CA1210697A - Free-flowing, high density, non-agglomerated fat- soluble vitamin powders - Google Patents

Abstract

FREE-FLOWING, HIGH DENSITY, NON-AGGLOMERATED
FAT-SOLUBLE VITAMIN POWDERS
Abstract of the Disclosure Vitamin-active powders which are free-flowing and have higher density than conventional fat-soluble vitamin powders are prepared utilizing a silicon-containing particu-late material having a particle size distribution of about 50 to about 500 microns.

Description

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FREE-FLOWING, HIGH DENSITY, NON-~GGLOMERATED
_ FAT-SOLUBLE VIT _ N POWDERS
Background of the Invention 1~ Field of the Invention This invention relates to fat-soluble vitamin active powders prepared by adsorption of said vitamin on the surface of silicon-containing materials.

2. Description of the Prior Art Here~ofore, vitamin A and other oily medicaments have been prepared in powder form by adsorption of the oily vitamin product onto the surface of such porous fine powders as silicic acid, ~ilicic anhydride and calcium silicate as disclosed in U. S. 3,247,064 and U. S. 2,858,215. These products tend to b~ extremely dusty and di~ficult to handle, and their densities are much lower than 0.5 grams per cubic centimeter. Such powders generally were prepared in agglomerated form in an effort to increase the density of such powders. The agglomerated forms o ~he powders su~fer a loss in free-flowing characteristics as a resul~ of such 2n agglomeration.

Such prior art fat-soluble vitamin powders also have been prepared utilizing various processes including spray-drying a vitamin slurry or emulsion containing hydrolyzed gelatin while introducing ultra-fine particle size absorbents into the spray-drying chamber such as disclosed in U. S. 3,947,596 and 3,914,430.

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6~7 Summary of the Inventio_ This invention relates to free-flowing, fat-soluble vitamin powders prepared utilizing an adsorbent silica-containing particulate material having a particle size in the range of about 50 to 500 microns and a process for the preparation of said powders.
Deta_ ed Descri~ion o the Invention Free-flowing, fat~soluble vita~in powders suitable for direct compression into tablets can be prepared by mixing said vitamins in the form of liquids together with a silicon-containing adsorbent material having a particle size in the range of about 50 to about 500 microns with an average particle size of about 100 microns. In the process of the invention, the fat-soluble vitamins are met~red into the adsorbent powder materials which are malntained under constant agitation 50 as to allow the liquids to become adsorbed on the surfaces of the powder. The fat-soluble vitamin can be mixed with various stabilizing agents known to those skill~d in the art to maintaln the potency of the vitamin over reasonable periods of storage. The fat-soluble vitamin in liquid form can be reduced in viscosity before mixing, if necessary, by the application of a moderate amount of heat. This speeds the process of adsorption upon the addition of the vitamin to the adsorbent powder.

In the process of the invention, no water, diluents, emulsifiers or other adjuvents need be added to the vitamin which is utilized in the liquid form in the process of the invention. Thus, the various processes of the prior art which involve the use of wa~er and emulsi-fiers, such as gelatin and starch, and spray-drying tech-niques are unnecessary to the process of the invention. It has been observed that the mixing process of the invention results in some release of heat as the liquid vitamin is adsorbed on the surface of the adsorbent powder. This is advantagaous in that the adsorption of the liquid vitamin is increased as the temperature of the mixture increases.
While this invention includes products and processes prepared utilizing various fat-soluble vitamins, the preferred embodiment of this invention i~ a free-flowing, substantially non-agglolnerated, high density vitamin E powder suitable for direct compression t~bleting techniques.
Vitamin E comprises a group of na~ural substances 2a known as tocopherols. These fat-soluble, closely related chemical compounds are found in vegetable oils such as wheat germ oil, rice oil, soybean oil and the like. The greatest biological activity of the tocopherols is found in the alpha-tocopherol while the isomers beta-, gamma-, d lta-, epsilon-, ~eta- and eta-tocopherols have vitamin E activity g z~697 to a lesser extent. T~e ~ocopherols and their es~er~ such as tocopherol acetate, tocopherol p~lmitate, toc~pherol succinnate and ~he like are normally water-insoluble and oily, waxy or low-melting products which make them unsuit-able for certain pharmaceutical applications, particularly those in which a powder is required such as in vitamin tablets and capsules.
Any of the tocopherols, their esters or compound~
convertible to either tocopherols or their esters are suitable for use in the process of this invention. In order to insure the desired stability of activity of the vi~amin E
in the final powder form, it is preferred to use tocopherol esters in the process of ~his invention. The preferred ester for use in accordance with this invention is dl-alpha-tocopherol acetate (vitamin ~ acetate). In the preparation of the powders oE the invention, sufficient tocopherol ac~tate or other fat-soluble vitamin is used to insure that the resulting powders contain from about 40 to 60 percent by weight activity. The amount of vitamin activity expressed as present in the powder i5 that which would be present if the vitamin activity is present as the pure vitamin.
The process of the invention is also applicable to the other fat-soluble vltamins which are generally con-sidered ~o be vitamins A, D and R. The products and processes of the invention contemplate the use of at least ~3L2~

one fat~soluble vitamin in the preparation of said vitamin powders. In addition, it is contemplated that mixtures of vitamins or other nutrient materials which are soluble or dispersible in the fat-soluble vitamins can be utilized in the process of the invention to prepare free-flowin~, substan~ially non-agglomerated, vitamin-active, powdered products~
Of critical importance in the process disclosed and claimed herein is th~ use of fine particle size adsor-bent materials. These adsorbents are in the main silicon-containing particulate materials such as silicic acid, silicon dioxide and various silicates such as calcium silicake. However, materials other than the various silicon-containing particulates may be equally effective since it is believed not so much that the chemical composi-tion o the adsorbent is critical bu~ rather the physical properties of the adsorbent, The adsorbent must be capable of an appreciable capacity to adsorb water or oil, for instance, an oil adsorption capacity of about 150 to about 400 pounds per 100 pounds. The particle size distribution of the adsorbent must be about 50 to about 500 microns with an avera~e particle size of about 100 microns~ Suitable adsorbent materials include silicic acid, silicas, alkali metal silicates, magnesium carbonate~ d ays, dicalcium phosphate~ ~ricalcium phosphate, and the like. The pre-~2~697 ferred material for the process of $his invention i~ anamorphous silicon dioxide which is characterized as a white powder which is insoluble in water and has a particle size dis~ribution of about 50 to about 500 microns with an average particle size of about 100 microns.
A characteristic of the products of the invention which distinguishes these products from those oE the prior art is the fac~ that the free-flowing, fat-soluble vitamin powders are substantially non-agglomerated~ The simple mixing of a fat-soluble vitamin into the adsorbent material does not result in agglomeration of the particles of the adsorbent material where the rate of addition of the fat-soluble vitamin is carefully controlled to prevent the formation of agglomerates during the mixing process.
The density of the ~itamin products of the invention is greater than 0.5 grams per cubic centimeter which is substantially greater than products of the prior art prepared, for instance, utilizing spray drying pro-cessesO Since no water is added during the preparation of such powders, the moi~ture content of the powders is influenced mainly by ~he amount of moisture absorbed from the air during preparation of the powders.
The fat-soluble vitamin powders of the invention have tableting properties which are substantially superior to those vitamin powder~ of the prior art making the ILZ~6~

tableting process more eficient and trouble free as the result of improved flow propertie3 and reduced sticking of the powder product to the tableting machine table. Varia-tior,s in tablet weights, the inadvertent preparation of soft tablets, and the lamination and cracking of tablets are substantially reduced utilizing the vitami.n powders of the invention.
The fat-soluble, vitamin products of the invention have greater bio-potency than those products prepared by th~
methods of the prior art~ In an evaluation for bio potency, as shown in the examples, the vitamin E powders of the invention were found to provide substantially greater bio-availability as compared to other vitamin E powders prepared utilizing other adsorbents having a particle size outside the range of about 50 to about 500 microns and an average particle size of about 100 microns.
The following examples illustrate the various aspects of the invention but are not intended to limit its scope. Where not otherwise specified throughout this 2~ specification and claims, temperatures are given in degrees centigrade and parts, percentages and proportions are by weight~

~Z~ig7 Example 1 This example illus~ra~es the procedure for the preparation of a free-flowing, high density, non-agglomerated vitamin E acetate powder suitable for direct compression in the formation of tablets.
Utilizing a three kilogram capacity laboratory V-blender (Patterson-Kelley) equipped with an oil addition funnel and a powder intensifier bar, sufficient hydrated silicon dioxide (lO00 grams) sold under the trademark "Hi-Sil 210" by PPG Industries, was added to make a two kilogrambatch of finished vitamin E powder. A feed grade vitamin E
acetate in the amount of 1050 grams was warmed to a tempera-ture of 60C and then introduced slowly (over a period of 20 minutes) through an addition funnel connected to the intensifier bar of the blender. The blender was operated at 20 rpm with the intensifier bar operating at 1000 rpm, while the addition was taking place.
After enough vitamin E acetate was added to produce vitamin E powder with a l to 2 percent by weight overage in potency beyond 50 percent by weight, the resul-tant adsorbate was allowed to mix for another 20 minutes under the same blender conditions. The warm vitamin E
powder was discharged from the blender and collected. After cooliny the powder to room temperature, the bulk density and particle size was determined by adding 1000 ml of the vi~amin E powder to a 1 liter graduated cylinder. The cylinder and vitamin E powder were weighed to the nearest 0.1 gram, and then the cylinder wa~ tapped 12 times ~n the bench top and the resultant volume recorded to the nearest milliliter. The bulk density in pounds per cubic foot was calculated from these measurements.
The particle size distribution was evaluated utilizing a CSC Scientific Sieve Shaker utilizing a 10 gram sample and a No, 5 setting for a period of 15 minutes.
lQ The finished vitamin E powder had a bulk density of .503 grams per cubic centimeter be~ore tappiny in the manner described above and .559 grams per cubic centimeter after tapping. The sieve analysis of this product was as follo~s:
Percent by weight retained upon the 20 mesh sieve - 2.6 percent by weight.
Percent retained on 40 mesh sieve - 6.9 percent by weightO
Percent retained on 60 mesh sieve - 18~3 percent by weight.
Percent retained on 80 mesh sieve - 14.6 percent by weight, Percent retained on 100 mesh sieve - 9.1 percent by weight, _ 9 _ ~Z~697 Percent passing through 100 mesh sieve - 48.5 percent by weight.
The flowability oE the vitamin E powder was evaluated u~ilizing a test procedure described as follows:
A device sold under the txademark FLODEX was used to test flowability. In this method~ a 50 gram sample is added to a cylinder assembly having a calibrated opening at the bottom thereof. The flow index is the reciprocal times 1000 of the diameter of the smallest oriface through which the powder will flow. The Elowability was found to be 250 which is the highest pos~ible flodex flowability rating.
Example 2 ~Comparative example - orming no part of this invention~
Example 1 was repeated utilizing a silicon dioxide sold under the trademark Zeosyl 110 by the JO M. ~uber Corporation.
The bulk density was found to be 0.389 grams per cubic centimeter before tapping and 0.422 grams per cubic centimeter after tapping. The particle size, as indicated ~ by the proportion of particles retained on standard sieves ranging from 20 mesh through 100 mesh, was evaluated on a Cenco-Meinzer sieve shaker with a setting of 7 ~or a period of 10 minutes using a 25 gram sample size. Results were as follows:

6~7 Percent by weight re~ained on the 40 mesh sieve -Ø
Percent by weight retained on the 60 mesh sieve -1.~.
Percent by weight retained on the 80 mesh sieva -13,5O
Percent by weight retained on the 100 mesh sieve -15.9.
Percen~ by weight passing through 100 mesh sieve -66.7u The flowability index as determined by the above procedure was less than 50 ~essentially no flow)~
The physical properties of the two grades of silicon dioxide utilized in Examples 1 and ~ are as follows:

:~lZ~ 7 TABLE I
cal Properties of Silicon ~ioxide P3w~ers Hi-Sil 210 (fines) ~ yl llOSD
BuLk Density 5grams/cc) 0.56 - 0.59 0.42 (lbs/Et3) 15.54 11.4 Flowabilit~ >250 no flow Par~icle Size ~stribution (% weight retained) 20 mesh sieve 0 40 mesh sieve 19 2.0 60 mesh sieve 39.2 1.~2 80 mesh sieve 20.6 13.48 100 mesh sieve 8.8 66.68 (~ weight passing through) 100 mesh sie~e 12~4 In addition to the evaluation of the physical proper~ies of the vitamin E prepared utili7.ing the above grades of silicon dioxide~ the biopotencies of ~he vitamin E
2~ powders of Examples 1 and 2 were evaluat~d utilizing selenium-deEicient, vitamin E-depleted chicks. The chick shows reduced g~owth, impaired efficiency of feed utiliza-"- ~2~ 7 tion, and the di~ease exudative diathesis unless fed adequate amounts of vitamin E or seleniu~. Use o~ a low selenium, tocopherol-free semi-purified base diet supple-mented with graded levels of each of the vitamin E prepara-tions shown in Examples 1 and 2 results in incremental improvements in growth and feed utilization and in reduced incidence of exudative diathesis. The latter parameter is most specific for available vitamin E in the diet and was used to evaluate biopotency. In making these comparative studies, a standard source of vitamin E (dl-alpha-tocopherol acetate, USP having a potency of 97.6 percent was utilized as a standard source of vitamin E against which to compare the vitamin E powders under evaluation.
In the test procedure, day-old male vitamin E- and selenium-depleted single comb, white leghorn chicks were used. These were housed in thermostatically controlled battery brooders equipped with raised wire floor3. Feed and water was provided as required. The chicks were fed a low ~elenium tless than 0.02 ppm) tocopherol-free semi-purified diet containing adequate amounts of all other nutrients.

The diet was supplemented with graded leYels of vitamin E.
The chicks were reared to two weeks of age. The gain in incidence of exudative diathesis wa~ recorded for triplicate lots of ten chicks each per treatment. The experiment was a 7x6 factorial design employing 1080 chicks.

~2~4J 6~7 The comparative results of the eficacies of the various sources oE vitamin E are shown in Table II below.
These results indicate a substantial improvement in bio-availablility of the vitamin E in the powder prepared in Example 1 as opposed to the vitamin E powder of Example 2.
The close similarity to the standard vitamin E oil used for comparative purposes indicates that very little improvement can be attained over the present efficacy of the vitamin E
powder of Example 1 which is ~ubstantially superior in bio-availability to the vitamin E powder of Example 2 TABLE II

Relative Efficien~ of Vit~n E ~ers in Preventing Exudative ~athesis Source of Vit ~ n E EC50+ (IU/kg) 95~ Confidenoe Limits Standard Vitamdn E Oil ..
dl-alpha-tocophe~ol acetate, USP
97.~
poten~y 20 13.1 - 30.6 Example 1 Vitamin E p~er 23.7 21.6 - Z6.0 Exa~ple 2 Vitamin E p~er 35.7 26.4 - 53.1 ~ level required to protect 50 per~ent of the chlck population fnom exudative diathesis expressed in international units of each prepara-tion.

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Wh.ile this invention has been described with reference to certain ~pecific e~bodiments, it will be recognized by those skilled in the art that many variations are possible without departing from the scope and spirit of the invention, and it will be ~lnderstood that it is intended to cover all changes and modifications of the invention disclosed herein for the purposes of illustration which do not constitute departures from the spirit and scope of the invention.

Claims (7)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A stable, biologically available vitamin-containing composition in substantially non-agglomerated particulate form consisting essentially of:
(a) a nutrient material comprising at least one fat-soluble vitamin material, and (b) a silicon-containing particulate material having a particle size distribution of about 50 to about 500 microns.

2. The composition of claim 1 wherein said fat-soluble vitamin material is selected from the group con-sisting of vitamins A, D, E, K and esters thereof and said silicon-containing particulate material is an amorphous silicon dioxide.

3. The composition of claim 2 wherein said composition has an active vitamin content of about 40 to about 60 percent and said fat-soluble vitamin is vitamin E
or vitamin E acetate.

4. A process for making a dry, finely divided, free-flowing vitamin-containing substantially non-agglomerated particulate composition comprising:

(a) adding a silicon-containing material having a particle size distribution of about 50 to about 500 microns to a container and there-after (b) adding thereto while mixing a liquid form of a nutrient material comprising a fat-soluble vitamin material.

5. The process of claim 4 wherein said fat-soluble vitamin material is selected from the group con-sisting of vitamins A, D, E and K and esters thereof and said silicon-containing particulate material is an amorphous silicon dioxide.

6. The process of claim 5 wherein the proportions of (a) and (b) are adjusted to produce a vitamin product having about 40 to about 60 percent vitamin-active compo-nent.

7. The process of claim 7 wherein said fat-soluble vitamin is vitamin E or vitamin E acetate.