WO2025145066A1

WO2025145066A1 - An improved process for preparation of ethiodized oil

Info

Publication number: WO2025145066A1
Application number: PCT/US2024/062130
Authority: WO
Inventors: Bandla Pavan Kumar Reddy; Pankaj Vasudev PARMAR; Dipesh Satishbhai PATEL; John Muthiah Raja Jeyakumar; Shriprakash Dhar DWIVEDI; Kalpeshkumar Mahendrabhai PATEL; Ketankumar Bhogilal PATEL; Dhruvkumar Pravinbhai PATEL
Original assignee: Navinta LLC
Current assignee: Navinta LLC
Priority date: 2023-12-28
Filing date: 2024-12-27
Publication date: 2025-07-03
Anticipated expiration: 2026-06-28

Abstract

An improved process is provided for the preparation of pure and stable ethiodized oil. The disclosed process is simple, cost effective and provides the preparation of pure and stable ethiodized oil by using phosphoric acid having suitable strength of about 92% to 98% at a suitable temperature range and involves use of a specific amount of stabilizer.

Description

TITLE OF THE INVENTION

AN IMPROVED PROCESS FOR PREPARATION OF ETHIODIZED OIL

FIELD OF THE INVENTION

[0001] The present invention relates to an improved process for the preparation of pure and stable ethiodized oil. Particularly, the present invention relates to a commercially feasible, facile and robust process to prepare a pharmaceutically acceptable pure and stable ethiodized oil. More particularly, the present invention relates to an improved process for the preparation of pure and stable ethiodized oil, which involves the use of phosphoric acid having a strength of between about 92 % to 98% and also involves the use of a suitable amount of stabilizer.

BACKGROUND OF THE INVENTION

[0002] Ethiodized oil (Brand Name: LIPIODOL®) was first approved by USFDA prior to January 1 , 1982 for use as a radio-opaque contrast agent. It comprises iodinated ethyl esters of fatty acids of poppy seed oil. The commercially available ethiodized oil is a mixture of several iodo esters along with some esters without iodine. Poppy seed oil contains a mixture of fatty acids and ethiodized oil prepared from it, so ethiodized oil is also a mixture of compounds. Main components of poppy seed oil are stearic acid, palmitic acid, oleic acid and linoleic acid. Iodination of ethyl ester of this mixture produces a mixture of iodinated products and des-iodo esters. It is used as a contrast agent for hysterosalpingography in adults, lymphography in adults and pediatric patients and for imaging tumors in adults with known hepatocellular carcinoma (HCC). LIPIODOL® is produced and marketed by the French company Guerbet. [0003] Indian Patent Application No. 201941036172A discloses a process for preparation of ethiodized oil, which includes the steps of a) esterifying a solution of poppy seed oil in a suitable solvent to form the respective ethyl esters of fatty acids of poppy seed oil; b) hydroiodonating the ethyl ester of fatty acids of poppy seed oil to form the ethiodized oil using suitable iodinating agent and silicon reagent; and c) purifying the ethiodized oil by chromatography using suitable solvents.

[0004] US10487037B2 discloses a process for preparation of iodinated fatty acid ethyl ester, which comprises the steps of a) subjecting a fatty acid ester selected from the group consisting a fatty acid ethyl ester and a triglyceride to a protonation reaction with phosphoric acid to form a protonated fatty acid ester; and in step b) (after step a), subjecting the protonated fatty acid ester to an iodination reaction with an alkali metal iodide to obtain an iodinated fatty acid ester. This process involves the use of 86.4% phosphoric acid.

[0005] EP0198344B1 discloses a process for the iodination of fats, fatty acids or their derivatives by means of hydrogen iodide. The process is performed with aqueous hydrogen iodide in presence of a dehydrating agent like polyphosphoric acid and a portion of starting material is sufficient for stabilization of the resulting iodinated acid derivatives.

[0006] US 6124357A discloses a process for obtaining iodinated fatty esters, which are stable and free from toxic impurities. The reaction involves use of alkaline iodide with an alky Isily lated reagent in an organic medium giving rise in the presence of water to hydroiodic acid in-situ reacting with the fatty acid ester(s) or derivatives thereof in such as a way that all the double bonds initially present in the fatty acid ester(s) or derivatives thereof reacts with hydroiodic acid (HI) in a proportion of one molecule of hydroiodic acid per double bond. The patent mentions poppy seed oil as a fatty acid.

[0007] Chinese Patent No. CN 101245007B discloses a process for preparation of stable iodized vegetable fatty acids ethyl ester. The process involves use of red phosphorous along with iodine and water and requires a reaction time of 36 hours.

[0008] Chinese Patent No. CN103045373B discloses a method for preparing iodinated vegetable oil ethyl ester in which vegetable oil and hydrogen iodide gas are subjected to an addition reaction to generate iodinated vegetable oil. The addition reaction is implemented at a temperature of 25°C for a period ranging from 16 hours to 96 hours.

[0009] Chinese Patent Application No. CN101676255A discloses a synthetic method for preparing iodinated vegetable fatty acid and ester thereof. In the synthetic method, vegetable fatty acid prepared from vegetable oil via saponification and acidification reactions is subjected to an iodination reaction with hydroiodic acid to obtain iodinated vegetable fatty acid. The iodination reaction is implemented at a temperature ranging from 0 °C to 50 °C for a period ranging from 1 hour to 96 hours.

[0010] The present inventors have found following drawbacks for the above-mentioned prior art processes: a) Due to use of silicon reagent, e.g., trimethylsilyl chloride, the synthesized mixture of iodinated fatty acid ethyl ester product does not match with compounds in LIPIODOL® by HPLC; b) The 13-14% water present in 86.4% of phosphoric acid causes ester hydrolysis resulting in formation of hydrolyzed products. Furthermore, HPLC results of synthesized iodinated fatty acid ethyl ester did not exactly match with HPLC results of LIPIODOL®; c) Use of polyphosphoric acid is undesired as it is a highly viscous liquid and is not easy to handle on commercial scale; d) Use of aqueous hydrogen iodide increases the formation of hydrolysis products as compared to alkali metal iodide; e) Red phosphorous is not easy to handle at commercial level as it is both air and water sensitive, and it also increases the reaction time. f) The ethiodized oil prepared by the above prior art processes does not having comparable stability with respect to Reference Listed Drug (RLD).

[0011] Hence, there is a need to develop an alternative process for preparation of pure and stable ethiodized oil, which is simple, viable on a commercial scale, cost effective and provides pure and stable ethiodized oil product.

[0012] The present inventors have found an improved process for the preparation of pure and stable ethiodized oil, which fulfills the aforesaid objectives.

SUMMARY OF THE INVENTION

[0013] One embodiment of the present invention is to provide an improved process for preparation of pure and stable ethiodized oil, comprising the steps of: a) iodinating an ethyl ester of poppy seed oil with at least one of a mixture of an iodinating agent and phosphoric acid and a mixture of phosphoric acid and a dehydrating agent at a first temperature range to obtain a crude ethiodized oil; b) purifying the crude ethiodized oil; c) adding a poppy seed oil to the pure ethiodized oil obtained in step (b) to get a stable ethiodized oil; and d) isolating the pure and stable ethiodized oil.

[0014] In certain embodiments of the present invention, the method further includes the step of maintaining a reaction mass obtained in step (a) at a second temperature range, which may in a range of between about 25°C to about 30°C.

[0015] In certain embodiments of the present invention, the purification of ethiodized oil of step (b) includes: i. Purifying the crude ethiodized oil of step (a) by column chromatography followed by aging at a specific temperature to get ethiodized oil; ii. decolorizing the ethiodized oil as obtained in step (i) with an activated charcoal and an organic solvent; iii. removing the activated charcoal; iv. washing the product layer with a free iodine adsorbing agent followed by washing with purified water; v. drying the product layer with a drying agent followed by filtration; and vi. distilling the filtrate of step (v) to get pure ethiodized oil.

[0016] Another embodiment of the present invention provides the use of a different strength of phosphoric acid to achieve the desired isomer ratio of diiodo stearate with respect to LIPIODOL®. In some embodiments, 92% or more strength of phosphoric acid is used to obtain the pure ethiodized oil product.

[0017] In certain embodiments of the present invention, the specific amount of poppy seed oil used as a stabilizer in step (c) is in a range from about 2 % to about 4%.

[0018] In certain embodiments of the present invention, step (c) further includes purging of nitrogen.

[0019] In some embodiments, the present invention provides a pure and stable ethiodized oil having a comparable purity and stability with LIPIODOL® as measured by HPLC. [0020] In certain embodiments, the present invention also provides pure and stable ethiodized oil having a comparable iodine content with LIPIODOL®.

[0021] The purity of the ethiodized oil is measured as a sum of an area percent of ethyl stearate, ethyl mono-iodostearate, ethyl di-iodostearate and ethyl palmitate in HPLC and may be at least about 97% for the pure material.

[0022] The stability of the ethiodized oil is indicated by an absence of free iodine as measured by USP method showing absence of blue color.

[0023] In some embodiments, the present invention provides a pure and stable ethiodized oil having no detectable level of free iodine as measured by USP method.

[0024] Yet another embodiment of present invention provides a process for the preparation of pure ethyl ester of poppy seed oil of formula 3, including the steps of: a) treating crude ethyl ester of poppy seed oil with an adsorbing agent and an organic solvent; and b) distilling the organic solvent to get a pure ethyl ester of poppy seed oil.

[0025] Other features and advantages of the present invention will become apparent from the following more detailed description, which illustrates, by way of example, the principle of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1 illustrates HPLC data for LIPIODOL® (RLD).

[0027] FIG. 2 illustrates HPLC data for iodination performed as per Example 2.

[0028] FIG. 3 illustrates HPLC data for iodination performed as per Example 3. [0029] FIG. 4 illustrates HPLC data of iodination performed as per Example 4.

[0030] FIG. 5 illustrates HPLC data of iodination performed as per Example 5.

[0031] FIG. 6 illustrates HPLC data of iodination performed as per Example 6.

[0032] FIG. 7 illustrates HPLC data for iodination performed as per Example 7.

[0033] FIG. 8 illustrates HPLC data for ethiodized oil API with 2% weight of poppy seed oil after 30 days as per Example 11 .

[0034] FIG. 9 illustrates HPLC data for ethiodized oil API with 2.2% weight of poppy seed oil after 30 days as per Example 12.

[0035] FIG. 10 illustrates HPLC data for ethiodized oil API with 3% weight of poppy seed oil after 30 days as per Example 13.

[0036] FIG. 11 illustrates HPLC data for ethiodized oil API with 4% weight of poppy seed oil after 30 days as per Example 14.

DETAILED DESCRIPTION OF THE INVENTION

[0037] The following detailed description is merely exemplary in nature and is not intended to limit the disclosed invention described herein. Furthermore, there is no intention to be bound by any theory presented in the preceding background or the following detailed description.

[0038] The term “about” as used in connection with a numerical value throughout the specification and the claims denotes an interval of accuracy, familiar and acceptable to a person skilled in the art. In general, such interval of accuracy is ±10%. Thus, “about ten” means 9 to 11. All numbers in this description indicating amounts, ratios of materials, physical properties of materials, and/or use are to be understood as modified by the word “about,” except as otherwise explicitly indicated.

[0039] “At least one”, as used herein, means one or more, i.e., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or more. If used in combination with a compound, the term does not mean the absolute number of molecules but rather to the number of different types of said compound.

[0040] The term “substantially”, as used herein, means at least about 80%, preferably at least about 90%, more preferably at least about 99%, for example at least about 99.9%. In some embodiments, the term substantially can mean completely, or about 100%.

[0041] As used herein, the term “comprising” means including, made up of, composed, characterized by or having.

[0042] The term “alkali metal” as used herein refers to metals or ions of metals found in Group I of the periodic table. Preferred alkali metals include, but are not limited to, lithium, sodium and potassium.

[0043] Generally, phosphoric acid is available as 85% phosphoric acid in water. However, many methods are available in literature to produce phosphoric acid of higher strength up to 98% strength. The present inventors have surprisingly found that the reactivity and selectivity of phosphoric acid of various strengths is different and only some strengths give ethiodized oil of desired quality.

il

Eth l Ol t

Ethiodized oil (Crude) (Formula-1A) a) Column purification b) Stabilizer t

Ethiodized oil (Pure and stable)

(Formula-1)

Scheme-1 : Process for preparation of pure and stable Ethiodized oil [0044] One embodiment of the present invention provides a process for preparation of an ethiodized oil illustrated above in Scheme-1. The method includes the steps of: a) iodinating an ethyl ester of poppy seed oil with at least one of a mixture of an iodinating agent and phosphoric acid and a mixture of phosphoric acid and another dehydrating agent at a first temperature to obtain a crude ethiodized oil; b) purifying the crude ethiodized oil; c) adding poppy seed oil to the pure ethiodized oil obtained in step (b) to get stable ethiodized oil; and d) isolating the pure and stable ethiodized oil obtained in step (c).

[0045] In certain embodiments, the method also includes the step of maintaining a reaction mass obtained in step (a) at a second temperature, which may be in a range between about 25°C to about 30°C.

[0046] In certain embodiments, the step of purifying the ethiodized oil of step (b) includes the steps of: i. Purifying the crude ethiodized oil of step (a) by column chromatography followed by aging at a third temperature to get ethiodized oil; ii. decolorizing the ethiodized oil obtained in step (i) with an activated charcoal and an organic solvent; iii. removing the activated charcoal; iv. washing a product layer with a free iodine adsorbing agent followed by washing with purified water; v. drying the product layer with a drying agent followed by filtration; and vi. distilling the filtrate of step (v) to get pure ethiodized oil. [0047] In some embodiments, the process further includes the step of maintaining a reaction mass obtained in step (a) at a second temperature, which may be in a range of between about 25°C to about 30°C.

[0048] A suitable strength of phosphoric acid may be between about 92% to 98% or more. In some embodiments, the strength of phosphoric acid is at least about 94% to 96%.

[0049] The third temperature used in step (i) for the aging is in a range between about 70°C to 90°C.

[0050] The iodinating agent may be selected from sodium iodide, potassium iodide, lithium iodide and molecular iodine, and mixtures thereof. In some embodiments, the iodinating agent is sodium iodide.

[0051] The dehydrating agent may be phosphorus pentoxide.

[0052] The first temperature for step (a) may be between about 22°C to about 32°C. In some embodiments, the first temperature may be between about 25°C to about 30°C.

[0053] The poppy seed oil used as a stabilizer in step (c) may be provided in an amount from about 2% to about 4% by total weight of the composition.

[0054] Step (c) of the process may further include purging of nitrogen.

[0055] Various suitable organic solvents used in step (ii) may be selected from the cyclohexane, Methyl t-butyl ether, toluene, diethyl ether, n- hexane, n-heptane, petroleum ether, benzene, and a mixture thereof. In some preferred embodiments, the organic solvent is cyclohexane.

[0056] The free iodine adsorbing agent used in step (iv) may be selected from sodium thiosulfate, potassium thiosulfate, sodium sulfite, potassium sulfite, and a mixture thereof. In some preferred embodiments, the iodine adsorbing agent is sodium thiosulfate. [0057] The drying agent used in step (v) may be selected from sodium sulfate, potassium sulfate, magnesium sulfate, molecular sieve, and a mixture thereof. In some preferred embodiments, the drying agent is magnesium sulfate.

[0058] The present invention provides a pure and stable ethiodized oil that has a free iodine content comparable with the Reference Listed Drug (RLD) LIPIODOL®.

[0059] Another embodiment of the present invention provides a process for the preparation of pure ethyl ester of poppy seed oil of formula. The method includes the steps of: a) treating a crude ethyl ester of poppy seed oil with an adsorbing agent and an organic solvent; and b) distilling the organic solvent to get a pure ethyl ester of poppy seed oil.

[0060] A suitable organic solvent used for purifying the ethyl ester of poppy seed oil may be selected from the cyclohexane, MTBE, toluene, diethyl ether, n-hexane, n-heptane, petroleum ether, benzene, and a mixture thereof. In some embodiments, the organic solvent may be cyclohexane.

[0061] A suitable adsorbing agent used for purifying the ethyl ester of poppy seed oil may be selected from the silica, acidic resin, neutral resin, basic resin, alumina, and mixtures thereof. In some preferred embodiments, the adsorbing agent is acidic silica.

[0062] Surprisingly, it was observed during preparation of ethiodized oil that when 92% or higher strength of phosphoric acid is used in the reaction, it leads to a lesser possibility of formation of hydrolyzed product. Furthermore, the HPLC data for the ethiodized oil obtained as per the inventive process precisely matched with HPLC data for the RLD LIPIODOL® (Fig. 1 ). The comparative HPLC results illustrated in FIGS. 2-7 are outlined below in Table- 1 :

[0063] From the results in Table-1 , it was discovered unexpectedly that when iodination was performed using phosphoric acid (H3PO4) with a strength of below about 92% and sodium iodide (Nal), a mixture of iodinated ethyl ester fatty acids obtained did not match with HPLC results of LIPIODOL®. Furthermore, it was also observed that when the iodination reaction is performed with trimethylsilyl chloride (TMSCI), sodium iodide and water, a mixture of iodinated ethyl ester fatty acid product obtained also does not match with HPLC results of LIPIODOL®. Hence, a pure ethiodized oil product is formed only when phosphoric acid of 92% or higher strength is used in the iodination reaction.

[0064] The presence or absence of free iodine in the ethiodized oil sample is measured by titrimetric test as described in USP specification for ethiodized oil. The degradation of ethiodized oil produces free iodide. The inventors have used the USP method for free iodine content as a way to measure the stability of the ethiodized oil produced by the present invention. The total iodine content (free as well as covalently bound) is also measured by the USP method. The total iodide content of LIPIODOL® and the samples of the present invention is summarized below in Table-2:

[0065] The comparative HPLC results for LIPIODOL® as compared with the present invention at different temperature range using H3PO4 of 96% strength are specified below in Table-3:

[0066] From the results in Table-3, it was unexpectedly observed that when iodination was performed with 96% phosphoric acid (H3PO4) and sodium iodide at below 20°C or above 30°C temperature, the mixture of iodinated ethyl ester fatty acids obtained did not match with HPLC results of LIPIODOL®. Hence, the pure ethiodized oil product was formed only when temperature range used between 25°C to 30°C for the iodination reaction.

[0067] Furthermore, the present inventors have observed that when crude ethyl ester of poppy seed oil is purified by using adsorbing agent and an organic solvent, it reduces the total unknown impurities as well as consumption of excess organic solvents. The comparative HPLC results for crude ethyl ester of poppy seed oil as compared to pure ethyl ester of poppy seed oil are summarized below in Table-4:

[0068] Ethiodized oil prepared as per the present invention was studied for its stability profile. Stability studies were done at the time intervals of initial, 15 days and 30 days. Surprisingly, the present inventors have observed that the purity and stability data for the ethiodized oil prepared as per the present invention are comparable to the RLD LIPIODOL®. The purity of the ethiodized oil measured as the sum of area percentage for ethyl stearate, ethyl monoiodostearate, ethyl di-iodostearate and ethyl palmitate in HPLC chromatogram is not less than 97%. Ethiodized oil was analyzed by HPLC, wherein column was a series of two omega polar C18 1000 A, 250mm x 4.6 mm column x 5 pm particle size or equivalent; mobile phase was Methanol:Water:lsopropylalcohol:Acetonitrile (75:10:5:10); and Rl detector was used. It was observed that the addition of poppy seed oil to the ethiodized oil increases the stability of the ethiodized oil product. The best stability was observed with addition of 2 to 4% of poppy seed oil as a stabilizer. The stability data of the ethiodized oil prepared as per present invention is provided in Tables 5A, 5B, 6A, 6B, 7A, 7B, 8A and 8B below.

[0069] EXAMPLES

[0070] Example 1 : Preparation of Ethyl ester of Poppy seed oil (Formula-3)

[0071] Poppy seed oil (100 g) of Formula-2 was dissolved in 500 mL of Dysol-B (mixture of ethanol and toluene) and stirred for 10-15 minutes at room temperature. Sulfuric acid (10 mL) was added into the reaction mass and stirred further for 10-15 minutes. Then, temperature of the reaction mass was raised to between about 60°C to about 70°C. The mixture was stirred for about 66 hours between 60°C to 70°C. After the completion of reaction, the solvent was distilled to obtain residue. To this residue, Methyl tert-Butyl Ether (MTBE) and water were added, and the MTBE layer separated from the aqueous layer. The MTBE was washed with an aqueous sodium bicarbonate solution and MTBE was distilled out from the organic layer, which was further purified by column chromatography to get ethyl ester of poppy seed oil of Formula-3 (100 g).

[0072] Example 2: Preparation of Ethiodized oil (Use of 96% of Phosphoric acid)

[0073] Phosphoric acid (50 mL, 86%) was added into Phosphorus pentoxide (22 g) keeping the temperature below 40°C. After completion of the addition, the temperature was raised to 45°C to 50°C and the reaction mass was maintained at this temperature until a clear solution was formed. This solution has a strength of 96% (phosphoric acid). To this solution, ethyl ester of poppy seed oil (5gm) of formula-3 as obtained in Example-1 was added under stirring. The reaction was cooled to room temperature and added 25 g of sodium iodide and the reaction mass was then maintained at 25°C to 30°C for 14 hours. After the completion of reaction, cyclohexane (50 mL) was added followed by water (50 mL) while keeping the temperature of solution below 15°C and then temperature was raised to 20°C to 30°C. The cyclohexane layer was separated, and aqueous layer was extracted with cyclohexane. The combined organic layer was washed with sodium thiosulphate solution. Cyclohexane was distilled from the organic layer to get crude ethiodized oil of formula-1A, which was further purified by column chromatography to get pure ethiodized oil of formula-1 (6.0 g). See Fig. 2 for HPLC chromatogram.

[0074] Example 3: Preparation of Ethiodized oil (Use of 94% of Phosphoric acid) [0075] Phosphoric acid (50 mL, 86%) was added into Phosphorus pentoxide (15.5 g) keeping the temperature below 40°C. After completion of the addition, the temperature was raised to 45°C to 50°C and the reaction mass was maintained at this temperature until a clear solution was obtained. This solution has a strength of 94% (phosphoric acid). To this solution ethyl ester of poppy seed oil (5 g) of formula-3 obtained in Example-1 was added under stirring. The reaction mass was cooled to room temperature and 25 g of sodium iodide was added. The reaction mass was maintained at about 25°C to 30°C for about 14 hours. After completion of the reaction, cyclohexane (50 mL) was added followed by water (50 mL), while keeping the temperature of the solution below 15°C and then temperature was raised to 20°C to 30°C. The cyclohexane layer was separated, and aqueous layer was extracted with cyclohexane. The combined organic layer was washed with sodium thiosulphate solution. Cyclohexane was distilled from the organic layer to get crude ethiodized oil of formula-1 A, which was further purified by column chromatography to get pure ethiodized oil of formula-1 (6.0 g). See Fig. 3 for HPLC chromatography data.

[0076] Example 4: Preparation of Ethiodized oil (Use of 92% of Phosphoric acid)

[0077] Phosphoric acid (50 mL, 86%) was added into Phosphorus pentoxide (11 g) keeping the temperature below 40°C. After completion of the addition, the temperature was raised to 45°C to 50°C and the reaction mass was maintained at this temperature until a clear solution was obtained. This solution has a strength of 92% (phosphoric acid). To this solution, ethyl ester of poppy seed oil (5 g) of formula-3 obtained in Example-1 was added under stirring. The reaction mass was cooled to room temperature and 25 g of sodium iodide was added, and the reaction mass was maintained at about 25°C to 30°C for about 14 hours. After the completion of reaction, cyclohexane (50 mL) was added to the reaction followed by water (50 mL) and keeping the temperature of the solution below 15°C. Then, the temperature was raised to 20°C to 30°C. The cyclohexane layer was separated, and an aqueous layer was extracted with cyclohexane. The combined organic layer was washed with sodium thiosulphate solution. Cyclohexane was distilled from the organic layer to get crude ethiodized oil of formula-1 A, which was further purified by column chromatography to get pure ethiodized oil of formula-1 (6.0 g). See Fig. 4 for HPLC chromatogram.

[0078] Example 5: Preparation of Ethiodized oil (Use of 89% of phosphoric acid)

[0079] Ethyl ester of poppy seed (5gm) of formula-3 as obtained in Example-1 was added to the Phosphoric acid (50 mL, 89%) under the stirring. 25 g of sodium iodide was added, and the reaction mass was maintained at about 25°C to 30°C for about 40 hours. After completion of the reaction, Cyclohexane (50 mL) was added to the reaction mixture followed by water (50 mL) while keeping the temperature of solution below 15°C. The temperature was raised to 20°C to 30°C. The cyclohexane layer was separated, and aqueous layer was extracted with cyclohexane. The combined organic layer was washed with sodium thiosulphate solution. Cyclohexane was distilled from the organic layer to get crude ethiodized oil of formula-1 A, which was further purified by column chromatography to get ethiodized oil of formula-1 (5.0 g). See Fig. 5 for HPLC chromatography data.

[0080] Example 6: Preparation of Ethiodized oil (Use of 86% of phosphoric acid)

[0081] Ethyl ester of poppy seed (5gm) of formula-3 as obtained in Example-1 was added into Phosphoric acid (50 mL, 86%) under stirring. 25 g of sodium iodide was added, and the reaction mass was maintained at about 25°C to 30°C for about 40 hours. After completion of the reaction, Cyclohexane (50 mL) was added to the reaction mixture followed by water (50 mL) while keeping the temperature of the solution below 15°C, and then the temperature was raised to 20°C to 30°C. The cyclohexane layer was separated and aqueous layer was extracted with cyclohexane. The combined organic layer was washed with sodium thiosulphate solution. Cyclohexane was distilled from the organic layer to get crude ethiodized oil of formula-1 A, which was further purified by column chromatography to get ethiodized oil of formula-1 (5.0 g). See Fig. 6 for HPLC chromatogram.

[0082] Example 7: Preparation of Ethiodized oil (Use of Trimethylsilyl chloride and Sodium Iodide)

[0083] Sodium iodide (250g) was suspended in acetonitrile (300 mL). Trimethylsilyl chloride (150mL) and water (5 mL) were added to the reaction mixture at 0°C - 5 °C. To this reaction mass, 50g of ethyl ester of poppy seed oil of formula-3 obtained in Example-1 in acetonitrile (500 mL) was added at 0°C to 5 °C. The temperature of the reaction mass was raised to 25 °C to 30 °C. After completion of reaction, the reaction mixture was diluted with cyclohexane followed by slow addition of 10% sodium thiosulfate solution. The organic layer was separated and washed with 10% sodium thiosulfate solution. The volatiles along with excess solvent were removed by evaporation to yield crude ethiodized oil of formula-1 A, which was further purified by column chromatography to get ethiodized oil of formula-1. See. Fig. 7 for HPLC chromatogram.

[0084] Example 8: Preparation of Ethyl ester of Poppy seed oil (Formula-3)

[0085] Poppy seed oil (305 g) of Formula-2 was dissolved in 1525 mL of Dysol-B (Mixture of ethanol and toluene) and stirred for 10-15 minutes at room temperature. Sulfuric acid (30.5 mL) was added into the reaction mass and stirred further for 10-15 minutes. The temperature of the reaction mass was raised to between about 60°C to about 70°C. The mixture was stirred for about 6 hours between 60°C to 70°C. After the completion of reaction, the solvent was distilled to obtain residue. To this residue, MTBE and water were added, and the MTBE layer separated from the aqueous layer. The MTBE was washed with aqueous sodium bicarbonate solution and MTBE was distilled out from the organic layer to get crude ethyl ester of poppyseed oil. Cyclohexane (1525 mL) and silica (305 g) were added into the crude ethyl ester of poppyseed oil and stirred for 20-30 minutes. Then, the cyclohexane was decanted from the mixture and the same decantation process was performed twice with cyclohexane (915 mL). The cyclohexane was distilled out from the organic layer to get the ethyl ester of poppy seed oil (Formula-3) (275 g).

[0086] Example 9: Preparation of crude Ethiodized oil

[0087] Phosphoric acid (2750 mL, 86%) was added into Phosphorus pentoxide (1210 g) keeping the temperature below 40°C. After completion of the addition, the temperature was raised to 45°C to 50°C and the reaction mass was maintained at this temperature until a clear solution was formed. This solution has a strength of 96% (phosphoric acid). To this solution, ethyl ester of poppy seed oil (275 g) as obtained in Example-1 was added under stirring. The reaction was cooled to room temperature and added 412.5 g of sodium iodide and the reaction mass was then maintained at 25°C to 30°C for 24 hours. After the completion of reaction, cyclohexane (825 mL) was added followed by water (550 mL) while keeping the temperature of solution below 15°C and then temperature was raised to 20°C to 30°C. The cyclohexane layer was separated, and aqueous layer was extracted with cyclohexane.-Cyclohexane was distilled from the organic layer to get crude Ethiodized oil (440 g).

[0088] Example 10: Preparation of pure Ethiodized oil:

[0089] Crude ethiodized oil (414 g) as obtained from Example 9 was purified by column chromatography followed by solvent removal to get Ethiodized oil residue, which was further treated at 87±3°C for 60 minutes followed by cooling to 50±5°C. The obtained material was decolorized with activated charcoal (13.75 g) in cyclohexane (550 ml) at 50±5°C for 50 to 60 minutes. The charcoal was removed through celite bed. Cyclohexane layer was washed with 5% W/V sodium thiosulphate solution (550 ml) at 60±05°C for 30 minutes. The cyclohexane layer was washed further with 5% W/V sodium thiosulphate (550 ml) solution at 25±5°C ftwo times followed by two purified water (550 ml) washes at 25±5°C. Cyclohexane layer was dried with magnesium sulphate and filtered through 0.2-micron filter. The filtered product was distilled keeping the temperature below 40°C under vacuum to get pure ethiodized oil (360 g).

[0090] Example 11 : Preparation of pure stable Ethiodized oil (2% poppy seed oil):

[0091] The pure ethiodized oil (88.2 g) as obtained in Example 10 was transferred under nitrogen atmosphere and mixed with 2% poppy seed oil (1 .8 g) to make pure and stable ethiodized oil API and the material was packed in an amber glass bottle under nitrogen atmosphere. The ethiodized oil API was placed for hold time study to check impact of 2 wt. % of poppy seed oil on stability of the product (Table-5A & 5B). See. Fig. 8 for HPLC chromatogram.

[0092] Table 5A: Stability data of the Ethiodized oil prepared as per

Example 11 :

AGS: Amber Glass Bottle; RLD: Reference Listed Drug

[0093] Table 5B: Stability data of the Ethiodized oil prepared as per Example 11 :

AGS: Amber Glass Bottle; RLD: Reference Listed Drug

[0094] Example 12: Preparation of pure stable Ethiodized oil (2.2% poppy seed oil)

[0095] The pure ethiodized oil as obtained in Example 10 was unloaded under nitrogen atmosphere (88.02 g) and mixed with 2.2% poppy seed oil (1 .98 g) to make pure and stable ethiodized oil API and the material was packed in an amber glass bottle under nitrogen atmosphere. The ethiodized oil API was placed for hold time study to check impact of 2.2 wt. % of poppy seed oil on stability of the product (Table 6A & 6B). See. Fig. 9 for HPLC chromatogram.

[0096] Table 6A: Stability data of the Ethiodized oil prepared as per Example 12:

AGS: Amber Glass Bottle; RLD: Reference Listed Drug

[0097] Table 6B: Stability data of the Ethiodized oil prepared as per Example 12:

AGS: Amber Glass Bottle; RLD: Reference Listed Drug.

[0098] Example 13: Preparation of pure stable Ethiodized oil (3% poppy seed oil):

[0099] The pure ethiodized oil as obtained in Example 10 was unloaded under nitrogen atmosphere (87.3 g) and mixed with 3% poppy seeds oil (2.7 g) to make pure and stable ethiodized oil API and the material was packed in an amber glass bottle under nitrogen atmosphere. The ethiodized oil API was placed for hold time study to check impact of 3 wt. % of poppy seed oil on stability of the product (Table 7A & 7B). See. Fig. 10 for HPLC chromatogram.

[00i00]Table 7A: Stability data of the Ethiodized oil prepared as per

Example 13:

AGS: Amber Glass Bottle; RLD: Reference Listed Drug [00101] Table 7B: Stability data of the Ethiodized oil prepared as per Example 13:

[OO1O2]AGS: Amber Blass Bottle; RLD: Reference Listed Drug

[00103] Example 14: Preparation of pure stable Ethiodized oil (4% poppy seed oil):

[00104] The pure Ethiodized oil as obtained in Example 10 was unloaded under nitrogen atmosphere (86.4 g) and mixed with 4% poppy seed oil (3.6 g) to make pure and stable ethiodized oil API and the material was packed in an amber glass bottle under nitrogen atmosphere. The ethiodized oil API was placed for hold time study to check impact of 4 wt. % of poppy seed oil on stability of the product (Table 8A & 8B). See. Fig. 11 for HPLC chromatogram.

[00i05]Table 8A: Stability data of the Ethiodized oil prepared as per

Example 14

AGS: Amber Glass Bottle; RLD: Reference Listed Drug

[00106] Table 8B: Stability data of the Ethiodized oil prepared as per Example 14:

AGS: Amber Blass Bottle; RLD: Reference Listed Drug.

[00107] It should be noted that the invention in its broader aspects is not limited to the specific details, representative compositions, methods, and processes, and illustrative examples described in connection with the preferred embodiments and preferred methods. Modifications and equivalents will be apparent to practitioners skilled in this art and are encompassed within the spirit and scope of the appended claims.

Claims

What is claimed is:

1 . A process for preparation of ethiodized oil, comprising the steps of: a) iodinating an ethyl ester of poppy seed oil with at least one of a mixture of an iodinating agent and phosphoric acid and a mixture of phosphoric acid and a dehydrating agent at a first temperature range to obtain a crude ethiodized oil; b) purifying the crude ethiodized oil; c) adding a poppy seed oil to the purified ethiodized oil obtained in step (b) to get a stabilized ethiodized oil; and d) isolating the purified and stabilized ethiodized oil.

2. The process according to claim 1 , wherein the first temperature range is between about 22°C to about 32°C.

3. The process according to claim 1 , further comprising the step of maintaining a reaction mass obtained in step (a) at second temperature range.

4. The process according to claim 3, wherein the second temperature range is between about 25°C to about 30 °C.

5. The process according to claim 1 , wherein the phosphoric acid has a strength of at least about 92% to at least about 98%.

6. The process according to claim 1 , wherein the dehydrating agent is phosphorus pentoxide.

7. The process according to claim 1 , wherein the iodinating agent is selected from sodium iodide, potassium iodide, lithium iodide, molecular iodine, and a mixture thereof.

8. The process according to claim 1 , wherein the step of purifying the crude ethiodized oil comprises the steps of: i. purifying the crude ethiodized oil by column chromatography followed by aging at a third temperature range to obtain ethiodized oil; ii. decolorizing the ethiodized oil as obtained in step (i) with an activated charcoal and an organic solvent; iii. removing the activated charcoal; iv. washing a product layer with a free iodine adsorbing agent followed by washing with purified water; v. drying the product layer with a drying agent followed by filtration; and vi. distilling a filtrate to obtain pure ethiodized oil.

9. The process according to claim 8, wherein the third temperature range is between about 70° to about 90°C.

10. The process according to claim 8, wherein the organic solvent is selected from cyclohexane, MTBE, toluene, diethyl ether, n-hexane, n-heptane, petroleum ether, benzene, and a mixture thereof.

11 . The process according to claim 8, wherein the free iodine adsorbing agent is selected from sodium thiosulfate, potassium thiosulfate, sodium sulfite, potassium sulfite, sodium bisulfite, potassium bisulfite and a mixture thereof.

12. The process according to claim 8, wherein the drying agent is selected from sodium sulphate, potassium sulfate, magnesium sulfate, molecular sieve, and a mixture thereof.

13. The process according to claim 1 , wherein the poppy seed oil is added in an amount of between about 2 wt. % to about 4 wt. %.

14. The process according to claim 1 , wherein step (c) further comprises purging the reaction mass with nitrogen.

15. A process for preparation of a pure ethyl ester of poppy seed oil, comprising the steps of: a) treating a crude ethyl ester of poppy seed oil with an adsorbing agent and an organic solvent; and b) distilling the organic solvent to get the pure ethyl ester of poppy seed oil of formula 3:

16. The process according to claim 15, wherein the organic solvent is selected from cyclohexane, methyl tert-butyl ether, toluene, diethyl ether, n- hexane, n-heptane, petroleum ether, benzene, and a mixture thereof.

17. The process according to claim 15, wherein the adsorbing agent is selected from silica, acidic resin, neutral resin, basic resin, alumina, and mixtures thereof.

18. The process according to claim 1 , wherein the purified ethiodized oil has a purity of at least about 97%.

19. The process according to claim 1 , wherein the stabilized ethiodized oil is essentially free of free iodine.