الفهرس 
RiboflavineOnly 14 pages are availabe for public view
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Abstract
Although classified among the water-soluble vitamins, riboflavine is very sparingly soluble in water. A contri¬bution to the investigation of some major problems encount¬ered in the formulation of preparations of riboflavine-specifically solutions - is presented in this thesis. The two major problems dealt with were solubility and solubili¬zation (part 1), as well as, stability (part 2). Inside this frame of work, investigations were directed to throw some light on the rules and mechanisms governing the series of phenomena which are grouped under the name of ”hydrotropy” br Part 1 br In this part, the effect of temperature, pHf as well as, of several hydrotropic agents on the solubility of ribofla¬vins was investigated. A study of the mechanisms governing the hydrotropic action of these agents were also presented. Complex formation between riboflavine and these agents was studied spectrophotome trie ally, ..The formation constant and the molar extinction coefficient of the formed complex¬es, as well as, the enthalpy and entropy changes of complex formation were also calculated. Besides this, investigation of the solubility of riboflavine in the presence of micellar br ructurea» and non—aqueous solvents was also studied, ese investigations reveal the following: br 1. The solubility of riboflavine in water is increased with increasing temperature -#102;-#114;-#111;-#109; 10° to 40°C, however, the increase in solubility proceeds at different rates depending on the temperature; above 30°C,the rate is greater than that below this temperature. br 2. Increasing the pH -#102;-#114;-#111;-#109; 2.75 to 3.83 increases the sol¬ubility of riboflavine; at pH-values -#102;-#114;-#111;-#109; 3.83 to 8.50, the solubility of riboflavine is not altered, while at pH-values higher than 8.50, the solubility is greatly increased. br 3. The following anions exert a salting-out effect towards riboflavine: F~, CI”, S0~ , HgPO^ and HP0^~, while the Br”, I””, NOJ , CIO^ and SCN~ exhibit a salting-in effect. br 4. The alkali and alkali earth metals decrease the solubil¬ity of riboflavine in water. br 5. The sodium salts of the lower fatty acids, and those of the hydroxy aliphatic acids suppress the solubility of ribo¬flavine in water. On the other hand, their amides and chloro derivatives exhibit a solubilizing effect towards riboflavine. br thiourea and urethane increase the solubility of oflavine in water; thiourea being a better solubili-’;*r than urea or urethane. The solubilizing effect of ”urea or urethane is attributed to molecular complex s-lt; formation with riboflavine. On the other hand, the solubilizing action of thiourea is due to its hydrotro-pic activity, besides complex formation with riboflavine. br • All of the investigated aromatic compounds exhibit a solubilizing effect towards riboflavine. The majority of these compounds form molecular complexes with ribo¬flavine; their solubilizing power runs parallel with the stability of the formed complex. On the other hand, the entropy changes for all of the systems studied dec¬rease in complex formation processes, and the values of the molar extinction coefficient of the complexes are independent of temperature. This reveals the formation of only one species of one to one molecular complex. In addition, it may be concluded that complex formation may be attributed to charge-transfer force or to hydro¬gen bonding, since the enthalpy changes are only few kcal/mole. br 8. The solubilizing power of the sodium salts of the follow¬ing acids towards riboflavine shows this .sequence in terms of decreasing activityJ 1-naphthoic, diphenyl br acetic, benzoic, phenyl acetic, nicotinic and mandelic. acids. br • 9. Nicotinamide exhibits a solubilizing action towards riboflavine which is greater than that of sodium nico-tinate. br 10. The introduction of a hydroxyl or amino group in the ortho- position of the aromatic nucleus of sodium benzoate increases its solubilizing power, while the o-chloro and the o-nitro derivatives are less active. br On the other hand, the introduction of a hydroxyl, amino or methyl group in the para- position enhances the sol¬ubilizing action of sodium benzoate. br 11. Sodium p-aminosalicylate possesses a pronounced solub¬ilizing effect towards riboflavine due to the great stability of its molecular complex with riboflavine. br 12. The introduction of more than one hydroxyl group into the nucleus of sodium benzoate increases, to a great extent, its solubilizing power towards riboflavine; solubilization is proportional to the number of hydro¬xyl groups attached to the aromatic nucleus. br 15. Gentisic acid, sodium gentisate and gentisic acid br ©thanolamide possess great solubilizing action towards br rj the latter compound, in virtue of the very -gt;ility of its molecular complex with riboflavine, Eta a surprisingly great solubilizing effect towards .avlne. br kicylic acid ethanolamide is a better solubilizer for *lavine than sodium salicylate. br non-ionic surface-active agents increase the solu-fMlity of riboflavine only to a little extent. On the ^ Other hand, the solubilizing power of the ionic surface-r; active agents towards riboflavine is greater than that ( of the non-ionic ones. ) The solubility of riboflavine in 1,2-propylene glycol, polyethylene glycol 200 and polyethylene glycol 400 is greater than that in water; the solubilizing effect of polyethylene glycol 400 being greater than that of 1,2-propylene glycol or polyethylene glycol 200. br ^he great similarity between the above-mentioned results and most of the previously reported ones regarding the effect of hydrotropic agents on the solubility of compounds of various and very different chemical structure asj amidopyrlne, isopropylphenazone, l-phenyl~5-methyl pyrazolone (5)» caffeine, theobromine, p-aminoazobenzene, •Y-butyrolaefcone, diethylether, aniline, acetone, br 4-dinitrophenol and veronal, reveals that the action of hydrotropic agents is, to a great extent, independent the structure of the solubilized substance itself, ms, the following rules governing the process of hydro- , tropy can be concluded: br A) The hydrotropic activity of the inorganic salts is generally weak; of this class of compounds only the thiocyanates and the perchlorates, owing to their large ionic radius, show a relatively high hydrotropic action. br B) Water-soluble aromatic compounds with one or more hydro-xyl, amino or carboxylic groups directly attached to the aromatic nucleus possess a high hydrotropic activity; the corresponding aliphatic derivatives lack this hydrotropic action. On the other hand, when the aromatic nucleus is not directly attached to the hy-#68;-#82;-#79;-#80;hilic carbo¬xylic group, its solubilizing effect is decreased. The hydroxyl and amino groups are more effective for increas¬ing the solubilizing power of the molecule when present in br ^the ortho- positian to the carboxylic group than when .introduce^ into the para- position. br i br C) Increasing the hy-#68;-#82;-#79;-#80;hobic part of the molecule by br increasing the number of aromatic rings increases greatly its hydrotropic activity. br ncreasing the size of the alkyl groups attached to the ifflomatlc nucleus of the molecule increases its hydrotro-pic action. br Aromatic compounds with more than one hydroxyl group attached to the aromatic nucleus are powerful hydrotropic agents. br Part 2 br This part deals with the study of the stability of riboflavine solutions. This comprises investigations for finding out and furnishing the most suitable conditions for stabilizing solutions of this vitamin. This was covered by the investigation of the effect of the factors associat¬ed with the nature of the vehicle, its hydrogen ion con¬centration, as well as, with buffer systems on the stabi¬lity’ of riboflavine solutions. On the other hand, invest¬igation of the stability of riboflavine in solubilized systems was also attempted. The investigations included in this part reveal that; br 1. The stability of riboflavine is not affected by the ionic strength of the solution. br 2, The degradation of riboflavine in solution proceeds as a fiist-ordej? reaction independent of its hydrogen ion concentration or the type of buffer system used. br le stability of riboflavine solutions is highly depen¬dent oc the pH. In the pH range of 2.2 to 3.0, the ^stability is very low; above pH 3.0, the stability of I riboflavine is increased reaching its absolute maximum at pH 4,5, At pH-values higher than 4.5, the stability decreases once again, the degradation rate increases gradually in the pH range of 4.5 to 6.0; beyond which, there is a very sharp increase in the degradation rate of riboflavine. br The stability of riboflavine in Clark and Lub’s phthalate buffer solutions is very great as compared to its stab¬ility in the Sorensen*s glycine or in the Mcllvaine’s citric acid-phosphate buffer solutions. br . 1,2-Propylene glycol, polyethylene glycol 200 and poly¬ethylene glycol 400, in proportion to their concentrat¬ion, exhibit a stabilizing effect towards riboflavine solutions; polyethylene glycol 200 being more efficient than 1,2-propylene glycol or polyethylene glycol 400. The degradation rate constant of riboflavine decreases linearly with increasing glycol concentration. br . The stability of riboflavine in solubilized systems in presence of hydrotropic agents capable of complexation with riboflavine is proportional to the stability of the formed complex. br oate and its hydroxy derivatives exhibit a jlsing action towards riboflavine solutions kept -C. Sodium benzoate itself possesses no stabili-properties towards riboflavine solutions kept at ~-lt;3f due to dissociation of the formed complex at this ga temperature. On the other hand, the hydroxy deri-. stives of sodium benzoate exert a stabilizing effect owards riboflavine solutions kept at 70°C, due to the Relatively high stability of their respective molecular complexes with riboflavine. br odium p-aminobenzoate and sodium p-aminosalicylate increase the stability of riboflavine solutions; the .stabilizing effect of the latter solubilizer being greater than that of the former one. br Sodium gentisate and gentisic acid ethanolamide possess great stabilizing action towards riboflavine solutions. The stabilizing effect of gentisic acid ethanolamide, in virtue of the high stability of its molecular complex with riboflavine, is extremely great.