Method and composition for recovering mevalonic acid or its salt or lactone from aqueous solution using water solvent crystallization

Abstract

Compositions and methods for producing crystalline forms of organic acids or their salts or lactones from aqueous solutions are provided. More specifically, methods for producing crystalline forms of salts of mevalonic acid (also referred to as X-MVA) from aqueous solutions are provided, the methods comprising subjecting an aqueous solution comprising the X-MVA to a purification step to produce a purified solution, and crystallizing the X-MVA from the purified solution by water solvent crystallization. Methods for producing mevalonate lactone from an aqueous solution comprising X-MVA are also provided, the methods comprising subjecting an aqueous solution comprising the X-MVA to cation exchange, thereby converting the aqueous solution comprising the X-MVA into an aqueous solution comprising mevalonate lactone (MVL). Methods for producing mevalonate lactone monohydrate crystals are also provided.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 892,760, filed on August 28, 2019, and U.S. Provisional Application No. 63 / 012,492, filed on April 20, 2020, each of which is incorporated herein by reference in its entirety. Technical Field

[0002] The present disclosure relates to the technical field of organic acid separation, and more particularly to a method for recovering organic acids and their salts or lactones from aqueous solutions using water solvent crystallization. Background Art

[0003] Known processes for isolating and purifying organic acids from solutions such as fermentation media are very complex and usually involve an organic solvent extraction step or solid phase absorption.

[0004] An important aspect of the industrial use of organic acids, such as carboxylic acids, produced by fermentation of carbohydrate-containing substrates using various microorganisms is the cost-effectiveness and efficiency of removing and purifying the organic acids or their salts or lactones from these aqueous fermentation solutions, which contain not only the organic acids or organic acid salts or lactones, but also additional organic acids, other fermentation by-products, the microorganisms and their components, and residues of the substrate, such as sugars, proteins, lipids and other trace organic and inorganic compounds.

[0005] The classic way to purify organic acids produced by microorganisms from fermentation media is to protonate the target acid by lowering the pH of the medium and performing liquid / liquid extraction using partially miscible organic solvents (Organic Laboratory Techniques, 3rd edition, pages 49-67. Ralph Fessenden, Joan Fessenden, Patty Feist 2001, Brooks / Co le Publishers).

[0006] US2014 / 0371486 describes a method for purifying carboxylic acids from a fermentation medium using solid phase adsorption. The method comprises removing biomass and any solids present from the fermentation medium, finely cleaning the biomass-free and solid-free fermentation medium by nanofiltration, and removing the carboxylic acids from the finely cleaned biomass-free and solid-free fermentation medium by adsorption to one or more solid phases having tertiary amino groups. KR20180070117 describes a method for producing mevalonolactone from biosynthesized mevalonic acid using phosphoric acid.

[0007] US5034105 describes a method for crystallizing succinic acid from an unsaturated solution of a succinate salt by subjecting the salt solution to electrodialysis to form a supersaturated solution, which is then crystallized by adding an effective amount of acetic acid to the solution to enhance the crystallization of succinic acid.

[0008] The disadvantage of these methods is that additional substances are provided to the process, which substances must no longer be present in the target product, or trace amounts of these substances in the target product may lead to limited quality and applicability of the product. The practical implementation of these methods is also associated with considerable technical complexity and considerable energy consumption in some cases.

[0009] Therefore, there remains a need to develop more efficient, reliable, environmentally friendly and / or economically viable processes for purifying and recovering organic acids and their salts and lactones and for producing crystalline forms of organic acids and their salts or lactones. Summary of the invention

[0010] Compositions and methods for producing crystalline forms of organic acids or their salts or lactones from aqueous solutions are provided. In one aspect, crystallized mevalonolactone*monohydrate (MVL*H2O) and methods of crystallizing mevalonolactone*monohydrate (MVL*H2O) are disclosed.

[0011] More specifically, in one aspect, the present specification provides a method for producing a crystalline form of a salt of mevalonic acid (also referred to as X-MVA) from an aqueous solution, the method comprising subjecting an aqueous solution comprising the X-MVA to nanofiltration to produce a permeate and crystallizing the X-MVA from the permeate by crystallization from an aqueous solvent ( Figure 1A ).

[0012] In another aspect, the present specification provides a method for producing water-soluble mevalonate lactone from an aqueous solution, wherein the method comprises: a) producing a crystalline form of a salt of mevalonate from an aqueous solution by subjecting an aqueous solution comprising the salt of mevalonate (X-MVA) to nanofiltration to produce a permeate, and crystallizing the salt of mevalonate from the permeate by water solvent crystallization to produce crystals of the salt of mevalonate; and, b) dissolving the crystals of (a) in water to produce a water-soluble salt of mevalonate, and subjecting the liquid to cation exchange, thereby converting the water-soluble salt of mevalonate into water-soluble mevalonate lactone (X-MVA). Figure 1B ).

[0013] In yet another aspect, the present specification provides a method for producing mevalonolactone from an aqueous solution comprising a salt of mevalonate (X-MVA), the method comprising subjecting the aqueous solution comprising the salt of mevalonate to cation exchange, thereby converting the aqueous solution comprising the salt of mevalonate into an aqueous solution comprising mevalonolactone (MVL), and optionally producing high-purity (>90% purity) MVL from the aqueous solution by concentrating the solution, producing mevalonolactone*monohydrate (MVL*H2O) from the concentrated solution, and dissolving the mevalonolactone*monohydrate (MVL*H2O) crystals in water to obtain a high-purity MVL solution ( Figure 2 ).

[0014] Also provided are compositions and methods for producing a crystalline form of mevalonolactone* monohydrate (MVL*H2O).

[0015] Additional embodiments of the methods and compositions of the disclosure are presented herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The present disclosure can be more fully understood from the following detailed description and the accompanying drawings, which constitute a part of this application.

[0017] picture

[0018] Figure 1A Depicted is a schematic representation of a method for producing a crystalline form of a salt of mevalonic acid (X-MVA), such as but not limited to Na-MVA, from an aqueous solution, the method comprising subjecting an aqueous solution comprising the salt of mevalonic acid (Na-MVA) to nanofiltration to produce a permeate and crystallizing the salt of mevalonic acid from the permeate by water solvent crystallization. The water solvent crystallization comprises evaporating the permeate to obtain a slurry comprising concentrated X-MVA, followed by cooling the slurry to produce crystals of a salt of mevalonic acid, such as Na-MVA crystals.

[0019] Figure 1B Depicted is a schematic representation of a method for producing water-soluble mevalonolactone (MVL) from an aqueous solution, wherein the method comprises Figure 1A Crystals of a salt of mevalonic acid (such as Na-MVA crystals) obtained by the method described in are dissolved in water to produce a water-soluble salt of mevalonic acid (X-MVA), and the liquid is subjected to cation exchange to convert the water-soluble salt of mevalonic acid (X-MVA) into water-soluble mevalonic acid lactone (MVL), and the water-soluble mevalonic acid lactone is optionally concentrated via evaporation.

[0020] Figure 2Depicted is a schematic representation of a process for producing mevalonolactone from an aqueous solution comprising a salt of mevalonate (X-MVA), the process comprising subjecting the aqueous solution comprising the salt of mevalonate to cation exchange, thereby converting the aqueous solution comprising the salt of mevalonate into an aqueous solution comprising mevalonolactone (MVL), and optionally concentrating the solution into a slurry that can produce mevalonolactone* monohydrate crystals when stored at a low temperature of less than about 23° C. The mevalonolactone* monohydrate crystals can optionally be further dissolved in water and concentrated to produce a highly concentrated and pure MVL liquid (>90% purity).

[0021] Figure 3 The picture shows the typical shape of mevalonolactone* monohydrate (MVL*H2O) crystals. DETAILED DESCRIPTION

[0022] Compositions and methods for recovering organic acids and their salts and lactones from aqueous solutions using water solvent crystallization are provided. In one aspect, a method of crystallizing mevalonolactone*monohydrate (MVL*H2O) and crystallizing mevalonolactone*monohydrate (MVL*H2O) is disclosed.

[0023] More specifically, in one aspect, the object of the present invention is to provide a method for recovering a salt of mevalonic acid (X-MVA) from a solution containing the salt of mevalonic acid (X-MVA). In another aspect, the object of the present invention is to provide a method for recovering mevalonic acid lactone (MVL) from a solution containing a salt of mevalonic acid (X-MVA), mevalonic acid lactone (MVL), mevalonic acid lactone*monohydrate (MVL*H2O) or a combination thereof. The entire process for recovering a salt of mevalonic acid and / or recovering mevalonic acid lactone can be preferably carried out in an aqueous solution without using an organic solvent.

[0024] The methods described herein can produce a high purity MVL product (>90% purity) that has a water-like appearance with little or no color formation. Thus, the MVL produced by the methods described herein can be scaled up for large-scale manufacturing and is of particular interest to the personal care industry, where a highly purified MVL product that is colorless and transparent with little or no trace of colored contaminants present is of great value.

[0025] This detailed description is intended only to familiarize others skilled in the art with applicant's invention, its principles, and its practical applications so that others skilled in the art can adapt and apply the invention in its various forms as they may best suit the requirements of a particular use. This detailed description and its specific examples, while indicating certain embodiments, are intended only for illustrative purposes. Therefore, this specification is not limited to the embodiments described and various modifications may be made.

[0026] This document is organized into several sections for ease of reading; however, the reader will appreciate that statements made in one section may apply to other sections. In this manner, the headings used for the different sections of this disclosure should not be interpreted as limiting.

[0027] The headings provided herein are not intended to limit the various aspects or embodiments of the compositions and methods of the invention, which aspects or embodiments may be obtained by reference to the specification as a whole. Therefore, the terms defined below are more fully defined when the specification is referenced as a whole.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present compositions and methods belong. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present compositions and methods, representative exemplary methods and materials will now be described.

[0029] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent was specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with the cited publication.

[0030] definition

[0031] In the specification and throughout the examples and claims, the following definitions apply:

[0032] The terms "mevalonic acid (MVA)" or "(R)-mevalonic acid" are used interchangeably herein and refer to a mevalonic acid having the chemical formula C6H 12 O4 and a molar mass of 148.16 g / mol (3R)-3,5-dihydroxy-3-methylvaleric acid. The carboxylate anion of mevalonate is called mevalonate. Mevalonate as described herein is the biologically active R-enantiomer.

[0033] The terms "salt of mevalonic acid" or "mevalonate" or "X-MVA" are used interchangeably herein and refer to a salt of mevalonic acid, wherein X is a cation and MVA is the carboxylate anion of mevalonic acid (thus X-MVA). The salt of mevalonic acid may be selected from the group consisting of sodium mevalonate (Na-MVA), potassium mevalonate (K-MVA), ammonium mevalonate (NH4-MVA), lithium mevalonate (Li-MVA), any other monovalent salt of mevalonic acid, or any combination thereof.

[0034] The terms "mevalonolactone" or "(R)-mevalonolactone" or "MVL" are used interchangeably herein and refer to (R)-3-hydroxy-3-methyl-delta-valerolactone.

[0035] Aqueous solutions described herein include solutions containing organic acids and organic acid lactones that interconvert to reach equilibrium concentrations. For example, mevalonic acid and mevalonic acid lactone tend to equilibrate with each other. In this specification, unless otherwise stated, solutions containing organic acids do also contain lactone forms.

[0036] Mevalonolactone monohydrate is also known as MVL*H2O.

[0037] SAC refers to strong acid cation exchange resin.

[0038] WAC refers to weak acid cation exchange resin.

[0039] DS refers to the dry matter content expressed in % by weight. The dry matter can be determined by Karl Fischer titration with water.

[0040] RDS refers to refractive dry matter content, expressed in % by weight based on the correlation between the refractive index of aqueous sugar solutions and DS.

[0041] IX or IEX refers to the ion exchange process

[0042] BV / h refers to the volumetric flow rate through the ion exchange material contained in a column or process. BV refers to the bed volume, i.e., the volume of ion exchange material in a specified ionic form contained in a column or process.

[0043] Purity refers to the content of a component (such as Na-MVA, MVL, MVL*H2O) in terms of DS or RDS. Area % calculation programs report the area of ​​each peak as a percentage of the total area of ​​all peaks in a chromatogram (such as an HPLC chromatogram). For example, a mevalonolactone purity of at least 90% refers to the percentage of the peak area corresponding to MVL (90 in this case) relative to the total peak area (100) using chromatographic analysis. Purity can be measured using HPLC (Rezex ROA-Organic Acid H+(8%) column).

[0044] HPLC refers to high performance liquid chromatography.

[0045] The sodium mevalonate purity is the amount of sodium mevalonate (as if all mevalonic acid, mevalonate salts and mevalonolactone were in the form of sodium mevalonate) divided by the total amount of dry matter.

[0046] The mevalonolactone purity is the total amount of mevalonolactone (as if all mevalonic acid, mevalonate and mevalonolactone were in the form of mevalonolactone) divided by the total amount of dry matter.

[0047] Mevalonate yield refers to the amount of mevalonate in the target fraction (such as nanofiltration permeate or centrifuge cake) divided by the amount of mevalonate in the feed fraction (such as nanofiltration feed or centrifuge feed), as if all mevalonate, mevalonate, and mevalonolactone were in the mevalonate form.

[0048] Mevalonolactone yield refers to the amount of mevalonolactone in the target fraction (such as the cation exchange product or centrifuge cake) divided by the amount of mevalonolactone in the feed fraction (such as the cation exchange feed or centrifuge feed), as if all of the mevalonate, mevalonate, and mevalonolactone were in the form of mevalonolactone.

[0049] Color refers to the color value according to the International Committee for Uniform Methods of Sugar Analysis ("ICUMSA") Sugar Color Grading System.

[0050] The DSC thermogram was measured by using a Mettler Toledo DSC822e differential scanning calorimeter. The measurement was carried out in a standard 40 μL aluminum crucible in a flowing nitrogen atmosphere with a flow rate of 80 mL / min. The temperature range was 0-50°C and the heating rate was 2°C / min.

[0051] Optical rotation was measured from an aqueous solution with a mevalonolactone concentration of 2 g / 100 mL at a temperature of 20°C by using an Anton Paar MCP 300 Sucromet with a 100 mm cuvette and Na 589 light.

[0052] The meanings of the abbreviations are as follows: “sec” means second, “min” means minute, “h” or “hr.” means hour, “d” means day, “μL” means microliter, “mL” means milliliter, “L” means liter, “μM” means micromole, μm means micrometer, “mM” means millimole, “M” means mole, “mmol” means millimole, “μmole” means micromole, “kg” means kilogram, “g” means gram, “μg” means microgram, “ng” means nanogram, “U” means unit, “bp” means base pair, and “kb” means kilobase.

[0053] Starting Materials

[0054] The solution used in the method comprises an aqueous solution comprising an organic acid or a salt or lactone thereof. More specifically, in one aspect, the starting material is an aqueous solution comprising at least MVA and / or a salt of mevalonic acid (X-MVA). In one aspect, the starting material is an aqueous solution comprising mevalonic acid lactone (MVL) or mevalonic acid lactone monohydrate (MVL*H2O). The starting material can be selected from, for example, a liquid derived from fermentation and / or an aqueous solution containing MVA, a salt of mevalonic acid, mevalonic acid lactone, mevalonic acid lactone monohydrate or any combination thereof.

[0055] In some embodiments, the aqueous solution comprises (or is derived in whole or in part from) a fermentation product. In some such embodiments, the aqueous solution is (or is derived in whole or in part from) a fermentation product for preparing MVA, X-MVA and / or MVL to be purified. In some embodiments, the fermentation comprises culturing a recombinant microorganism in an aqueous medium comprising carbohydrates, the recombinant microorganism comprising at least one recombinant polynucleotide sequence encoding an enzyme (or enzymes) capable of producing MVA, X-MVA and / or MVL. The product of the fermentation process may be referred to as a fermentation "product" or "medium". The product typically comprises a variety of components, including, for example, monovalent and divalent salts, sugars, oligosaccharides, monosaccharides, amino acids, polypeptides, proteins, organic acids, nucleic acids, etc., in addition to the X-MVA and / or MVL to be purified. The aqueous solution may comprise some alcohol or other solvents from the fermentation.

[0056] Examples of enzymes that can be used to produce MVA include MvaE (acetyl-CoA acetyltransferase / HMG-CoA reductase) and MvaS (hydroxymethylglutaryl-CoA synthase). The mvaE gene encodes a polypeptide (MvaE) having thiolase and HMG-CoA reductase activities. The mvaS gene encodes a polypeptide (MvaS) having HMG-CoA synthase activity. Enzymes capable of producing MVA (and corresponding nucleotide sequences) may be derived from, but are not limited to, Listeria grayi, Enterococcus faecalis (Streptococcus faecalis), Enterococcus faecium, Enterococcus gallinarum, and Enterococcus casseliflavus.

[0057] The fermentation medium can be a medium obtained from the fermentation of any organism capable of producing MVA or MVL. In some embodiments, the fermentation medium is a medium obtained from fermentation of Escherichia coli. In some aspects, the starting aqueous solution can be a pH-neutral fermentation medium, such as but not limited to a fermentation medium obtained from fermentation with Escherichia coli, wherein the fermentation medium comprises mevalonic acid as a salt. The starting aqueous solution can also be a fermentation medium at low pH (pH 3-5), wherein the fermentation medium comprises mevalonic acid partially in acid form and partially as a salt of mevalonic acid. The fermentation medium can be a clarified fermentation medium, wherein the clarification is obtained by ultrafiltration of the feed fermentation medium.

[0058] In some embodiments, the organic acid to be purified is MVA, and the MVA starting solution comprises (or is derived in whole or in part from) the product of a fermentation process, wherein the fermentation process comprises culturing a recombinant microorganism in an aqueous medium, the recombinant microorganism comprising

[0059] Recombinant polynucleotide sequences encoding MvaE and MvaS.

[0060] The fermentation medium can be clarified by removing biomass and any insoluble solids from the fermentation medium by at least one of pre-coat filtration, microfiltration, centrifugation or ultrafiltration. Ultrafiltration can be beneficial, for example, to remove large biomolecules such as endotoxins, proteins, nucleic acids and lipopolysaccharides.

[0061] The cellular biomass can be separated from the fermentation product, for example, by utilizing filtration, centrifugation, sedimentation, and / or other processes suitable for removing cellular biomass.

[0062] Nanofiltration

[0063] As described herein, in one aspect, the present invention is directed to a purification process for producing a crystalline form of a salt of mevalonic acid (also referred to as X-MVA or mevalonic acid X) from an aqueous solution, the process comprising subjecting an aqueous solution comprising said salt of mevalonic acid (X-MVA) to nanofiltration to produce a permeate and crystallizing said salt of mevalonic acid from said permeate by crystallization in an aqueous solvent (see also Figure 1A and Examples 1-4).

[0064] Nanofiltration (NF) is a pressure-driven membrane filtration process. Nanofiltration provides two fractions: retentate and permeate.

[0065] In one aspect of the present invention, the NF process is intended to purify salts of mevalonic acid (such as but not limited to sodium mevalonate, potassium mevalonate, lithium mevalonate, ammonium mevalonate or other monovalent salts of mevalonate) into a permeate (also referred to as filtrate). The retentate (also referred to as concentrate) from the process is a waste containing antifoam, endotoxins, color components, divalent salts and larger molecules. In one embodiment of the present invention, an aqueous solution is used as a feed for nanofiltration to obtain a permeate with a high content of salts of mevalonic acid (at least 60% sodium mevalonate in the permeate, Examples 1-4) and only a small amount of waste material.

[0066] The starting aqueous solution can be a pH-neutral fermentation medium, such as, but not limited to, a fermentation medium obtained from fermentation with E. coli, wherein the fermentation medium comprises mevalonic acid as a salt. The starting aqueous solution can also be a fermentation medium at low pH (pH 3-5), wherein the fermentation medium comprises mevalonic acid partly in the acid form and partly as a salt of mevalonic acid.

[0067] The nanofiltration according to the invention can be carried out as a batch process or as a continuous process.

[0068] Nanofiltration is typically carried out at a temperature in the range of 5 to 80° C., preferably 30 to 75° C., and most preferably 50 to 70° C. The pressure in nanofiltration is typically in the range of 5 to 60 bar, preferably 10 to 50 bar, and most preferably 20 to 45 bar. The pH may be in the range of 1 to 10, preferably 3 to 9, and most preferably 6 to 9. The pH depends on the composition of the starting solution and the stability of the membrane used for nanofiltration and the components to be recovered. If necessary, the pH of the starting solution may be adjusted to a desired value before nanofiltration.

[0069] Nanofiltration is typically performed at 1 to 100 l / m 2 h, preferably 2 to 50 l / m 2 h, and most preferably 3 to 12 l / m 2 h, which depends on the concentration and viscosity of the nanofiltration feed.

[0070] The nanofiltration membrane used in the present invention can be selected from polymeric membranes and inorganic membranes, which have a MgSO4 retention rate of 50 to 99% (at 25°C, 2g / l concentration, 8 bar, pH 6), preferably 70 to 99% (at 25°C, 2g / l concentration, 8 bar, pH 6), more preferably 80 to 98% (at 25°C, 2g / l concentration, 8 bar, pH 6), and most preferably 90 to 98% (at 25°C, 2g / l concentration, 8 bar, pH 6). In one aspect, the nanofiltration membrane is a nanofiltration membrane XN45, which has a MgSO4 retention rate of about 92-98%.

[0071] Nanofiltration membranes with MgSO4 retention of 99% or higher have too high a retention of monovalent salts and a low MWCO, and therefore too high a retention of X-MVA salts. Membranes with MgSO4 retention of <90% MgSO4 retention do not provide as high a purity, since small divalent salts also pass through.

[0072] In some embodiments, the molecular weight cutoff (MWCO) of the membrane is in the range of about 100 to about 700 Dalton MWCO membranes, such as, but not limited to, TriSep XN45 membranes. The TriSep XN45 membrane is characterized by a 300-500 Dalton MWCO membrane. In some embodiments, the membrane has a molecular weight cutoff (MWCO) in the range of about 150 to about 400 Daltons. In some embodiments, the membrane has a molecular weight cutoff (MWCO) in the range of about 150 to about 300 Daltons, such as, but not limited to, Suez duratherm EXL DL and DK membranes. Suez duratherm EXL DL and DK membranes are characterized by 150-300 Dalton MWCO membranes. Both MWCO and MgSo4 retention are important parameters for selecting nanofiltration membranes. In one aspect, the membrane used for the process is a nanofiltration membrane having a MWCO greater than 150Da and a high divalent salt rejection (>90% MgSO4), such as, but not limited to, TriSepXN45 type membranes.

[0073] In some embodiments, the membrane has a molecular weight cutoff (MWCO) in the range of about 100 to about 900 Daltons and a MgSO retention rate of about 50% to 99% at 25° C. In some embodiments, the membrane has a molecular weight cutoff (MWCO) in the range of about 150 to about 500 Daltons and a MgSO retention rate of about 80% to 99% at 25° C. In some embodiments, the membrane has a molecular weight cutoff (MWCO) in the range of about 150 to about 300 Daltons and a MgSO retention rate of about 98% to 99% at 25° C.

[0074] Nanofiltration membranes useful in the present invention may have a negative or positive charge. The membranes may be ionic membranes, i.e. they may contain cationic or anionic groups, but even neutral membranes are useful. The nanofiltration membranes may be selected from hydrophobic membranes and hydrophilic membranes.

[0075] Typical forms of nanofiltration membranes include spiral wound membranes. Membrane configurations may also be selected from, for example, flat plates, tubes, and hollow fibers. "High shear" membranes may also be used, such as vibrating membranes and rotating membranes. The shape of the membrane may be tubular, spiral, or flat.

[0076] The nanofiltration device useful in the present invention comprises at least one nanofiltration membrane element, which separates the starting material (feed) into a retentate and a permeate portion. The nanofiltration device typically also includes a device for controlling pressure and flow, such as a pump and a valve and a flow and pressure meter and a controller. The device may also include a plurality of nanofiltration membrane elements arranged in parallel or in series in different combinations in a pressure vessel.

[0077] The yield of X-MVA (salt of mevalonic acid, such as, for example, sodium mevalonate) in the nanofiltration is typically greater than 70%, preferably greater than 80%, and most preferably greater than 90% based on the sodium mevalonate present in the starting material.

[0078] The sodium mevalonate content in the permeate is greater than 50% by DS, preferably greater than 60% by DS, more preferably greater than 70% by DS, and most preferably greater than 80% by DS.

[0079] The nanofiltration permeate can be further concentrated by evaporation or any means known in the art to further concentrate the salt of mevalonic acid, such as but not limited to evaporation under reduced pressure (vacuum evaporation) to produce a concentrated aqueous slurry. The sodium mevalonate content in the concentrated aqueous slurry can be greater than 60% by DS, preferably between 65% and 95% by DS.

[0080] The nanofiltration permeate may be subjected to further purification steps selected from ion exchange, evaporation, electrodialysis and filtration. These further purification steps may be performed before or after the membrane filtration.

[0081] In addition, the recovered mevalonic acid salt fractions may be subjected to one or more further steps, such as evaporation, concentration, filtration, ion exchange, activated carbon treatment, sterile filtration, crystallization, intermediate crystallization, nanofiltration, and chromatographic fractionation. The recovered one or more mevalonic acid salt fractions may be processed in different ways depending on the purity of the fractions.

[0082] In some embodiments, the permeate collected from the nanofiltration and / or concentrated aqueous slurry is subjected to a subsequent crystallization step.

[0083] In one aspect, as described herein, the method is a method for producing a crystalline form of a salt of mevalonic acid (X-MVA) from an aqueous solution, the method comprising subjecting an aqueous solution comprising the salt of mevalonic acid to a purification step, wherein the purification step produces a purified solution comprising X-MVA having a purity of at least 60%, and crystallizing the salt of mevalonic acid from the purified solution by crystallization from an aqueous solvent, wherein the purification step comprises subjecting the aqueous solution comprising the salt of mevalonic acid to nanofiltration to produce a permeate, wherein the permeate comprises X-MVA having a purity of at least 60%.

[0084] Alternatively, in one aspect, the method is a method for producing a crystalline form of a salt of mevalonic acid (X-MVA) from an aqueous solution, the method comprising subjecting an aqueous solution comprising the salt of mevalonic acid to a purification step, wherein the purification step produces a purified solution comprising X-MVA having a purity of at least 60%, and crystallizing the salt of mevalonic acid from the purified solution by crystallization from an aqueous solvent, wherein the purification step comprises subjecting the aqueous solution comprising the salt of mevalonic acid to microfiltration, electrodialysis, ion exchange, filtration, activated carbon treatment, evaporation, concentration, sterile filtration, chromatographic fractionation, or any combination thereof.

[0085] Cation Exchange

[0086] In one aspect, the present specification provides a method for producing water-soluble mevalonate lactone from an aqueous solution, wherein the method comprises: a) producing a crystalline form of a salt of mevalonate from an aqueous solution by the following steps: subjecting an aqueous solution comprising the salt of mevalonate (X-MVA) to nanofiltration to produce a permeate, and crystallizing the salt of mevalonate from the permeate by water solvent crystallization to produce crystals of the salt of mevalonate; and b) dissolving the crystals of (a) in water to produce a water-soluble salt of mevalonate, and subjecting the liquid to cation exchange, thereby converting the water-soluble salt of mevalonate into water-soluble mevalonate lactone (X-MVA). Figure 1B and Examples 9-12).

[0087] In another aspect, the present specification provides a method for producing mevalonolactone from an aqueous solution comprising a salt of mevalonate (X-MVA), the method comprising subjecting an aqueous solution comprising the salt of mevalonate to cation exchange, thereby converting the aqueous solution comprising the salt of mevalonate into an aqueous solution comprising mevalonolactone (MVL) ( Figure 2 ).

[0088] Strong Acid Cation Exchange Resin (SAC Resin)

[0089] SAC resins can have styrene or acrylic backbones. In one embodiment of the invention, the resin is a sulfonated polystyrene-co-divinylbenzene resin. Other alkenyl aromatic polymer resins such as those based on monomers such as alkyl-substituted styrene or their mixtures can also be applied. The resin can also be cross-linked with other suitable aromatic cross-linking monomers, such as divinyl toluene, divinyl xylene, divinyl naphthalene, divinyl benzene, or with aliphatic cross-linking monomers, such as isoprene, ethylene glycol diacrylate, ethylene glycol dimethacrylate, N, N'-methylenebisacrylamide or mixtures thereof. The cross-linking degree of the resin is typically from about 1% to about 20% of the cross-linking agent such as divinyl benzene (DVB), preferably from about 3% to about 8%.

[0090] The SAC resin used for ion exchange of the present invention can be in the form of polyvalent, divalent or monovalent cations. The monovalent cation form can be selected from, for example, H + 、Na + and K + An example of a divalent cation is Ca 2+ Mg 2+ 、Zn 2+ , Sr 2+ and Ba 2+ An example of a trivalent cation is Al 3+ In a preferred embodiment of the present invention, the SAC resin used for the ion exchange of the present invention is monovalent H + The typical average particle size of the resin is from 10 μm to 2000 μm, preferably from 300 μm to 1200 μm.

[0091] In one embodiment, a monovalent SAC resin is used for ion exchange of a salt of mevalonic acid (X-MVA) to produce mevalonolactone (MVL), wherein the monovalent cation is in the form of H + form.

[0092] Weak Acid Cation Exchange Resin (SAC Resin)

[0093] WAC resin is an acrylic cation exchange resin with carboxyl functional groups. Acrylic WAC resins are typically derived from the group consisting of acrylates, acrylonitrile, acrylic acid and mixtures thereof. Acrylates are selected from the group consisting of methyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate. The matrix of the WAC resin may also be other than acrylic acid. The active functional groups of the WAC resin may also be other than carboxyl groups. For example, they may be selected from other weak acids. The WAC resin may be in the form of H + 、Na + , K + , Ca 2+ or Mg 2+ In the form of H + Or Na+ Other ionic forms may also be used.

[0094] WAC resin is crosslinked with an aromatic crosslinker, preferably divinylbenzene (DVB). It can also be crosslinked with an aliphatic crosslinker, such as isoprene, 1,7-octadiene, trivinylcyclohexane, diethylene glycol divinyl ether. The degree of crosslinking is from 1% to 20%, preferably from 3% to about 8% DVB.

[0095] The average particle size of the WAC resin is from 10 μm to 2000 μm, preferably from 300 μm to 1200 μm.

[0096] Ion exchange is preferably carried out by using a cation exchange resin, especially a strong acid cation resin, especially H + Ionic form.

[0097] In one embodiment, a monovalent WAC resin is used for ion exchange of a salt of mevalonic acid (X-MVA) to produce mevalonolactone (MVL), wherein the monovalent cation is in the form of H + form.

[0098] Solvent crystallization

[0099] As described herein, in one aspect, the present invention is directed to a process for producing a crystalline form of a salt of mevalonic acid (also referred to as X-MVA or mevalonic acid X) from an aqueous solution, the process comprising subjecting an aqueous solution comprising the salt of mevalonic acid (X-MVA) to a purification step such as, but not limited to, nanofiltration to produce a high purity solution (permeate) allowing crystallization of the X-MVA, and crystallizing the salt of mevalonic acid (X-MVA) from the permeate by crystallization in an aqueous solvent. Figure 1A and Examples 5-8).

[0100] In another aspect of the present invention, the present specification provides a method for producing mevalonolactone from an aqueous solution containing a salt of mevalonate (X-MVA), the method comprising subjecting the aqueous solution containing the salt of mevalonate to cation exchange, thereby converting the aqueous solution containing the salt of mevalonate into an aqueous solution containing mevalonolactone (MVL), and then optionally concentrating the MVL solution and crystallizing the solution to obtain MVL* monohydrate crystals ( Figure 2 and Examples 13-20).

[0101] The term "aqueous solvent crystallization" refers to crystallization performed using an aqueous solvent such as water without using any organic solvent.

[0102] Crystallization of X-MVA in water solvent

[0103] The crystallization of X-MVA can be carried out by conventional methods such as cooling crystallization or precipitation crystallization at a temperature ranging from 10° C. to 80° C. The crystallization of X-MVA can also advantageously be carried out by boiling crystallization or boiling and cooling crystallization.

[0104] In one embodiment of the present disclosure, the crystallization of X-MVA is carried out from a solution (feed solution) having a purity of X-MVA of greater than 60%, preferably greater than 70%, more preferably greater than 80%, most preferably greater than 90%, and especially greater than 95% by DS. Crystallization typically provides a crystalline X-MVA product having a purity of greater than 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, preferably greater than 95%, and most preferably greater than 99% by DS.

[0105] The solution containing X-MVA is first evaporated to an appropriate dry matter content (e.g., about 60% to 90% DS), depending on the X-MVA content of the solution. The slurry DS concentration must be high enough to have crystallization potential (supersaturation). The minimum DS content depends on the temperature and purity of the slurry. The higher the slurry purity, the lower the slurry DS required. If the DS is too high, crystallization will be delayed or the crystal suspension will become too thick for effective crystal separation. In one embodiment of the present invention, the slurry containing Na-MVA has a purity of 65-99%.

[0106] The supersaturated solution can be seeded with crystals of X-MVA. The seeds, if used, are crystals in dry form or they are suspended in a solvent, preferably in water, and the crystal size is preferably reduced, for example, by crushing or grinding. The evaporation temperature of the solution containing X-MVA can range between 30°C and 80°C. After seeding, the crystallized material is cooled while mixing until the crystallization yield and viscosity are optimal for crystal separation. The cooling time is preferably 10 to 60 hours. The temperature drop during cooling is preferably 5°C to 40°C. The seeded slurry comprising Na-MVA may be cooled to a temperature of about 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C to about 75°C or more. Cooling can be carried out for about 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours or more time period. Cooling can be carried out under continuous stirring or mixing. Mixing can be beneficial to controlled crystallization. Mixing prevents crystal sedimentation, keeps crystal growth and reduces spontaneous crystal formation. Mixing also promotes useful heat and mass transfer. Then the crystalline material can be mixed for a period of time, preferably 0.5 to 24 hours, at the final temperature, to reach the maximum crystallization yield. For example, by filtering or centrifuging, the crystal is separated from the mother liquor.

[0107] In one embodiment of the present invention, X-MVA crystals with high purity are X-MVA crystals with a content of more than 97% by DS, preferably more than 98% by DS, and more preferably more than 99% by DS, obtained from a solution with an X-MVA content of more than 65% by DS by one crystallization step (= single-stage crystallization) without dissolution and recrystallization steps. The single-stage crystallization may include boiling and cooling steps, but does not include a recrystallization step.

[0108] In another embodiment of the invention, the crystallization of X-MVA includes washing as a further step. Washing is typically performed in conjunction with separating the crystals from the mother liquor. Additional washing may be performed by mixing an aqueous washing solvent with the crystallization filter cake and then separating the crystals. The washing solvent may be water. This embodiment of the invention typically provides X-MVA with a purity greater than 98%.

[0109] Seeds can be prepared by various processes. In some embodiments, dry seed crystals are milled to obtain a smaller particle size. The desired amount of seed crystals can depend on, for example, the size of the seed crystals. In some embodiments, crystallization is initiated without adding seed crystals to a supersaturated solution. In some such embodiments, for example, seeding is achieved using spontaneous seeding.

[0110] In some embodiments, initiation of crystallization (e.g., addition of seed crystals) is performed when the dry solids content of the slurry is at least about 60% (by weight). In some embodiments, initiation of crystallization (e.g., addition of seed crystals) is performed when the dry solids content of the slurry is at least about 70% (by weight). In some embodiments, initiation of crystallization (e.g., addition of seed crystals) is performed when the dry solids content of the slurry is at least about 80% (by weight). In some embodiments, initiation of crystallization (e.g., addition of seed crystals) is performed when the dry solids content of the slurry is from about 60% to about 90% (by weight). In some embodiments, initiation of crystallization (e.g., addition of seed crystals) is performed when the dry solids content of the slurry is from about 70% to about 90% (by weight). In some embodiments, initiation of crystallization (e.g., addition of seed crystals) is performed when the dry solids content of the slurry is from about 80% to about 90% (by weight). In some embodiments, initiation of crystallization (eg, addition of seed crystals) is performed when the dry solids content of the slurry is from about 80% to about 88% by weight.

[0111] If the crystal growth potential and viscosity allow, evaporation can be continued after seeding. After evaporation, the crystallized material is cooled and mixed until the crystal content and viscosity are optimal for crystal separation. The crystallized material is typically cooled to a temperature of from 10°C to 75°C. The crystallized material can then be mixed for a period of time (preferably from 0.5 hours to 24 hours) at the final temperature to achieve the maximum crystallization yield, after which the crystals are separated by, for example, filtration or centrifugation. The process of the present invention typically includes washing the crystals as a further step. Washing is typically carried out in conjunction with separating the crystals from the mother liquor. Additional washing can be performed by mixing the washing solvent with the crystallization filter cake and then separating the crystals. The washing solvent can be water.

[0112] In some embodiments, one or more recrystallizations are performed to increase the purity of X-MVA. Recrystallization can be performed, for example, by dissolving X-MVA crystals in water (typically deionized water), allowing the resulting solution to be supersaturated with respect to X-MVA (via, for example, evaporation), seeding, and crystallizing using the above-described crystallization by cooling method.

[0113] In some embodiments, the yield is increased by crystallizing the mother liquor produced by the initial crystallization. This crystallization can be performed, for example, by bringing the mother liquor to a supersaturated state for X-MVA (via, for example, evaporation), seeding, and crystallizing using the above-described crystallization by cooling method.

[0114] The crystallization described in this specification does not require the presence of an organic solvent in the solution. Crystalline X-MVA is obtained free of organic solvent. Crystalline X-MVA produced without the addition of any organic solvent in the crystallization step is substantially free of organic solvent.

[0115] Although organic solvents can be added to aqueous solutions to improve crystallization and crystal separation performance, such addition of organic solvents has disadvantages such as, but not limited to, obtaining crystals or purified products containing small amounts of these organic solvents, which are undesirable in commercial compositions such as personal care compositions.

[0116] Crystallization of MVL* monohydrate in water solvent

[0117] As described herein, it has been surprisingly and unexpectedly discovered that when a high purity MVL slurry is prepared by the methods described herein and cooled at a temperature below 23°C for several weeks, mevalonolactone monohydrate (MVL*H2O) crystals spontaneously form. These mevalonolactone monohydrate (MVL*H2O) crystals can be used as a seed material to further promote the crystallization of MVL*H2O as described herein. MVL*H2O crystallization is completed at temperatures below the melting point, including temperatures below 23°C, 22°C, 21°C, 20°C, 19°C, 18°C, 17°C, 16°C, 15°C, 14°C, 13°C, 12°C, 11°C, 10°C, 9°C, 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, 1°C, and as low as 0°C. Crystallization of MVL*H2O may occur below 0°C to as low as the freezing point of the solution. In one embodiment of the invention, the crystallization of MVL* monohydrate (MVL*H2O) is carried out from an aqueous solution having a MVL purity of greater than 55%, preferably greater than 70%, more preferably greater than 80%, most preferably greater than 90% and especially greater than 95% by DS. The crystallization typically provides a crystalline MVL*H2O product having a purity of greater than 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, preferably greater than 95% and most preferably greater than 99% by DS.

[0118] In one aspect, cooling crystallization of MVL*H2O is preferred to isothermal crystallization for practical reasons. Isothermal crystallization requires very high seeding supersaturation, which results in a less controllable process than cooling crystallization. MVL*H2O releases a large amount of heat during crystallization, and this heat must be removed from the system to achieve the desired crystallization yield. In some cases, such as with very high seeding supersaturation, crystallization is very rapid and the temperature of the crystallization suspension can rise significantly. This can be overcome by employing effective cooling means or by using lower seeding supersaturation and controlled cooling.

[0119] The solution containing MVL is first evaporated to an appropriate dry matter content (e.g., about 65% to 90% DS), depending on the MVL content of the solution. The slurry DS concentration must be high enough to have crystallization potential (supersaturation). The minimum DS content depends on the temperature and purity of the slurry. The higher the slurry purity, the lower the slurry DS required. If the DS is too high, crystallization will be delayed or the crystal suspension will become too thick for effective crystal separation. The supersaturated solution can be seeded with seeds of MVL*H2O crystals. The seeds (if used) are crystals in dry form or they are suspended in a solvent, preferably in water, and the crystal size is preferably reduced, for example, by crushing or grinding. After seeding, the crystallized material is cooled while mixing until the crystallization yield and viscosity are optimal for crystal separation.

[0120] The conditions used to crystallize MVL*H2O are further described in Examples 13-20.

[0121] In one aspect, mevalonolactone*monohydrate (MVL*H2O) crystals can be heated to a temperature such that the crystals become liquid (such as, but not limited to, room temperature of about 23°C-30°C) without adding any additional water. This liquid contains about 87% MVL and 13% water.

[0122] Mevalonolactone monohydrate (MVL*H2O) crystals can be dissolved in water to produce highly purified MVL (>90% purity) that has a water-like appearance and viscosity with little or no color. This highly purified MVL solution can be further concentrated by evaporation while maintaining a water-like appearance.

[0123] Compositions comprising MVA, X-MVA, MVL and / or MVL*H2O

[0124] Crystalline X-MVA or compositions comprising crystalline X-MVA can be used as ingredients, for example, in dietary supplements, infant and human nutrition products, pharmaceuticals, and cosmetics.

[0125] MVA, X-MVA, MVL and / or MVL*H2O purified by the process of the present specification or compositions comprising MVA, X-MVA, MVL and / or MVL*H2O described herein can be used as ingredients of, for example, dietary supplements, personal care compositions (such as but not limited to skin care, oral care, hair care compositions), pharmaceuticals and cosmetics.

[0126] For the purpose of using MVA or MVL in the personal care industry, it is of great value if the purified product is colorless and transparent with little or no trace of colored contaminants present. As described herein, the highly purified MVL product produced by the methods described herein has a colorless and transparent appearance with little or no residual color.

[0127] Non-limiting examples of the compositions and methods disclosed herein are as follows:

[0128] 1. A method for producing a crystalline form of an organic acid or a salt thereof from an aqueous solution, the method comprising subjecting an aqueous solution comprising the organic acid or a salt thereof to nanofiltration to produce a permeate, and crystallizing the organic acid or a salt thereof from the permeate by water solvent crystallization.

[0129] 2. The method of embodiment 1, wherein the water solvent crystallization comprises evaporating the permeate to obtain a slurry comprising at least 60% DS, followed by cooling the slurry to produce crystals of the organic acid or salt thereof.

[0130] 3. The method of embodiment 1, wherein the aqueous solution is a fermentation medium.

[0131] 4. The method of embodiment 3, wherein the fermentation medium is clarified by removing biomass and any solids from the fermentation medium by at least one of pre-coat filtration, microfiltration, or ultrafiltration.

[0132] 5. The method of embodiment 3, wherein the fermentation medium is a medium obtained by fermentation of Escherichia coli.

[0133] 6. The method of embodiment 2, further comprising removing the crystals of the organic acid or its salt from the slurry by filtration and centrifugation.

[0134] 7. The method of embodiment 1, wherein the organic acid is a carboxylic acid.

[0135] 8. The method of embodiment 7, wherein the carboxylic acid is selected from the group consisting of hydroxycarboxylic acids and dicarboxylic acids.

[0136] 9. The method of embodiment 8, wherein the hydroxycarboxylic acid is selected from the group consisting of malic acid, glycolic acid, isocitric acid, mandelic acid, lactic acid, tartronic acid, tartaric acid, citric acid, β-hydroxybutyric acid, mevalonic acid, and salicylic acid.

[0137] 10. A process for producing a crystalline form of a salt of mevalonic acid (X-MVA) from an aqueous solution, the process comprising subjecting an aqueous solution comprising the salt of mevalonic acid to a purification step, wherein the purification step produces a purified solution comprising X-MVA having a purity of at least 60%, preferably between 60-99%, and crystallizing the salt of mevalonic acid from the purified solution by crystallization from an aqueous solvent.

[0138] 11. The method of claim 10, wherein the purifying step comprises subjecting the aqueous solution comprising the salt of mevalonic acid to nanofiltration to produce a permeate, wherein the permeate comprises X-MVA having a purity of at least 60%.

[0139] 11b. A method for producing a crystalline form of a salt of mevalonic acid from an aqueous solution, the method comprising subjecting an aqueous solution comprising the salt of mevalonic acid (X-MVA) to nanofiltration to produce a permeate, and crystallizing the salt of mevalonic acid from the permeate by water solvent crystallization.

[0140] 12. The method of embodiments 10, 11 and 11b, wherein the water solvent crystallization comprises evaporating the purified solution or permeate to obtain a slurry comprising at least 60% DS, followed by cooling the slurry to produce X-MVA crystals.

[0141] 12b. The method of embodiment 11b, wherein the permeate has an X-MVA purity of at least 60%, optionally between 65-95%.

[0142] 12c. The method of embodiment 12, wherein the slurry has an X-MVA purity of at least 60%, optionally between 65-95%.

[0143] 13. The method of embodiment 10, wherein the aqueous solution is a fermentation medium.

[0144] 14. The method of embodiment 13, wherein the fermentation medium is clarified by removing biomass and any solids from the fermentation medium by at least one of pre-coat filtration, microfiltration, or ultrafiltration.

[0145] 15. The method of embodiment 13, wherein the fermentation medium is a medium obtained from fermentation of Escherichia coli.

[0146] 16. The method of embodiment 12, further comprising removing the crystals from the slurry by filtration and centrifugation.

[0147] 16b. The method of embodiment 11, wherein the nanofiltration utilizes a nanofiltration membrane having a separation cutoff of from about 150 Da to about 700 Da.

[0148] 17. The method of embodiment 10, wherein the nanofiltration utilizes a nanofiltration membrane capable of retaining at least 60-98 wt% of divalent salts while having a monovalent salt rejection of less than 30 wt%.

[0149] 18. A method for producing water-soluble mevalonolactone from an aqueous solution, wherein the method comprises:

[0150] a) producing a crystalline form of a salt of mevalonic acid (X-MVA) from an aqueous solution by subjecting the aqueous solution comprising the salt of mevalonic acid to nanofiltration to produce a permeate, and crystallizing the salt of mevalonic acid from the permeate by water solvent crystallization to produce crystals of the salt of mevalonic acid; and,

[0151] b) dissolving the crystals of (a) in water to produce a water-soluble mevalonic acid salt, and subjecting the liquid to cation exchange to convert the water-soluble mevalonic acid salt into water-soluble mevalonic acid lactone.

[0152] 18b. The method of embodiment 18, wherein the permeate has an X-MVA purity of at least 60%, optionally between 65-95%.

[0153] 18c. The method of embodiment 18, wherein the permeate is concentrated to produce a slurry, and then the salt of mevalonate is crystallized from the slurry by water solvent crystallization to produce crystals of the salt of mevalonate.

[0154] 18d. The method of embodiment 18c, wherein the slurry has an X-MVA purity of at least 60%, optionally between 65-95%.

[0155] 18e. The method of embodiment 18, wherein the water-soluble mevalonolactone has a purity of at least 60%, optionally between 65-95%.

[0156] 18f. The method of embodiment 18, wherein the water-soluble mevalonolactone of b) is further concentrated to produce a highly concentrated MVL liquid of at least 90% DS.

[0157] 19. The method of embodiment 10 or embodiment 18, wherein the salt of mevalonate is selected from the group consisting of sodium mevalonate (Na-MVA), potassium mevalonate (K-MVA), ammonium mevalonate (NH4-MVA), lithium mevalonate (Li-MVA), any other monovalent salt of mevalonic acid, or any combination thereof.

[0158] 20. The method of embodiments 18, 18b, 18c, 18d, 18e, 18f or 19, wherein the water-soluble mevalonolactone has a purity of at least 90% (percentage corresponding to the peak area of ​​MVL relative to the total peak area using HPLC analysis).

[0159] 21. A method for producing mevalonolactone from an aqueous solution comprising a salt of mevalonate (X-MVA), the method comprising subjecting the aqueous solution comprising the salt of mevalonate to a cation exchange, thereby converting the aqueous solution comprising the salt of mevalonate into an aqueous solution comprising mevalonolactone (MVL).

[0160] 22. The method of embodiment 21, wherein the salt of mevalonate is selected from the group consisting of sodium mevalonate (Na-MVA), potassium mevalonate (K-MVA), ammonium mevalonate (NH4-MVA), lithium mevalonate (Li-MVA), any other monovalent salt of mevalonic acid, or any combination thereof.

[0161] 23. The method of embodiment 21, further comprising concentrating the aqueous solution comprising mevalonolactone into a liquid comprising at least 65% to 90% DS.

[0162] 24. The method of embodiment 23, further comprising cooling the liquid at 0-25°C to obtain mevalonolactone monohydrate (MVL*H2O) crystals.

[0163] 25. The method of claim 24, further comprising dissolving / dissolving the MVL*H2O crystals in water to obtain a dilute liquid of highly purified mevalonate lactone, wherein the dilute liquid has a mevalonate lactone purity of at least 90% (the percentage is corresponding to the peak area of ​​MVL relative to the total peak area using HPLC analysis).

[0164] 25b. The method of claim 25, wherein the diluted liquid comprising the highly purified mevalonolactone is further concentrated to produce a highly concentrated MVL liquid of at least 90% DS.

[0165] 26. The method of embodiment 21, wherein the aqueous solution is a fermentation medium.

[0166] 27. The method of embodiment 26, wherein the fermentation medium is clarified by removing biomass and any solids from the fermentation medium by at least one of pre-coat filtration, microfiltration, or ultrafiltration.

[0167] 28. The method of embodiment 26, wherein the fermentation medium is a medium obtained from fermentation of Escherichia coli.

[0168] 29. A pharmaceutical composition or a home care composition or a nutritional composition or a personal care composition or a cosmetic composition comprising the MVL produced by any one of embodiments 20-26 or a dissolved form thereof.

[0169] 30. A crystalline X-MVA obtained by the method of any one of embodiments 1-17.

[0170] 31. A crystalline mevalonolactone* monohydrate (MVL*H2O) obtained by the method described in Example 24.

[0171] 32. A crystalline mevalonolactone* monohydrate (MVL*H2O) having the molecular formula C6H 10 O3*H2O.

[0172] 33. A crystalline mevalonolactone* monohydrate (MVL*H2O) wherein the melting point is below 25°C.

[0173] 34. A composition comprising mevalonolactone monohydrate (MVL*H2O) crystals.

[0174] 35. A composition comprising dissolved mevalonolactone monohydrate (MVL*H2O) crystals.

[0175] Examples

[0176] In the following examples, unless otherwise stated, parts and percentages are by weight, and degrees are in degrees Celsius. It should be understood that, although these examples illustrate embodiments of the present disclosure, they are given by way of illustration only. From the above discussion and these examples, those skilled in the art may make various changes and modifications to the present disclosure to adapt it to various uses and conditions. Such modifications should also be considered to fall within the scope of the appended claims.

[0177] Example 1

[0178] Liquid Nanofiltration (NF) of Sodium Mevalonate (Na-MVA) with Tight Nanofiltration Membranes

[0179] This example describes the nanofiltration of an aqueous solution containing an organic acid or its salt, such as sodium mevalonate (Na-MVA) liquid using a tight nanofiltration membrane.

[0180] The process equipment includes a plate and frame filter (Alfa Laval Labstak M20), feed and percolation pumps, heat exchangers, cooling units, 70-liter feed tanks, and inlet and outlet pressure gauges and pressure control valves. The total membrane area is 0.65 m 2The membranes installed were Desal-5 DL (Suez, approximate molecular weight cutoff of 150-300 Daltons, >98% MgSO4 retention at 25°C) and XN45 ( / Microdyn Nadir, approximate molecular weight cutoff of 300-500 Daltons, 90-96% MgSO4 retention at 25°C). MgSO4 retention is specified at 1-2 g / L concentration, 7-8 bar, 25°C, pH 6-8, and 10-25% recovery.

[0181] Ultrafiltration permeate from an E. coli based fermentation of sodium mevalonate was used as feed. The goal was to pass the sodium mevalonate while retaining the impurities (other salts, color, antifoam, protein).

[0182] 63.4 kg of feed was fed into a 70 liter feed box. The dry feed concentration based on sucrose RDS was 6.8 g / 100 g, the conductivity was 17.7 mS / cm, and the pH was 7.8. The permeate was collected from the DL membrane and the permeate of the XN45 membrane was recycled back to the feed box. The composition of the feed is shown in Table 1, where HPLC and IC analyses are given on a % / sucrose RDS basis.

[0183] Table 1. Feed composition (%)

[0184] Sodium mevalonate, % 66.4 glucose,%* 0.6 Acetate, %** 2.1 Phosphate, %** 1.6 Sulfate, %** 0.5 other,% 28.8

[0185] *HPLC (Rezex ROA-Organic Acid H+ (8%) column).

[0186] **Ion chromatography

[0187] The feed was maintained at 50-68°C and water was used for diafiltration. The filtration pressure was 20-33 bar and the concentrate DS (dry matter) concentration was controlled to keep the flux above 7 kg / m 2 / h (the lowest flux point observed).

[0188] After batch filtration, three permeate fractions and a final concentrate fraction were collected. The results for the permeate fractions and the final concentrate, including HPLC and IC analysis, are shown in Table 2 based on % / sucrose RDS.

[0189] Table 2. HPLC analysis

[0190]

[0191]

[0192] *HPLC (Rezex ROA-Organic Acid H+ (8%) column).

[0193] **Ion chromatography

[0194] The total mevalonate recovery was calculated to be 49.9%. The average permeate sodium mevalonate purity was 75.6%.

[0195] The sulfate removal was 78.1% and the phosphate removal was 71.0% calculated from the feed and concentrate samples. For the DL membrane, the sodium mevalonate retention was measured from 5 points and the average was 76.7%. After collecting 41 kg of permeate, the DL and XN45 mevalonate retentions were measured in parallel starting from the 4th sample point and the retentions of DL and XN45 were 71.0% and 41.8%, respectively.

[0196] Example 2

[0197] Liquid Nanofiltration of Sodium Mevalonate Using an Open Nanofiltration (NF) Membrane

[0198] This example describes the nanofiltration of an aqueous solution containing an organic acid or salt thereof, such as sodium mevalonate liquid nanofiltration using an open nanofiltration membrane.

[0199] The process equipment includes a plate and frame filter (Alfa Laval Labstak M20), feed and percolation pumps, heat exchangers, cooling units, 100-liter feed tanks, and inlet and outlet pressure gauges and pressure control valves. The total membrane area is 0.72 m 2 The membrane installed is XN45 ( / Minard, approximate molecular weight cutoff 300-500 Daltons, 90-96% MgSO4 retention at 25°C). MgSO4 retention is specified at 1-2 g / L concentration, 7-8 bar, 25°C, pH 6-8, and 10-25% recovery.

[0200] Ultrafiltration permeate from an E. coli based fermentation of sodium mevalonate was used as feed. The goal was to pass the sodium mevalonate while retaining the impurities (other salts, color, antifoam, protein).

[0201] 80.0 kg of feed was fed into a 100 liter feed box. The feed concentration was 6.6 g / 100 g based on sucrose RDS. The pH was adjusted to 8.8 with NaOH. The concentration of defoamer Foamblast 882 was measured to be 1337 mg / L. The composition of the feed is shown in Table 3, where HPLC and IC analyses are given as % / sucrose RDS.

[0202] Table 3. Feed composition (%)

[0203] Sodium mevalonate, %* 55.6 glucose,%* 0.8 Acetate, %** 2.2 Phosphate, %** 1.1 Sulfate, %** 0.5 other,% 39.8

[0204] *HPLC (Rezex ROA-Organic Acid H+ (8%) column).

[0205] **Ion chromatography

[0206] The feed was maintained at 46-51°C. The filtration pressure was 10-25 bar to control the flux above 7 kg / m 2 / h (the lowest flux point observed).

[0207] After batch filtration, two permeate fractions and a final concentrate fraction were collected. The results of the permeate fractions and the final concentrate based on % / sucrose RDS, including HPLC and IC analysis, are shown in Table 4.

[0208] Table 4. HPLC analysis

[0209] Total permeate 1 Total Permeate 2 Final concentrate Mass, kg 67.3 9.5 5.3 Dry solid, g / 100g 4.1 8.6 16.3 Sodium mevalonate, %* 65.3 69.3 35.1 glucose,%* 1.0 0.7 0.6 Acetate, %** 3.4 1.3 0.3 Phosphate, %** 0.4 0.6 2.3 Sulfate, %** 0.2 0.1 0.9 other,% 29.7 28.0 60.8

[0210] *HPLC (Rezex ROA-Organic Acid H+ (8%) column).

[0211] **Ion chromatography

[0212] The total mevalonate recovery was calculated to be 82.1%. The antifoam concentration measured from the 29.5% concentrated evaporated permeate sample was 84.4 mg / l, which means that 99% of the antifoam was removed from the product permeate fraction. The antifoam concentration of the final concentrate was measured to be 13230.0 mg / l. The sodium mevalonate retention was measured from 3 points and the average value was 23.6%.

[0213] Example 3

[0214] Liquid Nanofiltration of Sodium Mevalonate Using an Open Nanofiltration (NF) Membrane

[0215] This example describes the nanofiltration of an aqueous solution containing an organic acid or salt thereof, such as sodium mevalonate liquid nanofiltration using an open nanofiltration membrane.

[0216] The process equipment includes a plate and frame filter (Alfa Laval Labstak M20), feed and percolation pumps, heat exchangers, cooling units, 100-liter feed tanks, and inlet and outlet pressure gauges and pressure control valves. The total membrane area is 0.72 m 2 The membrane installed is XN45 ( / Minard, approximate molecular weight cutoff 300-500 Daltons, 90-96% MgSO4 retention at 25°C). MgSO4 retention is specified at 1-2 g / L concentration, 7-8 bar, 25°C, pH 6-8, and 10-25% recovery.

[0217] Ultrafiltration permeate from an E. coli based fermentation of sodium mevalonate was used as feed. The goal was to pass the sodium mevalonate while retaining the impurities (other salts, color, antifoam, protein).

[0218] 79.7 kg of feed was fed into a 100 liter feed box. The feed concentration was 7.0 g / 100 g. The pH was adjusted to 8.25 with 50 grams of 30% NaOH. The composition of the feed is shown in Table 5, with HPLC analysis given on a % / sucrose RDS basis (Table 6).

[0219] Table 5. Feed composition (%)

[0220]

[0221]

[0222] *HPLC (Rezex ROA-Organic Acid H+ (8%) column).

[0223] **Ion chromatography

[0224] The feed was maintained at 46-51°C. The filtration pressure was 10-25 bar to control the flux above 7 kg / m 2 / h (the lowest flux point observed).

[0225] After batch filtration, the permeate fraction and the final concentrate fraction were collected. A portion of the total permeate was evaporated to 28.7% dry solids. The results (including HPLC analysis) for the permeate fraction and the final concentrate based on % / sucrose RDS are shown in Table 6.

[0226] Table 6. HPLC analysis

[0227] Total permeate Final concentrate Evaporation of permeate Mass, kg 75.0 4.7 - Dry solid, g / 100g 6.1 17.6 30.2 Sodium mevalonate, %* 69.3 47.6 75.1 Acetate, %** 2.1 0.4 2.5 Phosphate, %** 0.1 0.5 0.2 Sulfate, %** 0.3 0.9 0.4 other,% 28.3 50.5 21.8

[0228] *HPLC (Rezex ROA-Organic Acid H+ (8%) column), **IC

[0229] The total mevalonate yield was calculated to be 86.8%.

[0230] Example 4

[0231] Liquid Nanofiltration of Sodium Mevalonate Using an Open Spiral Wound Nanofiltration (NF) Membrane

[0232] This example describes the nanofiltration of an aqueous solution containing an organic acid or salt thereof, such as sodium mevalonate liquid nanofiltration using an open spiral wound nanofiltration membrane.

[0233] The process equipment includes a plate and frame filter (Alfa Laval Labstak M20), feed and percolation pumps, heat exchangers, cooling units, 1000-liter feed tanks, and inlet and outlet pressure gauges and pressure control valves. The total membrane area is 14.8m 2 The membrane installed is 4040XN45 with 31mil spacer ( / Minard, approximate molecular weight cutoff 300-500 Daltons, 90-96% MgSO4 retention at 25°C). MgSO4 retention is specified at 1-2 g / L concentration, 7-8 bar, 25°C, pH 6-8, and 10-25% recovery.

[0234] Ultrafiltration permeate from an E. coli based fermentation of sodium mevalonate was used as feed. The goal was to pass the sodium mevalonate while retaining the impurities (other salts, color, antifoam, protein).

[0235] 600 kg of feed was fed into a 1000 liter feed box. The feed concentration was 6.7 g / 100 g. The pH was adjusted to 8.5 with 30% NaOH. The composition of the feed is shown in Table 7, where the HPLC analysis is given on a % / sucrose RDS basis.

[0236] Table 7. Feed composition (%)

[0237] Sodium mevalonate, % 64.5 Acetate, % 1.2 other,% 34.3

[0238] The feed was maintained at 45-52°C. The filtration pressure was 10-25 bar to control the flux above 5 kg / m 2 / h (the lowest flux point observed).

[0239] After batch filtration, the permeate fraction and the final concentrate fraction were collected. The total permeate was evaporated to 39.1% dry solids. The results (including HPLC analysis) for the permeate fraction and the final concentrate based on % / sucrose RDS are shown in Table 8.

[0240] Table 8. HPLC analysis

[0241] Total permeate Final concentrate Evaporation of permeate Mass, kg 606.0 45 - Dry solid, g / 100g 5.5 16.7 39.1 Sodium mevalonate, % 68.8 52.2 75.5 Acetate, % 1.8 0.7 1.9 other,% 29.4 47.1 22.6

[0242] The total mevalonate yield was calculated to be 87.5%.

[0243] Example 5

[0244] Crystallization of Sodium Mevalonate (Na-MVA) in Water

[0245] This example describes the aqueous crystallization of an organic acid or salt thereof, such as sodium mevalonate (Na-MVA), and the preparation of sodium mevalonate seed crystals.

[0246] The crystallization feed material is an aqueous slurry containing sodium mevalonate. The sodium mevalonate purity of the slurry is 96% by DS. The aqueous slurry containing ≥ 95% sodium mevalonate by DS can be produced by dissolving a known commercially available sodium mevalonate salt in deionized water or by mixing a known commercially available sodium mevalonate salt with a nanofiltration permeate containing sodium mevalonate prepared according to Examples 1-4.

[0247] The feed slurry (Rotavapor R-151) was evaporated at a temperature of 70°C. When the DS (dry substance) was about 54%, crystals formed by spontaneous nucleation. After nucleation, evaporation was continued at 70°C for 2 hours until the DS of the crystalline material was 81.8%.

[0248] The evaporated crystalline mass was transferred to a 2-liter cooling crystallizer. The crystalline mass was kept at 70° C. for 1 hour and then cooled to a temperature of 40° C. within 20 hours under continuous stirring.

[0249] 930 g of the resulting crystalline material was centrifuged with 20 mL of washing water (batch centrifugation, basket diameter 22.5 cm, 3500 rpm, 5 min). The sodium mevalonate yield in the centrifugation was 45%, the sodium mevalonate purity of the centrifuge cake was ≥98% by DS, and the sodium mevalonate purity of the centrifuge mother liquor was 94% by DS.

[0250] The crystallized filter cake was dried in a heating cabinet at 60° C. for 19 hours. The water content of the dried filter cake was ≤0.2% by weight.

[0251] Sodium mevalonate crystals prepared according to this process were used as seeds in Examples 6, 7 and 8. Prior to use, the crystals were ground in a porcelain mill.

[0252] Example 6

[0253] Crystallization of Sodium Mevalonate (Na-MVA) in Water

[0254] This example describes the crystallization of an organic acid or its salt, such as sodium mevalonate (Na-MVA), in an aqueous solvent.

[0255] The crystallization feed material was the evaporated nanofiltration permeate prepared according to Example 4. Prior to crystallization, the slurry was treated with activated carbon powder to remove color. The carbon treatment was performed by adding 600 g of Norit DX 1 carbon powder to 76 kg of the evaporated slurry (about 20 g of carbon powder per 1 kg DS). The slurry was heated to a temperature of 50° C. and kept stirring at constant temperature for 45 min. The carbon powder was then separated from the slurry by filtration with a filter aid (Seitz depth filter, 1.1 kg Kenite 300 filter aid). The resulting slurry had a sodium mevalonate purity of 73% based on DS, a color of 6300 ICUMSA, and a DS of 24.1%.

[0256] 41 kg of the charcoal treated feed slurry was evaporated to a DS of 86.0% (Luwa thin film evaporator NL3-210 / 1600 / 10 and Rotavapor R-153 evaporator). 4 g of 10% Struktol J 650 defoamer was added during evaporation to avoid foaming. 11.6 kg of the resulting slurry was transferred to a 10 liter cooling crystallizer and seeded twice at a temperature of 70° C.: first with 0.3 g of dry sodium mevalonate (prepared according to Example 5) and then with 2.0 g of dry sodium mevalonate 0.6 hours after the first seeding. The first seeding resulted in almost no crystal formation.

[0257] The seeded slurry was cooled to a temperature of 48° C. over 16 hours with continuous stirring. After cooling to 48° C., the crystalline mass was maintained at 48° C. for 2 hours.

[0258] 10.7 kg of the resulting crystalline material was centrifuged with 170 mL of washing water (batch centrifugation, basket diameter 40.5 cm, 2050 rpm, 10 min). The mevalonate yield in the centrifugation was 33%. The sodium mevalonate purity of the centrifuge cake was 94% by DS, the water content of the undried cake was 5.3% by weight, and the color was 5200 ICUMSA. The sodium mevalonate purity of the centrifuge mother liquor was 68% by DS, and the color was 82000 ICUMSA.

[0259] Example 7

[0260] Crystallization of Sodium Mevalonate (Na-MVA) in Water

[0261] This example describes the crystallization of an organic acid or salt thereof, such as sodium mevalonate (MVA), in an aqueous solvent.

[0262] The crystallization feed material was the evaporated nanofiltration permeate prepared according to Example 4, which was treated with activated carbon according to the procedure described in Example 6 (20 g Norit DX 1 carbon powder per 1 kg DS, contact time 45 min, contact temperature 50° C., carbon powder was separated by using a Seitz depth filter with Kenite 300 filter aid). The sodium mevalonate purity of the feed was 73% based on DS, and the color was 6300 ICUMSA.

[0263] The feed slurry was evaporated to a DS of 86.2% (Lova thin film evaporator NL3-210 / 1600 / 10 evaporator and Rotavapor R-153 evaporator). 11.7 kg of the resulting slurry was transferred to a 10 liter cooling crystallizer and seeded with 2.0 g of dry sodium mevalonate seeds (prepared according to Example 5) at a temperature of 69° C. The seeded slurry was cooled to a temperature of 44° C. over 16 hours with continuous stirring. The crystalline material was then diluted to a DS of 85.4% by adding deionized water. The diluted crystalline material was cooled to a temperature of 40° C. over 3 hours and maintained at 40° C. for 2 hours.

[0264] 10.9 kg of the resulting crystalline material was centrifuged with 170 mL of washing water (batch centrifugation, basket diameter 40.5 cm, 2050 rpm, 10 min). The mevalonate yield in the centrifugation was 37%. The sodium mevalonate purity of the centrifuge cake was 95% by DS, the water content of the undried cake was 7.0% by weight, and the color was 1100 ICUMSA. The sodium mevalonate purity of the centrifuge mother liquor was 67% by DS, and the color was 14000 ICUMSA.

[0265] Example 8

[0266] Crystallization of Sodium Mevalonate (Na-MVA) in Water

[0267] This example describes the aqueous solvent crystallization of an organic acid or salt thereof, such as sodium mevalonate (Na-MVA), from a slurry prepared by dissolving a crystallization filter cake in deionized water.

[0268] The sodium mevalonate crystals from Example 6 and Example 7 were combined and dissolved in deionized water. The resulting solution was treated with activated carbon according to the procedure described in Example 6 (20 g of Norit DX 1 carbon powder per 1 kg DS, contact time 45 min, contact temperature 50° C., the carbon powder was separated by Buchner filtration using Kenite 300 filter aid), filtered through a 0.2 μm sterile filter, and evaporated to 83.5% DS (Rotavapor R-151 evaporator). The sodium mevalonate purity of the slurry was 96% based on DS, and the color was 1300 ICUMSA.

[0269] 5.6 kg of the evaporated slurry was transferred to a 6-liter cooling crystallizer and seeded with 1.6 g of dry sodium mevalonate seeds (prepared according to Example 5) at a temperature of 68° C. The seeded slurry was cooled to a temperature of 40° C. over 18 hours with continuous stirring. After cooling to 40° C., the crystalline mass was kept at 40° C. for 4 hours.

[0270] 5.1 kg of the resulting crystalline material was centrifuged with 150 mL of washing water (batch centrifugation, basket diameter 40.5 cm, 2050 rpm, 10 min). The mevalonate yield in the centrifugation was 42%. The sodium mevalonate purity of the centrifuge cake was ≥98% by DS, the water content of the undried cake was 1.5% by weight, and the color was 100 ICUMSA. The sodium mevalonate purity of the centrifuge mother liquor was 94% by DS, and the color was 3400 ICUMSA.

[0271] Example 9.

[0272] Cation Exchange of Crystalline Na-MVA with Mevalonolactone (MVL)

[0273] This example describes the cation exchange of a liquid solution of dissolved Na-MVA crystals to produce a dilute liquid containing mevalonate (MVL) which can optionally be concentrated by evaporation (see also Figure 1B ).

[0274] The process equipment includes a jacketed glass column with an inner diameter of 45 mm and a total length of 1000 mm, a feed container placed above the column, a peristaltic pump at the column output, and a Büchi rotavapor R200 rotary laboratory evaporator. 1 liter of Dowex 88 strong acid cation exchange resin is loaded into the column to obtain a bed length of about 700 mm. At a temperature of 25°C, the resin is backwashed and regenerated into H2SO4 at a flow rate of 2 BV / h using 4 liters (4 bed volumes) of 5% H2SO4. + form.

[0275] Sodium mevalonate crystals with a purity of about 98% / DS from a water-based crystallization process are dissolved in water to form a 24.2% solution. The goal is to exchange the sodium cations and produce a pure mevalonic acid or mevalonolactone slurry.

[0276] 957 grams of feed solution were passed through the column at room temperature (about 25°C) at a rate of 1 BV / h and eluted with water. The pH of the feed was 9.78 and the conductivity was 39.4 mS / cm. Product collection began when the column output brix was 0.4% and ended when the output brix was 1.2%. 1322 grams of slightly colored product were collected. The column was regenerated again as H +The column was stirred for 24 hours at room temperature (about 25 ° C) and the material was passed through the column at a rate of 1 BV / h. Product collection started at a column output Brix of 3.0% and ended at an output Brix of 1.4%. 1641 grams of colorless product were collected. The material was evaporated to 99.1% KF-DS in a rotary evaporator with a MVL purity of 95.5% / DS.

[0277] The results (including HPLC analysis) for feed and ion exchange (IEX) product are shown in Table 9 on a % / dry matter basis.

[0278] Table 9. HPLC analysis

[0279] Feed IEX Product 1 IEX Product 2 Mass, g 957.4 1322.0 1641.0 Dry solid, g / 100g (KF-DS) 24.2 13.7 10.4 Conductivity mS / cm 39.4 2.5 4.5 pH 9.8 2.9 1.8 Mevalonolactone, % 75.0 94.3 97.6 Others in HPLC, % 1.5 2.3 2.3

[0280] The calculated total mevalonolactone yield for the IEX process was 95.6%.

[0281] The specific rotation of the slurry containing mevalonolactone prepared according to this process was -34.7° (water, c=1, 20°C).

[0282] Example 10.

[0283] Cation Exchange of Na-MVA Solution with Mevalonolactone (MVL)

[0284] This example describes the cation exchange of an aqueous solution containing Na-MVA to produce an aqueous solution containing mevalonate (MVL), which can optionally be concentrated by evaporation (see also Figure 2 ).

[0285] The process equipment includes a 100 liter box, a Seitz depth filter, three jacketed glass columns with an inner diameter of 130 mm and a total length of 1500 mm, a feed container placed above the column, a peristaltic pump at the column output, and a LUWA wiped film evaporator. 13 liters of Dowex 88 strong acid cation exchange resin (Dow) are loaded into each column to obtain a bed length of about 1000 mm. At a temperature of 25° C., the resin is backwashed in series with 130 liters (about 3.3 bed volumes) of 5% H2SO4 at a flow rate of 2 BV / h and regenerated into H + form.

[0286] The purpose is to exchange the sodium cations and produce a mevalonic acid or mevalonolactone slurry for further purification. Powdered activated carbon is used to remove color that may precipitate in the IEX feed.

[0287] The nanofiltration permeate with a purity of 75.5% / DS Na-MVA and a color of 10986 ICUMSA units was evaporated to 39.1% Brix. 76.2 kg of the solution was heated to a temperature of 50-60°C and 2% / DS Norit DX1 powdered activated carbon was added and mixed for 45 min. A filtration filter with a filtration area of ​​0.56 m 2 T2600 filter plate (Pall) and 1kg / m 2 The suspension was filtered through a Seitz depth filter using Kenite 300 (IMERYS Filtration) diatomaceous earth filter aid as a pre-coat. 110 liters of the filtrate having a 24.1% Brix was evaporated to a 53% Brix solution having a color of 6496 ICUMSA units. 14.8 kg of this material was diluted to 39.8% Brix for IEX feed and heated to 50°C.

[0288] 20.05 kg of feed solution was passed through the column at 50°C at a rate of 2 BV / h and elution was continued with water. Product collection began at the last column output brix of 0.5% and ended at an output brix of 4.0% and a pH of 2.5. The product was collected in two fractions. The fractions were combined and evaporated. The evaporated combined IEX product had a color of 2362 ICUMSA units and a MVL purity of about 76% / DS.

[0289] The results for the feed and IEX product are listed in Table 10.

[0290] Table 10. Feed and IEX products

[0291] Feed IEX Product 1 IEX Product 2 Mass, kg 20.1 18.1 17.9 Dry solid, (KF-DS) 39.8 12.0 22.7 Conductivity mS / cm 32.3 4.1 3.9 pH 8.5 1.9 1.8

[0292] Example 11.

[0293] Cation Exchange of Na-MVA Solution with Mevalonolactone (MVL)

[0294] This example describes the cation exchange of an aqueous solution containing Na-MVA to produce an aqueous solution containing mevalonate (MVL), which can optionally be concentrated by evaporation (see also Figure 2 ).

[0295] The process equipment includes a 100-liter box, a Seitz deep filter, three jacketed glass columns with an inner diameter of 130 mm and a total length of 1500 mm, a feed container placed above the column, a peristaltic pump at the column output, and a Lowa wiped film evaporator. 13 liters of Dowex 88 strong acid cation exchange resin (Dow) are loaded into each column to obtain a bed length of about 1000 mm. At a temperature of 25° C., 130 liters (about 3.3 bed volumes) of 5% H2SO4 are used to backwash the resin in series at a flow rate of 2BV / h and regenerate it into H + form.

[0296] The purpose is to exchange the sodium cations and produce a mevalonic acid or mevalonolactone slurry for further purification. Powdered activated carbon is used to remove color that may precipitate in the IEX feed.

[0297] The nanofiltration permeate with a purity of 78.8% / DS Na-MVA and a color of 8887 ICUMSA units was evaporated to 42.0% Brix. 41.4 kg of the solution was heated to a temperature of 55-58°C and 2.2% / DS Norit DX1 powdered activated carbon was added and mixed for 70 min. A filtration filter with a filtration area of ​​0.28 m 2 T2600 filter plate (Pall Corporation) and 1kg / m 2 The suspension was filtered through a Seitz depth filter using Kenite 300 (Iris Filtration) diatomaceous earth filter aid as pre-coat. 56 liters of filtrate had a Brix of 23.8% and a color of 2124 ICUMSA units. The material was evaporated to 31.1% Brix for IEX feed.

[0298] 35.7 kg of feed solution was passed through the column at 25°C at a rate of 2 BV / h and elution was continued with water. Product collection started when the last column output brix was 0.5% and ended when the output brix was 2.0% and the pH reached 2.5. The product and residue were collected. The evaporated IEX product had an MVL purity of about 78-83% / DS. The results for the feed and IEX product are listed in Table 11.

[0299] Table 11. Feed and IEX products

[0300] Feed IEX Products Remaining part Mass, kg 35.7 34.1 14.3 Dry solid, (KF-DS) 31.1 18.0 16.4 Conductivity mS / cm 42.8 6.9 6.8 pH 7.6 1.7 3.6

[0301] Example 12.

[0302] Cation Exchange of Na-MVA Solution with Mevalonolactone (MVL)

[0303] This example describes the cation exchange of an aqueous solution containing Na-MVA to produce an aqueous solution containing mevalonate (MVL), which can optionally be concentrated by evaporation (see also Figure 2 ).

[0304] The process equipment includes three jacketed glass columns with an inner diameter of 130 mm and a total length of 1500 mm, a feed container placed above the column, and a peristaltic pump located at the column output end. 13 liters of Dowex 88 strong acid cation exchange resin (Dow) were loaded into each column to obtain a bed length of about 1000 mm. At a temperature of 25° C., the resin was backwashed in series with 130 liters (about 3.3 bed volumes) of 5% H2SO4 at a flow rate of 2 BV / h and regenerated into H + form.

[0305] The goal is to exchange the sodium cation and produce a mevalonic acid or mevalonolactone syrup for further purification.

[0306] The mother liquor from the end of the crystallization of Na-MVA having a purity of 68.2% / DS Na-MVA and a color of 82952 ICUMSA units was diluted to 39.4% Brix.

[0307] 17.0 kg of feed solution was passed through the column at 25°C at a rate of 2 BV / h and elution was continued with water. Product collection started at the last column output brix of 0.8% and ended at an output brix of 2.0%. The product was collected in three fractions. The fractions were combined and evaporated. The evaporated combined IEX product had an MVL purity of about 70-73% / DS.

[0308] The results for the feed and IEX product are listed in Table 12.

[0309] Table 12. Feed and IEX products

[0310]

[0311] Example 13

[0312] Crystallization of mevalonolactone monohydrate in water and preparation of MVL*H2O seed crystals

[0313] This example describes the crystallization of mevalonolactone monohydrate from an aqueous solvent and the preparation of mevalonolactone monohydrate seed crystals.

[0314] A high purity MVL slurry was prepared by the method described herein ( Figure 1A and Figure 1B , Examples 1-9). Unexpectedly and surprisingly, it was observed that when this high MVL purity slurry was refrigerated (at about 6°C) for several weeks, mevalonolactone monohydrate (MVL*H2O) crystals formed spontaneously by themselves.

[0315] The MVL purity (98% DS (HPLC, H+ form of resin, area %)) and water content (about 6% w / w) of the slurry were high enough to make crystallization of MVL*H2O possible.

[0316] The crystals were filtered and centrifuged in a filter tube (2 min, 570 g, about 15° C.) to remove the mother liquor from the surface of the crystals. These crystals and mother liquor were then analyzed. Due to the crystallization conditions, the water content of the crystals was 10.8% (by Karl Fischer method), which was slightly lower than the theoretical value of 12.1%. The water content of the mother liquor was 3.2%, which means that the mother liquor had been concentrating during the formation of the monohydrate crystals. The MVL purity of the crystals was 98.8% DS, and the MVL purity of the mother liquor was 97.7% / DS. These MVL*H2O crystals were used as seeds in Example 14. Before use, the crystals were ground in a porcelain mill.

[0317] Example 14

[0318] Crystallization of Mevalonolactone Monohydrate in Water Solvent

[0319] This example describes the aqueous solvent crystallization of mevalonate lactone monohydrate from a mevalonate lactone slurry produced by subjecting the sodium mevalonate crystallization mother liquor to cation exchange.

[0320] The centrifuged mother liquor from Example 6 containing sodium mevalonate was treated with cation exchange according to Example 12 to obtain a liquid containing mevalonolactone. The resulting slurry had a mevalonolactone purity of 71% by DS and a color of 34000 ICUMSA.

[0321] The feed slurry was evaporated to a DS of 93.7% (Rotavapor R-153 evaporator). 2.1 kg of the resulting slurry was transferred to a 2-liter cooling crystallizer and seeded at a temperature of 11° C. with 0.4 g of dry seeds of mevalonolactone monohydrate (prepared according to Example 13). The seeded slurry was cooled to a temperature of 7° C. over 16 hours under continuous stirring. After cooling to 7° C., stirring was continued at 7° C. for 50 hours. Deionized water was added during the isothermal stage to dilute the crystalline material in the following three portions: (1) 40 g was added 23 hours after seeding, (2) 50 g was added 43 hours after seeding, and (3) 10 g was added 47 hours after seeding. The DS of the resulting crystalline material was 89.1%.

[0322] 1.7 kg of crystalline material was centrifuged in a batch centrifuge without washing water (basket diameter 22.5 cm, 4000 rpm, 3 min). The mevalonate lactone yield in the centrifuge was 52%. The mevalonate lactone purity of the centrifuge cake was 94% by DS, the water content of the undried cake was 10.8% by weight, and the color was 5200 ICUMSA. The mevalonate lactone purity of the centrifuge mother liquor was 56% by DS, and the color was 52000 ICUMSA.

[0323] Mevalonolactone monohydrate crystals prepared according to this process were used as seeds in Example 15. Prior to use, the crystals were ground in a porcelain mill.

[0324] Example 15

[0325] Crystallization of Mevalonolactone Monohydrate in Water Solvent

[0326] This example describes the aqueous solvent crystallization of mevalonolactone monohydrate from a slurry containing mevalonolactone produced by using nanofiltration followed by a cation exchange step ( Figure 2 ).

[0327] The nanofiltration permeate containing sodium mevalonate prepared according to Example 4 was treated with cation exchange according to Example 10 to obtain a liquid containing mevalonolactone. The resulting slurry had a mevalonolactone purity of 76% by DS and a color of 2400 ICUMSA.

[0328] The feed slurry was evaporated to a DS of 90.7% (Rotavapor R-153 evaporator). 6.3 kg of the resulting slurry was transferred to a 6-liter cooling crystallizer and seeded with 0.5 g of dry mevalonolactone monohydrate seeds (prepared according to Example 14) at a temperature of 12° C. The seeded slurry was cooled to a temperature of 6° C. over 17 hours under continuous stirring. After cooling to 6° C., stirring was continued at 6° C. for 5 hours. Deionized water was added during the 6° C. constant temperature stage to dilute the crystalline material in the following three portions: (1) 50 g was added 18 hours after seeding, (2) 40 g was added 19 hours after seeding, and (3) 70 g was added 20 hours after seeding. The DS of the resulting crystalline material was 88.1%.

[0329] 5.2 kg of the resulting crystalline material was centrifuged in 4 batches (batch centrifugation, basket diameter 22.5 cm, 3500 rpm, 3 min) using wash water in an amount equal to 27-33 mL / kg of material DS. A sample of the crystallization cake and a sample of the mother liquor were collected from the first centrifugation. The mevalonate lactone yield in the first centrifugation was 71%. The mevalonate lactone purity of the first centrifugation cake was 93% by DS, the water content of the undried cake was 12.7 wt%, and the color was 560 ICUMSA. The mevalonate lactone purity of the first centrifugation mother liquor was 55% by DS, and the color was 5700 ICUMSA.

[0330] Mevalonolactone monohydrate crystals prepared according to this process were used as seeds in Examples 16 and 17. Prior to use, the crystals were ground in a porcelain mill.

[0331] Example 16

[0332] Crystallization of Mevalonolactone Monohydrate in Water Solvent

[0333] This example describes the aqueous solvent crystallization of mevalonolactone monohydrate from a slurry containing mevalonolactone produced by using nanofiltration followed by a cation exchange step ( Figure 2 ).

[0334] The nanofiltration permeate containing Na-MVA prepared according to Example 3 was treated with cation exchange according to Example 11 to produce a liquid containing MVL. The resulting slurry had a mevalonolactone purity of 81% by DS and a color of 1200 ICUMSA.

[0335] The feed slurry was evaporated to a DS of 84.1% (Rotavapor R-153 evaporator). 6.2 kg of the resulting slurry was transferred to a 6-liter cooling crystallizer and seeded with 1.0 g of mevalonolactone monohydrate dry seeds (prepared according to Example 15) at a temperature of 16° C. The seeded slurry was maintained at 16° C. for 3 hours and then cooled to a temperature of 6° C. over 11 hours with continuous stirring. After cooling to 6° C., stirring was continued at 6° C. for 7 hours.

[0336] 5.5 kg of the resulting crystalline material was centrifuged in 5 batches (batch centrifugation, basket diameter 22.5 cm, 3500 rpm, 3 min) using wash water in an amount equal to 72-79 mL / kg of material DS. A sample of the crystallization cake and a sample of the mother liquor were collected from the first centrifugation. The mevalonate lactone yield in the first centrifugation was 62%. The mevalonate lactone purity of the first centrifugation cake was ≥97% by DS, the moisture content of the undried cake was 11.6 wt%, and the color was 61 ICUMSA. The mevalonate lactone purity of the first centrifugation mother liquor was 64% by DS, and the color was 2700 ICUMSA.

[0337] Example 17

[0338] Crystallization of Mevalonolactone Monohydrate in Water Solvent

[0339] This example describes the aqueous solvent crystallization of mevalonolactone monohydrate from a mixture of centrifuge mother liquor and diluted crystalline material.

[0340] The crystallization feed material was an aqueous slurry containing mevalonolactone. It was obtained by combining the centrifuge mother liquor from Example 16 and the diluted crystalline material recovered from washing the apparatus with deionized water. The mevalonolactone purity of the resulting slurry was 70% by DS and the color was 2400 ICUMSA.

[0341] The feed was evaporated to 85.3% DS (Rotavapor R-153), and 2.8 kg of the resulting slurry was transferred to a 2-liter cooling crystallizer. The slurry was seeded twice: first with 1.0 g of mevalonolactone monohydrate dry crystals (prepared according to Example 15) at a temperature of 13° C., and then with 1.0 g of mevalonolactone monohydrate dry crystals at a temperature of 10° C. The first seeding resulted in almost no crystal formation.

[0342] The seeded slurry was maintained at 10° C. for 35 min and then cooled to a temperature of 4° C. over 16 hours with continuous stirring. After cooling to 4° C., stirring was continued at 4° C. for 2 hours.

[0343] 2.5 kg of the resulting crystalline material was centrifuged in 2 batches (batch centrifugation, basket diameter 22.5 cm, 3500 rpm, 3 min). The amount of wash water in the first centrifugation was equal to 90 mL / kg DS. The mevalonate lactone yield obtained in the centrifugation was 42%. The mevalonate lactone purity of the centrifugal filter cake was ≥97% by DS, the water content of the undried filter cake was 14.7% by weight, and the color was 33 ICUMSA. The mevalonate lactone purity of the centrifugal mother liquor was 58% by DS, and the color was 4200 ICUMSA.

[0344] A second centrifugation was performed without washing water. The mevalonate yield in the centrifugation was 54%. The mevalonate purity of the centrifuge cake was ≥97% by DS, the water content of the undried cake was 11.7% by weight, and the color was 120 ICUMSA. The mevalonate purity of the centrifuge mother liquor was 53% by DS, and the color was 4600 ICUMSA.

[0345] Mevalonolactone monohydrate crystals prepared according to this process were used as seeds in Examples 18 and 19. Prior to use, the crystals were ground in a porcelain mill.

[0346] Example 18

[0347] Crystallization of Mevalonolactone Monohydrate in Water Solvent

[0348] This example describes the aqueous solvent recrystallization of mevalonolactone monohydrate crystals dissolved in deionized water.

[0349] The crystallization feed material was an aqueous slurry containing mevalonolactone. It was obtained by adding deionized water to dissolve and dilute 2.2 kg of the centrifuge cake from Example 15. The mevalonolactone purity of the obtained slurry was 92% by DS and the color was 560 ICUMSA.

[0350] The feed slurry was evaporated to 80.8% DS (Rotavapor R-153 evaporator), and 2.3 kg of the resulting slurry was transferred to a 2-liter cooling crystallizer. The slurry was cooled under continuous stirring without seeding in two steps: (1) from 20° C. to 15° C. in 2 hours, and (2) from 15° C. to 10° C. in 10 hours. After cooling to 10° C., stirring was continued at 10° C. for 6 hours. This did not result in any spontaneous crystal formation.

[0351] The slurry was seeded with 0.5 g of mevalonolactone monohydrate dry seed (prepared according to Example 17) at a temperature of 10°C. The cooling water temperature in the crystallizer jacket was kept constant at 7°C. Crystal formation started immediately after seeding. Due to the heat of crystallization, the temperature of the crystalline material first rose from 10°C to 16°C within 50 min after seeding, and then dropped from 16°C to 12°C within 3 hours. After cooling to 12°C, the cooling water temperature was increased from 7°C to 12°C, and stirring was continued at 12°C for 1 hour.

[0352] 2.2 kg of the resulting crystalline material was centrifuged in 2 batches (batch centrifugation, basket diameter 22.5 cm, 3500 rpm, 3 min) using wash water in an amount equal to 65-66 mL / kg of material DS. A sample of the crystallization cake and a sample of the mother liquor were collected from the first centrifugation. The mevalonate lactone yield in the first centrifugation was 52%. The mevalonate lactone purity of the first centrifugation cake was ≥98% by DS, the moisture content of the undried cake was 13.6 wt %, and the color was 35 ICUMSA. The mevalonate lactone purity of the first centrifugation mother liquor was 87% by DS, and the color was 1100 ICUMSA.

[0353] Example 19

[0354] Crystallization of Mevalonolactone Monohydrate in Water Solvent

[0355] This example describes the aqueous solvent recrystallization of mevalonolactone monohydrate crystals dissolved in deionized water.

[0356] The crystallization feed material was an aqueous slurry containing mevalonolactone. It was obtained by combining 2.0 kg of the centrifuge cake from Example 16 with 320 g of the centrifuge cake from Example 17. Prior to mixing, the mevalonolactone product from Example 16 was diluted to 80.9% DS with deionized water, and the resulting slurry was treated with activated carbon according to the procedure described in Example 6 (20 g Norit DX 1 carbon powder per 1 kg DS, contact time 1 hour, contact temperature 50°C, carbon powder was separated by Buchner filtration using Kenite 300 filter aid). The mevalonolactone purity of the crystallization feed slurry was ≥97% by DS, and the color was 34 ICUMSA.

[0357] The feed slurry was evaporated to a DS of 78.3% (Rotavapor R-151 evaporator). 2.6 kg of the resulting slurry was transferred to a 5-liter cooling crystallizer and seeded with 0.4 g of mevalonolactone monohydrate dry seeds (prepared according to Example 17) at a temperature of 17° C. The seeded slurry was maintained at 17° C. for 1.5 hours and then cooled to a temperature of 13° C. over 15 hours with continuous stirring. After cooling to 13° C., stirring was continued at 13° C. for 5 hours.

[0358] 2.4 kg of the resulting crystalline material was centrifuged in 2 batches (batch centrifugation, basket diameter 22.5 cm, 3500 rpm, 3 min) using wash water in an amount equal to 65-71 mL / kg of material DS. A sample of the crystallization cake and a sample of the mother liquor were collected from the first centrifugation. The mevalonate lactone yield in the first centrifugation was 50%. The mevalonate lactone purity of the first centrifugation cake was ≥98% by DS, the moisture content of the undried cake was 12.1 wt %, and the color was 3 ICUMSA. The mevalonate lactone purity of the first centrifugation mother liquor was 96% by DS, and the color was 70 ICUMSA.

[0359] Mevalonolactone monohydrate crystals prepared according to this process were used as seeds in Example 20. Prior to use, the crystals were ground in a porcelain mill.

[0360] Example 20

[0361] Crystallization of Mevalonolactone Monohydrate in Water Solvent

[0362] This example describes the water solvent crystallization of mevalonolactone monohydrate and the preparation of an aqueous high purity mevalonolactone slurry.

[0363] The crystallization feed material was an aqueous slurry containing mevalonolactone. It was obtained by combining the second centrifuge cake from Example 17 with the centrifuge mother liquors from Examples 18 and 19. The slurry was diluted to 51.2% DS by adding deionized water, and the resulting solution was treated with activated carbon according to the procedure described in Example 6 (20 g Norit DX1 carbon powder per 1 kg DS, contact time 1 hour, contact temperature 50°C, carbon powder was separated by Buchner filtration using Kenite 300 filter aid). The mevalonolactone purity of the resulting slurry was 93% by DS, and the color was 170 ICUMSA.

[0364] The charcoal treated feed slurry was evaporated to 80.3% DS (Rotavapor R-153 evaporator). 2.6 kg of the resulting slurry was transferred to a 2 liter cooling crystallizer and seeded with 0.6 g of mevalonolactone monohydrate dry seeds (prepared according to Example 19) at a temperature of 18°C. The seeded slurry was maintained at 18°C ​​for 1 hour and then cooled to a temperature of 13°C over 15 hours with continuous stirring. After cooling to 13°C, stirring was continued at 13°C for 4 hours.

[0365] 2.3 kg of crystalline material was centrifuged in 2 batches (batch centrifugation, basket diameter 22.5 cm, 3500 rpm, 3 min) using wash water in an amount equal to 67-68 mL / kg of material DS. A sample of the crystallization cake and a sample of the mother liquor were collected from the first centrifugation. The mevalonate lactone yield in the first centrifugation was 51%. The mevalonate lactone purity of the first centrifugation cake was ≥98% by DS, the moisture content of the undried cake was 12.3 wt%, and the color was 3 ICUMSA. The mevalonate lactone purity of the first centrifugation mother liquor was 87% by DS, and the color was 370 ICUMSA.

[0366] DSC analysis of mevalonolactone monohydrate crystals prepared according to this process produced an endothermic peak with a peak maximum at 22.6°C.

[0367] The centrifuge cakes were combined and diluted to 57.4% DS by adding deionized water to obtain a liquid mevalonolactone product. The resulting slurry was evaporated to ≥97% DS (Rotavapor R-153 evaporator). The mevalonolactone purity of the evaporated slurry was ≥98% by DS and the color was 2 ICUMSA.

[0368] Typical conditions for crystallizing MVL*H2O are shown in Tables 13A-13E.

[0369] Table 13A. Conditions for crystallizing MVL*H2O with feed purity between 50-100% DS and 55-99% DS

[0370] <![CDATA[ Min-Max ]]> <![CDATA[ Preferably ]]> Feed purity (% DS) 50-100 55-99 Temperature(℃) 0-24 0-24 DS content (%) 65-95 70-88

[0371] Table 13B. Conditions for crystallization of MVL*H2O. The purity of the feed was between 55-70% DS.

[0372] <![CDATA[ Min-Max ]]> <![CDATA[ Preferably ]]> Temperature(℃) 0-20 0-14 DS content (%) 82-95 84-88

[0373] Table 13C. Conditions for crystallization of MVL*H2O. The purity of the feed was between 70-80% DS.

[0374] <![CDATA[ Min-Max ]]> <![CDATA[ Preferably ]]> Temperature(℃) 0-22 0-16 DS content (%) 79-94 81-88

[0375] Table 13D. Crystallization MVL*H 2 O conditions. The purity of the feed was between 80-93% DS.

[0376] <![CDATA[ Min-Max ]]> <![CDATA[ Preferably ]]> Temperature(℃) 0-24 3-20 DS content (%) 72-90 74-86

[0377] Table 13E. Conditions for crystallization of MVL*H2O. The purity of the feed was between 93-98% DS.

[0378] <![CDATA[ Min-Max ]]> <![CDATA[ Preferably ]]> Temperature(℃) 0-24 3-20 DS content (%) 65-90 70-86

[0379] Alternatively, MVL*H2O can be crystallized at temperatures below 0°C to as low as the freezing point of the mother liquor if cooling equipment is available and the viscosity of the crystalline material is acceptable.

[0380] Example 21

[0381] Characterization of Mevalonolactone Monohydrate (MVL*H2O)

[0382] With the formula C6H 10 Further characterization of the crystalline mevalonolactone monohydrate of O3*H2O (MVL*H2O) is as follows.

[0383] AX-ray crystal structure

[0384] The X-ray diffraction of MVL*H2O was measured.

[0385] B. Melting point

[0386] The melting point (mp) of MVL-monohydrate (MVL*H2O) is between 20-25°C, preferably 21-24°C. °C depends on the crystal purity. Crystallization is only possible below mp. The melting point is determined by using a differential scanning calorimeter (DSC) peak temperature. The DSC thermogram is measured by using a Mettler Toledo DSC822e differential scanning calorimeter. The measurement is carried out in a standard 40 μL aluminum crucible in a flowing nitrogen atmosphere with a flow rate of 80 mL / min. The temperature range is 0-50°C and the heating rate is 2°C / min.

[0387] C. Crystal water content

[0388] The theoretical water content of MVL-monohydrate is 12.15% (DS content 87.85%) based on molecular weight calculation. (The molecular weight of MVL*H2O is 148.16 g / mol). This corresponds to crystals crystallized under conditions with excess water. If the water in the crystallization slurry is less than the crystallization water content, the mother liquor will continue to concentrate during crystallization, and the crystallization water content of the formed crystals will be lower than the theoretical value. As described in Example 13, it was observed that the crystallization water content of the formed MVL-monohydrate crystals was 10.8% (by the Karl Fischer method). For slurries with high slurry DS (96 and 89), it was also observed that the crystallization water content of the formed MVL-monohydrate crystals was 10-11%.

[0389] D. Solubility in water

[0390] Solubility is a property that characterizes a crystalline compound. Crystallization is possible only at concentrations above the solubility in a supersaturated slurry. Solubility determines the minimum DS concentration for crystallization at a given temperature. Solubility is determined by standard methods, such as analyzing the equilibrium concentration of a crystal suspension.

[0391] The solubility of MVL*H2O in water was determined by using crystals with a purity of 93% and calculated to a purity of 100. The equilibrium DS content was measured and calculated in the range of 0-20°C (Table 14).

[0392] Table 14. MVL*H 2 O Solubility

[0393]

[0394] E. Crystal shape

[0395] Figure 3 The typical shape of mevalonolactone monohydrate (MVL*H2O) crystals is shown. The crystals tend to grow large and fast, and release a lot of crystallization heat.

Claims

1. A method for producing a crystalline form of a salt of mevalonic acid from an aqueous solution, the method comprising subjecting the aqueous solution comprising the salt of mevalonic acid to a purification step, wherein the purification step produces a purified solution comprising the salt of mevalonic acid having a purity of at least 60%, and crystallizing the salt of mevalonic acid from the purified solution by crystallization from an aqueous solvent, in, The purifying step comprises subjecting the aqueous solution comprising the salt of mevalonic acid to nanofiltration to produce a permeate, wherein the permeate comprises the salt of mevalonic acid having a purity of at least 60%, and The nanofiltration is based on a pressure-driven membrane filtration process.

2. The method of claim 1, wherein: The water solvent crystallization comprises evaporating the purified solution or the permeate to obtain a slurry comprising at least 60% dry matter (DS), followed by cooling the slurry to produce crystals of a salt of mevalonic acid.

3. The method of claim 1, wherein: The aqueous solution is the fermentation medium.

4. The method of claim 3, wherein: The fermentation medium is clarified by removing biomass and any solids from the fermentation medium by at least one of pre-coat filtration, microfiltration, or ultrafiltration.

5. The method of claim 3, wherein: The fermentation medium is a medium obtained by fermentation of Escherichia coli.

6. The method of claim 2, further comprising removing the crystals from the slurry by filtration and centrifugation.

7. The method of claim 1, wherein: The nanofiltration utilizes a nanofiltration membrane capable of retaining 60-98 wt% of divalent salts while having a rejection of less than 30 wt% of monovalent salts.

8. The method of claim 1, wherein the method further comprises: The resulting mevalonic acid salt crystals are dissolved in water to produce a water-soluble mevalonic acid salt, and the liquid is subjected to cation exchange to convert the water-soluble mevalonic acid salt into water-soluble mevalonic acid lactone.

9. The method of claim 8, further comprising concentrating the water-soluble mevalonolactone, wherein the concentrated mevalonolactone has a mevalonolactone purity of at least 90%, the percentage corresponding to the peak area of ​​mevalonolactone relative to the total peak area using HPLC analysis.

10. A method for producing mevalonolactone from an aqueous solution comprising a salt of mevalonate, the method comprising subjecting the aqueous solution comprising the salt of mevalonate to cation exchange, thereby converting the aqueous solution comprising the salt of mevalonate into an aqueous solution comprising mevalonolactone, Wherein the method further comprises: concentrating the aqueous solution comprising mevalonolactone into a liquid comprising 65% to 90% DS; and / or Cooling the aqueous solution or liquid at 0-25° C. to obtain mevalonolactone monohydrate crystals; and / or dissolving the mevalonolactone monohydrate crystals in water to obtain a diluted liquid containing mevalonolactone having a mevalonolactone purity of at least 90%.

11. The method of claim 1, claim 8 or claim 10, wherein: The salt of mevalonate is selected from the group consisting of sodium mevalonate (Na-MVA), potassium mevalonate (K-MVA), ammonium mevalonate (NH4-MVA), lithium mevalonate (Li-MVA), any other monovalent salt of mevalonic acid, or any combination thereof.

12. The method of claim 10, wherein: The aqueous solution is a fermentation medium, wherein the fermentation medium is optionally clarified by removing biomass and any solids from the fermentation medium by at least one of pre-coat filtration, microfiltration or ultrafiltration, and / or wherein the fermentation medium is a medium obtained from E. coli fermentation.

13. A composition comprising mevalonolactone monohydrate crystals, wherein the mevalonolactone monohydrate crystals are prepared by the method according to any one of claims 10 to 12.

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