Method for separating mixture of lactide and glycolide

Abstract

The invention relates to a method for separating a mixture comprising lactide (s) and glycolide, comprising the following steps: a) providing a mixture comprising lactide (s) and glycolide, the mixture being provided in the molten state, b) determining the crystallization point of the mixture, and c) separating the mixture comprising lactide (s) and glycolide, c) determining the required amount of lactide or glycolide to be recovered from the mixture, d) selecting a suitable crystallization temperature (Tc) on the basis of the required amount of lactide or glycolide to be recovered determined in step c), e) subjecting the mixture to melt crystallization at the temperature Tc, thereby obtaining a mother liquor and a crystallized product, wherein the crystalline product comprises crystalline lactide or crystalline glycolide, and f) recovering the crystalline product. The process of the present invention may comprise additional steps for further purifying the recovered crystalline product and / or increasing the amount of recovered crystalline product.

Description

Technical Field

[0001] The present invention relates to a method for separating a mixture of lactide (plurality of lactides) and glycolide. More particularly, the present invention relates to a method for recovering lactide or glycolide from a mixture of lactide (plurality of lactides) and glycolide by melt crystallization at a suitable crystallization temperature, wherein the crystallization temperature is determined according to the crystallization point of the mixture. Background Art

[0002] Blends of lactide and glycolide have gained commercial significance due to the emergence of PLGA copolymers in the market. Over the past two decades, poly(lactic-co-glycolic acid) or PLGA copolymers have indeed been one of the most attractive polymer candidates for the manufacture of devices for drug delivery and tissue engineering applications. PLGA is biocompatible and biodegradable with a wide range of erosion times and tunable mechanical properties. In particular, PLGA has been extensively studied for the development of devices for the controlled delivery of small molecule drugs, proteins and other macromolecules for both commercial use and research. PLGA copolymers also offer exciting opportunities for technical grade polyesters due to their faster degradation at lower composting temperatures and better barrier properties compared to, for example, polylactic acid (PLA).

[0003] PLGA is a copolymer of lactic acid and glycolic acid. PLGA is usually synthesized by ring-opening copolymerization of two different monomers, which are cyclic dimers of glycolic acid and lactic acid, glycolide (i.e., 1,4-dioxane-2,5-dione) and lactide (3,6-dimethyl-1,4-dioxane-2,5-dione), respectively. The polymers can be synthesized as random copolymers or block copolymers, thereby imparting additional polymer properties. During the polymerization process, consecutive monomer units (of glycolic acid or lactic acid) are linked together in PLGA by ester bonds, resulting in linear aliphatic polyesters as the product. Other topologies are possible if desired, which then require the use of multifunctional initiators (for star shapes) or branching agents such as bicyclic molecules, (poly)epoxides, or free radical chemistry.

[0004] In order to obtain lactide and glycolide, for example, for the preparation of PLGA, the art has proposed to synthesize or recycle lactide or glycolide from its respective acid or polymer separately. For example, EP 2 559725A1 reports the separate recovery of lactide from lactic acid or recovered PLA, or the separate recovery of glycolide from glycolic acid or recovered PGA. The disclosed method for recovering lactide from polylactic acid (PLA) or recovering glycolide from polyglycolic acid (PGA) comprises a first step, wherein PLA or PGA is contacted with a hydrolysis medium and hydrolyzed and degraded into oligomers. In a further step, the oligomer obtained in the first step is cyclized and depolymerized into lactide or glycolide.

[0005] However, in the prior art, mixtures of lactide and glycolide may also be significantly available, for example as byproducts or product solutions obtained during the polymerization of PLA, PGA or PLGA. Such mixtures provide suitable but hitherto unexplored starting materials for obtaining lactide and / or glycolide. Summary of the invention

[0006] The present invention aims to provide a method for recovering lactide or glycolide from a mixture comprising lactide (multiple lactides) and glycolide. One object of the present invention is to provide a method for separating a mixture, which can be applied to any mixture of lactide (multiple lactides) and glycolide, i.e., to mixtures from various sources.

[0007] In one aspect, a method for separating a mixture comprising lactide(s) and glycolide is provided, wherein the method comprises the following steps:

[0008] a) providing a mixture comprising lactide(s) and glycolide, wherein the mixture is provided in a molten state, and preferably, the total combined amount of lactide(s) and glycolide in the mixture is at least 70.0 wt %, based on the total weight of the mixture,

[0009] b) determining the crystallization point of the mixture,

[0010] c) determining the desired amount of lactide or glycolide to be recovered from the mixture,

[0011] d) selecting a suitable crystallization temperature (T) based on the desired amount of lactide or glycolide to be recovered determined in step c) c ),

[0012] e) heating the mixture at the temperature T c to obtain a mother solution and a crystallized product, wherein the crystallized product comprises crystallized lactide or crystallized glycolide, and

[0013] f) recovering the crystalline product.

[0014] In a preferred embodiment of the method of the present invention, the total combined amount of lactide (plurality of lactides) and glycolide in the mixture is at least 75.0 wt%, or at least 80.0 wt%, or at least 85.0 wt%, or at least 90.0 wt%, or at least 95.0 wt%, based on the total weight of the mixture.

[0015] In certain preferred embodiments of the method of the present invention, the crystallization point of the mixture is determined by constructing a phase diagram of glycolide and lactide (said lactide being the major lactide in said mixture).

[0016] In certain preferred embodiments of the method of the present invention, the crystallization temperature (T c ) is in the range of 30°C to 95°C, or 50°C to 95°C, or 50°C to 80°C, or 60°C to 90°C.

[0017] In certain embodiments of the process of the present invention, it is preferred that the crystallized product recovered in step f) is melted into a molten product and the molten product is provided as a new mixture in step a) of the separation process of the present invention, thereby recovering a purified crystallized product and a new mother liquor from the recovered crystallized product, thereby further purifying the crystallized product.

[0018] Alternatively or additionally, in certain embodiments of the process of the present invention, the mother liquor obtained in step e) is provided as a new mixture in step a) of the separation process of the present invention, thereby recovering an additional amount of crystallized product and a new mother liquor.

[0019] According to certain embodiments of the present method, at least 50%, or at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90% of the amount of lactide or glycolide contained in the (initial) mixture is recovered as a crystalline product.

[0020] In certain embodiments of the method, melt crystallization comprises

[0021] - at least one layer crystallization, and preferably, the layer crystallization comprises at least one falling film crystallization and / or at least one static crystallization, and / or

[0022] - At least one suspension crystallization.

[0023] The crystalline product obtained by practicing the method of the present invention and the optional purified crystalline product can be recovered by filtration, centrifugation or other solid-liquid separation means or any combination thereof.

[0024] In certain embodiments, the present invention provides a method for separating lactide from a mixture of lactide (plurality of lactides) and glycolide. To this end, the present invention provides a method for separating lactide from a mixture comprising lactide (plurality of lactides) and glycolide, wherein the method comprises the following steps:

[0025] a) providing a mixture comprising lactide(s) and glycolide, wherein the mixture is provided in a molten state, and preferably, the total combined amount of lactide(s) and glycolide in the mixture is at least 70.0 wt %, based on the total weight of the mixture,

[0026] b) determining the crystallization point of the mixture,

[0027] c) determining the desired amount of lactide to be recovered from said mixture,

[0028] d) selecting a suitable crystallization temperature (T) based on the desired amount of lactide to be recovered determined in step c) c ),

[0029] e) heating the mixture at the temperature T c The melt crystallization is carried out at a temperature of preferably c ) between 30°C and 95°C, or between 50°C and 95°C, or between 60°C and 90°C, thereby obtaining a mother liquor and crystallized lactide; and

[0030] f) recovering the crystallized lactide,

[0031] g) Optionally, the crystallized lactide is further purified by melting the crystallized lactide recovered in step f) into a molten product and providing the molten product as a new mixture in step a), thereby recovering purified crystallized lactide and a new mother liquor from the recovered crystallized lactide.

[0032] h) Optionally, in step a) the mother liquor obtained in any of the previous steps is provided as a new mixture, thereby recovering an additional amount of crystallized lactide and a new mother liquor.

[0033] In certain embodiments of the method of the present invention, the amount of glycolide contained in the crystallized lactide (in wt%) is less than 0.5 times, for example less than 0.2 times, the amount of glycolide (in wt%) in the initial mixture. In certain embodiments of the method, the purification factor of glycolide in the crystallized lactide is in the range of 2 to 20.

[0034] In certain other embodiments, the present invention provides a method for separating glycolide from a mixture of lactide (plurality of lactides) and glycolide. To this end, the present invention provides a method for separating glycolide from a mixture comprising lactide (plurality of lactides) and glycolide, wherein the method comprises the following steps:

[0035] a) providing a mixture comprising lactide(s) and glycolide, wherein the mixture is provided in a molten state, and preferably, the total combined amount of lactide(s) and glycolide in the mixture is at least 70.0 wt %, based on the total weight of the mixture,

[0036] b) determining the crystallization point of the mixture,

[0037] c) determining the desired amount of glycolide to be recovered from said mixture,

[0038] d) selecting a suitable crystallization temperature (T) based on the desired amount of glycolide to be recovered determined in step c) c ),

[0039] e) heating the mixture at the temperature T c The melt crystallization is carried out at a temperature of preferably c ) between 50° C. and 80° C., for example, between 60° C. and 80° C., thereby obtaining a mother liquor and crystallized glycolide containing glycolide crystals; and

[0040] f) recovering the crystallized glycolide,

[0041] g) Optionally, the crystallized glycolide is further purified by melting the crystallized glycolide recovered in step f) into a molten product and providing the molten product as a new mixture in step a), thereby recovering purified crystallized glycolide and a new mother liquor from the recovered crystallized glycolide.

[0042] h) Optionally, in step a) the mother liquor obtained in any of the previous steps is provided as a new mixture, thereby recovering an additional amount of crystallized glycolide and a new mother liquor.

[0043] In certain embodiments of the present method, the crystallized glycolide comprises an amount of lactide (multiple lactides) (in wt%) less than 0.5 times, for example less than 0.2 times, of the amount of lactide (multiple lactides) (in wt%) in the initial mixture. In certain embodiments of the present method, the purification factor of the lactide of the crystallized glycolide is in the range of 2 to 20.

[0044] The present method can obtain a separate glycolide or lactide, such as L-lactide, from a mixture containing these components. Preferably, such mixtures are characterized in that they contain glycolide and (mainly) lactide (e.g., L-lactide); and these components exhibit a phase equilibrium relationship that defines a liquid-solid phase compartment represented by a phase diagram projection, in which lactide (e.g., L-lactide) and glycolide can be crystallized separately. The composition of the product stream is selected so that a substantially pure lactide stream (e.g., L-lactide stream) or a substantially pure glycolide stream is formed by melt crystallization. The advantage of the present method is that the number of processing steps is limited, thereby reducing capital and energy costs, and providing a simple and efficient method for recovering lactide or glycolide.

[0045] The present invention can be used to separate any mixture comprising lactide and glycolide. In other words, the mixture of lactide (plurality of lactides) and glycolide used in the method of the present invention can come from any source, for example, can be obtained as by-product, side stream or impurity from different production processes, for example, in the process for producing lactide, glycolide, PLA, PGA and PLGA.

[0046] In certain embodiments of the method of the present invention, the mixture comprising lactide (plurality of lactides) and glycolide provided in step a) is obtained as a by-product in a method for preparing poly(lactic acid)-co-glycolic acid (PLGA) by ring-opening copolymerization of lactide (plurality of lactides) and glycolide.

[0047] In certain other embodiments of the method of the present invention, the mixture comprising lactide(s) and glycolide provided in step a) is obtained by thermal depolymerization of PLGA.

[0048] In certain other embodiments of the method of the present invention, the mixture comprising lactide(s) and glycolide provided in step a) is prepared from a mixture comprising lactic acid and glycolic acid, and is preferably prepared by the following steps:

[0049] a1) providing a mixture comprising lactic acid and glycolic acid;

[0050] a2) polycondensing the mixture comprising lactic acid and glycolic acid under conditions effective to form lactic acid / glycolic acid co-oligomers; and

[0051] a3) depolymerizing the lactic acid / glycolic acid co-oligomers formed in step a2) to form a mixture comprising lactide(s) and glycolide.

[0052] Lactic acid and glycolic acid and mixtures thereof can be obtained as described herein.

[0053] Independent and dependent claims set out particular and preferred features of the invention. Features of dependent claims may, where appropriate, be combined with features of the independent claim or other dependent claims.

[0054] The present invention will now be further described. In the following paragraphs, different aspects of the present invention are defined in more detail. Unless otherwise clearly indicated to the contrary, each aspect so defined can be combined with any other one or more aspects. In particular, any feature indicated as being preferred or advantageous can be combined with any other feature or features indicated as being preferred or advantageous. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 The phase diagram of L-lactide and glycolide determined according to Example 1 is shown.

[0056] Figure 2 The phase diagram of racemic lactide and glycolide determined according to Example 2 is shown.

[0057] Figure 3 The phase diagram of meso-lactide and glycolide determined according to Example 3 is shown. DETAILED DESCRIPTION

[0058] In describing the present invention, the terms used should be interpreted in accordance with the following definitions, unless the context requires otherwise.

[0059] Unless otherwise defined, all terms, including technical and scientific terms, used in disclosing the present invention have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs. As further guidance, term definitions are included to better understand the teachings of the present invention.

[0060] In the following paragraphs, different aspects of the present invention are defined in more detail. Unless otherwise clearly stated to the contrary, each aspect so defined may be combined with any other one or more aspects. In particular, any feature indicated as being preferred or advantageous may be combined with any other one or more features indicated as being preferred or advantageous.

[0061] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in conjunction with that embodiment is included in at least one embodiment of the present invention. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing throughout this specification do not necessarily all refer to the same embodiment, but may refer to the same embodiment. In addition, in one or more embodiments, as will be apparent to those skilled in the art in light of this disclosure, particular features, structures, or characteristics may be combined in any suitable manner. Furthermore, although some embodiments described herein include other features that are not included in other embodiments, the combination of features of different embodiments is intended to fall within the scope of the present invention and to form different embodiments, as will be understood by those skilled in the art.

[0062] As used herein, the terms "comprising," "comprises," and "comprised of" are synonymous with "including," "includes," or "containing," "contains," and are inclusive or open-ended and do not exclude additional, unrecited members, elements, or method steps. It should be understood that the terms "comprising," "comprisies," and "comprised of" as used herein include the terms "consisting of," "consists," and "consists of."

[0063] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, "a step" means one step or more than one step.

[0064] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0065] Numerical ranges expressed by endpoints include all integers and, where appropriate, fractions within the range (e.g., when referring to, for example, multiple elements, 1 to 5 may include 1, 2, 3, 4, and when referring to, for example, measured values, 1.5, 2, 2.75, and 3.80 may also be included). The expression of endpoints also includes the endpoint values ​​themselves (e.g., 1.0 to 5.0 includes 1.0 and 5.0). Any numerical range described herein is intended to include all subranges contained therein.

[0066] When referring to a measurable value (e.g., a parameter, an amount, a time interval, etc.), the term "about" as used herein is intended to encompass variations of ±10% or less, preferably ±5% or less, more preferably ±1% or less of the specified value, as long as such variations are suitable for implementation in the disclosed invention. It should be understood that the value referred to by the modifier "about" itself is also specifically and preferably disclosed.

[0067] The terms "wt %", "vol %" or "mol %" refer to the weight percent of a component, the volume percent of a component or the mole percent of a component, respectively, based on the total weight, total volume or total moles of material including the component.

[0068] When describing the present invention, the terms used should be interpreted in accordance with the following definitions, unless the context dictates otherwise.

[0069] Preferred statements (features), embodiments and uses of the present invention are set forth below. Unless there is a clear contrary statement, each statement and embodiment of the present invention so defined can be combined with any other statement and / or embodiment. In particular, any feature indicated as preferred or advantageous can be combined with any other one or more features or statements indicated as preferred or advantageous. To this end, the present invention is particularly realized by any one or any combination of one or more of the following numbered statements and embodiments and any other aspects and / or embodiments.

[0070] 1. A method for separating a mixture comprising lactide(s) and glycolide, wherein the method comprises the following steps:

[0071] a) providing a mixture comprising lactide(s) and glycolide, wherein the mixture is provided in a molten state, and preferably, wherein the total combined amount of lactide(s) and glycolide in the mixture is at least 70.0 wt %, based on the total weight of the mixture,

[0072] b) determining the crystallization point of the mixture,

[0073] c) determining the desired amount of lactide or glycolide to be recovered from the mixture,

[0074] d) selecting a suitable crystallization temperature (T) based on the desired amount of lactide or glycolide to be recovered determined in step c) c ),

[0075] e) heating the mixture at the temperature T c to obtain a mother solution and a crystallized product, wherein the crystallized product comprises crystallized lactide or crystallized glycolide, and

[0076] f) recovering the crystalline product.

[0077] 2. A method according to statement 1, wherein the total combined amount of lactide (multiple lactides) and glycolide in the mixture is at least 70.0 wt% based on the total weight of the mixture, for example, at least 75.0 wt%, or at least 80.0 wt%, or at least 85.0 wt%, or at least 90.0 wt%, or at least 95.0 wt% based on the total weight of the mixture.

[0078] 3. The method according to any of the preceding statements, wherein the lactide is selected from the group consisting of L-lactide, D-lactide, meso-lactide and any mixture thereof (including racemic lactide).

[0079] 4. A method according to any of the preceding statements, comprising the step of determining the main lactide in the mixture.

[0080] 5. The method according to any of the preceding statements, wherein the major lactide in the mixture is L-lactide, D-lactide, meso-lactide or racemic-lactide.

[0081] 6. The method according to any of the preceding statements, wherein the crystallization point of the mixture is determined by establishing a phase diagram of glycolide and predominantly lactide in the mixture.

[0082] 7. A method according to any of the preceding statements, wherein the phase diagram selected in step c) is a eutectic phase diagram established for the main lactide and glycolide in the mixture, and is preferably established by preparing a series of mixtures consisting of defined amounts of the main lactide and glycolide; and determining the crystallization points of the mixtures.

[0083] 8. A method according to any one of the preceding statements, wherein the crystallization temperature (T c ) is in the range of 30°C to 95°C, or 50°C to 95°C, or 50°C to 80°C, or 60°C to 90°C.

[0084] 9. The method according to any one of the preceding statements, comprising step g) of further purifying the crystallized product by melting the crystallized product recovered in step f) into a molten product and providing the molten product as a new mixture in step a) of the separation method according to any one of the preceding statements, thereby recovering a purified crystallized product and a new mother liquor from the recovered crystallized product.

[0085] 10. The method according to any of the preceding statements, wherein the method of statement 9 is repeated at most 10 times, preferably at most 5 times, more preferably at most 3 times.

[0086] 11. A process according to any of the preceding statements, comprising step h) of providing the mother liquor obtained in step e) as a new mixture in step a) of the separation process according to any of the preceding statements, thereby recovering an additional amount of crystallized product and a new mother liquor.

[0087] 12. The process according to any of the preceding statements, wherein the process of statement 11 is repeated until a desired total yield of crystalline product is achieved.

[0088] 13. A process according to any of the preceding statements, wherein at least 50%, or at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90% of the amount of lactide or glycolide contained in the mixture is recovered as a crystalline product.

[0089] 14. The method according to any of the preceding statements, wherein the melt crystallization comprises at least one layer crystallization, and preferably the layer crystallization comprises at least one falling film crystallization and / or at least one static crystallization.

[0090] 15. The method according to any of the preceding statements, wherein the melt crystallization comprises at least one suspension crystallization.

[0091] 16. A process according to any of the preceding statements, wherein the crystallized product and optionally purified crystallized product is recovered by filtration, centrifugation or other solid-liquid separation means or any combination thereof.

[0092] 17. A process according to any one of the preceding statements 1 to 16, wherein lactide is separated from a mixture comprising lactide(s) and glycolide, and wherein the process comprises the steps of:

[0093] a) providing a mixture comprising lactide(s) and glycolide, wherein the mixture is provided in a molten state,

[0094] b) determining the crystallization point of the mixture,

[0095] c) determining the desired amount of lactide to be recovered from said mixture,

[0096] d) selecting a suitable crystallization temperature (T) based on the desired amount of lactide to be recovered determined in step c) c ),

[0097] e) heating the mixture at the temperature T c The melt crystallization is carried out at a temperature of preferably c ) between 30°C and 95°C, or between 50°C and 95°C, or between 60°C and 90°C, thereby obtaining a mother liquor and a crystalline product; and

[0098] f) recovering the crystallized lactide.

[0099] 18. A method according to any of the preceding statements, wherein the total combined amount of lactide (plurality of lactides) and glycolide in the mixture is at least 70.0 wt%, based on the total weight of the mixture, for example, at least 75.0 wt%, or at least 80.0 wt%, or at least 85.0 wt%, or at least 90.0 wt%, or at least 95.0 wt%, based on the total weight of the mixture.

[0100] 19. The method according to any of the preceding statements, wherein the lactide is selected from the group consisting of L-lactide, D-lactide, meso-lactide, and any mixture thereof (including racemic lactide).

[0101] 20. A method according to any one of the statements, wherein the crystallization temperature (T c ) is between 30°C and 95°C, or between 50°C and 95°C, or between 60°C and 90°C.

[0102] 21. A method according to any one of the statements, comprising step g) of further purifying the crystallized lactide by melting the crystallized lactide recovered in step f) into a molten product and providing the molten product as a new mixture in step a), thereby recovering purified crystallized lactide and a new mother liquor from the recovered crystallized lactide.

[0103] 22. The method according to any of the preceding statements, wherein the method of statement 21 is repeated at most 10 times, preferably at most 5 times, more preferably at most 3 times.

[0104] 23. The process according to any of the preceding statements, comprising a step h) of providing in step a) the mother liquor obtained in any of the preceding steps as a new mixture, thereby recovering an additional amount (additional yield) of crystallized lactide and a new mother liquor.

[0105] 24. A process according to any one of the preceding statements, wherein the process of statement 23 is repeated until a desired total amount of crystallized lactide (total yield) is reached.

[0106] 25. A process according to any of the preceding statements, wherein at least 50%, or at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90% of the amount of lactide contained in the mixture is recovered as crystallized lactide.

[0107] 26. The process according to any of the preceding statements, wherein the recovered crystallized lactide comprises less than 1.0 wt%, preferably less than 0.5 wt%, of glycolide, based on the total weight of the crystallized lactide.

[0108] 27. A process according to any of the preceding statements, wherein the recovered crystallized lactide comprises an amount of glycolide (in wt %) which is less than 0.5 times, for example less than 0.2 times, the amount of glycolide (in wt %) in the mixture.

[0109] 28. The process according to any of the preceding statements, wherein the purification factor of the recovered crystallized lactide and glycolide is in the range of 2 to 20.

[0110] 29. A process according to any one of statements 1 to 16, wherein glycolide is separated from a mixture comprising lactide(s) and glycolide, wherein the process comprises the steps of:

[0111] a) providing a mixture comprising lactide(s) and glycolide, wherein the mixture is provided in a molten state,

[0112] b) determining the crystallization point of the mixture,

[0113] c) determining the desired amount of glycolide to be recovered from said mixture,

[0114] d) selecting a suitable crystallization temperature (Tc) based on the desired amount of glycolide to be recovered determined in step c),

[0115] e) subjecting the mixture to melt crystallization at the temperature Tc, preferably the crystallization temperature (Tc) is between 50°C and 80°C, such as between 60°C and 80°C, thereby obtaining a mother liquor and crystallized glycolide containing glycolide crystals; and

[0116] f) recovering the crystallized glycolide.

[0117] 30. A method according to any one of statements 1 to 16 and 29, wherein the total combined amount of lactide (plurality of lactides) and glycolide in the mixture is at least 70.0 wt% based on the total weight of the mixture, for example, at least 75.0 wt%, or at least 80.0 wt%, or at least 85.0 wt%, or at least 90.0 wt%, or at least 95.0 wt% based on the total weight of the mixture.

[0118] 31. A method according to any one of statements 1 to 16 and 29 to 30, wherein the lactide is selected from the group consisting of L-lactide, D-lactide, meso-lactide and any mixture thereof (including racemic lactide).

[0119] 32. A method according to any one of statements 1 to 16 and 29 to 31, wherein the crystallization temperature (Tc) is between 50°C and 80°C, such as between 60°C and 80°C.

[0120] 33. A method according to any one of statements 1 to 16 and 29 to 32, comprising further purifying the crystallized glycolide by melting the crystallized glycolide recovered in step f) into a molten product and providing the molten product as a new mixture in step a), thereby recovering purified crystallized glycolide and a new mother liquor from the recovered crystallized glycolide.

[0121] 34. The method according to any one of statements 1 to 16 and 29 to 33, wherein the method of statement 33 is repeated at most 10 times, preferably at most 5 times, more preferably at most 3 times.

[0122] 35. A process according to any one of statements 1 to 16 and 29 to 34, further comprising providing in step a) the mother liquor obtained in any of the preceding steps as a new mixture, thereby recovering an additional amount of crystallized glycolide and new mother liquor from the recovered crystallized glycolide.

[0123] 36. The process of any one of Statements 1 to 16 and 29 to 35, wherein the process of Statement 35 is repeated until a desired total yield of crystallized glycolide is achieved.

[0124] 37. A process according to any one of statements 1 to 16 and 29 to 36, wherein at least 50%, or at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90% of the amount of glycolide contained in the mixture is recovered as crystalline glycolide.

[0125] 38. A process according to any one of statements 1 to 16 and 29 to 37, wherein the crystallized glycolide comprises less than 1.0 wt%, preferably less than 0.5 wt%, of lactide, based on the total weight of the crystallized glycolide.

[0126] 39. A method according to any one of statements 1 to 16 and 29 to 38, wherein the amount of lactide (multiple lactides) contained in the crystallized glycolide (measured in wt%) is less than 0.5 times, for example less than 0.2 times, the amount of lactide (multiple lactides) in the mixture (measured in wt%).

[0127] 40. A process according to any one of statements 1 to 16 and 29 to 39, wherein the purification factor of the lactide of the recovered crystallized glycolide is in the range of 2 to 20.

[0128] 41. A method according to any of the preceding statements, wherein the mixture comprising lactide (plurality of lactides) and glycolide provided in step a) is obtained as a by-product in a method for preparing poly(lactic acid)-co-glycolic acid (PLGA) by ring-opening copolymerization of lactide (plurality of lactides) and glycolide.

[0129] 42. A method according to any of the preceding statements, wherein the mixture comprising lactide(s) and glycolide provided in step a) is recovered as a by-product in a process for ring-opening copolymerization of lactide(s) and glycolide into PLGA by the following steps:

[0130] i. subjecting lactide(s) and glycolide to ring-opening copolymerization under conditions effective to produce a reaction mixture comprising PLGA and unreacted lactide(s) and unreacted glycolide,

[0131] ii. separating unreacted lactide(s) and unreacted glycolide from the PLGA, preferably by degassing the reaction mixture, thereby recovering a vapor product comprising unreacted lactide(s) and unreacted glycolide; and

[0132] iii. condensing the vapor product to obtain a mixture comprising lactide(s) and glycolide as a condensed product.

[0133] 43. The method according to any of the preceding statements, wherein the mixture comprising lactide(s) and glycolide provided in step a) is obtained by thermal depolymerization of PLGA.

[0134] 44. The method according to any of the preceding statements, wherein the mixture comprising lactide(s) and glycolide provided in step a) is prepared from a mixture comprising lactic acid and glycolic acid, preferably by the following steps:

[0135] a1) providing a mixture comprising lactic acid and glycolic acid;

[0136] a2) polycondensing the mixture comprising lactic acid and glycolic acid under conditions effective to form lactic acid / glycolic acid co-oligomers; and

[0137] a3) depolymerizing the co-oligomers of lactic acid / glycolic acid formed in step a2) to form a mixture comprising lactide(s) and glycolide.

[0138] 45. The method of statement 44, wherein the mixture comprising lactic acid and glycolic acid provided in step a1) is prepared by hydrolyzing PLA, PGA and PLGA in any suitable combination to produce lactic acid and glycolic acid.

[0139] 46. ​​The method according to statement 44 or 45, wherein the lactic acid provided in step a1) is produced by fermentation.

[0140] 47. Method according to any one of statements 44 to 46, wherein the glycolic acid provided in step a1) is produced by fermentation.

[0141] 48. The process according to any one of statements 44 to 47, wherein the glycolic acid provided in step a1) is prepared from synthesis gas.

[0142] 49. A method according to any one of statements 44 to 48, wherein the mixture comprising lactic acid and glycolic acid provided in step a1) is prepared by the following steps

[0143] i. copolymerizing lactide(s) and glycolide under conditions effective to produce a reaction mixture comprising PLGA and unreacted lactide(s) and unreacted glycolide,

[0144] ii. separating unreacted lactide(s) and unreacted glycolide from the PLGA, preferably by degassing the reaction mixture, thereby recovering a product stream comprising unreacted lactide(s) and unreacted glycolide; and

[0145] iii. hydrolyzing the product stream comprising unreacted lactide(s) and unreacted glycolide under conditions effective to produce a mixture comprising lactic acid and glycolic acid.

[0146] The present invention relates to a method for separating a mixture of lactide (plurality of lactides) and glycolide. More specifically, the present invention relates to a method for recovering lactide or glycolide from a mixture of lactide (plurality of lactides) and glycolide by melt crystallization at a suitable crystallization temperature, wherein the crystallization temperature is determined according to the composition of the mixture and the desired amount of lactide or glycolide to be recovered from the mixture.

[0147] More specifically, the present invention relates to a method for separating a mixture comprising lactide(s) and glycolide, wherein the method comprises the following steps:

[0148] a) providing a mixture comprising lactide(s) and glycolide, wherein the mixture is provided in a molten state, and preferably, wherein the total combined amount of lactide(s) and glycolide in the mixture is at least 70.0 wt %, based on the total weight of the mixture,

[0149] b) determining the crystallization point of the mixture,

[0150] c) determining the desired amount of lactide or glycolide to be recovered from the mixture,

[0151] d) selecting a suitable crystallization temperature (T) based on the desired amount of lactide or glycolide to be recovered determined in step c) c ),

[0152] e) heating the mixture at the temperature T c to obtain a mother solution and a crystallized product, wherein the crystallized product comprises crystallized lactide or crystallized glycolide,

[0153] f) recovering the crystalline product,

[0154] g) optionally, further purifying the crystallized product by melting the crystallized product recovered in step f) into a molten product and providing the molten product as a new mixture in step a) of the separation method of the present invention, thereby recovering a purified crystallized product and a new mother liquor from the recovered crystallized product, and

[0155] h) Optionally, in step a) the mother liquor obtained in any of the previous steps is provided as a new mixture, thereby recovering an additional amount of crystallized product and a new mother liquor.

[0156] The present invention provides a method for separating a mixture comprising lactide (plural lactides) and glycolide. The mixture to be separated according to the present method is also referred to as the "initial" mixture or "original" mixture in the text. This is the mixture provided at the beginning of the separation process.

[0157] The present method can obtain a crystalline product comprising or consisting of crystallized lactide or crystallized glycolide. Therefore, the crystalline product obtained by the separation method can contain or consist of crystallized lactide or crystallized glycolide. Whether crystallized lactide or crystallized glycolide is obtained may depend on the composition of the initial mixture to be separated.

[0158] Crystallized lactide comprises, preferably consists essentially of "lactide crystals", and crystallized glycolide comprises, preferably consists essentially of "glycolide crystals". The present invention advantageously allows obtaining high purity and high yield of crystallized lactide or crystallized glycolide, respectively, lactide crystals and glycolide crystals.

[0159] As mentioned above, the mixture to be separated according to the present invention comprises glycolide and lactide(s).

[0160] Glycolide refers to the cyclic ester of two glycolic acid molecules.

[0161] Lactide refers to the cyclic ester of two lactic acid molecules. Lactide has three stereoisomeric forms, namely "L-lactide", which is a dimer of two L-lactic acid molecules, "D-lactide", which is a dimer of two D-lactic acid molecules, and "meso-lactide", which is a dimer formed by one L-lactic acid molecule and one D-lactic acid molecule. An equal weight (50 / 50 wt% / wt%) mixture of L-lactide and D-lactide is also called "rac-lactide" or "racemic lactide".

[0162] The term "lactide" as used herein includes L-lactide, D-lactide, meso-lactide, or a mixture of two or more of the above, including racemic lactide (a 50 / 50 mixture of L-lactide and D-lactide). In certain embodiments, the lactide in the mixture to be separated according to the present method consists of only one type of lactide stereoisomer, such as L-lactide, or D-lactide, or meso-lactide. In certain other embodiments, the lactide in the mixture to be separated according to the present method consists of two or more lactide stereoisomers, and is, for example, composed of a mixture of L-lactide and D-lactide or a mixture of L-lactide and meso-lactide. In one example, the lactide in the mixture to be separated according to the present separation method consists of racemic lactide.

[0163] In certain embodiments of the present invention, the mixture to be separated comprises mainly lactide. In this context, when referring to the lactide in the mixture, the term "mainly" refers to a stereoisomeric form of lactide, which has a molar percentage higher than any other single lactide stereoisomer available in the mixture. For example, when there are equal amounts of L-lactide and D-lactide in the mixture, the main lactide can be L-lactide, or D-lactide, or meso-lactide, or racemic-lactide. It should be understood that in embodiments where the lactide in the mixture to be separated is racemic lactide, L-lactide and D-lactide are both present in the same molar percentage. In such embodiments, racemic lactide (i.e., a 50 / 50 mixture of L-lactide and D-lactide) should be understood as "mainly lactide".

[0164] In certain embodiments of the invention, it is preferred that the total combined amount of lactide (s) and glycolide in the mixture to be separated according to the invention is at least 70.0 wt%, based on the total weight of the mixture, such as at least 75.0 wt%, or at least 80.0 wt%, or at least 85.0 wt%, or at least 90.0 wt%, or at least 95.0 wt%, or at least 99.0 wt% or at least 99.5 wt%, based on the total weight of the mixture. Those skilled in the art will recognize that the mixture to be separated may contain impurities, which may affect (lower) the crystallization point.

[0165] The mixture of lactide(s) and glycolide used in step a) of the present method is in a molten state, ie, liquid.

[0166] Step b) of the separation method involves determining the crystallization point of the mixture to be separated. The crystallization point of the mixture to be separated will depend on the composition and concentration of the different components contained in the mixture, for example on the type of one or more lactides present in the mixture.

[0167] In certain preferred embodiments of the present method, the crystallization point of the mixture is determined by constructing a phase diagram of glycolide and lactide, which is the major lactide in the mixture.

[0168] Therefore, the present method also involves a step of determining the main lactide in the mixture to be separated. This can be done using analytical methods known to those skilled in the art. In one example, the main lactide in the mixture of lactide and glycolide according to the present invention is L-lactide. In another example, the main lactide in the mixture of lactide and glycolide according to the present invention is D-lactide. In another example, the main lactide in the mixture of lactide and glycolide according to the present invention is meso-lactide. In another example, the main lactide in the mixture of lactide and glycolide to be separated according to the present invention is racemic lactide.

[0169] In the context of the present invention, a phase diagram is intended to refer to a diagram that is used to show the conditions under which thermodynamically different phases (e.g., solid, liquid, or gas) occur and coexist in equilibrium, specifically, the temperature at which the desired component crystallizes after cooling. The phase diagram used in the present invention may refer to any suitable phase diagram, such as a binary phase diagram (also referred to herein as a eutectic phase diagram), a ternary phase diagram, a multi-component phase diagram.

[0170] In certain preferred embodiments, the phase diagram selected in step c) of the present method is a eutectic phase diagram established for the main lactide (e.g., L-lactide) and glycolide. Such eutectic phase diagram is preferably established by preparing a series of mixtures consisting of defined amounts of the main lactide (e.g., L-lactide) and glycolide; and determining the crystallization point of the mixture.

[0171] The next step of the separation process involves determining the desired amount of lactide or glycolide to be recovered from the mixture. Based on the desired amount of lactide or glycolide to be recovered, the appropriate crystallization temperature (T c ). In one example, the desired amount of lactide or glycolide to be recovered from the mixture and the corresponding crystallization temperature required to achieve that amount can be determined based on a phase diagram established for the mixture. The amount of crystals increases as the temperature decreases, and the amount can be predicted by the lever rule in the binary equilibrium phase diagram. The further the original composition (initial mixture) is from the eutectic point, the more crystals can be harvested by cooling the mixture.

[0172] According to the present separation method, preferably, the crystallization temperature (T c ) is in the range of 30°C to 95°C. In certain embodiments of the present separation method, the crystallization temperature (T c ) is in the range of 50°C to 95°C. In certain embodiments of the present separation method, the crystallization temperature (T c ) is in the range of 50°C to 80°C. In certain embodiments of the present separation method, the crystallization temperature (T c ) is in the range of 60°C to 90°C.

[0173] Then, at the determined crystallization temperature T c The mixture is subjected to a melt crystallization step to obtain a mother liquor and a crystallized product.

[0174] Crystallization involves purifying a chemical from a liquid mixture by solidifying the desired components. In melt crystallization, no solvent is added. Crystals are formed by cooling the "melt". Melt crystallization can be performed in a variety of crystallization units.

[0175] In certain embodiments of the method, the melt crystallization may include at least one layer crystallization step. In a preferred embodiment of the method, the at least one layer crystallization step includes at least one falling film crystallization step and / or at least one static crystallization step.

[0176] In certain embodiments of the present method, melt crystallization may include a falling film crystallization step. Falling film crystallization may be performed in a falling film crystallizer. Such a crystallizer is typically composed of a vertical tube system. A collection vessel below the tube sheet contains a liquid product (here, mother liquor). Both the product and the heat transfer medium (HTM) flow in the form of a falling film. The mixture flows downward on the inner surface of the tube, and the liquid used for cooling and heating is distributed to wet the outer surface of the tube. During the crystallization process, a cold heat transfer medium is used to cool the tube, and crystals adhere to the wall surface. These crystals may be further purified by so-called partial melting or sweating (which is achieved by slightly increasing the temperature of the heat transfer medium). Finally, crystals are harvested by remelting above the melting point of the pure component to provide a purified liquid. The product (mixture) and heat transfer medium distribution system are designed to balance the flow through the tube. Optimal performance is achieved by precisely controlling the heating and cooling curves and fine-tuning the amount of partial melts.

[0177] In some embodiments of the present method, melt crystallization may include at least one static crystallization step. Static crystallization may be carried out in a static crystallizer. Static crystallization is a process that is usually heated or cooled by an internal circulation of a heat transfer medium using a vertical plate. These plates are suspended in a liquid product (mixture). The heat transfer medium is slowly cooled to below the suitable crystallization temperature of the stagnant product determined herein so that a layer of crystals is grown on the plate. In addition, in this type of layer crystallization, a partial melting stage and a product recovery stage are applied by increasing the temperature.

[0178] Alternatively or additionally, the melt crystallization used in the inventive method can also include at least one suspension crystallization step. Suspension crystallization is understood to be crystallization from a liquid due to cooling while applying agitation, wherein the crystal forms a suspension with the liquid. Suspension crystallization can be carried out in any type of stirred vessel, and notable examples include scraped wall crystallizers, forced circulation crystallizers, and fluidized bed crystallizers. The crystals in the suspension (or slurry) can be separated by any means, such as by filters, centrifuges, and hydraulic wash columns.

[0179] The crystallized product (i.e., containing or consisting of crystals) formed during the melt crystallization process can be separated from the mother liquor by any method known to those skilled in the art and deemed suitable. Preferably, the crystallized product and the optional purified crystallized product (obtained as described herein) are recovered by filtration, centrifugation or other solid-liquid separation means or any combination thereof. In one example, the crystallized product (crystals) can be separated and recovered, for example, in a wash column, a centrifugal filter or a filter press.

[0180] In certain embodiments of the present method, it is preferred to further purify the crystallized product recovered in step f) of the method. To this end, certain embodiments of the present method involve a further step g), which further comprises recovering a purified crystallized product and a new mother liquor from the crystallized product by melting the crystallized product recovered in step f) into a molten product and providing the molten product as a new mixture in step a).

[0181] The term "new mixture" as used herein is intended to refer to a mixture having a different composition compared to the initial mixture as defined herein (ie the original mixture provided at the beginning of the separation process).

[0182] The term "new mother liquor" as used herein is intended to mean a mother liquor having a different composition after carrying out the first cycle of the separation process of the invention compared to the initial mother liquor, ie the mother liquor obtained directly from the initial mixture as defined herein.

[0183] The process of the present invention, in particular step g) of the process, can be repeated, for example up to 10 times, preferably up to 5 times, more preferably up to 3 times, for example up to 2 times or up to 1 time. If necessary, an additional purification step according to step g) of the present separation process can improve the purity of the resulting crystalline product. The term "purified crystalline product" as used in this context is intended to refer to a crystalline product (crystalline lactide or crystalline glycolide) having a higher purity (i.e., a lower amount of the corresponding undesired dilactone) than the crystalline product obtained in the previous cycle of the separation process.

[0184] For example, when the crystallized product is crystallized lactide, it is preferred that the recovered crystallized lactide (i.e., the product recovered after carrying out the method of the present invention) contains less than 1.0 wt%, preferably less than 0.5 wt%, of glycolide based on the total weight of the crystallized lactide. Similarly, when the crystallized product is crystallized glycolide, it is preferred that the recovered crystallized glycolide (i.e., the product recovered after carrying out the method of the present invention) contains less than 1.0 wt%, preferably less than 0.5 wt%, of lactide based on the total weight of the crystallized glycolide.

[0185] In some embodiments, when the crystallized product is crystallized lactide, it is preferred that the amount of glycolide contained in the crystallized lactide recovered by the method of the present invention (in wt%) is less than 0.5 times, such as less than 0.4 times, or less than 0.3 times, or less than 0.2 times the amount of glycolide in the (initial) mixture (in wt%). In other words, it is preferred that the present separation method allows the purification factor of glycolide of the recovered crystallized lactide to be at least 2, such as a purification factor in the range of 2 to 20, such as 3 to 17, or 5 to 15.

[0186] Likewise, when the crystallized product is crystallized glycolide, it is preferred that the amount of lactide (plurality of lactides) contained in the recovered crystallized glycolide (in wt%) is less than 0.5 times, such as less than 0.4 times, or less than 0.3 times, or less than 0.2 times the amount of lactide (plurality of lactides) (in wt%) in the (initial) mixture. In other words, it is preferred that the present separation method allows the purification factor of lactide of the recovered crystallized glycolide to be at least 2, such as a purification factor in the range of 2 to 20, such as 3 to 17, or 5 to 15.

[0187] The term "purification factor" as used in this context can generally be defined as:

[0188] Purification factor = [weight % of undesirable components in the initial mixture containing lactide(s) and glycolide] / [weight % of undesirable components in the crystallized product]

[0189] Wherein "initial mixture" means the mixture provided at the beginning of the separation process;

[0190] wherein the "crystallized product" is crystallized glycolide or crystallized lactide, and wherein when the crystallized product is crystallized glycolide or crystallized lactide, the "unwanted component" refers to lactide or glycolide, respectively.

[0191] In certain preferred embodiments, the method may further involve step h), comprising providing the mother liquor obtained in any of the previous steps as a new mixture in step a, thereby recovering an additional amount (additional yield) of the crystallized product and a new mother liquor. The terms "new mixture" and "new mother liquor" are as defined above.

[0192] This additional step corresponds to a concentration of the mother liquor and can increase the amount (yield) of the recovered crystallized product. Preferably, the process of the invention, in particular step h) thereof, is repeated until the desired total yield of the crystallized product is reached. For example, the desired total yield of the crystallized product can be such that the amount of the crystallized product (e.g. crystallized lactide or crystallized glycolide) is at least 50%, for example at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90% of the amount of the product (e.g. lactide or glycolide, respectively) contained in the initial mixture.

[0193] In other words, in a preferred embodiment of the present separation process, at least 50%, for example at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90% of the amount of lactide or glycolide contained in the (initial) mixture is recovered as crystalline lactide or crystalline glycolide, respectively.

[0194] In certain embodiments, a method of the present invention is provided, wherein lactide is separated from a mixture comprising lactide(s) and glycolide, and wherein the method comprises the following steps:

[0195] a) providing a mixture comprising lactide(s) and glycolide, wherein the mixture is provided in a molten state, and preferably, the total combined amount of lactide(s) and glycolide in the mixture is at least 70.0 wt%, based on the total weight of the mixture, such as at least 75.0 wt%, or at least 80.0 wt%, or at least 85.0 wt%, or at least 90.0 wt%, or at least 95.0 wt%, based on the total weight of the mixture,

[0196] b) determining the crystallization point of the mixture,

[0197] c) determining the desired amount of lactide to be recovered from said mixture,

[0198] d) selecting a suitable crystallization temperature (T) based on the desired amount of lactide to be recovered determined in step c) c ),

[0199] e) heating the mixture at the temperature T c The melt crystallization is carried out at a temperature of preferably c ) between 30°C and 95°C, or between 50°C and 95°C, or between 60°C and 90°C, thereby obtaining a mother liquor and crystallized lactide; and

[0200] f) recovering the crystallized lactide.

[0201] In one example, the major lactide in the mixture of lactide and glycolide according to the present invention is L-lactide. In another example, the major lactide in the mixture of lactide and glycolide according to the present invention is D-lactide. In another example, the major lactide in the mixture of lactide and glycolide according to the present invention is meso-lactide.

[0202] In a preferred embodiment, the method further comprises a step g) of further purifying the crystallized lactide by melting the crystallized lactide recovered in step f) into a molten product and providing the molten product as a new mixture in step a), thereby recovering purified crystallized lactide and a new mother liquor from the crystallized lactide. This step g) may be repeated, for example, up to 10 times, preferably up to 5 times, more preferably up to 3 times, for example up to 2 times or up to 1 time. If necessary, these additional purification steps according to step g) of the present separation method for separating lactide may improve the purity of the obtained crystallized lactide. For example, it is preferred that the recovered crystallized lactide (i.e., the product recovered after carrying out the method of the present invention) contains less than 1.0 wt%, preferably less than 0.5 wt%, of glycolide based on the total weight of the crystallized lactide.

[0203] In some embodiments, it is preferred that the amount of glycolide contained in the crystallized lactide recovered by the method of the present invention is less than 0.5 times the amount of glycolide in the (initial) mixture (in wt%), such as less than 0.4 times, or less than 0.3 times, or less than 0.2 times. In other words, it is preferred that the present separation method allows obtaining a purification factor of glycolide of the recovered crystallized lactide of at least 2, such as a purification factor in the range of 2 to 20, such as 3 to 17, or 5 to 15.

[0204] Additionally or alternatively, a preferred embodiment of the present method further comprises a step h) in which the mother liquor obtained in any of the previous steps of the present method is provided as a new mixture in step a), thereby recovering an additional amount of crystallized lactide and a new (concentrated) mother liquor. The additional concentration step of the mother liquor according to step h) of the present separation method can increase the amount of crystallized lactide recovered. Optionally, step h) can be repeated until the desired total yield of crystallized lactide is reached. Preferably, the desired total yield of crystallized lactide can be at least 50%, such as at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90% of the amount of lactide contained in the initial mixture. In other words, in a preferred embodiment of the present lactide separation method, at least 50%, such as at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90% of the amount of lactide contained in the (initial) mixture is recovered as crystallized lactide.

[0205] In certain preferred embodiments of the present method, a separation method is provided, wherein L-lactide is separated from a mixture comprising L-lactide and optionally other lactide and glycolide, and wherein the method comprises the following steps:

[0206] a) providing a mixture comprising L-lactide and optionally other lactide(s) and glycolide, wherein the mixture is provided in a molten state, and

[0207] Preferably, the total combined amount of L-lactide and glycolide in the mixture is at least 70.0 wt%, based on the total weight of the mixture, for example at least 75.0 wt%, or at least 80.0 wt%, or at least 85.0 wt%, or at least 90.0 wt%, or at least 95.0 wt%, based on the total weight of the mixture.

[0208] b) determining the crystallization point of the mixture,

[0209] c) determining the desired amount of L-lactide to be recovered from said mixture,

[0210] d) selecting a suitable crystallization temperature (T) based on the desired amount of L-lactide to be recovered determined in step c) c ),

[0211] e) heating the mixture at the temperature T c The melt crystallization is carried out at a temperature of preferably c ) between 30° C. and 95° C., or between 50° C. and 95° C., or between 60° C. and 90° C., thereby obtaining a mother liquor and crystallized L-lactide containing L-lactide crystals; and

[0212] f) recovering the crystallized L-lactide,

[0213] g) optionally, further purifying the crystallized L-lactide by melting the crystallized L-lactide recovered in step f) into a molten product and providing the molten L-lactide as a new mixture in step a), thereby recovering purified crystallized L-lactide and a new mother liquor from the crystallized L-lactide, and

[0214] h) Optionally, in step a) the mother liquor obtained in any of the previous steps is provided as a new mixture, thereby recovering an additional amount of crystallized L-lactide and a new mother liquor.

[0215] In a preferred embodiment of the present method, the amount of glycolide contained in the recovered crystallized L-lactide (in wt%) is less than 0.5 times, such as less than 0.2 times, the amount of glycolide (in wt%) in the mixture. In a preferred embodiment of the present method, the purification factor of the glycolide of the recovered crystallized L-lactide is in the range of 2 to 20, such as 3 to 17, or 5 to 15.

[0216] In certain other embodiments, a method of the present invention is provided, wherein glycolide is separated from a mixture comprising lactide(s) and glycolide, and wherein the method comprises the steps of:

[0217] a) providing a mixture comprising lactide(s) and glycolide, wherein the mixture is provided in a molten state,

[0218] Preferably, the total combined amount of lactide (plurality of lactides) and glycolide in the mixture is at least 70.0 wt%, based on the total weight of the mixture, for example at least 75.0 wt%, or at least 80.0 wt%, or at least 85.0 wt%, or at least 90.0 wt%, or at least 95.0 wt%, based on the total weight of the mixture.

[0219] b) determining the crystallization point of the mixture,

[0220] c) determining the desired amount of glycolide to be recovered from said mixture,

[0221] d) selecting a suitable crystallization temperature (T) based on the desired amount of glycolide to be recovered determined in step c) c ),

[0222] e) heating the mixture at the temperature T c The melt crystallization is carried out at a temperature of preferably c ) between 50° C. and 80° C., for example, between 60° C. and 80° C., thereby obtaining a mother liquor and crystallized glycolide containing glycolide crystals; and

[0223] f) recovering the crystallized glycolide,

[0224] g) optionally, further purifying the crystallized glycolide by melting the crystallized glycolide recovered in step f) into a molten product and providing the molten product as a new mixture in step a), thereby recovering purified crystallized glycolide and a new mother liquor from the crystallized glycolide, and

[0225] h) Optionally, in step a) the mother liquor obtained in any of the previous steps is provided as a new mixture, thereby recovering an additional amount of crystallized glycolide and a new mother liquor.

[0226] In a preferred embodiment, the method further comprises a step g) of further purifying the crystallized glycolide by melting the crystallized glycolide recovered in step f) into a molten product and providing the molten product as a new mixture in step a), thereby recovering purified crystallized glycolide and a new mother liquor from the recovered crystallized glycolide. This step g) can be repeated, for example, up to 10 times, preferably up to 5 times, more preferably up to 3 times, for example up to 2 times or up to 1 time. If necessary, the purity of the obtained crystallized lactide can be improved according to the additional purification step of step g) of the present separation method for separating glycolide. For example, it is preferred that the recovered crystallized glycolide (i.e., the product recovered after implementing the method of the present invention) contains less than 1.0 wt%, preferably less than 0.5 wt% of lactide (plurality of lactides), based on the total weight of the crystallized glycolide.

[0227] In some embodiments, it is preferred that the amount of lactide (plurality of lactides) contained in the crystallized glycolide recovered by the method of the present invention is less than 0.5 times, such as less than 0.4 times, or less than 0.3 times, or less than 0.2 times the amount of lactide (plurality of lactides) (in wt%) in the (initial) mixture. In other words, it is preferred that the present separation method allows the purification factor of the lactide of the recovered crystallized glycolide to be at least 2, such as a purification factor in the range of 2 to 20, such as 3 to 17, or 5 to 15.

[0228] Additionally or alternatively, a preferred embodiment of the present method further comprises a step h), in which the mother liquor obtained in any of the previous steps is provided as a new mixture in step a), thereby recovering an additional amount (additional yield) of crystallized glycolide and a new, further concentrated mother liquor. The additional concentration step of the mother liquor according to step h) of the present glycolide separation method can increase the amount (yield) of crystallized glycolide recovered. Optionally, the method of the present invention, in particular its step h), is repeated until the desired total yield of crystallized glycolide is reached. Preferably, the desired total yield of crystallized glycolide can be at least 50%, such as at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90% of the amount of glycolide contained in the initial mixture. In other words, in a preferred embodiment of the present separation method for separating glycolide, at least 50%, such as at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90% of the amount of glycolide contained in the mixture is recovered as crystallized glycolide.

[0229] The present method involves a first step in which a mixture of lactide (s) and glycolide is provided. The mixture comprising lactide (s) and glycolide for separation according to the method defined herein can be obtained from various sources and / or as a by-product or side stream from various processes (e.g., for the manufacture of PLA, PGA or PLGA).

[0230] The term polylactic acid (PLA) refers to a polymer of lactic acid units, produced, for example, by ring-opening polymerization of L-lactide, D-lactide, meso-lactide or a mixture of two or three of these lactides. It can also be a mixture of polymers from the pure lactide or mixed lactide. The number average molecular weight of PLA is usually >10000 g / mol.

[0231] The term polyglycolide (PGA) refers to a polymer of glycolic acid units, produced, for example, by ring-opening polymerization of glycolide. Typically, the number average molecular weight of PGA is >10000 g / mol.

[0232] The term poly(lactic-co-glycolic acid) (PLGA) refers to a copolymer of glycolic acid and lactic acid. PLGA polymers can be random copolymers or block copolymers.

[0233] In one example, the mixture of lactide(s) and glycolide provided in step a) of the present method can be obtained starting from PLGA.

[0234] In certain embodiments, the mixture of lactide (plurality of lactides) and glycolide provided in step a) of the present method can be obtained by thermal depolymerization of PLGA. For example, PLGA can be catalytically backbited by adding excess catalyst and / or applying a temperature above 200° C. during the production process.

[0235] In certain other examples, a mixture comprising lactide (multiple lactides) and glycolide can be obtained as a byproduct or side stream formed during the production of PLGA. For example, in some embodiments, the mixture of lactide (multiple lactides) and glycolide provided in step a) of the present method can be prepared or recovered as a byproduct in the process of ring-opening copolymerization of lactide (multiple lactides) and glycolide into PLGA. Preferably, in this example, the mixture of lactide and (multiple lactides) glycolide provided in step a) of the present separation method is prepared by the following steps:

[0236] I. subjecting lactide(s) and glycolide to ring-opening copolymerization under conditions effective to produce a reaction mixture comprising PLGA and unreacted lactide(s) and unreacted glycolide,

[0237] II. separating unreacted lactide(s) and unreacted glycolide from the PLGA, preferably by degassing the reaction mixture to recover a vapor product comprising unreacted lactide(s) and unreacted glycolide; and

[0238] III. Condensing the vapor product to obtain a mixture comprising lactide(s) and glycolide as a condensed product.

[0239] Those skilled in the art will recognize that when PLGA copolymers are produced with conventional catalysts such as IV group alkoxides, tin oxide and tin alkanoates (particularly tin octoate), the rate of glycolide ring-opening polymerization is generally faster than lactide under the same conditions. PLGA copolymerizations tend to exhibit gradient copolymerization behavior, and the reaction product before degassing can generally contain very small amounts of residual glycolide (<0.5wt%), while lactide, depending on the final polymerization temperature, can account for about 2%-5% of the mass. Therefore, in practice, such gradient copolymerizations will be able to recycle a condensed lactide stream containing only a small amount of glycolide. If desired, the copolymerization reaction can be altered by injecting glycolide multiple times, and the amount of glycolide remaining in the product sent to the degassing stage of the method can be increased. In addition, catalysts can be used to alter copolymerization kinetics.

[0240] In certain embodiments, a mixture comprising lactide(s) and glycolide can be obtained starting from a mixture of lactic acid and glycolic acid.

[0241] For example, the mixture of lactide(s) and glycolide provided in step a) is prepared from a mixture of lactic acid and glycolic acid by the following steps:

[0242] a1) providing a mixture of lactic acid and glycolic acid;

[0243] a2) polycondensing the mixture of lactic acid and glycolic acid under conditions effective to form lactic acid / glycolic acid co-oligomers; and

[0244] a3) depolymerizing the lactic acid / glycolic acid co-oligomers formed in step a2) to form a mixture comprising lactide(s) and glycolide.

[0245] The mixture of lactic acid and glycolic acid used in step a1) can be obtained in various ways.

[0246] In one example, a mixture of glycolic acid and lactic acid can be prepared by hydrolyzing PLA, PGA and PLGA in any suitable combination to produce glycolic acid and lactic acid. For example, a mixture of glycolic acid and lactic acid can be prepared by hydrolyzing PLA and PGA. For example, a mixture of glycolic acid and lactic acid can be prepared by hydrolyzing PLA and PLGA. For example, a mixture of glycolic acid and lactic acid can be prepared by hydrolyzing PGA and PLGA. For example, a mixture of glycolic acid and lactic acid can be prepared by hydrolyzing PLGA. For example, a mixture of glycolic acid and lactic acid can be prepared by hydrolyzing PLA, PGA and PLGA.

[0247] In another example, lactic acid and / or glycolic acid can be produced by fermentation.

[0248] In yet another example, glycolic acid can also be produced starting from syngas and oxygen, for example by producing a dimethyl oxalate intermediate.

[0249] In certain embodiments, the mixture of lactic acid and glycolic acid used in step a1) can be prepared by a method comprising the following steps:

[0250] (i) copolymerizing lactide(s) and glycolide under conditions effective to produce a reaction mixture comprising PLGA and unreacted lactide and unreacted glycolide,

[0251] (ii) separating unreacted lactide(s) and unreacted glycolide from the PLGA, preferably by degassing the reaction mixture, thereby recovering a product stream comprising unreacted lactide(s) and unreacted glycolide; and

[0252] (iii) hydrolyzing the product stream comprising unreacted lactide(s) and unreacted glycolide under conditions effective to produce a mixture comprising lactic acid and glycolic acid.

[0253] Step a2) of the above method involves subjecting the mixture of lactic acid and glycolic acid to polycondensation under conditions effective to form lactic acid / glycolic acid co-oligomers. In one example, the polycondensation conditions used in step a2) may include heating to a temperature of about 100° C. to 180° C. and applying a pressure of about 10 mbar to 500 mbar. Preferably, no catalyst is used in this polycondensation process. Those skilled in the art are familiar with conditions suitable for achieving an effective polycondensation reaction.

[0254] Step a3) of the above method involves the depolymerization of the lactic acid / glycolic acid co-oligomers formed in step a2) to form a mixture comprising lactide (multiple lactides) and glycolide. In one example, the depolymerization conditions used in step a3) may include heating to a temperature of about 175°C to 225°C in the presence of a suitable catalyst and applying a pressure of about 2mbar to 50mbar. Those skilled in the art are familiar with the conditions and catalysts that can be used to obtain effective depolymerization. It should also be understood that the mixture produced by the above method (including the depolymerization step a3) may contain a large amount of compounds different from lactide and glycolide, such as mixed dilactones (e.g., 3-methyl glycolide) and the like. In addition, this type of mixture, i.e., containing lactide, glycolide and other components (e.g., other dilactones), can be separated by applying the separation method according to the present invention.

[0255] The following examples are only used to illustrate the present invention and should not be construed as limiting the scope in any way. Although the present invention is shown only in its partial form, it should be clear to those skilled in the art that the present invention is not limited thereto, but various changes and modifications can be made without departing from the scope of the present invention.

[0256] Example

[0257] Example 1: L-lactide and glycolide

[0258] In this example, a phase diagram of L-lactide and glycolide was constructed.

[0259] A mixture of glycolide and L-lactide was prepared. 200 g scale of both monomers were weighed in the correct mass percentage in a PE sealed bag. After weighing, they were double sealed in an aluminum bag. The sample was placed in a freezer and warmed to room temperature before use.

[0260] Crystallization experiments were performed in a 500 mL jacketed vessel equipped with a stirring bar and a programmable water heating bath. A total of 200 g of the monomer mixture was placed in the vessel and heated to 98 ° C in about 20 minutes. Cooling was then performed in steps of 5 K every 5 minutes while seed crystals were continuously added (to avoid supercooling). Seed crystals usually persist when the temperature is within 10 K of the crystallization point determined later. After determining the first rough indication of the crystallization point, the mixture was heated to 98 ° C again and then cooled to 3 ° C-5 ° C higher than the previously determined temperature. A final cooling rate of 2 K / h was then used to find the exact crystallization temperature (again using the seed crystals that continue to exist).

[0261] Determine the crystallization point and plot it on Figure 1 In the phase diagram shown, the eutectic point was determined to be located at about 46 wt% lactide and about 51°C.

[0262] Example 2: Racemic lactide and glycolide

[0263] In this example, a phase diagram of racemic lactide and glycolide was constructed. A mixture of glycolide and racemic lactide was prepared in the same manner as described in Example 1. Crystallization experiments were performed in the same manner as reported in Example 1. The crystallization point was determined and plotted on Figure 2 The phase diagram shown.

[0264] The eutectic point was determined to be at about 31 wt% racemic lactide and about 61 °C.

[0265] Example 3: Meso-lactide and glycolide

[0266] In this example, a phase diagram of meso-lactide and glycolide was constructed. A mixture of glycolide and meso-lactide was prepared in the same manner as described in Example 1. Crystallization experiments were performed in the same manner as reported in Example 1. The crystallization point was determined and plotted on Figure 3 The phase diagram shown.

[0267] The eutectic point was determined to be located at about 70 wt% meso-lactide and about 29°C.

[0268] Example 4: Multiple cycles of suspension crystallization

[0269] In this example, melt crystallization between L-lactide and glycolide was carried out using a 250 ml jacketed vessel equipped with a thermostat and a magnetic stirrer.

[0270] A 90 wt% / 10 wt% L-lactide / glycolide mixture was prepared by adding 180 g L-lactide (Lumilact L, TotalEnergies Corbion) and 20 g glycolide (Glycolide, PJ Chem) to a jacketed vessel. The mixture was melted at 98°C with stirring at 300 rpm. After melting, the mixture was cooled at 20°C / h to 2°C above the theoretical crystallization temperature. The cooling rate was then changed to 2°C / h, and lactide seeds were added after each 1°C of cooling. At 89°C, lactide seeds persisted and the mixture was maintained for 30 minutes. After 30 minutes, cooling was continued at 2°C / h to 78°C (according to Figure 1 The phase diagram in , this is the expected temperature at which about 50 wt% of crystals are formed, wt% based on the total original amount of material). The crystals and mother liquor were separated by a basket centrifuge (Hermle Sieva, 6000 rpm) with a 25 μm filter. The crystals were collected and stored in sealed PE bags.

[0271] The next day, the resulting crystals were crystallized for the second time in the same manner, with a final crystallization temperature of 92°C. The sample was methylated, and the contents of methyl lactate and methyl glycolate were determined using gas chromatography. Using a pure glycolide calibration curve, the glycolide content was then determined, and the results are reported in Table 1.

[0272] Table 1: Glycolide content of subsequent suspension crystallization

[0273] Sample description Glycolide content (GC, wt%) Crystals after the first crystallization 0.7 Mother liquor after the first crystallization 17 Crystals after the second crystallization 0.1 Mother liquor after the second crystallization 1.2

Claims

1. A method for separating a mixture comprising lactide (plurality of lactides) and glycolide, wherein: The method comprises the following steps: a) providing a mixture comprising lactide(s) and glycolide, wherein the mixture is provided in a molten state, and preferably, wherein the total combined amount of lactide(s) and glycolide in the mixture is at least 70.0 wt %, based on the total weight of the mixture, b) determining the crystallization point of the mixture, c) determining the desired amount of lactide or glycolide to be recovered from the mixture, d) selecting a suitable crystallization temperature (T) based on the desired amount of lactide or glycolide to be recovered determined in step c) c ), e) heating the mixture at the temperature T c to obtain a mother solution and a crystallized product, wherein the crystallized product comprises crystallized lactide or crystallized glycolide, and f) recovering the crystalline product.

2. The method according to claim 1, wherein: The crystallization point of the mixture is determined by constructing a phase diagram of glycolide and lactide, which is the major lactide in the mixture.

3. A method according to any one of the preceding claims, wherein: The crystallization temperature (T c ) is in the range of 30°C to 95°C, or 50°C to 95°C, or 50°C to 80°C, or 60°C to 90°C.

4. A method according to any one of the preceding claims, wherein: The crystallized product is further purified by melting the crystallized product recovered in step f) into a molten product and providing the molten product as a new mixture in step a) of the separation method according to any one of the preceding claims, thereby recovering a purified crystallized product and a new mother liquor from the recovered crystallized product.

5. A method according to any one of the preceding claims, wherein: The mother liquor obtained in step e) is provided as a new mixture in step a) of the separation process according to any one of the preceding claims, thereby recovering an additional amount of crystallized product and a new mother liquor.

6. A method according to any one of the preceding claims, wherein: At least 50%, or at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90% of the amount of lactide or glycolide contained in the mixture is recovered as a crystalline product.

7. A method according to any one of the preceding claims, wherein: Melt crystallization includes - at least one layer crystallization, and preferably, the layer crystallization comprises at least one falling film crystallization and / or at least one static crystallization, and / or - At least one suspension crystallization.

8. A method according to any one of the preceding claims, wherein: The crystalline product and optionally the purified crystalline product are recovered by filtration, centrifugation or other solid-liquid separation means or any combination thereof.

9. A method according to any one of the preceding claims, wherein: Lactide is separated from a mixture comprising lactide(s) and glycolide, and wherein the method comprises the steps of: a) providing a mixture comprising lactide(s) and glycolide, wherein the mixture is provided in a molten state, and preferably, wherein the total combined amount of lactide(s) and glycolide in the mixture is at least 70.0 wt %, based on the total weight of the mixture, b) determining the crystallization point of the mixture, c) determining the desired amount of lactide to be recovered from said mixture, d) selecting a suitable crystallization temperature (T) based on the desired amount of lactide to be recovered determined in step c) c ), e) heating the mixture at the temperature T c The melt crystallization is carried out at a temperature of preferably c ) between 30°C and 95°C, or between 50°C and 95°C, or between 60°C and 90°C, thereby obtaining a mother liquor and crystallized lactide; and f) recovering the crystallized lactide, g) optionally, further purifying the crystallized lactide by melting the crystallized lactide recovered in step f) into a molten product and providing the molten product as a new mixture in step a), thereby recovering purified crystallized lactide and a new mother liquor from the recovered crystallized lactide, and h) Optionally, in step a) the mother liquor obtained in any of the previous steps is provided as a new mixture, thereby recovering an additional amount of crystallized lactide and a new mother liquor.

10. The method according to claim 9, wherein: The crystallized lactide comprises glycolide in an amount (by wt%) less than 0.5 times, for example less than 0.2 times, the amount (by wt%) of glycolide in the mixture.

11. The method according to claim 9 or 10, wherein: The crystallized lactide and glycolide have a purification factor ranging from 2 to 20.

12. The method according to any one of claims 1 to 8, wherein: Separating glycolide from a mixture comprising lactide(s) and glycolide, wherein the method comprises the following steps: a) providing a mixture comprising lactide(s) and glycolide, wherein the mixture is provided in a molten state, and preferably, wherein the total combined amount of lactide and glycolide in the mixture is at least 70.0 wt %, based on the total weight of the mixture, b) determining the crystallization point of the mixture, c) determining the desired amount of glycolide to be recovered from said mixture, d) selecting a suitable crystallization temperature (T) based on the desired amount of glycolide to be recovered determined in step c) c ), e) heating the mixture at the temperature T c The melt crystallization is carried out at a temperature of preferably c ) between 50° C. and 80° C., for example, between 60° C. and 80° C., thereby obtaining a mother liquor and crystallized glycolide containing glycolide crystals; and f) recovering the crystallized glycolide, g) optionally, further purifying the crystallized glycolide by melting the crystallized glycolide recovered in step f) into a molten product and providing the molten product as a new mixture in step a), thereby recovering purified crystallized glycolide and a new mother liquor from the recovered crystallized glycolide, and h) Optionally, in step a) the mother liquor obtained in any of the previous steps is provided as a new mixture, thereby recovering an additional amount of crystallized glycolide and a new mother liquor.

13. The method according to any one of claims 1 to 8 and 12, wherein The crystallized glycolide comprises an amount of lactide(s) (by wt%) less than 0.5 times, for example less than 0.2 times, the amount of lactide(s) (by wt%) in the mixture.

14. The method according to any one of claims 1 to 8 and claims 12 to 13, wherein The crystallized lactide has a purification factor of lactide in the range of 2 to 20.

15. A method according to any one of the preceding claims, wherein: The mixture comprising lactide(s) and glycolide provided in step a) is obtained as a by-product in a method for preparing poly(lactic acid-co-glycolic acid) (PLGA) by ring-opening copolymerization of lactide and glycolide.

16. A method according to any one of the preceding claims, wherein: The mixture comprising lactide(s) and glycolide provided in step a) is obtained by thermal depolymerization of PLGA.

17. A method according to any one of the preceding claims, wherein: The mixture comprising lactide (plurality of lactides) and glycolide provided in step a) is prepared from a mixture comprising lactic acid and glycolic acid, and is preferably prepared by the following steps: a1) providing a mixture comprising lactic acid and glycolic acid; a2) subjecting the mixture comprising lactic acid and glycolic acid to polycondensation under conditions effective to form copolymerized oligomers of lactic acid / glycolic acid; and a3) depolymerizing the co-oligomers of lactic acid / glycolic acid formed in step a2) to form a mixture comprising lactide(s) and glycolide.

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