Specification
FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"A PROCESS FOR THE PREPARATION OF LIOTHYRONINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"
Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House,
HDO - Corporate Bldg, Wing .A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
The following specification particularly describes the invention and the manner in which it is to be Derformed.
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of liothyronine and its pharmaceutically acceptable salts thereof and a pharmaceutical composition comprising the same.
BACKGROUND OF THE INVENTION
Liothyronine sodium is the sodium salt of a synthetic form of the natural thyroid hormone L-triiodothyronine (T3) useful in the treatment of thyroid disorders and is available in the market under the brand names CYTOMEL®, LEVOTHROID®, LEVOXYL®, TIROSINT®, LEVO-T®. Liothyronine sodium is chemically described as 0-(4-Hydroxy-3-iodophenyl)-3,5-diiodo-L-tyrosine sodium salt and has the following structure:
Tetrahedron Letters Vol. 38(40) 1997, 6965-6968 discloses a process for the preparation of liothyronine sodium, with yields of less than 40%, which is illustrated by the scheme below:
robust process commercial scale
The present invention provides a simple, ecofriendly, inexpensive, reproducible, for preparation of liothyronine sodium, which is well suited on a
2
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of liothyronine and its pharmaceutically acceptable salts thereof and a pharmaceutical composition comprising the same.
In one aspect, the present invention provides a process for the preparation of liothyronine sodium of formula I
I comprising reacting the compound 5-iodo-l-oxaspiro[2.5]-octa-4,7-dien-6-one of
with the compound 3,5-diiodo-L-tyrosine of Formula II or a salt thereof
3
Formula III or a salt thereof
in the presence of alkoxide or hydroxide or carbonate of sodium metal and an organic solvent.
In another aspect, the present invention provides liothyronine sodium, prepared by the process herein described, having less than about 5.0 area percent, as measured by HPLC of levothyroxine impurity of structural formula IV
In yet another aspect, the present invention provides liothyronine sodium, prepared by the process herein described, having less than about 3.0% area percent, as measured by HPLC of levothyroxine impurity of structural formula IV.
In yet another aspect, the present invention provides liothyronine sodium, prepared by the process herein described, having less than about 2.50% area percent, as measured by HPLC of levothyroxine impurity of structural formula IV.
The present invention provides the liothyronine or a pharmaceutically acceptable salt thereof, prepared by the process herein described, having a chemical purity of at least about 98%, more preferably at least about 99%, as measured by area under HPLC.
The present invention encompasses liothyronine or a pharmaceutically acceptable salt thereof, prepared by the process herein described, having less than about 2.5% of any single impurity as measured by area under HPLC peaks.
The present invention provides the liothyronine or a pharmaceutically acceptable salt thereof, prepared by the process herein described, has less than about 2% of any single chemical impurity and less than about 5% of total impurities as measured by area under HPLC peaks.
4
In still another aspect, the present invention provides the liothyronine sodium , prepared by the process herein described, having an X-ray powder diffraction (XRPD) pattern with peaks at about 6.59, 16.47, 18.24, 19.63, 21.31, 22.05, 23.62, and 25.42 + 0.2 degrees 2-theta, which is substantially in accordance with Fig. 1.
In another aspect, the present invention provides the liothyronine sodium, prepared by the process herein described, having a differential scanning calorimetry (DSC) thermogram curve which is substantially in accordance with Fig. 1.
In a further aspect, the present invention, provides a pharmaceutical composition comprising liothyronine or its pharmaceutically acceptable salts, prepared by the process herein described, and at least a pharmaceutically acceptable carrier. ,
BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES
Fig. 1: X-ray powder diffraction pattern of liothyronine sodium prepared by Example 1. Fig. 2: Differential scanning calorimetry thermogram curve liothyronine sodium prepared
by Example 1. Fig. 3: Thermogravimetric analysis endotherm curve of liothyronine sodium prepared by
Example 1. Fig. 4: SEM photograph of liothyronine sodium crystal particles prepared by
Example 1.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of liothyronine and its pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising the same.
In one embodiment, the present invention provides a process for the preparation of liothyronine sodium of formula I
5
I comprising reacting the compound 5-iodo-l-oxaspiro[2.5]-octa-4,7-dien-6-one of
with the compound 3,5-diiodo-L-tyrosine of Formula II or a salt thereof
Formula III or a salt thereof
II in the presence of alkoxide or hydroxide or carbonate of sodium metal and an organic solvent.
The alkoxide or hydroxide or carbonate of sodium metal include, but are not limited to, sodium methoxide sodium hydroxide, sodium carbonate, sodium bicarbonate. Preferably sodium methoxide is used.
The reaction can take place over a wide range of temperatures. In general, the reaction is carried at temperatures of about 5°C to about 30°C, preferably from about
6
10°C to about 30°C, which may vary depending on the nature of the reactants and the solvents employed.
The time required for the reaction to complete may vary depending on the reaction temperature and the nature of the reagents and solvents employed. The time required for completion of the reaction can be from about 1 hour to about 20 hours, preferably from about 1 hour to about 10 hours.
The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, however, it is preferable that the solvent has no adverse effect on the reaction or on the reagents involved and preferably the solvent renders some degree of dissolution of the reagents. The solvents that can be used include, but are not limited to, alcohols such as methanol, ethanol, isopropanol, n-butanol, tertiary butyl alcohol and the like or mixtures thereof; polar solvents such as N,N-dim.ethylformarnide (DMF), dimethylsulfoxide (DMSO), dimethyl acetamide (DMA), acetonitrile and the like or mixtures thereof. Preferably, methanol is used.
Typically, the molar amounts of compound of formula II and compound of formula III may range from about equimolar amounts or more, preferably about 1 to about 2.
The molar amount of alkoxide or hydroxide or carbonate of sodium metal may be about 1 to about 4 times the molar amount of the compound of formula III, preferably about I to about 2.
The compounds of formula III and II or a salt thereof used herein as the starting materials, can be prepared according to the method described in Tetrahedron Letters Vol. 38(40) 1997, PP-6965-6968, which is incorporated herein by reference.
After completion of the reaction, the isolation of the desired compound from the reaction mixture can be carried out by conventional separation techniques known in the art. However, in consideration of the physical properties of the desired compound, combined techniques, such as crystallization, extraction, washing, column chromatography, etc. may be employed.
Herein, the recovery of the liothyronine salt can be achieved by any conventional methods known in the art, preferably, Filtration.
7
The process may optionally include further drying by any method known in the art of the product obtained from the solution.
When employed, the drying is carried at temperatures of about 30°C to about 100° C, preferably from about 60°C to about 65 °C under vacuum.
The time required for drying can be from about 1 hour to about 20 hours, preferably from 1 hour to about 10 hours.
Like any synthetic compound, liothyronine or a pharmaceutically acceptable salt thereof can contain extraneous compounds or impurities that can come from many sources.
One of the potential impurities of liothyronine or its pharmaceutically acceptable salts is levothyroxine of formula IV.
which may be formed in coupling of intermediate compounds of formulae III and II to afford the compound of formula I.
In the process disclosed in Tetrahedron Letters Vol. 38(40) 1997, PP-6965-6968, during coupling of intermediates of formulae III and II to form the compound lyothyronine sodium, sodium borate buffer is used as a base which affords compound of formula I, in yields of less than about 60% and purity levels of less than about 90%. Subsequently, low yields translate to a. reduction in the overall yield of liothyronine sodium.
Further, the usage of sodium borate buffer as a base poses several disadvantages, which include safety concerns, storage issues and its restrictive use on a commercial scale. Added thereto, the use of sodium borate buffer leads to a boric acid by-product
8
formation, which is hazardous. Thus, sodium borate buffer, as a base, negates the suitability and feasibility of a process, in which it is used, on an industrial scale.
It is also recognized in the pharmaceutical formulation art that the levels of impurity in a drug, would make the product unacceptable to market. Further, the employment of multiple purifications steps is warranted to render an impure product to be marketable; subsequently, making the process cost ineffective and economically unfeasible.
Moreover, for a new drug product to gain marketing approval, manufacturers are mandated to submit to the regulatory authorities, evidence to show that the product is acceptable for human administration. Such a submission must include, among other things, analytical data to show the impurity profile of the product to demonstrate that the impurities are absent, or are present only at a negligible amount.
Further, the U.S. Food and Drug Administration's Center for Drug Evaluation and Research (CDER) has promulgated guidelines recommending that new drug and generic drug applicants identify organic impurities of 0.1% or greater in the active ingredient. Unless an impurity is a human metabolite, has been tested for safety, or was present in a composition that was shown to be safe in clinical trials, the CDER further recommends that the drug applicant reduce the amount of the impurity in the active ingredient to below 0.1 %.
These extraneous materials can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in liothyronine or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. It is also known in the art that impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. In addition to stability, which is a factor in the shelf life of the API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small
9
; amounts, and are preferably substantially absent. For example, the International Conference on Harmonization of Technical Requirements for Registration for Human Use ("ICH") Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process. The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during
: processing of the API, liothyrohine calcium, it must be analyzed for purity, typically, by HPLC, TLC or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
Impurities in an API known in the art may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. Impurities in liothyronine or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
The International Conference on Harmonization of Technical Requirements for Registration for Human Use ("ICH") Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
10
As noted above, one of the potential impurities which arise during the formation of liothyronine sodium is levothyroxine of formula IV.
The limit of levothyroxine impurity of formula IV in liothyronine sodium as per USP' is not more than (NMT) 5% w/w by HPLC.
In light of the evolving and more rigorous requirements demanded of drug manufacturers and the prevailing disadvantages present with the prior art, there is a need for an improved process for the preparation of liothyronine sodium, which circumvents the usage of potentially hazardous and expensive chemicals like sodium borate, the formation of a potential impurity levothyroxine of formula IV and other process-related impurities; while ensuring a target liothyronine sodium product with optimum yield and purity.
In another aspect, the present invention provides liothyronine sodium, prepared by the process herein described, having less than about 5.0 area percent, as measured by HPLC, of levothyroxine impurity of structural formula IV
In yet another aspect, the present invention provides liothyronine sodium, prepared by the process herein described, having less than about 3.0% area percent, as measured by HPLC, of levothyroxine impurity of structural formula IV.
In yet another aspect, the present invention provides liothyronine sodium, prepared by the process herein described, having less than about 2.5% area percent, as measured by HPLC, of levothyroxine impurity of structural formula IV.
11
The present invention provides the liothyronine or a pharmaceutically acceptable salt thereof, prepared by the process herein described, having a chemical purity of at least about 98%, more preferably at least about 99%, as measured by area under HPLC.
If desired liothyronine can be subjected to acid -base purification followed by conversion to its sodium salt, thereof.
In one embodiment, the present invention encompasses liothyronine or a< pharmaceutically acceptable salt thereof, prepared by the process herein described, having less than about 2.5% of any single. impurity as measured by area under HPLC peaks.
In yet another embodiment, the present invention provides the liothyronine or a pharmaceutically acceptable salt thereof, prepared by the process herein described, has less than about 2% of any single chemical impurity and less than about 5% of total impurities as measured by area under HPLC peaks.
In still another aspect, the present invention provides the liothyronine sodium, prepared by the process herein described, having an X-ray powder diffraction ^(XRPD) pattern with peaks at about 6.59, 16.47, 18.24, 19.63, 21.31, 22.05, 23.62, and 25.42 ± 0.2 degrees 2-theta, which is substantially in accordance with Fig. 1.
The characterization of the crystalline form of liothyronine sodium, is analysed by X-ray powder diffraction, X-ray powder diffraction measurements were performed on a Philips X'pert PRO Diffractometer using Cu Ka radiation (Cu K
Documents
Application Documents
| # |
Name |
Date |
| 1 |
1400-mum-2009-abstract.doc |
2018-08-10 |
| 1 |
abstract1.jpg |
2018-08-10 |
| 2 |
1400-mum-2009-form 5.pdf |
2018-08-10 |
| 2 |
1400-mum-2009-abstract.pdf |
2018-08-10 |
| 3 |
1400-mum-2009-form 3.pdf |
2018-08-10 |
| 4 |
1400-mum-2009-form 2.pdf |
2018-08-10 |
| 4 |
1400-mum-2009-claims.pdf |
2018-08-10 |
| 5 |
1400-mum-2009-correspondence.pdf |
2018-08-10 |
| 6 |
1400-mum-2009-form 2(title page).pdf |
2018-08-10 |
| 7 |
1400-mum-2009-form 1.pdf |
2018-08-10 |
| 7 |
1400-mum-2009-description(complete).pdf |
2018-08-10 |
| 8 |
1400-mum-2009-drawing.pdf |
2018-08-10 |
| 9 |
1400-mum-2009-form 1.pdf |
2018-08-10 |
| 9 |
1400-mum-2009-description(complete).pdf |
2018-08-10 |
| 10 |
1400-mum-2009-form 2(title page).pdf |
2018-08-10 |
| 11 |
1400-mum-2009-correspondence.pdf |
2018-08-10 |
| 12 |
1400-mum-2009-form 2.pdf |
2018-08-10 |
| 12 |
1400-mum-2009-claims.pdf |
2018-08-10 |
| 13 |
1400-mum-2009-form 3.pdf |
2018-08-10 |
| 14 |
1400-mum-2009-form 5.pdf |
2018-08-10 |
| 14 |
1400-mum-2009-abstract.pdf |
2018-08-10 |
| 15 |
abstract1.jpg |
2018-08-10 |