Solid dispersion comprising an orexin receptor antagonist

Abstract

A solid dispersion comprising suvorexant or a salt thereof in amorphous form and at least one pharmaceutically acceptable matrix compound, wherein the matrix compound is (i) a polymer and wherein the solid dispersion contains the suvorexant or salt thereof in an 5 amount of at least 50 weight-% based on the combined weight of the suvorexant or salt thereof and the at least one matrix compound, or (ii) a silicon-based inorganic adsorbent.

Claims

1. A solid dispersion comprising suvorexant ([(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone) or a salt thereof in amorphous form and at least one pharmaceutically acceptable matrix compound, wherein the at least one matrix compound is (i) a polymer and wherein the solid dispersion contains the suvorexant or salt thereof in an amount of at least 50 weight-% based on the combined weight of the suvorexant or salt thereof and the at least one matrix compound, or (ii) a silicon-based inorganic adsorbent.

2. The solid dispersion of claim 1, wherein at least 80% by weight of the suvorexant or salt thereof present in the solid dispersion is present in amorphous form.

3. The solid dispersion of claim 1, wherein in the adsorption-desorption isotherm of the at least one matrix compound in (ii), the relative mass difference m(adsorption) between 50% and 90% relative humidity at 25 C. is greater than or equal to 40%, determined according to dynamic vapor sorption measurement.

4. The solid dispersion of claim 1, wherein in the adsorption-desorption isotherm of the at least one matrix compound in (ii), the relative mass difference m(adsorption) between 0 and less than 50% relative humidity at 25 C. is less than or equal to 20%, determined according to dynamic vapor sorption measurement.

5. The solid dispersion of claim 1, wherein the polymer in (i) is a cellulose derivative or a polyvinyl caprolactam polyvinyl acetate polyethylene glycol graft polymer.

6. The solid dispersion of claim 1, wherein in the adsorption-desorption isotherm of the at least one matrix compound in (ii), the mass difference m(desorption) at 75% relative humidity and 25 C. is greater than or equal to the mass difference m(adsorption) at 75% relative humidity and 25 C., determined according to dynamic vapor sorption measurement.

7. The solid dispersion of claim 1, wherein the silicon-based inorganic adsorbent is selected from the group consisting of silica, silicates, and a combination of two or more thereof.

8. The solid dispersion of claim 1, wherein the solid dispersion in (ii) contains the suvorexant or the at least one salt thereof in an amount in the range of from 10 to 70 weight-%, based on the combined weight of the suvorexant or the at least one salt thereof and the at least one matrix compound.

9. The solid dispersion of claim 1, consisting of suvorexant or a salt thereof, the at least one matrix compound and optionally at least one solvent.

10. A process for preparing a solid dispersion comprising suvorexant or a salt thereof in amorphous form and at least one pharmaceutically acceptable matrix compound, the process comprising (a) providing suvorexant or a salt thereof (b) dissolving or dispersing suvorexant provided in (a) and the at least one matrix compound in a solvent to form a mixture (c) removing at least part-of the solvent to give the solid dispersion, and wherein the matrix compound is (i) a polymer and wherein the solid dispersion contains the suvorexant or salt thereof in an amount of at least 50 weight-% based on the combined weight of the suvorexant or salt thereof and the at least one matrix compound, or a silicon-based inorganic adsorbent.

11. The process of claim 10, wherein at least 80% by weight of all suvorexant comprised in the solid dispersion is amorphous.

12. The process of claim 10, wherein in step (c), the solution is evaporated.

13. A solid dispersion, obtainable or obtained by the process according to claim 10.

14. A process for the preparation of suvorexant of which at least 95 weight-%-are present in its amorphous form, comprising (a1) providing suvorexant of which at least 95 weight-% are present in at least one crystalline form; (a2) dissolving at least a portion of the suvorexant provided according to (a1) in at least one solvent, obtaining a solution comprising the suvorexant; (a3) subjecting at least a portion of the solution obtained according to (a2), optionally after concentrating, to rapid-drying, obtaining the suvorexant of which at least 95 weight-% are present in its amorphous form.

15. The process of claim 14, wherein the rapid drying of step (a3) is carried out by spray-drying.

16. A pharmaceutical composition, comprising a solid dispersion according to claim 1.

17. A method for treating a sleep disorder in a patient in need thereof, the method comprising administering a pharmaceutical composition, comprising a solid dispersion according to claim 1, to a patient suffering from a sleep disorder.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1: shows a PXRD pattern of a solid dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone and Soluplus with a weight ratio of 1:1. The Y-axis shows the counts, the X-axis precision of the 2 theta angle (copper).

(2) FIG. 2: shows the PXRD pattern of a solid dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with Soluplus, with a weight ratio 1:1 after storage for four weeks at 40 C. and a relative humidity of 75%. X-axis: counts, Y-axis: 2 theta angles (copper).

(3) FIG. 3: shows a PXRD pattern of a solid dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone and hydroxypropylmethylcellulose acetate succinate with a weight ratio of 1:1. The Y-axis shows the counts, the X-axis precision of the 2 theta angle (copper).

(4) FIG. 4: shows the PXRD pattern of a solid dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with hydroxypropylmethylcellulose acetate succinate with a weight ratio 1:1 after storage for four weeks at 40 C. and a relative humidity of 75%. X-axis: counts, Y-axis: 2 theta angles (copper).

(5) FIG. 5: shows a PXRD pattern of a solid dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone and hydroxypropylmethylcellulose (Methocel E5) with a weight ratio of 1:1. The Y-axis shows the counts, the X-axis precision of the 2 theta angle (copper).

(6) FIG. 6: shows the PXRD pattern of a solid dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with hydroxypropylmethylcellulose (Methocel E5) with a weight ratio 1:1 after storage for four weeks at 40 C. and a relative humidity of 75%. X-axis: counts, Y-axis: 2 theta angles (copper).

(7) FIG. 7: shows a PXRD pattern of a solid dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone and Syloid 72 FP with a weight ratio of 1:1. The Y-axis shows the counts, the X-axis precision of the 2 theta angle (copper).

(8) FIG. 8: shows a PXRD pattern of a solid dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone and Syloid 244 FP with a weight ratio of 1:1. The Y-axis shows the counts, the X-axis precision of the 2 theta angle (copper).

(9) FIG. 9: shows a PXRD pattern of a solid dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone and Syloid AL-1 FP with a weight ratio of 1:1. The Y-axis shows the counts, the X-axis precision of the 2 theta angle (copper).

(10) FIG. 10: shows a PXRD pattern of a solid dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and Aerosil 200 with a weight ratio of 1:1. The Y-axis shows the counts, the X-axis precision of the 2 theta angle (copper).

(11) FIG. 11: shows a PXRD pattern of a solid dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone and Neusilin US2 with a weight ratio of 1:1. The Y-axis shows the counts, the X-axis precision of the 2 theta angle (copper).

(12) FIG. 12: shows a PXRD pattern of a solid dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone and Neusilin UFL2 with a weight ratio of 1:1. The Y-axis shows the counts, the X-axis precision of the 2 theta angle (copper).

(13) FIG. 13: shows a PXRD pattern of amorphous [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone. The Y-axis shows the counts, the X-axis precision of the 2 theta angle (copper).

(14) FIG. 14: shows the DVS isotherm of the matrix compound Syloid 72 FP, recorded as described in Example V. The x axis shows the r.h. (relative humidity, in %) values, with tick marks, from left to right, at 0.0; 10.0; 20.0; 30.0; 40.0; 50.0; 60.0; 70.0; 80.0; 90.0; and 100.0. The y axis shows the m values (in %), with tick marks, from bottom to top, at 10.0; 0.0; 10.0; 20.0; 30.0; 40.0; 50.0; 60.0; 70.0; 80.0; and 90.0. The m(desorption) values are obtained from the desorption isotherm (symbols: .circle-solid.), the m(adsorption) values are obtained from the adsorption isotherm (symbols: .square-solid.).

(15) FIG. 15: shows the DVS isotherm of the matrix compound Syloid 244 FP, recorded as described in Example V. The x axis shows the r.h. (relative humidity, in %) values, with tick marks, from left to right, at 0.0; 10.0; 20.0; 30.0; 40.0; 50.0; 60.0; 70.0; 80.0; 90.0; and 100.0. The y axis shows the m values (in %), with tick marks, from bottom to top, at 20.0; 0.0; 20.0; 40.0; 60.0; 80.0; and 100.0. The m(desorption) values are obtained from the desorption isotherm (symbols: .circle-solid.), the m(adsorption) values are obtained from the adsorption isotherm (symbols: .square-solid.).

(16) FIG. 16: shows the DVS isotherm of the matrix compound Neusilin UFL2, recorded as described in Example V. The x axis shows the r.h. (relative humidity, in %) values, with tick marks, from left to right, at 0.0; 10.0; 20.0; 30.0; 40.0; 50.0; 60.0; 70.0; 80.0; 90.0; and 100.0. The y axis shows the m values (in %), with tick marks, from bottom to top, at 20.0; 10.0; 0.0; 10.0; 20.0; 30.0; 40.0; 50.0; 60.0; and 70.0. The m(desorption) values are obtained from the desorption isotherm (symbols: .circle-solid.), the m(adsorption) values are obtained from the adsorption isotherm (symbols: .square-solid.).

(17) FIG. 17: shows the DVS isotherm of the matrix compound Neusilin US2, recorded as described in Example V. The x axis shows the r.h. (relative humidity, in %) values, with tick marks, from left to right, at 0.0; 10.0; 20.0; 30.0; 40.0; 50.0; 60.0; 70.0; 80.0; 90.0; and 100.0. The y axis shows the m values (in %), with tick marks, from bottom to top, at 20.0; 10.0; 0.0; 10.0; 20.0; 30.0; 40.0; 50.0; 60.0; 70.0; and 80.0. The m(desorption) values are obtained from the desorption isotherm (symbols: .circle-solid.), the m(adsorption) values are obtained from the adsorption isotherm (symbols: .square-solid.).

(18) FIG. 18: shows the DVS isotherm of the matrix compound Soluplus, recorded as described in Example V. The x axis shows the r.h. (relative humidity, in %) values, with tick marks, from left to right, at 0.0; 10.0; 20.0; 30.0; 40.0; 50.0; 60.0; 70.0; 80.0; 90.0; and 100.0. The y axis shows the m values (in %), with tick marks, from bottom to top, at 5.0; 0.0; 5.0; 10.0; 15.0; 20.0; 25.0; 30.0; 35.0; 40.0; and 45.0. The m(desorption) values are obtained from the desorption isotherm (symbols: .circle-solid.), the m(adsorption) values are obtained from the adsorption isotherm (symbols: .square-solid.).

(19) FIG. 19: shows the DVS isotherm of the matrix compound Syloid AL-1 FP, recorded as described in Example V. The x axis shows the r.h. (relative humidity, in %) values, with tick marks, from left to right, at 0.0; 10.0; 20.0; 30.0; 40.0; 50.0; 60.0; 70.0; 80.0; 90.0; and 100.0. The y axis shows the m values (in %), with tick marks, from bottom to top, at 20.0; 15.0; 10.0; 5.0; 0.0; 5.0; 10.0; and 15.0. The m(desorption) values are obtained from the desorption isotherm (symbols: .circle-solid.), the m(adsorption) values are obtained from the adsorption isotherm (symbols: .square-solid.).

(20) FIG. 20: shows the DVS isotherm of the matrix compound Aerosil 200 recorded as described in Example V. The x axis shows the r.h. (relative humidity, in %) values, with tick marks, from left to right, at 0.0; 10.0; 20.0; 30.0; 40.0; 50.0; 60.0; 70.0; 80.0; 90.0; and 100.0. The y axis shows the m values (in %), with tick marks, from bottom to top, at 2.0; 1.0; 0.0; 1.0; 2.0; 3.0; 4.0; and 5.0. The m(desorption) values are obtained from the desorption isotherm (symbols: .circle-solid.), the m(adsorption) values are obtained from the adsorption isotherm (symbols: .square-solid.).

(21) FIG. 21: shows the dissolution profiles of the tablets according to Example VII.21 prepared based solid dispersions comprising Kollidon VA64. The x axis shows the time/min with tick marks, from left to right, at 0, 20, 40, 60, 80. The y axis shows the amount of suvorexant released/%, based on the suvorexant content of the tablet prior to dissolution, with tick marks, from bottom to top, at 0, 20, 40, 60, 80, 100. The symbol .diamond-solid. indicates the values for the tablets obtained from solid dispersion prepared by dissolving and drying, the symbol .square-solid. indicates the values for the tablets obtained from solid dispersion prepared by milling.

(22) FIG. 22: shows the dissolution profiles of the tablets according to Example VII.21 prepared based solid dispersions comprising Soluplus. The x axis shows the time/min with tick marks, from left to right, at 0, 20, 40, 60, 80. The y axis shows the amount of suvorexant released/%, based on the suvorexant content of the tablet prior to dissolution, with tick marks, from bottom to top, at 0, 20, 40, 60, 80, 100. The symbol .diamond-solid. indicates the values for the tablets obtained from solid dispersion prepared by dissolving and drying, the symbol .square-solid. indicates the values for the tablets obtained from solid dispersion prepared by milling.

(23) FIG. 23: shows the dissolution profiles of the tablets according to Example VII.21 prepared based solid dispersions comprising HPMCAS. The x axis shows the time/min with tick marks, from left to right, at 0, 20, 40, 60, 80. The y axis shows the amount of suvorexant released/%, based on the suvorexant content of the tablet prior to dissolution, with tick marks, from bottom to top, at 0, 20, 40, 60, 80, 100. The symbol .diamond-solid. indicates the values for the tablets obtained from solid dispersion prepared by dissolving and drying, the symbol .square-solid. indicates the values for the tablets obtained from solid dispersion prepared by milling.

(24) FIG. 24: shows the dissolution profiles of the tablets according to Example VII.21 prepared based solid dispersions comprising Neusilin UFL. The x axis shows the time/min with tick marks, from left to right, at 0, 20, 40, 60, 80. The y axis shows the amount of suvorexant released/%, based on the suvorexant content of the tablet prior to dissolution, with tick marks, from bottom to top, at 0, 20, 40, 60, 80, 100. The symbol .diamond-solid. indicates the values for the tablets obtained from solid dispersion prepared by dissolving and drying, the symbol .square-solid. indicates the values for the tablets obtained from solid dispersion prepared by milling.

(25) FIG. 25: shows the dissolution profiles of the tablets according to Example VII.22 prepared based solid dispersions comprising Kollidon VA64, and additionally comprising either no surfactant (symbol: x), or Tween 80 (symbol: .box-tangle-solidup.), or Kolliphor 188 (symbol: .diamond-solid.), or SDS (symbol: .square-solid.) as surfactant. The x axis shows the time/min with tick marks, from left to right, at 0, 10, 20, 30, 40, 50, 60, 70. The y axis shows the amount of suvorexant released/%, based on the suvorexant content of the tablet prior to dissolution, with tick marks, from bottom to top, at 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100.

(26) The present invention is further illustrated by the following examples.

EXAMPLES

I. Preparation of Solid Dispersions

Example 1: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with Soluplus as Polymer (Matrix Compound)

(27) 151 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and 151 mg Soluplus were dissolved in 10 mL dichloromethane. After filtration, the clear solution was evaporated on a rotavapor at room temperature. The foam-like residue was dried under vacuum at room temperature for 18 hours. The resulting solid dispersion was analyzed using PXRD which showed that the [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone was present in amorphous form (cf. FIG. 1).

Example 2: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with Soluplus as Polymer (Matrix Compound)

(28) 113 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and 113 mg of Soloplus were dissolved in 20 mL methyl THF. Subsequently the solvent was evaporated on a rotavapor at 40 C. and the residue was dried under vacuum for 18 hours.

Example 3: Stability of the Solid Dispersion According to Example 1

(29) 48 mg of the solid dispersion according to Example 1 were exposed to 75% relative humidity at 40 C. for four weeks. Afterwards, the solid dispersion was analyzed using PXRD which confirmed that [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone underwent no crystallization in the presence of Soluplus after four weeks (cf. FIG. 2).

Example 4: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with hydroxylpropylmethylcellulose Acetate Succinate as Polymer (Matrix Compound)

(30) 151 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and 151 mg of hydroxypropylmethylcellulose acetate succinate were suspended in 40 mL CH.sub.2Cl.sub.2. The solvent was evaporated on a rotavapor and the residue was dried under vacuum at room temperature for 18 hours. The resulting solid dispersion was analyzed using PXRD which showed that the [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone was present in amorphous form (cf. FIG. 3).

Example 5: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with hydroxylpropylmethylcellulose Acetate Succinate as Polymer (Matrix Compound)

(31) 103 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and 103 mg of hydroxypropylmethylcellulose acetate succinate were dissolved 20 ml methyl THF. Subsequently, the solvent was evaporated on a rotavapor at 40 C. and the residue was dried under vacuum for 18 hours.

Example 6: Stability of the Solid Dispersion According to Example 4

(32) 53 mg of the solid dispersion according to Example 4 were exposed to 75% relative humidity at 40 C. for four weeks. Afterwards, the solid dispersion was analyzed using PXRD which confirmed that [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone underwent no crystallization in the presence of Soluplus after four weeks (cf. FIG. 4).

Example 7: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with Methocel E5 as Polymer (Matrix Compound)

(33) 168 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and 168 mg of Methocel E5 were suspended in 50 mL CH.sub.2Cl.sub.2. The solvent of the clear solution was evaporated on a rotavapor and the residue was dried under vacuum at room temperature for 18 hours.

(34) The resulting solid dispersion was analyzed using PXRD which showed that the [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone was present in amorphous form (cf. FIG. 5).

Example 8: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with Methocel E5 as Polymer (Matrix Compound)

(35) 109 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and 109 mg of Methocel E5 were dissolved in a solvent mixture of 23 mL THF and 6 mL H.sub.2O. Subsequently the solvent was evaporated on a rotavapor at 40 C. and the residue was dried under vacuum for 18 hours.

Example 9: Stability of the Solid Dispersion According to Example 7

(36) 53 mg of the solid dispersion according to Example 7 were exposed to 75% relative humidity at 40 C. for four weeks. Afterwards, the solid dispersion was analyzed using PXRD which confirmed that [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone underwent no crystallization in the presence of Soluplus after four weeks (cf. FIG. 6).

Example 10: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl) phenyl]methanone with Syloid 72 FP as Carrier (Matrix Compound)

(37) 152 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and 153 mg of Syloid 72 FP were suspended in 50 mL CH.sub.2Cl.sub.2. The suspension was stirred at room temperature for 15 hours. Subsequently, the solvent was removed on a rotavapor at 40 C. The residue was dried under vacuum at room temperature for 2 days. The resulting solid dispersion was analyzed using PXRD which showed that the [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone was present in amorphous form (cf. FIG. 7).

Example 11: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with Syloid 244 FP as Carrier (Matrix Compound)

(38) 159 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and 160 mg of Syloid 244 FP were suspended in 50 mL CH.sub.2Cl.sub.2. The suspension was stirred at room temperature for 15 hours. Subsequently, the solvent was removed on a rotavapor at 40 C. The residue was dried under vacuum at room temperature for 2 days. The resulting solid dispersion was analyzed using PXRD which showed that the [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone was present in amorphous form (cf. FIG. 8).

Example 12: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with Syloid AL-1 FP as Carrier (Matrix Compound)

(39) 167 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and 169 mg of Syloid AL-1 FP were suspended in 50 mL CH.sub.2Cl.sub.2. The suspension was stirred at room temperature for 15 hours. Subsequently, the solvent was removed on a rotavapor at 40 C. The residue was dried under vacuum at room temperature for 2 days. The resulting solid dispersion was analyzed using PXRD which showed that the [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone was present in amorphous form (cf. FIG. 9).

Example 13: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with Aerosil 200 as Carrier (Matrix Compound)

(40) 163 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and 168 mg of Aerosil 200 were suspended in 50 mL CH.sub.2Cl.sub.2. The suspension was stirred at room temperature for 15 hours. Subsequently, the solvent was removed on a rotavapor at 40 C. The residue was dried under vacuum at room temperature for 2 days. The resulting solid dispersion was analyzed using PXRD which showed that the [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone was present in amorphous form (cf. FIG. 10).

Example 14: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with Neusilin US2 as Carrier (Matrix Compound)

(41) 153 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and 154 mg of Neusilin US2 were suspended in 50 mL CH.sub.2Cl.sub.2. The suspension was stirred at room temperature for 15 hours. Subsequently, the solvent was removed on a rotavapor at 40 C. The residue was dried under vacuum at room temperature for 2 days. The resulting solid dispersion was analyzed using PXRD which showed that the [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone was present in amorphous form (cf. FIG. 11).

Example 15: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with Neusilin UFL2 as Carrier (Matrix Compound)

(42) 153 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and 155 mg of Neusilin UFL2 were suspended in 50 mL CH.sub.2Cl.sub.2. The suspension was stirred at room temperature for 15 hours. Subsequently, the solvent was removed on a rotavapor at 40 C. The residue was dried under vacuum at room temperature for 2 days. The resulting solid dispersion was analyzed using PXRD which showed that the [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl) phenyl]methanone was present in amorphous form (cf. FIG. 12).

Example 16: Preparation of Solid Dispersions by Spray Drying

(43) 750 mg suvorexant and 250 mg polymer as indicated in tables 1 and 2 below were dissolved in 250 mL dichloromethane at room temperature. Amorphous solid dispersions were obtained by spray-drying with the following parameters:

(44) TABLE-US-00001 TABLE 1 Spray-drying parameters inlet temperature outlet temperature spray rate of feed [ C.] [ C.] [mL/min] 43-55 33-40 3-5

(45) The yields are listed in the following Table 2:

(46) TABLE-US-00002 TABLE 2 Yields obtained polymer yield [%] HPMC 89 HPC 91 Soluplus 94

II. Characterization of the Solid Dispersions

(47) X-ray powder diffraction patterns were obtained with a PANalytical X'Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalpha1,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector. The patterns were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013 2-Theta with 40 s per step (255 channels) in the angular range of 2 to 40 2-Theta at ambient conditions.

III. Preparation of Amorphous Suvorexant

III.1 Preparation by Spray-Drying

Example 17: Preparation the Amorphous Form of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone Via Spray Drying

(48) 1 g suvorexant was dissolved in 50 mL dichloromethane at room temperature. Amorphous suvorexant was obtained by spray-drying through the nozzle of a Bchi Spray Dryer. The process parameters were set as follows:

(49) TABLE-US-00003 TABLE 3 Spray-drying parameters inlet temperature outlet temperature spray rate of feed [ C.] [ C.] [mL/min] 43-55 33-40 3-5

(50) The amorphous suvorexant was obtained in 95% yield.

III.2 Preparation by Evaporation on a Rotavapor

Example 18: Preparation the Amorphous Form of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone

(51) 200 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone were dissolved in 5 mL CH.sub.2Cl.sub.2. The solvent was evaporated on a rotavapor at 40 C., the residue was dried under vacuum at room temperature for 2 days. The resulting solid was analyzed using PXRD which showed that the [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone was present in amorphous form (cf. FIG. 13).

III.3 Characterization

(52) See above under paragraph II.

IV. Determination of the Moisture Stability

(53) 20-200 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone and a specific amount of the matrix compound relative to the amount of the API as indicated in Table 3 below were suspended in 50 mL CH.sub.2Cl.sub.2. The suspension was stirred at room temperature for 15 hours. Subsequently, the solvent was removed on a rotavapor at 40 C. The residue was dried under vacuum at room temperature for 2 days to give a solid dispersion comprising suvorexant in amorphous only. The long term stability was measured as follows: 40-100 mg of a given solid composition were exposed to an atmosphere having a relative humidity of 75% and a temperature of 40 C. for a period of time as indicated in Table 3 below, if stable and if not having deliquesced, and analysed via XRD as described above in paragraph II with respect to the amorphousness.

(54) TABLE-US-00004 TABLE 4 API loading [weight-%, based on the total weight of the sum of API + matrix matrix compound compound] t (time of stability) none 100 1 week < t < 2 weeks Soluplus 20 1 day < t < 1 week 40 1 day < t < 1 week 50 t > 4 weeks 60 t > 4 weeks 80 t > 4 weeks 95 t > 4 weeks HPMCAS 50 t > 4 weeks 60 t > 4 weeks 80 t > 4 weeks 95 t > 4 weeks Methocel E5 50 t > 4 weeks 60 t > 4 weeks 80 t > 4 weeks 95 t > 4 weeks Syloid 72 FP 20 t > 4 weeks 40 t > 4 weeks 50 t > 6 weeks 60 1 week < t < 2 weeks 75 <1 day Syloid 244 FP 20 t > 4 weeks 40 t > 4 weeks 50 t > 6 weeks 60 t > 4 weeks 75 <1 day Syloid AL-1 FP 20 t > 4 weeks 40 1 day < t < 10 days 50 1 day < t < 2 weeks Neusilin US2 20 t >4 weeks 40 t >4 weeks 50 t >6 weeks 60 1 day < t < 1 week 75 1 day < t < 1 week 95 1 day < t < 1 week Neusilin UFL 20 t > 4 weeks 40 t > 4 weeks 50 t > 2 weeks 60 2 weeks < t < 4 weeks Aerosil 200 20 t > 4 weeks 40 t > 4 weeks 50 t > 4 weeks 60 t > 4 weeks

V. Dynamic Vapor Sorption (DVS) Measurements at 75% Relative Humidity and 25 C.

(55) The adsorption-desorption isotherms from which the values of m(desorption) and m(adsorption) at 75% relative humidity and at 25 C. were obtained, were recorded with an SPSx-1 moisture sorption analyzer (ProUmid GmbH & Co. KG, Ulm, Germany). The measurement cycle was started at 40% relative humidity (RH) and first decreased to 3% RH and 0% RH. Then RH was increased to 5% to 10% RH, afterwards to 90% RH in 10% steps and further to 95% RH. The desorption cycle started with a 5% step to 90% RH, then from 90% to 10% RH in 10% steps, to 5% RH and to 0% RH. The last step was the increase of RH to 40%. The time per step was set to a minimum of 1 hour and a maximum of 3 hours. If an equilibrium condition with a constant mass of 0.01% within 1 hour was reached before the maximum time for all examined samples the sequential humidity step was applied before the maximum time of 3 hours. If no equilibrium was achieved the consecutive humidity step was applied after the maximum time of 3 hours. The temperature was (250.1) C.

(56) To obtain the m(desorption) and m(adsorption) values, the recorded adsorption-desorption isotherms shown in the Figures of the present invention were analysed by comparing the value of m(desorption), plotted on the y axis, of a given desorption isotherm with the value of m(adsorption), plotted on the y axis, of the respective adsorption isotherm, both at 75% r.h., plotted on the x axis.

VI. Preparation of Solid Dispersions

Example 19: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with Kollidon VA64 as Carrier (Matrix Compound) and Kolliphor P188 Micro as Surfactant

(57) 781 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone, 360 mg Kollidon VA64 and 60 mg Kolliphor P188 micro were dissolved in 10 mL dichloromethane. After filtration, the clear solution was evaporated on a rotavapor at 40 C. The foam-like residue was dried under vacuum at room temperature for 18 hours.

Example 20: Preparation of a Solid Dispersion of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] methanone with Kollidon VA64 as Carrier (Matrix Compound) and Tween 80 as Surfactant

(58) 783 mg of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone, 361 mg Kollidon VA64 were dissolved in 10 mL dichloromethane. 60 mg Tween 80 were dissolved in 5 mL dichloromethane. The two solutions were combined and filtrated. Then the clear solution was evaporated on a rotavapor at 40 C. The foam-like residue was dried under vacuum at room temperature for 18 hours.

VII. Preparation of Tablets

Example 21: Preparation of Compositions Comprising a Solid Dispersion of Suvorexant in the Form of Tablets

(59) Tablets were prepared employing the solid dispersions comprising amorphous suvorexant. The solid dispersions were prepared either by dissolving (steps (a), (b), and (c), as described herein), or by milling (steps (a), (b) and (c), as described herein). In particular, with regard to the preparation of the solid dispersions by dry-milling the components as indicated, using a Retsch mill having a 25 ml milling cell, wherein milling was carried out for 20 min at a milling frequency of 27.5 Hz. The tablets prepared had the following composition as described in Table 5. As matrix compounds, Kollidon VA64, Soluplus, HPMCAS and Neusilin UFL were used.

(60) TABLE-US-00005 TABLE 5 General composition of tablets Component of tablet Amount component/mg Amorphous Suvorexant 20.00* Matrix compound 10.80* Microcrystalline cellulose (Avicel PH 15) 82.50 Lactose monohydrate (FlowLac 100) 110.45 Croscarmellose sodium (Ac-Di-Sol) 23.00 Magnesium stearate 1.25 Total weight: 250.00 *Part of solid dispersion. Suvorexant concentration of solid dispersion: 65 weight-%

(61) The tablets were prepared according to the following procedure: The solid dispersion, the microcrystalline cellulose, the lactose monohydrate and the croscarmellose sodium were mixed in a suitable container for 3-5 minutes. Magnesium stearate was added and mixed for another 1 minute. The final blend was compressed using a tooling 9 mm round into tablets. The respectively obtained tablets were subjected to a dissolution test. Thus dissolution test was carried using a paddle apparatus having a volume of 1000 ml, a rotation speed of 50 r.p.m., wherein, as dissolution medium, 0.1 M HCl was employed. The obtained dissolution profiles are shown in FIG. 21 to 24.

(62) In Table 6 below, the results of the experiments are described. With regard to the solid dispersion employed, it is described if the suvorexant contained in the solid dispersion is amorphous after the preparation of the solid dispersion. Further, it is described if the suvorexant is stable in its amorphous form after the stability test (3 weeks at 40 C. and 75% r.h.; see section IV above). Further, it is described which dissolution values were obtained for the individual tablets.

(63) TABLE-US-00006 TABLE 6 Characterization of suvorexant and tablets Matrix compound Kollidon Soluplus HPMCAS Neusilin Content of solid dispersion of matrix 80 80 80 40 compound prepared by dissolving/drying/weight-% Content of solid dispersion of matrix 65 65 65 65 compound prepared by milling/weight-% Suvorexant present in amorphous yes yes yes yes form only in solid dispersion (after dissolving/drying)? Suvorexant present in amorphous yes yes yes yes form only in solid dispersion (after milling)? Suvorexant present in amorphous yes yes yes yes form only in the tablets based on solid dispersion (dissolving/drying) Stability test passed for tablets based yes yes yes yes on solid dispersion prepared by dissolving/drying and stored for the 3 weeks in aluminium blister? Stability test passed for tablets based yes yes yes yes on solid dispersion prepared by dissolving/drying and stored for the 3 weeks in PVC blister? Dissolution (after 1 hour) of tablets 54 52 36 71 based on solid dispersion prepared by dissolving/drying/% Dissolution (1 hour) of tablets based 64 42 28 41 on solid dispersion prepared by milling/%

Example 22: Preparation of Compositions Comprising a Solid Dispersion of Suvorexant in the Form of Tablets Further Comprising a Surfactant

(64) Tablets were prepared employing the solid dispersions comprising amorphous suvorexant.

(65) The solid dispersions were prepared by dissolving (steps (a), (b), and (c) as described herein. As matrix compound, Kollidon VA64 was used. In addition to the amorphous suvorexant and the matrix compound, a surfactant was employed. For the different tablets, Tween 80, Kolliphor 188, and SDS (sodium dodecyl sulfate) were employed. The solid dispersion had an amorphous suvorexant content of 65 weight-%, a matrix compound content of 30 weight-%, and a surfactant content of 5 weight-%.

(66) In Table 7 below, the results of the experiments are described. With regard to the solid dispersion employed, it is described if the suvorexant contained in the solid dispersion is amorphous after the preparation of the solid dispersion.

(67) TABLE-US-00007 TABLE 7 Experimental results of Example 22 Suvorexant present in amorphous Type of surfactant form only in solid dispersion? None yes Tween 80 yes Kolliphor 188 yes SDS yes

(68) The respectively obtained tablets were subjected to a dissolution test. Thus dissolution test was carried out as described in Example 21 above. The obtained dissolution profiles are shown in FIG. 25. Clearly, Kolliphor 188 was found to be a preferred surfactant since compared to a tablet which does not contain Kolliphor 188, the dissolution was increased after 1 hour.

CITED LITERATURE

(69) US 20080132490 A1 WO 2008/069997 Cox et al. (2010) Journal of Medicinal Chemistry, 53 (14): 5320-5332 WO 2012/148553 WO 2013/181174