 30.0778 2.96867 772.97 6.95 41 32.0066 2.79404 2912.38 21.03 42 33.8727 2.64426 889.01 21.58 43 34.4956 2.59792 348.52 3.17 44 34.9783 2.56317 903.78 9.01 45 37.0354 2.42539 496.62 8.55 46 38.003 2.36583 824.61 5.71

[00772] In other renderings, image U3 also or alternatively features a DSC thermometer very similar to that shown in Figure 154. In other renderings, image U3 also or alternatively features a TGA thermometer very similar to that shown in Figure 154. In other renderings, image U3 also or alternatively features TGA and DSC thermometers very similar to those shown in Figure 154. In other renderings, image U3 also or alternatively features a TGA thermometer that exhibits approximately 20.0% weight loss after heating to approximately 200°C. In other renderings, image U3 also or alternatively features a DSC thermometer that exhibits endothermic events at approximately 169°C, approximately 207°C, and approximately 329°C.

[00773] Another aspect of the current detection relates to a morphological image, the U4 image, of rhysmetrum. The U4 image is a nitromethane solute. In some embodiments, the U4 image is characterized by an XRPD pattern that includes peaks at 8.1° ± 0.2°, 12.9° ± 0.2°, 16.3° ± 0.2°, 23.8° ± 0.2°, and 29.5° ± 0.2° 2-theta. In other embodiments, the U4 image is characterized by an XRPD pattern that includes any three, four, or five selected peaks from 8.1° ± 0.2°, 12.9° ± 0.2°, 16.3° ± 0.2°, 23.8° ± 0.2°, and 29.5° ± 0.2° 2-theta. In some renderings, the XRPD pattern of image U4 also includes one or more additional peaks from Table U4 less than ±0.2° 2-theta. In other renderings, image U4 is also characterized, or alternatively, by an XRPD pattern very similar to that shown in Figure 155. In still other renderings, image U4 is also characterized, or alternatively, by an XRPD pattern with peaks very similar to those presented in Table U4 less than ±0.2° 2-theta. Table U4 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 8.14 10.85305 4915.91 25.75 2 8.3515 10.5786 3662.1 13.77 3 10.2545 8.6194 2988.84 11.19 4 11.404 7.75304 1001.28 6.8 5 11.6122 7.61448 4048.09 10.2 6 12.1998 7.24899 1445.13 4.95 7 12.8758 6.86991 4789.66 27.24 8 13.1469 6.72884 6210.96 20.9 9 14.684 6.02776 1378.32 4.9 10 16.3138 5.42903 12975.16 100 11 16.5089 5.36534 2996.2 9.88 12 16.7149 5.29966 1824.01 9.88 13 17.4647 5.07378 2767.83 13.27 14 18.3584 4.82874 2743.75 17.07 15 19.2336 4.61096 4809.17 21.37 16 20.2142 4.38944 3085.63 30.99 17 20.5533 4.31778 1205.67 3.74 18 22.1947 4.00202 653.07 2.91 19 22.735 3.90813 3017.54 21 20 23.3293 3.8099 3893.23 16.67 21 23.8427 3.729 13662.49 60.8 22 24.0145 3.70272 11574.38 47.19 23 24.5005 3.63035 715.72 4.37 24 24.863 3.57824 2083.42 13.04 25 25.3906 3.50507 1252.35 3.17 26 25.9278 3.43365 613.49 2.52 27 26.4553 3.36637 1721.07 10.45 28 26.7375 3.33148 2721.8 15.26 29 27.4832 3.24276 2384.48 9.68 30 28.1679 3.16547 560.04 5.34 31 29.536 3.02188 3881.6 39.24 32 30.4967 2.92884 497.47 2.51 33 31.0859 2.87466 596.17 6.5 34 31.7109 2.81942 2123.7 6.75 35 32.0308 2.79199 955.4 19.76 36 32.9884 2.71309 1156.79 9.91 37 34.4978 2.59776 623.91 3.72 38 36.2583 2.47556 759.81 15.66

[00774] Another aspect of the current detection relates to a morphological image, image U5, of rhizometrum. Image U5 is an o-xylen solute. In some embodiments, image U5 is characterized by an XRPD pattern that includes peaks at 8.7° ± 0.2°, 11.1° ± 0.2°, 15.5° ± 0.2°, 24.5° ± 0.2°, and 32.4° ± 0.2° 2-theta. In other embodiments, image U5 is characterized by an XRPD pattern that includes any three, four, or five peaks selected from 8.7° ± 0.2°, 11.1° ± 0.2°, 15.5° ± 0.2°, 24.5° ± 0.2°, and 32.4° ± 0.2° 2-theta. In some representations, the XRPD pattern of image U5 also includes one or more additional peaks from Table U5 less than ±0.2° 2-theta. In other representations, image U5 also or alternatively features an XRPD pattern very similar to that shown in Figure 156. In still other representations, image U5 is also or alternatively characterized by an XRPD pattern with peaks very similar to those presented in Table U5 less than ±0.2° 2-theta. Table U5 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 8.7671 10.07807 5444.62 43.05 2 9.8261 8.99414 370.22 2.35 3 11.1095 7.95784 8590.02 32.04 4 11.2145 7.88362 5529.61 29.39 5 11.3199 7.81039 6819.29 27.02 6 11.7163 7.54707 528.86 3.1 7 12.1226 7.29502 2969.31 14.93 8 12.6275 7.00441 1072.48 10.06 9 13.5633 6.5232 3636.75 15.5 10 15.4558 5.72846 15846.41 100 11 15.9914 5.53777 3287.57 23.02 12 17.8761 4.95795 1593.85 17.88 13 18.2048 4.86915 806.44 18.97 14 19.704 4.50192 754.89 2.73 15 20.0462 4.42584 2361.7 16.11 16 20.5008 4.32872 1881.55 8.21 17 20.6807 4.29147 2432.41 14.04 18 21.1724 4.1929 949.25 13.4 19 21.8626 4.06207 1868.82 6.54 20 22.775 3.90136 463.3 4.41 21 23.4014 3.79832 1275.66 6.28 22 23.6624 3.75702 3979.64 24.86 23 24.3813 3.64784 4167.45 19.84 24 24.5608 3.62159 3965.47 32.77 25 24.7244 3.59799 2743.56 7.98 26 25.2801 3.52014 740.11 10.39 27 25.7951 3.45102 404.93 8.94 28 26.6191 3.34603 1124.94 8.05 29 27.2918 3.26507 2777.97 10.46 30 27.6399 3.22473 834.35 3.34 31 28.1447 3.16803 420.62 4.63 32 28.7004 3.10794 833.96 8.61 33 29.0356 3.07282 1060.05 5.3 34 29.7716 2.9985 1050.39 8.7 35 31.4977 2.83801 661.31 10.7 36 32.3609 2.76425 2807.15 30.92 37 33.6289 2.66287 1555.13 12.9 38 34.4682 2.59992 540.68 4.12 39 35.5409 2.52387 525.66 5.04 40 38.7308 2.32303 618.14 4.43

[00775] Another aspect of the current detection relates to a morphological image, image U6, of rhizometrum. Image U6 is a trifluoroethanol (TFE) solute. In some embodiments, image U6 exhibits an XRPD pattern that includes peaks at 10.6° ± 0.2°, 11.5° ± 0.2°, 18.8° ± 0.2°, 20.0° ± 0.2°, and 23.5° ± 0.2° 2-theta. In some embodiments, image U6 exhibits an XRPD pattern that includes any three, four, or five peaks selected from 10.6° ± 0.2°, 11.5° ± 0.2°, 18.8° ± 0.2°, 20.0° ± 0.2°, and 23.5° ± 0.2° 2-theta. In some representations, the XRPD pattern of image U6 also includes one or more additional peaks from Table U6 less than ±0.2° 2-theta. In other representations, image U6 also or alternatively features an XRPD pattern very similar to that shown in Figure 157. In still other representations, image U6 also or alternatively features an XRPD pattern with peaks very similar to those presented in Table U6 less than ±0.2° 2-theta. Table U6 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 10.2855 8.5935 1221.6 3.13 2 10.64 8.30793 4450.82 10.19 3 11.2786 7.8389 1006.48 2.56 4 11.5805 7.63527 8107.31 20.03 5 13.1776 6.71323 2867.25 6.9 6 16.3418 5.41981 2343.64 6.28 7 16.7821 5.27859 1792.64 5.49 8 17.539 5.05246 832.58 1.71 9 18.7949 4.71759 5015.16 13.29 10 20.0422 4.42672 6147.48 21.2 11 20.4209 4.34546 5634.03 14.83 12 20.7197 4.28347 2722.33 8.69 13 21.3405 4.16025 3181.13 9.25 14 22.2617 3.99013 3847.45 13.79 15 22.4369 3.95936 1528.74 3.58 16 23.4727 3.78694 24977.35 100 17 24.2408 3.66866 1763.31 4.53 18 25.3089 3.5162 3166.32 8.44 19 25.4237 3.50058 3181.91 10.15 20 25.9656 3.42874 1734.37 5.03 21 26.5704 3.35206 740.79 2.27 22 26.9475 3.30599 580.8 1.89 23 28.0752 3.17572 1381.74 4.35 24 28.7584 3.1018 512.02 1.04 25 29.4154 3.03401 849.8 5.18 26 30.1439 2.96232 2755.47 8.96 27 30.4676 2.93157 1898.21 7.55 28 31.2718 2.85799 2317.11 6.42 29 31.594 2.82958 1338.27 10.69 30 32.1368 2.78302 1777.92 6.28 31 33.8147 2.64866 1912.72 5.54 32 34.8863 2.56972 493.45 0.85 33 35.2723 2.54247 308.84 1.05 34 38.1646 2.35618 590.14 2.73

[00776] In other representations, image U6 is also characterized, or alternatively, by a DSC thermometer very similar to that shown in Figure 158. In other representations, image U6 is also characterized, or alternatively, by a TGA thermometer very similar to that shown in Figure 158. In other representations, image U6 is also characterized, or alternatively, by TGA and DSC thermometers very similar to those shown in Figure 158. In other representations, image U6 is also characterized, or alternatively, by a TGA thermometer that exhibits approximately 18.4% weight loss after heating to approximately 150°C. In other representations, image U6 is also characterized, or alternatively, by a DSC thermometer that exhibits endothermic events at approximately 234°C and approximately 333°C.

[00777] Another aspect of the current detection relates to a morphological image, image U7, of rhysmetrum. Image U7 is a solute containing several solvents. In some embodiments, image U7 exhibits an XRPD pattern that includes peaks at 9.5° ± 0.2°, 11.5° ± 0.2°, 21.4° ± 0.2°, 23.0° ± 0.2°, and 23.8° ± 0.2° 2-theta. In other embodiments, image U7 exhibits an XRPD pattern that includes any three, four, or five peaks selected from 9.5° ± 0.2°, 11.5° ± 0.2°, 21.4° ± 0.2°, 23.0° ± 0.2°, and 23.8° ± 0.2° 2-theta. In some representations, the XRPD pattern of image U7 also includes one or more additional peaks from Table U7 less than ±0.2° 2-theta. In other representations, image U7 is also characterized, or alternatively, by an XRPD pattern very similar to that shown in Figure 159. In still other representations, image U7 is also characterized, or alternatively, by an XRPD pattern with peaks very similar to those presented in Table U7 less than ±0.2° 2-theta. Table U7 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 5.733 15.40315 609.05 19.81 2 9.4924 9.30957 1191.98 38.34 3 11.4559 7.71801 2220.15 60.36 4 15.2516 5.80469 507.63 18.74 5 16.3238 5.42573 615.58 26.67 6 16.7611 5.28515 571.82 77.56 7 18.8686 4.69932 766.07 62.06 8 20.1651 4.40002 241.05 10.6 9 21.4339 4.14233 1389.25 80.98 10 21.6493 4.10159 830.35 37.07 11 22.9737 3.86806 1112.38 100 12 23.8804 3.72321 389.29 46.21 13 25.4361 3.4989 405.43 39.04 14 28.7589 3.10175 170.48 18.31 15 29.58 3.01749 173.3 8.96 16 30.1465 2.96207 230.12 7.6 17 32.2998 2.76934 298.82 17.94 18 32.9596 2.7154 300.07 19.68 19 34.4843 2.59875 248.43 17.05 20 34.9241 2.56702 240.37 16.69 21 35.5067 2.52623 122.04 10.98

[00778] In other representations, image U7 is also characterized, or alternatively, by a DSC thermometer very similar to that shown in Figure 160. In other representations, image U7 is also characterized, or alternatively, by a TGA thermometer very similar to that shown in Figure 160. In other representations, image U7 is also characterized, or alternatively, by TGA and DSC thermometers very similar to those shown in Figure 160. In other representations, image U7 is also characterized, or alternatively, by a TGA thermometer that includes approximately 9.7% weight loss between approximately 100°C and approximately 150°C. In other representations, image U7 is also characterized, or alternatively, by a DSC thermometer that includes endothermic events at approximately 73°C, approximately 130°C, and approximately 320°C.

[00779] Another aspect of the current discovery relates to a morphological image, image U8, of rhysmetrum. Image U8 is a cyclohexanone solute. In some embodiments, image U8 exhibits an XRPD pattern that includes peaks at 13.9° ± 0.2°, 14.9° ± 0.2°, 21.6° ± 0.2°, 25.1° ± 0.2°, and 28.2° ± 0.2° 2-theta. In some embodiments, image U8 exhibits an XRPD pattern that includes any three, four, or five peaks selected from 13.9° ± 0.2°, 14.9° ± 0.2°, 21.6° ± 0.2°, 25.1° ± 0.2°, and 28.2° ± 0.2° 2-theta. In some representations, the XRPD pattern of image U8 also includes one or more additional peaks from Table U8 less than ±0.2° 2-theta. In other representations, image U8 also or alternatively features an XRPD pattern very similar to that shown in Figure 161. In still other representations, image U8 also or alternatively features an XRPD pattern with peaks very similar to those presented in Table U8 less than ±0.2° 2-theta. Table U8 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 7.0126 12.59507 4556.49 17.58 2 10.0758 8.77188 2461.27 8.64 3 10.4677 8.44428 3024.26 11.46 4 10.6665 8.28734 3728.07 16.52 5 11.5336 7.6662 365.56 1.51 6 12.4455 7.10646 1640.65 6.28 7 13.8697 6.37975 28881.39 100 8 14.0057 6.31811 4180.07 10.8 9 14.8859 5.94643 5285.02 18.66 10 15.8756 5.57789 2038.42 7.06 11 16.6412 5.32297 1435.74 4.54 12 17.663 5.01727 964.9 10.4 13 17.9553 4.93625 2500.78 7.7 14 18.1664 4.87935 2884.34 8.09 15 18.6183 4.76193 7581.22 25.5 16 19.2347 4.61069 2947.7 9.26 17 19.5383 4.53974 3462.39 10.71 18 20.1985 4.39281 1721.77 7.1 19 20.5221 4.32427 3024.84 9.86 20 20.6546 4.29683 713.21 1.9 21 21.0499 4.21702 3209.58 12.77 22 21.1829 4.19085 1203.8 4.21 23 21.4096 4.14698 4280.37 14.99 24 21.6371 4.10389 13519.49 49.15 25 21.7673 4.07964 4176.77 14.23 26 22.7537 3.90495 11349.39 39.81 27 23.2209 3.82744 3995.98 13.49 28 24.5375 3.62496 1685.5 5.95 29 24.9789 3.5619 3929.99 13.88 30 25.143 3.53903 12533.09 44.16 31 25.4839 3.49245 10963.84 37.87 32 26.705 3.33547 950.15 3.72 33 26.9635 3.30407 2360.02 8.95 34 27.2095 3.27476 5024.1 26.45 35 27.5123 3.23939 652.76 2.13 36 27.7061 3.21717 969.93 2.87 37 27.9137 3.19372 5548.14 18.58 38 28.2795 3.15323 10331.67 51.2 39 28.9425 3.08249 1302.9 3.42 40 29.8159 2.99415 3287.86 17.79 41 29.9247 2.98351 4631.07 16.79 42 30.7063 2.90933 1156.34 4.26 43 31.0624 2.87679 4726.46 17.64 44 31.776 2.81379 2159.38 9.24 45 32.6672 2.73903 1577.76 7.2 46 33.0917 2.70486 1495.52 2.91 47 33.1863 2.69736 2249.17 15.01 48 34.0413 2.63154 699.14 1.98 49 34.6723 2.58508 456.82 3.63 50 35.1084 2.55397 627.8 2.63 51 35.4353 2.53115 658.28 1.97 52 36.0102 2.49205 1327.57 4.38 53 36.145 2.48306 503.07 3.46 54 37.5634 2.3925 479.48 1.36 55 37.8626 2.37428 603.7 4.4 56 38.1928 2.3545 808.06 2.72 57 38.928 2.31172 382.27 3.33 58 39.4781 2.28076 1343.97 6.09

[00780] In other representations, image U8 is also or alternatively characterized by a DSC thermometer very similar to that shown in Figure 162. In other representations, image U8 is also or alternatively characterized by a TGA thermometer very similar to that shown in Figure 162. In other representations, image U8 is also or alternatively characterized by TGA and DSC thermometers very similar to those shown in Figure 162. In other representations, image U8 is also or alternatively characterized by a TGA thermometer exhibiting approximately 18.4% weight loss after heating to approximately 200 °C. In other representations, image U8 is also or alternatively characterized by a DSC thermometer exhibiting endothermic events at approximately 192 °C and approximately 333 °C.

[00781] Another aspect of the current detection relates to a morphological image, image U9, of rhymetime. Image U9 is a methyl acetate solute. In some embodiments, image U9 exhibits an XRPD pattern involving peaks at 10.5° ± 0.2°, 11.0° ± 0.2°, 11.8° ± 0.2°, 19.8° ± 0.2°, and 24.4° ± 0.2° 2-theta. In some embodiments, image U9 exhibits an XRPD pattern involving any three, four, or five peaks selected from 10.5° ± 0.2°, 11.0° ± 0.2°, 11.8° ± 0.2°, 19.8° ± 0.2°, and 24.4° ± 0.2° 2-theta. In some representations, the XRPD pattern of image U9 also includes one or more additional peaks from Table U9 less than ±0.2° 2-theta. In other representations, image U9 also or alternatively features an XRPD pattern very similar to that shown in Figure 163. In still other representations, image U9 also or alternatively features an XRPD pattern with peaks very similar to those presented in Table U9 less than ±0.2° 2-theta. Table U9 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 7.6885 11.48933 671.89 1.61 2 10.4601 8.45042 5836.26 18.4 3 10.8149 8.17399 5564.51 14.11 4 10.9786 8.05248 3695.47 16.74 5 11.7758 7.50902 4950.95 15.76 6 12.1382 7.28564 1508.91 6.41 7 13.0491 6.77906 1438.25 9.74 8 14.6314 6.04931 3218.99 8.71 9 16.0848 5.50583 136.28 1.75 10 17.1691 5.16048 3178.15 7.69 11 18.7268 4.73458 1085.39 3.47 12 19.5372 4.53998 1409.37 12.25 13 19.8037 4.47949 5716.78 13.73 14 20.2287 4.38632 731.55 3.39 15 21.1973 4.18802 925.59 2.2 16 21.7293 4.08668 2265.31 11.57 17 22.1518 4.00969 1982.76 7.52 18 22.3534 3.97398 3347.05 11.81 19 22.8432 3.88985 1906.28 6.41 20 23.7089 3.74975 1415.86 13.34 21 24.3676 3.64986 25497.61 100 22 25.4685 3.49453 1437.08 5.17 23 26.7314 3.33223 311.08 1.45 24 27.3642 3.2566 3329.09 13.02 25 27.8413 3.20186 1122.34 2.26 26 29.4889 3.0266 968.96 5.06 27 29.8906 2.98684 579.97 2.47 28 30.445 2.9337 1009.5 2.94 29 32.0635 2.78921 2122.14 22.17 30 32.8747 2.72222 557.57 0.99 31 33.8796 2.64373 554.21 2.18 32 35.8627 2.50196 1523.79 8.06 33 36.3251 2.47116 321.07 2.64 34 39.6202 2.27291 561.36 0.94

[00782] In other renderings, image U9 also features, or alternatively features, a DSC thermometer very similar to that shown in Figure 164. In other renderings, image U9 also features, or alternatively features, a TGA thermometer very similar to that shown in Figure 164. In other renderings, image U9 also features, or alternatively features, TGA and DSC thermometers very similar to those shown in Figure 164. In other renderings, image U9 also features, or alternatively features, a TGA thermometer that exhibits approximately 13.9% weight loss after heating to approximately 175°C. In other renderings, image U9 also features, or alternatively features, a DSC thermometer that exhibits endothermic events at approximately 110°C, approximately 154°C, and approximately 333°C.

[00783] Another aspect of the current discovery relates to a co-crystal of resmeteorum triethyl citrate, image C1. In some representations, image C1 features an XRPD pattern that includes peaks at 7.1° ± 0.2°, 9.3° ± 0.2°, 10.1° ± 0.2°, 12.5° ± 0.2°, and 23.5° ± 0.2° 2-theta. In some representations, image C1 features an XRPD pattern that includes any three, four, or five peaks selected from 7.1° ± 0.2°, 9.3° ± 0.2°, 10.1° ± 0.2°, 12.5° ± 0.2°, and 23.5° ± 0.2° 2-theta. In some representations, the XRPD pattern of image C1 also includes one or more additional peaks from Table C1 less than ±0.2° 2-theta. In other representations, image C1 also features, or alternatively displays, an XRPD pattern very similar to that shown in Figure 165. In yet other representations, image C1 also features, or alternatively displays, an XRPD pattern with peaks very similar to those presented in Table C1 less than ±0.2° 2-theta. Table C1 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 6.9261 12.75215 7410 63.36 2 7.1357 12.37808 10474.93 80.71 3 9.325 9.4764 7092.72 66.8 4 10.1773 8.68462 7066.21 75.61 5 10.547 8.38096 3215.86 48.77 6 10.9581 8.0675 315.15 15.97 7 11.5424 7.66037 1551.33 10.22 8 12.1751 7.26368 627.35 4.87 9 12.5168 7.06613 11534.98 98.12 10 13.8824 6.37397 1669.18 16.77 11 14.2749 6.19958 1479.93 10.47 12 14.5907 6.06607 1782.76 13.47 13 15.5307 5.70098 2854.44 22.94 14 16.636 5.32462 3483.72 42.3 15 17.1764 5.15828 1873.39 19.28 16 17.4582 5.07567 5286.33 51.91 17 17.7624 4.9894 1480.41 11.67 18 18.0054 4.92261 3072.46 27.05 19 18.6068 4.76484 634.51 13.07 20 19.9126 4.45522 1548.48 8.69 21 20.4593 4.33741 7697.27 68 22 20.875 4.25197 3464.14 25.31 23 21.1905 4.18935 4196.07 35.78 24 21.3976 4.14927 2696.13 40.43 25 21.7908 4.07528 1683.43 12.75 26 21.9811 4.04044 4042.97 32.02 27 22.6241 3.92704 1400.15 15.29 28 22.9197 3.87705 2627.87 26.83 29 23.1943 3.83176 8670.52 78.2 30 23.5388 3.77645 9211.7 100 31 24.1116 3.68802 1048.25 10.9 32 24.4772 3.63376 2415.74 21.7 33 24.9164 3.5707 2119.26 21.68 34 25.4118 3.5022 4939.26 61.46 35 25.9764 3.42734 595.39 4.03 36 26.217 3.39643 775.31 3.36 37 26.8826 3.31382 855.66 18.43 38 28.2579 3.1556 1326.55 25.47 39 28.8017 3.09724 1233.57 20.31 40 29.1517 3.06084 3228.96 34.48 41 29.4566 3.02985 1361.99 24.88 42 30.3351 2.94408 4441.42 51.69 43 30.7001 2.9099 783.67 13.42 44 31.4059 2.8461 370.48 19.52 45 34.2481 2.61613 591.61 7.18 46 34.6407 2.58737 1385.6 13.73 47 35.0133 2.56069 1051.49 9.94 48 35.9659 2.49502 666.62 10.23 49 36.2324 2.47728 478.84 2.48 50 36.4846 2.46073 701.84 5.82 51 36.9727 2.42936 273.82 6.85 52 38.0376 2.36375 429.8 6.09

[00784] In other renderings, Image C1 also features, or alternatively features, a DSC thermometer very similar to that shown in Figure 167. In other renderings, Image C1 also features, or alternatively features, a TGA thermometer very similar to that shown in Figure 167. In other renderings, Image C1 also features, or alternatively features, TGA and DSC thermometers very similar to those shown in Figure 167. In other renderings, Image C1 also features, or alternatively features, a TGA thermometer that includes approximately 37% weight loss at 250°C. In other renderings, Image C1 also features, or alternatively features, a DSC thermometer that includes endothermic events at approximately 84°C and approximately 330°C.

[00785] In other incarnations, image C1 also features, or alternatively features, a spectrum 1 The 1H NMR is very similar to that shown in Figure 166. In other representations, image C1 also features, or alternatively features, an FTIR spectrum very similar to the FTIR spectrum of image C1 shown in Figure 168. In other representations, image C1 also features, or alternatively features, a Raman spectrum very similar to the Raman spectrum of image C1 shown in Figure 169.

[00786] Another aspect of the current detection relates to the common crystal rhisometerum cytosine, image C2. In some representations, image C2 features an XRPD pattern that includes peaks at 8.7° ± 0.2°, 10.8° ± 0.2°, 13.6° ± 0.2°, 17.6° ± 0.2°, and 21.6° ± 0.2° 2-theta. In some representations, image C2 features an XRPD pattern that includes any three, four, or five peaks selected from 8.7° ± 0.2°, 10.8° ± 0.2°, 13.6° ± 0.2°, 17.6° ± 0.2°, and 21.6° ± 0.2° 2-theta. In some representations, the XRPD pattern of image C2 also includes one or more additional peaks from Table C2 less than ±0.2° 2-theta. In other representations, image C2 also features, or alternatively features, an XRPD pattern very similar to that shown in Figure 170. In still other representations, image C2 also features, or alternatively features, an XRPD pattern with peaks very similar to those presented in Table C2 less than ±0.2° 2-theta. Table C2 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 4.2417 20.81454 6779.84 16.96 2 8.6536 10.20998 11155.15 26.7 3 9.88 8.94524 1601.25 3.14 4 10.8246 8.16668 23480.34 63.11 5 12.7804 6.92099 2165.61 5.18 6 13.5506 6.52925 13047.3 22.53 7 13.9824 6.32859 2944.7 8.07 8 16.2805 5.44007 4661.81 12.84 9 16.4467 5.38546 4174.67 6.97 10 16.5909 5.33898 3406.55 5.12 11 16.9747 5.21913 2233.45 4.96 12 17.6316 5.02614 28850.83 100 13 19.8626 4.46634 1194.58 2.11 14 20.1138 4.41111 5508.4 12.45 15 21.2616 4.1755 6253.95 23.38 16 22.22 3.99753 1835.84 4.59 17 23.8092 3.73418 810.52 3.98 18 24.0005 3.70485 2299.78 5.05 19 24.6804 3.6043 1487.54 4.33 20 25.0678 3.54947 1798.92 4.5 21 25.5959 3.47742 3463.58 11.26 22 26.1005 3.41132 3883.75 14.19 23 26.7606 3.32866 2333.38 6.98 24 27.0217 3.29709 3061.49 4.96 25 28.1868 3.16339 2407.88 7.84 26 28.8991 3.08702 1201.84 1.38 27 29.4837 3.02713 518.5 0.68 28 29.9913 2.97704 1513.51 7.16 29 30.4181 2.93623 2166.29 8.5 30 30.6672 2.91295 4648.41 13.13 31 31.1483 2.86904 2530.12 6.6 32 31.9573 2.79824 420.2 1.18 33 32.6534 2.74016 811.94 2.17 34 33.541 2.66965 1458.65 4.4 35 34.3951 2.60528 558.98 1.92 36 38.9825 2.30861 666.92 5.07

[00787] In other renderings, image C2 also features, or alternatively features, a DSC thermometer very similar to that shown in Figure 172. In other renderings, image C2 also features, or alternatively features, a TGA thermometer very similar to that shown in Figure 172. In other renderings, image C2 also features, or alternatively features, TGA and DSC thermometers very similar to those shown in Figure 172. In other renderings, image C2 also features, or alternatively features, a TGA thermometer that includes approximately 0.6% weight loss down to 200°C. In other renderings, image C2 also features, or alternatively features, a DSC thermometer that includes two overlapping main heat absorption events with an onset at 283°C.

[00788] In other incarnations, image C2 also features, or alternatively features, a spectrum 1 The 1H NMR is very similar to that shown in Figure 171. In other representations, image C2 also features, or alternatively features, an FTIR spectrum very similar to the FTIR spectrum of image C2 shown in Figure 173. In other representations, image C2 also features, or alternatively features, a Raman spectrum very similar to the Raman spectrum of image C2 shown in Figure 174.

[00789] Another aspect of the current discovery relates to the co-crystal of calcium pantothenate rhisometrum, image C3. In some representations, image C3 features an XRPD pattern that includes peaks at 5.8° ± 0.2°, 11.5° ± 0.2°, 19.2° ± 0.2°, 20.0° ± 0.2°, and 23.4° ± 0.2° 2-theta. In some representations, image C3 features an XRPD pattern that includes any three, four, or five peaks selected from 5.8° ± 0.2°, 11.5° ± 0.2°, 19.2° ± 0.2°, 20.0° ± 0.2°, and 23.4° ± 0.2° 2-theta. In some representations, the XRPD pattern of image C3 also includes one or more additional peaks from Table C3 less than ±0.2° 2-theta. In other representations, image C3 also features, or alternatively displays, an XRPD pattern very similar to that shown in Figure 175. In yet other representations, image C3 also features, or alternatively displays, an XRPD pattern with peaks very similar to those presented in Table C3 less than ±0.2° 2-theta. Table C3 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 5.7696 15.30563 22440.66 100 2 7.4184 11.90701 862.12 2.97 3 9.5642 9.23984 871.39 2.57 4 10.4609 8.44977 1361.55 3.65 5 11.5407 7.6615 13739.68 58.04 6 13.7701 6.42567 653.77 2.22 7 14.2594 6.20627 2714.99 9.25 8 15.6688 5.65104 1684.12 5.92 9 17.2084 5.14878 825.37 6.69 10 18.0978 4.8977 379.21 6.95 11 18.6228 4.76079 3650.03 10.41 12 19.0191 4.66248 1534.7 4.89 13 19.2142 4.61556 4204.99 17.47 14 19.9543 4.44602 5981.2 36.07 15 20.3591 4.35851 765.78 1.61 16 20.964 4.2341 1179.54 3.44 17 22.5076 3.9471 3547.03 13.85 18 22.7854 3.8996 1760.47 11.8 19 23.4466 3.7911 5524.06 27.72 20 24.0248 3.70116 345.38 2.71 21 24.5578 3.62202 1921.27 8.97 22 26.5729 3.35174 680 4.09 23 26.9246 3.30876 863.39 3.19 24 27.7587 3.21119 2628.23 14.76 25 29.0589 3.07041 381.82 4.34 26 29.967 2.9794 778.9 5.55 27 30.3237 2.94516 433.23 1.04 28 30.7629 2.90411 464.56 3.75 29 33.3805 2.68211 409.05 2.18 30 35.3781 2.53511 318.03 5.11

[00790] Another aspect of the current discovery relates to a co-crystal of resmeteorum dimethylglycine, image C4. Image C4 also contains 0.7 molar equivalents of isopropanol (IPA). In some incarnations, image C4 exhibits an XRPD pattern that includes peaks at 11.3° ± 0.2°, 14.1° ± 0.2°, 18.0° ± 0.2°, 19.7° ± 0.2°, and 22.7° ± 0.2° 2-theta. In some representations, image C4 features an XRPD pattern that includes any three, four, or five peaks selected from 11.3° ± 0.2°, 14.1° ± 0.2°, 18.0° ± 0.2°, 19.7° ± 0.2°, and 22.7° ± 0.2° 2-theta. In some representations, the XRPD pattern of image C4 also includes one or more additional peaks from Table C4 that are less than ± 0.2° 2-theta. In other representations, image C4 also or alternatively features an XRPD pattern that is substantially similar to that shown in Figure 176. In still other representations, image C4 also or alternatively features an XRPD pattern with peaks that are substantially as presented in Table C4 that are less than ± 0.2° 2-theta. Table C4 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 6.5477 13.48825 3665.71 19.03 2 7.1047 12.43206 613.6 13.75 3 7.8204 11.29578 415.18 5.6 4 9.7683 9.04724 1331.71 6.46 5 11.3349 7.80009 3765.11 28.22 6 12.9853 6.81224 1285.26 7.28 7 14.1252 6.26493 9971.23 48.39 8 15.5508 5.69367 937.65 3.07 9 16.2021 5.46621 3087.99 12.34 10 16.8237 5.26563 5629.33 33.77 11 17.476 5.07053 493.16 1.38 12 18.0202 4.9186 13001.49 58.77 13 18.6194 4.76166 3029.98 19.12 14 19.5498 4.5371 7380.09 33.49 15 19.6908 4.50491 23734.61 100 16 19.819 4.47607 11027.13 51.9 17 20.0724 4.42012 1617.62 12.73 18 20.3159 4.36768 1351.34 20.35 19 20.8841 4.25012 678.99 16.23 20 21.7405 4.0846 1191.74 9.65 21 21.8982 4.05554 5028.84 42.16 22 22.3505 3.97448 3487.88 23.18 23 22.7003 3.91402 13412.39 86.29 24 23.2407 3.82422 1329.08 8.33 25 24.061 3.69566 6030.99 45.22 26 24.451 3.6376 1758.21 6.11 27 24.7721 3.59117 2571.7 11.72 28 25.1048 3.54433 1084.58 6.78 29 25.3457 3.51118 1178.74 4.84 30 25.5582 3.48246 567.17 1.38 31 26.6289 3.34483 3771.59 18.38 32 26.842 3.31875 1603.75 5.43 33 26.9627 3.30416 2098.16 13.01 34 27.2087 3.27485 862.91 12.33 35 27.9475 3.18993 7483.08 31.47 36 28.2373 3.15785 6180.38 26.6 37 28.4273 3.13718 4393.75 24.02 38 28.991 3.07745 1304.24 16.97 39 29.5089 3.02461 2219.41 16.2 40 29.7641 2.99925 1589.71 9.27 41 29.9038 2.98555 1332.73 11.01 42 30.8447 2.89659 1328.55 5.14 43 31.1249 2.87115 846.5 2.94 44 31.3829 2.84813 1284.97 3.86 45 32.7435 2.73283 1299.62 9.56 46 33.2809 2.68992 1110.71 3.77 47 33.4806 2.67432 1371.34 5.11 48 34.0381 2.63179 868.41 3.68 49 34.7889 2.57669 404.6 7.43 50 35.14 2.55174 1963.14 10.98 51 35.6794 2.51439 1188.88 5.31 52 36.2797 2.47415 642.79 4.75 53 36.6985 2.44688 1037.1 5.49 54 37.2998 2.4088 636.75 2.79 55 37.7636 2.38028 505.16 3.48 56 38.9614 2.30981 546.34 1.46 57 39.3733 2.28659 426.2 2.55 58 39.7446 2.26608 282.9 1.15

[00791] In other representations, image C4 also features, or alternatively features, a DSC thermometer very similar to that shown in Figure 178. In other representations, image C4 also features, or alternatively features, a TGA thermometer very similar to that shown in Figure 178. In other representations, image C4 also features, or alternatively features, TGA and DSC thermometers very similar to those shown in Figure 178. In other representations, image C4 also features, or alternatively features, a TGA thermometer with two weight loss steps: 4.4% at 75 °C (approx. 0.5 IPA equivalents) and an additional 2.1% at 125 °C (approx. 0.2 IPA equivalents). In other representations, image C4 also features, or alternatively features, a DSC thermometer with several overlapping heat absorption states with peaks at 68 °C (wide) and 130 °C (double heat absorption), with a clear start of dissociation after the last heat absorption.

[00792] In other incarnations, the C4 image also features, or alternatively features, a spectrum 1 H NMR is very similar to that shown in Figure 177.

[00793] Another aspect of the current detection relates to the rhisometrum dichloroacetic acid co-crystal, image C5. In some representations, image C5 features an XRPD pattern that includes peaks at 3.5° ± 0.2°, 6.9° ± 0.2°, 10.3° ± 0.2°, 13.7° ± 0.2°, and 17.2° ± 0.2° 2-theta. In some representations, image C5 features an XRPD pattern that includes any three, four, or five peaks selected from 3.5° ± 0.2°, 6.9° ± 0.2°, 10.3° ± 0.2°, 13.7° ± 0.2°, and 17.2° ± 0.2° 2-theta. In some representations, the XRPD pattern of image C5 also includes one or more additional peaks from Table C5 less than ±0.2° 2-theta. In other representations, image C5 also or alternatively features an XRPD pattern very similar to that shown in Figure 179. In still other representations, image C5 also or alternatively features an XRPD pattern with peaks very similar to those presented in Table C5 less than ±0.2° 2-theta. Table C5 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 3.4511 25.58093 14898.62 42.77 2 6.8779 12.84154 36701.69 100 3 10.3113 8.572 25333.87 59.04 4 11.914 7.42227 605.93 1.96 5 12.1102 7.30245 872.05 2.39 6 13.7568 6.43187 13014.53 31.58 7 13.8721 6.37867 2288.98 6.53 8 14.3149 6.18232 583.48 1.9 9 15.5631 5.68919 1715.74 4.91 10 17.2099 5.14833 17391.34 35.91 11 17.6458 5.02212 1484.29 17.1 12 18.1643 4.87992 999 2.82 13 18.975 4.67322 2927.02 11.41 14 19.3637 4.58028 3873.19 11.96 15 19.5949 4.52673 4027.44 11.54 16 19.7382 4.4942 2114.48 6.35 17 20.0838 4.41765 8676.18 27.84 18 20.6918 4.28918 560.83 0.89 19 20.8908 4.24878 498.86 1.98 20 21.5949 4.1118 1076.28 4.19 21 22.1406 4.01168 3740.36 11.82 22 22.7221 3.91032 2695.21 6.5 23 23.1472 3.83946 5468.96 20.51 24 23.8142 3.73341 2798.11 11.92 25 23.9408 3.71395 3221.06 13.84 26 24.2097 3.67331 936.41 2.71 27 24.3733 3.64902 3585.55 11.38 28 24.5021 3.63012 3181.48 11.93 29 24.8841 3.57525 1034.58 3.48 30 25.0516 3.55173 3168.92 10.97 31 25.9703 3.42813 507.45 1.1 32 26.3112 3.38448 3202.7 10.83 33 26.6386 3.34362 473.98 0.9 34 27.2874 3.26559 822.15 2.14 35 27.7066 3.21711 1197.9 2.5 36 28.0226 3.18156 4566.78 14.62 37 28.1932 3.16268 856.38 3.74 38 28.3486 3.14571 1303.11 3.27 39 29.2367 3.05214 1269.14 5.94 40 29.4214 3.0334 1637.5 10.47 41 29.976 2.97852 1095.54 7.86 42 31.2608 2.85898 1007.39 3.09 43 31.3496 2.85108 765.3 3.82 44 31.8788 2.80495 938.72 5.77 45 32.3037 2.76902 1994.52 7.75 46 32.5057 2.75227 938.01 3.2 47 32.7188 2.73483 912.41 5.07 48 34.1293 2.62496 900.17 4.41 49 34.8415 2.57292 4774.16 16.13 50 35.868 2.5016 476.97 3.08 51 36.3477 2.46968 503.12 2.87 52 36.8015 2.44026 936.64 2.77 53 37.3021 2.40865 468.91 4.06 54 37.9901 2.3666 1568.55 4.15 55 38.4547 2.33907 644.05 1.7 56 39.6403 2.2718 437.41 2.07 57 39.7744 2.26445 878.31 2.48

[00794] In other representations, image C5 also or alternatively features a DSC thermometer very similar to that shown in Figure 181. In other representations, image C5 also or alternatively features a TGA thermometer very similar to that shown in Figure 181. In other representations, image C5 also or alternatively features TGA and DSC thermometers very similar to those shown in Figure 181. In other representations, image C5 also or alternatively features a TGA thermometer with approximately 37.8% weight loss at approximately 200 °C and subsequent decomposition onset at 339 °C. In other representations, image C5 also or alternatively features a DSC thermometer with major heat absorption at approximately 106 °C (onset), minor broad heat absorption at approximately 186 °C (peak), and major heat absorption at approximately 319 °C (onset).

[00795] In other incarnations, image C5 also features, or alternatively features, a spectrum 1 The 1H NMR is very similar to that shown in Figure 180. In other representations, image C5 also or alternatively has an FTIR spectrum very similar to the FTIR spectrum of image C5 shown in Figure 182. In other representations, image C5 also or alternatively has a Raman spectrum very similar to the Raman spectrum of image C5 shown in Figure 183.

[00796] Another aspect of the current discovery relates to the rhisometrum diethylamine co-crystal, image C6. In some representations, image C6 exhibits an XRPD pattern involving peaks at 10.0° ± 0.2°, 12.2° ± 0.2°, 13.1° ± 0.2°, 22.2° ± 0.2°, and 22.8° ± 0.2° 2-theta. In some representations, image C6 exhibits an XRPD pattern involving any three, four, or five peaks selected from 10.0° ± 0.2°, 12.2° ± 0.2°, 13.1° ± 0.2°, 22.2° ± 0.2°, and 22.8° ± 0.2° 2-theta. In some representations, the XRPD pattern of image C6 also includes one or more additional peaks from Table C6 less than ±0.2° 2-theta. In other representations, image C6 also or alternatively features an XRPD pattern very similar to that shown in Figure 184. In still other representations, image C6 also or alternatively features an XRPD pattern with peaks very similar to those presented in Table C6 less than ±0.2° 2-theta. Table C6 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 5.2971 16.66952 956.19 6.93 2 10.0353 8.80712 10048.41 48.75 3 10.5941 8.34385 748.1 2.95 4 11.3562 7.78556 2933.07 13.66 5 11.6624 7.58182 618.08 1.97 6 12.201 7.24827 10453.06 51.23 7 12.8627 6.87684 8532 42.44 8 13.0877 6.75913 13507.33 62.99 9 13.5181 6.54488 703.62 2.69 10 14.9977 5.90237 417.24 1.56 11 15.9405 5.55533 1657.11 7.27 12 16.1198 5.49393 972.38 8.09 13 16.4983 5.36874 988.85 4.26 14 17.816 4.97451 2691.05 15.33 15 19.5738 4.53159 2042.05 13.69 16 20.1002 4.41407 7413.88 49.48 17 20.5808 4.31207 2067.3 8.2 18 21.0706 4.21292 779.55 2 19 21.3142 4.16532 2264.18 13.97 20 21.831 4.06787 713.14 1.49 21 22.157 4.00876 12628.99 61.1 22 22.7951 3.89796 16857.94 100 23 23.2212 3.82739 2627.77 10.72 24 23.4978 3.78295 2030.34 8.4 25 23.7006 3.75104 2169.77 10.18 26 24.0386 3.69905 3784.33 24.57 27 24.3971 3.64551 5226.85 51.43 28 24.6639 3.60667 2076.74 12.18 29 25.3796 3.50657 1219.38 5.27 30 25.6402 3.47152 1412.87 6.03 31 25.8604 3.44245 1943.82 8.18 32 26.222 3.3958 671.53 2.01 33 26.72 3.33362 1823.98 7.83 34 26.9607 3.30441 1500.07 5.82 35 27.5673 3.23306 7351.27 57.33 36 27.9076 3.19441 870.6 6.47 37 28.4923 3.13016 2089.22 14.3 38 28.6246 3.11599 2068.34 12.37 39 28.8681 3.09026 1242.14 7.72 40 29.2654 3.04921 590.16 2.03 41 29.9528 2.98078 559.87 3.61 42 30.4643 2.93188 1249.74 7.9 43 30.9511 2.88687 835.55 3.82 44 32.9726 2.71435 1417.52 12.43 45 33.4488 2.67679 1437.79 8.58 46 34.0547 2.63054 505.85 2.13 47 34.5804 2.59175 668.49 10.5 48 35.3935 2.53405 964.15 12.11 49 35.9588 2.49549 520.72 3.57 50 36.6043 2.45295 460.98 2.73 51 37.6447 2.38752 1029.39 7.36 52 38.2271 2.35247 723.81 5.14 53 38.4998 2.33643 392.41 1.68 54 39.2005 2.29627 801.46 3.68 55 39.9227 2.25638 390.97 1.63

[00797] Another aspect of the current detection relates to the rhizometrum salt, 4-aminopyridine, image C7. In some representations, image C7 features an XRPD pattern that includes peaks at 4.5° ± 0.2°, 8.9° ± 0.2°, 24.5° ± 0.2°, 27.3° ± 0.2°, and 16.9° ± 0.2° 2-theta. In some representations, image C7 features an XRPD pattern that includes any three, four, or five peaks selected from 4.5° ± 0.2°, 8.9° ± 0.2°, 24.5° ± 0.2°, 27.3° ± 0.2°, and 16.9° ± 0.2° 2-theta. In some representations, the XRPD pattern of image C7 also includes one or more additional peaks from Table C7 less than ±0.2° 2-theta. In other representations, image C7 also or alternatively features an XRPD pattern very similar to that shown in Figure 185. In still other representations, image C7 also or alternatively features an XRPD pattern with peaks very similar to those presented in Table C7 less than ±0.2° 2-theta. Table C7 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 4.4968 19.63459 5394.36 46.04 2 8.916 9.9101 10862.26 100 3 10.4586 8.45162 651.07 5.76 4 11.3466 7.79211 671.17 10.31 5 11.7719 7.5115 1096.16 17.91 6 13.4936 6.5567 2050.08 14.97 7 14.9666 5.91455 253.9 17.51 8 15.5118 5.7079 663.98 11.36 9 16.6027 5.33523 2135.36 24.32 10 16.9116 5.23845 1742.49 51.75 11 17.5071 5.06159 2399.38 25.68 12 19.2074 4.61718 679.33 8.17 13 20.6392 4.29999 857.59 10.58 14 21.4114 4.14664 737.24 6.01 15 22.4511 3.9569 800.23 15.59 16 23.5027 3.78218 1491.64 24.98 17 24.5506 3.62306 4901.5 88.91 18 26.2463 3.39271 1079.75 13.87 19 27.3535 3.25784 2638.14 61.44 20 28.7129 3.10662 799.05 12.02 21 31.7118 2.81934 364.03 24.05

[00798] In other representations, image C7 also or alternatively features a DSC thermometer very similar to that shown in Figure 187. In other representations, image C7 also or alternatively features a TGA thermometer very similar to that shown in Figure 187. In other representations, image C7 also or alternatively features TGA and DSC thermometers very similar to those shown in Figure 187. In other representations, image C7 also or alternatively features a TGA thermometer that includes approximately 1.1% weight loss at 100 °C, an additional 2.2% weight loss at 225 °C, and the onset of decomposition at 255 °C. In other incarnations, the C7 image also features, or alternatively features, a DSC thermometer that includes a simple broad heat absorption at 76°C (peak), a simple heat absorption at 178°C (peak) overlaid with heat ejection at 181°C (beginning), followed by a broad heat absorption at 216°C (peak) and a sharp principal heat absorption at 267°C (beginning).

[00799] In other incarnations, image C7 also features, or alternatively features, a spectrum 1 The 1H NMR is very similar to that shown in Figure 186. In other representations, image C7 also or alternatively has an FTIR spectrum very similar to the FTIR spectrum of image C7 shown in Figure 188. In other representations, image C7 also or alternatively has a Raman spectrum very similar to the Raman spectrum of image C7 shown in Figure 189.

[00800] Another aspect of the current detection relates to the resmetrium imidazole salt, image C8. In some representations, image C8 features an XRPD pattern that includes peaks at 6.3° ± 0.2°, 7.3° ± 0.2°, 17.4° ± 0.2°, 21.9° ± 0.2°, and 22.3° ± 0.2° 2-theta. In some representations, image C8 features an XRPD pattern that includes any three, four, or five peaks selected from 6.3° ± 0.2°, 7.3° ± 0.2°, 17.4° ± 0.2°, 21.9° ± 0.2°, and 22.3° ± 0.2° 2-theta. In some representations, the XRPD pattern of image C8 also includes one or more additional peaks from Table C8 that are less than ± 0.2° 2-theta. In other representations, image C8 also or alternatively features an XRPD pattern that is substantially similar to that shown in Figure 190. In still other representations, image C8 also or alternatively features an XRPD pattern with peaks that are substantially as presented in Table C8 that are less than ± 0.2° 2-theta. Table C8 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 6.2524 14.12472 3005.04 14.58 2 7.0862 12.4645 4809.14 27.85 3 7.3455 12.02511 8640.74 36.84 4 8.6787 10.18049 1756.62 8.2 5 10.3378 8.5501 569.97 6.24 6 12.9882 6.81068 2588.75 12.26 7 14.0702 6.2893 1703.76 8.4 8 14.4565 6.12208 2916.63 12.87 9 15.7439 5.62426 2342.27 8.12 10 15.9734 5.54396 2763.27 13.52 11 17.4447 5.07955 17484.1 100 12 19.1315 4.63533 1677.97 17.6 13 20.5562 4.31717 1229.52 8.28 14 21.2516 4.17744 1315.99 8.79 15 21.9175 4.052 9895.77 54.81 16 22.3273 3.97855 4961.51 37.18 17 22.7788 3.9007 3978.35 17 18 23.1023 3.84681 749.57 5.35 19 23.9212 3.71695 2296.43 8.15 20 24.32 3.65689 1810.96 6.88 21 24.6027 3.61552 2213.63 6.31 22 25.5351 3.48557 4733.93 36.97 23 25.9072 3.43634 1459.28 8.23 24 26.78 3.32629 886.59 3.55 25 27.1031 3.28737 1957.23 6.56 26 27.284 3.26598 1260.48 4.17 27 27.8688 3.19876 566.33 4.14 28 28.2819 3.15297 2235.96 8.73 29 29.0381 3.07256 3622.15 16.34 30 29.4019 3.03537 816.08 4.67 31 29.7999 2.99572 2357.71 10.22 32 30.1602 2.96076 1355.01 8.49 33 30.5964 2.91953 1061.22 5 34 30.9424 2.88767 857.8 4.12 35 31.6997 2.82038 716.21 2.58 36 32.2004 2.77766 792.45 3.07 37 33.7749 2.65169 1717.39 12.67 38 34.8224 2.57428 1682.15 10.95 39 35.3445 2.53745 250.46 1.79 40 37.7409 2.38165 422.24 2.84

[00801] In other renderings, image C8 also or alternatively features a DSC thermometer very similar to that shown in Figure 192. In other renderings, image C8 also or alternatively features a TGA thermometer very similar to that shown in Figure 192. In other renderings, image C8 also or alternatively features TGA and DSC thermometers very similar to those shown in Figure 192. In other renderings, image C8 also or alternatively features a TGA thermometer that includes approximately 3.1% weight loss at 175°C and approximately 13.4% additional weight loss at approximately 275°C. In other renderings, image C8 also or alternatively features a DSC thermometer that includes heat expulsion events at 150°C (start) and at 231°C (start).

[00802] In other incarnations, image C8 also features, or alternatively features, a spectrum 1 The 1H NMR is very similar to that shown in Figure 191. In other representations, image C8 also or alternatively has an FTIR spectrum very similar to the FTIR spectrum of image C8 shown in Figure 193. In other representations, image C8 also or alternatively has a Raman spectrum very similar to the Raman spectrum of image C8 shown in Figure 194.

[00803] Another aspect of the current detection of prismmeterum tromethamine salt, image C9, is shown. In some inscriptions, image C9 features an XRPD pattern that includes peaks at 7.3° ± 0.2°, 9.0° ± 0.2°, 20.2° ± 0.2°, 21.1° ± 0.2°, and 22.5° ± 0.2° 2-theta. In some inscriptions, image C9 features an XRPD pattern that includes any three, four, or five peaks selected from 7.3° ± 0.2°, 9.0° ± 0.2°, 20.2° ± 0.2°, 21.1° ± 0.2°, and 22.5° ± 0.2° 2-theta. In some representations, the XRPD pattern of image C9 also includes one or more additional peaks from Table C9 less than ±0.2° 2-theta. In other representations, image C9 also or alternatively features an XRPD pattern very similar to that shown in Figure 195. In still other representations, image C9 also or alternatively features an XRPD pattern with peaks very similar to those presented in Table C9 less than ±0.2° 2-theta. Table C9 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 7.3512 12.01577 13097.05 2.93 2 8.0985 10.9086 3557.41 0.92 3 8.7713 10.07325 3101.57 0.67 4 8.9951 9.8231 7924.58 2.06 5 11.1154 7.95367 4332.3 1.16 6 13.4438 6.58088 195.72 0.03 7 14.2038 6.23046 3649.25 0.67 8 16.4904 5.3713 2546.23 1.5 9 16.732 5.29427 6407.22 1.19 10 17.1762 5.15834 3898.19 1.34 11 17.5949 5.03654 605.15 0.42 12 18.0216 4.91823 3108.23 0.74 13 18.2299 4.86249 2724.72 0.46 14 18.4071 4.81608 7067.73 1.51 15 19.2779 4.60047 3095.98 0.96 16 19.6314 4.51842 2335.22 0.68 17 20.1896 4.39474 574584 100 18 20.6108 4.30586 1554.1 0.36 19 21.1344 4.20036 10878.77 3.39 20 21.2529 4.1772 4419.81 0.99 21 21.6364 4.10402 8282.58 2.15 22 22.0944 4.01996 1015.2 0.73 23 22.5817 3.9343 21917.72 3.75 24 22.7283 3.90926 2576.55 1.03 25 23.2806 3.81775 6072.32 1.62 26 23.3777 3.80212 4980.11 1.41 27 24.1897 3.6763 1816.71 0.31 28 24.8801 3.57582 5794.71 1.32 29 25.218 3.52867 1445.35 0.22 30 25.3851 3.50582 1178.21 0.21 31 25.5263 3.48674 808.96 0.45 32 25.7 3.46357 1448.52 0.22 33 26.1444 3.4057 692.62 0.16 34 26.3835 3.37537 542.39 0.11 35 26.6178 3.3462 2028.37 0.31 36 26.9642 3.30398 1441.77 1.46 37 27.1471 3.28214 6605.28 1.23 38 27.9199 3.19302 3105.96 0.78 39 28.1809 3.16404 1750.19 0.39 40 28.3544 3.14507 2670.28 0.48 41 28.9084 3.08605 2151.67 0.53 42 29.0958 3.0666 1521.36 0.4 43 29.6323 3.01229 1755.39 0.32 44 29.9566 2.98041 687.13 0.12 45 30.1664 2.96016 1002.8 0.18 46 31.3726 2.84904 1365.64 0.25 47 32.1245 2.78405 1144.62 0.33 48 32.7628 2.73126 485.35 0.08 49 33.1783 2.698 759.38 0.12 50 33.4113 2.67971 787.78 0.19 51 33.6996 2.65745 1205.27 0.19 52 34.0362 2.63193 1639.99 0.34 53 34.1975 2.61988 1986.11 0.45 54 34.8657 2.57119 423.7 0.17 55 35.436 2.5311 718.19 0.17 56 36.0916 2.48662 688.05 0.26 57 36.4068 2.46581 871.63 0.21 58 37.2686 2.41074 2450.5 0.65 59 37.7721 2.37976 437.11 0.13 60 38.517 2.33543 1978.08 0.57

[00804] In other representations, image C9 also or alternatively features a DSC thermometer very similar to that shown in Figure 197. In other representations, image C9 also or alternatively features a TGA thermometer very similar to that shown in Figure 197. In other representations, image C9 also or alternatively features TGA and DSC thermometers very similar to those shown in Figure 197. In other representations, image C9 also or alternatively features a TGA thermometer with approximately 6.5% weight loss at about 130 °C, followed by the onset of apparent disintegration at about 184 °C. In other representations, image C9 also or alternatively features a DSC thermometer with broad and sharp heat absorption at 104 °C and 134 °C (onset), respectively, preceded by a slight heat absorption with a peak at 87 °C.

[00805] In other incarnations, the C9 image also features, or alternatively features, a spectrum 1 H NMR is very similar to that shown in Figure 196.

[00806] Another aspect of the current detection relates to a morphological image, image N1, of rhymetime. Image N1 is the solute of methyl ethyl ketone (MEK). In some embodiments, image N1 exhibits an XRPD pattern that includes peaks at 10.9° ± 0.2°, 14.3° ± 0.2°, 17.0° ± 0.2°, 21.9° ± 0.2°, and 24.5° ± 0.2° 2-theta. In some embodiments, image N1 exhibits an XRPD pattern that includes any three, four, or five peaks selected from 10.9° ± 0.2°, 14.3° ± 0.2°, 17.0° ± 0.2°, 21.9° ± 0.2°, and 24.5° ± 0.2°. In some representations, the XRPD pattern of image N1 also includes one or more additional peaks from Table N1 less than ±0.2° 2-theta. In other representations, image N1 also or alternatively features an XRPD pattern very similar to that shown in Figure 198. In still other representations, image N1 also or alternatively features an XRPD pattern with peaks very similar to those presented in Table N1 less than ±0.2° 2-theta. Table N1 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 7.6195 11.59325 227.8 5.14 2 10.0757 8.77197 939.47 44.32 3 10.3428 8.54599 1278.89 15.51 4 10.8609 8.13944 3804.94 100 5 11.1045 7.96141 314.81 40.83 6 12.0455 7.34153 1613.84 50.39 7 13.1234 6.74086 819.86 19.74 8 13.8041 6.40995 1153.6 24.01 9 14.3283 6.17658 895.51 86.51 10 16.3568 5.41487 811.19 32.49 11 17.0277 5.20299 1731.67 94.67 12 18.1418 4.88592 289.14 28.46 13 19.4874 4.55148 1154.73 57.04 14 21.8941 4.05628 1031.23 95.25 15 23.626 3.76272 1020.71 43.47 16 24.4653 3.6355 2134.48 94.84 17 26.8413 3.31883 389.12 13.02 18 27.7525 3.2119 363.06 21.59 19 29.3571 3.0399 1668.9 73.24

[00807] In other incarnations, image N1 also features, or alternatively features, a spectrum 1 H NMR is very similar to that shown in Figure 199.

[00808] Another aspect of the current detection relates to a morphological image, image N2, of rhizometrum. Image N2 is an undissolved image. In some embodiments, image N2 exhibits an XRPD pattern that includes peaks at 14.5° ± 0.2°, 15.3° ± 0.2°, 23.8° ± 0.2°, 24.6° ± 0.2°, and 25.3° ± 0.2° 2-theta. In some embodiments, image N2 exhibits an XRPD pattern that includes any three, four, or five peaks selected from 14.5° ± 0.2°, 15.3° ± 0.2°, 23.8° ± 0.2°, 24.6° ± 0.2°, and 25.3° ± 0.2° 2-theta. In some representations, the XRPD pattern of image N2 also includes one or more additional peaks from Table N2 less than ±0.2° 2-theta. In other representations, image N2 also or alternatively features an XRPD pattern very similar to that shown in Figure 200. In still other representations, image N2 also or alternatively features an XRPD pattern with peaks very similar to those presented in Table N2 less than ±0.2° 2-theta. Table N2 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 6.2663 14.09334 2852.02 32.67 2 7.8732 11.2202 705.29 8.09 3 10.3922 8.50549 2528.98 24.35 4 14.535 6.08919 2143.29 43.99 5 15.3228 5.77788 2674.8 37.85 6 16.5117 5.36443 235.66 9.16 7 17.0883 5.18469 190.66 1.43 8 17.4241 5.08551 302.66 4.03 9 18.0852 4.90107 3321.2 47.44 10 19.6774 4.50795 1234.89 46.91 11 20.5752 4.31322 1913.72 34.23 12 20.9718 4.23255 2028.86 25.11 13 23.2086 3.82944 1766.15 42.79 14 23.8044 3.73492 2148.36 49.74 15 24.598 3.61619 3544.84 89.23 16 25.3153 3.51532 4617.71 100 17 26.0942 3.41214 353.47 5.67 18 27.0614 3.29233 363.11 4.07 19 28.5772 3.12106 432.66 9.95 20 30.0278 2.9735 625.61 10.38 21 31.6802 2.82208 510.09 7.54 22 33.0301 2.70977 437.49 11.47 23 38.8411 2.31668 130.71 4.5

[00809] In other incarnations, the N2 image also features, or alternatively features, a spectrum 1 The 1H NMR is very similar to that shown in Figure 201. In other representations, image N2 also features, or alternatively features, a DSC thermometer very similar to that shown in Figure 202. In other representations, image N2 also features, or alternatively features, a TGA thermometer very similar to that shown in Figure 202. In other representations, image N2 also features, or alternatively features, TGA and DSC thermometers very similar to those shown in Figure 202.

[00810] Another aspect of the current detection relates to a morphological image, image N3, of rhysmetrum. Image N3 is an acetylacetone solute. In some embodiments, image N3 exhibits an XRPD pattern that includes peaks at 8.0° ± 0.2°, 9.9° ± 0.2°, 10.7° ± 0.2°, 11.4° ± 0.2°, and 13.7° ± 0.2° 2-theta. In some embodiments, image N3 exhibits an XRPD pattern that includes any three, four, or five peaks selected from 8.0° ± 0.2°, 9.9° ± 0.2°, 10.7° ± 0.2°, 11.4° ± 0.2°, and 13.7° ± 0.2° 2-theta. In some representations, the XRPD pattern of image N3 also includes one or more additional peaks from Table N3 less than ±0.2° 2-theta. In other representations, image N3 also or alternatively features an XRPD pattern very similar to that shown in Figure 203. In still other representations, image N3 also or alternatively features an XRPD pattern with peaks very similar to those presented in Table N3 less than ±0.2° 2-theta. Table N3 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 0.8029 109.9342 13255.92 100 2 8.052 10.97144 1941.45 0.59 3 9.8654 8.95843 1918.38 0.54 4 10.7384 8.23202 1710.24 0.45 5 11.3642 7.78007 1652.69 0.51 6 13.6705 6.47226 3138.35 0.53 7 14.688 6.02614 733.35 0.14 8 15.3982 5.74976 531.38 0.1 9 16.7155 5.29946 635.32 0.12 10 16.9352 5.2312 1285.42 0.3 11 17.1356 5.1705 1834.66 0.64 12 17.4816 5.06893 311.92 0.27 13 17.8233 4.97249 1741.08 0.35 14 17.9328 4.94238 1669.72 0.4 15 18.089 4.90005 1025 0.41 16 18.584 4.77065 177.41 0.07 17 19.3373 4.58646 1761.37 0.32 18 19.5881 4.52829 752.74 0.09 19 19.7425 4.49323 790.84 0.34 20 20.0959 4.41501 498.21 0.14 21 20.7634 4.27456 843.34 0.19 22 21.5241 4.12518 416.29 0.05 23 21.9276 4.05017 1177.93 0.23 24 22.3843 3.96855 544.66 0.12 25 22.5487 3.93998 962.21 0.14 26 22.8701 3.88534 1861.79 0.6 27 23.4626 3.78855 571.89 0.09 28 23.6586 3.75761 1187.86 0.31 29 23.7975 3.73599 807.83 0.08 30 24.1026 3.68939 2275.47 0.35 31 24.3013 3.65966 520.61 0.12 32 24.572 3.61996 665.76 0.08 33 24.8865 3.57492 501.17 0.24 34 25.251 3.52413 516.61 0.16 35 26.0039 3.42378 678.55 0.16 36 26.3744 3.37652 515.35 0.06 37 26.9439 3.30643 870.97 0.16 38 27.24 3.27116 913.7 0.4 39 27.5016 3.24063 1037.98 0.18 40 28.1013 3.17282 450.67 0.06 41 28.5053 3.12877 877.34 0.16 42 29.1372 3.06233 672.38 0.1 43 29.4506 3.03045 636.92 0.14 44 29.6446 3.01106 380.14 0.13 45 29.8929 2.98662 685.66 0.27 46 32.6436 2.74096 722.41 0.22 47 32.8698 2.72261 330.99 0.05 48 33.101 2.70412 284.88 0.06 49 34.1844 2.62086 577.23 0.19 50 37.5755 2.39176 278.69 0.07 51 37.9901 2.3666 611 0.12

[00811] In other incarnations, the N3 image also features, or alternatively features, a spectrum 1 H NMR is very similar to that shown in Figure 204.

[00812] Another aspect of the current detection relates to a morphological image, image N4, of rhizometrum. Image N4 is the solute of methyl ethyl ketone (MEK). In some embodiments, image N4 exhibits an XRPD pattern that includes peaks at 10.0° ± 0.2°, 10.9° ± 0.2°, 23.5° ± 0.2°, 24.1° ± 0.2°, and 24.5° ± 0.2° 2-theta. In other embodiments, image N4 exhibits an XRPD pattern that includes any three, four, or five peaks selected from 10.0° ± 0.2°, 10.9° ± 0.2°, 23.5° ± 0.2°, 24.1° ± 0.2°, and 24.5° ± 0.2° 2-theta. In some representations, the XRPD pattern of image N4 also includes one or more additional peaks from Table N4 less than ±0.2° 2-theta. In other representations, image N4 also or alternatively features an XRPD pattern very similar to that shown in Figure 205. In still other representations, image N4 also or alternatively features an XRPD pattern with peaks very similar to those presented in Table N4 less than ±0.2° 2-theta. Table N4 Number 2-Theta (degree) d (angstrom) Height (centi-poise) Relative intensity I 1 3.3394 26.4363 985.77 3.77 2 6.6734 13.23459 835.05 11.91 3 10.0176 8.82271 8815.3 51.97 4 10.684 8.27379 5027.56 32.57 5 10.9303 8.08...

Claims

1. A method of treating nonalcoholic steatohepatitis (NASH), comprising:determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject is determined to weigh less than 100 kg. 2. The method according to claim 1, wherein the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 100 mg per day. 3. The method according to claim 1, wherein the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 80 mg per day. 4. The method according to any one of the preceding claims, wherein the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3. 5. The method according to any one of the preceding claims, wherein the method is of improving noncirrhotic nonalcoholic steatohepatitis. 6. The method according to any one of the preceding claims, wherein the solid oral dosage form comprises resmetirom. 7. A method of treating liver fibrosis comprising:determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject is determined to weigh less than 100 kg; andwherein the human subject has liver fibrosis associated with nonalcoholic steatohepatitis (NASH). 8. The method according to claim 7, wherein the method is of improving the liver fibrosis. 9. The method according to claim 7 or 8, wherein the human subject has liver fibrosis characterized as fibrosis stage F2. 10. The method according to claim 7 or 8, wherein the human subject has liver fibrosis characterized as fibrosis stage F3. 11. The method according to any one of claims 8-10, wherein the method is of improving the liver fibrosis by one stage in the human subject. 12. The method according to claim 10, wherein the method is of improving the liver fibrosis by two stages in the human subject. 13. The method according to any one of claims 7-12, wherein the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 100 mg per day. 14. The method according to any one of claims 7-12, wherein the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 80 mg per day. 15. The method according to any one of claims 7-14, wherein the solid oral dosage form comprises resmetirom. 16. The method according to any one of claims 1-15, wherein the solid oral dosage form is a tablet. 17. The method according to any one of claims 1-16, wherein the human subject is an adult human subject. 18. A method of treating noncirrhotic nonalcoholic steatohepatitis (NASH), comprising:determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject is determined to weigh 100 kg or more and the human subject is using a moderate CYP2C8 inhibitor; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject is determined to weigh less than 100 kg and the human subject is using a moderate CYP2C8 inhibitor. 19. The method according to claim 18, wherein the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 80 mg per day. 20. The method according to claim 18, wherein the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 60 mg per day. 21. The method according to claim 19, wherein the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 100 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 100 mg per day is reduced to the reduced dosage of 80 mg per day. 22. The method according to claim 20, wherein, the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 80 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 80 mg per day is reduced to the reduced dosage of 60 mg per day. 23. The method according to any one of claims 18-22, wherein the moderate CYP2C8 inhibitor is selected from the group consisting of rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, crisaborole, nabilone, bexarotene, ritonavir, nicardipine, loratadine, eltrombopag, diltiazem, enzalutamide, ketoconazole, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate, spironolactone, amlodipine, saquinavir, abiraterone, genistein, lenvatinib, pioglitazone, clotrimazole, nilotinib, teriflunomide, topiroxostat, lovastatin, troglitazone, amitriptyline, pirtobrutinib, belinostat, bezafibrate, candesartan, cholecalciferol, cimetidine, colchicine, dabrafenib, deferasirox, diethylstilbestrol, enasidenib, erlotinib, ethinylestradiol, fenofibrate, gemfibrozil, idelalisib, isoniazid, ketoprofen, letermovir, lumacaftor, mefenamic acid, midostaurin, montelukast, nilutamide, opicapone, phenelzine, piroxicam, pyrimethamine, quercetin, raloxifene, repaglinide, rifampicin, rofecoxib, salmeterol, sorafenib, sulfaphenazole, tegaserod, terbinafine, terfenadine, thiazolidinediones, ticlopidine, trametinib, triazolam, troleandomycin, valproic acid, verapamil, vismodegib, clopidogrel, and zafirlukast. 24. The method according to any one of claims 18-22, wherein the moderate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and / or pioglitazone. 25. The method according to any one of claims 18-24, wherein the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3. 26. The method according to any one of claims 18-25, wherein the method is of improving noncirrhotic nonalcoholic steatohepatitis. 27. The method according to any one of claims 18-26, wherein the solid oral dosage form comprises resmetirom. 28. The method according to any one of claims 18-27, wherein the solid oral dosage form is a tablet. 29. The method according to any one of claims 18-28, wherein the human subject is an adult human subject. 30. A method of treating liver fibrosis comprising:determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject is determined to weigh 100 kg or more and the human subject is using a moderate CYP2C8 inhibitor; or  (ii)  resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject is determined to weigh less than 100 kg and the human subject is using a moderate CYP2C8 inhibitor; andwherein the human subject has liver fibrosis associated with nonalcoholic steatohepatitis (NASH). 31. The method according to claim 30, wherein the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 80 mg per day. 32. The method according to claim 30, wherein the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 60 mg per day. 33. The method according to claim 31, wherein the human subject used the resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 100 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 100 mg per day is reduced to the reduced dosage of 80 mg per day. 34. The method according to claim 32, wherein the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 80 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 80 mg per day is reduced to the reduced dosage of 60 mg per day. 35. The method according to any one of claims 30-34, wherein the method is of improving the liver fibrosis. 36. The method according to any one of claims 30-35, wherein the human subject has liver fibrosis characterized as fibrosis stage F2. 37. The method according to any one of claims 30-35, wherein the human subject has liver fibrosis characterized as fibrosis stage F3. 38. The method according to any one of claims 35-37, wherein the method is of improving the liver fibrosis by one stage in the human subject. 39. The method according to claim 36, wherein the method is of improving the liver fibrosis by two stages in the human subject. 40. The method according to any one of claims 30-39, wherein the moderate CYP2C8 inhibitor is selected from the group consisting of rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, crisaborole, nabilone, bexarotene, ritonavir, nicardipine, loratadine, eltrombopag, diltiazem, enzalutamide, ketoconazole, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate, spironolactone, amlodipine, saquinavir, abiraterone, genistein, lenvatinib, pioglitazone, clotrimazole, nilotinib, teriflunomide, topiroxostat, lovastatin, troglitazone, amitriptyline, pirtobrutinib, belinostat, bezafibrate, candesartan, cholecalciferol, cimetidine, colchicine, dabrafenib, deferasirox, diethylstilbestrol, enasidenib, erlotinib, ethinylestradiol, fenofibrate, gemfibrozil, idelalisib, isoniazid, ketoprofen, letermovir, lumacaftor, mefenamic acid, midostaurin, montelukast, nilutamide, opicapone, phenelzine, piroxicam, pyrimethamine, quercetin, raloxifene, repaglinide, rifampicin, rofecoxib, salmeterol, sorafenib, sulfaphenazole, tegaserod, terbinafine, terfenadine, thiazolidinediones, ticlopidine, trametinib, triazolam, troleandomycin, valproic acid, verapamil, vismodegib, clopidogrel, and zafirlukast. 41. The method according to any one of claims 30-39, wherein the moderate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and / or pioglitazone. 42. The method according to any one of claims 30-41, wherein the solid oral dosage form comprises resmetirom. 43. The method according to any one of claims 30-42, wherein the solid oral dosage form is a tablet. 44. The method according to any one of claims 30-43, wherein the human subject is an adult human subject. 45. Resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating nonalcoholic steatohepatitis (NASH), the method comprising:determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject is determined to weigh less than 100 kg. 46. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 45, wherein the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3. 47. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 45, wherein the method is of improving noncirrhotic nonalcoholic steatohepatitis. 48. Resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating liver fibrosis, the method comprising:determining a weight of a human subject; and based on determination of the weight of the human subject, administering orally to the human subject a solid oral dosage form comprising:(i) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject is determined to weigh less than 100 kg; andwherein the human subject has liver fibrosis associated with nonalcoholic steatohepatitis (NASH). 49. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 48, wherein the method is of improving the liver fibrosis. 50. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 48 or 49, wherein the human subject has liver fibrosis characterized as fibrosis stage F2. 51. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 48 or 49, wherein the human subject has liver fibrosis characterized as fibrosis stage F3. 52. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 49-51, wherein the method is of improving the liver fibrosis by one stage in the human subject. 53. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 51, wherein the method is of improving the liver fibrosis by two stages in the human subject. 54. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 48-53, wherein the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 100 mg per day. 55. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 48-53, wherein the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 80 mg per day. 56. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 45-55, wherein the solid oral dosage form is a tablet. 57. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 45-56, wherein the human subject is an adult human subject. 58. Resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating noncirrhotic nonalcoholic steatohepatitis (NASH), the method comprising:determining a weight of a human subject; and based on determination of the weight of the human subject, administering orally to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject is determined to weigh 100 kg or more and the human subject is using a moderate CYP2C8 inhibitor; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject is determined to weigh less than 100 kg and the human subject is using a moderate CYP2C8 inhibitor. 59. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 58, wherein the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3. 60. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 58 or 59, wherein the method is of improving noncirrhotic nonalcoholic steatohepatitis. 61. Resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating liver fibrosis, the method comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject is determined to weigh 100 kg or more and the human subject is using a moderate CYP2C8 inhibitor; or  (ii)  resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject is determined to weigh less than 100 kg and the human subject is using a moderate CYP2C8 inhibitor; andwherein the human subject has liver fibrosis associated with nonalcoholic steatohepatitis (NASH). 62. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 61, wherein the method is of improving the liver fibrosis. 63. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 61 or 62, wherein the human subject has liver fibrosis characterized as fibrosis stage F2. 64. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 61 or 62, wherein the human subject has liver fibrosis characterized as fibrosis stage F3. 65. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 62-64, wherein the method is of improving the liver fibrosis by one stage in the human subject. 66. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 64, wherein the method is of improving the liver fibrosis by two stages in the human subject. 67. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 58-66, wherein the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 80 mg per day. 68. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 58-66, wherein the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 60 mg per day. 69. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 67, wherein the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 100 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 100 mg per day is reduced to the reduced dosage of 80 mg per day. 70. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 68, wherein the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 80 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 80 mg per day is reduced to the reduced dosage of 60 mg per day. 71. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 58-70, wherein the moderate CYP2C8 inhibitor is selected from the group consisting of rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, crisaborole, nabilone, bexarotene, ritonavir, nicardipine, loratadine, eltrombopag, diltiazem, enzalutamide, ketoconazole, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate, spironolactone, amlodipine, saquinavir, abiraterone, genistein, lenvatinib, pioglitazone, clotrimazole, nilotinib, teriflunomide, topiroxostat, lovastatin, troglitazone, amitriptyline, pirtobrutinib, belinostat, bezafibrate, candesartan, cholecalciferol, cimetidine, colchicine, dabrafenib, deferasirox, diethylstilbestrol, enasidenib, erlotinib, ethinylestradiol, fenofibrate, gemfibrozil, idelalisib, isoniazid, ketoprofen, letermovir, lumacaftor, mefenamic acid, midostaurin, montelukast, nilutamide, opicapone, phenelzine, piroxicam, pyrimethamine, quercetin, raloxifene, repaglinide, rifampicin, rofecoxib, salmeterol, sorafenib, sulfaphenazole, tegaserod, terbinafine, terfenadine, thiazolidinediones, ticlopidine, trametinib, triazolam, troleandomycin, valproic acid, verapamil, vismodegib, clopidogrel, and zafirlukast. 72. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 58-70, wherein the moderate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and / or pioglitazone. 73. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 45-72, wherein the solid oral dosage form comprises resmetirom.

74. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 58-73, wherein the solid oral dosage form is a tablet. 75. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 58-74, wherein the human subject is an adult human subject.  

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