Specification
The invention relates to carnitine granulates and methods for their production.
Background of the invention
Carnitine (vitamin BT; 3-hydroxy-4-trimethylammonio-butanoate) is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids for the generation of metabolic energy. Camitine exists in two stereoisomers. The biologically active form is L-camitine, whilst its enantiomer, D-camitine, is biologically inactive. Pure L-carnitine can be obtained by microbiological processes or by organic synthesis with subsequent purification steps.
Due to its vitamin-like function, L-camitine has a broad range of pharmaceutical, food and cosmetic applications. L-camitine is known to have positive effects on energy metabolism and the cardiovascular, muscular and nervous system of humans and animals. L-camitine is also useful for other purposes, for instance as a nutrient for yeast and bacteria growth. Camitine can be administered orally to humans and animals.
Solid L-camitine has a high hygroscopy. Thus powder mixtures have a low stability, in particular storability, and are only of limited use in industry, especially in the food industry.
Various attempts have been made in the art to overcome the problem of hygroscopy. In order to reduce the hygroscopy, EP 0434088 B1 suggests using a salt of L-camitine with L-tartric acid in the preparation of tablets or capsules.
US 2009/0082449 discloses methods for obtaining camitine powders or granulates. The camitine Is coated on a solid carrier in order to obtain a coated granulate. In a first method, it is suggested to coat the solid earner with an aqueous carnitine solution by preparing an aqueous suspension and spray-drying. However, a spray-drying process requires large amounts of water in the spray-drying solution. This is problematic, because the water has to be evaporated subsequently, which requires a large amount of energy and also time. In a second method, it is suggested to mix solid camitine with a solid carrier. In a third method, a liquid solution of a starting material comprising a low amount of carnitine, such as a permeate or a fermentation product, is mixed with a carrier and subjected to a drying process in order to obtain a granulate. Again, relatively large amounts of water have to be used which subsequently have to be removed in an energy and time consuming process. As outlined in section [0093], the granules tend to fomn agglomerated particles.
A method for producing granulates coated with camitine chloride is disclosed in JP 08-012569. According to this method, aqueous solutions comprising usually 30 to 60% by weight carnitine chloride are admixed with earners which are preferably silica caniers. After drying, the product can be admixed with organic binders and pressed into tablets and the like.
However, the methods known in the art have various drawbacks. At first, removing high amounts of water from a granulate is time and energy consuming. Further, granulates produced by methods in the art usually have a limited flowability. The decrease in fiowability over time is indicative
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of hygroscopy of the carnitine. Tfie flowability of a granulate and the maintenance of the flowability over an extended time period are important product properties. A good flowability is important for handling a granulate, for instance when packaging and proportioning the granulate. Granulates of low flowability tend to stick to surfaces, such as interior surfaces of containers and devices. This is problematic when a granulate is packed and proportioned by mechanical devices. Even further, the hygroscopy is problematic when carnitine or a carnitine granulate is admixed with other components, as for example in feed products for animals, in food products, feed products or feed and food additives, the camitine is often admixed with other nutrients or other feed or food additives. Due to the hygroscopy of the camitine, reduced flowability and caking is observed in such mixtures.
Problem underiving the invention
The problem underiying the invention is to provide a camitine granulate and methods for the production of a camitine granulate, which overcome the above-mentioned problems.
Specifically, the invention shall provide a simple and convenient method for obtaining carnitine granulates. The method shall require a low number or process steps, low amounts of energy, and shall be carried out during a relatively short time span. Energy intensive steps like spray-drying and drying at high temperatures for extended times shall be avoided.
A further problem underiying the invention is to provide a camitine having a low hygroscopy and high flowability. The camitine shall be storable for extended time periods without essential deterioration of the material. Specifically, caking of the camitine shall be reduced or inhibited even over extended time periods. Further, also mixtures of the camitine with other
components, for instance in a feed product, shall have the desired high flowability and low tendency towards caking. It would be of benefit if the carnitine or carnitine fonnulations can be stored for a longer period of time without using cost Intensive special packing to limit or avoid caking.
Another problem underlying the invention is to provide carnitine granulates having a relatively large particle size. This is advantageous, because in general a larger particle size enhances the flowability.
Another problem underlying the invention is to provide a process for preparing a carnitine granulate, in which the dusting of starting products or intermediate products is avoided.
Disclosure of the invention
Surprisingly, the problem underlying the invention is solved by the methods, carnitine granulates and uses according to the claims. Further inventive embodiments are disclosed throughout the description.
Subject of the invention is a method for the production of a carnitine granulate, comprising the steps of
(a) providing an aqueous solution comprising at least 65% (w/w) carnitine,
(b) providing a particulate carrier comprising silica, the carrier having an average particle size of more than 150 pm, and
(c) mixing the aqueous solution and the earner.
Carnitine is a zwitterion, which comprises a carboxyl group and a quaternary ammonium group. The camitine comprising solution in step (a) is generally obtainable by dissolving camitine or a salt thereof in water. The camitine used for preparing the solution in step (a) is preferably the
zwitterionic carnitine. However, it is also possible to use a carnitine salt for preparing the solution, such as a chloride, sulphate or nitrate salt. The carnitine used in step (a) for providing the aqueous solution is preferably not a salt of a carnitine with an optically active anion. According to the invention, a low hygroscopy is obtainable without providing carnitine in the form of a complex salt, for example an organic salt, especially one comprising more than 3 carbon atoms, such as a tartrate or citrate.
The aqueous solution in step (a) comprises at least 65% (w/w), preferably more than 70%, more than 75% or more than 76.5% (w/w) L-camitine. In preferred embodiments, the solution is close to saturation or a saturated solution or an oversaturated solution. Preferably, the solution is a clear solution.
In general, aqueous solutions comprising such high levels of L-camitine are obtainable at enhanced temperature. In a preferred embodiment of the invention, the temperature of the aqueous solution is at least 60°C, preferably at least 70''C or at least 75°C. Preferably, the temperature is between 60 and QO'C, more preferably between 75 and 85''C. It was found that the adjustment of such an enhanced temperature is also advantageous, because the fomiation of stable granules in step (c) is supported. This might be due to the decreased viscosity of the heated solution. Thus after preparing the aqueous solution in step (a) at an enhanced temperature, it is preferred to mix the solution with the carrier in step (c) at the same or essentially the same temperature, or without cooling the solution in between.
For example, the solution in step (a) is obtained by providing 15 to 35% (w/w) water in a vessel, adding 65 to 85% (w/w) carnitine or a salt thereof and stirring at elevated temperature until the carnitine is dissolved whilst reducing the viscosity of the solution.
In a preferred embodiment, the aqueous solution in step (a) essentially consists of water and carnitine. Impurities, for example side products from the production process may be present. Based on the total amount of solids in the aqueous solution, the level of non-camitine solids may be below 5%, below 2% or below 1% (w/w). In another embodiment of the invention, the carnitine is used in combination with at least one other soluble component. For example, further active agents might be included, depending on the use of the final product. In a food product, other nutrients could be included, for example vitamins, amino acids, dietary minerals, for example chromium picolinate. In addition or alternatively, auxiliary agents can be included, for example those which enhance the stability or handling of the granulate.
The aqueous solution in step (a) should have a viscosity such that it can be poured or sprayed with common apparatuses. In a prefen-ed embodiment of the invention, the viscosity of the camitine solution step (a) is between 0.5 to 150 mPas, more preferably between 0.8 and 50 mPas, measured at 70°C, or at the temperature at which solution (a) is prepared.
According to the invention, the average particle diameter of the particulate carrier is above 150 pm, preferably above 180 pm, above 200 pm or above 220 pm. Surprisingly, it was found that stable granulates, which have a high flowability and low hygroscopy, are obtainable when carriers with large particle diameters are used in the specific process of the invention. In a preferred embodiment of the invention, the average particle diameter (d50) of the canier is between 150 and 1000 pm, more preferably between 180 and 800 pm or between 220 and 500 pm. In a specific preferred embodiment, it was found that an optimal canier size, especially for a food product or food additive, is between about 200 and about 300 pm. The average particle diameter (d50 pm) can be detemiined
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according to ISO 13320:2009. By the method of the invention, also earners having average particle diameters above 1000 pm can be used, but such products are generally less applicable in phamiaceutical, food or feed applications.
In a preferred embodiment, the ratio of dry carnitine to carrier used as starting compounds in the inventive method is preferably between 0.5:1 and 5:1 or between 1:1 and 2.5:1, more preferably between 1.3:1 and 2:1 (w/w).
In a preferred embodiment of the invention, the BET surface of the carrier is between 100 and 1000 m^/g, more preferably between 150 and 600 m^/g or between 200 and 500 m^/g as detennined by ISO 5794-1. The BET surface relates to the specific surface of the particles. In general particles having a high BET surface (m^/g) absorb higher amounts of water.
The carrier used according to the invention comprises silica. In a preferred embodiment, the carrier is a microgranulated silica carrier. Microgranulated silica is known in the art and commercially available. Depending on the production process, the particles are usually more or less spherical. According to the invention, the carriers shall be capable of absorbing at least a certain amount of water. Such carriers are commercially available for example under the trademark Tixosil from Rhodia or under the trademark SIPERNAT from Evonik Industries. For example, useful silica carriers according to the invention are Tixosil 68, Tixosil 38X and SIPERNAT 2200, each having an average particle size above 150 pm. Preferably, the silica carrier essentially consists of SiOa. It may comprise minor amounts of impurities due to anions and cations, such as sulphate and sodium, or other metal oxides, such as iron oxide. Usually, the SiOa content of particles is above 95 or above 98 wt.%. In
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another embodiment of the invention, the canier comprises silica in combination with at least one other metal oxide, for example alumina. In these canier materials, the silica content may be above 10%, above 50% or above 80 % (w/w).
In a preferred embodiment of the invention, in step (c) the aqueous solution is fed into a mixer containing the earner whilst the mixer is agitated. The mixer can be a common device, such as a vertical mixer, vertical screw mixer, paddle mixer, horizontal mixer or spherical mixer. The aqueous solution can be fed into the mixture for example by a spray nozzle or a simple open tube. It is preferred that the feeding of the aqueous solution into the mixer is extended over a certain time interval in order to ensure that the solution is evenly absorbed by the carrier. For example, the feeding of the aqueous solution may be carried out over a period of 20 minutes to 3 hours, preferably between 30 minutes and 2 hours. In general, the feeding speed should be adjusted such that the solution can be absorbed effectively by the carrier in order to obtain a unifomn coating. During step (c), the aqueous solution is preferably maintained at an enhanced temperature. Preferably, the temperature or temperature range is selected as in step (a). In addition, the mixer might be heated. The overall process can be carried out as a batch process or as a continuous process.
In a prefen-ed embodiment of the invention, an anticaking agent is added. Antical
The inventive carnitine granulate and the inventive method solve the above mentioned problems. The method of the invention allows the preparation of a carnitine granulate in a relatively simple manner. The inventive method can be carried out whilst consuming low amounts of energy and in a short time, whilst applying simple standard equipment.
In the method of the invention, the process, the solution and the carrier can be adjusted, such that the water used is essentially absorbed by the granules. Thus an energy consuming drying step, such as a spray-drying step, is not necessary. Preferably, the method of the invention does not comprise a spray-drying step. Further, it is not necessary to dry the coated carrier at enhanced temperatures and/or for an extended time. In contrast, when admixing an aqueous solution comprising a high concentration of carnitine at an elevated temperature with a carrier according to the invention, it is possible to obtain a carnitine granulate without subsequent heating and drying steps. Preferably, drying temperatures above SCC or above 50°C and/or drying times above 10 or above 30 minutes are not applied. As used herein, "dry" means that the granules are essentially not wet or moist on the surface. However, they usually have an internal water content, because a portion of the water used in the coating process is adsorbed into the core of the particles.
By the inventive process, a carnitine granulate with highly advantageous properties is obtained. Surprisingly, the camitine granulate has a low hygroscopy and remains flowable over extended storing time periods. Even when storing the granulate for about 3 months, the flowability is not affected negatively. A carnitine granulate having a high average particle size is obtainable, which improves the flowability.
According to the invention, it is not necessary to introduce stability enhancing additives, such as organic binders, into the granule coatings. In
a preferred embodiment, the inventive carnitine granulate essentially consists of the carnitine, the carrier and the anticaking agent, which is preferably silica-based.
Working example
Preparation of aqueous carnitine solution
10.5 kg of water are fed into a stinred vessel.
34.2 kg of dry carnitine (Levocamitine) are added in to the vessel.
The vessel is heated up to SCC and stirred until the solids have been dissolved completely.
Preparation of microaranulated silica
23 kg of micro granulated silica (Tixosii 68, Rhodia) are fed
into a mixer (e.g. Nauta type or horizontal paddle mixer). The mixer is turned on.
Feeding of aqueous carnitine solution and mixing
The carnitine solution will be fed at 75 to 80°C into the running mixer via a spray nozzle or open tube/pipe.
In the first feeding step approx.
2/3 of the aqueous solution are fed in to the mixer within 20
minutes or longer.
After completion of the first feeding step the Silica/camitine/water is mixed for 15min without feeding of the camitine/water solution.
In the second feeding step the rest of the aqueous solution is fed in to the mixer within 10 minutes or longer.
684 g of an anti-caking agent (silica) are added at once.
After another 7 minutes of mixing time the product is discharged.
67 kg of granulated carnitine are obtained.
A granulate with good flowability and low hygroscopiclty was obtained. The average particle diameter d50 was about 262 pm. The average particle diameter (d50 pm) was detennined according to ISO 13320:2009.
The repose angle of the granulate was detennined to be 34.6°, compared to 53.3° of a commercially available feed formulation. The repose angle was detennined by the method of DIN ISO 4324.
The HAUSNER ratio was detennined to be 1.18 (indicating free flowing), compared to 1.41 (indicating non-flowing) of a commercially available feed formulation. The HAUSNER ratio was detennined according to DIN 53194.
We Claim:
1. A method for the production of a carnitine granulate, comprising the
steps of
(a) providing an aqueous solution comprising at least 65% (w/w) carnitine,
(b) providing a particulate carrier comprising silica, the carrier having an average particle size of more than 150 um, and
(c) mixing the aqueous solution and the carrier, whereby a drying step is excluded.
2. The method of claim 1, wherein the temperature of the aqueous solution is above 60°C.
3. The method of at least one of the preceding claims, wherein the viscosity of the carnitine solution in step (a) is between 0.5 to 150 mPas.
4. The method of at least one of the preceding claims, wherein the average particle diameter of the carrier is between 150 and 500 um.
5. The method of at least one of the preceding claims, wherein the BET surface of the carrier is between 100 and 1000 m2/g.
6. The method of at least one of the preceding claims, wherein in step (c) the aqueous solution is fed into a mixer containing the carrier whilst the mixer is agitated.
7. The method of at least one of the preceding claims, wherein an anticaking agent is added.
8. The method of at least one of the preceding claims, wherein the anticaking agent is hydrophobized silica particles.
9. The method of at least one of claims 6 to 8, wherein in step (c) the aqueous solution is fed into the mixer during at least two time intervals, between which the feeding is interrupted whilst agitating the mixture.
10. The method of at least one of the preceding claims, wherein step (c) comprises the steps of
(d) feeding a first portion of the aqueous solution into the mixer,
(c2) agitating the mixture for at least 3 minutes whilst no aqueous solution is fed into the mixer,
(c3) feeding a second portion of the aqueous solution into the mixer,
(c4) agitating the mixture for at least 3 minutes whilst no aqueous solution is fed into the mixer,
wherein an anticaking agent is added during or after step (c3) or (c4),
wherein the mixer is agitated during steps (d) to (c4).
11. A carnitine granulate, obtainable by a method of any of the preceding claims.
12. A carnitine granulate having an average particle size of more than 150
urn, wherein the granules essentially consist of a silica carrier coated with carnitine, wherein the granulate optionally comprises an anticaking agent.
13. The carnitine granulate of claim 12, wherein the carnitine granules
comprise 30 to 95% (w/w) silica carrier and 70 to 5% (w/w) carnitine,
based on the total amount of solids.
is
14. The method or carnitine granulate of any of the preceding claims, wherein the carnitine is L-carnitine.
15. The use of a carnitine granulate of any of claims 11 to 14 in a feed or food composition, a pharmaceutical composition or a cosmetic composition.
Dated this the 5fh Day of June, 2012
MANISHA SINGffNAIR
Agent for the Applicant [IN/PA-740]
LEX ORBIS IP PRACTICE