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
5 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
10 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.
15 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.
20
The structure is given below:
The orexins (hypocretins) comprise two neuropeptides produced in the
25 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
3
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,
5 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
10 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.
15 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
20 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;
25 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,
30 hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic
hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic
4
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
5 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
10 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, postchemotherapy pain; post-stroke pain; post-operative pain; neuralgia; emesis,
nausea, vomiting; conditions associated with visceral pain such as irritable bowel
15 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 disinhibitiondementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration;
20 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
25 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
30 Tmax of approximately 1.5 hours.
5
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
5 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,
10 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-Aminoethyl) -(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
15 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.
20
Merck’s patent no. US9108959B2 discloses crystalline Form I & Form II of
Suvorexant.
Merck’s patent no.US9969725B2 discloses crystalline Suvorexant hydrochloride,
25 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
30 composition is prepared by a process comprising hot melt extrusion of a mixture
comprising suvorexant and copovidone.
6
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;
5 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
10 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 caprolactam15 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
20 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-methyl2-(2H-1 ,2,3-triazol-2-yl)phenyl]methanone) or a salt thereof in amorphous form
25 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.
30
7
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
5 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
10 least one pharmaceutically acceptable excipient.
In another objective, the present invention provides a process for the preparation of
amorphous form of Suvorexant (1).
15 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
20 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
25 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
30 c) isolating the solid dispersion of Suvorexant (1).
8
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).
5
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,
10 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:
15 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
20 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
25 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.
30
9
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.
5 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
10 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
15 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)
20 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
25 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
30 cyclodextrin (1:3).
10
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.
5 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
10 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
15 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
20 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
25 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).
30
11
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, isobutanol, 2-butanol, tert-butanol, and the like.
5 In an embodiment, the suitable pharmaceutically acceptable excipient used in stepb) 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
10 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
15 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
20 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,
25 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,
30 sucralose, calcium phosphate, polydextrose, α,β,γ-cyclodextrins, sulfo butyl ether
beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium
12
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.
5
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
10 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.
15
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
20 100°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
25 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
30 completion of drying of the product.
13
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).
5 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).
10
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
15 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).
20 The solid dispersion of Suvorexant with sodium caprylate is characterized by its Xray 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),
25 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).
30
14
The solid dispersion of Suvorexant with hydroxypropyl-β-cyclodextrin (HPβCD) is
characterized by its X-ray powder diffraction (XRD) pattern as illustrated in figure3.
5 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:
10 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,
15 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.
20 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
25 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.
30
15
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
5 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,
10 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.
15
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).
20 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
25 (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
30 propane.
16
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.
5 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.
10 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-
15 (5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H1,2,3-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
20 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
25 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
30 croscarmellose, α-cyclodextrin, β-Cyclodextrin, γ-cyclodextrin, hydroxypropyl
beta cyclodextrin (HPβCD), Sulfobutylether-β-cyclodextrin (SBCED) or the like.
17
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
5 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
10 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
15 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.
20 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.
25 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
30 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.
18
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
5 or 1:10 was used.
In another embodiment, the solid dispersion of Suvorexant obtained with
hydroxypropyl beta cyclodextrin could be crystalline or amorphous.
10 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
15 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,
20 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
25 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
30 salcaprozate sodium which is used for the treatment of insomnia.
19
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.
5 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
10 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
15 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
20 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.
20
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.
5 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.
10 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
15 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).
20 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
25 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
21
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
5 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/cm2
10 The 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

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
5 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
10 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
15 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
20 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).
25 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,
27
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
5 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
10 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:
15 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,
20 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:
25 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-
30 propanol, 1-butanol, 2-butanol, and the like; “ketone solvents” such as
28
acetone, 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,
5 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
10 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
15 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
20 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
25 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
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
29
conditions resulted in a mean Cmax of about 450 ng/ml to about 550ng/ml and
a mean AUC0-t of 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
5 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-t of 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
10 used for the treatment of insomnia.