How to make high quality tricaprylin

Abstract

The present invention provides an efficient method for producing tricaprylin with high purity. The process of the present invention produces high purity tricaprylin by applying at least one of the following conditions: (i) preferably selective derivatization of halide-based impurities present in the resulting reaction product and / or treating or contacting the resulting reaction product with at least one nucleophile; (ii) carrying out the esterification at a temperature not exceeding 180°C; (iii) using glycerol or a protected form or precursor thereof, preferably solketal (isopropylideneglycerol), as starting material; and (iv) operating and / or carrying out the esterification in the absence of a metal-based catalyst.

Description

[Technical field]

[0001] The present invention relates to the technical field of fatty acid polyol esters, in particular fatty acid glycerol esters, and to related metabolic and medical treatment concepts for related diseases.

[0002] In particular, the present invention relates to a method for producing high quality tricaprylin (synonymously referred to as trioctanoyl glyceride, tricaprylglycerol, trioctanoin glycerol, tricapryloyl glycerol, octanoic acid-1,2,3-propane trilester, glycerol tricaprylate, tricaprylglycerin, glycerol trioctanoate, glyceryl tricaprylate, capryl triglyceride, tricaprylin, tricaprylglycerol, etc.), as well as to the inventive reaction product (i.e. tricaprylin) thus obtainable or thus prepared, and to its respective uses and applications, in particular in pharmaceutical compositions such as drugs or medicines, or in foods, in food products, in food or nutritional compositions and / or medical foods, and further uses or uses thereof.

[0003] Furthermore, the present invention relates to a pharmaceutical composition, in particular a drug or pharmaceutical product, comprising the reaction product of the present invention (i.e. tricaprylin) obtainable or produced according to the method of the present invention, usually together with a physiologically acceptable excipient, and further to the respective applications or uses thereof.

[0004] Furthermore, the present invention relates to a food, nutritional composition or food composition, in particular a food supplement, functional food, novel food, food additive, diet food, power snack, appetite suppressant, and strength and / or endurance sports supplement comprising the reaction product of the present invention (i.e. tricaprylin) obtainable or produced according to the method of the present invention, and further to the application or use thereof.

[0005] Furthermore, the present invention relates to the use of the reaction product of the present invention (i.e. tricaprylin) as an additive or auxiliary, in particular as a carrier or excipient, solubilizer, release agent, surface treatment agent, transport agent, lubricant, hydrophobizing agent, film-forming or protecting agent, and viscosity modifier, preferably as a carrier or excipient, in pharmaceutical compositions, in particular drugs or pharmaceuticals, in foods, nutritional compositions or food compositions, in food products and / or medical foods, and also in cosmetic compositions.

[0006] Finally, the present invention also relates to the use of a nucleophile for purifying tricaprylin. [Background technology]

[0007] In human energy metabolism, glucose is a short-term available energy carrier that is metabolized to energy in mitochondria by releasing water and carbon dioxide. Glycogen stores in the liver are already emptied during nighttime sleep. However, the human central nervous system (CNS) and heart, in particular, require a permanent energy supply.

[0008] The physiological alternative to glucose that is primarily supplied to the central nervous system is the so-called ketone bodies (also synonymously called keto bodies).

[0009] The term ketone bodies is a collective term for three compounds, which are primarily produced in catabolic metabolic states (fasting, weight loss diets, low-carbohydrate diets, etc.) and can lead to ketosis. The term ketone bodies includes in particular acetoacetate (also synonymously called acetoacetate) and acetone, as well as 3-hydroxybutyrate (hereinafter also synonymously called β-hydroxybutyrate or BHB or 3-BHB) or its salts (i.e. 3-hydroxybutyrate or β-hydroxybutyric acid), the latter being the most important of the three aforementioned compounds. 3-hydroxybutyrate or its salts physiologically exists as the (R) enantiomer, i.e. (R) 3-hydroxybutyrate (also synonymously called (3R) 3-hydroxybutyrate, to emphasize the center of chirality at the 3-position) or its salts.

[0010] These ketone bodies are also physiologically supplied in large quantities from lipids stored in the body through lipolysis during fasting or starvation, and almost completely replace glucose, which is an energy source.

[0011] Ketone bodies are produced in the liver from acetyl-CoA (=acetyl-CoA) derived from β-oxidation; they represent the transportable form of acetyl-CoA in the human body. However, to be able to utilize ketone bodies, the brain and muscles must first adapt by expressing the enzymes necessary to convert ketone bodies back to acetyl-CoA. Especially during fasting, ketone bodies contribute significantly to energy production. For example, after a period of time, the brain can get by with only one-third of the daily glucose intake.

[0012] Physiologically, ketone bodies are synthesized from two molecules of activated acetate in the form of acetyl coenzyme A, a normal intermediate product of fatty acid degradation, which is further extended to the intermediate product 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) using an acetyl coenzyme A unit and the enzyme HMG-CoA-synthase, and finally cleaved to acetoacetate by HMG-CoA-lyase. These three steps are carried out exclusively in the liver mitochondria (i.e., the linen cycle), and 3-hydroxybutyrate is finally generated in the cytoplasm by D-β-hydroxybutyrate dehydrogenase. HMG-CoA is also the end product of the degradation of the amino acid leucine, and acetoacetate is generated during the degradation of the amino acids phenylalanine and tyrosine.

[0013] Acetoacetate undergoes spontaneous decarboxylation to form acetone, which is sometimes detected on the breath of diabetics and dieters. It is not further utilized by the body. However, the percentage of acetone in ketone bodies is small.

[0014] Acetoacetate is thus reductively converted to the physiologically relevant forms 3-hydroxybutyric acid or 3-hydroxybutyrate, but can also decompose to the physiologically unusable acetone, releasing carbon dioxide, which is detectable in severe ketosis, ketoacidosis (e.g., in type 1 diabetic patients not supplemented with insulin), and can be detected by the sense of smell in urine and in exhaled air.

[0015] 3-Hydroxybutyric acid is currently used and sold in the weight training field as its sodium, magnesium, and calcium salts.

[0016] However, 3-hydroxybutyrate is unknown or known only in small amounts to humans from an evolutionary perspective, because plants do not produce 3-hydroxybutyrate and 3-hydroxybutyrate in animal organisms occurs only in emaciated animal carcasses in a state of ketosis. 3-hydroxybutyrate in its free acid and salt form is also very bitter in taste and causes severe vomiting and nausea.

[0017] Moreover, patients, especially newborns but also adults, cannot permanently tolerate large amounts of salts of 3-hydroxybutyric acid.

[0018] Furthermore, the plasma half-life of 3-hydroxybutyrate and its salts is very short, with ketosis lasting only 3-4 hours even after ingestion of a few grams, which can be life-threatening in patients with metabolic disorders.

[0019] Therefore, in the case of the treatment of such metabolic diseases, fatty acid polyol esters, in particular fatty acid glycerol esters, in particular the so-called medium chain triglycerides (i.e. the so-called MCT or MCT oils and fats), are currently used in ketogenic therapy, i.e. in particular caproic, caprylic and capric acids from the corresponding triglycerides (i.e. the saturated linear C6-, C8- and C8- fatty acids). 10 -fatty acids) is intended for metabolic conversion.

[0020] Medium chain triglycerides (also known synonymously as MCT, MCT fat, MCT oil, etc.) are triglycerides containing two to three fatty acids, or medium chain fatty acids (MCFAs), with straight-chain saturated aliphatic tails of 5 to 12 carbon atoms, especially 6 to 12 carbon atoms. Abundant food sources for the commercial extraction of MCTs include palm kernel oil and coconut oil.

[0021] Thus, according to this definition, medium-chain triglycerides (MCT) are triglycerides that contain medium-chain fatty acids. These include, among others, caproic acid (C6:0), caprylic acid (C8:0), capric acid (C10:0) and lauric acid (C12:0). These acids are saturated fatty acids and are found mainly in tropical vegetable fats such as coconut oil (about 60%) and palm kernel oil (about 55%), and in butter. They are also found in small amounts in dairy fats (about 10%). Pure MCT oil does not occur in nature, only as a mixture with other triglycerides. MCTs have a somewhat lower calorific value or food energy (3475 kJ / 100 g) compared to fats (3852 kJ / 100 g) and a lower smoke point compared to conventional long-chain fats (LCT = long-chain triglycerides).

[0022] MCT oils are obtained industrially by hydrolysis of coconut or palm kernel oil, fractionation of the medium-chain fatty acids, and subsequent esterification with glycerol. Pure MCT oil is colorless to yellowish in color, has a neutral odor and taste, and has a very low viscosity. It is described as a vegetable oil (i.e., neutral oil or oleum neutrale).

[0023] The German Pharmacopoeia, 10th edition, 1991 (i.e. Deutsches Arzneibuch 10 or DAB 10) and the corresponding European Pharmacopoeia (Ph. Eur., especially Ph. Eur. 10.0, monograph No. 0686 "Triglycerides, medium chain [Triglycerida saturata medium]") are as follows: 50-80% caprylic acid C8, 50-80% capric acid C 10 25-45%, lauric acid C 12 up to 3% and caproic acid C6 up to 2% (Reference: Hagar's Handbook of Pharmaceutical Practice, 5th Edition, ISBN 978-3-642-63389-8, continued on page 1059).

[0024] MCTs have a wide range of applications and formulations. MCT oils have been produced industrially since 1995 and are used for various purposes due to their specific properties. In 1994, MCTs attracted interest, especially in the food sector, after the US Food and Drug Administration (FDA) accepted the GRAS application (Generally Recognized as Safe). Due to their physical properties, industrially obtained MCT oils are also used in the production of cosmetics (ointments, creams, bath oils, etc.) and pharmaceuticals (tablets, coated tablets, etc.), in particular as carriers and excipients, solubilizers, release agents, surface treatment agents, transport agents, lubricants, hydrophobizing agents, film-forming agents, protective agents and viscosity modifiers. Furthermore, due to their metabolic peculiarities, they are also used in dietetic foods (e.g. MCT oil and MCT margarine) and artificial nutritional products (e.g. enteral and parenteral). These products are classified as nutritional foods for special medical purposes (e.g. balanced diet) according to the German Nutritional Products Ordinance (the so-called German “Diaetverordnung”).

[0025] There is also a great deal of interest in the physiological properties and metabolism of MCTs: Due to their short fatty acid chain length, MCT fats are relatively water-soluble and metabolized without bile acids. Their structure also does not require cleavage by pancreatic lipase (i.e., an enzyme in the pancreas). Ketone bodies are transported in the blood directly to the liver, bypassing the lymphatic system, where they are preferentially oxidized over conventional fats, promoting the production of ketone bodies. Transport of medium-chain fatty acids (MCFAs) to mitochondria (i.e., the site of fatty acid oxidation) occurs independently of carnitine. The tolerable daily intake varies from person to person and is about 50 to about 100 g or more of MCT fat. To avoid side effects (diarrhea, cramps, headaches, etc.), it is common to start with about 20 g of MCT fat per day. This amount can be gradually increased by 5 to 10 g per day. When following a dietary therapy using MCT oils and fats, it is essential to supplement with fat-soluble vitamins and essential fatty acids (such as omega-3 and omega-6). Fat-soluble vitamins are better absorbed when MCT oils are used.

[0026] Due to their metabolic properties, MCT fats have become a valuable component of nutritional therapy in diets for a variety of clinical indications.

[0027] Medium-chain triglycerides were first used in clinical nutrition in the 1950s as a dietary treatment for malabsorption syndromes, as they are more water-soluble and absorbed by the body more quickly than traditional long-chain fats. In cases of lymphangiectasia (widening of lymphatic vessels), Whipple's disease (a rare infection), and pneumothorax (accumulation of lymphatic fluid in the chest cavity), MCT fats help relieve lymphatic congestion. In premature infants, medium-chain fats are used to achieve weight gain, as the digestive system is not yet fully developed.

[0028] Since MCT fats are metabolized independently of pancreatic enzymes and only need to be broken down by gastric lipase, their use is indicated in cases of exocrine pancreatic insufficiency with pronounced steatorrhea (fatty stools or the presence of fat in the feces) when enzyme supplementation does not produce the desired effect. Exocrine pancreatic insufficiency occurs, for example, in chronic pancreatitis and cystic fibrosis. Furthermore, their use in combination with pancreatic supplements is also useful. Another classic application area of ​​MCT fats is short bowel syndrome, in which impaired digestion, especially of edible oils and fats, is observed depending on the extent and site of the resected intestine. If the large intestine is preserved, medium-chain fatty acids are well absorbed and can replace conventional fats. In rare inborn errors of metabolism such as β-oxidation defects of long-chain fatty acids (LCHAD) and very long-chain fatty acids (VLCAD), medium-chain fatty acids are an essential source of energy. MCT fats are also used in artificial nutrition (i.e. enteral and parenteral) for various diseases, mainly of the digestive tract.

[0029] MCT fats are more ketogenic than conventional fats and oils, and therefore are also used in the ketogenic diet (KD), especially as a partial replacement for LCT fats. The ketogenic diet is applied to drug-resistant epilepsy and rare congenital metabolic diseases (pyruvate dehydrogenase deficiency, GLUT1 deficiency, etc.). The nutrient ratio of the classical ketogenic diet is usually 3-4 fats, 1 carbohydrate and protein. The ketogenic diet with MCT fats is considered a promising alternative to the classical diet in children and adults, because the high ketogenicity of MCT fats allows the ratio of fats to carbohydrates and proteins to be shifted in favor of carbohydrates. The ketogenic diet is also used to treat brain tumors, Parkinson's disease, migraine headaches, Alzheimer's disease, and NAFLD (non-alcoholic fatty liver disease / hepatitis). Due to the metabolic properties of MCT fats and their lower energy content compared to conventional fats, MCT fats are also used in the field of weight management and metabolic syndrome.

[0030] The use of MCT oils in the nutritional therapy of various diseases should be distinguished from their use in sports nutrition, where MCT oils are known as a fast energy source and are primarily used in endurance sports.

[0031] Medium-chain fatty acids are contraindicated in those at risk of ketoacidosis and in those with impaired medium-chain fatty acid oxidation (MCAD deficiency, MCADD, or medium-chain acyl-CoA dehydrogenase deficiency). Due to their low smoke point, medium-chain fatty acids have limited heat resistance.

[0032] Specifically, a fatty acid polyol ester, and in particular a fatty acid glycerol ester, of particular interest is tricaprylin (also called trioctanoyl glyceride, tricaprylglycerol, trioctanoin glycerol, tricapryloyl glycerol, octanoic acid-1,2,3-propane triyl ester, synonymously called glycerol tricaprylate, tricaprylglycerol, glycerol tricaprylate, glycerol trioctanoate, glyceryl tricaprylate, capryl triglyceride, tricaprylin, tricaprylglycerol, etc.). Tricaprylin is a triglyceride of caprylic acid, usually produced by esterification of caprylic acid with glycerol. Tricaprylin is a clear to pale yellow liquid. It forms crystals from acetone / ethanol (95%). Tricaprylin is odorless.

[0033] Tricaprylin is used, for example, in pharmaceutical formulations as a neutral carrier or excipient, as an absorption enhancer, as a solubilizer of active agents. It is also used in the preparation of water-in-oil multiple emulsions to incorporate water-soluble drugs, and as an oily phase to obtain stable microcapsules. Tricaprylin also acts as a vehicle in topical creams and lotions, as well as cosmetic formulations. It is also used as a lipid base to enhance penetration, with excellent emollient effects and skin-soothing properties. It is a non-greasy ingredient with low viscosity, so it spreads very well. Despite its skin-permeability, tricaprylin does not interfere with natural skin breathing, so it is used in baby oils, massage oils, face masks, etc. It is an excellent dispersant, and acts as a solubilizer, humectant, and binder in color cosmetics. Because it is easily miscible with natural oils and surfactants, tricaprylin is also used as a fat component in two-phase bubble baths. In addition, it is used in sunscreen creams and oils due to its compatibility with organic and inorganic filter agents. It is also used as a fixative in perfumes and fragrances.

[0034] However, as mentioned above, fatty acid polyol esters, in particular fatty acid glycerol esters, especially the so-called medium chain triglycerides (MCTs), and especially tricaprylin, have also been used as active ingredients or compounds in pharmaceutical compositions.

[0035] Specifically, tricaprylin-containing compositions were previously marketed under the trademark "Axona" as medical foods for the clinical dietary management of the disturbances in metabolic processes associated with mild to moderate Alzheimer's disease. The marketed formulation consists of tricaprylin fractionated from palm kernel oil. During digestion, caprylic triglyceride is broken down into ketone bodies, which provide an alternative energy source for the brain. Its use is based on the fact that in Alzheimer's disease, the brain's ability to utilize its normal energy source (i.e. glucose) is impaired.

[0036] As a result, there is a high demand and growing interest in the prior art for fatty acid polyol esters, especially fatty acid glycerol esters such as medium chain triglycerides (MCTs), especially tricaprylin.In particular, there is a growing demand in the pharmaceutical and food industries for higher fatty acid polyol esters, especially higher fatty acid glycerol esters, which have high active substances and low impurities, especially harmful impurities.

[0037] However, conventional manufacturing methods for producing fatty acid polyol esters, especially fatty acid glycerol esters, such as medium chain triglycerides (MCT), especially tricaprylin, but also others, including subsequent multi-stage purification treatments (multi-stage distillation at high temperatures as described above), produce relatively high levels of impurities and by-products, especially due to the required high processing temperatures, the starting materials and reagents used, especially halogen-containing substances (e.g., those derived from hydrochloric acid HCl and metal-based catalysts used in the esterification process). In particular, when triglycerides with low acid and hydroxyl values ​​and high degrees of esterification are required, the necessary extensive esterification conditions, especially high temperatures above 180°C and up to 230°C, the necessary subsequent multi-stage purification treatments (multi-stage distillation at high temperatures as described above), and the use of metal-based catalysts result in the formation of high contents of toxic by-products and impurities, especially toxic halide-based by-products and impurities.

[0038] In particular, conventional production processes for producing fatty acid polyol esters, especially fatty acid glycerol esters, including subsequent multi-stage purification treatments (multi-stage distillation as described above at high temperatures), usually also produce relatively high levels of impurities and by-products, especially toxic impurities and by-products, such as, for example, genotoxic glycidol esters of fatty acids (also synonymously referred to as glycidyl esters of fatty acids or simply GE or GE fatty acids) and nephrotoxic fatty acid esters of monochloropropanediol (also synonymously referred to as MCPD fatty acid esters or simply MCPD esters), especially fatty acid esters of 3-monochloropropanediol (3-MCPDE fatty acid esters or 3-MCPD esters) and fatty acid esters of 2-monochloropropanediol (2-MCPD fatty acid esters or 2-MCPD esters).

[0039] The following exemplary reaction scheme illustrates the formation of the three aforementioned toxic by-products, namely 3-MCPD fatty acid esters, 2-MCPD fatty acid esters and glycidol fatty acid esters, for the triglyceride tricaprylin selected as a non-limiting example, when high temperatures (e.g., temperatures above 200° C.) are applied to fatty acid triglycerides (e.g., tricaprylin) in the presence of chlorine-containing substances originating from the manufacturing process. The substance 3-chloro-1,2-propanediol is generated from glycerin when it reacts with 3-MCPD in the presence of chlorine-containing substances or chlorides, respectively.

[0040] [ka] Summary of the Invention [Problem to be solved by the invention]

[0041] Especially for pharmaceutical and nutritional applications, control of the impurity profile is crucial, especially for known toxic by-products such as 3-MCPD fatty acid esters, 2-MCPD fatty acid esters, and glycidol fatty acid esters.

[0042] The generation of such undesirable toxic by-products, such as those caused by harsh process conditions during conventional fat / oil esterification / condensation methods, has been well known for decades, but no attempt has been made to avoid such harsh conditions by improving or modifying the manufacturing process, because it is known that mild esterification conditions using bio-based catalysts and low esterification temperatures reduce the generation of toxic by-products, such as the three aforementioned toxic by-products, i.e., 3-MCPD fatty acid esters, 2-MCPD fatty acid esters and glycidol fatty acid esters, but at the same time only result in triglycerides with undesirably high acid and hydroxyl values ​​and relatively low triglyceride content, at low conversion and yield.

[0043] As a result, instead of trying to avoid the production of undesirable toxic by-products, rather costly and burdensome pre- and / or post-treatment methods are implemented to remove these undesirable toxic by-products from the desired end product obtained under harsh esterification conditions (especially high temperatures above 180 ° C and up to 230 ° C, use of metal-based catalysts, etc.). Such burdensome post-treatment methods consist in particular of the addition of strong alkaline reagents such as KOH, multi-stage distillation cascades, heat treatment with strong aqueous alkaline solutions, etc. (e.g. WO2019 / 038320A1, WO2014 / 012548A1, etc.), which affect and deteriorate such product quality, and also the overall yield and efficiency. For example, WO2021 / 070209A1 discloses a complex multi-stage extraction process for purifying triglycerides, using a saline / organic solvent two-phase extraction system with chlorinated organic solvents.

[0044] However, such post-treatment methods rarely remove the last traces of undesirable toxic by-products, which remain in the final product. This is particularly dangerous when high doses of fatty acid polyol esters, especially fatty acid glycerol esters, MCTs such as tricaprylin, are applied in pharmaceutical and nutritional applications (especially for parenteral applications), leading to the accumulation of such undesirable traces of undesirable toxic by-products in the human body, thus exceeding the authorized threshold levels of undesirable toxic by-products regulated by law.

[0045] Moreover, such costly and burdensome work-up methods aimed only at the retroactive or retroactive removal of undesirable toxic by-products are also inefficient, since they often lead to undesirable entrainment of the product and do not improve or affect product quality or product purity, such as the degree of esterification or the residual amount of other impurities (e.g., total halogenated substance content and total acid content).

[0046] For example, the European Union (EU) through its respective legal regulations (e.g. EU Regulations 2020 / 1322 and 2018 / 290) strictly limits the concentration of such toxic by-products and impurities for food applications, especially for infants and young children. For example, the maximum permitted content of nephrotoxic 3-MCPD fatty acid esters in liquid infant formula, follow-on formula, special medical foods for infants and young children, and infant formula is only 15 mg / kg (i.e. 15 ppm), while the maximum permitted content of genotoxic glycidol fatty acid esters in the same formulations is even more limited at only 6.0 mg / kg (i.e. 6.0 ppm). As a result, the permissible exposure levels of these toxic by-products in nutritional applications are very limited.

[0047] It is therefore difficult to stay below maximum exposure levels, especially for monographed drug substances (i.e. active pharmaceutical ingredients) such as MCT oil, where the total daily intake is well above 10 g / day. In the case of parenteral administration, this is even more difficult, since hazardous substances can enter the human body directly.

[0048] Permanent or lifelong administration of fatty acid polyol esters, especially fatty acid glycerol esters, such as medium chain triglycerides (MCT), especially tricaprylin but also others, involves doses or intakes of up to 100 g / day. For this, particularly high purity grades are required. In contrast to nutritional applications, in the case of pharmaceutical applications, the patient's tolerance level is very low, also in terms of toxic impurities, since the drug is taken by seriously ill patients whose health is in any case compromised.

[0049] It would therefore be desirable to envisage an efficient process for the direct production of high quality fatty acid polyol esters, in particular fatty acid glycerol esters, such as MCT (e.g. tricaprylin), having high purity or minimal levels of by-products and impurities, respectively, while at the same time exhibiting a high degree of esterification and good stability, in particular storage stability and high active ingredient content, in particular without the need for additional cost-intensive and burdensome post-treatment operations.

[0050] As a result, the prior art has not lacked attempts to find efficient production processes, but has failed to improve the efficiency and performance of existing processes. However, so far, no efficient manufacturing processes have been devised in the prior art. Also, access to such higher fatty acid polyol esters, especially fatty acid glycerol esters, such as MCT (e.g. tricaprylin), is not possible or easy according to the prior art.

[0051] The problem underlying the present invention is therefore to provide an efficient method for producing triglycerides of fatty acids (i.e. fatty acid glycerol triesters), in particular tricaprylin, in particular triglycerides having a high degree of purity, wherein the aforementioned drawbacks and / or obstacles of the prior art should at least partially be avoided or at least essentially be overcome.

[0052] Such a production process should in particular make available the respective fatty acid polyol esters, in particular fatty acid glycerol esters, such as MCT (in particular tricaprylin), in an efficient manner, in particular of improved quality and without significant amounts of toxic by-products or impurities, and such a production process should be feasible on an industrial level, in particular on a large-scale level, and should not involve excessive and cost-intensive post-treatments, as envisaged in the prior art processes.

[0053] Quite surprisingly, the applicant has found that when applying at least one of the following conditions in the preparation process: (i) preferably selective derivatization of halide-based impurities present in the resulting reaction product and / or treating or contacting the resulting reaction product with at least one nucleophile, (ii) carrying out the esterification at a temperature not exceeding 180° C., (iii) using glycerol or a protected form or precursor thereof, preferably solketal (isopropylideneglycerol), as starting material, (iv) operating and / or carrying out the esterification in the absence of a metal-based catalyst; tricaprylin of particularly high purity can be directly and efficiently prepared, in a particularly economical and industrially feasible manner. It was not foreseeable that the application of at least one of these conditions or a combination thereof would lead to a significant improvement in the preparation of tricaprylin. [Means for solving the problem]

[0054] Therefore, in order to solve the above-mentioned problems, the present invention proposes, according to a first aspect thereof, a method for producing particularly high purity tricaprylin as defined in claim 1; further particularly special and / or advantageous embodiments of the inventive method are the subject of the respective dependent claims.

[0055] Furthermore, the present invention relates according to a second aspect to the tricaprylin of the invention obtainable or obtained by the process of the invention according to the respective independent claim (i.e. claim 23) and to the tricaprylin of the invention according to the respective independent claim (i.e. claim 24); further particularly special and / or advantageous embodiments of this aspect of the invention are the subject of the respective dependent claims.

[0056] Similarly, the present invention relates according to a third aspect to a pharmaceutical composition, in particular a medicament or medicinal product, according to the respective independent claim (claim 26); further particularly special and / or advantageous embodiments of this aspect of the invention are the subject matter of the respective dependent claims.

[0057] Furthermore, the present invention also relates, according to a fourth aspect of the invention, to a tricaprylin according to the invention for or for use in the preventive and / or therapeutic treatment of diseases of the human or animal body, according to the respective independent claims (claims 29 and 30).

[0058] Furthermore, the present invention relates according to a fifth aspect to a tricaprylin according to the invention for the preventive and / or therapeutic treatment of diseases of the human or animal body or for the manufacture of a medicament for the preventive and / or therapeutic treatment of diseases of the human or animal body according to the respective independent claims (claims 31 to 33).

[0059] Furthermore, the present invention relates according to a sixth aspect to a food and / or nutritional or food composition, and / or a food product and / or a medical food according to the respective independent claim (claim 34); further particularly special and / or advantageous embodiments of the food and / or nutritional or food composition, and / or the food product and / or medical food according to the invention are the subject of the respective dependent claims.

[0060] Likewise, the present invention relates, according to a seventh aspect, to the use of the inventive tricaprylin according to the respective independent claim (claim 36); further particularly special and / or advantageous embodiments of the use according to the invention are the subject of the respective dependent claims.

[0061] Furthermore, according to an eighth aspect of the present invention, the present invention further relates to the use of tricaprylin according to the present invention according to each independent claim (claims 38 to 42).

[0062] Finally, the present invention relates according to a ninth aspect to the use of a nucleophile for purifying tricaprylin and / or for preferably selectively removing or derivatizing halide-based impurities present in tricaprylin according to the respective independent claim (claim 43); further particularly special and / or advantageous embodiments of the use according to the invention are the subject of the respective dependent claims.

[0063] The following features, embodiments, advantages, etc. are described below only with respect to one aspect of the present invention in order to avoid repetition, but it goes without saying that they also apply to other aspects of the present invention as appropriate, without requiring separate mention.

[0064] Furthermore, it goes without saying that individual aspects and embodiments of the invention are also considered to be disclosed in any combination with other aspects and embodiments of the invention, and in particular any combination of features and embodiments resulting from reference to any claim is also considered to be broadly disclosed with respect to all resulting combination possibilities.

[0065] It should further be noted that with regard to all relative or percentage weight-based data provided below, in particular relative amount or weight data, within the scope of the present invention, these are selected by the skilled artisan in such a way that they always add up to 100% by weight or 100% by weight, respectively, including all components or ingredients, in particular as defined below; however, this is self-evident to the skilled artisan.

[0066] Moreover, those skilled in the art can deviate from the following range specifications, if desired, without departing from the scope of the invention.

[0067] Furthermore, it applies that all values ​​or parameters etc. specified below can in principle be determined or identified by standardized or explicitly defined measurement methods or by determination or measurement methods well known to the person skilled in the art.

[0068] With this being said, the present invention will now be described in more detail.

[0069] The subject of the present invention is therefore, according to a first aspect thereof, a method for producing tricaprylin (i.e. trioctanoylglyceride or tricaprylglycerol), in particular in high purity, Here, formula (I) CH2(OH)-CH(OH)-CH2(OH) (I) or a protected form or precursor thereof, preferably solketal (isopropylideneglycerol), as a starting material, and reacting and / or converting it to tricaprylin, As the reaction product, Formula (II) CH2[OC(O)R 1 ]-CH[OC(O)R 1 ]-CH2[OC(O)R 1 ] (II) producing tricaprylin of wherein in formula (II) the radical R 1 represents a linear saturated aliphatic C7-alkyl radical of formula -(CH2)6-CH3 (i.e., an n-heptyl radical); wherein the process comprises at least one esterification step, in particular using C8-fatty acids, in particular linear saturated or mono- or poly-unsaturated C8-fatty acids and / or their anhydrides and / or esters (preferably C1-C4-alkyl esters), preferably using caprylic acid (i.e. n-octylic acid or 1-heptanecarboxylic acid) of formula CH3-(CH2)6-COOH and / or its anhydrides or esters (preferably C1-C4-alkyl esters); Here, the method (i) selectively derivatizing the halide-based impurities present in the resulting reaction product, in particular the MCPD fatty acid esters (fatty acid esters of monochloropropanediol, in particular MCPD caprylic acid ester) and glycidol esters of fatty acids (in particular glycidol caprylic acid ester) and / or derivatizing the resulting reaction product with at least one nucleophile, in particular a nucleophile capable of removing halide-based impurities, preferably hydrogen sulfite (bisulfite, HSO - ), sulfite (SO3 2- ), hydrogen thiosulfate (HS2O3 - ), thiosulfate (S2O3 2- ), hydrogen phosphite (H2PO3 - ), Phosphite (HPO3 2- ) and phosphines and combinations thereof, more preferably hydrogen sulfites (bisulfites, HSO - ), in particular for the preferably selective derivatization of halide-based impurities, in particular MCPD fatty acid esters (fatty acid esters of monochloropropanediol) and glycidol esters of fatty acids; (ii) at least one esterification stage is operated and / or carried out at a temperature not exceeding 180°C, in particular not exceeding 150°C, in particular not exceeding 120°C, preferably not exceeding 100°C, more preferably not exceeding 80°C, even more preferably not exceeding 50°C; (iii) the 1,2,3-propanetriol of formula (I) or a protected form thereof, preferably solketal (isopropylideneglycerol), used as starting material is at least essentially free of chlorinated species, in particular having a total chlorinated species content of at most 1 ppm, in particular at most 0.5 ppm, preferably at most 0.1 ppm, based on the 1,2,3-propanetriol of formula (I) or a protected form thereof, preferably solketal (isopropylideneglycerol); (iv) at least one esterification step is carried out in the absence of a metal-based catalyst; and in particular by a combination of at least two, preferably a combination of at least three, more preferably a combination of all four of the above features and / or conditions (i) to (iv).

[0070] As mentioned above, the Applicant has very surprisingly discovered that tricaprylin can be produced in this way in an efficient and economical manner and in a particularly high degree of purity, in particular of a quality suitable for pharmaceutical or clinical use as well as for nutritional use.

[0071] Thus, tricaprylin is now available in such high purity for the first time in a direct and efficient manner through the manufacturing process according to the invention.

[0072] In particular, and very surprisingly, when the last one of the aforementioned features and / or conditions (i) to (iv) is applied, the formation of toxic by-products and impurities, such as, for example, genotoxic glycidyl esters of fatty acids and nephrotoxic fatty acid esters of monochloropropanediol, such as 3-MCPD and 2-MCPD fatty acid esters, can be efficiently avoided or at least a priori minimized, without the need for burdensome and costly post-treatment operations for their removal, as envisaged in the prior art. Potential traces of harmful by-products and impurities are easily and efficiently removed by the aforementioned criterion (i), as detailed below.

[0073] For, as the Applicant has surprisingly and unexpectedly found, the application of at least one, in particular a combination of at least two, preferably a combination of at least three and more preferably a combination of all four of the above mentioned features and / or conditions (i) to (iv) results in tricaprylin of high purity, i.e. irrespective of the specific reaction pathway of this substance.

[0074] In particular, absolutely surprisingly, the application of at least one, in particular a combination of at least two, preferably a combination of at least three, more preferably a combination of all four of the above features and / or conditions (i)-(iv) results in tricaprylin with a high degree of purity, which simultaneously unifies a combination of five purity characteristics (1)-(5), so-called; (1) very low acid value (AV), (2) very low hydroxyl value (OHV), (3) very high triglyceride content, (4) very low total content of MCPD fatty acid esters (fatty acid esters of monochloropropanediol), (5) very low total content of glycidol esters of fatty acids. Such combinations of purity characteristics (1)-(5) were previously considered incompatible or unachievable in the prior art. However, as the applicant has surprisingly found, this purity specification can be reached independently of the specific synthesis route, when applying at least one, in particular a combination of at least two, preferably a combination of at least three, more preferably a combination of all four of the above features and / or conditions (i)-(iv).

[0075] In this respect, the following findings by the Applicant are very surprising: In the prior art, it is mainly the high-temperature post-treatment procedures, in particular the multi-stage purification treatment (multi-stage distillation at high temperature or more), that are considered to be responsible for the formation of high levels of impurities and by-products (mainly due to glycidol fatty acid esters and MCPD fatty acid esters); because purification treatments under the application of heat or high temperatures are known to result in these toxic by-products. However, as the Applicant has now surprisingly discovered, the de novo synthesis of fatty acid polyol esters, in particular fatty acid glycerol esters, such as medium chain triglycerides (MCT), in particular tricaprylin, but also others, per se, apart from the necessary subsequent multi-stage purification post-treatments (multi-stage distillation at high temperature or more), produces large amounts of these undesirable toxic by-products, when, moreover, in order to achieve a high degree of esterification while having a low acid value and low hydroxyl value, significant esterification conditions are applied, in particular high temperatures above 180°C and up to 230°C and the use of metal-based catalysts. It is therefore quite surprising to discover by the applicant that the avoidance intent with regard to these toxic by-products must start very early in the production line (i.e. instead of the synthesis itself and in the above mentioned selection of the purity grade of the glycerol-based starting material).

[0076] In natural fats and oils, especially palm oil, a lot of effort has been made in the last decade to find optimized refining conditions to reduce the content of harmful by-products, especially MCPDE and glycidol fatty acid esters, but in the case of traditional condensation reactions to produce synthetic triglycerides, there was no systematic attempt in the prior art to find suitable conditions. However, a simple transfer of teachings from studies related to the refining of natural oils is not possible, since these teachings focus only on a posteriori or retrospective impurity reduction of by-products already formed and present in the final product, but do not take into account the simultaneous need for high quality (i.e. the need a priori to avoid at the origin the formation of these undesirable toxic by-products). Moreover, these prior teachings do not present a root cause analysis of the origin of toxic by-products, especially MCPD and glycidol fatty acid esters. do not have.

[0077] As a result, as the Applicant has unexpectedly found, and absolutely surprisingly, that the application of at least one of the features and / or conditions (i) to (iv), in particular a combination of at least two, preferably at least three and more preferably all four of said features and / or conditions (i) to (iv), makes it possible to efficiently reach the above-defined purity specification, which is a unified combination of the above-mentioned five purity characteristics (1) to (5). Thus, according to the invention, said features and / or conditions, in particular said features and / or conditions (ii) to (iv), prevent the formation of toxic by-products, such as glycidol fatty acid esters and MCPD fatty acid esters, at their origin by avoiding the causes of their formation, while the prevailing feature and / or condition (i) makes it possible to efficiently and selectively remove traces of these toxic by-products, despite them being otherwise produced or introduced.

[0078] Thus, the applicant is able to provide for the first time a concept for producing high purity tricaprylin with high yield and conversion, in other words, the applicant is able to provide for the first time a universal respective concept for this purpose.

[0079] By preferably selective derivatization of halide-based impurities present in the resulting reaction product, by treatment of the resulting reaction product with at least one nucleophile, by selecting relatively mild esterification conditions in the absence of metal-based catalysts, and / or by selecting the purity grade of the glycerol starting material, it is surprisingly possible to obtain tricaprylin exhibiting multiple combinations of product properties of high triglyceride content, low acid and hydroxyl values, and low total content of MCPD and glycidol fatty acid esters, while avoiding harsh esterification conditions and burdensome and inefficient pre- and post-treatments.

[0080] Apart from this, the aforementioned features and / or conditions (i) to (iv) can be easily implemented in or used to modify known processes and plants for the production of this substance, so that the process of the present invention is at the same time highly flexible and compatible with known prior art processes and plants for the production of this substance.

[0081] In contrast, the prior art production of this substance by conventional synthetic processes with burdensome and costly work-up is very complex, expensive and inefficient, since the prior art synthetic processes generate significant amounts of the aforementioned toxic by-products and impurities, which must be separated from the respective crude products in complex and often multi-stage work-up operations. In particular, the burdensome and costly work-up operations do not allow the improvement of the product quality in terms of a high degree of esterification and low acidity of the final product. Also, the yield of the production process is not affected in this way.

[0082] Within the scope of the present invention, it has now become possible for the first time to provide an efficiently functioning production process in which tricaprylin is produced with a high content of this substance, a high degree of esterification and a very low acid value, while at the same time being free or at least essentially free of the aforementioned toxic by-products and impurities.

[0083] Furthermore, the process according to the present invention is economical to operate and can be carried out on a large scale.

[0084] In particular, the process of the present invention uses commercially available starting compounds and allows relatively simple process control even in large-scale implementation.

[0085] In contrast to conventional prior art manufacturing processes that require further complex post-treatment operations, the manufacturing process according to the present invention achieves excellent yields without such complex post-treatment operations, and the production of toxic by-products is minimized or avoided altogether.

[0086] Moreover, the process according to the invention is easy to carry out and economical. In particular, the process according to the invention, in particular the esterification, is usually carried out in the absence and / or without solvent (i.e. as a mass reaction or as a material reaction or as a so-called bulk reaction); as a result, the reaction products obtained are not contaminated with solvents and there is no need to remove and dispose of the solvent or recycle it in a cost- and energy-intensive manner after carrying out the process or reaction. Furthermore, no toxic by-products are formed, or at least essentially no toxic by-products are formed.

[0087] In summary, as previously mentioned, the present invention relates to a method for producing tricaprylin (i.e. trioctanoyl glyceride or tricaprylglycerol), particularly in high purity, Formula (I) CH2(OH)-CH(OH)-CH2(OH) (I) or a protected form or precursor thereof, preferably solketal (isopropylideneglycerol), is used as a starting material to react and / or be converted to tricaprylin, Formula (II) CH2[OC(O)R 1 ]-CH[OC(O)R 1 ]-CH2[OC(O)R 1 ] (II) The method of the present invention produces, as a reaction product, tricaprylin of wherein in formula (II) the radical R 1 represents a linear saturated aliphatic C7-alkyl radical of formula -(CH2)6-CH3 (i.e., an n-heptyl radical), The process herein comprises at least one esterification step, in particular using C8-fatty acids, in particular linear saturated or mono- or poly-unsaturated C8-fatty acids and / or their anhydrides and / or esters (preferably C1-C4-alkyl esters), preferably using caprylic acid (i.e. n-octylic acid or 1-heptanecarboxylic acid) of formula CH3-(CH2)6-COOH and / or its anhydrides or esters (preferably C1-C4-alkyl esters).

[0088] As mentioned above, the method of the invention is characterized by at least one of the following features and / or conditions (i) to (iv), in particular by a combination of at least two, preferably at least three of the following features and / or conditions (i) to (iv), which are explained in more detail below, the so-called: (i) a preferably selective derivatization of halide-based impurities present in the resulting reaction product is carried out, in particular of MCPD fatty acid esters (fatty acid esters of monochloropropanediol, in particular MCPD caprylic acid ester) and glycidol esters of fatty acids (in particular glycidol caprylic acid ester) and / or the resulting reaction product is derivatized with at least one nucleophile, in particular with a nucleophile capable of removing halide-based impurities, preferably hydrogen sulfite (bisulfite, HSO - ), sulfite (SO3 2- ), hydrogen thiosulfate (HS2O3 - ), thiosulfate (S2O3 2- ), hydrogen phosphite (H2PO3 - ), Phosphite (HPO3 2- ) and phosphines and combinations thereof, more preferably hydrogen sulfites (bisulfite, HSO3 - ), in particular for the preferably selective derivatization of halide-based impurities, in particular MCPD fatty acid esters (fatty acid esters of monochloropropanediol) and glycidol esters of fatty acids; (ii) at least one esterification stage is operated and / or carried out at a temperature not exceeding 180°C, in particular not exceeding 150°C, in particular not exceeding 120°C, preferably not exceeding 100°C, more preferably not exceeding 80°C, even more preferably not exceeding 50°C; (iii) the 1,2,3-propanetriol of formula (I) or a protected form thereof, preferably solketal (isopropylideneglycerol), used as starting material is at least essentially free of chlorinated species, in particular having a total chlorinated species content of at most 1 ppm, in particular at most 0.5 ppm, preferably at most 0.1 ppm, based on the 1,2,3-propanetriol of formula (I) or a protected form thereof, preferably solketal (isopropylideneglycerol); (iv) at least one esterification step is carried out in the absence of a metal-based catalyst;

[0089] With regard to feature and / or condition (i), the following should be emphasized and taken into account: it is envisaged to carry out a preferably selective derivatization of halide-based impurities present in the resulting reaction product, in particular MCPD fatty acid esters (fatty acid esters of monochloropropanediol, in particular MCPDE caprylic acid ester) and glycidol esters of fatty acids (in particular glycidol caprylic acid ester), and / or the resulting reaction product is derivatized by at least one nucleophile, in particular by a nucleophile capable of removing halide-based impurities, preferably by hydrogen sulfite (bisulfite, HSO3 - ), sulfite (SO3 2- ), hydrogen thiosulfate (HS2O3 - ), thiosulfate (S2O3 2- ), hydrogen phosphite (H2PO3 - ), Phosphite (HPO3 2- ) and phosphines and combinations thereof, more preferably hydrogen sulfites (bisulfites, HSO - ), in particular for the preferably selective derivatization of halide-based impurities, in particular of MCPD fatty acid esters (fatty acid esters of monochloropropanediol, in particular MCPD caprylate) and glycidol esters of fatty acids (in particular glycidol caprylate).

[0090] As the Applicant has surprisingly found, the aforementioned nucleophiles can be used to preferably selectively derivatize halide-based impurities, especially MCPD fatty acid esters (fatty acid esters of monochloropropanediol, especially MCPD caprylic acid ester), and even more effectively glycidol esters of fatty acids (especially caprylic acid glycidol ester). This is even more surprising, since these halide-based impurities are usually present in very small, especially trace amounts; nevertheless, treatment with the aforementioned nucleophiles usually results in the selective derivatization of these substances, which can then be easily removed or eliminated, i.e. separated from the final reaction product, according to the following reaction scheme (see below).

[0091] The following reaction schemes show, purely by way of example and not by way of limitation, the selective derivatization of halide-based impurities, i.e., on the one hand, the selective derivatization of MCPD fatty acid esters (upper reaction) and, on the other hand, the selective derivatization of glycidol fatty acid esters (lower reaction), in which sodium hydrogen sulfite (sodium bisulfite, NaHSO3) is used as the nucleophile (purely by way of example and not by way of limitation) and the radicals R each independently represent a linear saturated C7-alkyl radical. As can be seen from the reaction schemes, the nucleophile is preferably derivatized via the so-called nucleophilic substitution, preferably via the so-called S N Through a reaction mechanism such as 2, the organically bound chlorine atom in the MCPD fatty acid ester is replaced, and the chlorine atom is removed as sodium chloride, which can be easily separated in the aqueous phase together with the replacement product (reaction above). As can be seen from this reaction scheme, the nucleophile reacts with the glycidol fatty acid ester under ring opening, and a water-soluble product can also be obtained (reaction below). Separation of the purified triglyceride product after separation of the aqueous phase can be carried out, for example, via distillation (e.g., short path distillation).

[0092] [ka]

[0093] As the above reaction scheme shows, halide-based impurities (i.e., MCPD fatty acid esters and glycidol fatty acid esters) can be efficiently removed by selective reaction with nucleophiles (here, e.g., bisulfite = hydrogen sulfite). Halide-based impurities (even if only in trace amounts) are selectively converted to water-soluble molecules and can be easily removed, especially by washing with water or short path distillation.

[0094] Thus, by virtue of the feature and / or condition (i) of the present invention, halide-based impurities, particularly MCPD and glycidol fatty acid esters, can be selectively removed by derivatization, but without affecting or influencing other relevant product properties such as, for example, acid value (AV), hydroxyl value (OHV) and triglyceride content.

[0095] Thus, the above feature and / or condition (i) is an efficient means for selectively removing toxic halide-based impurities, such as genotoxic glycidol esters of fatty acids and nephrotoxic MCPD fatty acid esters. The resulting derivatized products can be easily removed by wash-off or short-path distillation (in the case of short-path distillation, the derivatized products are usually left or retained in the distillation bottoms (septic tank)). As also shown in the reaction scheme above, the chlorine atoms are preferably converted to harmless sodium chloride, which is easily washed away in the aqueous phase.

[0096] Generally, the above characteristics and / or conditions (i) are preferably carried out as one-step or single-step processing.However, it is also possible to repeatedly treat and / or contact the tricaprylin to be purified with nucleophilic agent, especially in cases where the level of impurities is high, particularly in cases where the level of impurities is high.However, it is preferred to treat and / or contact the tricaprylin to be purified with nucleophilic agent in one step (i.e., without repeated treatment and / or contact); as an alternative embodiment, it is also possible to use a higher amount or concentration of nucleophilic agent instead of repeated treatment and / or contact, especially in cases where the level of impurities is high.

[0097] As a result, the feature and / or condition (i) of the present invention allows selective removal or elimination of low, preferably even trace amounts of toxic halide-based impurities in an efficient and selective manner, i.e. without affecting other required and desired properties of the resulting product (e.g. low acid and hydroxyl values ​​and high triglyceride content, etc.).

[0098] With regard to feature and / or condition (ii), the following should be emphasized and taken into consideration: according to said feature and / or condition (ii), it is envisaged that at least one esterification stage is operated and / or carried out at a temperature not exceeding 180°C, in particular not exceeding 150°C, in particular not exceeding 120°C, preferably not exceeding 100°C, more preferably not exceeding 80°C and even more preferably not exceeding 50°C.

[0099] Surprisingly, as the applicant has found, limiting the temperature during at least one esterification stage is also an efficient means to avoid the formation of toxic impurities during esterification, especially MCPD and glycidol fatty acid esters. Nevertheless, high conversions, high yields and high esterification levels, especially high triglyceride contents due to low acid and hydroxyl values, are reached for the process of the present invention, especially when other characteristics and / or conditions are taken into account, especially when applying the synthesis route described below.

[0100] As a result, the process of the invention makes it possible for the first time to carry out at least one esterification stage under relatively mild conditions, in particular with a view to avoiding the formation of toxic by-products of the type mentioned above, while at the same time ensuring high esterification levels, in particular high triglyceride contents, and good conversions and yields.

[0101] In particular, in combination with at least one of the other features and / or conditions (i), (iii) and / or (iv) mentioned above, feature and / or condition (ii) of the present invention gives superior results.

[0102] With regard to feature and / or condition (iii), the following should be emphasized and taken into account: According to said feature and / or criterion (iii), the 1,2,3-propanetriol of formula (I) or a protected form thereof, preferably solketal (isopropylideneglycerol), used as starting material is at least essentially free of chlorinated species and contains a total content of chlorinated species of at most 1 ppm, in particular at most 0.5 ppm, preferably at most 0.1 ppm, based on the 1,2,3-propanetriol of formula (I) or a protected form thereof, preferably solketal (isopropylideneglycerol).

[0103] As the Applicant has surprisingly found, the presence of chlorinated species, in particular the so-called total chlorinated species content, has a decisive influence with regard to the formation of toxic by-products in the final reaction product, namely the formation of toxic MCPD and glycidol fatty acid esters.

[0104] The choice of the purity grade of the starting materials, 1,2,3-propanetriol or its protected form, preferably in the form of solketal, therefore plays a crucial role in avoiding the formation of toxic by-products during the esterification, such as MCPDE and glycidol fatty acid esters, which is quite surprising. By choosing these starting materials as being at least essentially free of chlorinated species, in particular as having a specified total chlorinated species content, the formation of these toxic by-products is effectively prevented or at least minimized to the greatest extent.

[0105] In the prior art, it was never known and never realized until now that the content of chlorinated species in the starting material in the form of 1,2,3-propanetriol or its protected forms (e.g. solketal) has a decisive influence on the purity of the final reaction product obtained (i.e. tricaprylin).

[0106] The starting product, 1,2,3-propanetriol or a protected form thereof, preferably solketal, of the required purity is generally commercially available.

[0107] The 1,2,3-propanetriol with the required purity used in the present invention can be obtained from petrochemical feedstocks, for example from epichlorin-hydrin, or from oleochemical feedstocks, for example from the hydrolysis of natural fats and oils. Petrochemically or oleochemically derived glycerol with the appropriate purity and quality is obtained mainly by purification by physical techniques (for example distillation or membrane filtration, such as membrane ultrafiltration).

[0108] As the Applicant's experimental data surprisingly show, in contrast to the chlorinated species content of glycerol or its protected derivatives (e.g. solketal) as starting material, the chlorinated species content of the remaining starting materials, i.e. C8-fatty acids, in particular linear saturated or mono- or poly-unsaturated C8-fatty acids and / or their anhydrides and / or esters (preferably C1-C4-alkyl esters), preferably caprylic acid and / or its anhydrides or esters (preferably C1-C4-alkyl esters), at least as used in the esterification step, is carried out with caprylic acid and / or its anhydrides and / or esters having a total chlorinated species content in the range of 20 ppm to 100 ppm, at the same time 1,2,3-propanetriol or its protected form, preferably solketal, is used with a purity grade according to the invention (i.e. a total chlorinated species content of at most 1 ppm, in particular at most 0.5 ppm, preferably at most 0.1 ppm). In turn, as further experimental data by the Applicant also surprisingly show, 1.2.3-propanetriol or a protected form thereof, preferably solketal, consisting of a total chlorinated species content in the range of 20 ppm to 100 ppm can be obtained even if the remaining starting materials, i.e. C8-fatty acids, in particular linear saturated or mono- or poly-unsaturated C8-fatty acids and / or their anhydrides and / or esters, preferably caprylic acid and / or its anhydrides or esters, are of high purity grade (i.e. a total content of chlorinated species of max. 1 ppm, in particular max. 0.5 ppm, preferably max. 0.1 ppm).Further experimental data by the Applicant then surprisingly show that 1,2,3-propanetriol or its protected forms, preferably solketal, consisting of a total chlorinated species content in the range of 20 ppm to 100 ppm, is such that during esterification toxic MCPD and glycidol fatty acid esters are significantly generated, even if the remaining starting materials, i.e. C8-fatty acids, in particular linear saturated or mono- or poly-unsaturated C8-fatty acids and / or their anhydrides and / or esters, preferably caprylic acid and / or its anhydrides or esters, have a high purity grade (i.e. a total content of chlorinated species of max. 1 ppm, in particular max. 0.5 ppm, preferably 0.1 ppm).Without being bound to a particular theory, this surprising phenomenon may be explained by the fact that 1,2,3-propanetriol or its protected forms, preferably solketal, at least mainly contains chlorinated species in organically bound form, which contribute to the formation of MCPD and glycidol fatty acid esters during esterification. On the other hand, in the case of C8-fatty acids, in particular linear saturated or mono- or poly-unsaturated C8-fatty acids and / or their anhydrides and / or esters, preferably caprylic acid and / or its anhydrides or esters, these substances may at least mainly contain entrained chlorinated species in inorganic form, in particular as inorganic salts such as NaCl, which cannot contribute at all (or at best only negligibly) to the formation of MCPD and glycidol fatty acid esters during esterification.

[0109] As a result, overall, the purity of the aforementioned glycerol-based and solketal-based starting materials, in particular the specific selection with respect to the content of chlorinated species, and also the minimization of the total content of chlorinated species in these starting materials, plays an important role for the purity and quality of the final reaction product.

[0110] With regard to feature and / or criterion (iv), the following should be emphasized and taken into consideration: According to said feature and / or measure (iv), it is envisaged that at least one esterification step is carried out and / or is carried out in the absence of a metal-based catalyst.

[0111] At least one esterification step in the absence of a metal-based catalyst is an important issue in the process of the present invention, since such metal-based catalysts often introduce or incorporate large amounts of undesirable halides, especially chlorides, which may lead to the undesirable formation of harmful by-products during esterification, especially MCPD and glycidol fatty acid esters. By avoiding such metal-based catalysts during esterification, the uncontrolled and undesirable introduction or incorporation of halide-based impurities is effectively avoided or prevented.

[0112] Furthermore, in contrast to the enzyme-based catalysts used during esterification according to the methods of the present invention according to certain embodiments, metal-based catalysts (e.g., tetrabutyl titanate, etc.) require relatively high temperatures (e.g., 190°C to 230°C) for esterification, thus resulting in the undesirable and uncontrolled formation of the aforementioned toxic by-products, particularly MCPD and glycidol fatty acid esters.

[0113] As a result, feature and / or condition (iv) of the present invention also contributes significantly to obtaining a final reaction product having excellent purity and other desired properties in terms of properties such as low acid number, low hydroxyl number and high triglyceride content.

[0114] Thus, overall, in accordance with the present invention, the process of the present invention produces highly pure tricaprylin.

[0115] In particular, according to the method of the present invention, the reaction product, in particular Radical R 1represents a linear saturated aliphatic C7-alkyl radical of the formula -(CH2)6-CH3 (i.e., an n-heptyl radical), CH2[OC(O)R 1 ]-CH[OC(O)R 1 ]-CH2[OC(O)R 1 ] (II) is characterized by and / or exhibits the following properties (1) to (5) in combination thereof and / or meets the following product specifications: (1) acid value (AV), in particular as measured according to the European Pharmacopoeia 2.5.1 (European Pharmacopoeia 10.0): ≦0.5 mg KOH / g, in particular ≦0.2 mg KOH / g, preferably ≦0.1 mg KOH / g; and (2) hydroxyl value (OHV) measured according to the European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0): ≦0.5 mg KOH / g, in particular ≦0.2 mg KOH / g, preferably ≦0.1 mg KOH / g; and (3) triglyceride content as determined by European Pharmacopoeia 2.2.28 (European Pharmacopoeia 10.0): ≧99%, in particular ≧99.2%, preferably ≧99.5%, respectively, based on the reaction product; and (4) the total content of MCPD fatty acid esters, determined in particular by the method of DGF C-VI 18(10) (German Fat Society standard method): ≦0.5 ppm, in particular ≦0.2 ppm, preferably ≦0.1 ppm, each based on the reaction product; and (5) The total content of glycidol esters of fatty acids, determined in particular by the method of DGF C-VI 18(10) (German Fat Society standard method): ≦0.5 ppm, in particular ≦0.2 ppm, preferably ≦0.1 ppm, each based on the reaction product.

[0116] In particular, in other words, according to the invention, the method is carried out as described above and / or features and / or conditions (i) to (iv), in particular a combination of at least two, preferably at least three of features and / or conditions (i) to (iv), are applied and / or implemented, provided that the reaction product, in particular Radical R 1 represents a linear saturated aliphatic C7-alkyl radical of the formula -(CH2)6-CH3 (i.e., an n-heptyl radical), CH2[OC(O)R 1 ]-CH[OC(O)R 1 ]-CH2[OC(O)R 1 ] (II) The tricaprylin in the composition is characterized by and / or exhibits the following properties (1) to (5) in combination thereof and / or meets the following product specifications: (1) acid value (AV), in particular as measured according to the European Pharmacopoeia 2.5.1 (European Pharmacopoeia 10.0): ≦0.5 mg KOH / g, in particular ≦0.2 mg KOH / g, preferably ≦0.1 mg KOH / g; and (2) hydroxyl value (OHV) measured according to the European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0): ≦0.5 mg KOH / g, in particular ≦0.2 mg KOH / g, preferably ≦0.1 mg KOH / g; and (3) triglyceride content as determined by European Pharmacopoeia 2.2.28 (European Pharmacopoeia 10.0): ≧99%, in particular ≧99.2%, preferably ≧99.5%, respectively, based on the reaction product; and (4) the total content of MCPD fatty acid esters, determined in particular by the method of DGF C-VI 18(10) (German Fat Society standard method): ≦0.5 ppm, in particular ≦0.2 ppm, preferably ≦0.1 ppm, each based on the reaction product; and (5) The total content of glycidol esters of fatty acids, determined in particular by the method of DGF C-VI 18(10) (German Fat Society standard method): ≦0.5 ppm, in particular ≦0.2 ppm, preferably ≦0.1 ppm, each based on the reaction product.

[0117] Surprisingly, the reaction product of the present invention unites the five aforementioned properties (1) to (5) in a comprehensive combination, which were previously considered mutually exclusive, because according to the prior art methods, increasing the triglyceride content and decreasing the acid and hydroxyl values ​​usually leads to a high total content of MCPD and glycidol fatty acid esters due to the drastic esterification conditions; conversely, according to the prior art, decreasing the total content of MCPDE and glycidol fatty acid esters leads to a relatively low triglyceride content with high acid and hydroxyl values.

[0118] In contrast to this prior art, the present invention makes it possible for the first time to provide all five aforementioned properties (1) to (5) in combination in one and the same product. As a result, the inventive reaction product obtained from the inventive process is highly suitable for food and pharmaceutical applications, even for parenteral applications at high doses and / or concentrations.

[0119] According to the invention, the inventive reaction product obtained from the inventive process has a very low acid value (AV), i.e. an acid value (AV) of ≦0.5 mg KOH / g, in particular ≦0.2 mg KOH / g, preferably ≦0.1 mg KOH / g, in particular as measured by the European Pharmacopoeia 2.5.1 (European Pharmacopoeia 10.0). The so-called acid value parameter indicates the residual free acid resulting from the esterification. The lower the acid value, the higher the quality of the product. In particular, a very low acid value as envisaged in the present invention results in a high stability, in particular a good long-term and / or storage stability, as well as a good preservation stability, of the resulting reaction product (i.e. tricaprylin).

[0120] As indicated above, according to the present invention, the acid value (AV) is usually determined according to the European Pharmacopoeia 2.5.1 (European Pharmacopoeia 10.0). The acid value (also synonymously called neutralization value, acid value, acidity) is the mass (in milligrams) of potassium hydroxide (KOH) required to neutralize one gram of a chemical substance, and in particular the acid value is a measure of the number of carboxylic acid groups in a compound (here tricaprylin). The indicated standard European Pharmacopoeia 2.5.1 is based on the titration method.

[0121] Apart from the parameter acid value (AV), the hydroxyl value (OHV) of the inventive reaction products obtained from the process of the invention also plays an important role. According to the invention, the inventive reaction products also have a very low hydroxyl value (OHV), i.e. a hydroxyl value (OHV) determined in particular according to the European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0), ≦0.5 mg KOH / g, in particular ≦0.2 mg KOH / g, preferably ≦0.1 mg KOH / g. In this case, the hydroxyl value (OHV) is an indicator of the degree of esterification, which indicates that the degree of esterification of the inventive reaction products is very high.

[0122] According to the invention, the hydroxyl value (OHV) is determined in particular according to the European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0). The hydroxyl value measured according to this method is defined as the number of milligrams of potassium hydroxide (KOH) required to neutralize the acetic acid incorporated during the acetylation of one gram of a chemical substance (here, tricaprylin) containing free hydroxyl groups. The hydroxyl value is therefore a measure of the content of free hydroxyl groups in a chemical substance (here, tricaprylin) and is usually expressed as the mass of potassium hydroxide (KOH) in milligrams corresponding to the hydroxyl group content in one gram of the chemical substance. The indicated measurement method European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0) consists of acetylating the free hydroxyl groups of the reaction product (here, tricaprylin) with acetic anhydride in a pyridine solvent, and after the reaction is over, water is added to convert the remaining unreacted acetic anhydride into acetic acid, which is then titrated with potassium hydroxide to measure.

[0123] Thus, in the case of the reaction product of the invention, the tricaprylin of the invention, apart from a very low acid value (AV), also contains at the same time a very low hydroxyl value (OHV) as described above, which corresponds to a high degree of esterification.

[0124] Furthermore, as a third parameter and / or property (3), the reaction products of the present invention have a very high triglyceride content, i.e. a triglyceride content of ≧99%, in particular ≧99.2%, preferably ≧99.5%, based on the reaction product, in particular measured according to the European Pharmacopoeia 2.2.28 (European Pharmacopoeia 10.0). These extremely high values ​​for the triglyceride content also indicate a high purity grade of the reaction products of the present invention. The triglyceride content of the products of the present invention is measured in particular according to the European Pharmacopoeia 2.2.28 (European Pharmacopoeia 10.0). This method is based on measurement by gas chromatography.

[0125] Apart from the parameters and / or properties of low acid value (AV), low hydroxyl value (OHV) and high triglyceride content, the reaction products of the invention are also characterized by an extremely low total content of MCPD fatty acid esters and glycidol fatty acid esters: the total content of MCPD fatty acid esters (fatty acid esters of monochloropropanediol), determined in particular according to the method DGF C-VI 187(10) (German Fat Society standard method), is respectively ≦0.5 ppm, in particular ≦0.2 ppm, preferably ≦0.1 ppm, based on the reaction product; the total content of glycidol esters of fatty acids, determined in particular according to the method DGF C-VI 187(10) (German Fat Society standard method), is respectively ≦0.5 ppm, in particular ≦0.2 ppm, preferably ≦0.1 ppm, based on the reaction product.

[0126] The indicated quantitative method of DGF C-VI 18(10) allows reliable quantification of these toxic impurities. In particular, the reaction product of the invention obtained from the process of the invention combines a very low total content of these toxic esters with high triglyceride content levels and low acid and hydroxide values, as described above.

[0127] As a result, the five-fold combination of the aforementioned features and / or parameters (1)-(5) is a unique characteristic of the reaction product resulting from the process of the present invention, distinguishing it from similar prior art reaction products. Thus, for the first time, the process of the present invention makes it possible to produce a high purity grade of tricaprylin exhibiting low acid and hydroxyl values, while at the same time providing a very high triglyceride content and an extremely low total content of toxic MCPD and glycidol fatty acid esters.

[0128] According to a particular embodiment, the present invention relates to a method for producing tricaprylin (i.e. trioctanoyl glyceride or tricaprylglycerol), in particular tricaprylin (i.e. trioctanoyl glyceride or tricaprylglycerol) having a high degree of purity, in particular a method as described and defined above, Formula (I) CH2(OH)-CH(OH)-CH2(OH) (I) 1,2,3-propanetriol (glycerol, glycerin) or a protected form or precursor thereof, preferably solketal (isopropylideneglycerol), is used as a starting material to react and / or convert to tricaprylin, As a reaction product, a compound represented by the formula (II) CH2[OC(O)R 1 ]-CH[OC(O)R 1 ]-CH2[OC(O)R 1 ] (II) is generated, wherein in formula (II) the radical R 1 represents a linear saturated aliphatic C7-alkyl radical of formula -(CH2)6-CH3 (i.e., an n-heptyl radical), wherein the process comprises at least one esterification step using C8-fatty acids, in particular linear saturated or mono- or poly-unsaturated C8-fatty acids and / or their anhydrides and / or esters (preferably C1-C4-alkyl esters), preferably using caprylic acid (i.e. n-octylic acid or 1-heptanecarboxylic acid) of formula CH3-(CH2)6-COOH and / or its anhydrides or esters (preferably C1-C4-alkyl esters); wherein the method is characterized by at least one of the following features and / or conditions (i) to (iv), in particular by a combination of at least two, preferably a combination of at least three, more preferably a combination of all four of the following features and / or conditions (i) to (iv): (i) A preferably selective derivatization of halide-based impurities present in the resulting reaction product, in particular MCPD fatty acid esters (fatty acid esters of monochloropropanediol, in particular MCPD caprylic acid ester) and glycidol esters of fatty acids (in particular glycidol caprylic acid ester) is carried out and / or the resulting reaction product is derivatized with at least one nucleophile, in particular with a nucleophile capable of removing halide-based impurities, preferably with hydrogen sulfite (bisulfite, HSO - ), sulfite (SO3 2- ), hydrogen thiosulfate (HS2O3-), thiosulfate (S2O3 2- ), hydrogen phosphite (H2PO3 - ), Phosphite (HPO3 2- ) and phosphines and combinations thereof for preferably selective derivatization of halide-based impurities, in particular for preferably selective derivatization of MCPDE fatty acid esters (fatty acid esters of monochloropropanediol) and glycidol esters of fatty acids; (ii) at least one esterification stage is operated and / or carried out at a temperature not exceeding 180°C, in particular not exceeding 150°C, in particular not exceeding 120°C, preferably not exceeding 100°C, more preferably not exceeding 80°C, even more preferably not exceeding 50°C; (iii) the 1,2,3-propanetriol of formula (I) or a protected form thereof, preferably solketal (isopropylideneglycerol), used as starting material is at least essentially free of chlorinated species, in particular having a total chlorinated species content of at most 1 ppm, in particular at most 0.5 ppm, preferably at most 0.1 ppm, based on the 1,2,3-propanetriol of formula (I) or a protected form thereof, preferably solketal (isopropylideneglycerol); (iv) at least one esterification step is carried out in the absence of a metal-based catalyst; wherein the process is carried out as described above and / or a combination of at least two, preferably at least three, of the features and / or conditions (i) to (iv), in particular the features and / or conditions (i) under R(iv), is applied and / or implemented, with the proviso that the reaction product, in particular the tricaprylin of formula (II) above, in combination, is characterized and / or exhibits the following properties (1) to (5) and / or meets the following product specifications: (1) acid value (AV), in particular as measured according to the European Pharmacopoeia 2.5.1 (European Pharmacopoeia 10.0): ≦0.5 mg KOH / g, in particular ≦0.2 mg KOH / g, preferably ≦0.1 mg KOH / g; and (2) hydroxyl value (OHV) measured according to the European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0): ≦0.5 mg KOH / g, in particular ≦0.2 mg KOH / g, preferably ≦0.1 mg KOH / g; and (3) triglyceride content as determined by European Pharmacopoeia 2.2.28 (European Pharmacopoeia 10.0): ≧99%, in particular ≧99.2%, preferably ≧99.5%, respectively, based on the reaction product; and (4) the total content of MCPD fatty acid esters, determined in particular by the method of DGF C-VI 18(10) (German Fat Society standard method): ≦0.5 ppm, in particular ≦0.2 ppm, preferably ≦0.1 ppm, each based on the reaction product; and (5) The total content of glycidol esters of fatty acids, determined in particular by the method of DGF C-VI 18(10) (German Fat Society standard method): ≦0.5 ppm, in particular ≦0.2 ppm, preferably ≦0.1 ppm, each based on the reaction product.

[0129] According to further particular embodiments of the present invention, the process of the present invention is carried out as described above and / or the features and / or conditions (i) to (iv), in particular a combination of at least two, preferably at least three of the features and / or conditions (i) to (iv), is applied and / or implemented, with the proviso that the reaction product, in particular the tricaprylin of formula (II) above, in combination, is characterized and / or exhibits the following properties (1) to (5) and / or meets the following product specifications: (1) Acid value (AV), as determined in particular by European Pharmacopoeia 2.5.1 (European Pharmacopoeia 10.0): ≦0.1 mg KOH / g; and (2) Hydroxyl value (OHV) as determined by European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0): ≦0.1 mg KOH / g; and (3) triglyceride content as determined by European Pharmacopoeia 2.2.28 (European Pharmacopoeia 10.0): ≧99.5%, in particular ≧99.6%, preferably ≧99.8%, respectively, based on the reaction product; and (4) the total content of MCPD fatty acid esters, determined in particular by the method of DGF C-VI 18(10) (standard method of the German Society of Fat Science): ≦0.1 ppm based on the reaction product; and (5) The total content of glycidol esters of fatty acids, determined in particular by the method of DGF C-VI 18(10) (standard method of the German Fat Society): ≦0.1 ppm, based on said reaction products.

[0130] Such reaction products, in particular tricaprylin of the above general formula (II), are particularly suitable for applications requiring high purity grades and at the same time high active ingredient levels, such as nutritional and especially pharmaceutical applications and uses (e.g. even parenteral applications at high doses and / or concentrations).

[0131] As mentioned above, the process of the invention comprises at least one esterification step, in particular using C8-fatty acids, in particular linear saturated or mono- or poly-unsaturated C8-fatty acids and / or their anhydrides and / or esters (preferably C1-C4-alkyl esters), preferably using caprylic acid (i.e. n-octylic acid or 1-heptanecarboxylic acid) of formula CH3-(CH2)6-COOH and / or its anhydrides or esters (preferably C1-C4-alkyl esters).

[0132] According to a particular embodiment of the process of the invention, in at least one esterification step, caprylic acid and / or its anhydrides or esters of formula CH3-(CH2)6-COOH (preferably C1-C4-alkyl esters) are used.

[0133] As described above, according to the method of the present invention, a reaction product represented by the formula (II) CH2[OC(O)R 1 ]-CH[OC(O)R 1 ]-CH2[OC(O)R 1 ] (II) of tricaprylin is provided and / or produced. wherein in formula (II) the radical R 1 represents a linear saturated aliphatic C7-alkyl radical of the formula -(CH2)6-CH3 (i.e., an n-heptyl radical).

[0134] In this regard, according to certain embodiments of the method of the present invention, the reaction product is tricaprylin; and / or In the above formula (II), the radical R 1represents a linear saturated aliphatic C7-alkyl radical; and / or in at least one esterification step, octanoic (caprylic) acid and / or its anhydrides and / or esters (preferably C1-C4-alkyl esters) are used; It is expected.

[0135] As already detailed above, according to the invention, the method of the invention is characterized by at least one of the above defined features and / or conditions (i) to (iv), in particular by a combination of at least two of the above defined features and / or conditions (i) to (iv), preferably by a combination of at least three, more preferably by a combination of all four.

[0136] In this regard, according to a particular embodiment of the method of the invention, it is envisaged that the method of the invention is characterised by a combination of at least two, preferably a combination of at least three, more preferably a combination of all four of the above defined features and / or conditions (i) to (iv).

[0137] According to another particular embodiment of the process of the invention, it is envisaged that the method of the invention is characterized by a combination of at least two, preferably at least three, of the aforementioned features and / or conditions (ii) to (iv), optionally in combination with the aforementioned feature and / or condition (i).

[0138] Furthermore, according to yet another particular embodiment of the method of the invention, it is envisaged that the method of the invention is characterized by a combination of the above feature and / or condition (i) and at least two of the above features and / or measurements (ii) to (iv).

[0139] Finally, according to further particular embodiments of the method of the invention, it is envisaged that the method of the invention is characterized by any combination of the aforementioned features and / or conditions (i) to (iv).

[0140] As already explained, according to the present invention, when applying the aforementioned characteristics and / or conditions (i) and / or (ii) and / or (iii) and / or (iv), a particularly high purity tricaprylin is obtained according to the above mentioned product specifications.

[0141] According to a particular embodiment of the method of the invention, it is particularly preferred that the entire method and / or in particular the entire method including any pre-treatment and / or post-treatment steps is operated and / or carried out at a temperature not exceeding 180°C, in particular not exceeding 160°C, in particular not exceeding 150°C, preferably not exceeding 120°C.

[0142] In other words, according to this particular embodiment of the method of the invention, the method further comprises the further features and / or conditions (v): (v) It is particularly preferred that the overall process and / or in particular the entire process including any optional pre-treatment and / or post-treatment steps is / are characterised by being operated and / or carried out at a temperature not exceeding 180°C, in particular at a temperature not exceeding 160°C, in particular at a temperature not exceeding 150°C, preferably at a temperature not exceeding 120°C.

[0143] This measure (v) allows for efficient prevention of toxic by-products, such as MCPD or glycidol fatty acid esters, which are normally formed at temperatures higher than their nominal values.

[0144] According to another particular embodiment of the method of the invention, it is particularly preferred that the entire method and / or in particular the entire method including any pre-treatment and / or post-treatment steps, if any, is operated and / or carried out in the absence of a metal-based catalyst.

[0145] In other words, according to this particular embodiment of the method of the invention, the method further comprises the further feature and / or condition (vi), (vi) the entire process and / or in particular the entire process including any pre-treatment and / or post-treatment steps, if any, is operated and / or carried out in the absence of a metal-based catalyst; It is preferably characterized by:

[0146] The absence of metal-based catalysts throughout the entire process and / or in particular the entire process, including any pre- and / or post-treatment steps, is a significant problem in the process of the present invention, since such metal-based catalysts introduce or incorporate significant amounts of undesirable halides, particularly chlorides. The halides, particularly chlorides, thus introduced or incorporated may cause the undesirable formation of toxic by-products, particularly MCPD and glycidol fatty acid esters, during esterification. By avoiding such metal-based catalysts throughout the entire process and / or in particular the entire process, including any pre- and / or post-treatment steps, the uncontrolled and undesirable introduction or incorporation of halide-based impurities is effectively avoided or prevented.

[0147] As already explained, the process of the present invention comprises at least one esterification step.

[0148] In general, it is preferred that at least one esterification stage is carried out and / or carried out as a single stage esterification or alternatively as a two stage or multi-stage esterification.

[0149] According to a particular embodiment of the process of the invention, at least one esterification stage comprises It is preferred to carry out and / or perform the process as a one-step esterification using an anhydride of a C8-fatty acid, in particular caprylic anhydride, reacted with 1,2,3-propanetriol of formula (I) or a protected form or precursor thereof, preferably solketal. Alternatively, according to another particular embodiment of the process of the invention, at least one esterification step is carried out and / or performed as a two-step or multi-step esterification (i.e. in a first step using 1,2,3-propanetriol of formula (I) or a protected form or precursor thereof, preferably solketal, C8-fatty acid, in particular caprylic acid and / or their esters, reacted with 1,2,3-propanetriol of formula (I) or a protected form or precursor thereof, preferably solketal, in a subsequent step further esterification, further esterification of the free and / or remaining OH groups, preferably esterification using an anhydride of a C8-fatty acid, in particular caprylic anhydride, is carried out).

[0150] In general, according to certain embodiments of the method of the invention, it is preferred that at least one esterification stage is carried out and / or performed in the absence and / or without a solvent. This means that at least one esterification stage is carried out as a reaction / esterification in mass or as a reaction / esterification in substance or as a so-called bulk reaction (i.e. bulk esterification). This has the advantage that the reaction product obtained is not contaminated with any solvent and that after the at least one esterification stage has been carried out, the solvent does not have to be removed and disposed of and reused in a cost- and energy-intensive manner. Nevertheless, surprisingly, the at least one esterification stage proceeds with high conversions and yields, at least essentially without the formation of any significant by-products. Furthermore, avoiding the use of a solvent during the at least one esterification stage also facilitates the recycling of the esterification catalyst, if used, and in particular ensures that the esterification catalyst can be recycled without reactivation, since the solvent may deactivate or even poison such an esterification catalyst.

[0151] The temperature range applied to the at least one esterification stage may vary over a wide range. Usually, according to the present invention, it is preferred if the at least one esterification stage is carried out and / or performed at a moderate temperature, i.e. in the range of 5°C to 95°C, in particular in the range of 10°C to 85°C, preferably in the range of 15°C to 80°C, more preferably in the range of 20°C to 75°C, even more preferably in the range of 25°C to 80°C. This moderate temperature regime applied to the at least one esterification stage effectively prevents the formation of particularly toxic by-products and ensures an efficient esterification. However, the skilled person can deviate from these range specifications if necessary or in single or exceptional cases, without departing from the scope of the present invention.

[0152] Also, the pressure range applied to the at least one esterification stage may vary over a wide range. In general, according to the present invention, it is preferred that the at least one esterification stage is carried out and / or performed at a pressure in the range of 0.0001 bar to 10 bar, in particular in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, more preferably in the range of 0.05 bar to 1 bar, and even more preferably at a pressure of about 1 bar. This pressure regime applied to the at least one esterification stage can ensure an efficient esterification. However, the skilled person can deviate from these range specifications as necessary or in single or exceptional cases without departing from the scope of the present invention.

[0153] Basically, according to the invention, it is possible for at least one esterification step to be carried out and / or performed in the absence of a catalyst, or alternatively, for at least one esterification step to be carried out and / or performed at least partially in the presence of an enzyme as catalyst and / or at least partially in the presence of an enzyme-based catalyst. If an enzyme and / or an enzyme-based catalyst is used as catalyst, it is preferred that the catalyst is recycled after at least one esterification step; this improves efficiency and process economics, especially when the method of the invention is carried out on a large scale or industrial level.

[0154] As used herein, the phrases "enzyme (used) as a catalyst" and "enzyme-based catalyst" are used synonymously.

[0155] In this respect, according to a particular embodiment of the method of the invention, at least one esterification step is carried out and / or performed in the absence of a catalyst when using 1,2,3-propanetriol of formula (I) or its protected form or precursor, preferably an anhydride of a C8-fatty acid reacted with solketal, in particular caprylic anhydride. Alternatively, according to another particular embodiment of the method of the invention, it is preferred that at least one esterification step is carried out and / or performed when using 1,2,3-propanetriol of formula (I) or its protected form or precursor, preferably an anhydride of a C8-fatty acid reacted with solketal, in particular caprylic acid and / or their esters; as mentioned above, when an enzyme and / or an enzyme-based catalyst is used as catalyst, it is preferred that the catalyst is recycled after at least one esterification step.

[0156] As mentioned above, according to a particular embodiment of the invention, at least one esterification stage can be carried out at least partially in the presence of an enzyme as a catalyst and / or at least partially in the presence of an enzyme-based catalyst (preferably in the absence and / or without a solvent, as mentioned above), which ensures high esterification efficiency, in particular high conversions and yields due to excellent degrees of esterification and low acid and hydroxyl values ​​under mild esterification conditions.

[0157] Generally, when at least one esterification step is carried out at least partially in the presence of an enzyme as a catalyst and / or in the presence of an enzyme-based catalyst, it is preferred that the enzyme is in particular selected from synthetases (ligases), catalases, esterases, lipases and combinations thereof.

[0158] In particular, Candida antarctica, Mucor miehei (Rhizomucor miehei), Thermomyces lanuginosus, Candida rugosa, Aspergillus oryzae, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus delemar and Pseudomonas spp. sp.) and combinations thereof, preferably Candida Antarctica, Mucor miehei (Rhizomucor miehei) and Thermomyces lanuginosus, more preferably Candida Antarctica. These species give particularly good esterification results.

[0159] Furthermore, said enzymes can be used in particular in immobilized form, in particular immobilized on a support, preferentially on a polymeric support, preferably on a polymeric organic support, more preferably on a hydrophobic support, even more preferably on a poly(meth)acrylic resin-based support, which significantly improves the handling, use and recycling of the enzymes as catalysts.

[0160] In particular, as mentioned above, it is preferred to recycle the enzyme after at least one esterification step for the reasons given above.

[0161] In general, if at least one esterification stage is carried out at least partly in the presence of an enzyme as a catalyst and / or at least partly in the presence of an enzyme-based catalyst, the temperature range applied to the at least one esterification stage may vary over a wide range. In particular in such cases, the at least one esterification stage can be carried out and / or performed at a temperature in the range of 5° C. to 95° C., in particular in the range of 10° C. to 85° C., preferably in the range of 15° C. to 80° C., more preferably in the range of 20° C. to 75° C., and even more preferably in the range of 25° C. to 70° C. However, the skilled person can deviate from these range specifications if necessary or in single or exceptional cases without departing from the scope of the invention.

[0162] Also, if at least one esterification step is carried out at least partially in the presence of an enzyme as a catalyst and / or at least partially in the presence of an enzyme-based catalyst, the amount of enzyme applied in at least one esterification step can vary within wide ranges. In particular in such cases, the enzyme is used in an amount in the range of 0.0001 to 25% by weight, in particular in the range of 0.001 to 20% by weight, preferably in the range of 0.01 to 15% by weight, more preferably in the range of 0.05 to 10% by weight, based on the total amount of all starting compounds. However, the skilled person can deviate from these range specifications if necessary or in single or exceptional cases, without departing from the scope of the invention.

[0163] In particular, according to a particular embodiment of the invention, the enzyme is present in an amount of 1×10 based on the total amount of all starting compounds. -6 Within the range of ~5mol%, especially 1×10 -5 Within the range of ~2.5 mol%, preferably 1×10 -4 Within the range of 1.5 mol%, more preferably 1×10 -3 Amounts in the range of up to 1 mol % can be used, however, those skilled in the art can deviate from these range specifications if necessary or in single or exceptional cases without departing from the scope of the invention.

[0164] Furthermore, if at least one esterification stage is carried out at least partly in the presence of an enzyme as a catalyst and / or at least partly in the presence of an enzyme-based catalyst, the pressure range applied to the at least one esterification stage may also vary over a wide range. In particular in that case, the at least one esterification stage can be carried out and / or performed at a pressure in the range of 0.0001 bar to 10 bar, in particular in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, more preferably in the range of 0.05 bar to 1 bar, and even more preferably at a pressure of about 1 bar. However, the skilled person can deviate from these range specifications if necessary or in single or exceptional cases without departing from the scope of the invention.

[0165] As mentioned above, the present invention is based on a general concept / method for producing high purity tricaprylin in high yield and high conversion, which concept / method is independent of any specific synthetic route. Therefore, the applicant's concept is general applicable for this purpose.

[0166] As a result, numerous synthetic routes are applicable within the scope of the present invention, and these possible synthetic routes are described in more detail below.

[0167] According to a particular embodiment of the invention, the reaction product obtainable or obtained from the process of the invention can be prepared, for example, via one of the following synthetic routes (A) to (F): (A) According to the (first) synthetic route (A), Formula (I) CH2(OH)-CH(OH)-CH2(OH) (I) 1,2,3-propanetriol (glycerol, glycerin) is first reacted with caprylic acid or an ester thereof, preferably in the presence of an enzyme as a catalyst (especially as defined above) and / or in the presence of an enzyme-based catalyst, to preferably produce a diglyceride, more preferably a 1,3-diglyceride, then reacting, preferably in the absence of a catalyst, with caprylic anhydride; producing a reaction product of formula (II) as defined above, in particular tricaprylin; Otherwise, (B) According to the (second) synthetic route (B), Formula (I) CH2(OH)-CH(OH)-CH2(OH) (I) 1,2,3-propanetriol (glycerin, glycerol) is first reacted with caprylic acid or an ester thereof, preferably in the presence of an enzyme as a catalyst (especially as defined above) and / or in the presence of an enzyme-based catalyst, so as to produce a diglyceride, more preferably a 1,3-diglyceride, Then, reacting with caprylic acid or an ester thereof, preferably in the presence of an enzyme as a catalyst and / or in the presence of an enzyme-based catalyst (more preferably an enzyme for regioselective esterification of the 2-position of 1,3-diglycerides, such as, for example, Pseudomonas cepacia lipase or Burkholderia cepacia lipase), producing a reaction product of formula (II) as above, in particular tricaprylin; Otherwise, (C) According to the (third) summation route (C), Formula (I) CH2(OH)-CH(OH)-CH2(OH) (I) 1,2,3-propanetriol (glycerin, glycerol) is reacted with capric anhydride, preferably in the absence of a catalyst, producing a reaction product of formula (II) as described above, in particular tricaprylin; Otherwise, (D) According to the (fourth) synthetic route (D), a protected form or a precursor of 1,2,3-propanetriol of formula (I) above, preferably solketal (isopropylideneglycerol), is reacted with capric anhydride in the absence of a catalyst, In particular, a deprotection reaction, in particular ring opening (preferably acid induced) and optionally removal of acetone, is carried out after monoesterification of the free OH-groups of the protected form or precursor of 1,2,3-propanetriol of formula (I) above, followed by a further esterification with caprylic anhydride, producing a reaction product of formula (II) as defined above, in particular tricaprylin; Otherwise, (E) According to the (fifth) synthetic route (E), a protected form or precursor of 1,2,3-propanetriol of formula (I) above, preferably solketal (isopropylideneglycerol), is reacted with capric acid or its ester in the presence of an enzyme as catalyst (especially as defined above) and / or in the presence of an enzyme-based catalyst, followed by a deprotection reaction, in particular ring-opening (preferably acid-induced) and removal of acetone, preferably to give monoglycerides, more preferably terminal monoglycerides and / or 1-monoglycerides, Then, preferably in the absence of a catalyst, react with caprylic anhydride, producing a reaction product of formula (II) as defined above, in particular tricaprylin; Otherwise, (F) According to the (sixth) synthetic route (F), a protected form or precursor of 1,2,3-propanetriol of formula (I) above, preferably solketal (isopropylideneglycerol), is reacted, optionally in the presence of an enzyme as catalyst (especially as defined above) and / or in the presence of an enzyme-based catalyst, with at least one linear mono- or poly-unsaturated (preferably mono-unsaturated) aliphatic C8-fatty acid and / or its ester and / or anhydride, preferably with at least one linear mono-unsaturated aliphatic C8-fatty acid and / or its ester and / or anhydride, to preferably produce a triglyceride of a linear mono- or poly-unsaturated (preferably mono-unsaturated) aliphatic C8-fatty acid, Then, preferably in the presence of at least one hydrogenation catalyst, the double bonds of the linear mono- or poly-unsaturated (preferably mono-unsaturated) aliphatic C8-fatty acid radicals of the triglyceride are hydrogenated, Producing a reaction product of formula (II) as defined above, in particular tricaprylin.

[0168] The above (first) synthetic route (A) can be illustrated in a non-limiting manner and for visualization purposes only by the following simplified reaction scheme showing the preparation of the inventive reaction product tricaprylin.

[0169] [ka]

[0170] The above (second) synthetic route (B) can be illustrated in a non-limiting manner and for visualization purposes only by the following simplified reaction scheme showing the preparation of the inventive reaction product tricaprylin.

[0171] [ka]

[0172] The above (third) synthetic route (C) can be illustrated in a non-limiting manner and for visualization purposes only by the following simplified reaction scheme showing the preparation of the inventive reaction product tricaprylin.

[0173] [ka]

[0174] The above (fourth) synthetic route (D) can be illustrated in a non-limiting manner and for visualization purposes only by the following simplified reaction scheme showing the preparation of the inventive reaction product tricaprylin.

[0175] [ka]

[0176] The above (fifth) synthetic route (E) can be illustrated in a non-limiting manner and for visualization purposes only by the following simplified reaction scheme showing the preparation of the inventive reaction product tricaprylin.

[0177] [ka]

[0178] The above (sixth) synthetic route (F) can be illustrated in a non-limiting manner and for visualization purposes only by the following simplified reaction scheme showing the preparation of the inventive reaction product tricaprylin.

[0179] [ka]

[0180] Overall, the applicant can provide a universal concept and method, respectively, for producing high purity tricaprylin in high yield and high conversion, which concept / method is independent of any specific synthetic route. The applicant's concept is therefore universal for this purpose. The inventive method is at the same time very flexible and compatible with known prior art production methods and plants of these substances, since the aforementioned inventive features and / or conditions (i)-(iv) can be easily introduced into known production methods and plants of these substances or can be used to modify known production methods and plants for these substances.

[0181] In particular, the process of the present invention produces high purity tricaprylin and simultaneously unifies a combination of at least five purity characteristics, namely: (1) very low acid value (AV), (2) very low hydroxyl value (OHV), (3) very high triglyceride content, (4) very low total content of MCPD fatty acid esters, and (5) very low total content of glycidol esters of fatty acids. Although such combinations of purity characteristics (1) to (5) have been previously considered incompatible or unattainable, the applicant has surprisingly discovered that the process of the present invention makes it possible for the first time to achieve such a combination of purity characteristics.

[0182] A further subject matter, according to the second aspect of the present invention, is a reaction product obtainable or obtained by the method according to the present invention.In other words, according to this aspect of the present invention, the present invention relates to tricaprylin obtainable or obtained by the method according to the present invention as defined and defined above.

[0183] In particular, a subject of the invention, according to this aspect of the invention, is tricaprylin, in particular tricaprylin obtainable or obtained by the method according to the invention of the invention, The tricaprylin is Formula (II) CH2[OC(O)R 1 ]-CH[OC(O)R1 ]-CH2[OC(O)R 1 ] (II) Corresponding to, wherein in formula (II) the radical R 1 represents a linear saturated aliphatic C7-alkyl radical of formula -(CH2)6-CH3 (i.e., an n-heptyl radical); wherein the tricaprylin of formula (II) is characterized and / or exhibits the following properties (1) to (5) in combination thereof and / or meets the following product specifications: (1) an acid value (AV), in particular as measured according to the European Pharmacopoeia 2.5.1 (European Pharmacopoeia 10.0): ≦0.5 mg KOH / g, in particular ≦0.2 mg KOH / g, preferably ≦0.1 mg KOH / g; and (2) Hydroxyl value (OHV), in particular as measured according to the European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0): ≦0.5 mg KOH / g, in particular ≦0.2 mg KOH / g, preferably ≦0.1 mg KOH / g; and (3) triglyceride content, in particular as determined by European Pharmacopoeia 2.2.28 (European Pharmacopoeia 10.0): ≧99%, in particular ≧99.2%, preferably ≧99.5%, based on tricaprylin; and (4) the total content of MCPD fatty acid esters, determined in particular by the method of DGF C-VI 18(10) (standard method of the German Society of Fat Science): ≦0.5 ppm, in particular ≦0.2 ppm, preferably ≦0.1 ppm, based on said tricaprylin; and (5) In particular, the total content of glycidol esters of fatty acids, determined by the method of DGF C-VI 18(10) (standard method of the German Fat Society), is ≦0.5 ppm, in particular ≦0.2 ppm, preferably ≦0.1 ppm, based on said tricaprylin.

[0184] In particular, a subject of the present invention is tricaprylin, in particular according to the above definition, wherein the tricaprylin of formula (II) is characterized and / or exhibits the following properties (1) to (5) in combination thereof and / or the following product specifications: (1) Acid value (AV), as determined in particular by European Pharmacopoeia 2.5.1 (European Pharmacopoeia 10.0): ≦0.1 mg KOH / g; and (2) Hydroxyl value (OHV) as determined by European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0): ≦0.1 mg KOH / g; and (3) triglyceride content as determined by European Pharmacopoeia 2.2.28 (European Pharmacopoeia 10.0): ≧99.5%, in particular ≧99.6%, preferably ≧99.8%, based on tricaprylin; and (4) The total content of MCPD fatty acid esters, determined in particular by the method of DGF C-VI 18(10) (standard method of the German Society of Fat Science): ≦0.1 ppm based on tricaprylin; and (5) The total content of glycidol esters of fatty acids, determined in particular by the method of DGF C-VI 18(10) (standard method of the German Society of Fat Science), is ≦0.1 ppm based on tricaprylin.

[0185] The reaction product of the present invention, i.e., tricaprylin, is associated with and incorporates a number of advantageous and special properties and characteristics; therefore, in order to avoid unnecessary repetition, reference is made to the above description.

[0186] In particular, the reaction product of the present invention, i.e. the tricaprylin of the present invention, is particularly suitable for applications requiring high purity grades and at the same time high active ingredient levels, such as nutritional applications, especially pharmaceutical applications and uses (e.g. also parenteral applications at high doses and / or concentrations).

[0187] Moreover, the reaction product of the present invention, i.e. the tricaprylin of the present invention, unites in an overall combination the five aforementioned properties (1) to (5) which have been considered mutually exclusive up until now. For, according to the prior art methods, increasing the triglyceride content and decreasing the acid and hydroxyl values ​​usually leads to a high total content of MCPD and glycidol fatty acid esters under aggressive esterification conditions; whereas, according to the prior art, decreasing the total content of MCPD and glycidol fatty acid esters leads to a relatively low triglyceride content with a high acid and hydroxyl value. In contrast to this prior art, the present invention makes it possible for the first time to provide all the aforementioned five properties (1) to (5) in combination in one and the same product. As a result, the reaction product of the present invention (i.e. the tricaprylin) obtained from the process of the present invention is highly suitable for food and pharmaceutical applications, even for parenteral applications at high doses and / or concentrations.

[0188] For further details relating to the second aspect of the present invention, in order to avoid unnecessary repetition, reference may be made to the above explanations and remarks relating to the first aspect of the present invention (i.e. the method of the present invention), which explanations and remarks apply mutatis mutandis accordingly to this second aspect of the present invention.

[0189] Likewise, the present invention relates, according to a third aspect thereof, to a pharmaceutical composition, in particular a medicament or drug, comprising the tricaprylin of the invention according to the above definition, in particular together with a physiologically acceptable excipient.

[0190] In particular, according to this aspect of the invention, the present invention relates to a method for treating diseases of the human or animal body, in particular diseases involving disorders of energy metabolism, in particular ketone body metabolism such as brain trauma, stroke, hypoxia, cardiovascular diseases such as myocardial infarction, refeeding syndrome, anorexia, epilepsy, dementia, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, fat metabolism diseases such as glucose transporter deficiency (GLUT1 deficiency), VL-FAOD, and mitochondrial thiolase deficiency, Hansch et al. The present invention relates to a pharmaceutical composition for, or for use in, the prophylactic and / or therapeutic treatment of, mitochondrial pathologies such as Langerhans' disease, cancers such as T-cell lymphoma, astrocytoma, glioblastoma, HIV, rheumatic diseases such as rheumatoid arthritis and arthritis, diseases of the gastrointestinal tract such as chronic inflammatory bowel disease, in particular lysosomal storage diseases such as ulcerative colitis, Crohn's disease, glycosphingolipidoses, in particular Niemann-Pick disease, diabetes, migraine headaches, epilepsy, in particular infantile spasms, and the effects and side effects of chemotherapy.

[0191] In particular, according to this aspect of the invention, the invention relates to a pharmaceutical composition for or for use in the prophylactic and / or therapeutic treatment of diseases of the human body selected from among Alzheimer's disease, in particular mild to moderate Alzheimer's disease; migraines and migraines; and epilepsy, in particular infantile convulsions.

[0192] For further details relating to the third aspect of the present invention, in order to avoid unnecessary repetition, reference may be made to the above explanations and references relating to the first and second aspects of the present invention, which explanations and references apply mutatis mutandis accordingly to this third aspect of the present invention.

[0193] Further, according to a fourth aspect of the present invention, the present invention relates to a method for treating diseases of the human or animal body, in particular diseases associated with disorders of energy metabolism, in particular ketone body metabolism such as brain trauma, stroke, and hypoxia, cardiovascular diseases such as myocardial infarction, renutation syndrome, anorexia, epilepsy, dementia, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, lipid metabolism diseases such as glucose transporter deficiency (GLUT1 deficiency) and VL-FAOD, mitochondrial thiolase deficiency, and mitochondrial disorders such as Huntington's disease. It also relates to a tricaprylin of the invention as defined above for or for use in the prophylactic and / or therapeutic treatment of cancers such as pulmonary tuberculosis, T-cell lymphoma, astrocytoma, glioblastoma, HIV, rheumatic diseases such as rheumatoid arthritis and arthritis, diseases of the gastrointestinal tract such as chronic inflammatory bowel diseases, in particular ulcerative colitis and Crohn's disease, lysosomal storage diseases such as glycosphingolipidoses, in particular Niemann-Pick disease, diabetes, migraine headaches, epilepsy, in particular infantile spasms, effects and side effects of chemotherapy.

[0194] In particular, according to this aspect of the invention, the invention relates to a tricaprylin of the invention as defined above for or for use in the preventive and / or therapeutic treatment of diseases of the human body selected from among Alzheimer's disease, in particular mild to moderate Alzheimer's disease; migraines and migraines; and epilepsy, in particular infantile convulsions.

[0195] For further details relating to the fourth aspect of the present invention, in order to avoid unnecessary repetition, reference may be made to the above explanations and references relating to the first, second and third aspects of the present invention, which explanations and references apply mutatis mutandis accordingly to this fourth aspect of the present invention.

[0196] Further, according to a fifth aspect of the present invention, the present invention relates to a method for treating diseases of the human or animal body, in particular diseases associated with disorders of energy metabolism, in particular ketone body metabolism such as brain trauma, stroke, and hypoxia, cardiovascular diseases such as myocardial infarction, renutation syndrome, anorexia, epilepsy, dementia, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, fat metabolism diseases such as glucose transporter deficiency (GLUT1 deficiency) and VL-FAOD, mitochondrial diseases such as mitochondrial thiolase deficiency and Huntington's disease, T The present invention also relates to the use according to the invention of a tricaprylin according to the above definition for the preventive and / or therapeutic treatment or for the manufacture of a medicament for the preventive and / or therapeutic treatment of cancers such as cellular lymphoma, astrocytoma, glioblastoma, HIV, rheumatic diseases such as rheumatoid arthritis and arthritis, diseases of the gastrointestinal tract such as chronic inflammatory bowel diseases, in particular ulcerative colitis and Crohn's disease, lysosomal storage diseases such as glycosphingolipidoses, in particular Niemann-Pick disease, diabetes, migraine headaches, epilepsy, in particular infantile spasms, effects and side effects of chemotherapy.

[0197] In particular, according to this aspect of the invention, the invention relates to the use according to the invention of the tricaprylin according to the invention as defined above for the preventive and / or therapeutic treatment or for the manufacture of a medicament for the preventive and / or therapeutic treatment of diseases of the human body selected from among Alzheimer's disease, in particular mild to moderate Alzheimer's disease; migraines and migraines; and epilepsy, in particular infantile convulsions.

[0198] In particular, according to this aspect of the invention, the invention relates to the use according to the invention of the tricaprylin of the invention as defined above for the preventive and / or therapeutic treatment of catabolic conditions such as starvation, dieting or low carbohydrate nutrition or for the manufacture of a medicament.

[0199] For further details relating to the fifth aspect of the present invention, in order to avoid unnecessary repetition, reference may be made to the above explanations and references relating to the first, second, third and fourth aspects of the present invention, which explanations and references apply mutatis mutandis accordingly to this fifth aspect of the present invention.

[0200] Furthermore, the present invention relates according to a sixth aspect to a food and / or nutritional or food composition and / or food product and / or medical food comprising the tricaprylin of the present invention according to the above definition.

[0201] In particular, according to this aspect of the invention, the food and / or nutritional composition or food composition and / or food product and / or medical food is preferably, for example, a dietary supplement, a functional food, a novel food, a food additive, a food supplement, a diet food, a power snack, an appetite suppressant, or a strength and / or endurance sports supplement.

[0202] For further details relating to the sixth aspect of the present invention, in order to avoid unnecessary repetition, reference may be made to the above explanations and references relating to the first, second, third, fourth and fifth aspects of the present invention, which explanations and references apply mutatis mutandis accordingly to this sixth aspect of the present invention.

[0203] Likewise, the present invention relates to the use according to the invention of the tricaprylin according to the above definition in a food and / or in a nutritional or food composition and / or in a food product and / or in a medical food, according to a seventh aspect of the invention.

[0204] In particular, according to this aspect of the invention, the food and / or nutritional composition or food composition and / or food product and / or medical food is preferably, for example, a dietary supplement, a functional food, a novel food, a food additive, a food supplement, a diet food, a power snack, an appetite suppressant, or a strength and / or endurance sports supplement.

[0205] For further details relating to the seventh aspect of the present invention, in order to avoid unnecessary repetition, reference may be made to the above explanations and references relating to the first, second, third, fourth, fifth and sixth aspects of the present invention, which explanations and references apply mutatis mutandis accordingly to this seventh aspect of the present invention.

[0206] The present invention also relates according to an eighth aspect to the use according to the invention of the tricaprylin according to the invention as defined above in pharmaceutical compositions, in particular drugs or medicinal products, foods, nutritional or food compositions, food products and / or medical foods, as additives or auxiliaries, in particular carriers or excipients, solubilizers, release agents, surface treatment agents, as transport agents, lubricants, hydrophobizing agents, film-forming or protective agents or viscosity modifiers, preferably as carriers or excipients, in cosmetic compositions.

[0207] In particular, according to this aspect of the invention, the present invention relates to the use according to the invention of the tricaprylin according to the invention as defined above, as a carrier or excipient in a pharmaceutical composition, in particular a drug or medicament.

[0208] Furthermore, according to this aspect of the invention, the invention also relates to the use according to the invention of the tricaprylin according to the above definition as an active substance (i.e. active ingredient) in a pharmaceutical composition, in particular a drug or medicinal product, a food, a nutritional or food composition, a food product and / or a medical food or a cosmetic composition, in particular together with an excipient, in particular together with a physiologically acceptable excipient.

[0209] Further according to this aspect of the invention, the present invention relates to the use according to the invention of the inventive tricaprylin as defined above as an active substance (i.e. active ingredient, API) in a pharmaceutical composition.

[0210] Furthermore, according to this aspect of the invention, the present invention also relates to the use according to the invention of the tricaprylin according to the above definition as an active substance (i.e. active ingredient, API) in a pharmaceutical composition, in particular a drug or medicinal product, in particular together with a physiologically acceptable excipient.

[0211] For further details relating to the eighth aspect of the present invention, in order to avoid unnecessary repetition, reference may be made to the above explanations and references relating to the first, second, third, fourth, fifth, sixth and seventh aspects of the present invention, which explanations and references apply mutatis mutandis accordingly to this eighth aspect of the present invention.

[0212] Finally, the present invention also relates to the use of a nucleophile for purifying tricaprylin, in particular tricaprylin of formula (II) as defined above, and / or for removing or derivatizing, preferably selectively, halide-based impurities present in tricaprylin, in particular tricaprylin of formula (II) as defined above, according to a ninth aspect of the present invention.

[0213] In particular, according to this aspect of the invention, the nucleophile is preferably hydrogen sulfite (bisulfite, HSO - ), sulfite (SO3 2- ), hydrogen thiosulfate (HS2O3 - ), thiosulfate (S2O3 2- ), hydrogen phosphite (H2PO3 - ), Phosphite (HPO3 2- ) and phosphines, and combinations thereof, or more preferably hydrogen sulfites (bisulfites, HSO - ) is preferred.

[0214] Typically, according to certain embodiments of this aspect of the invention, the tricaprylin to be purified is treated and / or contacted with a nucleophile.

[0215] Generally, it is preferred that the tricaprylin to be purified is treated and / or contacted with said nucleophile as a one-step or single-step process.However, it is also possible to repeatedly treat and / or contact the tricaprylin to be purified with the nucleophile, especially in two or more cycles and / or as a multi-step process, especially when the level of impurities is high.However, it is preferred to treat and / or contact the tricaprylin to be purified with the nucleophile in one step (i.e. without repeated treatment or contact); it is also possible to use a higher amount or high concentration of nucleophile instead of repeated treatment and / or contact, especially when the level of impurities is high, as an alternative embodiment.

[0216] In particular, according to another particular embodiment of this aspect of the invention, said nucleophile is used to purify tricaprylin from halide-based, particularly chlorine-based, impurities and / or to remove halide-based, particularly chlorine-based, impurities from tricaprylin, particularly chlorine-based impurities selected from the group consisting of MCPD fatty acid esters (fatty acid esters of monochloropropanediol), glycidol esters of fatty acids, and combinations thereof.

[0217] In particular, according to yet another particular embodiment of this aspect of the invention, the halide-based impurity is a chlorine-based impurity, in particular a chlorine-based impurity selected from the group consisting of MCPD fatty acid esters (fatty acid esters of monochloropropanediol), glycidol esters of fatty acids, and combinations thereof.

[0218] In particular, according to further particular embodiments according to this aspect of the invention, the tricaprylin to be purified is usually treated and / or contacted with a nucleophile, particularly preferably with an aqueous solution of the nucleophile.

[0219] In particular, the tricaprylin to be purified is treated and / or contacted with said nucleophile under reaction conditions, in particular reaction temperature and / or reaction time, sufficient to remove impurities.

[0220] In particular, the tricaprylin to be purified is treated and / or contacted with said nucleophile at a temperature in the range of 10° C. to 175° C., preferably in the range of 25° C. to 120° C., more preferably in the range of 50° C. to 100° C., and / or for a time in the range of 0.001 to 50 hours, preferably in the range of 0.01 to 30 hours, more preferably in the range of 0.1 to 20 hours.

[0221] Thus, overall, for example, hydrogen sulfite (bisulfite, HSO3 - ), sulfite (SO3 2- ), hydrogen thiosulfate (HS2O3 - ), thiosulfate (S2O3 2- ), hydrogen phosphite (H2PO3 - ), Phosphite (HPO3 2- Nucleophiles such as phosphines and the like and combinations thereof are excellent reactants for purifying tricaprylin, particularly for removing halide-based impurities, particularly chlorine-based impurities, from tricaprylin, particularly for removing chlorine-based impurities (via selective derivatization of the halide-based impurities) selected from the group consisting of MCPD fatty acid esters (fatty acid esters of monochloropropanediol), glycidol esters of fatty acids, and combinations thereof.

[0222] For further details relating to the ninth aspect of the present invention, in order to avoid unnecessary repetition, reference may be made to the above explanations and references relating to the first, second, third, fourth, fifth, sixth, seventh and eighth aspects of the present invention, which explanations and references apply mutatis mutandis accordingly to this ninth aspect of the present invention.

[0223] Further embodiments, modifications and variations of the present invention can be readily recognized or realized by those skilled in the art upon reading this specification, without departing from the scope of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0224] The present invention is illustrated by the following examples, which are not intended to limit the invention in any way, but are intended to illustrate exemplary and non-limiting implementations and configurations of the invention. EXAMPLES

[0225] Manufacturing Example The process according to the invention is illustrated by the following examples, in which different modes of synthesis are applied, as explained in detail below.

[0226] In all inventive examples, the starting materials 1,2,3-propanetriol (glycerin, glycerol) and solketal (isopropylideneglycerin) used, respectively, are at least essentially free of chlorinated species, i.e., each contains a total chlorinated species content of up to 0.1 ppm (based on 1,2,3-propanetriol or solketal, respectively). Furthermore, the concentration of the sum of MCPD fatty acid esters and glycidol fatty acid esters is below the detection limit (the sum of MCPD and glycidol esters is below 0.1 ppm, respectively, based on glycerol or solketal, respectively).

[0227] Moreover, in all inventive examples, the esterification is carried out at a temperature not exceeding 100°C, preferably not exceeding 80°C.

[0228] Also, in all the present examples, the esterification is carried out in the absence of a metal-based catalyst.

[0229] Finally, all of the inventive examples include selective derivatization, i.e., chemical treatment with nucleophiles, to remove traces of halide-based impurities, especially MCPD and glycidol fatty acid esters. Although in all of the inventive examples the product purity requirements are met without such treatment, such selective derivatization, i.e., chemical treatment with nucleophiles, selectively removes even traces of impurities present, thus further increasing the purity grade.

[0230] 1. Synthetic Route (A) Tricaprylin is prepared according to the above mentioned synthetic route (A). For this purpose, the following procedure is applied:

[0231] Caprylic acid (i.e. saturated linear C8-fatty acid or octanoic acid) is reacted with glycerol at 80°C under vacuum (<100 mbar) in the presence of an immobilized enzyme (CALB lipase on a polymeric support from Candida antarctica, e.g. Novozym® 435 from Sigma-Aldrich or Merck or Lipozym® 435 from Stroem Chemicals; 1% by weight based on the reaction mixture) as catalyst. Caprylic acid is used in an amount of up to 300 mol%, preferably up to 100 mol%, based on the OH-groups of glycerol. The excess caprylic acid is then removed using a short-path distillation (≪180°C, preferably 120°C-130°C; ≪0.1 mbar, preferably <2 mbar). Dicaprylin, especially 1,3-dicaprylin (1,3-diglyceride of caprylic acid) is obtained.

[0232] The dicaprylin is then reacted with caprylic anhydride at a temperature below 180° C., preferably between 80° C. and 150° C., until the hydroxyl value (OHV) is less than 0.1 mg KOH / g. The resulting product is treated in the usual manner to remove caprylic acid formed as a by-product (i.e., short path distillation, etc.).

[0233] The resulting tricaprylin product is analyzed as follows: Acid value (AV) as determined by the European Pharmacopoeia 2.5.1 (European Pharmacopoeia 10.0): ≦0.1 mg KOH / g; and Hydroxyl value (OHV) as determined by European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0): ≦0.1 mg KOH / g; and Triglyceride content as determined by European Pharmacopoeia 2.2.28 (European Pharmacopoeia 10.0): ≥ 99.4% based on reaction products; and Total content of MCPD fatty acid esters as determined by the method of DGF C-VI 18(10) (German Fat Society standard method): ≦0.14 ppm based on the reaction product; and Total content of glycidol esters of fatty acids determined by the method of DGF C-VI 18(10) (German Fat Society standard method): ≦0.12 ppm each, based on said reaction products.

[0234] The tricaprylin product is further subjected to treatment (80°C, 6 hours) in the form of an aqueous solution of sodium hydrogen sulfite (NaHSO3) as a nucleophile (selective derivatization of halide-based impurities, i.e., MCPD fatty acid esters and glycidol fatty acid esters). Separation of the aqueous phase and drying of the resulting tricaprylin product further improves the overall product quality, since the triglyceride content increases to more than 99.5% and the content of MCPD fatty acid esters and the sum of the content of glycidol esters of fatty acids are each below the detection limit (i.e., below 0.1 ppm, respectively). Optionally, the product thus treated can also be further treated with bleaching earth and / or activated carbon, optionally followed by deodorization (e.g., using pressurized steam). The tricaprylin product after treatment with sodium hydrogen sulfite (NaHSO3) and optional further treatment is analyzed as follows: Acid value (AV) (European Pharmacopoeia 2.5.1): ≦0.1 mg KOH / g; Hydroxyl value (OHV) (European Pharmacopoeia 2.5.3): ≦0.1 mg KOH / g; Triglyceride content (European Pharmacopoeia 2.2.28): ≥ 99.5% based on tricaprylin; Total content of MCPD fatty acid esters (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin; Total content of glycidol esters of fatty acids (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin.

[0235] Comparable results are obtained when other nucleophiles (i.e., sodium hydrogen thiosulfate (NaHS2O3), sodium hydrogen phosphite (NaH2PO3) and phosphines) are used in place of sodium hydrogen sulfite (NaHSO3).

[0236] The above preparation procedure was repeated in a similar manner using different starting materials, namely the respective C1-C4-esters of caprylic acid, with comparable results.

[0237] In a similar manner, triheptanoin on the one hand and caproic acid (C6) / caprylic acid (C8) / capric acid (C 10 ) are produced with comparable results (properties after treatment with bisulfite for triheptanoin and MCT respectively: acid number: ≦0.1 mg KOH / g, hydroxyl number: ≦0.1 mg KOH / g, triglyceride content: ≧99.5%, total content of MCPD fatty acid esters: ≦0.1 ppm, total content of glycidol esters: ≦0.1 ppm).

[0238] Comparison Procedure (not of the present invention) In a non-patent embodiment, the synthesis route (A) of tricaprylin is carried out with the following deviations: the glycerol used as starting material has a total chlorinated species content of about 30 ppm. The esterification catalyst used is a metal-based catalyst based on tetrabutyl titanate (TBT). The esterification is carried out in the temperature range of 190°C to 230°C.

[0239] The resulting tricaprylin is analyzed as follows: acid value (European Pharmacopoeia 2.5.1: >0.6 mg KOH / g, hydroxyl value (European Pharmacopoeia 2.5.3): >0.7 mg KOH / g, triglyceride content (European Pharmacopoeia 2.2.28): 97.5% based on tricaprylin, total content of MCPD fatty acid esters (DGF C-VI18(10)): 0.9 ppm based on tricaprylin, total content of glycidol esters of fatty acids (DGF C-VI18(10)): 0.7 ppm based on tricaprylin.

[0240] Subsequent treatment with sodium bisulfite (NaHSO3) in the form of an aqueous solution (80 °C, 6 h) allows both the total content of MCPDE fatty acid esters and the total content of glycidol esters of fatty acids to be reduced to values ​​of approximately 0.4 ppm, respectively, while the parameters of acid value, hydroxyl value and triglyceride content are not improved or affected.

[0241] 2. Synthetic Route (B) Tricaprylin is prepared according to the above mentioned synthetic route (B). For this purpose, the following procedure is applied: Caprylic acid (i.e. saturated linear C8-fatty acid or octanoic acid) is reacted with glycerol at 80°C under vacuum (<100 mbar) in the presence of an immobilized enzyme (CALB lipase on a polymeric support from Candida antarctica, e.g. Novozym® 435 from Sigma-Aldrich or Merck or Lipozym® 435 from Strem Chemicals; 1% by weight based on the reaction mixture) as catalyst. Caprylic acid is used in an amount of up to 300 mol%, preferably up to 100 mol%, based on the OH-groups of glycerol. Excess caprylic acid is then removed using short-path distillation (180°C, preferably 120°C-130°C; 0.1 mbar, preferably 2 mbar). Dicaprylin, especially 1,3-dicaprylin (1,3-diglyceride of caprylic acid) is obtained. Dicaprylin is then reacted with caprylic acid in the presence of enzymes, specifically enzymes that regioselectively esterify the 2-position of 1,3-diglycerides (e.g., Pseudomonas fluorescens lipase in the first approach and Burkholderia cepacia lipase in the alternative second approach, each immobilized on chitosan), at 50 °C until the hydroxyl value (OHV) is less than 0.1 mg KOH / g.

[0242] The resulting tricaprylin product is analyzed as follows: Acid value (AV) (European Pharmacopoeia 2.5.1): ≦0.1 mg KOH / g; Hydroxyl value (OHV) (European Pharmacopoeia 2.5.3): ≦0.1 mg KOH / g; Triglyceride content (European Pharmacopoeia 2.2.28): ≥ 99.5% based on tricaprylin; Total content of MCPD fatty acid esters (DGF C-VI 18(10)): ≤ 0.17 ppm based on tricaprylin; Total content of glycidol esters of fatty acids (DGF C-VI 18(10)): ≤ 0.19 ppm based on tricaprylin.

[0243] The tricaprylin product is further subjected to treatment (80°C, 6 hours) with aqueous sodium bisulfite (NaHSO3) as a nucleophile (selective derivatization of halide-based impurities, i.e., MCPD fatty acid esters and glycidol fatty acid esters). Separation of the aqueous phase and drying of the resulting tricaprylin product further improves the overall product quality, since the content of MCPD fatty acid esters and the sum of the content of glycidol esters of fatty acids are below the detection limit, respectively (i.e., ≦0.1 ppm, respectively). Optionally, the product thus treated can also be further treated with bleaching earth and / or activated carbon, optionally followed by deodorization (e.g., using pressurized steam).

[0244] The resulting tricaprylin product after treatment with sodium bisulfite (NaHSO3) and optional further processing is analyzed as follows: Acid value (AV) (European Pharmacopoeia 2.5.1): ≦0.1 mg KOH / g; Hydroxyl value (OHV) (European Pharmacopoeia 2.5.3): ≦0.1 mg KOH / g; Triglyceride content (European Pharmacopoeia 2.2.28): ≥ 99.5% based on tricaprylin; Total content of MCPD fatty acid esters (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin; Total content of glycidol esters of fatty acids (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin.

[0245] The above preparation procedure was repeated in a similar manner using different starting materials, namely the respective C1-C4-esters of caprylic acid, with comparable results.

[0246] In a similar manner, triheptanoin on the one hand and caproic acid (C6) / caprylic acid (C8) / capric acid (C 10Medium chain triglycerides (MCT) based on triheptanoin are also produced with comparable results (Properties after treatment with bisulfite for triheptanoin and MCT respectively: acid number: ≦0.1 mg KOH / g, hydroxyl number: ≦0.1 mg KOH / g, triglyceride content: ≧99.5%, total content of MCPD fatty acid esters: ≦0.1 ppm, total content of glycidol esters: ≦0.1 ppm).

[0247] 3. Synthetic Route (C) Tricaprylin is prepared according to the previously described synthetic route (C). For this purpose, the following procedure is applied: Caprylic anhydride (i.e. linear saturated C8-fatty acid anhydride or octanoic anhydride) is reacted with glycerol at less than 180° C., preferably between 80° C. and 150° C., until the hydroxyl value (OHV) is less than 0.1 mg KOH / g. The caprylic acid produced (by-product) is then removed using short path distillation (<180° C., preferably 120° C.-130° C.; <0.1 mbar, preferably <2 mbar).

[0248] The resulting tricaprylin product is analyzed as follows: Acid value (AV) (European Pharmacopoeia 2.5.1): ≦0.1 mg KOH / g; Hydroxyl value (OHV) (European Pharmacopoeia 2.5.3): ≦0.1 mg KOH / g; Triglyceride content (European Pharmacopoeia 2.2.28): ≥ 99.5% based on tricaprylin; Total content of MCPD fatty acid esters (DGF C-VI 18(10)): ≤ 0.16 ppm based on tricaprylin; Total content of glycidol esters of fatty acids (DGF C-VI 18(10)): ≤ 0.12 ppm based on tricaprylin.

[0249] The tricaprylin product is further subjected to treatment (80°C, 6 hours) with aqueous sodium bisulfite (NaHSO3) as a nucleophile (selective derivatization of halide-based impurities, i.e., MCPDE fatty acid esters and glycidol fatty acid esters). Separation of the aqueous phase and drying of the resulting tricaprylin product further improves the overall product quality, since the content of MCPD fatty acid esters and the sum of the content of glycidol esters of fatty acids are below the detection limit, i.e., ≦0.1 ppm, respectively. Optionally, the product thus treated can also be further treated with bleaching earth and / or activated carbon, optionally followed by deodorization (e.g., using pressurized steam).

[0250] The tricaprylin product after treatment with sodium bisulfite (NaHSO3) and optional further processing is analyzed as follows: Acid value (AV) (European Pharmacopoeia 2.5.1): ≦0.1 mg KOH / g; Hydroxyl value (OHV) (European Pharmacopoeia 2.5.3): ≦0.1 mg KOH / g; Triglyceride content (European Pharmacopoeia 2.2.28): ≥ 99.5% based on tricaprylin; Total content of MCPD fatty acid esters (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin; Total content of glycidol esters of fatty acids (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin.

[0251] In a similar manner, triheptanoin on the one hand and caproic acid (C6) / caprylic acid (C8) / capric acid (C 10 ) are produced with comparable results (properties after treatment with bisulfite for triheptanoin and MCT respectively: acid number: ≦0.1 mg KOH / g, hydroxyl number: ≦0.1 mg KOH / g, triglyceride content: ≧99.5%, total content of MCPDE fatty acid esters: ≦0.1 ppm, total content of glycidol esters: ≦0.1 ppm).

[0252] 4. Synthetic Route (D) Tricaprylin is prepared according to the above mentioned synthetic route (D). For this purpose, the following procedure is applied: Solketal and caprylic anhydride (straight chain saturated C8-fatty acid anhydride or octanoic anhydride) are placed in a flask and the system is evacuated. The mixture is reacted at a temperature below 180°C, preferably between 80°C and 150°C, for 6 hours. Caprylic acid formed as a by-product is then distilled off at 130°C and below 20 mbar. Solketal monoester of caprylic acid is obtained with a purity of less than 95%.

[0253] The solketal monoester of caprylic acid is then subjected to an acid-induced deprotection reaction (i.e., ring opening) using either dilute sulfuric acid or dilute phosphoric acid to adjust the pH value, preferably to about 1, to remove acetone formed as a by-product of the deprotection.

[0254] The resulting caprylic acid glycerol monoester (i.e., caprylic acid monoglyceride) is then further reacted with caprylic anhydride at 80° C. for 90 minutes to obtain triglyceride (i.e., tricaprylin). After completion of the reaction, caprylic acid formed as a by-product is distilled off at 130° C. under 20 mbar.

[0255] The resulting tricaprylin product is analyzed as follows: Acid value (AV) (European Pharmacopoeia 2.5.1): ≦0.1 mg KOH / g; Hydroxyl value (OHV) (European Pharmacopoeia 2.5.3): ≦0.1 mg KOH / g; Triglyceride content (European Pharmacopoeia 2.2.28): ≥ 99.5% based on tricaprylin; Total content of MCPD fatty acid esters (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin; Total content of glycidol esters of fatty acids (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin.

[0256] The tricaprylin product is further subjected to treatment (80°C, 6 hours) with aqueous sodium bisulfite (NaHSO3) as a nucleophile (selective derivatization of halide-based impurities, i.e., MCPD fatty acid esters and glycidol fatty acid esters). Separation of the aqueous phase and drying of the resulting tricaprylin product further improves the overall product quality, since the triglyceride content increases to more than 99.5% and the content of MCPD fatty acid esters and the sum of the content of glycidol esters of fatty acids are below the detection limit, i.e., below 0.1 ppm each. Optionally, the product thus treated can also be further treated with bleaching earth and / or activated carbon, optionally followed by deodorization (e.g., using pressurized steam). The tricaprylin product after treatment with sodium bisulfite (NaHSO3) and optional further treatment is analyzed as follows: Acid value (AV) (European Pharmacopoeia 2.5.1): ≦0.1 mg KOH / g; Hydroxyl value (OHV) (European Pharmacopoeia 2.5.3): ≦0.1 mg KOH / g; Triglyceride content (European Pharmacopoeia 2.2.28): ≥ 99.5% based on tricaprylin; Total content of MCPD fatty acid esters (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin; Total content of glycidol esters of fatty acids (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin.

[0257] In a similar manner, triheptanoin on the one hand and caproic acid (C6) / caprylic acid (C8) / capric acid (C 10 ) based medium chain triglycerides (MCT) are also produced with comparable results; (Properties after treatment with bisulfite for triheptanoin and MCT respectively: acid number: ≦0.1 mg KOH / g, hydroxyl number: ≦0.1 mg KOH / g, triglyceride content: ≧99.5%, total content of MCPD fatty acid esters: ≦0.1 ppm, total content of glycidol esters: ≦0.1 ppm).

[0258] 5. Synthetic Route (E) Tricaprylin is prepared according to the above mentioned synthetic route (E). For this purpose, the following procedure is applied: Solketal and caprylic acid (i.e. linear saturated C8-fatty acid or octanoic acid) are mixed with immobilized enzyme as catalyst (CALB lipase on a polymeric support from Candida antarctica, e.g. Novozym® 435 from Sigma-Aldrich or Merck or Lipozym® 435 from Strem Chemicals; 1% by weight based on the reaction mixture) and reacted at 80°C for 6 hours under N2 atmosphere. The enzyme is then filtered. Solketal monoester of caprylic acid is obtained.

[0259] The solketal monoester of caprylic acid is then subjected to an acid-induced deprotection reaction (i.e., ring opening) using either dilute sulfuric acid or dilute phosphoric acid to adjust the pH value, preferably to about 1, to remove acetone formed as a by-product of the deprotection.

[0260] The resulting caprylic acid glycerol monoester (i.e., caprylic acid monoglyceride) is then further reacted with caprylic anhydride at 80° C. for 90 minutes to obtain the triglyceride (i.e., tricaprylin). After completion of the reaction, the caprylic acid formed as a by-product is distilled off at 130° C. under 20 mbar.

[0261] The resulting tricaprylin product is analyzed as follows: Acid value (AV) (European Pharmacopoeia 2.5.1): ≦0.1 mg KOH / g; Hydroxyl value (OHV) (European Pharmacopoeia 2.5.3): ≦0.1 mg KOH / g; Triglyceride content (European Pharmacopoeia 2.2.28): ≥ 99.4% based on tricaprylin; Total content of MCPD fatty acid esters (DGF C-VI 18(10)): ≤ 0.15 ppm based on tricaprylin; Total content of glycidol esters of fatty acids (DGF C-VI 18(10)): ≤ 0.12 ppm based on tricaprylin.

[0262] The tricaprylin product is further subjected to treatment (80°C, 6 hours) with aqueous sodium bisulfite (NaHSO3) as a nucleophile (selective derivatization of halide-based impurities, i.e., MCPD fatty acid esters and glycidol fatty acid esters). Separation of the aqueous phase and drying of the resulting tricaprylin product further improves the overall product quality, since the triglyceride content increases to more than 99.5% and the content of MCPD fatty acid esters and the sum of the content of glycidol esters of fatty acids are below the detection limit (i.e., below 0.1 ppm, respectively). Optionally, the product thus treated can also be further treated with bleaching earth and / or activated carbon, optionally followed by deodorization (e.g., using pressurized steam). The resulting tricaprylin product after treatment with sodium bisulfite (NaHSO3) and optional further processing is analyzed as follows: Acid value (AV) (European Pharmacopoeia 2.5.1): ≦0.1 mg KOH / g; Hydroxyl value (OHV) (European Pharmacopoeia 2.5.3): ≦0.1 mg KOH / g; Triglyceride content (European Pharmacopoeia 2.2.28): ≥ 99.5% based on tricaprylin; Total content of MCPD fatty acid esters (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin; Total content of glycidol esters of fatty acids (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin.

[0263] In a similar manner, triheptanoin, on the one hand, and caproic acid (C6) / caprylic acid (C8) / capric acid (C 10 ) based medium chain triglycerides (MCTs) are also produced with comparable results. (Properties of triheptanoin and MCT after treatment with bisulfite: acid value: ≦0.1 mg KOH / g, hydroxyl value: ≦0.1 mg KOH / g, triglyceride content: ≧99.5%, total content of MCPD fatty acid esters: ≦0.1 ppm, total content of glycidol esters: ≦0.1 ppm).

[0264] 6. Synthetic Route (F) Tricaprylin is prepared according to the above mentioned synthetic route (F). For this purpose, the following procedure is applied: 2-Octenoic acid is esterified with glycerol (≦0.1 ppm of MCPD fatty acid esters and glycidol esters combined; ≦0.1 ppm total content of chlorinated species) in the presence of immobilized enzyme as catalyst (CALB lipase on a polymeric support from Candida antarctica, e.g. Novozym® 435 from Sigma-Aldrich or Merck or Lipozym® 435 from Strem Chemicals; ≦0.5% by weight, preferably ≦0.1% by weight based on the reaction mixture) under vacuum (≦100 mbar) at 70° C. Water formed as a reaction by-product is continuously withdrawn. Esterification is carried out until the hydroxyl value (OHV) is ≦0.1 mg KOH / g.

[0265] The excess 2-octenoic acid is then removed using short path distillation (<180°C, <10 mbar, preferably 120-130°C, <2 mbar). The triglyceride of 2-octenoic acid is obtained.

[0266] The triglyceride of 2-octenoic acid is then hydrogenated using a conventional hydrogenation catalyst (i.e. preferably a transition metal catalyst on a catalyst support, e.g. Pd, Pt, Ru, Rh, Ni, etc.) in a concentration of ≦10% by weight based on the triglyceride of 2-octenoic acid. The hydrogenation is carried out at a temperature between 50° C. and 180° C., preferably between 80° C. and 120° C., and at a hydrogen pressure of less than 50 bar, preferably between 5 bar and 30 bar. The hydrogenation is continued until the iodine value of the reaction mixture is less than 1.0 g per 100 g. The catalyst is then filtered and the reaction product is chemically washed / treated, treated with bleaching earth / activated carbon, then filtered. The chemical washing / treatment is carried out as defined above with sodium bisulfite (NaHSO3) in the form of an aqueous solution (80° C., 6 hours).

[0267] It is then deodorized using pressurized steam (HPW-steam) to remove residual 2-octenoic acid at temperatures between 120°C and below 180°C and pressures below 10 mbar.

[0268] The tricaprylin product after sodium bisulfite (NaHSO3) treatment is analyzed as follows: Acid value (AV) (European Pharmacopoeia 2.5.1): ≦0.1 mg KOH / g; Hydroxyl value (OHV) (European Pharmacopoeia 2.5.3): ≦0.1 mg KOH / g; Triglyceride content (European Pharmacopoeia 2.2.28): ≥ 99.5% based on tricaprylin; Total content of MCPD fatty acid esters (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin; Total content of glycidol esters of fatty acids (DGF C-VI 18(10)): ≤ 0.1 ppm based on tricaprylin.

[0269] However, the above preparation procedure was repeated in a similar manner using different starting materials, namely 4-octenoic acid, 7-octenoid acid, 2-octenoid acid, 4-octenoid acid and 7-octenoid acid, and a triple mixture of 2-octenoid acid, 4-octenoid acid and 7-octenoid acid, with comparable results.

[0270] In a similar manner, triheptanoin on the one hand and caproic acid (C6) / caprylic acid (C8) / capric acid (C 10 ) based medium chain triglycerides (MCT) are produced with comparable results (properties after treatment with bisulfite for triheptanoin and MCT respectively: acid value: ≦0.1 mg KOH / g, hydroxyl value: ≦0.1 mg KOH / g, triglyceride content: ≧99.5%, total content of MCPD fatty acid esters: ≦0.1 ppm, total content of glycidol esters: ≦0.1 ppm).

[0271] Inventive feature and / or condition (i): Selective derivatization / treatment with at least one nucleophile To demonstrate the effectiveness of criterion (i) of the present invention, in particular the selective derivatization of halide impurities, i.e. the selective removal of halide impurities (in particular MCPD and glycidol fatty acid esters), a treatment of a commercial triglyceride according to criterion (i) of the present invention is carried out.

[0272] A commercial product based on MCT oil (triglyceride) has a glycidol ester content of 70 ppm. After treatment with aqueous sodium bisulfite at 80° C. for 6 hours, the glycidol ester content is reduced to 9.11 ppm.

[0273] Another commercial product (MCT60 / 40) based on MCT oil (triglycerides) has a 3-MCPD fatty acid ester content of 8 ppm. After treatment with aqueous sodium bisulfite at 80°C for 6 hours, the 3-MCPD content is reduced to 2.21 ppm; thus, a reduction of about 3.5 times is achieved.

[0274] Further commercially available products (Miglyol® 812N, C8 / C 10The 3-MCPD fatty acid ester content of the glycerol triglyceride is 1.56 ppm. After 15 hours of treatment with 12% aqueous sodium bisulfite at 80° C., the 3-MCPD content is reduced to 0.16 ppm; thus, a reduction of about 9.7 times is achieved.

[0275] Comparable results can be obtained by using other nucleophiles (i.e., sodium hydrogen thiosulfate (NaHS2O3), sodium hydrogen phosphite (NaH2PO3) or phosphines) instead of sodium hydrogen sulfite (NaHSO3).

[0276] Therefore, the feature and / or condition (i) of the present invention effectively reduces the content of halide-based impurities, especially MCPD and glycidol fatty acid esters. However, based only on the criterion (i) of the present invention, especially when starting from commercial or prior art triglycerides of low purity grade, it is not always sufficient to meet the entire product specification consisting of the 5-fold purity / grade requirement in items (1) to (5) defined above; however, at least two features, in particular (4) the total content of MCPD fatty acid esters is less than 0.1 ppm and (5) the total content of glycidol esters is less than 0.1 ppm, can be efficiently adjusted and / or effected by this criterion (i).

[0277] conclusion The applicant is able to provide a universal concept / method for producing high purity tricaprylin (as well as triglycerides of other fatty acids which can be used to prepare mixtures with tricaprylin) in high yields and high conversions, which concept / method is independent of any particular synthetic route.

[0278] The process of the invention is at the same time very flexible and compatible with known prior art production methods and plants for these substances, since the aforementioned inventive features and / or conditions (i) to (iv) can be easily implemented in known production methods and plants for these substances or can be used to modify known production methods and plants for these substances.

[0279] In particular, the method of the present invention produces high purity tricaprylin (but also triglycerides of other fatty acids can be produced, which can be used to produce mixtures with tricaprylin) and at the same time unifies a combination of at least five purity properties; namely, (1) very low acid value (AV), (2) very low hydroxyl value (OHV), (3) very high triglyceride content, (4) very low total content of MCPD fatty acid esters, and (5) very low total content of glycidol esters of fatty acids, where this purity specification can be reached independently of a particular synthetic route. Such combinations of purity properties (1)-(5) have been previously thought to be incompatible or unattainable, but as the applicant has surprisingly discovered, the method of the present invention makes such a combination of purity properties possible for the first time.

[0280] In addition, for example, hydrogen sulfite (bisulfite, HSO - ), sulfite (SO3 2- ), hydrogen thiosulfate (HS2O3 - ), thiosulfate (S2O3 2- ), hydrogen phosphite (H2PO3 - ), Phosphite (HPO3 2- Nucleophiles such as phosphines and combinations thereof are excellent reactants for purifying tricaprylin and for removing halide-based impurities, particularly chlorine-based impurities, from tricaprylin (i.e., selective derivatization of halide-based impurities), particularly chlorine-based impurities selected from the group consisting of MCPD fatty acid esters (fatty acid esters of monochloropropanediol), glycidol esters of fatty acids, and combinations thereof.

Claims

1. A method for producing tricaprylin, comprising the steps of: Formula (I) CH ２ (OH)-CH(OH)-CH ２ (OH) (I) at least one starting material selected from 1,2,3-propanetriol or solketal is reacted to convert to tricaprylin; Formula (II) CH ２ [O-C(O)R １ ]-CH[O-C(O)R １ ]-CH ２ [O-C(O)R １ ] (II) producing, as a reaction product, tricaprylin of In this case, in formula (II), the radical R １ is represented by the formula -(CH ２ ) ６ -CH ３ Linear saturated aliphatic C ７ represents an alkyl radical, Wherein, tricaprylin of formula (I) has the following properties (1) to (5) in combination thereof: (1) Acid value (AV) as measured by European Pharmacopoeia 2.5.1 (European Pharmacopoeia 10.0): ≦0.5 mg KOH / g; and (2) Hydroxyl value (OHV) as measured by European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0): ≦0.5 mg KOH / g; and (3) Triglyceride content as measured by European Pharmacopoeia 2.2.28 (European Pharmacopoeia 10.0): ≧99% based on the reaction product; and (4) The total content of MCPD fatty acid esters, as measured by the method of DGF C-VI 18(10) (German Fatty Society standard method): ≦0.5 ppm based on the reaction product; and (5) The total content of glycidol esters of fatty acids, measured by the method of DGF C-VI 18(10) (German Fat Society standard method): ≦0.5 ppm based on the reaction product To show: Here, the method is ８ - comprising at least one esterification stage using fatty acids and their anhydrides and C 1 -C 4 -alkyl esters; wherein the method comprises the following features and / or conditions (i) to (iv): (i) selective derivatization of halide-based impurities selected from fatty acid esters of monochloropropanediol and glycidol esters of fatty acids present in the resulting reaction product is carried out by treating the resulting reaction product with a nucleophile selected from the group consisting of bisulfites, sulfites, hydrogen thiosulfates, thiosulfates, hydrogen phosphites, phosphites and phosphines, and combinations thereof; (ii) at least one esterification stage is carried out at a temperature not exceeding 180°C; (iii) starting materials selected from 1,2,3-propanetriol and solketal of formula (I) are used and are selected to be free of chlorinated species and contain a maximum total chlorinated species content of 1 ppm based on the 1,2,3-propanetriol and solketal of formula (I); (iv) at least one esterification step is carried out in the absence of a metal-based catalyst.

2. In the formula (II), the radical R １ Linear saturated aliphatic C ７ -representing an alkyl radical; and 2. The process according to claim 1, characterized in that in at least one esterification step, at least one compound is used selected from octanoic acid and its anhydrides and esters.

3. The overall process, including any additional pre-treatment and / or post-treatment steps, is carried out at a temperature not exceeding 180° C.; and 3. The process according to claim 1 or 2, characterized in that the overall process, including any additional pre-treatment and / or post-treatment steps, is carried out in the absence of metal-based catalysts.

4. said at least one esterification step being carried out in the absence of a solvent; and 3. The process according to claim 1 or 2, characterized in that at least one esterification step is carried out at least partially in the absence of a catalyst or, alternatively, in the presence of an enzyme as catalyst.

5. Tricaprylin is Formula (II) CH ２ [O-C(O)R １ ]-CH[O-C(O)R １ ]-CH ２ [O-C(O)R １ ] (II) That is, In this case, in formula (II), the radical R １ is represented by the formula -(CH ２ ) ６ -CH ３ Linear saturated aliphatic C ７ -representing an alkyl radical; wherein the tricaprylin of formula (II) has the following properties (1) to (5): (1) Acid value (AV) as measured by European Pharmacopoeia 2.5.1 (European Pharmacopoeia 10.0): ≦0.5 mg KOH / g; and (2) Hydroxyl value (OHV) as measured by European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0): ≦0.5 mg KOH / g; and (3) Triglyceride content as measured by European Pharmacopoeia 2.2.28 (European Pharmacopoeia 10.0): ≧99% based on the tricaprylin; and (4) The total content of MCPD fatty acid esters, as measured by the method of DGF C-VI 18(10) (German Society of Fat Science Standard Method): ≦0.5 ppm based on the tricaprylin; and (5) The total content of glycidol esters of fatty acids, as measured by the method of DGF C-VI 18(10) (German Society of Fat Science Standard Method): ≦0.5 ppm based on the tricaprylin; Tricaprylin, characterized in that it exhibits the above in combination.

6. The tricaprylin is Formula (II) CH ２ [O-C(O)R １ ]-CH[O-C(O)R １ ]-CH ２ [O-C(O)R １ ] (II) That is, wherein in formula (II), the radical R1 is of the formula -(CH ２ ) ６ -CH ３ Linear saturated aliphatic C ７ -representing an alkyl radical; wherein the tricaprylin of formula (II) has the following properties (1) to (5): (1) Acid value (AV) as measured by European Pharmacopoeia 2.5.1 (European Pharmacopoeia 10.0): ≦0.2 mg KOH / g; and (2) Hydroxyl value (OHV) as measured by European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0): ≦0.2 mg KOH / g; and (3) Triglyceride content as measured by European Pharmacopoeia 2.2.28 (European Pharmacopoeia 10.0): ≧99.2% based on tricaprylin; and (4) The total content of MCPD fatty acid esters as measured by the method of DGF C-VI 18(10) (German Society of Fatty Acids Standard Method): ≦0.2 ppm based on the tricaprylin; and (5) The total content of glycidol esters of fatty acids measured by the method of DGF C-VI 18(10) (German Fat Society standard method): ≦0.2 ppm based on the tricaprylin; 6. Tricaprylin according to claim 5, characterized in that it exhibits the following combination:

7. The tricaprylin is Formula (II) CH ２ [O-C(O)R １ ]-CH[O-C(O)R １ ]-CH ２ [O-C(O)R １ ] (II) That is, In this case, in formula (II), the radical R １ is represented by the formula -(CH ２ ) ６ -CH ３ Linear saturated aliphatic C ７ -representing an alkyl radical; wherein the tricaprylin of formula (II) has the following properties (1) to (5): (1) Acid value (AV) as measured by European Pharmacopoeia 2.5.1 (European Pharmacopoeia 10.0): ≦0.1 mg KOH / g; and (2) Hydroxyl value (OHV) as measured by European Pharmacopoeia 2.5.3 (European Pharmacopoeia 10.0): ≦0.1 mg KOH / g; and (3) Triglyceride content as measured by European Pharmacopoeia 2.2.28 (European Pharmacopoeia 10.0): ≧99.5% based on tricaprylin; and (4) The total content of MCPD fatty acid esters as measured by the method of DGF C-VI 18(10) (German Fat Society Standard Method): ≦0.1 ppm based on the tricaprylin; and (5) The total content of glycidol esters of fatty acids measured by the method of DGF C-VI 18(10) (German Fat Society standard method): ≦0.1 ppm based on the tricaprylin; 6. Tricaprylin according to claim 5, characterized in that it exhibits the following combination:

8. A pharmaceutical composition comprising the tricaprylin according to claim 5 or 6 together with a physiologically acceptable excipient.

9. 7. A food-based product selected from the group consisting of food, nutritional composition, food composition, food product and medical food comprising tricaprylin according to claim 5 or 6.

10. A cosmetic composition comprising tricaprylin according to claim 5 or 6.

11. An additive for use as at least one of a carrier or excipient, a solubilizer, a release agent, a surface treatment agent, a transport agent, a lubricant, a hydrophobizing agent, a film-forming or protective agent, and a viscosity modifier, comprising the tricaprylin according to claim 5 or 6.

12. The additive according to claim 11, characterized in that it is applied to at least one of a pharmaceutical composition, a pharmaceutical product, a cosmetic product and a food-based product selected from the group consisting of a food, a nutritional composition, a food composition, a food product and a medical food.

13. 1. A method for purifying tricaprylin containing halide impurities, comprising: the method comprising at least one step of selective removal and derivatization of halide-based impurities present in the purified tricaprylin by treatment with at least one nucleophilic agent; The method of claim 1, wherein the nucleophile is selected from the group consisting of bisulfites, sulfites, hydrogen thiosulfates, thiosulfates, hydrogen phosphites, phosphites and phosphines, and combinations thereof.

14. 14. The method of claim 13, wherein the halide-based impurities are selected from the group consisting of fatty acid esters of monochloropropanediol, glycidol esters of fatty acids, and combinations thereof.

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