A process for the preparation of solid forms of suvorexant

Abstract

The present invention relates to a process for the preparation of solid forms of Suvorexant (1) with at least one pharmaceutically acceptable excipient It further relates to a process for the preparation of amorphous form of Suvorexant (1). The present invention is further directed to a pharmaceutical composition comprising a solid dispersion of suvorexant with at least one pharmaceutically acceptable excipient and process for the preparation thereof.

Description

[0001]“A PROCESS FOR THE PREPARATION OF SOLID FORMS OF SUVOREXANT” CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 202341047499 filed on July 14, 2023, Indian Provisional Patent Application No. 202441026499 filed on Mar 30, 2024, and Indian Provisional Patent Application No.202341069321 filed on Oct 14, 2023. FIELD OF THE INVENTION The present invention relates to a process for the preparation of solid forms of Suvorexant (1) with at least one pharmaceutically acceptable excipient. It further relates to a process for the preparation of amorphous form of Suvorexant (1). The present invention is further directed to a pharmaceutical composition comprising a solid dispersion of suvorexant with at least one pharmaceutically acceptable excipient and process for the preparation thereof. BACKGROUND OF THE INVENTION Suvorexant is marketed under the trade name BELSOMRA. The Chemical name is [(7R)-4-(5-chloro-2-benzoxazolyl) hexahydro-7-methyl-1H-1,4-diazepin-1-yl] [5- methyl-2-(2H-1,2,3-triazol2-yl) phenyl] methanone. Its empirical formula is C23H23ClN6O2. Suvorexant is a white to off-white powder that is insoluble in water. The structure is given below: The orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: the orexin A (OX-A) (a 33 amino acid peptide) and the orexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcoleptic or insomniac patients (Chemelli R. M. et al., Cell, 1999, 98, 437-451). Orexins have also been indicated as playing a role in arousal, reward, learning and memory (Harris, et al., Trends Neurosci., 2006, 29 (10), 571-577). Two orexin receptors have been cloned and characterized in mammals. They belong to the super family of G-protein coupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): the orexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2 receptor (OX2 or OX2R) is capable to bind OX-A as well as OX-B. The physiological actions in which orexins are presumed to participate are thought to be expressed via one or both of OX 1 receptor and OX 2 receptor as the two subtypes of orexin receptors. Orexin receptors are found in the mammalian brain and the scientific literature suggests that they may be involved in various pathologies such as depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; eating disorders such as anorexia, bulimia, cachexia, and obesity; addictive feeding behaviors; binge / purge feeding behaviors; cardiovascular diseases; diabetes; appetite / taste disorders; emesis, vomiting, nausea; asthma; cancer; Parkinsons disease; Cushings syndrome / disease; basophile adenoma; prolactinoma; hyperprolactinemia; hypophysis tumour / adenoma; hypothalamic diseases; inflammatory bowel disease; gastric diskinesia; gastric ulcers; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g. HIV, post- chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; emesis, nausea, vomiting; conditions associated with visceral pain such as irritable bowel syndrome, and angina; migraine; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet lag syndrome; and neurodegenerative disorders including nosological entities such as disinhibition- dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration; epilepsy; seizure disorders and other diseases related to general orexin system dysfunction. BELSOMRA label indicates that suvorexant exposure increases in a less than strictly dose-proportional manner over the range of 10-80 mg because of decreased absorption at higher doses. Suvorexant pharmacokinetics are similar in healthy subjects and patients with insomnia. Suvorexant peak concentrations occur at a median Tmax of 2 hours (range 30 minutes to 6 hours) under fasted conditions. The mean absolute bioavailability of 10 mg is 82%. Ingestion of BELSOMRA with a high-fat meal resulted in no meaningful change in AUC or Cmax but a delay in Tmax of approximately 1.5 hours. The prior art process discloses process for the preparation of Suvorexant, which are illustrated below: Merck’s US7951797B2 discloses a process for the preparation of Suvorexant using Benzyl chloroformate (Cbz-Cl) protecting group and dibenzoyl-tartaric acid as resolving agent. The solid obtained was purified using mixture of hexane and ethyl acetate to obtain pure Suvorexant. Merck’s US 9108959 B2 discloses a process for the preparation of Suvorexant, which involves coupling of 5-methyl-2-[l,2,3] triazol-2-yl-benzoic acid and (R)-5- Chloro-2-(5-methyl-[l,4] diazepan-l-yl)-benzoxazole. The preparation of diazepine intermediate is carried out by racemic direct reductive amination of 4-[(2-Amino- ethyl) -(5-chlorobenzoxazol-2-yl) amino] butan-2-one-bis-methane sulfonic acid salt with a reducing agent in the presence of a weak base, followed by chiral resolution. Dr. Reddy’s patent application no. US 20160272627 discloses crystalline Form A, Form B, Form C, Form D, Form E, Form G, Form H, Amorphous and solid dispersion of Suvorexant. Merck’s patent no. US9108959B2 discloses crystalline Form I & Form II of Suvorexant. Merck’s patent no.US9969725B2 discloses crystalline Suvorexant hydrochloride, crystalline suvorexant methane sulfonate, crystalline suvorexant dodecyl sulfate and crystalline suvorexant p-toluene sulfonate. Merck’s US10,098,892B2 discloses a pharmaceutical composition comprising: suvorexant in an amorphous form; and copovidone; wherein the pharmaceutical composition is prepared by a process comprising hot melt extrusion of a mixture comprising suvorexant and copovidone. Merck’s US11,160,811B2 discloses a pharmaceutical composition comprising: suvorexant in an amorphous form; hydroxypropyl methyl cellulose acetate succinate; lactose monohydrate; croscarmellose sodium; colloidal silicon dioxide; and magnesium stearate; wherein the pharmaceutical composition is prepared by a process comprising spray drying of a mixture comprising suvorexant and hydroxypropyl methyl cellulose acetate succinate, and which comprises 5 mg, 10 mg, 15 mg or 20 mg of suvorexant, and wherein the suvorexant is present in a form that contains at least 90 weight % of the amorphous form of suvorexant relative to other morphological forms of suvorexant. Merck’s US20220062295 discloses a pharmaceutical composition comprising: suvorexant in an amorphous form; and a polymer selected from the group consisting of a polyvinylpyrrolidone-polyvinyl acetate copolymer, a polyvinyl caprolactam- polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methyl cellulose acetate succinate and a polyvinyl pyrrolidinone-polyvinyl acetate copolymer; wherein the pharmaceutical composition comprises 5 mg, 10 mg, 15 mg or 20 mg of suvorexant, and wherein the suvorexant is present in a form that contains at least 90 weight % of the amorphous form of suvorexant relative to other morphological forms of suvorexant. Sandoz’s WO2015158910A2 discloses a solid dispersion comprising suvorexant ([(7R)-4-(5-chloro-1 ,3-benzoxazol-2-yl)-7- methyl-1 ,4-diazepan-1 -yl][5-methyl- 2-(2H-1 ,2,3-triazol-2-yl)phenyl]methanone) or a salt thereof in amorphous form and at least one pharmaceutically acceptable matrix compound, wherein the at least one matrix compound is (i) a polymer and wherein the solid dispersion contains the suvorexant or salt thereof in an amount of at least 50 weight-% based on the combined weight of the suvorexant or salt thereof and the at least one matrix compound, or (ii) a silicon-based inorganic adsorbent. Thus, there is need of preparing solid forms of Suvorexant (1) with a suitable pharmaceutically acceptable excipient which is commercially viable and economical having good yields with high purity and desired physiochemical properties and pharmaceutical composition comprising such forms would obtain consistent drug release profiles or PK profiles. OBJECTIVE OF THE INVENTION Accordingly, in one objective, the present invention provides a process for the preparation of solid forms comprising solid dispersions of Suvorexant (1) with at least one pharmaceutically acceptable excipient. In another objective, the present invention provides a process for the preparation of amorphous form of Suvorexant (1). In another objective, the present invention provides solid forms of Suvorexant (1) so obtained is having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC. In further objective, the present invention provides a pharmaceutical composition comprising a solid dispersion of suvorexant with at least one pharmaceutically acceptable excipient and process of the preparation thereof. SUMMARY OF THE INVENTION Accordingly, in one aspect, the present invention provides a process for the preparation of solid forms comprising solid dispersion of Suvorexant (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Suvorexant (1) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step a), and c) isolating the solid dispersion of Suvorexant (1). In another aspect, the present invention provides a process for the preparation of amorphous form of Suvorexant (1), comprising the steps of: 1) dissolving Suvorexant (1) in a solvent or mixture of solvents, and 2) isolating the amorphous form of Suvorexant (1). In another aspect, the present invention provides a process for the preparation of amorphous form of Suvorexant (1), comprising the steps of: i. heating Suvorexant to 145-150°C under vacuum, ii. cooling the reaction mass to 100°C, iii. adding water at below 100°C, and iv. isolating the amorphous form of Suvorexant (1). In another aspect, the present invention provides another process for the preparation of amorphous form of Suvorexant (1), comprising the steps of: I. dissolving Suvorexant (1) in a solvent or mixture of solvents, II. spray drying the solution obtained in step I), and III. isolating the amorphous form of Suvorexant (1). In another aspect, the present invention provides solid forms of Suvorexant (1) so obtained is having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC. In further aspect, the present invention is to provide a pharmaceutical composition comprising an orexin receptor antagonist, or a pharmaceutically acceptable salt thereof. Accordingly, one aspect of the present invention is to provide a pharmaceutical composition comprising a solid dispersion of Suvorexant with a suitable pharmaceutically acceptable excipient. In another aspect, the present invention provides a pharmaceutical composition comprising a solid dispersion of Suvorexant with Salcaprozate sodium and process of the preparation thereof. In another aspect, the present invention provides a pharmaceutical composition comprising a solid dispersion of Suvorexant with Sodium caprylate and process of the preparation thereof. Yet in another aspect, the present invention provides a pharmaceutical composition comprising a solid dispersion of Suvorexant with hydroxypropyl beta cyclodextrin and process of the preparation thereof. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of solid dispersion of Suvorexant (1) with Salcaprozate sodium Figure 2: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of solid dispersion of Suvorexant (1) with Sodium caprylate Figure 3: Illustrates the characteristic powdered X-Ray Diffraction (PXRD) pattern of solid dispersion of Suvorexant (1) with hydroxypropyl-β-cyclodextrin (HPβCD) Figure 4: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous form of Suvorexant (1) by melt crystallization. Figure 5: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous form of Suvorexant (1) by spray drying. Figure 6: PXRD pattern of solid dispersion of Suvorexant with Salcaprozate sodium (1:0.65). Figure 7: PXRD pattern of Example 12 of Suvorexant Tablets containing solid dispersion of Suvorexant with Salcaprozate sodium (1:0.65). Figure 8: PXRD pattern of Example 12A of Suvorexant Placebo Tablets. Figure 9: PXRD pattern of solid dispersion of Suvorexant with hydroxypropyl beta cyclodextrin (1:3). Figure 10: PXRD pattern of Example 16 of Suvorexant Tablets containing solid dispersion of Suvorexant with hydroxypropyl beta cyclodextrin (1:3). Figure 11: PXRD pattern of Example 16A of Suvorexant Placebo Tablets. DETAILED DESCRIPTION OF THE INVENTION As used herein, the term “solid dispersion” is defined as a dispersion of drug in a solid matrix where the matrix was either a small molecule or polymer. Preferably solid dispersion relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two components (polymer and API) form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer. To arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion. As used herein, the term “excipient” refers to play a significant role in stabilizing amorphous solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs. Accordingly, in one embodiment, the present invention provides a process for the preparation of solid forms comprising solid dispersions of Suvorexant (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Suvorexant (1) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step a), and c) isolating the solid dispersion of Suvorexant (1). In an embodiment, the suitable solvent used in step-a) is selected from alcohol solvents such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso- butanol, 2-butanol, tert-butanol, and the like. In an embodiment, the suitable pharmaceutically acceptable excipient used in step- b) selected from but not limited to polyvinylpyrrolidone, (povidone or PVP; PVP of different grades like K-IS, K-30, K-60, K-90 and K-120 may be used), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), copovidone, Eudragit, Soluplus, polyethylene glycol (macrogol or PEG), polyethylene glycol-6000 (PEG-6000), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethyl ethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), sulfo butyl ether-β-cyclodextrin (SBECD), hydroxypropyl beta cyclodextrin (HPβCD), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, Isomaltose. raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, α,β,γ-cyclodextrins, sulfo butyl ether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, Salcaprozate sodium, sodium caprylate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like. In an embodiment, isolating involves removal of solvent is carrying out by suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as Buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration by gravity or suction, thin film drying, centrifugation or any other suitable techniques known in the art. In an embodiment, drying solid dispersion of Suvorexant (1) by a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer. Solid dispersion of Suvorexant (1) prepared according to the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but are not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or Micronisation may be performed before drying, or after the completion of drying of the product. In an embodiment, the present invention provides the ratio of the amount of Suvorexant (1) within the solid form to the amount of the excipient which ranges from about 1: 0.1 to about 1:10 (w / w). In another embodiment, the present invention provides a process for the preparation of solid dispersion of Suvorexant (1) with Salcaprozate sodium which comprises: a) dissolving Suvorexant (1) in a solvent or mixture of solvents, b) adding Salcaprozate sodium to the solution obtained in step a), and c) isolating the solid dispersion of Suvorexant (1). The solid dispersion of Suvorexant with Salcaprozate sodium is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in figure 1. In another embodiment, the present invention provides a process for the preparation of solid dispersion of Suvorexant (1) with Sodium caprylate which comprises: a) dissolving Suvorexant (1) in a solvent or mixture of solvents, b) adding sodium caprylate to the solution obtained in step a), and c) isolating solid dispersion of Suvorexant (1). The solid dispersion of Suvorexant with sodium caprylate is characterized by its X- ray powder diffraction (XRD) pattern as illustrated in figure 2. In another embodiment, the present invention provides a process for the preparation of solid dispersion of Suvorexant (1) with hydroxypropyl-β-cyclodextrin (HPβCD), which comprises: a) dissolving Suvorexant (1) in a solvent or mixture of solvents, b) adding hydroxypropyl-β-cyclodextrin (HPβCD) to the solution obtained in step a), and c) isolating the solid dispersion of Suvorexant (1). The solid dispersion of Suvorexant with hydroxypropyl-β-cyclodextrin (HPβCD) is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in figure- 3. In the present invention, the starting material Suvorexant (1) can be used in the form of amorphous or crystalline or any other physical form. In another embodiment, the present invention provides a process for the preparation of amorphous form of Suvorexant (1), comprising the steps of: 1) dissolving Suvorexant (1) in a solvent or mixture of solvents; and 2) isolating the amorphous form of Suvorexant (1). In an embodiment, the suitable solvent used in step-1) is selected from alcohol solvents such as methanol, ethanol, 1 -propanol, 2-propanol, 1-butanol, 2-butanol, and the like. In an embodiment, isolating involves removing the solvent from the mixture used in step 1) is same as defined in the foregoing embodiment. In another embodiment, the present invention provides a process for the preparation of amorphous form of Suvorexant (1), comprising the steps of: i. heating Suvorexant to 145-150°C under vacuum, ii. cooling the reaction mass to 100°C, iii. adding water at below 100°C, and iv. isolating the amorphous form of Suvorexant (1). In another embodiment, the present invention provides amorphous form of Suvorexant (1) by melt crystallization characterized by X-ray powder diffraction pattern as shown in figure 4. In another embodiment, the present invention provides another process for the preparation of amorphous form of Suvorexant (1), comprising the steps of: I. dissolving Suvorexant (1) in a solvent or mixture of solvents, II. spray drying the solution obtained in step I), and III. isolating the amorphous form of Suvorexant (1). In an embodiment, the suitable solvent used in step-I) is selected from alcohol solvents such as methanol, ethanol, 1 -propanol, 2-propanol, 1-butanol, 2-butanol, and the like; “ketone solvents” such as acetone, methyl ethyl ketone, acetyl acetone, methyl isobutyl ketone and the like; or its mixture thereof. In an embodiment, the present invention provides amorphous form of Suvorexant (1) by spray drying characterized by X-ray powder diffraction pattern as shown in figure 5. In another embodiment, the present invention provides solid forms of Suvorexant (1) obtained in the present invention is having total impurities less than 1.0%w / w and preferably less than 0.5%(w / w). In another embodiment, the present invention provides solid forms of Suvorexant (1) obtained in the present invention has water content is less than 10.0% (w / w), preferably less than 5.0% (w / w). In another embodiment, the present invention provides solid forms of Suvorexant (1) is essentially free of residual solvents. “Essentially free of residual solvents” herein refers to solid forms of Suvorexant (1) having less than 5000ppm of each solvent and preferably less than 3000 ppm and still more preferably less than 200 ppm. Organic solvents used in the present invention involve Methanol, Dichloromethane, ethyl acetate, n-Heptane, Toluene, Acetone and 2,2-Dimethoxy propane. In another embodiment, the present invention provides solid forms of Suvorexant (1) so obtained is having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC. In another embodiment, the present invention provides solid dispersion of Suvorexant with hydroxypropyl-β-cyclodextrin (HPβCD) or Salcaprozate sodium, in which the bulk density of solid dispersion can be between about 0.25g / ml to about 0.50g / ml. Accordingly, the present invention provides a pharmaceutical composition comprising an orexin receptor antagonist, or a pharmaceutically acceptable salt thereof. The present invention relates to a solid dispersion comprising suvorexant ([(7R)-4- (5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H- 1,2,3-triazol-2-yl)-phenyl] methanone) or a salt thereof in amorphous form as orexin receptor antagonist and at least one pharmaceutically acceptable excipient. In some embodiments, the suitable pharmaceutically acceptable excipients used in the present invention may be selected from a group comprising of lactose, maltose, sucrose, sorbitol, mannitol, polysorbate, maltodextrin, saccharose, cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), polyethylene glycol (PEG), polyethylene glycol-4000 (PEG-4000), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone K-30, (PVP K-30), Copovidone, povidone, magnesium stearate, polyvinyl acetate, hydroxyethyl cellulose (HEC), hydroxy propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy propyl methyl cellulose acetate succinate (HPMC-AS), hydroxy propyl methyl cellulose -E3, (HPMC-E3), Soluplus, Neusilin, Salcaprozate sodium, Sodium caprylate, Eudragit, Eudragit-EPO, Dicalcium phosphate (DCP) , croscarmellose, sodium croscarmellose, α-cyclodextrin, β-Cyclodextrin, γ-cyclodextrin, hydroxypropyl beta cyclodextrin (HPβCD), Sulfobutylether-β-cyclodextrin (SBCED) or the like. Preferably Salcaprozate sodium, Sodium caprylate and hydroxypropyl beta cyclodextrin (HPβCD) were used in the present invention. In another embodiment, the ratio of Suvorexant and the pharmaceutically acceptable excipients used in solid dispersion may range from 1:0.1 to 1:10, preferably 1:0.1 or 1:0.5 or 1:0.65 or 1:1 or 1:2 or 1:3 or 1:4 or 1:5 or 1:6 or 1:7 or 1:8 or 1:9 or 1:10 was used. Thus, the present invention preferably relates to a solid dispersion, as described above, wherein at least 80% by weight, more preferably at least 85% by weight, more preferably at least 90% by weight, more preferably at least 95% by weight, more preferably at least 96% by weight, more preferably at least 97%, more preferably at least 98% by weight, more preferably at least by weight 99% by weight, more preferably at least by weight 99.9% by weight, more preferably all of the suvorexant present in the solid dispersion is present in amorphous form. In another embodiment, the solid dispersion of Suvorexant obtained with salcaprozate sodium could be crystalline or amorphous. In another embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of suvorexant with salcaprozate sodium that may range from 1:0.1 to 1:10. Preferably, 1:0.1 or 1:0.5 or 1:0.65 or 1:1 or 1:2 or 1:3 or 1:4 or 1:5 or 1:6 or 1:7 or 1:8 or 1:9 or 1:10 was used. In another embodiment, the solid dispersion of Suvorexant obtained with sodium caprylate could be crystalline or amorphous. In another embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of suvorexant with sodium caprylate and may range from 1:0.1 to 1:10. Preferably, 1:0.1 or 1:0.5 or 1:0.65 or 1:1 or 1:2 or 1:3 or 1:4 or 1:5 or 1:6 or 1:7 or 1:8 or 1:9 or 1:10 was used. In another embodiment, the ratio of Suvorexant and hydroxypropyl beta cyclodextrin used in solid dispersion may range from 1:0.1 to 1:10. Preferably, 1:0.1 or 1:0.5 or 1:0.65 or 1:1 or 1:2 or 1:3 or 1:4 or 1:5 or 1:6 or 1:7 or 1:8 or 1:9 or 1:10 was used. In another embodiment, the solid dispersion of Suvorexant obtained with hydroxypropyl beta cyclodextrin could be crystalline or amorphous. A solid dispersion of suvorexant together with one or more pharmaceutically acceptable excipients of the present invention may be further formulated as: solid oral dosage forms such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using techniques such as direct blending, dry granulation, wet granulation, extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients. In another embodiment, a pharmaceutical composition comprising a solid dispersion of Suvorexant obtained with hydroxypropyl beta cyclodextrin or salcaprozate sodium which is used for the treatment of insomnia. The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples: Example 1: Preparation of solid dispersion of Suvorexant (1) with Salcaprozate sodium To a mixture of Suvorexant (1) (15g) and Salcaprozate sodium (15 g), methanol (600 ml) was added at 25-30°C and stirred for 5-10 mins. The obtained solution was spray dried using spray dryer through following conditions: Inlet Temperature : 60°C Aspirator : 1600 Feed Rate : 20ml / min The solid so obtained was unloaded and dried under vacuum for 12-15 hour at below 50°C to yield solid dispersion of Suvorexant (1) with Salcaprozate sodium. Yield: 65%(w / w). The PXRD pattern of the obtained compound is shown in figure 1. P-XRD Method of Analysis: PXRD analysis of solid dispersion of Suvorexant was carried out by using BRUKER / D8 ADVANCE diffractometer using Cu Kα radiation of wavelength 1.5406 A° and continuous scan speed of 0.03° / min. Example 2: Preparation of solid dispersion of Suvorexant (1) with Sodium caprylate To a mixture of Suvorexant (1) (15g) and Sodium caprylate (15g), methanol (600 ml) was added at 25-30°C and stirred for 5-10 mins. Spray dried the obtained solution using spray dryer through following conditions: Inlet Temperature : 60°C Aspirator : 1600 Feed Rate : 20ml / min The solid obtained was unloaded and dried under vacuum for 12-15 hour at below 50°C to yield solid dispersion of Suvorexant (1) with Sodium caprylate. Yield: 65%(w / w). The PXRD pattern of the obtained compound is shown in figure 2. Example 3: Preparation of solid dispersion of Suvorexant (1) with hydroxypropyl-β-cyclodextrin (HPβCD). To a mixture of Suvorexant (15.0g) and hydroxypropyl-β-cyclodextrin (HPβCD) (45 g), methanol (20 volumes) was added at 25-30°C and stirred for 5-10 mins. Spray dried the obtained solution using spray dryer through following conditions: Inlet Temperature : 60°C Aspirator : 1600 Feed Rate : 20ml / min The solid obtained was unloaded and dried under vacuum for 12-15 hour at below 50°C to get solid dispersion of Suvorexant (1) with hydroxypropyl-β-cyclodextrin (HPβCD). Yield: 65%(w / w). The PXRD pattern of the obtained compound is shown in figure 3. Example 4: Preparation of amorphous solid dispersion of Suvorexant (1) with hydroxypropyl-β-cyclodextrin (HPβCD) To a mixture of Suvorexant (15 g) and hydroxypropyl-β-cyclodextrin (HPβCD) (45 g) methanol (20 volumes) was added to and fed into a ATFD at a vacuum of 600- 720 mm Hg and a jacket temperature of 45-54°C. The obtained solid was dried in a vacuum tray drier at a vacuum of 670 mm Hg and a temperature of 70°C for 5 hours to get solid dispersion of Suvorexant (1) with hydroxypropyl-β-cyclodextrin (HPβCD). Yield: 65%(w / w). Example 5: Preparation of amorphous solid dispersion of Suvorexant (1) with hydroxypropyl-β-cyclodextrin (HPβCD). To Suvorexant (15 g) and hydroxypropyl-β-cyclodextrin (HPβCD) (45 g), methanol (20 volumes) was added to at 25-30°C and stirred for 5-10 mins. The solvent was distilled completely at below 50°C under vacuum in a Buchi Rotavapor and maintained for about 15 min after complete evaporation. The solid obtained was dried under vacuum for 12-15 hour at below 50°C to get solid dispersion of Suvorexant (1) with hydroxypropyl-β-cyclodextrin (HPβCD). Yield: 65%(w / w). Example 6: Preparation of amorphous form of Suvorexant (1) 100 g of suvorexant was heated to 145-150°C. After complete melting apply high vacuum to the reaction mass at the same temperature and maintain for 30-60 minutes. After 30-60 minutes, the high vacuum was removed and cooled to 100°C. 1000 ml of chilled water was added at below 100°C and stirred for 1-2 hours at room temperature. Filtered the reaction mass, washed with chilled water, and dried to get amorphous form of Suvorexant (1). Yield: 90-95 g; The PXRD pattern of the obtained compound is shown in figure 4. Example 7: Preparation of amorphous form of Suvorexant (1) 100 g of Suvorexant (1) was dissolved in 1000 ml of (1:1) methanol and acetone at room temperature. The reaction mass was stirred for 5 to 10 minutes at the same temperature to get a clear solution. The total reaction mixture was then transferred to a beaker and spray dried with the below parameters: Inlet Temperature : 50°C Aspirator : 1600 Feeding : 10 mL N2 Pressure : 2.0 kg / cm2The solid obtained was unloaded and dried at below 50°C for 12-15 hours to get amorphous form of Suvorexant (1). Yield: 55-60 g; The PXRD pattern of the obtained compound is shown in figure 5. EXAMPLE 8: Preparation of amorphous form of Suvorexant (1) 1.0 g of Suvorexant (1) was dissolved in 50 ml of methanol at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapor under reduced pressure at 50°C. The obtained product was re-dissolved in methanol (20 mL) at 25°C and the solvent was evaporated in rotavapor under reduced pressure at 50°C for 20 minutes to obtain title compound. Example 9-14: Suvorexant tablets S. Name of 9 10 11 12 12A 13 14 No Ingredient 1 Crystalline 10% - - - - - - Suvorexant 2 Amorphous - 10% - - - - - Suvorexant 3 Suvorexant solid - - 10% - - - - dispersion with Suvorexant: Salcaprozate sodium (1:1) 4 Suvorexant solid - - 10% - - - dispersion with Suvorexant: Salcaprozate sodium (1:0.65) 5 Suvorexant solid - - - - - 10% - dispersion with Suvorexant: Sodium caprylate (1:1) 6 Suvorexant solid - - - - - - 10% dispersion with Suvorexant: Sodium caprylate (1:0.65) 7 Lactose 35% 35% 35% 35% 45% 35% 35% monohydrate 8 Microcrystalline 50% 50% 50% 50% 50% 50% 50% cellulose 9 Croscarmellose 2% 2% 2% 2% 2% 2% 2% sodium 10 Magnesium 3% 3% 3% 3% 3% 3% 3% stearate Tablet weight (%w / w) 100% 100% 100% 100% 100% 100% 100% Process for preparation of Example 9-14 Suvorexant formulations: Suvorexant (in the form of Crystalline or Amorphous or Suvorexant solid dispersion), lactose monohydrate, microcrystalline cellulose and croscarmellose sodium was sifted together and blended. The pre-lubricated blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets. Process for preparation of Example 12A Placebo Suvorexant Tablet: Lactose monohydrate, microcrystalline cellulose and croscarmellose sodium were sifted together and blended. The pre-lubricated blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets. Example 15-18: Suvorexant tablets S. Name of Ingredient 15 16 16A 17 18 No 1 Suvorexant solid dispersion 10% - - - - with Suvorexant: hydroxypropyl beta cyclodextrin (1:2) 2 Suvorexant solid dispersion - 10% - - - with Suvorexant: hydroxypropyl beta cyclodextrin (1:3) 3 Suvorexant solid dispersion - - - 10% - with Suvorexant: hydroxypropyl beta cyclodextrin (1:4) 4 Suvorexant solid dispersion - - - - 10% with Suvorexant: Salcaprozate sodium (1:6) 5 Lactose monohydrate 35% 35% 45% 35% 35% 6 Microcrystalline cellulose 50% 50% 50% 50% 50% 7 Croscarmellose sodium 2% 2% 2% 2% 2% 8 Magnesium stearate 3% 3% 3% 3% 3% Tablet weight (%w / w) 100% 100% 100% 100% 100% Process for preparation of Example 15-18 Suvorexant formulations: Suvorexant (in the form of Suvorexant solid dispersion with hydroxypropyl beta cyclodextrin), lactose monohydrate, microcrystalline cellulose and croscarmellose sodium was sifted together and blended. The pre-lubricated blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets. Process for preparation of Example 16A Placebo Suvorexant Tablet: Lactose monohydrate, microcrystalline cellulose and croscarmellose sodium were sifted together and blended. The pre-lubricated blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets. Dissolution study data on Suvorexant Tablets of Example 9-18 were tested in 0.4% SLS in water, 900mL, 75rpm, Paddle: Suvorexant 80% (Q) drug release in 45 minutes Tablets Example 9 Meets drug release criteria Example 10 Meets drug release criteria Example 11 Meets drug release criteria Example 12 Meets drug release criteria Example 13 Meets drug release criteria Example 14 Meets drug release criteria Example 15 Meets drug release criteria Example 16 Meets drug release criteria Example 17 Meets drug release criteria Example 18 Meets drug release criteria Dissolution study data on Suvorexant Tablets of Example 9-18 in 0.2% SLS in 0.1N HCl, 900mL, 75rpm, Paddle: Suvorexant At least 40% (Q) drug release in 30 minutes Tablets Example 9 Meets drug release criteria Example 10 Less than 40% drug release in 30 minutes Example 11 Meets drug release criteria Example 12 Meets drug release criteria Example 13 Meets drug release criteria Example 14 Meets drug release criteria Example 15 Meets drug release criteria Example 16 Meets drug release criteria Example 17 Meets drug release criteria Example 18 Meets drug release criteria PXRD study conclusion data on Example 12 and Example 16 Suvorexant Tablets: Based on X-Ray Diffraction (PXRD) patterns of Figures 6, 7, 8, 9, 10 and 11, it was concluded that the input solid dispersion of suvorexant with sodium Salcaprozate (1:0.65) or Suvorexant: hydroxypropyl beta cyclodextrin (1:3) got retained with no conversions observed in Suvorexant Tablets. Bioequivalence testing was carried out for example 12 under Fasting and Fed conditions on invention Suvorexant 20mg tablets against BELSOMRA 20mg tablets, it was concluded that invention Suvorexant tablets formulation was bioequivalent to BELSOMRA 20mg tablets with respect to pharmacokinetic parameters of Cmax and AUC t. Upon oral administration of the Suvorexant tablets to healthy adult subjects under fasting and fed conditions results in a mean Cmaxof about 450 ng / ml to about 600ng / ml and mean AUC0-t of about 5500 ng.hr / ml to about 6500 ng.hr / ml. Bioequivalence testing was carried out for example 16 under Fasting and Fed conditions on invention Suvorexant 20mg tablets against BELSOMRA 20mg tablets, it was concluded that invention Suvorexant tablets formulation was bioequivalent to BELSOMRA 20mg tablets with respect to pharmacokinetic parameters of Cmax and AUC t. Upon oral administration of the Suvorexant tablets to healthy adult subjects under fasting and fed conditions results in a mean Cmax of about 450 ng / ml to about 550ng / ml and mean AUC0-tof about 5900 ng.hr / ml to about 7000 ng.hr / ml.

Claims

We claim:

1. A process for the preparation of solid dispersion comprising Suvorexant (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Suvorexant (1) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the mixture obtained in step-a), and c) isolating the solid dispersion of Suvorexant (1).

2. The process as claimed in claim 1 wherein, the pharmaceutically acceptable excipient used in step-b) is selected form polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone, PVP-K30, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethyl ethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose-E5 (HPMC-E5), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), syloid, eudragit, copovidone, salcaprozate sodium, hydroxypropyl-β-cyclodextrin (HPβCD) and sodium caprylate.

3. The process as claimed in claim 1 wherein, the ratio of Suvorexant (1) with at least one pharmaceutically acceptable excipient ranges from about 1: 0.1 to about 1:10 (w / w).

4. A process for the preparation of solid dispersion of Suvorexant (1) with hydroxypropyl-β-cyclodextrin (HPβCD), comprising the steps of: a) dissolving Suvorexant (1) in a solvent or mixture of solvents,b) adding hydroxypropyl-β-cyclodextrin (HPβCD) to the solution obtained in step a), and c) isolating the solid dispersion of Suvorexant (1).

5. A process for the preparation of solid dispersion of Suvorexant (1) with Salcaprozate Sodium, comprising the steps of: a) dissolving Suvorexant (1) in a solvent or mixture of solvents, b) adding Salcaprozate sodium to the solution obtained in step a), and c) isolating the solid dispersion of Suvorexant (1).

6. The process as claimed in claim 4 and 5 wherein, the solid dispersion of Suvorexant (1) with hydroxypropyl-β-cyclodextrin (HPβCD) is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in figure-3 and Salcaprozate Sodium XRD) pattern is illustrated in figure 1.

7. A process for the preparation of amorphous form of Suvorexant (1), comprising the steps of: 1) dissolving Suvorexant (1) in a solvent or mixture of solvents, and 2) isolating the amorphous form of Suvorexant (1).

8. A process for the preparation of amorphous form of Suvorexant (1), comprising the steps of: i.heating Suvorexant (1) to 145-150°C under vacuum, ii.cooling the reaction mass to 100°C, iii. adding water at below 100°C, and iv.isolating the amorphous form of Suvorexant (1).

9. A process for the preparation of amorphous form of Suvorexant (1), comprising the steps of: I. dissolving Suvorexant (1) in one or more solvent (s), II. spray drying the solution obtained in step I), and III. isolating the amorphous form of Suvorexant (1).

10. The process as claimed in any of the proceeding claims, wherein the solvent is selected from alcohol solvents such as methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, and the like; “ketone solvents” such asacetone, methyl ethyl ketone, acetyl acetone, methyl isobutyl ketone and the like; or its mixture thereof.

11. The process as claimed in any of the proceeding claims, wherein isolating the solid forms of Suvorexant (1) involves removal of solvent by decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as Buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration by gravity or suction, thin film drying, centrifugation.

12. A pharmaceutical composition comprising: amorphous solid dispersion of suvorexant and hydroxypropyl beta cyclodextrin in the ratio of 1:0.1 to 1:10; and at least one pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising: amorphous solid dispersion of suvorexant and salcaprozate sodium in the ratio of 1:0.1 to 1:10; and atleast one pharmaceutically acceptable excipients.

14. The pharmaceutically acceptable excipients in any of the proceeding claims 12 and 13 is selected from lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate and combinations thereof.

15. The pharmaceutical composition in any of the proceeding claims 12 and 13 is prepared by a direct compression process.

16. The amorphous solid dispersion in any of the proceeding claims 12 and 13 is prepared by a process comprising hot melt extrusion or spray drying.

17. The amorphous solid dispersion in any of the proceeding claims 12 and 13 is having a bulk density of 0.25g / ml to 0.5g / ml.

18. The pharmaceutical composition of claim 12 is having a drug release of atleast 80% in 45 minutes in 0.4% SLS in 900ml of water and atleast 40% in 30 minutes in 0.2% SLS in 900ml of water and wherein oral administration of a single 20mg suvorexant tablets to healthy adult subjects under fasting and fedconditions resulted in a mean Cmax of about 450 ng / ml to about 550ng / ml and a mean AUC0-tof about 5900 ng.hr / ml to about 7000 ng.hr / ml.

19. The pharmaceutical composition of claim 13 is having a drug release of atleast 80% in 45 minutes in 0.4% SLS in 900ml of water and atleast 40% in 30 minutes in 0.2% SLS in 900ml of water and wherein oral administration of a single 20mg suvorexant tablets to healthy adult subjects under fasting and fed conditions resulted in a mean Cmax of about 450 ng / ml to about 600ng / ml and mean AUC0-tof about 5500 ng.hr / ml to about 6500 ng.hr / ml.

20. A pharmaceutical composition in any of the proceeding claims 12 and 13 is used for the treatment of insomnia.

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