Crystallization process for the purification of halogenated aromatic compounds

Abstract

The invention concerns a process for the purification of an antimicrobial agent, comprising the steps of: (i) providing a crude aqueous slurry of the antimicrobial agent in combination with at least one impurity arising from the synthesis of the antimicrobial agent; (ii) separating the slurry into a substantially aqueous antimicrobial agent-free phase and a substantially non-aqueous antimicrobial agent-containing phase; (iii) dissolving the substantially non-aqueous antimicrobial agent-containing phase in an organic solvent or solvent mixture; and (iv) crystallising a substantially pure antimicrobial agent product from the resulting solution; and wherein the antimicrobial agent is a halogenated aromatic or heteroaromatic compound, or a derivative thereof.

Description

[0001] THOMAS SWAN GFI0753 BMF P13464WO

[0002] PROCESS

[0003] TECHNICAL FIELD

[0004] The present invention concerns a process for the purification of a halogenated aromatic or heteroaromatic antimicrobial agent, such as DCMX, PCMX or PCIVIC, a purified form of the antimicrobial agent, and formulations and uses thereof.

[0005] BACKGROUND

[0006] Antimicrobial agents are important chemicals in everyday life, with a wide range of uses across a variety of different industry sectors, from more obvious uses in personal care, household care, institutional cleaning, and medicine to less obvious uses in paints, coatings, leathers, papers, textiles, plastics, lubricants, inks, and adhesives.

[0007] Antimicrobial agents typically work by either killing microorganisms (microbicide) or stopping their growth (bacteriostatic agent). The main classes of antimicrobial agents are disinfectants, for example non-selective agents such as bleach, which kill a wide range of microbes on non-living surfaces to prevent the spread of illness, antiseptics, which are applied to living tissue and help reduce infection during surgery, and antibiotics, which destroy microorganisms within the body.

[0008] Aromatic agent compounds, or derivatives thereof, often contain aromatic or heteroaromatic groups, which may be substituted with halogens. Chloroxylenol, also known as 4-chloro-3,5-dimethylphenol or poro-chloro-meto-xylenol (PCMX) (CAS number 88-04-0, marketed for example as Casamed™), is one such example, and is a chlorine substituted phenol with a white appearance. PCMX is widely used as an antiseptic and disinfectant. It is an important intermediate for synthetic dyes and pigments, a raw material for medicines, pesticides and organic synthesis, and an important example of an antimicrobial agent. In recent years, owing to the removal of other antimicrobial agents, such as hexachlorophene and triclosan, from the market as a result of safety concerns, the use of PCMX has been rising and its production is in high demand.

[0009] PCMX is favoured for its broad-spectrum efficacy, relatively low toxicity, and stable nature. Formulations containing PCMX are frequently used in hospitals and households as antiseptics, disinfectants, and sanitizers. PCMX is also used as a preservative, in personal care applications for THOMAS SWAN GFI0753 BMF P13464WO example. It is also commonly used in antibacterial soaps, wound-cleansing, and other household antiseptic applications, amongst a broader range of applications spanning an array of sectors. It is listed as one of WHO's Essential medicines in 2021; "essential medicines” are those that satisfy the priority health care needs of the population.

[0010] Para-chlorocresol, also known as 4-chloro-3-methylphenol or para-chloro-meta-cresol (PCIVIC) (CAS number 59-50-7), is another example of a chlorine substituted phenol, which is a potent disinfectant and antiseptic. It is also used as a preservative in some cosmetics and medicinal products.

[0011] PCIVIC (p-chloro-m-cresol) and PCMX (p-Chloro-m-xylenol) are both part of the chlorophenol chemical class, and PCIVIC contains one methyl group on the aromatic ring, while PCMX has two methyl groups. Currently, routes to synthesise PCMX and PCMC rely on the chlorination of aromatic compounds. In the case of PCMX, the chlorination of meta-xylenol (MX), and for PCMC, the chlorination meta-cresol (MC).

[0012] Conventional industrial PCMX production processes require the use of the solvent perchloroethylene (PERC). PERC has been a common non-polar solvent in this and other industrial processes but is under increasing regulatory scrutiny from a health and environmental perspective. It is difficult to fully purify PCMX made by such processes and typically, the final product of conventional industrial processes to produce PCMX will have residual PERC levels in the region of 1,500 to 2,000 ppm.

[0013] Synthesis of PCMX in the presence of PERC is well known in the art.

[0014] For example, CN 104326881 A describes a preparation method of PCMX, involving PERC as a solvent, benzyl thiophenol and aluminium chloride as co-catalysts, sulfuric chloride as a chlorinating agent. Oxidative chlorination is carried out through two phases of low-temperature chlorination and high- temperature chlorination, followed by steps of water-washing layering, cooling, and crystallising, centrifuging, and washing, and drying to obtain the product. According to the method, the conversion rate can reach more than 95%, finished product PCMX yield is increased, and the by-product can be effectively reduced.

[0015] US 4,245,127 A describes the chlorination of xylenols with a chlorinating agent such as sulfuryl chloride in the presence of a metal chloride catalyst and discloses the use of PERC as a solvent for the synthesis of PCMX. The purity of the product after crystallisation is said to be 99.7%. THOMAS SWAN GFI0753 BMF P13464WO

[0016] Such processes ultimately suffer from the problem of residual PERC in the end-product. The use of other organic solvents in PCMX manufacture has been contemplated but without commercial realisation.

[0017] Attempts have been made in the art to provide the synthesis of aromatic or heteroaromatic agents, such as PCMX and other phenol or xylenol derivatives, in the absence of any organic solvent, including PERC.

[0018] For example, CN 102199075 A describes an aqueous based method for preparing PCMX, using 1- hydroxy-3,5-dimethylbenzene as a starting material and chlorinating with hydrochloric acid in the presence of a bivalent copper salt as catalyst, and oxygen as an oxidizing agent. CN 113105312 B describes a similar method using a protonic solvent and sulfuryl chloride to perform chlorination. US 8,993,813 B describes a method for the preparation of 4-isopropyl-3-methylphenol (p-thymol) from distillation residues of thymol production. CN 101823941 B describes a green industrial preparation method of 5-dimethyl-4-chlorobenzene with water as the solvent, and a chlorinating agent of sulfuryl chloride or chlorine, where the chlorination reaction is carried out through the mode of multistage temperature control.

[0019] Whatever process is used to synthesise PCMX, inevitably there exist impurities in the crude product. Typically, these impurities comprise meta-xylenol (MX), ortho-chloro-meta-xylenol (OCMX) and / or dichloro-meta-xylenol (DCMX). Much commercial attention has been paid to the removal of such impurities. However, much of this has focused on PERC itself as a crystallisation (or re-crystallisation) solvent and - as has been established - PERC is becoming increasingly undesirable as an industrial material. Furthermore, PCMX when crystallised from PERC forms needle-like crystals which tend to be fragile and consequently liable to caking, which results in poor powder flow properties.

[0020] Therefore, there have been attempts made in the art to improve the process of purification.

[0021] For example, CN 102775278 B discloses a PCMX crystallisation and purification method which is said to comprise the step of crystallising PCMX from aqueous solution. However, PCMX and its conventionally associated impurities are rather insoluble in water, and it seems unlikely that this process could be operated effectively or on an industrial scale. THOMAS SWAN GFI0753 BMF P13464WO

[0022] The present application seeks to obviate the problems associated with the state of the art and provide an improved means for the purification of halogenated aromatic or heteroaromatic antimicrobial agents, or derivatives thereof, such as PCMX and PCIVIC, by workup and crystallisation, to provide the antimicrobial agents in a pure crystalline form, as an antimicrobial agent product.

[0023] SUMMARY OF THE INVENTION

[0024] According to a first aspect of the present invention, there is provided a process for the purification of an antimicrobial agent, comprising the steps of:

[0025] (i) providing a crude aqueous slurry of the antimicrobial agent in combination with at least one impurity arising from the synthesis of the antimicrobial agent;

[0026] (ii) separating the slurry into a substantially aqueous antimicrobial agent-free phase and a substantially non-aqueous antimicrobial agent-containing phase;

[0027] (iii) dissolving the substantially non-aqueous antimicrobial agent-containing phase in an organic solvent or solvent mixture; and

[0028] (iv) crystallising a substantially pure antimicrobial agent product from the resulting solution; and wherein the antimicrobial agent is a halogenated aromatic or heteroaromatic compound, or a derivative thereof.

[0029] Optionally, step (iv) may be repeated any number of times - either with the same or with a different organic solvent or solvent mixture; and under the same or under different conditions, until the desired purity of antimicrobial agent is reached.

[0030] By "substantially pure" and by "desired purity" we mean that the crystallised antimicrobial agent product contains less than about 20000 ppm, preferably less than about 15000 ppm, more preferably less than 10000 ppm, still more preferably less than about 5000 ppm, still more preferably less than about 3000 ppm, still more preferably less than about 1500 ppm, still more preferably less than about 1250 ppm, still more preferably less than about 1000 ppm, still more preferably less than about 750 ppm, most preferably less than about 500 ppm of total impurities arising from the synthesis of the antimicrobial agent, and / or less than about less than 7500 ppm, preferably less than about 5000 ppm, more preferably less than about 3000 ppm, still more preferably less than about 1500 ppm, still more preferably less than about 1250 ppm, still more preferably less than about 1000 ppm, still more THOMAS SWAN GFI0753 BMF P13464WO preferably less than about 750 ppm, most preferably less than about 500 ppm of any singular impurity arising from the synthesis of the antimicrobial agent.

[0031] Separation of the slurry into a substantially aqueous antimicrobial agent-free phase and a substantially non-aqueous antimicrobial agent-containing phase may be effected by filtration, followed by any number of aqueous washes and re-filtration.

[0032] Advantageously, by separating the slurry in this manner, the separated non-aqueous antimicrobial containing phase does not need to be recrystallised using an organic solvent, which avoids the use of these solvents, which can be harmful to the environment, and avoids the need to recrystallise, a process that often requires excessive amounts of solvent to be carried out.

[0033] Additionally, it can be difficult using filtration to remove all undesirable materials from the solid phase. As well as the one or more impurities arising from the synthesis of the antimicrobial agent, the crude aqueous slurry will likely contain other contaminants in the aqueous phase. For example, if the synthetic process disclosed in CN 102199075 A is employed, the aqueous phase of the crude slurry will likely contain hydrochloric acid and copper catalyst as contaminants. Because these materials may to some extent embed themselves in the antimicrobial agent - or otherwise become entrapped or entangled therein -they can be difficult to remove completely, even with repeated washing. The same problem is likely to present itself in connection with any crude product generated by an aqueousbased synthetic process. Typically, in such cases the aqueous phase contaminants may include chlorinating agents, oxidising agents, and / or catalysts.

[0034] Consequently, in accordance with the invention separation of the slurry into a substantially aqueous antimicrobial agent-free phase and a substantially non-aqueous antimicrobial agent-containing phase may alternatively be effected by providing the non-aqueous antimicrobial agent-containing phase in molten form and separating the molten phase from the immiscible aqueous phase.

[0035] The molten slurry or dispersion may be maintained under pressure to prevent boiling / evaporation of the aqueous phase.

[0036] Maintaining the crude antimicrobial agent in molten form may be further advantageous in the event that the molten form of the product may be preferred in the latter stages of its synthesis in order to provide higher product yields. THOMAS SWAN GFI0753 BMF P13464WO

[0037] Separation of the molten phase from the immiscible phase gives rise to another advantage, namely a broader choice of commercially viable solvents for the subsequent dissolution and crystallisation stages. Put simply, the dissolution process requires less energy because the solute is already in molten form; and the lower energy criterion effectively expands the range of potential solvent(s). An additional factor that contributes to the broader choice is that of increased solvent stability as the crude aqueous is separated first.

[0038] Preferably during the crystallisation process conditions of temperature and concentration (and optionally pressure) are selected to maintain the antimicrobial agent in its metastable zone. The metastable zone is to be understood as a specific region in the phase diagram of a substance where a solution or melt can exist temporarily in a state that is thermodynamically unstable. In this zone, the substance remains in a supersaturated or supercooled state, meaning it contains a higher concentration of solute or is at a lower temperature than its equilibrium state would typically allow.

[0039] The inventors have advantageously found that by maintaining the antimicrobial agent in its metastable zone, through controlling of the rate of cooling during the crystallisation process, there is provided a uniform crystalline product without, or with minimal, fouling or agglomeration occurring. This provides an improved process compared to processes known in the art, for example single-step processes, such as liner or crash-cooling methods, which cannot maintain a metastable zone. The inventors have advantageously found that by operating within the metastable zone, they have been able to induce controlled nucleation and subsequent crystal growth, leading to the formation of desired crystal structures with specific properties.

[0040] According to a second aspect of the present invention there is provided an antimicrobial agent product obtainable and / or obtained by the process according to the first aspect of the invention.

[0041] The antimicrobial agent product is preferably provided in substantially pure form, as aforesaid.

[0042] Furthermore, the antimicrobial agent product is preferably substantially free from contaminants in the nature of chlorinating agents, oxidising agents, and / or catalysts.

[0043] By "substantially free from" in this invention it is preferably meant that the antimicrobial agent product comprises less than about lOOOOppm, preferably less than about 5000 ppm, more preferably THOMAS SWAN GFI0753 BMF P13464WO less than about 3000ppm, still more preferably less than about 1500ppm, still more preferably less than about 1250ppm, still more preferably less than about lOOOppm, still more preferably less than about 750ppm, most preferably less than about 500ppm of any or all contaminants arising in an aqueous phase from the synthesis of the antimicrobial agent.

[0044] According to a third aspect of the invention, there is provided the use of the antimicrobial agent product according to the second aspect of the invention.

[0045] The use may comprise use in personal care, household care, institutional cleaning and medicine, paints, coatings, leathers, papers, textiles, plastics, lubricants, inks, and adhesives.

[0046] Any feature discussed in reference to one of the aspects of the present invention applies equally to all of the other aspects discussed herein.

[0047] DETAILED DESCRIPTION

[0048] An antimicrobial agent is any substance, natural or synthetic, that kills microorganisms (biocide or microbicide) or inhibits their growth (bacteriostatic agent), thereby helping to prevent or treat infections in humans, animals, on surfaces, or in products. These agents target a range of microorganisms, including bacteria, viruses, fungi, and protozoa, and play a critical role in maintaining health and preventing disease spread.

[0049] Antimicrobial Agent

[0050] According to the invention, the antimicrobial agent is a halogenated aromatic or heteroaromatic compound, or a derivative thereof.

[0051] The halogenated aromatic or heteroaromatic compound may be further optionally substituted.

[0052] By "halogenated", it is meant that the compound comprises a halogen substituent. The term "halogen" as used herein mean a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0053] By "aromatic" compound, we mean a compound of the class of cyclic (ring-shaped) organic molecules characterized by a specific arrangement of alternating single and double bonds within the ring, leading THOMAS SWAN GFI0753 BMF P13464WO to a stable, planar structure, and with a "delocalized" n-electron system, where electrons are not confined to specific bonds but rather spread out over the entire ring, contributing to the compound's stability through conjugation. These compounds typically comprise an aryl group. An aryl group is a monocyclic or polycyclic ring system having from 5 to 20 carbon atoms. The aryl group is preferably a "Cs-i2 aryl group" and is an aryl group constituted by 6, 7, 8, 9, 10, 11 or 12 carbon atoms and includes condensed ring groups such as monocyclic ring group, or bicyclic ring group and the like. Specifically, examples of "Cg-io aryl group" include phenyl group, biphenyl group, indenyl group, naphthyl group or azulenyl group and the like. It should be noted that condensed rings such as indan and tetrahydro naphthalene are also included in the aryl group.

[0054] By "heteroaromatic" compound, we mean an aromatic compound which contains heteroatoms (e.g. O, N, S) as part of the cyclic conjugated n-system. These compounds typically comprise a heteroaryl group. A heteroaryl group is an aryl group having, in addition to carbon atoms, from one to four ring heteroatoms which are preferably selected from O, S, N, P and Si. A heteroaryl group preferably has from 5 to 20, more preferably from 5 to 14 ring atoms. Specifically, examples of a heteroaryl group include pyridine, imidazole, methylimidazole and dimethylaminopyridine.

[0055] By "optionally substituted", we mean that a compound which can be substituted may be optionally substituted; that is, we do not mean that only the first species mentioned in the list may be optionally substituted. The term optionally substituted when used herein means unsubstituted or substituted with a suitable group. Suitable groups will be known to the skilled person. Generally, such groups would not significantly detrimentally affect the function of the substituted group or of a larger moiety to which the substituted group is attached. In some cases, the skilled person would expect the substituent to improve the function of the substituted group. For example, an optionally substituted aromatic would comprise phenol, which is a phenyl group substituted with a hydroxyl group. In a further example, an optionally substituted aromatic would comprise xylenol(s), which is a phenyl group substituted with a hydroxyl group and two methyl groups.

[0056] The halogenated aromatic or heteroaromatic compound may preferably be a halogenated phenol, or a derivative thereof.

[0057] In embodiments thereof, the halogenated aromatic or heteroaromatic compound may be a halogenated xylenol, such as for example, chloroxylenol. In such embodiments, the antimicrobial agent may be selected from DCMX, or PCMX. THOMAS SWAN GFI0753 BMF P13464WO

[0058] In some embodiments thereof, the halogenated aromatic or heteroaromatic compound may be a halogenated cresol. In such embodiments, the antimicrobial agent may be selected from PCIVIC, or 2- chloro-m-cresol.

[0059] In some embodiments, the compound may be a derivative of a halogenated aromatic or heteroaromatic compound. In such embodiments, the compound may be a halogenated quinone for example, such as 2,6-dichlorobenzoquinone. Quinones are oxidized derivatives of aromatic compounds and are considered to be an antiaromatic compound.

[0060] Thus, in preferred embodiments in accordance with the above, the antimicrobial agent may be selected from DCMX, PCMX, PCMC, 2-chloro-m-cresol, 2,6-dichlorobenzoquinone, or trichlorophenol. In most preferred embodiments, the antimicrobial agent is PCMX.

[0061] Purification Process

[0062] According to the invention, there is provided a process for the purification of an antimicrobial agent.

[0063] In embodiments of the invention, the yield of purified antimicrobial agent product may be from about 80% to about 100%, from about 85% to about 100%, from about 90% to about 100%, from about 92% to about 98%, from about 94% to about 96%, or from about 95% to about 96%. Alternatively, the yield of purified antimicrobial agent product may be greater than about 80%, greater than about 85%, greater than about 90%, or greater than about 95%.

[0064] According to the invention, the antimicrobial agent is provided as a crude aqueous slurry or dispersion.

[0065] The crude aqueous slurry may comprise a crude reaction product, a partially purified reaction product, or a crude reaction product mixture. By the term partially purified, we mean that the product may have undergone at least one step to purify the product and / or remove any impurities, for example a washing step, prior to the purification process.

[0066] The crude reaction product, partially purified reaction product, or crude product mixture may comprise a substantially PERC free antimicrobial agent, or an antimicrobial agent contaminated with PERC. THOMAS SWAN GFI0753 BMF P13464WO

[0067] The antimicrobial agent comprised within the crude aqueous slurry or dispersion, may be produced by any suitable means known in the art, such as, for example, batch synthesis or flow synthesis. The antimicrobial agent may be produced under high pressure conditions. The antimicrobial agent may be produced in the presence of a catalyst. The antimicrobial agent may be produced in the presence of any suitable solvent system, such as for example, PERC.

[0068] For example, in embodiments where the crude product is a halogenated phenol, such as a chlorinated phenol, it may be prepared by any process known in the art. For example, by the chlorination of a phenol. A general scheme for this process is shown in Scheme 1.

[0069] Scheme 1

[0070] For a specific example, in embodiments where the crude product is PCMX, the PCMX may be prepared using any process known in the art. For example, by chlorinating 3,5-dimethylphenol (meta-xylenol or MX) in a batch process, which uses a biphasic reaction mixture comprising aqueous hydrochloric acid, hydrogen peroxide, copper(ll) chloride and tetrachloroethene (perchloroethylene or PERC), as shown in Scheme 2.

[0071] MX PCMX

[0072] Scheme 2

[0073] The reaction shown in Scheme 2 may result in the formation of by-products, including but not limited to, 2-chloro-3,5-dimethylphenol (ortho-chloro-meta-xylenol or OCMX), 2,4-dichloro-3,5- THOMAS SWAN GFI0753 BMF P13464WO dimethylphenol (dichloro-meta-xylenol or DCMX) and 2,4,6-trichloro-3,5-dimethylphenol (trichloro- meta-xylenol or TCMX).

[0074] In embodiments where the crude aqueous slurry or dispersion comprises a substantially PERC free antimicrobial agent, the product is provided in molten form as a melt.

[0075] It has been found that providing the antimicrobial agent in molten form is advantageous as it avoids the use of additional solvents. This opens up the availability of additional safe and environmentally friendly solvents during downstream crystallization processes, incompatible with the reaction and workup stages.

[0076] In addition, in embodiments when the antimicrobial agent is PCMX, a molten crude increases the conversion of MX into PCMX during the final stages of the reaction, irrespective of the reagent used, advantageously increasing the yield.

[0077] The crude antimicrobial agent, comprised within the crude aqueous slurry or dispersion, may be the product of the reaction in the presence or absence of PERC, and may further comprise the following residual impurities: a MX content of about 0% to about 20%, about 0% to about 15%, about 1% to about 10%, or about 1% to about 5%; or an OCMX content of about 0% to about 20%, about 0% to about 15%, about 1% to about 10%, or about 1% to about 5%; or a DCMX content of about 0% to about 20%, about 0% to about 15%, about 1% to about 10%, or about 1% to about 5%; or a PCMX content of about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, or about 85% to about 95%; or a copper content of less than about 5%, less than about 2%, less than about 1.5%, less than about 1%, or less than about 0.5%; or ash content of less than about 5%, less than about 2%, less than about 1.5%, less than about 1%, or less than about 0.5%; or a combination thereof, wherein the content of residual impurities is determined by gas chromatography, or any other suitable method. THOMAS SWAN GFI0753 BMF P13464WO

[0078] The crude aqueous slurry may be a direct product of the reaction in the presence or absence of PERC and may therefore be a warm 80°C slurry in a 0.2% HCI and 0.2% CuCL aqueous solution, for example.

[0079] The process for the purification of the antimicrobial agent may remove impurities, or significantly decrease a number of impurities, including, but not limited to, the impurities listed above.

[0080] In particular embodiments, the impurities may be selected from PERC, OCMX, DCMX, TCMX, or a combination thereof.

[0081] In particular embodiments, step (iv), the crystallisation stage, may be conducted by any suitable crystallisation process, such as for example, single-batch, continuous or multi-batch crystallisation processes.

[0082] Single-batch crystallisation is to be understood as a process where a solvent and solute are charged to a crystal liser, and the crystal product is allowed to form, and upon completion, the crystal product is separated from the solute. The crystallisation process may include cooling, adding an anti -solvent, evaporation, or a combination thereof. The crystallisation process may include a chemical reaction wherein two or more reactants are mixed to form a solid product insoluble in the reaction mixture; a common example of this would be the reaction of an acid and a base to form a salt. Advantageously, by providing the antimicrobial agent to the crystallisation in molten form, agglomeration of the crystal product is prevented, and a higher crystallisation efficiency can be achieved.

[0083] Continuous crystallisation is to be understood as a process where solvent and solute are continuously added to a crystal I iser, whilst the crystal product is continuously removed. The crystallisation process may include cooling, adding an anti-solvent, evaporation, or a combination thereof. The crystallisation process may include a chemical reaction wherein two or more reactants are mixed to form a solid product insoluble in the reaction mixture; a common example of this would be the reaction of an acid and a base to form a salt.

[0084] Cooling may be achieved by means of a cooling jacket or condenser. The inventors have found that use of a cooling jacket or condenser facilitates the control of the rate of cooling. The temperature of the crystallisation solution may be held at a temperature close to its nucleation point. The inventors have advantageously found that holding the crystallisation solution at its nucleation point controls the THOMAS SWAN GFI0753 BMF P13464WO growth of the pure antimicrobial agent product, for example pure PCMX crystals, and producing crystals with a uniform size distribution, which is desirable.

[0085] A continuous crystallisation process may be conducted in a continuous oscillatory baffled reactor, such as a Rattlesnake® reactor, a mixed suspension mixed product removal crystalliser, a tubular or plug flow crystalliser, a laminar-flow tubular crystalliser, a coiled flow inverter crystalliser, a segmented / slug flow crystalliser, a spinning disk reactor, such as a SpinPro® reactor, a Taylor reactor, such as a LCTR®, one or more continuously stirred reactors or any other suitable crystalliser in the art and their combination thereof.

[0086] Advantageously, the inventors have found that continuous crystallisation provides a more efficient and effective process compared to process of the art and is highly flexible. The smaller size of the crystalliser has been found to, along with maximized heat transfer properties, facilitate higher solute concentration and better mixing, resulting in a more efficient and effective process. The inventors have further found that a continuous crystallisation process creates a more uniform mixing, and stable temperature and concentration conditions throughout the crystallisation process. This cannot be as easily achieved with batch crystallisation.

[0087] Multi-stage batch crystallisation processes comprise a series of stages which are carried out over a period of time. For example, the multi-stage batch crystallisation process may comprise a series of stages in which a starting solution is provided at a starting temperature, and in each consecutive step the solution is cooled to a subsequent temperature, in a stepwise manner. The solution may be held at each consecutive step for a period of time. In alternative embodiments, the temperature may be decreased according to a fixed cooling rate. The cooling may be achieved by means of a cooling jacket or condenser.

[0088] A multi-stage batch crystallisation process may comprise a multiplicity of stages. In one embodiment, the multi-stage batch crystallisation process may comprise at least one step, at least two steps, at least three steps or at least four steps. In most preferred embodiments the multi-stage batch crystallisation process may comprise three or four steps.

[0089] Therefore, the multi-stage batch process may comprise (a) providing a starting solution with an elevated temperature and / or pressure at a first step; (b) decreasing the temperature between the first step and the second step such that the temperature of the solution in the second step is lower THOMAS SWAN GFI0753 BMF P13464WO than the temperature of the starting solution in the first step, optionally (c) decreasing the temperature between the second step and the third step such that the temperature of the solution in the third step is lower than the temperature of the starting solution in the second step.

[0090] For example, in a particular embodiment where the multi-stage batch crystallisation process comprises three steps, the starting solution may be provided as a saturated solution at about 60°C and cooled to about 50°C and held for about 30 minutes, and then cooled to about 30°C and held for about 30 minutes, and then cooled to about 5°C and held for about 30 minutes, prior to the filtration step.

[0091] In step (iii), there is provided a solution of the substantially non-aqueous antimicrobial agentcontaining phase in an organic solvent or solvent mixture. This solution is the starting solution for crystallisation.

[0092] The solution may be saturated or unsaturated. In a preferred embodiment, the starting solution is saturated.

[0093] The solution may be provided to the crystallisation step at an elevated temperature and / or pressure. The elevated temperature may be at least about 40°C, at least about 50°C, at least about 60°C, at least about 70°C, at least about 80°C.

[0094] In preferred embodiments, the solution may be provided to the crystallisation step at about 40°C, about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, about 100°C, about 110°C, or about 120°C.

[0095] During the crystallisation process conditions of temperature and concentration (and optionally pressure) may be selected to maintain the antimicrobial agent in its metastable zone.

[0096] Thus, in the crystallisation step, step (iv), the solution may be fast-cooled or slow-cooled.

[0097] The temperature may be decreased by about between 5 and 40°C, by between about 5 and 30°C, by between about 5 and 20°C, by between about 5 and 10°C between consecutive steps. For example, the temperature may be decreased by about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C or about 40°C between consecutive steps. For example, the decrease in THOMAS SWAN GFI0753 BMF P13464WO temperature may be between the starting solution and the first stage and / or the first stage and the second stage.

[0098] The decrease in temperature between the different steps of a multi-stage batch process may be the same or different. For example, the decrease in temperature between the starting solution (i.e.., first step) and the second step may be greater than the decrease in temperature between the second step and the third step. Alternatively, the decrease in temperature between the starting solution and the second step may be less than the decrease in temperature between the second step and the third step. In other embodiments, the decrease in temperature between the starting solution and the second step may be the same as the decrease in temperature between the second step and the third step.

[0099] The temperature may be decreased by a fixed cooling rate of between about 0.05°C / min and about 5°C / min, or between about 0.05°C / min and about 4°C / min, or between about 0.05°C / min and about 3°C / min, or between about 0.1°C / min and about 2°C / min.

[0100] For example, the temperature may be decreased by a fixed cooling rate of about 0.1°C / min, about 0.5°C / min, about l°C / min, about 1.5°C / min, about 2°C / min, about 2.5°C / min, about 3°C / min, about 3.5°C / min, about 4°C / min, about 4.5°C / min, about 5°C / min.

[0101] The temperature of the crystallisation solution may be held at a temperature close to its nucleation point. The inventors have advantageously found that holding the crystallisation solution at its nucleation point controls the growth of the pure antimicrobial agent product, for example pure PCMX crystals, and producing crystals with a uniform size distribution, which is desirable.

[0102] The inventors have further found that a uniform size distribution can be controlled when the crystallisation temperature is reduced as an approximate cubic function. Therefore, the reduction in crystallisation temperature may be as an approximate cubic function.

[0103] The crystallisation process may be conducted in a mixed suspension mixed product removal crystal liser, or any other suitable crystal liser apparatus.

[0104] The solution may be stirred or shaken during the crystallisation process. This advantageously maintains the slurry in a suspension, prevents agglomeration, and ensures uniform crystal formation. THOMAS SWAN GFI0753 BMF P13464WO

[0105] In embodiments where the solution is stirred, the solution may be stirred at between about 20 and about 1000 rpm, between about 50 and about 800 rpm, between about 100 and about 600 rpm. For example, the solution may be stirred at about 20 rpm, about 50 rpm, about 100 rpm, about 200 rpm, about 300 rpm, about 400 rpm, about 500 rpm, about 600 rpm, about 700 rpm, about 800 rpm, about 900 rpm, or about 1000 rpm.

[0106] The inventors have advantageously found that shaking or stirring the solution during the crystallisation process prevents the formation of cakes or agglomeration of the crystalline product and leads to the formation of more uniform crystals.

[0107] The crystallisation process may be subject to direct nucleation control or constant supersaturation control.

[0108] The crystallisation process may be seeded or unseeded.

[0109] The crystallisation process may be monitored by analytical methods.

[0110] The crystallisation process may be conducted in a solvent or a solvent mixture (i.e., comprise at least two solvents). In preferred embodiments the solvent or solvent mixture may be non-carcinogenic, non-chlorinated, non-hazardous, non-flammable, not a respiratory sensitiser, or a combination thereof.

[0111] The solvent may be preferably a renewable or green solvent.

[0112] The solvent may be selected from alcohols, esters, ethers, aromatics, ketones, hydrocarbons, dialkyl carbonates, ionic liquids, deep eutectic solvents, or other suitable solvents such as water, or a combination thereof.

[0113] The solvent may be selected from toluene, xylene, sulfolane, water, isooctane, cyclohexane, heptane, methylcyclohexane, cyrene, limonene, isopropanol, ethyl acetate, ethanol, n-propyl acetate, isopropyl acetate, ethyl propionate, methyl butyrate, ethyl isobutyrate, ethyl butyrate, methyl butyrate, tertbutylmethyl ether, 2-methyltetrahydrofuran, dialkyl carbonates (such as diethylcarbonate, for example), choline chloride, urea, glycerol, or a combination thereof. Preferably, the solvent is selected THOMAS SWAN GFI0753 BMF P13464WO from xylene, heptane, methylcyclohexane, n-propyl acetate, isopropylacetate, or a combination thereof.

[0114] In embodiments where the solvent is xylene, it may be comprise any of xylene's isomers, such as ortho-xylene, meta-xylene, or para-xylene, or any combination of xylene's isomers.

[0115] In embodiments where the crystallisation is conducted in a solvent mixture, the solvent mixture may comprise a mixture of a solvent and an anti-solvent. The solvent will have a high solubility of the antimicrobial agent, and the anti-solvent will have a low solubility of the antimicrobial agent.

[0116] In embodiments where the crystallisation is conducted in a solvent mixture, the solvents that comprise the solvent mixture may be combined in any suitable proportion.

[0117] Advantageously, the crystallisation solvents of the present invention are safe, easy to handle, recyclable, cost-efficient and readily commercially available.

[0118] Filtration of the crystallisation product may be achieved by any suitable method in the art. Suitable methods may include, but are not limited to, solid-liquid separation technologies such as pressure filter drying or centrifugation, or gravity filtration.

[0119] The filtered antimicrobial agent product is dried. Drying of the filtered product may include heating, placing under vacuum or a combination thereof.

[0120] Any remaining filtrates present after the filtration and / or drying step may be isolated and recycled. In the recycling step, any remaining residues may be removed, and the crystallisation solvent may be collected for further use, i.e., recycled back into the process.

[0121] The purified antimicrobial agent product may be about 90% pure, about 91% pure, about 92% pure, about 93% pure, about 94% pure, about 95% pure, about 96% pure, about 97% pure, about 98% pure, about 99% pure, about 99.2% pure, about 99.4% pure, about 99.5% pure, about 99.7% pure, or about 100% pure. In most preferred embodiments the purified antimicrobial agent product may be at least about 98% pure, at least about 99% pure, at least about 99.5% pure, or at least about 99.7% pure. THOMAS SWAN GFI0753 BMF P13464WO

[0122] The purity of the purified antimicrobial agent product may be determined by gas or liquid chromatography.

[0123] The purified antimicrobial agent product may be substantially free of PERC.

[0124] By substantially free of PERC, we mean that the purified antimicrobial agent product may have less than about 1500 ppm, less than about 1200 ppm, less than about 1000 ppm, less than about 800 ppm, less than about 600 ppm, less than about 400 ppm or less than about 200 ppm PERC content.

[0125] The purified antimicrobial agent may have from about 1500 to about 0 ppm, from about 1000 to about 0 ppm, from about 800 to about 0 ppm, from about 600 to about 0 ppm, from about 400 to about 0 ppm or from about 200 to about 0 ppm PERC content.

[0126] In preferred embodiments, the purified antimicrobial agent product is free of PERC. By free of PERC, we mean that there is about 0 ppm or about 0 % PERC content.

[0127] In embodiments where the purified antimicrobial agent product is PCMX, the purified PCMX may comprise residual impurities, including but not limited to, MX, OCMX, DCMX, solvent, catalyst (for example a metal-based catalyst, such as a copper-based catalyst), and / or water.

[0128] In embodiments where the antimicrobial agent is PCMX, the purified PCMX may have the following properties and residual impurities: a melting point of about 110°C to about 120°C, about 112°C to about 118°C, or about 113°C to about 117°C, about 114°C to about 116°C, about 114.2°C to about 115.4°C; and / or

[0129] MX content of about 0% to about 2%, about 0.01% to about 1 %, about 0.01% to about 0.5%, about 0.01% to about 0.2%, about 0.02% to about 0.2%; and / or

[0130] OCMX content of 0% to about 2%, about 0.01% to about 1.5%, about 0.03% to about 1%, about 0.03% to about 0.5%, about 0.03% to about 0.2%; and / or

[0131] DCMX content 0% to about 2%, about 0.01% to about 1.5%, about 0.025% to about 1%, about 0.05% to about 0.5%, about 0.01 to about 0.3%; and / or solvent content of 0% to about 2%, about 0.05% to about 1.5%, about 0.1% to about 1%, about 0.2% to about 0.5%, about 0.3% to about 0.4%; and / or copper content of about 0 ppm to about 100 ppm, about 0 ppm to about 70 ppm, about 0 ppm to about 50 ppm, about 0 ppm to about 20 ppm, about 0 ppm to about 30 ppm, about 1 ppm to THOMAS SWAN GFI0753 BMF P13464WO about 30 ppm, wherein copper content is determined by atomic absorption; and / or inductively coupled plasma (ICP) water content of 0% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.02% to about 0.5%, about 0.02% to about 0.3%, wherein water content is determined by Karl-Fisher; or any combination thereof, wherein the content of residual impurities is determined by gas chromatography, or any other suitable method.

[0132] The process may further comprise the following steps:

[0133] (v) pre-processing the antimicrobial agent; and / or

[0134] (vi) repeating steps (ii) and (iii) if required, wherein, if present, pre-processing step (v) comes after step (i) and before step (ii), and / or alternatively after step (iii) and before step (iv), and wherein, if present, step (vi) comes after step (iii) and before step (iv).

[0135] For example, the pre-processing step may occur prior the crystallisation step and / or after the dissolution step.

[0136] Pre-processing may be conducted on the crude aqueous slurry, or the substantially non-aqueous antimicrobial agent-containing solution.

[0137] Pre-processing the antimicrobial agent may comprise any suitable work-up procedure, such as washing with an acid, washing with water, hot filtration, dissolution in a solvent followed by filtration and evaporation to remove insoluble impurities, or a combination thereof. In some embodiments, there may be more than one pre-processing step.

[0138] Pre-processing may consist of washing with an acid may comprise washing with HCI, such as for example 37% HCI solution, or any other suitable acid. In embodiments where pre-processing comprises washing with HCI, the solution may be less than 40% HCI solution, less than 35% HCI solution, less than 30% HCI solution, less than 20% HCI solution, or less than 15% HCI solution.

[0139] Hot filtration may be conducted using any suitable solvent system in the art. THOMAS SWAN GFI0753 BMF P13464WO

[0140] Dissolution in a solvent followed by filtration and evaporation to remove insoluble impurities, may comprise dissolving the antimicrobial agent in a suitable solvent, such as for example isopropanol, filtering, and then evaporating the isopropanol to produce a partly purified antimicrobial agent.

[0141] Advantageously, pre-processing has been found to help remove additional insoluble particles prior to crystallisation and therefore reduces the amount of solvent required in the crystallisation process, whilst also increasing the product purity.

[0142] The pre-processing stage may further include a hot-split step. The hot-split step may for example comprise the steps of stopping the stirring of the crude reaction product mixture (i.e., molten product mixture), allowing the crude product mixture to settle, removing the aqueous fraction (if present) from the mixture, and splitting the mixture into separate streams. Each split mixture may then be charged with the crystallisation solvents. In some instances, the molten product may be further washed, for example with water, prior to, or after charging with the crystallisation solvent. For example, the crude product mixture may be charged with the crystallisation solvent and stirred, settled, and split. The resulting solution may be split into at least two separate streams, for example the crystallisation solvent and aqueous waste stream. The aqueous stream may be removed. This procedure may be repeated several times, including multiple hot-split steps.

[0143] The hot split-step step may be conducted under pressure. The pressure may be released when the crystallisation solvent is loaded.

[0144] Alternatively, pre-processing may comprise melting the antimicrobial agent in a suitable solvent, such as for example water, and carrying out an azeotropic distillation of PERC to isolate the antimicrobial agent. The azeotropic distillation may be carried out under pressure. Azeotropic distillation may be carried out prior to a hot-split step. In some cases, the distillate collected may be further split to isolate PERC from the water.

[0145] The process may further include solvent recycling, wherein the solvent is recycled for reuse back into the process.

[0146] Antimicrobial Agent Product THOMAS SWAN GFI0753 BMF P13464WO

[0147] According to the invention, there is provided an antimicrobial agent product obtainable and / or obtained by the aforesaid process according to the first aspect.

[0148] The antimicrobial agent product may be pure PCMX or pure PCIVIC. In a preferred embodiment, the pure antimicrobial agent product is pure PCMX.

[0149] By "substantially pure" and by "desired purity" we mean that the crystallised antimicrobial agent product contains less than about 20000 ppm, preferably less than about 15000 ppm, more preferably less than 10000 ppm, still more preferably less than about 5000 ppm, still more preferably less than about 3000 ppm, still more preferably less than about 1500 ppm, still more preferably less than about 1250 ppm, still more preferably less than about 1000 ppm, still more preferably less than about 750 ppm, most preferably less than about 500 ppm of total impurities arising from the synthesis of the antimicrobial agent, and / or less than about 7500 ppm, preferably less than about 5000 ppm, more preferably less than about 3000 ppm, still more preferably less than about 1500 ppm, still more preferably less than about 1250 ppm, still more preferably less than about 1000 ppm, still more preferably less than about 750 ppm, most preferably less than about 500 ppm of any singular impurity arising from the synthesis of the antimicrobial agent.

[0150] In particular embodiments, the antimicrobial agent product may be about 85% pure, about 90% pure, about 91% pure, about 92% pure, about 93% pure, about 94% pure, about 95% pure, about 96% pure, about 97% pure, about 98% pure, about 99% pure, about 99.2% pure, about 99.4% pure, about 99.5% pure, about 99.7% pure, or about 100% pure. In most preferred embodiments the purified antimicrobial agent product may be at least about 99% pure, preferably at least about 99.4% pure, more preferably at least about 99.5% pure, or still more preferably at least about 99.7% pure. The purity may be determined by gas chromatography.

[0151] The antimicrobial agent product may be from about 90% to about 100%, from about 98% to about 100%, from about 99% to about 100%, from about 99.0% to about 99.9%, from about 99.2% to about 99.9% pure, from about 99.4% to about 99.9%, or from about 99.6% to about 99.8%. The purity may be determined by gas chromatography.

[0152] Use of Antimicrobial Agent Product THOMAS SWAN GFI0753 BMF P13464WO

[0153] According to the invention there is provided the use of an antimicrobial agent product obtainable and / or obtained by the process according to the first aspect.

[0154] The antimicrobial agent product may be used in, but not limited to, personal care, household care, institutional cleaning and medicine, paints, coatings, leathers, papers, textiles, plastics, lubricants, inks, and adhesives.

[0155] In particular embodiments the antimicrobial agent product may be used in laundry detergents or cleaning products, such as disinfectant products. In such cases, the antimicrobial agent may enable the prevention of infections, reduce microbial contamination, prevent build up of odour-causing bacteria, reduce microbial presence on skin and in oral care, and / or prevent microbial decomposition (i.e. act as a preservative).

[0156] In alternative embodiments, the antimicrobial agent product may be used in adhesive and sealant products, construction products, lubricant and grease products, paint and coating products, plastic and polymer products, wash tanks, diaper pails, laundry equipment, laundry products, hospitals, health and personal care products, cleaning and furniture care products, fabric, textile and leather products, ink, toner and colorant products, or a combination thereof.

[0157] Advantageously, such applications where there is direct or indirect release to the drains or the environment will substantially benefit from a no-PERC antimicrobial agent product, due to reduced pollution. Therefore, the present invention provides the production of a more environmentally friendly antimicrobial agent, compared to those in the art.

[0158] In a specific example, where the antimicrobial agent product is PCMX, the use may be broad. PCMX is effective against a broad spectrum of bacteria, algae, and fungi. Notably, it is used in well-known household antiseptics such as Dettol™. Regulatory limits typically include up to 0.5% in cosmetics in the EU, and a 4.8% solution is listed by the World Health Organization as an essential medicine for antiseptic use. Advantageously, as an active ingredient, PCMX has replaced more toxic compounds like hexachlorophene and triclosan in many hygiene products.

[0159] Advantageously, where the antimicrobial agent product PCMX is perc-free has a less intense phenolic odour, which makes the product when purified by the process of the present invention beneficial in terms of subsequent formulation, as it reduces the unfavourable odour. THOMAS SWAN GFI0753 BMF P13464WO

[0160] In embodiments where the antimicrobial agent is PCMX, the use may be selected from, but not limited to: antiseptics and disinfectants in hospitals and households; antibacterial soaps and wound-cleansing products; a preservative in cosmetics, cooling fluids, and topical medications; an ingredient in personal care products like skin creams, conditioners, and deodorants; a preservative in paints, coatings, adhesives, and binders; treatment in the leather industry; and a preservative in metal working fluids.

[0161] Figures

[0162] According to the invention there is disclosed a method for purifying halogenated aromatic or heteroaromatic antimicrobial agents, such as PCMX or PCMC. Those skilled in the art can learn from the contents of this document and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.

[0163] Any feature discussed in reference to one of the aspects of the present invention applies equally to all of the other aspects discussed herein.

[0164] The invention will now be more particularly described with reference to the following examples and figures, in which;

[0165] Figure 1 shows a flow chart of a process for the purification of an antimicrobial agent in accordance with an embodiment of the present invention;

[0166] Figure 2 shows a flow chart of a process for the purification of an antimicrobial agent in accordance with an embodiment of the present invention;

[0167] Figure 3 shows a schematic diagram representing a multi-stage batch crystallisation process and apparatus in accordance with an embodiment of the present invention; and

[0168] Figure 4 shows the Cubic Cooling Profile for the crystallisation of 30% wt. / wt. crude PCMX from n-heptane with a nucleation point (n.p.) of ~72°C. THOMAS SWAN GFI0753 BMF P13464WO

[0169] Referring to Figure 1, there is shown a flow chart of a process for the purification of an antimicrobial agent in accordance with an embodiment of the present invention. A crude reaction mixture (101) is provided to the process, and may comprise, for example, 1.2 wt. PCMX slurry in aqueous solution. The aqueous solution may further comprise residual amounts of HCI and CuClj. Alternatively, the crude reaction mixture (101) may comprise molten PCMX. The crude mixture (101) is provided at an elevated temperature, for example the temperature may be 80°C. The crude reaction mixture (101) is passed to a hot-split step (102), in which the mixture is charged with the crystallisation solvent (103), and then stirred, settled, and split into the crystallisation solution (104) and aqueous waste (105), which is removed. The crystallisation solution (104) is then passed to the crystallisation stage (106), where the antimicrobial agent product is crystallised from solution. This is a single batch or continuous or multi-stage process. The solution is stirred during crystallisation to maintain a suspension. The resultant crystalline suspension (107) is passed to filtration and drying (108), where the purified antimicrobial agent (109) is collected. The remaining filtrates (110) are isolated and passed to a recycling step (111), where residues (112) are removed, and the crystallisation solvent (103) is collected for further use.

[0170] Referring to Figure 2, there is shown a flow chart of a process for the purification of an antimicrobial agent in accordance with an embodiment of the present invention. A crude aqueous slurry (201) of the antimicrobial agent in combination with at least one impurity arising from the synthesis of the antimicrobial agent is provided. The slurry is transferred (202) to a separation vessel where the slurry is separated into a substantially non-aqueous antimicrobial agent-containing phase (203) and a substantially aqueous antimicrobial agent-free phase (204). The aqueous phase is removed (205) and may be recycled or sent to a water treatment facility. The antimicrobial agent-containing phase (203) is isolated (206). A solvent mixture (207), which may comprise water and / or an organic solvent is added to the isolated antimicrobial agent-containing phase (206), and the mixture may be stirred or mixed. The substantially non-aqueous antimicrobial agent-containing phase (208) is separated from the substantially aqueous antimicrobial agent-free phase (209). The aqueous phase is removed (210) and may be recycled or sent to a water treatment facility. The antimicrobial agent-containing phase (208) is isolated (211). The substantially non-aqueous antimicrobial agent-containing phase (211) is dissolved in an organic solvent or solvent mixture (212), and the substantially pure antimicrobial agent is crystallised. The substantially pure antimicrobial agent product is isolated in a filtration step (213) from the resulting solution (214). The product is dried to produce the substantially pure antimicrobial agent (215). THOMAS SWAN GFI0753 BMF P13464WO

[0171] Referring to Figure 3, there is shown a schematic diagram representing a continuous crystallisation process and apparatus in accordance with an embodiment of the invention. The crystallisation solution (301), which may comprise a substantially non-aqueous antimicrobial agent-containing phase in an organic solvent or solvent mixture is provided to a feed chamber (302). The solution (301) is heated to an elevated temperature in the feed chamber (302), such as a temperature of 60-80°C. The solution (301) is transferred through an in-line filter (303) and pumped, by means of a pump (304), into a first crystallisation chamber (305), which may be a continuously stirred tank-reactor, through a feed line. Waste (306) from the in-line filter (303) is removed. The crystallisation chamber (305) is equipped with a stirrer or shaker to prevent agglomeration and ensure uniform crystal formation. The first crystallisation chamber (305) may also be equipped with analytical equipment such as a temperature probe (307) and a focused beam reflectance measurement (FBRM) system (308) for monitoring the size, shape, and count of growing crystals. The solution in crystallisation chamber (305) is cooled to a first cooled temperature, for example 50°C, over a prolonged period to allow for crystal formation. Cooling is achieved by means of a cooling jacket or condenser. After the required residence time, the partially crystalline solution is passed to a second crystallisation chamber (309), which may be a continuously stirred -tank-reactor. The second crystallisation chamber (309) is equipped with a stirrer or shaker to prevent agglomeration and ensure uniform crystal formation. The second crystallisation chamber (309) may also be equipped with analytical equipment such as a temperature probe (307) and a focused beam reflectance measurement (FBRM) system (308) for monitoring the size, shape, and count of growing crystals. The solution in the second crystallisation chamber (309) is cooled to a second cooled temperature, for example 30°C, over a prolonged period to allow for crystal formation. The prolonged period may be between 12 and 48 hours, or more preferably 12 and 24 hours. Cooling is achieved by means of a cooling jacket or condenser. After the required residence time, the partially crystalline solution is passed to a third crystallisation chamber (310). The third crystallisation chamber (310), which may be a continuous stirred-tank reactor, which is equipped with a stirrer or shaker to prevent agglomeration and ensure uniform crystal formation. The third crystallisation chamber (310) may also be equipped with analytical equipment such as a temperature probe (307) and a focused beam reflectance measurement (FBRM) system (308) for monitoring the size, shape, and count of growing crystals, and an FTIR (311). The solution in the third crystallisation chamber (310) is cooled to a third cooled temperature, for example 5°C, over a prolonged period to allow for crystal formation. The prolonged period may be between 2 and 6 hours, or it may be preferably greater than 6 hours. Cooling is achieved by means of a cooling jacket or condenser. After the required residence time, the crystalline solution is passed to an isolation system (312). In the THOMAS SWAN GFI0753 BMF P13464WO isolation system (312), filtration occurs, and waste (313) is removed, and the crystalline material dried to produce the antimicrobial agent product (314).

[0172] EXAMPLES

[0173] Example 1 - Crystallisation of Crude Parachlorometaxylenol (PCMX) from Various Solvents

[0174] Crude PCMX may be crystallised from various solvents to remove undesirable phenolic components. Typically, PCMX is purified by cooling crystallisation from tetrachloroethylene (perklone, PERC) with a phenol loading weight range of 30-40 wt. %. In addition to high purity PCMX, the product colour and appearance are also key quality criteria.

[0175] The solubilities of pure PCMX in various solvents was determined and the results are highlighted in in Table 1.

[0176] Each sample was analysed by gravimetric solubility, where an excess of solid was charged to a vial, followed by each solvent before stirring for the specified temperatures overnight. The resulting slurries were then filtered, separated into smaller aliquots, and dried under vacuum at 40°C. The resulting dry masses were measured at regular intervals to determine if the solid samples were free of solvent. Solubilities were calculated as the difference between the initial aliquot mass and the corresponding dry mass.

[0177] Table 1 THOMAS SWAN GFI0753 BMF P13464WO

[0178] From the results of the validation gravimetric experiments, it is clear that the solubility of PCMX within most tested pure solvents is not suitable for cooling crystallisation. This is due to the solubility having minimal temperature dependence resulting in low recovery potential. For effective cooling crystallisation, PCMX must be highly soluble at elevated temperatures, and only partially soluble at low temperatures. The results in Table 1 show that apolar, hydrocarbon solvents such as heptane, methylcyclohexane (MCH) and mixed xylene isomers (xylenes) give preferred solubility behaviour.

[0179] In representative examples, crude PCMX of the below noted composition of Table 2 was suspended in an appropriate amount of the desired solvent to achieve a 30% wt. / wt. ratio of crude to solvent.

[0180] Table 2 summarises the typical input composition of crude PCMX purified by crystallisation.

[0181] Table 2 Resulting slurries were heated to 80°C to fully dissolve all material, before allowing to cool to ambient temperature with stirring. The resulting slurries were then filtered, before washing the resulting solids

[0182] T1 THOMAS SWAN GFI0753 BMF P13464WO two times with 1.5 mass equivalents of fresh solvent. The resulting crystalline powders were then dried under reduced pressure.

[0183] Table 3

[0184] Table 3 compares the results of the purification of the crude PCMX sample by different solvents. It is evident that comparable purification of PCMX to PERC is possible by using various different solvents, with additional examples also possible from, but not limited to, aromatic solvents such as xylenes and chlorobenzene.

[0185] Example 2 - Controlled Cooling Crystallisation of PCMX

[0186] The crystallisation of PCMX from different solvents can be more effectively controlled by modulating the rate at which the solution is cooled. The cubic cooling profile of PCMX was determined.

[0187] Understanding the temperature at which crystals begin to form, known as the nucleation point (n.p.) allows for more effective control of the crystallisation and purification process. Additionally, holding the crystallisation solution at a temperature approximate to its nucleation point allows for controlled growth of pure PCMX crystals, with a more uniform size distribution. The inventors have found that further reducing the crystallisation temperature as an approximate cubic function allows continued controlled crystal growth, allowing for effective purification and more uniform size distribution.

[0188] In the apparatus, this is achieved by controlling the jacket temperature setpoints, which are adjusted to ensure a contents temperature that matches the desired nucleation point. THOMAS SWAN GFI0753 BMF P13464WO

[0189] Table 4

[0190] Table 4 shows an example of a cubic cooling profile for controlling the crystallisation of PCMX with a nucleation point of n.p.

[0191] Table 5

[0192] Table 5 summarises the nucleation points determined for crude PCMX in preferred solvents at optimum wt. / wt. loadings.

[0193] Referring to Figure 4, there is shown a graphical representation of the cubic cooling profile for the crystallisation of 30% wt. / wt. ratio of crude PCMX from n-heptane with a nucleation point (n.p.) of ~72°C, showing the different consecutive steps and the residence times for each step. Example 3 - Controlled Cooling Crystallisation of DCMX

[0194] As with PCMX, the crystallisation of dichlorometaxylenol (DCMX) from different solvents can be effectively controlled by modulating the rate at which the solution is cooled. THOMAS SWAN GFI0753 BMF P13464WO

[0195] In representative examples, a sample of crude DCMX of the below noted composition of Table 6 was suspended in an appropriate amount of the desired solvent to achieve a 40% wt. / wt. ratio of crude sample to solvent. Table 6 summarises the typical input composition of crude PCMX purified by crystallisation.

[0196] Table 6

[0197] A cubic cooling profile as outlined in Table 4 was used to purify the sample of crude DCMX. Following filtration and washing with fresh solvent, the recovery, appearance, and purity of DCMX were assessed for preferred solvents, n-heptane, and MCH. The results are summarised in Table 7 below, detailing the performance of the crystallisation of crude DCMX in these preferred solvents.

[0198] Table 7

[0199] Example 4 - Panel testing of PCMX samples crystallised from different solvent systems.

[0200] A panel was asked to rank six different PCMX samples based on the intensity of their odour.

[0201] The samples were anonymised (with letter assigned as the sole reference, see Table 8 below). The panel was asked to rank these samples from 1 as the lowest odour to 6 as the strongest odour. The results of this study are shown in Table 8 below. THOMAS SWAN GFI0753 BMF P13464WO

[0202] Table 8

Claims

THOMAS SWAN GFI0753 BMF P13464WOCLAIMS1. A process for the purification of an antimicrobial agent, comprising the steps of:(i) providing a crude aqueous slurry or dispersion of the antimicrobial agent in combination with at least one impurity arising from the synthesis of the antimicrobial agent;(ii) separating the slurry or dispersion into a substantially aqueous antimicrobial agent- free phase and a substantially non-aqueous antimicrobial agent-containing phase;(iii) dissolving the substantially non-aqueous antimicrobial agent-containing phase in an organic solvent or solvent mixture; and(iv) crystallising a substantially pure antimicrobial agent product from the resulting solution; and wherein the antimicrobial agent is a halogenated aromatic or heteroaromatic compound, or a derivative thereof.

2. A process according to claim 1 wherein separation of the slurry or dispersion into a substantially aqueous antimicrobial agent-free phase and a substantially non-aqueous antimicrobial agent-containing phase is effected by filtration.

3. A process according to claim 1 wherein separation of the slurry or dispersion into a substantially aqueous antimicrobial agent-free phase and a substantially non-aqueous antimicrobial agent-containing phase is effected by providing the non-aqueous antimicrobial agent-containing phase in molten form and separating the molten phase from the immiscible aqueous phase.

4. A process according to claim 3 wherein the molten slurry or dispersion is maintained under pressure to prevent boiling / evaporation of the aqueous phase.

5. A process according to claim 3 or claim 4 wherein during the crystallisation process conditions of temperature and concentration (and optionally pressure) are selected to maintain the antimicrobial agent in its metastable zone.

6. A process according to any one of claims 1 to 5 wherein the antimicrobial agent is selected from PCMX or PCIVIC.THOMAS SWAN GFI0753 BMF P13464WO7. A process according to any one of claims 1 to 6 wherein the antimicrobial agent product is substantially PERC free.

8. A process according to any one of claims 1 to 7 wherein steps iii) and iv) are conducted in a solvent or a solvent mixture, wherein the solvent or solvent mixture is selected from alcohols, esters, ethers, aromatics, ketones, hydrocarbons, or a combination of two or more thereof.

9. A process according to claim 8 wherein the solvent or solvent mixture is selected from toluene, xylene, sulfolane, water, isooctane, cyclohexane, heptane, methylcyclohexane, cyrene, limonene, isopropanol, ethyl acetate, ethanol, n-propyl acetate, isopropyl acetate, ethyl propionate, methyl butyrate, ethyl isobutyrate, ethyl butyrate, methyl butyrate, or a combination of two or more thereof.

10. A process according to claim 9 wherein the solvent or solvent mixture is selected from heptane, methylcyclohexane, n-propyl acetate, isopropylacetate, or a combination thereof.

11. A process according to any one of claims 8 to 10 wherein the solvent is recycled for reuse back into the process.

12. A process according to any one of claims 8 to 11 being a multi-stage process comprising:(a) providing a starting solution with an elevated temperature and / or pressure at a first step;(b) decreasing the temperature between the first step and the second step such that the temperature of the solution in the second step is lower than the temperature of the starting solution in the first step.

13. The process according to claim 12 wherein the process further comprises:(c) decreasing the temperature between the second step and the third step such that the temperature of the solution in the third step is lower than the temperature of the starting solution in the second step.

14. The process according to claim 12 or claim 13 wherein the elevated temperature is at least about 40°C, at least about 50°C, at least about 60°C, at least about 70°C, at least about 80°C.THOMAS SWAN GFI0753 BMF P13464WO15. The process according to any one of claims 12 to 14 wherein the temperature is decreased by about between 5 and 40°C, by between about 5 and 30°C, by between about 5 and 20°C, by between about 5 and 10°C.

16. An antimicrobial agent product obtainable and / or obtained by the process of any one of claims 1 to 15.

17. An antimicrobial agent product according to claim 16 provided in substantially pure form.

18. Use of the antimicrobial agent product of claim 16 or claim 17.

19. Use according to claim 18 in personal care, household care, institutional cleaning and medicine, paints, coatings, leathers, papers, textiles, plastics, lubricants, inks, and adhesives.

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