Method for producing lactide composite

Abstract

Provided is a method for producing a lactide composite.　This method involves the use of lactide, which is a cyclic dimer of lactic acid, heating a mixture of molten lactide and a low-molecular-weight substance, and reacting the molten lactide and the low-molecular-weight substance without opening the ring of lactide to produce a lactide composite.

Description

Method for producing lactide complex

[0001] The present invention relates to a method for producing a lactide complex.

[0002] Lactide, a dimer of lactic acid, is used as a raw material for synthesizing biodegradable polymers. In particular, polylactic acid obtained by ring-opening polymerization of lactide is widely used as a material to replace conventional petroleum-derived plastics. Patent Document 1 discloses a method for producing polyesters by mixing a cyclic ester such as a lactide with an alkylaluminum compound and ring-opening polymerizing the cyclic ester with a ring-opening polymerization catalyst. Patent Document 2 discloses polylactic acid having a number-average molecular weight of 100,000 or more obtained by ring-opening polymerization of lactide. Patent Document 3 discloses a biodegradable block copolymer having L-lactide and D-lactide formed by random copolymerization or alternating copolymerization of lactide and a cyclic ester compound. Currently, the use of lactide is limited to its use as a raw material for synthesizing biodegradable polymers such as those described above, and its use presupposes ring-opening polymerization of lactide. As disclosed in Patent Documents 1 to 3, various ring-opening polymerization catalysts, such as organolithium-based, organopotassium-based, organozinc-based, organomagnesium-based, organotin-based, organocalcium-based, organotitanium-based, and amine-based ring-opening polymerization catalysts, and ring-opening polymerization initiators, such as various alcohols, are used for the ring-opening polymerization of lactide. These catalysts and the like are components necessary for ring-opening lactide.

[0003] International Publication No. 2016 / 117473 Japanese Patent Application Laid-Open No. 2015-30814 Japanese Patent Application Laid-Open No. 2014-47317

[0004] A main object of the present invention is to provide a novel method for producing a lactide composite using lactide.

[0005] A method for producing a lactide complex according to one embodiment of the present invention includes a reaction step of using lactide, which is a cyclic dimer of lactic acid, by heating a mixture of molten lactide and a low molecular weight substance and reacting the molten lactide with the low molecular weight substance without ring-opening the lactide, wherein the molten lactide is any one of L-lactide, D-lactide, and DL-lactide, and the molecular weight of the low molecular weight substance is 2000 or less, and the mixture is stirred in the reaction step.

[0006] A method for producing a lactide complex in one embodiment includes a reaction step of heating a mixture of molten lactide and a low molecular weight substance, and reacting the molten lactide with the low molecular weight substance without ring-opening the lactide. The production method of this embodiment preferably satisfies one or more of the following (1) to (9): (1) The mixture is obtained by melting solid lactide and adding the low molecular weight substance to the molten lactide. (2) The heating is performed at a temperature of 80°C or higher and 180°C or lower. (3) The reaction step is performed under a reduced pressure environment of 5 mmHg or higher and 300 mmHg or lower. (4) The mixture is stirred in the reaction step. (5) The molten lactide is obtained by melting any one of L-lactide, D-lactide, and DL-lactide. (6) The molecular weight of the low molecular weight substance is 2000 or less. (7) The low molecular weight substance has any of a C=O bond, a P=O bond, an N=O bond, an N-H bond, and an S=O bond. (8) The number of moles of the molten lactide in the mixture is 5 to 500 times the number of moles of the low molecular weight substance. (9) The method includes, after the reaction step, a removal step of removing unreacted lactide and unreacted low molecular weight substance with an aqueous solvent.

[0007] The production method of the present invention can produce a novel lactide composite using lactide.

[0008] 1 is an IR spectrum of lactide. 2 is an IR spectrum of a lactic acid polymer. 3 is an IR spectrum of the lactide complex obtained in Example 1. 4 is an IR spectrum of the lactide complex obtained in Example 2. 5 is a mass spectrum of lactide. (a) and (b) are mass spectra of a lactic acid polymer. (a) and (b) are mass spectra of the lactide complex obtained in Example 1. (a) and (b) are mass spectra of the lactide complex obtained in Example 2. 6 is an explanatory diagram showing an example of an apparatus for producing a lactide complex.

[0009] <<Method for Producing Lactide Composite>> A method for producing a lactide composite according to one embodiment of the present invention (hereinafter referred to as the production method of one embodiment) will be described below. The production method of one embodiment includes a reaction step of heating a mixture of molten lactide and a low molecular weight substance, and reacting the molten lactide with the low molecular weight substance without ring-opening the lactide. According to the production method of one embodiment, a novel lactide composite can be produced.

[0010] The structure of the lactide complex produced by the production method of one embodiment is not necessarily clear at present. However, from the measurement results of IR spectrum and mass spectrum described below, it is presumed that the produced lactide complex is formed by multiple bonds between a plurality of lactide molecules that interact with each other via low-molecular-weight substances.

[0011] (Lactide) The lactide used in the production method of one embodiment is not limited, and conventionally known lactides can be appropriately selected and used. In the present disclosure, lactide refers to a cyclic dimer of lactic acid. The lactide used in the production method of one embodiment is any of L-lactide, D-lactide, and DL-lactide. The melting point of L-lactide is approximately 94°C to 96°C. The melting point of D-lactide is approximately 95°C to 98°C. The melting point of DL-lactide is approximately 116°C to 124°C. The lactide used in the production method of one embodiment may be one type, or two or more types. For example, any one of D-lactide, L-lactide, and DL-lactide may be used, or two or more types of these lactides may be used in combination.

[0012] Examples of molten lactide include molten D-lactide and molten L-lactide. In one embodiment of the production method, either molten D-lactide or molten L-lactide may be used, or both may be used. For example, when DL-lactide is used or when D-lactide and L-lactide are used in combination, the molten lactide will include both molten D-lactide and molten L-lactide.

[0013] A production method according to one embodiment includes a reaction step of heating a mixture of a molten lactide of at least one of D-lactide, L-lactide, and DL-lactide with a low molecular weight substance, and reacting the molten lactide with the low molecular weight substance without ring-opening of the lactide.A production method according to one embodiment includes a reaction step of heating a mixture of a molten lactide, one or both of molten D-lactide and L-lactide with a low molecular weight substance, and reacting the molten lactide with the low molecular weight substance without ring-opening of the lactide.

[0014] (Low Molecular Weight Substance) The low molecular weight substance used in the production method of one embodiment is not limited and can be appropriately selected depending on the application of the lactide complex to be produced. The low molecular weight substance used in the production method of one embodiment may be one type or two or more types.

[0015] The molecular weight of the low molecular weight substance is not limited, and in one example, the molecular weight of the low molecular weight substance is 2000 or less. In one example, the molecular weight of the low molecular weight substance is 10 or more. In another example, the molecular weight of the low molecular weight substance is 1500 or less. In another example, the molecular weight of the low molecular weight substance is 100 or more. In this disclosure, molecular weight refers to the number average molecular weight (Mn). The molecular weight of the low molecular weight substance may be greater than 2000. Alternatively, it may be less than 10 as long as it is greater than 0.

[0016] An example of a low molecular weight substance is a physiologically active substance. Examples of physiologically active substances include vitamins, amino acids, hydroxy acids, steroid hormones, and amino acid derivative hormones. Examples of such physiologically active substances include retinol, thiamine, thiamine phosphate, riboflavin, niacin, pantothenic acid, pantetheine, pyridoxal, pyridoxal phosphate, pyridoxamine, pyridoxine, biotin, folic acid, tetrahydrofolic acid, cyanocobalamin, methylcobalamin, hydroxocobalamin, ascorbic acid, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ergocalciferol, cholecalciferol, tocopherol, and tocotrienol. Examples of such an amino acid include salicylic acid, calcium salicylate, citric acid, sodium citrate, glutamine, glutamic acid, sodium glutamate, alanine, arginine, asparagine, aspartic acid, cysteine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, malic acid, citric acid, cortisol, androgen, adrenaline, dopamine, acetylcholine, and thyroxine.

[0017] Examples of small molecule substances include those used in fields such as reagents, synthetic raw materials, pharmaceuticals, pesticides, cosmetics, foods, functional foods, food additives, and feeds.

[0018] The low molecular weight substance used may be a water-soluble low molecular weight substance, or a water-insoluble or poorly water-soluble low molecular weight substance. Note that, in one embodiment, a production method can produce a water-insoluble or poorly water-soluble lactide complex while using a water-soluble low molecular weight substance. Therefore, a low molecular weight substance that is water-soluble but is desired to be used as a water-insoluble or poorly water-soluble substance can be suitably used. In the present disclosure, a water-soluble low molecular weight substance means a substance in which 0.1 g of the low molecular weight substance can be dissolved in 100 ml of water and no precipitation of the low molecular weight substance can be confirmed after 3 hours.

[0019] An example of a low molecular weight substance has any of a C=O bond (or C=O group), a P=O bond (or P=O group), an N=O bond (or N=O group), an N-H bond (or N-H group), and an S=O bond (or S=O group). A low molecular weight substance having any of these bonds has good reactivity with lactide. The thermal decomposition temperature of the low molecular weight substance may be higher than, lower than, or the same as the melting point of lactide. An example of a low molecular weight substance has a thermal decomposition temperature higher than the melting point of lactide, and in the reaction process, a mixture of molten lactide and the low molecular weight substance is heated at a temperature lower than the thermal decomposition temperature of the low molecular weight substance. The mixture of molten lactide and the low molecular weight substance may be heated at a temperature equal to or higher than the thermal decomposition temperature of the low molecular weight substance. The low molecular weight substance may be a solid, or may be dissolved or dispersed in an appropriate solvent.

[0020] 9 shows an example of a production apparatus 10 that can be used in the production method of one embodiment. The production apparatus 10 shown in the figure includes a reaction vessel 1, an air-cooled tube 2, a vacuum gauge 3, a water-cooled tube 4, a thermometer 5, a stirring means (stirring rod) 6, a heating means 7, and a collection vessel 8. The production apparatus as an example has a pressure reducing means. The collection vessel 8 as an example collects lactide that can be sublimated by heating.

[0021] In one embodiment of the manufacturing method, solid lactide (which may be crystalline lactide) is introduced into a reaction vessel 1, and the solid lactide is melted before the introduction of the low molecular weight substance. This method can increase the yield of the produced lactide complex. The lactide can be melted by heating the reaction vessel 1 to a temperature higher than the melting point of lactide. The reaction vessel 1 can be heated by appropriately selecting various heating means. Examples of the heating means include various heaters such as a mantle heater. As an example, the reaction vessel 1 is heated using a combination of an oil bath and a heater. Next, the low molecular weight substance is added to the molten lactide. This results in a mixture of molten lactide and the low molecular weight substance. The low molecular weight substance is preferably added while stirring the molten lactide. This method can increase the yield of the produced lactide complex. As an example, the mixture is obtained by mixing solid lactide and the low molecular weight substance, and then melting the solid lactide. Hereinafter, the term "mixture" refers to a mixture of molten lactide and a low molecular weight substance.

[0022] Although there are no limitations on the amounts of molten lactide and low-molecular-weight substance blended relative to the total mass of the mixture, they are preferably blended so that the number of moles of molten lactide is 5 to 500 times the number of moles of the low-molecular-weight substance. Such a blending allows the molten lactide and the low-molecular-weight substance to react sufficiently, thereby increasing the yield of the lactide complex produced.

[0023] The low molecular weight substance used is preferably one that gives an aqueous solution in which 0.1 g of the low molecular weight substance is dissolved in 100 ml of water with a pH of 4 or more and 9 or less. Use of such a low molecular weight substance can increase the yield of the produced lactide complex. An acid may be added to the functional group of the low molecular weight substance so that an aqueous solution in which 0.1 g of the low molecular weight substance is dissolved in 100 ml of water has a pH of 4 or more and 9 or less. Examples of such acids include hydrochloric acid, free carbonic acid, phosphoric acid, nitric acid, and sulfuric acid. Furthermore, metal salts in which the hydrogen atoms of these acids are substituted with metal ions may be used. Examples of metal ions include sodium ions, potassium ions, and calcium ions. Furthermore, the low molecular weight substance may be a derivative having an ester bond, an ether bond, or the like.

[0024] <Reaction step> The reaction step is a step in which a mixture of molten lactide and a low molecular weight substance is heated to react the molten lactide with the low molecular weight substance without ring-opening the lactide. Through this step, a lactide complex in which lactide and the low molecular weight substance have reacted can be produced.

[0025] In one embodiment of the manufacturing method, molten lactide is reacted with a low molecular weight substance without ring-opening the lactide. The method for reacting molten lactide with a low molecular weight substance without ring-opening the lactide is not limited, and any of the various conventionally known means capable of ring-opening or ring-opening polymerization of lactide may be avoided. For example, the mixture may be heated without using any of various ring-opening polymerization catalysts or ring-opening polymerization initiators. A low molecular weight substance that does not have the function of ring-opening lactide may be selected as the substance to be reacted with the molten lactide. One example of the manufacturing method does not use a component capable of ring-opening lactide.

[0026] Although the lactide used in the production method of one embodiment has the property of being easily decomposed in water, the produced lactide complex is not decomposed in water and is water-insoluble or poorly water-soluble. The mechanism by which the lactide complex becomes water-insoluble or poorly water-soluble is not currently clear, but the results of the examples described below make it clear that the lactide complex is water-insoluble or poorly water-soluble despite containing components derived from lactide and low-molecular-weight substances.

[0027] Heating in the reaction step is preferably carried out while stirring the mixture. This configuration can increase the yield of the produced lactide complex. In the configuration shown in the figure, the mixture in the reaction vessel 1 is stirred with a stirring rod 6, but stirring may be carried out by other means. Examples of other stirring means include a magnetic stirrer. The stirring speed of the mixture is preferably 50 rpm or more, and more preferably 150 rpm or more and 500 rpm or less.

[0028] The heating temperature in the reaction step is not limited, but 180°C or less is preferable. In this form, the produced lactide complex can be easily converted into a powder. There is no limit to the lower limit of the heating temperature, as long as the lactide can be maintained in a molten state during the reaction. The mixture in the reaction step may be heated to a temperature equal to or higher than the melting point of lactide, or may be heated below the melting point of lactide if mixing of the molten lactide with the low-molecular-weight substance causes a freezing point depression. As an example, the heating temperature of the mixture is 80°C or higher and 180°C or lower. In the form shown in the figure, the temperature of the mixture is measured with a contact thermometer, but the temperature of the mixture may also be measured with a non-contact thermometer.

[0029] The heating time is not limited and may be determined appropriately depending on the low molecular weight substance used. In one embodiment, the mixture is heated at the above heating temperature for 0.5 hours to 8 hours.

[0030] The reaction step may be carried out in a normal pressure environment or a reduced pressure environment. In a preferred embodiment, the reaction step is carried out in a reduced pressure environment. In a more preferred embodiment, the reaction step is carried out in a reduced pressure environment of 5 mmHg or more and 300 mmHg or less. This embodiment can increase the yield of the lactide complex produced. Furthermore, it can suppress the loss of lactide that can be partially sublimated by heating when collected in the collection vessel 8. In the embodiment shown in the figure, the pressure inside the reaction vessel 1 is reduced by a pressure reducing means. Examples of the pressure reducing means include a vacuum pump and an aspirator. The pressure inside the reaction vessel 1 may also be reduced by other means.

[0031] <Removal Step> The production method of one embodiment may include a removal step of removing unreacted lactide and unreacted low-molecular-weight substances after the reaction step.

[0032] In one example of the removal step, an aqueous solvent is added to the reaction vessel 1 after the reaction step. Examples of aqueous solvents include water and alcohol. Since lactide is easily decomposed in water, when a water-soluble low molecular weight substance is used in the production method of one embodiment, the lactide and the low molecular weight substance can be dissolved in the aqueous solvent. On the other hand, the produced lactide complex is water-insoluble or poorly water-soluble and therefore does not dissolve in the aqueous solvent, and exists as a precipitate or suspended matter in the reaction vessel 1. Therefore, the unreacted lactide and the unreacted low molecular weight substance can be removed by discharging the aqueous solvent containing the unreacted lactide and the unreacted low molecular weight substance from the reaction vessel 1. In other words, removal of the unreacted lactide and the unreacted low molecular weight substance using the aqueous solvent 1 is an optional step in the production method of one embodiment. Note that the properties of the produced lactide complex do not change before and after the addition of the aqueous solvent 1.

[0033] The removing step is preferably carried out after the reaction step, when the temperature of the produced lactide complex has reached 100°C or lower.

[0034] In one example of the removal step, after the reaction step, alcohol is added in an amount approximately 1 to 5 times the amount of lactide used to a reaction vessel 1 containing the produced lactide complex, unreacted lactide, and unreacted low-molecular-weight substances (hereinafter collectively referred to as the aggregate), to form an aggregate liquid containing the aggregate. Examples of alcohol include methyl alcohol and ethyl alcohol. The aggregate liquid is removed from the reaction vessel 1, and gradually added to water in an amount 10 times or more the amount of the aggregate liquid while stirring, and the stirring is continued for 24 hours or more. The water is replaced every 3 to 4 hours, allowing the removal of unreacted lactide and unreacted low-molecular-weight substances.

[0035] In another example of the removal step, the assembly liquid obtained in the same manner as above is sealed in a dialysis tube or the like and dialyzed against running water for 5 days or more to remove unreacted lactide and unreacted low-molecular-weight substances. Examples of the dialysis tube include a cellulose tube.

[0036] <Purification Step> The production method of one embodiment may include a purification step of purifying the produced lactide complex after the reaction step.

[0037] In one example of the purification step, the lactide complex obtained as a precipitate or suspension is filtered or centrifuged, and then dried by various drying means to purify the lactide complex. Examples of drying means include heat drying, freeze drying, and spray drying. The purified lactide complex is, for example, in the form of a powder, oil, or glass.

[0038] A preferred method for producing a lactide complex in one embodiment uses lactide, a cyclic dimer of lactic acid, and includes a reaction step of heating a mixture of molten lactide and a low molecular weight substance and reacting the molten lactide with the low molecular weight substance without ring-opening of the lactide, wherein the molten lactide is one or more of L-lactide, D-lactide, and DL-lactide, the molecular weight of the low molecular weight substance being 2000 or less, and the mixture is stirred in the reaction step.A preferred method for producing a lactide complex in one embodiment uses lactide, a cyclic dimer of lactic acid, and includes a reaction step of heating a mixture of molten D-lactide, molten L-lactide, or both, and a low molecular weight substance and reacting the molten lactide with the low molecular weight substance without ring-opening of the lactide, the molecular weight of the low molecular weight substance being 2000 or less, and the mixture is stirred in the reaction step.

[0039] Next, a method for producing a lactide complex will be described with reference to an example.

[0040] Example 1 300 g of D-lactide was placed in a reaction vessel, and the reaction vessel was heated to 116°C to melt the D-lactide. While maintaining the reaction vessel heating, 35.5 g of powdered pyridoxine hydrochloride was gradually added over 2 minutes while stirring the molten D-lactide at 300 rpm, yielding a mixture of D-lactide and pyridoxine hydrochloride. The pressure inside the reaction vessel was reduced to 30 mmHg, and the mixture was heated for 4 hours while stirring at 250 rpm, with the temperature of the reaction vessel controlled at 135°C to 145°C, to react the D-lactide with pyridoxine hydrochloride. After completion of the reaction, the mixture was left at room temperature for 15 minutes, and then 500 ml of warmed methanol was added to the reaction vessel to obtain a suspension. The suspension was placed in a dialysis tube, and 300 ml of water was added, followed by dialysis for 10 days. The mixture was centrifuged (1000 rpm x 30 min) using a centrifuge, and the precipitate was collected. This precipitate was freeze-dried to obtain the lactide complex of Example 1. The lactide complex of Example 1 is a complex of D-lactide and pyridoxine hydrochloride. The mass of the obtained lactide complex was 179.42 g.

[0041] Example 2: 300 g of D-lactide was placed in a reaction vessel, which was then heated to 122°C to melt the D-lactide. While maintaining the heating of the reaction vessel, 20.1 g of powdered sodium L-malate was gradually added over 2 minutes while stirring the molten D-lactide at 300 rpm, yielding a mixture of D-lactide and sodium L-malate. The pressure inside the reaction vessel was reduced to 30 mmHg, and the mixture was heated for 4 hours while stirring at 250 rpm, with the temperature of the reaction vessel controlled at 130°C to 140°C, to allow the D-lactide and sodium L-malate to react with each other. After the reaction was completed, the mixture was left at room temperature for 15 minutes, and then 500 ml of warmed methyl alcohol was added to the reaction vessel to obtain a suspension. The suspension was placed in a dialysis tube, and 300 ml of water was added, followed by dialysis for 10 days. The mixture was centrifuged (1000 rpm x 30 min) using a centrifuge, and the precipitate was collected. This precipitate was freeze-dried to obtain the lactide complex of Example 2. The lactide complex of Example 2 was a complex of D-lactide and sodium L-malate. The mass of the obtained lactide complex was 167.1 g.

[0042] (Measurement of IR Spectra) The IR spectra of lactide, the lactic acid polymer, and the lactide composite of Example 2 were measured under the following measurement condition 1, and the IR spectrum of the lactide composite of Example 1 was measured under the following measurement condition 2. The measurement results are shown in Figs. 1 to 4. Fig. 1 is the IR spectrum of lactide, Fig. 2 is the IR spectrum of the lactic acid polymer, Fig. 3 is the IR spectrum of the lactide composite obtained in Example 1, and Fig. 4 is the IR spectrum of the lactide composite obtained in Example 2.

[0043] (Measurement Condition 1) Test method: Infrared spectroscopic analysis (FT-IR) Pretreatment: KBr tablet method (a frozen sample was returned to room temperature, crushed in a mortar, and formed into KBr tablets for testing) Measurement method: Transmission method Measurement range: 4000 cm-1 to 400 cm-1 Resolution: 4 cm-1 Number of accumulations: 40 times Equipment used: Nicolet 8700 FT-IR (manufactured by Thermo Fisher Scientific)

[0044] (Measurement Condition 2) Test method: Infrared spectroscopic analysis (FT-IR) Measurement method: ATR method (ATR crystal ZnSe) Measurement range: 4000 cm-1 to 650 cm-1 Resolution: 4 cm-1 Number of accumulations: 40 times Apparatus used: Nicolet 8700 FT-IR (manufactured by Thermo Fisher Scientific)

[0045] (Mass Spectral Measurement) Lactide, the lactic acid polymer, the lactide composite of Example 1, and the lactide composite of Example 2 were dissolved in a solvent, and mass spectrometry was performed under measurement condition 3 below. The solvent used to dissolve lactide was dimethyl sulfoxide, the solvent used to dissolve the lactic acid polymer and the lactide composite of Example 2 was acetone, and the solvent used to dissolve the lactide composite of Example 1 was methanol. The results of the mass spectrometry are shown in Figures 5 to 8. Figure 5 shows the mass spectrum of lactide, Figures 6(a) and 6(b) show the mass spectrum of the lactic acid polymer, Figures 7(a) and 7(b) show the mass spectrum of the lactide composite obtained in Example 1, and Figures 8(a) and 8(b) show the FD mass spectrum of the lactide composite obtained in Example 2.

[0046] (Measurement Condition 3) Test method: FD / MS Apparatus: JMS-T200GC mass spectrometer (manufactured by JEOL Ltd.) Ionization method: FD(+) Counter electrode: -10 kV Emitter: Carbon Measurement scanning range: m / z 25 to 2000

[0047] As shown in Figure 1, the specific absorption bands in the IR spectrum of lactide are at 1770 cm-1, 1270 cm-1, and 1097 cm-1, whereas the specific absorption bands in the IR spectrum of a lactic acid polymer are at 1758 cm-1, 1186 cm-1, and 1086 cm-1, as shown in Figure 2, and the specific absorption bands of the two are clearly different. If the lactide complexes of Examples 1 and 2 are lactic acid polymers in which lactide has been ring-opened, lactide in a free state, or simple adsorbates of lactide, the specific absorption bands in the IR spectrum of the lactide complexes of Examples 1 and 2 should completely coincide with the specific absorption bands of lactide or a lactic acid polymer. As shown in Figures 3 and 4, the IR spectrum of the lactide complex of Example 1 exhibits specific absorption bands at 1747 cm-1, 1183 cm-1, and 1085 cm-1, while the IR spectrum of the lactide complex of Example 2 exhibits specific absorption bands at 1759 cm-1, 1187 cm-1, and 1092 cm-1. These specific absorption bands are clearly different from those of lactide or lactic acid polymers. These absorption bands were also confirmed in the difference spectrum between the lactide complex and the low molecular weight compound. These measurement results clearly demonstrate that the lactide complexes of Examples 1 and 2 are not ring-opened lactic acid polymers of lactide, free lactide, or simple adsorbates of lactide.

[0048] Furthermore, as shown in Figure 5, the specific fragment of the mass spectrum of lactide is 39, whereas as shown in Figures 6(a) and (b), the specific fragment of the mass spectrum of the lactic acid polymer is 43, and the specific fragments of the two are clearly different. Here, as shown in Figures 7(a) and (b), in the lactide complex of Example 1, which used pyridoxine hydrochloride, which can be measured by mass spectrometry, as the low molecular weight compound, specific fragment 45 and a mountain-shaped fragment aggregate can be confirmed between 300 and 1300. In this mountain-shaped fragment aggregate, multiple fragments spaced at intervals of 144 can be confirmed, which corresponds to the molecular weight of lactide, 144. On the other hand, in the lactide complex of Example 1, specific fragment 39 of lactide and specific fragment 43 of the lactic acid polymer cannot be confirmed.

[0049] 8( a) and 8(b), in the lactide complex of Example 2, in which sodium L-malate containing a metal salt, which is not capable of mass spectrometry, was used as the low molecular weight substance, specific fragment 39 of lactide, specific fragment 43 of the lactic acid polymer, and specific fragment 45, which is the same as that of the lactide complex of Example 1, were all confirmed. It is presumed that in the mass spectrometry of the lactide complex of Example 2, the measurement environment (high temperature, high vacuum) caused the complex of D-lactide and sodium L-malate to separate and decompose, liberating multiply bonded lactide, which then re-reacted under high temperature and high vacuum conditions, resulting in a mixture of lactide, multiply bonded lactide, and the same specific fragment as the lactic acid polymer. If the lactide complex of Example 2 is formed by ring-opening polymerization of lactide, it is presumed that only specific fragment 43 of the lactic acid polymer would be measured, or that sodium L-malate would be unable to be measured due to the presence of a metal salt.

[0050] The above IR spectrum and mass spectrum measurement results revealed that the lactide conjugates of Examples 1 and 2 were formed by reacting with a low molecular weight substance while maintaining the cyclic structure of lactide.

[0051] Next, examples of producing lactide complexes using D-lactide, L-lactide, and DL-lactide will be described with reference to Reference Examples 1 to 5. Reference Example A is a comparative production example in which a lactide complex could not be produced.

[0052] Reference Example 1 is a production example of a lactide complex in which D-lactide (molten D-lactide) is used and reacted with a low molecular weight substance. Reference Examples 2 to 4 are production examples of lactide complexes in which L-lactide (molten L-lactide) is used and reacted with a low molecular weight substance. Reference Example 5 is a production example of a lactide complex in which DL-lactide (molten DL-lactide) is used and reacted with a low molecular weight substance. Reference Example A is a production example in which D-lactide is not melted.

[0053] Reference Example 1: 225.12 g of D-lactide was placed in a reaction vessel, and the reaction vessel was heated to 120°C to melt the D-lactide. While maintaining the reaction vessel heating, 14.9 g of powdered sodium salicylate was gradually added over 2 minutes while stirring the molten D-lactide at 250 rpm, yielding a mixture of D-lactide and sodium salicylate. The pressure inside the reaction vessel was reduced to 30 mmHg, and the mixture was heated for 4 hours while stirring at 250 rpm, with the temperature of the reaction vessel controlled at 125°C to 135°C, to react the D-lactide and sodium salicylate. After completion of the reaction, the mixture was left at room temperature for 15 minutes, and then 600 ml of methyl alcohol was added to the reaction vessel to obtain a suspension. The suspension was placed in a dialysis tube, and 600 ml of water was added and dialyzed for 7 days. The precipitate, which was a lactide complex, was collected by centrifugation (500 rpm x 30 min) using a centrifuge, and was freeze-dried to obtain 186.89 g of a D-lactide-sodium salicylate complex.

[0054] Reference Example 2 300 g of L-lactide was placed in a reaction vessel, and the reaction vessel was heated to 117°C to melt the L-lactide. While maintaining the heating of the reaction vessel, 17.01 g of powdered water-soluble trisodium L-ascorbic acid 2-phosphate (molecular weight: 322.05) was gradually added over 2 minutes while stirring the molten L-lactide at 300 rpm, yielding a mixture of L-lactide and trisodium L-ascorbic acid 2-phosphate. The pressure inside the reaction vessel was reduced to 30 mmHg, and the mixture was heated for 4 hours while stirring at 250 rpm, with the heating temperature of the reaction vessel controlled at 105°C to 115°C, to react the L-lactide and trisodium L-ascorbic acid 2-phosphate. After completion of the reaction, the mixture was left at room temperature for 10 minutes, and then 500 ml of methyl alcohol was added to the reaction vessel while stirring at 300 rpm to yield a suspension. The suspension was placed in a dialysis tube, and 50 ml of water was added thereto and dialyzed for 10 days. The precipitate, which was a lactide complex, was collected by centrifugation (1000 rpm x 30 min) using a centrifuge. The precipitate was freeze-dried to obtain 148 g of L-lactide-L-ascorbic acid 2-phosphate trisodium complex.

[0055] Reference Example 3: 200 g of L-lactide and 10.08 g of water-soluble and hygroscopic acetylcholine chloride (molecular weight: 181.66) were mixed and prepared into a fine powder mixture using a mortar. This mixture was placed in a reaction vessel, and the reaction vessel was heated to 115°C while stirring the mixture at 300 rpm to melt the mixture. The reaction vessel was then depressurized to 30 mmHg, and the mixture (molten mixture) was heated for 4 hours while stirring at 250 rpm, with the reaction vessel temperature controlled at 130-135°C, to react L-lactide and acetylcholine chloride. After completion of the reaction, the mixture was left at room temperature for 10 minutes while stirring at 250 rpm. Then, 400 ml of methanol heated to 65°C was added to the reaction vessel while stirring at 300 rpm to obtain a methanol solution. This methanol solution was placed in a dialysis tube (cellulose tube), 50 ml of water was added, and the mixture was dialyzed in running water for 14 days. The solid matter formed in the solution in the dialysis tube was freeze-dried to obtain 64.89 g of an L-lactide-acetylcholine complex.

[0056] Reference Example 4: 300 g of L-lactide was charged into a reaction vessel, and the reaction vessel was heated to 100°C to melt the L-lactide. While maintaining the reaction vessel at 111°C and stirring the molten L-lactide at 300 rpm, 22.85 g of oil-soluble (poorly water-soluble) vitamin A acetate (molecular weight: 328.49) (fine powder form) was gradually added over 2 minutes to obtain a mixture of L-lactide and vitamin A acetate. The pressure in the reaction vessel was then reduced to 30 mmHg, and the mixture was heated for 3.5 hours while stirring at 250 rpm, with the temperature of the reaction vessel controlled at 130 to 135°C, to react the L-lactide with the vitamin A acetate. After the reaction was complete, the mixture was left at room temperature for 15 minutes while stirring at 250 rpm. Then, 500 ml of methanol heated to 65°C was added to the reaction vessel while stirring at 300 rpm to obtain a methanol solution. This methanol solution was placed in a dialysis tube (cellulose tube), and 50 ml of water was added. The mixture was dialyzed in running water for 14 days. The solid matter that formed in the solution in the dialysis tube was freeze-dried to obtain 145.56 g of L-lactide-vitamin A acetate complex.

[0057] Reference Example 5: 275 g of DL-lactide was placed in a reaction vessel, and the reaction vessel was heated to 126°C to melt the DL-lactide. While maintaining the reaction vessel heating, 8 g of powdered water-soluble cyanocobalamin (molecular weight: 1355.37) was gradually added over 2 minutes while stirring the molten DL-lactide at 300 rpm, yielding a mixture of DL-lactide and cyanocobalamin. The pressure inside the reaction vessel was reduced to 30 mmHg, and the mixture was heated for 4 hours while stirring at 250 rpm, with the temperature of the reaction vessel controlled at 145°C to 150°C, to react the DL-lactide and cyanocobalamin. After completion of the reaction, the mixture was left at room temperature for 20 minutes, and then 500 ml of methyl alcohol was added to the reaction vessel while stirring at 300 rpm to obtain a suspension. The suspension was placed in a dialysis tube, and 50 ml of water was added, followed by dialysis for 14 days. The solid matter generated in the solution inside the dialysis tube was removed and freeze-dried to obtain 60.44 g of a DL-lactide-cyanocobalamin complex.

[0058] (Reference Example A) 22.5 g of D-lactide and 1.5 g of sodium salicylate were placed in a mortar and thoroughly ground and mixed to obtain a powder mixture of D-lactide and sodium salicylate. This powder mixture was placed in a beaker and left to stand in a desiccator at room temperature and under a reduced pressure of 30 mmHg for 4 hours. 50 ml of methyl alcohol was then added to the powder mixture to obtain a solution. The solution was placed in a dialysis tube, and 50 ml of water was added, followed by dialysis for 7 days. No floating matter was observed in the dialysis tube. The solution in the dialysis tube was placed in a flask, and the water was removed under reduced pressure. No residue was observed in the flask.

[0059] In Reference Examples 1 to 5, in which lactide was melted, the formation of a precipitate (or solid) that remained insoluble in water was confirmed, and the amount of the remaining precipitate (or solid) was greater than the amount of the raw material low-molecular-weight substance. On the other hand, in Reference Example A, in which lactide was not melted, no precipitate that remained insoluble in water was confirmed. These results also clearly demonstrate that a lactide composite can be produced by melting lactide and reacting it with a low-molecular-weight substance.

[0060] DESCRIPTION OF SYMBOLS 1: Reaction vessel 2: Air cooling tube 3: Vacuum gauge 4: Water cooling tube 5: Thermometer 6: Stirring means 7: Heating means 8: Collection vessel 10: Lactide production apparatus

Claims

1. A method for producing a lactide complex, comprising: using lactide, which is a cyclic dimer of lactic acid; and heating a mixture of the molten lactide and a low molecular weight substance to react the molten lactide with the low molecular weight substance without ring-opening the lactide; the molten lactide is any one of L-lactide, D-lactide, and DL-lactide; the molecular weight of the low molecular weight substance is 2000 or less; and the mixture is stirred in the reaction step.

2. The method for producing a lactide complex according to claim 1, wherein the mixture is obtained by melting solid lactide and adding the low molecular weight substance to the molten lactide.

3. The method for producing a lactide complex according to claim 1 or 2, wherein the heating is carried out at a temperature of 80°C or higher and 180°C or lower.

4. The method for producing a lactide complex according to claim 1 or 2, wherein the reaction step is carried out under a reduced pressure environment of 5 mmHg or more and 300 mmHg or less.

5. The method for producing a lactide complex according to claim 1 or 2, wherein the low molecular weight substance has any one of a C=O bond, a P=O bond, an N=O bond, an N-H bond, and an S=O bond.

6. The method for producing a lactide complex according to claim 1 or 2, wherein the number of moles of the molten lactide in the mixture is 5 to 500 times the number of moles of the low molecular weight substance.

7. A method for producing a lactide complex according to claim 1 or 2, comprising a removal step of removing unreacted lactide and unreacted low molecular weight substances with an aqueous solvent after the reaction step.

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