Crystalline 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propyl)thieno[2,3-b]pyridine-5-carboxamide potassium salt (PRX-3140) for a particle delivery system (PDS)

Abstract

The present invention relates to a crystalline microparticle form of 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propyl)thieno[2,3-b]pyridine-5-carboxamide potassium salt (PRX-3140) (I) for a particle delivery system (PDS) having good bioavailability and stability for the treatment of Alzheimer's disease (AD) and other dementias including post-traumatic stress disorder (PTSD) that affect the cholinergic and / or serotonergic systems. In other aspects, the present invention relates to an oral dosage form, a method of synthesizing the crystalline microparticle form, the preparation of a particle delivery system (PDS), and a final dosage form (FDF). JPEG2025518713000025.jpg49169

Description

Technical Field

[0001] Background The present disclosure generally relates to novel crystalline forms of a compound of formula I: ##STR00001## also known as 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propyl)thieno[2,3-b]pyridine-5-carboxamide potassium salt, or potassium 7-isopropyl-6-oxo-5-(3-piperidin-1-yl-propylcarbamoyl)-6,7-dihydro-thieno[2,3-b]pyridine-4-olate, a particulate delivery system of this crystalline compound, a method for preparing such a composition, and its therapeutic use. The compounds of the present disclosure were first described in U.S. Patent No. 7,488,736 and subsequently in U.S. Patent No. 7,982,040 and foreign patents. The crystalline potassium salt compositions described herein enable the compound to be administered to a patient by a non-invasive route such as by oral administration.

Chemical Formula

Background Art

[0002] The compounds of the present disclosure referred to as PRX-3140 or PRX-03140 in the literature are selective partial agonists for the 5-hydroxytryptamine receptor 4 (5-HT4) and ligands for the Sigma-1 and Sigma-2 receptors. PRX-3140 is a highly selective and potent (Ki = 22 - 37 nM) 5-HT4R agonist in radioligand binding assays, with a greater than 100-fold difference in affinity compared to all other 5-HT receptors tested. PRX-3140 acts as a partial agonist in cell lines expressing any of the human 5-HT4aR, 5-HT4bR or 5-HT4eR isoforms, stimulating cAMP production by 30% - 60% compared to 5-HT. PRX-3140 also demonstrates binding to both the Sigma-1 and Sigma-2 receptors (Ki = 79 - 100 nM and 99 - 160 nM respectively) in radioligand binding assays, but does not demonstrate significant affinity for over 50 other receptors tested, including GPCRs, ion channels and receptor tyrosine kinases. Specific ligand binding to a receptor is defined as the difference between total binding and non-specific binding determined in the presence of excess unlabeled ligand. The inhibition constant (Ki) was calculated from the Cheng Prusoff equation (Ki = IC50 / (1+(L / KD)), where L = the concentration of radioligand in the assay, Kd = the affinity of the radioligand for the receptor, and Hill coefficient = 1).

[0003] PRX-3140 is being developed for Alzheimer's disease (AD) and other dementias that affect the cholinergic and / or serotonergic systems, including post-traumatic stress disorder (PTSD). Extensive non-clinical studies, including in vitro and in vivo pharmacology, safety pharmacology, genotoxicity, and single and repeated dose toxicity studies, have been completed in two species, rats and beagle dogs. Initial clinical studies, including safety, tolerability, and pharmacokinetics of PRX-3140, have demonstrated high oral bioavailability, safety, and efficacy of the compound at up to 250 milligrams. In addition to its high oral bioavailability, PRX-3140 achieves a brain / serum partition ratio of 0.93 one hour after oral administration in preclinical studies. PRX-3140 demonstrates high CNS permeability without inducing significant distal gastrointestinal motility, as observed with gastrointestinal active 5-HT4 agonists (e.g., cisapride, tegaserod). Oral administration of drugs such as PRX-3140 is generally preferred over intravenous administration for reasons of patient comfort and compliance. However, many drugs are variably absorbed when delivered orally. Considerable efforts have been made over the past decade to produce drug particles from 100 nanometers to several hundred microns in size for their improved dissolution properties and ability to be more efficiently absorbed. Through several experiments, the inventors have surprisingly discovered a new solid form of the PRX-3140 form, including a fine particle crystalline form of the PRX-3140 potassium salt. This crystalline form has unexpectedly good properties, is more suitable for formulation processing, storage, and industrial production, and has better bioavailability. Compared to the known solid forms of PRX-3140 described in U.S. Patent No. 7,488,736 and subsequently U.S. Patent No. 7,982,040, the fine particle crystalline form of the PRX-3140 potassium salt of the present invention has at least one or more excellent properties and achieves unexpected effects. Specific improvements include, for example, higher solubility in water, faster dissolution rate, better stability, lower hygroscopicity, better flowability, and good processing and handling properties. Preferably, the new solid form in the present invention has improved stability.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Means for Solving the Problems

[0005] Summary of the Invention The present disclosure addresses this need by providing crystalline potassium salt compositions, methods of preparation, and treatments of compounds for Alzheimer's disease (AD) and other dementias affecting the cholinergic and / or serotonergic systems, including post-traumatic stress disorder (PTSD). In certain embodiments, the present disclosure provides a compound of Formula I or a potassium salt of PRX-3140, a crystalline microparticle form of the potassium salt of PRX-3140, and novel methods of preparing compositions containing them. In certain embodiments, the present disclosure provides novel crystalline microparticle forms of the potassium salt of PRX-3140 that may offer advantages including improved bioavailability and stability compared to other crystalline or amorphous forms. In other embodiments, the present disclosure provides oral dosage forms of crystalline microparticle forms of the potassium salt of PRX-3140 and additives with improved stability. In further embodiments, the present disclosure provides novel methods for the synthesis of novel crystalline microparticle forms of the potassium salt of PRX-3140, the preparation of a crystalline PRX-3140 potassium salt particle delivery system (PDS), and the preparation of a novel final dosage form (FDF) of crystalline microparticle PRX-3140 potassium salt. In certain embodiments, the present disclosure provides novel crystalline forms of microparticle potassium salt of PRX-3140 that may offer advantages including improved bioavailability and stability compared to other crystalline or amorphous forms.

[0006] In certain embodiments, the present disclosure provides a composition comprising a crystalline form of a potassium salt of a compound of Formula I shown in FIG. 1, ##STR00001##.

Chemical formula

[0007] In some embodiments, the composition comprises a crystalline form of a compound of Formula I: ##STR00001##, the crystalline form comprising major peaks at 2-theta of 22.3 + / - 0.3 degrees, 25.3 + / - 0.3 degrees, and 5.4 + / - 0.3 degrees, and optionally further comprising at least one peak selected from 2-theta of 25.8 + / - 0.3 degrees, 15.9 + / - 0.3 degrees and 29.9 + / - 0.3 degrees, and is Form I characterized by an X-ray powder diffraction pattern. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 2-theta of 21.6 + / - 0.3 degrees, 16.5 + / - 0.3 degrees, and 20.3 degrees. The X-ray powder diffraction pattern may further comprise peaks at 2-theta of 21.3 + / - 0.3 degrees, 17.1 + / - 0.3 degrees, 16.3 + / - 0.3 degrees, 33.1 + / - 0.3 degrees, 45.6 + / - 0.3 degrees, and 13.7 + / - 0.3 degrees. In some embodiments, crystalline Form I is characterized substantially by the X-ray powder diffraction patterns shown in FIGS. 3A and 3B. In some embodiments, more than 90% by weight of the compound of Formula I in the composition can be in crystalline Form I. In some embodiments, the compound of Formula I: ##STR00001## is in Form I and is present in an amount in the range of about 0.01% to about 99.99% by mass of the composition. In some embodiments, the composition has an average diameter of less than about 1 mm, 0.5 mm, or 0.3 mm. In some embodiments, the compound is stable for at least 12 months at 5 degrees Celsius and 60% relative humidity or 25 degrees Celsius and 60% relative humidity. In a further embodiment, the formation of degradation products is less than 0.5% by weight per year at 5 degrees Celsius and 60% relative humidity or 25 degrees Celsius and 60% relative humidity.In a further embodiment, the compound decomposition product is of formula II: ##STR00002##. 5-hydroxy-8-(methylethyl)-8H-1,2-oxathiino[6.5-b]pyridine-2,2,7-trione, or 5-hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxathiino[6,5-b]pyridine-2,2,7(8H)-trione, and of formula III: ##STR00003##. [7-(methylethyl)-1,4,6-trioxo(5,7-dihydrothieno[2,3-b]pyridin-5-yl)]-N-(3-piperidylpropyl)carboxamide, or 1,4,6-trioxo-N-[3-(piperidin-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide. In a further embodiment, when the composition contains an amount of less than 0.5% by weight of the compound of formula II: ##STR00002##. 5-hydroxy-8-(methylethyl)-8H-1,2-oxathiino[6.5-b]pyridine-2,2,7-trione, or 5-hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxathiino[6,5-b]pyridine-2,2,7(8H)-trione, and of formula III: ##STR00003##. [7-(methylethyl)-1,4,6-trioxo(5,7-dihydrothieno[2,3-b]pyridin-5-yl)]-N-(3-piperidylpropyl)carboxamide, or 1,4,6-trioxo-N-[3-(piperidin-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide, the composition is white or light brown. Formula II: ##STR00002##

Chem.

Chem.

[0008] In certain embodiments, a particulate delivery system (PDS) is described that comprises a crystalline form of a compound of formula I: ##STR00001## and at least one pharmaceutically acceptable additive. In certain embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 2-theta of 22.3 + / - 0.3 degrees, 25.3 + / - 0.3 degrees, and 5.4 + / - 0.3 degrees. In certain embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 2-theta of 25.8 + / - 0.3 degrees, 15.9 + / - 0.3 degrees, and 29.9 + / - 0.3 degrees. In certain embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 2-theta of 21.6 + / - 0.3 degrees, 16.5 + / - 0.3 degrees, and 20.3 degrees. In certain embodiments, the X-ray powder diffraction pattern further comprises peaks at 2-theta of 25.8 + / - 0.3 degrees, 15.9 + / - 0.3 degrees, 29.9 + / - 0.3 degrees, 21.6 + / - 0.3 degrees, 16.5 + / - 0.3 degrees, and 20.3 degrees. In certain embodiments, the crystalline form of the compound of formula I is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 3A or FIG. 3B. In certain embodiments, the particulate delivery system containing more than 90% by weight of the compound of formula I: ##STR00001## is Form I. In certain embodiments, the particulate delivery system containing the crystalline compound of formula I: ##STR00001## is Form I and is present in an amount in the range of about 0.01% to about 99.99% by weight, about 10% to about 90% by weight, or about 10% to about 50% by weight. In certain embodiments, the particulate delivery system is formulated for oral, parenteral, or topical delivery. In certain embodiments, the particulate delivery system is formulated for oral delivery as tablets, caplets, capsules, or pills. In certain embodiments, the particulate delivery system has an average diameter of less than about 1 mm, 0.5 mm, or 0.3 mm. In certain embodiments, the pharmaceutically acceptable additive is a polymer, a water-soluble polymer, and is selected from starch, cellulose, or polyethylene glycol. In certain embodiments, the particulate delivery system comprises a second additive selected from magnesium stearate, stearic acid, hydroxypropyl-beta-cyclodextrin, silicon dioxide, or mannitol.In a further embodiment, the second additive is sugar. In certain embodiments, the particulate delivery system is formulated for oral administration and may contain from 0.01 mg to 200 mg of the present compound. In certain embodiments, the particulate delivery system contains the present compound and is stable for at least 12 months at 5 °C and 60% relative humidity or at 25 °C and 60% relative humidity. In a further embodiment, the formation of degradation products is less than 0.5% by weight per year at 5 °C and 60% relative humidity or at 25 °C and 60% relative humidity. In a further embodiment, the compound degradation products are of formula II: ##STR00002##. 5-hydroxy-8-(methylethyl)-8H-1,2-oxathiino[6.5-b]pyridine-2,2,7-trione, or 5-hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxathiino[6,5-b]pyridine-2,2,7(8H)-trione, and of formula III: ##STR00003##. [7-(methylethyl)-1,4,6-trioxo(5,7-dihydrothieno[2,3-b]pyridin-5-yl)]-N-(3-piperidylpropyl)carboxamide, or 1,4,6-trioxo-N-[3-(piperidin-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide. In a further embodiment, when the composition contains less than 0.5% by weight of the compounds of formula II: ##STR00002##. 5-hydroxy-8-(methylethyl)-8H-1,2-oxathiino[6.5-b]pyridine-2,2,7-trione, or 5-hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxathiino[6,5-b]pyridine-2,2,7(8H)-trione, and of formula III: ##STR00003##. [7-(methylethyl)-1,4,6-trioxo(5,7-dihydrothieno[2,3-b]pyridin-5-yl)]-N-(3-piperidylpropyl)carboxamide, or 1,4,6-trioxo-N-[3-(piperidin-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide, the composition is white or light brown.

[0009] The present invention also describes a method for manufacturing a particulate delivery system of the compounds of the present composition, comprising blending the present composition with an additive to form a mixture, treating the mixture to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, and grinding or milling the coarse particles to form particles having an average diameter of less than about 0.5 mm. In a further embodiment, the present invention also describes a method for manufacturing a particulate delivery system of the compounds of the present composition, comprising blending the present composition with a polymer to form a mixture, treating the mixture to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, and jet milling the coarse particles to form particles having an average diameter of less than about 1 micrometer.

[0010] In certain embodiments, the present disclosure provides a method for treating Alzheimer's disease (AD) and other dementias that affect cholinergic and / or serotonergic systems, comprising administering to a patient in need thereof an effective amount of a composition of the present compound. In a further embodiment, the present disclosure provides a method for treating post-traumatic stress disorder (PTSD), comprising administering to a patient in need thereof an effective amount of a composition of the present compound.

[0011] In certain embodiments, the present disclosure provides a method of treating a subject having Alzheimer's disease (AD) and other dementias that affect cholinergic and / or serotonergic systems, the method comprising administering to the subject a composition comprising a crystalline form of a compound of formula I: ##STR00001## wherein at least 90% by weight of the compound of formula I in the composition is in the crystalline form, and the crystalline form is Form I characterized by an X-ray powder diffraction pattern comprising major peaks at 22.3 + / - 0.3 degrees, 25.3 + / - 0.3 degrees, and 5.4 + / - 0.3 degrees, and the composition is prepared by blending the composition with an additive to form a mixture, treating the mixture to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, and milling or grinding the coarse particles to form particles having an average diameter of less than about 500 micrometers.

[0012] In one aspect, the present disclosure provides an industrially scalable process for producing a crystalline form of a compound of formula I: ##STR00001## wherein the crystalline form is Form I, obtaining methyl 2-isopropylaminothiophene-3-carboxylate by reductive amination of methyl 2-aminothiophene-3-carboxylate with sodium triacetoxyborohydride in anhydrous dichloromethane and formic acid under argon followed by workup with potassium hydroxide; acylating and cyclizing methyl 2-isopropylaminothiophene-3-carboxylate in pyridine and butyronitrile with methylmalonyl chloride and then adding a sodium methoxide solution to obtain methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylate; The step of obtaining 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide hydrochloride by amidation of methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylate with 3-piperidin-1-yl-propylamine and acidification with hydrochloric acid, The step of preparing potassium 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylate (3-piperidin-1-yl-propyl)-amide by adding 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide hydrochloride, MTBE, water, potassium hydroxide solution and sodium bicarbonate to obtain 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide, then dissolving it in acetonitrile and adding potassium hydroxide in water to obtain crystalline potassium 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylate (3-piperidin-1-yl-propyl)-amide (PRX-3140 potassium salt), comprising, On the other hand, a process is provided in which the crystalline form of the compound of formula I: ##STR00001## and the crystalline form of Form I are obtained by pulverizing and sieving the powder.

[0013] In another aspect, the present disclosure is a method for producing a composition comprising the crystalline fine particle form I of PRX-3140 potassium salt, comprising: blending the crystalline fine particle form I of PRX-3140 potassium salt with a stabilizer to form a mixture, treating the above mixture to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, and Grinding the coarse particles to form particles having an average diameter in the range of about 0.1 micrometer to about 0.5 mm A method is provided that includes this.

[0014] In one aspect, the present disclosure is an industrially scalable process for manufacturing its PRX-3140 potassium salt, The step of obtaining methyl 2-isopropylaminothiophene-3-carboxylate by reductive amination of methyl 2-aminothiophene-3-carboxylate using sodium triacetoxyborohydride in anhydrous dichloromethane and formic acid under argon, followed by post-treatment with potassium hydroxide; The step of obtaining methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylate by acylation and cyclization of methyl 2-isopropylaminothiophene-3-carboxylate in pyridine and butyronitrile using methylmalonyl chloride, followed by addition of a sodium methoxide solution; The step of obtaining (3-piperidin-1-yl-propyl)-amide hydrochloride of 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid by amidation of methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylate using 3-piperidin-1-yl-propylamine and acidification using hydrochloric acid; 4-Hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide hydrochloride, MTBE, water, potassium hydroxide solution and sodium bicarbonate are added to obtain 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide, which is then dissolved in acetonitrile and potassium hydroxide in water is added to obtain crystalline 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide potassium salt (PRX-3140 potassium salt). Process for the preparation of 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide potassium salt comprising On the other hand, a process is provided in which the crystalline form of the compound of formula I: ##STR00001## and the crystalline form of Form I are obtained by pulverizing and sieving a powder. In some embodiments, the present disclosure provides for the crystallization of the input 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide free base and acetonitrile, and by adding potassium hydroxide in water, to obtain a crystalline 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide potassium salt solid and a mother liquor, followed by separation and drying. The crystalline form of the compound of formula I: ##STR00001## of Form I contains more than 90% of the desired compound. In further embodiments, the present disclosure provides for dissolving the input free base in acetonitrile at a first temperature by heating to about 20° C. to about 100° C., and then crystallizing by cooling the solution to a second temperature. In further embodiments, the present disclosure provides for crystallization by cooling the solution to a temperature in the range of about 0° C. to about 20° C. In further embodiments, the present disclosure provides for crystallization by cooling the solution to a temperature in the range of about 0° C. to about 20° C. over a period of 0.5 hours to 10 days. In further embodiments, the present disclosure provides for crystallization by cooling the solution to a temperature in the range of about 0° C. to about 20° C. over a period of 2 to 4 hours. In further embodiments, the present disclosure provides for separation of the crystalline solid and the mother liquor, and the separation can be by filtration, decantation, suction, or any suitable method. In yet another further embodiment, the present disclosure provides for separation of the crystalline solid and the mother liquor, and the separation can be by filtration while washing with a solvent and drying to a constant weight in vacuo. In further embodiments, the present disclosure provides for crystallization using a second solvent, in one embodiment crystallization using methyl tert-butyl ether (MTBE). In further embodiments, the present disclosure provides a crystalline solid washed one or more times with acetonitrile. In further embodiments, the present disclosure provides a crystalline solid dried under reduced pressure at a temperature in the range of about 20° C. to about 100° C.

[0015] In another embodiment, the present disclosure provides a compound of formula I: ##STR00001## [Chemical formula] provides a crystalline form of the compound of, Form I is characterized by an X-ray powder diffraction pattern further comprising at least one peak selected from 2-theta of 22.3 + / - 0.3 degrees, 25.3 + / - 0.3 degrees, 5.4 + / - 0.3 degrees, 25.8 + / - 0.3 degrees, 15.9 + / - 0.3 degrees, 29.9 + / - 0.3 degrees, 21.6 + / - 0.3 degrees, 16.5 + / - 0.3 degrees, and 20.3 degrees, More than 90% by weight of the compound of formula I: ##STR00001## is Form I.

[0016] In another embodiment, the present disclosure provides a crystalline form of a compound of formula I: ##STR00001## [Chemical formula] provides a crystalline form of the compound of, The crystalline form is Form I, characterized by an X-ray powder diffraction pattern further comprising at least one peak selected from 2-theta of 22.3 + / - 0.3 degrees, 25.3 + / - 0.3 degrees, 5.4 + / - 0.3 degrees, 25.8 + / - 0.3 degrees, 15.9 + / - 0.3 degrees, 29.9 + / - 0.3 degrees, 21.6 + / - 0.3 degrees, 16.5 + / - 0.3 degrees, and 20.3 + / - 0.3 degrees, More than 90% by weight of the compound of formula I: ##STR00001## is Form I, The composition has crystalline particles of the compound of formula I: ##STR00001## having an average diameter of less than about 500 μm, The compound is stable for at least 12 months at 5 degrees Celsius and 60% relative humidity or at 25 degrees Celsius and 60% relative humidity.

[0017] In another embodiment, the present disclosure provides a method for manufacturing a particulate delivery system of a compound of the composition, the method comprising blending the composition with an additive to form a mixture, treating the mixture to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, and grinding or milling the coarse particles to form particles having an average diameter of less than about 0.5 mm. In a further embodiment, the present invention also provides a method for manufacturing a particulate delivery system of a compound of the composition, the method comprising blending the composition with a polymer to form a mixture, treating the mixture to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, and jet milling the coarse particles to form particles having an average diameter of less than about 1 micrometer.

[0018] In yet another embodiment, the present disclosure a crystalline form of a compound of formula I: ##STR00001##, characterized as Form I by an X-ray powder diffraction pattern comprising major peaks at 2-theta of 22.3 + / - 0.3 degrees, 25.3 + / - 0.3 degrees, 5.4 + / - 0.3 degrees, 25.8 + / - 0.3 degrees, 15.9 + / - 0.3 degrees, 29.9 + / - 0.3 degrees, 21.6 + / - 0.3 degrees, 16.5 + / - 0.3 degrees, and 20.3 degrees, and a particulate delivery system comprising the crystalline form of the compound and at least one pharmaceutically acceptable additive. more than 90% by weight of the compound of formula I: ##STR00001## is in Form I. the composition having crystalline particles of a compound of formula I: ##STR00001## having an average diameter of less than about 500 μm. the compound being stable for at least 12 months at 5 degrees Celsius and 60% relative humidity or at 25 degrees Celsius and 60% relative humidity. the particulate delivery system being formulated for oral delivery.

[0019] In yet another embodiment, the present disclosure provides an industrially scalable process for manufacturing a crystalline form of a compound of formula I: ##STR00001##, the crystalline form being Form I. The step of obtaining methyl 2-isopropylaminothiophene-3-carboxylate by the reductive amination of methyl 2-aminothiophene-3-carboxylate using sodium triacetoxyborohydride in anhydrous dichloromethane and formic acid under argon, followed by post-treatment with potassium hydroxide, The step of acylating and cyclizing methyl 2-isopropylaminothiophene-3-carboxylate in pyridine and butyronitrile using methyl malonyl chloride, and then adding a sodium methoxide solution to obtain methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylate, The step of amidating methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylate using 3-piperidin-1-yl-propylamine and acidifying with hydrochloric acid to obtain 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide hydrochloride, The step of preparing crystalline 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide potassium salt (PRX-3140 potassium salt) by adding 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide hydrochloride, MTBE, water, a potassium hydroxide solution, and sodium bicarbonate to obtain 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide, and then dissolving it in acetonitrile and adding potassium hydroxide in water, comprising, On the one hand, a crystalline form of a compound of formula I: ##STR00001##, wherein the crystalline form of Form I is obtained by pulverizing and sieving a powder, and the crystallization is carried out by cooling a solution to a temperature in the range of about 0 °C to about 20 °C over 2 to 4 hours, and the crystalline solid is dried under reduced pressure at a temperature in the range of about 20 °C to about 100 °C, and the crystalline form is Form I, and is obtained by pulverizing and sieving a powder, and the crystalline form of the compound of formula I: ##STR00001## of Form I contains more than 90% of the desired compound, providing a process.

Brief Description of the Drawings

[0020] The novel features of the present invention are described in detail in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description which illustrates exemplary embodiments in which the principles of the present invention are utilized, and to the appended drawings.

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DETAILED DESCRIPTION OF THE INVENTION

[0033] DETAILED DESCRIPTION I. TERMINOLOGY Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0034] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term "or" means "and / or". The terms "comprising", "having", "including", and "containing" should be construed as open-ended terms (i.e., meaning "including but not limited to").

[0035] The recitation of a range of values is intended to be merely a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. All endpoints of a range are included within the range and may be combined independently.

[0036] All of the methods described in this specification can be performed in a suitable order unless otherwise indicated herein or unless clearly inconsistent with the context. The use of any examples or illustrative language (e.g., "such as") is merely intended to better explain the invention and does not limit the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating that any non-claimed element is essential to the practice of the invention described herein. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field of this disclosure.

[0037] Furthermore, this disclosure encompasses all variations, combinations, and substitutions in which one or more limitations, elements, clauses, and descriptive terms from one or more of the recited claims are introduced into another claim. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends on the same base claim. When elements are presented as a list in, for example, a Markush group format, each subgroup of the elements is also disclosed and any element can be removed from the group.

[0038] All compounds are understood to include all possible isotopes of the atoms present in the compound. Isotopes include atoms having the same atomic number but different mass numbers. General examples, without limitation, include hydrogen isotopes such as tritium and deuterium, and carbon isotopes such as 11C, 13C, and 14C.

[0039] The open-ended term "comprising" includes the intermediate term "consisting essentially of" and the closed term "consisting of".

[0040] A significant change is any detectable change that is statistically significant, where p < 0.05 in a standard parametric test of statistical significance such as Student's t-test. II. Synthesis of Crystalline Fine Particle Form I of PRX-3140 Potassium Salt

[0041] The present disclosure includes the following embodiments, which should not be construed as limiting. Rather, these embodiments are illustrative and are provided to explain the invention to those skilled in the art. Like reference numerals refer to like elements throughout.

[0042] It has unexpectedly been discovered that the crystalline 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide potassium salt (PRX-3140 potassium salt) can be obtained by dissolving the 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide free base in acetonitrile and adding potassium hydroxide in water, followed by heating and subsequent cooling. This process is different from the normal crystallization procedures of U.S. Pat. Nos. 7,488,736 and 7,982,040 that use an aqueous solution of potassium tert-butoxide mixed with dichloromethane and ethyl acetate, and unexpectedly provides a crystalline solid containing more than 90% of the desired 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide potassium salt (PRX-3140 potassium salt).

[0043] In one aspect, the present disclosure provides an industrially scalable process for manufacturing the potassium salt of PRX-3140, comprising: (A) a reductive amination of methyl 2-aminothiophene-3-carboxylate with 2,2-dimethoxypropane using sodium triacetoxyborohydride in anhydrous dichloromethane and formic acid under argon, followed by workup with potassium hydroxide to obtain methyl 2-isopropylaminothiophene-3-carboxylate (3); (B) an acylation and cyclization of methyl 2-isopropylaminothiophene-3-carboxylate (3) in pyridine and butyronitrile using methylmalonyl chloride, followed by addition of a sodium methoxide solution to obtain methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylate (5); (C) an amidation of methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylate (5) using 3-piperidin-1-yl-propylamine (6), and acidification of the resulting crude PRX-3140 with hydrochloric acid to obtain 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide hydrochloride (8); and (D) adding 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide hydrochloride (8), MTBE, water, a potassium hydroxide solution, and sodium bicarbonate to obtain 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide and the free base, then dissolving in acetonitrile and adding potassium hydroxide in water to obtain the crystalline 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide potassium salt (PRX-3140 potassium salt).Provided is a process comprising the step of preparing the potassium salt of 3 - b]pyridine - 5 - carboxylic acid(3 - piperidin - 1 - yl - propyl) - amide. Crystalline fine particle form I of the potassium salt of PRX - 3140 is obtained by pulverizing and sieving the powder.,

[0044] The first step of the disclosed process is the crystallization of the charged 4 - hydroxy - 7 - isopropyl - 6 - oxo - 6,7 - dihydro - thieno[2,3 - b]pyridine - 5 - carboxylic acid(3 - piperidin - 1 - yl - propyl) - amide free base and acetonitrile, and the addition of potassium hydroxide in water to obtain a crystalline 4 - hydroxy - 7 - isopropyl - 6 - oxo - 6,7 - dihydro - thieno[2,3 - b]pyridine - 5 - carboxylic acid(3 - piperidin - 1 - yl - propyl) - amide potassium salt(PRX - 3140 potassium salt) solid and mother liquor, followed by separation and drying. The crystalline solid contains more than 90% of the desired PRX - 3140 potassium salt. Crystallization can be carried out by heating the charged free base to dissolve it in acetonitrile at a first temperature and then cooling the solution to a second temperature for crystallization. The solution can be held at the second temperature for several hours to allow sufficient crystallization. For example, the charged free base can be dissolved in acetonitrile at 45°C to 50°C and then the resulting solution can be cooled to 0°C to 5°C and held at the second temperature for 0.5 hours to 10 days, preferably 2 hours to 4 hours. In some cases, a longer holding time at the second temperature may be required. The crystalline solid and the mother liquor can be separated by filtration, decantation, suction, or any suitable method. The separated crystalline solid can be washed with a suitable solvent to remove impurities and dried with or without using heat and / or reduced pressure to remove the solvent. Preferably, the crystalline solid is recovered by filtration, washed with a solvent, and dried in vacuo to a constant weight. The separated mother liquor can be concentrated in vacuo to obtain a solid or non - solid, and dried with or without using heat and / or reduced pressure to remove the solvent. Preferably, the concentrated mother liquor is dried in vacuo to a constant weight.

[0045] It was unexpectedly discovered that acetonitrile is a particularly useful solvent for carrying out this step. Other solvents such as MTBE can also be used as the second solvent. Crystallization can be carried out by dissolving the input crystalline solid in the second solvent at a first temperature of 20 to 100 °C, and then cooling the solution by only 20 to 100 °C to a second temperature to effect crystallization. The solution can be held at the second temperature for several hours to allow sufficient crystallization. For example, the solid formed from the concentrated first mother liquor can be dissolved in acetonitrile at 30 to 70 °C, preferably 40 to 60 °C, and then the resulting solution is cooled to -10 to 20 °C or 0 to 10 °C and held at the second temperature for 0.5 hours to 10 days or 2 hours to 72 hours. In some cases, a longer holding time at the second temperature may be required. The crystalline solid and the mother liquor can be separated by filtration, decantation, suction, or any suitable method. The separated crystalline solid can be washed with a suitable solvent to remove impurities and dried with or without heat and / or reduced pressure to remove the solvent. The separated mother liquor can be concentrated in vacuo to obtain a solid, and dried with or without heat and / or reduced pressure to remove the solvent. Preferably, the mother liquor is separated from the crystalline solid by suction, concentrated, and dried in vacuo to a constant weight. III. Crystal Form

[0046] In certain embodiments, the present disclosure provides crystalline microparticle Form I of PRX-3140 potassium salt. The present disclosure further provides pharmaceutical compositions of PRX-3140 potassium salt comprising the crystalline forms described herein. The crystalline forms of PRX-3140 potassium salt can provide advantages in bioavailability and stability suitable for use as an active ingredient in a pharmaceutical composition. Variations in the crystal structure of a pharmaceutical substance or active ingredient can affect the dissolution rate of the pharmaceutical formulation or active ingredient (which can affect bioavailability), manufacturability (e.g., ease of handling, ability to consistently prepare a known strength dose), and stability (e.g., thermal stability, shelf life). Such variations can affect the preparation or formulation of pharmaceutical compositions in various dosage forms or delivery forms, such as solid oral dosage forms including tablets and capsules. Compared to other forms, such as non-crystalline or amorphous forms, crystalline forms can provide desired or appropriate hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Thus, the crystalline forms of PRX-3140 potassium salt can provide advantages such as improving the manufacturing process of the active pharmaceutical agent or the stability or shelf life of the formulated form of the compound or active ingredient, and / or having appropriate bioavailability and / or stability as an active pharmaceutical agent.

[0047] It has been found that the use of certain solvents and fractional crystallization methods produces various polymorphic forms of PRX-3140 potassium salt, including polymorphic Form I, which can exhibit one or more of the above-described favorable properties. The preparation processes of the polymorphs described herein and the characterization of these polymorphs are described in more detail below.

[0048] In certain embodiments, the present disclosure provides polymorphic form I of the potassium salt of PRX-3140, wherein at least 90% by weight is the potassium salt of PRX-3140. In some embodiments, polymorphic form I exhibits an X-ray diffraction (XRD) pattern substantially as shown in FIG. 3. In some embodiments, polymorphic form I has an XRD pattern that includes at least two, at least three, at least four, at least five, or at least six of the major peaks, as an XRD pattern substantially as shown in FIG. 3. The crystal structure of the present invention is substantially pure, single, and substantially free of any other crystalline form or amorphous state. "Substantially pure" as used in the present invention, when used with respect to a novel crystal form, means that this novel crystal form constitutes at least 80% by weight, more preferably at least 90% by weight, particularly at least 95% by weight, and particularly at least 99% by weight of the compound.

[0049] For example, when referring to an XRD pattern, the term "substantially shown" includes patterns that are not necessarily identical to the pattern shown in this specification but are within the limits of experimental error or deviation when considered by a person skilled in the art. The relative intensities of XRD peaks may vary depending on particle size, sample preparation method, sample mounting procedure, and the specific equipment used. The crystal form in the present invention is confirmed by the characterization of the X-ray powder diffraction pattern shown by the compound, and means having a unique regular molecular arrangement or configuration within the crystal lattice. It is well known to those skilled in the art that experimental error depends on apparatus conditions, sample preparation, and sample purity. The two-theta angle of the peaks in the XRD pattern usually varies slightly depending on the equipment and the sample. The difference in peak angles may vary, such as 1 degree, 0.8 degree, 0.5 degree, 0.3 degree, 0.1 degree, etc., depending on different equipment, different samples, etc. Generally, the tolerance is + / -0.2 degrees. Therefore, the difference in peak angles cannot be used as the sole measure. Since the relative intensity of the peaks can vary depending on the sample, sample preparation, and other experimental conditions, the order of peak intensities may not be the only or decisive factor. The influence of experimental factors such as sample height causes an overall shift in the peak angle, which usually allows for a specific shift. Therefore, those skilled in the art can understand that any crystal form having unique peaks identical or similar to the powder X-ray diffraction pattern of the present invention belongs to the scope of the present invention. "Single crystal form" refers to the single crystal form determined by powder X-ray diffraction.

[0050] Furthermore, variations in equipment and other factors can affect the two-theta value. Therefore, it should be understood that when a specified two-theta angle is provided, the specified two-theta angle may differ only by a specified value such as + / -0.5 degrees, + / -0.4 degrees, + / -0.3 degrees, + / -0.2 degrees, or + / -0.1 degrees. As used herein, "major peak" refers to an XRD peak having a peak intensity greater than the baseline, such as exceeding 100 or 500, depending on the baseline noise and the other test factors mentioned above.

[0051] In certain embodiments, the present disclosure provides a PRX-3140 compound of Formula I in a composition wherein at least 90% by weight is in crystalline form of a potassium salt. Crystalline Form I includes major peaks at 2-theta of 22.3 + / - 0.3 degrees, 25.3 + / - 0.3 degrees, and 5.4 + / - 0.3 degrees, and optionally further includes at least one peak selected from 2-theta of 25.8 + / - 0.3 degrees, 15.9 + / - 0.3 degrees and 29.9 + / - 0.3 degrees, and may be characterized by an X-ray powder diffraction pattern. In some embodiments, the X-ray powder diffraction pattern further includes at least one peak selected from 2-theta of 21.6 + / - 0.3 degrees, 16.5 + / - 0.3 degrees, and 20.3 degrees. The X-ray powder diffraction pattern may further include peaks at 2-theta of 21.3 + / - 0.3 degrees, 17.1 + / - 0.3 degrees, 16.3 + / - 0.3 degrees, 33.1 + / - 0.3 degrees, 45.6 + / - 0.3 degrees, and 13.7 + / - 0.3 degrees. In some embodiments, Crystalline Form I is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 3. More than 90%, 95% or 99% by weight of the compound of Formula I in the composition may be in Crystalline Form I. In some embodiments, the composition includes 0.01 mg to 200 mg of Crystalline Form I, such as about 10 mg, 25 mg, 50 mg, 75 mg, 100 mg or 200 mg of Crystalline Form I.

[0052] In some embodiments, a composition comprising a crystalline form of the potassium salt of PRX-3140 comprises 0.01%, 0.05%, 0.01%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% of the potassium salt of PRX-3140 (wt / wt) or (w / v) of the composition. In some embodiments, a composition comprising a crystalline form of the potassium salt of PRX-3140 comprises 0.01%, 0.05%, 0.01%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% of the potassium salt of PRX-3140 (wt / wt) or (w / v) of the composition.

[0053] The compounds and compositions of the present disclosure can be administered to a subject in need thereof by any route known in the art, including but not limited to oral, parenteral, topical, and intraluminal delivery. Accordingly, the compositions disclosed herein are formulated to be compatible with the intended route of administration.

[0054] In some embodiments, compositions comprising a crystalline form of the PRX-3140 potassium salt further comprise an additive. Such additives can be compatible with the intended route of administration. IV. Method for Manufacturing a Particle Delivery System (PDS)

[0055] The present disclosure also provides a method for manufacturing a composition of the present disclosure comprising particles of a crystalline form of the PRX-3140 potassium salt encapsulated by an additive, blending a crystalline form of the PRX-3140 potassium salt with an additive to form a mixture, processing the above mixture to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, and grinding or milling the above coarse particles to form particles having an average diameter of less than about 500 micrometers comprising.

[0056] In certain embodiments, the particles have an average diameter in the range of about 0.1 micron to about 0.1 mm. The particulate material, also referred to as "particles" manufactured according to the present disclosure, may be such that small particles in the size range of nanometers to micrometers are desirable. Examples can include nanoparticle and microparticle forms of a medicament comprising a crystalline form of the PRX-3140 potassium salt. There are numerous possibilities and combinations.

[0057] In one embodiment, a system for preparing the compositions of the present disclosure may include grinding the crystalline form of PRX-3140 potassium salt in a mortar and pestle or ball mill. In another embodiment, a system for preparing the compositions of the present disclosure may include, for example, a Venturi-type nozzle or "T-shaped" valve for introducing cryogenic gas into a jet mill. Without wishing to be bound by any particular theory, it has been observed that using a combination of cryogenic (generally below 0 degrees Celsius) dry gas prior to introduction into the jet mill can eliminate moisture-induced agglomeration while promoting brittle fracture of the particles upon collision, acting synergistically to result in a significant improvement in particle size reduction efficiency. Suitable cryogenic liquids for use in this method include liquid argon, liquid nitrogen, liquid helium, or any other liquefied gas having a temperature low enough to cause brittle fracture of the particles. The cryogenic liquid may also prevent milling losses and thermal damage to the feed material caused by volatilization or overheating of the components.

[0058] In one embodiment, the powder is placed in a temperature-controlled vessel such as a jacketed hopper or screw feeder, or pre-frozen. Inputs of cryogenic liquids and gases are opened and the flow and temperature are set to the desired process conditions. A cryogenic gas injection system, such as liquid nitrogen mixed with nitrogen gas, can be connected as the main carrier gas in various gas injection setups to standard commercially available jet mills such as Trost Gem-T, Trost T-15, Fluid Air Aljet, Hosikawa Alpine AS Spiral Jet Mill, Sturtevant Micronizer, or similar systems. The pre-operation setup of the system may include attaching a temperature probe or flow meter, such as a TSI Model 4040 flow meter or similar system, to the gas input or the top of the cyclone (instead of the air bleed bag), setting the carrier gas to different input pressures, and recording gas flow and temperature measurements (CFM). The milling process can be started by turning on the powder feeder. After passing the powder through the milling area, the jet-milled powder is collected in a cup or similar receiver unit (typically particles of about 1 to 10 microns) or from the bag above the cyclone (particles less than 1 micron), depending on the exact operating conditions. Particles having a diameter in the range of less than about 1 micron to about 10 microns can be produced by passing the powder through the jet mill multiple times (or passes) from the cup under similar operating conditions to obtain the desired particle size.

[0059] In certain embodiments, the particles can have an average diameter in the range of about 0.1 mm (100 microns) to about 3 mm. For example, the particles can have a diameter of less than about 2.06 mm (corresponding to a 10 mesh sieve), less than about 1.68 mm (corresponding to a 12 mesh sieve), less than about 1.40 mm (corresponding to a 14 mesh sieve), less than about 1.20 mm (corresponding to a 16 mesh sieve), less than about 1.00 mm (corresponding to an 18 mesh sieve), less than about 0.853 mm (corresponding to a 20 mesh sieve), less than about 0.710 mm (corresponding to a 25 mesh sieve), less than about 0.599 mm (corresponding to a 30 mesh sieve), or less than about 0.500 mm (corresponding to a 35 mesh sieve). In some embodiments, the particles can have a diameter of less than about 300 microns and may be able to pass through a 50 mesh sieve. In certain embodiments, the particles have a diameter of about 0.6 mm or less.

[0060] In certain embodiments, the release-controlled polymer is heated before blending with the crystalline form of the PRX-3140 potassium salt.

[0061] In some embodiments, the present disclosure provides a method of manufacturing a composition of the present disclosure comprising particles of the crystalline form of the PRX-3140 potassium salt encapsulated by a release-controlled polymer, using a process that is at least in part a continuous manufacturing process. The method comprises blending the crystalline form of the PRX-3140 potassium salt with a release-controlled polymer to form a mixture, heating the mixture to a temperature sufficient for extrusion of the mixture, extruding the mixture to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, cooling the coarse particles, and processing the coarse particles (e.g., by milling, grinding, or crushing) to form particles having an average diameter of less than about 0.1 mm and may include.

[0062] In certain embodiments, the particles can have an average diameter in the range of from about 0.1 mm (100 microns) to about 3 mm. For example, the particles can have a diameter of less than about 2.06 mm (corresponding to a 10 mesh sieve), less than about 1.68 mm (corresponding to a 12 mesh sieve), less than about 1.40 mm (corresponding to a 14 mesh sieve), less than about 1.20 mm (corresponding to a 16 mesh sieve), less than about 1.00 mm (corresponding to an 18 mesh sieve), less than about 0.853 mm (corresponding to a 20 mesh sieve), less than about 0.710 mm (corresponding to a 25 mesh sieve), less than about 0.599 mm (corresponding to a 30 mesh sieve), or less than about 0.500 mm (corresponding to a 35 mesh sieve). In some embodiments, the particles can have a diameter of less than about 300 microns and may be able to pass through a 50 mesh sieve. In certain embodiments, the particles can have a diameter of about 0.1 mm or less.

[0063] In certain embodiments, the release-controlled polymer may be heated before blending with the crystalline form of the PRX-3140 potassium salt. V. Pharmaceutical Composition (Final Dosage Form)

[0064] The present disclosure further provides a pharmaceutical composition (sometimes referred to as the "final dosage form" or "FDF") comprising a composition according to the present disclosure.

[0065] In some embodiments, the pharmaceutical composition may further comprise at least one additive (such as a release-controlling polymer, surfactant, and / or metal salt, etc.), such as pharmaceutically acceptable additives. Examples of pharmaceutically acceptable additives can be those described in Remington’s Pharmaceutical Sciences by E.W. Martin, and can include cellulose, starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, etc. In some embodiments, the pharmaceutical composition may also contain a pH buffer and a wetting or emulsifying agent.

[0066] In some embodiments, the pharmaceutical composition can be formulated for oral administration. In this embodiment, the pharmaceutical composition can be in the form of, for example, tablets, capsules, or other oral dosage forms. Such oral dosage forms can be prepared by conventional means. The pharmaceutical composition can also be prepared as a liquid, such as a syrup or suspension. The liquid can contain a suspending agent (such as sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), an emulsifying agent (lecithin or acacia), a non-aqueous vehicle (such as almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils), and a preservative (such as methyl or propyl - p-hydroxybenzoate or sorbic acid). The preparation can also contain flavoring agents, coloring agents, and sweetening agents. Alternatively, the composition can be provided as a dry product for constitution with water or another suitable vehicle.

[0067] For buccal and sublingual administration, the composition can take the form of tablets or lozenges according to conventional protocols.

[0068] The pharmaceutical composition can also be formulated for rectal administration as a suppository or retention enema containing a conventional suppository base such as PEG, cocoa butter, or other glycerides.

[0069] In some embodiments, the pharmaceutical compositions described herein provide improved dissolution of the crystalline form of PRX-3140 potassium salt as compared to the non-encapsulated crystalline form of PRX-3140 potassium salt and / or another dosage form (e.g., a more invasive dosage form, etc.). For example, the dissolution can be increased by, for example, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 93%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, or 200% when measured by a Vankel tablet dissolution apparatus approved by the United States Pharmacopeia, or can be increased by, for example, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, or 1000-fold.

[0070] In some embodiments, the pharmaceutical compositions described herein provide improved oral bioavailability of the crystalline form of PRX-3140 potassium salt as compared to the non-encapsulated crystalline form of PRX-3140 potassium salt and / or another dosage form (e.g., a more invasive dosage form, etc.). For example, the absorption can be increased by, for example, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 93%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, or 200% when measured by an in vivo pharmacokinetic study in a preclinical animal model or human clinical evaluation, or can be increased by, for example, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, or 1000-fold.

[0071] In some embodiments, the pharmaceutical composition described herein is an immediate-release formulation. In such embodiments, the pharmaceutical composition provides a more rapid onset of action of the crystalline form of PRX-3140 potassium salt compared to the non-encapsulated crystalline form of PRX-3140 potassium salt and / or another dosage form (e.g., a more invasive dosage form, etc.). For example, the onset of action can be reduced by, for example, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 93%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, or 200% when measured, for example, by in vivo pharmacokinetic studies in preclinical animal models or human clinical evaluations, or can be reduced by, for example, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, or 1000-fold.

[0072] In some embodiments, the pharmaceutical composition described herein is a controlled-release formulation. In such embodiments, the pharmaceutical composition described herein provides a more rapid onset of action of the crystalline form of PRX-3140 potassium salt.

[0073] In some embodiments, the pharmaceutical composition described herein has reduced absorption variability compared to non-encapsulated insoluble drugs and / or another dosage form (e.g., a more invasive dosage form, etc.).

[0074] In some embodiments, the pharmaceutical composition described herein is associated with improved patient compliance compared to another pharmaceutical composition (which may be another dosage form, e.g., a more invasive dosage form, etc.) comprising the crystalline form of PRX-3140 potassium salt.

[0075] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral delivery. Compositions intended for oral use can be prepared in solid or fluid unit dosage forms. In at least some embodiments, the present compositions are formulated for oral delivery as tablets, caplets, capsules, pills, powders, troches, elixirs, suspensions, syrups, wafers, chewing gums, dragees, lozenges, and the like.

[0076] In some embodiments, the oral dosage forms are solid oral dosage forms such as tablets, caplets, and capsules. In some embodiments, the capsules are hard capsules or soft capsules. In other embodiments, the capsules are gelatin capsules, gelatin-free capsules, "cap-in-cap" capsules, alginate capsules, hydroxypropylmethylcellulose (HPMC) capsules, polyvinyl alcohol (PVA) capsules, hypromellose capsules, or starch capsules.

[0077] In some embodiments, the oral compositions comprising the crystalline form of the PRX-3140 potassium salt further comprise one or more additives. In some embodiments, the oral compositions comprising the crystalline form or polymorph thereof of the PRX-3140 potassium salt further comprise one or more additives. Thus, the compositions designed for oral administration can be made using inert or active additives or using the edible carriers disclosed herein.

[0078] In various embodiments, the compositions provided herein include one or more additives in an amount of from about 1 wt% to about 99.99 wt%, from about 5 wt% to about 95 wt%, from about 5 wt% to about 90 wt%, from about 10 wt% to about 80 wt%, from about 15 wt% to about 70 wt%, from about 20 wt% to about 60 wt%, from about 30 wt% to about 95 wt%, from about 50 wt% to about 90 wt%, from about 60 wt% to about 90 wt%, from about 60 wt% to about 80 wt%, or from about 70 wt% to about 80 wt%. In certain embodiments, the compositions provided herein include one or more additives in an amount of about 99.99 wt%, about 95 wt%, about 90 wt%, about 85 wt%, about 80 wt%, about 75 wt%, about 70 wt%, about 65 wt%, about 60 wt%, about 55 wt%, or about 50 wt%. In certain embodiments, the compositions provided herein include one or more additives in an amount of about 99.99%, about 99%, about 98 wt%, about 97 wt%, about 96 wt%, about 95 wt%, about 94 wt%, about 93 wt%, about 92 wt%, about 91 wt%, about 90 wt%, about 89 wt%, about 88 wt%, about 87 wt%, about 86 wt%, or about 85 wt%. In certain embodiments, the compositions provided herein include one or more additives in an amount of about 85 wt%, about 84 wt%, about 83 wt%, about 82 wt%, about 80 wt%, about 79 wt%, about 78 wt%, about 77 wt%, about 76 wt%, about 75 wt%, about 74 wt%, about 73 wt%, about 72 wt%, about 71 wt%, about 70 wt%, about 69 wt%, about 68 wt%, about 67 wt%, about 66 wt%, or about 65 wt%. In certain embodiments, the compositions provided herein include one or more additives in an amount of about 55 wt%, about 54 wt%, about 53 wt%, about 52 wt%, about 51 wt%, about 50 wt%, about 49 wt%, about 48 wt%, about 47 wt%, about 46 wt%, or about 45 wt%. In certain embodiments, the compositions provided herein include one or more additives in an amount of about 30 wt%, about 29 wt%, about 28 wt%, about 27 wt%, about 26 wt%, about 25 wt%, about 24 wt%, about 23 wt%, about 22 wt%, about 21 wt%, or about 20 wt%.

[0079] Examples of additives that can be used in compositions formulated for oral administration are provided herein and include, but are not limited to, bulking agents, binders, fillers, disintegrants, lubricants, glidants, release control agents, enteric coatings, film formers, plasticizers, colorants, sweeteners, flavoring agents, or one or more of these, or any combination thereof.

[0080] Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, starches such as sucrose, corn starch, potato starch, or starch pastes, pregelatinized starch, and starches such as starch 1500, PEG 6000, methocel, wallocel HM, Luvitec, Luvicaparolactam, Avicel, SMCC, UNIPURE, gelatin, acacia, and other natural and synthetic gums, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium), polyvinylpyrrolidone, methyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose (e.g., numbers 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL PH 101, AVICEL PH 103, AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pennsylvania), and mixtures thereof. In some embodiments, the binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose. Suitable anhydrous or low moisture additives or adjuvants include AVICEL PH 103 and Starch 1500 LM.

[0081] Examples of fillers suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), sugars such as dextrose, sucrose, lactose, salts such as calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, starches, microcrystalline cellulose, powdered cellulose, cellulose-based bases such as methylcellulose, carboxymethylcellulose dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0082] One or more binders or fillers in the composition are typically present in the composition or dosage form at about 10% to about 99% (wt / wt). In some embodiments, the binder and / or filler in the composition constitutes about 15% - 99%, about 20% - 60%, about 25% - 55%, about 30% - 50%, about 35% - 60%, about 50% - 99% (wt / wt) of the composition.

[0083] To provide tablets that disintegrate when exposed to an aqueous environment, a disintegrant can be used in the composition. Tablets with too much disintegrant may disintegrate during storage, while tablets with too little may not disintegrate at the desired rate or under the desired conditions. Therefore, a sufficient amount of disintegrant should be used to form the solid oral dosage form, which is not so much as to detrimentally alter the release of the active ingredient and not so little. In some embodiments, the disintegrant is deep within the oral solid dosage form to delay disintegration. The amount of disintegrant used varies depending on the type of formulation and is readily recognizable to those skilled in the art.

[0084] Typical compositions contain 0.5% - 15% (wt / wt) of a disintegrant. In some embodiments, the composition contains 1% - 5% (wt / wt) of a disintegrant in the composition. In another embodiment, the disintegrant is 1% - 25%, 2% - 20%, 5% - 15%, 8% - 12%, or about 10% (wt / wt) of the composition.

[0085] Disintegrants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polyacrylate, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0086] Lubricants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil), zinc stearate, magnesium stearate or potassium stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional lubricants include, for example, colloidal silica gels (AEROSIL 200 manufactured by W.R. Grace Co. of Baltimore, Maryland), coagulated aerosols of synthetic silica (sold by Degussa Co. of Plano, Texas), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Massachusetts), Q7-9120 (Dow Corning), and mixtures thereof. When used, lubricants are typically used in amounts less than 1% (wt / wt) of the composition or dosage form into which they are incorporated. In yet another embodiment, the lubricant is 0.1% - 3%, 0.5% - 1% (wt / wt), etc. of the present composition.

[0087] Plasticizers may be added to control the flexibility or adaptability of oral dosage forms such as capsules, caplets, or tablet shells, and as a result, may improve the mechanical properties of pH-sensitive materials of coatings on the oral dosage form. Suitable plasticizers include, but are not limited to, petroleum (e.g., paraffinic process oil, naphthenic process oil, and aromatic process oil), squalene, squalane, vegetable oils (e.g., olive oil, camelia oil, castor oil, tall oil, and peanut oil), silicone oil, dibasic acid esters (e.g., dibutyl phthalate and dioctyl phthalate), liquid rubbers (e.g., polybutene and liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate ISM), hexyl laurate, diethyl sebacate and diisopropyl sebacate, triethyl citrate, triacetin, diethylene glycol, polyethylene glycol, polypropylene glycol, phthalate, sorbitol, glycol salicylate, chlorpheniramine, and glycerin or mixtures thereof. The amount of plasticizer may vary depending on the chemical composition of the pharmaceutical formulation. In one embodiment, at least one plasticizer is sorbitol, dimethyl isosorbide, or glycerol. In another embodiment, the plasticizer is 1% - 10%, 3% - 5% (wt / wt), etc. of the composition.

[0088] Examples of flow promoters include, but are not limited to, colloidal silicon dioxide, cellulose, calcium phosphate, dibasic or tribasic, etc.

[0089] Examples of sweeteners or sweetening agents include sucrose, saccharin, dextrose, maltose, sugar substitutes, aspartame, xylitol, mannitol, cyclamate, sucralose, maltitol, sorbitol, acesulfame K, etc.

[0090] Examples of flavoring agents include peppermint, methyl salicylate, peppermint, spearmint, methyl salicylate, raspberry, redberry, strawberry, pineapple, orange, cherry, etc.

[0091] The compositions formulated for oral delivery disclosed herein, such as tablets, caplets, and capsules, can be coated with one or more enteric coating agents, release controlling agents, or film forming agents to control or delay the disintegration and absorption of the composition containing the crystalline form of the compound of Formula I in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. Thus, in some embodiments, the tablets can be enteric-coated tablets, the caplets can be enteric-coated caplets, or the capsules can be enteric-coated capsules. The enteric-coated tablets, enteric-coated caplets, or enteric-coated capsules of the present disclosure can be prepared by techniques known in the art.

[0092] The pharmaceutical formulations disclosed herein can include release controlling agents. Examples of release controlling agents suitable for use include, but are not limited to, pH-dependent polymers, acid-insoluble polymers, methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, zein, synthetic waxes, microcrystalline waxes, paraffin waxes, carnauba waxes, and waxes including beeswax, polyethoxylated castor oil derivatives, hydrogenated oils, glyceryl mono-, di-, tri-behenates, glyceryl monostearate, glyceryl distearate, stearyl alcohol, cetyl alcohol and polyethylene glycol and other long-chain alcohols, and mixtures thereof. In some embodiments, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. In other embodiments, the reagent with controlled release is a digestible waxy substance such as hard paraffin wax.

[0093] In some embodiments, the composition may include one or more pH-dependent polymers, such as acid-insoluble polymers. The pH-dependent polymers become increasingly permeable above pH 5.0, but are impermeable at pH values below 5.0, whereas the acid-insoluble polymers are soluble under neutral to weakly alkaline conditions. Such release-control polymers are targeted at the upper small intestine and the colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, alginates such as sodium alginate or potassium alginate, shellac, pectin, acrylic acid-methylacrylic acid copolymers (available as a powder or 30% aqueous dispersion under the trade names EUDRAGIT® L and EUDRAGIT® S from Rohm America In, Piscataway, NJ, or as a 30% dispersion under the trade name EASTACRYL® from Eastman Chemical Co., Kingsport, TN). Additional examples include EUDRAGIT® L100-55, EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12,5, EUDRAGIT® S100, EUDRAGIT® S12,5, EUDRAGIT® FS 30D, EUDRAGIT® E100, EUDRAGIT® E 12,5, and EUDRAGIT® PO. In at least one embodiment, the composition includes EUDRAGIT® L100-55. EUDRAGIT® RS and RL as well as EUDRAGIT® NE and NM are also polymers useful for the purposes of the present disclosure. In some embodiments, the composition includes EUDRAGIT® L30D 55. In another embodiment, the preparation includes EUDRAGIT® FS 30D. Those skilled in the art will appreciate that at least some of the acid-insoluble polymers listed herein are also biodegradable.

[0094] For oral dosage forms of time-delayed or sustained-release pharmaceutical formulations, glyceryl monostearate, glyceryl distearate and acid-insoluble polymers, such as polymethacrylate pH-sensitive polymer-based coatings can be used (e.g., as coating materials for enteric coatings of capsules, caplets, and tablets, i.e., enteric coating agents). Commercial sources of sustained-release oral dosage forms are available, for example, DRCaps made from hypromellose (HPMC) manufactured by Capsugel (USA) are available. Such sustained-release oral dosage forms are acid-resistant and can withstand the acidity found in the stomach for at least 30 minutes, at least 1 hour, at least 1.5 hours or at least 2 hours, etc. Such sustained-release oral dosage forms can release at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the crystalline form of the compound of formula I in the intestine (small intestine, large intestine / colon, etc.).

[0095] In one aspect of the present disclosure, enteric-coated tablets, enteric-coated caplets, and enteric-coated capsules may not be coated. Hard uncoated capsules having enteric properties using intrinsic enteric capsule technology (e.g., EnTrinsic Drug Delivery available from Capsugel) are suitable for the purposes of the present disclosure.

[0096] In various embodiments, the enteric-coated tablet is a hard tablet made of a free-flowing powder of the crystalline form of the compound of formula I. In various embodiments, the enteric-coated capsule is a capsule made of a free-flowing powder of the crystalline form of the compound of formula I. In various embodiments, the enteric-coated tablet is a hard tablet made of a free-flowing powder of the crystalline form of the compound of formula I. In various embodiments, the enteric-coated capsule is a capsule made of a free-flowing powder of the crystalline form of the compound of formula I.

[0097] In some embodiments, the enteric capsule is a non-animal based capsule such as a hypromellose capsule (e.g., commercially available self-gelling Vcaps, Vcaps Plus, Vcaps enteric, other enteric capsules made using Xcellodose, ENCODE colon delivery technology, and Capsugel's EnTrinsicTM drug delivery technology). Other technologies known in the art and commercially available for formulating oral solid dosage forms in enteric form (e.g., Qualicaps, USA, Nutrascience, USA, etc.) are also available. In at least one embodiment, the capsule is an API-containing capsule, which means that the free base of the compound of Formula I or a crystalline form of its salt is filled into the capsule without solvent. In such an API-containing capsule oral dosage form, the crystalline form of the compound of Formula I, which is the active ingredient, can be a free-flowing powder or a micronized powder. When Dosage Form I is a capsule, in at least one embodiment, the capsule can be a seamless capsule or a banded capsule.

[0098] The dissolution of the oral dosage forms disclosed herein is tested by a dissolution test according to the current method of USP711. In some embodiments, the oral dosage forms disclosed herein are protected from the acidic environment of the stomach and do not dissolve for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, 6 hours, at least 7 hours or at least 8 hours. In at least one embodiment, the oral dosage form does not release PRX-3140 for at least 6 hours. In another embodiment, the oral dosage form does not release PRX-3140 for at least 2 hours. VI. Method for manufacturing a pharmaceutical composition

[0099] In a further embodiment, the present disclosure provides a method for manufacturing a pharmaceutical composition, which further comprises formulating particles.

[0100] In certain embodiments, the particles are formulated into unit dosages such as tablets or capsules.

[0101] In some embodiments where the pharmaceutical composition further comprises at least one additive, the present disclosure also provides a method of manufacturing a pharmaceutical composition, further comprising mixing the particles with at least one additive to form a second mixture and formulating the second mixture.

[0102] In certain embodiments, the particles are formulated into unit dosages such as tablets or capsules. VII. Treatment Methods

[0103] The pharmaceutical compositions described herein may be useful for treating any disease or condition for which administration of the corresponding insoluble drug is desired. For example, a composition comprising a crystalline form of a compound of Formula I may be useful for treating Alzheimer's disease (AD) and other dementias including post-traumatic stress disorder (PTSD) that affect the cholinergic and / or serotonergic systems. The terms "treating," "treatment," and "treat" refer to (1) a decrease in the severity or duration of a disease or condition, (2) an improvement in one or more symptoms associated with a disease or condition that may not necessarily result in a cure of the disease or condition. In some embodiments, the treatment method further comprises preventing a disease or condition. Suitable subjects include, for example, humans and other mammals such as, for example, mice, rats, dogs, and non-human primates.

[0104] In yet another aspect, the present disclosure provides a method of treating Alzheimer's disease (AD) and other dementias including post-traumatic stress disorder (PTSD) that affect the cholinergic and / or serotonergic systems, the method comprising administering an effective amount of the pharmaceutical composition of the present disclosure to a patient in need thereof.

[0105] Other embodiments of the present disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. The specification and examples are intended to be considered only as exemplary, with the true scope and spirit of the disclosure being indicated by the following claims.

Examples

[0106] Examples Example 1 - Small scale preparation of 50 grams of crystalline PRX-3140 potassium salt. U.S. Patent Nos. 7,488,736 and 7,982,040 described the preparation of PRX-3140 in a six-step process. The supply of 3-piperidin-1-yl-propylamine enables the synthesis of crystalline fine particle form I of PRX-3140 potassium salt in a four-step process on a 50 gram scale, as shown in Figure 2.

[0107] Step 1. Reduction amination - Methyl 2 - isopropylaminothiophene - 3 - carboxylate (3). In a 3 L three - necked round - bottom flask equipped with a mechanical stirrer, methyl 2 - aminothiophene - 3 - carboxylate (90.52 g, 0.5758 mol) and sodium triacetoxyborohydride (207.48 grams, 0.979 mol) were added. Anhydrous dichloromethane (640 mL) was added and the mixture was stirred for 2 minutes. Then a solution of formic acid (53.01 g, 1.1517 mol) and 2,2 - dimethoxypropane (299.88 g, 2.8793 mol) was added and the mixture was stirred for 30 minutes at 15 - 32 °C (internal temperature) under argon (cooled with cold water if necessary). The dropping funnel was rinsed with anhydrous dichloromethane (92 mL) and charged into the reaction mixture. After the addition was complete, the resulting mixture was stirred at 25 - 30 °C for 2 hours. The reaction mixture was added to an aqueous potassium hydroxide (304.1 g, 4.607 mol) solution (905 mL) at 5 °C, the temperature was maintained below 40 °C, the reaction flask was rinsed with dichloromethane (100 mL) and added to the mixture. The resulting mixture was stirred at room temperature for 0.5 hour, then filtered and the residue was washed with dichloromethane (300 mL). The filtrate was diluted with water (0.5 L) and the phases were separated. The aqueous phase was extracted with dichloromethane (0.5 L). The combined organic phases were mixed with water (0.5 L) and stirred for 0.5 hour. The phases were separated again and the organic phase was dried over Na2SO4. By filtration and concentration, 114.7 grams of the crude product was obtained as a red oil, which was dissolved in heptane (0.50 L), stirred with neutral alumina (90 g) for 0.5 hour, then filtered and the filtrate was evaporated. The title compound (105.8 g, 92%) was obtained as a yellow - tinged oil. HPLC purity: 98.2%. 1H NMR (300 MHz, CDCl3) δ 7.35 (br s, 1 H), 7.00 (d, J = 5.7 Hz, 1H), 6.14 (dd, J = 5.7, 1.2 Hz, 1H), 3.78 (s, 3H), 3.56 - 3.44 (m, 1H), 1.32 (s, 3H), 1.29 (s, 3H).

[0108] Step 2. Acylation and Cyclization - Methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylate (5). A solution of the starting amine 3 (89.7 grams, 0.450 mol) and pyridine (71.2 grams, 0.900 mol) in butyronitrile (0.9 L) was heated to 70 - 75 °C with stirring under argon. A solution of methyl malonyl chloride (116.7 grams, 0.855 mol) in butyronitrile (0.45 L) was added dropwise to the reaction mixture, and the temperature was maintained at 70 - 75 °C (internal temperature) with vigorous stirring (especially at first, heating was turned off from time to time). At the end of the addition, the temperature was held for 8 - 10 minutes, and then sodium methoxide solution (25%, 390.0 grams, 415 mL, 1.80 mol) was added at the same temperature over 10 minutes. The resulting mixture was stirred at the same temperature for 10 minutes and then cooled to room temperature. Water (0.45 L) was added and the mixture was stirred at room temperature for 20 minutes. The phases were separated and the organic phase was extracted with water (0.45 L). The combined aqueous phases were washed with EtOAc (2 × 0.45 L). The aqueous phase was then acidified to pH 4.0 - 4.5 with 1:5 v / v HCl / water at room temperature. The resulting solid was filtered and washed with water (2 × 180 mL). The filter cake was dried in a vacuum oven at 45 - 50 °C overnight. The title compound was obtained as a yellow solid (68.48 g, 57%). HPLC purity: 98.1%. The filtrate was cloudy overnight and a second harvest (9.68 g, 8%, HPLC purity: 87.4%) was obtained by a second filtration, which was not used in the next step. 1H NMR (300 MHz, CDCl3) δ 7.32 (d, J = 5.7 Hz, 1H), 6.90 (d, J = 6.0 Hz, 1H), 4.00 (s, 3H), 1.70 - 1.60 (m, 1H), 1.64 (s, 3H), 1.61 (s, 3H).

[0109] Step 3. Amidation and Salt Formation 4-Hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide hydrochloride (8). A mixture of methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylate (5, 2 g, 7.48 mmol) and 3-piperidin-1-yl-propylamine (6, 1.12 g, 7.85 mmol, 1.05 equiv) was heated at 90 - 95 °C for 2 h. TLC analysis indicated completion of the reaction. The reaction mixture was cooled to room temperature, diluted with water (5 mL), and 1M HCl (7.4 mL) was added. The organic layer was separated and washed with water (4 mL). The organic layer was treated with concentrated hydrochloric acid (1.4 g). The organic phase was concentrated to about 11 mL (9.9 g). n-Butanol (10 mL) was added to the residue. The mixture was reconcentrated to a volume of about 11 mL (9.9 g). The residue was heated to 50 °C and diluted with MTBE (20 mL). The mixture was stirred at 50 °C for 40 min, cooled to room temperature, and then held at -10 °C overnight. The slurry was filtered at 0 - 5 °C. The filter cake was washed with n-butanol / MTBE (1:3, 2 × 4 mL) and dried on a rotary evaporator to give 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide hydrochloride (8, 2.35 g, yield: 75%, HPLC: 99.65%) as a white solid. Starting with 66.35 g of ester 5, 84.5 g of the title compound 8 was obtained (yield: 82%). 1 H NMR (300 MHz, DMSO-d6) δ 10.24 (br t, J = 5.4 Hz, 1H), 9.91 (br s, 1H), 7.38 (d, J = 5.7 Hz, 1H), 7.32 (d, J = 5.7 Hz, 1H), 3.47 - 3.30 (m, 4H), 3.08 - 2.98 (m, 2H), 2.90 - 2.76 (m, 2H), 2.05 - 1.93 (m, 2H), 1.82 - 1.62 (m, 6H), 1.57 (s, 3H), 1.55 (s, 3H), 1.44 - 1.26 (m, 1H).

[0110] Procedure 4: Preparation of 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide potassium salt (PRX-3140 potassium salt). A mixture of 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide hydrochloride (8, 2.35 g, 5.68 mmol), MTBE (23.5 mL), water (11.75 mL) and 1 M KOH solution (5.6 mL) was stirred at room temperature for 20 minutes. The mixture still had insoluble hydrochloride. NaHCO3 (0.49 gram) was added to the above mixture and stirring was continued for 0.5 hour. The mixture became a clear solution. The organic layer was separated. The aqueous layer was extracted with additional MTBE (20 mL). The combined organic layers were concentrated to dryness to obtain 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide (2.17 grams) as the free base.

[0111] The above free base (2.17 grams, 5.68 mmol) was dissolved in acetonitrile (23.5 mL) at 45 - 50 °C. To the above solution was added a solution of KOH (0.43 grams, 6.53 mmol) in water (1.8 mL). The resulting mixture was stirred at 50 °C for 0.5 hour, cooled to room temperature, and then cooled at 0 - 5 °C for 3 hours. The solid was filtered to obtain 3 grams of wet product, which was dissolved in a mixture of acetonitrile (42 mL) and water (3 mL) at 50 °C. The solution was filtered to remove insoluble solids. The filtrate was concentrated to a volume of 21 mL. Acetonitrile (21 mL) was added and the solution was concentrated to a volume of 21 mL. This process was repeated twice. The residue was placed in an ice bath for 3 hours, filtered, and the filter cake was washed with acetonitrile (0 °C, 2 × 6 mL) and dried on a rotary evaporator to obtain crystalline 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidin-1-yl-propyl)-amide potassium salt (1.75 grams, yield: 74.2%, HPLC: 99.9%, KF: 1.19%) as a white solid. A batch starting from 84.5 grams of hydrochloride 8 was converted to 76.3 grams of crystalline fine particle form I of PRX-3140 potassium salt (yield: 90%, HPLC: 99.6%, KF: 0.66%). 1H NMR (300 MHz, DMSO-d6) δ 10.79 (t, J = 5.3 Hz, 1H), 7.13 (d, J = 5.4 Hz, 1H), 6.80 (d, J = 5.4 Hz, 1H), 3.19 - 3.11 (m, 2H), 2.70 - 2.40 (m, 6H), 1.62 - 1.30 (m, 15H).

[0112] Example 2 - X-ray diffraction of crystalline PRX-3140 potassium salt prepared at two scales. Using the crystalline fine particle form I of the PRX-3140 potassium salt samples of Example 1 and the scaled-up batch, the differences in the crystal structures of the two samples were identified by standard X-ray diffraction (XRD) measurements. In both examples, the same peaks shown in Figures 3 and 4 and Tables 1 and 2 were obtained respectively.

Table 1

Table 2

[0113] Example 3 - Photo-stability experiment of PRX-3140 potassium salt. Two samples of the crystalline fine particle form I of PRX-3140 potassium salt were prepared for the photo-stability test. (1) 1.5 grams that spread evenly over the entire glass petri dish and covered with a transparent quartz cover, and (2) 1.5 grams that spread evenly over the entire glass petri dish and covered with aluminum foil. The samples were exposed to low-temperature white fluorescence of 1.2 million lux hours and UVA light of 200 watt hours / m2 at 40 °C / 75% RH according to the ICH photo-stability guideline Q1B. The samples were exposed for 2 days and tested using HPLC.

[0114] The control photo-stability sample of PRX-3140 potassium salt met the specifications and showed HPLC results comparable to those obtained for the t = 0 sample, but an increase in water content from 0.9% w / w to 3.1% w / w was observed. The exposure was carried out in a cabinet set at 25 °C / 60% RH. The samples were significantly lumpy and needed to be ground to obtain accurate assay results.

Table 3

[0115] Figure 4 shows the HPLC chromatograms of the photostability experiment of PRX-3140 potassium salt: (A) non-exposed control sample and (B) photostability-exposed sample of PRX-3140 potassium salt. After exposure to UVA and white light, changes in the crystalline fine particle form I of PRX-3140 potassium salt were evident. The samples changed color, especially on the upper exposed surface of the material, and there were obvious changes in the HPLC data. The irradiated photostability samples of PRX-3140 potassium salt met the USP stability specifications of (1) total impurities of 2.0% area or less and (2) no single impurity exceeding 0.5% area, and the reported assay value of 94.2% w / w was below the specification limit. The single impurity profile met the specification (<0.2%), but significant changes were observed. In particular, in the region of the chromatogram between RRT 1.5 and 2.1, the number of trace impurities increased. The total impurities increased from 0.20% in the control sample to 0.77% in the exposed sample. In the exposed sample, an impurity with RRT 1.83 that did not exist before exposure was formed at 0.16%. Other changes included a change in the appearance of the material to a sticky solid and an increase in the water content to 4.3% w / w.

[0116] Example 4 - Forced degradation experiment of crystalline PRX-3140 potassium salt. The crystalline fine particle form I of PRX-3140 potassium salt was subjected to a forced degradation experiment using 24-hour exposure to acid, base, or hydrogen peroxide. The samples were neutralized and analyzed using LC-UV-MS. The conditions for LC-UV-MS are listed in Table 4.

Table 4

[0117] Control Sample: Figure 6A is the HPLC UV chromatogram of the standard (control) of crystalline fine particle form I of PRX-3140 potassium salt at 250 nm. The UV spectrum of the parent molecule is shown in Figure 6B. The maxima are observed at 220, 250, and 320 nm. The chromatograms of all samples were collected at all three wavelengths, and 250 nm was set as the main wavelength based on λmax. The starting material was 98.6% pure based on the peak area at 250 nm. The mass spectrum at 12.2 minutes of the parent molecule, PRX-3140, is shown in Figure 6C. The protonated PRX-3140 molecular ion [M+H]+ is observed at 378.2 m / z.

[0118] Sample Preparation: 50 mg of crystalline fine particle form I of PRX-3140 potassium salt was weighed into a 25 mL volumetric flask and made up to volume with water (2 mg / mL stock). 1 mL of the stock was added to four 4 mL vials. 1 mL of either 1N HCl, 1N NaOH, 3% H2O2, or DI water (control) was added to the appropriate vial, mixed, and stored at room temperature for 24 hours. After storage, the acid and base samples were neutralized by the addition of 1 mL of their respective counter solutions. 1 mL of water was added to the peroxide sample and the control so that all samples had a final concentration of 0.67 mg / mL. The samples were analyzed using LC-UV-MS.

[0119] Table 5 lists a comparison of the control, acid, base, and peroxide samples showing percent peak area vs. relative retention time (RRT) at 250 nm. Some minor changes can be observed between the controls using the acid and base samples, but the overall purity (peak area) of the parent molecule is only slightly higher for the acid and base samples. Some of the trace impurities appear to react with the acid or base and reform the parent. The greatest change in purity was observed in the peroxide sample where two major impurities were formed, and the purity at 250 nm went from 98.6 to 80.6%.

Table 5

[0120] Acid-decomposed sample: Based on the purity peak area at 250 nm, the control was 98.6% and the acid sample was 98.9%. 1N HCl over 24 hours had a very small effect on the PRX-3140 potassium salt.

[0121] Base-decomposed sample: Based on the purity peak area at 250 nm, the control was 98.6% and the base sample was 98.7%. 1N NaOH over 24 hours had a very small effect on the PRX-3140 potassium salt.

[0122] Peroxide-decomposed sample: The UV chromatogram of the peroxide-decomposed sample at 250 nm is shown at full scale in Figure 7A. Two major impurity peaks are observed at 9.6 minutes and 13.3 minutes (RRT 0.78 and 1.05 respectively). Based on the purity peak area at 250 nm, the control was 98.6% and the peroxide sample was 80.6%. 3% hydrogen peroxide was reacted with PRX-3140 for 24 hours to form two major decomposition products.

[0123] Figure 7B is the mass spectrum of PRX-3140a at 9.6 minutes (RRT 0.78). [M+H]+ was observed at 258.0 m / z, the ammonium adduct [M+H+NH3]+ was observed at 275.1, the sodium adduct [M+Na]+ was observed at 280.1, and the sodium dimer [2M+Na]+ was observed at 537.1 m / z. It should be noted that this is a labile molecule and it is necessary to lower the fragmentor voltage from 150 to 70 V to see the protonated molecular ion. At higher voltages, molecular fragments were observed at 216.0, 198.0, and 152.0. The proposed structure of PRX-3140a is Formula II: ##STR00002##. 5-Hydroxy-8-(methylethyl)-8H-1,2-oxathiino[6.5-b]pyridine-2,2,7-trione or 5-Hydroxy-8-(propan-2-yl)-2H-2λ6-[1,2]oxathiino[6,5-b]pyridine-2,2,7(8H)-trione, which has the chemical formula C10H11NO5S and is shown in Figure 5.

[0124] Figure 7C is the mass spectrum of PRX-3140b at 13.3 minutes (RRT 1.05). [M+H]+ is observed at 394.2 m / z and [2M+H]+ is observed at 787.4 m / z. This compound is observed in the control, acid, and base samples but at very low levels (<0.03%). In the peroxide sample, this peak is 9.1%. The proposed structure of PRX-3140b is Formula III: ##STR00003##. [7-(methylethyl)1,4,6-trioxo(5,7-dihydrothiopheno[2,3-b]pyridin-5-yl)]-N-(3-piperidylpropyl)carboxamide, or 1,4,6-trioxo-N-[3-(piperidin-1-yl)propyl]-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-1λ4-thieno[2,3-b]pyridine-5-carboxamide, which has the chemical formula C19H27N3O4S and is shown in Figure 5.

[0125] Example 5 - Decomposition experiment of PRX-3140 with 30% peroxide. The crystalline fine particle form I of the potassium salt of PRX-3140 was subjected to a second forced degradation experiment using a 24-hour exposure to 30% hydrogen peroxide. The sample was evaporated to dryness and analyzed using LC / UV / MS and NMR. Two major degradation products were observed in LC / UV / MS.

[0126] Sample preparation: 60 mg (55 μL) of 30% hydrogen peroxide (0.5 mmol) was added dropwise at 0 °C to a suspension of the starting potassium salt of PRX-3140 (208 mg, 0.5 mmol) in 5 mL of dry acetone. The resulting suspension was stirred under argon and allowed to warm spontaneously to room temperature overnight (18 hours). The solvent was removed at room temperature under vacuum, then acetonitrile (5 mL) was added to the residue and evaporated to dryness at 40 °C. The weight of the residue of the PRX-3140 30% peroxide sample was 300 mg.

[0127] The 1H NMR of the crude 30% peroxide sample is shown in Figure 8A. For comparison, the 1H NMR of the potassium salt of PRX-3140 is shown in Figure 8B.

[0128] The solid portion of the PRX-3140 30% peroxide sample was subjected to LC / UV / MS analysis. A 2 milligram sample was weighed into a 4 mL vial. 2 mL of 20 / 80 methanol / water was added to the vial and vortexed vigorously. Figure 9A is the HPLC chromatogram of the H2O2 sample at 250 nm. Three major peaks containing the parent molecule are observed at 12.5 minutes. After 18 hours of exposure to 30% hydrogen peroxide, a purity of 29.6% is observed for the parent molecule PRX-3140. The UV spectrum of the parent molecule at 12.5 minutes is shown in Figure 9B. Maxima are observed at 220, 250, and 320 nm. Chromatograms of all samples were collected at all three wavelengths with 250 nm as the main wavelength based on lambda max. Figure 10A is the UV spectrum of the peak at 8.9 minutes. There is no high-end absorption (320 nm) compared to the parent molecule. Figure 10B is the UV spectrum of the peak at 12.9 minutes. The spectrum is identical to that of the parent molecule shown in Figure 9B. The mass spectrum of the parent molecule PRX-3140 at 12.5 minutes is shown in Figure 11A. The protonated molecular ion [M+H]+ is observed at 378.2 m / z. Figure 11B is the mass spectrum of PRX-3140a at 8.9 minutes (RRT 0.73 compared to 0.78 in Example 4). [M+H]+ is observed at 258.0 m / z, [M+H+NH3]+ is observed at 275.1, [M+Na]+ is observed at 280.1, and [2M+Na]+ is observed at 537.1 m / z. It should be noted that this is a labile molecule and it is necessary to lower the fragmentor voltage from 150 V to 70 V to see the protonated molecular ion. At higher voltages, molecular fragments were observed at 216.0, 198.0, and 152.0. The proposed structure of PRX-3140a is shown in Figure 5. Figure 11C is the mass spectrum of the major degradation product of PRX-3140b at a relative retention time (RRT) of 1.04 (compared to 1.05 in Example 4) at 12.9 minutes. [M+H]+ at 394.2 m / z could be the parent molecule + oxygen (+O). The proposed structure of PRX-3140B is shown in Figure 5.

[0129] Example 6 - Compatibility Experiment of PRX - 3140 Additive. The additive test and compatibility experiment were conducted on the crystalline fine particle form I of the potassium salt of PRX - 3140. The inventors used the crystalline fine particle form I of a potassium salt sample of PRX - 3140 mixed with (1) starch, pre - gelatinized, NF (Colorcon), (2) microcrystalline cellulose (Avicel PH - 105, DuPont), (3) magnesium stearate NF (Avantor), (4) stearic acid, NF (Letco), (5) lecithin, granular food grade (Spectrum), (6) polyethylene glycol 3,350, USP (Dow), (7) HPB - cyclodextrin (CTD), (8) silicon dioxide, FCC (Spectrum), and (9) mannitol USP (Spectrum) to conduct a binary blend (50:50 w / w) additive compatibility experiment. The samples were analyzed by the HPLC assay described in Example 2. The samples were stored at 40°C / 75% RH, and the assay and purity were tested by LC - UV - MS on days 0, 30, 60, and 90. At each time point, the powder samples were weighed and diluted with 50:50 methanol:DI water. The samples for HPLC analysis were filtered through a 0.45 micron PTFE filter for injection.

Table 6

[0130] The PRX - 3140:lecithin (50:50) sample decomposed over the 90 - day experiment, and the degradation product of PRX - 3140a (RRT 1.06) increased to more than 1%. Figure 12A shows the PRX - 3140:lecithin (50:50) time 0 sample, and Figure 12B shows the 90 - day sample demonstrating the increase in PRX - 3140B (RRT 1.05) on day 90 at 40 degrees Celsius.

[0131] Example 7 - Preparation of PRX-3140 Potassium Salt PDS. 10 g of crystalline fine particle form I of PRX-3140 potassium salt (Alchem Laboratories Corp.) and 10 g of microcrystalline cellulose (Avicel PH-105, DuPont) were mixed in a 50 mL tube. The powder was then pulverized using a Retsch mill to make a fine powder. Particles less than 600 microns were separated by sieving (30 mesh). The resulting white powder was obtained in a yield of over 90% of crystalline PRX-3140 potassium salt PDS powder containing particles with a diameter of less than 500 microns.

[0132] Example 8 - Preparation of Immediate Release Oral PRX-3140 Potassium Salt Capsules. An immediate release oral dosage form (gelatin capsule) containing crystalline fine particle form I of the PRX-3140 potassium salt particles prepared in Example 7 was dry mixed with additional microcrystalline cellulose (Avicel PH-105, DuPont) to achieve the correct capsule filling weight (400 - 500 mg) to achieve the desired dosage. Transparent gelatin #1 capsules were then filled with the mixture using a Torpac Profill 3700 machine to obtain capsules containing 320 mg of PRX-3140 potassium salt PDS containing 50 mg of PRX-3140. Samples were taken to verify load uniformity, content uniformity, and dissolution time.

[0133] Example 9 - Dissolution of Immediate Release Oral PRX-3140 Potassium Salt. The capsules from Example 8 were exposed to an acidic buffer for 60 minutes to mimic the gastric environment. To demonstrate dissolution, the release of over 75% of PRX-3140 in solution in the acidic buffer at 15 - 30 minutes was tested using a USP dissolution apparatus and HPLC.

Claims

1. Formula I: 【Transformation 7】 ##STR00001## A composition comprising the compound, The compound of formula I comprises a crystalline form of the compound of formula I, and the composition further (a) Equation II: 【Transformation 8】 ##STR00002## Compounds of, and / or (b) Formula III: 【Chemistry 9】 ##STR00003## A composition containing the compound.

2. The composition according to claim 1, wherein the crystalline form of the compound of formula I is form I, characterized by an X-ray powder diffraction pattern having major peaks at 22.3 ±0.3 degrees, 25.3 ±0.3 degrees, and 5.4 ±0.3 degrees in theta.

3. The composition according to claim 1, wherein the crystalline form of the compound of formula I is form I, characterized by an X-ray powder diffraction pattern having at least one peak selected from two thetas at 22.3 ±0.3 degrees, 25.3 ±0.3 degrees, 5.4 ±0.3 degrees, 25.8 ±0.3 degrees, 15.9 ±0.3 degrees, 29.9 ±0.3 degrees, 21.6 ±0.3 degrees, 16.5 ±0.3 degrees, and 20.3 degrees.

4. The composition according to claim 1, wherein the crystalline form of the compound of formula I is substantially form I, characterized by the X-ray powder diffraction pattern shown in Figure 3A or Figure 3B.

5. The composition according to claim 1, wherein more than 90% by weight of the compound of formula I is a crystalline form of form I characterized by an X-ray powder diffraction pattern having major peaks at 22.3 ±0.3 degrees, 25.3 ±0.3 degrees, and 5.4 ±0.3 degrees in the 2-theta region.

6. The composition according to claim 1, wherein the compound of formula I is in a crystalline form of form I, characterized by an X-ray powder diffraction pattern having major peaks at 22.3 ±0.3 degrees, 25.3 ±0.3 degrees, and 5.4 ±0.3 degrees, and is present in an amount ranging from about 0.01% by mass to about 99.99% by mass of the composition.

7. The composition according to claim 1, wherein the crystalline particles of the compound of formula I have an average diameter of less than about 1 mm.

8. The composition according to claim 1, wherein the crystalline particles of the compound of formula I have an average diameter of less than about 500 μm.

9. The composition according to claim 1, wherein the compound of formula I is stable for at least 12 months at 5 degrees Celsius and 60% relative humidity or 25 degrees Celsius and 60% relative humidity.

10. The composition according to claim 1, wherein the composition comprises, if present, less than 0.5% by weight of the compound of formula II, and, if present, less than 0.5% by weight of the compound of formula III.

11. Formula I: 【Chemistry 12】 ##STR00001## A particulate delivery system comprising the compound and at least one pharmaceutically acceptable additive, The compound of formula I comprises a crystalline form of the compound of formula I, and the particulate delivery system further (a) Equation II: 【Chemistry 13】 ##STR00002## Compounds of, and / or (b) Formula III: 【Chemistry 14】 ##STR00003## A particulate delivery system containing the compound.

12. The particulate delivery system according to claim 11, wherein the crystalline form of the compound of formula I is form I, characterized by an X-ray powder diffraction pattern having major peaks at two thetas, 22.3 ±0.3 degrees, 25.3 ±0.3 degrees, and 5.4 ±0.3 degrees.

13. The particulate delivery system according to claim 11, wherein the crystalline form of the compound of formula I is form I, characterized by an X-ray powder diffraction pattern having at least one peak selected from two thetas at 22.3 ±0.3 degrees, 25.3 ±0.3 degrees, 5.4 ±0.3 degrees, 25.8 ±0.3 degrees, 15.9 ±0.3 degrees, 29.9 ±0.3 degrees, 21.6 ±0.3 degrees, 16.5 ±0.3 degrees, and 20.3 degrees.

14. The particulate delivery system according to claim 11, wherein the crystalline form of the compound of formula I is substantially form I, characterized by the X-ray powder diffraction pattern shown in Figure 3A or Figure 3B.

15. The particulate delivery system according to claim 11, wherein more than 90% by weight of the compound of formula I is a crystalline form of form I characterized by an X-ray powder diffraction pattern having major peaks at two thetas, 22.3 ±0.3 degrees, 25.3 ±0.3 degrees, and 5.4 ±0.3 degrees.

16. The particulate delivery system according to claim 11, wherein the compound of formula I is in a crystalline form of form I, characterized by an X-ray powder diffraction pattern having major peaks at two thetas of 22.3 ±0.3 degrees, 25.3 ±0.3 degrees, and 5.4 ±0.3 degrees, and is present in an amount ranging from about 0.01% by mass to about 99.99% by mass of the composition.

17. The particulate delivery system according to claim 11, wherein the particles of the compound of formula I in crystalline form have an average diameter of less than about 1 mm.

18. The particulate delivery system according to claim 11, wherein the particles of the compound of formula I in crystalline form have an average diameter of less than about 500 μm.

19. The particulate delivery system according to claim 11, wherein the at least one pharmaceutically acceptable additive is a polymer.

20. The particulate delivery system according to claim 19, wherein the polymer is selected from starch, cellulose, and polyethylene glycol.

21. The particulate delivery system according to claim 11, wherein the particulate delivery system contains 0.01 mg to 200 mg of the compound of formula I.

22. The particulate delivery system according to claim 11, wherein the compound of formula I is stable for at least 12 months at 5 degrees Celsius and 60% relative humidity, or at 25 degrees Celsius and 60% relative humidity.

23. The particulate delivery system according to claim 11, wherein the particulate delivery system comprises, if present, less than 0.5% by weight of the compound of formula II, and, if present, less than 0.5% by weight of the compound of formula III.

24. A method for manufacturing a particulate delivery system according to claim 11, Blending the compound of formula I with at least one pharmaceutically acceptable additive to form a mixture, The mixture is processed to form coarse particles having an average diameter in the range of about 0.1 mm to about 5 mm, and The aforementioned coarse particles are crushed or milled to form particles having an average diameter of less than approximately 500 μm. Methods that include...

25. The composition according to claim 1 for use in treating Alzheimer's disease (AD) and other dementias affecting the cholinergic and / or serotonergic systems in patients who require treatment for Alzheimer's disease (AD) and other dementias affecting the cholinergic and / or serotonergic systems.

26. Formula I: 【Chemistry 12】 ##STR00001## A particulate delivery system comprising the compound and at least one pharmaceutically acceptable additive, The compound of formula I comprises a crystalline form of the compound of formula I, and the particulate delivery system further (a) Equation II: 【Chemistry 13】 ##STR00002## Compounds of, and / or (b) Formula III: 【Chemistry 14】 ##STR00003## Contains the compound, The crystalline form of the compound of formula I is characterized by an X-ray powder diffraction pattern having at least one peak selected from two thetas at 22.3 ±0.3 degrees, 25.3 ±0.3 degrees, 5.4 ±0.3 degrees, 25.8 ±0.3 degrees, 15.9 ±0.3 degrees, 29.9 ±0.3 degrees, 21.6 ±0.3 degrees, 16.5 ±0.3 degrees, and 20.3 degrees. More than 90% by weight of the compound of formula I is in form I, The compound of formula I has an average diameter of less than approximately 500 μm. The compound of formula I is stable for at least 12 months at 5 degrees Celsius and 60% relative humidity or 25 degrees Celsius and 60% relative humidity. A microparticle delivery system, wherein the aforementioned microparticle delivery system is formulated for oral delivery.

27. Formula I: 【Chemistry 12】 ##STR00001## A process for producing the crystalline form of a compound, (a) Under argon, sodium triacetoxyborohydride in anhydrous dichloromethane and formic acid is used, and then potassium hydroxide is used to reductively aminate methyl 2-aminothiophene-3-carboxylate, Na ２ SO ４ The process involves drying to obtain methyl 2-iso-propylaminothiophene-3-carboxylate. (b) A step to obtain methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylate by acylation and cyclization of methyl 2-iso-propylaminothiophene-3-carboxylate in pyridine and butyronitrile using methyl malonyl chloride, followed by the addition of sodium methoxide solution, washing with water and ethyl acetate, acidification with hydrochloric acid, and drying. (c) A step to obtain 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylate by amidation and salt formation of methyl 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide hydrochloride, and (d) Add 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)amide hydrochloride, MTBE, water, potassium hydroxide solution and sodium bicarbonate to obtain 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)amide to obtain a free base, and then acetonitol Preparation of 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide potassium salt by dissolving it in water and adding potassium hydroxide in acetonitrile to obtain crystalline 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide potassium salt. A process that includes this.

28. The process according to claim 27, further comprising crystallization of the introduced 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide free base and acetonitrile, and the addition of potassium hydroxide in water to obtain a crystalline 4-hydroxy-7-isopropyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid (3-piperidine-1-yl-propyl)-amide potassium salt solid and mother liquor, and subsequent separation and drying, wherein more than 90% by weight of the compound of formula I obtained from the process is the crystalline form of the compound of formula I.

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