CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional
Patent Application No. IN202341047500 filed on Jul 14, 2023.
5 FIELD OF THE INVENTION
The present invention relates to a process for the preparation of solid forms of 7-
(4,7-diazaspiro [2.5] octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b] pyridazin-6-yl)
pyrido-4H-[1,2-a] pyrimidin-4-one (1) with at least one pharmaceutically
acceptable excipient.
10
BACKGROUND OF THE INVENTION
Risdiplam is chemically known as 7-(4,7-diazaspiro [2.5] octan-7-yl)-2-(2,8-
dimethylimidazo[1,2-b] pyridazin-6-yl) pyrido-4H-[1,2-a] pyrimidin-4-one
compound of formula (1).
15
Risdiplam was developed by Genentech Inc. It is a survival of motor neuron 2
(SMN2) splicing modifier indicated for the treatment of spinal muscular atrophy
(SMA) in patients 2 months of age and older. It was approved by USFDA in Aug
2020.
20
US 9,969,754 discloses Risdiplam and process for the preparation thereof. US’754
further discloses the process for purifying Risdiplam through column
chromatography.
25 US2021/0403487 (US’487) discloses crystalline forms A, B, C, D, E, F and G of
Risdiplam and process of preparation thereof.
3
WO2022/048675 discloses co-crystal of Risdiplam with vanillin and process of
preparation thereof.
WO2021/021775 discloses crystalline forms 2, 3, 4 and amorphous form of
5 Risdiplam and process of preparation thereof.
Polymorphism is the occurrence of different crystalline forms of a single compound
and it is a property of some compounds and complexes. Thus, polymorphs are
distinct solids sharing the same molecular formula, yet each polymorph may have
10 distinct physical properties. Therefore, a single compound may give rise to a variety
of polymorphic forms where each form has different and distinct physical properties,
such as different solubility profiles, different melting point temperatures and/or
different x-ray diffraction peaks. Since the solubility of each polymorph may vary,
identifying the existence of pharmaceutical polymorphs is essential for providing
15 pharmaceuticals with predicable solubility profiles. It is desirable to investigate all
solid-state forms of a drug, including all polymorphic forms, and to determine the
stability, dissolution, and flow properties of each polymorphic form.
Polymorphic forms of a compound can be distinguished in a laboratory by X-ray
20 diffraction spectroscopy and by other methods such as, infrared spectrometry.
Additionally, polymorphic forms of the same drug substance or active
pharmaceutical ingredient, can be administered by itself or formulated as a drug
product (also known as the final or finished dosage form), and are well known in the
pharmaceutical art to affect, for example, the solubility, stability, flowability,
25 tractability and compressibility of drug substances and the safety and efficacy of
drug products.
Furthermore, amorphous forms of a drug may offer significant advantages over
crystalline forms of the same drug in solid dosage form manufacturing process such
30 as compressibility, economically or environmentally suitable solvents or process, or
higher purity or yield of the desired product.
4
OBJECTIVE OF THE INVENTION
Accordingly, in one objective, the present invention provides a process for the
preparation of solid forms comprising solid dispersions of Risdiplam (1) with at least
one pharmaceutically acceptable excipient.
5
In another objective, the present invention provides solid forms of Risdiplam (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.
10 SUMMARY OF THE INVENTION
Accordingly, in the first aspect, the present invention provides a process for the
preparation of solid forms comprising solid dispersions of Risdiplam (1) with at least
one pharmaceutically acceptable excipient, comprising the steps of:
a) dissolving Risdiplam (1) in a solvent or mixture of solvents,
15 b) adding at least one pharmaceutically acceptable excipient to the solution
obtained in step a), and
c) isolating solid dispersion of Risdiplam (1).
In the second aspect, the present invention provides a stable amorphous form of
20 Risdiplam (1) using pharmaceutically acceptable excipients selected from
Salcaprozate sodium and sodium caprylate.
In the third aspect, the present invention provides solid forms of Risdiplam (1) so
obtained is having purity greater than 99% by HPLC, preferably greater than 99.5%
25 by HPLC, more preferably greater than 99.9% by HPLC.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1: Illustrates the PXRD pattern of solid dispersion of Risdiplam (1) with
Salcaprozate sodium.
30 Figure 2: Illustrates the PXRD pattern of solid dispersion of Risdiplam (1) with
Sodium caprylate.
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
5 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
10 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.
15 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.
In the present application, solid dispersion and premix are used interchangeably to
20 describe solid states disclosed herein.
Accordingly, in the first embodiment, the present invention provides a process for
the preparation of solid forms comprising solid dispersions of Risdiplam (1) with at
least one pharmaceutically acceptable excipient, comprising the steps of:
25 a) dissolving Risdiplam (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 solid dispersion of Risdiplam (1).
6
In the process of the first embodiment, the suitable solvent used in step-a) is selected
from alcohol solvents such as methanol, ethanol, n-propanol, iso-propanol, nbutanol, iso-butanol, 2-butanol, tert-butanol, and the like.
5 In the process of the first embodiment, the suitable pharmaceutically acceptable
excipient used in step-b) selected from but not limited to syloid,
polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30,
K-60, K-90 and K-120 may be used), co-povidone, crospolyvinylpolypyrrolidone,
polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), cross-copovidone,
10 Eudragit, 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, hydroxyethyl
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), hydroxypropyl methylcellulose-E5 (HPMC-E5),
hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose
acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P),
20 Salcaprozate sodium, sodium caprylate, hydroxypropyl methylcellulose acetate
phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl
cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose,
magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate,
talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose,
25 sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, 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,
30 polydextrose, α-, β-, γ-cyclodextrins, sulfobutylether beta-cyclodextrin, sodium
stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol
7
alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate,
glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate
phthalates and the like.
5 In the process of the first 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
10 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 the process of the first embodiment, drying solid dispersion of Risdiplam (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,
20 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 Risdiplam (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.
8
In the process of the first embodiment, the present invention provides the ratio of
the amount of Risdiplam (1) within the solid form to the amount of the excipient
which ranges from about 1: 1 to about 1:5 (w/w), preferably 1:5 was used.
5 In the first aspect of the first embodiment, the present invention provides a process
for the preparation of solid dispersion of Risdiplam (1) with Salcaprozate sodium
which comprises:
a) dissolving Risdiplam (1) in a solvent or mixture of solvents,
b) adding Salcaprozate sodium to the solution obtained in step a), and
10 c) isolating the solid dispersion of Risdiplam (1).
The solid dispersion of Risdiplam (1) with Salcaprozate sodium is characterized by
its X-ray powder diffraction (XRD) pattern as illustrated in figure 1.
15 In the first aspect of the first embodiment, the present invention provides a process
for the preparation of solid dispersion of Risdiplam (1) with Sodium caprylate which
comprises:
a) dissolving Risdiplam (1) in a solvent or mixture of solvents,
b) adding sodium caprylate to the solution obtained in step a), and
20 c) isolating the solid dispersion of Risdiplam (1).
The solid dispersion of Risdiplam (1) with sodium caprylate is characterized by its
X-ray powder diffraction (XRD) pattern as illustrated in figure 2.
25 In the present invention, the starting material Risdiplam (1) can be used in the form
of amorphous or crystalline or any other physical form.
In the third aspect, the present invention provides solid forms of Risdiplam (1) so
obtained is having purity greater than 99% by HPLC, preferably greater than 99.5%
30 by HPLC, more preferably greater than 99.9% by HPLC.
9
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.
5
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:
10 Example 1: Preparation of solid dispersion of Risdiplam (1) with Salcaprozate
sodium
Risdiplam (1) (5g) and Salcaprozate sodium (25 g) was added to Methanol (85 vol.)
at 25-30°C and stirred for 5 min. The reaction mass temperature was raised to 60-
65°C and stirred. Spray dried the obtained solution using spray dryer through
15 following conditions:
Inlet Temperature : 70°C
Outlet Temperature : 30°C
N2 pressure : 2Kg
Aspirator : 1600
Feed pump : 40 RPM
The solid obtained was unloaded and dried under vacuum to yield solid dispersion
of Risdiplam (1) with Salcaprozate sodium. The PXRD pattern of the obtained
compound is shown in figure 1.
Example 2: Preparation of solid dispersion of Risdiplam (1) with sodium
20 caprylate
Risdiplam (1) (5g) and sodium caprylate (25.0 g) was added to Methanol (85 vol.)
at 25-30°C and stirred for 5 min. The reaction mass temperature was raised to 60-
65°C and stirred. Spray dried the obtained solution using spray dryer through
following conditions:
Inlet Temperature : 70°C
Outlet Temperature : 30°C
10
N2 pressure : 2Kg
Aspirator : 1600
Feed pump : 40 RPM
The solid obtained was unloaded and dried under vacuum to yield solid dispersion
of Risdiplam (1) with sodium caprylate. The PXRD pattern of the obtained
compound is shown in figure 2.
11
We Claim:
1. A process for the preparation of solid dispersion comprising Risdiplam (1) with
at least one pharmaceutically acceptable excipient, comprising the steps of:
a) dissolving Risdiplam (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 Risdiplam (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), carboxymethylethyl cellulose (CMEC),
ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose,
hydroxyethylcellulose, 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, sodium
caprylate.
3. The process as claimed in claim 1, wherein the solvent is selected from alcohol
solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-
butanol, and the like or its mixture thereof.
25 4. The process as claimed in claim 1, wherein isolating the solid dispersion of
Risdiplam involves removal of solvent by 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,
12
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.
5 5. The process as claimed in claim 1, wherein the ratio of Risdiplam (1) with at
least one pharmaceutically acceptable excipient ranges from about 1: 1 to about
1:5 (w/w).
6. The process as claimed in claim 1 wherein, the solid dispersion of Risdiplam
(1) with at least one pharmaceutically acceptable excipient is characterized by
10 its X-ray powder diffraction (XRD) pattern as illustrated in figure-1 and 2