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JP-7857352-B2 - Preparation of sufentanyl citrate and sufentanyl base

JP7857352B2JP 7857352 B2JP7857352 B2JP 7857352B2JP-7857352-B2

Inventors

  • ジョージ ヘルムート クレム
  • ブライアン オーアー
  • ジョエル マクレナガン

Assignees

  • マリンクロッド エルエルシー

Dates

Publication Date
20260512
Application Date
20240718
Priority Date
20150527

Claims (14)

  1. A process for preparing solid sufentanyl citrate, wherein the process comprises: (a) Forming a first mixture of sufentanyl citrate by heating a first portion of sufentanyl base together with citric acid in water, wherein the molar ratio of citric acid to sufentanyl base is 2.5:1 to 4.0:1, the first portion of sufentanyl base constitutes 10% to 20% of the total amount of sufentanyl base , and the heating is performed to a temperature in the range of 70°C to 85°C ; (b) Cooling the first mixture of sufentanyl citrate , wherein the cooling is performed to a temperature within the range of 23°C or lower ; (c) Forming a second mixture of sufentanyl citrate by heating the second portion of sufentanyl base together with citric acid in water, wherein the molar ratio of citric acid to sufentanyl base is 0.9:1 to 1.1:1, the second portion of sufentanyl base constitutes 80% to 90% of the total amount of sufentanyl base , and the heating is performed to a temperature in the range of 90°C to 100°C ; (d) Adding the second mixture of sufentanyl citrate to the first mixture of sufentanyl citrate without cooling to form a combined mixture; A process comprising (e) cooling the combined mixture to a temperature in the range of 0°C to 5°C to form a solid sufentanyl citrate; and (f) recovering the solid sufentanyl citrate.
  2. The process according to claim 1, wherein the molar ratio of citrate to sufentanyl base in (a) is 2.8:1.
  3. The process according to claim 1 , further comprising maintaining the temperature of the first mixture of sufentanyl citrate until (d).
  4. The process according to claim 1, wherein the molar ratio of citrate to sufentanyl base in (c) is 1:1.
  5. The process according to claim 1, wherein the addition of (d) is carried out over an extended period of time so that the combined mixture maintains a temperature in the range of 10°C to 23°C.
  6. The process according to claim 5 , wherein the extended period is 0.5 hours to 4 hours.
  7. The process according to claim 1, wherein the recovery in (f) includes filtration.
  8. The process according to claim 1, further comprising drying the solid sufentanyl citrate.
  9. The process according to claim 1, wherein the first portion of the sufentanyl base constitutes 15% of the total amount of the sufentanyl base, and the second portion of the sufentanyl base constitutes 85% of the total amount of the sufentanyl base.
  10. The process according to claim 1, wherein, before forming the first mixture of sufentanyl citrate, a first solution of citric acid is formed by mixing 4 mL to 6 mL of water per gram of citric acid.
  11. The process according to claim 1, wherein a second solution of citric acid is formed by mixing 12 mL to 20 mL of water per gram of citric acid before forming the second mixture of sufentanyl citrate.
  12. The process according to claim 1, (g) Contacting the mixture remaining after the recovery of the solid sufentanyl citrate with a proton acceptor to form a mixture of sufentanyl bases; (h) cooling the mixture of sufentanyl bases to form a solid sufentanyl base, and (i) recovering the solid sufentanyl base.
  13. The process according to claim 12 , further comprising contacting a solid sufentanyl base with a nonpolar solvent to form a crystalline sufentanyl base.
  14. The process according to claim 13 , wherein the proton acceptor comprises a hydroxide and the nonpolar solvent is an alkane.

Description

This invention generally relates to the preparation of sufentanyl salts and free bases. Sufentanil is a member of a series of potent fentanyl analogs. It exhibits high selectivity and affinity (approximately 10 times higher than fentanyl) for the "mu" opioate receptor. Compared to fentanyl, sufentanil's pharmacokinetic profile shows a smaller volume distribution, resulting in an intermediate with a terminal phase half-life between alfentanil and fentanyl. Furthermore, sufentanil does not cause histamine release like fentanyl. 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. 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 (e.g., 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 to address the latter problem. 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. This process includes (a) contacting a sufentanyl base with a polar non-aqueous solvent to form a mixture characterized by a volume-to-mass ratio of the polar non-aqueous solvent to the sufentanyl base being approximately 2:1 to approximately 12:1, and (b) contacting the mixture with citric acid to form a mixture of sufentanyl citrates characterized by the mixture containing no oil phase. Other aspects of this disclosure provide a process for forming sufentanyl citrate from a sufentanyl base in the presence of water. This process includes (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, characterized in that the molar ratio of citric acid to sufentanyl base is about 2:1 to about 5. Further aspects of this disclosure provide a process for forming sufentanyl bases from sufentanyl citrate. This 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 solid sufentanyl bases; and (d) recovering the solid sufentanyl bases. Other features and repeating forms of the present invention are described in more detail below. 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 hardened 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. This disc