The present invention relates to a method of converting lipstatin to orlistat. The present invention also relates to crystalline solid orlistat (e.g., form I and form II).
Orlistat is currently available for the treatment of obesity. It has the chemical name (2S, 3S, 5S)-5-[(S)-2-formamido-4-methylvaleryloxy]-2-hexy-3-hydroxyhexadecanoic acid lactone [a/k/a xe2x80x9cN-formyl-L-leucine ester with (3S, 4S)-3-hexyl-4-[(2S)-2-hydroxytridecyl]-2-oxetanonexe2x80x9d, (xe2x88x92)-tetrahydrolipstatin, tetrahydrolipstatin, and orlipastat] and its chemical formula is: 
Orlistat has been purified from a fermentation broth of Streptomyces toxytricini (See U.S. Pat. No. 4,598,089 and Eur. Pat. Appl. 129,748). U.S. Pat. No. 4,598,089 is directed to orlistat and its use in treating obesity. The cultivation, fermentation and purification of orlistat produced in Streptomyces toxytricini were disclosed. The process involves purifying orlistat using a silica gel chromatography. The desired orlistat may then be subjected to further purification with a reverse-phase chromatography; thus, multiple chromatographies are required. The repeated purification processes is costly and impractical for large scale manufacturing.
U.S. Pat. No. 4,983,746 relates to a process for the artificial synthesis of orlistat which involves producing oxetanone derivatives; and esterification of the acid derivatives with an alcohol. The disadvantage of artificially synthesizing orlistat is its high cost, especially with industrial scale production.
EP 638317 describes a pharmaceutical composition including orlistat. However, there is no disclosure regarding the production and purification of orlistat. Such obtained orlistat is not desirable for preparing a pharmaceutical composition as it requires high purity.
There is a continuous need to improve the preparation of orlistat.
The present invention also relates to the solid state physical properties of orlistat. These properties can be influenced by controlling the conditions under which orlistat is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient""s stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient""s bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are determined by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. A particular crystalline form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, or other parameters including solid state 13C NMR spectrometry and infrared spectrometry. The polymorphic form may also give rise to thermal behavior different from that of the amorphous material or another crystalline form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others.
The present invention provides a process of preparing orlistat, comprising the steps of hydrogenating lipstatin in an organic solvent in the presence of a catalyst to obtain orlistat. Preferably, the organic solvent is selected from the group consisting of acetonitrile, alcohol, and acetone. Most preferably, the organic solvents are methanol and acetone.
Preferably, the catalyst is selected from the group consisting of palladium and nickel. Preferably, the hydrogenating step is performed at a temperature between about 10xc2x0 C. to about 50xc2x0 C. Preferably, the hydrogenating step is performed at reaction pressure of less than 5 bar. More preferably, the hydrogenating step is performed at reaction pressure between about 1 to about 3 bar. Most preferably, the hydrogenating step is performed at reaction pressure of about 1 bar.
The present invention provides a crystalline solid orlistat, or hydrate or solvate thereof, characterized by data selected from the group consisting of a XRD pattern with peaks at 5.8, 18.5, 19.5 and 22.3xc2x10.2 degrees two-theta and a DSC melting endotherm at about 46.7xc2x0 C.
Preferably, the crystalline solid orlistat is characterized by a XRD pattern with peaks at 5.8, 18.5, 19.5 and 22.3xc2x10.2 degrees two-theta.
Preferably, the crystalline solid orlistat is further characterized by a XRD pattern substantially as depicted in FIG. 1.
Preferably, the crystalline solid orlistat characterized by a DSC melting endotherm at about 46.7xc2x0 C.
The present invention provides a crystalline solid orlistat, or hydrate or solvate thereof, characterized by data selected from the group consisting of a XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0xc2x10.2 degrees two-theta, and a DSC melting endotherm at about 46.6xc2x0 C.
Preferably, the crystalline solid orlistat is characterized by a XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0xc2x10.2 degrees two-theta.
Preferably, the crystalline solid orlistat is further characterized by a XRD pattern substantially as depicted in FIG. 2.
Preferably, the crystalline solid orlistat is characterized by a DSC melting endotherm at about 46.6xc2x0 C.
The present invention provides a process of preparing crystalline solid orlistat, or hydrate or solvate thereof, characterized by data selected from the group consisting of a XRD pattern with peaks at 5.8, 18.5, 19.5 and 22.3xc2x10.2 degrees two-theta and a DSC melting endotherm at about 46.7xc2x0 C., comprising the steps of:
(a) dissolving orlistat in a solvent;
(b) adding an anti-solvent or water to the solvent; and
(c) isolating the crystalline solid orlistat.
Preferably, the solvent is a lower alkyl alcohol, acetone, acetonitrile, acetone, ethyl acetate, isobutyl acetate, methyl isobutyl ketone, and hexane.
Preferably, the lower alkyl alcohol is selected from the group consisting of methanol, ethanol, n-propanol, and isopropanol. Preferably, the anti-solvent is a hydrocarbon. More preferably, the hydrocarbon is selected from the group consisting of hexane, cyclohexane and heptane. Most preferably, the solvent is methanol and the anti-solvent is hexane. Preferably, the steps (a) to (c) are repeated at least once to increase the purity of the crystalline solid orlistat.
The present invention provides the crystalline solid orlistat prepared in accordance with the process comprising the steps of:
(a) dissolving orlistat in a solvent;
(b) adding an anti-solvent or water to the solvent; and
(c) isolating the crystalline solid orlistat.
The present invention provides a process for preparing a crystalline solid orlistat, or hydrate or solvate thereof, characterized by data selected from the group consisting of a XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0xc2x10.2 degrees two-theta, and a DSC melting endotherm at about 46.6xc2x0 C., comprising the steps of:
(a) mixing orlistat in hexane to form a mixture at a first temperature;
(b) lowering the first temperature of the mixture sufficiently to precipitate; and
(c) isolating crystalline solid orlistat.
Preferably, steps (a) to (c) are repeated at least once to increase the purity of the crystalline solid orlistat.
The present invention provides the crystalline solid orlistat prepared in accordance with the process comprising the steps of:
(a) mixing orlistat in hexane to form a mixture at a first temperature;
(b) lowering the first temperature of the mixture sufficiently to precipitate; and
(c) isolating crystalline solid orlistat.
The present invention provides a process of preparing a mixture of crystalline solid orlistat, or hydrate or solvate thereof, characterized by data selected from the group consisting of a XRD pattern with peaks at 5.8, 18.5, 19.5 and 22.3xc2x10.2 degrees two-theta, a DSC melting endotherm at about 46.7xc2x0 C., a XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2 and 22.0xc2x10.2 degrees two-theta, and a DSC melting endotherm at about 46.6xc2x0 C., comprising the steps of:
(a) dissolving orlistat in a solvent; and
(b) inducing crystallization to obtain the mixture of crystalline solid orlistat.
Preferably, the solvent is at least one alcohol selected from the group consisting of methanol, ethanol, n-propanol, 1-propanol, 2-propanol, isopropanol, 1-butanol, i-butanol, sec-butanol, tert-butanol, N,N-dimethyl formamide, dimethyl sulfoxide, acetonitrile, acetone, ethyl acetate, isobutyl acetate, methyl isobutyl ketone, and acetic acid. Preferably, the solvent is an aliphatic hydrocarbon. More preferably, the aliphatic hydrocarbon is selected from the group consisting of hexane, pentane and heptane. Preferably, the solvent contains water. More preferably, the solvent is methanol. Most preferably, the mixture of methanol and water is present in a v/v ratio of about 1:0.3. Preferably, the solvent is a mixture of a first alcohol in combination with a second alcohol selected from the group consisting of methanol, ethanol, isopropanol, propanol, butanol, sec-butanol and t-butanol. Preferably, the crystallization step is induced by adding an anti-solvent or cooling.
The present invention provides the crystalline solid orlistat having a purity of at least about 95%. More preferably, the crystalline solid orlistat has a purity of at least about 98%.
The present invention provides a process of preparing orlistat, comprising the steps of:
a) preparing fermentation broth containing lipstatin;
b) extracting lipstatin from the fermentation broth;
c) hydrogenating the lipstatin to obtain orlistat; and
d) separating the orlistat.
Preferably, the hydrogenating step c) is carried out in an organic solvent in the presence of a catalyst to obtain orlistat.