Patent Description:
The temperature of the air surrounding the earth is increasing, a process referred to as global warming. One of the main focuses to reduce this warming effect is to reduce the amount of greenhouse gases emitted into the atmosphere. Greenhouse gases are emitted from several different sources, both natural and artificial; however, the two sources with the most emphasis are the agricultural and fossil fuel industries. Within agriculture, ruminants and in particular cattle are the major contributors to the biogenic methane formation, and it has been estimated that the prevention of methane formation from ruminants would almost stabilize atmospheric methane concentrations.

<NUM>,<NUM>-Propandiol mononitrate (in the following referred to propandiol mononitrate, respectively PDMN) and derivatives thereof have been reported to be highly efficient in reducing the formation of methane in ruminants without affecting microbial fermentation in a way that would be detrimental to the animal (<CIT>).

The article by Guyader et al. (<NPL>) relates to the inhibition of methanogenesis in the rumen by known methanogenesis inhibitors such as <NUM>-nitrooxypropanol (NOP). In this study, in vitro rumen simulation tests were carried out with a substrate composition wherein <NUM>% of the active NOP compound is mixed together with <NUM>% of dicalcium phosphate and <NUM>% of a NOP-carrier which is a mixture of <NUM>% silica and <NUM>% propylene glycol.

However, propandiol mononitrate and derivatives thereof have been found not to be effectively retained under conventional storage conditions, in particular when absorbed onto standard carrier systems commonly used in the feed industry. Furthermore, it has been found that the incorporation of propandiol mononitrate absorbed on silica into standard feed premixes even further reduces the storage stability thereof. The lack of retention of the active in conventional product forms for the feed industry is, however, highly unwanted as accordingly an appropriate dosage is not possible without undue burden, i.e. sophisticated packaging, analysis of the active content before use or overdosing. Moreover, all these methods add significant additional costs-in-use which are not readily accepted by the end user.

Thus, there is an ongoing need for product forms and methods, which overcome the above-mentioned problems by enabling the storage over a period of time without significant losses of the active, i.e. of propandiol mononitrate respectively derivatives thereof.

Surprisingly, it has now been found that the addition of an inorganic phosphate to a powderous formulation of propandiol mononitrate absorbed onto silica, also after incorporation thereof into a mineral premix significantly increased the retention of propandiol mononitrate.

The invention is set out in the appended set of claims <NUM>-<NUM>.

Thus, in a first embodiment the present invention relates to a storage stable mixture (<NUM>) comprising.

The amount of the powderous formulation (A) in the storage stable mixture (<NUM>) is at least <NUM> wt. -%, more preferably at least <NUM> wt. -%, based on the total weight of the storage stable mixture (<NUM>).

More preferably, the amount of the powderous formulation (A) in the storage stable mixture (<NUM>) is selected in the range from <NUM> to <NUM> wt. -%, most preferably in the range from <NUM> to <NUM> wt. -%, such as in the range of <NUM> to <NUM> wt. -%, based on the total weight of the storage stable mixture (<NUM>).

The amount of the at least one inorganic phosphate (total) in the storage stable mixture (<NUM>) is at least <NUM> wt. -%, more preferably at least <NUM> wt. -%, most preferably at least <NUM> wt. -%, based on the total weight of the storage stable mixture (<NUM>).

More preferably, the amount of the at least one inorganic phosphate in the storage stable mixture (<NUM>) is selected in the range from <NUM> to <NUM> wt. -%, most preferably in the range from <NUM> to <NUM> wt. -%, such as in the range of <NUM> to <NUM> wt. -%, based on the total weight of the storage stable mixture (<NUM>).

The term 'storage-stable' as used herein refers to an improved retention of the compound of formula (I) in the mixture according to the present invention compared to the respective mixture without the at least one inorganic phosphate. Preferably, the retention is improved by at least <NUM> %, more preferably by at least <NUM> %, most preferably by at least <NUM>% compared to the respective mixture without any inorganic phosphate.

In another preferred embodiment of the present invention, the weight-ratio (w/w) of the inorganic phosphate to the powderous formulation is at least <NUM>, more preferably at least <NUM>, most preferably at least <NUM>.

In all embodiments of the present invention, the weight-ratio (w/w) of the inorganic phosphate to the compound of formula (I) is at least <NUM>.

Even more advantageously in all embodiments of the present invention the weight-ratio (w/w) of the inorganic phosphate to the compound of formula (I) is selected in the range of <NUM>:<NUM> to <NUM>:<NUM> (i.e. <NUM> parts of inorganic phosphate to <NUM> part of a compound of formula (I) to <NUM> parts of inorganic phosphate to <NUM> part of a compound of formula (I)), more preferably in the range of <NUM>:<NUM> to <NUM>:<NUM>.

The term' powderous formulation' as used herein refers to solid formulations in powder form which freely flow (i.e. free flowing powders).

The amount of silica in the powderous formulations according to the present invention is generally selected in the range of <NUM> to <NUM> wt. -%, such as in the range of <NUM> to <NUM> wt. -%, <NUM> to <NUM> wt. -% or <NUM> to <NUM> wt.

In all embodiments of the present invention the powderous formulation (A) is preferably a powderous formulation (B) comprising.

The term 'edible oil' refers to oils commonly used in feed applications. Preferred edible oils to be used in the powderous formulations are propyleneglycol, canola oil, corn oil, rapeseed oil, sunflower oil, middle chain triglyceride (MCT), soy bean oil and glycerol as well as mixtures thereof. The most preferred edible oil to be used in the powderous formulation is propyleneglycol.

The powderous formulations may furthermore contain small amounts of customary additives commonly used in the preparation of powderous formulations for feed application.

Therefore, the powderous formulations (B) may be powderous formulations (C) which further comprise (iv) <NUM> to <NUM> wt-%, based on the total weight of the formulation, of an additive.

The powderous formulation is generally prepared by a process wherein the compound of formula (I) is, optionally diluted in the edible oil and further optionally admixed with the additive(s), sprayed onto or admixed with a silica.

Alternatively, the powderous formulations can be prepared by a process wherein the compound of formula (I) is, optionally in the presence of the edible oil and further optionally admixed with the additive(s), diluted in an organic solvent suitable for the preparation of feed products such as e.g. dichloromethane which dilution is then sprayed onto or admixed with silica followed by evaporation of the organic solvent.

The powderous formulations may be adsorbates.

For the purposes of the present invention, adsorbates are, in particular, preparations in which at least <NUM> wt. -%, in particular at least <NUM> wt. -%, preferably at least <NUM> wt. -%, particularly preferably at least <NUM> wt. -%, in particular at least <NUM> wt. -% of the components to be adsorbed (i.e. all constituents of the adsorbate without the silica, i.e. the compound(s) of formula (I), and optionally the edible oil and the additives) are present in the internal pore volume of the silica. The internal pore volume of a carrier can be determined as void volume by the DPB (dibutyl phthalate) method DIN <NUM>.

Particular preference is given to adsorbates of which at least <NUM> wt. -%, preferably at least <NUM> wt. -%, in particular at least <NUM> wt. -%, is present in the internal pore volume of the silica.

Silica is a well-known carrier material in the feed and food industry and refers to white microspheres of amorphous silica (also referred to as silicone dioxide) and is available in a great variety of particle sizes. Particular suitable silica to be used in powderous formulations is amorphous precipitated silica e.g. available as Ibersil D-<NUM> at IQE Group, Sipernat <NUM> at Evonik or Tixosil <NUM> at Solvay, Zeofree <NUM> from J. Huber Cooperation or Newsil C50 from Quechen Silicon Chemical Co Ltd.

Preferably the silica which is used in powderous formulations has an average particle size D(v, <NUM>) > <NUM>. More preferably the particle size of the silica is selected in the range of <NUM> to <NUM>, most preferably in the range of <NUM> to <NUM>, even more preferably in the range of <NUM> to <NUM>.

The particle sizes as given herein are measured by a Malvern Master Sizer <NUM> following the recommendations outlined in ISO13320-<NUM> for particle size analysis via laser diffraction methods (laser diffraction light scattering). During this laser diffraction measurement, particles are passed through a focused laser beam. The particles scatter light at an angle that is inversely proportional to their size. The angular intensity of the scattered light is then measured by a series of photosensitive detectors. The map of scattering intensity versus angle is the primary source of information used to calculate the particle size. For the measurement of the silica a dry powder feeder (Malvern Scirocco) was used.

Advantageously, the silica which is used in the powderous formulations furthermore exhibits a pH in the range of pH <NUM> to <NUM> (measured as a <NUM>% suspension in distillated water), such as preferably in the range of pH <NUM> to <NUM>.

The term 'additive' as used herein refers to additives commonly used in the preparation of powderous formulations for feed application. Preferred additives to be used in the powderous formulations are thickeners, such as in particular gums or cellulose derivatives such as xanthan gum, karaya gum and/ or ethylcellulose.

Particular advantageous powderous formulations are powderous formulation (A) which are powderous formulations (D) consisting essentially of.

Even more advantageous powderous formulations are powderous formulations (A) which are powderous formulations (E) consisting essentially of.

An especially preferred powderous formulation is a powderous formulation (A) which is a powderous formulations (F) consisting essentially of.

The compounds of formula (I) preferably have a boiling point below <NUM> at <NUM> bar (<NUM> Torr), preferably a boiling point in the range of <NUM> and <NUM> at <NUM> bar (<NUM> Torr).

The compounds of formula (I) are known and either commercially available or can be prepared in analogy to the processes as e.g. disclosed in <CIT>.

Particular advantageous compounds of formula (I) to be used in the powderous formulations according to the present invention are the compounds wherein n is an integer between <NUM> and <NUM> and R<NUM> is -OH, -COOH or -ONO<NUM> and with the proviso that if n is <NUM> the hydrocarbon chain may be interrupted by -NH- such as in particular the compounds of formula R<NUM>-(CH<NUM>)<NUM>-NH-(CH<NUM>)<NUM>-ONO<NUM>. Even more preferred are compounds of formula (I) wherein n is an integer between <NUM> and <NUM> and R<NUM> is -OH, -COOH or -ONO<NUM>.

Even more advantageous compounds of formula (I) to be used in the powderous formulations are propandiol mononitrate (<NPL>), <NUM>-nitrooxynonanol, <NUM>-nitroxy pentanoic acid (<NPL>), <NUM>-nitroxy hexanoic acid (<NPL>), bis(<NUM>-hydroxyethyl)amine dinitrate (<NPL>), <NUM>,<NUM>-bis-nitrooxybutane (<NPL>) and <NUM>,<NUM>-bis-nitrooxypentane (<NPL>). The most preferred compound of formula (I) to be used in the powderous formulations is propandiol mononitrate.

Thus, a very specific powderous formulation is a powderous formulation (A) which is a powderous formulation (G) consisting essentially of.

The term 'powderous formulation consisting essentially of' indicates that the addition of all wt-% of the listed ingredients of the powderous formulations adds up to <NUM> wt. -% (i.e. the amount of silica is adjusted accordingly) with the proviso, however, that it cannot be excluded that small amount of impurities or water (moisture) may be present in the powderous formulations such as e.g. in amounts of less than <NUM> wt. -%, preferably less than <NUM> wt. -%, more preferably less than <NUM> wt. -%, which impurities/ water (moisture) are introduced via the respective raw materials or processes used and which are not added separately.

The powderous formulations (A) to (G) with all the preferences and definitions as given herein can additionally be coated with customary coatings in the art such as wax or fats. If present, such coating is generally applied in amounts of <NUM> to <NUM> wt. -% based on the total weight of the powderous form. Advantageously, the coating comprises at least one wax and/or at least one fat, which has a dropping point (Tropfpunkt) of from <NUM> to <NUM>.

The dropping point of a material as used herein refers to the temperature (in °C) when the material begins to melt under standardized conditions. Thus, the material is heated so long until it changes the state of matter from solid to liquid. The dropping point is the temperature when the first dropping is released from the material. The determination of the dropping point is carried out as described in the standard norm DIN ISO <NUM>.

Particularly suitable waxes to be used as coating include organic compounds consisting of long alkyl chains, natural waxes (plant, animal) which are typically esters of fatty acids and long chain alcohols as well as synthetic waxes, which are long-chain hydrocarbons lacking functional groups.

Particularly suitable fats to be used as coating include a wide group of compounds which are soluble in organic solvents and largely insoluble in water such as hydrogenated fats (or saturated fats) which are generally triesters of glycerol and fatty acids. Suitable fats can have natural or synthetic origin. It is possible to hydrogenate a (poly)unsaturated fat to obtain a hydrogenated (saturated) fat.

Preferred examples of waxes and fats to be used as coating are glycerine monostearate, carnauba wax, candelilla wax, sugarcane wax, palmitic acid, stearic acid hydrogenated cottonseed oil, hydrogenated palm oil and hydrogenated rapeseed oil as well as mixtures thereof.

In a preferred embodiment, the powderous formulations (A) to (G) with all the preferences and definitions as given herein are not coated.

The term 'inorganic phosphate' according to the present invention refers to any inorganic phosphate suitable for feed application (inorganic feed phosphate) such as the calcium phosphates in different forms (mono-, di- and monodi-calcium phosphates) as well as magnesium, calcium-sodium, calcium-magnesium, ammonium and sodium phosphates as well as mixtures thereof.

Generally, the inorganic feed phosphates are derived from natural rock phosphate - the rock being chemically treated to make the phosphorus available for animals in the form of quality feed phosphates.

Preferably in all embodiments of the present invention the at least one inorganic phosphate is a mono-, di- or tri-calcium phosphate such as most preferably dicalcium phosphate.

Commercially available inorganic phosphate grades suitable for the purpose of the present invention are e.g. commercially available at Foodchem International Corporation.

It is well understood, that the storage stable mixtures (<NUM>) according to the present invention may contain additional active and/ or feed ingredients and/ or edible oils conventionally used in the feed industry and/ or in feed products.

Thus, in a further embodiment, the present invention relates to a storage stable mixture (<NUM>) with all the definitions and preferences as given herein which is a storage stable mixture (<NUM>) further comprising (a3) at least one active ingredient and/ or at least one feed ingredient and optionally (a4) at least one edible oil.

In a particular advantageous embodiment, the storage stable mixture (<NUM>) is a storage stable mixture (<NUM>) comprising.

In a particular preferred embodiment, the at least one active ingredient is selected from the group consisting of water-soluble and/ or fat-soluble vitamins, trace and/ or macro minerals, amino acids as well as mixtures thereof.

Particularly suitable fat-soluble vitamins encompass vitamin A, vitamin D3, vitamin E, and vitamin K, e.g. vitamin K3. Particularly suitable water-soluble vitamins encompass vitamin B12, biotin and choline, vitamin B1, vitamin B2, vitamin B6, niacin, folic acid and panthothenate, e.g. Ca-D-panthothenate as well as mixtures thereof.

Particularly suitable trace minerals encompass manganese (e.g. in the form of manganese oxide), zinc (e.g. in the form of zinc oxide), iron (e.g. in the form of iron sulphate), copper (e.g. in the form of copper sulphate), iodine (e.g. in the form of sodium iodine), selenium, and cobalt as well as mixtures thereof.

Particularly suitable macro minerals encompass calcium (e.g. in the form of limestone and calcium (mono, di or triphosphate), magnesium, phosphorus and sodium (e.g. in the form of sodium chloride) as well as mixtures thereof.

The at least one feed ingredient is selected from the group consisting of roughage and concentrates as well as mixtures thereof.

In one particular advantageous embodiment according to the present invention, the storage stable mixture (<NUM>) according to the present invention is a premix (1A) consisting essentially of the ingredients (a1) and (a2), characterized in that the weight ratio of the at least one inorganic phosphate to the compound of formula (I) is at least <NUM>.

In a further preferred embodiment, the storage stable mixture (<NUM>) is a premix (1B) consisting essentially of.

In another preferred embodiment, the storage stable mixture (<NUM>) according to the present invention is a premix (2A) consisting essentially of (a1) to (a3) and optionally (a4) and wherein (a3) is at least one additional active ingredient selected from the group consisting of water-soluble and/ or fat-soluble vitamins, trace and/ or macro minerals, amino acids as well as mixtures thereof with the proviso that the ingredients (a1) to (a4) sum up to <NUM> wt. -%, characterized in that the weight ratio of the at least one inorganic phosphate to the compound of formula (I) is at least <NUM>.

In a further preferred embodiment, the storage stable mixture (<NUM>) is a premix (2B) consisting essentially of.

It is noted that next to all the preferences given herein, particular preferred edible oils to be used in the storage stable mixtures according to the present invention are corn oil, rapeseed oil, sunflower oil, canola oil and or soy bean oil as well as mixtures thereof, such as most preferably soy bean oil.

The term 'premix' as used herein designates a preferably uniform mixture of the listed ingredients which are generally used to facilitate uniform dispersion of active ingredients into a larger mix.

The term 'premix consisting essentially of' indicates that the addition of all wt-% of the listed ingredients of the premix adds up to <NUM> wt. -% with the proviso, however, that it cannot be excluded that small amount of impurities or water (moisture) may be present in the powderous formulations according to the present invention such as e.g. in amounts of less than <NUM> wt. -%, preferably less than <NUM> wt. -%, more preferably less than <NUM> wt. -%, which impurities/ water (moisture) are introduced via the respective raw materials or processes used and which are not added separately.

All the above disclosed premixes can be used as such or admixed to feed products.

Additionally, all the above disclosed premixes can be used in the production of feed products.

It is well understood, that the storage stable mixture (<NUM>) according to the present invention may also be a feed product.

Thus, in another preferred embodiment, the storage stable mixture (<NUM>) according to the present invention is a feed product (2a) consisting essentially of (a1) to (a3) and optionally (a4) and wherein (a3) is (a3/<NUM>) at least one additional active ingredient selected from the group consisting of water-soluble and/ or fat-soluble vitamins, trace and/ or macro minerals, amino acids as well as mixtures thereof and (a3/<NUM>) at least one feed ingredient selected from the group of roughage and concentrate, characterized in that the weight ratio of the at least one inorganic phosphate to the compound of formula (I) is at least <NUM>.

The term roughage (also known as forage) and concentrate are well known to a person skilled in the art. Roughage is primarily composed of cellulosic materials such as plant stems and leaves, e.g. hay, introduced grass, native grass, green roughage, straw, tree leaves, etc.; brans such as rice bran, etc. as well as crude fibers such as e.g. brewery's byproducts. The concentrates are generally comprised of the conventional components such as mainly proteins, starch and fats. The concentrate components thus include, for example cereals such as corn, wheat, barley, rye, oat, wheat flour etc.; oil meals such as soybean meal, sunflower oil meal, etc.; feeds of animal origin such as fish meal, mead-and-bone meal, animal oils (e.g. beef oil, lard oil, bone oil, etc.) without being limited thereto.

In another embodiment, the invention relates to the use of an inorganic phosphate to enhance the retention (i.e. reduce the evaporation) of a compound of formula (I) in a powderous formulation comprising (i) the compound according to formula (I) and (ii) silica, characterized in that the weight ratio of the at least one inorganic phosphate to the compound of formula (I) is at least <NUM>.

Preferably, the retention is at least <NUM> %, preferably at least <NUM> %, more preferably at least <NUM>%, most preferably at least <NUM> % such as in particular at least <NUM> %.

Also disclosed herein but not forming part of the present invention is a method of improving the retention (i.e. reducing the evaporation) of a compound of formula (I) in a powderous formulation, said method comprising admixing the powderous formulation with an inorganic phosphate. The ratio (w/w) of the at least one inorganic phosphate (total) to the powderous formulation may be selected in the range of <NUM>:<NUM> to <NUM>:<NUM>, preferably in the range of <NUM>:<NUM> to <NUM>:<NUM>, most preferably in the range of <NUM>:<NUM> to <NUM>:<NUM> or <NUM>:<NUM> to <NUM>:<NUM>, as these formulations are particular suitable to effectively retain the compound of formula (I) over storage.

Also disclosed herein but not forming part of the present invention is a method of improving the retention (i.e. reducing the evaporation) of a compound of formula (I) in a powderous formulation such as in particular in the powderous formulations (A), (B), (C), (D), (E), (F) or (G), said method comprising the step of preparing a mixture or a premix with all the definitions and preferences as given herein.

Preferably, the mixture/ premix exhibits a retention of at least <NUM> %, preferably at least <NUM> % most preferably at least <NUM> % such as in particular at least <NUM> %.

The term 'retention' as used therein refers to a retention of the compound of formula (I) with all the definitions and preferences as given herein over a storage time of at least <NUM> weeks (reclosed (i.e. a bag which has been rolled twice for closure and then fixated with a clip) PE or aluminium bag; <NUM>; <NUM> % relative humidity (r.

Also disclosed herein but not forming part of the present invention is a method to enhance the retention of a compound of formula (I) in a powderous formulation and with all the definitions and preferences as given herein in a feed product, said method comprising the step of adding a mixture with all the definitions and preferences as given herein with/ to the feed product.

Also disclosed herein but not forming part of the present invention is a method to enhance the storage stability of a feed product comprising a powderous formulation such as in particular the powderous formulations (A), (B), (C), (D), (E), (F) or (G), said method comprising the step of adding at least one inorganic phosphate to the feed composition. Preferably, the ratio (w/w) of the at least one inorganic phosphate (total) to the powderous formulation is selected in the range of <NUM>:<NUM> to <NUM>:<NUM>, preferably in the range of <NUM>:<NUM> to <NUM>:<NUM>, most preferably in the range of <NUM>:<NUM> to <NUM>:<NUM> or <NUM>:<NUM> to <NUM>:<NUM>, as these formulations are particular suitable to effectively retain the compound of formula (I) during storage.

Preferably, the amount of the mixture according to the present invention in the feed product is selected such, that the amount of the compound of formula (I) is in the range of <NUM> to <NUM>/ kg of feed product, preferably in the range of <NUM> to <NUM>/ kg of feed product, most preferably in the range of <NUM> to <NUM>/ kg of feed product.

The term feed product refers in particular to ruminant feed compositions as well as to feed additives.

It is well understood that all the definitions and preferences of the inorganic phosphate, powderous formulations, compounds of formula (I), active and/ or feed ingredients and edible oils etc. as given herein also apply to the mixtures, premixes, feed products, uses and methods according to the present disclosure as outlined above.

The invention is illustrated by the following Examples. All temperatures are given in °C and all parts and percentages are related to weight.

Agilent High Performance Liquid Chromatography <NUM> Infinity system, using an Aquasil C18, <NUM> x <NUM>, <NUM> column and detecting at <NUM>. The column oven was set to <NUM>, the autosampler not temperature controlled. The mobile phase consisted of mobile phase A (<NUM> Milli-Q-water + <NUM> acetonitrile + <NUM> methane sulfonic acid) and mobile phase B (<NUM> Milli-Q-water + <NUM> acetonitrile + <NUM> methane sulfonic acid) which were used in gradient mode (<NUM>: <NUM> % B, <NUM>: <NUM> % B, <NUM>: <NUM> % B, <NUM>: <NUM> % B, <NUM>: <NUM> % B, <NUM>: <NUM> % B (= end of run)) with a flow of <NUM>/min.

To <NUM> of silica (Newsil C50) placed on a beaker, are added <NUM> of a <NUM> wt. -% propandiol mononitrate (PDMN) solution in propyleneglycol under gentle agitation at room temperature. After <NUM> minutes agitation, the adsorption is completed and a free-flowing powder is obtained.

<NUM> of PF-PDMN and <NUM> of an inorganic carrier as outlined in table <NUM> have been mixed with a TURBULA® Shaker-Mixer (<NUM> rotations/min) for <NUM>, sieved through a <NUM> sieve and mixed again for <NUM> to obtain homogenous mixtures (<NUM> batches). Then <NUM> of the respective mixtures were stored in reclosed PE bags at <NUM> under controlled atmosphere (<NUM> % r. H) for <NUM> month. Afterwards the remaining content of PDMN was determined by HPLC. The results (as relative concentration to the initial value set to <NUM>%) are presented Table <NUM>.

Claim 1:
A storage stable mixture comprising
(a1) at least <NUM> wt.-%, based on the total weight of the mixture, of a powderous formulation comprising
(i) a compound of formula (I)
<CHM>
wherein
n is an integer from <NUM> to <NUM>
R<NUM> is selected from the group consisting of H, C<NUM>-C<NUM>alkyl, phenyl, -OH, -NH<NUM>, -CN, -COOH, -O(C=O)R<NUM>, -NHC(=O)R<NUM>, SO<NUM>NHR<NUM>, and -ONO<NUM>, and
R<NUM> is C<NUM>-C<NUM>alkyl, phenyl, pyridyl such as preferably <NUM>-pyridyl with the proviso that when n is > <NUM> the hydrocarbon chain may be interrupted by -O- or -NH-, and
(ii) silica, and
(a2) at least <NUM> wt.-%, based on the total weight of the mixture, of at least one inorganic phosphate, characterized in that the weight ratio of the at least one inorganic phosphate to the compound of formula (I) is at least <NUM>.