Recently, a new patent application became accessible to the public, WO2018146698 (A1), filed by Biophore India, a DMF holder for the production of Betadex Sulfobutyl Ether Sodium (SBECD, Dexolve, Captisol). Obviously, this application claims to invent an improved method for the preparation of this remarkable excipient. But impoved how? Let’s see. The claims are the following, with some strictly personal observations:
1. A process for preparing sulfobutylether beta-cyclodextrin sodium of formula (I)
the said process comprising the steps of:
a) treating beta-cyclodextrin with an aqueous base to form activated beta- cyclodextrin; – nothing new here
b) reacting the activated cyclodextrin with an appropriate quantity of 1,4-butane sultone; – same as always
c) adjusting pH of the reaction mass to 6-6.5 using aqueous hydrochloric acid – this is interesting since the USP NF has a limit for residual chloride content, although indeed they are not claiming USP compliance
and removing coloured impurities by the process comprising treatment with neutral charcoal, stirring and filtering the reaction mass under vacuum through Hyflo at 25-30 °C; – quite common approach
d) removing the unreacted 1,4-butane sultone by a process comprising washing the reaction mass with an organic solvent and separating the aqueous and organic layers followed by ultrafiltration by employing 1.0 KD membrane; – I assume this should be the invention, since this is not used by others, although does not seem either practical, or safe to intentionally add an organic solvent to the process
e) treating the retentate with neutral charcoal and again passing through ultrafiltration using 10 KD membrane system to eliminate bacterial endotoxins; and – common technology again
f) the aqueous solution of sulfobutylether beta cyclodextrin sodium was freeze dried by lyophilization to produce sulfobutylether beta cyclodextrin sodium (I); wherein the characteristics of sulfobutylether beta cyclodextrin sodium (I) obtained comprises of:
a. UV absorbance in the range of 245 nm to 270 nm and 320 nm to 350 nm at 500 mg/mL concentration is greater than 0.5 A. U, b. UV absorbance in the range of 245 nm to 270 nm and 320 nm to 350 nm at 300 mg/mL concentration is greater than 1.0 A. U, so the obtained product was purified from colored impurities (see 1/c), but not too much, in order not to infringe Cydex patents. I wonder what was left within and how is this controlled.
c. Bulk density greater than 0.67 g/cm , – to circumvent Ligand patent, not really inventive
d. Tap density greater than 0.76 g/cm , – to circumvent Ligand patent, not really inventive
e. 1,4-butane sultone content less than 0.5 ppm or – this is a USP requirement, not an achievement
f. having BET (Bacterial endotoxins) less than 10 IU/g. – if one knows the process and material understand that this is not inventive either
2. The process as claimed in claim 1, wherein the aqueous base used in step a) is selected from sodium hydroxide or sodium bicarbonate. – good idea to add carbonate, surely it will not be incompatible with any API or formulation components.
3. The process as claimed in claim 1, wherein the 1, 4-butane sultone quantity used in step b) is in between 7-9.5 equivalents. – this should be trivial to achieve the proper degree of substitution
4. The process as claimed in claim 1, wherein organic solvent used in step d) is selected from the group comprising of dichloromethane, ethyl acetate, methylene chloride, diethyl ether or methyl tert-butyl ether. – nice solvents to inject (!)
5. The process as claimed in claim 1, wherein the sulfobutylether beta cyclodextrin sodium (I) comprises less than 0.5% (w/w) of unreacted beta cyclodextrin. – USP requirement is 0.1%, so this is not too good.
6. The process as claimed in claim 1 , wherein the sulfobutylether beta cyclodextrin sodium (I) has average degree of substitution of 6.2 to 6.9. – USP requirement, nothing new.
7. A process for preparing sulfobutylether beta cyclodextrin sodium of formula (I) having bacterial endotoxins less than 10 IU/g, the said process comprising the steps of: a) purifying crude aqueous sulfobutylether beta cyclodextrin sodium by ultrafiltration using 700 Dalton to 1.0 KD membrane; b) concentrating the aqueous layer to 15-30% of (w/v) by vacuum distillation; c) passing the concentrated aqueous sulfobutylether beta cyclodextrin sodium through 10 KD membrane in ultrafiltration; and d) lyophilization of aqueous sulfobutylether beta cyclodextrin sodium (I) obtained in step (c) to obtain sulfobutylether beta cyclodextrin sodium (I) having bacterial endotoxins less than 10 IU/g. – as above
8. The process as claimed in Claim 1, wherein the sulfobutylether beta cyclodextrin sodium is obtained is an amorphous powder. – it cannot be anything else
Novel? Inventive? Industrially feasible? You can decide for yourself.