Manufacturing process for cyclodextrin derivatives

Abstract

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 - 32 . (canceled) 
     
     
         33 . A process for preparing a derivatized cyclodextrin, the process comprising: reacting a cyclodextrin starting material, a substituent precursor, and an optional catalyst to provide a raw product comprising a derivatized cyclodextrin,
 wherein the raw product comprises 1% or less of an initial amount of the substituent precursor;   wherein the reacting is performed in a continuous or semi-continuous manner comprising:   providing a feedstock comprising a liquid or gas medium, the cyclodextrin starting material, the substituent precursor, and the optional catalyst, and   continuously or semi-continuously flowing the feedstock into a reactor and flowing out of the reactor the raw product comprising a derivatized cyclodextrin; wherein the cyclodextrin starting material comprises an unsubstituted cyclodextrin selected from the group consisting of: an α-cyclodextrin, a β-cyclodextrin, a γ-cyclodextrin, and combinations thereof.   
     
     
         34 . The process of  claim 33 , wherein the process does not include after the reacting, adding a reagent to the raw product in order to degrade the substituent precursor. 
     
     
         35 . The process of  claim 33 , wherein the substituent precursor and the cyclodextrin starting material are present in a molar ratio of 1:1 to 50:1. 
     
     
         36 . The process of  claim 33 , wherein the substituent precursor is selected from the group consisting of: a sulfoalkylating agent, an alkylating agent, a hydroxyalkylating agent, and combinations thereof. 
     
     
         37 . The process of  claim 33 , wherein the substituent precursor is selected from the group consisting of: butane sultone, diethyl sulfate, and combinations thereof. 
     
     
         38 . The process of  claim 33 , wherein the optional catalyst is selected from the group consisting of: an alkalinizing agent, an acidifying agent, a phase transfer agent, an enzyme, a transition metal compound, and combinations thereof. 
     
     
         39 . The process of  claim 33 , further comprising pre-heating at least one of the cyclodextrin starting material, the substituent precursor, or a combination thereof. 
     
     
         40 . The process of  claim 33 , wherein the providing comprises a process selected from the group consisting of:
 (i) mixing the cyclodextrin starting material with the optional catalyst to form a mixture, and mixing portions of the mixture with portions of the substituent precursor to form the feedstock;   (ii) mixing the cyclodextrin starting material with the substituent precursor to form a mixture, and mixing portions of the mixture with portions of the optional catalyst to form the feedstock;   (iii) mixing the optional catalyst with the substituent precursor to form a mixture, and mixing the mixture with portions of the cyclodextrin starting material to form the feedstock; and   (iv) mixing portions of the cyclodextrin starting material, the substituent precursor, and the optional catalyst substantially simultaneously to form the feedstock.   
     
     
         41 . The process of  claim 40 , wherein the mixing comprises flowing any of the mixtures through a flow-through mixer. 
     
     
         42 . The process of  claim 40 , wherein the feedstock has a residence time in the reactor of 0.5 seconds to 4 hours. 
     
     
         43 . The process of  claim 40 , wherein the feedstock has a residence time in the reactor of 0.5 sec to 30 minutes, and the reactor temperature is 70° C. to 200° C. 
     
     
         44 . The process of  claim 40 , wherein the feedstock has a pH of 9 to 14, the feedstock has a residence time in the reactor of 0.5 sec to 20 minutes, and the temperature of the reactor is 90° C. to 160° C. 
     
     
         45 . The process of  claim 33 , further comprising separating the derivatized cyclodextrin from the raw product, wherein the separating includes at least one of filtering, centrifuging, decanting, or a combination thereof. 
     
     
         46 . The process of  claim 33 , further comprising isolating the derivatized cyclodextrin, wherein the isolating includes at least one of drying, sterile filtering, concentrating, and combinations thereof. 
     
     
         47 . The process of  claim 33 , further comprising purifying the derivatized 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. 
     
     
         48 . The process of  claim 33 , wherein the derivatized cyclodextrin is present in the raw product in a yield of 70% or higher based upon the amount of the cyclodextrin starting material. 
     
     
         49 . The process of  claim 33 , wherein a molar ratio of the substituent precursor to the cyclodextrin starting material of 3:1 to 18:1 provides a derivatized cyclodextrin having an average degree of substitution of 2 to 12; or wherein a molar ratio of the substituent precursor to the cyclodextrin starting material of 1:1 to 5:1 provides a derivatized cyclodextrin having an average degree of substitution of 4 or less; or wherein a molar ratio of the substituent precursor to the cyclodextrin starting material of 5:1 to 14:1 provides a derivatized cyclodextrin having an average degree of substitution of 3 to 7. 
     
     
         50 . The process of  claim 33 , wherein the derivatized cyclodextrin includes a substituent selected from the group consisting of: a sulfoalkyl ether group, an ether group, an alkyl ether group, an alkenyl ether group, a hydroxyalkyl ether group, a hydroxyalkenyl ether group, a thioalkyl ether group, an aminoalkyl ether group, a mercapto group, an amino group, an alkylamino group, a carboxyl group, an ester group, a nitro group, a halo group, an aldehyde group, a 2,3-epoxypropyl group, and combinations thereof. 
     
     
         51 . A process for preparing a derivatized cyclodextrin, the process comprising:
 combining in a liquid or gas medium a cyclodextrin starting material, a sulfoalkylating agent present in a molar excess relative to the cyclodextrin starting material, and an alkalinizing agent present in a molar excess relative to the one or more sulfoalkylating agents to form a feedstock; and   reacting the feedstock by continuously or semi-continuously flowing the feedstock into and out of a reactor for a residence time of 0.5 sec to 4 hours, at a temperature of 30° C. to 200° C., and at a pressure of 1 bar or higher to form a raw product comprising the derivatized cyclodextrin.   
     
     
         52 . A product prepared by the process of  claim 33 .