The present invention relates to novel polymorphic form of lumefantrine and process for its preparation. The novel polymorphic form of lumefantrine has been designated as Form I of lumefantrine. The present invention further provides highly pure lumefantrine.
Lumefantrine earlier known as Benflumetol or Benzfluorenol is chemically (Z)-2,7-dichloro-9-[(4-chlorophenyl)methylene]-a-[(dibutylamino)methyl]]-9H-fluorene-4-methanol having the structural formula I.
(Formula Removed)
FORMULA I
Lumefantrine belongs to the class of antimalarial agents and is reported to be originally synthesized in the 1970's by the Academy of Military Medical Sciences, China. Artemether + Lumefantrine, a fixed dose combination of two active ingredients, artemether, a sesquiterpene lactone derivative of a naturally occurring substance, artemisinin, and lumefantrine, a synthetic racemic fluorene derivative, is indicated in artemisinin-based combination therapy (ACT) used to treat malaria including the stand by-emerging treatment of adults and children with infections due to P. falciparum or mixed infections including P. falciparum-the deadliest form of the disease. The combination has gametocytocidal action.
P.falciparum and p.virax are the two dominant species with relative frequency of 60% and 40% respectively. However, this proportion varies from place to place and from
season to season. In malaria epidemic situations, P. falciparum is the dominant parasite species and almost all malaria deaths happen due to infections by this species. Moreover, the biological diversity of P. falciparum, its ability to develop resistance to a number of anti-malarial drugs has been a major challenge in malaria chemotherapy.
Chinese patent No. CN 109680C (hereinafter referred to as the '680 patent) discloses a five-step process for the preparation of Benzfluorenol (Lumefantrine), which is obtained as yellow crystals. Lumefantrine obtained by the process of '680 patent however is not significantly pure.
The present inventors have now prepared a novel polymorphic form of Lumefantrine designated herein after as Form I of lumefantrine. The inventors have found that when lumefantrine is prepared by following the process reported in the '680 Patent, the purity of lumefantrine obtained is about 90% or less. Surprisingly the present inventors have prepared lumefantrine in highly pure form having purity of about 98% or more.
The term "highly pure Lumefantrine" in the context of the present invention relates to Lumefantrine or salt thereof having purity 95% or more as measured by sensitive HPLC method.
A first aspect of the present invention provides polymorphic Form I of Lumefantrine having X-Ray Diffraction pattern (XRD) as depicted in Figure I of the accompanied drawings. The XRD of form I shows characteristic 29 values at 5.50, 10.76, 11.06, 13.50, 14.30, 14.90, 15.42, 16.98, 18.00, 18.50, 19.12, 19.78, 20.08, 20.90, 21.54, 21.92, 22.98, 23.70, 24.20, 25.32, 26.48, 26.98, 27.50, 28.16, 28.54, 28.98, 30.14, 31.48, 31.96, 32.10, 32.74, 34.52, 36.92, 38.02. The novel polymorphic form I of Lumefantrine has characteristic Differential Scanning Calorimetric (DSC) thermogram as depicted in Figure II of the accompanied drawings wherein the characteristic endothermic absorption is observed between 120°C and 130°C. The Fourier
Transform Infrared (FTIR) spectrum of Form I of lumefantrine has been depicted in Figure III of the accompanied drawings.
A second aspect of the present invention provides highly pure lumefantrine, wherein the purity is 95% or more by HPLC. More preferably highly pure lumefantrine refers to lumefantrine having purity of 98% or more by HPLC.
A third aspect of the present invention provides a process for preparation of polymorphic Form I of Lumefantrine wherein the said process comprises of,
a) suspending Lumefantrine in a suitable organic solvent
b) heating the resultant mass to reflux
c) cooling the solution of step b) to room temperature
d) isolating highly pure polymorphic form I of lumefantrine
Lumefantrine can be prepared by methods known in the art such as for example the process reported in the '680 patent or according to the process of the present invention.
Firstly, lumefantrine is suspended in a suitable organic solvent. The suspension can be optionally warmed to get a clear solution. The resultant mass is heated to reflux temperature for about 0.5 to 1 hour. The clear solution so obtained or the suspension as such is cooled to about 25-30°C and stirred for minimum of 2 hours. The product so obtained is filtered, washed and dried under vacuum at ambient temperature for 6 hours to obtain highly pure polymorphic form I of lumefantrine having a purity of 95% or more, preferably having purity of 98% or more by HPLC.
Suitable solvent includes any solvent or solvent mixture in which lumefnatrine is soluble at ambient temperature or upon heating. Suitable solvents comprises of C1-4 alkanols; C3.10 ketones; polar aprotic solvents; chlorinated hydrocarbons; non-polar aprotic solvents; C2-10 esters; C4.8 ethers.
The solution of lumefantrine in suitable organic solvent can be prepared at ambient temperature or at elevated temperature up to the reflux temperature of the organic solvent used for preparing the solution. The solution thus obtained can be optionally filtered to remove contaminants or undissolved particles.
A fourth aspect of the present invention provides a process for preparation of highly pure lumefantrine wherein the said process comprises of,
a) treating 2-(dibutylamino)-1-(2,7-dichloro-9/-/-fluoren-4-yl)ethanol with p-chlorobenzaldehyde in the presence of a base in an organic solvent
b) cooling the reaction mixture of step a) to 10°C or less for less than 10 hour,
c) isolating lumefantrine from the reaction mass
d) suspending lumefantrine obtained in step b) in a suitable organic solvent
e) heating the resultant mass to reflux
f) cooling the solution of step b) to room temperature
g) isolating highly pure polymorphic form I of lumefantrine
The base is selected from a group comprising of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide and potassium t-butoxide and the like. Suitable organic solvents have already been described in the first aspect of the present invention. The reaction mixture of step b) is preferably cooled to 5 to 10°C.
A pharmaceutical composition comprising highly pure lumefantrine or salt thereof having purity of 95% or more along with a pharmaceutical^ acceptable carrier / diluent.
A method of prophylaxis or treatment of malaria which comprises of administering to a mammal in need thereof a therapeutically effective amount of highly pure lumefantrine or salt thereof having purity of 95% or more.
A pharmaceutical composition comprising Form I of lumefantrine along with a pharmaceutical^ acceptable carrier or diluent.
A method of prophylaxis or treatment of malaria, which comprises of administering to a mammal in need thereof a therapeutically effective amount of Form I of lumefantrine.
Figure 1 depicts the X-Ray Diffraction Pattern of polymorphic form I of lumefantrine.
Figure 2 depicts Differential Scanning Calorimetric (DSC) thermogram of polymorphic
form I of lumefantrine.
Figure 3 depicts Fourier Transform Infrared (FTIR) spectrum of polymorphic form I of
lumefantrine.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF POLYMORPHIC FORM I OF LUMEFANTRINE
a) Preparation of Lumefantrine
To a mixture of ethanol (600 ml) and 2-(dibutylamino)-1-(2,7-dichloro-9/-/-fluoren-4-yl)ethanol (40 g) is added sodium hydroxide (4.74 g) at room temperature. This mixture is stirred for 0.5 hours and p-chlorobenzaldehyde (15.96 g) is added at room temperature followed by further stirring for 60 hours. The reaction mixture is cooled to 5 to 10°C and filtered. The solid so obtained is washed with water (500 ml) and dried first at room temperature and then at 45 to 50°C to obtain crude Lumefantrine. Yield = 31 g
b) preparation of highly pure polymorphic form I of Lumefantrine
Crude Lumefantrine (30 g) is taken in ethanol (360 ml) and heated to 65-70°C for 30
minutes. The solution is allowed to cool to 25°C and stirred for 2 hours. The product
so obtained is filtered, washed with ethanol (15 ml) and dried under vacuum at 45 to
50°C for 6 hours to afford highly pure polymorphic form I of Lumefantrine.
Yield = 18 g
Purity > 98% by HPLC

WE CLAIM:
1. Form I of Lumefantrine.
2. Form I of Lumefantrine having a XRPD pattern wherein characteristic 20 values are obtained at 5.50, 10.76, 11.06, 13.50, 14.30, 14.90, 15.42, 16.98, 18.00, 18.50, 19.12, 19.78, 20.08, 20.90, 21.54, 21.92, 22.98, 23.70, 24.20, 25.32, 26.48, 26.98, 27.50, 28.16, 28.54, 28.98, 30.14, 31.48, 31.96, 32.10, 32.74, 34.52, 36.92, 38.02.
3. Form I of Lumefantrine having characteristic endothermic melting point between 120-130°C.
4. Highly pure Lumefantrine having purity of 95% or more by HPLC.
5. A highly pure Lumefantrine of claim 4 having purity of 98% or more by HPLC.
6. A process for preparation of polymorphic form I of Lumefantrine wherein the said
process comprises of,
a) suspending Lumefantrine in a suitable organic solvent
b) heating the resultant mass to reflux
c) cooling the solution of step b) to room temperature
d) isolating polymorphic form I of lumefantrine
7. A process for preparation of highly pure Lumefantrine wherein the said process
comprises of,
a) treating 2-(dibutylamino)-1-(2,7-dichloro-9H-fluoren-4-yl)ethanol with p-chlorobenzaldehyde in the presence of a base in an organic solvent
b) cooling the reaction mixture of step a) to 10°C or less
c) isolating lumefantrine from the reaction mass
d) suspending lumefantrine obtained in step b) in a suitable organic solvent
e) heating the resultant mass to reflux

f) cooling the solution of step b) to room temperature
g) isolating highly pure polymorphic form I of lumefantrine

8. The process according claim 6 and 7 wherein the organic solvent is selected from the group comprising of alkanols, ketones, nitriles, chlorinated hydrocarbons, polar aprotic solvents, esters, ethers or mixtures thereof.
9. A pharmaceutical composition comprising Form I of lumefantrine or highly pure lumefantrine having purity of 95% or more along with a pharmaceutical^ acceptable carrier /diluent.
10. A method of prophylaxis or treatment of malaria which comprises of administering
to a mammal in need thereof a therapeutically effective amount of Form I of
lumefantrine or highly pure lumefantrine having purity of 95% or more.