Specification
PROCESS FOR AMORPHOUS FORM OF LOPINAVIR
FIELD OF THE INVENTION
The present application relates to a process for the preparation of substantially pure Lopinavir, and to a process for preparing amorphous form of Lopinavir.
BACKGROUND
Lopinavir is chemically designated as [1S-[1R*, (R*),3R*,4R*]]-N-[4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-phenylmethy) pentyl]tetrahydro-alpha-(1-methylethyl)-2-oxo-1 (2H)-pyrimidineacetamide,represented by the chemical structure of Formula (I).
Formula (I)
Lopinavir is an inhibitor of the HIV protease and is sold in US as Kaletra in Co-formulation with Ritonavir. Ritonavir inhibits the CYP3A-mediated metabolism of Lopinavir thereby providing increased levels of Lopinavir.
US 5914332 (hereinafter referred to as the '332 patent) discloses Lopinavir or a pharmaceutically acceptable salt, ester or prodrug thereof as an inhibitor of human immunodeficiency virus (HIV) protease. The '332 patent also describes a process for the preparation of amorphous form of Lopinavir by addition of water to a solution of Lopinavir in an organic solvents, such as methanol or isopropanol. The process requires a huge quantity of water for precipitating the compound, which is not preferable for large scale production and is also not environment friendly as the amount of effluent generated will be very high.
There remains a need to provide a process for the preparation of substantially pure Lopinavir and a process for the preparation of amorphous form of Lopinavir, which may be easily scaleable for large scale production and environment friendly.
SUMMARY
In an embodiment, the present application provides a process for the preparation of substantially pure Lopinavir of Formula (I), which includes one or more of the following steps, individually or in the sequence recited:
(a) treating Lopinavir compound of Formula (I) with a ketone solvent; and
(b) isolating the substantially pure Lopinavir of Formula (I).
In an embodiment, the present application provides a process for the preparation of amorphous form of Lopinavir, which includes:
(a) providing a solution of Lopinavir in a solvent
(b) removing the solvent from a solution of Lopinavir;
(c) recovering Lopinavir; and
(d) optionally drying.
In an embodiment, the present application provides an amorphous form of Lopinavir that is obtained by the process of the present invention characterized by its powder X-ray diffraction (PXRD) pattern substantially in accordance with Fig. 1.
In an embodiment, the present application also provides a pharmaceutical composition comprising amorphous form of Lopinvair along with one or more pharmaceutically acceptable carriers, excipients or diluents.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of powder X-ray diffraction(PXRD) pattern of amorphous form of Lopinavir prepared according to the process of the present application.
DETAILED DESCRIPTION
While the specification concludes with the claims particularly pointing and distinctly claiming the invention, it is believed that the present invention will be better understood from the following description. All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25°C and normal pressure unless otherwise designated. All temperatures are in Degrees Celsius unless specified otherwise. As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
Note that while the specification and claims may refer to a final product such as, for example, a tablet or other dosage form of the invention as, for example, containing particles having a certain particle size or distribution, or a certain type of, for example, a specific form of a filler, it may be difficult to tell from the final dosage form that the recitation is satisfied. However, such a recitation may be satisfied if the materials used prior to final production (in the case of a tablet for example, blending and tablet formulation), for example, meet that recitation. Indeed, as to any property or characteristic of a final product which cannot be ascertained from the dosage form directly, it is sufficient if that property resides in the components recited just prior to final production steps.
Where this document refers to a material, such as in this instance, Lopinavir and the unique amorphous forms, salts, solvates and/or optical isomers thereof by reference to patterns, spectra or other graphical data, it may do so by qualifying that they are "substantially" shown or depicted in a Figure, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra and other graphical data can be shifted in their positions, relative intensities, or other values due to a number of factors known to those of skill in the art. For example, in the crystallographic and powder X-ray diffraction arts, shifts in peak positions or the relative intensities of one or more peaks of a pattern can occur because of, without limitation: the equipment used, the sample preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length of data collection, and the like. However, those of ordinary skill in the art should be able to compare the figures herein with a pattern generated of an unknown form of, in this case, Lopinavir, and confirm its identity as one of the forms disclosed and claimed herein. The same holds true for other techniques which may be reported herein.
In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure which uniquely define that crystalline form, salt, solvate, and/or optical isomer, within any associated and recited margin of error, for purposes of identification.
A reference to a molecule such as, in this case, Lopinavir, unless otherwise specified or inconsistent with the disclosure in general, refers to any salt, crystalline or amorphous form, optical isomer and/or solvate form thereof.
When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is about 99% pure or more. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities and unreacted starting materials. In the case of stereoisomers, "pure" also means 99% of one enantiomer or diastereomer, as appropriate. "Substantially" pure means, the same as "pure" except that the lower limit is about 98% pure or more and likewise, "essentially" pure means the same as "pure" except that the lower limit is about 95% pure.
In an embodiment, the present application provides a process for the preparation of substantially pure Lopinavir of Formula (I), which includes one or more of the following steps, individually or in the sequence recited:
(a) treating Lopinavir compound of Formula (I) with a ketone solvent; and
(b) isolating the substantially pure Lopinavir of Formula (I).
Step a) involves treating Lopinavir compound of Formula (I) with a ketone solvent.
Suitable ketone solvents that may be used in step a) include but are not limited to: acetone, butanone; 2-pentanone, 3-pentanone or mixtures thereof.
The quantity of solvent that may be used in step a) may be less than about 6 times or less than about 4 times or less than about 2 times or any other suitable quantity by volume to the weight of Lopinavir of Formula (I).
Suitable temperatures that may be used in step a) may be less than about 150°C, or less than about 100°C, or less than about 80°C, or less than about 60°C, or less than about 40°C, or less than about 20°C, or less than about 0°C, or less than about -20°C, or any other suitable temperatures.
The reaction mixture obtained in step a) may be optionally followed by removal of any insoluble solids or particles by methods such as filtration, decantation, centrifugation, gravity filtration, suction filtration or any other technique known in the art for the removal of solids.
Step b) involves isolating the substantially pure Lopinavir of Formula (I).
The isolation in step b) may be effected by methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent and the like. The suitable temperatures for isolation may be less than about 100°C or less than about 60°C or less than about 40°C or less than about 20°C or less than about 5°C or less than about 0°C or less than about -10°C or less than about -20°C or any other suitable temperatures. Suitable times for isolation may be less than about 5 hours or less than about 3 hours or less than about 2 hours or less than about 1 hour or longer times may be used. However, the exact temperatures and times required for complete isolation may be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry. Stirring or other alternate methods such as shaking, agitation and the like, that mix the contents may also be employed for isolation.
Suitable techniques that may be used for the removal of solvent include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization) and the like, optionally under reduced pressure.
The substantially pure compound of Formula (I) may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration or any other technique for the recovery of solids. The substantially pure compound of Formula (I) thus isolated may carry some amount of occluded mother liquor and thus have higher than desired levels of impurities.
If desired, the solid may be washed with a suitable solvent or a mixture of solvents such as those used in step a) to wash out the impurities.
The recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying may be carried out at temperatures less than about 150°C or less than about 120°C or less than about 100°C or less than about 80°C or less than about 60°C or any other suitable temperatures as long as the compound of Formula (I) is not degraded in quality, at atmospheric pressure or under reduced pressure. The drying may be carried out for any desired time until the required purity is achieved.
"Substantially pure" as used herein, unless otherwise defined refers to the compound that may contain less than about 2% or less than about 1% or less than about 0.5% or less than about 0.3% or less than about 0.2% or less than about 0.1% or less than about 0.05% or less than about 0.03% or less than about 0.02% or less than about 0.01% by weight, of each impurity including, without limitation, the amide impurity of Formula (la), ester impurity of Formula (lb), and THPA isomer impurity of Formula (Ic) or any other corresponding impurity as measured by HPLC.
"Amide impurity of Formula (la)" refers to N-{1-Benzyl-4-[2-(2, 6-dimethyl-phenoxy)-acetylamino]-2-hydroxy-5-phenyl-pentyl}-2-(2, 6-dimethyl-phenoxy)-acetamide;
"ester impurity of Formula (lb)" refers to (2, 6-Dimethyl-phenoxy)-acetic acid 3-tert-butyloxycarbonylamino-1 -{1 -[2-(2, 6-dimethyl-phenoxy)-acetylamino]-2-phenyl-ethyl}-4-phenyl-butyl ester;
"THPA isomer impurity of Formula (Ic)" refers to (2S, 3S, 5S)-2-(2, 6-Dimethyl phenoxy acetyl) amino-3-hydroxy-5-[2R-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1, 6-diphenyl hexane;
The High Performance Liquid Chromatography (HPLC) method used for the analysis of the amide impurity of Formula (la), ester impurity of Formula (lb) and THPA isomer impurity of Formula (Ic) utilizes Zorbax SB-Phenyl or equivalent column. Additional parameters of the method are as shown in Table 1.
Table 1
Flow 1.0ml/min
Elution Gradient
Wavelength 210 nm
Injection volume 15 µl
Temperature 27°C
Mobile phase Buffer: 0.01 M potassium dihydrogen phosphate and adjust pH to 7.3 with potassium hydroxide solution. Mobile phase A: Buffer and acetonitrile in the ratio of 900:100 (v/v)
Mobile phase B: acetonitrile, methanol and water in the ratio of 800:100:100 (v/v)
Diluent Acetonitrile and water in the ratio of 1:1
Run time 70 minutes
Impurity name RRT (relative retention time)
Amide impurity of Formula (la) 2.20
Ester impurity of Formula (lb) 2.42
THPA isomer impurity of Formula (Ic) 1.13
In an embodiment, the present application provides a process for the preparation of amorphous form of Lopinavir, which includes:
(a) providing a solution of Lopinavir in a solvent;
(b) removing the solvent from that solution;
(c) recovering Lopinavir; and
(d) optionally drying.
Step a) Providing a solution of Lopinavir in a solvent which can be accomplished in any conventional manner, including:
(I) directly using a reaction mixture containing Lopinavir that is obtained in the course of a manufacturing process, or
(II) dissolving Lopinavir in a suitable solvent.
Any physical form of Lopinavir, such as crystalline, amorphous or their mixtures may be utilized for providing the solution of Lopinavir in step a).
Lopinavir that may be used as the input for the process of the present application may be obtained by any process including the processes described in the art. For example Lopinavir may be prepared by the processes described in US 5914332.
Solvents that may be used for providing the solution of Lopinavir include, but are not limited to; alcohols such as methanol, ethanol, isopropyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and tert-butyl alcohol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; ketones such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate and t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether, methyl t-butyl ether and 1,4-dioxane; nitriles such as acetonitrile and propionitrile; water; and mixtures thereof. The dissolution temperatures used to provide a Lopinavir solution may range from about 20°C to about the reflux temperature depending on the solvent used for dissolution. Any other temperature may also be acceptable as long as a clear solution of Lopinavir is obtained without affecting its quality.
The solution may optionally be treated with carbon or other absorbent and filtered to remove colour or to improve clarity of the solution.
The solution may be filtered suitably by filtration, centrifugation, decantation and other techniques commonly known in the art. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite. Depending upon the equipment used, concentration and temperature of the solution, the filtration apparatus may optionally be preheated to avoid premature crystallization.
In step b), suitable techniques which may be used for the removal of solvent include but not limited to rotational evaporating device such as Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD") and lyophilization.
The solvent may be removed from the solution at atmospheric pressure or under reduced pressure. The solvent may be removed at any temperatures as long as it does not affect the quality of the product. It may range from about 20°C to about 200°C.
The compound obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used.
The product thus obtained may be optionally dried to afford the desired amorphous form of Lopinavir.
Drying may be suitably carried out in a tray dryer, vacuum oven, Buchi Rotavapor, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying may be carried out at temperatures of about ambient temperature to about 100°C, with or without vacuum. The drying may be carried out for any time period such as from about 15 minutes to several hours.
In an embodiment, the present application provides an amorphous form of Lopinavir that is obtained by the process of the present invention characterized by its powder X-ray diffraction (PXRD) pattern substantially in accordance with Fig. 1. PXRD data reported herein may be obtained using Bruker Axe D8 Advance Powder X-ray Diffractometer at Cu Ka radiation, having the wavelength 1.5406 A.
In an embodiment, the present application also provides a pharmaceutical composition comprising amorphous form of lopinvair along with one or more pharmaceutically acceptable carriers, excipients or diluents.
The pharmaceutical compositions of Lopinavir along with one or more pharmaceutically acceptable excipients of the present application 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 solutions, dispersions, and freeze dried compositions. Formulations may be in the form 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, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. Compositions may be presented as
uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that find use in the present application include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Certain specific aspects and embodiments of the present application may be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the application in any manner.
Example-1: Preparation of (2S,3S,5S)-2-(2. 6-imethvl Phenoxvacetvl) Amino-3-Hvdroxv-5-Amino-1.6-Diphenvl Hexane.
2-6-dimethyl phenoxyacetic acid (23 g), dichloromethane (100 ml) are charged in to a round bottom flask at a temperature of 25-35°C and stirred for a period of 5-10 minutes. Thionyl chloride (17.2 g) is added slowly to the above reaction mixture for a period of 15-20 minutes. The reaction mixture is heated to a temperature of 35-40°C and maintained at a temperature of 35-40°C for a period of 3-4 hours. The reaction mixture is distilled completely at a temperature of below 50°C under vacuum and cooled to a temperature of 25-35°C. Dichloromethane (50.0 ml) is charged to the reaction mass and the solvent is completely distilled at a temperature of below 50°C under vacuum. The reaction mass is cooled to a temperature of 25-35°C and dichloromethane (100 ml) is charged to the reaction mass and stirred for a period of 5-10 minutes under nitrogen atmosphere to dissolve 2, 6-dimethylphenoxyacetyl chloride.
Water (300 ml), sodium bicarbonate (41.6 gm) and dichloromethane (400 ml) are charged to the above reaction mixture and stirred for a
Documents
Application Documents
| # |
Name |
Date |
| 1 |
1744-che-2008 correspondence others.pdf |
2011-09-03 |
| 1 |
1744-che-2008 form-1 19-08-2008.pdf |
2008-08-19 |
| 2 |
1744-che-2008 correspondence 19-08-2008.pdf |
2008-08-19 |
| 2 |
1744-che-2008 description (provisional).pdf |
2011-09-03 |
| 3 |
1744-che-2008 form-3 20-10-2008.pdf |
2008-10-20 |
| 3 |
1744-che-2008 drawing.pdf |
2011-09-03 |
| 4 |
1744-CHE-2008 FORM-5 14-07-2009.pdf |
2009-07-14 |
| 4 |
1744-che-2008 form-1.pdf |
2011-09-03 |
| 5 |
1744-che-2008 form-3.pdf |
2011-09-03 |
| 5 |
1744-CHE-2008 FORM-3 14-07-2009.pdf |
2009-07-14 |
| 6 |
1744-che-2008 form-2 14-07-2009.pdf |
2009-07-14 |
| 6 |
1744-che-2008 abstract (14-07-2009).pdf |
2009-07-14 |
| 7 |
1744-CHE-2008 FORM-1 14-07-2009.pdf |
2009-07-14 |
| 7 |
1744-che-2008 claims (14-07-2009).pdf |
2009-07-14 |
| 8 |
1744-che-2008 correspondence others(14-07-2009).pdf |
2009-07-14 |
| 8 |
1744-CHE-2008 DRAWINGS 14-07-2009.pdf |
2009-07-14 |
| 9 |
1744-CHE-2008 DESCRIPTION(COMPLETE) 14-07-2009.pdf |
2009-07-14 |
| 10 |
1744-CHE-2008 DRAWINGS 14-07-2009.pdf |
2009-07-14 |
| 10 |
1744-che-2008 correspondence others(14-07-2009).pdf |
2009-07-14 |
| 11 |
1744-CHE-2008 FORM-1 14-07-2009.pdf |
2009-07-14 |
| 11 |
1744-che-2008 claims (14-07-2009).pdf |
2009-07-14 |
| 12 |
1744-che-2008 form-2 14-07-2009.pdf |
2009-07-14 |
| 12 |
1744-che-2008 abstract (14-07-2009).pdf |
2009-07-14 |
| 13 |
1744-che-2008 form-3.pdf |
2011-09-03 |
| 13 |
1744-CHE-2008 FORM-3 14-07-2009.pdf |
2009-07-14 |
| 14 |
1744-CHE-2008 FORM-5 14-07-2009.pdf |
2009-07-14 |
| 14 |
1744-che-2008 form-1.pdf |
2011-09-03 |
| 15 |
1744-che-2008 form-3 20-10-2008.pdf |
2008-10-20 |
| 15 |
1744-che-2008 drawing.pdf |
2011-09-03 |
| 16 |
1744-che-2008 description (provisional).pdf |
2011-09-03 |
| 16 |
1744-che-2008 correspondence 19-08-2008.pdf |
2008-08-19 |
| 17 |
1744-che-2008 form-1 19-08-2008.pdf |
2008-08-19 |
| 17 |
1744-che-2008 correspondence others.pdf |
2011-09-03 |