Oligomerization of alpha-hydroxy acids

Abstract

The present disclosure relates to an assembly of a system 100 for carrying out oligomerization of alpha-hydroxy acids, comprising a reaction vessel 101, a distillation column 102, an inlet valve 103, a fractionating head 104, a condenser 105, a vessel 108 for feeding an alpha-hydroxy acid, a peristaltic pump 109, a stirring device 110 for stirring the reaction vessel 101, a heating device 111 for heating the reaction vessel 101, a device 112 for measuring the temperature of the reaction vessel 101, and a device 113 for heating, adjusting, regulating or maintaining the temperature of the distillation column 102, the method is characterized in that the alpha-hydroxy acid is fed in batches into the reaction vessel 101 in a controlled mode via an inlet valve 103 located near the distal end of the distillation column 102 so as to synthesize / obtain an oligomer having a molecular weight in the range of 900 Da to 1200 Da within 5 hours, the alpha-hydroxy acid being less than 2% in the distillate collector 107.

Description

[0001] Cross - reference to related applications and priority

[0002] This application claims priority to Indian Patent Application No. 202221067248, filed on November 23, 2022, which is incorporated herein by reference. Technical Field

[0003] The present subject matter generally relates to a method for synthesizing oligomers. More specifically, the present subject matter relates to an assembly for oligomerization of α - hydroxy acids. Background Art

[0004] α - hydroxy acids or alpha - hydroxy acids (AHAs) are a class of naturally occurring compounds composed of carboxylic acids with a hydroxyl group substituted on an adjacent carbon. Although α - hydroxy acids are typically prepared by adding hydrogen cyanide to a ketone or aldehyde followed by acidic hydrolysis of the resulting cyanohydrin product, they are also commonly generated by fermenting chemical components under controlled conditions, e.g., treating an aldehyde and hydrocyanic acid or α - hydroxy nitrile with a microorganism having nitrilase or nitrile hydratase activity in an aqueous medium. Prominent examples of AHAs are glycolic acid, lactic acid, and citric acid.

[0005] Polymeric products of α - hydroxy acids are a class of interesting biodegradable, biocompatible, and bioabsorbable polymers that break down into physiologically tolerable, non - toxic degradation products that are eliminated from the organism or completely bioabsorbed. Other advantages of poly α - hydroxy acids in biomedical applications are that their physical - mechanical properties can be controlled, their surface properties can be chemically or physically modified, and the ability to immobilize cells or biomolecules inside or on their surface. Thus, over the past decade, they have found interesting applications in technologies such as tissue engineering, skeletal systems, cardiovascular devices, artificial organs, ophthalmology, controlled drug delivery systems, etc. These biodegradable polymers do not cause persistent inflammatory or toxic reactions when implanted in the body, and their degradation time can be matched to the healing or regeneration process, thus demonstrating appropriate permeability and processability for the intended biomedical applications. Poly α - hydroxy acids, particularly polyglycolic acid (PGA), polylactic acid (PLA), and their copolymers of polylactic - co - glycolic acid (PLGA) are a new class of commercial polymers with wide applications in the biomedical field.

[0006] It is generally known that the synthesis of polylactic acid and polyglycolic acid includes four main steps: i) oligomerization of α - hydroxy acids to the desired molecular weight (degree of polymerization (DP)=8 - 45), ii) depolymerization of the oligomers and formation of cyclic dimers, iii) purification of the cyclic dimers, and iv) ring - opening polymerization of the dimers.

[0007] Ring-opening polymerization (ROP) of cyclic diesters produces high molecular weight polymers (MW > 100,000 g / mol) in a relatively short time, thus facilitating the mechanism for such large-scale industrial production. The polymers produced in the ROP reaction are usually linear and have a narrow molecular weight distribution range, which is generally difficult to achieve by other polymerization techniques. This process is particularly useful in the polymerization of α-hydroxy acids such as lactic acid, which determines the yield and desired properties of the final polymer product. α-Hydroxy acids are usually condensed to their oligomers by removing by-product water (which can be advantageously achieved by simple evaporation) in one or more steps at atmospheric pressure or reduced back pressure until an oligomer composition with an average DP range of 8 to 45 is obtained. Solvents that form azeotropes with water can also be used for the oligomerization of α-hydroxy acids to: remove the water formed during the condensation reaction; mix and boil the mixture; stabilize the amount of solvent in the reaction medium, and then distill off the remaining / excess water.

[0008] Large amounts of α-hydroxy acids, such as glycolic acid and lactic acid, are usually lost during oligomerization due to co-distillation with water. This is because α-hydroxy acids have a high affinity for water, especially when the boiling point of the α-hydroxy acid is close to the boiling point range of water. This makes the process of removing water by distillation during oligomerization extremely difficult. In addition, forming oligomers by performing conventional water distillation requires a long reaction time. As a result, many times, the resulting oligomers do not have the desired properties.

[0009] The prior art describes oligomerization carried out in a batch reactor, such that the required time is greater than 6 hours. In addition to the very long reaction duration, the processes cited in the prior art are also complex and involve the presence of complex structural or process elements, such as stirred tank reactors, multi-stage distillation columns, falling film reboilers, homogeneous catalysts, water removal under a high vacuum of 100 mbar to 200 mbar, etc.

[0010] However, the prior art does not teach continuous feeding of lactic acid in a fractionation column to reduce the loss of lactic acid and reduce the total time required for oligomerization.

[0011] To this end, the inventors of the present disclosure were motivated to assemble an oligomerization assembly to perform rapid oligomerization of α-hydroxy acids by batch or continuous feeding of α-hydroxy acids through a packed column and using the same column to avoid the loss of α-hydroxy acids with water. Summary of the Invention

[0012] The present disclosure relates to a system 100 for assembling the oligomerization of α-hydroxy acids, and the system assembly 100 includes: a reaction vessel 101. It is filled with a part of all α-hydroxy acids, and is configured to be connected to the proximal end of a distillation column 102; the distillation column 102 is configured to receive α-hydroxy acids via an inlet valve 103 near its distal end; the inlet valve 103 is used to feed the remaining α-hydroxy acids in a controlled mode, and is configured to be connected to a container 108; the distal end of the distillation column 102 is also configured to be connected to the proximal end of a fractionation head 104; the distal end of the fractionation head 104 is configured to be connected to the proximal end of a condenser 105, and at the same time, there is a device for connecting to a distillate collector 107; the distal end of the condenser 105 and the distillate collector 107 are provided with devices for connecting to a vacuum pump 106; it is characterized in that the α-hydroxy acids are fed into the reaction vessel 101 in batches or continuously via the inlet valve 103.

[0013] In a related exemplary embodiment, the present disclosure discloses a process for the oligomerization of α-hydroxy acids by the system 100 described above. The process includes: (a) filling a part of all α-hydroxy acids into the reaction vessel 101; (b) reducing and further maintaining the reduced pressure of the system 100; (c) heating the reaction vessel 101 to the reflux temperature to oligomerize the α-hydroxy acids; (d) maintaining the temperature of the distillation column 102 to evaporate water; (e) feeding the remaining α-hydroxy acids into the reaction vessel 101 via the inlet valve 103 for further oligomerization; (f) maintaining the reflux temperature of the reaction vessel 101 to achieve the oligomerization of α-hydroxy acids while removing water; (g) cooling the reaction vessel 101; and (h) releasing the vacuum and removing the oligomer composition from the system 100.

[0014] This summary of the invention is not intended to identify all essential features of the claimed subject matter, nor is it intended to be used to determine or limit the scope of the claimed subject matter. Brief Description of the Drawings

[0015] The detailed description of the drawings is outlined with reference to the accompanying drawings. In the drawings, the leftmost digit of the reference numeral indicates the figure in which the reference numeral first appears. In all the drawings, the same reference numerals are used to refer to similar features and components.

[0016] Figure 1Disclosed is a system / system component 100 for oligomerizing α-hydroxy acids, wherein the system / system component 100 includes: a reaction vessel 101, a distillation column 102, an inlet valve 103, a fractionation head 104, a condenser 105, a vacuum pump device 106 for adjusting and regulating the vacuum within the system 100, a distillate collector 107, a container 108 for α-hydroxy acid feed, a peristaltic pump 109, a stirring device 110 for stirring the reaction vessel 101, a heating device 111 for heating the reaction vessel 101, a device 114 for adjusting and regulating the heating device 111 for heating the reaction vessel 101, a device 112 for measuring the temperature of the reaction vessel 101, and a device 113 for adjusting or maintaining the temperature of the distillation column 102.

[0017] Figure 2 Shows the development of the molecular weight of lactic acid oligomers over reaction time during oligomerization without batch addition of lactic acid.

[0018] Figure 3(A) shows the development of the molecular weight of lactic acid oligomers over reaction time during oligomerization with batch addition of lactic acid.

[0019] Figure 3(B) shows the gradual decrease of the remaining lactic acid in the reaction vessel during oligomerization with batch addition of lactic acid. Detailed Description

[0020] Throughout the specification, reference to "each embodiment", "some embodiments", "an embodiment", "an alternative embodiment", or "one embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the phrases "in each embodiment", "in some embodiments", "in an embodiment", "in one embodiment", "in an alternative embodiment", or "in a related embodiment" appearing at various places throughout the specification do not necessarily refer to the same embodiment. Additionally, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0021] Throughout the present specification, reference to "the system", "system components", "the current system", or "the present system" means the same system. Further reference throughout the specification to "a plurality of components", "components", "a plurality of features", or "features" means one or a group of components embodying the system.

[0022] Before describing the apparatus and process, it should be understood that the present disclosure is not limited to the particular apparatus and process described, as there may be multiple possible embodiments that are not explicitly shown in the present disclosure but are still feasible within the scope of the present disclosure.

[0023] Also, the technical solutions provided by the present disclosure will be described clearly and completely below. Examples where specific conditions may not be specified have been carried out under conventional conditions or in the manner recommended by the manufacturer.

[0024] The present disclosure relates to the oligomerization of α-hydroxy acids (AHAs).

[0025] For the purposes of the present disclosure, oligomerization is defined as the process of converting α-hydroxy acids into their oligomeric forms; oligomers are molecules formed by the condensation of several monomer units.

[0026] In one embodiment, the present disclosure relates to the oligomerization of α-hydroxy acids, wherein the boiling point range of the α-hydroxy acids is from 90 °C to 200 °C; particularly from 100 °C to 150 °C.

[0027] As is known to those skilled in the art, α-hydroxy acids or alpha-hydroxy acids (AHAs) are a class of compounds consisting of a hydroxyl group on the carbon α adjacent to or up to the carboxylic acid functional group, or simply put, a class of compounds containing a carbon atom carrying a hydroxyl group and a carboxylic acid group. α-Hydroxy acids are typically prepared by adding hydrogen cyanide to a ketone or aldehyde and then subjecting the resulting cyanohydrin product to acidic hydrolysis. Prominent examples include glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, etc. In a preferred embodiment, the monomeric α-hydroxy acid is selected from lactic acid and glycolic acid.

[0028] It is well known that lactic acid is an organic compound produced by the fermentation of carbohydrates by different microorganisms. Although most lactic acid bacteria exhibit amylase activity responsible for lactic acid production, they require complex nutrients and a slightly lower fermentation temperature (<45 °C) for production. Due to the production of amylase in the initial step, this may sometimes lead to low productivity, resulting in a long lag phase, increasing costs and the risk of contamination. Certain fungi, including Rhizopus spp., are also known to produce high levels of lactic acid.

[0029] In one embodiment, the AHA (α-hydroxy acid) is lactic acid, with the molecular formula CH3CH(OH)COOH. It is highly soluble in water and can be produced by chemical or biosynthesis, or isolated from natural sources. Lactic acid or its conjugate base lactate (or lactate anion) is used as a synthetic intermediate in many organic syntheses and various biochemical industries.

[0030] In another embodiment, the AHA (α-hydroxy acid) is glycolic acid. As is known to those skilled in the art, glycolic acid is hydroxyacetic acid, with the chemical formula HOCH2CO2H. It is a colorless, odorless, hygroscopic crystalline solid that is also highly soluble in water. Glycolic acid is widely present in nature and is also widely used in various skin care products. Glycolate, the salt or ester of glycolic acid, is sometimes spelled "glycollate".

[0031] As is known to skilled artisans, glycolic acid is naturally produced by various microorganisms through the oxidation of ethylene glycol and the hydrolysis of glycolonitrile. It is also known that chemolithotrophic iron bacteria and sulfur-oxidizing bacteria used in acid bioleaching produce glycolic acid through partially unknown metabolic pathways.

[0032] The present disclosure also relates to a system assembled for oligomerizing α-hydroxy acids.

[0033] In one embodiment, the system components include a reaction vessel. For the purposes of the present disclosure, it should be clarified that in the present disclosure, the term "reaction vessel" refers to a vessel, reactor, container, flask, beaker, or any such device for containing reactants participating in a reaction.

[0034] In a related embodiment, the reaction vessel is a flask; preferably, a round-bottom flask; more preferably, a round-bottom flask having more than one neck, particularly a three-neck round-bottom flask.

[0035] In another embodiment, the system components include a distillation column. As is known to those skilled in the art, a distillation column provides a surface for condensing and evaporating a fluid before the fluid vapor enters a condenser. Thus, it aids in separation and thus in concentrating the more volatile components in one fraction and the less volatile components in another fraction.

[0036] In a related embodiment, the distillation column is used for simple, fractional, steam, or reactive distillation; particularly reactive distillation.

[0037] Reactive distillation is an intensified technique that combines a chemical reaction with separation in one device through distillation. In many separation processes, a hypothetical region or stage called a theoretical plate can be perceived, where two phases, such as the liquid phase and vapor phase of a substance, establish equilibrium with each other.

[0038] In yet another embodiment, the distillation column is filled with a structured material. The packing optimizes the separation process by providing a large wetted surface area where chemical separation or mass transfer can occur. In the mass transfer process, separation is typically achieved by the counteracting forces of heat and pressure that push water vapor upward or the force of gravity that pushes liquid substances downward. The packing amplifies these forces and promotes a faster and more efficient chemical separation process.

[0039] There are various forms of packing materials, and they are selected according to their materials to suit the required surface area, weight, corrosion resistance, and pressure drop. Thus, for example, metal packing materials are known for their strength, but plastic packing materials are generally more cost-effective. Ceramic packing materials are fragile, but they are highly demanded for corrosive substances such as chemical waste because of their good corrosion resistance.

[0040] Some of the requirements that a packing material must meet to function effectively include chemical inertness to the components to be separated, high strength but low weight. Equally important is having a sufficient number of channels for the fluid to flow through without obstruction or pressure drop, and a sufficient surface area for fluid contact.

[0041] While there are two main types of packings - random packings and structured packings, structured packings are organized packings that direct the liquid material into a specific shape. It uses disks made of materials such as metals, plastics, or ceramics, whose internal structure is arranged in different types of honeycomb shapes found within a cylindrical column. Structured packing cartridges are precisely designed to provide a large surface area for fluid contact without creating resistance that hinders its flow. Certain types of structured packing materials have additional texture designs to increase contact through liquid diffusion, which is particularly important in low-pressure applications where internal pressure alone cannot be relied upon to diffuse the liquid.

[0042] Structured packings generally have a lower pressure drop, allowing for a greater flow rate than random packings, which is beneficial in separations involving extremely low pressures or high flow rates. The low pressure provides other advantages such as higher volatility, which is beneficial in difficult separation processes, while improving energy efficiency and reducing foaming.

[0043] Due to its tightly organized internal infrastructure, structured packings also improve efficiency and show the ability to fill larger volumes. Additionally, the potentially higher capacity of structured packings in turn leads to a higher operating rate.

[0044] Thus, in yet another embodiment, the distillation column is filled with a structural material; in particular, a packing with a theoretical plate number in the range of 5 to 25. In a preferred embodiment, the distillation column includes a structured packing with a theoretical plate number in the range of 5 to 15.

[0045] In a related embodiment, the system components include at least one valve, in particular an inlet valve. As is known to those skilled in the art, a valve is a device or natural object that regulates, directs, or controls the flow rate of a fluid (gas, liquid, fluidized solid, or slurry) by opening, closing, or partially obstructing various channels. For the purposes of this disclosure, the type of valve is at least one of a hydraulic valve, a motor-driven valve, a manual valve, or a pneumatic valve.

[0046] In yet another embodiment, the system components include at least one fractionation head. As is well known, a fractionation head is a pneumatic valve located between the condenser and the top of the column, which helps to maintain the required reflux ratio in the distillation column. This ensures that the α-hydroxy acid refluxes closer to the reaction vessel, and in most cases only water is distilled out, thereby reducing the loss of the corresponding α-hydroxy acid in the distillate. For the purposes of this disclosure, the fractionation head is at least one of a manual fractionation head or a magnetic fractionation head; preferably a magnetic fractionation head.

[0047] In another embodiment, the system components include a condenser, which is a known laboratory device that operates by reducing the temperature of the vapor to cause condensation, that is, by cooling to turn them into a liquid.

[0048] In yet another embodiment, the system components include a vacuum pump, which is typically used to reduce the pressure of the system.

[0049] In a related embodiment, the system components further include a distillate collector, which is typically used to collect the distillate obtained during distillation. As described in the previous paragraph, for the purposes of this disclosure, it should be clarified that the term "collector" refers to a multi-necked flask, vessel, container, or any such device configured with multiple necks for containing the distillate obtained during the oligomerization process.

[0050] This disclosure discloses that in one embodiment, the reaction vessel is configured to be connected to a distillation column, preferably at the proximal end of the distillation column.

[0051] In another embodiment, the distillation column is further configured to be connected to a fractionation head, preferably at its distal end; and more preferably, the distal end of the distillation column is configured to be connected to the proximal end of the fractionation head.

[0052] In yet another embodiment, the fractionation head is configured to be connected to a condenser and a distillate collector; preferably, the distal end of the fractionation head is configured to be connected to the condenser; more preferably, the distal end of the fractionation head is configured to be connected to the proximal end of the condenser, while being provided with means for connecting to the distillate collector.

[0053] In yet another embodiment, the condenser and the distillate collector are configured to be connected to a vacuum pump; in particular, the distal end of the condenser is configured to be connected to the vacuum pump, and one of the necks of the distillate collector is connected to the vacuum pump.

[0054] This disclosure also discloses that in one embodiment, the distillation column is configured to receive an α-hydroxy acid via an inlet valve, particularly an inlet valve near its distal end.

[0055] Now referring to this disclosure Figure 1 , in one embodiment, the α-hydroxy acid is fed batchwise or continuously in a controlled mode into the reaction vessel 101 via an inlet valve 103 located near the distal end of the distillation column 102. The controlled addition mode or manner of the α-hydroxy acid is achieved by using a device 109 for regulating the addition, such as a peristaltic pump or any other metering pump. Further, since the entire system itself operates under vacuum or reduced back pressure, the controlled opening of the valve also drives the controlled addition of the α-hydroxy acid.

[0056] For the purposes of this disclosure, the controlled mode may include a batch mode, a fed-batch mode, a continuous mode, a semi-continuous mode, or any combination thereof.

[0057] In addition, according to Figure 1 , an exemplary embodiment of the present disclosure relates to a system 100 for assembling for the oligomerization of α-hydroxy acids. The system assembly 100 includes: a reaction vessel 101 filled with a part of all α-hydroxy acids, which is configured to be connected to the proximal end of a distillation column 102; a distillation column 102 configured to receive α-hydroxy acids via an inlet valve 103 near its distal end; an inlet valve 103 for feeding the remaining α-hydroxy acids in a controlled mode, which is configured to be connected to a container 108; the distal end of the distillation column 102 is also configured to be connected to the proximal end of a fractionation head 104; the distal end of the fractionation head 104 is configured to be connected to the proximal end of a condenser 105, and at the same time, there is a device for connecting to a distillate collector 107; the distal end of the condenser 105 and the distillate collector 107 are provided with devices for connecting to a vacuum pump 106; it is characterized in that the α-hydroxy acids are fed into the reaction vessel 101 in batches or continuously via the inlet valve 103.

[0058] In one embodiment, the system assembly further includes a stirring device for stirring the reaction vessel.

[0059] For the purposes of the present disclosure, a "stirring device" may refer to a device or apparatus for agitating, shaking, or mixing components. In a preferred embodiment, the stirring device is at least one of an electric, overhead, magnetic, manual, or mechanical stirrer, particularly an anchor-type overhead stirrer.

[0060] In another embodiment, the system assembly further includes a heating device for heating the reaction vessel.

[0061] For the purposes of the present disclosure, the term "heating device" refers to a device or apparatus for raising or maintaining the temperature of reactants or reaction components. In a preferred embodiment, the heating device is at least one of a heating hood, a steam heater, or an oil heater, particularly a heating hood.

[0062] In yet another embodiment, the system assembly further includes a device for adjusting, measuring, or regulating the temperature of the reaction vessel.

[0063] For the purposes of the present disclosure, a "device for measuring the temperature of the reaction vessel" refers to at least one of a digital thermometer, a thermocouple coupled to a thermostat, or a liquid-filled capillary thermometer, particularly a thermocouple coupled to a thermostat.

[0064] As is known to those skilled in the art, a thermostat is a device that maintains a system at a constant temperature. It typically consists of a bimetallic strip that expands and contracts with temperature changes, thereby disconnecting or making contact with the power supply.

[0065] In a preferred embodiment, the device for measuring the temperature of the reaction vessel is inserted into the heat pocket of the reaction vessel; more preferably, a thermocouple is inserted into the heat pocket of the reaction vessel.

[0066] In one embodiment, the system components further include means for adjusting or regulating the vacuum within the system.

[0067] In a preferred embodiment, the "means for adjusting or regulating the vacuum within the system" is a vacuum pump, as disclosed in the above paragraph.

[0068] In another embodiment, the system components further include means for heating, adjusting, regulating, or maintaining the temperature of the distillation column. In a preferred embodiment, the means for heating, adjusting, regulating, or maintaining the temperature of the distillation column is a heating tape, particularly including hot water or oil circulation.

[0069] In yet another embodiment, the "means for connecting to the distillate collector" is an outlet valve.

[0070] In another embodiment, the "means for regulating and adjusting the heating means for heating the reaction vessel" is a rheostat, commonly referred to as a regulator, lever, controller, button, or knob.

[0071] Further, in a related embodiment, the system components further include means for adjusting or regulating the flow rate of the α-hydroxy acid, particularly during the process of filling the reaction vessel. In a preferred embodiment, the means for adjusting or regulating the flow rate of the α-hydroxy acid is a peristaltic pump.

[0072] Now referring Figure 1 , an exemplary embodiment of the present disclosure relates to a system as described in the previous paragraphs, wherein the system 100 further includes:

[0073] A stirring device 110 for stirring the reaction vessel 101;

[0074] A heating device 111 for heating the reaction vessel 101;

[0075] A device 112 for measuring the temperature of the reaction vessel 101;

[0076] A device 106 for adjusting or regulating the vacuum within the system 100;

[0077] A device 109 for adjusting or regulating the flow rate of the α-hydroxy acid; and

[0078] A device 113 for regulating or maintaining the temperature of the distillation column 102.

[0079] The present disclosure also relates to a process for oligomerizing α-hydroxy acids. As is known to those skilled in the art, α-hydroxy acids are condensed into their oligomeric forms by removing water in one or more steps at atmospheric pressure or reduced pressure until an oligomer composition with an average degree of polymerization (DP) is obtained.

[0080] In one embodiment, the process includes charging a portion of the total α-hydroxy acid into a reaction vessel.

[0081] In another embodiment, the process includes reducing and further maintaining the reduced pressure of the system.

[0082] In yet another embodiment, the process includes heating and maintaining the temperature of the reaction vessel to enable the removal of water from the α-hydroxy acid.

[0083] In a related embodiment, the process includes increasing and further maintaining the increased temperature of a distillation column to evaporate water.

[0084] In one embodiment, the process includes feeding the remaining α-hydroxy acid into the reaction vessel for further oligomerization.

[0085] In another embodiment, the process includes cooling the reaction vessel.

[0086] In yet another embodiment, the process includes releasing the vacuum and removing the oligomer composition from the system.

[0087] Figure 1 Yet another exemplary embodiment of the present disclosure is shown and relates to a process for oligomerizing α-hydroxy acids by the system 100 described above, the process comprising:

[0088] (a) Charging a portion of the total α-hydroxy acid into reaction vessel 101;

[0089] (b) Reducing and further maintaining the reduced pressure of the system 100;

[0090] (c) Heating reaction vessel 101 to the reflux temperature to oligomerize the α-hydroxy acid;

[0091] (d) Maintaining the temperature of distillation column 102 to evaporate water;

[0092] (e) Feeding the remaining α-hydroxy acid into reaction vessel 101 via inlet valve 103 for further oligomerization;

[0093] (f) Maintaining the reflux temperature of reaction vessel 101 to effect oligomerization of the α-hydroxy acid while removing water;

[0094] (g) Cooling reaction vessel 101; and

[0095] (h) Release the vacuum and remove the oligomer composition from the system 100.

[0096] In a related embodiment, the temperature for oligomerization varies between 140 °C and 220 °C, particularly between 160 °C and 200 °C.

[0097] In yet another related embodiment, the temperature of the distillation column 102 is maintained between 30 °C and 120 °C, particularly between 50 °C and 100 °C.

[0098] In one embodiment, the vacuum of the system is maintained between 100 mbar and 760 mbar, particularly between 300 mbar and 600 mbar.

[0099] In another embodiment, after charging the α-hydroxy acid into the reaction vessel, the reaction vessel is continuously heated for 40 minutes to 200 minutes; particularly 60 minutes to 180 minutes.

[0100] The present disclosure also discloses that in one embodiment, a portion of the α-hydroxy acid varies between 1% w / w and 99% w / w of the total α-hydroxy acid, particularly between 10% w / w and 90% w / w.

[0101] In another embodiment, the remaining α-hydroxy acid varies between 40% and 90%, particularly between 60% and 80%.

[0102] In yet another embodiment, the present disclosure discloses that the rate of charging the remaining α-hydroxy acid into the reaction vessel is less than 10% w / w of the reaction mass per minute, particularly less than 5% w / w of the reaction mass per minute.

[0103] In one embodiment, the α-hydroxy acid collected in the distillate collector is less than 5% w / w of the total α-hydroxy acid input, particularly less than 2% w / w of the total input.

[0104] The present disclosure discloses an oligomerization system and process that act synergistically to help maximize the yield of the oligomer composition and minimize the waste of the starting α-hydroxy acid.

[0105] In one embodiment, the oligomerization process is completed within 10 hours, particularly within 5 hours.

[0106] The present disclosure discloses an oligomerization system and process that act synergistically to help reduce the time required for oligomerization and thus reduce the total operating time of the system.

[0107] The present disclosure also discloses that in one embodiment, the molecular weight range of the oligomer is from 400 Da to 2700 Da, preferably from 600 Da to 2500 Da, more preferably from 900 Da to 1200 Da.

[0108] In another embodiment, the oligomer composition comprises oligomers having from 4 to 20 monomer units, preferably from 5 to 15 monomer units.

[0109] In yet another embodiment, the oligomers produced are α-hydroxy acid oligomers, particularly lactic acid oligomers or glycolic acid oligomers or mixed oligomers.

[0110] In one embodiment, the oligomer composition comprises lactic acid oligomers.

[0111] Now referring to Figure 1 , one exemplary embodiment of the present disclosure relates to a system 100 for oligomerizing lactic acid. The system assembly 100 includes: a reaction vessel 101 filled with a portion of all lactic acid, configured to be connected to the proximal end of a distillation column 102; a distillation column 102 configured to receive lactic acid via an inlet valve 103 near its distal end; an inlet valve 103 for feeding the remaining α-hydroxy acid in a controlled mode, configured to be connected to a container 108; the distal end of the distillation column 102 is also configured to be connected to the proximal end of a fractionation head 104; the distal end of the fractionation head 104 is configured to be connected to the proximal end of a condenser 105, while being provided with means for connecting to a distillate collector 107; the distal end of the condenser 105 and the distillate collector 107 are provided with means for connecting to a vacuum pump 106; characterized in that lactic acid is fed into the reaction vessel 101 in batches or continuously via the inlet valve 103.

[0112] Further referring to Figure 1 , one embodiment of the present disclosure relates to a system as described in the previous paragraph, wherein the system 100 further includes:

[0113] a stirring device 110 for stirring the reaction vessel 101;

[0114] a heating device 111 for heating the reaction vessel 101;

[0115] a device 112 for measuring the temperature of the reaction vessel 101;

[0116] a device 106 for adjusting or regulating the vacuum within the system 100;

[0117] a device 109 for adjusting or regulating the lactic acid flow rate; and

[0118] a device 113 for regulating or maintaining the temperature of the distillation column 102.

[0119] Additionally, referring to Figure 1 , one exemplary embodiment of the present disclosure relates to a process for oligomerizing lactic acid in the previously described system 100, the process comprising:

[0120] (a) Charge a part of all the lactic acid into the reaction vessel 101;

[0121] (b) Reduce and further maintain the reduced pressure of the system 100;

[0122] (c) Heat the reaction vessel 101 to the reflux temperature to oligomerize lactic acid;

[0123] (d) Maintain the temperature of the distillation column 102 to evaporate water;

[0124] (e) Feed the remaining lactic acid into the reaction vessel 101 for further oligomerization;

[0125] (f) Maintain the reflux temperature of the reaction vessel 101 to achieve oligomerization of lactic acid while removing water;

[0126] (g) Cool the reaction vessel 101; and

[0127] (h) Release the vacuum and remove the oligomer composition of lactic acid from the system 100.

[0128] Another exemplary embodiment of the present disclosure relates to a system and process for oligomerizing lactic acid. The process includes: charging a part of the total lactic acid solution into a three-neck round-bottom flask; attaching a thermocouple to one side neck to measure the temperature, attaching a distillation column filled with steel gauze to the other side neck, and connecting an overhead stirrer to the central neck for continuous stirring, such that the temperature of the packed column is maintained at about 55 °C to 60 °C to avoid lactic acid loss; attaching a fractionating head to the column to maintain an ideal reflux ratio, and connecting a water condenser at the top of the column to avoid lactic acid loss; maintaining the system at a vacuum pressure of about 500 mbar throughout the process; stirring at a speed of about 400 revolutions per minute; gradually raising the temperature of the reaction vessel to about 40 °C to 50 °C, and distilling off free water; then raising the temperature to about 170 °C and keeping it constant for the first hour; subsequently feeding the remaining part of lactic acid at a rate of about 0.78 L / h to 1.0 L / h through a feed valve installed near the top of the column using a peristaltic pump; and maintaining the vessel at about 170 °C for about 3 hours with continuous stirring to obtain the desired oligomer molecular weight and composition, thereby adding lactic acid in batches; maintaining the system such that only lactic acid flows into the stirred tank reactor while free water evaporates and is collected as distillate. The heated column with structured packing helps to separate lactic acid and water vapor, thereby reducing lactic acid loss in the distillate.

[0129] In a related embodiment, the molecular weight range of the lactic acid oligomer is from 900 Da to 1500 Da.

[0130] In a preferred embodiment, the oligomer composition comprises lactic acid oligomers, in particular, wherein the molecular weight range of the lactic acid oligomers is from 900 Da to 1200 Da.

[0131] In another embodiment, the oligomer composition comprises glycolic acid oligomers.

[0132] In addition, in one embodiment, the process disclosed above is a batch process.

[0133] Optionally, in another embodiment, the process disclosed above is a continuous process.

[0134] Further optionally, in yet another embodiment, the process disclosed above is a fed-batch process.

[0135] Various modifications to the embodiments will be apparent to those skilled in the art, and the general principles herein can be applied to other embodiments. However, those of ordinary skill in the art will readily recognize that the present disclosure is not intended to be limited to the embodiments shown, but rather should be accorded the widest scope consistent with the principles and features described herein.

[0136] The foregoing description should be construed as illustrative and not in any limiting sense. Those of ordinary skill in the art will understand that certain modifications may fall within the scope of the present disclosure.

[0137] The features and properties of the present disclosure will be described in further detail below with reference to examples.

[0138] Example 1

[0139] Oligomerization process without batch addition of lactic acid

[0140] For this experiment, about 300 grams of lactic acid (purity measured by determination was about 87%, and purity measured by HPLC was about 63%) was charged into a three-necked round-bottom flask. A thermocouple was attached to one side neck to measure the temperature, a distillation column (about 25 mm in diameter and about 0.5 feet in height) filled with steel gauze was attached to another neck, and an overhead stirrer was connected to the central neck for continuous stirring.

[0141] Further, a fractionating head was attached to the column to maintain the reflux ratio, and a water condenser was attached to the top of the column to avoid loss of water or lactic acid. The vacuum of the system was always maintained at about 500 mbar using a vacuum controller. Stirring was maintained at about 400 revolutions per minute using the overhead stirrer. The temperature of the reaction vessel was gradually increased. Water was distilled off at about 40 °C to 50 °C, after which the temperature was raised to 170 °C and maintained at about 170 °C for about 3 hours. The distillate was collected during this process. The following results were obtained at the end of this process (see Table 1):

[0142] Table 1

[0143]

[0144]

[0145] In this study, the oligomerization process carried out without continuous addition of lactic acid over approximately 7 hours produced lactic acid oligomers with molecular weights ranging from 900 Da to 1200 Da, and the concentration of lactic acid in the remaining distillate was 6 - 8%.

[0146] Example 2

[0147] Study on the oligomerization process without batch addition of lactic acid: Study on the development of oligomer molecular weight over reaction time

[0148] To study the development of molecular weight over time in the oligomerization process without continuous addition of lactic acid, the experiment described in Example 1 was repeated, and the following results were determined.

[0149] Table 2 includes comprehensive information on the development of molecular weight over time during the oligomerization process (without continuous addition of lactic acid).

[0150] Table 2

[0151]

[0152] From Figure 2 it can be seen that the above process produced lactic acid oligomers with a molecular weight of approximately 2151 Da in about 450 minutes, and approximately 0.18% of lactic acid remained in the reaction flask.

[0153] Example 3

[0154] Oligomerization process with batch addition of lactic acid

[0155] For this experiment, approximately 300 grams of lactic acid (with a measured purity of approximately 87% by assay and 63% by HPLC) was charged into a three - necked round - bottom flask.

[0156] A thermocouple was attached to one side neck to measure the temperature, a distillation column filled with structured wire mesh packing (with a diameter of approximately 25 mm and a height of approximately 0.5 feet) was attached to the other side neck, and an overhead stirrer was connected to the central neck for continuous stirring. The temperature of the packed column was maintained at approximately 60 °C to avoid loss of lactic acid.

[0157] Furthermore, a fractionating head was attached to the column to maintain the reflux ratio, and a water condenser was attached to the top of the column to avoid loss of water or lactic acid. The vacuum of the system was maintained at approximately 500 mbar throughout the process. Stirring was maintained at approximately 400 revolutions per minute with the overhead stirrer. The temperature of the reaction flask was gradually increased. Then, free water was distilled off at a temperature of approximately 40 °C to 50 °C.

[0158] After about 35 minutes, the temperature of the reaction flask increased to about 170 °C. During the first 1 hour, the temperature was maintained at about 170 °C.

[0159] After maintaining this temperature for about 1 hour, the remaining portion of lactic acid (about 1000 grams) was fed at a flow rate of about 15 mL / min (0.780 L / h to 1 L / h) through a feed valve installed near the top of the column. This flow rate, along with the maintained column temperature, helped to avoid loss of lactic acid and maintain the temperature of the reaction flask after stirring. This helped to complete the oligomerization within 5 hours. A higher flow rate would reduce the reaction temperature in the bottom flask of the system, resulting in an extended oligomerization time, while a lower flow rate would cause loss of lactic acid in the distillate. It should be noted that during the feeding of lactic acid, most of the free water was distilled out without loss of lactic acid. A skilled person can adjust the flow rate of adding the remaining portion of lactic acid and also further vary the temperature of the structured column such that the free monomeric lactic acid refluxes to the bottom of the system without distilling out from the top of the column.

[0160] After completion of feeding, the reaction vessel was maintained at about 170 °C and continuously stirred for about 3 hours to obtain the desired molecular weight and composition of the oligomer.

[0161] As Figure 3(A) and 3(B) shown, the desired oligomers with a molecular weight of about 900 Da to 1200 Da and a lactic acid content of less than 2% were obtained. Further, the loss of lactic acid in the distillate was observed to be only about 2% w / w to 5% w / w of the input / starting lactic acid.

[0162] Table 3 shows the approximate / average results of two batches of oligomerization involving batch addition of lactic acid.

[0163] Table 3 Properties of Lactic Acid Oligomers

[0164]

[0165] Example 4

[0166] Study of the Oligomerization Process with Batch Addition of Lactic Acid: Tracking the Development / Formation of Oligomer Molecular Weight over Reaction Time

[0167] To study the development of molecular weight over time during the oligomerization process with continuous addition of lactic acid, the experiment described in Example 3 was repeated and the following results were determined.

[0168] Table 4 gives comprehensive information on the development of molecular weight over time during the oligomerization process with batch addition of lactic acid.

[0169] Table 4: Properties of Lactic Acid Oligomers

[0170]

[0171] Example 5

[0172] Oligomerization process of glycolic acid

[0173] For this experiment, a three-necked round-bottom flask was charged with approximately 300 grams of glycolic acid (purity measured to be 70% by assay).

[0174] A thermocouple was attached to one neck to measure the temperature, a distillation column (approximately 50 mm in diameter and 800 mm in height) filled with steel gauze packing was attached to the other neck, and an overhead stirrer was connected to the central neck for continuous stirring. The temperature of the packed column was maintained at approximately 60 °C to avoid loss of glycolic acid. Further, a fractionating head was attached to the column to maintain reflux, and a water condenser was attached to the top of the column to avoid loss of water or glycolic acid. Throughout the process, the vacuum of the system was maintained at approximately 500 mbar. Stirring was maintained at approximately 400 revolutions per minute with the overhead stirrer. The temperature was gradually increased.

[0175] After 35 minutes, the temperature reached approximately 170 °C. For the first 1 hour, the temperature was maintained at approximately 170 °C.

[0176] After maintaining this temperature for approximately 1 hour, continuous feeding of glycolic acid (1000 grams) was started at a flow rate of approximately 15 mL / min through a feed valve installed near the top of the column. It should be noted that during the continuous feeding of glycolic acid, free water was distilled out without loss of glycolic acid.

[0177] After completion of feeding, the reaction vessel was maintained at approximately 170 °C with continuous stirring for approximately 5 hours to obtain the desired oligomer molecular weight and composition.

[0178] The desired oligomers with a molecular weight of approximately 900 Da to 1200 Da were obtained in a yield of approximately 70% to 85%.

[0179] Table 5 shows the results of the oligomerization of glycolic acid involving batch addition.

[0180] Properties of the glycolic acid oligomers obtained in Table 5

[0181]

[0182] *The molecular weight of the glycolic acid oligomers was determined by H 1 NMR (nuclear magnetic resonance).

[0183] Any of the foregoing paragraphs or the examples, illustrations, and alternatives of the specification and drawings, including any of their aspects or individual features, may be employed independently or in any combination. Features described in connection with one embodiment apply to all embodiments unless the features are incompatible.

[0184] Preferred embodiments of the present disclosure have been described in detail above. It should be understood that, without creative efforts, those skilled in the art can make many modifications and variations based on the concepts of the present disclosure. Therefore, all technical solutions that can be obtained by those skilled in the art based on the concepts of the present disclosure through logical analysis, reasoning, or limited experiments on the basis of the prior art should fall within the protection scope determined by the claims.

Claims

1. A system 100 for oligomerizing α-hydroxy acids, the system components 100 comprising: A reaction vessel 101 filled with a portion of all the α-hydroxy acids, configured to be connected to the proximal end of a distillation column 102; The distillation column 102, configured to receive α-hydroxy acids via an inlet valve 103 near its distal end; The inlet valve 103 for feeding the remaining α-hydroxy acids in a controlled mode, configured to be connected to a container 108; The distal end of the distillation column 102 is also configured to be connected to the proximal end of a fractionation head 104; The distal end of the fractionation head 104 is configured to be connected to the proximal end of a condenser 105, while being provided with means for connecting to a distillate collector 107; The distal end of the condenser 105 and the distillate collector 107 are provided with means for connecting to a vacuum pump 106; Characterized in that: The α-hydroxy acids are fed batchwise into the reaction vessel 101 via the inlet valve 103.

2. The system according to claim 1, wherein, The α-hydroxy acids are fed batchwise or continuously in a controlled mode into the reaction vessel 101 via the inlet valve 103 located near the distal end of the distillation column 102.

3. The system according to claim 1, wherein The system 100 further comprises: A stirring device 110 for stirring the reaction vessel 101; A heating device 111 for heating the reaction vessel 101; A device 112 for measuring the temperature of the reaction vessel 101; A device 106 for adjusting or regulating the vacuum within the system 100; A device 109 for adjusting or regulating the flow rate of the α-hydroxy acids; and A device 113 for regulating or maintaining the temperature of the distillation column 102.

4. A process for oligomerizing α-hydroxy acids by the system 100 according to claim 1, the process comprising: (a) Loading a portion of all the α-hydroxy acids into the reaction vessel 101; (b) Reducing and further maintaining the reduced pressure of the system 100; (c) Heating the reaction vessel 101 to the reflux temperature to oligomerize the α-hydroxy acids; (d) Maintaining the temperature of the distillation column 102 to evaporate water; (e) Feeding the remaining α-hydroxy acids into the reaction vessel 101 via the inlet valve 103 for further oligomerization; (f) Maintaining the reflux temperature of the reaction vessel 101 to effect oligomerization of the α-hydroxy acids while removing water; (g) Cooling the reaction vessel 101; and (h) Releasing the vacuum and removing the oligomer composition from the system 100.

5. The process according to claim 4, wherein In step (c), the reflux temperature for oligomerization varies between 160 °C and 200 °C.

6. The process according to claim 4, wherein, In step (d), the temperature of the distillation column 102 is maintained between 50 °C and 100 °C.

7. The process according to claim 4, wherein, The distillation column 102 comprises packing with a theoretical plate number range of 5 to 15.

8. The process according to claim 4, wherein The vacuum of the system 100 is maintained between 300 mbar and 600 mbar.

9. The process according to claim 4, wherein, After loading all the α-hydroxy acids into the reaction vessel 101, the reaction vessel 101 is continuously heated for 60 minutes to 180 minutes.

10. The process according to claim 4, wherein, A portion of all the α-hydroxy acids varies between 10% w / w and 90% w / w of all the α-hydroxy acids.

11. The process according to claim 4, wherein, The boiling point range of the α-hydroxy acid is from 100 °C to 150 °C.

12. The process according to claim 4, wherein The remaining α-hydroxy acid varies between 60% and 80%.

13. The process according to claim 4, wherein, The rate of loading the remaining α-hydroxy acid into the reaction vessel is less than 5% w / w of the reaction mass per minute.

14. The process according to claim 4, wherein, The α-hydroxy acid collected in the distillate collector 107 is less than 2% w / w of the total input amount of the α-hydroxy acid.

15. The process according to claim 4, wherein, The oligomerization process is completed within 5 hours.

16. The process according to claim 4, wherein The molecular weight range of the oligomer is from 600 Da to 2500 Da.

17. The claim according to claims 1 and 4, wherein, The monomeric α-hydroxy acid is selected from lactic acid and glycolic acid.

18. The claim according to claim 17, wherein, The α-hydroxy acid is the lactic acid.

19. The claim according to claim 17, wherein, The α-hydroxy acid is the glycolic acid.

20. The claim according to claim 4, wherein, The oligomer composition comprises oligomers having 5 to 15 monomer units.

21. The claim according to claim 20, wherein, The oligomer composition comprises the lactic acid oligomer.

22. The claim according to claim 21, wherein, The molecular weight range of the lactic acid oligomer is from 900 Da to 1200 Da.

23. The claim according to claim 20, wherein, The oligomer composition comprises the glycolic acid oligomer.

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