JOURNAL OF PHARMACEUTICAL OCTOBER 1982 VOLUME 71 NUMBER 10 SCIENCES @

LITERATURE SURVEY

Vitamins in Pharmaceutical Formulations

ELMER DeRITTER Received from the Product Development and Application, Roche Chemical Division, Hoffmann-LaRoche, Nutley, NJ 071 10.

Keyphrases 0 -pharmaceutical formulations, literature choice of the optimal pH is a crucial factor. Interactions survey Pharmaceutical formulations-vitamins, literature survey between some of the vitamins and between vitamins and other product constituents must also be considered. Suc- cessful development of products requires knowl- edge of the fundamental aspects of the physical and CONTENTS chemical properties of the various forms of the vitamins Solubility of the Vitamins 1073 available, the use of adequate techniques of manufacture, Stability Characteristics of the Vitamins 1074 and the addition of suitable manufacturing overages based Degradation Studies 1075 on critical stability studies. Mutual Interactions of the Vitamins 1077 pH-Stability Relationships 1078 In Aqueous Model Systems 1078 SOLUBILITY OF THE VITAMINS In Aqueous Products 1079 Vitamins are categorized into two general groups: fat- Factors that Enhance Vitamin Stability 1079 Reduction of Water Content 1079 soluble and water-soluble. The fat-soluble vitamins include Antioxidants 1080 vitamins A, E, and K and (). Vi- Chelating Agents 1080 tamin A is available as the free alcohol, , and its Other Compounds 1080 acetate, palmitate, and propionate esters. is Coating and Encapsulation 1082 listed by USP as both d- and dl-forms of and Preparation of Adsorbates 1082 Protection from Light 1083 its acetate and acid succinate esters. Cholecalciferol is Lyophilization 1083 normally utilized in pharmaceuticals as Formulation of Vitamin Products 1083 (vitamin D2) or cholecalciferol (vitamin D3), both of which Aqueous Emulsions of Fat-Soluble Vitamins 1083 are equally active in humans. Oil-soluble forms of vitamin Injectables 1083 Tablets 1085 K include phytonadione (vitamin KI), , Oral Single Vitamin Liquids 1086 menadiol diacetate, and menadiol dibutyrate. Jncorpora- Oral Multivitamin Liquids 1086 tion of fat-soluble vitamins into an aqueous preparation Ointments, Creams, and Lotions 1087 requires the use of an efficient emulsifying agent (e.g., Syrups 1087 polysorbate 80) to produce homogeneous and physically Capsules 1087 Prediction of Vitamin Stability from Accelerated Aging Tests 1088 stable formulations. In the case of , there are a Bioauailability Testing of Vitamin Products 1088 number of water-soluble forms such as menadiol sodium Absorption and Excretion Patterns of the Vitamins 1088 diphosphate, the dipotassium salt of menadiol disulfate, Absorption Tests 1090 and menadione sodium bisulfite. Outline of the Testing Program 1090 References 1092 Solubilities of the water-soluble vitamins at 25" in water are listed in Table I. For several of the relatively insoluble The formulation of pharmaceutical vitamin products vitamins such as and , the solubility is having adequate physical and chemical stability as well as dependent on the nature of the crystal structure. For acids suitable taste, odor, color, and freedom from bacterial such as biotin and folic acid, addition of alkali significantly contamination can entail numerous problems arising from increases solubility. In the case of biotin it is possible to the differing physical form, stability, and solubility char- prepare a 20% aqueous solution of the sodium salt by this acteristics of the individual vitamins. For liquid products, method. Figure 1 illustrates the increasing solubility of

0022-3549182101000- 1073$0 1.00/0 Journal of Pharmaceutical Sciences I 1073 @ 1982. American Pharmaceutical Association Vol. 71,No. 10. October 1982