HK1188779A - L-proline and citric acid co-crystals of (2s, 3r, 4r, 5s, 6r)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2h-pyran-3,4-5-triol - Google Patents

Description

L-proline and citric acid cocrystals of (2S,3R,4R,5S,6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional application 61/483, 887, filed on 9/5/2011, which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to L-proline and citric acid co-crystals of (2S,3R,4R,5S,6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, pharmaceutical compositions comprising said co-crystals, and their use in the treatment of glucose-related disorders such as type2diabetes and syndrome X.

Background

Diabetes is a medical term for the presence of elevated blood sugar. People with diabetes either fail to produce insulin, produce too little insulin, or fail to respond to insulin, resulting in the accumulation of glucose in the blood. The most common form of diabetes is type2diabetes, once referred to as adult-onset diabetes or non-insulin dependent diabetes mellitus (NIDDM), which can account for > 90% of adult diabetes. However, as the young population becomes increasingly overweight or obese, type2diabetes is becoming more prevalent in adolescents and children. Diabetes may also involve gestational diabetes, type 1 diabetes, or autoimmune diabetes, once known as juvenile onset diabetes and 11/2 diabetes, also known as latent autoimmune diabetes of adults or LADA. Diabetes may occur due to poor eating habits or lack of physical activity (e.g., sedentary lifestyle), genetic mutations, pancreatic injury, drug (e.g., AIDS therapy) or chemical (e.g., steroids) exposure or disease (e.g., cystic fibrosis, down's syndrome, cushing's syndrome). Two rare classes of gene defects that cause diabetes are referred to as juvenile adult onset diabetes (MODY) and Atypical Diabetes (ADM).

Type2diabetes (non-insulin dependent diabetes mellitus or NIDDM) is a metabolic disorder that involves abnormal glucose metabolism and insulin resistance, as well as long-term complications involving the eyes, kidneys, nerves and blood vessels. Type2diabetes is commonly developed in adults (middle or later) and is described as the body's inability to produce sufficient insulin (abnormal insulin secretion) or its inability to utilize insulin efficiently (resistance to insulin action in target organs or tissues). More specifically, patients with type2diabetes have a relative insulin deficiency. That is, in these patients, plasma insulin levels are normal to high in absolute terms, but lower than expected in terms of the plasma glucose levels present.

Type2diabetes is characterized by the following clinical signs or symptoms: sustained elevated plasma glucose concentration or hyperglycemia; polyuria; polydipsia and/or polyphagia; chronic microvascular complications such as retinopathy, nephropathy and neuropathy; and macrovascular complications such as hyperlipidemia and hypertension, which can lead to blindness, end stage renal disease, amputation, and myocardial infarction.

Syndrome X, also known as Insulin Resistance Syndrome (IRS), metabolic syndrome, or metabolic syndrome X, is a disorder showing risk factors for the development of type2diabetes and cardiovascular diseases, including glucose intolerance, hyperinsulinemia and insulin resistance, hypertriglyceridemia, hypertension and obesity.

Diagnosis of type2diabetes includes assessment of symptoms and measurement of glucose in urine and blood. Blood glucose level determination is necessary for accurate diagnosis. More specifically, the fasting blood glucose level is determinedThe standard method used. However, the Oral Glucose Tolerance Test (OGTT) is considered to be more sensitive than fasting blood glucose levels. Type2diabetes is associated with impaired Oral Glucose Tolerance (OGT). OGTT can therefore be helpful in the diagnosis of type2diabetes, although this is not usually necessary for the diagnosis of diabetes (EMANCIPATOR K,Am J Clin Pathol11 months 1999; page 665-: 665-74; type2Diabetes mellitis, DecisionResources inc., 3.2000). OGTT allows an assessment of pancreatic beta cell secretory function and insulin sensitivity, which aids in the diagnosis of type2diabetes and in assessing the severity or progression of the disease (e.g., CAUMO, a. et al,J Clin Endocrinol Metab2000, 4396, page 4402, volume 85 (11)). More specifically, the OGTT is particularly helpful in establishing the degree of hyperglycemia in patients with multiple borderline fasting blood glucose levels, but who have not yet been diagnosed with diabetes. Furthermore, OGTTs can be used to detect patients with symptoms of type2diabetes, where a potential diagnosis of abnormal carbohydrate metabolism has been clearly established or denied.

Thus, glucose tolerance abnormalities can be diagnosed in individuals who have lower fasting blood glucose levels than are required for diagnosis of type2diabetes, but who have a plasma glucose response during the OGTT that is between normal and diabetic. Abnormal glucose tolerance is considered a pre-diabetic condition, and abnormal glucose tolerance (defined by OGTT) is a potent predictor of the development of type2diabetes (HAFFNER, s.m.,Diabet Med8 months 1997; 14Suppl 3: s12-8).

Type2diabetes is a progressive disease that is associated with impaired pancreatic function and/or other insulin-related processes, and worsens with elevated plasma glucose levels. Type2diabetes, therefore, often has long-term pre-diabetic stages, and various pathophysiological mechanisms can lead to pathological hyperglycaemia and impaired glucose tolerance, for example impaired glucose utilization and availability, insulin action and/or insulin production in the pre-diabetic stages (GOLDBERG, r.b.,Med Clin North Ammonth 7, 1998; pages 805 and 821Volume 82 (4)).

The pre-diabetic stage associated with glucose intolerance may also be associated with abdominal obesity, insulin resistance, hyperlipidemia and a tendency to hypertension, i.e. syndrome X (GROOP L et al,Am J Hypertens9 months 1997; 10(9Pt 2): 172S-180S; HAFFNER, s.m.,J Diabetes Complications3-4 months 1997; pages 69-76, volume 11 (2); BECK-NIELSEN, h, et al,Diabet Med1996, month 9; 13(9Suppl 6): s78-84).

Thus, defects in carbohydrate metabolism are critical for the onset of type2diabetes and impaired glucose tolerance (DIUNNEEN, s.f.,Diabet Med8 months 1997; 14Suppl 3: s19-24). In fact, there is a continuous band from abnormal glucose tolerance and impaired fasting glucose tolerance to definitive type2diabetes mellitus (RAMLO-halt, b.a. et al,Prim Care, 12 months 1999; 771-.

Early intervention in individuals at risk of developing type2diabetes, which may prevent or delay progression to type2diabetes and related complications and/or syndrome X, has been focused on reducing the morbid hyperglycemia or impaired glucose tolerance. Thus, by effectively treating impaired oral glucose tolerance and/or high blood glucose levels, one can prevent or inhibit the progression of this disorder to type2diabetes or syndrome X.

Typical treatments for glucose disorders, including type2diabetes and syndrome X, focus on maintaining blood glucose levels as close to normal as possible, including diet and exercise, and, when necessary, treatment with antidiabetic agents, insulin, or combinations thereof. Type2diabetes mellitus, which cannot be controlled by diet management, is treated with oral antidiabetic agents, including but not limited to: sulfonylureas (e.g., without limitation, first-generation drugs: chlorpropamide, tolazamide, tolbutamide, second-generation drugs: glyburide, glipizide, and third-generation drugs: glimepiride), biguanides (e.g., metformin), thiazolidinediones (e.g., rosiglitazone, pioglitazone, troglitazone), alpha-glucosidase inhibitors (e.g., acarbose, miglitol), meglitinides (e.g., repaglinide), other insulin sensitizing compounds, and/or other anti-obesity agents (e.g., orlistat or sibutramine). For syndrome X, the antidiabetic agent is additionally combined with pharmacological agents for treating concomitant diseases (e.g., hypotensive agents for hypertension, hypolipidemic agents for hyperlipidemia).

First line therapy typically includes metformin and sulfonylureas as well as thiazolidinediones. Metformin monotherapy is a first line of choice, particularly for the treatment of type2 diabetic patients who are also obese and/or dyslipidemia. The lack of an adequate response to metformin is usually followed by treatment with metformin in combination with sulfonylureas, thiazolidinediones or insulin. Sulfonylurea monotherapy (including all generations of drugs) is also a common first line of choice. Another first-line therapy option may be thiazolidinediones. Combinations of these agents are administered to patients who do not respond appropriately to oral anti-diabetic monotherapy. When glycemic control cannot be maintained by oral antidiabetic agents alone, insulin therapy is used either as monotherapy or in combination with oral antidiabetic agents. These same strategies, optionally in combination with additional strategies (e.g. antihypertensive), can be used for the treatment of syndrome X.

In addition to antidiabetic agents, therapy may include additional treatment with anti-obesity agents, such as orlistat, pancreatic lipase inhibitors that prevent breakdown and absorption of fat; or sibutramine, anorexic agents, and reuptake inhibitors of serotonin, norepinephrine, and dopamine in the brain. Other potential additional anti-obesity agents include, but are not limited to: anorexic agents that act through an adrenergic mechanism, such as benzphetamine, phenmetrazine, phentermine, diethylpropion, mazindol, sibutramine, phenylpropanolamine, or ephedrine; anorexic agents that act through serotonergic mechanisms, such as quinazine, fluoxetine, sertraline, fenfluramine, or dexfenfluramine; anorexics that act through dopamine mechanisms, e.g., apomorphine; anorexics that act through histaminergic mechanisms (e.g., histamine mimetics, H3 receptor modulators); enhancers of energy expenditure, such as β -3 adrenergic agonists and stimulators of uncoupling protein function; leptin and leptin mimetics; a neuropeptide Y antagonist; melanocortin-1, 3 and 4 receptor modulators; a cholecystokinin agonist; glucagon-like peptide-1 (GLP-1) mimetics and analogs (e.g., exenatide); androgens (e.g., dehydroepiandrosterone and derivatives such as etiocholandione), testosterone, anabolic steroids (e.g., oxandrolone), and steroid hormones; galanin receptor antagonists; cytokine agents, such as ciliary neurotrophic factor; an amylase inhibitor; intestinal statin agonists/mimetics; orexin/orexin antagonists; a urothelin antagonist; bombesin agonists; modulators of protein kinase a; corticotropin releasing factor mimics; cocaine and amphetamine regulated transcript mimetics; calcitonin gene-related peptide mimetics; and fatty acid synthase inhibitors.

There remains a need to provide effective treatments for glucose-related disorders such as high glucose levels, type2diabetes, syndrome X, and the like. There is also a need to provide effective treatments for glucose-related disorders that also slow or prevent the progression and/or development of type2 diabetes.

Disclosure of Invention

The invention relates to L-proline co-crystals of compounds of formula (I-X)

The invention also relates to citric acid co-crystals of compounds of formula (I-X)

Preferably, the co-crystal of L-proline and citric acid of the compound of formula (I-X) according to the invention is crystalline. The present invention also relates to methods of making co-crystals of compounds of formula (I-X), as described in more detail herein.

An example of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a co-crystal former of a compound of formula (I-X) as described herein. Illustrative of the invention are pharmaceutical compositions prepared by mixing a co-crystal former of a compound of formula (I-X) as described herein and a pharmaceutically acceptable carrier. The present invention features a method of making a pharmaceutical composition comprising admixing a co-crystal former of a compound of formula (I-X) as described herein and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating and/or preventing a glucose-related disorder comprising administering to a subject in need thereof a crystalline co-crystal of a compound of formula (I-X) as described herein.

Drawings

Figure 1 shows a representative pXRD spectrum of: l-proline (top), the compound of formula (I-X) (bottom) and the crystalline L-proline co-crystal of the compound of formula (I-X) (middle).

Figure 2 shows a representative nominal pXRD spectrum for the L-proline co-crystal of the compound of formula (I-X) in crystalline form.

Figure 3 shows a representative pXRD spectrum of: citric acid (top), the compound of formula (I-X) (bottom) and a crystalline co-crystal of citric acid of the compound of formula (I-X) (middle).

Figure 4 shows a representative nominal pXRD spectrum for the citric acid co-crystal of the crystalline compound of formula (I-X).

Figure 5 shows a representative DSC scan for a crystalline L-proline co-crystal of the compound of formula (I-X).

Figure 6 shows a representative DSC scan for a crystalline compound of formula (I-X) for the citric acid co-crystal.

Detailed Description

The invention relates to co-crystals of compounds of formula (I-X)

(which is also known as (2S,3R,4R,5S,6R) -2- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol). More particularly, the present invention relates to L-proline co-crystals of compounds of formula (I-X); and a citric acid co-crystal of the compound of formula (I-X). In one embodiment of the invention, the L-proline co-crystal of the compound of formula (I-X) is crystalline. In another embodiment of the invention, the citric acid co-crystal of the compound of formula (I-X) is crystalline.

The compounds of formula (I-X) exhibit inhibitory activity against sodium-dependent glucose transporters such as SGLT 2. The compounds of formula (I-X) may be prepared according to the methods disclosed by Nomura, S. et al in U.S. patent publication No. US2005/0233988A1, published 10/20/2005, which is incorporated herein by reference.

The present invention also relates to a method of treating and/or preventing a glucose-related disorder, preferably type2diabetes, comprising administering to a subject in need thereof a co-crystal of a compound of formula (I-X) as described herein.

As used herein, a "+" designation shall indicate the presence of a stereogenic center.

In the case where the compounds according to the invention have at least one chiral center, they may therefore be present in enantiomeric form. When the compounds have two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Preferably, if the compound is present as an enantiomer, the enantiomer is present in an enantiomeric excess of greater than or equal to about 80%, more preferably in an enantiomeric excess of greater than or equal to about 90%, more preferably in an enantiomeric excess of greater than or equal to about 95%, still more preferably in an enantiomeric excess of greater than or equal to about 98%, and most preferably in an enantiomeric excess of greater than or equal to about 99%. Similarly, if the compound is present as a diastereomer, the diastereomer is present in greater than or equal to about 80% diastereomeric excess, more preferably in greater than or equal to about 90% diastereomeric excess, still more preferably in greater than or equal to about 95% diastereomeric excess, still more preferably in greater than or equal to about 98% diastereomeric excess, and most preferably in greater than or equal to about 99% enantiomeric excess.

In addition, some crystal forms of the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of the present invention.

As used herein, unless otherwise indicated, the term "isolated form" shall mean that the compound is present in a form separate from any solid mixture, solvent system, or biological environment formed with the additional compound. In one embodiment of the invention, the L-proline co-crystal of the compound of formula (I-X) is present in isolated form. In another embodiment of the invention, the citric acid co-crystal of the compound of formula (I-X) is present in isolated form.

As used herein, unless otherwise indicated, the term "substantially pure form" shall mean a mole percentage of impurities in the isolated crystalline form of less than about 5 mole%, preferably less than about 2 mole%, more preferably less than about 0.5 mole%, and most preferably less than about 0.1 mole%. In one embodiment of the invention, the L-proline co-crystal of the compound of formula (I-X) is present in substantially pure form. In another embodiment of the invention, the citric acid co-crystals of the compound of formula (I-X) are present in substantially pure form.

The present invention also relates to a method of treating and preventing (preferably, preventing the development of) a glucose-related disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of any one of the co-crystals of a compound of formula (I-X) described herein.

The methods of the invention relate to the treatment and/or prevention (including progression and delay of onset) of "glucose-related disorders". As used herein, the term "glucose-related disorder" shall be defined as any disorder characterized by or developing as a result of high glucose levels. Glucose related disorders shall include diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood fatty acid levels, elevated blood glucose levels, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, or hypertension. In particular, the "glucose-related disorder" is diabetes (type 1 and type2diabetes, etc.), diabetic complications (such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), obesity, or postprandial hyperglycemia.

In one embodiment of the invention, the glucose related disorder is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis and hypertension.

In another embodiment of the invention, the glucose related disorder is selected from the group consisting of type 1 diabetes, type2diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, obesity and postprandial hyperglycemia. In another embodiment of the invention, the glucose related disorder is selected from the group consisting of type 1 diabetes, type2diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, obesity and delayed wound healing. In another embodiment of the invention, the glucose related disorder is selected from the group consisting of poor glycemic control, type2diabetes, syndrome X, gestational diabetes, insulin resistance, hyperglycemia. In another embodiment of the invention, the glucose related disorder is type2 diabetes.

In another embodiment, the glucose related disorder is selected from the group consisting of high glucose levels, pre-diabetes, impaired oral glucose tolerance, poor glycemic control, type2diabetes, syndrome X (also known as metabolic syndrome), gestational diabetes, insulin resistance, and hyperglycemia.

Treatment of a glucose-related disorder may include lowering glucose levels, improving glycemic control, reducing insulin resistance, and/or preventing the development of a glucose-related disorder (e.g., preventing the development of type2diabetes in a patient with impaired oral glucose tolerance or high glucose levels).

As used herein, the terms "syndrome X", "metabolic syndrome" and "metabolic syndrome X" shall mean a disorder of risk factors showing development of type2diabetes and cardiovascular disease, and which is characterized by insulin resistance and hyperinsulinemia and may be accompanied by one or more of the following: (a) glucose intolerance, (b) type2diabetes, (c) dyslipidemia, (d) hypertension, and (e) obesity.

As used herein, unless otherwise indicated, the terms "treating", and the like shall include the management and care of a subject or patient (preferably a mammal, more preferably a human) for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present invention to prevent the onset of symptoms or complications, to alleviate symptoms or complications, or to eliminate the disease, condition, or disorder.

As used herein, unless otherwise indicated, the term "preventing" shall include (a) reducing the frequency of one or more symptoms; (b) reducing the severity of one or more symptoms; (c) delay or avoidance of development of additional symptoms; and/or (d) delaying or avoiding the development of the disorder or condition.

One skilled in the art will recognize that, in the context of a method of prevention wherein the present invention is directed to a subject in need thereof (i.e., a subject in need of prevention), any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented. Furthermore, a subject in need thereof may also be a subject (preferably a mammal, more preferably a human) that does not exhibit any symptoms of the disorder, disease or condition to be prevented, but is deemed by a physician, clinician or other medical professional to be at risk of developing the disorder, disease or condition. For example, the subject may be considered at risk of developing a disorder, disease, or condition (and thus in need of prophylactic or preventative treatment) due to the subject's medical history, including but not limited to family history, predisposition to the disease, co-existing disorder or condition (with concurrent morbidity), genetic testing, and the like.

As used herein, the term "subject" refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

The optimal dosage to be administered is readily determined by one skilled in the art and may vary with, for example, the mode of administration, the strength of the formulation, the mode of administration and the advancement of the condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust the dosage.

One skilled in the art will recognize that both in vivo and in vitro assays using appropriate, known and generally accepted cell and/or animal models can envision the ability of a test compound or co-therapy to treat or prevent a given disorder. Those skilled in the art will also recognize that human clinical trials (including human first use trials, dose exploration trials, and efficacy trials) conducted in healthy patients and/or patients with a given disease may be accomplished according to methods well known in the clinical and medical arts.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

To provide a more concise description, some quantitative expressions are recited herein as a range from about an amount X to about an amount Y. It should be understood that when a range is recited, the range is not limited to the upper and lower limits recited, but includes the entire range from about the X amount to about the Y amount or any amount therebetween.

To provide a more accurate description, some of the quantitative representations presented herein are not modified by the term "about". It is to be understood that each quantity given herein is intended to refer to the actual given value, and it is also intended to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to experimental and/or measurement conditions for such given value, whether or not the term "about" is explicitly used.

Suitable solvents, bases, reaction temperatures and other reaction parameters and components are given in the detailed description below. Those skilled in the art will recognize that the list of examples is not intended to, and should not be construed as, limiting in any way the invention set forth in the claims below.

One skilled in the art will recognize that if the reaction steps of the present invention can be carried out in a variety of solvents or solvent systems, the reaction steps can also be carried out in a mixture of suitable solvents or solvent systems.

If the process for preparing the compounds according to the invention yields mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or the individual enantiomers may be prepared by enantiospecific synthesis or by resolution. For example, the compounds may be resolved into their component enantiomers by standard techniques, for example by salt formation with an optically active acid (e.g., (-) -di-p-toluoyl-D-tartaric acid and/or (+) -di-p-toluoyl-L-tartaric acid), followed by formation of diastereomeric pairs by fractional crystallization and regeneration of the free base. The compounds can also be resolved by the formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using a chiral HPLC column.

In addition, the percent enantiomeric excess (% ee) can be determined by chiral HPLC relative to a standard. The enantiomeric excess can be calculated as follows:

[ (R mol-S mol)/(R mol + S mol) ]. times.100%

Wherein R moles and S moles are the mole fraction of the R and S enantiomers in the mixture such that R moles + S moles = 1. Alternatively, the enantiomeric excess can also be calculated from the specific optical rotation of the desired enantiomer and the mixture prepared as follows:

ee=([α-obs]/[α-maX])×100。

the present invention relates to L-proline co-crystals of compounds of formula (I-X), preferably crystalline L-proline co-crystals of compounds of formula (I-X). The invention also relates to citric acid co-crystals of the compound of formula (I-X), preferably crystalline.

Preparation of crystalline L-proline and citric acid co-crystals：

The L-proline and citric acid co-crystals of the compounds of formula (I-X) were prepared as part of the co-crystal screen. Briefly, approximately 15mg of a compound of formula (I-X) was added to each well of a 48-well mill block, along with approximately 1 molar equivalent of a co-crystal former (L-proline or citric acid, respectively) and 10 μ L of a solvent selected from acetone, ethanol, isopropyl acetate, toluene, water. Six (6) separate experiments (5 solvents and 1 dry well) were performed for each co-crystal formation. The wells were subjected to 10 minutes ball milling and immediately subjected to pXRD analysis.

Crystalline L-proline co-crystals of compounds of formula (I-X) were additionally prepared by slurrying a compound of formula (I-X) (about 1g) and L-proline in acetone at 1: 1 stoichiometry.

Crystalline citric acid co-crystals of compounds of formula (I-X) were additionally prepared by thermal crystallization of a compound of formula (I-X) (about 1g) and citric acid in isopropyl acetate at 1: 1 stoichiometry.

Physical and chemical stability of L-proline and citric acid co-crystal：

The physical stability of the crystalline L-proline co-crystal of the compound of formula (I-X) was tested by storing about 10mg of the co-crystal in a 10mL serum gland flask under the following conditions: (a) sealing at 5 ℃; (b)25 ℃/60% RH, open; (c) sealing at 40 ℃; (d)40 ℃/75% RH, open; (e) sealing at 60 ℃; and (f)80 ℃, hermetically sealed; stability data were collected on day 1, week 2 and week 4. It has been found that the L-proline co-crystal of the compound of formula (I-X) in crystalline form is physically stable up to 4 weeks under all these conditions with no visible color change.

Samples of the L-proline co-crystal of the compound of formula (I-X) in crystalline form subjected to the physical stability test were taken on day 1, week 2 and week 4 for further testing of chemical stability/degradation. The crystalline L-proline co-crystal of the compound of formula (I-X) (about 10mg) was diluted with 50: 50 water: acetonitrile solution (10mL) and then further diluted 10-fold for HPLC measurement. All crystalline L-proline cocrystal samples appeared chemically stable on day 1, week 2 and week 4. No degradation peak was observed and the measured% area remained consistent at each time point.

The physical stability of the crystalline compound of formula (I-X) was similarly tested by storing about 10mg of the co-crystal in a 10mL serum gland flask under the following conditions: (a) sealing at 5 ℃; (b)25 ℃/60% RH, open; (c) sealing at 40 ℃; (d)40 ℃/75% RH, open; (e) sealing at 60 ℃; and (f)80 ℃, hermetically sealed; stability data were collected on day 1, week 2 and week 4. It was found that the citric acid co-crystals of the compound of formula (I-X) in crystalline form were physically stable up to 4 weeks under all these conditions, although a small amount of degradation (< 0.3% relative to the basal peak) was observed when stored at 25 ℃/60% RH, when stored at 40 ℃/75% RH and when stored at 60 ℃ or 80 ℃.

Samples of the citric acid co-crystal of the compound of formula (I-X) in crystalline form subjected to the physical stability test were taken on day 1, week 2 and week 4 for further testing of chemical stability/degradation. The crystalline citric acid co-crystal of the compound of formula (I-X) (about 10mg) was diluted with 50: 50 water: acetonitrile solution (10mL) and further diluted 10-fold for HPLC measurement. All crystalline citric acid co-crystal samples appeared chemically stable when stored at 5 ℃, sealed and 40 ℃, sealed on day 1, week 2 and week 4. Small degradation peaks were observed at week 1, week 2 and week 4, stored at 25 ℃/60% RH, open samples and stored at 60 ℃, sealed samples; although the peak purity of these samples remained > 99%. Very small degradation peaks were also observed for the sealed samples stored at 40 ℃/75% RH, open and 80 ℃ at week 1, week 2 and week 4; although the peak purity of these samples remained > 99%.

pXRD, DSC, TGA and DVX measurements:

the crystalline L-proline co-crystal of the compound of formula (I-X) and the crystalline citric acid co-crystal of the compound of formula (I-X) are further characterized by powder X-ray diffraction (pXRD), Dynamic Scanning Calorimetry (DSC), thermogravimetric analysis (TGA) and dynamic vapor adsorption/Desorption (DVS).

pXRD: using a gas with a GADDS^TMBruker AXSD8Discover X-ray diffractometer (general area diffraction detection system), Bruker AXS HI-STAR area detector (general area diffraction detection system), and copper source at a distance of 15.05 cm/system calibrationAn automated X-y-z stage, and a 0.5mm collimator to obtain a powder X-ray powder diffraction pattern. The sample was compacted into pellet form and mounted on an x-y-z stage. The power was set at 40kV and 40mA in the reflection mode while the sample remained fixed and diffraction patterns were collected at ambient conditions. The exposure time for each sample was approximately 1 minute. A spatial remapping method is performed to obtain a diffraction pattern to account for geometric pincushion distortion of the area detector, which is then normalized by setting bin normalization by integrating in steps of 0.02 degrees along chi from-118.8 to-61.8 degrees and 2 theta from 2.1 to 37 degrees. Diffraction patterns were obtained on a Bruker machine using EVA software, except using the Jade software.

DSC: an aliquot of the sample was weighed into an aluminum sealed sample pan. The sample trays were loaded into an apparatus (Q1000 differential scanning calorimeter, TA instrument) equipped with an autosampler. By moving from T at a rate of 10 ℃/min_min(usually room temperature) to T_maxThe sample was heated alone (typically 300 ℃) to obtain a thermogram, using an empty aluminum sealing disk as a control. Dry nitrogen was used as the sample purge gas and was set at a flow rate of 50 ml/min. The thermal conversion was observed and analyzed using analytical software provided with the instrument.

TGA: an aliquot of the sample was transferred to a platinum sample pan. The tray was placed on a loading platform and then loaded automatically into the apparatus (Q500 thermogravimetric analyzer, TA instruments) using control software. By passing from T at 10 ℃/min_min(usually room temperature) to T_max(typically 300 ℃) A sample purge flow of 60ml/min and an equilibrium purge flow of 40ml/min under flowing dry nitrogenThe sample was heated alone to obtain a thermogram. Thermal conversion (e.g., weight change) was observed and analyzed using analysis software provided with the instrument.

DVS: moisture was adsorbed on a DVS-1 instrument (Surface Measurement Systems, Allentown, Pa.) for characterization. In each case, the drying curve of the samples was plotted from ambient to 0% Relative Humidity (RH), then over 2 cycles of adsorption (0% RH to 90% RH) and desorption (90% RH to 0% RH) at 25 ℃ in a 10% RH step. Samples were allowed to equilibrate at a specific% RH for each step, stabilizing the weight gain or loss before the instrument proceeded to the next step in the process.

Crystalline L-proline eutectic nature：

Characterizing the crystalline L-proline co-crystal of the compound of formula (I-X) by powder X-ray diffraction (pXRD) pattern; the co-crystal pattern was compared with the pXRD pattern of the co-crystal component, more specifically, the pXRD of the compound of formula (I-X) and the pXRD of L-proline.

Fig. 1 hereafter shows a representative measured pXRD pattern for the following: l-proline (top), the compound of formula (I-X) (bottom) and the crystalline L-proline co-crystal of the compound of formula (I-X) (middle).

In one embodiment, the crystalline L-proline co-crystal of the compound of formula (I-X) may be characterized by its powder X-ray diffraction pattern, which includes the peaks listed in table 1 below.

Table 1: crystalline L-proline co-crystals of compounds of formula (I-X)

Preferably, the L-proline co-crystal of the crystalline compound of formula (I-X) is characterized by its pXRD pattern comprising peaks having a relative intensity greater than or equal to about 25%, preferably greater than or equal to about 40%.

In another embodiment of the invention, the crystalline L-proline co-crystal of the compound of formula (I-X) may be characterized by the following pXRD peaks ° 2 Θ: 3.74, 9.50, 10.98, 17.78, 18.62, 21.94, 23.43 and 26.82; as shown by the nominal peak pXRD spectrum shown in figure 2.

The L-proline co-crystal of the crystalline compound of formula (I-X) was further characterized using Differential Scanning Calorimetry (DSC), measured at 10 ℃/min from 25 ℃ to 300 ℃ and was found to exhibit a well-defined melting point of 188 ℃ and was relatively flat at 180 ℃.

The L-proline co-crystal of the compound of formula (I-X) in crystalline form was further characterized using thermogravimetric analysis (TGA), measured at 10 ℃/min from 25 ℃ to 300 ℃ and found to exhibit a 1% weight loss up to 180 ℃ (which is believed to be due to loss of residual solvent), then further up to 25% weight loss at 280 ℃, which corresponds to a loss of 1 molar equivalent of L-proline.

The L-proline co-crystal of the compound of formula (I-X) in crystalline form was further characterized using Dynamic Vapor Sorption (DVS), measured at 25 ℃ from 0% RH to 90% RH (2 full cycles). The crystalline L-proline cocrystal of the compound of formula (I-X) was found to be hygroscopic, although no weight gain was observed until the% RH had reached 40%. Between 40% RH and 90% RH, the mass of the eutectic increases by 12%, which is lost (with some hysteresis) during the desorption portion of the measurement cycle. Observation of pXRD collected after DVS run (isolated at 0% RH) with this sample indicated no irreversible formal transformation.

Crystalline citric acid eutectic properties：

Characterizing the crystalline citric acid co-crystal of the compound of formula (I-X) by powder X-ray diffraction (pXRD) pattern; the co-crystal pattern was compared to the pXRD pattern of the co-crystal component, more specifically, the pXRD of the compound of formula (I-X) and the pXRD of citric acid.

Fig. 3 hereafter shows a representative measured pXRD pattern for the following: citric acid (top), the compound of formula (I-X) (bottom) and a crystalline co-crystal of citric acid of the compound of formula (I-X) (middle).

In one embodiment, the citric acid co-crystal of the crystalline compound of formula (I-X) may be characterized by its powder X-ray diffraction pattern comprising the peaks listed in table 2 below.

Table 2: crystalline citric acid co-crystals of a compound of formula (I-X)

Preferably, the citric acid co-crystal of the crystalline compound of formula (I-X) is characterized by its pXRD pattern, which comprises a peak having a relative intensity greater than or equal to about 5%, more preferably greater than or equal to about 10%.

In another embodiment of the invention, the citric acid co-crystal of the crystalline compound of formula (I-X) can be characterized by the following pXRD peaks ° 2 Θ: about 4.2, 9.16, 12.39, 16.54, 17.69, 19.70, 23.63, and 25.66; as shown by the nominal peak pXRD spectrum shown in figure 4.

The citric acid co-crystals of the crystalline compound of formula (I-X) were further characterized using Differential Scanning Calorimetry (DSC), measured at 10 ℃/min from 25 ℃ to 300 ℃ and found to exhibit a single well-defined melting point of 156 ℃.

The citric acid co-crystal of the crystalline compound of formula (I-X) was further characterized using thermogravimetric analysis (TGA), measured at 10 ℃/min from 25 ℃ to 300 ℃ and found to exhibit no significant weight loss up to 0.38% at 155 ℃. This weight loss is believed to be due to loss of residual solvent and does not indicate the presence of the hydrate form.

The citric acid co-crystals of the crystalline compound of formula (I-X) were further characterized using Dynamic Vapor Sorption (DVS), measured at 25 ℃ from 0% RH to 90% RH (2 full cycles). The crystalline citric acid co-crystal of the compound of formula (I-X) was found to be non-hygroscopic with an increasing mass of 0.5% observed from 0% to 80% RH, the mass of which was lost again upon desorption. Observation with this sample taken pXRD after DVS run (isolated at 0% RH) indicated no formal transformation.

The invention also includes pharmaceutical compositions comprising any of the crystalline co-crystals of the compounds of formula (I-X) described herein together with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compounds with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral formulations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral formulations may also be coated with substances such as sugars or with an enteric coating to regulate the primary site of absorption. For parenteral administration, the carrier will typically consist of sterile water and other ingredients may be added to increase solubility or to preserve. Injectable suspensions or solutions may also be prepared using aqueous carriers along with suitable additives.

To prepare the pharmaceutical compositions of the present invention, one or more of the compositions of the present invention as the active ingredient are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral such as intramuscular. In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, fats and oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral formulations such as powders, capsules, caplets, soft capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are obviously employed. Tablets may be sugar-coated or enteric-coated, if desired, by standard techniques. For parenteral dosage forms, the carrier will typically comprise sterile water, but may also comprise other ingredients, for example for purposes such as to aid solubility or preservation. Suspensions for injection may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain per dosage unit (e.g., per tablet, per capsule, per powder, per injection, per teaspoonful, etc.) the amount of active ingredient required to deliver the effective dose as described above. The pharmaceutical compositions herein will comprise from about 0.1 to about 1000mg or any amount or range therein per unit dosage unit (e.g., per tablet, per capsule, per powder, per injection, per suppository, per teaspoonful, etc.) and may be administered in a dosage of from about 0.01 to about 500 mg/kg/day or any amount or range therein, preferably from about 0.5 to about 100 mg/kg/day or any amount or range therein. However, the dosage may vary depending on the requirements of the patient, the severity of the condition being treated and the compound employed. Daily administration or post-cycle administration (post-periodic dosing) may be employed.

Preferably, these compositions are in unit dosage forms, such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for parenteral oral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be in a form suitable for once weekly or once monthly administration; for example, insoluble salts of the active compounds, such as the decanoate, may be suitable to provide depot formulations for intramuscular injection. To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutically acceptable carrier, such as conventional tableting ingredients, for example corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutically acceptable diluents, such as water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equivalent dosage forms such as tablets, pills and capsules. The solid dosage composition is then subdivided into unit dosage forms of the type described above containing from 0.01 to about 1,000 mg, or any amount or range therein, of the active ingredient of the present invention. Tablets or pills of the novel composition may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, a tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of a coating covering the former. The two components may be separated by an enteric layer which serves to prevent disintegration in the stomach, thereby leaving the inner component intact in the duodenum or delayed in release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acid materials along with materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid formulations which may be incorporated into the novel compositions of the present invention for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils (cottonseed, sesame, coconut or peanut oil), as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums (e.g., tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin).

The methods of treating glucose-related disorders described herein can also employ pharmaceutical compositions comprising any of the compounds defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may comprise between about 0.01mg and about 1000mg of the compound or any amount or range therein; preferably from about 0.1mg to about 500mg of the compound, and may be in any form suitable for the mode of administration chosen. Carriers include necessary and inert pharmaceutical excipients including, but not limited to, binders, suspensions, lubricants, flavorants, sweeteners, preservatives, dyes, and coating materials. Compositions suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release), granules and powders; and liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

Advantageously, the compositions of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily. In addition, the compounds of the present invention may be administered in intranasal form by topical use of suitable intranasal vehicles, or via transdermal drug patches well known to those of ordinary skill in the art. Administration is in the form of a transdermal delivery system, and dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be combined with an oral, non-toxic pharmaceutically inert carrier (e.g., ethanol, glycerol, water, and the like). In addition, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture, as desired or necessary. Suitable disintegrants include, but are not limited to, starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., acacia, tragacanth) or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

The liquid forms are suitably flavored suspending or dispersing agents, such as synthetic and natural gums, e.g., tragacanth, acacia, methylcellulose, and the like. For parenteral administration, sterile suspensions and solutions are desirable. When intravenous administration is desired, isotonic formulations, which typically contain suitable preservatives, are employed.

To prepare the pharmaceutical compositions of the present invention, the compound of formula (I) is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral. Suitable pharmaceutically acceptable carriers are well known in the art. Some such pharmaceutically acceptable carriers are described in the American pharmaceutical Association and the British society for pharmacyThe Handbook o(Pharmaceutical EXcipientsIs found in (1).

Methods of formulating pharmaceutical compositions have been described in a number of publications, for example, edited by Lieberman et al, published by Marcel DekkerPharmaceutical Dosage Forms： TabletsSecond edition, revised and extended edition, volumes 1-3; edited by Avisl et alPharmaceutical Dosage Forms：Parenteral MedicationsVolumes 1-2; and edited by Lieberman et alPharnaceutical Dosage Forms：Disperse SystemsVolumes 1-2.

Whenever glucose related therapy is required, the co-crystals of the crystalline compounds of formula (I-X) of the present invention may be administered in any of the aforementioned compositions and administered in accordance with dosage regimens established in the art.

The daily dosage of the product may vary over a wide range of about 0.01 to about 1000mg per adult per day, or any amount or range therein. For oral administration, the compositions are preferably in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500mg of the active ingredient, the dosages being adjusted according to the condition of the patient to be treated.

Preferably, the crystalline co-crystal of the compound of formula (I-X) is administered at a dosage level of about 0.01mg to about 500mg per kilogram body weight per day, or 0.01mg to about 200mg per kilogram body weight per day, or any amount or range therein. Preferably, the range is from about 0.01 to about 50mg or any amount or range therein per kilogram body weight per day, more preferably from about 0.05mg to about 10mg or any amount or range therein, more preferably from about 1 to about 5mg or any amount or range therein per kilogram body weight per day. In one embodiment, an effective amount of a co-crystal of a compound of formula (I-X) in crystalline form is provided at a dosage level of 10mg, 25mg, 50mg, 100mg, 150mg, or 300mg, or any amount or range therein. The co-crystal of the compound of formula (I-X) in crystalline form may be administered by oral administration 1 to 4 times per day.

The optimal dosage to be administered can be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the formulation, the mode of administration and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust the dosage.

One skilled in the art will recognize that both in vivo and in vitro experiments using appropriate, known and generally accepted cell and/or animal models can predict the ability of a test compound to treat or prevent a given disease.

Those skilled in the art will also recognize that human clinical trials (including human first use trials, dose exploration trials, and efficacy trials) conducted in healthy patients and/or patients with a given disease may be accomplished according to methods well known in the clinical and medical arts.

The following examples are given to aid in the understanding of the present invention and are not intended to, and should not be construed to, limit in any way the invention as set forth in the claims which follow thereafter.

Example 1

Crystalline L-proline co-crystals of compounds of formula (I-X)

The compound of formula (I-X) (100mg) was added to wig-L-bug bottles together with L-proline (26.30mg) (1: 1.1 molar equivalents API: CCF), mill balls and acetone (20. mu.l). wig-L-bug was subjected to milling for 10 minutes. After milling, the recovered solid was confirmed by pXRD as an L-proline co-crystal of the compound of formula (I-X) in the desired crystalline form.

Example 2

Crystalline L-proline co-crystals of compounds of formula (I-X)

The compound of formula (I-X) (50.18mg) was added to a 4mL Erlenmeyer flask along with L-proline (13.15mg) (1: 1.1 molar equivalents API: CCF), followed by acetone (2 mL). The capped bottle was simply heated with a hot air gun. A white solid material rapidly precipitated from the solution and was collected and confirmed by pXRD to be an L-proline co-crystal of the compound of formula (I-X) in the desired crystalline form.

Example 3

Crystalline citric acid co-crystals of a compound of formula (I-X)

The compound of formula (I-X) (100mg) was charged to wig-L-bug bottle together with citric acid (43.83mg) (1: 1.1 molar equivalents API: CCF), mill balls and isopropyl acetate (20. mu.l). wig-L-bug was subjected to milling for 10 minutes. After milling, the recovered solid was confirmed by pXRD to be the citric acid co-crystal of the compound of formula (I-X) in the desired crystalline form.

Example 4

Crystalline citric acid co-crystals of a compound of formula (I-X)

The compound of formula (I-X) (50.72mg) was added to a 4mL Erlenmeyer flask along with citric acid (21.83mg) (1: 1.1 molar equivalents API: CCF) followed by isopropyl acetate (1 mL). The capped bottle was heated with a hot air gun until the solid material was completely dissolved. Upon cooling no crystals were observed to form, the lid was opened and the solvent was allowed to slowly evaporate. After 2 days (after about 20% reduction of the solvent), seeds of the desired substance were added to the saturated solution and a white solid crystalline substance precipitated within a few hours. The isolated material was confirmed by pXRD to be a crystalline citric acid co-crystal of the compound of formula (I-X).

Example 5

Solid oral dosage forms-examples of prophetic examples

As a specific example of an oral composition, 100mg of a crystalline L-proline co-crystal of a compound of formula (I-X) (prepared as described herein) is formulated with lactose finely divided enough to provide a total amount of 580 to 590mg to fill hard O-shaped capsules.

Example 6

Solid oral dosage forms-examples of prophetic examples

As a specific example of an oral composition, 100mg of a crystalline citric acid co-crystal of a compound of formula (I-X) (prepared as described herein) is formulated with lactose finely divided enough to provide a total amount of 580 to 590mg to fill an O-shaped hard capsule.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims (10)

1. An L-proline co-crystal of a compound of formula (I-X)

(I-X)。

2. The L-proline co-crystal of claim 1, wherein the co-crystal is crystalline.

3. An L-proline co-crystal according to claim 2, comprising the following pXRD peak degrees 2 Θ: 3.74, 9.50, 10.98, 17.78, 18.62, 21.94, 23.43 and 26.82.

4. The L-proline co-crystal according to claim 2, wherein the co-crystal exhibits a melting point of 188 ℃ as measured by DSC.

5. A crystalline L-proline co-crystal of a compound of formula (I-X)

(I-X)。

6. A citric acid co-crystal of a compound of formula (I-X)

(I-X)。

7. The citric acid co-crystal of claim 6, wherein the co-crystal is crystalline.

8. The citric acid co-crystal of claim 7, comprising the following pXRD peak degrees 2 θ: 4.2, 9.16, 12.39, 16.54, 17.69, 19.70, 23.63 and 25.66.

9. The citric acid co-crystal of claim 7, wherein the co-crystal exhibits a melting point of about 156 ℃ as measured by DSC.

10. A crystalline citric acid co-crystal of a compound of formula (I-X)

(I-X)。