Process for the preparation of pharmaceutical hydrogenated palm oil glycerides

Abstract

This invention discloses a method for preparing pharmaceutical-grade hydrogenated palm oil glyceride. The steps are as follows: stearic acid, palmitic acid, and glycerol are melted, a catalyst is added, vacuum is applied, and the mixture is heated to react; the temperature is lowered, pharmaceutical-grade activated clay is added, and the mixture is stirred; the material is transferred to a pressure vessel; the outlet of the pressure vessel is opened, and the mixture is filtered to obtain crude hydrogenated palm oil glyceride, which is then fed into the material storage tank of a three-stage molecular distillation apparatus; the process parameters of the three-stage molecular distillation apparatus are set at a temperature of 160℃~250℃ and a pressure ≤30Pa, and the crude hydrogenated palm oil glyceride is forced into the cavity of the three-stage molecular distillation apparatus through a vacuum feeder, the feed flow rate is controlled, and the collected heavy component, pure hydrogenated palm oil glyceride, is transported through a pipeline to a rotary drum condenser crystallizer and slicing machine to obtain pharmaceutical-grade hydrogenated palm oil glyceride. This invention is simple to operate, uses readily available raw materials, has a high production yield, is environmentally friendly and pollution-free, and produces a high-purity product that meets pharmaceutical requirements.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, and in particular relates to a method for preparing an oil ester. Background Technology

[0002] Pharmaceutical-grade hydrogenated palm oil glyceride is a pharmaceutical excipient used as a gel in pharmaceutical preparations, administered via vaginal delivery. It is currently used in Fleet Laboratories Limited's progesterone vaginal sustained-release gel product, which has completed clinical trials and has been approved for marketing by the FDA and the EU. Progesterone vaginal sustained-release gel is a progestin-type drug, commonly used clinically for progesterone supplementation in assisted reproductive technologies. Its effects are the same as oral medications and progesterone injections. Since progesterone is a key component in decidual tissue development and essential for increasing the receptivity of the endometrium to implantation of a fertilized egg, it also plays a role in maintaining pregnancy after implantation. In cases of insufficient progesterone in women, this drug can be used to supplement progesterone. As an original drug, this product is included in the National Medical Products Administration's list of generic reference preparations (batch 27).

[0003] Currently, existing technologies generally use the hydrogenation reduction method to synthesize hydrogenated palm oil glycerides.

[0004] Hydrogenated palm oil glycerides are obtained by separating and removing high-melting-point stearin from natural palm oil, followed by hydrogenation. This process uses a large amount of solvent, causes significant environmental pollution, has poor operational safety, high production costs, and is not suitable for industrial production. Furthermore, the finished product still contains a small amount of incompletely hydrogenated unsaturated fatty acid glycerides (approximately 1.5%), which are easily oxidized and deteriorated by light and temperature in the air. Additionally, the fatty acid composition varies significantly between batches, making it difficult to control the content of each component through the process, thus failing to meet pharmaceutical requirements. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing pharmaceutical-grade hydrogenated palm oil glycerides that is simple in process, safe in operation, low in cost, and whose product quality standards meet enterprise standards.

[0006] The technical solution of this invention is summarized as follows:

[0007] The preparation method of pharmaceutical-grade hydrogenated palm oil glycerides includes the following steps:

[0008] (1) Stearic acid, palmitic acid and glycerol are added to the reaction vessel in a mass ratio of (4.3~5.5):(4.7~5.8):1, and the temperature is raised to 65℃~80℃ until the materials are completely melted and stirred evenly.

[0009] (2) Add catalyst equivalent to 5% to 30% of the mass of glycerol while stirring, evacuate the vacuum, and wait until the pressure drops to ≤-0.09MPa. Then, start heating to 135 to 185℃ and react for 4 to 10 hours. Cool down to 85 to 100℃, add 200-mesh pharmaceutical activated clay equivalent to 0.5% to 5% of the mass of glycerol into the reaction vessel, and continue stirring for 1 to 3 hours. Transfer the material in the reaction vessel into a pressure vessel.

[0010] (3) Open the outlet of the pressure vessel, start the plate and frame filter, filter at 85℃~100℃ and working pressure≤0.3Mpa, and the filtrate obtained is crude hydrogenated palm oil glyceride, which is then passed into the material storage tank of the three-stage molecular distillation equipment.

[0011] (4) Set the process parameters of the three-stage molecular distillation equipment to a temperature of 160℃~250℃ and a pressure of ≤30Pa. Then, press the crude hydrogenated palm oil glycerol into the cavity of the three-stage molecular distillation equipment through a vacuum feeder. Control the feed flow rate to 5ml / min~50ml / min and collect the heavy component hydrogenated palm oil glycerol pure product into the finished product container.

[0012] (5) The pure hydrogenated palm oil glyceride is transported through a pipeline to a rotary drum condenser crystallizer with a rotation speed of 5-30 rpm and a cooling circulating water temperature of 12-18℃. The condenser slices are then used to obtain pharmaceutical hydrogenated palm oil glyceride.

[0013] Preferably, the mass ratio of stearic acid, palmitic acid and glycerin in step (1) is (4.7-5.2):(5.0-5.5):1.

[0014] The amount of catalyst used in step (2) is equivalent to 12% to 25% of the mass of glycerol.

[0015] The catalyst is solid superacid HND-260, solid superacid silicon-based No. 6 or 282-1 type ion exchange resin.

[0016] The amount of 200-mesh pharmaceutical activated clay added is equivalent to 1.5% to 4% of the mass of glycerin.

[0017] In step (4), the process parameters of the three-stage molecular distillation equipment are set to a temperature of 180℃~230℃.

[0018] Advantages of this invention:

[0019] 1. Compared with traditional hydrogenation processes, the pharmaceutical-grade hydrogenated palm oil glycerides prepared by the method of the present invention have higher purity, lower content of unsaturated fatty acid glycerides (approximately 0.1%), higher stability, controllable process, and product quality standards that fully meet enterprise standards, thus satisfying pharmaceutical requirements.

[0020] 2. The solid superacid HND-260, solid superacid silicon-based No. 6, and ion exchange resin type 282-1 catalyst used in this invention have the advantages of high reactivity, low dosage, and fast reaction rate.

[0021] 3. The production process used in this invention is simple to operate, the raw materials are readily available, the operation is highly safe, the production yield is high, and it is environmentally friendly and pollution-free, making it suitable for industrial production. Detailed Implementation

[0022] The following embodiments provide a further detailed description of the present invention and should not be construed as limiting the scope of the claims of the present invention.

[0023] The catalysts used in this invention are solid superacid HND-260 (Jiangyin Nanda Synthetic Chemical Co., Ltd.), solid superacid silicon-based No. 6 (Qinzhou Yamei Chemical Co., Ltd.), or 282-1 type ion exchange resin (Jiangsu Secos Resin Co., Ltd.), but this invention is not limited thereto.

[0024] Example 1

[0025] A method for preparing pharmaceutical-grade hydrogenated palm oil glycerides, characterized by comprising the following steps:

[0026] (1) Add 430g stearic acid, 580g palmitic acid and 100g glycerol to the reaction vessel, heat to 65℃ until all materials are melted, and stir evenly;

[0027] (2) Add 5g of solid superacid catalyst HND-260 under stirring, evacuate, and wait until the pressure drops to ≤-0.09MPa. Then, start heating to 185℃ and react for 4 hours. Cool down to 85℃, add 0.5g of 200-mesh pharmaceutical activated clay to the reaction vessel, and continue stirring for 3 hours. Transfer the material in the reaction vessel to a pressure vessel.

[0028] (3) Open the outlet of the pressure vessel, start the plate and frame filter, control the temperature at 85℃ and the working pressure at 0.3Mpa during filtration, and the filtrate obtained is crude hydrogenated palm oil glycerol ester, which is then fed into the material storage tank of the three-stage molecular distillation equipment.

[0029] (4) Set the process parameters of the three-stage molecular distillation equipment to 160°C and 30Pa, and press the crude hydrogenated palm oil glycerol into the cavity of the three-stage molecular distillation equipment through a vacuum feeder. Control the feed flow rate to 5ml / min and collect the heavy component hydrogenated palm oil glycerol pure product into the finished product container.

[0030] (5) The pure hydrogenated palm oil glyceride is transported through a pipeline to a rotary drum condenser crystallizer. The process parameters are set at a speed of 5 rpm and a cooling circulating water temperature of 18°C. The condenser slices are then used to obtain pharmaceutical-grade hydrogenated palm oil glyceride.

[0031] After the sampled products passed the testing, they were repackaged and stored. 839.1g of pharmaceutical-grade hydrogenated palm oil glyceride was obtained, with a purification yield of 89.76%. All quality indicators met the enterprise standards, as shown in Table 1.

[0032] Example 2

[0033] A method for preparing pharmaceutical-grade hydrogenated palm oil glycerides, characterized by comprising the following steps:

[0034] (1) Add 550g stearic acid, 470g palmitic acid and 100g glycerol to the reaction vessel, heat to 80℃, until all materials are melted, and stir evenly;

[0035] (2) Add 30g of solid superacid silica-based catalyst No. 6 under stirring, evacuate the vacuum, wait until the pressure drops to ≤-0.09MPa, start heating to 135℃, react for 10 hours; cool down to 100℃, add 5g of 200-mesh pharmaceutical activated clay into the reaction vessel, continue stirring for 1 hour; transfer the material in the reaction vessel into a pressure vessel;

[0036] (3) Open the outlet of the pressure vessel, start the plate and frame filter, control the temperature at 100℃ and the working pressure at 0.2Mpa during filtration, and the filtrate obtained is crude hydrogenated palm oil glycerol ester, which is then fed into the material storage tank of the three-stage molecular distillation equipment.

[0037] (4) Set the process parameters of the three-stage molecular distillation equipment to 250°C and 10Pa, press the crude hydrogenated palm oil glycerol into the cavity of the three-stage molecular distillation equipment through a vacuum feeder, control the feed flow rate to 50ml / min, and collect the heavy component hydrogenated palm oil glycerol pure product into the finished product container.

[0038] (5) The pure hydrogenated palm oil glyceride is transported through a pipeline to a rotary drum condenser crystallizer. The process parameters are set at a speed of 30 rpm and a cooling circulating water temperature of 12°C. The condenser slices are then used to obtain pharmaceutical-grade hydrogenated palm oil glyceride.

[0039] After the sampled product passed the inspection, it was repackaged and stored. 833.9g of pharmaceutical-grade hydrogenated palm oil glyceride was obtained, with a purification yield of 89.21%. Testing showed that all quality indicators met the enterprise standards, as shown in Table 1.

[0040] Example 3

[0041] A method for preparing pharmaceutical-grade hydrogenated palm oil glycerides, characterized by comprising the following steps:

[0042] (1) Add 470g stearic acid, 550g palmitic acid and 100g glycerol to the reaction vessel, heat to 75℃ until all the materials are melted, and stir evenly.

[0043] (2) Add 25g of catalyst 282-1 type ion exchange resin under stirring, evacuate, and when the pressure drops to ≤-0.09MPa, start heating to 150℃ and react for 7 hours; cool down to 95℃, add 4g of 200 mesh pharmaceutical activated clay to the reaction vessel, and continue stirring for 2 hours; transfer the material in the reaction vessel to a pressure vessel;

[0044] (3) Open the outlet of the pressure vessel, start the plate and frame filter, control the temperature at 90℃ and the working pressure at 0.2Mpa during filtration, and the filtrate obtained is crude hydrogenated palm oil glyceride, which is then fed into the material storage tank of the three-stage molecular distillation equipment.

[0045] (4) Set the process parameters of the three-stage molecular distillation equipment to 180°C and 20Pa, and press the crude hydrogenated palm oil glycerol into the cavity of the three-stage molecular distillation equipment through a vacuum feeder. Control the feed flow rate to 30ml / min and collect the heavy component hydrogenated palm oil glycerol pure product into the finished product container.

[0046] (5) The pure hydrogenated palm oil glyceride is transported through a pipeline to a rotary drum condenser crystallizer. The process parameters are set at a speed of 10 rpm and a cooling circulating water temperature of 15°C. The condenser slices are then used to obtain pharmaceutical hydrogenated palm oil glyceride.

[0047] After sampling and testing, the product was repackaged and stored. 851.0g of pharmaceutical-grade hydrogenated palm oil glyceride was purified with a yield of 91.04%. All quality indicators met the enterprise standards, as shown in Table 1.

[0048] Example 4

[0049] A method for preparing pharmaceutical-grade hydrogenated palm oil glycerides, characterized by comprising the following steps:

[0050] (1) Add 520g stearic acid, 500g palmitic acid and 100g glycerol to the reaction vessel, heat to 70℃, until all materials are melted, and stir evenly;

[0051] (2) Add 12g of solid superacid catalyst HND-260 under stirring, evacuate the vacuum, and wait until the pressure drops to ≤-0.09MPa. Then, start heating to 160℃ and react for 5 hours. Cool down to 90℃, add 1.5g of 200-mesh pharmaceutical activated clay to the reaction vessel, and continue stirring for 1.5 hours. Transfer the material in the reaction vessel to a pressure vessel.

[0052] (3) Open the outlet of the pressure vessel, start the plate and frame filter, control the temperature at 95℃ and the working pressure at 0.15Mpa during filtration, and the filtrate obtained is crude hydrogenated palm oil glycerol ester, which is then fed into the material storage tank of the three-stage molecular distillation equipment.

[0053] (4) Set the process parameters of the three-stage molecular distillation equipment to 230°C and 15Pa, press the crude hydrogenated palm oil glycerol into the cavity of the three-stage molecular distillation equipment through a vacuum feeder, control the feed flow rate to 15ml / min, and collect the heavy component hydrogenated palm oil glycerol pure product into the finished product container.

[0054] (5) The pure hydrogenated palm oil glyceride is transported through a pipeline to a rotary drum condenser crystallizer. The process parameters are set at a speed of 20 rpm and a cooling circulating water temperature of 13°C. The condenser slices are then used to obtain pharmaceutical-grade hydrogenated palm oil glyceride.

[0055] After the sampled products passed the testing, they were repackaged and stored. 856.4g of pharmaceutical-grade hydrogenated palm oil glyceride was purified with a yield of 91.62%. All quality indicators met the enterprise standards, as shown in Table 1.

[0056] Example 5

[0057] A method for preparing pharmaceutical-grade hydrogenated palm oil glycerides, characterized by comprising the following steps:

[0058] (1) Add 500g stearic acid, 520g palmitic acid and 100g glycerol to the reaction vessel, heat to 73°C until all the materials are melted, and stir evenly.

[0059] (2) Add 20g of solid superacid catalyst HND-260 under stirring, evacuate the vacuum, and wait until the pressure drops to ≤-0.09MPa. Then, start heating to 155℃ and react for 6 hours. Cool down to 93℃, add 2g of 200-mesh pharmaceutical activated clay to the reaction vessel, and continue stirring for 1.8 hours. Transfer the material in the reaction vessel to a pressure vessel.

[0060] (3) Open the outlet of the pressure vessel, start the plate and frame filter, control the temperature at 93℃ and the working pressure at 0.18Mpa during filtration, and the filtrate obtained is crude hydrogenated palm oil glycerol ester, which is then fed into the material storage tank of the three-stage molecular distillation equipment.

[0061] (4) Set the process parameters of the three-stage molecular distillation equipment to 200℃ and 18Pa, press the crude hydrogenated palm oil glycerol into the cavity of the three-stage molecular distillation equipment through a vacuum feeder, control the feed flow rate to 20ml / min, and collect the heavy component hydrogenated palm oil glycerol pure product into the finished product container.

[0062] (5) The pure hydrogenated palm oil glyceride is transported through a pipeline to a rotary drum condenser crystallizer. The process parameters are set at a speed of 15 rpm and a cooling circulating water temperature of 14°C. The condenser slices are then used to obtain pharmaceutical hydrogenated palm oil glyceride.

[0063] After the sampled product passed the inspection, it was repackaged and stored. 862.7g of pharmaceutical-grade hydrogenated palm oil glyceride was purified with a yield of 92.28%. Testing showed that all quality indicators met the enterprise standards, as shown in Table 1.

[0064] Table 1. Enterprise Standards and Test Results of Hydrogenated Palm Oil Glycerides

[0065] .

Claims

1. A method for preparing pharmaceutical-grade hydrogenated palm oil glycerides, characterized by: Includes the following steps: (1) Stearic acid, palmitic acid and glycerol are added to the reaction vessel in a mass ratio of (4.3~5.5):(4.7~5.8):1, and the temperature is raised to 65℃~80℃ until all the materials are melted and stirred evenly. (2) Add catalyst equivalent to 5%~30% of the mass of glycerol while stirring, evacuate the vacuum, and wait until the pressure drops to ≤-0.09MPa. Then, start heating to 135~185℃ and react for 4~10 hours. Cool down to 85~100℃, add 200-mesh pharmaceutical activated clay equivalent to 0.5%~5% of the mass of glycerol into the reaction vessel, and continue stirring for 1~3 hours. Transfer the material in the reaction vessel into a pressure vessel. (3) Open the outlet of the pressure vessel, start the plate and frame filter, filter at 85℃~100℃ and working pressure ≤0.3Mpa, and the filtrate obtained is crude hydrogenated palm oil glyceride, which is then passed into the material storage tank of the three-stage molecular distillation equipment. (4) Set the process parameters of the three-stage molecular distillation equipment to a temperature of 160℃~250℃ and a pressure of ≤30Pa. Then, press the crude hydrogenated palm oil glycerol into the cavity of the three-stage molecular distillation equipment through a vacuum feeder. Control the feed flow rate to 5ml / min~50ml / min and collect the heavy component hydrogenated palm oil glycerol pure product into the finished product container. (5) The pure hydrogenated palm oil glycerol is transported through a pipeline to a rotary drum condenser crystallizer with a rotation speed of 5-30 rpm and a cooling circulating water temperature of 12-18℃. The condenser slices are used to obtain pharmaceutical hydrogenated palm oil glycerol. The catalyst is solid superacid HND-260 or solid superacid silicon-based No. 6.