CA3224856C

CA3224856C - Novel crystalline forms of sugammadex

Info

Publication number: CA3224856C
Application number: CA3224856A
Authority: CA
Inventors: Patrick LARPENT; Dirk STUEBER; Richard J. Varsolona
Original assignee: Werthenstein BioPharma GmbH; Merck Sharp and Dohme LLC
Current assignee: Werthenstein BioPharma GmbH; Merck Sharp and Dohme LLC
Priority date: 2020-09-09
Filing date: 2021-09-08
Publication date: 2024-05-07
Anticipated expiration: 2041-09-08
Also published as: CA3235932A1; CA3236101A1; WO2022055918A1; CA3234416A1; CA3224856A1

Abstract

The present disclosure provides a novel crystalline forms of sugammadex, designated herein as crystalline form Type 7 of sugammadex, crystalline form Type 10 of sugammadex, crystalline form Type 12 of sugammadex, and crystalline form Type 13 of sugammadex, pharmaceutical compositions thereof, and methods for their use in the reversal of neuromuscular blockade induced by rocuronium bromide or by vecuronium bromide in adults undergoing surgery.

Description

TITLE OF THE INVENTION
NOVEL CRYSTALLINE FORMS OF SUGAMMADEX
FIELD OF THE INVENTION
The present disclosure provides novel crystalline forms of sugammadex, designated herein as crystalline form Type 7 of sugammadex, crystalline form Type 10 of sugammadex, crystalline foini Type 12 of sugammadex, and crystalline form Type 13 of sugammadex, pharmaceutical compositions thereof, and methods for their use in the reversal of neuromuscular blockade induced by recuronium bromide and yecuronium bromide in adults undergoing surgery BACKGROUND OF THE INVENTION
Sugammadex is a modified cyclodextrin haying the following structure:
NaO-Na0 Sce0.7ili 0 :Ho =
- (KSOH

H01) ok0 p NaeIC-5 ONa o 0(NICJI-b /-1 S
Na0 sugammadex Sugammadex was approved in 2008 by the EMEA and in 2015 by the USFDA (and elsewhere) for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery. It is administered intravenously by injection in the form of a sterile solution under the brand name BRIDION . Sugammadex is disclosed in W02001/040316, published June 7, 2001, together with a method for its synthesis. An improved synthesis of sugammadex is disclosed in PCT International Patent Application No.
W02019/236436, filed June 03, 2019. Other methods of producing sugammadex are also disclosed in the art. Once produced, the active ingredient is typically isolated as a wet cake and then dried under vacuum to obtain a powder meeting purity and residual solvent specifications.
The powder is then dissolved in water for injection, the pH adjusted, and the resulting solution is filtered and filled into vials, sterilized and stored for use.

SUMMARY OF THE INVENTION
In one aspect, the present disclosure provides novel crystalline forms of sugammadex. In one embodiment, there is provided crystalline form type 7 of sugammadex. In another embodiment, there is provided crystalline form type 10 of sugammadex. In another embodiment, there is provided crystalline form type 12 of sugammadex. In another embodiment, there is provided crystalline form type 13 of sugammadex.
In another aspect, the present disclosure provides methods for the use of each of the aforementioned crystalline forms of sugammadex in the preparation of a medicament for use in the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery in accordance with its approved label.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph of a Powder X-Ray Diffraction ("PXRD") pattern of sugammadex Type 7 crystalline form, generated using the equipment and methods described herein. The graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 theta (20) in degrees.
FIG. 2 is a graph of a Powder X-Ray Diffraction ("PXRD") pattern of sugammadex Type 10 crystalline form, generated using the equipment and methods described herein. The graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 theta (20) in degrees.
FIG. 3 is a graph of a Powder X-Ray Diffraction ("PXRD") pattern of sugammadex Type 12 crystalline form, generated using the equipment and methods described herein. The graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 theta (20) in degrees.
FIG. 4 is a graph of a Powder X-Ray Diffraction ("PXRD") pattern of sugammadex Type 13 crystalline form, generated using the equipment and methods described herein. The graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 theta (20) in degrees.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof That notwithstanding and except where stated otherwise,

2 the following definitions apply throughout the specification and claims.
C means degrees Celsius FIG (or FIG. or Fig. or Fig or fig. or fig) means Figure (or figure) and refers to the corresponding figure g means gram (or grams) mL means milliliter (or milliliters) "PXRD" is an abbreviation for powder x-ray diffraction CRYSTALLINE FORMS OF SUGAMMADEX
The crystalline forms of sugammadex described herein may be prepared according to the procedures described below. For each procedure, starting quantities of sugammadex may be obtained from any suitable synthesis, including those described in PCT
Publication No.
W02001/040316, published June 07, 2001; W02019/236436, filed June 07, 2018 and U.S.
Provisional Application No. 62/737140, Attorney Docket No. 24604, filed September 27, 2018.
PXRD
As those of ordinary skill in the art readily appreciate, the physical characteristics of a crystal may be effectively characterized by powder x-ray diffraction (PXRD) analysis. Such characterizations may be used to distinguish such crystals from other crystals. For each of the crystalline forms of sugammadex described herein, PXRD analysis was completed on a wet cake sample since drying the material leads to significant loss of crystallinity and to form change.
PXRD data reported herein were acquired on a Bruker D8 Advance System configured in the Bragg-Brentano configuration and equipped with a Cu radiation source with monochromatization to Ka achieved using a nickel filter. A fixed slit optical configuration was employed for data acquisition. Data were acquired between 3 and 40 20 and a step size of 0.018 . Samples were prepared by gently pressing the samples onto a shallow cavity zero background silicon holder. Wet cake samples were covered with Kapton (polyimide film, DuPont, USA) foil in order to maintain the wet-sample-condition throughout data collection.
Those skilled in the art will recognize that the measurements of the PXRD peak locations for a given crystalline form of the same compound will vary within a margin of error. The margin of error for the 2-theta values measured as described herein is typically +/- 0.2 20.
Variability can depend on such factors as the system, methodology, sample, and conditions used

3 Date Recue/Date Received 2024-03-08 for measurement. As will also be appreciated by the skilled crystallographer, the intensities of the various peaks reported in the figures herein may vary due to a number of factors such as orientation effects of crystals in the x-ray beam, the purity of the material being analyzed, and/or the degree of crystallinity of the sample. The skilled crystallographer also will appreciate that measurements using a different wavelength will result in different shifts according to the Bragg-Brentano equation. Such further PXRD patterns generated by use of alternative wavelengths are considered to be alternative representations of the PXRD patterns of the crystalline material of the present disclosure and as such are within the scope of the present disclosure.
Preparative Example 1: Crystalline Form Type 1 of Sugammadex Crystalline form Type 1 of sugammadex was prepared as follows:
1 g of sugammadex was added to 10 mL of a methanol/water mixture with a 10:1 ratio by volume at 25 C and while applying magnetic stirring, resulting in a slurry.
The slurry was kept at ambient temperature while stirring for 20 hours. A wet cake sample was produced by centrifuging an aliquot of the slurry to a wet paste. PXRD analysis of the wet cake produced the Type 1 pattern.
Preparative Example 2: Crystalline Form Type 11 of Sugammadex Crystalline form Type 11 of sugammadex was prepared as follows:
30 g of Sugammadex was dissolved in 90 ml purified water and the solution filtered through a lab glass frit filter. The solution was transferred into a clean 1L
glass reactor equipped with an overhead stirrer. The solution was heated to 40 C while stirring at 200 rpm. 350 ml of Me0H was added linearly over 70 min at what stage primary nucleation of Type-1 was observed. The agitation was increased to 350 rpm and the batch seeded with Type 2 particles triggering turnover of the entire batch to Type 2 within minutes. 550 mL of Me0H were finally added linearly over 110 min. The batch was cooled to 23 C over 1 h and further aged 1 h. The freshly crystallized batch of Type-2 was filtered on a Rosenmund pocket filter and displace-washed with 6V of a 86:4:10 (v:v:v) Et0H:MeOH:Water mixture. The resulting cake was then dried under a dry Nitrogen flow at 50 C for a minimum of 18 hours (h). PXRD
analysis of the dried cake produced the Type 11 pattern.

Crystalline form Type 7 of sugammadex was prepared as follows:
500 mg of sugammadex Type-1 was added to 5 mL of a ethanol/water/methanol mixture

4 with a respective 86:10:4 ratio by volume at 25 C and while applying magnetic stirring, resulting in a slurry. The slurry was kept at ambient temperature while stirring for 12 hours. A wet cake sample was produced by centrifuging an aliquot of the slurry to a wet paste.
PXRD analysis of the wet cake produces the Type 7 pattern.
Physical characterization of crystalline form Type 7 of sugammadex:
A PXRD pattern of crystalline form Type 7 of sugammadex generated using the equipment and procedures described above is displayed in FIG. 1. Thus, in another aspect, there is provided a crystalline form Type 7 of sugammadex characterized by a powder x-ray diffraction pattern substantially as shown in FIG. 1.
The intensity of the peaks (y-axis is in counts per second) were plotted versus the 2 theta angle (x-axis is in degrees 2 theta). In addition, the data were plotted with detector counts normalized for the collection time per step versus the 2-theta angle. Peak locations (on the 2-theta x-axis) consistent with these profiles are displayed in Table 1 (+/- 0.2 2 theta). The locations of these PXRD peaks are characteristic of the crystalline form Type 7 of sugammadex.
.. Thus, in another aspect, crystalline form Type 7 of sugammadex is characterized by a powder x-ray diffraction pattern having each of the peak positions listed in Table 1, +/- 0.2 2-theta.
Table 1: Diffraction peaks and corresponding d-spacings for crystalline form Type 7 of sugammadex Position [ Two Diagnostic Peak Peak Number d-spacing [A] Rel. Int. [%]
Theta] Set 1 5.64 15.66 48.22 1 .
2 6.07 14.55 42.56 1 3 6.83 12.93 27.54 1 4 7.19 12.28 27.55 1

5 9.25 9.55 35.54 2

6 9.88 8.94 29.53 2

7 10.72 8.25 27.92 1

8 13.64 6.49 59.32 1

9 14.84 5.96 39.05 2

10 15.17 5.84 28.93 3

11 16.39 5.40 39.96 2

12 16.97 5.22 66.27 2

13 17.81 4.98 58.58 2

14 18.27 4.85 43.98 3

15 19.16 4.63 65.59 2

16 19.31 4.59 63.33 2

17 19.65 4.51 72.44 2

18 20.71 4.29 100.00 1

19 21.14 4.20 57.91 3 Position [ Two Diagnostic Peak Peak Number d-spacing [A] Rel. Int. [%]
Theta] Set

20 21.90 4.06 65.35 2

21 22.63 3.93 49.89 3

22 23.20 3.85 35.69 3 In a further aspect, the PXRD peak locations displayed in Table 1 and/or FIG.
1 most characteristic of crystalline form Type 7 of sugammadex can be selected and grouped as "diagnostic peak sets" to conveniently distinguish this crystalline form from others. Selections of such characteristic peaks are set out in Table 1 in the column labeled Diagnostic Peak Set.
Thus, in another aspect, there is provided a crystalline form Type 7 of sugammadex characterized by a powder x-ray diffraction pattern comprising each of the 2-theta values listed in Diagnostic Peak Set 1 in Table 1, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 7 of sugammadex characterized by a powder x-ray diffraction pattern comprising each of the 2-theta values listed in Diagnostic Peak Set 2 in Table 1, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 7 of sugammadex characterized by a powder x-ray diffraction pattern comprising each of the 2-theta values listed in Diagnostic Peak Set 3 in Table 1, +/- 0.2 2-theta.
A further aspect of the disclosure is realized and characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/- 0.2 ) of Diagnostic Peak Set 1 plus Set 2. A further aspect of the disclosure is realized and characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/-0.2 ) of Diagnostic Peak Set 1 plus Set 2 plus Set 3. Still another aspect of the disclosure is realized where there are at least 3 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 4 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 5 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 6 peaks of Diagnostic Peak Set 1.
Another aspect of the disclosure is realized where there are at least 7 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 3 peaks of Diagnostic Peak Set 1 and 2. Another aspect of the disclosure is realized where there are at least 3 peaks of Diagnostic Peak Set 1 and 2 and 1 of Set 3.

Crystalline form Type 10 of sugammadex was prepared as follows:
In a 1L glass reactor, 30 g of sugammadex were added to 90 mL of water at 25 C while applying overhead stirring at 200 rpm, resulting in a clear solution. Under continued overhead stirring at 200 rpm, the solution was heated to 40 C and then kept at these conditions for 10 min.
Subsequently, 450 mL of methanol were added at constant rate over two hours while overhead stiffing at 200 rpm. The batch was then aged for 6 days at 300 rpm overhead stirring, triggering crystallization of large particles. An additional 453 mL of Me0H were added linearly over 3h while overhead stirring. The freshly crystallized batch of Type 3 was filtered on a glass filter and displace-washed with 3V of a 86:4:10 Et0H:MeOH:Water mixture by volume. The resulting wet cake was then quickly transferred to a 100 mL reactor and slurry-washed in 3V
of a 86:4:10 Et0H:MeOH:Water by volume under overhead stirring (350 rpm, 23 C) for 8 days.
A wet cake sample was produced by centrifuging an aliquot of the slurry to a wet paste.
PXRD analysis of the wet cake produces the Type 10 pattern.
Physical characterization of crystalline form Type 10 of sugammadex:
A PXRD pattern of crystalline form Type 10 of sugammadex generated using the equipment and procedures described above is displayed in FIG. 2. Thus, in another aspect, there is provided a crystalline form Type 10 of sugammadex characterized by a powder x-ray diffraction pattern substantially as shown in FIG. 2.
The intensity of the peaks (y-axis is in counts per second) were plotted versus the 2-theta angle (x-axis is in degrees 2 theta). In addition, the data were plotted with detector counts normalized for the collection time per step versus the 2-theta angle. Peak locations (on the 2-theta x-axis) consistent with these profiles are displayed in Table 2 (+/- 0.2 2 theta). The locations of these PXRD peaks are characteristic of the crystalline form Type 10 of sugammadex. Thus, in another aspect, crystalline form Type 10 of sugammadex is characterized by a powder x-ray diffraction pattern having each of the peak positions listed in Table 2, +/- 0.2 2-theta.
Table 2: Diffraction peaks and corresponding d-spacings for crystalline form Type 10 of sugammadex Position [ Two Diagnostic Peak Peak Number d-spacing [A] Rel. Int. [NI
Theta] Set 1 3.61 24.48 3.77 3 2 5.98 14.76 56.27 1 3 8.45 10.46 100.00 1 4 13.94 6.35 5.84 3 5 15.38 5.76 3.22 3 Position r Two Diagnostic Peak Peak Number d-spacing [A] Rel. Int. [%]
Theta] Set 6 16.76 5.28 21.76 2 7 17.75 4.99 56.84 1 8 18.55 4.78 7.88 3 9 18.92 4.69 6.80 3 20.08 4.42 11.78 2 11 21.30 4.17 60.58 1 12 22.11 4.02 4.11 3 13 22.67 3.92 7.75 3 In a further aspect, the PXRD peak locations displayed in Table 2 and/or FIG.
2 most characteristic of crystalline form Type 10 of sugammadex can be selected and grouped as "diagnostic peak sets" to conveniently distinguish this crystalline form from others. Selections 5 of such characteristic peaks are set out in Table 2 in the column labeled Diagnostic Peak Set.
Thus, in another aspect, there is provided a crystalline form Type 10 of sugammadex characterized by a powder x-ray diffraction pattern comprising each of the 2-theta values listed in Diagnostic Peak Set 1 in Table 2, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 10 of sugammadex 10 characterized by a powder x-ray diffraction pattern comprising each of the 2-theta values listed in Diagnostic Peak Set 2 in Table 2, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 10 of sugammadex characterized by a powder x-ray diffraction pattern comprising each of the 2-theta values listed in Diagnostic Peak Set 3 in Table 2, +/- 0.2 2-theta.
A further aspect of the disclosure is realized and characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/- 0.2 ) of Diagnostic Peak Set 1 plus Set 2, A further aspect of the disclosure is realized and characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/-0.2 ) of Diagnostic Peak Set 1 plus Set 2 plus Set 3. Still another aspect of the disclosure is realized where there are at least 2 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 3 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 4 peaks of Diagnostic Peak Set 1. Another Another aspect of the disclosure is realized where there are at least 3 peaks of Diagnostic Peak Set 1 and 1 peak of Diagnostic Peak 2. Another aspect of the disclosure is realized where there are at least 3 peaks of Diagnostic Peak Set 1 and 1 of Diagnostic Peak Set 2 and 1 of Diagnostic Peak Set 3.

Crystalline form Type 12 of sugammadex was prepared as follows:
A solution of sugammadex in water with a concentration of 200 mg/mL was prepared.
The solution was heated to 60 C and the water slowly evaporated, producing a white powder. A
dry sample was produced after the water had evaporated. PXRD analysis of the dry sample produced the Type 12 pattern.
Physical characterization of crystalline form Type 12 of sugammadex:
A PXRD pattern of crystalline fot ______________________________________ m Type 12 of sugammadex generated using the equipment and procedures described above is displayed in FIG. 3. Thus, in another aspect, there is provided a crystalline form Type 12 of sugammadex characterized by a powder x-ray diffraction pattern substantially as shown in FIG. 3.
The intensity of the peaks (y-axis is in counts per second) were plotted versus the 2-theta angle (x-axis is in degrees 2 theta). In addition, the data were plotted with detector counts normalized for the collection time per step versus the 2-theta angle. Peak locations (on the 2-theta x-axis) consistent with these profiles are displayed in Table 3 (+/- 0.2 2 theta). The locations of these PXRD peaks are characteristic of the crystalline form Type 12 of sugammadex. Thus, in another aspect, crystalline form Type 12 of sugammadex is characterized by a powder x-ray diffraction pattern having each of the peak positions listed in Table 3, +/- 0.2 2-theta.
Table 3: Diffraction peaks and corresponding d-spacings for crystalline form Type 12 of sugammadex Position [ Two Diagnostic Peak Peak Number d-spacing [A] Rel. Int. rol Theta] Set 1 4.60 19.21 13.63 2 2 5.50 16.07 14.57 2 3 6.40 13.81 36.33 1 4 7.55 11.70 100.00 1 5 8.12 10.88 9.87 2 6 9.06 9.75 6.03 3 7 10.00 8.84 11.70 2 8 10.43 8.48 11.37 2 9 11.94 7.41 11.05 2 10 12.17 7.26 31.55 1 11 12.59 7.03 17.66 2 12 12.84 6.89 20.52 2 13 13.79 6.41 6.25 3 14 14.75 6.00 4.29 3 15 15.27 5.80 5.60 3 Position [O Two Diagnostic Peak Peak Number d-spacing [A] Rel. Int. r/o]
Theta] Set 16 15.92 5.56 20.51 2 17 16.40 5.40 14.38 2 18 16.94 5.23 12.60 2 19 17.12 5.17 13.29 2 20 17.65 5.02 14.38 2 21 18.17 4.88 19.82 2 22 18.62 4.76 9.96 2 . .

23 19.28 4.60 12.23 2

24 20.20 4.39 7.20 3

25 20.49 4.33 9.09 2

26 21.10 4.21 5.25 3

27 21.43 4.14 6.65 3

28 22.16 4.01 9.10 2

29 22.52 3.94 7.73 3

30 22.67 3.92 8.25 3

31 22.97 3.87 8.23 3

32 24.16 3.68 6.51 3

33 24.63 3.61 5.97 3

34 37.07 2.42 17.47 2 In a further aspect, the PXRD peak locations displayed in Table 3 and/or FIG.
3 most characteristic of crystalline form Type 12 of sugammadex can be selected and grouped as "diagnostic peak sets" to conveniently distinguish this crystalline form from others. Selections of such characteristic peaks are set out in Table 3 in the column labeled Diagnostic Peak Set.
Thus, in another aspect, there is provided a crystalline form Type 12 of sugammadex characterized by a powder x-ray diffraction pattern comprising each of the 2-theta values listed in Diagnostic Peak Set 1 in Table 3, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 12 of sugammadex characterized by a powder x-ray diffraction pattern comprising each of the 2-theta values listed in Diagnostic Peak Set 2 in Table 3, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 12 of sugammadex characterized by a powder x-ray diffraction pattern comprising each of the 2-theta values listed in Diagnostic Peak Set 3 in Table 3, +/- 0.2 2-theta.
A further aspect of the disclosure is realized and characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/- 0.2 ) of Diagnostic Peak Set 1 plus Set 2. A further aspect of the disclosure is realized and characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+1-0.2 ) of Diagnostic Peak Set 1 plus Set 2 plus Set 3. Still another aspect of the disclosure is realized where there are at least 1 peaks of Diagnostic Peak Set I. Another aspect of the disclosure is realized where there are at least 2 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 3 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 2 peaks of Diagnostic Peak Set 1 and 3 peaks of Diagnostic Peak 2. Another aspect of the disclosure is realized where there are at least 2 peaks of Diagnostic Peak Set 1, 4 peaks of Diagnostic Peak 2 and 3 of Diagnostic Peak Set 3.

Crystalline form Type 13 of sugammadex was prepared as follows:
A 1 g sample of dried Sugammadex Type 111 was placed in a humidity chamber exhibiting 75% relative humidity at 25 C for 24 hours. PXRD analysis of the dry cake after 24 hours produced the Type 13 pattern.
Physical characterization of crystalline form Type 13 of sugammadex:
A PXRD pattern of crystalline form Type 13 of sugammadex generated using the equipment and procedures described above is displayed in FIG. 4. Thus, in another aspect, there is provided a crystalline form Type 13 of sugammadex characterized by a powder x-ray diffraction pattern substantially as shown in FIG. 4.
The intensity of the peaks (y-axis is in counts per second) were plotted versus the 2-theta angle (x-axis is in degrees 2 theta). In addition, the data were plotted with detector counts normalized for the collection time per step versus the 2-theta angle. Peak locations (on the 2-theta x-axis) consistent with these profiles are displayed in Table 4 (+/- 0.2 2 theta). The locations of these PXRD peaks are characteristic of the crystalline form Type 13 of sugammadex. Thus, in another aspect, crystalline form Type 13 of sugammadex is characterized by a powder x-ray diffraction pattern having each of the peak positions listed in Table 4, +/- 0.2 2-theta.
Table 4: Diffraction peaks and corresponding d-spacings for crystalline form Type 13 of sugammadex Position [ Two Diagnostic Peak Peak Number d-spacing [A] Rel. Int. [%]
Theta] Set 1 6.83 12.94 11.45 2 2 10.12 8.74 30.89 1 Position r Two Diagnostic Peak Peak Number d-spacing [A] Rel. Int. [%]
Theta] Set 3 10.72 8.25 13.45 3 4 11.37 7.78 14.79 3 13.90 6.37 26.92 1 6 14.59 6.07 36.09 1 7 16.32 5.43 52.60 1 8 16.73 5.30 77.09 1 9 17.26 5.14 100.00 1 18.39 4.82 55.94 1 11 19.42 4.57 70.29 1 12 20.86 4.26 49.54 1 13 21.70 4.09 32.53 3 14 22.12 4.02 52.63 3 22.52 3.95 51.04 3 16 22.98 3.87 41.30 3 17 23.34 3.80 40.57 3 In a further aspect, the PXRD peak locations displayed in Table 4 and/or FIG.
4 most characteristic of crystalline form Type 13 of sugammadex can be selected and grouped as "diagnostic peak sets" to conveniently distinguish this crystalline form from others. Selections 5 of such characteristic peaks are set out in Table 4 in the column labeled Diagnostic Peak Set.
Thus, in another aspect, there is provided a crystalline form Type 13 of sugammadex characterized by a powder x-ray diffraction pattern comprising each of the 2-theta values listed in Diagnostic Peak Set 1 in Table 4, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline forin Type 13 of sugammadex 10 characterized by a powder x-ray diffraction pattern comprising each of the 2-theta values listed in Diagnostic Peak Set 2 in Table 4, +/- 0.2 2-theta.
In another aspect, there is provided a crystalline form Type 13 of sugammadex characterized by a powder x-ray diffraction pattern comprising each of the 2-theta values listed in Diagnostic Peak Set 3 in Table 4, +/- 0.2 2-theta.
15 A further aspect of the disclosure is realized and characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/- 0.2 ) of Diagnostic Peak Set 1 plus Set 2. A further aspect of the disclosure is realized and characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+1-0.2 ) of Diagnostic Peak Set 1 plus Set 2 plus Set 3. Still another aspect of the disclosure is realized where there are at least 3 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 4 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 5 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 6 peaks of Diagnostic Peak Set 1.
Another aspect of the disclosure is realized where there are at least 7 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 8 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 9 peaks of Diagnostic Peak Set 1. Another aspect of the disclosure is realized where there are at least 3 peaks of Diagnostic Peak Set 1 and one of Diagnostic Peak set 2. Another aspect of the disclosure is realized where there are at least 3 peaks of Diagnostic Peak Set 1, one of Diagnostic Peak Set 2 and 3 of Diagnostic Peak Set 3.
PREPARATION OF DRUG PRODUCT
Crystallized Type 7, Type 10, Type 12 and Type 13 forms of sugammadex were prepared as described above, then isolated as a wet cake and then dried to obtain a powder meeting purity and residual solvent specifications. The drug product is then produced by a formulation and filling process. The dried sugammadex powder is dissolved in water for injection and the pH
adjusted to 7.5. The resulting solution is then filtered and filled into vials, stoppered and capped.
The bulk drug product is then terminally sterilized and stored for use.

Claims

1. A crystalline form Type 7 of sugammadex characterized by a powder x-ray diffraction pattern obtained using Cu K alpha radiation with at least peaks at diffraction angles degrees 2 theta (+/- 0.2 ) of: 5.64; 6.07; 6.83; 7.19; 10.72; 13.64; 20.71.

2. The crystalline form Type 7 of sugammadex according to claim 1, further characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/- 0.2 ) of: 5.64; 6.07; 6.83; 7.19; 9.25; 9.88; 10.72;
13.64; 14.84; 16.39; 16.97;
17.81; 19.16; 19.31; 19.65; 20.71; 21.90.

3. The crystalline form Type 7 of sugammadex according to claim 2, further characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/- 0.2 ) of: 5.64; 6.07; 6.83; 7.19; 9.25; 9.88; 10.72;
13.64; 14.84; 15.17; 16.39;
16.97; 17.81; 18.27; 19.16; 19.31; 19.65; 20.71; 21.14; 21.90; 22.63; 23.20.

4. The crystalline form Type 7 of sugammadex according to any one of claims 1-3, for use in the preparation of an injectable composition comprising sugammadex and a pharmaceutically-acceptable diluent for the reversal of neuromuscular blockade induced by recuronium bromide and vecuronium bromide in adults undergoing surgery.

5. Use of sugammadex in the manufacture of a medicament to reverse neuromuscular blockade in an adult subject undergoing surgery, said sugammadex comprising crystalline form Type 7 characterized by a powder x-ray diffraction pattern obtained using Cu K
alpha radiation with at least peaks at diffraction angles degrees 2 theta (+/-0.2 ) of 5.64; 6.07;
6.83; 7.19; 10.72; 13.64; 20.71.

6. The use according to claim 5, wherein the crystalline form Type 7 is further characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/- 0.2 ) of 5.64; 6.07; 6.83; 7.19; 9.25; 9.88; 10.72;
13.64; 14.84; 16.39; 16.97;
17.81; 19.16; 19.31; 19.65; 20.71; 21.90.

Date Recue/Date Received 2024-03-08

7. The use according to claim 6, wherein the crystalline form Type 7 is further characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/- 0.2 ) of 5.64; 6.07; 6.83; 7.19; 9.25; 9.88; 10.72;
13.64; 14.84; 15.17; 16.39;
16.97; 17.81; 18.27; 19.16; 19.31; 19.65; 20.71; 21.14; 21.90; 22.63; 23.20.

8. The use according to any one of claims 5-7, wherein the neuromuscular blockade was induced by at least one of recuronium bromide and vecuronium bromide.

9. The use according to any one of claims 5-8, wherein the medicament is in the form of powder.

10. A solution for injection, comprising the medicament as defined in claim 9.

11. A method for preparing a solution for injection, comprising adding a liquid pharmaceutically-acceptable diluent to the medicament as defined in claim 9.

12. A solution for injection, comprising the medicament as defined in any one of claims 5-7.

13. A solution for injection, comprising the crystalline form Type 7 of sugammadex as defined in any one of claims 1-3.

14. The solution of claim 13, further comprising one or more pharmaceutically-acceptable diluents.

15. A drug substance comprising about 5% to about 100% by weight of the crystalline form Type 7 of sugammadex as defined in any one of claims 1-3.

16. A drug substance comprising about 10% to about 100% by weight of the crystalline form Type 7 of sugammadex as defined in any one of claims 1-3.
Date Recue/Date Received 2024-03-08

17. A drug substance comprising about 25% to about 100% by weight of the crystalline form Type 7 of sugammadex as defined in any one of claims 1-3.

18. A drug substance comprising about 50% to about 100% by weight of the crystalline form Type 7 of sugammadex as defined in any one of claims 1-3.

19. A drug substance comprising about 75% to about 100% by weight of the crystalline faun Type 7 of sugammadex as defined in any one of claims 1-3.

20. A pharmaceutical composition comprising a therapeutically-effective amount of the crystalline form Type 7 of sugammadex as defined in any one of claims 1-3, and at least one pharmaceutically-acceptable diluent, for use in the reversal of neuromuscular blockade induced by recuronium bromide and vecuronium bromide in adults undergoing surgery.

21. Use of sugammadex to reverse neuromuscular blockade in a patient undergoing surgery, wherein the sugammadex comprises crystalline form Type 7 of sugammadex as defined in any one of claims 1-3.

22. The crystalline form Type 7 of sugammadex according to any one of claims 1-3, for use in the reversal of neuromuscular blockade in a patient undergoing surgery.

23. The crystalline form Type 7 of sugammadex as defined in claim 22, wherein the patient is an adult.

24. The crystalline form Type 7 of sugammadex as defined in claim 22 or 23, wherein the neuromuscular blockage was induced by recuronium bromide and vecuronium bromide.

25. The crystalline form Type 7 of sugammadex according to any one of claims 1-3 for use in a method of manufacturing a medicament for reversing neuromuscular blockade in patients undergoing surgery.

Date Recue/Date Received 2024-03-08

26. The crystalline form Type 7 of sugammadex as defined in claim 25, wherein the patients are adult patients.

27. The crystalline form Type 7 of sugammadex as defined in claim 25 or 26, wherein the neuromuscular blockade was induced by at least one of recuronium bromide and vecuronium bromide.

28. A medicament prepared by a method of manufacturing as defined in any one of claims 25-27, said medicament comprising sugammadex as a pharmaceutically-active ingredient.

29. Sugammadex wet-cake comprising the crystalline form Type 7 of sugammadex according to any one of claims 1-3.

30. A sterile pharmaceutical composition comprising the crystalline form Type 7 of sugammadex as defined in any one of claims 1-3 and at least one pharmaceutically-acceptable diluent.

Date Recue/Date Received 2024-03-08