DESC:
FIELD OF THE INVENTION
The present invention relates to an improved process for synthesis of sulphobutyl ether cyclodextrin (SBECD).

BACKGROUND OF THE INVENTION
SBECD is a class of polyanionic, hydrophilic water soluble cyclodextrin derivatives. The parent cyclodextrin can form an inclusion complex with certain active pharmaceutical ingredients (API) with the following advantages, the apparent increase in the aqueous solubility and stability of the API. However the disadvantage associated with the parent compound cyclodextrin are lower aqueous solubility and nephrotoxicity. It has been observed that derivatisation of cyclodextrin (and its variants and cyclodextrin) is beneficial in order to overcome the aforesaid drawbacks. Figure l illustrates the chemical reaction for the synthesis of SBECD from the reagents cyclodextrin (BCD) and 1, 4-butane sultone (BS).

WO 2015/008066 Al (Tammy et al, 2000) describes a flow synthesis of SBECD, the process being effectively divided into three main stages, i.e. initial reagent dissolution, reagent activation and a sulphoalkylation reaction. The reaction is then followed by downstream processing and purification, and ultimate isolation of the solid SBECD material. However, a problem associated with using a flow process described by Tammy et al is that the average degree of substitution reported is higher than that the current approved specification limits and also the flow system used cannot not be used for scale up. Embodiments describe a semi batch process and not completely continuous. Based on the concentration provided, maximum of 200 g/day can be produced with the system provided in the patent application.

Yi-Min Zhang in Tetrahedron 72 (2016) 3105-3112, reported synthesis of SBEBCD (Sulfonyl butyl ether ß cyclodextrin). However, the reported work is in small scale and is not a scalable model. Also, the reported average degree of substitution data does not match to the USP specification.

Therefore, there is a need to provide an improved process for preparing substituted cyclodextrins on a large scale, which meets the current specification limits and also meet the market demand with a small foot print. The present inventors have surprisingly developed an efficient process which ameliorates the aforesaid shortcomings of the prior art.

OBJECTS OF THE INVENTION
It is an object of the present invention to provide an improved process for preparing sulphobutyl ether cyclodextrin (SBECD).

It is another object of the present invention to provide a process for preparing sulphobutyl ether cyclodextrin (SBECD) on a large scale which meets the current specification limits and also meet the market demand with a small foot print.

It is another object of the present invention to provide an efficient process which uses lower amounts of reactants in the preparation of sulphobutyl ether cyclodextrin (SBECD).

It is yet another object of the present invention to provide sulphobutyl ether cyclodextrin (SBECD) having an average degree of substitution (ADS) ranging from 5.8 to 6.9 which meets the current specification limits.

SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided a continuous flow process for preparing sulphobutyl ether cyclodextrin (SBECD).
According to an aspect of the present invention, there is provided a continuous flow process for preparation of sulphoalkyl ether cyclodextrin which comprises the steps of:
(i) activation of cyclodextrin by mixing cyclodextrin is mixed with a base wherein the molar ratio of base to cyclodextrin is in range from 0.2:1 to 3:1; and
(ii) reaction of the activated cyclodextrin of step (i) with alkyl sultone, wherein the molar ratio of alkyl sultone to cyclodextrin ranges from 6.3:1 to 7.8:1.

In an aspect of the present invention there is provided that the process comprises alkyl sultone in step (ii) is provided in at least two lots at a varied temperature range wherein the temperature at first lot ranges from 70-80oC; and wherein the temperature at second lot ranges from 90-100oC.

According to an aspect of the present invention, there is provided the pressure in the reactor during step (ii) ranges from 0.5 bar to 10 bar.

According to another aspect of present invention, there is provided sulphobutyl ether cyclodextrin (SBECD) having an average degree of substitution (ADS) ranging from 5.8 to 6.9.

According to another aspect there is provided a pharmaceutical composition comprising the sulphoalkyl ether cyclodextrin compound having an average degree of substitution ranging from 5.8 to 6.9.

BRIEF DESCRIPTION OF THE DRAWINGS
The above and other aspects, features and advantages of certain exemplary embodiments of the present invention will be more apparent from the following description taken in conjunction with the accompanying drawings wherein:

Figure 1 illustrates the chemical reaction for the synthesis of sulphobutyl ether ß- cyclodextrin (SBECD) from ß-cyclodextrin (CD) and 1, 4-butane sultone (BS).

Figure 2 illustrates schematic representation of an apparatus for carrying out continuous flow (CF) synthesis for SBECD according to the present invention.

Figure 3 illustrates actual system for carrying out continuous flow (CF) synthesis for large scale production of SBECD according to the present invention.

Figure 4 illustrates IR spectra of the sample compound in Figure 4(a), IR spectrum of the standard in Figure 4(b) and comparable spectral data for both the sample compound and the standard in Figure 4(c).

Figure 5 illustrates HPLC chromatogram of the sample compound in Figure 5(a) and HPLC chromatogram of the standard in Figure 5(b).

Figure 6 illustrates NMR spectrum of the sample compound.

Figure 7 illustrates the graphical representation of the percentage concentration obtained in the sample compound in Figure 7(a); HPLC chromatograms of the sample compound solution in Figure 7(b), standard BCD compound (individual) in Figure 7(c)and mixture of standard BCD and standard SBECD in Figure 7(d).

Figure 8 illustrates the HPLC chromatograms of the sample compound showing the peak of 1,4-butane sultone and blank in Figure 8(a); peaks of blank in Figure 8(b); and peak of standard 1,4-butane sultone in Figure 8(c).

DETAILED DESCRIPTION OF THE INVENTION
The following description is provided to assist in a comprehensive understanding of exemplary embodiments of the invention. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary.
Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope of the invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness.

The terms and words used in the following description and claims are not limited to the bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustration purpose only and not for the purpose of limiting the scope of the invention as defined by the appended claims and their equivalents.

It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

Features that are described and/or illustrated with respect to one embodiment may be used in the same way or in a similar way in one or more other embodiments and/or in combination with or instead of the features of the other embodiments.

It should be emphasized that the term “comprises/comprising” when used in this specification is taken to specify the presence of stated features, steps or components but does not preclude the presence or addition of one or more other features, steps, components or groups thereof.

The present invention relates to derivatized sulphoalkyl ether cyclodextrin (SBECD) and a process for preparing the same.

In an embodiment of the present invention there is provided a process for preparing sulphoalkyl ether cyclodextrin. The present invention provides a continuous flow process for preparing sulphoalkyl ether cyclodextrin comprising the step of activation of cyclodextrin as in step (i).

In the step (i) of activation of cyclodextrin, the cyclodextrin is mixed with a base to form activated cyclodextrin, keeping the molar ratio of base to cyclodextrin in range from 0.2:1 to 0.3:1.

In a preferred embodiment, the molar ratio of base to cyclodextrin is 0.22:1.

In an embodiment, the base may be an alkali metal alkoxide like potassium hydroxide, lithium hydroxide, and sodium hydroxide. It is preferred that the base comprises of sodium hydroxide.

The present process allows control of average degree of substitution by varying the sodium hydroxide concentration with respect to the cyclodextrin.

The present invention uses less than 20% of the amount of base that is used in the prior art batch process and flow process. The base used in the process of activation of cyclodextrin hydroxyl groups, has a tendency to attack the alkyl sultone reagent, thereby reducing its effective concentration, and, as a result induces the decomposition of butyl sultone to form by-products.

The present invention provides that on activation of cyclodextrin, the brown colour of the reaction mass is changed into yellow colour.

In an embodiment of the present invention there is provided that the process for preparation of sulphoalkyl ether cyclodextrin further comprises a step (ii).

The present invention provides a process for preparation of sulphoalkyl ether cyclodextrin comprising step (ii), which is reaction of the activated cyclodextrin of step (i) with alkyl sultone to obtain sulphoalkyl ether cyclodextrin.

In an embodiment it is provided that in step (ii) the molar ratio of alkyl sultone to cyclodextrin ranges in step (ii) ranges from 6.3:1 to 7.8:1.

In a preferred embodiment the molar ratio of alkyl sultone to cyclodextrin is 7.6:1.

In an embodiment, the alkyl sultone may be any cyclic ester of alkyl sulphonic acid like 1, 4-butane sultone, 1, 3-propane sultone, 1, 4-butenesultone, 1, 3-propenesultone. The preferred sultone is 1, 4-butane sultone.

It is provided that if the molar ratio of reactants in the present process differs, then the final compound will not meet the required specification for peak distribution in average degree of substitution.

In an embodiment of the present invention there is provided a continuous flow process for preparing the sulphoalkyl ether cyclodextrin.

The present invention relates to a continuous flow process for preparing sulphoalkyl ether cyclodextrin comprising the steps of:
(i). Mixing cyclodextrin with a base to form activated cyclodextrin; and
(ii). Reacting the activated cyclodextrin of step (i) with alkyl sultone to obtain sulphoalkyl ether cyclodextrin, wherein the activation of cyclodextrin at step (i) is carried out in first flow reactor at a temperature ranging from 70-80 °C.

In an embodiment of the present invention there is provided that the reaction at step (ii) is performed in stirred tank reactor.

The present invention provides that the reaction at step (ii) is carried out in a first continuous stirred tank reactor at a temperature ranging from 70-80 °C followed by reaction in one or more continuous stirred tank reactors at a temperature ranging from 90-100 °C.

In an embodiment, the pressure at step (ii) ranges from 0.5 bar to 10 bar. Preferably, the pressure is 0.5 bar.

In an embodiment, the alkyl sultone at step (ii) is added in at least two lots.

In the first lot, the activated cyclodextrin is mixed with alkyl sultone in first continuous stirred tank reactor which is maintained at 70-80°C. The mixture of activated cyclodextrin and butyl sultone is continuously pumped to second continuous stirred tank reactor.

In the second lot, the alkyl sultone is pumped separately to the second continuous stirred tank reactor which enables lesser decomposition of butyl sultone and as well maintains the concentration of alkyl sultone. The temperature in the reactor is maintained at 90-100°C.

Maintaining a higher temperature for the second part of the step (ii) ensures the reaction is faster which increases the throughput and as well enables us to increase the average degree of substitution.

The sulphoalkyl ether cyclodextrin compound obtained by the process of present invention has an average degree of substitution ranging from 5.8 to 6.9.

In an embodiment, the present invention relates to a pharmaceutical composition comprising the sulphoalkyl ether cyclodextrin compound having an average degree of substitution ranging from 5.8 to 6.9.

In an embodiment of the present invention, the activation and sulphoalkylation reaction are carried out in the following steps:

Step 1: Activation of BCD - activation reaction is carried out inline by passing the solution of BCD and sodium hydroxide solution via a flow reaction kept at 75 °C.

Using this methodology, it was found that the colour of the reaction mass is yellow coloured as against brown colour if the activation is carried out in batch mode (described by Tammy et al).

Step 2: Activated BCD is mixed with butyl sultone (first lot) via a second flow reactor which is also maintained at 75°C. The mixture BCD and butyl sultone are continuously pumped to CSTR module 1.

Step 3: Second lot of butyl sultone is pumped separately to CSTR module 2 which enables lesser decomposition of butyl sultone and as well maintains the concentration of butyl sultone. Post the second lot addition of butyl sultone the reaction enters CSTR module 3 which is held at 95°C.

EXAMPLES:
Continuous flow (CF) synthesis for SBECD according to the present invention
Materials:
Beta cyclodextrin (BCD), 1,4-Butane sultone (BS), water and sodium hydroxide (NaOH).

Laboratory Equipment:
10 L Continuous stirred tank reactor (CSTR) vessel,3D printed flow reactors, tuthil and fuji pumps, Single fluid heating cooling system (Linea and Lauda chillers), ½ inchhaste alloy tubes for connections, Swagelok fittings, Nano filtration and spray drier.

Method:
The set-up for the continuous flow experiments consisted of three tuthil pumps and one fuji pump connected to a 3D printed flow reactors and 2 L CSTR jacketed continuous stirred tank reactor (CSTR).

The four pumps are connected as shown in the Figure 2 to the flow reactors via ½ inch haste alloy tubes. Each pump line had a pressure relief value and non-return valves were fitted in line in to prevent the reagent stream reverse flow as a result of differential flow pressure in either of the feed lines.

In a round bottom flask, a stock solution of BCD in water was first prepared as follows: 1 kg of BCD in 1.2 L of water and mixed with sodium hydroxide (0.31 kg, 8.79 eq.) this solution was pumped using pump 1 via a 3D printed reactor for activation.

The activated solution is then passed to a 2nd flow reactor wherein it comes in contact with butyl sultone pumped by (0.69 kg, 5.75 eq.) and then flows into to1stCSTR module. Pump 3 delivers second dose of butyl sultone (0.23 kg, 1.92 eq.) to 2nd CSTR module. The solution then passes through CSTR module 3, 4 and 5 which is maintained at 95°C to complete residence time required to get the required average degree of substitution. Figure 3 illustrates actual system for carrying out continuous flow (CF) synthesis for large scale production of SBECD according to the present invention.

Results: The compound obtained from the process is evaluated by using improved analytical methods like, IR, NMR, HPLC and qualitatively by using sodium test. The observations are further compared with the data of standard SBECD.

The sodium test was performed for 100.38mg of sample compound which is dissolved in 2ml water in a test tube followed by addition of 2ml of 15% potassium carbonate solution and heated to boil. No precipitate is formed. To the above solution 4ml of potassium pyroantimonate is added and heated to boil, cooled in ice water and rubbed the sides of test tube with a glass rod which results in formation of a dense precipitate is formed, which confirms the preparation of cyclodextrin compound.

Figure 4 (a) and figure 4 (b) represents the IR data of the compound obtained by the process of the present invention and the standard SBECD respectively. The IR spectrum of the compound is identical to the IR spectrum of the standard (Figure 4(c) and Figure 4(d)). Figure 5 (a) and figure 5(b) represents the HPLC chromatograms of the compound and standard respectively. The retention time of the compound was found to be 7.428, which is close to the retention time of the standard, 7.430. Figure 6 shows the NMR spectrum of the compound which also shows similar peak to the SBECD. The spectral data from Figure 4(a), Figure 5(a) and Figure 6 confirms the preparation of SBECD.

The compound so obtained by the continuous flow process is evaluated for average degree of substitution and compared with the average degree of substitution of the compound obtained by batch process. Specification of SBECD and results obtained from flow process batches is presented in below Table-1:

Test Specification
Batch Flow Flow Flow Flow
Average Degree of Substitution 6.2 – 6.9 6.3 6.3 6.3 6.3 6.3
Peak Distribution Peak I 0-0.3 0.0 0.0 0.0 0.0 0.0
Peak II 0-0.9 0.8 0.8 0.7 0.8 0.7
Peak III 0.5-5.0 4.7 3.2 3.1 04.1 3.1
Peak IV 2.0-10.0 8.8 8.7 8.3 8.8 8.3
Peak V 10.0-20.0 13.1 12.3 12.6 13.2 12.6
Peak VI 15.0-25.0 17.3 18.2 19.2 17.6 19.2
Peak VII 20.0-30.0 24.1 23.2 22.5 24.2 22.5
Peak VIII 10.0-25.0 20.8 18.9 19.5 22.5 19.5
Peak IX 2.0-12.0 11.1 10.9 10.3 10.5 10.3
Peak X 0-4.0 3.8 3.2 3.3 3.4 3.2
Table-1

Above table-1 represents the results for degree of substitution compared to batch manufacturing process. The sample obtained from flow process is comparable to the batch manufacturing process and is meeting the USP specification for SBECD. The above table represents the equivalency of the flow process to batch process and the consistency which can be achieved batch after batch in flow. The significant difference in the flow process is with respect to the degree of substitution which can be fixed at the start of the batch.

Flow process can synthesize compound from 5.8 to 6.9 by varying the flow parameters. As observed from the table summary, the present process can produce degree of substitution as per USP specification as well. The current USP35/NF30 specification limit for ADS of SBECD is 6.2-6.9.

The drawbacks of SBECD having ADS greater than 6.9 is that generally, the higher the degree of substitution, and therefore the amount of charge, the poorer the binding with the drug product.

Based on the above 4 batches profile in Table 1, the process was reproduced on 100 g scale. The obtained product data is meeting the required specifications. The released data has been shown below as Table-2.

Sl. No. Tests Results Specification Analytical data
1 Appearance Complies White or off white powder NA
2 Identification test
Identification A by FT-IR NA Figure 4(a)-4(d)
Identification B (Assay method) by HPLC Complies Retention time of the major peak of the sample solution corresponds to that of the standard solution, as obtained in assay Figure 5(a)-5(b)
Identification C
by Capillary electrophoresis NA Should meet the requirements of the test Average degree of substitution Each SBECD peak (I-X) meets the limit range (peak area %) as provided in Table 3
by NMR complies Should meet the requirements of Average degree of substitution Figure 6
Identification D complies Positive test for Sodium A dense white precipitate is formed
3 Assay (%w/w) on the anhydrous basis by HPLC 100.0 % 95.0. % -105.0 % Table 4
4 Limit of Beta Cyclodextrin (Betadex) (On anhydrous basis) 0.1 % Not more than 0.1 % Figure 7(a)-Figure 7(d)
5 Limit of 1,4-Butane Sultone by GC-MS 0.06 Not more than 0.5 ppm Figure 8(a-Figure 8(c)
6 Bacterial Endotoxin Test = 12 EU/g = 12 EU/g
7 Clarity of solution (30% w/v) Complies The solution is clear and essentially free from particles of foreign matter
8 Average Degree of Substitution by Capillary electrophoresis 6.5 6.2 - 6.9 Table 3
9 Average Degree of Substitution by NMR 6.0 5.9 – 6.6
10 Peak Distribution by Capillary Electrophoresis NA Each SBECD peak (I-X) meets the limit range (peak area %)
NA I (DS-1) 0-0.3 0.00
NA II (DS-2) 0-0.9 0.45
NA III (DS-3) 0.5-5.0 1.98
NA IV (DS-4) 2.0-10.0 5.31
NA V (DS-5) 10.0-20.0 11.77
NA VI (DS-6) 15.0-25.0 19.95
NA VII (DS-7) 20.0-30.0 24.92
NA VIII (DS-8) 10.0-25.0 21.94
NA IX (DS-9) 2.0 - 12.0 11.12
NA X (DS-10) 0-4.0 3.27
11 pH (30 % w/v in carbon dioxide free water) 5.99 4.3 - 6.5
12 Water Content 7.1% Not more than 7.5%
13 Bulk Density 0.34 g/mL Report Result
14 Residual Solvents content (ppm) by GC-HS
Ethanol 118 Not more than 1500 ppm
Table-2

The obtained compound is further evaluated for the average degree of substitution by using capillary electrophoresis. Table 3 shows the peak distribution of the compound, and the peak distribution shows the average degree of substitution of the compound is 6.5, which is within the permissible limit.

Table 3: Average degree of substitution with respect to peak distribution
Peak Name Peak Distribution Average Degree of Substitution
Peak I (DS-1) 0-0.3 0.00
Peak II (DS-2) 0-0.9 0.45
Peak III (DS-3): 0.5-5.0 1.98
Peak IV (DS-4) 2.0-10.0 5.31
Peak V (DS-5) 10.0-20.0 11.77
Peak VI (DS-6) 15.0-25.0 19.95
Peak VII (DS-7) 20.0-30.0 24.92
Peak VIII (DS-8) 10.0-25.0 21.94
Peak IX (DS-9) 2.0 - 12.0 11.12
Peak X (DS-10) 0-4.0 3.27

The obtained compound is further analyzed by determining the HPLC chromatogram peak area of the sample compound and is further compared with that of the standard. Table 4 represents HPLC chromatogram peak area for the sample compound (run in two trials) and standard (run in five trials). The average assay % anhydrous basis of the sample compound is found to be 100%.

Table 4: HPLC Chromatogram Peak area of the sample and standard.

Table-4

The compound is further analyzed for the presence of the reactants as in ß-cyclodextrin compound and alkyl sultone (1,4-butane sultone) in the final product. It was found that the obtained final product consists of 0.1% ß-cyclodextrin and 0.5 ppm of 1,4-butane sultone. Figure 7(a) shows the graphical representation of the percentage concentration obtained in the sample compound. Figure 7(b)-(d) shows the HPLC chromatograms of the sample compound solution, standard BCD compound (individual) and mixture of standard BCD and standard SBECD respectively. Figure 8(a)-8(c) shows the HPLC chromatograms of the sample compound showing the peak of 1,4-butane sultone and blank; peaks of blank; and peak of standard 1,4-butane sultone. Such low percentage and content of the reactants confirm the completion of the reaction, full utilization of the reactants and purity of the compound.

The 1.51547g of sample compound is further dissolved in 5mL of water, which resulted a clear solution showing and clarity of the solution and is essentially free from particles of foreign matter.

The present inventors have demonstrated the process for SBECD is completely under continuous flow process and it can be scale up to >50 kg/day which meets the current specification. Also a tighter ADS of 5.8 to 6.9 is obtained. The present process exhibits a specific average degree of substitution, for a lower input of base than that which is produced using the known batch process/flow process. The batch method of preparing substituted sulphoalkyl ether cyclodextrin produces a higher concentration of lower degrees of sulphoalkyl ether cyclodextrin substitution than that produced using continuous flow. Further, it has been observed that carrying out the process in lower temperature/molar ratio as compared to the present process results in reaction incompletion; whereas at higher temperature reagent degradation occurs.

ADVANTAGES OF THE INVENTION
• The continuous flow process described herein is a superior process compared to the prior art batch process and flow process, because it exhibits a greater reaction efficiency and results in a much tighter control of average degree of substitution of the resultant sulphoalkyl ether cyclodextrin.
• Uses less than 20% of the amount of base that is used in the prior art batch process and flow process. The process allows control of Average Degree of Substitution by varying the sodium hydroxide concentration. During this study and as per literature it was found that the base employed to chemically activate the cyclodextrin hydroxyl groups, has a tendency to attack the alkyl sultone reagent, thereby reducing its effective concentration, and, as a result induces the decomposition of butyl sultone to form by-products. As the amount of base used in the new process is the lowest reported so far, the decomposition of butyl sultone is minimum and results in a consistent ADS throughout the batches which provides SBECD with tighter ADS.
• Average degree of substitution is tighter (5.8 to 6.9) than prior art batch process and flow process (>7).
• The continuous flow process is more efficient with respect to average degree of substitution (ADS) owing to lesser decomposition of alkyl sultone by maintaining the concentration of cyclodextrin and alkyl sultone constant throughout the reaction. Alkyl sultone is added in lots to reaction mass to reduce the decomposition of butyl sultone to by-products and also to get consistent ADS. This enables the reaction to be carried out more efficiently with more efficient use of the starting materials and also less decomposition products from butyl sultone which needs tedious purification methods
• Scale up to >50 kg/day as compared to ~20 g/day obtained in prior art process (Tammy et.al)
• It will be possible to manufacture material compliant with the USP35/NF30 specification for sulphobutyl ether cyclodextrin. The process enables the production of sulphobutyl ether cyclodextrin on scale with a small manufacturing footprint.

It is to be understood that the present invention is susceptible to modifications, changes and adaptations by those skilled in the art. Such modifications, changes, adaptations are intended to be within the scope of the present invention.
,CLAIMS:1. A continuous flow process for preparation of sulphoalkyl ether cyclodextrin comprising the steps of:
(i) activation of cyclodextrin by mixing cyclodextrin with a base wherein the molar ratio of base to cyclodextrin is in range from 0.2:1 to 3:1; and
(ii) reaction of the activated cyclodextrin of step (i) with alkyl sultone, wherein the molar ratio of alkyl sultone to cyclodextrin ranges from 6.3:1 to 7.8:1.

2. The process as claimed in claim 1, wherein the temperature in step (i) ranges from 70-80 °C.

3. The process as claimed in claim 1, wherein the base is an alkali metal alkoxide.

4. The process as claimed in claim 3, wherein the alkali metal alkoxide is selected from the group of potassium hydroxide, lithium hydroxide, sodium hydroxide.

5. The process as claimed in claim 1, wherein the reaction in step (ii) alkyl sultone is provided in at least two lots at a varied temperature range wherein the temperature at first lot ranges from 70-80oC; and wherein the temperature at second lot ranges from 90-100oC.

6. The process as claimed in claim 1, wherein the alkyl sultone is cyclic ester of alkyl sulphonic acid.

7. The process as claimed in claim 6, wherein the alkyl sulphonic acid is selected from 1, 4-butane sultone, 1, 3-propane sultone, 1, 4-butenesultone, 1, 3-propenesultone.

8. The process as claimed in claim 1, wherein the pressure in the reactor during step (ii) ranges from 0.5 bar to 10 bar.

9. The process as claimed in any one of the preceding claims, wherein the obtained sulphoalkyl ether cyclodextrin compound comprises an average degree of substitution ranging from 5.8 to 6.9.

10. A sulphoalkyl ether cyclodextrin compound obtained by the process as claimed in any one of the claims 1 to 9 having an average degree of substitution ranging from 5.8 to 6.9.

11. A pharmaceutical composition comprising the sulphoalkyl ether cyclodextrin compound as claimed in claim 10.