Solid composition comprising suvorexant

The present invention relates to a solid composition comprising suvorexant, an orexin recep- tor antagonist, or a salt thereof and at least one pharmaceutically acceptable compound having an increased specific surface area.

Suvorexant, an orexin receptor antagonist with official name [(7R)-4-(5-chloro-l,3- benzoxazol-2-yl)-7-methyl- 1 ,4-diazepan- 1 -yl][5-methyl-2-(2H- 1 ,2,3-triazol-2-yl)phenyl]- methanone which has the structure according to formula (I)

is described, for example, in US 20080132490 Al, WO 2008/069997 A and Cox et al. (2010) Journal of Medicinal Chemistry, 53(14), pages 5320-5332. Alternative names for this compound are 5-chloro-2- {(5R)-5-methyl-4-[5-methyl-2-(2H- 1 ,2,3-thiazol-2-yl)benzoyl]- 1 ,4- diazepan-l-yl}-l,3-benzobenzoxazol and [(R)-4-(5-chloro-benzooxazol-2-yl)-7-methyl- [1 ,4]diazepan- 1 -yl]-(5-methyl-2-[ 1 ,2,3]triazol-2-yl-phenyl)-methanone.

Suvorexant is known to be a poorly soluble molecule which reaches only sufficient bioavailability in vivo when present in amorphous state.

In order to improve the solubility of suvorexant, WO 2015/158910 A suggests formulations containing a solid dispersion comprising suvorexant and a pharmaceutically acceptable matrix compound, wherein the matrix compound is a polymer or a silicon based inorganic compound.

In order to improve the solubility of suvorexant, WO 2013/181174 A suggests formulations containing a solubility enhancing polymer. However, these formulations provide suvorexant in an amorphous state which is known to be metastable. Therefore, there is the risk of polymorphic conversion. Moreover, manufacturing processes which usually include melt extru- sion are cost intensive. Further, such manufacturing processes are not easily applicable in an industrial scale since they tend to include many steps such as dissolving suvorexant in an organic solvent, the addition of polymer and the subsequent removal of the solvent. In addition, it has been seen that the high amount of polymer present in the formulation of WO 2013/181174 decreases the fast dissolution of the suvorexant. Hence, it is an object of the present invention to provide a novel solid composition comprising suvorexant which allows preparing tablets that do not exhibit the above mentioned disadvantages. The present inventors have found that solid compositions comprising suvorexant in a stable amorphous form and at least one pharmaceutically acceptable compound can be prepared. In particular, it has been observed that advantageously the solid compositions of the invention and the pharmaceutically acceptable formulations comprising the solid composition of the invention provide amorphous suvorexant having a good polymorphic stability or, in other words, no polymorphic transformation is observed. Thus the undesired conversion of the amorphous form to any other polymorphic forms taking place during the formulation process and during the storage is avoided. It has further been found that the solid compositions of the invention show a fast dissolution. As shown in Fig. 7, the pharmaceutical compositions comprising the solid composition of the invention have a faster dissolution profile with respect to pharmaceutical compositions comprising suvorexant polymorphic forms I and II. Advantageously, the solid compositions of the invention are prepared with a process which is simple and applicable on industrial scale and requires only few steps.

The solid compositions of the invention are characterized by comprising a pharmaceutically acceptable compound having an increased specific surface area with respect to the specific surface area of the pharmaceutically acceptable compound before being processed to the solid composition.

More specifically, the solid compositions of the invention may be prepared by milling su- vorexant together with a pharmaceutically acceptable compound of the invention. By milling the pharmaceutically acceptable compound, the specific surface area of the pharmaceutically acceptable compound is increased above a certain value. Without being bound to any theory, it is explained that the increase specific surface area allows an increased absorption of suvorexant on the pharmaceutically acceptable compound not only stabilizing suvorexant, but also maintaining a fast dissolution and good compressibility to form tablet.

Hence, the present invention relates to a solid composition comprising

i) suvorexant or a salt thereof in amorphous form and

ii) at least one pharmaceutically acceptable compound having an increased specific surface area as determined according to DIN-ISO 9277

wherein preferably the pharmaceutically acceptable compound in the solid composition has a specific surface area

which is at least of 1 mVg and /or which is greater of a factor of at least 1.5, preferably greater of a factor in the range of from 1.5 to 15, more preferably greater of a factor in the range of from 2 to 10, more preferably greater of a factor in the range of from 2.5 to 5 than the specific surface area of said pharmaceutically acceptable compound before being processed to form a solid composition.

The present invention is further directed to a process for the preparation of the solid composition of the invention comprising suvorexant or a salt thereof in amorphous form and at least one pharmaceutically acceptable compound, the process comprising:

a) mixing suvorexant or a salt thereof and at least one pharmaceutically acceptable compound wherein the pharmaceutically acceptable compound has a specific surface area; and

b) increasing the specific surface area of the pharmaceutically acceptable compound of a) by milling the mixture obtained in a) and obtaining the solid composition.

The present invention is further directed to a solid pharmaceutical formulation comprising the solid composition of the invention and a process for preparing said solid pharmaceutical formulation, the process comprising

c) processing the solid composition of the invention to a solid pharmaceutical formula- tion.

Solid composition

The present invention relates to a solid composition comprising

i) suvorexant or a salt thereof in amorphous form, and

ii) at least one pharmaceutically acceptable compound having an increased specific surface area,

wherein the specific surface area is as determined according to DIN-ISO 9277 as disclosed in Reference Example 1.

It has been observed that the pharmaceutically acceptable compound in the solid composition has a specific surface area that is increased with respect to the specific surface area of the pharmaceutically acceptable compound before being processed to form the solid composition. The pharmaceutically acceptable compound of the invention in the solid composition has a specific surface area of at least 1 m ² /g, preferably at least 3 m ² /g, more preferably at least 5 m ² /g, even more preferably at least 10 m ² /g.

Further, the present invention relates to a solid composition comprising

i) suvorexant or a salt thereof in amorphous form, and ii) at least one pharmaceutically acceptable compound having an increased specific surface area,

wherein the specific surface area is as determined according to DIN-ISO 9277 as disclosed in Reference Example 1 and wherein the pharmaceutically acceptable compound in the solid composition has a specific surface area which is greater of a factor of at least 1.5, preferably greater of a factor in the range of from 1.5 to 15, preferably greater of a factor in the range of from 1.5 to 10, more preferably greater of a factor in the range of from 2 to 7, more preferably greater of a factor in the range of from 2.5 to 5 than the specific surface area of said pharmaceutically acceptable compound before being processed to form the solid composition.

Further, the present invention relates to a solid composition comprising

i) suvorexant or a salt thereof in amorphous form, and

ii) at least one pharmaceutically acceptable compound having an increased specific surface area,

wherein the specific surface area is as determined according to DIN-ISO 9277 as disclosed in Reference Example 1 , and

wherein the pharmaceutically acceptable compound has a specific surface area of at least 1 m ² /g, preferably at least 3 m ² /g, more preferably at least 5 m ² /g, even more preferably at least 10 m ² /g and/or

wherein the pharmaceutically acceptable compound has a specific surface area which is greater of a factor of at least 1.5, preferably greater of a factor in the range of from 1.5 to 15, preferably greater of a factor in the range of from 1.5 to 10, more preferably greater of a factor in the range of from 2 to 7, more preferably greater of a factor in the range of from 2.5 to 5 than the specific surface area of said pharmaceutically acceptable compound before being pro- cessed to form a solid composition.

The processing to form the solid composition entails, for example, the milling of a mixture comprising suvorexant or a salt thereof and at least one pharmaceutically acceptable compound. If the solid composition of the invention comprises more than one pharmaceutically acceptable compound according to the invention all the pharmaceutically acceptable compounds have an increase of the specific surface area according to a factor as disclosed above.

In the context of the present invention, the specific surface area is as determined according to DIN-ISO 9277 the Brunauer-Emmet-Teller method (BET method) as explained in Reference Example 1. a) suvorexant

In the solid composition, suvorexant or the salt thereof is in an amorphous form. The term "amorphous" as used herein means a solid state of a body which does not have a long-range crystalline order as detectable by XRD (X-ray diffraction) when measurement is done at a wavelength of 0, 1 5419 nm, using Cu-Kalphal,2 radiation at a temperature in the range of 15 to 25 °C as disclosed in in Reference Example 2.

In the solid composition, the specific surface area is preferably at least 3 m ² /g, more preferably at least 5 m ² /g, more preferably at least 10 m ² /g. b) pharmaceutically acceptable compound of the solid composition of the invention

In the solid composition, the pharmaceutically acceptable compound is an organic compound or an inorganic compound. The organic compound or the inorganic compound preferably acts as a carrier. bl) organic non-polymeric compound of the solid composition of the invention

Preferably, the organic compound is an organic non-polymeric compound. A polymer is a macromolecule composed by many repeated subunits (monomer) that can be the same or different (copolymer). In the context of the present invention, an organic non-polymeric compound is an organic compound that is not made up of repeated subunits or when is made up of repeated subunits, the subunits number is < 10, preferably < 5, more preferably < 3.

Preferably, the organic non-polymeric compound of the invention has a molecular weight < 1000 Da, more preferably < 500 Da, even more preferably < 200 Da. For example, lactose, one of the organic non-polymeric compound according to the invention, has a molecular weight of 342.3 Da; mannitol, another organic compound according to the invention, has a molecular weight of 182.172 Da.

Regarding to the organic non-polymeric compound, preferably it is selected from the group consisting of saccharides, sugar alcohols and mixtures thereof. Preferably the saccharide is selected from the group consisting of monosaccharide and disaccharide and a mixture thereof. Preferably, the organic non-polymeric compound is selected from the group consisting of monosaccharides and disaccharides, more preferably the organic non-polymeric compound is a sugar or a sugar-derived compound.

Regarding the saccharide, it is preferably a disaccharide wherein the disaccharide is prefera- bly selected from the group consisting of lactose, saccharose maltose and a mixture thereof.

Regarding the pharmaceutically acceptable compound it is preferably selected form the group consisting of a sugar alcohol, preferably mannitol and a disaccharide preferably lactose, the pharmaceutically acceptable compound preferably having a specific surface area in the range of from 3 to 11 m ² /g, more preferably in the range of from 3.5 to 8 m ² /g, even more preferably in the range of from 3.8 to 7.7 m ² /g.

Regarding the sugar alcohol, it is preferably selected from the group consisting of mannitol, xylitol and sorbitol. Mixtures of disaccharides and sugar alcohols also may be used. Preferably the sugar alcohol is mannitol, more preferably D-mannitol. Regarding the specific surface area of the sugar alcohol before being processed to the solid composition of the invention, it is preferably a specific surface area lower than 1.4 m ² /g. Regarding mannitol, mannitol is com- mercially available under the trademark Pearlitol®. The specific surface area of commercially available Pearlitol® is below 1.2 m ² /g. For example, Pearlitol® 100SD has a specific surface area of 1.1 m ² /g, Pearlitol® 200SD has a specific surface area of 1.2 m ² /g, Pearlitol® 25C has a specific surface area of 0.8 m ² /g, Pearlitol® 50C has a specific surface area of 0.6 m ² /g, Pearlitol® 160C has a specific surface area of 0.3 m ² /g. Mannitol is also available under the trademark Partek® Delta mannitol. These values of specific surface area refer to the specific surface area of the sugar alcohol before being processed to the solid composition of the invention. The specific surface area of the commercially available sugar alcohol is increased in the solid composition of the invention of a factor as disclosed above. The specific surface area of the pharmaceutically acceptable compound in the solid composition of the invention is as dis- closed above. Preferably the specific surface area of mannitol in the solid composition is in the range of from 3 to 11 m ² /g, more preferably in the range of from 6 to 7.7 m ² /g.

Regarding the monosaccharide, a monosaccharide is preferably selected from the group consisting of glucose, fructose, galactose, ribose any xylose.

Regarding the disaccharide, preferably the disaccharide is lactose, more preferably lactose monohydrate. Regarding the specific surface area of the disaccharide before being processed to the solid composition of the invention, it is preferably a specific surface area lower than 1.5 m ² /g. Regarding lactose monohydrate, lactose monohydrate is commercially available under the trade mark Granulac®. The specific surface area of the commercially available Granulac® is below 1.5 m ² /g. For example, Granulac® 70 has a specific surface area of 0.26 m ² /g, Granulac® 140 has a specific surface area of 0.42 m ² /g, Granulac® 230 has a specific surface area of 0.89 m ² /g. These values of the specific surface area refer to the specific surface area of the disaccharide before being processed to the solid composition of the invention. The specific surface area of the commercially available pharmaceutically acceptable compounds is increased in the solid composition of the invention of a factor as disclosed above. The specific surface area of the pharmaceutically acceptable compound in the solid composition of the invention is as disclosed above. Preferably the specific surface area of lactose, preferably of lactose monohydrate in the solid composition is in the range of from 3 to 8 m ² /g, preferably in the range of from 3.5 to 5 m ² /g, more preferably in the range of from 3.8 to 4 m ² /g.

Regarding the organic non-polymeric compound, the preferred organic non-polymeric com- pounds are selected from the group consisting of mannitol and lactose. b2 ) inorganic compound

Pharmaceutically acceptable compounds according to the invention are also inorganic compounds.

Regarding the inorganic compound, preferably the inorganic compound is selected from the group consisting of silicates, silica, phosphates and mixtures thereof. Preferably the inorganic compound is selected from the group consisting of a silicate and a phosphate, more preferably the inorganic compound is a silicate.

Regarding silicates, preferred silicates comprise, preferably are, one or more of aluminosili- cates, wherein the one or more aluminosilicates preferably comprise at least one alkali metal element, at least one alkaline earth metal element, or at least one alkali metal element and at least one alkaline earth metal element, more preferably at least one alkaline earth metal ele- ment, more preferably magnesium. Thus, preferably, the silicate is an aluminosilicate which, more preferably, additionally contains at least one alkali metal element selected from the group consisting of Li, Na, K, Rb, Cs and a combination of two or more thereof, preferably from the group consisting of Li, Na, K, and a combination of two or more thereof, more preferably from the group consisting of Na, K, and a combination of two or more thereof, and/or at least one alkaline earth metal element selected from the group consisting of Mg, Ca, Sr, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, and a combination of two or more thereof. More preferably, the silicate is an aluminosilicate which additionally contains at least one alkaline earth metal element selected from the group consisting of Mg, Ca, Sr, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, and a combination of two or more thereof. More preferably, the silicate is an aluminosilicate which additionally contains Mg. Preferred silicates include, but are not restricted to, the commercially available compounds Neusilin®, preferably Neusilin® UFL2, Neusilin® US2, Neusilin® NFL2N and Neusilin® NS2N. Neusilin® grades UFL2 and US2 have a specific surface area of about 300 m ² /g. The Neusilin® grade NFL2N and NS2N have a specific surface area of about 250 m ² /g. As disclosed above, the specific surface area of the starting pharmaceutically acceptable compounds is increased in the solid composition of the invention of a factor as disclosed above due to the processing (milling) to solid composition. The specific surface area of the silicate in the solid composition of the invention is preferably > 300 m ² /g, more preferably the specif- ic surface area is at least 400 m ² /g.

Regarding the silica, preferred forms thereof include, but are not limited to, fumed silica, precipitated silica, silica gel, and colloidal silica. Preferred silica include, but are not restricted to, the commercially available compounds Syloid® 72 FP and Syloid® 244 FP. The specific sur- face area of the silica in the solid composition is increased with respect to the silica before being processing (milling) to the solid composition of the invention of a factor of at least 1.5, preferably of a factor in the range of from 1.5 to 15, preferably of a factor in the range of from 1.5 to 10, more preferably of a factor in the range of from 2 to 7, more preferably of a factor in the range of from 2.5 to 5.

Regarding the phosphate, preferred forms of phosphate include dicalcium phosphate, more preferably, dicalcium phosphate anhydrous (DCPA). Commercially available dicalcium phosphate anhydrous is known under the trademark Fujicalin® with a specific surface area of 40 m ² /g. Commercially available DCPA may have a specific surface area in the range of 0.8 to 1.10 m ² /g. The specific surface area of the phosphate is increased in the solid composition of the invention. For example commercially available DCPA -having a specific surface area in the range of 0.8 to 1.10 m ² /g before being processed (milled)- have a specific surface area at least 3 m ² /g, preferably a specific surface area at least 10 m ² /g in the solid composition of the invention. The specific surface area of the pharmaceutically acceptable compounds of step a) as disclosed below i.e. before being process (milled) to the solid composition is increased in the solid composition of the invention (i.e., after milling) of a factor at least 1.5, preferably of a factor in the range of from 1.5 to 15, preferably of a factor in the range of from 1.5 to 10, more preferably of a factor in the range of from 2 to 7, more preferably of a factor in the range of from 2.5 to 5 with respect to the specific surface area of said pharmaceutically acceptable compound before being processed (milled) to form a solid composition.

In the solid composition, the weight ratio of suvorexant or salt thereof relative to the pharmaceutically acceptable compound is preferably in the range of from 1 : 1 to 1 : 10, more preferably in the range of from 1 : 2 to 1 : 7, even more preferably in the range of from 1 : 3 to 1 : 5, more preferably, the weight ratio of suvorexant or salt thereof relative to the pharmaceutically acceptable compound, is in the range of from 1 : 3 to 1 : 5, such as from 1 : 5 to 1 : 4, from 1 : 4 to 1 : 3 or from 1 : 3 to 1 : 2. If more than one pharmaceutically acceptable compound is comprised in the solid composition, the weight ratios relate to the total weight of all the pharmaceutically acceptable compounds. In addition to suvorexant or salt thereof and the pharmaceutically acceptable compound, the solid composition may comprise at least a further compound. Preferably the at least a further compounds is selected from suitable pharmaceutically acceptable excipients. Preferably, at least 90 weight-%, preferably at least 95 weight- %, more preferably at least 99% of the solid composition consist of suvorexant and the pharmaceutically acceptable compound or a mixture of pharmaceutically acceptable compounds.

According to a preferred embodiment, the at least one pharmaceutically acceptable compound comprised in the solid composition consists of one pharmaceutically acceptable compound, i.e. no other pharmaceutically acceptable compound is comprised in the solid composition but the pharmaceutically acceptable compound. Regarding this preferred embodiment, preferably at least 95 weight-%, more preferably at least 96 weight-%, more preferably at least 97 weight-%), more preferably at least 98 weight-%), more preferably at least 99 weight- %, more preferably at least 99.5 weight-%, more preferably at least 99.9 weight-% of the solid composition consist of suvorexant or the salt thereof and the pharmaceutically acceptable compound. More preferably, the solid composition essentially consists of the pharmaceutically acceptable compound and suvorexant or the salt thereof. The term "essentially consists of as used in this context of the present invention describes a solid composition which, in addition to the su- vorexant or the salt thereof and the pharmaceutically acceptable compound, only contains impurities of the suvorexant or the salt thereof and/or of pharmaceutically acceptable compound which can be tolerated in view of the desired use if the solid composition or, which cannot be avoided. In a preferred embodiment, in the solid composition at least 90 weight-%, preferably at least 95 weight-%), more preferably at least 99 weight-%) of the suvorexant consists of amorphous suvorexant. In this case less than 10 weight- %, preferably less than 5 weight-%, more preferably less than 1 weight-% of the suvorexant consists of crystalline suvorexant, wherein preferably the crystalline suvorexant is form I or form II or a mixture thereof.

A preferred solid composition of the invention comprises suvorexant in an amorphous form and a pharmaceutically acceptable compound selected from the group consisting of a sugar alcohol such as mannitol and/or a disaccharide such as lactose, preferably having a specific surface area of at least 1 m ² /g, preferably at least 3 m ² /g, more preferably at least 5 m ² /g, more preferably at least 10 m ² /g. A preferred range is a range of from 3 to 11 m ² /g, a range of from 3.5 to 8 m ² /g, a range of from 3.8 to 7.7 m ² /g. Preferably, the pharmaceutically acceptable compound is a sugar alcohol, more preferably mannitol, even more preferably a mannitol having a specific surface area in the range of from 3 to 11 m ² /g, more preferably in the range of from 6 to 7.7 m ² /g. Preferably, the pharmaceutically acceptable compound is a saccharide, more preferably lactose, even more preferably a lactose having a specific surface area in the range of from 3 to 8 m ² /g, preferably in the range of from 3.5 to 5 m ² /g, more preferably in the range of from 3.8 to 4 m ² /g, wherein preferably lactose is lactose monohydrate. The solid composition of the invention as defined above is a solid composition obtainable or obtained by the process of the invention as disclosed herein below.

The solid composition of the invention as defined above is a solid composition preferably comprised in a solid pharmaceutical formulation, preferably as disclosed herein below, where- in the solid pharmaceutical formulation is preferably a tablet or a capsule, more preferably is a tablet. Preferably, the solid pharmaceutical formulation in the form of capsule is wherein the capsule is a gelatin capsule, preferably a soft gelatin capsule.

The term "tablet" as used herein is intended to comprise compressed pharmaceutical oral dos- age forms of ail shapes and sizes, whether coated or uncoated.

Process for preparing the solid composition

The present invention is further directed to a process for the preparation of the solid composi- tion of the invention comprising suvorexant or a salt thereof in amorphous form and at least one pharmaceutically acceptable compound.

Hence, the present invention relates to a process for preparing the solid composition of the invention, wherein the process comprises:

a) mixing suvorexant or a salt thereof and at least one pharmaceutically acceptable compound wherein the pharmaceutically acceptable compound has a specific surface area, and

b) increasing the specific surface area of the pharmaceutically acceptable compound of a) by milling the mixture obtained in a) and obtaining the solid composition, wherein the pharmaceutically acceptable compound after milling of b) has a specific surface area of at least 1 m ² /g, preferably at least 3 m ² /g, more preferably at least 5 m ² /g, even more preferably at least 10 m ² /g and wherein the specific surface area is as determined according to DIN-ISO 9277. Further the present invention relates to a process for preparing the solid composition of the invention, wherein the process comprises:

a) mixing suvorexant or a salt thereof and at least one pharmaceutically acceptable compound wherein the pharmaceutically acceptable compound has a specific surface area, and

b) increasing the specific surface area of the pharmaceutically acceptable compound of a) by milling the mixture obtained in a) and obtaining the solid composition, wherein the at least one pharmaceutically acceptable compound after milling in b) has a specific surface area which is greater of a factor of at least 1.5, preferably greater of a factor in the range of from 1.5 to 15, preferably greater of a factor in the range of from 1.5 to 10, more preferably greater of a factor in the range of from 2 to 7, more preferably greater of a factor in the range of from 2.5 to 5 than the specific surface area of said pharmaceutically acceptable compound in a) and wherein the specific surface area is as determined according to DIN-ISO 9277.

Further, the present invention relates to a process for preparing the solid composition of the invention, wherein the process comprises:

a) mixing suvorexant or a salt thereof and at least one pharmaceutically acceptable compound wherein the pharmaceutically acceptable compound has a specific surface area, and

b) increasing the specific surface area of the pharmaceutically acceptable compound of a) by milling the mixture obtained in a) and obtaining the solid composition, wherein the pharmaceutically acceptable compound after milling of b) has a specific surface area of at least 1 m ² /g, preferably at least 3 m ² /g, more preferably at least 5 m ² /g, even more preferably at least 10 m ² /g and/or

wherein the pharmaceutically acceptable compound after milling of b) has a specific surface area which is greater of a factor of at least 1.5, preferably greater of a factor in the range of from 1.5 to 15, preferably greater of a factor in the range of from 1.5 to 10, more preferably greater of a factor in the range of from 2 to 7, more preferably greater of a factor in the range of from 2.5 to 5 than the specific surface area of said pharmaceutically acceptable compound in a) i.e. before being processed to form a solid composition and wherein the specific surface area is as determined according to DIN-ISO 9277. The pharmaceutically acceptable compound after milling in b) has a specific surface area that in not less than 1 m ² /g. The pharmaceutically acceptable compound in b) has a specific surface area that is at least 1 m ² /g. Preferably, the specific surface area of the pharmaceutically acceptable compound in b) is at least 3 m ² /g, preferably at least 5 m ² /g, more preferably the specific surface area said pharmaceutically acceptable compound in b) is at least 10 m ² /g. Further, the present invention is directed to a process for the preparation of the solid composition of the invention comprising suvorexant or a salt thereof in amorphous form and at least one pharmaceutically acceptable compound having a specific surface area of at least 1 m ² /g the specific surface area being as determined according to DIN-ISO 9277, the process comprising:

a) mixing suvorexant and at least one pharmaceutically acceptable compound wherein the pharmaceutically acceptable compound has a specific surface area, obtaining a mixture, and

b) increasing the specific surface area of the pharmaceutically acceptable compound of a) by milling the mixture obtained in a), obtaining the solid composition,

wherein the at least one pharmaceutically acceptable compound after milling of b) has a specific surface area of at least 1 m ² /g, preferably at least 3 m ² /g, more preferably at least 5 m ² /g, even more preferably at least 10 m ² /g and/or

wherein the at least one pharmaceutically acceptable compound after milling in b) has a specific surface area which is greater of a factor of at least 1.5, preferably greater of a factor in the range of from 1.5 to 15, preferably greater of a factor in the range of from 1.5 to 10, more preferably greater of a factor in the range of from 2 to 7, more preferably greater of a factor in the range of from 2.5 to 5 than the specific surface area of said pharmaceutically acceptable compound in a) and wherein the specific surface area is as determined according to DIN-ISO 9277.

Regarding the specific surface area of the pharmaceutically acceptable compound in a) it is smaller than the specific surface area of the pharmaceutically acceptable compound in b). It is explained that the specific surface area of pharmaceutically acceptable compound of a) is increased by the milling of b). Preferably, the pharmaceutically acceptable compound in b) has a specific surface area which is greater of a factor of at least 1.5, preferably of a factor in the range of from 1.5 to 15, preferably of a factor in the range of from 1.5 to 10, more preferably of a factor in the range of from 2 to 7, more preferably of a factor in the range of from 2.5 to 5 than the specific surface area of said pharmaceutically acceptable compound in a).

Regarding the specific surface area of the pharmaceutically acceptable compound in b), it is at least 1 m ² /g. Preferably, the specific surface area of the pharmaceutically acceptable compound in b) is at least 3 m ² /g, preferably at least 5 m ² /g, more preferably the specific surface area said pharmaceutically acceptable compound in b) is at least 10 m ² /g.

It has been seen that a stabilizing effect is achieved when there is an increase of the specific surface area of the pharmaceutically acceptable compound with respect to starting specific surface area of the pharmaceutically acceptable compound of step a). For example, when the pharmaceutically acceptable compound of a) is a silicate the specific surface area can already be at least 1 m ² /g, yet it is the increase of the final specific surface area according to the factors described above that allows obtaining an advantageous dissolution profile and a suvorexant stable amorphous form. Step a)

As disclosed above the process of the invention comprises step a):

a) mixing suvorexant or a salt thereof and at least one pharmaceutically acceptable compound wherein the pharmaceutically acceptable compound has a specific surface area, obtaining a mixture.

A) suvorexant

The provision of suvorexant may be carried out by any method known to the person skilled in the art, such as, e.g., the methods described in WO2012/148553 Al . Suvorexant may be provided in any form, such as in crystalline or in amorphous form or as a mixture of crystalline and amorphous form. Suvorexant may be provided as a salt, preferably the salt is a pharma- ceutically acceptable salt.

Preferably, the suvorexant in (a) is provided in crystalline form such as described in WO 2012/148553 Al . Thus, suvorexant provided in a) may be present in crystalline form I or form II as described above, or may present as a mixture of form I or form II. Preferably, su- vorexant is provided in polymorphic crystalline form I or form II as disclosed above, even more preferably in polymorphic crystalline form I.

Regarding the crystalline form of suvorexant or the salt thereof, it is provided preferably in the form such as described in WO 2012/148553 Al . Thus, suvorexant in the solid composi- tion may be present in crystalline forms I or II or may present as a mixture of form I and form II.

Form I is characterized by the following XRDP peak values:

Pos. [°2Th.]

2.1947±0.2

3.3561±0.2

6.9524±0.2

10.4603±0.2

14.1262±0.2

15.2644±0.2

16.0273±0.2 17.5256±0.2

21.0662±0.2

22.4215±0.2

25.8414±0.2

Form II is characterized by the following XRDP peak values:

Pos. [°2Th.]

2.1278 ±0.2

11.2716±0.2

11.8308±0.2

12.1964±0.2

13.6736±0.2

14.3153±0.2

15.4344±0.2

16.4169±0.2

17.2498±0.2

17.6032±0.2

17.9378±0.2

18.9081±0.2

19.6779±0.2

21.0014±0.2

21.6376±0.2

23.6680±0.2

24.6272±0.2

26.3743±0.2

26.7454±0.2

27.5276±0.2

30.0721±0.2

32.9814±0.2

33.6808±0.2

Thus, suvorexant in a) may be in crystalline form I or form II or in a mixture of form I and form II.

Alternatively, suvorexant in (a) is provided in amorphous form. Thus, the present invention also relates to a process for preparing a solid composition and a solid composition obtained or obtainable by the herein described process, wherein in step (a) crystalline or amorphous suvorexant, preferably crystalline suvorexant in polymorphic crys- talline form I or form II, more preferably in polymorphic crystalline form I is provided.

B) pharmaceutically acceptable compound of the process of the invention provided in a)

In the solid composition of the invention, the pharmaceutically acceptable compound is an organic compound or an inorganic compound.

Bl ) organic non-polymeric compound of the process of the invention provided in a)

Preferably, the organic compound is an organic non-polymeric compound. A polymer is a macromolecule composed by many repeated subunits (monomer) that can be the same or different (copolymer). In the context of the present invention, an organic non-polymeric com- pound is a compound that is not made up of repeated subunits or when made up of repeated subunits, the subunits number is < 10, preferably < 5, more preferably < 3.

Preferably, the organic compound has a molecular weight < 1000 Da, more preferably < 500 Da, even more preferably < 200 Da. For example, lactose, one of the organic compound ac- cording to the invention, has a molecular weight of 342.3 Da, mannitol, another organic compound according to the invention, has a molecular weight of 182.172 Da.

Regarding to the organic non-polymeric compound, preferably it is selected from the group consisting of saccharides, sugar alcohols and mixtures thereof. Preferably the saccharide is selected from the group consisting of monosaccharides, disaccharide and mixtures thereof. Preferably, the organic non-polymeric compound is selected from the group consisting of monosaccharides and disaccharides, more preferably the organic non-polymeric compound is a sugar or a sugar-derived compound. Regarding the saccharide, it is preferably selected from the group of disaccharides wherein preferably the disaccharide is selected from the group consisting of lactose, saccharose, and maltose and a mixture thereof.

Regarding the sugar alcohol, it is preferably selected from the group of mannitol, xylitol, sor- bitol. Mixtures of disaccharides and sugar alcohols also may be used. Preferably the sugar alcohol is mannitol, more preferably D-mannitol. Regarding the sugar alcohol of step a) it preferably has a specific surface area lower than 1.4 m ² /g. Mannitol is commercially available under the trademark Pearlitol®. The specific surface area of the commercially available Pearlitol® may be below 1.4 m ² /g. For example, Pearlitol® 100SD has a specific surface area of 1.1 m ² /g, Pearlitol® 200SD has a specific surface area of 1.2 m ² /g, Pearlitol® 25C has a specific surface area of 0.8 m ² /g, Pearlitol® 50C has a specific surface area of 0.6 m ² /g, Pearlitol® 160C has a specific surface area of 0.3 m ² /g. Mannitol is also available under the trademark Partek® Delta mannitol. The specific surface area of the commercially available phar- maceutically acceptable compounds is increased in the solid composition of the invention of a factor as disclosed above.

Regarding the disaccharides, they are preferably selected from the group consisting of lactose, sucrose, maltitol, and a mixture thereof. Preferably, the disaccharide is lactose. Regarding the disaccharide of step a), it preferably has a specific surface area lower than 1.5 m ² /g. For example, lactose is commercially available under the trade mark Granulac®. The specific surface area of the commercially available Granulac® is below 1.5 m ² /g. For example, Granulac® 70 has a specific surface area of 0.26m ² /g, Granulac® 140 has a specific surface area of 0.42 m ² /g, Granulac® 230 has a specific surface area of 0.89m ² /g. The specific surface area of the commercially available pharmaceutically acceptable compounds is increased in the solid composition of the invention of a factor as disclosed above.

Regarding the organic non-polymeric compound, the preferred organic non-polymeric compounds are selected from the group consisting of mannitol and lactose. Mannitol and lactose are the preferred organic non-polymeric compounds according to the invention.

B2 ) inorganic compound of the process of the invention provided in a)

Pharmaceutically acceptable compound according to the invention are also inorganic compounds.

Regarding the inorganic compound, preferably it is selected from the group consisting of silicates, silica, phosphates and mixtures thereof. Preferably the inorganic compound is selected from the group consisting of a silicate or a phosphate, more preferably the inorganic compound is a silicate.

Regarding the silicate, preferred silicates comprise, preferably are, one or more of aluminosil- icates, wherein the one or more aluminosilicates preferably comprise at least one alkali metal element, at least one alkaline earth metal element, or at least one alkali metal element and at least one alkaline earth metal element, more preferably at least one alkaline earth metal ele- ment, more preferably magnesium. Thus, preferably, the silicate is an aluminosilicate which, more preferably, additionally contains at least one alkali metal element selected from the group consisting of Li, Na, K, Rb, Cs and a combination of two or more thereof, preferably from the group consisting of Li, Na, K, and a combination of two or more thereof, more preferably from the group consisting of Na, K, and a combination of two or more thereof, and/or at least one alkaline earth metal element selected from the group consisting of Mg, Ca, Sr, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, and a combination of two or more thereof. More preferably, the silicate is an aluminosili- cate which additionally contains at least one alkaline earth metal element selected from the group consisting of Mg, Ca, Sr, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, and a combination of two or more thereof. More preferably, the silicate is an aluminosilicate which additionally contains Mg. Preferred sili- cates include, but are not restricted to, the commercially available compounds Neusilin®, preferably Neusilin® UFL2, Neusilin® US2, Neusilin® NFL2N and Neusilin® NS2N. Neusilin® grades UFL2 and US2 have a specific surface area of about 300 m ² /g. The Neusilin® grade NFL2N and NS2N have a specific surface area of about 250 m ² /g. As disclosed above, the specific surface area of the pharmaceutically acceptable compound of a) is increased in the solid composition of the invention of a factor as disclosed above due to the processing (milling) to solid composition. The specific surface area of the silicate in the solid composition of the invention is preferably > 300 m ² /g, more preferably the specific surface area is at least 400 m ² /g. It is explained above, that the specific surface area of the phar- maceutically acceptable compound of a) is smaller than the specific surface area of pharmaceutically acceptable compound of b). Hence the specific surface area of the silicate of a) may be < 250 m ² /g or < 300 m ² /g. It is evident that in case the specific surface area of the silicate of a) is about 250 m ² /g, the specific surface area of the silicate after b) is >250 m ² /g with a specific surface area increase according to a factor of at least 1.5, preferably of a factor in the range of from 1.5 to 15, preferably of a factor in the range of from 1.5 to 10, more preferably of a factor in the range of from 2 to 7, more preferably of a factor in the range of from 2.5 to 5.

Regarding the silica, preferred forms thereof include, but are not limited to, fumed silica, pre- cipitated silica, silica gel, and colloidal silica. Preferred silica include, but are not restricted to, the commercially available compounds Syloid® 72 FP and Syloid® 244 FP. The specific surface area of the silica in the solid composition is increased with respect to the silica before being processing (milling) to the solid composition of the invention of a factor of at least 1.5, preferably of a factor in the range of from 1.5 to 15, preferably of a factor in the range of from 1.5 to 10, more preferably of a factor in the range of from 2 to 7, more preferably of a factor in the range of from 2.5 to 5.

Regarding the phosphate, preferred form includes dicalcium phosphate, more preferably, dicalcium phosphate anhydrous (DCPA). Commercially available dicalcium phosphate anhy- drous is known under the trademark Fujicalin® with a specific surface area of 36.9 m ² /g. Commercially available DCPA may have a specific surface area in the range of 0.8 to 1.10 m ² /g. The specific surface area of the phosphate is increased in the solid composition of the invention. For example commercially available DCPA having a specific surface area in the range of 0.8 to 1.10 m ² /g before being processed (milled) have a specific surface area at least 3 m ² /g, preferably a specific surface area at least 10 m ² /g in the solid composition of the invention. The specific surface area of the phosphate of a) increased in the solid composition of the invention of a factor of at least 1.5, preferably of a factor in the range of from 1.5 to 15, preferably of a factor in the range of from 1.5 to 10, more preferably of a factor in the range of from 2 to 7, more preferably of a factor in the range of from 2.5 to 5 with respect to the specific surface area of said pharmaceutically acceptable compound before being processed (milled) to form a solid composition.

In step a), the weight ratio of suvorexant or salt thereof relative to the pharmaceutically ac- ceptable compound is preferably in the range of from 1 : 1 to 1 : 10, more preferably in the range of from 1 : 2 to 1 : 7, even more preferably in the range of from 1 : 3 to 1 : 5, more preferably, the weight ratio of suvorexant or salt thereof relative to the pharmaceutically acceptable compound, is in the range of from 1 : 3 to 1 : 5, such as from 1 : 5 to 1 : 4, from 1 : 4 to 1 : 3 or from 1 : 3 to 1 : 2. If more than one pharmaceutically acceptable compound is com- prised in the solid composition, the weight ratios relate to the total weight of all pharmaceutically acceptable compounds.

In addition to suvorexant or salt thereof and the pharmaceutically acceptable compound, in step a) further compounds may be added. Preferably the at least a further compounds is se- lected from suitable pharmaceutically acceptable excipients. Preferably, at least 90 weight-%, preferably at least 95 weight-%, more preferably at least 99 weight-% of the mixture obtained in a) consist of suvorexant and the pharmaceutically acceptable compound or a mixture thereof. According to a preferred embodiment, the at least pharmaceutically acceptable compound contained in the mixture obtained in a) consists of one pharmaceutically acceptable compound, i.e. no other pharmaceutically acceptable compound are added in a) but the pharmaceutically acceptable compound. Regarding this preferred embodiment, preferably at least 95 weight-%), more preferably at least 96 weight-%o, more preferably at least 97 weight- %, more preferably at least 98 weight-%, more preferably at least 99 weight-%, more preferably at least 99.5 weight-%), more preferably at least 99.9 weight-%o of the solid composition consist of suvorexant or the salt thereof and the pharmaceutically acceptable compound. More preferably, the mixture obtained in a) essentially consists of the pharmaceutically acceptable compound and suvorexant or the salt thereof. The term "essentially consists of as used in this context of the present invention describes a mixture which, in addition to the suvorexant or the salt thereof and the pharmaceutically acceptable compound, only contains impurities of the suvorexant or the salt thereof and/or of pharmaceutically acceptable compound which can be tolerated in view of the desired use if the solid composition or, which cannot be avoided.

In a preferred embodiment, in the solid composition of a) at least 90 weight-%, preferably at least 95 weight-%, more preferably at least 99 weight- % of the suvorexant consists of crystalline suvorexant amorphous suvorexant or a mixture thereof, preferably at least 90 weight-%, preferably at least 95 weight-%, more preferably at least 99 weight-% of the suvorexant con- sists of crystalline suvorexant, more preferably at least 90 weight-%, preferably at least 95 weight-%, more preferably at least 99 weight-% of the suvorexant consist of polymorphic crystalline form I or II, even more preferably of form I.

Step b)

As disclosed above the process of the invention comprises step b)

b) increasing the specific surface area of the pharmaceutically acceptable compound of a) by milling the mixture obtained in a) and obtaining the solid composition. In step b) after milling, the at least one pharmaceutically acceptable compound has a specific surface area which is greater of a factor of at least 1.5, preferably greater of a factor in the range of from 1.5 to 15, preferably greater of a factor in the range of from 1.5 to 10, more preferably greater of a factor in the range of from 2 to 7, more preferably greater of a factor in the range of from 2.5 to 5 than the specific surface area of said pharmaceutically acceptable compound in a) the specific surface area being as determined according to DIN-ISO 9277.

The pharmaceutically acceptable compound after milling in b) has a specific surface area that in not less than 1 m ² /g. The pharmaceutically acceptable compound in b) has a specific surface area that is at least 1 m ² /g. Preferably, the specific surface area of the pharmaceutically acceptable compound in b) is at least 3 m ² /g, preferably at least 5 m ² /g, more preferably the specific surface area said pharmaceutically acceptable compound in b) is at least 10 m ² /g.

Suvorexant or the salt thereof in the solid composition of b) is obtained in amorphous form. In a preferred embodiment, in the solid composition of b) at least 90 weight-%, preferably at least 95 weight-%, more preferably at least 99 weight-% of the suvorexant consist of amorphous suvorexant. In this case less than 10 weight-%), preferably less than 5 weight-%), more preferably less than 1 weight-% of the suvorexant consist of crystalline suvorexant, wherein preferably the crystalline suvorexant is form I or form II or a mixture thereof. In step b) the milling of the mixture obtained in a) is carried out. Regarding the milling techniques, any milling techniques such as for example ball milling or jet milling that achieves an increase in the specific surface area according to the invention is within the scope of the pre- sent invention. The milling of step b) is carried out and optionally repeated until the specific surface area according to the invention and as disclosed above is obtained.

The skilled person understands that the process of the invention is carried out at a suitable temperature and that variation of the temperature of the process may be due to the choice of the pharmaceutically acceptable compound.

Regarding the milling time (duration of the milling step), the milling can be carried out for a time that is in in the range of from 10 to 60 min, preferably in the range of from 15 to 25 min. Regarding the frequency of the milling, the milling is preferably carried out at a frequency in the range of from 20 to 35 Hz, preferably in the range of from 25 to 30 Hz.

Regarding the specific surface area of the pharmaceutically acceptable compound in b), it is preferably a specific surface area which is greater of a factor of at least 1.5, preferably greater of a factor in the range of from 1.5 to 15, preferably greater of a factor in the range of from 1.5 to 10, even more preferably greater of a factor in the range of from 2 to 7, even more preferably greater of a factor in the range of from 2.5 to 5 than the specific surface area of said pharmaceutically acceptable compound in a). Regarding the specific surface area of the pharmaceutically acceptable compound in b) it is at least 1 m ² /g. Preferably, the specific surface area of the pharmaceutically acceptable compound in b) is at least 3 m ² /g, preferably at least 5 m ² /g, more preferably the specific surface area of said pharmaceutically acceptable compound in b) is at least 10 m ² /g. It has been seen that the stabilizing effect is achieved when there is an increase of the specific surface area with respect to the starting surface area of a). For example, when the pharmaceutically acceptable compound is a silicate the specific surface area in a) can be already at least 3 m ² /g, generally in the range between 250 m ² /g and 300 m ² /g yet it is the increased specific surface area in the final specific according to the factors described above that allows obtaining an advantageous dissolution profile and the suvorexant in a stable amorphous form.

Regarding the specific surface area of the silicate in the solid composition of the invention, it is preferably > 300 m ² /g, more preferably the specific surface area is at least 400 m ² /g Preferably, the process according to the invention is a process for preparing a solid composition of the invention comprising suvorexant in an amorphous form and at least one pharmaceutically acceptable compound selected from the group consisting of a sugar alcohol such as mannitol and/or a disaccharide such as lactose, preferably pharmaceutically acceptable compound having a specific surface area in the range of from 3 to 11 m ² /g, more preferably in the range of 3.5 to 8 m ² /g, even more preferably in the range of from 3.8 to 7.7 m ² /g. Preferably, the pharmaceutically acceptable compound in b') is a sugar alcohol, more preferably mannitol, even more preferably a mannitol having a specific surface area in the range of from 3 to 11 m ² /g, more preferably in the range of from 6 to 7.7 m ² /g. Preferably, the pharmaceutically acceptable compound in b') is a saccharide, more preferably lactose, even more preferably a lactose having a specific surface area in the range of from 3 to 8 m ² /g, preferably in the range of from 3.5 to 5 m ² /g, more preferably 3.8 to 4 m ² /g, wherein preferably lactose is lactose monohydrate; hence, the process comprises:

a') mixing suvorexant, preferably crystalline suvorexant form I or form II and a pharmaceutically acceptable compound selected form the group consisting of a sugar alcohol such as mannitol and a disaccharide such as lactose wherein the pharmaceutically acceptable compound has a specific surface area, b') increasing the specific surface area of the pharmaceutically acceptable compound by milling the mixture obtained in a'), obtaining the solid composition wherein the pharmaceutically acceptable compound is selected form the group consisting of a sugar alcohol such as mannitol and a disaccharide such as lactose.

Preferably in a'), the pharmaceutically acceptable compound is selected from the group consisting of a sugar alcohol such as mannitol and a disaccharide such as lactose, preferably having a specific surface area in the range of from 0.5 to 1.6 m ² /g, or in the range of from 1.1 to 1.6 m ² /g, or in the range of from 1.3 to 1.5 m ² /g. Preferably in a') the pharmaceutically acceptable compound is mannitol having a specific surface area in the range of from 0.5 to 1.5 m ² /g, preferably in the range of from 0.6 to 1.45 m ² /g, preferably in the range of from 1.2 to 1.4 m ² /g. Preferably in a') the pharmaceutically acceptable compound is lactose having a specific surface area in the range of from 0.7 to 1.6 m ² /g, preferably in the range of from 0.9 to 1.55 m ² /g, more preferably in the range of from 1.3 to 1.55 m ² /g.

Solid pharmaceutical formulation comprising the solid composition

The solid composition of the invention as defined above is a solid composition preferably comprised in a solid pharmaceutical formulation, preferably as disclosed herein below, wherein the solid pharmaceutical formulation is preferably a tablet or a capsule, more preferably is a tablet. Preferably, the solid pharmaceutical formulation in the form of capsule is wherein the capsule is a gelatin capsule, preferably a soft gelatin capsule.

Hence, the present invention is further directed to a solid pharmaceutical formulation com- prising the solid composition as disclosed above or obtainable or obtained by a process as disclosed above.

A preferred solid pharmaceutical formulation is a formulation comprising a solid composition according to the invention wherein the solid composition comprises suvorexant in an amor- phous form and pharmaceutically acceptable compound selected form the group consisting of a saccharide such as mannitol and a disaccharide such as lactose, preferably having a specific surface area in the range of from 3 to 11 m ² /g, more preferably in the range of 3.5 to 8 m ² /g, even more preferably in the range of from 3.8 to 7.7 m ² /g. Preferably, the pharmaceutically acceptable compound is a sugar alcohol, more preferably mannitol, even more preferably a mannitol having a specific surface area in the range of from 3 to 11 m ² /g, more preferably in the range of from 6 to 7.7 m ² /g. Preferably, the pharmaceutically acceptable compound is a disaccharide, more preferably lactose, even more preferably a mannitol having a specific surface area in the range of from 3 to 8 m ² /g, preferably in the range of from 3.5 to 5 m ² /g, more preferably 3.8 to 4 m ² /g, wherein preferably lactose is lactose monohydrate. Preferably in the solid pharmaceutical composition at least 90 weight-%, preferably at least 95 weight-%, more preferably at least 99 weight-% of the suvorexant consists of amorphous suvorexant. In this case less than 10 weight- %, preferably less than 5 weight- %, more preferably less than 1 weight-% of the suvorexant consists of crystalline suvorexant, wherein preferably the crystalline suvorexant is form I or form II or a mixture thereof.

Preferably, the solid pharmaceutical formulation further comprises one or more pharmaceutically acceptable excipients. Generally, there are no specific restrictions regarding the chemical nature and the specific role of the one or more pharmaceutically acceptable excipients. For example, the one or more pharmaceutically acceptable excipients may comprise one or more of a filler, a diluent, a lubricant, a sweetener, a stabilizing agent, a solubilizing agent, an antioxidant, a preservative, a flavoring agent, a binder, a colorant, an osmotic agent, a buffer, a granulating agent, a disintegrating agent. Preferably, the one or more pharmaceutically acceptable excipients comprise one or more of a binder, a diluent, a disintegrant, and a lubricant. More preferably, the one or more pharmaceutically acceptable excipients comprise, preferably are, a combination of a binder, a diluent, a disintegrant, and a lubricant, more preferably a combination of a binder, preferably a dry binder, a diluent, a disintegrant, and a lubricant.

The binder preferably comprises, more preferably is, one or more of acacia gum, starch, gelatin, sucrose, polyvinylpyrrolidone (Povidone), sorbitol, methylcellulose, sodium carboxy- methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, microcrystalline cellulose, said binder preferably comprising, more preferably being, microcrystalline cellulose.

The diluent preferably comprises, more preferably is, one or more of calcium carbonate, dicalcium phosphate, dry starch, calcium sulfate, cellulose, compressible sugars, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmi- tostearate, hydrogenated vegetable oil type I, inositol, kaolin, lactose, lactose monohydrate such as preferably spray-dried lactose monohydrate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, powdered sugar, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, preferably one or more of dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, lactose, lactose monohydrate such as preferably spray-dried lactose monohydrate, mannitol, microcrystalline cellulose, starch, tribasic calcium phosphate, said diluent preferably comprising, more preferably being, lactose monohydrate.

The disintegrant preferably comprises, more preferably is, one or more of agar, alginic acid, bentonite, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethyl- cellulose, cellulose, a cation exchange resin, cellulose, gums, citrus pulp, colloidal silicon dioxide, corn starch, croscarmellose sodium, crospovidone, guar gum, hydrous aluminum silicate, an ion exchange resin such as polyacrin potassium, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, modified cellulose gum, modified corn starch, montmorillonite clay, natural sponge, polyacrilin potassium, potato starch, powdered cellulose, povidone, pregelatinized starch, sodium alginate, sodium bicarbonate in admixture with an acidulant such as tartaric acid or citric acid, sodium starch glycolate, starch, silicates, preferably one or more of croscarmellose sodium, crospovidone, modified corn starch, povidone, pregelatinized starch, sodium starch glycolate, said disintegrant preferably comprising, more preferably being, croscarmellose sodium. The lubricant preferably comprises, more preferably is, one or more of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, preferably one or more of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, said lubricant preferably comprising, more preferably being, magnesium stearate.

Since a preferred form of the solid pharmaceutical formulation is in the form of a tablet, it may be preferred that the solid composition comprises a tablet core coated with a coating agent. The coating agent may comprise one or more of hydroxypropylmethylcellulose, hy- droxypropylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, cellulose acetate phthalate, sodium ethyl cellulose sulfate, carboxymethyl cellulose, polyvinylpyrolidone, zein, an acrylic polymer including methacrylic acid or methacrylic acid ester copolymers in- eluding methacrylic acid or methylmethacrylate copolymers, a polyvinyl alcohol. Preferably, the coating agent comprises, preferably is, a film coating agent.

Preferably, at least 95 weight-%, more preferably at least 96 weight-%, more preferably at least 97 weight-%), preferably at least 98 weight-%o, more preferably at least 99 weight- %, more preferably at least 99.5 weight-%, more preferably at least 99.9 weight-% of the solid pharmaceutical formulation, preferably the tablet, consist of the composition comprising the solid composition and the at least one pharmaceutically acceptable excipient and optionally the coating agent. The solid pharmaceutical formulation of the invention comprises a pharmaceutically acceptable amount of suvorexant or salt thereof.

The solid pharmaceutical formulation according to the invention may be packed in a packaging material selected from the group consisting of aluminum, polyvinylidenchloride, polyvi- nylchloride, polyethylene and polypropylene.

The solid pharmaceutical formulation of the invention is for use in treating or preventing of a sleep disorder, preferably insomnia, in a mammalian, preferably human, patient. The solid pharmaceutical formulation of the invention is for use in treating or preventing or controlling obesity in a mammalian, preferably human, patient.

Process for preparing a formulation comprising the solid composition According to the present invention, the solid composition is further processed to a final formulation. The final formulation is preferably a solid pharmaceutical formulation, preferably selected from the group consisting of tablet and capsules.

The process for preparing the solid pharmaceutical formulation, comprises

c) processing the solid composition of the invention as defined above or obtainable or obtained according to the process of the invention described above to a solid pharmaceutical formulation. Regarding the processing for preparing the solid pharmaceutical formulation of the invention, any processing suitable to obtain the solid pharmaceutical formulation is within the scope of the present invention. Preferably, the processing of c) comprises

cl) mixing the solid composition obtained in b) with one or more pharmaceutically acceptable excipients to obtain a mixture;

c2) optionally granulating the mixture of cl)

c3) compressing the mixture of cl) or c2) and obtaining a tablet.

Regarding to the one or more pharmaceutically acceptable excipients, one or more pharmaceutically acceptable excipients comprise one or more of a binder, a diluent, a disintegrant, and a lubricant as described above. Regarding c2) the granulation is a wet or dry granulating, preferably a dry granulating.

Thus, the present invention is directed to a process for the preparation of a solid pharmaceutical formulation, the process comprising

A) mixing suvorexant or a salt thereof and at least one pharmaceutically acceptable compound wherein the pharmaceutically acceptable compound has a specific surface area; and

B) increasing the specific surface area of pharmaceutically acceptable compound of A) by milling the mixture obtained in A) and obtaining the solid composition according to the invention, and

C) processing the solid composition of B) to a solid pharmaceutical formulation.

Step A) is the very same of step a), step B) is the very same of step b) and step C) is the very same of step c) as disclosed above. Preferably, the at least one pharmaceutically acceptable compound in B) has a specific surface area which is greater of a factor of at least 1.5, prefera- bly of a factor in the range of from 1.5 to 15, preferably of a factor in the range of from 1.5 to 10, more preferably of a factor in the range of from 2 to 7, more preferably of a factor in the range of from 2.5 to 5 than the specific surface area of said pharmaceutically acceptable compound in A) and wherein the specific surface area is as determined according to DIN-ISO 9277 and/or pharmaceutically acceptable compound in B) has a specific surface area that is at least 1 m ² /g. Preferably, the specific surface area of the pharmaceutically acceptable compound in B) is at least 3 m ² /g, preferably at least 5 m ² /g, more preferably the specific surface area of said pharmaceutically acceptable compound in b) is at least 10 m ² /g. Thus, the present invention is directed to a process for the preparation of a solid pharmaceutical formulation comprising suvorexant in an amorphous form and pharmaceutically acceptable compound selected from the group consisting of a sugar alcohol such as mannitol and/or a disaccharide such as lactose, preferably the pharmaceutically acceptable compound having a specific surface area in the range of from 3 to 11 m ² /g, more preferably in the range of 3.5 to 8 m ² /g, even more preferably in the range of from 3.8 to 7.7 m ² /g. Preferably, the pharmaceutically acceptable compound in B') below is a sugar alcohol, more preferably mannitol, even more preferably a mannitol having a specific surface area in the range of from 3 to 11 m ² /g, more preferably in the range of from 6 to 7.7 m ² /g. Preferably, the pharmaceutically accepta- ble compound in B') below is a saccharide, more preferably lactose, even more preferably a lactose having a specific surface area in the range of from 3 to 8 m ² /g, preferably in the range of from 3.5 to 5 m ² /g, more preferably 3.8 to 4 m ² /g, wherein the lactose is preferably lactose monohydrate. Hence, the process comprises:

A') mixing suvorexant, preferably suvorexant crystalline form I or form II, even more preferably suvorexant crystalline form I and pharmaceutically acceptable compound selected form the group consisting of a sugar alcohol such as mannitol and/or a disaccharide such as lactose wherein the pharmaceutically acceptable compound has a specific surface area; and

B') increasing the specific surface area of pharmaceutically acceptable compound of a) by milling the mixture obtained in A'), obtaining the solid composition wherein the pharmaceutically acceptable compound is selected form the group consisting of a sugar alcohol such as mannitol and a disaccharide such as lactose,

C) processing the solid composition of B') to a solid pharmaceutical formulation. Preferably in A'), the pharmaceutically acceptable compound is selected from the group consisting of a sugar alcohol such as mannitol and a disaccharide such as lactose, preferably having a specific surface area in the range of from 0.5 to 1.6 m ² /g, or in the range of from 1.1 to 1.6 m ² /g, or in the range of from 1.3 to 1.5 m ² /g. Preferably in A') the pharmaceutically acceptable compound is mannitol having a specific surface area in the range of from 0.5 to 1.5 m ² /g, preferably in the range of from 0.6 to 1.45 m ² /g, preferably in the range of from 1.2 to 1.4 m ² /g. Preferably in A') the pharmaceutically acceptable compound is lactose having a specific surface area in the range of from 0.7 to 1.6 m ² /g, preferably in the range of from 0.9 to 1.55 m ² /g, more preferably in the range of from 1.3 to 1.55 m ² /g. Regarding the processing of C) and C) to the solid pharmaceutical formulation, it can be carried out according to methods known in the art e.g. standard methods for preparing tablets and capsules. Method and uses

The solid composition, described above, and the solid pharmaceutical formulation described above are useful in a method of antagonizing orexin receptor activity. Thus, the solid compo- sition, described above, and the solid pharmaceutical formulation, as described above are for use as antagonists of orexin receptor activity. In particular, the solid composition, described above, and the solid pharmaceutical formulation, described above are used for treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with orexin receptors, in particular for enhancing the quality of sleep; augmenting sleep maintenance; increasing REM sleep; increasing stage 2 sleep; decreasing fragmentation of sleep patterns; treating insomnia; enhancing cognition; increasing memory retention; treating or controlling obesity; treating or controlling depression; treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis; or treating, controlling, ameliorating or reducing the risk of schizophrenia, in a mammalian patient in need thereof.

In particular, the solid composition, described above, and the solid pharmaceutical formulation, described above are used for treating in treating or preventing of a sleep disorder, in par- ticular for enhancing the quality of sleep or for treating insomnia in a mammalian patient. In particular, the solid composition, described above, or the solid pharmaceutical formulation, described above is used for treating or controlling obesity in a mammalian patient.

As used herein, the terms "treatment" and "treating" refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder. Further, the present invention also relates to a method for enhancing the quality of sleep in a mammalian patient in need thereof which comprises administering the solid pharmaceutical formulation to the patient. Further, the present invention also relates to method for treating insomnia in a mammalian patient in need thereof which comprises administering the solid pharmaceutical formulation, described above, to the patient. Further, the present invention also relates to a method for treating or controlling obesity in a mammalian patient in need thereof which comprises administering the solid pharmaceutical formulation, described above, to the patient. The dosage of suvorexant in the compositions of this invention may be varied, however, it is necessary that the amount of suvorexant be such that a suitable dosage form is obtained. The dosage regimen will be determined by the attending physician and other clinical factors. It is well known in the medical art that the dosage for anyone patient depends upon many factors including the patient's size, body surface area, age, sex, time and route of administration, general health and other drugs being administered concurrently. Efficacy can be monitored by periodic assessment. Suvorexant may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. A typical dosage can be, for example, in the range of 10 to 80 mg, such as 10, 20, 40 or 80 mg.

The invention is hence directed to a method for treating or preventing of a sleep disorder, preferably insomnia, in a mammalian, preferably human, patient, said method comprising administering the solid pharmaceutical formulation according to the invention comprising the solid composition according to the invention to the mammalian, preferably human, patient.

The invention is hence directed to the use of a solid pharmaceutical formulation according to the invention comprising the solid composition according to the invention for treating or preventing of a sleep disorder, preferably insomnia, in a mammalian, preferably human, patient. The invention is hence directed to a method for enhancing the quality of sleep in a mammalian, preferably human, patient in need thereof which method comprises administering the solid pharmaceutical formulation according to the invention comprising the solid composition according to the invention to the mammalian, preferably human, patient. The present invention is hence directed to a method for treating or preventing or controlling obesity in a mammalian, preferably human, patient, said method comprising administering the solid pharmaceutical formulation according to the invention comprising the solid composition according to the invention to the mammalian, preferably human, patient. The present invention is hence directed to the use of a pharmaceutical formulation administering the solid pharmaceutical formulation according to the invention comprising the solid composition according to the invention for treating or preventing or controlling obesity in a mammalian, preferably human, patient. The present invention is further illustrated by the following embodiments and combinations of embodiments as indicated by the respective dependencies and references. A solid composition comprising i) suvorexant according to formula (I)

or a salt thereof and ii) at least one pharmaceutically acceptable compound, wherein the at least one pharmaceutically acceptable compound has a specific surface area of at least 1 m ² /g as determined according to DIN-ISO 9277.

The solid composition of embodiment 1 , wherein the specific surface area is at least 3 m ² /g, preferably at least 5 m ² /g.

The solid composition of embodiment 1 or 2, wherein the specific surface area is at least 10 m ² /g.

The solid composition of any of embodiments 1 to 3, wherein the pharmaceutically acceptable compound has a specific surface area which is greater of a factor of at least 1.5, preferably greater of a factor in the range of from 1.5 to 15, preferably greater of a factor in the range of from 1.5 to 10, more preferably greater of a factor in the range of from 2 to 7, more preferably greater of a factor in the range of from 2.5 to 5 than the specific surface area of said pharmaceutically acceptable compound before being processed to form a solid composition.

The solid composition of embodiment 4, wherein the being processed to form a solid composition comprises milling a mixture comprising suvorexant or a salt thereof and the at least one pharmaceutically acceptable compound.

The solid composition of any of embodiments 1 to 5 wherein suvorexant is in an amorphous form.

The solid composition of any of embodiments 1 to 6, wherein the pharmaceutically acceptable compound is selected from the group consisting of an organic non-polymeric compound, mixtures of organic non-polymeric compounds, an inorganic compound and mixtures of inorganic compounds. The solid composition of embodiment 7, wherein the organic compound has a molecular weight < 1000 Da. The solid composition of embodiment 7 or 8, wherein the organic non-polymeric compound is selected from the group consisting of saccharides and sugar alcohols, wherein the saccharide is preferably selected from the group consisting of monosaccharides, di- saccharides and mixtures thereof, preferably the organic non-polymeric compound is selected from the group consisting of sugar alcohols and disaccharides, more preferably the organic non-polymeric compound is a sugar alcohol. The solid composition of any of embodiments 7 to 9, wherein the organic non- polymeric compound is a sugar alcohol selected from the group consisting of mannitol, xylitol, sorbitol, and a mixture thereof, preferably the sugar alcohol is mannitol. The solid composition of any of embodiments 7 to 10, wherein the organic non- polymeric compound is a disaccharide selected from the group consisting of lactose, sucrose, maltitol and a mixture thereof, preferably the disaccharide is lactose. The solid composition of any of embodiments 7 to 11, wherein the inorganic compound is selected from the group consisting of silicates, silica, phosphates and mixtures thereof, preferably the inorganic compound is a silicate or a phosphate, more preferably a silicate. The solid composition of any of embodiments 7 to 12, wherein the inorganic compound is a silicate and the silicate is one or more of aluminosilicates, wherein the one or more aluminosilicates preferably comprise at least one alkali metal element, at least one alkaline earth metal element, or at least one alkali metal element and at least one alkaline earth metal element, more preferably at least one alkaline earth metal element, more preferably magnesium. The solid composition of embodiment 13, wherein the silicate is preferably selected from the group consisting of calcium silicate, magnesium trisilicate, magnesium aluminum silicate (Neusilin®) and a mixture thereof, more preferably the silicate is magnesium aluminum silicate (Neusilin®). The solid composition of any of embodiments 7 to 14, wherein the inorganic compound is the silica and the silica is one or more of fumed silica, precipitated silica, silica gel, and colloidal silica.

The solid composition of any of embodiments 7 to 15, wherein the inorganic compound is a phosphate, preferably dicalcium phosphate anhydrous, more preferably Fujicalin®. The solid composition of any of embodiments 12 to 14, wherein the inorganic compound is a silicate and the specific surface area thereof is >250 m ² /g, preferably the specific surface area thereof is >300 m ² /g. The solid composition of embodiment 12 or 16, wherein the inorganic compound is a phosphate and the specific surface area thereof is at least 3 m ² /g, preferably the specific surface area thereof is at least 10 m ² /g. The solid composition of any of embodiments 1 to 18, wherein in the solid composition the suvorexant or salt thereof and the pharmaceutically acceptable compound are present in a weight ratio of suvorexant or salt thereof relative to the pharmaceutically acceptable compound in the range of from 1 : 1 to 1 : 10, preferably in the range of from 1 : 2 to 1 : 7, more preferably in the range of from 1 : 3 to 1 : 5, wherein, if more than one pharmaceutically acceptable compound is comprised in the solid composition, the weight ratios relate to the total weight of all pharmaceutically acceptable compounds. The solid composition of any of embodiments 1 to 19, wherein at least 90 weight-%, preferably at least 95 weight-%, more preferably at least 99 weight-% of the solid composition consist of suvorexant and the pharmaceutically acceptable compound. The solid composition of any of embodiments 1 to 20, wherein at least 90 weight-%, preferably at least 95 weight-%, more preferably at least 99 weight-% of the suvorexant consist of amorphous suvorexant. The solid composition of any of embodiments 1 to 21, wherein suvorexant is in an amorphous form and the pharmaceutically acceptable compound is selected form the group consisting of a sugar alcohol, preferably mannitol and a disaccharide, preferably lactose, preferably having a specific surface area in the range of from 3 to 11 m ² /g, more preferably in the range of from 3.5 to 8 m ² /g, even more preferably in the range of from 3.8 to 7.7 m ² /g. The solid composition of embodiment 22, wherein the pharmaceutically acceptable compound is mannitol having a specific surface area in the range of from 3 to 11 m ² /g, more preferably in the range of from 6 to 7.7 m ² /g. The solid composition of embodiment 22, wherein the pharmaceutically acceptable compound is lactose having a specific surface area in the range of from 3 to 8 m ² /g, preferably in the range of from 3.5 to 5 m ² /g, more preferably in the range of from 3.8 to 4 m ² /g. A process a for preparing a solid composition comprising suvorexant or a salt thereof and at least one pharmaceutically acceptable compound, having a specific surface area of at least 1 m ² /g as determined according to DIN-ISO 9277, the process comprising: a) mixing suvorexant and at least one pharmaceutically acceptable compound, wherein the pharmaceutically acceptable compound has a specific surface area obtaining a mixture, and b) increasing the specific surface area of the pharmaceutically acceptable compound by milling the mixture obtained in a), obtaining the solid composition, wherein preferably the solid composition is according to any of embodiments 1 to 24.

26. A process for preparing a solid composition comprising suvorexant or a salt thereof and at least one pharmaceutically acceptable compound, the process comprising: a) mixing suvorexant or a salt thereof and at least one pharmaceutically acceptable compound wherein the pharmaceutically acceptable compound has a specific surface area, and b) increasing the specific surface area of the pharmaceutically acceptable compound of a) by milling the mixture obtained in a), obtaining the solid composition, wherein the at least pharmaceutically acceptable compound in b) has a specific surface area which is greater of a factor of at least 1.5, preferably of a factor in the range of from 1.5 to 15, preferably of a factor in the range of from 1.5 to 10, more preferably of a factor in the range of from 2 to 7, more preferably of a factor in the range of from 2.5 to 5 than the specific surface area of said pharmaceutically acceptable compound in a), wherein the specific surface area is as determined according to DIN-ISO 9277 and wherein preferably the solid composition is according to any of embodiments 1 to 24.

27. The process of embodiment 26, wherein the pharmaceutically acceptable compound has a specific surface area of at least 1 m ² /g as determined according to DIN-ISO 9277.

28. The process of any of embodiments 25 to 27, wherein the specific surface area of b) is at least 3 m ² /g or at least 5 m ² /g as determined according to DIN-ISO 9277. 29. The process of embodiment 28, wherein the specific surface area is at least 10 m ² /g as determined according to DIN-ISO 9277.

30. The process of any of embodiments 25 to 29, wherein in the solid composition of b) suvorexant is in an amorphous form, and in the mixture obtained in a) suvorexant is in an amorphous form, or in a crystalline form or in mixture of crystalline suvorexant and amorphous suvorexant, preferably suvorexant is in an amorphous form.

31 The process of embodiment 30, wherein in the mixture obtained in a) the crystalline form is crystalline form I or crystalline form II, preferably is crystalline form I. 32. The process of any of embodiments 25 to 31, wherein the pharmaceutically acceptable compound has a specific surface area which is greater of a factor of at least 1.5, preferably of a factor in the range of from 1.5 to 15, preferably of a factor in the range of from 1.5 to 10, more preferably of a factor in the range of from 2 to 7, more preferably of a factor in the range of from 2.5 to 5 than the specific surface area of said pharmaceutically acceptable compound before being processed to form a solid composition.

33. The process of any of embodiments 25 to 32, wherein a pharmaceutically acceptable compound is an organic non-polymeric compound or an inorganic compound.

34. The process of embodiment 33, wherein the organic compound has a molecular weight < 1000 Da.

35. The process of embodiment 33 or 34, wherein the organic non-polymeric compound is selected from the group consisting of saccharides, sugar alcohols and mixtures thereof, wherein preferably the saccharide is selected from the group consisting of monosaccharides and disaccharides, preferably the organic non-polymeric compound is selected from the group consisting of sugar alcohols and disaccharides, more preferably the organic non-polymeric compound is a sugar alcohol.

36. The process of any of embodiments 33 to 35, wherein the organic non-polymeric compound is a sugar alcohol selected from the group consisting of mannitol, xylitol, sorbitol and a mixture thereof, preferably the saccharide is mannitol. 37. The process of any of embodiments 33 to 36, wherein the organic non-polymeric compound is a disaccharide selected from the group consisting of lactose, sucrose, maltitol, and a mixture thereof preferably the disaccharide is lactose.

38. The process of any of embodiments 33 to 37, wherein the organic non-polymeric compound is mannitol or lactose. 39. The process of any of embodiments 33 to 38, wherein the inorganic compound is selected from the group consisting of silicates, silica, phosphates and mixtures thereof, preferably the inorganic compound is a silicate or a phosphate, more preferably a silicate.

40. The process of any of embodiments 33 to 39, wherein inorganic compound is a silicate and the silicate is one or more of aluminosilicates, wherein the one or more aluminosili- cates preferably comprise at least one alkali metal element, at least one alkaline earth metal element, or at least one alkali metal element and at least one alkaline earth metal element, more preferably at least one alkaline earth metal element, more preferably magnesium. 41. The process of any of embodiments 33 to 40, wherein the inorganic compound is a silicate preferably selected from the group consisting of calcium silicate, magnesium trisil- icate, magnesium aluminum silicate (Neusilin®) and a mixture thereof, more preferably the silicate is magnesium aluminum silicate (Neusilin®). 42. The process of any of embodiments 33 to 41 wherein the silica is one or more of fumed silica, precipitated silica, silica gel, and colloidal silica.

43. The process of any of embodiments 33 to 42, wherein in b) the inorganic compound is a phosphate, preferably dicalcium phosphate anhydrous.

44. The process of any of embodiments 33 to 42, wherein in b) the inorganic compound is a silicate and the specific surface area is >300 m ² /g, preferably the specific surface area is at least 400 m ² /g.

45. The process of any of embodiments 33 to 44, wherein in b) the inorganic compound is a phosphate and the specific surface area thereof is at least 10 m ² /g, more preferably the phosphate is dicalcium phosphate anhydrous having a specific surface area at least 60 m ² /g.

46. The process of any of embodiments 25 to 45, wherein in the solid composition the su- vorexant or salt thereof and the pharmaceutically acceptable compound are present in a weight ratio of suvorexant or salt thereof relative to the pharmaceutically acceptable compound in the range of from 1 : 1 to 1 : 10, preferably in the range of from 1 : 2 to 1 : 7, more preferably in the range of from 1 : 3 to 1 : 5, wherein, if more than one pharmaceutically acceptable compound is comprised in the solid composition, the weight ratios relate to the total weight of all pharmaceutically acceptable compounds.

47. The process of any of embodiments 25 to 46, wherein in b) at least 90 weight-%, preferably at least 95 weight-%, more preferably at least 99 weight-% of the solid composi- tion consist of suvorexant and the pharmaceutically acceptable compound.

48. The process of any of embodiments 25 to 47, wherein in b) at least 90 weight- %, preferably at least 95 weight-%, more preferably at least 99 weight-% of the suvorexant consists of amorphous suvorexant and wherein less than 10 weight-%), preferably less than 5 weight-%), more preferably less than 1 weight- % of the suvorexant consist of crystal- line suvorexant, wherein preferably the crystalline suvorexant is form I or form II or a mixture thereof.

49. The process of any of embodiments 25 to 48, wherein the milling is carried out for a time in the range of from 10 to 60 min, preferably of from 15 to 25 min. The process of any of embodiments 25 to 49, wherein the milling is carried out at a frequency in the range of from 20 to 35 Hz, preferably in the range of from 25 to 30 Hz. The process of any of embodiments 25 to 50, wherein the specific surface area of the pharmaceutically acceptable compound of a) is increased of at least a factor 1.5 in the milling of b). The process of embodiment 51, wherein the specific surface area of the pharmaceutically acceptable compound of a) is increased of a factor in the range of from 1.5 to 15, preferably of a factor in the range of from 1.5 to 10, more preferably of a factor in the range of from 2 to 7, more preferably of a factor in the range of from 2.5 to 5 in the milling of b). The process of any of embodiments 25 to 52, wherein in step a) the pharmaceutically acceptable compound is an organic non-polymeric compound having a specific surface area <1.5 m ² /g, preferably <0.9 m ² /g. The process of any of embodiments 25 to 53, wherein in step a) the pharmaceutically acceptable compound is an inorganic compound which is a silicate having a specific surface area of <300 m ² /g, preferably of <250 m ² /g. The process of embodiment 54, wherein in b), the specific surface area is >300 m ² /g, preferably the specific surface area is at least 400 m ² /g. The process of any of embodiments 25 to 55, further comprising c) processing the solid composition obtained in b) to a solid pharmaceutical formulation. The process of embodiment 56, wherein the solid pharmaceutical formulation is selected from the group consisting of tablet and capsule, preferably tablet. The process of embodiment 56 or 57, wherein c) comprises cl) mixing the solid composition obtained in b) with one or more pharmaceutically acceptable excipients to obtain a mixture, c2) optionally granulating the mixture of cl), c3) compressing the mixture of cl) or c2) and obtaining a tablet.

The process of embodiment 58, wherein the granulation of c2) is a wet or dry granulating, preferably a dry granulating. 60. The process of embodiment 58 or 59, wherein the one or more pharmaceutically acceptable excipients comprise one or more of a binder, a diluent, a disintegrant, and a lubricant.

61. A solid composition obtainable or obtained by the process according to any of embodi- ments 25 to 55.

62. The solid composition of any of embodiments 1 to 24 or 61, preferably of embodiment 23 or 24, comprised in a solid pharmaceutical formulation.

63. The solid composition of embodiment 62, wherein the solid pharmaceutical formulation is a tablet or a capsule, preferably is a tablet. 64. The solid composition of embodiment 63, wherein the capsule, is a gelatin capsule, preferably a soft gelatin capsule.

65. A solid pharmaceutical formulation comprising the solid composition according to any of embodiments 1 to 24 or 61.

66. The solid pharmaceutical formulation of embodiment 65, which in the form of tablets or capsules.

67. The solid pharmaceutical formulation of embodiment 66, which is a tablet.

68. The solid pharmaceutical formulation of embodiment 66, wherein the capsule, is a gelatin capsule, preferably a soft gelatin capsule.

69. A solid pharmaceutical formulation comprising the solid composition according to any of embodiments 1 to 24 or the solid composition obtained or obtainable by a process according to any of embodiments 25 to 55.

70. A solid pharmaceutical formulation obtained or obtainable by the process according to any of embodiments 56 to 60.

71. The solid pharmaceutical formulation of any of embodiments 65 to 70, preferably of embodiment 67, further comprising one or more pharmaceutically acceptable excipients.

72. The solid pharmaceutical formulation of embodiment 71, wherein the one or more pharmaceutically acceptable excipients comprise one or more of a binder, a diluent, a disintegrant and a lubricant. 73. The solid pharmaceutical formulation of embodiment 71 or 72, wherein the one or more pharmaceutically acceptable excipients comprise, preferably is, a combination of a binder, a diluent, a disintegrant, and a lubricant, more preferably a combination of a binder, preferably a dry binder, a diluent, a disintegrant and a lubricant.

74. The solid pharmaceutical formulation of embodiment 72 or 73, wherein the binder comprises, preferably is, one or more of acacia gum, starch, gelatin, sucrose, polyvinylpyrrolidone (Povidone), sorbitol, methylcellulose, sodium carboxy-methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, microcrystalline cellulose, said binder preferably comprising, more preferably being, microcrystalline cellulose.

75. The solid pharmaceutical formulation of any of embodiments 72 to 74, wherein the diluent comprises, preferably is, one or more of calcium carbonate, dicalcium phosphate, dry starch, calcium sulfate, cellulose, compressible sugars, confectioner's sugar, dex- trates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil type I, inositol, kaolin, lactose, lactose monohydrate such as preferably spray-dried lactose monohydrate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, powdered sugar, pre-gelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, preferably one or more of dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, lactose, lactose monohydrate such as preferably spray-dried lactose monohydrate, mannitol, microcrystalline cellulose, starch, tribasic calcium phosphate, said diluent preferably comprising, more preferably being, lactose monohydrate.

76. The solid pharmaceutical formulation of any of embodiments 72 to 75, wherein the disintegrant comprises, preferably is, one or more of agar, alginic acid, bentonite, carbox- ymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylcellulose, cellulose, a cation exchange resin, cellulose, gums, citrus pulp, colloidal silicon dioxide, corn starch, croscarmellose sodium, crospovidone, guar gum, hydrous aluminum silicate, an ion exchange resin such as polyacrin potassium, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, modified cellulose gum, modified corn starch, montmorillonite clay, natural sponge, polyacrilin potassium, potato starch, powdered cellulose, povidone, pregelatinized starch, sodium alginate, sodium bicarbonate in admixture with an acidulant such as tartaric acid or citric acid, sodium starch glycolate, starch, silicates, preferably one or more of croscarmellose sodium, crosspovidone, modified corn starch, povidone, pregelatinized starch, sodium starch glycolate, said disintegrant preferably comprising, more preferably being, croscarmellose sodium.

77. The solid pharmaceutical formulation of any of embodiments 72 to 76, wherein the lubricant comprises, preferably is, one or more of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, preferably one or more of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, said lubricant preferably comprising, more preferably being, magnesium stearate. 78. The solid pharmaceutical formulation of any of embodiments 72 to 77, preferably of wherein the binder comprises, preferably is, microcrystalline cellulose, the diluent comprises, preferably is, lactose monohydrate, the disintegrant comprises, preferably is, croscarmellose sodium, and the lubricant comprises, preferably is, magnesium stearate.

79. The solid pharmaceutical formulation of any of embodiments 72 to 78, being a solid formulation in the form of a tablet, comprising a tablet core coated with a coating agent.

80. The solid pharmaceutical formulation of embodiment 79, wherein the coating agent comprises, preferably is, a film coating agent.

81. The solid pharmaceutical formulation of any of embodiments 66 to 74, wherein at least 95 weight-%, preferably at least 98 weight-%, more preferably at least 99 weight- %, of the pharmaceutical formulation consist of the solid composition according to any of embodiments 1 to 24 or 61 and the at least one pharmaceutically acceptable excipient and optionally the coating agent.

82. The solid pharmaceutical formulation of any of embodiments 72 to 81, wherein at least 99.9 weight-%, of the pharmaceutical formulation consist of the solid composition ac- cording to any of embodiments 1 to 24 or 61 and the at least one pharmaceutically acceptable excipient and optionally the coating agent.

83. A solid pharmaceutical formulation of any of embodiments 65 to 82, for use in treating or preventing of a sleep disorder, preferably insomnia, in a mammalian, preferably human, patient. 84. A method for treating or preventing of a sleep disorder, preferably insomnia, in a mammalian, preferably human, patient, said method comprising administering the solid pharmaceutical formulation according to any of embodiments 65 to 83 to the mammalian, preferably human, patient.

85. Use of a pharmaceutical formulation according to any of embodiments 65 to 83, for treating or preventing of a sleep disorder, preferably insomnia, in a mammalian, preferably human, patient.

86. A method for enhancing the quality of sleep in a mammalian, preferably human, patient in need thereof which method comprises administering the pharmaceutical formulation according to any of embodiments 65 to 83 to the mammalian, preferably human, patient. 87. A solid pharmaceutical formulation according to any of embodiments 65 to 83, for use in treating or preventing or controlling obesity in a mammalian, preferably human, patient.

88. A solid pharmaceutical formulation according to any of embodiments 65 to 83, for treat- ing or preventing or controlling obesity in a mammalian, preferably human, patient.

89. A solid pharmaceutical formulation according to any of embodiments 65 to 83, wherein said solid pharmaceutical formulation is packaged in a packaging material selected from the group consisting of aluminum, polyvinylidenchloride, polyvinylchloride, polyethylene and polypropylene. 90. A method for treating or preventing or controlling obesity in a mammalian, preferably human, patient, said method comprising administering the solid pharmaceutical formulation according to any of embodiments 65 to 83 to the mammalian, preferably human, patient.

91. Use of a pharmaceutical formulation according to any of embodiments 65 to 83 for treating or preventing or controlling obesity in a mammalian, preferably human, patient.

Examples

Suvorexant Forms I and II were prepared according to WO2012/148553. Abbreviation List

BET Brunauer-Emmet-Teller method

Ac-Di-Sol® croscarmellose sodium (from FMC BioPolymer)

Avicel® PH-105 microcrystalline cellulose (from FMC BioPolymer)

FlowLac® 100 spray-dried lactose (from Meggle Pharma)

Neusilin® UFL 2 aluminium magnesium silicate (from BCM Corp.)

Granulac lactose monohydrate

Pearlitol mannitol

Partek Delta mannitol

abs. absolute

General analytical methods

Reference Example 1: Specific Surface Area determination

The determination of the specific surface area of the pharmaceutically acceptable compounds of the invention was carried out according to the BET method (gas adsorption) as specified in DIN ISO 9277 and at the following conditions Measuring medium: Nitrogen

Baking temperature 50 °C under vacuum

Baking time lh

The density was assumed to have a theoretic value of 1.27 g/cm ³ .

The specific surface area of each pharmaceutically acceptable compound of the invention has been measured before and after milling.

Reference Example 2: Determination of XRDP pattern

X-ray powder diffraction patterns were obtained with a PANalytical X'Pert PRO diffractome- ter equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphal,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 step size 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 (15 to 25 °C).

Reference Example 3: Dissolution test

The dissolution profile of the solid composition of the invention and of the comparative fine form I, fine form II, coarse form II and coarse form II with mannitol have been determined according to USP<711> Dissolution test at the following conditions: apparatus Paddle 1000 ml, 0.1M HC1, 50 rpm.

Reference Example 4: Determination of the moisture stability

Tablets prepared according to the Examples below were packed in Alu/Alu blister and PVDC blister. The blisters were exposed for 3 weeks to an atmosphere having a relative humidity of 75 % rh and a temperature of 40 °C. The tablets were analyzed via XRDP as described in Reference Example 2 with respect to the amorphousness.

Example 1:

Table 1: Composition

* Form I before milling

20 mg of suvorexant form I were added to 60 mg of Granulac 230 (lactose). The mixture was milled in a Retsch mill (20 min, 27.5Hz) and a solid composition was obtained. The specific surface area of Granulac 230 after milling was of 3.818 m ² /g. The specific surface area has been measured according to Reference Example 1. The XRDP of the solid composition shows that the suvorexant comprised in the solid composition is amorphous. The XRDP is shown in Figure 1.

Example 2:

Table 2: Composition

* Form I before milling

20 mg of suvorexant form I were added to 100 mg of Pearlitol 50C (mannitol) (weight ratio: 1 : 5). The mixture was milled in a Retsch mill (20 min, 27.5Hz) and a solid composition was obtained.

The specific surface area of Pearlitol 50C after milling was of 7.608 m ² /g. The specific surface area has been measured according to Reference Example 1. The XRDP of the solid com- position shows that the suvorexant comprised in the solid composition is amorphous. The XRDP is shown in Figure 2.

Example 3:

Table 3: Composition

* Form I before milling

20 mg of suvorexant form I were added to 60 mg of Partek Delta (mannitol). The mixture was milled in a Retsch mill (20 min, 27.5Hz) and a solid composition was obtained. The XRDP of the solid composition shows that the suvorexant comprised in the solid composition is amorphous. The XRDP is shown in Figure 3.

Comparative Example 1

The specific surface area of Avicel PHI 05 (microcrystalline cellulose) was measured before and after milling (20 min, 27.5 HZ). The specific surface area of Avicel PHI 05 before milling was of 3.033 m ² /g and after milling is of 1.697 m ² /g. Differently from the pharmaceutically acceptable compound of the invention, in the case of microcrystalline cellulose a decrease of the specific surface area has been observed upon milling.

Example 4

Solid compositions were prepared according to the process of the invention by mixing suvorexant with a pharmaceutically acceptable compound according to the invention by milling for 20 min at a frequency of 27.5 Hz. Intermediates were further processed into tablets as described in Example 7. In Table 4 the polymorphic form of suvorexant before and after milling and the pharmaceutically acceptable compounds are reported.

Table 4

*Comparative Example: API, Mannitol, Lactose and Avicel PH105 were granulated with water, dried and processed into tablets according Example 7.

Dissolution test was carried out using the following conditions: Paddle, 1000 ml, 50rpm, 0.1N HC1. The results are reported in Table 4-1 below. Table 4-1

15 67 66 64 62 20 31 46 32

30 78 77 72 71 30 42 59 46

60 84 82 77 80 39 54 72 61

As seen from Examples A to D, the form I and form II of suvorexant are changed into an amorphous form in the milling process. The change of the polymorphic form is not observed when granulation is carried out (Example E).

Insufficient dissolution is observed when isolated API or granulation is used. This is valid for both polymorphic form I and II. A good dissolution is reached when the milling procedure is used in combination with use of Mannitol / Lactose / Neusilin according to the invention. The dissolution profiles are shown in Figure 7.

Example 5

Table 5: Tablet Composition

* Form I before milling

The solid composition of Example 1 was admixed with Avicel® PH-105, FlowLac® 100, Ac- Di-Sol® SD-711 and magnesium stearate in the quantity reported in Table 5. The obtained mixture was compressed shaped to round tablets having a weight of 250 mg. 12 tablets were prepared. The XRDP spectrum of the tablets was registered and compared with the XRDP spectrum of suvorexant and Granulac 230. The XRDPs are shown in Figure 4.

Example 6

Table 6: Tablet Composition Pearlitol 50C (mannitol) 100,00

Weight of the solid composition 120.00

Avicel PH 105 (microcrystalline cellulose) 82.50

Flowlac 100 alpha lactose monohydrate 21.25

Ac-di-Sol (croscarmellose sodium) 25.00

Magnesium-stearate 1.25

Total weight 250.00

* Form I before milling

The solid composition of Example 2 was admixed with Avicel® PH-105, FlowLac® 100, Ac- Di-Sol® SD-711 and magnesium stearate in the quantities reported in Table 6. The obtained mixture was compressed and shaped to round tablets having a weight of 250 mg. 12 tablets were prepared. The XRDP spectrum of the tablets was registered and compared with the XRDP spectrum of suvorexant and Pearlitol 50C. The XRDPs are shown in Figure 5.

Example 7

Table 7: Tablet Composition

* Form I before milling

The solid composition of Example 3 was admixed with Avicel® PH-105, FlowLac® 100, Ac- Di-Sol® SD-711 and magnesium stearate in the quantities reported in Table 7. The obtained mixture was compressed and shaped to round tablets having a weight of 250 mg. The XRDP spectrum of the tablets was registered and compared with the XRDP spectrum of suvorexant and Partek Delta. The XRDPs are shown in Figure 6.

Example 8

Table 8: Tablet Composition Suvorexant Form I* 20.00

Pearlitol 50C 60.00

Weight of the solid composition 80.00

Avicel PH 105 (microcrystalline cellulose) 82.50

Flowlac 100 alpha lactose monohydrate 61.25

Ac-di-Sol (croscarmellose sodium) 25.00

Magnesium-stearate 1.25

Total weight 250.00

* Form I before milling

20 mg of suvorexant form I were added to 60 mg of Pearlitol 50C (mannitol). The mixture was milled in a Retsch mill (20 min, 27.5Hz) and a solid composition was obtained. Suvorexant was found to be amorphous. The solid composition obtained was admixed with Av- icel® PH-105, FlowLac® 100, Ac-Di-Sol® SD-711 and magnesium stearate in the quantity reported in Table 8. The obtained mixture was compressed and shaped to round tablets having a weight of 250 mg.

Example 9

Table 9: Tablet Composition

* Form I before milling

20 mg of suvorexant form I were added to 100 mg of Granulac 230 (weight ratio: 1 : 5). The mixture was milled in a Retsch mill (20 min, 27.5Hz) and a solid composition was obtained. Suvorexant was found to be amorphous. The solid composition obtained was admixed with Avicel® PH-105, FlowLac® 100, Ac-Di-Sol® SD-711 and magnesium stearate in the quantity reported in Table 9. The obtained mixture was compressed shaped to round tablets having a weight of 250 mg. Example 10

The tablets obtained in Example 9 were packed in Alu/Alu blister and in polyvinylidene chloride (PVDC) blister. The blisters were exposed to the conditions disclosed in Reference Example 4 and tested for amorphousness according to Reference Example 2. The results are reported in Table 10 below:

Table 10: Stability test result

Different blister materials did not relevel significance difference in stability indicating that suvorexant formulations according to the invention provide a polymorphically stable amorphous suvorexant, i.e., no chance in amorphousness is observed. The stability to the moisture is independent from the packaging material used. Hence, advantageously there in no need to package the pharmaceutical formulations according to the invention in expensive impermeable blister such as aluminum blister.

Example 11

Suvorexant Form I and a first portion of lactose monohydrate ( 60.00 mg) were milled in a Retsch mill (20 min, 27.5Hz). A milled solid composition according to the invention comprising amorphous Suvorexant was obtained. Tablets were prepared by employing this solid com- position. The tablets prepared had the following composition as described in Table 11.

Table 11: Tablet Composition

Ingredients mg

Total weight: 250.00

Form I before milling

The tablets were prepared according to the following procedure: the milled composition, 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. The 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 HC1 was employed. After 30 minutes 72% of su- vorexant was already dissolved.

Short Description of the Figures

Fig. 1 shows the XRPD of the solid composition according to the invention of Example 1. Fig. 2 shows the XRPD of the solid composition according to the invention of Example 2. Fig. 3 shows the XRPD of the solid composition according to the invention of Example 3. Fig. 4 shows the XRDP of the tablets prepared in Example 5. The XRDP is compared with the XRDP spectra of suvorexant and of Granulac 230.

Fig. 5 shows the XRDP of the tablets prepared in Example 6. The XRDP is compared with the XRDP spectra of suvorexant and of Pearlitol 50C.

Fig. 6 shows the XRDP of the tablets prepared in Example 7. The XRDP is compared with the XRDP spectra of suvorexant and of Partek Delta.

Fig. 7 shows the dissolution pattern of the solid composition of the invention compared with fine crystalline form I and form II, coarse crystalline form II and a mixture of coarse crystalline form II and mannitol.

Fig. 8 shows the dissolution profile of the tablet of Example 11.

Cited Prior Art

US 20080132490 Al

WO 2008/069997 A

Cox et al. (2010) Journal of Medicinal Chemistry, 53(14), pages 5320-5332.

WO 2013/181174

WO 2012/148553 Al

WO2015/158910