The application of vitamins in pharmaceuticals and for the fortification of food and animal feeds can of course be achieved to a degree with vitamin-rich natural materials such as yeast, wheat-germ etc., or with concentrates or extracts prepared from such products. These, however, are now seldom able to meet the critical requirements of the modern processing industries. Most of such materials have rather low and also varying contents of the vitamins, and they often contain additional substances which adversely affect the organoleptic properties and storage stability of the products in which they are included; further, they frequently occur in forms unsuitable for many applications.
Advances in organic chemistry and the development of new techniques have now made possible the economic synthesis of most vitamins on an industrial scale, and the use of synthetic vitamins is now the predominant practice in human and animal nutrition as well as in medicinal products. Many experimental studies have shown that the synthetic compounds are identical in all biological properties with the naturally occurring vitamins, and the identity of the activity of the synthetic and the corresponding natural vitamins has been well established.
Application forms
The industrial production of vitamins with a high degree of purity, has largely solved the organoleptic problem as well as the difficulty of providing accurate, known quantities. A further problem, however, was that many vitamins are very sensitive substances, unstable in adverse environments, so that the development of more stable forms became necessary for their extended application in the food and animal feed industries. Certain other properties of some pure vitamins, such as their solubility, physical state, concentration etc., also restrict their usage possibilities, so that special forms had to be created, more suitable for specific applications.
Formulations of the vitamins suitable for the most varied purposes can be prepared by the following methods:
The synthesis of stable derivatives.
The addition of stabilisers (antioxidants).
Standardisation with suitable fillers.
Coating with suitable carrier substances.
The transformation of water-soluble vitamins into fat-soluble derivatives.
The transformation of fat-soluble vitamins into "water-soluble derivatives or water-dispersible formulations.
All these methods are used in the manufacture of commercial vitamin formulations. The simultaneous use of several of these procedures is often involved, the method of choice being determined by the desired relationship between physical properties and biological activity.
The most important properties relevant to the use of the various vitamins, and the usual commercial forms, are as follows.
Fat-soluble vitamins
Vitamin A is extremely sensitive to oxidation. Its destruction by atmospheric oxygen is accelerated catalytically by light, especially by ultraviolet light, and also by metal salts, peroxides, and heat, particularly in the presence of moisture. Destruction of the vitamin is also facilitated by the finely divided state which is necessary to ensure homogeneity and optimal absorption.
The instability of vitamin A-alcohol, the essential form of vitamin A, has led to the industrial preparation of its somewhat more stable esters, the acetate and palmitate. Additional stability can be achieved by dissolving these in vegetable oils; and further stabilisation obtained by the addition of anti-oxidants, which can also be combined with synergists and complexing agents. Such forms of vitamin A can be used directly in fats and oils.
The oily forms of vitamin A however, are unsuitable for processing in dry preparations such as animal feeds. For such purposes dry powder preparations have been developed, in which the vitamin A is deposited in a carrier substance. The most important carrier for stabilising vitamin A is gelatine, in which the vitamin A must be present as extremely finely divided droplets to ensure rapid absorption. The particle size of such powders should be between 150 and 500 , (diameter), and the concentration approx. 500,000 IU vitamin A per gramme, in order to ensure satisfactory dispersion in compound feeds and similar products.
The criteria of particle size and concentration necessitate compromise solutions. Larger particles, having relatively smaller surface areas, are more stable, but they result in more irregular distribution of the vitamin A in a mix. Smaller particles are less stable because of their relatively larger surface areas. Highly concentrated powders are thus unfavourable for the distribution of vitamin A in a feed; on the other hand lower concentrations lead to increased costs.
In addition to these dry powder forms, liquid water-miscible formulations have also been developed. The use of appropriate emulsifiers produces aqueous dispersions which are suitable for the preparation of solutions and syrups for human medicine, and for veterinary use as injections and for the enrichment of drinking water.
Vitamin D (D2 and D3) is also sensitive to oxidising agents, light, and acids. Since the considerations of stability and application for vitamin D closely resemble those for vitamin A, similar commercial forms have been developed (oily solutions, stabilised powders and aqueous dispersions).
Vitamin E is used mainly in the form of the relatively stable -tocopheryl acetate, since the unesterified tocopherols are rapidly oxidised and darkened by atmospheric oxygen. In the presence of moisture the vitamin E-ester is hydrolysed by acids or alkalis. Vitamin E is also therefore processed to more stable forms, and adsorbates, granulates and water-miscible preparations are now commercially available.
Vitamin K1 is slowly degraded by atmospheric oxygen, but is very rapidly affected by light and alkalis; it is however, relatively stable to heat.
Water-soluble vitamins
The water-soluble vitamins are generally stable in the pure state. In aqueous solution, however, they are more sensitive to a number of factors.
Thiamine hydrochloride, the most important commercial form of vitamin B1 is stable if protected from light and moisture. In aqueous solution the stability of vitamin B1 is markedly pH-dependent.
Stability is optimal at pH 3.0, and is still good at pH 4.5. In neutral or alkaline solution however, particularly in the presence of oxidising or reducing agents, or if heated, vitamin B1 is unstable and is converted to inactive compounds; heavy metals accelerate this destruction.
In the presence of vitamin B2, vitamin B, is oxidised in aqueous solution to thiochrome. This process is facilitated by increasing concentration of vitamin B2 and by the presence of atmospheric oxygen.
In dry preparations the degree of humidity is important for stability. When conditions are such that the hydrolysis and oxidative decomposition of thiamine are likely, it is advantageous to use the less sensitive thiamine mononitrate instead of the more usual hydrochloride. Thiamine mono-nitrate is also prepared in coated forms to improve its stability, and to reduce its odour and taste.
Vitamin B2 (Riboflavin) is unstable to powerful reducing agents, alkalis and light. It is only sparingly soluble in water; to increase the solubility of riboflavin, solubilisers such as nicotinamide or salicylic acid are used. Optimal stability of solutions is at pH 3.5-4.0.
The sodium salt of riboflavin-5'-phosphate is considerably more water-soluble. Its stability characteristics are similar to those of riboflavin, but it reacts with heavy metal ions and especially with calcium to form insoluble metal salts; the addition of chelating agents can prevent this reaction.
In aqueous solutions, riboflavin acts as an oxidising agent to vitamins B1, C and folic acid. It also acts as a photosensitiser and hydrogen acceptor in the light-induced oxidation of folic acid and vitamin C.
Riboflavin has an unpleasant, lasting bitter taste, but dry preparations of this vitamin are also available in coated form.
Vitamin B6 (Pyridoxine) in the usual commercial form of the hydro-chloride is generally stable to heat and oxygen. It is degraded by light in neutral or alkaline solutions, and to a lesser degree in acid solution; optimal stability is in the region of pH 3.0-5.0.
A coated preparation of pyridoxine hydrochloride is also commercially available for special applications.
Pure crystalline vitamin B12 (cyanocobalamin) is relatively stable to air in the dry state and in neutral to weakly acid solutions; optimal stability is at pH 4.5-5.0. Destruction of vitamin BI2 only occurs at elevated temperatures, but this destruction is increased in the presence of vitamin B1 and, more particularly, nicotinamide. In solution vitamin B12 is also sensitive to light, especially ultraviolet light. Vitamin C and its oxidation products (e.g. dehydroascorbic acid), in the presence of copper, manganese, molybdate or fluoride ions, as well as alkalis or reducing agents, degrade vitamin B12. Vitamins B2, B6 and panthenol, however, are compatible with vitamin B12.
Dry powder dilutions containing from 0.05% to 1.0% of vitamin B12 on a base of, e.g. mannitol or dicalcium phosphate; stabilised adducts on ion-exchangers; and preparations with a gelatine base are now commercially available. For animal feed supplementation, fermentation concentrates are commonly used; these have contents of up to i per cent vitamin B12.
Biotin is stable to oxygen, daylight and heat in the dry crystalline state. Ultraviolet light or powerful oxidising agents can destroy biotin. In strongly acid or alkaline solutions its biological activity falls rapidly. For the enrichment of animal feeds, a diluted product with a standardised content of 1% biotin is available.
Pure, crystalline folic acid is stable to air and heat, bat is degraded by light, especially ultra-violet light. It is most stable in neutral to weakly alkaline media. It is destroyed by acids, strong alkalis, metal salts and by reducing and oxidising agents. Vitamin B, is slightly - and vitamin B2 markedly - destructive to folic acid. Panthenol, nicotinamide and vitamin B6 however, are compatible with folic acid.
Nicotinic acid amide, in the pure anhydrous form and also in aqueous solution, is stable to air, daylight and heat. Ultraviolet light slowly destroys nicotinamide. Strong acids, strong alkalis and also some heavy metals reduce its biological activity.
Nicotinamide is also available in a coated form.
D-Pantothenic acid, as a compound, is very sensitive to many factors, and it is therefore produced commercially as the calcium and sodium salts which possess good stability providing moisture is excluded.
Aqueous solutions of pantothenic acid salts are only stable to a degree at pH 5.0-7.0; they are sensitive to heat and tend to hydrolyse, especially in the presence of acids and alkalis.
For liquid preparations, D-Panthenol (the alcohol corresponding to D-Pantothenic acid) - has been developed; its aqueous solutions at pH 4.0-7.0 are significantly more stable and can be heat-sterilised.
Crystalline Vitamin C (ascorbic acid) is relatively stable in air under anhydrous conditions; the sodium salt however, tends to turn yellow with time. Aqueous solutions of ascorbic acid are sensitive to oxidising agents, decomposition being accelerated by alkalis and traces of heavy metal ions (particularly Cu); to minimise oxidation, solutions are treated with metal (Cu)-complexing agents at a pH below 6.0. In multi-vitamin solutions and
syrups the stability of ascorbic acid falls as the content of water present increases. The vitamins B1, B2 and nicotinamide adversely affect the stability of ascorbic acid, but thiamine is compatible. Vitamin B2 absorbs blue light and, in the presence of air, can catalyse the photo-oxidation of ascorbic acid. The destructive effects of vitamin C and vitamin B2 are reciprocal; vitamin C is also destructive to folic acid and vitamin B12.Ascorbic acid is also available commercially as its sodium and calcium salts and in coated preparations.
Vitamin Compendium. The Properties of the Vitamins and their Importance in Human and Animal Nutrition. Vitamin and Chemicals Department. F. Hoffmann-La Roche & Co. Ltd, Basle. Switzerland
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