|Title of Invention||
PROCESS FOR PREPARATION OF HIGHLY PURE ISOTRETINOIN
|Abstract||The present invention discloses a process for preparation of isotretinoin and more specifically, to a purification process for obtaining highly pure isotretinoin that is useful as a keratolytic agent, particularly useful for the treatment of acne.|
|Full Text||FORM 2
THE PATENT ACT 1970
(39 of 1970)
The Patents Rules, 2003
(See section 10 and rulel3)
1. TITLE OF THE INVENTION: WA process for preparation of highly pure
2. APPLICANT (S)
(a) NAME: IPCA LABORATORIES LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai-400 067
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention and the manner in which it is
to be performed.
The present invention relates to a process for preparation of isotretinoin and more specifically, to a purification process for obtaining highly pure isotretinoin that is useful as a keratolytic agent, particularly useful for the treatment of acne.
Background of the Invention:
Isotretinoin (Formula I), also known as 13-cis-retinoic acid, is a medication used for the treatment of severe acne. It is sometimes used in prevention of certain skin cancers. It is a retinoid, meaning it is derived from vitamin A and is found in small quantities naturally in the body. Oral isotretinoin is marketed under various trade names, most commonly Accutane. It inhibits the sebaceous gland function and keratinization and is used for the treatment of dermatological diseases. It is very effective in very severe and nodulosystic acne and prevents scarring.
As mentioned above, isotretinoin whose structure represented in Formula I, structurally is a highly conjugated molecule consisting of a substituted cyclohexene moiety and a nine carbon polyene side chain with a terminal free carboxyl group. All but the C-13 double bond in the side chain possess cis geometry and therefore known as 13-cis-retinoic acid. Commercially available P-ionone has been conveniently used for the construction of the cyclohexene portion of isotretinoin. There are ample literatures available for the preparation of isotretinoin exploring various synthetic alternatives. For example by the process described in J. Organic Chemistry, 54, 2620-2628, 1989 or J. Chem. Soc.(Comm), 1984-97, 1968; US patent No. US0192351 and US patent No. US4556518. Most commonly used process starts from a [3-methyl-5(2,6,6-trimethyl-1 -cyclohexene-1 yl-2,4-pentadienyl]-triphenyl-phosphonium)halide, which is condensed with 5-hydroxy-lmethyl-2(5-H)-furanone. However, this condensation reaction yields a mixture of isomers of retinoic acid including the 11,13-di-cw-retinoic acid (Formula II), 9,13,-di-cw-retinoic acid (formula III), all-/ra«.s-retinoic acid (Formula IV) and 13-cis-retinoic acid (isotretinoin).
To improve the yield of 13-cis isomer, the above mixture is subjected to isomerization reaction thereby the undesired isomers are converted to the desired 13-cis-retinoic acid. The above isomerization reaction is effected either by use of heavy metal catalysts such as rhodium or palladium (please refer patent Numbers USO192351 and US patent No. US4556518) or by photochemical isomerization (please refer US6177579), however, in the photo-chemical isomerization reaction, the yield of 13-cis-retinoic acid is very low (nearly 44 %). The metal catalyzed isomerization reaction provides a higher isomeric conversion in the order of greater than 97%. However, the product obtained is contaminated with the heavy metals (in the order of about 30000-40000 ppm after isolation), which is not only in contrast to the required purity criteria, but also a factor contributing to the known instability of the product (for the instability studies on isotretinoin, please see Pharmaceutical Research 1992,
(9), 1203-1208). The crystallization methods so far reported do not effectively remove the trace metals and usually it remains, unless a thorough repeated crystallization from organic solvents is done, which is not only unacceptable for stability of the compound but also for economy of the process. This is because, the solubility of isotretinoin in organic or aqueous solvents is very low and very high volumes of solvents are required to completely dissolve the trace metal contaminated isotretinoin for crystallization. The higher temperature crystallization, although removes heavy metal to some extent, but such operations further degrades the product due to instability of isotretinoin under these conditions. Although isotretinoin is soluble in ethers like tetrahydrofuran or chlorinated hydrocarbons like methylene chloride, the crystallization from these solvents are not acceptable due to OVI issues and any further processing for removal of these solvents results in degradation of isotretinoin. Furthermore it is being disclosed that the isomeric retinoic acids are rather unstable in organic solvents, which instability is partially due to the presence of trace metals. Thus there is a long felt need in the art to get a process for effective removal of trace metals in isotretinoin, while it provides stability to the isotretinoin. These objectives are accomplished by the present invention by providing an improved process for isotretinoin objectively for the removal of trace metals.
Summary of the Invention
The present inventors have discovered that the prior art processes present substantial difficulties in producing pure isotretinoin substantially free of any trace metals in economically acceptable yield. The invention, therefore, aims to provide an improved process for making isotretinoin substantially free of trace metals. In accordance with one aspect, the invention provides a process for preparation of isotretinoin, which process includes a base and acid mediated treatment at controlled temperatures from aqueous solvents. The aqueous solvent is selected from water and water miscible solvents like primary or secondary or tertiary alcohols, ketones, aprotic polar solvents like dimethylformamide, acetonitrile etc. Preferably the solvent for isolation is a mixture of water and an alcohol. Particularly preferred alcohol for this purpose is methanol, ethanol, and
isopropanol. In a preferred embodiment of the invention, the process is operated in presence of catalytic quantities of antioxidants. The antioxidants may be appropriately selected from butylated hydroxytoluene (BHT) or butylatedhydroxyanisole (BHA) In a second aspect, but not least, the present invention provides an improved single-pot process for preparation of [3-methyl-5(2,6,6-trimethyl-l-cyclohexene-lyl-2,4-pentadienyl]-triphenyl-phosphonium) halide, and its condensation with 5-hydroxy-l-methyl-2(5-H)-furanone for obtaining isotretinoin, which is further isomerized and purified according to the present invention.
Detailed description of the Invention
Unless specified otherwise, all technical and scientific terms used herein have the same
meaning as commonly understood by one of ordinary skill in the art, to which this invention
belongs. Although any methods and materials similar or equivalent to those described herein
can be used in the practice or testing of the present invention, the preferred methods and
materials are described. To describe the invention, certain terms are defined herein
specifically as follows.
Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.
The term "isolating" is used to indicate separation or collection or recovery of the compound being isolated in the solid/liquid form either as crude or pure material. The term "substantially free" in the context of trace metals means that the product is free from contamination of said trace metals not more than 20 ppm, preferably less than 10 ppm and most preferably less than 5 ppm. The term "substantially free" in the context of other
chemical impurities means that the product is free from contamination of said impurities at least less than 0.5%, preferably less than 0.1% and most preferably less than 0.05%.
It should be understood that there exists equilibrium between a free species and salt form of a compound capable of forming salt with bases/acids (e.g., by virtue of having a carboxylic acid functionality in the molecule).
The inventors of the present invention have found that the use of solvent crystallization does not provide a reliable, consistent methodology to remove trace metals from isotretinoin. The inventors have recognized that small changes in manufacturing parameters might lead to impurities formation due to polymerization or oxidation of isotretinoin and contaminates the product with those impurities. One such impurity is the oxidized products of isotretinoin and their content increases with the crystallization conditions due to photo-oxidation. The inventors, on exploring various process alternatives, for a reliable process solution have found that the use of an improved purification procedure comprising treating the isotretinoin under controlled temperature with a base in an aqueous solvent to form a solution of isotretinoin permits reliable complete removal of trace metals from isotretinoin by adsorption followed by filtration or centrifugation. The isotretinoin from the aqueous solution is isolated by treatment with an acid in a controlled manner to obtain isotretinoin substantially free of trace metals and any oxidized impurities. Although low temperature operation takes care of oxidative degradation, it may be preferable to use catalytic quantity of an antioxidant to prevent any oxidation or formation of oxidized impurities. The antioxidants may be appropriately selected from butylated hydroxytoluene (BHT) or butylatedhydroxyanisole (BHA)
Aqueous solvent used for the above treatment is selected from water and water miscible solvents. Especially preferred water miscible polar solvents are alcohols, ketones such as acetone, polar aprotic solvents such as dimethyl formamide, acetonitrile, dimethyl sulphoxide. Especially preferred solvent is a combination of water and the above organic solvents. The invention permits the use of very small quantities/volume of solvent for
dissolution and purification, for example as low as 2 volume to 20 volume, which also reflects on the economy and environmental friendliness of the process. The preferable ratio of water range from 30 to 99% and especially preferred is a 50%. Preferably the reaction is performed at lower temperature, especially between -15 to +35 degrees.
The base used for dissolution of isotretinoin may be selected appropriately from an inorganic or organic class of compounds. The most preferred bases are sodium carbonate or bicarbonate, potassium carbonate and bicarbonate, hydroxides, lithium hydroxide, triethyl amine, methyl amine, ethyl amine, aqueous ammonia etc. The acid used for recovery of isotretinoin from the aqueous basic solution is selected from an appropriate organic or inorganic acid. Hydrochloric acid is especially preferred for this application.
In a preferred process condition, the isotretinoin containing trace metals is dissolved in basic aqueous solution at a temperature ranging from -15 to 35 degree. Preferably it is dissolved at a temperature between 0-5 °C. The aqueous base solution of isotretinoin is treated with charcoal and then filtered to remove any undissolved materials and trace metals. This solution is then treated with an acid especially inorganic acid to precipitate the isotretinoin from the aqueous solution. The precipitated solid isolated from the solvent by conventional means such as filtration.
The isotretinoin may be obtained by any known procedures and further isomerization with a metal catalyst such as rhodium or palladium.
In a second embodiment, the present invention provides a single-pot process for the preparation of [3-methyl-5(2,6,6-trimethyl-1 -cyclohexene-1 yl-2,4-pentadienyl]-triphenyl-phosphonium) halide, and its condensation with 5-hydroxy-l-methyl-2(5-H)-furanone for obtaining isotretinoin as a mixture of isomers (see below scheme).
The said process comprises treating the P-vinylionol of Formula V with triphenylphosphine in presence of a mineral acid salt at a pH in the range of 6.0 to 7 in a solvent to form [3-methyl-5(2,6,6-trimethyl-1 -cyclohexene-1 yl-2,4-pentadienyl]-triphenyl-phosphonium) halide which is further treated with 5-hydroxy-l-methyl-2(5-H)-furanone in presence of a base. The pyridinium hydrochloride is especially preferred as the mineral acid salt. Although base can be appropriately selected from organic or inorganic bases, inorganic bases are preferred for this application. Especially preferred bases are potassium hydroxide, or sodium hydroxide. The solvents are selected from non-aqueous solvents, especially alcohols. Methanol, ethanol and isopropanol are especially preferred for this reaction. The molar ratio of the reactants and reagents may appropriately choosen, however, equi-molar amounts or slight excess of 5-hydroxy-l-methyl-2(5-H)-furanone relative to the starting [3-methyl-5(2,6,6-trimethyl-l-cyclohexene-lyl-2,4-pentadienyl]-triphenyl-phosphonium) halide is employed for economy of the process. The reaction can be effected at or less than reflux temperature of the solvent used in the reaction, preferably at below 50 degree and most preferably below 20 degree Celsius.
The reaction yields a mixture of isomers of retinoic acid wherein the content of 13-cis-retinoic acid is about 20-25%. The isomeric mixture is then subjected to isomerization into 13-cis-retinoic acid using metal catalyst, for example, with palladium nitrate in an organic solvent. Polar aprotic solvents are preferred for this reaction as reaction medium, especially ethyl acetate and acetonitrile. After isomerization the product shows the following isomer content:
13-cw-retinoic acid : 98.5%
9,13-d/cw-retinoic acid : 0.2 to 0.3%
1 l,13- 8
all-frms-retinoic acid : 0.1 to 0.2%
palladium : 30000-40000 ppm
Oxidized impurities : 0.05 to 0.1%
The palladium contaminated isotretinoin is purified according to the afore-described process
of the present invention and the product of the following purity is obtained.
13-cis-retinoic acid: : >99.5%
9,13-dicis-retinoic acid : 0.05 to 0.1%
11,13-dicis-retinoic acid : 0.05 to 0.1%
all-trans Retinoic acid : 0.02 to 0.1%
Oxidized impurity : 0.05 to 0.1%
palladium : 0-10 ppm
The product after drying is also substantially free of bound organic solvents. Substantially
free of organic solvents herein means that the bound solvents are not more than 5000 ppm,
preferably not more than 1000 ppm and most preferably less than 100 ppm.
The process conditions are further illustrated in the Examples. It is surprising that the highly
unstable isotretinoin is stable under the operative conditions of the present invention which
permits reliable purification from heavy metals. The results of the invention are therefore
Also provided in accordance with the invention are pharmaceutical compounds comprising isotretinoin in substantially pure form, free from the oxidized impurities and trace metals. Preferably, the isotretinoin present in such compositions is obtained in substantially pure form by means of the process of the invention before being incorporated into a pharmaceutical product.
The examples provided below are illustrative and are not intended to limit the scope of the claimed invention.
100 grams of vinyl-|3-ionol was taken in 1500 ml methanol at room temperature. To a dissolved solution of vinyl-p-ionol, the pyridine (42 ml), hydrochloric acid (30%) 42 ml and Triphenyl phosphine (116.8 gm ) were added. The solution was then heated to reflux and maintained for 1 hour. The reaction mass was cooled and added 5-hydroxy-l-methyl-2(5-H)-furanone (44.2 gm) and potassium hydroxide (77 gm) and stirred at -10 to 15 degree temperature for 3 hours. After complete reaction, the crude product extracted with ethylacetate and hexane and the solvent was distilled under vacuum and the residue (100 gm) was taken for isomerization reaction.
100 grams of vinyl- P-ionol was taken in 1500 ml methanol at room temperature. To a dissolved solution of vinyl-pMonol, the pyridine (42 ml), hydrochloric acid (30%) 42 ml and Triphenyl phosphine (116.8 gm ) were added. The solution was then heated to reflux and maintained for 1 hour. The methanol was removed in vacuum and isopropanol (1000 ml) was added into the reaction. The reaction solution was cooled to -10 degree and 5-hydroxy-l-methyl-2(5-H)-furanone (44.2gm) and potassium hydroxide (77.28 gm in 760 ml isopropanol) was added and stirred at -15 to -10 degree temperature for 2.5 hours. The crude product was isolated by extraction with ethyl acetate & hexane mixture followed by washing with aqueous methanol and evaporation of organic solvent. The crude product is taken for isomerization reaction.
Example 3 Isomerization
100 gm of isotretinoin isomers obtained as in example 1 or 2 was suspended in 150 ml ethyl acetate. The solution was heated to 50 °C degree and the catalyst (prepared by mixing 100 mg palladium nitrate, 24 ml acetonitrile and 480 mg triethyl amine) was added into the solution and maintained the mixture for 1 hour. The solution was cooled to 30 degree and then chilled to below -5 degrees and maintained for 1.5 to 2 hours. The precipitated product
was filtered, washed with chilled ethanol (100 ml) and dried to obtain the crude product weighed 60 gm.
Purification of isotretinoin IPA/KOH
In a flask, 1000 ml isopropanol, 23 gm potassium hydroxide and 0.1 gm BHT were mixed
well. The mixture was cooled to below -5 degree and 100 gm crude isotretinoin was added
and stirred until dissolution. The solution was treated with activated charcoal, filtered and to
the filtrate 1000 ml water was added. The pH of the solution was adjusted with IN HC1
solution till the pH is 4-5. The precipitated product was filtered and washed with water,
followed by chilled ethanol and dried to obtain 98 gm pure isotretinoin (99.7%) and heavy
metal content less than 5 ppm.
Example 6 Purification from IPA/Aq. Ammonia
In a flask, 1000 ml isopropanol and 27 ml liquor ammonia were mixed well. The mixture was cooled to below -5 degree and 100 gm crude isotretinoin was added and stirred until dissolution. The solution was treated with activated charcoal, filtered and to the filtrate 1000 ml water was added. The pH of the solution was adjusted with IN HC1 solution till the pH is 4-5 . The precipitated product was filtered and washed with water, followed by chilled ethanol and dried to obtain 98 gm pure isotretinoin (purity 99.7%) and heavy metal content less than 5 ppm.
Example 6 Purification using acetonitrile and Triethylamine
In a flask, 1000 ml acetonitrile and 80 ml triethyl amine were mixed well. The mixture was cooled to below -5 degree and 100 gm crude isotretinoin and 0.1% butylated hydroxytoluene were added and stirred until dissolution. The solution was treated with activated charcoal, filtered and to the filtrate 1000 ml water was added. The pH of the solution was adjusted with IN HC1 solution till the pH is 4-5. The precipitated product was filtered and washed with
water, followed by chilled ethanol and dried to obtain 97 gm pure isotretinoin (99.7%) and heavy metal content not detected.
Example 7 Purification using water/NaOH/acetone
In a flask, 1000 ml water, 500 ml acetone and 16 gm sodium hydroxide, 0.1 gm butylatedhydroxyanisole were mixed well. The mixture was cooled to below -5 degree and 100 gm crude isotretinoin was added and stirred until dissolution. The solution was treated with activated charcoal (10 gm), filtered and to the filtrate 1000 ml water was added. The pH of the solution was adjusted with hydrochloric acid till the pH is 4-5. The precipitated product was filtered and washed with water, followed by chilled ethanol and dried to obtain 97 gm pure isotretinoin (99.7% purity) and heavy metal content less than 5 ppm.
1. A process for purification of crude isotretinoin obtained from a heavy metal catalyzed
isomerization reaction wherein the process comprises;
i. treating heavy metal contaminated isotretinoin with a base in a
solvent to obtain a solution;
ii. treating said solution with an adsobant followed by filtering the
reaction solution; and
iii. acidifying the reaction solution to obtain isotretinoin substantially
free from heavy metal and oxidized impurities.
2. The process as claimed in claim 1, wherein said base is an organic or inorganic base.
3. The process as claimed in claim 2, wherein the base is a metal hydroxide
4. The process as claimed in claim 2, wherein the base is ammonia or mono, di, or tiralkyl amine.
5. The process as claimed in claim 1, wherein the solvent is polar protic or aprotic solvent.
6. The process as claimed in claim 5, wherein the solvent is selected from water, alcohols, ketones, amides, nitriles or dimethylsulphoxide or their combinations thereof.
7. The process as claimed in claim 6, wherein the solvent is selected from acetone, methanol, ethanol, isopropanol, water, acetonitrile, dimethylformamide, or mixtures thereof.
8. The process as claimed in claim 1, wherein the purification is carried out in presence of an antioxidant.
9. The process as claimed in claim 8, wherein the antioxidant is butylated hydroxytoluene or butylated hydroxyanisole.
10. The process as claimed in claim 1 to 9, wherein the process operates at a temperature ranging from -15 to +35 °C.
11. The process as claimed in claim 10, wherein the temperature is 0 to 5 °C
12. The process as claimed in claim 1, wherein the crude isotretinoin is prepared by a
single pot process comprising
a. Reacting vinyl-p-ionol with Triphenylphosphine in presence of hydrochloric
acid and pyridine to form a reaction mass comprising [3-methyl-5(2,6,6-
trimethyl-1 -cyclohene-1 yl-2,4-penta dienylj-triphenyl-phosphonium)
b. Treating said crude reaction mass with 5-hydroxy-l-methyl-2(5-H)-furanone
in presence of a base to yield a mixture of isomeric retinoic acid; and
c. transforming said isomeric retinoic acid into 13-cis retinoic acid.
13. The process as claimed in claim 12, wherein the said base is metal hydroxide such as potassium hydroxide.
14. The process as claimed in claim 12, wherein the isomerization is in presence of a metal catalyst such as palladium.
15. Isotretinoin prepared according to any one of the preceding claim and contains not more than 10 ppm of metals.
Dated this 19th day of February 2007
Dr. P. Aruna sree Agent for the Applicant
The present invention discloses a process for preparation of. isotretinoin and more specifically, to a purification process for obtaining highly pure isotretinoin that is useful as a keratolytic agent, particularly useful for the treatment of acne.
|Indian Patent Application Number||315/MUM/2007|
|PG Journal Number||39/2010|
|Date of Filing||20-Feb-2007|
|Name of Patentee||IPCA LABORATORIES LIMITED|
|Applicant Address||48, Kandivli Industrial Estate, Charkop, Kandivli (West), Mumbai|
|PCT International Classification Number||A61K31/20; C07C61/16|
|PCT International Application Number||N/A|
|PCT International Filing date|