Chemical process and compositions comprising tiratricol

Abstract

The invention provides a process for the preparation of a composition comprising compound (1). Compound (1) is also known as tiratricol. The invention also provides compositions comprising the compound, in particular in a crystalline form. The compositions have a particularly beneficial purity profile.

Description

[0001] CHEMICAL PROCESS AND COMPOSITIONS

[0002] TECHNICAL FIELD

[0003] The present invention relates to compositions comprising tiratricol and to processes for preparing such compositions. Compositions according to the present invention may be used in methods of treatment, such as, for example the treatment of MCT8 deficiency. The processes of the invention represent an improvement over known processes as compositions according to the invention can be prepared with low amounts of impurities and at kilogram scale.

[0004] BACKGROUND OF THE INVENTION

[0005] MCT8 deficiency is a rare, X-linked disorder caused by mutations in the thyroid hormone transporter MCT8. Patients with MCT8 deficiency typically have profound early neurodevelopmental impairment and peripheral thyrotoxicosis. With no approved medical treatments for MCT8 deficiency, management is primarily focused on supportive care including nutritional support, physical and occupational therapy for neuromuscular dysfunction and medication to manage complications (e.g. antiepileptic medication).

[0006] Tiratricol is an endogenous available metabolite of thyroid hormone, with similar bioactive properties as T3. It is a naturally occurring metabolite of triiodothyronine (T3) that acts as a thyroid hormone analogue with high affinity for thyroid hormone receptors. It has been utilized in the suppression of thyroid-stimulating hormone (TSH) and investigated for therapeutic applications in conditions such as thyroid hormone resistance syndromes, certain thyroid cancers, dyslipidemia, and metabolic disorders. It was authorised as a medicine in France and was marketed under the name Teatrois between 1974 and 2020.

[0007] Tiratricol exhibits the ability to modulate metabolic activity and influence lipid profiles, making it a compound of significant interest for both clinical and research applications. Tiratricol enters the cell independently of MCT8, bypassing the pathophysiologic defect in MCT8 deficiency. Clinical trials for the use of tiratricol for the treatment of MCT8 deficiency are ongoing. Tiratricol can be obtained either by transformation of natural iodothyronines or through de novo synthetic routes. Early approaches employed chemical modification of triiodothyronine (T3) or related thyronine derivatives to introduce the acetic acid side chain (see for example US 3, 046, 306), effectively mimicking known metabolic pathways.

[0008] Known synthetic methods for the production of tiratricol have proved inefficient and sometimes potentially hazardous for large scale operations. The introduction and maintenance of the tri-iodinated substitution pattern is particularly demanding, with side reactions producing structurally similar impurities , in particular di- and -tetra-iodo analogues.

[0009] Accordingly, new and more efficient routes leading to tiratricol are needed. The processes and compounds described herein help meet these and other needs. The present disclosure fulfills these and other needs, as evident in reference to the following disclosure.

[0010] SUMMARY OF THE INVENTION

[0011] The invention provides a process for the preparation of a composition comprising compound 1 wherein said process comprises a) preparing an aqueous solution of the disodium salt of compound 1 (compound 2) b) adding said aqueous solution to a mixture of acetic acid and aqueous hydrochloric acid, c) heating the mixture, d) allowing compound 1 to crystallise, and e) isolating crystalline compound 1.

[0012] The process is especially effective in providing compound 1 in an enhanced level of purity and, in particular, in a favourable crystalline form.

[0013] According to a second aspect, the invention provides a composition comprising compound 1, or a pharmaceutically acceptable salt thereof,

[0014] (1) wherein the composition further comprises from 0.01% to 1.0% of compound 3 or a pharmaceutically acceptable salt thereof and / or from 0.01% to 0.5% of compound 10, or a pharmaceutically acceptable salt thereof.

[0015]

[0016] According to a third aspect, the invention provides compound 1 in crystalline form characterized by a powder X-ray diffractogram (XRPD) having characteristic peaks at 20 = 15.3±0.2°, 7.6±0.2° and 24.1±0.2°.

[0017] Provided is a composition comprising compound 1, or a pharmaceutically acceptable salt thereof, wherein the composition comprises no more than about 0.05% (for example no more than about 100 parts per million) of Impurity 201, Impurity 202, Impurity 203, Impurity 204, Impurity 205, Impurity 206, Impurity 207, Impurity 208, Impurity 209, Impurity 211, and / or Impurity 213.

[0018] Also provided herein is a process for preparing a composition comprising compound 1. Also provided is a pharmaceutical composition comprising a composition comprising compound 1 and a pharmaceutically acceptable carrier.

[0019] Also provided is a method of treating a MTC8 deficiency disorder in an individual, comprising administering to the individual in need thereof, a therapeutically acceptable amount of a composition comprising compound 1, or a pharmaceutical composition described herein. These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds, and / or compositions, and are each hereby incorporated by reference in their entirety.

[0020] BRIEF DESCRIPTION OF FIGURES

[0021] Figure 1 illustrates a chromatogram of the crude reaction mixture sampled during synthesis of compound 5 (Emcitate stage 2) using HPLC Method 1.

[0022] Figure 2 illustrates a chromatogram of impure compound 5 (Emcitate stage 2) spiked with compound 6, 4-methoxyphenol, Impurity 201, and Impurity 208 using HPLC Method 1 identifying the peaks corresponding to 4-methoxyphenol, Impurity 201, Impurity 208, Impurity 209, and compound 6 (Emcitate stage 1).

[0023] Figure 3 illustrates a chromatogram of impure compound 5 (Emcitate stage 2) using HPLC Method 1 identifying the peaks corresponding to Impurity 202, Impurity 203 / 204, Impurity 206 / 207, Impurity 209, Impurity 210, and Impurity 211.

[0024] Figure 4 illustrates a chromatogram of impure compound 5 (Emcitate stage 2) using HPLC Method 1 identifying the peaks corresponding to Impurity 202, Impurity 205, and Impurity 213.

[0025] Figure 5 illustrates a chromatogram of Impurity 002 using HPLC Method 1.

[0026] Figure 6 illustrates a chromatogram of Impurity 003 using HPLC Method 1.

[0027] Figure 7 illustrates a representative chromatogram of a validation batch of compound 1 using HPLC Method 1.

[0028] Figure 8 illustrates a spiking experiment to confirm the absence of compound 6. Two overlayed chromatograms generated using HPLC Method 1 are shown. The bottom line shows a sample of compound 1 and the top line shows a sample of compound 1 which has been spiked with a sample of compound 6 (Emcitate stage 1). Figure 9 illustrates a representative chromatogram of isolated compound 5 (Emcitate stage 2) using HPLC Method 1 showing that the peak corresponding to Impurity 213 is absent.

[0029] Figure 10 illustrates a spiking experiment to confirm the absence of Impurity 201. Two overlayed chromatograms generated using HPLC Method 2 are shown. The bottom line shows a sample of compound 1 and the top line shows a sample of compound 1 which has been spiked with a sample of Impurity 201.

[0030] Figure 11 shows an X-ray Powder Diffraction (XRPD) diffractogram for the crystalline form A of compound 1.

[0031] Figure 12 shows an X-ray Powder Diffraction (XRPD) diffractogram for the crystalline form B of compound 1.

[0032] Figure 13 shows an X-ray Powder Diffraction (XRPD) diffractogram for the crystalline form C of compound 1.

[0033] DEFINITIONS

[0034] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is, as "including, but not limited to." Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0035] Reference throughout this specification to "one embodiment" or "an embodiment" or "some embodiments" or "a certain embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in some embodiments" or "in a certain embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0036] Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0037] As used herein, "tiratricol" may be referred to as compound 1, EMCITATE, TRIAC or 3, 3', 5- triiodothyroacetic acid and has the following chemical structure:

[0038] Tiratricol and its pharmaceutically acceptable salts may form solvates, including hydrates. Solvates formed by the incorporation into the solid-state structure (e.g. crystal structure) of the compounds and salts described herein of molecules of a non-toxic pharmaceutically acceptable solvent. Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulfoxide. Solvates can be prepared by recrystallizing the compounds and salts with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals to analysis using well known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystallography. The solvates can be stoichiometric or nonstoichiometric solvates. In some embodiments, the solvate is a hydrate, such as a hemihydrate, monohydrate, or dihydrate.

[0039] As used herein, "about" means ± 20% of the stated value, and includes more specifically values of ± 10%, ± 5%, ± 2% and ± 1% of the stated value. As used herein, "administering to a patient" refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.

[0040] As used herein, "adjusting administration", "altering administration", "adjusting dosing", or "altering dosing " are all equivalent and mean tapering off, reducing or increasing the dose of the substance, ceasing to administer the substance to the patient, or substituting a different active agent for the substance.

[0041] As used herein, "co-administer" and "co-administration" and variants thereof mean the administration of at least two drugs to a patient either subsequently, simultaneously, or consequently proximate in time to one another (e.g., within the same day, or week or period of 30 days, or sufficiently proximate that each of the at least two drugs can be simultaneously detected in the blood plasma). When co-administered, two or more active agents can be coformulated as part of the same composition or administered as separate formulations. This also may be referred to herein as "concomitant" administration or variants thereof.

[0042] As used herein, "amelioration of the symptoms" of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the composition.

[0043] As used herein, "baseline" refers to the period of time just prior to initiation of therapy. The patient's condition just prior to initiation of therapy can be referred to as the patient's baseline condition.

[0044] As used herein, "detectable amount" means a quantity that is above the detection limit of the apparatus or assay used to quantify the amount of the substance being measured such that the presence of the substance can be confirmed with a high degree of statistical significance (e.g. 99% confidence). In certain embodiments, a "detectable amount" is greater than 0.10%, greater than 0.05%, greater than 0.01%, or greater than 0.001%.

[0045] As used herein the term "disorder" is intended to be generally synonymous, and is used interchangeably with, the terms "disease," "syndrome," and "condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms.

[0046] As used herein, a "dosage" is the prescribed administration of a specific amount, number, and frequency of doses over a specific period of time.

[0047] As used herein, a "dose" means the measured quantity of an active agent to be taken at one time by a patient. In certain embodiments, wherein the active agent is not a free base, the quantity is the molar equivalent to the corresponding amount of free base.

[0048] As used herein, "dosing regimen" means the dose of an active agent taken at a first time by a patient and the interval (time or symptomatic) at which any subsequent doses of the active agent are taken by the patient such as from about 20 to about 160 mg once daily, e.g., about 20, about 40, about 60, about 80, about 100, about 120, or about 160 mg once daily. The additional doses of the active agent can be different from the dose taken at the first time.

[0049] As used herein, "down-titration" of a compound refers to decrease the amount of a compound to achieve a therapeutic effect that occurs before dose-limiting intolerability for the patient. Down-titration can be achieved in one or more dose increments, which may be the same or different.

[0050] As used herein, "effective amount" and "therapeutically effective amount" of an agent, compound, drug, composition, or combination is an amount which is nontoxic and effective for producing some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient). The precise therapeutically effective amount for a subject may depend upon, e.g., the subject's size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0051] As used herein, "informing" means referring to or providing published material, for example, providing an active agent with published material to a user; or presenting information orally, for example, by presentation at a seminar, conference, or other educational presentation, by conversation between a pharmaceutical sales representative and a medical care worker, or by conversation between a medical care worker and a patient; or demonstrating the intended information to a user for the purpose of comprehension.

[0052] As used herein, "labeling" means all labels or other means of written, printed, graphic, electronic, verbal, or demonstrative communication that is upon a pharmaceutical product or a dosage form or accompanying such pharmaceutical product or dosage form.

[0053] As used herein, the terms "manage," "managing" and "management" refer to preventing or slowing the progression, spread or worsening of a disease or disorder, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease or disorder. In this regard, the term "managing" encompasses treating a subject who had suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease.

[0054] As used herein, "a medical care worker" means a worker in the health care field who may need or utilize information regarding an active agent, including a dosage form thereof, including information on safety, efficacy, dosing, administration, or pharmacokinetics. Examples of medical care workers include physicians, pharmacists, physician's assistants, nurses, aides, caretakers (which can include family members or guardians), emergency medical workers, and veterinarians.

[0055] As used herein, "Medication Guide" means an FDA-approved patient labeling for a pharmaceutical product conforming to the specifications set forth in 21 CFR 208 and other applicable regulations which contains information for patients on how to safely use a pharmaceutical product. A medication guide is scientifically accurate and is based on, and does not conflict with, the approved professional labeling for the pharmaceutical product under 21 CFR 201.57, but the language need not be identical to the sections of approved labeling to which it corresponds. A medication guide is typically available for a pharmaceutical product with special risk management information. As used herein, "patient" or "individual" or "subject" means a mammal, including a human, for whom or which therapy is desired, and generally refers to the recipient of the therapy.

[0056] As used herein, "pharmaceutically acceptable" refers to a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[0057] "Pharmacologically active" (or simply "active") as in a "pharmacologically active" (or "active") derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.

[0058] As used herein, in some embodiments, "pharmaceutically acceptable salt" refers to base addition salts with an inorganic or an organic base. Inorganic bases which may be used to prepare salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, manganese, aluminum hydroxides, carbonates, bicarbonates, phosphates, and the like; particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium hydroxides, carbonates, bicarbonates, or phosphates. Organic bases from which may be used to prepare salts include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some circumstances, for an appropriate compound, "pharmaceutically acceptable salt" may refer to acid addition salts with an inorganic or an organic acid. Lists of suitable salts are found in WO 87 / 05297, Johnston et al., published September 11, 1987; Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; and J. Pharm. Sei., 66, 2 (1977), each of which is incorporated herein by reference in its entirety. A reference for the preparation and selection of pharmaceutical salts of the present disclosure is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002 which is incorporated herein by reference in its entirety. The organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic,

[0059] 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4- chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic,

[0060] 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic, glucoheptonic, 3- phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid, and the like.

[0061] As used herein, "prevent," "preventing," and "prevention" are meant to include a method of delaying and / or precluding the onset of a disorder, disease, or condition, and / or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.

[0062] As used herein, a "product" or "pharmaceutical product" means a dosage form of an active agent plus published material, and optionally packaging.

[0063] As used herein, "product insert" means the professional labeling (prescribing information) for a pharmaceutical product, a patient package insert for the pharmaceutical product, or a medication guide for the pharmaceutical product.

[0064] As used herein, "professional labeling" or "prescribing information" means the official description of a pharmaceutical product approved by a regulatory agency (e.g., FDA or EMA) regulating marketing of the pharmaceutical product, which includes a summary of the essential scientific information needed for the safe and effective use of the drug, such as, for example indication and usage; dosage and administration; who should take it; adverse events (side effects); instructions for use in special populations (pregnant women, children, geriatric, etc.); safety information for the patient, and the like.

[0065] As used herein, "published material" means a medium providing information, including printed, audio, visual, or electronic medium, for example a flyer, an advertisement, a product insert, printed labeling, an internet web site, an internet web page, an internet pop-up window, a radio or television broadcast, a compact disk, a DVD, an audio recording, or other recording or electronic medium.

[0066] As used herein, "risk" means the probability or chance of adverse reaction, injury, or other undesirable outcome arising from a medical treatment. An "acceptable risk" means a measure of the risk of harm, injury, or disease arising from a medical treatment that will be tolerated by an individual or group. Whether a risk is "acceptable" will depend upon the advantages that the individual or group perceives to be obtainable in return for taking the risk, whether they accept whatever scientific and other advice is offered about the magnitude of the risk, and numerous other factors, both political and social. An "acceptable risk" of an adverse reaction means that an individual or a group in society is willing to take or be subjected to the risk that the adverse reaction might occur since the adverse reaction is one whose probability of occurrence is small, or whose consequences are so slight, or the benefits (perceived or real) of the active agent are so great. An "unacceptable risk" of an adverse reaction means that an individual or a group in society is unwilling to take or be subjected to the risk that the adverse reaction might occur upon weighing the probability of occurrence of the adverse reaction, the consequences of the adverse reaction, and the benefits (perceived or real) of the active agent. "At risk" means in a state or condition marked by a high level of risk or susceptibility. Risk assessment consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product.

[0067] As used herein, "safety" means the incidence or severity of adverse events associated with administration of an active agent, including adverse effects associated with patient-related factors (e.g., age, gender, ethnicity, race, target illness, abnormalities of renal or hepatic function, co-morbid illnesses, genetic characteristics such as metabolic status, or environment) and active agent-related factors (e.g., dose, plasma level, duration of exposure, or concomitant medication).

[0068] As used herein, a subject is said to "tolerate" a dose of a compound if administration of that dose to that subject does not result in an unacceptable adverse event or an unacceptable combination of adverse events. One of skill in the art will appreciate that tolerance is a subjective measure and that what may be tolerable to one subject may not be tolerable to a different subject. For example, one subject may not be able to tolerate headache, whereas a second subject may find headache tolerable but is not able to tolerate vomiting, whereas for a third subject, either headache alone or vomiting alone is tolerable, but the subject is not able to tolerate the combination of headache and vomiting, even if the severity of each is less than when experienced alone.

[0069] As used herein, "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0070] As used herein, "up-titration" of a compound refers to increasing the amount of a compound to achieve a therapeutic effect that occurs before dose-limiting intolerability for the patient. Up- titration can be achieved in one or more dose increments, which may be the same or different.

[0071] DETAILED DESCRIPTION

[0072] As mentioned above, the invention provides a process for the preparation of a composition comprising compound 1 wherein said process comprises a) preparing an aqueous solution of the disodium salt of compound 1 (compound 2) b) adding said aqueous solution to a mixture of acetic acid and aqueous hydrochloric acid, c) heating the mixture, d) allowing compound 1 to crystallise, and e) isolating crystalline compound 1.

[0073] The process is especially effective in providing compound 1 in an enhanced level of purity and, in particular, in a favourable crystalline form.

[0074] Compound 1 is 2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)acetic acid and it is also known as Tiratricol and Triac. It is known that the diiodinated analogue of compound 1 (2-(4- (4-hydroxyphenoxy)-3,5- diiodophenyl)acetic acid (also known as Diac)) and the tetraiodinated analogue of compound 1 (4-(4-Hydroxy-3,5-diiodophenoxy)-3,5-diiodobenzeneacetic acid (also known as Tetrac)) are commonly seen impurities in 2-(4-(4-hydroxy-3-iodophenoxy)-3,5- diiodophenyl)acetic acid (Tiratricol, also known as Triac). They are acceptable, but their quantities must be kept within limits. The invention provides a simple process for providing compound 1 in a good level of purity.

[0075] Provided is a process for the preparation of compound 1 comprising crystallizing compound 1 from a solution of a disodium salt of compound 1 (i.e., compound 2)

[0076] In some embodiments, crystallizing compound 1 comprises adding a mixture of acetic acid:water and HCI to the solution of compound 2. In some embodiments, the solution of compound 2 is added to the mixture of acetic acid:water and HCI.

[0077] In some embodiments, the addition occurs at elevated temperature, e.g., from about 30 to about 40 °C.

[0078] In some embodiments, the mixture of acetic acid:water and HCI comprises four volumes of acetic acid with 2.5 equivalents of 32% aqueous HCI.

[0079] In some embodiments the acid is a mixture of about 2.24 equivalents of 33% hydrochloric acid, about 4.21 relative weights of acetic acid, and about 0.53 volumes of water.

[0080] In an embodiment, the compound 2 is in aqueous solution and that solution is mixed with the mixture of acetic acid and aqueous HCI. That is to say that step b) is the step of mixing compound 2 in aqueous solution with the mixture of acetic acid and aqueous HCI.

[0081] In an embodiment, the mixture of acetic acid and water is heated to 25 to 45 °C, for example 30 to 40 °C, for example around 35 °C. In an embodiment, an initial portion of the solution of compound 2 (for example 10 to 50%, for example 10 to 30%, for example around 20% of the solution) may be added to the mixture initially over an initial period. The initial period may be from 5 minutes to 1 hour, for example 10 to 30 minutes. The remainder of the solution may then be added over a second addition period. The second addition period may be from 5 minutes to 3 hours, for example 10 minutes to 2 hours, for example 20 minutes to 2 hours.

[0082] For example, the mixture of acetic acid and water comprises acetic acid, aqueous HCI (with a % HCI content between 5 and 50%) and water in a weight ratio of 3-15 parts acetic acid : 0.3 to 3 parts HCI : 1 part water, for example 5-12 parts acetic acid : 0.5 to 23 parts HCI : 1 part water, for example 7-8 parts acetic acid : 0.8 to 1.2 parts HCI : 1 part water, for example 8.5 parts acetic acid : 0.95 parts HCI : 1 part water. The strength of the HCI may be in the range 5 and 50%, for example 20 to 40%, for example 30 to 40%, for example 31 to 35%, for example 33%.

[0083] Advantageously, the concentration and volume of HCI is selected so that it provides from 1.5 to 3.0 molar equivalents of HCI relative to the amount of compound 2. Further advantageously, the concentration and volume of HCI is selected so that it provides from 1.8 to 2.7 molar equivalents of HCI relative to the amount of compound 2, for example from 2.0 to 2.5 molar equivalents, for example 2.2 to 2.3 molar equivalents. Once the addition is complete, the mixture may be cooled. For example, it may be cooled to 5 to 15 °C, for example to around 10 °C.

[0084] The crystallisation can, optionally be accelerated by the addition of seed crystals. They may be added between the initial addition period and the second addition period.

[0085] When the crystallisation is judged to be sufficiently complete (for example after 20 minutes to 2 hours, for example 30 minutes to 90 minutes, or example around 60 minutes), the solid material is isolated by filtration. Thereafter, it may be washed with water and dried.

[0086] In some embodiments, compound 2 is in an aqueous solution. In some embodiments, the amount of water is about 5 volumes relative to compound 2. For example, from 1 to 10 kg of water is used for each kg of compound 2; advantageously, from 2 to 8 kg of water is used for each kg of compound 2, for example from 3 to 7 kg of water is used for each kg of compound 2; for example around 5 kg of water is used for each kg of compound 2.

[0087] In some embodiments, the solution of the disodium salt of compound 1 is treated with activated charcoal prior to crystallization. In some embodiments, treating with activated charcoal comprises treating a solution of the disodium salt of compound 1 in isopropanol, water, and acetic acid with activated carbon, then removing the activated carbon.

[0088] In some embodiments, it may be desirable to recrystallize the disodium salt of compound 1 (ie compound 2), prior to the preparation of the composition comprising compound 1 in accordance with the invention. In some embodiments, the disodium salt of compound 1 is obtained by iodination of compound

[0089] 3, or a salt thereof, by in situ formation of NaOl

[0090] In some embodiments, the NaOl is formed using NaOCI / Nal in aqueous NaOH.

[0091] In some embodiments, the disodium salt of compound 1 is obtained by mixing compound 3, water, sodium iodide, and sodium hydroxide; and adding an aqueous solution of sodium hypochlorite and sodium hydroxide.

[0092] In some embodiments, excess aqueous NaOH is used. In some embodiments, more than 2 equivalents, such as about 2.5 equivalents of 30% NaOH is used.

[0093] In some embodiments, excess Nal is used. In some embodiments, about 1.3 equivalents of Nal is used.

[0094] In some embodiments, an excess of NaOCI is used. In some embodiments, about 1.1 equivalents aqueous NaOCI is used.

[0095] In some embodiments, the reaction is performed at a temperature of from about 15 to about 35 °C (such as from about 15 to about 25 °C, such as 25 °C).

[0096] In some embodiments, the process further comprises purifying the disodium salt of compound 1. In some embodiments, the disodium salt is purified by extraction with a lower alkanol, such as 1-butanol, instead of direct crystallization.

[0097] The process further comprises precipitating the solid disodium salt of compound 1. In some embodiments, the solid disodium salt of compound 1 is precipitated by mixing an aqueous solution of the disodium salt of compound 1 with 1-butanol; separating the aqueous layer; and adding isopropanol to the 1-butanol solution. In some embodiments, precipitating the solid disodium salt further comprises adding water to the 1-butanol solution of the disodium salt of compound 1 prior to adding isopropanol. In some embodiments, the temperature during the addition of the isopropanol is maintained at about 35 °C to about 45 °C. In some embodiments, the temperature after the addition of the isopropanol is reduced to about 0 °C to about 5 °C and maintained for at least two hours.

[0098] In some embodiments, compound 3, or a salt thereof, is prepared by a process comprising reaction reacting compound 4 or a salt thereof, with a mixture of an iodide salt and a protic acid, to provide compound 3, or a salt thereof

[0099] In some embodiments, the iodide salt is sodium iodide.

[0100] In some embodiments, the protic acid is methanesulfonic acid.

[0101] In some embodiments, the temperature of the reaction is maintained at about 110 °C to about 125 °C.

[0102] In some embodiments, the reacting compound 4 or a salt thereof, with a mixture of an iodide salt and a protic acid, occurs in a solvent. In some embodiments, the solvent is acetic acid. In some embodiments, compound 4, or a salt thereof, is prepared by a process comprising reacting compound 5 or a salt thereof, with a diazotizing reagent; and reacting the resultant mixture with a triiodide salt, to provide compound 4, or a salt thereof.

[0103] In some embodiments, the diazotizing reagent is n itrosylsu If u ric acid.

[0104] In some embodiments, compound 5 is mixed with sulfuric acid prior to the addition of the nitrosylsulf u ric acid.

[0105] In some embodiments, the triiodide salt is formed from a mixture of an iodide salt and iodine.

[0106] In some embodiments, the iodide salt is potassium iodide.

[0107] In some embodiments, the mixture of potassium iodide and iodine is dissolved in a mixture of acetic acid and water.

[0108] In some embodiments, compound 5 and the nitrosylsu If u ric acid are reacted at a temperature of about 0 °C to about 15 °C.

[0109] In some embodiments, the reaction with the triiodide salt occurs at a temperature of about 30°C to about 40°C. In some embodiments, the process further comprises adding a reducing agent after the reaction with the triiodide salt. In some embodiments, the reducing agent is sodium metabisulfite.

[0110] In some embodiments, compound 5, or a salt thereof, is prepared by a process comprising reacting compound 6 or a salt thereof, with hydrogen gas, a hydrogenation catalyst, a base, and a solvent.

[0111] In some embodiments the hydrogenation catalyst is palladium (such as palladium on carbon), platinum (such as platinum on carbon or reduced platinum oxide), platinum / vanadium, or nickel (such as Raney nickel).

[0112] In some embodiments, the hydrogenation catalyst is palladium on carbon.

[0113] In some embodiments, the base is triethylamine and the solvent is a mixture of isopropanol and water.

[0114] In some embodiments, the amount of isopropanol is about 2.1 volumes relative to compound 6; the amount of water is about 3.1 volumes relative to compound 6; and the triethylamine is about 1.3 molar equivalents relative to compound 6.

[0115] In some embodiments, the reaction mixture containing compound 5 is filtered and compound 5 is then crystalized by addition of formic acid. In some embodiments, the formic acid is about 2.0 equivalents relative to compound 6.

[0116] In some embodiments, the formic acid is added at about 50 °C.

[0117] In some embodiments, compound 5, or a salt thereof, is prepared by a process comprising reducing compound 6 to provide compound 5, or a salt thereof. In some embodiments, compound 6 is dissolved in a solvent. In some embodiments, the solvent is a mixture of isopropanol and water. In some embodiments, the amount of isopropanol is about 2.1 volumes relative to compound 6. In some embodiments, the amount of water is about 3.1 volumes relative to compound 6. In some embodiments, the ratio of isopropanol to water is about 2:3. In some embodiments, the solvent is water. In some embodiments, the base is triethylamine. In some embodiments the triethylamine is about 1.3 molar equivalents relative to compound 6. In some embodiments, a hydrogenation catalyst is added to the mixture. In some embodiments, the hydrogenation catalyst is palladium on carbon. In some embodiments the hydrogenation catalyst is 5% palladium on carbon. In some embodiments the palladium on carbon is about 0.17 mol % relative to compound 6. In some embodiments oxygen is purged from the mixture. In some embodiments hydrogen gas is introduced to the reaction mixture. In some embodiments hydrogen gas is introduced to the mixture at a pressure greater than atmospheric pressure. In some embodiments hydrogen gas is introduced to the mixture at a pressure of about 10-20 bar. In some embodiments hydrogen gas is introduced to the mixture at a pressure of about 15 bar. In some embodiments, after the hydrogen gas is added the temperature of the mixture is allowed to warm to about 50°C to about 60°C. In some embodiments, the temperature of the mixture is maintained at about 55°C. In some embodiments, the mixture is agitated or stirred until hydrogen consumption ceases. In some embodiments, the reaction is continued for at least one hour after hydrogen consumption ceases. The product, compound 5, is isolated and purified using methods known in the art.

[0118] In some embodiments, compound 6, or a salt thereof, is prepared by a process comprising reacting 4-chloro-3,5-dinitrophenylacetic acid and 4- methoxyphenol with a base in a solvent.

[0119] In some embodiments, the solvent is a mixture of water and 1-butanol and the base is 50% aqueous potassium hydroxide.

[0120] In some embodiments, the amount of 1-butanol is about 2.5 volumes relative to 4- chloro-3,5- dinitrophenylacetic acid; and the amount of water is about 2.35 volumes relative to 4- chloro- 3,5-dinitrophenylacetic acid.

[0121] In some embodiments, compound 6 is crystalized by addition of formic acid.

[0122] In some embodiments, the formic acid is about 2.2 equivalents relative to 4-chloro-3,5- dinitrophenylacetic acid.

[0123] In some embodiments, the formic acid is added at about 60 °C.

[0124] In some embodiments, compound 6, or a salt thereof, is prepared by a process comprising combining compound 8 and compound 7. In some embodiments, 1.5 molar equivalents of compound 7 are used relative to compound 8. In some embodiments, the solvent is a mixture of 1-butanol and water. In some embodiments, the amount of n-butanol is about 2.5 volumes relative to compound 8. In some embodiments, the amount of water is about 2.0 volumes relative to compound 8. In some embodiments, the ratio of 1-butanol to water is about 10:9. In some embodiments, the base is potassium hydroxide. In some embodiments the potassium hydroxide is an aqueous solution. In some embodiments the potassium hydroxide is a 50% w / w solution in water. In some embodiments the potassium hydroxide is 2.3 molar equivalents relative to compound 8. In some embodiments, the potassium hydroxide is added at a temperature of about 20°C to about 30°C. In some embodiments, the potassium hydroxide is added at a temperature of below 15°C to about 25°C. In some embodiments, the potassium hydroxide is added over a period of at least 30 minutes. In some embodiments, after the potassium hydroxide is added the temperature of the mixture is raised to about 55°C to about 65°C. In some embodiments, after the potassium hydroxide is added the temperature of the mixture is warmed to about 60°C. In some embodiments, the mixture is held at about 55°C to about 65°C for about 2.5 to about 3.5 hours. In some embodiments, the mixture is held at about 60°C for about 3 hours. The product, compound 6, is isolated and purified using methods known in the art.

[0125] In some embodiments, compound 8, or a salt thereof, is prepared by nitrating compound 9. In some embodiments, to a solution of compound 9 in a solvent, such as sulfuric acid, is added a nitrating agent, such as nitric acid. In some embodiments, the amount of sulfuric acid is about 6 volumes relative to compound 9. In some embodiments, the amount of sulfuric acid is at least about 6 volumes relative to compound 9. In some embodiments, the amount of sulfuric acid is about 10 volumes relative to compound 9. The mixture is stirred, optionally at elevated temperatures. In some embodiments, the mixture is stirred and nitric acid is added at a temperature of about 30°C to about 40°C. In some embodiments, the mixture is stirred and nitric acid is added at a temperature of about 50°C to about 60°C. In some embodiments, the mixture is stirred and nitric acid is added at a temperature of about 50°C to about 65°C. In some embodiments, the nitric acid is added at a temperature of up to about 75°C. In some embodiments, the mixture is stirred and a first portion of nitric acid is added at a temperature of about 30°C to about 40°C. In some embodiments, the mixture is stirred and a first portion of nitric acid is added at a temperature of about 30°C to about 60°C. In some embodiments, the mixture is stirred and a first portion of nitric acid is added at a temperature of about 35°C. In some embodiments, the mixture is stirred and a second portion of nitric acid is added at a temperature of about 50°C to about 65°C. In some embodiments, the second portion of nitric acid is added at a temperature of about 50°C to about 60°C. In some embodiments, the second portion of nitric acid is added at a temperature of about 55°C. In some embodiments the first portion of nitric acid is about 1.1 molar equivalents relative to compound 9. In some embodiments the second portion of nitric acid is about 1.2 molar equivalents relative to compound 9. Disclosed herein is a pharmaceutical composition comprising the composition of compound 1 and a pharmaceutically acceptable carrier.

[0126] In some embodiments the composition does not include calcium hydrogen phosphate dihydrate. Disclosed herein is a method of treating a MTC8 deficiency disorder in an individual, comprising administering to the individual in need thereof, a therapeutically acceptable amount of a composition of compound 1 as disclosed herein, or a pharmaceutical composition disclosed herein.

[0127] In some embodiments the MCT8 deficiency disorder is Allan-Herndon-Dudley syndrome. Also provided is a process for the preparation of compound 1 as set forth in the scheme below. Also provided is compound 1 prepared by a process described herein. Also provided is a composition comprising compound 1, optionally wherein compound 1 is prepared by a process described herein, wherein the composition comprises no more than 1.0% of compound 3 or a salt thereof; or no more than 0.5% of compound 10, or a salt thereof; or no more than 0.15% (for example no more than about 100 parts per million) of the monosodium salt of compound 1; or no more than about 0.15% (for example no more than about 100 parts per million) of 4-chloro- 3,5-dinitrophenyl acetic acid; or no more than about 0.15% (for example no more than about 100 parts per million) of Compound 6; and or no more than about 0.15% (for example no more than about 100 parts per million) of Compound 5.

[0128] Also provided is a composition comprising compound 1, optionally wherein compound 1 is prepared by a process described herein, wherein the composition comprises no more than about 0.15% (for example no more than about 100 parts per million) of Impurity 301, Impurity 302, Impurity 303, Impurity 304, Impurity 305, Impurity 306, Impurity 307, Impurity 308, Impurity 401, Impurity 402, Impurity 403, Impurity 404, Impurity 405, Impurity 406, Impurity 407, and / or Impurity 408.

[0129] Provided is a composition comprising compound 1, or a pharmaceutically acceptable salt thereof, wherein the composition comprises no more than about 0.05% (for example no more than about 100 parts per million) of Impurity 201, Impurity 202, Impurity 203, Impurity 204, Impurity 205, Impurity 206, Impurity 207, Impurity 208, Impurity 209, Impurity 211, and / or Impurity 213.

[0130] In some embodiments, the composition comprises no more than about 100 parts per million of Impurity 201, Impurity 202, Impurity 203, Impurity 204, Impurity 205, Impurity 206, Impurity 207, Impurity 208, Impurity 209, Impurity 211, and / or Impurity 213.

[0131] In some embodiments, the composition comprises no more than about 0.05% (for example no more than about 100 parts per million) of Impurity 301, Impurity 302, Impurity 303, Impurity 304, Impurity 305, Impurity 306, Impurity 307, Impurity 308, Impurity 401, Impurity 402, Impurity 403, Impurity 404, Impurity 405, lmpurity406, Impurity 407, and / or Impurity 408.

[0132] In some embodiments, the composition comprises no more than about 0.1% of compound 2; or no more than about 1.0% of compound 3, or a salt thereof; or no more than about 0.5% of compound 10, or a salt thereof; or no more than about 0.05% (for example no more than about 100 parts per million) of 4-chloro- 3,5-dinitrophenyl acetic acid, or a salt thereof; or no more than about 0.05% (for example no more than about 100 parts per million) of Compound 6, or a salt thereof;

[0133] And or no more than about 0.05% (for example no more than about 100 parts per million) of

[0134] Compound 5, or a salt thereof

[0135] In some embodiments, the composition comprises no more than about 100 parts per million of Compound 5 and / or no more than about 100 parts per million of Compound 6.

[0136] The invention provides a composition comprising compound 1, or a pharmaceutically acceptable salt thereof,

[0137] (1) wherein the composition further comprises from 0.01% to 1.0% of compound 3 or a pharmaceutically acceptable salt thereof and / or from 0.01% to 0.5% of compound 10, or a pharmaceutically acceptable salt thereof. 0)

[0138] In particular, the invention provides such a composition wherein the composition comprises compound 3 in an amount between about 0.05% and 0.7%, more preferably between about 0.1% and 0.6%, more preferably between about 0.3% and 0.6%, more preferably between about 0.35% and 0.5%, and most preferably between about 0.35% and 0.36%.

[0139] In particular, the invention provides such a composition wherein the composition comprises compound 10 in an amount between about 0.05% and 0.5%, more preferably between about 0.1% and 0.5% more preferably between about 0.2% and 0.5%, more preferably between about 0.2% and 0.4%, most preferably between about 0.26% and 0.30%. For example, the composition comprises between about 0.35% and 0.5% of compound 3, and between about 0.26% and 0.30% of compound 10.

[0140] In a particular embodiment, the composition comprises around 0.35% of compound 3, and around 0.28% of compound 10.

[0141] Preferably, in a composition of the invention, the compound 1 is the free acid compound. Most preferably, the compound 1 is in crystalline form.

[0142] Also provided is compound 1 prepared by a process described herein. The invention also provides a composition comprising compound 1 prepared by a process described herein. The process described hereinabove and in further detail in the examples section provides compound 1 in crystalline form. The crystalline form obtained is in the form named Polymorph A. The invention therefore provides compound 1 in crystalline form characterized by a powder X-ray diffractogram (XRPD) having characteristic peaks at 20 = 15.3±0.2°, 7.6±0.2° and 24.1±0.2°.

[0143] Preferably, the crystalline form has a powder X-ray diffractogram that is further characterised by comprising additional one or more peaks, such as one additional peak or two additional peaks at 20 angles selected from the group selected from 9.4±0.2° and 22.9±0.2°. For example, it is further characterised by an additional peak at a 20 angle of 9.4±0.2°. Alternatively or additionally, it is further characterised by an additional peak at a 20 angle of 22.9±0.2°.

[0144] More preferably, the crystalline form has a powder X-ray diffractogram that is further characterised by comprising additional one or more peaks, such as one additional peak, two additional peaks or three additional peaks at 20 angles selected from the group selected from 21.4±0.2°, 22.0±0.2° and 25.7±0.2°. For example, it is further characterised by an additional peak at a 20 angle of 21.4±0.2°. Alternatively or additionally, it is further characterised by an additional peak at a 20 angle of 22.0±0.2°. Alternatively or additionally, it is further characterised by an additional peak at a 20 angle of 25.7±0.2°.

[0145] For example, the crystalline form is characterized by a powder X-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in Figure 11.

[0146] To date, two other crystalline forms have been identified: Form B and Form C. The composition of the invention is essentially free from Forms B and C. That is to say that it contains under 5% w / w of Form B and under 5% w / w of Form C, preferably under 1.0% w / w of FormB and under 1.0% w / w of Form C, for example under 0.5% w / w of FormB and under 0.5% w / w of Form C.

[0147] Form B of Compound 1 is characterized by a powder X-ray diffractogram (XRPD) having characteristic peaks at 20 - 23.1±0.2°, 19.9±0.2° and 24.9±0.2°. Generally, the crystalline form has a powder X-ray diffractogram that is further characterised by comprising additional one or more peaks, such as one additional peak, two additional peaks or three additional peaks at 20 angles selected from the group selected from, 25.6±0.2°, 35.1±0.2° and 21.6±0.2°. For example, it is further characterised by an additional peak at a 20 angle of 25.6±0.2°. Alternatively or additionally, it is further characterised by an additional peak at a 20 angle of 35.1±0.2°.

[0148] Alternatively or additionally, it is further characterised by an additional peak at a 20 angle of 21.6±0.2°. For example, the crystalline form has a powder X-ray diffractogram that is further characterised by comprising additional one or more peaks, such as one additional peak or two additional peaks at 20 angles selected from the group selected from 29.9±0.2° and 6.8±0.2°. For example, it is further characterised by an additional peak at a 20 angle of 29.9±0.2°. Alternatively or additionally, it is further characterised by an additional peak at a 20 angle of 6.8±0.2°.

[0149] Under certain conditions, Form B is more stable than Form A. However, in the presence of the combination of water, hydrochloric and acetic acid, Form A is the more stable. That is to say that under the crystallization conditions of the current invention (ie the conditions that enable the preparation of Compound 1 in higher purity than prior methods), Form A is more stable.

[0150] Amongst other advantages, Form A enables conditions to be used that provide the product composition is a higher level of purity than previously possible.

[0151] Form C of Compound 1 is characterized by a powder X-ray diffractogram (XRPD) having characteristic peaks at 20 - 22.3±0.2°, 26.7±0.2° and 22.8±0.2°. Generally, the crystalline form has a powder X-ray diffractogram that is further characterised by comprising additional one or more peaks, such as one additional peak, two additional peaks or three additional peaks at 20 angles selected from the group selected from 25.6±0.2°, 27.4±0.2° and 35.2±0.2°. For example, it is further characterised by an additional peak at a 20 angle of 25.6±0.2°. Alternatively or additionally, it is further characterised by an additional peak at a 20 angle of 27.4±0.2°. Alternatively or additionally, it is further characterised by an additional peak at a 20 angle of 35.2±0.2°. For example, the crystalline form has a powder X-ray diffractogram that is further characterised by comprising additional one or more peaks, such as one additional peak or two additional peaks at 20 angles selected from the group selected from 17.8±0.2° and 18.3±0.2°. For example, it is further characterised by an additional peak at a 20 angle of 17.8±0.2°. Alternatively or additionally, it is further characterised by an additional peak at a 20 angle of 18.3±0.2°.

[0152] It has been found that Form C turns amorphous when dried. That makes it unsuitable for use in a pharmaceutical product that is to be provided in tablet form.

[0153] The term "substantially in accordance with" with reference to XRPD means that usual variability in peak positions and relative intensities of the peaks are to be taken into account. For example, a typical precision of the 20 values is in the range of ± 0.2° 20. Thus, a diffraction peak that usually appears at 15.3° 20, for example, can appear between 15.1° and 15.5° 20 on most X- ray diffractometers under standard conditions. Furthermore, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only. Typically, XRPD measurements are carried out at a temperature of 20°C.

[0154] One of ordinary skill in the art will appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. In particular, it is generally known that intensities in an X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensities should not be relied on. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the mentioned diffraction angles. Consequently, it is to be understood that the crystal forms of the present invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figure 11. Rather, any crystal forms that provide X- ray diffraction patterns substantially identical to those disclosed in the accompanying

[0155] Figure fall within the scope of the present invention. The ability to ascertain substantial accordance of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.

[0156] Also provided is a pharmaceutical composition comprising compound 1 or a composition of compound 1, as described herein, and a pharmaceutically acceptable carrier.

[0157] The choice of pharmaceutically acceptable carrier or excipient, to a large extent, depends on factors, such as the particular mode of administration, the effect of the excipient on the solubility and stability of the active ingredient, and the nature of the dosage form. In some embodiments, the pharmaceutical composition does not include calcium hydrogen phosphate dihydrate. In some embodiments, the pharmaceutical composition further comprises calcium hydrogen phosphate, corn starch, lactose monohydrate, and magnesium stearate.

[0158] The pharmaceutical compositions may be provided in unit dosage forms or multiple- dosage forms. Unit-dosage forms, as used herein, refer to physically discrete units suitable for administration to human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampoules, syringes, and individually packaged tablets and capsules. Unit dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of multiple-dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.

[0159] In some embodiments, the pharmaceutical composition comprises 350 mcg compound 1.

[0160] In some embodiments, the pharmaceutical composition is formulated as a tablet. In some embodiments, the tablets are suspended in water before administration. In some embodiments, the tablets do not need to be crushed or ground before suspension. In some embodiments, the volume of water used to suspend the tablets is adjusted to each individual dose.

[0161] In some embodiments, the pharmaceutical composition is administered through a PEG tube. In some embodiments, when administering through a PEG tube, the pharmaceutical composition is suspended in water and given through the tube and the tube is then flushed with water.

[0162] Also provided is a method of treating a MTC8 deficiency disorder in an individual, comprising administering to the individual in need thereof, a therapeutically acceptable amount of compound 1, a composition comprising compound 1, or a pharmaceutical composition comprising compound 1.

[0163] In some embodiments, the dose being administered is individually adjusted based on serum TSH levels, (F)T4 and T3 levels of the individual.

[0164] In some embodiments, administration comprises an individualized dose titration schedule based on the following schedule:

[0165] Clinical experience in MCT8 deficiency with dose titration demonstrated that a maintenance dose for patients over 10 kg of body weight is frequently between 700-2100 micrograms (2-6 tablets of 350 micrograms) per day divided into 1-3 administrations. Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented only by way of illustration and to assist one of ordinary skill in using the disclosure. The examples are not intended in any way to otherwise limit the scope of the disclosure.

[0166] EXAMPLES

[0167] The following examples illustrate the invention.

[0168] Example 1

[0169] 2-(4-Chloro-3,5-dinitrophenyl)acetic acid (compound 8)

[0170] A reactor was charged with 240 L sulfuric acid. 40.0 kg of 4-chlorophenyl acetic acid was added and stirred until mostly dissolved and warmed to 35°C. 16.6 kg of nitric acid was added over 1 hour 52 minutes after which the temperature was 56°C. 18.1 kg of nitric acid was added over 2 hours 54 minutes at 50-65°C. At the end of the addition the temperature was 59°C. The reaction mixture was further stirred for 2 hours 27 minutes at 56°C. Conversion was checked by HPLC (< 2.5%-a / a mono-nitro intermediate). The reaction mixture was cooled to 34°C. The reaction mixture was added to a mixture of 720 L water and 12.1 kg nitric acid over 1 hour 17 minutes, during which the temperature of the quenching solution was maintained between 40- 65°C (starting temperature 49°C, ending temperature 58°C). The resulting suspension was cooled to 29°C over 37 minutes, stirred for an additional 5 minutes, filtered and the filter cake was washed with 925 L water. The wet product is isolated as white to yellow solid, purity: 95.9%-a / a by HPLC.

[0171] Example 2

[0172] 2-(4-Chloro-3,5-dinitrophenyl)acetic acid (compound 8) - Reaction monitoring Area percentages (%-a / a, 230 nm) of 4-chlorophenylacetic acid (starting material), 4- chloro-3- nitrophenylacetic acid (intermediate) and 4-chloro-3,5-dinitrophenylacetic acid (product) during reaction at 55°C. Example 3

[0173] 2-(4-Chloro-3,5-dinitrophenyl)acetic acid (compound 8) - Work up and filterability testing

[0174] Summarized results of the experiments done during process development of 4-chloro- 3,5- dinitrophenylacetic acid. Standard conditions: 6 vol. H2SO4, dose 2.3 eq. HNO3 over approximately 2 h, 1-2 h post stirring, followed by quench.

[0175] 11Reaction temperature,2)temperature of reaction mixture during quench,3)starting material stirred overnight at 55°C,4)reaction mixture further stirred overnight at 55°C,5)quench suspension further stirred overnight at 20°C,6)Product disposed,7)1.6 eq. HNO3 added to reaction solution before quench,8)0.8 eq. HNO3 added to reaction solution before quench,9)0.8 eq. HNO3 added to reaction solution before quench,10)0.8 eq. HNO3 added to reaction solution before quench,n)2.4 eq. HNO3 added to reaction solution before quench.

[0176] Example 4

[0177] 2-(4-(4-methoxyphenoxy)-3,5-dinitrophenyl)acetic acid (compound 6)

[0178] 4-Chloro-3,5-dinitrophenylacetic acid (25 kg water-wet, 13.2 kg on a dry basis) and 9.4 kg 4- methoxyphenol were suspended in 33 L of 1-butanol and 19 L of water. At 15-25°C, 13.1 kg of 50%-w / w aqueous potassium hydroxide was added over at least 30 min. An additional 2 L of water was added. The mixture was heated to 55-60°C over at least 30 min and stirred for 2.5- 3.5 h. At 55-60°C, 5.1 kg of 98-100% formic acid was added over at least 30 min. The mixture was seeded with 20 g 2-(4-(4-methoxyphenoxy)-3,5-dinitrophenyl)acetic acid and the slurry was aged for at least 30 min at this temperature. The slurry was cooled to -5°C-5°C over at least 1 h and stirred at that temperature for at least 1 h. The slurry was filtered and the cake sequentially washed with 38 kg water, 30 kg of isopropanol, and 38 kg water. The product was dissolved from the filter with a mixture of 26 kg water, 17 kg isopropanol, and 4.6 kg triethylamine, and obtained as the corresponding solution for use in Example 6. 21.5-22.0% w / w solution, HPLC purity 97.7-99.0% a / a.

[0179] Example s

[0180] 2-(4-(4-methoxyphenoxy)-3,5-dinitrophenyl)acetic acid (compound 6) -Potassium hydroxide equivalent screening The reactions were performed in a similar manner as Example 4, varying the equivalents of potassium hydroxide used.

[0181] Data from potassium hydroxide equivalent screening Example 6

[0182] 2-(4-(4-methoxyphenoxy)-3,5-dinitrophenyl)acetic acid (compound 6) - Potassium hydroxide equivalent screening The isolation conditions were investigated to improve the filtration times of the crude product. A factor for the isolation is the stirring time at the target crystallization temperature of 0°C and the stirring speed. Table 4 shows the influence of these two parameters. Prolonged stirring at 0°C leads to a clay like product suspension, which clogs the filter and significantly increases the filtration time. Elevated stirring speeds after the crystallization also decrease the filterability slightly.

[0183] Filtration times and their dependencies on the stirring speed and stirring time

[0184] Example ? 2-(3,5-diamino-4-(4-methoxyphenoxy)phenyl)acetic acid (compound 5)

[0185] 1.0 Equivalents of 2-(4-(4-methoxyphenoxy)-3,5-dinitrophenyl)acetic acid, 0.17 mol % of 5% palladium on carbon, 1.3 equivalents triethylamine, 3.1 volumes water, and 2.1 volumes isopropanol are charged to an autoclave. The autoclave is purged with nitrogen three times, then pressurized with 15 bar of hydrogen gas. The suspension is stir red and the temperature allowed to rise to about 50-60°C and held at 55°C for approximately 1 h. The reaction is checked for conversion by HPLC. The reaction is filtered, and the filter rinsed with a mixture of 1.2 volumes water and 0.8 volumes isopropanol. The resulting solution of compound 5 is transferred to a reactor, warmed to approximately 50°C, and 0.5 equivalents formic acid is added. The mixture is seeded with a small amount of compound 5 and the slurry is stirred for approximately 15 min at this temperature. An additional 1.5 equivalents of formic acid is added and stirred for at least 15 min. The slurry is cooled to 0-5°C over at least 1 h and stirred for an additional 3 h. The slurry is filtered and the cake washed with a mixture of 1.5 volumes water and 1.0 volumes isopropanol. The product is dried under vacuum at 50°C to give 2-(3,5-diamino-4-(4- methoxyphenoxy)phenyl)acetic acid as a light brown to dark brown solid, expected yield 90- 95%, expected purity > 99.0% a / a by HPLC.

[0186] Example s

[0187] 2-(3,5-diamino-4-(4-methoxyphenoxy)phenyl)acetic acid (compound 5)

[0188] 51 kg of 2-(4-(4-methoxyphenoxy)-3,5-dinitrophenyl)acetic acid solution in water / isopropanol / triethylamine (prepared according to the procedure of Example 4) was charged to an autoclave and 0.2 kg 5% palladium on carbon (Noblyst P1080) suspended in 5 L water was added. At 25- 40°C, the autoclave was flushed with nitrogen and pressurized with 10-20 bar of hydrogen gas. The suspension was stirred at 25-70°C (target 55°C) until hydrogen absorption ceased. The reaction was stirred for an additional 2 h at 50-60°C (target 55°C). The reaction was cooled to 20-35°C, filtered, and the filter rinsed with 12 kg water and 6.3 kg isopropanol. The resulting solution of compound 5 was transferred to a reactor, warmed to 45-50°C, and 0.8 kg formic acid was added. The mixture was seeded with 5 g of compound 5 and the slurry was aged for 10-15 min at this temperature. An additional 2.0 kg formic acid was added over 10 min and stirred for an additional 15 min. The slurry was cooled to -5-10°C over at least 1 h and stirred for an additional 3 h. The slurry was filtered and the cake washed with a mixture of 15 kg water and 8 kg isopropanol. The product was dried under vacuum at 50-60°C to give solid compound 5, purity 98.0-99.0% a / a by HPLC.

[0189] Batch control

[0190] Release control

[0191] Example 9

[0192] 2-(3,5-Diiodo-4-(4-methoxyphenoxy)phenyl)acetic acid (compound 4) A reactor was charged with 90 ml (5 volumes) acetic acid and 15.0 g (1.0 equivalents) 2-(3,5- diamino-4-(4-methoxyphenoxy)phenyl)acetic acid. 22.5 ml (1.5 volumes) of sulfuric acid was added at a temperature between 20-30°C. The reaction temperature was adjusted to between 0-10°C and 36.3 g (2.2 equivalents) of 40% nitrosylsulfuric acid was added over at least 30 min at a temperature between 5-15°C (target 5-10°C) and stirred for no more than 2 h (target 30 min) at a temperature between 5-15°C (target 5-10°C). In a separate reactor an iodination solution was prepared by charging 13.2 g (1.0 equivalents) of iodine, 30.2 g (3.5 equivalents) of potassium iodide, 15 ml (1 volume) acetic acid and 75 ml (5 volumes) water. This solution was seeded with 0.15 g of 2-(3,5-diiodo-4-(4-methoxyphenoxy)phenyl)acetic acid and the temperature was adjusted to between 30-40°C. The solution containing the diazotized 2-(3,5- diamino-4-(4- methoxyphenoxy)phenyl)acetic acid was added to the iodination solution over no more than two hours (target 30 min) at a temperature between 30-40°C. The transfer line was rinsed with 15 ml (1 volume) of a 5:1 mixture of acetic acid and sulfuric acid. The reaction mixture was stirred at a temperature between 30-40°C for at least 30 min. A solution of 10.0 g of sodium metabisulfite in 30 ml (2 volumes) of water over at least 30 min (target 1 hr) at a temperature between 30- 40°C (target 35°C). The solid was isolated by filtration and the filter cake washed with two portions of 30 ml (2 volumes) 6:4 acetic acid / water, and 30 ml (2 volumes) of water to give water wet, crude 2-(3,5-diiodo-4-(4-methoxyphenoxy)phenyl)acetic acid (compound 4).

[0193] Example 10

[0194] 2-(3,5-Diiodo-4-(4-methoxyphenoxy)phenyl)acetic acid (compound 4)

[0195] A reactor was charged with 58 kg acetic acid and the temperature maintained between 20-40°C (target 25°C). 8.4 kg of sulfuric acid was added at a temperature between 25-45°C (target 30- 35°C). 9.2 kg 2-(3,5-diamino-4-(4-methoxyphenoxy)phenyl)acetic acid was added portionwise over at least 20 min. at a temperature between 25-45°C (target 30-35°C). The addition port of the reactor was rinsed with 1 L of acetic acid. 25.2 kg of sulfuric acid was added over at least 15 min at a temperature between 25-45°C (target 30-35°C). The reaction temperature was adjusted to between 5°C-15°C (target 10°C). 22.3 kg of 40% nitrosylsulfuric acid was added over 20-60 min at a temperature between 5-15°C (target 10°C) and stirred for an additional 10-60 min (target 30 min) at a temperature between 0-15°C (target 5-15°C). In a separate reactor an iodination solution was prepared by charging 45 kg of water, 1.0 kg of urea, 18.5 kg of potassium iodide, 8.1 kg of iodine, and a mixture of 9 L acetic acid and 1 L water (rinsing the addition port) and adjusting the temperature to between 30-40°C (target 35°C). The solution containing the diazotized 2-(3,5-diamino-4-(4-methoxyphenoxy)phenyl)acetic acid was added to the iodination solution over at least 30 min (target 30 min) at a temperature between 30- 40°C (target 35°C). To the reactor containing the diazotized 2-(3,5-diamino-4-(4- methoxyphenoxy)phenyl)acetic acid was added 8.0 kg of acetic acid followed by 2.8 kg of sulfuric acid at a temperature below 30°C. The rinsing solution was stirred in the reactor for 5- 15 min and then transferred to the reactor containing the combined solutions. The reaction mixture was stirred at a temperature between 30-40°C (target 35°C) for at least 30 min (target 30-60 min). 6.1 kg of water was added followed by 15 L of a 38% sodium metabisulfite solution over at least 30 min (target 30 min) at a temperature between 30-40°C (target 35°C). The reaction mixture was stirred at a temperature between 30-40°C (target 35°C) for at least 10 min (target 15 min). The temperature was adjusted to between 20-30°C (target 25°C). 18 L of toluene was added followed by 36 L methyl tert-butyl ether over 2-30 min (target 5-10 min) at a temperature between 20-30°C (target 25°C). The reaction mixture was stirred for 5-20 min (target 5-10 min) at a temperature between 20-30°C (target 25°C) and then the phases were allowed to separate over at least 30 min and approximately 80% of the aqueous phase was removed. 36 L of water and 18 L of methyl tert-butyl ether were added and the reaction mixture was stirred for 5-20 min (target 5-10 min) at a temperature between 20-30°C (target 25°C) and then the phases were allowed to separate over at least 30 min and the aqueous phase was removed. The organic phase was washed two more times wherein 36 L of water was added and the reaction mixture was stirred for 5-20 min (target 5-10 min) at a temperature between 20-30°C (target 25°C) and then the phases were allowed to separate over at least 30 min and the aqueous phase was removed. The organic phase was transferred into a storage vessel and the reactor was washed with 10 L of methyl tert-butyl ether which was combined with the rest of the organic phase to give approximately 8.6 kg of 2-(3,5-diiodo-4-(4- methoxyphenoxy)phenyl)acetic acid (compound 4) as a crude solution in methyl tert-butyl ether. Purity from various batches was in the range of 91.8-92.0% a / a by HPLC.

[0196] The following impurities were identified, all structures are proposed and may not be fully determined or characterized:

[0197] Imp 301: Formed either by hydrolysis of 2-(3,5-diiodo-4-(4- methoxyphenoxy)phenyl)acetic acid or by carryover from the previous stage.

[0198] Imp 302: Formed by partial diazotation (postulated daughter impurity from the formamide Imp 202).

[0199] Imp 303: Formed by incomplete iodination.

[0200] Imp 304: Proposed structure: Formed by internal cyclization (presumably electrophilic substitution of the diazonium species and the phenol ether).

[0201] Imp 305: Proposed structure: Formed by internal cyclization of the formamide species Imp 202 (proposed).

[0202] Imp 309: Proposed structure: Incomplete diazotation of the methylated impurities Imp 203 + 204 or methylation of Imp 302 by decomposing methyl tert-butyl ether.

[0203] Imp 306: Proposed structure: Amide formed from 2-(3,5-diiodo-4-(4- methoxyphenoxy)phenyl)acetic acid and Imp 302. Imp 307: Formed by esterification by either methyl tert-butyl ether or methanol released from the methyl tert-butyl ether decomposition.

[0204] Imp 308: Formed by esterification by either MTBE or t-butanol released from the methyl tert-butyl ether decomposition. Batch yield examples

[0205] In process control for 2-(3,5-diiodo-4-(4-methoxyphenoxy)phenyl)acetic acid, crude solution in methyl-tert-butyl ether Example 11

[0206] 2-(3,5-Diiodo-4-(4-methoxyphenoxy)phenyl)acetic acid (compound 4)

[0207] The reaction was performed in the manner described in Example 10, however, urea was replaced with sulfamic acid (0.25 molar equivalents with respect to 2-(3,5-diamino-4-(4- methoxyphenoxy)phenyl)acetic acid. This resulted in reduced formation of nitrogen triiodide and gave a comparable product quality.

[0208] Example 12A

[0209] 2-(4-(4-Hydroxyphenoxy)-3,5-diiodophenyl)acetic acid (compound 3, "DIAC")

[0210] A reactor was charged with approximately 86 kg of 2-(3,5-diiodo-4-(4- methoxyphenoxy)phenyl)acetic acid as a crude solution in methyl tert-butyl ether and heated to reflux (90-120°C) and approximately 31-41 L (target 36 L) of solvent was distilled off. The distillation was maintained at a constant volume while 74 L acetic acid was added and a corresponding 74 L of solvent was distilled off. The solution was checked to ensure residual methyl tert-butyl ether was < 0.5% (if this assay fails: dose and distill off an additional 28 L of acetic acid at constant volume). A second reactor was charged with 60 kg acetic acid followed by 14.3 kg sodium iodide, then warmed to between 30-40°C and stirred for 5 minutes. The resulting sodium iodide suspension was transferred to the reactor with the acetic acid solution of 2-(3,5- diiodo-4-(4-methoxyphenoxy)phenyl)acetic acid and the second reactor was rinsed with 10 kg acetic acid. 9.2 kg of methanesulfonic acid and 5 kg acetic acid were added to the reaction mixture at a temperature of between 30-50°C. 4.0 kg of 50% phosphinic acid and 5 kg acetic acid were added to the reaction mixture at a temperature of between 30-50°C. The reaction mixture was heated to reflux (90-120°C) and while adding acetic acid (between 2-10 L) to maintain constant volume and distilled until an internal temperature of > 105°C was reached. The reaction was stirred at a temperature between 105-125°C (target 110°C) for at least 2 h. Then, while constantly dosing 54 L of acetic acid, 87-97 L (target 92 L) of solvent was distilled off at an internal temperature of between 105-125°C. The reaction mixture was cooled to 50-70°C and the reactor was purged with nitrogen for at least 10 min. The mixture was tested for conversion of starting material (< 0.5% a / a) and assay of iodomethane (< 50 ppm) (if either IPC fails: dose and distill off an additional 28 L of acetic acid at constant volume until both criteria are fulfilled). 37 L water is added to the reaction mixture and it is heated to reflux (85-95°C) and 32-42 L (target 37 L) of distillate is removed at constant volume at approximately 95°C while adding an additional 37 L of water. The reaction mixture was cooled to 50-70°C and the reactor was purged with nitrogen for at least 10 min. The mixture was tested for product purity, acetyl impurity, tert- butyl impurity, (< 0.5% a / a each), and iodomethane (< 50 ppm) (if assay fails: dose and distill off an additional 28 L of acetic acid at constant volume until criteria are fulfilled). 18 L of toluene was added to the reaction mixture and it was warmed to 80-90°C. 37 L of water was added to the reaction mixture over at least 1 h at 80-90°C. The reaction mixture was cooled over at least 2 h to a temperature of 15-25°C (target 20°C). The mixture was filtered and washed with a mixture of 9 L water and 10 L acetic acid and then washed with 18 L water followed by two washes with 18 L toluene each. The product was then dried in a spherical drier at a jacket temperature of 55-65°C for 4-12 h to yield 2-(4-(4-hydroxyphenoxy)-3,5- diiodophenyl)acetic acid as an off-white solid (yield 37.9-75.1% across multiple batches).

[0211] The following impurities were identified, all structures are proposed and may not be fully determined or characterized:

[0212] Imp 407 Imp 408 tButyl Impurity Dimer 974

[0213] Imp 401: Acetylated and demethylated daughter compound originating from Imp 302.

[0214] Imp 402: Demethylated daughter compound originating from Imp 302.

[0215] Imp 410: Proposed structure: Formed by oxidation of 2-(4-(4-hydroxyphenoxy)-3,5- diiodophenyl)acetic acid or demethylation of the corresponding Impurity 310.

[0216] Imp 403: Demethylated daughter compound originating from Imp 303.

[0217] Imp 404: Proposed structure: Substitution product from two 2-(4-(4-hydroxyphenoxy)- 3,5- diiodophenyl)acetic acid molecules.

[0218] Imp 405: Proposed structure: Demethylated daughter compound originating from Imp 306. Imp 406: Acetylation of 2-(4-(4-hydroxyphenoxy)-3,5-diiodophenyl)acetic acid at the demethylated phenol oxygen.

[0219] Imp 407: Proposed structure: Butylated 2-(4-(4-hydroxyphenoxy)-3,5- diiodophenyl)acetic acid,

[0220] Imp 408: Proposed structure: Ester product formed from two 2-(4-(4-hydroxyphenoxy)- 3,5- diiodophenyl)acetic acid molecules

[0221] Residual solvent after solvent swap

[0222] Conversion / purity and iodomethane assay

[0223] 1) after distilling off another two portions 2) after distilling off another portion 3) ist analysis, then the batch was aborted. Purity of 2-(3,5-diiodo-4-(4-hydroxyphenoxy)phenyl)acetic acid and acetylated side product Batch control, 2-(3,5-diiodo-4-(4-hydroxyphenoxy)phenyl)acetic acid, pure toluene wet, plant

[0224] Release control, 2-(3,5-diiodo-4-(4-hydroxyphenoxy)phenyl)acetic acid, pure dry, plant

[0225] Example 12B

[0226] 2-(4-(4-Hydroxyphenoxy)-3,5-diiodophenyl)acetic acid (compound 3, "DIAC")

[0227] A methyl tert-butyl ether solution of compound 4 (prepared from 6.0 kg of compound 5 using the procedure of Example 10) is charged to a first reactor and distilled under reduced pressure and stirring. It is continued until approximately 20-28 L methyl tert-butyl ether has been distilled off. The distillation is resumed, but now keeping the reactor volume nearly constant by continuous addition of acetic acid. Approximately 44-52 L is distilled off. A sample is withdrawn for IPC 1 (analysis of residual solvents). A second rector is charged with approximately 20 kg Acetic acid and 9.4 kg Sodium iodide (62.7 mol, 3.0 mol eq). The mixture is transferred to the first reactor and the charging ways rinsed with acetic acid.

[0228] 6.0 kg Methanesulfonic acid (62.4 mol, 3.0 mol eq) is charged to the first reactor, followed by a rinse with 6 kg Acetic acid. Solvent is distilled off until the temperature reaches approximately 115°C. Acetic acid is continuously added during the distillation to keep the reactor volume constant. The reaction mixture is refluxed for at least 2 hours and a new distillation is started. Approximately 60 L solvent is distilled off at normal pressure. Acetic acid is continuously added during the distillation to keep the reactor volume constant. The temperature is lowered to allow for sampling for IPC 2 (conversion by HPLC) and IPC 3 (content of Mel). The reactor content is heated to 60-90 °C and 30 kg purified water (5 eq w / w) is charged. The mixture is refluxed for at least 1 hour and a sample is withdrawn for IPC 4 (HPLC-purity). Temperature is adjusted to 65-85 °C and approximately 6 kg sodium bisulfite solution 38 % (0.95 eq w / w) is charged and the mixture is stirred for at least 10 minutes. A sample is withdrawn for IPC 5 (residual iodine check). Approximately 10 kg toluene (1.7 eq w / w) is added followed by not more than 23 kg purified water (3.2 eq w / w). The mixture is cooled to 15-25 °C and the solids are filtrated and washed with: 1) not less than 9.8 kg of a mixture of purified water and acetic acid 1:1 w / w; 2) not less than 19.2 kg purified water; 3) not less than 9.6 kg purified water; 4) approximately 21 kg toluene and finally with not less than 8.4 kg toluene. The wet compound is dried under reduced pressure at not more than 72 hours at <70 °C. A sample is withdrawn for I PC 6 (Loss on drying). Dry compound 3 is discharged from the dryer in a typical yield of 4.9 kg (47 % over 2 steps, i.e., from compound 3).

[0229] Example 13

[0230] 2-(3,5-diiodo-4-(3-iodo-4-oxidophenoxy)phenyl)acetate disodium salt (compound 2)

[0231] And

[0232] 2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)acetic acid (compound 1)

[0233] A reactor at a jacket temperature of < 30°C is charged with 3.95 volumes of water, 2.5 molar equivalents of 30% sodium hydroxide and 1.0 equivalents of 2-(3,5-diiodo-4-(4- hydroxyphenoxy)phenyl)acetic acid. 1.30 equivalents of sodium iodide is added. The addition port is rinsed with 0.53 volumes water and the temperature adjusted to 20-30°C (target 25°C). 1.10 equivalents of approximately 12% aqueous sodium hypochlorite solution is added over at least 2 h at 20-30°C (target 25°C), and the reaction mixture is stirred for at least 10 min and checked for the conversion of starting material. The reaction mixture is tested for peroxides and 5 volumes of 1-butanol is added. The mixture is warmed up to 30-40°C (target 35°C) and stirred for at least 10 min (target 15 min). The mixture is checked for complete dissolution, and stirring is stopped and the aqueous phase is removed at 30-40°C (target 35°C). Approx. 1.5 volumes water is added to the organic phase followed by addition of 13.7 volumes isopropanol over at least 10 min at 25-40°C (target 30-35°C). The mixture is stirred for at least 5 min at 25-40°C (target 30-35°C) (until crystallization starts), then it is further stirred for 30-150 min (target 30 min) at 15-40°C, cooled over at least 2 h to -5-5°C (target 2°C), and then stirred for at least 30 min. The suspension is filtered and the filter cake is washed with 2.1 volumes isopropanol. A reactor is charged with 16.2 volumes isopropanol, 1.58 volumes water, and 0.13 volumes acetic acid. The system is rinsed with 0.26 volumes water and the solution is warmed to 40-50°C (target 45°C). The filter cake is dissolved with the warm solvent mixture and transferred back into the reactor. 0.075 relative weight of activated carbon is added and the mixture is stirred at 40-50°C (target 45°C) for at least 30 min (target 1 h). The mixture is filtered and the filter is washed with 0.89 volumes isopropanol and 0.11 volumes water to give a solution of 2-(3,5- diiodo-4-(3-iodo-4- oxidophenoxy)phenyl)acetate monosodium salt in isopropanol / water / acetic acid. This solution (approximately 66 kg) was transferred to a reactor and the temperature is adjusted to 30-40°C (target 35°C). 0.0079 relative weight of 2-(3,5-diiodo-4-(3- iodo-4- oxidophenoxy)phenyl)acetic acid is added as seeding crystals. The addition port is rinsed with 0.26 volumes of isopropanol and 0.29 relative weight of 30% aqueous sodium hydroxide is immediately added over approximately 5-120 min at 30-40°C (target 35°C). The suspension is stirred for an additional 30-60 min, then cooled over at least 2 h to -5-5°C (target 0°C) and then stirred for at least 30 min. The bulk suspension is filtered and the filter cake is washed with 2.1 volumes isopropanol. The filter cake is slurry washed with 3.9 volumes heptane followed by a displacement wash with 2.1 volumes heptane to give 2-(3,5-diiodo-4-(3-iodo-4- oxidophenoxy)phenyl)acetate disodium salt.

[0234] The filter cake is dissolved with 5.0 volumes water. The reactor and the filter are rinsed with 0.5 volumes water and the combined solutions are transferred into a storage vessel. A reactor is charged with 4.21 relative weights of acetic acid, 2.24 equivalents of 33% hydrochloric acid, and 0.53 volumes of water and the temperature is adjusted to 30-40°C (target 35°C). To the hydrochloric acid solution approximately 20% of the solution of 2-(3,5-diiodo-4-(3-iodo-4- oxidophenoxy)phenyl)acetate disodium salt is added over 10-30 min at 30-40°C (target 35°C) and the mixture is seeded with 0.00079 relative weight of 2-(3,5-diiodo-4-(3-iodo-4- oxidophenoxy)phenyl)acetic acid. Afterwards, the rest of the solution is dosed over 20-120 min. The suspension is stirred for 15-150 min then cooled to 5-15°C (target 10°C) over at least 30 min and stirred for at least 30 additional min. The suspension is filtered by centrifugation and the wet cake was washed with 6.3 volumes of water precooled to 5-15°C (target 10°C). The filtered material is dried at 50-60°C for 3-13 h to give 2-(4-(4-hydroxy-3-iodophenoxy)-3,5- diiodophenyl)acetic acid. To investigate the importance of the number of equivalents of hypochlorite on the quality of the reaction product, a series of experiments were carried out in which different amounts of hypochlorite were added. It is seen that 1.10 equivalents of sodium hypochlorite in reaction runs 1, 6 and 11 gives the best purity of the product. A higher amount of sodium hypochlorite leads to increased TETRAC level and lower amount leads to increased DIAC level.

[0235] Example 14

[0236] 2-(3,5-diiodo-4-(3-iodo-4-oxidophenoxy)phenyl)acetate disodium salt (Compound 2) and

[0237] 2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)acetic acid (Compound 1)

[0238] A reactor was charged with 15 kg water, 2.6 kg 30% sodium hydroxide, and 3.8 kg 2- (3,5- diiodo-4-(4-hydroxyphenoxy)phenyl)acetic acid. 1.5 kg sodium iodide was added. The addition port was rinsed with 2 kg water and the temperature adjusted to 25°C. 18.8 kg aqueous sodium hypochlorite solution was added over at least 2 h at 25°C, followed by rinsing the vessel containing the sodium hypochlorite solution with 2 kg water, stirring the reaction mixture for 10 min and checking the conversion of starting material. The reaction mixture was tested for peroxides, and 15 kg of 1-butanol was added. The mixture was warmed up to 35°C and stirred for 15 min. After checking for complete dissolution, stirring was stopped and the aqueous phase removed at 35°C. 6.0 kg water was added to the organic phase followed by addition of 41 kg isopropanol over 10 min. The mixture was stirred for at least 10 min at 20-35°C (until crystallization starts), then it was further stirred for 30-35 min, cooled over at least 2 h to 0°C, and then stirred for at least 30 min. The suspension was filtered and the filter cake washed with 6 kg isopropanol. A reactor was charged with 49 kg isopropanol, 6 kg water, and 0.5 kg acetic acid and the solution was warmed to 45°C. The filter cake was dissolved with the warm solvent mixture and transferred back into the reactor. 0.3 kg activated carbon (Norit CAP super) was added and the mixture was stirred at 45°C for 1 h. The mixture was filtered and the filter was washed with a mixture of 2.7 kg isopropanol and 0.4 kg water to give a solution of 2- (3,5-diiodo-4-(3-iodo-4-oxidophenoxy)phenyl)acetate monosodium salt in isopropanol / water / acetic acid. This solution (approximately 66 kg) was transferred to a reactor and the temperature was adjusted to 35°C. 3 g of 2-(3,5-diiodo-4-(3-iodo-4- oxidophenoxy)phenyl)acetic acid as seeding crystals was added and immediately 1.1 kg 30% aqueous sodium hydroxide was dosed over approximately 10 min. The suspension was stirred for 30-60 min, then cooled over at least 2 h to 0°C and then stirred for at least 30 min. The bulk suspension was filtered and the filter cake was washed with 6 kg isopropanol. The filter cake was slurry washed with 11 kg heptane followed by a displacement wash with 5 kg heptane to give 2- (3,5-diiodo-4-(3-iodo-4-oxidophenoxy)phenyl)acetate disodium salt.

[0239] The filter cake was dissolved with 19 kg water. The reactor and the filter were rinsed with 1.9 kg water and the combined solutions were transferred into a storage vessel. A reactor was charged with 17 kg acetic acid, 1.9 kg 33% hydrochloric acid, and 2 kg water and the temperature was adjusted to 35°C. To the hydrochloric acid solution approximately 20% of the solution of 2- (3,5- diiodo-4-(3-iodo-4-oxidophenoxy)phenyl)acetate disodium salt was added over 10-30 min and the mixture was seeded with 30 g of 2-(3,5-diiodo-4-(3-iodo-4- oxidophenoxy)phenyl)acetic acid. Afterwards, the rest of the solution was dosed over 20-120 min. The suspension was stirred for approximately 30 min then cooled to 10°C over at least 30 min and stirred for at least 30 additional min. The suspension was filtered by centrifugation and the wet cake was washed with 24 kg water. The filtered material was dried at 50-60°C for 3-13 h to give 2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)acetic acid. Yield across multiple batches was 12.6-41.3%.

[0240] It should be noted that crystallisation occurs also without the addition of seed crystals. The following impurities were identified:

[0241] 2-(4-(4-hydroxyphenoxy)-3,5- (4-(4-hydroxy-3,5-diiodophenoxy)- diiodophenyl)acetic acid 3,5-diiodobenzeneacetic acid Compound 3 Compound 10

[0242] DIAC TETRAC

[0243] DIAC: Unconverted starting material. TETRAC: Formed by over-iodination.

[0244] Batch yield examples In process control - Reaction (Iodination)

[0245] In process control - Extraction and 1st crystallization (2-(3,5-diiodo- 4-(3-iodo-4- oxidophenoxy)phenyl)acetate disodium salt, crude)

[0246] In process control - 2nd crystallization (2-(3,5-diiodo-4-(3-iodo-4 oxidophenoxy)phenyl)acetate disodium salt, pure)

[0247] 11Criterion stricter compared to release control because during acidification Tetrac is not purged at all

[0248] Batch control - 2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)acetic acid, pure water wet

[0249] Release control for 2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)acetic acid, pure dry Release control for 2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)acetic acid, pure dry, externally milled

[0250]

[0251]

[0252] In process control, 2-(3,5-diiodo-4-(4-hydroxyphenoxy)phenyl)acetate disodium salt, wet filter cake

[0253] In process control, compound 1, post iodination, butanol addition

[0254] Example 15 After isolation the dried material was externally milled. The results of the micronization are summarized below.

[0255] Micronization of 2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)acetic acid Release control for 2-(4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)acetic acid, pure dry, externally milled

[0256]

[0257] It is seen in the batch analysis tables, that the purity level of compound 1 (2-(4-(4-hydroxy-3- iodophenoxy)-3,5-diiodophenyl)acetic acid) at the various stages of the purification of Example 14 were as follows, averaged over the 4 batches:

[0258] It is seen that the conversion of the disodium salt (compound 2) to the acid (compound 1) using the conditions as described reduces the level of Diac impurity and raises the level of acid (compound 1) itself. The data thus show that performing the crystallisation in the mixture of acetic acid and hydrochloric acid brings a marked improvement in the purity level of the composition.

[0259] It is also seen that the purity level is maintained after milling.

[0260] It is also seen that the level of Diac impurity is decreased and the level of the disodium salt (compound 2) itself is raised by the step of purifying the initial crude disodium salt by dissolving in isopropanol, water and acetic acid, treating with activated carbon, filtering the dissolved material, cooling and treating with sodium hydroxide, and isolating by filtration.

[0261] Example 16

[0262] The impurity levels of potential mutagenic impurities arising from the synthesis of compound 1 were measured in the batches of compound 1 prepared according to the methods disclosed herein. Potential mutagenic impurities, 000-series impurities are formed duringthe synthesis of compound 8 and 200-series impurities are formed during the synthesis of compound 5: The impurity levels were measured by HPLC according to the following methods. For measuring the presence of Impurity 002, Impurity 003, Impurity 202, Impurity 203, Impurity 204, Impurity 205, Impurity 206, Impurity 207, Impurity 208, Impurity 209, Impurity 210, and Impurity 211, HPLC Method 1 was used.

[0263] HPLC Method 1

[0264] A gradient reversed-phase HPLC using mobile phases (A): 0.02% TFA in water and (B): 0.02% TFA in acetonitrile, UV detection at 230 nm, Column: XSelect HSS PFP, 150 x 4.6 mm, 3.5 pm (Waters, art. No. 186005862), 380 pl Mixer (G4204-60235) and a Ghostbuster column (Welch, art. 06100-31000) installed prior to the injection loop, sample concentration of 1.2 mg / ml, flow rate 1.2 ml / min, column temperature 2O0C and total run time 40 minutes.

[0265] Solvent Gradient

[0266] Retention Times of Impurities Generated During Synthesis of Compound 5 Representative chromatograms of various impurities using HPLC Method 1 can be found in FIG. 1 (compound 5 crude reaction mixture), FIGS. 2-4 (impure compound 5 showing retention times of 4-methoxyphenol, compound 8, Impurity 201, Impurity 202, Impurity 203 / 204, Impurity 205, Impurity 206 / 207, Impurity 208, Impurity 209, Impurity 210, Impurity

[0267] 211, and Impurity 213), and FIGS. 5-6 (showing retention times of Impurity 002 and 003).

[0268] Analysis of validation batches of compound 1 prepared using the methods disclosed herein, analyzed using HPLC method 1, consistently demonstrated that the following impurities were not present in concentrations greater than 100 ppm: compound 5, Impurity 002, Impurity 003, Impurity 202, Impurity 203, Impurity 204, Impurity 205, Impurity 206, Impurity 207, Impurity 208, Impurity 209, Impurity 210, and Impurity 211. For a chromatogram of a representative validation batch see FIG. 7.

[0269] The absence of compound 6 in quantities greater than 100 ppm was demonstrated using HPLC Method 1, but due to a peak close in retention time to compound 6 an experiment was performed wherein the sample was spiked with compound 6. This experiment showed that the peak with a similar retention time was not compound 6 and that compound 6 was not present in concentrations greater than 100 ppm in any of the batches of compound 1. See FIG. 8.

[0270] The absence of Impurity 213 in quantities greater than 100 ppm was demonstrated using HPLC Method 1, but intermediate compound 5 was analyzed and the absence of compound 6 at that stage was taken as confirmation that it was absent in final compound 1. See FIG. 9.

[0271] The levels of Impurity 201 were measured using HPLC Method 2, also using a spiking experiment to distinguish between Impurity 201 and a peak with a similar retention time, and the concentration of Impurity 201 was determined to be below 100 ppm in all validation batches. See FIG. 10.

[0272] HPLC Method 2

[0273] A gradient reversed-phase HPLC using mobile phases (A): 0.02% TFA in water and (B): 0.02% TFA in acetonitrile, UV detection at 230 nm, Column: XSelect HSS PFP, 150 x 4.6 mm, 3.5 pm (Waters, art. No. 186005862), 380 pl Mixer (G4204-60235) and a Ghostbuster column (Welch, art. 06100-31000) installed prior to the injection loop, sample concentration of 1.2 mg / ml, flow rate 1.2 ml / min, column temperature 2O0C and total run time 41 minutes.

[0274] Solvent Gradient

[0275] Example 17 - Analysis of crystalline forms of compound 1

[0276] The crystalline product obtained from the process in Example YY was analysed using an X- ray powder diffractometer. The diffractogram is shown in Figure 11. It is seen that its most intense peaks are as follows: Crystalline form B of compound (1) can be obtained by conversion from Form A by slurrying in water. The compound in crystalline from B was analysed using an X-ray powder diffractometer. The diffractogram is shown in Figure 12. It is seen that its most intense peaks are as follows:

[0277] Under certain conditions, Form B is more stable than Form A. However, in the presence of the combination of water, hydrochloric and acetic acid, Form A is the more stable. That is to say that under the crystallization conditions of the current invention (ie the conditions that enable the preparation of Compound 1 in higher purity than prior methods), Form A is the more stable crystalline form. Amongst other advantages, Form A enables conditions to be used that provide the product composition is a higher level of purity than previously possible.

[0278] Crystalline form C of compound (1) can be obtained by conversion from Form A by slurrying in methanol. The compound in crystalline from C was analysed using an X-ray powder diffractometer. The diffractogram is shown in Figure 13. It is seen that its most intense peaks are as follows:

[0279] It has been found that Form C turns amorphous when dried. That makes it unsuitable for use in a pharmaceutical product that is to be provided in tablet form. The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.

[0280] These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure. CLAUSES

[0281] 1. A composition comprising compound 1, or a pharmaceutically acceptable salt thereof wherein the composition comprises no more than about 0.05% of Impurity 201, Impurity 202, Impurity 203, Impurity 204, Impurity 205, Impurity 206, Impurity 207,

[0282] Impurity 208, Impurity 209, Impurity 211, and / or Impurity 213.

[0283] 2. The composition of clause 1 wherein the composition comprises no more than about 100 parts per million of Impurity 201, Impurity 202, Impurity 203, Impurity 204, Impurity 205, Impurity 206, Impurity 207, Impurity 208, Impurity 209, Impurity 211, and / or Impurity 213.

[0284] 3. The composition of clause 1 wherein the composition comprises no more than about 0.05% of Impurity 301, Impurity 302, Impurity 303, Impurity 304, Impurity 305, Impurity 306, Impurity 307, Impurity 308, Impurity 401, Impurity 402, Impurity 403, Impurity 404, Impurity 405, Impurity 406, Impurity 407, and / or Impurity 408. 4. The composition of clause 1 wherein the composition comprises no more than about

[0285] 0.1% of compound 2; or no more than about 1.0% of compound 3, or a salt thereof; or no more than about 0.5% of compound 10, or a salt thereof; or no more than about 0.05% of 4-chloro-3,5-dinitrophenyl acetic acid, or a salt thereof; or no more than about 0.05% of Compound 6, or a salt thereof;

[0286] And or no more than about 0.05% of Compound 5, or a salt thereof (5).

[0287] 5. The composition of clause 4 wherein the composition comprises no more than about 100 parts per million of Compound 5 and / or no more than about 100 parts per million of Compound 6.

[0288] 6. The composition of clause 1, prepared by crystallizing compound 1 from a solution of a disodium salt of compound 1

[0289] 7. A pharmaceutical composition comprising the composition of clause 1 and a pharmaceutically acceptable carrier.

[0290] 8. The pharmaceutical composition of clause 7, wherein the composition does not include a detectable amount calcium hydrogen phosphate dihydrate.

[0291] 9. A method of treating a MTC8 deficiency disorder in an individual, comprising administering to the individual in need thereof, a therapeutically acceptable amount of a composition of clause 1.

[0292] 10. The method of clause 9 wherein the MCT8 deficiency disorder is Allan-Herndon- Dudley syndrome.

[0293] 11. A process for the preparation of a composition comprising compound 1 comprising adding a mixture of acetic acid:water and HCI to a solution of the disodium salt of compound 1 and isolating crystalline compound 1.

[0294] 12. The process of clause 11, wherein the temperature of the reaction is maintained at about 300C to about 40 °C. 13. The process of clause 11, wherein the mixture of acetic acid:water and HCI comprises four volumes of acetic acid with 2.5 equivalents of 32% aqueous HCI.

[0295] 14. The process of clause 11, wherein the disodium salt of compound 1 is obtained by iodination of compound 3, or a salt thereof, by in situ formation of NaOl

[0296] 15. The process of clause 14, wherein the NaOl is formed using NaOCI / Nal in NaOH / water.

[0297] 16. The process of clause 15, wherein the iodination reaction is performed at a temperature of from about 15 °C to about 25 °C. 17. The process of clause 14, wherein compound 3, or a salt thereof, is prepared by a process comprising reacting compound 4 or a salt thereof, with a mixture of an iodide salt and a protic acid, to provide compound 3, or a salt thereof (3).

[0298] 18. The process of clause 17, wherein the iodide salt is sodium iodide and the protic acid is methanesulfonic acid. 19. The process of clause 17, wherein the temperature of the reaction is maintained at about 110 °C to about 115 °C.

[0299] 20. The process of clause 17, wherein compound 4, or a salt thereof, is prepared by a process comprising reacting compound 5 or a salt thereof, with nitrosylsulfuric acid; and reacting the resultant mixture with a triiodide salt, to provide compound 4, or a salt thereof.

[0300] 21. The process of clause 20, wherein the triiodide salt is formed from a mixture of an iodide salt and iodine. The process of clause 21, wherein the iodide salt is potassium iodide. The process of clause 20, wherein compound 5, or a salt thereof, or a salt thereof, with hydrogen gas, palladium on carbon, a base, and a solvent. The process of clause 23, wherein the base is triethylamine and the solvent is a mixture of isopropanol and water; the amount of isopropanol is about 2.1 volumes relative to compound 6; the amount of water is about 3.1 volumes relative to compound 6; and the triethylamine is about 1.3 molar equivalents relative to compound 6. The process of clause 24, wherein the reaction mixture containing compound 5 is filtered and compound 5 is then crystalized by addition of about 2.0 equivalents of formic acid relative to compound 6. The process of clause 25, wherein the formic acid is added at about 50°C. 27. The process of clause 23, wherein compound 6, or a salt thereof, is prepared by a process comprising reacting 4-chloro-3,5-dinitrophenylacetic acid and 4-methoxyphenol with a base in a solvent.

[0301] 28. The process of clause 27, wherein the solvent is a mixture of water and 1-butanol and the base is 50% aqueous potassium hydroxide; the amount of 1-butanol is about 2.5 volumes relative to 4-chloro-3,5-dinitrophenylacetic acid; and the amount of water is about 2.35 volumes relative to 4-chloro-3,5-dinitrophenylacetic acid.

[0302] 29. The process of clause 28, wherein compound 6 is crystalized by addition of about 2.2 equivalents of formic acid relative to 4-chloro-3,5-dinitrophenylacetic acid.

[0303] 30. The process of clause 29, wherein the formic acid is added at about 60 °C.

Claims

CLAIMS:

1. A process for the preparation of a composition comprising compound 1wherein said process comprises a) preparing an aqueous solution of the disodium salt of compound 1 (compound 2)b) adding said aqueous solution to a mixture of acetic acid and aqueous hydrochloric acid, c) heating the mixture, d) allowing compound 1 to crystallise, and e) isolating crystalline compound 1.

2. The process as claimed in claim 1 wherein in step c), the mixture is maintained at a temperature of between about 30 °C to about 40 °C, preferably to about 35 °C.

3. The process as claimed in claim 1 or claim 2, wherein in the mixture of acetic acid and hydrochloric acid, the molar ratio between hydrochloric acid and acetic acid is between about 1:1 and about 1:10, preferably between about 1:1 and about 1:5, more preferably between about 1:2 and about 1:4, and more preferably about 1:3.

4. The process as claimed in any one of claims 1 to 3 wherein step d) includes cooling the mixture.

885. The process as claimed in any one of claims 1 to 4 wherein said process further comprises a step la), before step a) of preparing compound 2 by iodination of compound 3, or a salt thereof, optionally by in situ formation of NaOL6. The process as claimed in claim 5, wherein step la) comprises mixing compound 3, water, sodium iodide, and sodium hydroxide; and adding an aqueous solution of sodium hypochlorite.

7. The process as claimed in claim 6, wherein, in step la), the amount of sodium hypochlorite added is between about 1.0 and about 1.2 mol eq., preferably about 1.1 mol eq.

8. A composition comprising compound 1, or a pharmaceutically acceptable salt thereof,wherein the composition further comprises from 0.01% to 1.0% of compound 3 or a pharmaceutically acceptable salt thereof and / or from 0.01% to 0.5% of compound 10, or a pharmaceutically acceptable salt thereof.

899. The composition as claimed in claim 8, wherein the composition comprises compound 3 in an amount between about 0.05% and 0.7%, more preferably between about 0.1% and 0.6%, more preferably between about 0.3% and 0.6%, more preferably between about 0.35% and 0.5%, and most preferably between about 0.35% and 0.36%.

10. The composition as claimed in claim 8 or 9, wherein the composition comprises compound 10 in an amount between about 0.05% and 0.5%, more preferably between about 0.1% and 0.5% more preferably between about 0.2% and 0.5%, more preferably between about 0.2% and 0.4%, most preferably between about 0.26% and 0.30%.

11. The composition as claimed in claim 10 wherein the composition comprises between about 0.35% and 0.5% of compound 3, and between about 0.26% and 0.30% of compound 10.

12. The composition as claimed in claim 11, wherein the composition comprises around 0.35% of compound 3, and around 0.28% of compound 10.

13. The composition as claimed in any one of claims 8 to 12, wherein the compound 1 is the free acid compound.

14. The composition as claimed in any one of claims 8 to 13, wherein the compound 1 is in crystalline form.

15. The composition as claimed claim 14, wherein the compound 1 is in crystalline form characterized by a powder X-ray diffractogram (XRPD) having characteristic peaks at 20 = 15.3±0.2°, 7.6±0.2° and 24.1±0.2°.

16. The composition as claimed claim 15, wherein the crystalline form has a powder X-ray diffractogram that is further characterised by comprising an additional one or more peaks, such as one additional peak or two additional peaks at 20 angles selected from the group selected from 9.4±0.2° and 22.9±0.2°, and preferably is further characterized by comprising additional one or more peaks, such as one additional peak, two additional peaks or three additional peaks at 20 angles selected from the group selected from 21.4±0.2°, 22.0±0.2° and 25.7±0.2°.

17. Compound 1in crystalline form characterized by a powder X-ray diffractogram (XRPD) having characteristic peaks at 20 = 15.3±0.2°, 7.6±0.2° and 24.1±0.2°.

18. The compound as claimed claim 17, wherein the crystalline form has a powder X-ray diffractogram that is further characterised by comprising an additional one or more peaks, such as one additional peak or two additional peaks at 20 angles selected from the group selected from 9.4±0.2° and 22.9±0.2°, and preferably is further characterized by comprising additional one or more peaks, such as one additional peak, two additional peaks or three additional peaks at 20 angles selected from the group selected from 21.4±0.2°, 22.0±0.2° and 25.7±0.2°.

19. A pharmaceutical composition comprising the composition as claimed in any of claims 8 to 16 or a compound as claimed in claim 17 or 18 and a pharmaceutically acceptable carrier.

20. A composition as claimed in any of claims 8 to 16, a compound as claimed in claim 17 or 18 or a pharmaceutical composition as claimed in claim 19 for use in a method of treating aMCT8 deficiency disorder, for example wherein said MCT8 deficiency disorder is Allan- Herndon-Dudley syndrome.

21. A method of treating a MCT8 deficiency disorder in an individual, comprising administering to the individual in need thereof, a therapeutically acceptable amount of a composition as claimed in any of claims 8 to 16, a compound as claimed in claim 17 or 18 or a pharmaceutical composition as claimed in claim 19, optionally wherein said MCT8 deficiency disorder is Allan-Herndon-Dudley syndrome.92

Images