Patent Document

FIELD OF INVENTION 
       [0001]    The present invention relates to biocidal agents designed to protect industrial products against microbial, bacterial, fungal and algal infections. In particular, the present invention relates to co-crystals containing 3-iodopropynyl butylcarbamate (IPBC) and to compositions containing said co-crystals which have improved physical, chemical and workability properties compared with the use of IPBC. 
       DESCRIPTION OF THE STATE OF THE ART 
       [0002]    3-Iodopropynyl butylcarbamate (IPBC) is a biocide used as a preservative, fungicide and algaecide in industrial formulations such as paints and coatings, in metalworking and in the protection and preservation of wood. It is also added to polymer formulations to prevent the growth of fungi and bacteria in products obtained from polymers. It is also present in personal care products and cosmetics to prevent the growth of bacteria and fungi. 
         [0003]    In some of its applications, IPBC can be added directly to the formulation concerned at room temperature. However, the compound is difficult to use in industrial products and processes. Its solubility in water is extremely low (156 ppm at 20° C.), and it tends to be uneven and sticky, which makes it unsuitable for automatic manufacturing devices. The product melts at the temperature of 67° C., above which it degrades rapidly. It is therefore considered unusable in compositions which must be used above said temperature. 
         [0004]    The product can be prepared with high yields and purity as disclosed in U.S. Pat. No. 6,999,208. 
         [0005]    The crystalline and molecular structure of IPBC was described by E. V. Avtomonov et al, Zeitschrifit fuer Naturforschung, B: Chemical Sciences, 52(2), 256-258, 1997. 
         [0006]    Co-crystals between IPBC and a second component are not known. 
         [0007]    The definition of co-crystal has long been debated in the crystallography sphere. The simplest definition is a crystalline structure consisting of two or more components in a precise stoichiometric ratio, where each component can be an atom, an ion or a molecule (G. P. Stahly et al., A survey of co-crystals reported prior to 2000 , Crystal Growth  &amp;  Design , 9(10), 4212-4229, 2009). However, this definition includes many types of compounds, such as hydrates, solvates and clathrates, so the definition is sometimes extended by specifying that the components of the co-crystals are solid in their pure forms under room conditions (J. H. ter Horst et al, Discovering new co-crystals,  Crystal Growth  &amp;  Design . 9 (3), 1531-1537, 2009). Another definition present in the literature is that co-crystals consist of two or more components that form a single crystalline structure having unique properties (G. P. Stahly, Diversity in Single- and Multiple-Component Crystals. The Search for and Prevalence of Polymorphs and Cocrystals,  Crystal Growth  &amp;  Design  7(6), 1007-1026, 2007). 
         [0008]    Co-crystals are orderly structures, and their components interact through non-covalent interactions, such as hydrogen bonds, ionic interactions, van der Waals interactions and π interactions. The properties of co-crystals, such as their melting point, solubility, chemical stability and mechanical properties, differ from those of their individual components. 
         [0009]    The formation of co-crystals wherein one of the components is a substance with biological activity is an increasingly common approach in the pharmaceutical industry, because it allows the chemico-physical properties of the active ingredient of interest to be optimised. See, for example: M. J. Zaworokto et al, The role of cocrystals in pharmaceutical science,  Drug Discovery Today,  13, 440, 2008; O. Almarsson et al, Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical cocrystals represent a new path to improved medicines?  Chem. Comm.,  1889, 2004; P. Vishweshwar et al, Pharmaceutical cocrystals.  J. Pharm. Sciences,  95, 499, 2006; A. V. Trask, An overview of pharmaceutical cocrystals as intellectual property.  Mol. Pharma.  4, 30, 2007; W. Jones et al., Pharmaceutical cocrystals: an emerging approach to physical property enhancement.  MRS Bull.  31, 875, 2006. 
         [0010]    Examples of co-crystallisation approaches used to generate new supramolecular materials are reported in US2011152266 (A1), GB2476202 (A), CA2738866 (A1), WO2011035456 (A1), KR20100091127 (A), WO2010011926 (A2), WO2010128977 (A1), MX2008015937 (A), KR20090015912 (A), WO2009116055 (A1), US2009247749 (A1), WO2008108639 (A1), US2008280858 (A1), WO2008021559 (A2), WO2007067727 (A2), US2006149521 (A1), CN1757780 (A) and WO2005089375 (A2). In all cases, the co-crystals are formed by non-covalent interactions involving hydrogen bonds, π-π (stacking) interactions or ion-π interactions. 
         [0011]    Methods for generating new molecular entities involving IPBC are described in US20040143011A1 and US7851516B2. However, these documents do not suggest the formation of co-crystals involving the iodoacetylenyl group and halogen bond interaction like those forming the object of the present application. 
       DEFINITIONS 
       [0012]    For the purpose of the present application, “co-crystal” is defined as a crystal that contains in the crystal unit cell at least one molecule of IPBC and at least one molecule of a second compound, called the “co-crystallisation agent”, which can be liquid or solid at room temperature. 
         [0013]    For the purpose of the present application, the term “halogen bond” (XB) indicates a non-covalent interaction involving the iodine atom of IPBC, which acts as electron density acceptor. This type of bond is indicated in the present application by the graphical representation D - - - I, wherein I is the iodine atom (Lewis acid, electron acceptor, XB-donor) and D is an electron-donor species (Lewis base, XB-acceptor). For a discussion of the halogen bond, see P. Metrangolo, F. Meyer, T. Pilati, G. Resnati, G. Terraneo, Halogen Bonding in Supramolecular Chemistry,  Angewandte Chemie International Edition, Volume  47(33), 6114-6127, 2008. 
       DISCLOSURE OF THE INVENTION 
       [0014]    The object of the present invention is co-crystals of the compound 3-iodopropynyl butylcarbamate with a co-crystallisation agent, wherein said agent is in the liquid or solid state at room temperature and is bonded to IPBC via at least one halogen bond. The co-crystals according to the invention have more advantageous chemico-physical properties than IPBC, such as better water solubility, greater heat stability, better powder flowability and better compressibility for tablet formation. 
         [0015]    The co-crystals according to the invention are obtained by synthesis in the solid state or in solution. They can be formed by a supramolecular approach involving assembly of IPBC with selected chemical species called co-crystallisation agents, which are able to establish non-covalent interactions involving the iodine atom (halogen bond, XB) present on the molecular structure of IPBC. The co-crystallisation agents used in the present invention are: organic bases, in particular aliphatic amines or aromatic heterocyclic derivatives containing at least one basic nitrogen atom; halides; phosphates; and carboxylates. 
         [0016]    A further object of the invention is a composition containing a co-crystal as defined above, and additives. 
         [0017]    A further object of the invention is the use of a co-crystal as defined above, or a composition as defined above, as a biocide, in particular as a preservative, antibacterial, fungicide or algaecide. 
         [0018]    A further object of the invention is industrial products containing a co-crystal as defined above. 
         [0019]    Finally, a further object of the invention is a process for the preparation of a co-crystal as defined above, comprising: a) placing IPBC in contact with a co-crystallisation agent able to form at least one halogen bond with said IPBC, under crystallisation conditions such as to form a solid phase wherein the IPBC and said agent are bonded together via at least one halogen bond; and b) optional isolation of the co-crystals formed in step a). 
       DETAILED DESCRIPTION OF THE INVENTION 
       [0020]    In one embodiment of the invention the co-crystallisation agent is selected from aromatic heterocycles containing at least one basic nitrogen atom, and is preferably selected from pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, thiazole, isothiazole, oxazole, isoxazole; their derivatives functionalized with C 1 -C 6  alkyl; C 2 -C 6  alkenyl; C 2 -C 6  alkyl groups containing an epoxy group; C 3 -C 7  cycloalkyl groups; benzyl groups; C 6 -C 10  aryl groups; C 1 -C 6  alkoxyl groups; halides; carboxyamide; carbonyl optionally in the form of an acetal or a ketal deriving from a C 1 -C 6  alcohol or optionally in the form of a cyclic ketal deriving from a C 2 -C 6  alkane-1,2-diol or a C 2 -C 6  alkane-1,3-diol; hydroxyl; C 1 -C 6 -alkoxycarbonyl groups; sulfhydryl; C 1 -C 6  alkylthio groups; C 1 -C 6 -alkylsulfinyl groups; C 1 -C 6 -alkylsulfonyl groups; sulfonamide; and benzocondensed derivatives thereof, such as quinoline and isoquinoline. 
         [0021]    In one embodiment said aromatic heterocycles useful as co-crystallisation agents are selected from pyridine and derivatives of pyridine of general formula (I) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0022]    wherein L is selected from —(CH 2 ) n —, wherein n is 0 or an integer between 1 and 6, and —C(O)—NH—(CH 2 ) m —NH—C(O)—, wherein m is an integer between 2 and 6, and wherein in said compound (I) one or both pyridine rings can be benzocondensed. 
         [0023]    In a preferred embodiment the compounds of formula (I) are selected from 4,4′-bipyridyl, 4-[2-(4-pyridinyl)ethyl]pyridine and N,N′-bis(4-pyridylcarbonyl)-1,6-hexanediamine. 
         [0024]    In another embodiment of the invention the co-crystallisation agent is an aliphatic amine of formula R 1 R 2 R 3 N wherein R 1 , R 2  and R 3  are independently selected from the group containing hydrogen, C 1 -C 6  alkyl and C 3 -C 7  cycloalkyl; or R 1  is as defined above and R 2  and R 3 , taken together with the nitrogen atom to which they are bonded, form a 4-7 member nitrogenous heterocyclic ring optionally containing one oxygen or sulphur atom or a further nitrogen atom, said further nitrogen atom being substituted by an R 1  group as defined above; or the aliphatic amines are selected from the group of bicyclic tertiary amines of formula (II) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein p, q and r are independently selected from the integers 2 or 3. 
         [0025]    Examples of aliphatic amines useful for the purposes of the present invention are triethylamine, diisopropylethylamine, tributylamine, N-methylpiperidine, N-methylmorpholine and N,N′-dimethylpiperazine. In a preferred embodiment the bicyclic tertiary amine of formula (II) is 1,4-diazabicyclo[2.2.2]octane. 
         [0026]    In another embodiment of the invention, the co-crystallisation agent is an organic or inorganic halide. 
         [0027]    When an organic halide is used, it is preferably a tetraalkyl ammonium halide of formula R 4 N + X −  wherein each R can independently be a C 1 -C 6  alkyl and X −  is a halide. 
         [0028]    In a preferred embodiment the organic halide is tetrabutyl ammonium halide, preferably tetrabutyl ammonium chloride or tetrabutyl ammonium iodide. 
         [0029]    In another embodiment of the invention, the co-crystallisation agent is an inorganic halide, and is preferably an alkali or alkaline-earth metal or transition metal halide selected from iron and zinc, or a tin halide. Examples of inorganic halides usable as co-crystallisation agents according to the present invention are iodides such as cuprous iodide and potassium iodide; chlorides such as ammonium chloride, magnesium chloride, potassium chloride, stannous chloride, calcium chloride, ferric chloride, sodium chloride and zinc (II) chloride. 
         [0030]    In a preferred embodiment the inorganic halide is calcium chloride or zinc (II) chloride. 
         [0031]    In another embodiment of the invention, the co-crystallisation agent is an inorganic phosphate, such as monobasic ammonium phosphate, dibasic ammonium phosphate, dibasic magnesium phosphate, tribasic magnesium phosphate, monobasic calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium pyrophosphate, ferric phosphate, ferric pyrophosphate, monobasic potassium phosphate, dibasic potassium phosphate, tribasic potassium phosphate, potassium pyrophosphate, sodium aluminium phosphate, monobasic sodium phosphate, dibasic sodium phosphate, tribasic sodium phosphate or sodium pyrophosphate. 
         [0032]    In another embodiment of the invention the co-crystallisation agent is an alkali or alkaline-earth metal or transition metal carboxylate. Examples of carboxylates useful for the purpose of the present invention are acetates, such as calcium acetate, sodium acetate and zinc acetate; citrates, such as ammonium citrate, calcium citrate, iron (III) citrate, ammonium iron (III) citrate, sodium citrate and potassium citrate; and benzoates, such as sodium benzoate. 
         [0033]    In the co-crystals according to the invention, IPBC and the co-crystallisation agent are present in a molar ratio ranging between 2:1 and 4:1. 
         [0034]    The preferred co-crystals according to the invention are:
       co-crystal containing 3-iodopropynyl butylcarbamate and pyridine in a 1:1 molar ratio;   co-crystal containing 3-iodopropynyl butylcarbamate and 4-[2-(4-pyridinyl)ethyl]pyridine in a 2:1 molar ratio;   co-crystal containing 3-iodopropynyl butylcarbamate and 4,4′-bipyridine in a 2:1 molar ratio;   co-crystal containing 3-iodopropynyl butylcarbamate and 1,4-diazabicyclo[2.2.2]octane in a 2:1 molar ratio;   co-crystal containing 3-iodopropynyl butylcarbamate and tetrabutyl ammonium iodide in a 3:1 molar ratio;   co-crystal containing 3-iodopropynyl butyl carbamate and tetrabutyl ammonium chloride in a 2:1 molar ratio;   co-crystal containing 3-iodopropynyl butylcarbamate and calcium chloride in a 4:1 molar ratio;   co-crystal containing 3-iodopropynyl butylcarbamate and zinc chloride in a 4:1 molar ratio   co-crystal containing 3-iodopropynyl butylcarbamate and N,N′-bis(4-pyridylcarbonyl)-1,6-hexanediamine in a 2:1 molar ratio.       
 
         [0044]    Further preferred co-crystals according to the invention are:
       co-crystal containing 3-iodopropynyl butylcarbamate and 4-[2-(4-pyridinyl)ethyl]pyridine in a 2:1 molar ratio, having characteristic X-ray powder diffraction (XRPD) peaks at 2θ angle values of 5.12, 5.68, 11.44, 16.95, 22.22, 22.66, 24.97 and 27.88±0.05°, and unit cell dimensions [a=30.666(3) b=4.9869(4) c=21.068(2)] and [α=90.00 β=92.115(6) γ=90.00];   co-crystal containing 3-iodopropynyl butylcarbamate and 4,4′-bipyridine in a 2:1 molar ratio, having characteristic X-ray powder diffraction (XRPD) peaks at 2θ angle values of 6.23 and 21.93±0.05°, and unit cell dimensions a=28.683(2) b=4.9270(4) c=21.429(2)] and [α=90.00 β=99.92(2) γ=90.00];   co-crystal containing 3-iodopropynyl butylcarbamate and tetrabutyl ammonium iodide in a 3:1 molar ratio, having characteristic X-ray powder diffraction (XRPD) peaks at 2θ angle values of 9.28, 14.48, 16.32, 17.73, 20.25, 20.69, 21.10, 21.33, 22.26, 22.90, 23.60, 23.97, 24.30, 25.01, 26.13, 26.51, 27.90 and 28.40±0.1°, and unit cell dimensions [a=10.7688(9) b=20.204(2) c=23.735(2)] and [α=90.00 β=94.778(2) γ=90.00];   co-crystal containing 3-iodopropynyl butylcarbamate and calcium chloride in a 4:1 molar ratio, having characteristic X-ray powder diffraction peaks (XRPD) at 2θ angle values of 9.67 and 22.28±0.05°;   co-crystal containing 3-iodopropynyl butylcarbamate and N,N′-bis(4-pyridylcarbonyl)-1,6-hexanediamine in a 2:1 molar ratio, having characteristic X-ray powder diffraction (XRPD) peaks at 2θ angle values of 11.83 and 22.78±0.05°, and unit cell dimensions [a=29.4501(18) b=5.1100(3) c=27.9417(17)] and [α=90.00 β=118.566(3) γ=90.00];   co-crystal containing 3-iodopropynyl butylcarbamate and pyridine in a 1:1 molar ratio, having a  13 C-NMR spectrum substantially as depicted in  FIG. 20  wherein the chemical shift may vary from 4.00 ppm up to 14 ppm;   co-crystal containing 3-iodopropynyl butylcarbamate and 1,4-diazabicyclo[2.2.2]octane (DABCO) in a 2:1 molar ratio, having an orthorhombic unit cell, Pccn, a: 9.8955(7); b: 31.623(2); c: 8.9335(6) and V=2795.55 A 3 ;   co-crystal containing 3-iodopropynyl butylcarbamate and tetrabutylammonium chloride in a 2:1 molar ratio, having an IR spectrum substantially as depicted in  FIG. 22 ;   co-crystal containing 3-iodopropynyl butylcarbamate and zinc chloride in a 4:1 molar ratio, having a DSC plot substantially as depicted in  FIG. 23 , showing two peaks at 118° C. and 139° C.       
 
         [0054]    “Characteristic peaks in the XRPD spectrum” means peaks with a relative intensity exceeding 40% compared with the peak of greatest intensity, taken as 100. 
         [0055]    The crystallisation methods used to prepare the co-crystals according to the invention comprise slow and fast evaporation of solutions containing IPBC and the co-crystallisation agent in the desired stoichiometric ratios, wherein the formation of the co-crystal takes place in solution by slow and fast evaporation of the solvent; fast precipitation from quasi-saturated solvent solutions containing IPBC and the co-crystallisation agent; grinding (dry or in the presence of drops of solvent) of a mixture of IPBC and the co-crystallisation agent; melting of the mixture of IPBC and the co-crystallisation agent; mechano-chemical solid-phase synthesis in a ball mill; or a combination of said methods. The choice of one or more of said methods is made on the basis of the physical state (solid or liquid) of the IPBC and/or the co-crystallisation agent at the temperature at which the formation of the co-crystal is conducted. 
         [0056]    In one embodiment of the invention, the co-crystals are synthesised in solution. 
         [0057]    If both IPBC and the co-crystallisation agent are in the solid state, each substance, in the exact molar ratios, is dissolved separately in a suitable solvent, such as methanol, ethanol, chloroform, dichloromethane, acetonitrile or ethyl acetate. The two solutions are then mixed together, and the resulting mixture is left to evaporate. The evaporation is performed slowly if a single crystal is to be obtained or rapidly, for example with the aid of a vacuum evaporation system, if the co-crystal is to be obtained in powder form. 
         [0058]    However, if the co-crystallisation agent is a liquid, a quasi-saturated solution of IPBC is prepared in a suitable solvent, such as methanol, ethanol, chloroform, dichloromethane, acetonitrile or ethyl acetate. The liquid co-crystallisation agent is then added to said solution in an exact molar ratio. The resulting mixture is left to evaporate. The evaporation is performed slowly if a single crystal is to be obtained or rapidly, for example with the aid of a vacuum evaporation system, if the co-crystal is to be obtained in powder form. 
         [0059]    In another embodiment of the invention, the co-crystals are synthesised in the solid state. IPBC and the co-crystallisation agent, weighed in the exact molar ratio desired for the co-crystal, are mixed together and placed in a metal container of various dimensions. One or more metal balls of various dimensions are introduced into the container. The container is placed in a ball mill and vibrated with a frequency of 10-30 Hz for a time ranging between 5 and 30 minutes, depending on the dimensions of the container. The product recovered from the container is the co-crystal, which requires no further purification. 
         [0060]    The co-crystals according to the invention containing IPBC are suitable to protect industrial materials such as adhesives, glues, paper, cardboard, leather, wood and wood-based materials, coating materials, paints, plastic materials, industrial coolants, industrial lubricants, metalworking fluids, body care products such as wet wipes, toilet paper, cosmetics, and other materials which can be infested or decomposed by micro-organisms. Examples of micro-organisms which can cause the degradation or deterioration of industrial materials, against which the co-crystals according to the invention can be advantageously used, are bacteria, fungi (in particular fungi and moulds that attack wood), yeasts,  algae  and mucous organisms such as slime. Specific examples are micro-organisms of the genus  Alternaria , such as  Alternaria tenuis, Aspergillus , such as  Aspergillus niger, Chaetomium , such as  Chaetomium globosum, Coniophora , such as  Coniophora puetana, Lentinus,  such as  Lentinus tigrinus, Penicillium , such as  Penicillium glaucum, Polyporus , such as  Polyporus versicolor, Aureobasidium , such as  Aureobasidium pullulans, Sclerophoma , such as  Sclerophoma pityophila, Trichoderma , such as  Trichoderma viride, Escherichia , such as  Escherichia coli, Pseudomonas , such as  Pseudomonas aeruginosa , and  Staphylococcus , such as  Staphylococcus aureus.    
         [0061]    Depending on their chemico-physical properties, the co-crystals according to the invention can be incorporated in formulations such as solutions, emulsions, suspensions, powders, foams, pastes, granules, tablets and inhalers, or microencapsulated in polymers. The formulations according to the invention can be prepared by conventional methods. For example, the formulations can be prepared by mixing the co-crystals with diluents, such as liquid solvents or gases liquefied under pressure, and/or with solid diluents, if necessary also using surfactants, such as emulsifying agents and/or dispersing agents and/or foaming agents. If the diluent used is water, organic solvents can also be used as co-solvents. The solvents usable are aromatic solvents such as toluene and xylene; chlorinated aliphatic or aromatic hydrocarbons such as dichloromethane and chlorobenzene; aliphatic hydrocarbons such as cyclohexane; alcohols such as butanol, ethylene glycol and their ethers and esters; ketones such as acetone and ethyl methyl ketone, or cyclohexanone; highly polar solvents such as water, dimethyl sulphoxide and dimethylformamide. Examples of gases liquefied under pressure are liquids which are gaseous at room pressure and temperature, such as halogenated hydrocarbons, butane, propane, nitrogen and carbon dioxide. 
         [0062]    Suitable solid diluents are pulverised natural or synthetic minerals such as kaolins, clays, talc, gypsum, quartz, fossil flours, and silica, alumina and silicate powders. 
         [0063]    Suitable emulsifying and/or foaming agents are, for example, non-ionic or anionic emulsifying agents such as polyoxyethylene esters with fatty acids, ethers between polyoxyethylene and fatty alcohols, alkyl- or aryl-sulphonates, and alkylsulphates. An example of a suitable dispersing agent is methylcellulose. 
         [0064]    The formulations generally contain between 0.1% and 95% by weight of the co-crystals, preferably between 2% and 75% by weight. 
         [0065]    A further object of the present invention is therefore compositions with a biocidal activity containing a co-crystal of IPBC according to the invention and at least one solvent or diluent. The compositions according to the invention can also contain additives which assist the process of obtaining the composition and, if necessary, other biocidal agents such as agents with an antimicrobial, fungicidal, bactericidal, herbicidal, insecticidal or algaecidal activity. In this case, the co-crystals according to the invention and the other biocidal agents can be present in solution, suspension or emulsion. The solvents or diluents can be water or conventional organic solvents. Compositions containing a co-crystal according to the invention and another biocidal agent as active ingredients can present a broader action spectrum than the individual active ingredients and/or a synergic effect. Examples of other biocidal agents which can be present in the compositions according to the invention include azaconazole, bromuconazole, cyproconazole, dichlorobutrazole, diniconazole, diuron, hexaconazole, metconazole, penconazole, propiconazole, tebuconazole, dichlofluanid, tolylfluanid, fluorfolpet, methfuroxam, carboxin, cyclohexyl-benzo[b]thiophene carboxamide S,S-dioxide, fenpiclonil, 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile, butenafine, imazalil, N-methyl-isothiazolin-3-one, 5-chloro-N-methyl-isothiazolin-3-one, N-octyl-isothiazolin-3-one, dichloro-N-octyl-isothiazolinone, mercaptobenzothiazole, thiocyano-methylthiobenzothiazole, tiabendazole, benzisothiazolinone, N-(2-hydroxypropyl)aminomethanol, benzyl hemiformal, N-methylol-chloroacetamide, N-(2-hydroxypropyl)aminomethanol, glutaraldehyde, omadine, Zn-omadine, dimethyl dicarbonate, 2-bromo-2-nitro-1,3-propanediol, bethoxazin, o-phthaldialdehyde, 2,2-dibromo-3-cyano-propionamide, 1,2-dibromo-2,4-dicyano-butane, 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (DMDMH), tetramethylolacetylenediurea (TMAD), ethylene glycol hemiformal, p-hydroxybenzoic acid and p-hydroxybenzoic acid esters (parabens), such as ethyl p-hydroxybenzoate (E214), ethyl-p-hydroxybenzoate sodium salt (E215), propyl p-hydroxybenzoate (E216), propyl p-hydroxybenzoate sodium salt (E217), methyl-p-hydroxybenzoate (E218) and methyl-p-hydroxybenzoate sodium salt (E219), carbendazim, chlorophene, 3-methyl-4-chlorophenol and o-phenylphenol. 
         [0066]    The weight ratio between the co-crystals of the invention and the other biocidal agents can vary within a wide range. Said ratio preferably ranges between 50:1 and 1:50. 
         [0067]    The compositions with antimicrobial activity of the invention contain the co-crystals of the invention or a mixture of the co-crystals of the invention and another biocidal agent in a concentration of between 0.1% and 95% by weight, preferably between 0.1% and 60% by weight. 
         [0068]    The concentrations at which the co-crystals of the invention or their combination with another biocidal agent are used depend on the nature and incidence of the micro-organisms to be controlled, and the composition of the material to be protected. The ideal quantity for use can be determined by a series of tests. In general, for most applications the concentration is between 0.001% and 5% by weight, preferably between 0.05% and 2% by weight, depending on the material to be protected. 
         [0069]    Compositions containing the co-crystals of the invention have better physical and chemical properties (such as greater solubility in water and greater heat stability) and workability properties (such as better powder flowability and better compressibility for tablet formation) than compositions containing IPBC. 
         [0070]    A further object of the invention is therefore the use of a co-crystal or composition of the invention as biocide in industrial products, in particular as a preservative, antibacterial, fungicide or algaecide, especially in paints, coatings, metalworking fluids, protection and preservation of wood, and in body care products or cosmetic formulations. 
     
    
     
       DESCRIPTION OF FIGURES 
         [0071]      FIG. 1 : Graphical representation of the co-crystal of example 1. 
           [0072]      FIG. 2 : IR spectrum of the co-crystal of example 1. 
           [0073]      FIG. 3 : XRPD tracing of the co-crystal of example 1. 
           [0074]      FIG. 4 : DSC tracing of the co-crystal of example 1. 
           [0075]      FIG. 5 : Graphical representation of the co-crystal of example 2. 
           [0076]      FIG. 6 : IR spectrum of the co-crystal of example 2. 
           [0077]      FIG. 7 : XRPD tracing of the co-crystal of example 2. 
           [0078]      FIG. 8 : DSC tracing of the co-crystal of example 2. 
           [0079]      FIG. 9 : Graphical representation of the co-crystal of example 3. 
           [0080]      FIG. 10 : API IR spectrum of the co-crystal of example 3. 
           [0081]      FIG. 11 : XRPD tracing of the co-crystal of example 3. 
           [0082]      FIG. 12 : DSC tracing of the co-crystal of example 3. 
           [0083]      FIG. 13 : API IR spectrum of the co-crystal of example 4. 
           [0084]      FIG. 14 : XRPD tracing of the co-crystal of example 4. 
           [0085]      FIG. 15 : DSC tracing of the co-crystal of example 4. 
           [0086]      FIG. 16 : Graphical representation of the co-crystal of example 5. 
           [0087]      FIG. 17 : API IR spectrum of the co-crystal of example 5. 
           [0088]      FIG. 18 : XRPD tracing of the co-crystal of example 5. 
           [0089]      FIG. 19 : DSC tracing of the co-crystal of example 5. 
           [0090]      FIG. 20 :  13 C-NMR of the co-crystal of example 6. 
           [0091]      FIG. 21 : Ball and stick representation from single crystal analysis of the co-crystal of example 7. DABCO hydrogen atoms are omitted for clarity. 
           [0092]      FIG. 22 : IR spectrum of the co-crystal of example 8. 
           [0093]      FIG. 23 : DSC plot of the co-crystal of example 9. 
           [0094]      FIG. 24 : Pictures of cones of pure IPBC (A, C) and co-crystal (IPBC) 4 :CaCl 2  (B, D) powders, taken after flowing the powders through the funnel. 
       
    
    
       [0095]    The invention will now be illustrated by the following examples. 
       EXAMPLES 
     Materials and Methods 
       [0096]    The IR spectra were obtained with a Nicolet Nexus FTIR spectrophotometer equipped with the U-ATR device. The values are reported as wave numbers, and are rounded to 1 cm −1  after automatic assignment. The melting points were obtained by differential scanning calorimetry (DSC, Mettler Toledo 823e). 
         [0097]    Single-Crystal X-Ray Diffraction The data were collected at different temperatures with a Bruker KAPPA APEX II diffractometer with Mo-Kα radiation (λ=0.71073) and a CCD detector. The Bruker KRYOFLEX device was used for the low-temperature acquisitions. The structures were resolved and refined with the SIR2004 and SHELXL-97 programs respectively. The refinement was performed by the full-matrix least squares method on F 2 . The hydrogen atoms were placed using standard geometric models and with their thermal parameters based on those of their geminal atoms. 
         [0098]    X-Ray Powder Diffraction 
         [0099]    The X-ray powder diffraction experiments were conducted with a Bruker D8 Advance diffractometer operating in reflection mode with Ge-monochromatic Cu Kα1 radiation (λ=1.5406 Å) and with a position-sensitive linear detector. The powder diffraction data was collected at room temperature with a 20 interval of 5-40°, using increments of 0.016° and an exposure time of 1.5 s per increment. 
       Example 1 
     Co-Crystal Containing 3-Iodopropynyl Butylcarbamate and 4-[2-(4-Pyridinyl)Ethyl]pyridine in a 2:1 Molar Ratio (Co-Crystal 1) 
       [0100]    
       
                 
         
             
             
         
       
     
         [0101]    This example demonstrates the ability of IPBC to co-crystallise with a neutral aromatic amine able to act as halogen bond acceptor, such as 4-[2-(4-pyridinyl)ethyl]pyridine. 
         [0102]    Rapid precipitation of the two compounds in a quasi-saturated acetonitrile solution leads to the formation of a solid white powder with a melting point of between 81° C. and 83° C. 
         [0103]    Single-crystal X-ray diffraction demonstrates that in the co-crystal, IPBC and 4-[2-(4-pyridinyl)ethyl]pyridine are present in a molar ratio of 2:1, as shown in  FIG. 1 . The basic structural pattern in the co-crystal is a trimer unit wherein 4-[2-(4-pyridinyl)ethyl]pyridine acts as bridge between two IPBC molecules via two halogen bonds I - - -  N. 
         [0104]    The dimensions and angles of the crystallographic unit cell are [a=30.666(3) b=4.9869(4) c=21.068(2)] and [α=90.00 β=92.115(6) γ=90.00] respectively. 
         [0105]    The IR spectrum of the co-crystal and its characteristic bands are reported in  FIG. 2 . 
         [0106]      FIG. 3  shows the X-ray powder diffraction (XRPD) of the co-crystal, the main peaks of which, in the 5-40° 2θ value range, are shown in Table 1. 
         [0107]    The DSC thermogram of co-crystal 1 is reported in  FIG. 4 . 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                 Angle(2θ)* 
                 d (Å) 
                 Intensity 
                 % 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 2th = 5.117° 
                 17.25577 
                 2521 
                 51.2 
               
               
                   
                 2th = 5.684° 
                 15.53601 
                 4923 
                 100.0 
               
               
                   
                 2th = 8.644° 
                 10.22081 
                 1240 
                 25.2 
               
               
                   
                 2th = 8.924° 
                 9.90129 
                 1792 
                 36.4 
               
               
                   
                 2th = 9.274° 
                 9.52842 
                 907 
                 18.4 
               
               
                   
                 2th = 11.445° 
                 7.72521 
                 3010 
                 61.1 
               
               
                   
                 2th = 12.225° 
                 7.23443 
                 490 
                 10.0 
               
               
                   
                 2th = 14.471° 
                 6.11592 
                 932 
                 18.9 
               
               
                   
                 2th = 15.726° 
                 5.63077 
                 310 
                 6.3 
               
               
                   
                 2th = 16.087° 
                 5.50517 
                 408 
                 8.3 
               
               
                   
                 2th = 16.402° 
                 5.40011 
                 592 
                 12.0 
               
               
                   
                 2th = 16.951° 
                 5.22630 
                 2000 
                 40.6 
               
               
                   
                 2th = 17.228° 
                 5.14312 
                 872 
                 17.7 
               
               
                   
                 2th = 17.997° 
                 4.92493 
                 576 
                 11.7 
               
               
                   
                 2th = 18.382° 
                 4.82269 
                 644 
                 13.1 
               
               
                   
                 2th = 19.133° 
                 4.63491 
                 368 
                 7.5 
               
               
                   
                 2th = 19.692° 
                 4.50459 
                 476 
                 9.7 
               
               
                   
                 2th = 20.105° 
                 4.41308 
                 507 
                 10.3 
               
               
                   
                 2th = 21.176° 
                 4.19213 
                 350 
                 7.1 
               
               
                   
                 2th = 21.524° 
                 4.12518 
                 1449 
                 29.4 
               
               
                   
                 2th = 21.800° 
                 4.07364 
                 894 
                 18.2 
               
               
                   
                 2th = 22.221° 
                 3.99734 
                 4665 
                 94.8 
               
               
                   
                 2th = 22.663° 
                 3.92047 
                 2184 
                 44.4 
               
               
                   
                 2th = 23.181° 
                 3.83400 
                 1450 
                 29.5 
               
               
                   
                 2th = 24.580° 
                 3.61886 
                 373 
                 7.6 
               
               
                   
                 2th = 24.967° 
                 3.56356 
                 2850 
                 57.9 
               
               
                   
                 2th = 25.348° 
                 3.51083 
                 400 
                 8.1 
               
               
                   
                 2th = 25.876° 
                 3.44043 
                 339 
                 6.9 
               
               
                   
                 2th = 26.404° 
                 3.37283 
                 302 
                 6.1 
               
               
                   
                 2th = 27.191° 
                 3.27701 
                 783 
                 15.9 
               
               
                   
                 2th = 27.882° 
                 3.19725 
                 4091 
                 83.1 
               
               
                   
                 2th = 28.258° 
                 3.15564 
                 451 
                 9.2 
               
               
                   
                 2th = 28.838° 
                 3.09341 
                 1892 
                 38.4 
               
               
                   
                 2th = 29.185° 
                 3.05747 
                 373 
                 7.6 
               
               
                   
                 2th = 30.311° 
                 2.94642 
                 344 
                 7.0 
               
               
                   
                 2th = 30.988° 
                 2.88354 
                 260 
                 5.3 
               
               
                   
                 2th = 32.914° 
                 2.71904 
                 255 
                 5.2 
               
               
                   
                 2th = 33.516° 
                 2.67160 
                 361 
                 7.3 
               
               
                   
                 2th = 34.345° 
                 2.60901 
                 250 
                 5.1 
               
               
                   
                 2th = 34.793° 
                 2.57641 
                 883 
                 17.9 
               
               
                   
                 2th = 35.051° 
                 2.55803 
                 443 
                 9.0 
               
               
                   
                 2th = 35.850° 
                 2.50285 
                 270 
                 5.5 
               
               
                   
                 2th = 36.589° 
                 2.45396 
                 519 
                 10.5 
               
               
                   
                 2th = 37.072° 
                 2.42311 
                 464 
                 9.4 
               
               
                   
                 2th = 37.905° 
                 2.37175 
                 254 
                 5.2 
               
               
                   
                 2th = 38.291° 
                 2.34872 
                 309 
                 6.3 
               
               
                   
                 2th = 39.015° 
                 2.30676 
                 228 
                 4.6 
               
               
                   
                 2th = 39.738° 
                 2.26645 
                 438 
                 8.9 
               
               
                   
                   
               
               
                   
                 *Values ± 0.05° 
               
             
          
         
       
     
         [0108]    The co-crystal thus obtained has a higher melting point, higher thermal stability, better workability and higher degree of crystallinity than IPBC. It is easily manageable in the operations required to form tablets, such as compression. 
       Example 2 
     Co-Crystal Containing 3-Iodopropynyl Butylcarbamate and 4,4′-Bipyridine in a 2:1 Molar Ratio (Co-Crystal 2) 
       [0109]    
       
                 
         
             
             
         
       
     
         [0110]    This example demonstrates the ability of IPBC to co-crystallise with another neutral aromatic amine able to act as halogen bond acceptor, such as 4,4′-dipyridine. 
         [0111]    In this case the formation of the co-crystal was effected by slow precipitation from an ethanol solution, which leads to the formation of a white powder. 
         [0112]    The basic structural motif in the co-crystal is a trimeric unit, bonded via halogen bonds, consisting of one molecule of 4,4′-bipyridine and two molecules of IPBC, as shown in  FIG. 5 . 
         [0113]    The co-crystal is a solid crystalline product with a melting point of between 112° C. and 114° C. The dimensions and angles of the crystallographic unit cell are [a=28.683(2) b=4.9270(4) c=21.429(2)] and [α=90.00 β=99.92(2) γ=90.00] respectively. 
         [0114]    The IR spectrum of the co-crystal and its characteristic bands are reported in  FIG. 6 . 
         [0115]      FIG. 7  shows the X-ray powder diffraction (XRPD) of the co-crystal, the main peaks of which, in the 5-40° 2θ value range, are shown in Table 2. 
         [0116]    The DSC thermogram of co-crystal 2 is reported in  FIG. 8 . 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 2 
               
               
                   
                   
               
               
                   
                 Angle(2θ)* 
                 d (Å) 
                 Intensity 
                 % 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 2th = 6.234° 
                 14.16728 
                 8558 
                 100.0 
               
               
                   
                 2th = 8.358° 
                 10.57069 
                 353 
                 4.1 
               
               
                   
                 2th = 9.560° 
                 9.24440 
                 679 
                 7.9 
               
               
                   
                 2th = 12.160° 
                 7.27286 
                 269 
                 3.1 
               
               
                   
                 2th = 12.521° 
                 7.06371 
                 1737 
                 20.3 
               
               
                   
                 2th = 13.187° 
                 6.70850 
                 197 
                 2.3 
               
               
                   
                 2th = 13.841° 
                 6.39289 
                 399 
                 4.7 
               
               
                   
                 2th = 16.255° 
                 5.44854 
                 2148 
                 25.1 
               
               
                   
                 2th = 16.825° 
                 5.26536 
                 663 
                 7.7 
               
               
                   
                 2th = 18.651° 
                 4.75371 
                 507 
                 5.9 
               
               
                   
                 2th = 18.861° 
                 4.70134 
                 1402 
                 16.4 
               
               
                   
                 2th = 19.248° 
                 4.60750 
                 1051 
                 12.3 
               
               
                   
                 2th = 19.892° 
                 4.45974 
                 187 
                 2.2 
               
               
                   
                 2th = 20.400° 
                 4.34990 
                 797 
                 9.3 
               
               
                   
                 2th = 21.931° 
                 4.04952 
                 5931 
                 69.3 
               
               
                   
                 2th = 22.695° 
                 3.91488 
                 453 
                 5.3 
               
               
                   
                 2th = 23.110° 
                 3.84554 
                 991 
                 11.6 
               
               
                   
                 2th = 23.835° 
                 3.73028 
                 1084 
                 12.7 
               
               
                   
                 2th = 24.461° 
                 3.63616 
                 319 
                 3.7 
               
               
                   
                 2th = 24.826° 
                 3.58348 
                 679 
                 7.9 
               
               
                   
                 2th = 25.194° 
                 3.53200 
                 3287 
                 38.4 
               
               
                   
                 2th = 26.333° 
                 3.38179 
                 452 
                 5.3 
               
               
                   
                 2th = 27.465° 
                 3.24488 
                 325 
                 3.8 
               
               
                   
                 2th = 27.980° 
                 3.18637 
                 877 
                 10.2 
               
               
                   
                 2th = 28.475° 
                 3.13207 
                 786 
                 9.2 
               
               
                   
                 2th = 28.928° 
                 3.08399 
                 349 
                 4.1 
               
               
                   
                 2th = 29.463° 
                 3.02919 
                 427 
                 5.0 
               
               
                   
                 2th = 29.735° 
                 3.00209 
                 298 
                 3.5 
               
               
                   
                 2th = 30.264° 
                 2.95086 
                 255 
                 3.0 
               
               
                   
                 2th = 30.571° 
                 2.92189 
                 319 
                 3.7 
               
               
                   
                 2th = 31.311° 
                 2.85455 
                 198 
                 2.3 
               
               
                   
                 2th = 32.653° 
                 2.74021 
                 176 
                 2.1 
               
               
                   
                 2th = 33.314° 
                 2.68732 
                 203 
                 2.4 
               
               
                   
                 2th = 33.439° 
                 2.67760 
                 232 
                 2.7 
               
               
                   
                 2th = 33.914° 
                 2.64116 
                 241 
                 2.8 
               
               
                   
                 2th = 34.205° 
                 2.61934 
                 475 
                 5.6 
               
               
                   
                 2th = 34.762° 
                 2.57862 
                 234 
                 2.7 
               
               
                   
                 2th = 36.146° 
                 2.48303 
                 206 
                 2.4 
               
               
                   
                 2th = 37.672° 
                 2.38589 
                 384 
                 4.5 
               
               
                   
                 2th = 38.213° 
                 2.35331 
                 596 
                 7.0 
               
               
                   
                 2th = 38.614° 
                 2.32980 
                 258 
                 3.0 
               
               
                   
                   
               
               
                   
                 *Values ± 0.05° 
               
             
          
         
       
     
         [0117]    The co-crystal thus obtained has a higher melting point, higher thermal stability, better workability and higher degree of crystallinity than IPBC. It is easily manageable in the operations required to form tablets, such as compression. 
       Example 3 
     Co-Crystal Containing 3-Iodopropynyl Butylcarbamate and Tetrabutyl Ammonium Iodide in a 3:1 Molar Ratio (Co-Crystal 3) 
       [0118]    
       
                 
         
             
             
         
       
     
         [0119]    This example demonstrates the ability of IPBC to co-crystallise with a halide deriving from an organic salt such as tetrabutylammonium iodide. 
         [0120]    The co-crystal was formed by mechano-chemical synthesis in a ball mill, using a stoichiometric ratio of 1:3 between tetrabutyl ammonium iodide and IPBC. 
         [0121]    The co-crystal obtained contains one molecule of tetrabutyl ammonium iodide and three molecules of IPBC, as shown in the graphical representation in  FIG. 9 . 
         [0122]    The co-crystal is a solid crystalline product with a melting point between 42° C. and 47.5° C. The dimensions and angles of the crystallographic unit cell are a=10.7688(9) b=20.204(2) c=23.735(2)] and [α=90.00 β=94.778(2) γ=90.00] respectively. 
         [0123]    The IR spectrum of the co-crystal and its characteristic bands are reported in  FIG. 10 . 
         [0124]      FIG. 11  shows the X-ray powder diffraction (XRPD) of the co-crystal, the main peaks of which, in the 5-40° 2θ value range, are shown in Table 3. 
         [0125]    The DSC thermogram of co-crystal 3 is reported in  FIG. 12 . 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 3 
               
               
                   
                   
               
               
                   
                 Angle(2θ)* 
                 d (Å) 
                 Intensity 
                 % 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 2th = 9.285° 
                 9.51690 
                 513 
                 53.5 
               
               
                   
                 2th = 14.485° 
                 6.11006 
                 445 
                 46.5 
               
               
                   
                 2th = 16.322° 
                 5.42635 
                 469 
                 49.0 
               
               
                   
                 2th = 17.432° 
                 5.08330 
                 346 
                 36.1 
               
               
                   
                 2th = 17.729° 
                 4.99868 
                 537 
                 56.1 
               
               
                   
                 2th = 18.440° 
                 4.80755 
                 373 
                 38.9 
               
               
                   
                 2th = 20.246° 
                 4.38272 
                 517 
                 54.0 
               
               
                   
                 2th = 20.698° 
                 4.28791 
                 438 
                 45.7 
               
               
                   
                 2th = 21.072° 
                 4.21276 
                 423 
                 44.2 
               
               
                   
                 2th = 21.331° 
                 4.16217 
                 629 
                 65.7 
               
               
                   
                 2th = 22.261° 
                 3.99035 
                 958 
                 100.0 
               
               
                   
                 2th = 22.903° 
                 3.87977 
                 590 
                 61.6 
               
               
                   
                 2th = 23.605° 
                 3.76596 
                 613 
                 64.0 
               
               
                   
                 2th = 23.968° 
                 3.70974 
                 484 
                 50.5 
               
               
                   
                 2th = 24.305° 
                 3.65910 
                 616 
                 64.3 
               
               
                   
                 2th = 25.009° 
                 3.55775 
                 580 
                 60.5 
               
               
                   
                 2th = 25.670° 
                 3.46761 
                 363 
                 37.9 
               
               
                   
                 2th = 26.129° 
                 3.40770 
                 406 
                 42.4 
               
               
                   
                 2th = 26.507° 
                 3.35996 
                 423 
                 44.2 
               
               
                   
                 2th = 26.730° 
                 3.33240 
                 343 
                 35.8 
               
               
                   
                 2th = 27.359° 
                 3.25726 
                 326 
                 34.0 
               
               
                   
                 2th = 27.893° 
                 3.19608 
                 432 
                 45.1 
               
               
                   
                 2th = 28.399° 
                 3.14030 
                 389 
                 40.6 
               
               
                   
                 2th = 28.918° 
                 3.08502 
                 372 
                 38.8 
               
               
                   
                 2th = 30.514° 
                 2.92722 
                 311 
                 32.5 
               
               
                   
                 2th = 31.221° 
                 2.86256 
                 302 
                 31.5 
               
               
                   
                 2th = 31.654° 
                 2.82441 
                 322 
                 33.6 
               
               
                   
                 2th = 32.085° 
                 2.78741 
                 349 
                 36.4 
               
               
                   
                 2th = 32.592° 
                 2.74517 
                 308 
                 32.2 
               
               
                   
                 2th = 33.490° 
                 2.67360 
                 323 
                 33.7 
               
               
                   
                 2th = 34.033° 
                 2.63217 
                 246 
                 25.7 
               
               
                   
                 2th = 34.608° 
                 2.58975 
                 249 
                 26.0 
               
               
                   
                 2th = 34.973° 
                 2.56357 
                 314 
                 32.8 
               
               
                   
                 2th = 35.533° 
                 2.52440 
                 269 
                 28.1 
               
               
                   
                 2th = 36.332° 
                 2.47069 
                 261 
                 27.2 
               
               
                   
                 2th = 36.772° 
                 2.44214 
                 278 
                 29.0 
               
               
                   
                 2th = 37.328° 
                 2.40703 
                 225 
                 23.5 
               
               
                   
                 2th = 38.414° 
                 2.34144 
                 277 
                 28.9 
               
               
                   
                   
               
               
                   
                 *Values ± 0.1° 
               
             
          
         
       
     
         [0126]    The co-crystal thus obtained has a lower melting point, higher solubility and better workability in an aqueous medium than IPBC. In particular, its aqueous solubility is approx. 40% greater than that of IPBC. 
       Example 4 
     Co-Crystal Containing 3-Iodopropynyl Butylcarbamate and Calcium Chloride in a 4:1 Molar Ratio (Co-Crystal 4) 
       [0127]    
       
                 
         
             
             
         
       
     
         [0128]    This example demonstrates the ability of IPBC to co-crystallise with a halide deriving from an inorganic salt such as calcium chloride. 
         [0129]    The co-crystal was formed by mechano-chemical synthesis in a ball mill, using a stoichiometric ratio of 1:4 between calcium chloride and IPBC. 
         [0130]    The composition of the co-crystal was detected by analysing the DSC trace, where the presence of peaks of the starting products was not observed. 
         [0131]    The co-crystal is a solid crystalline product with a melting point of 83-86° C. 
         [0132]    The IR spectrum of the co-crystal and its characteristic bands are reported in  FIG. 13 . 
         [0133]      FIG. 14  shows the X-ray powder diffraction (XRPD) of the co-crystal, the main peaks of which, in the 5-40° 2θ value range, are shown in Table 4. 
         [0134]    The DSC thermogram of co-crystal 4 is reported in  FIG. 15 . 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 4 
               
               
                   
                   
               
               
                   
                 Angle(2θ) 
                 d (Å) 
                 Intensity 
                 % 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 2th = 6.581° 
                 13.41984 
                 5844 
                 16.2 
               
               
                   
                 2th = 7.314° 
                 12.07749 
                 10715 
                 29.7 
               
               
                   
                 2th = 8.160° 
                 10.82602 
                 4892 
                 13.6 
               
               
                   
                 2th = 9.674° 
                 9.13549 
                 16217 
                 45.0 
               
               
                   
                 2th = 11.059° 
                 7.99382 
                 7263 
                 20.1 
               
               
                   
                 2th = 11.991° 
                 7.37478 
                 4418 
                 12.3 
               
               
                   
                 2th = 13.299° 
                 6.65245 
                 6966 
                 19.3 
               
               
                   
                 2th = 15.631° 
                 5.66483 
                 4674 
                 13.0 
               
               
                   
                 2th = 15.982° 
                 5.54118 
                 6113 
                 17.0 
               
               
                   
                 2th = 17.374° 
                 5.10003 
                 8718 
                 24.2 
               
               
                   
                 2th = 18.517° 
                 4.78765 
                 9325 
                 25.9 
               
               
                   
                 2th = 19.365° 
                 4.57995 
                 11180 
                 31.0 
               
               
                   
                 2th = 20.091° 
                 4.41616 
                 3184 
                 8.8 
               
               
                   
                 2th = 21.313° 
                 4.16552 
                 4102 
                 11.4 
               
               
                   
                 2th = 22.282° 
                 3.98664 
                 36057 
                 100.0 
               
               
                   
                 2th = 23.054° 
                 3.85484 
                 3660 
                 10.2 
               
               
                   
                 2th = 23.469° 
                 3.78751 
                 3136 
                 8.7 
               
               
                   
                 2th = 24.435° 
                 3.63994 
                 6628 
                 18.4 
               
               
                   
                 2th = 24.990° 
                 3.56041 
                 12456 
                 34.5 
               
               
                   
                 2th = 26.159° 
                 3.40384 
                 5054 
                 14.0 
               
               
                   
                 2th = 26.775° 
                 3.32689 
                 4703 
                 13.0 
               
               
                   
                 2th = 27.659° 
                 3.22252 
                 11372 
                 31.5 
               
               
                   
                 2th = 28.514° 
                 3.12789 
                 5945 
                 16.5 
               
               
                   
                 2th = 29.588° 
                 3.01671 
                 6588 
                 18.3 
               
               
                   
                 2th = 30.368° 
                 2.94095 
                 2644 
                 7.3 
               
               
                   
                 2th = 31.158° 
                 2.86817 
                 4800 
                 13.3 
               
               
                   
                 2th = 31.838° 
                 2.80850 
                 8422 
                 23.4 
               
               
                   
                 2th = 32.766° 
                 2.73101 
                 2388 
                 6.6 
               
               
                   
                 2th = 33.979° 
                 2.63621 
                 4478 
                 12.4 
               
               
                   
                 2th = 34.729° 
                 2.58102 
                 3049 
                 8.5 
               
               
                   
                 2th = 35.337° 
                 2.53800 
                 2887 
                 8.0 
               
               
                   
                 2th = 36.000° 
                 2.49271 
                 2816 
                 7.8 
               
               
                   
                 2th = 36.603° 
                 2.45308 
                 2980 
                 8.3 
               
               
                   
                 2th = 37.030° 
                 2.42574 
                 3009 
                 8.3 
               
               
                   
                 2th = 37.436° 
                 2.40037 
                 3085 
                 8.6 
               
               
                   
                 2th = 38.110° 
                 2.35946 
                 4670 
                 13.0 
               
               
                   
                 2th = 38.968° 
                 2.30947 
                 3168 
                 8.8 
               
               
                   
                 2th = 39.475° 
                 2.28092 
                 2995 
                 8.3 
               
               
                   
                   
               
               
                   
                 * Values ± 0.05° 
               
             
          
         
       
     
         [0135]    The co-crystal thus obtained has a higher melting point, higher solubility and better workability in an aqueous medium than IPBC. In particular, its aqueous solubility is approx. 50% greater than that of IPBC. 
       Example 5 
     Co-Crystal Containing 3-Iodopropynyl Butylcarbamate and N,N′-Bis(4-Pyridylcarbonyl)-1,6-Hexanediamine in a 2:1 Molar Ratio (Co-Crystal 5) 
       [0136]    
       
                 
         
             
             
         
       
     
         [0137]    In this example, IPBC was co-crystallised with N,N′-bis(4-pyridylcarbonyl)-1,6-hexanediamine by slow evaporation from alcohol solutions and by mechano-chemical synthesis in a ball mill, using a ratio of 1:2 between the co-crystallisation agent and IPBC. 
         [0138]    In the co-crystal obtained there is a ratio of 1:2 between the co-crystallisation agent and IPBC, as shown in the graphical representation in  FIG. 16 . 
         [0139]    The co-crystal is a solid crystalline product with a melting point of 132° C. The dimensions and angles of the crystallographic unit cell are [a=29.4501(18) b=5.1100(3) c=27.9417(17)] and [α=90.00 β=118.566(3) γ=90.00] respectively. 
         [0140]    The IR spectrum of the co-crystal and its characteristic bands are reported in  FIG. 17 . 
         [0141]      FIG. 18  shows the X-ray powder diffraction (XRPD) of the co-crystal, the main peaks of which, in the 5-40° 2θ value range, are shown in Table 5. 
         [0142]    The DSC thermogram of co-crystal 5 is reported in  FIG. 19 . 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 5 
               
               
                   
                   
               
               
                   
                 Angle(2θ) 
                 d (Å) 
                 Intensity 
                 % 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 2th = 5.887° 
                 14.99966 
                 1231 
                 18.2 
               
               
                   
                 2th = 6.951° 
                 12.70619 
                 545 
                 8.1 
               
               
                   
                 2th = 10.380° 
                 8.51551 
                 690 
                 10.2 
               
               
                   
                 2th = 11.831° 
                 7.47444 
                 3530 
                 52.3 
               
               
                   
                 2th = 13.013° 
                 6.79759 
                 324 
                 4.8 
               
               
                   
                 2th = 13.477° 
                 6.56468 
                 591 
                 8.8 
               
               
                   
                 2th = 13.961° 
                 6.33814 
                 1111 
                 16.5 
               
               
                   
                 2th = 14.270° 
                 6.20161 
                 272 
                 4.0 
               
               
                   
                 2th = 15.441° 
                 5.73399 
                 1653 
                 24.5 
               
               
                   
                 2th = 16.713° 
                 5.30018 
                 510 
                 7.6 
               
               
                   
                 2th = 17.132° 
                 5.17156 
                 244 
                 3.6 
               
               
                   
                 2th = 17.945° 
                 4.93909 
                 411 
                 6.1 
               
               
                   
                 2th = 18.816° 
                 4.71240 
                 331 
                 4.9 
               
               
                   
                 2th = 19.095° 
                 4.64417 
                 378 
                 5.6 
               
               
                   
                 2th = 19.516° 
                 4.54479 
                 300 
                 4.4 
               
               
                   
                 2th = 20.075° 
                 4.41964 
                 366 
                 5.4 
               
               
                   
                 2th = 20.950° 
                 4.23697 
                 1050 
                 15.6 
               
               
                   
                 2th = 21.366° 
                 4.15541 
                 563 
                 8.3 
               
               
                   
                 2th = 21.916° 
                 4.05229 
                 740 
                 11.0 
               
               
                   
                 2th = 22.784° 
                 3.89988 
                 6751 
                 100.0 
               
               
                   
                 2th = 23.513° 
                 3.78060 
                 855 
                 12.7 
               
               
                   
                 2th = 23.856° 
                 3.72703 
                 939 
                 13.9 
               
               
                   
                 2th = 24.326° 
                 3.65609 
                 332 
                 4.9 
               
               
                   
                 2th = 25.096° 
                 3.54550 
                 509 
                 7.5 
               
               
                   
                 2th = 25.760° 
                 3.45568 
                 376 
                 5.6 
               
               
                   
                 2th = 26.944° 
                 3.30641 
                 653 
                 9.7 
               
               
                   
                 2th = 27.924° 
                 3.19254 
                 305 
                 4.5 
               
               
                   
                 2th = 28.684° 
                 3.10973 
                 548 
                 8.1 
               
               
                   
                 2th = 29.094° 
                 3.06678 
                 276 
                 4.1 
               
               
                   
                 2th = 29.709° 
                 3.00471 
                 330 
                 4.9 
               
               
                   
                 2th = 30.531° 
                 2.92568 
                 430 
                 6.4 
               
               
                   
                 2th = 31.214° 
                 2.86315 
                 419 
                 6.2 
               
               
                   
                 2th = 31.568° 
                 2.83188 
                 367 
                 5.4 
               
               
                   
                 2th = 32.461° 
                 2.75600 
                 241 
                 3.6 
               
               
                   
                 2th = 32.802° 
                 2.72810 
                 284 
                 4.2 
               
               
                   
                 2th = 34.124° 
                 2.62537 
                 365 
                 5.4 
               
               
                   
                 2th = 34.688° 
                 2.58393 
                 478 
                 7.1 
               
               
                   
                 2th = 36.154° 
                 2.48246 
                 505 
                 7.5 
               
               
                   
                 2th = 36.966° 
                 2.42976 
                 398 
                 5.9 
               
               
                   
                 2th = 37.750° 
                 2.38110 
                 561 
                 8.3 
               
               
                   
                 2th = 39.102° 
                 2.30185 
                 457 
                 6.8 
               
               
                   
                   
               
               
                   
                 * Values ± 0.05° 
               
             
          
         
       
     
         [0143]    The co-crystal thus obtained has a higher melting point, higher thermal stability, better workability and higher degree of crystallinity than IPBC. It is easily manageable in the operations required to form tablets, such as compression. 
       Example 6 
     Co-Crystal Containing 3-Iodopropynyl Butylcarbamate and Pyridine in a 1:1 Molar Ratio (Co-Crystal 6) 
       [0144]    In this example, IPBC was co-crystallised with pyridine. 
         [0145]    The co-crystal was prepared dissolving in the 1:1 molar ratio IPBC in pyridine. 
         [0146]    The cocrystal is liquid at room temperature, but the formation of a halogen bonded system between IPBC and pyridine can be confirmed looking at the chemical shift variation of  13 C-NMR for the carbon bound to iodine. 
         [0147]    Previous studies have demonstrated that the  13 C signals of the iodinated carbons of iodoethynyl moieties undergo major low-field shifts on changing the solvent from chloroform to dimethylsulphoxide as a consequence of the XB occurring with the oxygen atoms of the solvent. [ref. Rege, P. D.; Malkina, O. L.; Goroff, N. S.  J. Am. Chem. Soc.  2002, 124, 370-371. Gao, K.; Goroff, N. S.  J. Am. Chem. Soc.  2000, 122, 9320-9321.]. The ≡C—I signals of deuterochloroform solutions of pure IPBC is at 3.68 ppm, in the cocrystal with pyridine the ≡C—I chemical shift varies from 4.00 ppm up to 14 ppm depending of the concentration of pyridine used, as shown in  FIG. 20 . 
       Example 7 
       [0148]    
       
                 
         
             
             
         
       
     
       Co-Crystal Containing 3-Iodopropynyl Butylcarbamate and 1,4-Diazabicyclo[2.2.2]Octane (DABCO) in a 2:1 Molar Ratio (Co-Crystal 7) 
       [0149]    In this example, IPBC was co-crystallised with the bicyclic tertiary amine 1,4-diazabicyclo[2.2.2]octane (DABCO), to give a co-crystal IPBC:DABCO with molar ratio 2:1. 
         [0150]    IPBC was co-crystallised with DABCO by slow evaporation from alcohol/haloalkane solutions, using a ratio of 1:2 between the co-crystallisation agent and IPBC. 
         [0151]    Melting point: 35-38° C. 
         [0152]    The structure of the IPBC.DABCO co-crystal from single crystal crystallographic analysis is shown in  FIG. 21 , wherein DABCO hydrogen atoms are omitted for clarity. 
         [0153]    Crystallographic data: orthorhombic, Pccn, a: 9.8955(7); b: 31.623(2); c: 8.9335(6) and V=2795.55 A 3 . 
       Example 8 
     Co-Crystal Containing 3-Iodopropynyl Butylcarbamate and Tetrabutylammonium Chloride (TBACl) in a 2:1 Molar Ratio (Co-Crystal 8) 
       [0154]    In this example, IPBC was co-crystallised with tetrabutylammonium chloride (TBACl) to give a IPBC:TBACl co-crystal with molar ratio 2:1. 
         [0155]    The co-crystal was formed by heating the two components up to 50° C. using a stoichiometric ratio of 1:2 between tetrabutyl ammonium chloride and IPBC. 
         [0156]    The co-crystal is liquid at room temperature. 
         [0157]    Melting point −15° C. 
         [0158]    The formation of a halogen bonded co-crystal between IPBC and TBACl can be confirmed looking at the IR wave number variation for C≡C group. The triple bond stretching band is at 2198 cm −1  in the pure IPBC while it is red-shifted at 2181 cm −1  for the (IPBC) 2 :TBACl cocrystal, as shown in  FIG. 22 . 
       Example 9 
     Co-Crystal Containing 3-Iodopropynyl Butylcarbamate and Zinc Chloride in a 4:1 Molar Ratio (Co-Crystal 9) 
       [0159]    This example demonstrates the ability of IPBC to co-crystallise with a halide deriving from a transition metal, such as zinc chloride, to give a IPBC:ZnCl 2  co-crystal with molar ratio 4:1 
         [0160]    The co-crystal was prepared using the same procedure employed for example 4. 
         [0161]    The formation of a halogen bonded cocrystal between IPBC and ZnCl 2  can be confirmed looking at the DSC plot ( FIG. 23 ) showing two peaks at 118° C. and 139° C. (mixture of polymorphs) and the absence of the IPBC melting peak. 
       Example 10 
     Evaluation of Flowing Characteristics of Powders Containing the Halogen Bonded (IPBC) 4 :CaCl 2  Complex or Pure IPBC 
       [0162]    In this example the angle of response of powders containing the halogen bonded (IPBC) 4 :CaCl 2  complex of example 4 was compared to that of powders containing pure IPBC ( FIG. 24 ). The angle of response estimates the flow characteristics of the powders, 
         [0163]    The use of pure IPBC in industrial products faces significant manufacturing drawbacks. IPBC is difficult to handle because it tends to be clumpy and sticky, this implies that it cannot be fed easily from the blending equipment and the automatic feeding device. 
         [0164]      FIG. 24  shows that the cohesive properties of powder for co-crystal (IPBC) 4 :CaCl 2  are drastically different compared to the pure IPBC. Co-crystal (IPBC) 4 :CaCl 2  has values of angle of repose between 13° and 20° which indicates that it has excellent free-flow powder characteristic. On the contrary for the pure IPBC it is impossible to evaluate any angle of repose since the cohesive forces in the powder are too strong and its powder does not form an appropriate cone shape but tends to aggregate in irregular pillared shape. The cylindrical shape of IPBC cones indicates clearly the high cohesion of the powders, while the flat cone shape of co-crystal (IPBC) 4 :CaCl 2  indicates improved flow powder properties.

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