Refining method of light dimeticone pharmaceutic adjuvant

Abstract

The invention provides a refining method of a light dimeticone pharmaceutic adjuvant, and relates to the field of pharmacy. The refining method comprises the following steps: heating a dimethyl cyclosiloxane crude product to a first temperature, stirring, and removing low-boiling-point substances under a first negative pressure condition to obtain a refined solution; mixing the refined liquid with a weakly alkaline aqueous solution, stirring, standing and separating liquid to obtain an upper layer oily substance; heating the upper-layer oily substance to a second temperature, introducing water vapor under normal pressure, carrying out first water vapor distillation, discarding a distillation light liquid, and carrying out second water vapor distillation on the distillation substrate under a second negative pressure condition to obtain a distillation light liquid; and separating the distilled light liquid, removing a water layer, drying an oil layer under reduced pressure, and sterilizing and filtering to obtain a medicinal-grade cyclomethylsilicone product. According to the refining method provided by the invention, the current situation that the medicinal cyclomethylsilicone is single in component, many in impurities and poor in emulsification and lubrication effects in a medicinal preparation is solved, the application effect of the preparation is effectively improved, and the problem that the cyclomethylsilicone cannot meet the medicinal requirement is solved.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, and particularly relates to a refining method for a light dimethicone oil-based pharmaceutical excipient. Background Technology

[0002] Cyclomethyl silicone is a type of dimethyl silicone oil, also known as dimethylcyclosiloxane, and belongs to the category of light, low-viscosity silicone oils. Cyclomethyl silicone is fully methylated and contains repeating units with the molecular formula [-(CH3)2SiO-]. n Cyclomethylsiloxanes, wherein n is 4, 5, or 6, or a mixture thereof. Cyclomethylsiloxanes are used as emollients, humectants, and thickeners in pharmaceutical preparations and are harmless to humans. They are mainly used in topical preparations and cosmetic formulations, such as water-in-oil creams.

[0003] Since the 1970s, cyclomethyl silicones have been used in cosmetic formulations at concentrations of 0.1% to 50%, and have become the most widely used silicone in the cosmetic industry. Their high volatility and moderate solvent characteristics make cyclomethyl silicones ideal for topical formulations, as their low heat of vaporization results in a non-wet feel when applied to the skin. The structural formula of cyclomethyl silicone is as follows: Cyclomethylsiloxanes are fully methylated and contain repeating units with the molecular formula [-(CH3)2SiO-]. n The cyclomethylsiloxanes, wherein n is 4, 5, or 6, or a mixture thereof. n of 4, 5, or 6 correspond to: octamethylcyclotetrasiloxane (hereinafter referred to as D4, boiling point 175℃), decamethylcyclopentasiloxane (hereinafter referred to as D5, boiling point 210℃), and dodecylcyclohexasiloxane (hereinafter referred to as D6, boiling point 245℃). Because D4 octamethylcyclotetrasiloxane may be harmful to the human body, the content of the D4 component is limited in pharmaceutical-grade cyclomethylsiloxanes. Trace amounts of the D4 component can promote the activity of cyclomethylsiloxanes. Furthermore, products containing D5 have stronger stability, and products containing D6 have stronger loading capacity, better moisturizing properties, and higher viscosity. Therefore, mixtures containing trace amounts of D4, D5, and D6 have the highest medicinal effect. Commercially available cyclomethylsiloxanes are mostly prepared by distillation. Different monomers can be obtained through distillation based on differences in boiling point. Therefore, most commercially available products are monomers, not mixtures containing all three or two of these components, which cannot meet the specific requirements of the high-end pharmaceutical field. If the D4, D5, and D6 monomers are obtained by separate distillation and then physically mixed, there is a significant risk to their quality. D4 has a boiling point of 175°C, and the distillation purification process easily leaves behind large amounts of short-chain dimethylsiloxanes, such as octamethyltrisiloxane; D5 monomers are prone to leaving behind decamethyltetrasiloxane; and because D6 has a boiling point of 245°C, the energy consumption for distillation is also relatively high.

[0004] For example, patent document CN202010256194.7 uses distillation to purify and prepare octamethylcyclotetrasiloxane (D4), with a distillation temperature of 170-180℃, which is energy-intensive. For example, patent document CN201410020179.7 describes the preparation of octamethylcyclotetrasiloxane (D4) using vacuum distillation and purification. The distillation temperature reaches 100–110°C, and the theoretical plate number and vacuum degree of the distillation column need to be strictly controlled. Therefore, to obtain D5 and D6 with higher boiling points through vacuum distillation, even higher temperature conditions are required, above 150°C.

[0005] For example, patent document CN201310285459.6 describes the preparation of decamethylcyclopentasiloxane (D5) by vacuum distillation and purification, with a distillation temperature of 140-160℃, and requires a special vacuum distillation apparatus.

[0006] Meanwhile, pharmaceutical-grade cyclomethyl silicone, as detected by thermogravimetric analysis (TGA), is highly volatile or decomposes above 100°C. Therefore, high-temperature distillation often results in low yields and high levels of impurities. Consequently, there is an urgent need to develop a purification and preparation process for pharmaceutical-grade cyclomethyl silicone. This process should be energy-efficient and reduce consumption while yielding cyclomethyl silicone products with low impurity residues, stable quality, and high pharmaceutical activity.

[0007] In view of this, the present invention is hereby proposed. Summary of the Invention

[0008] The purpose of this invention is to provide a refining method for a lightweight dimethicone-based pharmaceutical excipient to solve the above-mentioned problems.

[0009] To achieve the above objectives, the present invention adopts the following technical solution: A method for refining a light dimethicone-based pharmaceutical excipient, comprising: The crude dimethylcyclosiloxane is heated to a first temperature, stirred, and then the low-boiling substances (mainly hexamethylcyclotrisiloxane (D3) and straight-chain short-chain dimethylsiloxane polymers, etc.) are removed under a first negative pressure to obtain a purified liquid. The refined liquid and the weakly alkaline aqueous solution are mixed, stirred, allowed to stand, and separated (to remove acidic impurities) to obtain the upper oily substance; The upper oily substance is heated to a second temperature, and steam is introduced under normal pressure to perform a first steam distillation (to further remove low-boiling-point impurities such as hexamethylcyclotrisiloxane (D3)). The light distillate is discarded, and a second steam distillation is performed under a second negative pressure (to remove excessive impurities such as dodecylcyclohexasiloxane (D6) and tetradecylcycloheptasiloxane (hereinafter referred to as D7)) to obtain the distillate. The distillate was separated to remove the water layer, and the oil layer was dried under reduced pressure and filtered to obtain a pharmaceutical-grade cyclomethyl silicone product.

[0010] The crude dimethylcyclosiloxane contains components such as hexamethylcyclotrisiloxane (hereinafter referred to as D3), octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), dodecylcyclohexasiloxane (D6), and tetradecylcycloheptasiloxane (hereinafter referred to as D7). It is prepared by adding dimethyl dichlorosilane, an industrial basic raw material, dropwise to water to obtain a mixture of dimethyl cyclic compounds D4, D5, D6, and D7; or by rearranging tetramethyl disiloxane and iodine in dichloromethane to obtain a mixture of dimethyl cyclic compounds D4, D5, D6, and D7.

[0011] Preferably, the pharmaceutical-grade cyclomethyl silicone product is a mixture of octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, and dodecylcyclohexasiloxane, wherein the content of octamethylcyclotetrasiloxane is controlled between 0.05wt% and 0.5wt%.

[0012] Optionally, the content of the octamethylcyclotetrasiloxane can be any value between 0.05wt%, 0.1wt%, 0.15wt%, 0.2wt%, 0.25wt%, 0.3wt%, 0.35wt%, 0.4wt%, 0.45wt%, 0.5wt%, or 0.05wt%-0.5wt%.

[0013] Preferably, the first temperature is 50-80°C.

[0014] Optionally, the first temperature can be any value between 50°C, 60°C, 70°C, 80°C, or 50-80°C.

[0015] Preferably, the pressure of the first negative pressure condition is not higher than -0.085 MPa, and the time for removing low-boiling substances is 0.5-3 hours.

[0016] Optionally, the pressure of the first negative pressure condition can be -0.085 MPa, -0.090 MPa, -0.095 MPa, -0.1 MPa or any value not higher than -0.085 MPa, and the time for removing low-boiling substances can be any value between 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h or 0.5-3 h.

[0017] Preferably, the weakly alkaline aqueous solution is a sodium carbonate aqueous solution with a mass concentration of 0.05-1.0%, preferably 0.3%; the dosage is 0.1-3.0 w / w of the crude dimethylcyclosiloxane, preferably 0.5 w / w.

[0018] Optionally, the mass concentration of the weakly alkaline aqueous solution can be any value between 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, or 0.05-1.0%, and the amount used can be any value between 0.1 w / w, 0.5 w / w, 1 w / w, 1.5 w / w, 2 w / w, 2.5 w / w, 3 w / w, or 0.1-3.0 w / w of the crude dimethylcyclosiloxane.

[0019] Preferably, the second temperature is 80-100℃, and the first steam distillation time is 0.5-1h, preferably 45min. The longer the time, the lower the D4 content.

[0020] Optionally, the second temperature can be any value between 80-100°C, and the first steam distillation time can be any value between 0.5-1h.

[0021] Preferably, the temperature of the second steam distillation is 80-100°C, more preferably 95°C.

[0022] Optionally, the temperature of the second steam distillation can be any value between 80°C, 90°C, 100°C, or 80-100°C.

[0023] Preferably, the pressure of the second negative pressure condition is -0.06 MPa to -0.1 MPa, more preferably -0.095 MPa.

[0024] Optionally, the pressure of the second negative pressure condition can be -0.06 MPa, -0.07 MPa, -0.08 MPa, -0.09 MPa, -0.1 MPa, or any value between -0.06 MPa and -0.1 MPa.

[0025] Preferably, the temperature of the vacuum drying is 50-80℃, more preferably 60℃; the pressure is -0.06Mpa to -0.1Mpa, more preferably -0.09Mpa; and the time is 0.5-2h, more preferably 1h.

[0026] Optionally, the temperature of the vacuum drying can be any value between 50℃, 60℃, 70℃, 80℃ or 50-80℃, the pressure can be any value between -0.06Mpa, -0.07Mpa, -0.08Mpa, -0.09Mpa, -0.1Mpa or -0.06Mpa to -0.1Mpa, and the time can be any value between 0.5h, 1h, 1.5h, 2h or 0.5-2h.

[0027] Preferably, the pore size of the sterilization filter element is no higher than 0.45 μm, and more preferably 0.22 μm.

[0028] The beneficial effects of this invention are: The purification method for light dimethicone-based pharmaceutical excipients provided in this application can further remove impurities such as short-chain linear polydimethylsiloxanes and D3 from industrial-grade crude cyclomethylsiloxanes. Simultaneously, it can further remove excess D4 components, thereby obtaining highly pharmaceutically active cyclomethylsiloxanes, with the D4 content controlled between 0.05-0.5%. Through the first and second steps of pre-purification, acidic impurities are removed. Steam distillation is the core technology of this method, controlling two stages: atmospheric pressure and reduced pressure, to obtain pharmaceutical-grade high-purity cyclomethylsiloxanes through fractional purification. The entire purification process controls the purification temperature below 100℃, compared to traditional distillation processes that control above 150℃, significantly reducing energy consumption. This method effectively improves product purity, meets pharmaceutical requirements, and solves the problem of formulation applications with high requirements in various fields. Attached Figure Description

[0029] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0030] Figure 1 The infrared spectrum (IR) of pharmaceutical-grade cyclic methyl silicone; Figure 2 Thermogravimetric analysis (TGA) plot of pharmaceutical-grade cyclomethyl silicone. Detailed Implementation

[0031] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0032] The standards for pharmaceutical-grade cyclomethyl silicone are shown in Table 1 below: Table 1: Quality Standards for Cyclomethyl Silicone Cyclomethylsiloxane has limited requirements for acidic impurities and non-volatile impurities, as well as requirements for the content of substances that affect the performance of the formulation.

[0033] The information on the raw materials used and their sources in the following specific embodiments is shown in Table 2: Table 2. List of Main Raw Materials Example 1 like Figure 1 As shown in the figure, this embodiment provides a refining method for a lightweight dimethicone-based pharmaceutical excipient, as detailed below: Add 500g of crude dimethylcyclosiloxane to a three-necked flask and start stirring. Heat to 60℃, stir thoroughly, and maintain a vacuum of P≤-0.085Mpa for 1 hour under reduced pressure. Stop vacuum distillation, add 250ml of 0.5% sodium carbonate aqueous solution to the purified liquid in the reaction flask, stir for 15min, let stand for 15min, extract and separate to obtain the upper oil-ester layer. Heat the upper oil-ester layer to 90℃, introduce steam under normal pressure, and distill for 45min. Discard the distillate, then turn on the vacuum again, maintaining a vacuum of P=-0.095Mpa to -0.098Mpa, and continue introducing steam for a second steam distillation for 2 hours. The distillation yields the cyclomethylsiloxane product. Separate to remove the aqueous layer, dry under reduced pressure at 60℃, P≤-0.09Mpa, and filter through a 0.45um filter cartridge for sterilization to obtain 380g of pharmaceutical-grade cyclomethylsiloxane. The product is then tested. D3 not detected, D4 contained 0.20%, D5 contained 52.3%, D6 contained 47.6%, D7 not detected, and acid content not detected.

[0034] Figure 1 The infrared spectrum (IR) of pharmaceutical-grade cyclic methyl silicone; Figure 2 Thermogravimetric analysis (TGA) plot of pharmaceutical-grade cyclomethyl silicone.

[0035] Example 2 This embodiment provides a refining method for lightweight dimethicone-based pharmaceutical excipients, as detailed below: Add 500g of crude dimethylcyclosiloxane to a three-necked flask and start stirring. Heat to 60℃, stir thoroughly, and maintain a vacuum of P≤-0.085Mpa for 1 hour under reduced pressure. Stop vacuum distillation, add 250ml of 0.5% sodium carbonate aqueous solution to the purified liquid in the reaction flask, stir for 15min, let stand for 15min, extract and separate to obtain the upper oil-ester layer. Heat the upper oil-ester layer to 80℃, introduce steam under normal pressure, and distill for 45min. Discard the distillate, then turn on the vacuum again, maintaining a vacuum of P=-0.095Mpa to -0.098Mpa, and continue introducing steam for a second steam distillation for 2 hours. The distillate yields the cyclomethylsiloxane product. Separate to remove the aqueous layer, dry under reduced pressure at 60℃, P≤-0.09Mpa, and filter through a 0.22um filter cartridge for sterilization to obtain 414g of pharmaceutical-grade cyclomethylsiloxane. The product is then tested. D3 not detected, D4 contains 0.45%, D5 contains 71.25%, D6 contains 28.30%, D7 not detected, acid content not detected.

[0036] Example 3 This embodiment provides a refining method for lightweight dimethicone-based pharmaceutical excipients, as detailed below: Add 500g of crude dimethylcyclosiloxane to a three-necked flask and start stirring. Heat to 60℃, stir thoroughly, and maintain a vacuum of P≤-0.085Mpa for 1 hour under reduced pressure. Stop vacuum distillation, add 250ml of 0.5% sodium carbonate aqueous solution to the purified liquid in the reaction flask, stir for 15min, let stand for 15min, extract and separate to obtain the upper oil-ester layer. Heat the lower oil-ester layer to 100℃, introduce steam under normal pressure, and distill for 45min. Discard the distillate, then turn on the vacuum again, maintaining a vacuum of P=-0.095Mpa to -0.098Mpa, and continue introducing steam for a second steam distillation for 2 hours. The distillation yields the cyclomethylsiloxane product. Separate to remove the aqueous layer, dry under reduced pressure at 60℃, P≤-0.09Mpa, and filter through a 0.22um filter for sterilization to obtain 373g of pharmaceutical-grade cyclomethylsiloxane. The product is then tested. D3 not detected, D4 contained 0.06%, D5 contained 51.24%, D6 contained 48.70%, D7 not detected, and acid content not detected.

[0037] Comparative Example Basic experimental design: Step ①: Add 500g of crude dimethylcyclosiloxane to a three-necked flask and start stirring. Heat to 70℃, stir thoroughly, control the vacuum degree P≤-0.09Mpa, and stir under reduced pressure for 1.0h; then stop vacuum distillation. Step 2: Add 150 ml of 0.3% sodium carbonate aqueous solution to the purified solution in the reaction flask, stir for 15 min, let stand for 15 min, extract and separate to obtain the upper oil ester layer.

[0038] Step 3: Atmospheric distillation—The upper oil layer is heated to 95℃, steam is introduced under atmospheric pressure, and the distillate is distilled for 1.0 h. The distillate is then discarded. Vacuum distillation—The vacuum is turned on, and the vacuum degree is controlled from P=-0.095Mpa to -0.098Mpa. Steam is introduced again, and a second steam distillation is carried out for 2.5 h. The distillation yields the cyclomethyl silicone product.

[0039] The aqueous layer was extracted, dried under reduced pressure at 60℃ and P≤-0.09Mpa, and then filtered through a 0.45um filter cartridge for sterilization to obtain pharmaceutical-grade cyclomethyl silicone.

[0040] Under the same refining formula and refining conditions as described above, the following experiments were conducted without performing step ① (vacuum distillation), step ② (alkali washing), and step ③ (vapor distillation at atmospheric pressure): A comparative study of the cyclic methyl silicones obtained was performed. The results are shown in Table 3. Table 3. Experimental Results of Different Processes (without steps) The purpose of this invention is to prepare a highly pharmaceutically active cyclomethyl silicone, strictly controlling the D4 component to 0.05-0.5%, controlling impurities such as D3 through process control, and optimizing the acid content of the product. As shown in the table above, the third step, atmospheric distillation with steam, significantly affects the purification effect. Only a complete process flow can achieve the most ideal product quality.

[0041] In summary, this invention uses industrial-grade crude dimethylcyclosiloxane as raw material, heats it to a specific temperature, stirs it thoroughly, and removes straight-chain low-boiling substances under reduced pressure; a weakly alkaline aqueous solution is added to the purified liquid, stirred and allowed to stand, and extracted to remove acidic impurities, yielding an upper oil layer; the oil layer is then heated to a certain temperature, steam is introduced, and the mixture is distilled at atmospheric pressure for a period of time, followed by a certain degree of negative pressure for a second steam distillation; the distillate is extracted to separate the aqueous layer, which is then dried under reduced pressure and sterilized by filtration to obtain pharmaceutical-grade cyclomethylsiloxane; moreover, this purification method is simple, the entire process does not exceed 100°C, the process has low energy consumption, and the product quality is superior, making it highly competitive in the market.

[0042] Please note that the technical features of the above embodiments can be combined arbitrarily. For the sake of brevity, not all possible combinations of the technical features in the above embodiments have been described. However, as long as the combination of these technical features does not contradict each other, it should be considered within the scope of this specification. The above embodiments only illustrate several implementation methods of this application, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the invention patent. It should be pointed out that for those skilled in the art, several modifications and improvements can be made without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

Claims

1. A method for refining a light dimethicone-based pharmaceutical excipient, characterized in that, include: Step 1: Heat the crude dimethylcyclosiloxane to a first temperature, stir, and remove low-boiling substances under a first negative pressure to obtain a purified solution; Step 2: Mix the refined liquid with a weakly alkaline aqueous solution, stir, let stand, and separate the liquids to obtain the upper oily substance; Step 3: Heat the upper oily substance to a second temperature, introduce steam under normal pressure to perform a first steam distillation, discard the first distillate, and perform a second steam distillation on the substrate under a second negative pressure to obtain a second distillate. The second distillate was separated to remove the water layer, and the oil layer was dried under reduced pressure and filtered to obtain a pharmaceutical-grade cyclomethyl silicone product.

2. The refining method for light dimethicone-based pharmaceutical excipients according to claim 1, characterized in that, The pharmaceutical-grade cyclomethyl silicone product is a mixture of octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, and dodecylcyclohexasiloxane, wherein the content of octamethylcyclotetrasiloxane is controlled between 0.05wt% and 0.5wt%.

3. The refining method for lightweight dimethicone-based pharmaceutical excipients according to claim 1, characterized in that, In step 1, the first temperature is 50-80℃.

4. The refining method for lightweight dimethicone-based pharmaceutical excipients according to claim 1, characterized in that, In step 1, the pressure of the first negative pressure condition is not higher than -0.085 MPa, and the time for removing low-boiling substances is 0.5-3 hours.

5. The refining method for light dimethicone-based pharmaceutical excipients according to claim 1, characterized in that, The weakly alkaline aqueous solution is a sodium carbonate aqueous solution with a mass concentration of 0.05-1.0%, and the amount used is 0.1-3.0 w / w of the crude dimethylcyclosiloxane.

6. The refining method for light dimethicone-based pharmaceutical excipients according to claim 1, characterized in that, In step 3, the second temperature is 80-100℃, and the first steam distillation time is 0.5-1h.

7. The refining method for light dimethicone-based pharmaceutical excipients according to claim 1, characterized in that, In step 3, the temperature of the second steam distillation is 80-100℃.

8. The refining method for lightweight dimethicone-based pharmaceutical excipients according to claim 1, characterized in that, In step 3, the pressure of the second negative pressure condition is -0.06 MPa to -0.1 MPa.

9. The refining method for lightweight dimethicone-based pharmaceutical excipients according to claim 1, characterized in that, The vacuum drying process is carried out at a temperature of 50-80℃, a pressure of -0.06Mpa to -0.1Mpa, and a time of 0.5-2h.

10. The refining method for lightweight dimethicone-based pharmaceutical excipients according to claim 1, characterized in that, The filter element of the sterilization filter has a pore size of no more than 0.45 μm.

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