U.S. patent application number 15/823782 was filed with the patent office on 2018-03-22 for sofosbuvir in crystalline form and process for its preparation.
The applicant listed for this patent is HC-PHARMA AG. Invention is credited to Graziano CASTALDI, Marta CASTALDI, Mauro GABOARDI, Sara HELMY.
Application Number | 20180079771 15/823782 |
Document ID | / |
Family ID | 51628377 |
Filed Date | 2018-03-22 |
United States Patent
Application |
20180079771 |
Kind Code |
A1 |
GABOARDI; Mauro ; et
al. |
March 22, 2018 |
SOFOSBUVIR IN CRYSTALLINE FORM AND PROCESS FOR ITS PREPARATION
Abstract
Sofosbuvir in crystalline Form .alpha., process for its
production and use in pharmaceutical compositions.
Inventors: |
GABOARDI; Mauro; (Novara,
IT) ; CASTALDI; Marta; (Sizzano (NO), IT) ;
CASTALDI; Graziano; (Briona (NO), IT) ; HELMY;
Sara; (Alexandria, EG) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
HC-PHARMA AG |
Zug |
|
CH |
|
|
Family ID: |
51628377 |
Appl. No.: |
15/823782 |
Filed: |
November 28, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15308253 |
Nov 1, 2016 |
9845335 |
|
|
PCT/EP2015/067422 |
Jul 29, 2015 |
|
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15823782 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07F 9/65586 20130101;
C07H 19/10 20130101; A61P 31/14 20180101; A61K 31/7064 20130101;
A61K 31/7072 20130101; G01L 27/007 20130101; G01L 15/00 20130101;
C07H 1/06 20130101; A61P 1/16 20180101; A61K 31/7068 20130101; G01L
27/002 20130101; A61K 31/706 20130101; C07H 19/06 20130101 |
International
Class: |
C07H 19/10 20060101
C07H019/10; G01L 27/00 20060101 G01L027/00; G01L 15/00 20060101
G01L015/00; C07F 9/6558 20060101 C07F009/6558 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 1, 2014 |
IT |
MI02014A001411 |
Claims
1. Sofosbuvir in crystalline Form .alpha. characterized by an XRPD
comprising the following peaks: 7.96; 10.28; 12.32; 16.64; 18.56;
19.28; 19.88; 20.72; 21.88; 23.08; 24.24; 25.16; 27.00;
27.96.+-.0.2.degree. 2.theta..
2. A process for the preparation of Sofosbuvir according to claim 1
wherein it comprises a step of dissolution of Sofosbuvir in ketones
and a crystallization step of the solution obtained by said
dissolution.
3. The process according to claim 2, wherein said ketones are
selected from the group consisting of acetone, methyl ethyl ketone,
isobutyl methyl ketone and diethyl ketone.
4. The process according to claim 2, wherein said ketones are
selected from the group consisting of methyl ethyl ketone and
isobutyl methyl ketone.
5. The process according to claim 2, wherein said crystallization
is obtained by cooling or by solvent evaporation.
6. The process according to claim 2 wherein it comprises: i.
dissolution of Sofosbuvir in isobutyl methyl ketone at a
temperature whithin the range of 50-60.degree. C.; ii. cooling the
solution obtained from step i to a temperature of 20.degree. C.
till the precipitation of the product; iii. filtration of the
product obtained from step ii.; and iv. under vacuum drying of the
product obtained from step iii.
7. A pharmaceutical composition comprising Sofosbuvir according to
claim 1.
8. The process according to claim 2, wherein said Sofosbuvir
obtained with said process has a PSD wherein the size of the 90% of
the particles is in the range of 10-50 .mu.m.
9. The process according to claim 2, wherein said Sofosbuvir
obtained with said process has the following PSD: d(0.1): 1.831
.mu.m; d(0.5): 5.263 .mu.m; d(0.9): 20.369 .mu.m.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. application Ser.
No. 15/308,253, filed on Nov. 1, 2016, which in turn is a 371 of
PCT/EP2015/067422 filed Jul. 29, 2015, which claims the benefit of
Italian Patent Application No. M102014A001411, filed Aug. 1, 2014;
the contents of each of which are incorporated herein by
reference.
FIELD OF INVENTION
[0002] The present invention relates to a stable polymorphic form
of Sofosbuvir and a method for its preparation.
BACKGROUND OF THE INVENTION
[0003] Sofosbuvir is a prodrug used for the treatment of hepatitis
C.
[0004] Hepatitis C is an infectious disease caused by Hepatitis C
virus (HCV) which affects primarily the liver. The infection is
often asymptomatic but its chronic infection can lead to the
scarring of the liver and finally to cirrhosis, which is generally
apparent after many years. In some cases the liver cirrhosis can
develop liver failure, liver cancer, esophageal and gastric
varices. HCV is transmitted primarily by direct contact with
infected blood, often caused by intravenous drug use, poorly
sterilized equipment and blood transfusions.
[0005] Hepatitis C virus causes a chronic infection in 50-80% of
the peoples who are infected with, among them about 40-80% is
treated. In general, the pharmacological treatment is recommended
in patients with liver changes caused by virus; the reference
treatment is a combination of pegylated interferon alpha and
ribavirin to be taken for a period of 24 or 48 weeks, depending on
the HCV virus genotype. It is observed that this treatment leads to
improvements in 50-60% of cases. In phenotypes which are more
difficult to be treated these two drugs are used in combination
with boceprevir and telaprevir bringing the cure rate from 40% to
70%. The side effects of the treatment are frequent: half patients
have flu like symptoms and one third has emotional problems,
moreover the treatment carried out during the first six months is
more effective than once hepatitis C has become chronic.
[0006] Sofosbuvir is a drug for the treatment of hepatitis C,
approved at the beginning of the year by EMA, it is taken orally
and acts with a direct mechanism of action on the life cycle of the
virus abolishing its replication as being a prodrug inhibitor
pan-genotype of RNA polymerase NS5B RNA-dependent of HCV, it can be
incorporated into HCV RNA NS5B polymerase and acts as a chain
terminator.
[0007] Sofosbuvir has moreover shown a reduced number of
complications of the liver disease and a reduced number of adverse
effects than patients undergoing other treatments.
[0008] Sofosbuvir is a compound of formula (I)
##STR00001##
[0009] chemically known as isopropyl
(2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidine-1-yl)-4-fluoro-3-hydroxy-4-
-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]-aminopropanoate,
marketed as Sovaldi.RTM. and described in U.S. Pat. No.
8,563,530.
[0010] Some polymorphic forms of Sofosbuvir are known in the
literature.
[0011] U.S. Pat. No. 8,618,076 describes crystalline, hydrated and
solvated forms of Sofosbuvir, named as Form I (crystalline), Form 2
(crystalline), Form 3 (chloroform solvate), Form 4 (hydrate), Form
5 (crystalline) and Form 6 (crystalline) and describes also two
amorphous forms.
[0012] Polyphormism is the property of the molecules to assume more
than one crystalline or amorphous form in their solid state. Some
substances are know to exist in only one crystalline or amorphous
form; others indeed can have two or more crystalline forms.
Polymorphs are different solids with the same molecular formula but
with different physical properties that can be advantageous or
disadvantageous compared with the other polymorphic forms of the
same family.
[0013] The morphology of organo-chemical active ingredients is
important for their pharmaco chemical development. A crystalline
form, compared to other crystalline forms, can have many
advantages. A suitable process for a crystalline form can give to
active ingredient's manufacturers several advantages, such as, the
use of steps or solvents cheap or with a low environmental impact,
higher yields and higher purity of the desired product.
[0014] The polymorphism, the number of crystalline forms of an
organo-chemical compound, their stability and their behavior in a
living organism are never predictable. The different polymorphs of
a compound have different energies of the crystal lattice and show
in this way, different physical properties of the solid state (such
as shape, density, melting point, colour, stability, dissolution
rate, ease of grinding, granulation etc.). In polymorphism, these
morphological differences can have drastic effects on the
flowability of the ground solid (the flowability regards the
easiness whereby the material is treated during the processing into
a pharmaceutical product), on shipping and storage stability of
different forms of administration, on the ability to produce
different forms of administration, on solubility in polar or non
polar, protic or aprotic solvents, on solubility in aqueous
solutions, on solubility in gastric juices, on blood solubility and
finally on bioavailability.
[0015] The dissolution rate of an active ingredient in the gastric
fluid of a patient can have therapeutical effects because it
determines the maximum concentration that an active ingredient can
reach in the blood by oral administration. Other important
properties of polymorphic forms affect the easiness of transforming
the active ingredient form in pharmaceutical dosages, on the
flowability of a powder or a granulate form and the surface
properties that determine if the crystals of the form will stick
each other once compressed in a tablet.
[0016] A polymorphic form can have a different thermic behavior
compared to an amorphous form or any other polymorphic form.
Thermic behavior can be measured in laboratory through techniques
such as capillary melting point and differential scanning
calorimetry (DSC) and can be used to distinguish various
polymorphic forms. A polymorphic form can have different
spectroscopical properties that can be detected trough the X-Ray
Powder diffraction (XRPD).
[0017] The discovery of new polymorphic forms of a pharmaceutical
compound gives another possibility to improve the characteristics
of said product. An expert of pharmaceutical techniques extends
his/her knowledge of forms useful for the development of a
pharmaceutical form with a targeted release profile or with other
characteristics such as fluidity and dissolution rate in aqueous
liquids.
SUMMARY OF THE INVENTION
[0018] The aim of the present invention is to give a new stable and
not hygroscopic crystalline form which can be prepared with an
ease, repeatable method with excellent yields and easy industrial
applicability.
[0019] We have now found a stable and not hygroscopic crystalline
form of Sofosbuvir suitable for the preparation of stable
pharmaceutical formulations as obtainable with a distribution of
the particle sizes such to allow a good compressibility and
flowability.
[0020] It is therefore object of the present invention a
crystalline form of Sofosbuvir, from now on named also as Form
.alpha., characterized by an XRPD comprising peaks at about 7.96;
10.28; 12.32; 16.64; 17.00; 18.56; 19.28; 19.88; 20.72; 21.88;
23.08; 24.24; 25.16; 27.00; 27.96.+-.0.2.degree. 2.theta. according
to FIG. 1.
BRIEF DESCRIPTION OF THE FIGURES
[0021] FIG. 1: XRPD of Sofosbuvir Form .alpha..
[0022] The new polymorphic form is also characterized by a
distribution of the particles sizes (PSD) where the size of the 90%
of the particles is from 10 to 50 .mu.m and by the following
parameters:
TABLE-US-00001 Bulk Density 0.22 g/ml Tapped Density 0.29 g/ml
Compressibility index 24.4 Hausner ratio 1.32
[0023] It is a further object of the present invention a process
for the preparation of Sofosbuvir in crystalline Form .alpha. which
comprises a step of dissolution of Sofosbuvir in ketones and a
crystallization step of the solution obtained by said
dissolution.
[0024] The ketones used for the process object of the present
invention are selected among the group consisting of acetone, metyl
ethyl ketone, isobutyl methyl ketone and diethyl ketone: the
ketones are preferably selected among the group consisting of metyl
ethyl ketone and isobutyl methyl ketone.
[0025] Preferably, said crystallization step is obtained by cooling
of the solution or by a slow solvent evaporation.
[0026] According to a preferred embodiment, the process of the
present invention comprises the following steps:
[0027] i. dissolution of Sofosbuvir in isobutyl methyl ketone at a
temperature within the range of 50-60.degree. C.;
[0028] ii. cooling of the solution obtained from step i. to a
temperature of 20.degree. C. under stirring till the precipitation
of the product;
[0029] iii. separation by filtration of the product obtained from
step ii;
[0030] iv. under vacuum drying of the product obtained from step
iii.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The process for the preparation of Sofosbuvir Form .alpha.
according to the present invention is particularly simple and of
easy industrial applicability.
[0032] Therefore, further objects of the present invention are the
use of Sofosbuvir Form .alpha. as a medicament and pharmaceutical
compositions containing it as an active ingredient in mixture with
a suitable carrier.
[0033] All the terms used in the present application, unless
otherwise indicated, are to be understood in their common meaning
as known in the art. The term "about" comprises the usual
experimental error of any measurement.
[0034] Although the present invention has been described in its
characterizing features, their equivalents and modifications
obvious to the skilled in the art are included in the present
invention.
[0035] The present invention will be now illustrated through some
examples without limiting it.
EXAMPLES
[0036] Diffraction spectra XRPD were carried out through a
diffractometer APD 2000 Ital Structures at ambience temperature
using a tube CuKa (40 Kv, 30 Ma) as X ray source. The data were
collected through a 2q continuous scan at a scan speed of
0.02.degree./s in the range of 3.degree.-40.degree. in 2q.
Example 1
[0037] 5 g of Sofosbuvir were suspended in 15 ml of isobutyl methyl
ketone into a reaction flask under stirring, the temperature was
kept at about 50/60.degree. C. and the mixture was kept under such
conditions until complete dissolution. The temperature was brought
to about 20.degree. C. and the mixture was kept under stirring for
about one hour. The resultant solid was filtered and washed with
isobutyl methyl ketone (2.times.5 ml) at the temperature of
20.degree. C. and dried in oven under vacuum at 45-50.degree. C. to
give 4.5 g of Sofosbuvir Form .alpha..
[0038] PSD=d(0.1):1.831 .mu.m; [0039] d(0.5):5.263 .mu.m; [0040]
d(0.9):20.369 .mu.m.
Example 2
[0041] 5 g of Sofosbuvir were suspended in 15 ml of methyl ethyl
ketone into a reaction flask under stirring, the temperature was
brought to about 50-60.degree. C., the reaction mixture was kept
under such conditions until complete dissolution and the resultant
solution was transferred into a crystallizer. The solvent was
evaporated at room temperature to give 5 g of Sofosbuvir Form
.alpha..
Example 3
[0042] 5 g of Sofosbuvir were suspended in 15 ml of acetone into a
reaction flask under stirring, the temperature was brought to about
50-60.degree. C., the reaction mixture was kept under such
conditions until complete dissolution and the resultant solution
was transferred into a crystallizer. The solvent was evaporated at
room temperature to give 5 g of Sofosbuvir Form .alpha..
* * * * *