Dust and binderfree, free flowing spray granulates or microgranulates of riboflavin from pure riboflavin and a process for their preparation.

p0001The present invention relates to free-flowing, non-dusting binderless Riboflavinsprühgranulate or -mikrogranulate pure riboflavin and a method for their preparation of finely divided pure riboflavin.

p0002Riboflavin (vitamin B2) is varied uses in the food and pharmaceutical industries as a major, or even as a coloring additive to food and pharmaceuticals. It falls in its synthetic manufacture or biotechnologically partially in the form of very fine powders, partly in the form of long yellow needles. In both forms, the riboflavin has very poor handling and flow properties.

p0003The finely divided powder such as atomised considerably, has a very low bulk density (usually less than 0.2 g / ml), invites easily electrostatically to, shows a poor flowability and can be further processed only with great problems therefore. Another serious disadvantage of the fine powder is that it is practically not suitable for producing tablets with a riboflavin 25 wt .-% cost (see. V. Buhler, "Vademecum for vitamin Formulations", Scientific Publishing Company, Stuttgart, pages 98 to 99).

p0004Also available with slow crystallizing in the heat acicular riboflavin leads due to its poor flow properties and as a result of dust and charge phenomena to problems in the further processing, such as in the Mehlvitaminierung or tableting.

p0005To solve these problems, the riboflavin was partially granulated to obtain the addition of granulating a product having acceptable flow and compression properties. Thus, EP-A-02 19276 vitamin-containing granules are described which contain 90 to 99% vitamin and a binder.

p0006Although these granules are procedurally well for further processing, be it for direct, for preparing other riboflavin-containing drug products or containing vitamin B2 food and feed, it often remains unsatisfactory, that it does not consist of pure drug. This is particularly true for pharmaceutical goods, since the Pharmacopoeia prescribes a riboflavin with a minimum content of 98% of riboflavin.

p0007To binder-free riboflavin to have for the pharmaceutical industry are available, riboflavin is EP-A-0307767 solved according to the process in a solvent and a second solvent in which riboflavin is not soluble but which is miscible with the first solvent, precipitated in the form of spherulitic crystals with good handling characteristics. However, this method is technically difficult to perform and requires a high technical effort because working with larger amounts of solvents and the resulting solvent mixtures must be reprocessed.

p0008It was therefore to develop a process by means of which can be prepared in a technically simple manner, from finely divided pure riboflavin binderless riboflavin with good performance properties, the object of the invention ie granules, on the one hand low dust generation, good flow properties, as large as possible bulk weight show and very low electrostatic charge, but can be distributed in the processing again easily finely other.

p0009It has now surprisingly been found that a riboflavin granulate with excellent performance properties are obtained in the fluidized bed spray drying an aqueous or water-containing suspension of finely divided pure riboflavin.

p0010The invention is a process for preparing free-flowing well, non-dusting binderless Riboflavinsprüh- or -mikrogranulaten from finely divided pure riboflavin, which is characterized in that an aqueous or water-containing suspension of the pure finely divided riboflavin<ul><li>a) a fluidized-bed spray</li><li>b) one or Einstoffdüsenzerstäubungstrocknung</li><li>c) a disk-type</li></ul> supplies without the suspension appreciable amounts of binders may be added.

p0011Particularly advantageously, the novel process designed, when we apply the aqueous or water-containing suspension of the pure finely divided riboflavin a fluidized bed spray drying.

p0012The invention also free-flowing, non-dusting binderless Riboflavinsprühgranulate or -mikrogranulate as obtained in the present process of pure riboflavin.

p0013The starting material for the novel finely divided pure riboflavin is used as in the prior art, for example, the simple spray drying an aqueous suspension of riboflavin or during rapid cases of acidified aqueous riboflavin solutions at temperatures below about 50⁰C, preferably 20 to 30⁰C, or but with rapid cases and rapid cooling of hot aqueous riboflavin solutions at a pH from 0.8 to 6.5, is obtained. This finely divided riboflavin usually has an average largest particle diameter of about 0.1 to 50 microns, preferably 10 to 30 microns, and a bulk density of less than 0.2 g / ml.

p0014Larger-piece needle-shaped riboflavin, as obtained for example in the purification of crude riboflavin according to DE-OS 3,421,714 by slow precipitation of riboflavin from acidic aqueous riboflavin solutions at temperatures between 90 and 100⁰C, is in the form of its suspension not as a starting material for the novel process suitable. With slow cases at temperatures above 50⁰C got bigger divided acicular riboflavin but can be converted by reprecipitation or by wet milling (for example in a colloid mill) in suitable finely divided riboflavin.

p0015As pure riboflavin we call invention riboflavin having a purity 96-100, preferably 98 to 100%, which none of the usual binding agent or granulation was added.

p0016The finely divided pure riboflavin is advantageously used in the form of an aqueous suspension containing riboflavin 5 to 30, preferably 15 to 25 wt .-%. But you can also use a suspension of riboflavin at a not too high boiling solvent when this solvent contains water. The water content in the suspension should be at least about 10 wt -.% Amount. especially water-miscible solvents of suitable solvents such as C₁ to C₄-alkanols, into consideration.

p0017In contrast to the known spray-drying of riboflavin or suspensions in which this usually is sprayed by means of a two-fluid nozzle into a drying tower, in accordance with the invention applied fluidized bed spray drying, the suspension is continuously or intermittently sprayed into a fluidized bed of dry reaction product. The drying device is equipped with devices that allow to obtain a specific particle size fraction and the granulation maintain (see. K. Kroell, drying technology, Volume II "dryers and drying methods", 2nd edition, Springer-Verlag, Berlin, 1978, pages 221 to 223). Is advantageous to use in a spray dryer with an integrated fluidized bed (abbreviation: FSD = fluidized spray dryer), as described in Chem-Ing.-Tech.<u>59</u> has been described (1987) no. 2, pages 112-117, especially page 115th

p0018To carry out the spray fluidized invention of riboflavin suspensions procedure is generally followed in which one<ul><li>a) riboflavin submitted in the form of a dry powder, a spray or micro granulate in a fluidized bed dryer in a 20 to 100⁰C, preferably 50 to 90⁰C, especially 60 to 80⁰C, held fluidized bed,</li><li>b) adding an aqueous or water-containing suspension of finely divided riboflavin is added in accordance with the drying rate in sprayed form,</li><li>c) after a suitable residence deducts the riboflavin particles from the fluidized bed and is separated by a suitable device in particle fractions,</li><li>d) the particle fraction having a particle size in the range of about 50 to 450 microns and</li><li>e) the finer particles and / or the products obtained by milling larger particles fine particles recycled into the granulation process.</li></ul>

p0019The fluidized bed spray drying can be carried out discontinuously and continuously. Is particularly advantageous to operate continuously.

p0020To perform the process first such riboflavin must first go Riboflavintrockenpulver as corresponds to the prior art, are produced by means of which one can produce a fluidized bed. In the batchwise process can provide a relatively fine product in the fluidized bed. Depending on the residence time of the particles in the fluidized bed dryer is then obtained a dry product with a smaller or larger particle size range. Particles in the size range of about 50 to 450 microns have the desired handling characteristics and are therefore recovered as a useful product. Smaller particles and obtained by suitable milling of larger particles riboflavin is used as fluidized bed material for further batches.

p0021To carry out the continuous process, the aqueous or water-containing suspension of finely divided riboflavin is continuously consisting of a dry riboflavin is sprayed into a fluidized bed. The speed the spraying is adjusted so that the fluidized bed has a the desired degree of drying corresponding temperature. You will therefore ultimately determined by the difference between the inlet and outlet temperature of the fluidizing gas.

p0022In the continuous process one goes out only for the initial start of the fluidized bed dryer of finely divided riboflavin in the fluidized bed. After obtaining a dry product of nearly constant particle size ratio Of this continuously, a certain part is removed and separated into particle size fractions. The particle fraction having a particle size range of 50 to 450 microns is discharged as a product of value and the fine particles and / or the products obtained by milling larger particles fine particles are recycled continuously to maintain the granulation into the fluidized bed. Place about the taken off as desired product quantity Riboflavin is continuously sprayed in the form of aqueous suspension of finely divided riboflavin in the fluidized bed.

p0023The fluidizing gas used to form the fluidized bed generally has an inlet temperature of 60 to 250, preferably from 140 to 185⁰C and an exit temperature of 40 to 140, preferably 60 to 85⁰C, whereby temperatures of about 20 to 100, preferably 50 to 90⁰C, in particular 60 to 80 ° C, resulting in a fluidized bed.

p0024In carrying out the fluid-bed drying according to the invention generally result - depending on the grain size control - following particle size fractions:<ul><li>1. about 6 to 30% in the particle size range up to 100 microns</li><li>2. about 25 to 85% in the particle size range of 100 to 300 microns</li><li>3. about 1 to 70% in the particle size range from 250 to 400 .mu.m.</li></ul>

p0025To carry out the Einstoffdüsenzerstäubungstrocknung according to the invention generally uses a Einstoffhohlkegeldüse as it is, for example, offered by the company Delawan under the designation "SDX-Standard". But hollow cone nozzles Lechler, Schlick and Lurgi Company and hollow cone nozzles according to EP-A2 0,121,877 can be used. The atomization is generated here by the pressure of a pump which feeds liquid to be dried the Einstoffhohlkegeldüse. The space required for the atomization pressure can be up to 80 bar absolute, preferably only prints 15 to 25 bar absolute applied. The bottle containing the liquid to be dried solids can be up to 45 wt.%, Preferably 15 to 30 wt.% Amount.

p0026The riboflavin is entered by means of the described Einstoffhohlkegeldüse in a heated drying tower, dried here and discharged at the bottom of the tower. The drying tower inlet temperature of the drying gas is generally about 100 to 200, preferably from 130 to 170⁰C, the residence time is generally about 20 to 40 seconds. To obtain a non-dusting vitamin B₂-microgranule fraction obtained in the drying tower dry goods a suitable separator must be supplied. As separator of the drying tower-discharge cone can be formed, as described for example in the patent DE 33 44 509th In this separator, the dust-free micro-granulate is deposited as useful fraction, while the smaller particles (&lt;20 microns) leaving the drying tower with the drying gas. This fine material is separated in downstream separators (cyclones, filters) from the gas stream and can be the mixed material to be dried aqueous riboflavin suspensions (repatriation). The proportion of dust-fine fraction depends on the solids content of the hollow cone nozzle fed feed suspension and the nozzle pressure. The fines can be approximately 5 to 40%. At a solids content of the effluent of about 25 to 30% and a nozzle pressure of about 15 bar of recirculated fine fraction is only about 5 to 10%.

p0027The product obtained in this way has a particle size range of 30 to 200 microns.

p0028The microgranules thus obtained is characterized by excellent handling characteristics.

p0029Also by disk-type of riboflavin suspensions can be prepared at a binders microgranules even without the addition of significant quantities, having after the removal of the fines (&lt;20 microns) as described above, very good handling characteristics.

p0030The Riboflavinsprüh- or -mikrogranulate produced in a technically simple manner by the inventive process have spanked over the previously known and commercially available Riboflavinpräparaten significant performance advantages. They offer particular advantages in applications where the presence of binders or granulating is undesirable.

example 1

p0031(Riboflavin content 99.5%; bulk density about 0.1 kg / l PharmaWare) In a fluidized bed dryer was about 2.5 kg / h of a 20% aqueous suspension of a very finely divided riboflavin by means of a two 20⁰C continuously into a fluidized bed is sprayed from riboflavin about the same composition. The fluidized gas inlet temperature was 170⁰C. The injection amount was such that a fluidized bed temperature of 71 hired to 72⁰C.

p0032A part of the fluidized bed charge was continuously withdrawn and continuously separated by screening into 3 particle fractions. The dry product obtained had the following particle size distribution:<ul><li>1) 20 to 30% of a product having a particle size range <100 microns</li><li>2) 30 to 40% of the desired product with a particle size range of 100 to 300 microns</li><li>3) 30 to 50% of a product having a particle size range> 300 microns.</li></ul>

p0033The coarse fraction 3) was ground to a particle size range of &lt;250 microns and then) continuously fed back into the fluidized bed together with the fine fraction. 1

p0034About 0.5 kg / h to the desired Riboflavinsprühgranulat (particle size range 125 to 250 microns) were obtained as desired product.

example 2

p0035In a fluidized bed dryer, 2.5 kg / h of a 20% aqueous suspension of a very finely divided commercial riboflavin (bulk density about 0.1 kg / l; riboflavin 96% feed grade) sprayed into a Riboflavinwirbelbett. had the swirl gas a gas inlet temperature of 160 to 170⁰C. The injection amount was such that a fluidized bed temperature of 78 hired to 80⁰C.

p0036As in Example 1 about 0.5 kg / h was obtained at Riboflavinsprühgranulat with the desired particle size range of 125 to 250 microns.