Preparation of sufentanyl citrate and sufentanyl base

Abstract

To provide a formulation of sufentanyl citrate and sufentanyl base. [Solution] The present specification describes a processing method corresponding to the formation of sufentanyl citrate from a sufentanyl salt. One process comprises forming sufentanyl citrate in the presence of a polar non-aqueous solvent. Another process comprises forming sufentanyl citrate in the presence of water. One aspect of this disclosure comprises a process for forming sufentanyl citrate from a sufentanyl base in the presence of a polar non-aqueous solvent.

Description

Technical Field

[0001] The present invention generally relates to the formulation of sufentanil salts and free bases.

Background Art

[0002] Sufentanil is a member of a series of potent fentanyl analogs. It has high selectivity and affinity (approximately 10 times higher than fentanyl) for the "mu" opioid receptor. In comparison with fentanyl, the pharmacokinetic profile of sufentanil shows a smaller volume of distribution, and as a result, it becomes an intermediate with a terminal-phase half-life intermediate between alfentanil and fentanyl. Furthermore, sufentanil does not cause histamine release as fentanyl does. The chemical name of sufentanil is N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide. In its citrate form, its chemical name is N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide, 2-hydroxy-1,2,3-propanetricarboxylate.

[0003] The classical approach to preparing sufentanyl citrate involves forming the salt from the sufentanyl base with citric acid (used in approximately a 1:1 ratio) in water with all components added beforehand. Unfortunately, this approach results in the salt forming an oily substance from the solution, followed by crystallization. This conventional process also presents several other problems. Firstly, after the crystallization of the oily product, manual intervention is required to remove the aggregate from the side walls of the reaction vessel. This uncontrolled crystallization causes the product to solidify into clumps, requiring sieving or grinding to obtain a fine powder sufficient for use in pharmaceutical formulations. Grinding such a strongly solidified compound is also extremely harmful and poses a problem of exposure to the surrounding environment. Furthermore, since the reaction does not produce a homogeneous phase, purification and sterile filtration are impossible. One-step reprocessing is also impossible (for example, the product does not redissolve in the medium). If the resulting sufentanyl citrate does not meet the specifications (for example, due to analytical, HPLC, or granulation issues), the salt must be converted back to its base form, and the citrate crystallization process must be repeated from the beginning. Therefore, there is a need for improved methods for salt formation and isolation that address the latter problem. [Overview of the project]

[0004] Broadly speaking, one aspect of the present disclosure therefore encompasses a process for forming sufentanyl citrate from a sufentanyl base in the presence of a polar non-aqueous solvent. The process includes (a) contacting a sufentanyl base with a polar non-aqueous solvent to form a mixture characterized in that the volume-to-mass ratio of the polar non-aqueous solvent to the sufentanyl base is about 2:1 to about 12:1, and (b) contacting the mixture with citric acid to form a mixture of sufentanyl citrates characterized in that the mixture of sufentanyl citrates does not contain an oil phase.

[0005] Other aspects of the present disclosure provide a process for forming sufentanyl citrate from a sufentanyl base in the presence of water. The process comprises (a) forming a mixture of citric acid and water such that the volume-to-mass ratio of water to citric acid is about 2:1 to about 12:1, and (b) adding a sufentanyl base to the mixture to form a sufentanyl citrate, wherein the molar ratio of citric acid to sufentanyl base is about 2:1 to about 5.

[0006] Further aspects of the present disclosure provide a process for forming a sufentanyl base from sufentanyl citrate. The process includes (a) contacting sufentanyl citrate with at least one polar solvent to form a mixture; (b) contacting the mixture with a proton acceptor to form a mixture of sufentanyl bases; (c) cooling the mixture of sufentanyl bases to form a solid sufentanyl base; and (d) recovering the solid sufentanyl base.

[0007] Other features and repeating forms of the present invention are described in more detail below. [Modes for carrying out the invention]

[0008] The production of sufentanyl citrate is uniquely and notably difficult compared to other sufentanyl analogs, and generally other active pharmaceuticals, because, as is characteristic of sufentanyl citrate, it initially separates from its mother liquor as an oily substance before crystallization. This oily product first coats the bottom and sides of the reaction vessel, stirrer, and stirring shaft, and solidifies into a glassy substance within a few hours. The solidified product then must be removed by hand, and each time this process is performed, the manufacturing operator is exposed to the toxic and hard compound for several hours. Scraping the walls of the reaction vessel is also undesirable. In the terminology of development chemists, any process in which an oily substance is formed or its product adheres to the reaction vessel or other equipment is considered "unmeasurable" because, in contrast to a laboratory setting where the material can be collected under visual observation and moved by hand, the process cannot be carried out using standard manufacturing operations and equipment, such as pumps, impellers, centrifuges, and filters.

[0009] The disclosure herein provides a process for the preparation of sufentanyl citrate that overcomes the latter limitations, eliminates the need for intensive manual intervention, and provides a measurable and stable process for the production of sufentanyl citrate. The disclosure includes a process for forming sufentanyl citrate from sufentanyl base and for recovering the sufentanyl base from its mother liquor. When the method described herein is applied, the crystallized sufentanyl citrate product remains well suspended in its mother liquor and does not aggregate as is the case with conventionally prepared sufentanyl citrate. The process disclosed herein proceeds through a homogeneous solution phase, is reversible, and is compatible with purification filtration and a one-step reprocessing. As a result, yield and processing capacity are improved.

[0010] (I) Process for preparing sufentanyl citrate from sufentanyl base in a polar non-aqueous solvent. One aspect of the disclosure comprises a process for forming sufentanyl citrate from a sufentanyl base in the presence of a polar non-aqueous solvent. This process includes (a) contacting a sufentanyl base with a polar non-aqueous solvent to form a mixture characterized in that the volume-to-mass ratio of the polar non-aqueous solvent to the sufentanyl base is about 2:1 to about 12:1. The mixture is then (b) contacted with citric acid to form sufentanyl citrate. In some embodiments, the process may further include (c) cooling the above mixture to form a solid sufentanyl citrate, and (d) recovering the solid sufentanyl citrate.

[0011] As used herein, the term “mixture” refers to a homogeneous (in solution) or heterogeneous (suspended) matrix material. In some embodiments, the mixture may be a homogeneous or heterogeneous solution.

[0012] (a) Step A - Reaction mixture Step (a) of the process includes contacting a sufentanyl base with a polar non-aqueous solvent to form a mixture. The process begins with the formation of a reaction mixture comprising a sufentanyl base and a polar non-aqueous solvent, where the volume-to-mass ratio of the polar non-aqueous solvent to the sufentanyl base is about 2:1 to about 12:1.

[0013] As used herein, a “non-aqueous” solvent refers to a solvent or solvent system without the addition of water components, but is not necessarily “anhydrous” or “dry,” meaning that trace amounts of water, such as water absorbed from the atmosphere or water derived from citric acid itself that can exist as a monohydrate, may be present in the solvent. The solvent may be a polar non-aqueous proton solvent or a polar non-aqueous aproton solvent. Non-limiting examples of suitable polar non-aqueous proton solvents include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, isobutanol, 1-butanol, 2-butanol, sec-butanol, and t-butanol, diols such as propylene glycol, amides such as formamide and acetamide, and any combination thereof. Non-limiting examples of suitable polar non-aqueous aproton solvents include acetone, acetonitrile, diethoxymethane, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethylpropanamide (or dimethylpropionamide, DMP), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), 1,2-dimethoxyethane (DME), dimethoxymethane, bis(2-methoxyethyl) ether, and N,N-dimethyl This includes acetamide (DMA), N-methyl-2-pyrrolidinone (NMP), 1,4-dioxane, ethyl formate, formamide, hexachloroacetone, hexamethylphosphoramide, methyl acetate, N-methylacetamide, N-methylformamide, methylene chloride, methoxyethane, morpholine, nitrobenzene, nitromethane, propionitrile, pyridine, sulfolane, tetramethylurea, tetrahydrofuran (THF), 2-methyltetrahydrofuran, tetrahydropyran (THF), trichloromethane, and combinations thereof. Certain polar nonaqueous solvents that may be used include, for example, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, methyl ethyl ketone, and C1-C5 alcohols, methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol, IPA), 1-butanol, 2-butanol, sec-butanol, and tert-butanol, as well as combinations thereof.

[0014] In certain embodiments, the polar non-aqueous solvent may be a solvent licensed as Class 3 by the U.S. Food and Drug Administration (FDA). The FDA defines Class 3 solvents as those that are generally accepted as pharmaceuticals and have no known adverse effects on human health. Available data have shown that Class 3 solvents are less toxic than other solvents in acute or short-term studies and are negative in genotoxicity tests. The FDA considers amounts of these residual solvents of 50 mg or less per day (equivalent to 5,000 ppm or 0.5 percent) to be acceptable without justification. Higher amounts may also be acceptable if the solvents are reported to be practical in relation to manufacturing capability and good manufacturing practices (GMP). Examples of suitable polar non-aqueous FDA Class 3 solvents include, but are not limited to, acetic acid, acetone, anisole, 2-butanol, butyl acetate, tert-butyl methyl ether, DMSO, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), 2-methyl-1-propanol, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran (THF). In exemplary embodiments, the solvent may be ethyl acetate, isopropyl acetate, MEK, MIBK, 1-butanol, 2-butanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol, IPA), or 2-methyl-1-propanol (isobutanol).

[0015] Generally, the volume-to-mass ratio of the solvent to the sufentanyl base is in the range of about 2:1 to about 12:1. In various embodiments, the volume-to-mass ratio of the solvent to the sufentanyl base may be in the range of about 2:1 to about 12:1, about 2.5:1 to about 10:1, about 3:1 to about 8:1, or about 3.5:1 to about 6:1. In exemplary embodiments, the volume-to-mass ratio of the solvent to the sufentanyl base may be about 4:1 to about 5:1.

[0016] (b) Step A - Reaction conditions Generally, contact between the polar non-aqueous solvent and the sufentanyl base is carried out at temperatures ranging from about 20°C to about 90°C. In various embodiments, the reaction may be carried out at temperatures ranging from about 20°C to about 30°C, about 30°C to about 40°C, about 40°C to about 50°C, about 50°C to about 60°C, about 60°C to about 70°C, about 70°C to about 80°C, or about 80°C to about 90°C. In exemplary embodiments, the reaction may be carried out at a temperature of about 50°C. In other exemplary embodiments, the contact may be carried out at a temperature ranging from about 60°C to about 80°C, for example, about 70°C. The contact may be carried out in an inert atmosphere (e.g., in the presence of nitrogen or argon) and under atmospheric pressure. Contact between the polar non-aqueous solvent and the sufentanyl base may be facilitated by stirring, mixing, shaking, or any other method known in the art.

[0017] Typically, this contact step is continued for a sufficient amount of time for the sufentanyl base to be incorporated into the mixture. In some embodiments, the mixture may be a homogeneous solution. Generally, the contact may be continued for about 1 minute to about 60 minutes. In some embodiments, the reaction may be continued for about 1 minute to about 5 minutes, about 5 minutes to about 10 minutes, about 10 minutes to about 15 minutes, about 15 minutes to about 20 minutes, about 20 minutes to about 25 minutes, about 25 minutes to about 30 minutes, about 30 minutes to about 35 minutes, about 35 minutes to about 40 minutes, about 40 minutes to about 45 minutes, about 45 minutes to about 50 minutes, about 50 minutes to about 55 minutes, or about 55 minutes to about 60 minutes.

[0018] In some embodiments, the mixture may be filtered (purified by filtration) before proceeding to the next step. In particular, the mixture may be filtered, as described above, at a temperature ranging from about 20°C to about 90°C to remove, for example, insoluble sufentanyl base or other impurities before proceeding with the reaction with citric acid.

[0019] (c) Step B - Reaction mixture The process of step (b) further includes contacting the mixture from step (a) with citric acid to form sufentanyl citrate. The process begins with the formation of a reaction mixture comprising the mixture from step (a) and citric acid, which may be added directly to the mixture from step (a) as a solid or solution in a solvent, as described in detail earlier.

[0020] The reaction mixture contains citric acid. The citric acid may exist as an anhydrous if its crystalline structure does not involve any water molecules, or as a hydrate if its crystalline structure involves one or more water molecules. Suitable examples of hydrates include citric acid hemihydrate, citric acid monohydrate, citric acid sesquihydrate, citric acid dihydrate, and citric acid trihydrate.

[0021] In some embodiments, the citric acid may be dissolved in a solvent as defined in Section (I)(a) above. In exemplary embodiments, the solvent may be ethyl acetate, isopropyl acetate, methyl isobutyl ketone, methyl ethyl ketone, or a C1-C5 alcohol. Generally, the volume-to-mass ratio of the solvent to the citric acid is in the range of about 0.1:1 to about 10:1. In various embodiments, the volume-to-mass ratio of the solvent to the citric acid may be in the range of about 0.1:1 to about 10:1, about 0.2:1 to about 8:1, about 0.3:1 to about 6:1, about 0.4:1 to about 4:1, or about 0.5:1 to about 2:1. In exemplary embodiments, the volume-to-mass ratio of the solvent to the citric acid may be about 0.5:1 to about 2:1, or 1:1.

[0022] The amount of citric acid added to the reaction mixture may and will vary. Generally, the molar ratio of citric acid to sufentanyl base may be in the range of about 0.9:1 to about 1.5:1. In various embodiments, the molar ratio of citric acid to sufentanyl base may be in the range of about 0.9:1 to about 1.5:1, about 0.92:1 to about 1.4:1, about 0.94:1 to about 1.3:1, about 0.96:1 to about 1.2:1, or about 0.98:1 to about 1.1:1. In exemplary embodiments, the molar ratio of citric acid to sufentanyl base may be in the range of about 0.9:1 to about 1.1:1.

[0023] (d) Step B - Reaction conditions The temperature at which citric acid is in contact with the mixture of (a) may and will vary. Generally, the contact is carried out at a temperature in the range of about 20°C to about 90°C. In various embodiments, the contact may be carried out at a temperature of about 20°C to about 30°C, about 30°C to about 40°C, about 40°C to about 50°C, about 50°C to about 60°C, about 60°C to about 70°C, about 70°C to about 80°C, or about 80°C to about 90°C. In exemplary embodiments, the contact may be carried out at a temperature of about 80°C. In other exemplary embodiments, the contact may be carried out at a temperature of about 60°C to about 75°C, for example, at about 70°C. The contact may be carried out in an inert atmosphere (e.g., in the presence of nitrogen or argon) and under atmospheric pressure. The contact between the citric acid and the sufentanyl base in the mixture of (a) may be facilitated by stirring, mixing, shaking, or any other method known in the art. In various embodiments, the mixture of step (b) may not contain substantially or entirely the oil phase containing the sufentanyls. In particular, in embodiments where the polar nonaqueous solvent is 2-propanol, the mixture of (b) may not contain the oil phase at all.

[0024] Typically, this reaction is continued for a sufficient time until the reaction is complete, which is determined by any of a number of methods known in the art. In this regard, a "completed reaction" generally means that the reaction mixture contains a significantly decreased amount of the sulfentanyl base and a significantly increased amount of the sulfentanyl citrate compared to their respective amounts present at the start of the reaction. In a completed reaction, the amount of the sulfentanyl base remaining in the reaction mixture may be less than about 3% or less than about 1%. Generally, the reaction may be continued for about 0.5 hours to about 24 hours. In some embodiments, the reaction may be continued for about 0.5 hours to about 1 hour, about 1 hour to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 6 hours, about 6 hours to about 8 hours, about 8 hours to about 12 hours, about 12 hours to about 18 hours, or about 18 hours to about 24 hours.

[0025] In embodiments where the citrate is dissolved in a solvent before being added to the mixture of step (a), the citrate solution may be added over a period of about 1 minute to about 60 minutes. In some embodiments, the citrate solution may be added over a period of about 1 minute to about 5 minutes, about 5 minutes to about 10 minutes, about 10 minutes to about 15 minutes, about 15 minutes to about 20 minutes, about 20 minutes to about 25 minutes, about 25 minutes to about 30 minutes, about 30 minutes to about 35 minutes, about 35 minutes to about 40 minutes, about 40 minutes to about 45 minutes, about 45 minutes to about 50 minutes, about 50 minutes to about 55 minutes, or about 55 minutes to about 60 minutes. In certain embodiments, the citrate solution may be added over a period of about 50 minutes.

[0026] In some embodiments, the mixture may be filtered (purification filtration) before proceeding to the next step. In particular, the mixture may be filtered at a temperature in the range of about 20°C to about 90°C as described above.

[0027] The sphentanil citrate in the mixture may be isolated from the mixture using techniques known to those skilled in the art. Non-limiting examples of suitable techniques include precipitation, extraction, evaporation, distillation, chromatography, and crystallization. In an exemplary embodiment, the sphentanil citrate may be isolated according to the methods described in Sections (I)(e)-(f) below. The sphentanil citrate may be used as is or may be converted to other compounds using techniques familiar to those skilled in the art.

[0028] The yield of sphentanil citrate can vary and will vary. Generally, the yield of sphentanil citrate will be at least about 35%. In one embodiment, the yield of sphentanil citrate will be in the range of about 35% to about 65%. In other embodiments, the yield of sphentanil citrate will be in the range of about 65% to about 75%. In still other embodiments, the yield of sphentanil citrate will be in the range of about 75% to about 85%. In a further embodiment, the yield of the sphentanil citrate will be in the range of about 85% to about 95%. In yet other embodiments, the yield of the sphentanil citrate will be more than about 95%. In yet further embodiments, the yield of the sphentanil citrate will be more than about 99%.

[0029] (e) Step C In some embodiments, the process further includes step (c), which comprises cooling the mixture from step (b) to form a solid sufentanyl citrate. Generally, the reaction mixture in step (c) is the same as the reaction mixture in step (b), however, in some embodiments, the reaction mixture in step (b) may be seeded with sufentanyl citrate crystals. For example, in embodiments where the polar non-aqueous solvent is 2-propanol, seed crystals of sufentanyl citrate may be added to the mixture in step (b). Generally, the molar ratio of sufentanyl citrate seed crystals to sufentanyl citrate in the mixture may range from about 0.0001 to 1 to about 0.05 to 1. In various embodiments, the molar ratio of sufentanyl citrate seed crystals to sufentanyl citrate in the mixture may be in the range of about 0.0001:1 to about 0.0005:1, about 0.0005:1 to about 0.001:1, about 0.001:1 to about 0.005:1, about 0.005:1 to about 0.01:1, or about 0.01:1 to about 0.05:1. In exemplary embodiments, the molar ratio of sufentanyl citrate seed crystals to sufentanyl citrate in the mixture may be in the range of about 0.001:1 to about 0.05:1.

[0030] The temperature at which the reaction mixture in step (b) may be seeded is variable and will vary. Generally, the temperature will be in the range of about 30°C to about 70°C. In various embodiments, the temperature may be in the range of about 30°C to about -40°C, about 40°C to about 50°C, about 50°C to about 60°C, or about 60°C to about 70°C. In a preferred embodiment, the temperature at which the reaction may be seeded may be about 60°C.

[0031] (b) The temperature at which the mixture is cooled may and will vary. Generally, the temperature will be in the range of about -20°C to about 70°C. In various embodiments, the temperature may be in the range of about -20°C to about -10°C, about -10°C to about 0°C, about 0°C to about 5°C, about 5°C to about 10°C, about 10°C to about 20°C, about 20°C to about 30°C, about 30°C to about 40°C, about 40°C to about 50°C, about 50°C to about 60°C, or about 60°C to about 70°C. In some embodiments, the temperature at which the reaction is cooled may be in the range of about -5°C to about 5°C. In a preferred embodiment, the temperature of the cooled reaction may be about 50°C.

[0032] Typically, the reaction is allowed to continue for a sufficient amount of time, as described above, until the reaction is complete. For example, the cooling step may be continued until no more solid sufentanyl citrate is formed (by visual detection or laser method). Generally, the reaction may continue for about 0.5 hours to about 24 hours. In some embodiments, the reaction may continue for about 0.5 hours to about 1 hour, about 1 hour to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 6 hours, about 6 hours to about 8 hours, about 8 hours to about 12 hours, about 12 hours to about 18 hours, or about 18 hours to about 24 hours.

[0033] (f) Step D In some embodiments, the process may further include step (d), which comprises recovering a solid sufentanyl citrate from the mixture of step (c). In particular, this solid sufentanyl citrate may be recovered from the mixture of step (c) by filtration, for example, by vacuum filtration. The temperature at which this recovery step is performed may and will vary. Generally, the temperature may be in the range of about -20°C to about 60°C. In various embodiments, the temperature may be in the range of about -20°C to about -10°C, about -10°C to about 0°C, about 0°C to about 5°C, about 5°C to about 10°C, about 10°C to about 20°C, about 20°C to about 30°C, about 30°C to about 40°C, about 40°C to about 50°C, or about 50°C to about 60°C. In an exemplary embodiment, the temperature of the recovery step may be about 50°C.

[0034] The yield of solid sufentanyl citrate may and will vary. Typically, the yield of solid sufentanyl citrate will be at least about 35%. In one embodiment, the yield of solid sufentanyl citrate will range from about 35% to about 65%. In another embodiment, the yield of solid sufentanyl citrate will range from about 65% to about 75%. In yet another embodiment, the yield of solid sufentanyl citrate will range from about 75% to about 85%. In yet another embodiment, the yield of solid sufentanyl citrate will range from about 85% to about 95%. In yet another embodiment, the yield of solid sufentanyl citrate will be greater than about 95%. In yet another embodiment, the yield of sufentanyl citrate will be greater than about 99%. In an exemplary embodiment, the solid sufentanyl citrate recovered in step (d) will have a yield of at least about 85%.

[0035] The solid sufentanyl citrate may also be further dried using any method known in the art to remove any residual solvent. Suitable methods include vacuum filtration, oven drying, and vacuum decompression, for example, on a rotary evaporator or attached to a high-pressure manifold. In a further embodiment, the solid sufentanyl citrate may be dried at a temperature rising, for example, from about 35°C to about 65°C.

[0036] In various embodiments, the solid sufentanyl citrate recovered in step (d) may contain less than 5000 ppm of solvent, for example, less than 4500 ppm, less than 4000 ppm, less than 3500 ppm, less than 3000 ppm, less than 2500 ppm, less than 2000 ppm, less than 1500 ppm, less than 1000 ppm, less than 500 ppm, or less than 100 ppm. In other embodiments, the solid sufentanyl citrate recovered in step (d) may contain more than 5000 ppm of solvent. In a preferred embodiment, the solid sufentanyl citrate recovered in step (d) may contain less than 2000 ppm of solvent.

[0037] (g) Further processing After the recovery of the solid sufentanyl citrate, the mixture remaining from step (d) may be further processed according to section (III) below to give a recoverable solid sufentanyl base.

[0038] (II) Process for preparing sufentanyl citrate from sufentanyl base in an aqueous system Another aspect of the present disclosure provides a process for forming sufentanyl citrate from sufentanyl base in the presence of water. Generally, the process includes (a) forming a mixture of citric acid and water, and (b) adding the sufentanyl base to the mixture to form sufentanyl citrate. The process for forming sufentanyl citrate in the presence of water can be divided into two iterative forms of the general process.

[0039] The first aqueous method comprises forming a mixture with a high concentration of citric acid during the first step process (a1), where the volume-to-mass ratio of water to citric acid is about 2:1 to about 12:1, and adding a sufentanyl base during the second step process (b1), where the molar ratio of citric acid to sufentanyl base in the mixture from (a1) is in the range of about 2:1 to about 5:1, and step (b1) is generally carried out at a temperature of 85°C or below. In some embodiments, this iterative form further comprises (c1) cooling the mixture from step (b1) to form a solid sufentanyl citrate, and (d1) recovering the solid sufentanyl citrate.

[0040] The second aqueous method involves forming two different mixtures of sufentanyl citrate, where one mixture is added to the other. The first (high citrate-containing) mixture of sufentanyl citrate is divided into (a2) forming a first mixture of citrate and water such that the volume-to-mass ratio of water to citrate is about 2:1 to about 12:1, and (b2) adding about 4% to about 35% of sufentanyl base in total to the first mixture of citrate and water such that the molar ratio of citrate to sufentanyl base is about 2:1 to about 5:1. The method further includes (c2) cooling the first mixture of sufentanyl citrate. The second (low-citric acid-containing) mixture of sufentanyl citrate is divided into (d2) forming a second mixture of citric acid and water such that the volume-to-mass ratio of water to citric acid is about 10:1 to about 22:1, and (e2) adding about 65% to about 96% of sufentanyl base in total to the second mixture of citric acid and water such that the molar ratio of citric acid to sufentanyl base is about 0.5:1 to about 2:1. The method further comprises (f2) adding the second (low-citric acid-containing) mixture of sufentanyl citrate from step (e2) to the first (high-citric acid-containing) mixture of sufentanyl citrate from step (c2), and (g2) cooling the mixture from step (f2) to form solid sufentanyl citrate. The method further comprises (h2) recovering the solid sufentanyl citrate.

[0041] Each of these methods is described in detail below.

[0042] (a) Water System Law 1 (i) Step A1 In the first iteration of the process of preparing sufentanyl citrate from sufentanyl base in the presence of water, step (a1) comprises forming a mixture of citric acid and water.

[0043] This citric acid may exist in any form as previously described in Section (I)(c). Generally, the volume-to-mass ratio of water to citric acid may range from about 2:1 to about 12:1. In various embodiments, the volume-to-mass ratio of water to citric acid may range from about 2:1 to about 12:1, about 3:1 to about 11:1, about 4:1 to about 10:1, about 5:1 to about 9:1, or about 6:1 to about 8:1, or about 6.5:1 to about 7.5:1. In some embodiments, the volume-to-mass ratio of water to citric acid may be about 7:1.

[0044] The reaction between citric acid and water is carried out at a temperature of approximately 100°C or lower. For example, the temperature may be in the range of approximately 20°C to approximately 40°C, approximately 40°C to approximately 60°C, approximately 60°C to approximately 80°C, or approximately 80°C to approximately 100°C. In an exemplary embodiment, the temperature may be in the range of approximately 20°C to approximately 30°C.

[0045] Generally, citric acid is added in part. This contact step is continued for a sufficient amount of time for the citric acid to be incorporated into the mixture. In some embodiments, the mixture may be a homogeneous solution. Generally, the contact may be continued for about 1 minute to about 60 minutes. In some embodiments, the reaction may be continued for about 1 minute to about 5 minutes, about 5 minutes to about 10 minutes, about 10 minutes to about 15 minutes, about 15 minutes to about 20 minutes, about 20 minutes to about 25 minutes, about 25 minutes to about 30 minutes, about 30 minutes to about 35 minutes, about 35 minutes to about 40 minutes, about 40 minutes to about 45 minutes, about 45 minutes to about 50 minutes, about 50 minutes to about 55 minutes, or about 55 minutes to about 60 minutes. The contact between citric acid and water may be facilitated by stirring, mixing, shaking, or any other method known in the art.

[0046] The reaction may be carried out in an inert atmosphere (for example, in the presence of nitrogen or argon) and under atmospheric pressure. In various embodiments, the mixture of (a1) may not contain substantially or completely insoluble chemical species. In some embodiments, the mixture of (a1) may be filtered (purified filtration) to remove insoluble impurities before proceeding to the next step.

[0047] (ii) Step B1 Step (b1) of this repeated form includes adding a sufentanyl base to the mixture of (a1).

[0048] In general, the molar ratio of citrate to sufentanyl base may range from about 2:1 to about 5:1. In various embodiments, the molar ratio of citrate to sufentanyl base may range from about 2.0:1 to 5.0:1, about 2.25:1 to 4.5:1, about 2.5:1 to about 4.0:1, or about 2.75:1 to about 3.5:1. In exemplary embodiments, the molar ratio of citrate to sufentanyl base may range from about 2.0:1 to about 3.0:1.

[0049] The reaction between the sufentanyl base and the citrate mixture is generally carried out at a temperature of about 85°C or lower. For example, the temperature may be in the range of about 20°C to about 40°C, about 40°C to about 60°C, about 60°C to about 70°C, or about 70°C to about 85°C. In an exemplary embodiment, the temperature may be in the range of about 60°C to about 85°C.

[0050] Generally, the sufentanyl base is added in part. Contact between the sufentanyl base and citric acid may be continued for about 0.5 hours to about 24 hours. In some embodiments, the reaction may be continued for about 0.5 hours to about 1 hour, about 1 hour to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 6 hours, about 6 hours to about 8 hours, about 8 hours to about 12 hours, about 12 hours to about 18 hours, or about 18 hours to about 24 hours. Contact between the sufentanyl base and citric acid may be facilitated by stirring, mixing, shaking, or any other method known in the art.

[0051] The reaction may be carried out in an inert atmosphere (e.g., in the presence of nitrogen or argon) and under atmospheric pressure. In various embodiments, the mixture of (b1) may not contain substantially or entirely the oil phase containing the sufentanyls. In some embodiments, the mixture of (b1) may be filtered to remove insoluble sufentanyl bases and / or other impurities before proceeding to the next step.

[0052] (iii) Step C1 In various embodiments, this iterative form may further include (c1) cooling the mixture from step (b1) to form a solid sufentanyl citrate, and (d1) recovering the solid sufentanyl citrate from the mixture in step (c1).

[0053] In some embodiments, this iterative form may further include cooling the mixture from step (b1) to form a solid sufentanyl citrate. The temperature at which the mixture in (b1) is cooled may and will vary. Generally, the temperature may be in the range of about -20°C to about 60°C. In various embodiments, the temperature may be in the range of about -20°C to about -10°C, about -10°C to about 0°C, about 0°C to about 5°C, about 5°C to about 10°C, about 10°C to about 20°C, about 20°C to about 30°C, about 30°C to about 40°C, about 40°C to about 50°C, or about 50°C to about 60°C. In some embodiments, the temperature of the reaction may be in the range of about 0°C to about 5°C. In other embodiments, the temperature of the reaction may be less than about -5°C.

[0054] Typically, the reaction is allowed to continue for a sufficient amount of time until it is complete. For example, the cooling step may continue until no more solid sufentanyl citrate is formed (by visual detection or laser method). Generally, the reaction may continue for about 0.5 hours to about 24 hours. In some embodiments, the reaction may continue for about 0.5 hours to about 1 hour, about 1 hour to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 6 hours, about 6 hours to about 8 hours, about 8 hours to about 12 hours, about 12 hours to about 18 hours, or about 18 hours to about 24 hours.

[0055] (iv) Step D1 This iterative form may also include recovering a solid sufentanyl citrate after step (c1). The solid sufentanyl citrate may be recovered from the mixture in step (c1) by filtration, for example, by vacuum filtration. The temperature at which this recovery step is performed may and will vary. Generally, the temperature may be in the range of about -20°C to about 60°C. In various embodiments, the temperature may be in the range of about -20°C to about -10°C, about -10°C to about 0°C, about 0°C to about 5°C, about 5°C to about 10°C, about 10°C to about 20°C, about 20°C to about 30°C, about 30°C to about 40°C, about 40°C to about 50°C, or about 50°C to about 60°C. In an exemplary embodiment, the temperature of the recovery step may be in the range of about 0°C to about 25°C.

[0056] The yield of solid sufentanyl citrate can and will vary. Typically, the yield of solid sufentanyl citrate will be at least about 35%. In one embodiment, the yield of solid sufentanyl citrate will range from about 35% to about 65%. In another embodiment, the yield of solid sufentanyl citrate will range from about 65% to about 75%. In yet another embodiment, the yield of solid sufentanyl citrate will range from about 75% to about 85%. In yet another embodiment, the yield of the solid sufentanyl citrate will range from about 85% to about 95%. In yet another embodiment, the yield of the solid sufentanyl citrate will be greater than about 95%. In yet another embodiment, the yield of sufentanyl citrate will be greater than about 99%. In an exemplary embodiment, the solid sufentanyl citrate recovered in step (d1) will have a yield of at least about 90%.

[0057] The solid sufentanyl citrate may also be further dried using any method known in the art to remove moisture. Suitable methods include vacuum filtration, oven drying, and vacuum decompression, for example, on a rotary evaporator or attached to a high-pressure manifold. In a further embodiment, the solid sufentanyl citrate may be dried at a temperature rising, for example, from about 35°C to about 65°C.

[0058] The mixture remaining after the recovery of solid sufentanyl citrate in step (d1) may be further treated according to the following section (III) to give a solid sufentanyl base.

[0059] (b) Water-based method 2 A second iterative form of the process for compounding sufentanyl citrate from sufentanyl base in the presence of water comprises forming two different mixtures of sufentanyl citrate and then combining the two mixtures.

[0060] (i) Step A2 The first step of this iterative form involves forming a first mixture of citric acid and water, which has a high concentration of citric acid. Forming the mixture of citric acid and water is essentially the same as described above in Section (II)(a)(i).

[0061] In general, the volume-to-mass ratio of water to citric acid in this high-citric acid mixture may range from about 2:1 to about 12:1. In various embodiments, the volume-to-mass ratio of water to citric acid in the high-citric acid mixture may range from about 1:1 to about 9:1, about 2:1 to about 8:1, about 3:1 to about 7:1, or about 4:1 to about 6:1. In some embodiments, the volume-to-mass ratio of water to citric acid in the high-citric acid mixture may be about 5:1.

[0062] (ii) Step B2 The next step in this iterative form involves adding about 4% to about 35% in total amount of sufentanyl base to the high-citric acid mixture of (a2) to form a first mixture of sufentanyl citrate (high-citric acid content). Generally, the molar ratio of citric acid to sufentanyl base may be in the range of about 2:1 to about 5:1. In various embodiments, the molar ratio of citric acid to sufentanyl base may be in the range of about 2.0:1 to 5.0:1, about 2.25:1 to 4.5:1, about 2.5:1 to about 4.0:1, or about 2.75:1 to about 3.5:1. In exemplary embodiments, the molar ratio of citric acid to sufentanyl base may be in the range of about 2.0:1 to about 3.0:1. In various embodiments, the amount of sufentanyl base added to the first mixture of aqueous citric acid may be in the range of about 4% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, or about 30% to about 35% of the total amount of sufentanyl base. In exemplary embodiments, the amount of sufentanyl base added to the first mixture of (a2) may be 10% to about 20%, or about 15%, of the total amount of sufentanyl base.

[0063] Generally, step (b2) of the process is carried out at a temperature of 90°C or lower. In various embodiments, the reaction is carried out at temperatures of about 20°C to about 40°C, about 40°C to about 60°C, about 60°C to about 80°C, or about 80°C to about 90°C. In exemplary embodiments, the temperature may be in the range of about 70°C to about 85°C.

[0064] The contact between the sufentanyl base and the high-citric acid mixture in step (b2) may be continued for about 0.5 hours to about 24 hours. In some embodiments, the reaction may be continued for about 0.5 hours to about 1 hour, about 1 hour to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 6 hours, about 6 hours to about 8 hours, about 8 hours to about 12 hours, about 12 hours to about 18 hours, or about 18 hours to about 24 hours. The contact between the sufentanyl base and the high-citric acid may be facilitated by stirring, mixing, shaking, or any other method known in the art.

[0065] The reaction may be carried out in an inert atmosphere (e.g., in the presence of nitrogen or argon) and under atmospheric pressure. In various embodiments, the mixture of (b2) may not contain substantially or entirely the oil phase containing the sufentanyls. In some embodiments, the mixture of (b2) may be filtered (purified filtration) to remove insoluble sufentanyl bases and / or other impurities before proceeding to the next step.

[0066] (iii) Step C2 The third step of this iterative form involves cooling the mixture of (b2) monosufentanyl citrate (high citrate content). This cooling step is carried out essentially as described above in section (II)(a)(iii).

[0067] (iv) Step D2 Step (d2) involves forming a second mixture of citric acid and water such that the concentration of citric acid is even lower than that in (a2) above.

[0068] In general, the volume-to-mass ratio of water to citric acid in this low-citric acid mixture may range from about 10:1 to about 22:1. In various embodiments, the volume-to-mass ratio of water to citric acid in the low-citric acid mixture may range from about 10:1 to about 22:1, about 12:1 to about 20:1, or about 14:1 to about 18:1. In some embodiments, the volume-to-mass ratio of water to citric acid may be about 16.5:1. The second mixture of citric acid and water may be formed basically as described above in Section (II)(a)(i).

[0069] (v) Step E2 The next step in this iterative form involves forming a second mixture of sufentanyl citrate (low citrate content) by adding about 65% to about 96% of sufentanyl base in total to the low citrate mixture of (d2). Generally, the molar ratio of citrate to sufentanyl base may be in the range of about 0.5:1 to about 3.0:1. In various embodiments, the molar ratio of citrate to sufentanyl base may be in the range of about 0.5:1 to 3.0:1, about 0.75:1 to 2.0:1, or about 0.9:1 to about 1.1:1. In exemplary embodiments, the molar ratio of citrate to sufentanyl base may be about 1.0:1. In various embodiments, the amount of sufentanyl base added to the mixture of (d2) may be in the range of about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, or about 90% to about 96% of the total amount of sufentanyl base used in the process. In exemplary embodiments, the amount of sufentanyl base added to the mixture of (d2) may be about 80% to about 90%, or about 85%, of the total amount of sufentanyl base.

[0070] Generally, step (e2) is carried out at a temperature of at least about 90°C. For example, the step may be carried out at a temperature of about 90°C to about 95°C, about 95°C to about 100°C, or higher than about 100°C.

[0071] Contact between the sufentanyl base and the low-citric acid mixture of step (e2) may be continued for about 0.5 hours to about 24 hours. In some embodiments, the reaction may be continued for about 0.5 hours to about 1 hour, about 1 hour to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 6 hours, about 6 hours to about 8 hours, about 8 hours to about 12 hours, about 12 hours to about 18 hours, or about 18 hours to about 24 hours. Contact between the sufentanyl base and citric acid may be facilitated by stirring, mixing, shaking, or any other method known in the art.

[0072] The reaction may be carried out in an inert atmosphere (e.g., in the presence of nitrogen or argon) and under atmospheric pressure. In various embodiments, the mixture of (e2) may not contain substantially or entirely the oil phase containing the sufentanyls. In some embodiments, the mixture of (e2) may be filtered (purified filtration) to remove insoluble sufentanyl bases and / or other impurities before proceeding to the next step.

[0073] (vi) Step F2 A second iteration further comprises (f2) adding a (warm) second mixture of sufentanyl citrate (low citrate content) from step (e2) to a first mixture of sufentanyl citrate (high citrate content) from step (c2). Generally, the first mixture of sufentanyl citrate is kept at a temperature in the range of about 5°C to about 30°C while the second mixture is being added to it. In some embodiments, the temperature of the first mixture may be in the range of about 5°C to about 10°C, about 10°C to about 20°C, or about 20°C to about 30°C. In an exemplary embodiment, the temperature of the first mixture is kept at about 10°C to about 23°C during the addition of the second mixture.

[0074] The addition of the second mixture to the first mixture may take place over a period of about 0.5 hours to about 4 hours. In various embodiments, the addition time may range from about 0.5 hours to about 1 hour, from about 1 hour to about 2 hours, or from about 2 hours to about 3 hours. In exemplary embodiments, the addition time may be about 2 hours. The first mixture may be stirred or mixed during the addition of the second mixture.

[0075] (vii) Step G2 The next step in the iterative form involves cooling the mixture of (f2) to form a solid sufentanyl citrate. This cooling step may be carried out essentially as described above in sections (II)(a)(iii).

[0076] (viii) Step H2 This iterative form further includes recovering the solid sufentanyl citrate from the mixture of step (g2) in (h2), essentially as described above in section (II)(a)(iv). The mixture remaining after the recovery of the solid sufentanyl citrate in step (h2) may be further treated according to section (III) below to give a solid sufentanyl base.

[0077] (III) Process for forming a sufentanyl base from sufentanyl citrate in a solvent Another aspect of the present disclosure provides a process for forming a sufentanyl base from sufentanyl citrate. This process comprises (a) contacting sufentanyl citrate with at least one polar solvent to form a mixture, and (b) contacting the mixture with a proton acceptor (base) to form a sufentanyl base. The process further comprises (c) optionally cooling the mixture from step (b) to form a solid sufentanyl base, and (d) recovering the solid sufentanyl base.

[0078] In various embodiments, step (a) of the process of forming a sufentanyl base from sufentanyl citrate is omitted, and the process is carried out using the mixture remaining after the recovery of solid sufentanyl citrate during either of the processes described in detail in section (I) or (II). In particular, sections (I)(g), (II)(a)(iv), and (II)(b)(viii).

[0079] (a) Step A - Reaction mixture Step (a) of the process includes contacting sufentanyl citrate with at least one polar solvent to form a mixture. The process is initiated by forming a mixture comprising sufentanyl citrate and at least one polar solvent. This at least one polar solvent may be any polar non-aqueous solvent described in Section (I)(a), water, or a combination thereof. In various embodiments, the at least one polar solvent may be selected from the group consisting of ethyl acetate, isopropyl acetate, methyl isobutyl ketone, methyl ethyl ketone, C1-C5 alcohols, or water. In some exemplary embodiments, the at least one polar solvent may be 2-propanol. In other exemplary embodiments, the at least one polar solvent may be water. In yet another exemplary embodiment, the polar solvent may include ethanol and water.

[0080] Generally, the volume-to-mass ratio of the solvent to sufentanyl citrate is in the range of about 0.5:1 to about 200:1. In various embodiments, the volume-to-mass ratio of the solvent to sufentanyl citrate may be in the range of about 0.5:1 to 200:1, about 1.25:1 to 150:1, about 2.5:1 to 100:1, or about 3.75:1 to about 50:1. In exemplary embodiments, the volume-to-mass ratio of the solvent to sufentanyl citrate may be in the range of about 5:1 to about 25:1.

[0081] (b) Step A - Reaction conditions Generally, contact between the polar solvent and sufentanyl citrate is carried out at temperatures ranging from about 20°C to about 90°C. In various embodiments, this temperature may be in the range of about 20°C to about 30°C, about 30°C to about 40°C, about 40°C to about 50°C, about 50°C to about 60°C, about 60°C to about 70°C, about 70°C to about 80°C, or about 80°C to about 90°C. Typically, contact between the polar solvent and sufentanyl citrate is continued for a sufficient amount of time until a homogeneous mixture is formed. The contact time may range from about a few minutes to about a few hours.

[0082] In some embodiments, the mixture may be filtered (purified by filtration) before proceeding to the next step. In particular, the mixture may be filtered, for example, at a temperature in the range of about 20°C to about 90°C to remove insoluble sufentanyl citrate before proceeding with the reaction with the proton acceptor, as described above.

[0083] (c) Step B - Reaction mixture Step (b) of the process further includes contacting the mixture from step (a) with a proton acceptor to form a sufentanyl base. Generally, the pKa of a suitable proton acceptor is in the range of about 7 to about 13. This proton acceptor may be organic or inorganic. Typical inorganic salts include, but are not limited to, borates (e.g., Na3BO3), di- and tri-basic phosphates (e.g., Na2HPO4 and Na3PO4), bicarbonates (e.g., NaHCO3, KHCO3, mixtures thereof, etc.), hydroxide salts (e.g., NaOH, KOH, mixtures thereof, etc.), carbonates (e.g., Na2CO3, K2CO3, mixtures thereof, etc.), and any combination thereof. In exemplary embodiments, the proton acceptor includes a hydroxide. In specific embodiments, the proton acceptor may be potassium hydroxide, sodium hydroxide, or a combination thereof.

[0084] The molar ratio of sufentanyl citrate to the proton receptor may be in the range of about 1:1.0 to about 1:6.0. In some embodiments, the molar ratio of sufentanyl citrate to the proton receptor may be in the range of about 1:1.0 to about 1:6.0, about 1:1.1 to about 1:5.0, about 1:1.3 to about 1:4.0, or about 1:1.5 to about 1:3.0. In some embodiments, the molar ratio of sufentanyl citrate to the proton receptor may be in the range of about 1:1.6 to about 1:2.0.

[0085] (d) Step B - Reaction conditions The temperature at which the reaction is carried out is and will be variable. Generally, the reaction is carried out at temperatures ranging from about 20°C to about 90°C. In various embodiments, the reaction is carried out at temperatures ranging from about 20°C to about 30°C, about 30°C to about 40°C, about 40°C to about 50°C, about 50°C to about 60°C, about 60°C to about 70°C, about 70°C to about 80°C, or about 80°C to about 90°C. In exemplary embodiments, the reaction is carried out at a temperature of about 35°C. The reaction may be carried out in an inert atmosphere (e.g., in the presence of nitrogen or argon) and under atmospheric pressure.

[0086] Typically, the reaction is allowed to continue for a sufficient amount of time until it is complete. Upon completion, the amount of sufentanyl citrate remaining in the reaction mixture may be less than about 3% or less than about 1%. Generally, the reaction may continue for about 0.5 hours to about 24 hours. In some embodiments, the reaction may continue for about 0.5 hours to about 1 hour, about 1 hour to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 6 hours, about 6 hours to about 8 hours, about 8 hours to about 12 hours, about 12 hours to about 18 hours, or about 18 hours to about 24 hours.

[0087] The sufentanyl base may be isolated from the reaction mixture using techniques known to those skilled in the art. Non-limiting examples of suitable techniques include precipitation, extraction, evaporation, distillation, chromatography, and crystallization. In exemplary embodiments, the sufentanyl base may be isolated according to the methods described in sections (III)(e) to (f) below. The sufentanyl base may be used as is or converted into other compounds using techniques familiar to those skilled in the art.

[0088] The yield of sufentanyl base can and will vary. Typically, the yield of sufentanyl base will be at least about 35%. In one embodiment, the yield of sufentanyl base will range from about 35% to about 65%. In another embodiment, the yield of sufentanyl base will range from about 65% to about 75%. In yet another embodiment, the yield of sufentanyl base will range from about 75% to about 85%. In yet another embodiment, the yield of sufentanyl base will range from about 85% to about 95%. And in yet another embodiment, the yield of sufentanyl base will be greater than about 95%.

[0089] (e) Step C In some embodiments, step (c) of the process further includes cooling the mixture from step (b) to form a solid sufentanyl base. Generally, the reaction mixture in step (c) is the same as the reaction mixture in step (b), however, in some embodiments, the reaction mixture in step (b) may be seeded with sufentanyl base crystals. Generally, the molar ratio of sufentanyl base to sufentanyl base seed crystals in the mixture may be in the range of about 0.0001:1 to about 0.05:1. In various embodiments, the molar ratio of sufentanyl base to sufentanyl base seed crystals in the mixture may be in the range of about 0.0001:1 to about 0.05:1, about 0.00025:1 to about 0.05:1, about 0.0005:1 to about 0.05:1, or about 0.00075:1 to about 0.05:1. In exemplary embodiments, the molar ratio of sufentanyl base seed crystals to sufentanyl base in the mixture may be in the range of about 0.001:1 to about 0.05:1.

[0090] The temperature at which the mixture is cooled may and will vary. Generally, the temperature may be in the range of about -20°C to about 60°C. In various embodiments, the temperature may be in the range of about -20°C to about -10°C, about -10°C to about 0°C, about 0°C to about 5°C, about 5°C to about 10°C, about 10°C to about 20°C, about 20°C to about 30°C, about 30°C to about 40°C, about 40°C to about 50°C, or about 50°C to about 60°C. In exemplary embodiments, the temperature may be in the range of about 0°C to about 5°C.

[0091] Typically, step (c) is continued for a sufficient amount of time for the reaction to be completed, as described in detail earlier. For example, the cooling step may be continued until no more solid sufentanyl base is formed (confirmed by visual detection). Generally, the reaction may be continued for about 0.5 hours to about 24 hours. In some embodiments, the reaction may be continued for about 0.5 hours to about 1 hour, about 1 hour to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 6 hours, about 6 hours to about 8 hours, about 8 hours to about 12 hours, about 12 hours to about 18 hours, or about 18 hours to about 24 hours.

[0092] (f) Step D In some embodiments, the process may further include step (d), which comprises recovering a solid sufentanyl base from the mixture of step (c). In particular, the solid sufentanyl base may be recovered from the reaction mixture of step (c) by filtration, for example, by vacuum filtration. The solid sufentanyl base may also be further dried using any method known in the art to remove any residual solvent. Suitable methods include vacuum filtration, oven drying, and vacuum depressurization, for example, on a rotary evaporator or attached to a high-pressure manifold. In further embodiments, the solid sufentanyl base may be dried at a temperature rising, for example, from about 35°C to about 65°C.

[0093] In some embodiments, the solid sufentanyl base may be contacted with a nonpolar solvent to form a crystalline sufentanyl base. Typical nonpolar solvents include, but are not limited to, alkanes and substituted alkane solvents (including cyclic alkanes), aromatic hydrocarbons, and combinations thereof. Specific nonpolar solvents that may be employed include, for example, benzene, chlorobenzene, chloroform, cyclohexane, dichloromethane, dichloroethane, fluorobenzene, heptane, hexane, toluene, and combinations thereof. In exemplary embodiments, the nonpolar solvent may be an alkane such as, for example, pentane, hexane, heptane, cyclopentane, cyclohexane, cycloheptane, or combinations thereof.

[0094] The yield of sufentanyl base can and will vary. Typically, the yield of solid sufentanyl base will be at least about 35%. In one embodiment, the yield of solid sufentanyl base will range from about 35% to about 65%. In another embodiment, the yield of solid sufentanyl base will range from about 65% to about 75%. In yet another embodiment, the yield of solid sufentanyl base will range from about 75% to about 85%. In yet another embodiment, the yield of solid sufentanyl base will range from about 85% to about 95%. In yet another embodiment, the yield of solid sufentanyl base will be greater than about 95%. In an exemplary embodiment, the solid sufentanyl base recovered in step (d) will have a yield of at least about 90%.

[0095] In various embodiments, the solid sufentanyl base recovered in step (d) may contain a solvent in a concentration of less than 5000 ppm, for example, less than 4500 ppm, less than 4000 ppm, less than 3500 ppm, less than 3000 ppm, less than 2500 ppm, less than 2000 ppm, less than 1500 ppm, less than 1000 ppm, less than 500 ppm, or less than 100 ppm.

[0096] Even if the present invention is described in detail, it will be clear that it can be modified and altered without departing from the spirit of the invention as defined in the appended claims. [Examples]

[0097] The following examples include demonstrating specific embodiments of the present invention. Those skilled in the art will understand that the techniques disclosed in these examples represent the techniques discovered by the inventors as functioning well in practice of the present invention. However, those skilled in the art will understand that many modifications can be made in the specific embodiments disclosed without departing from the spirit and scope of the present invention, and similar results can be obtained, and therefore all things expressed should be construed as illustrative and not as limitations.

[0098] Example 1: Sufentanyl citrate (IPA + anhydrous citric acid) - Method A Sufentanyl base (1.09 g, 2.81 mmol) was stirred and dissolved in 2-propanol (8 mL) by heating (approximately 35°C). Anhydrous citric acid (0.56 g, 2.91 mmol, 1.04 equivalents) was added, and the mixture was further heated to 40°C until completely dissolved. This mixture was sterile filtered through a suitable filter. Sufentanyl citrate crystals (0.05 mol%) were seeded into this reaction mixture at 40°C, and the temperature was maintained to allow crystallization to occur, thus avoiding the oil phase. This reaction mixture was cooled to <5°C and maintained at that temperature for approximately 2 hours. The solid was filtered over a Buchner funnel and washed with 1 mL of cold (<5°C) 2-propanol. After drying in a convection oven at 58°C to 62°C, the product was a white powder (1.47 g, 90.7%). This product typically contains 4600 ppm of residual 2-propanol, which was analyzed to be 99.29 wt%.

[0099] Example 2: Sufentanyl citrate (IPA + anhydrous citric acid) - Method B Sufentanyl base (130.71 g, 338.14 mmol) was stirred and dissolved in 2-propanol (378 mL) by heating at approximately 72°C. Anhydrous citric acid (65.66 g, 341.74 mmol) was dissolved in 2-propanol (351.5 mL) and added to the 2-propanol-sufentanyl base solution, and stirred for approximately 50 minutes. During this addition, the temperature of the reaction mixture was maintained at at least 62°C, then heated to 75°C, and filtered for sterilization. The reaction was cooled to approximately 62°C, and sufentanyl citrate (220 mg, 0.38 mmol, 0.001 mol%) was seeded. The reaction mixture was maintained at 60°C for 4 hours, then cooled to room temperature (approximately 25°C), and maintained at room temperature for 16 hours with stirring, then cooled to between approximately 0°C and 5°C with stirring for approximately 30 minutes. This reaction mixture, containing solid sufentanyl citrate, was filtered through a Buchner funnel and washed with cold (<5°C) 2-propanol (125 mL). Following this procedure, after 3 days of vacuum air drying on a Buchner funnel, white crystals were produced (190.42 g, 97.3%). Analysis showed that the substance contained 99 to 101 wt.% sufentanyl citrate, with less than 5000 ppm of residual 2-propanol.

[0100] Example 3: Sufentanyl citrate (IPA + citric acid monohydrate) - Method A Sufentanyl base (1.02 g, 2.63 mmol) was stirred and dissolved in 2-propanol (8 mL) by heating (approximately 35°C). Citric acid monohydrate (0.58 g, 2.76 mmol, 1.05 equivalents) was added, and the mixture was further heated to 40°C until completely dissolved. This mixture was sterile filtered through a suitable filter. Sufentanyl citrate crystals (0.05 mol%) were seeded into this reaction mixture at 40°C, and the temperature was maintained to allow crystallization to occur, thus avoiding the oil phase. The reaction mixture was then cooled to <5°C and maintained at that temperature for approximately 2 hours. The solid was filtered over a Buchner funnel and washed with 1 mL of cold (<5°C) 2-propanol. After drying in a convection oven at 58°C to 62°C, the product was a white powder (1.43 g, 93.7%). This product typically contains 4800 ppm of residual 2-propanol, which was analyzed to be 100.28 wt%.

[0101] Example 4: Sufentanyl citrate (IPA + citric acid monohydrate) - Method B Sufentanyl base (1.02 g, 2.63 mmol) was placed in a 25 mL three-way flask containing 2-propanol (4 mL) and stirred with a magnetic stirrer. This mixture was heated to 51°C to completely dissolve the sufentanyl. Citric acid monohydrate (0.59 g, 2.81 mmol, 1.07 equivalents) was placed in a separable flask containing 2-propanol (3.9 mL) and stirred at room temperature (approximately 22°C) to dissolve. This citric acid solution was added to the sufentanyl solution and stirred. The temperature of the combined solution was 39°C. The solution was cooled to room temperature while continuing to stir. After about 30 minutes, the solution became cloudy, and the sufentanyl citrate slowly emerged from the solution. The suspension of this product was cooled in an ice bath for 2 hours (0-5°C), filtered, and air-dried for 2 hours to obtain sufentanil citrate, a white powder solid (1.34 g, 88.2%).

[0102] Example 5: Sufentanyl citrate (2-propanol + citric acid monohydrate) - Method A with trace control of residual 2-propanol Sufentanyl base (13.00 g, 33.63 mmol) and citric acid monohydrate (7.21 g, 34.31 mmol, 1.02 equivalents) were added to a 250 mL flask equipped with a mechanical stirrer under a nitrogen atmosphere. 2-propanol (57 mL) was added to the flask, the slurry was stirred to mix the contents, and then heated to 80°C to dissolve. The warm solution was filtered through a 0.45 μm filter, and the flask and filter were rinsed with 2-propanol (9 mL). The clear warm solution was cooled to 60°C, and sufentanyl citrate (20 mg, 0.034 mmol, 0.10 mol%) was added. The turbid solution was cooled to 50°C over 1-2 hours and held for 18 hours. The white slurry was filtered at 50°C over a Buchner funnel, and the solid was washed with 13.0 mL of 2-propanol. The isolated solid was dried in a convection oven at 60°C until the weight was constant. The result was a product that was a white powder (17.85 g, 91.7%), typically containing 1041 ppm of residual 2-propanol and analyzed as 99.86 wt.%.

[0103] Example 6: Sufentanyl citrate (1-butanol + citric acid monohydrate) Sufentanyl base (1.01 g, 2.61 mmol) was stirred, and 1-butanol (8 mL) was dissolved at room temperature (approximately 23°C). Citric acid monohydrate (0.58 g, 2.76 mmol, 1.06 equivalents) was added. This mixture was sterile filtered through a suitable filter, and the mixture was stirred overnight. The suspension was cooled to <5°C and held for 2 hours, and the solid was filtered over a Buchner funnel and washed with 2 mL of cold (<5°C) 1-butanol. After drying in a convection oven at 55–65°C, the product was a white powder (1.44 g, 95.4%). This product was analyzed to be typically 95.69 wt.%.

[0104] Example 7: Sufentanyl citrate (2-butanol + citric acid monohydrate) Sufentanyl base (1.05 g, 2.72 mmol) was stirred in 2-butanol (8 mL) at room temperature. The mixture was heated at 30°C for 30 minutes to obtain a solution, which was filtered and then cooled to room temperature. Citric acid monohydrate (0.60 g, 2.85 mmol, 1.00 equivalent) was added, and the mixture was stirred until completely dissolved. Crystallization occurred after 1 hour at room temperature. The suspension was stirred overnight, then cooled to <5°C and held for 2 hours. The solid was filtered over a Buchner funnel and washed with 2 mL of cold (<5°C) 2-butanol. After drying in a convection oven at 55–65°C, the product was a white powder (1.43 g, 91.2%). The product was analyzed to be typically 99.85 wt.%.

[0105] Example 8: Sufentanyl citrate (ethyl acetate + citric acid monohydrate) Sufentanyl base (1.04 g, 2.69 mmol) was stirred and heated to dissolve it in ethyl acetate (8 mL) at approximately 30°C. Citric acid monohydrate (0.62 g, 2.95 mmol, 1.10 equivalents) was added, and the mixture was further heated to approximately 76°C to approximately 78°C and held for 1 hour. The suspension was cooled to <5°C and held for approximately 0.5 hours. The solid was filtered over a Buchner funnel and washed with 2 mL of cold (<5°C) ethyl acetate. After drying in a convection oven at 58–62°C, the product was a white powder (1.46 g, 93.6%). The product typically contained 3100 ppm of residual ethyl acetate and was analyzed to be 98.79 wt.%.

[0106] Example 9: Sufentanyl citrate (isopropyl acetate + citric acid monohydrate) Sufentanyl base (1.01 g, 2.61 mmol) was stirred and heated to dissolve it in isopropyl acetate (8 mL) (approximately 30°C). Citric acid monohydrate (0.57 g, 2.71 mmol, 1.04 equivalents) was added, and the mixture was further heated to approximately 80°C and held for 1 hour. The suspension was cooled to <5°C and held for approximately 0.5 hours. The solid was filtered over a Buchner funnel and washed with 2 mL of cold (<5°C) isopropyl acetate. After drying in a convection oven at 45–54°C, the product was a white powder (1.27 g, 84.1%). The product was analyzed to be typically 99.54 wt.%.

[0107] Example 10: Sufentanyl citrate (methyl isobutyl ketone + citric acid monohydrate) Sufentanyl base (1.06 g, 2.74 mmol) was stirred and heated to dissolve it in methyl isobutyl ketone (8 mL) at approximately 30°C. Citric acid monohydrate (0.61 g, 2.90 mmol, 1.06 equivalents) was added. The reaction mixture was filtered as needed and then stirred overnight at room temperature. The suspension was cooled to <5°C and held for approximately 0.5 hours. The solid was filtered over a Buchner funnel and washed with 2 mL of cold (<5°C) methyl isobutyl ketone. After drying in a convection oven at 55–65°C, the product was a white powder (1.34 g, 84.3%). The product was analyzed to be typically 93.67 wt.%.

[0108] Example 11: Sufentanyl citrate (methyl ethyl ketone + citric acid monohydrate) Sufentanyl base (1.01 g, 2.61 mmol) was stirred, and methyl ethyl ketone (8 mL) was dissolved at room temperature. Citric acid monohydrate (0.57 g, 2.71 mmol) was added, and crystallization was observed after 5 minutes. The mixture was stirred at room temperature overnight. The suspension was cooled to <5°C and held for approximately 0.5 hours. The solid was filtered over a Buchner funnel and washed with 2 mL of cold (<5°C) methyl ethyl ketone. After drying in a convection oven at 55–65°C, the product was a white powder (1.47 g, 97.4%). The product was analyzed to be typically 96.27 wt.%.

[0109] Example 12: Sufentanyl citrate (25% v / v methanol aqueous solution + citric acid monohydrate) Sufentanyl base (0.97g, 2.51 mmol) was stirred and heated to 25% The compound was dissolved in 8 mL of v / v methanol aqueous solution (at approximately 55°C). Citric acid monohydrate (0.55 g, 2.62 mmol, 1.04 equivalents) was added, and the mixture was cooled. The reaction product was cooled to room temperature (crystallization occurred at 35.0°C). The suspension was stirred overnight. The reaction was then cooled to <5°C and held for 2 hours, then filtered over a Buchner funnel and washed with 2 mL of cold (<5°C) 25% v / v methanol aqueous solution. After drying in a convection oven at 55–65°C, the product was a white powder (1.20 g, 82.8%). The product was analyzed to be typically 100.26 wt.%.

[0110] Example 13: Sufentanyl citrate - aqueous method 1 Anhydrous citrate (4.32 g, 22.48 mmol) was dissolved in deionized water (30 mL). Sufentanyl base (3.00 g, 7.76 mmol, 0.34 equivalents) was added to this solution, and the mixture was then mixed and dissolved at 75°C to 85°C. The mixture was then cooled to room temperature, and the product was crystallized within 3 hours. The mixture was then cooled to 0 to 5°C and held for 1 to 3 hours. The mixture was filtered over a Buchner funnel and washed with 4 mL of water. The resulting solid containing water was dried in a vacuum oven (~200 mbar, 55 to 60°C for 16 hours under nitrogen purging). This yielded a white powder (3.60 g, 80.2%), which was analyzed to be 99.09 wt.%.

[0111] Example 14: Sufentanyl citrate - aqueous method 2 In reactor 1, anhydride citrate (10.46 g, 54.44 mmol, 2.81 equivalents) was dissolved in deionized water (53 mL). Sufentanyl base (7.50 g, 19.40 mmol) was added, and the reaction was heated under a nitrogen atmosphere until all solids were dissolved (75°C to 80°C), and then filtered. The filter was rinsed with deionized water (7.0 mL). The reaction was stirred and cooled to room temperature (approximately 23°C). The system was heated to 76.9°C to redissolve the solids. The temperature was then lowered to 42 to 44°C, resulting in a thick slurry of crystalline sufentanyl citrate, which became turbid within 1.2 hours and appeared within 1.8 hours. Under these conditions, no stickiness or viscosity was observed. This sufentanil citrate / water slurry was cooled and maintained at approximately 14°C.

[0112] In reactor 2, anhydride citrate (21.37 g, 111.2 mmol, 1.01 equivalents) was dissolved in deionized water (350 mL). Sufentanyl base (42.52 g, 110.0 mmol) was added, and the mixture was placed under a nitrogen atmosphere, heated, and stirred until the solid dissolved (95°C to 98°C), and then filtered. 50 mL of deionized water was added to the batch to rinse the filter. This warm sufentanyl citrate solution (contents of reactor 2) was added to the cold sufentanyl citrate aqueous slurry (reactor 1) over approximately 1 hour with vigorous stirring, and the temperature was maintained between 17.5°C and 18.5°C. After this addition was complete, the reaction mixture was stirred at room temperature overnight and then cooled to 2.7°C over 1 hour. The sufentanyl citrate was recovered by filtration, washed with cold deionized water (50 mL), air-dried for 16 hours, and then dried in a vacuum oven (100-200 mbar, 56-62°C under nitrogen purging) for 16 hours. This procedure yielded a white powder (66.19 g, 88.4%) of sufentanyl citrate. This mother liquor was retained in preparation for the recovery of the sufentanyl base.

[0113] Example 15: Sufentanyl base (from the mother liquor of sufentanyl citrate) A combination of the mother liquor and water-containing cake-like washing product obtained from the preparation of sufentanyl citrate (Example 12, approximately 460 mL) was adjusted to a pH of 2.83, gradually increasing to 5.03 and then to 6.04 with a 50% w / w aqueous sodium hydroxide solution. After approximately 0.5 hours, the solution began to become turbid, and the pH was adjusted to 7.37 and then to 12.11 using a diluted solution of base (15% w / w). This suspension was cooled to 2.6°C over an ice bath in approximately 1 hour, and the sufentanyl base was recovered by filtration. The sufentanyl base was air-dried for 16 hours and then dried in a vacuum oven (100-200 mbar, 56-62°C with nitrogen purging) for 16 hours. This procedure yielded a white powder of recovered sufentanyl base (4.97 g, 9.9%, based on the 50.02 g total sufentanyl base used in Example 12).

[0114] Example 16: Sufentanyl base (from sufentanyl citrate) Sufentanyl citrate (65.40 g, 113.0 mmol) was mixed with ethanol (128 mL) and deionized water (200 mL) and then heated until dissolved (approximately 35°C). The pH of this solution was adjusted to >12.5 by adding 50% w / w aqueous sodium hydroxide solution and then cooled to <5°C on an ice bath. The product was filtered and washed with cold deionized water (approximately 20 mL). This crude sufentanyl base was air-dried, any residual water was removed using a Dean-Stark trap, and then dissolved in n-heptane (146 mL) at approximately 75°C. This warm n-heptane solution was passed through a filter bed of decolorized carbon (Darco®, 2.00 g) supported on bleached diatomaceous earth (Celite®, 2.00 g) and cooled to room temperature, followed by cooling to 0-5°C. The sufentanyl base was obtained by filtering the white prismatic substance through a Buchner funnel and subsequently washing with 2 mL of cold (<5°C) n-heptane. After air drying, the sufentanyl base was a white needle-shaped substance (43.46 g, 99.5%). This product was analyzed to be typically 100.40 wt.%. For example, the present invention provides the following items: (Item 1) A process for forming sufentanyl citrate from a sufentanyl base, the process comprising: (a) contacting a sufentanyl base with a polar non-aqueous solvent to form a mixture in which the volume-to-mass ratio of the polar non-aqueous solvent to the sufentanyl base is about 2:1 to about 12:1; and (b) contacting the mixture with citric acid to form a mixture of sufentanyl citrate that does not contain an oil phase. (Item 2) The process according to item 1, wherein the polar non-aqueous solvent is ethyl acetate, isopropyl acetate, methyl isobutyl ketone, methyl ethyl ketone, and C1-C5 alcohols, the molar ratio of citric acid to sufentanyl base is about 0.9:1 to about 1.5:1, and steps (a) and (b) are carried out at a temperature of about 20°C to about 90°C. (Item 3) The process according to either item 1 or item 2, wherein the polar non-aqueous solvent is isopropyl alcohol, and the volume-to-mass ratio of the polar non-aqueous solvent to the sufentanyl base is about 4:1 to about 8:1. (Item 4) The process according to any one of items 1 to 3, further comprising (c) cooling the mixture of sufentanyl citrate from step (b), and optionally seeding sufentanyl citrate crystals into the mixture of sufentanyl citrate to form solid sufentanyl citrate, and (d) recovering the solid sufentanyl citrate. (Item 5) The process according to item 4, wherein the solid sufentanyl citrate recovered in step (d) is contained in the polar non-aqueous solvent at a concentration of less than approximately 5000 ppm. (Item 6) A process for forming sufentanyl citrate from a sufentanyl base, the process comprising: (a) forming a mixture of citric acid and water in which the volume-to-mass ratio of water to citric acid is about 2:1 to about 12:1; and (b) adding a sufentanyl base to the mixture to form a sufentanyl citrate mixture in which the molar ratio of citric acid to sufentanyl base is about 2:1 to about 5:1. (Item 7) The process described in item 6, wherein step (b) is carried out at a temperature of 85°C or lower. (Item 8) The process according to either item 6 or 7, further comprising cooling the mixture from step (b) to form a solid sufentanyl citrate and recovering the solid sufentanyl citrate. (Item 9) The process according to either item 6 or item 7, wherein the process further comprises (c) cooling the mixture from step (b), (d) forming a mixture of citric acid and water with a volume-to-mass ratio of water to citric acid of about 10:1 to about 22:1, (e) adding the mixture from step (d) to the mixture from step (d) with a molar ratio of citric acid to sufentanyl base of about 65% to about 96% in total, to form a sufentanyl citrate with a molar ratio of citric acid to sufentanyl base of about 0.5:1 to about 2:1, (f) adding the mixture from step (e) to the mixture from step (c), (g) cooling the mixture from step (f) to form a solid sufentanyl citrate, and (h) recovering the solid sufentanyl citrate. (Item 10) The process according to item 9, wherein step (b) is carried out at a temperature of 90°C or less, step (e) is carried out at at least about 90°C, and step (f) is carried out over a period of about 45 minutes to about 3 hours. (Item 11) The process according to item 9, wherein 15% of the sufentanyl base in total is added during step (b), and 85% of the sufentanyl base in total is added during step (e). (Item 12) The process according to either item 4 or 9, further comprising: (i) contacting the mixture remaining after the recovery of the solid sufentanyl citrate with a proton acceptor such as a hydroxide salt to form a mixture of sufentanyl bases; (ii) cooling the mixture of sufentanyl bases to form a solid sufentanyl base; and (iii) recovering the solid sufentanyl base. (Item 13) The process according to item 12, further comprising contacting a solid sufentanyl base with a nonpolar solvent such as an alkane to form a crystalline sufentanyl base. (Item 14) A process for forming a sufentanyl base from sufentanyl citrate, the process comprising: (a) contacting sufentanyl citrate with at least one polar solvent to form a mixture; (b) contacting the mixture with a proton acceptor to form a mixture of sufentanyl bases; (c) cooling the mixture of sufentanyl bases to form a solid sufentanyl base; and (d) recovering the solid sufentanyl base. (Item 15) The process according to item 14, wherein at least one of the polar solvents is ethyl acetate, isopropyl acetate, methyl isobutyl ketone, methyl ethyl ketone, C1-C5 alcohol, or water, the volume-to-mass ratio of the polar solvent to sufentanyl citrate is about 1:1 to about 25:1, and the proton acceptor comprises a hydroxide. (Item 16) The process according to either item 14 or 15, further comprising contacting a solid sufentanyl base with a nonpolar solvent such as an alkane to form a crystalline sufentanyl base.

Claims

1. A process for preparing a solid sufentanyl citrate, wherein the process comprises: (a) Forming a mixture of citric acid and water at a temperature of 20°C to 100°C; (b) Adding a sufentanyl base to the mixture formed in step (a), wherein the molar ratio of citric acid to sufentanyl base is 2.0:1 to 5.0:1; (c) Cooling the mixture from step (b) to a temperature in the range of -20°C to 60°C; and (d) Recovering the solid sufentanyl citrate from the mixture from step (c). A process that encompasses all of these.

2. The process according to claim 1, wherein the volume-to-mass ratio of water to citric acid in the mixture of step (a) is 2:1 to 12:

1.

3. The process according to claim 2, wherein the volume-to-mass ratio of water to citric acid in the mixture of step (a) is 5:1 to 9:

1.

4. The process according to claim 3, wherein the volume-to-mass ratio of water to citric acid in the mixture of step (a) is 7:

1.

5. The process according to claim 1, wherein the temperature in step (a) is 20°C to 40°C.

6. The process according to claim 5, wherein the temperature in step (a) is 20°C to 30°C.

7. The process according to claim 1, wherein step (a) includes contacting the citric acid with the water for a period of 1 to 60 minutes.

8. The process according to claim 1, wherein the mixture formed in step (a) does not contain any insoluble chemical species.

9. The process according to claim 1, wherein step (a) further comprises filtering the mixture formed in step (a) to remove insoluble impurities.

10. The process according to claim 1, wherein the molar ratio of citrate to sufentanyl base is 2.0:1 to 3.0:

1.

11. The process according to claim 1, wherein step (b) is carried out at a temperature of 20°C to 85°C.

12. The process according to claim 11, wherein step (b) is carried out at a temperature of 60°C to 85°C.

13. The process according to claim 1, wherein step (b) comprises contacting the sufentanyl base and the citric acid for a period of 0.5 to 24 hours.

14. The process according to claim 1, wherein the mixture formed in step (b) does not contain an oil phase containing sufentanyls.

15. The process according to claim 1, further comprising step (b) filtering the mixture formed in step (b) to remove insoluble impurities.

16. The process according to claim 1, wherein step (c) comprises cooling the mixture from step (b) to a temperature in the range of 0°C to 5°C.

17. The process according to claim 1, wherein step (c) comprises maintaining the mixture at the cooled temperature for a period of 0.5 to 24 hours.

18. The process according to claim 1, wherein step (d) is carried out at a temperature of -20°C to 60°C.

19. The process according to claim 18, wherein step (d) is carried out at a temperature of 0°C to 25°C.

20. (e) The process according to claim 1, further comprising drying the solid sufentanyl citrate.

21. The process according to claim 20, wherein the drying is carried out by vacuum filtration, oven drying, or vacuum depressurization.

22. The process according to claim 20, wherein the drying is carried out at a temperature of 35°C to 65°C.