Crystalline form of triethylenetetramine tetrahydrochloride and its pharmaceutical use

1. A method of producing a crystalline form of triethylenetetramine tetrahydrochloride Form B having at least one of the following characteristics:

(i) an XRPD pattern having at least two peaks selected from the peaks at 22.9, 25.4, 25.8, 26.6, 34.6 and 35.3±0.1°2θ; and

(ii) a Raman spectrum having at least two peaks selected from the peaks at a Raman shift of 943, 1173, 1527 and 1612±5 cm −1 ;

wherein XRPD pattern peaks are as measured using a wavelength of 1.5418 Å,

which method comprises adding an anti-solvent to an aqueous solution of triethylenetetramine tetrahydrochloride and collecting the crystals obtained, wherein the anti-solvent addition is carried out at a temperature of 15° C. or below.

2. The method according to claim 1 , wherein the rate of addition of anti-solvent to the solution is no more than 0.5 ml/min per gram of TETA·4HCl dissolved in the aqueous solution.

3. The method according to claim 1 , which method comprises:

(i) adding anti-solvent to an aqueous solution of TETA·4HCl at temperature T1;

(ii) optionally adding TETA·4HCl Form B seed crystals;

(iii) optionally agitating the resulting mixture at T1;

(iv) optionally reducing the temperature to temperature T2 and agitating the mixture; and

(v) collecting the resulting crystals;

wherein T1 is 15° C. or below; and T2 is at least 5° C. lower than T1.

4. The method according to claim 3 , wherein the anti-solvent is added at a rate of addition of 0.5 ml/min per gram of TETA·4HCl or less.

5. A method according to claim 3 , which method comprises:

(i) adding anti-solvent to an aqueous solution of TETA·4HCl at temperature T1;

(ii) adding TETA·4HCl Form B seed crystals;

(iii) agitating the resulting mixture at T1;

(iv) reducing the temperature to temperature T2 and agitating the mixture; and

(v) collecting the resulting crystals:

wherein T1 is 15° C. or below; and T2 is 5° C. or below.

6. The method according to claim 5 , wherein the anti-solvent is added at a rate of addition of 0.2 ml/min per gram of TETA·4HCl or less.

7. The method according to claim 1 which further comprises drying the collected crystals at a temperature of below 40° C.

8. The method according to claim 7 wherein the collected crystals are dried at a temperature of below 30° C.

9. The method according to claim 1 wherein the collected crystals are combined with a pharmaceutically acceptable carrier to produce a pharmaceutical composition.

10. The method according to claim 9 , wherein the method further comprises compressing the mixture of crystals and pharmaceutically acceptable carrier to form a tablet and optionally sugar-coating or film-coating the tablet.

11. The method according to claim 7 wherein the collected crystals are combined with a pharmaceutically acceptable carrier to produce a pharmaceutical composition, optionally wherein the method further comprises compressing the mixture of crystals and pharmaceutically acceptable carrier to form a tablet and further optionally sugar-coating or film-coating the tablet.

12. The method according to claim 1 , wherein the method is a method of preparing a crystalline form having an XRPD pattern having peaks at 25.4, 34.6 and 35.3±0.1°2θ.

13. The method according to claim 1 , wherein the method is a method of preparing a crystalline form which contains at least 95 wt % of triethylenetetramine tetrahydrochloride Form B having at least one of the following characteristics:

(i) an XRPD pattern having at least two peaks selected from the peaks at 22.9, 25.4, 25.8, 26.6, 34.6 and 35.3±0.1°2θ; and

(ii) a Raman spectrum having at least two peaks selected from the peaks at a Raman shift of 943, 1173, 1527 and 1612±5 cm −1 .

14. The method according to claim 9 , wherein the method is a method of preparing a pharmaceutical composition which contains no more than 10 wt % of triethylenetetramine tetrahydrochloride Form A having an XRPD pattern having peaks at 25.2 and 35.7±0.1°2θ.

15. The method of producing a crystalline form of triethylenetetramine tetrahydrochloride Form B having at least one of the following characteristics:

(i) an XRPD pattern having at least two peaks selected from the peaks at 22.9, 25.4, 25.8, 26.6, 34.6 and 35.3±0.1°2θ; and

(ii) a Raman spectrum having at least two peaks selected from the peaks at a Raman shift of 943, 1173, 1527 and 1612±5 cm −1 ;

and which contains no more than 10 wt % of triethylenetetramine tetrahydrochloride Form A having an XRPD pattern having peaks at 25.2 and 35.7±0.1°2θ,

wherein XRPD pattern peaks are as measured using a wavelength of 1.5418 Å, which method comprises adding an anti-solvent to an aqueous solution of triethylenetetramine tetrahydrochloride and collecting the crystals obtained, wherein the anti-solvent addition is carried out at a temperature of 15° C. or below.

16. The method according to claim 15 , wherein the rate of addition of anti-solvent to the solution is no more than 0.5 ml/min per gram of TETA·4HCl dissolved in the aqueous solution.

17. The method according to claim 15 , which method comprises:

(i) adding anti-solvent to an aqueous solution of TETA·4HCl at temperature T1;

(ii) optionally adding TETA·4HCl Form B seed crystals;

(iii) optionally agitating the resulting mixture at T1;

(iv) optionally reducing the temperature to temperature T2 and agitating the mixture; and

(v) collecting the resulting crystals;

wherein T1 is 15° C. or below; and T2 is at least 5° C. lower than T1.

18. The method according to claim 17 , wherein the anti-solvent is added at a rate of addition of 0.5 ml/min per gram of TETA·4HCl or less.

19. The method according to claim 17 , which method comprises:

(i) adding anti-solvent to an aqueous solution of TETA·4HCl at temperature T1;

(ii) adding TETA·4HCl Form B seed crystals;

(iii) agitating the resulting mixture at T1;

(iv) reducing the temperature to temperature T2 and agitating the mixture; and

(v) collecting the resulting crystals:

wherein T1 is 15° C. or below; and T2 is 5° C. or below.

20. The method according to claim 19 , wherein the anti-solvent is added at a rate of addition of 0.2 ml/min per gram of TETA·4HCl or less.

21. The method according to claim 15 which further comprises drying the collected crystals at a temperature of below 40° C.

22. The method according to claim 21 wherein the collected crystals are dried at a temperature of below 30° C.

23. The method according to claim 15 wherein the collected crystals are combined with a pharmaceutically acceptable carrier to produce a pharmaceutical composition.

24. The method according to claim 23 , wherein the method further comprises compressing the mixture of crystals and pharmaceutically acceptable carrier to form a tablet and optionally sugar-coating or film-coating the tablet.

25. The method according to claim 21 wherein the collected crystals are combined with a pharmaceutically acceptable carrier to produce a pharmaceutical composition, optionally wherein the method further comprises compressing the mixture of crystals and pharmaceutically acceptable carrier to form a tablet and further optionally sugar-coating or film-coating the tablet.

26. The method according to claim 15 , wherein the method is a method of preparing a crystalline form having an XRPD pattern having peaks at 25.4, 34.6 and 35.3±0.1°2θ.

27. The method according to claim 15 , wherein the method is a method of preparing a crystalline form which contains at least 95 wt % of triethylenetetramine tetrahydrochloride Form B having at least one of the following characteristics:

(i) an XRPD pattern having at least two peaks selected from the peaks at 22.9, 25.4, 25.8, 26.6, 34.6 and 35.3±0.1°2θ; and

(ii) a Raman spectrum having at least two peaks selected from the peaks at a Raman shift of 943, 1173, 1527 and 1612±5 cm −1 .