Manufacturing process for cyclodextrin derivatives
A process and equipment assembly for reacting a substituent precursor with a cyclodextrin starting material to provide a raw product comprising a cyclodextrin derivative and 1% or less of an initial amount of the substituent precursor is provided. The process of the present invention provides cyclodextrin derivatives in substantially shorter time and with fewer side products than previous processes that utilize substantially the same starting materials.
1. A process for preparing a sulfoalkylether β-cyclodextrin, the process comprising: mixing a 3-cyclodextrin starting material with an alkalinizing agent batch-wise in a first reservoir to form a first starting material supply;
providing an alkyl sultone in a second reservoir to form a second starting material supply; and
combining and continuously or semi-continuously flowing the first and second starting material supplies through a flow-through reactor to form a raw product comprising the sulfoalkylether β-cyclodextrin; and
wherein the first starting material supply and the second starting material supply have a residence time in the flow-through reactor of 0.5 seconds to 4 hours.
2. The process of claim 1 , wherein the raw product comprises 1% or less of an initial amount of the alkyl sultone.
3. The process of claim 1 , wherein the process does not include adding a reagent to the raw product in order to degrade the alkyl sultone.
4. The process of claim 1 , wherein the alkyl sultone and the β-cyclodextrin starting material are present in a molar ratio of 1:1 to 50:1.
5. The process of claim 4 , wherein the alkyl sultone and the β-cyclodextrin starting material are present in a molar ratio of 1:1 to 40:1.
6. The process of claim 4 , wherein the alkyl sultone and the β-cyclodextrin starting material are present in a molar ratio of 3:1 to 18:1.
7. The process of claim 4 , wherein the alkyl sultone and the β-cyclodextrin starting material are present in a molar ratio of 6:1 to 12:1.
8. The process of claim 1 , wherein the alkyl sultone is butane sultone.
9. The process of claim 1 , wherein the alkalinizing agent and the β-cyclodextrin starting material are present in a molar ratio of 1:1 to 22:1.
10. The process of claim 9 , wherein the alkalinizing agent and the β-cyclodextrin starting material are present in a molar ratio of 4:1 to 7:1.
11. The process of claim 9 , wherein the alkalinizing agent and the β-cyclodextrin starting material are present in a molar ratio of 7:1 to 10:1.
12. The process of claim 9 , wherein the alkalinizing agent and the β-cyclodextrin starting material are present in a molar ratio of 10:1 to 12:1.
13. The process of claim 9 , wherein the alkalinizing agent and the β-cyclodextrin starting material are present in a molar ratio of 12:1 to 15:1.
14. The process of claim 1 , wherein the alkalinizing agent is a metal hydroxide.
15. The process of claim 14 , wherein the metal hydroxide is sodium hydroxide or potassium hydroxide.
16. The process of claim 1 , further comprising pre-heating the first starting material supply, the second starting material supply, or a combination thereof.
17. The process of claim 1 , wherein the temperature of the first reservoir is from 50° C. to 160° C.
18. The process of claim 17 , wherein the temperature of the first reservoir is from 60° C. to 160° C.
19. The process of claim 1 , wherein the first starting material supply and the second starting material supply are combined in a flow-through mixer.
20. The process of claim 1 , wherein the first starting material supply and the second starting material supply have a residence time in the flow-through reactor of 0.5 sec to 30 minutes.
21. The process of claim 1 , wherein the flow-through reactor temperature is 70° C. to 200° C.
22. The process of claim 21 , wherein the flow-through reactor temperature is 60° C. to 150° C.
23. The process of any of claim 1 , further comprising quenching any unreacted alkyl sultone present in the raw product.
24. The process of claim 1 , further comprising neutralizing the raw product.
25. The process of claim 1 , further comprising separating the sulfoalkylether β-cyclodextrin from the raw product, wherein the separating includes at least one of filtering, centrifuging, decanting, or a combination thereof.
26. The process of claim 1 , further comprising isolating the sulfoalkylether β-cyclodextrin, wherein the isolating includes at least one of drying, sterile filtering, concentrating, and combinations thereof.
27. The process of claim 1 , further comprising purifying the sulfoalkylether β-cyclodextrin, wherein the purifying includes at least one of extracting, diafiltrating, dialyzing, treating with a carbon medium, treating with an adsorption medium, treating with a color-removal medium, and combinations thereof.
28. The process of claim 1 , wherein the sulfoalkylether β-cyclodextrin is present in the raw product in a yield of 70% or higher based upon the amount of the β-cyclodextrin starting material.
29. The process of claim 1 , wherein the Average Degree of Substitution of the sulfoalkylether β-cyclodextrin is 3 to 7.
30. The process of claim 1 , wherein the Average Degree of Substitution of the sulfoalkylether β-cyclodextrin is 7 to 12.
31. A product prepared by the process of claim 1 .