University of Rhode Island DigitalCommons@URI Open Access Master's Theses 1969 The Solubility of Several Barbituric Acid Derivatives in Hydroalcoholic Mixtures Thomas L. Breon University of Rhode Island Follow this and additional works at: https://digitalcommons.uri.edu/theses Recommended Citation Breon, Thomas L., "The Solubility of Several Barbituric Acid Derivatives in Hydroalcoholic Mixtures" (1969). Open Access Master's Theses. Paper 183. https://digitalcommons.uri.edu/theses/183 This Thesis is brought to you for free and open access by DigitalCommons@URI. It has been accepted for inclusion in Open Access Master's Theses by an authorized administrator of DigitalCommons@URI. For more information, please contact [email protected]. ( THE SOLUBILITY OF SEVER...l'l,L BARBI'TURIC ACID DERIVATIVES I N HYDROA LCOI10LIC MIX'l'URES BY THOMAS L. BREON ( A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN PHARMACEUTICAL SCIENCES UNIVERSI'l'Y OF RHODE ISL..A.b<'D ( 1969 TITLE ABSTRACT ( SOLUBILITY OF SEVERAL BARBITURATES ( ( ·MASTER OF SCIENCE THESIS OF THOMAS L. BREON Approved: Thesis Committee: Dean of the Graduate School UNIVERSITY OF RHODE ISLAND 1969 ( ABSTRACT The solubility profiles for metharbital, butabar- bital, thiopental and thiamylal were determined in ethanol- 0 . w·ater solvent. systems at 25 c, in an attempt to define an approximate correlation between therapeutic activity and various solubility relationships. The relative lipophilic- ity of a drug molecule is an important factor in the physical and chemical processes involved when the therapeutic agent is introduced into a biological system. Binary solvent ( mixtures aid in delineating the relative polarity, in terms of dielectric constants, of these drugs. Spectrophotometric and, where applicable, gravimetric analyses, were utilized to determine the concentration of drug, in mg./ml., in the 41 solvent systems ranging in composition from pure ethanol to pure water. The dielectric requirement (DR) of the bar- biturates investigated, and thos e reported for barbital and vinbarbital, illustrated an approximate inverse relationship with the number of carbon atoms in the molecule. A similar correlation was found with the solubilities in pure water, and the ratios of the solubilities in ethanol and at the DR ( ii ( to the solubility in water. The therapeutic indices of duration of action and the period of time involved between administration of the drug and the time when the activity is first manifested, increased as the relative polarity of these barbiturates declined. The duration of these pharrna- cological parameters were also found to increase with a corresponding reduction in the hydrophilic nature of this series of compounds. ( iii TABLE OF CONTENTS PAGE ABSTRACT ii 'l'ABLE OF CONTENTS . iv LIS':l'S OF 'l.1 ABLES • v LIS'l1 OF FIGURES . viii I. INTRODUCTION 1 II. PAST WORK . 3 ( III. EXPERIMENTAL 15 IV. DISCUSSION 21 V. SUMMARY .. 88 VI. REFERENCES 90 VII. APPENDIX 95 A. Computer Program Calculating Least Squares . • . 96 B. Program Calculating Concentrations from Absorbances . 97 c. Program computing Ayerages and Standard Dev iation~ . 98 D. Program Computing Differences 98 E. Description of Polynomial Regression Program . • 99 F. Program calculating Ratios 99 iv ( LIST OF TABLES TABLE PAGE I. Ultraviolet absorption maxima in milli­ microns, determined spectrophotometrically compa red with literature values . 19 II. Substituents found in the noted positions for Barbituric Acid derivatives used in this study 22 III. Solubility of Barbital in ethanol-water mixtures in mg./ml. at 25°c, as a function of w/w percent water and dielectric con­ stant . 25 ( IV. Solubility of Metharbital in ethanol-water mixtures in mg./ml. at 25°c, as a function of w/w percent water and dielectric con­ stant . 28 v. Solubility of Butabarbital in ethanol-water 0 mixtures in mg./ml. at 2s c, as a function of w/w percent water and dielectric con­ stant . 34 VI. Solubility of Vinbarbital. in ethanol-water mixtures. in. mg. I m1 . at 2 5 ° c, as a function· of w/w percent wate r and dielectric con­ stant . 36 VII. Solubility of Thiopental in ethanol-water 0 mixtures in mg./ml. at 2s c, as a function of w/w percent water . and dielectric con­ stant . 40 v ( TABLE PAGE VIII. Solubility of Thiamvlal in ethanol-water mixtures in mg./ml.~ at 25°c, as a function of w/w percent water and dielectric con- stant ·. 43 IX. Solubilitv of Barbituric Acid in ethanol- wa t~r mix~ures in mg./ml. at 25°c, as a function.of w/w percent water and dielectric constant 46 X. Rates of change in solubility in mg./percent w/w water, calculated from the linear range of the solubility profiles . 49 XI. Differences in the solubility of Metharbi tal 0 and Barbital in mg./ml. at 2s c, as a function of percent w/w water and dielectric constant. 51 XII. Difference in the solubility of Butabarbital and Barbital in rng./ml. at 25°c, as a ( function of percent w/w water and dielectric con st ant . 54 XIII. Solubility of Vinbarbital in ethanol-water mixtures in rng./rnl. at 25°c, computed from a polynomial , versus w/w percent water and dielectric constant . 58 XIV. Differences in the solubility of Vinbarbital and Barbital in mg./rnl. at 25°c, as a function of percent w/w water and dielectric constant . • . 59 xv. Differences in the solubility of Thiopental and Barbital in mg./ml. at 25°c, as a function of percent w/w water and dielectric con- stant . .· • . 62 XVI. Differences in the solubility of Thiamylal and Barbital in mg./ml. at 25°c, as a function of percent w/w water and die- lectric constant . 65 ( vi ( TABLE PAGE XVII. Ratios of the solubilit y of Me tharbital to 0 Ba rbital at 2s c, as a fun ction of per­ cent w/w water a nd die lectric constant 69 XVIII. Ratios of the s olubility of Butabarbital to Barbital at 25°c, as a f unction of p ercent w/w wate r and dielectric c on­ sta nt . 71 XIX. Ra tios of the solubilit y of Vinbarbital 0 to Barbital at 2s c, as a function of percent w/w water and dielectric constant . 74 XX. Ra t ios of the solubility of Thiopental to Ba r b ital at 25° c, as a function of percent w/w water and dielectric con­ stant . 77 X...XI. Ratios o f the solubility of Thiamylal to 0 Barbital at 2s c, as a function of per­ ( cent w/w water and dielectric constant 79 XXII. Dielectric requirement, the solubilities in absolute ethanol, water and at the dielectric requirement in mg . /ml., as a function of the duration and onset of action 82 XXIII. Therapeutic action, and the ratios of the solubility in ethanol and at the dielectric requirement to the solubility in water 85 vii ( LIST OF FIGURES FIGURES PAGE Solubility of Barbital at 25°c in mg./ml. as a function of composition (w/w) for ethanol-water mixtures . · . 26 2. Solubility of Metharbital at 25°c in mg. /ml. as a function of composition (w/w) for ethanol-water mixtures . 29 3. Enol-keto tautomerism of the Barbituric Acid derivatives . 31 4. Solubility of Butabarbital at 25°c in mg. /ml. in the binary solvent systems ·c studied . 35 5. Solubility of Vinbarbital at 25°c in mg./ml. versus percent water by weight in the binary solvents studied . 37 0 6. Solubility of Thiopental at 25 c in mg./ml. as a function of composition (w/w) for ethanol-water mixtures . 41 7. Solubility of Thiamylal at 25°c in mg. /ml. as a function of percent w/w water 44 8. Solubility of Barbituric Acid at 25°c in mg./ml. as a function of composition (w/w) for ethanol-water mixtures . 47 9. Plot of the difference of the magnitude of s 1- ubility for Metharbital and Barbital in rn j. /ml. for the binary systems studied 52 ( viii f FIGURE PAGE 10. Plot of the difference in the magnitude of solubility for Butabarbital and Bar­ bital in mg./ml. as a function of com­ position (w/w) for ethanol-water mixtures 55 11. Difference in the magnitude of solubility for Vinbarbital and Barbital expressed in mg. /ml. plotted as a function of percent water by weight . 60 12. Plot of the difference in the magnitude of solubility for Thiopental and Barbital in mg./ml. for the binary systems investigated 63 13. Plot of the difference of the magnitude of solubility for Thiarny l al and Barbital ex­ presse d in rng./ml. as a f unction of solvent composition . • . 66 14. Solubili ty of Metharbita l relative tq the solubility o f Barbital versus percent by ( weight water in the solvent systems studied. • . 70 15. Ratio of the solubility of Butabarbital to the solubility of Barbital as a function of composition (w/w) for ethanol-water systems. 72 16. Plot of the solubility of Vinbarbital rela­ tive to the solubility of Barbital for each of the binary systems studied . 75 17. Solubility of Thiopental relative to the solubility of Barbital plotted as a function of solvent composition 78 18. Solubility of Thiamylal relative to the solubility of Barbital versus percent water by weight . so I \ ix t I. INTRODUCTION The pharmacological action exerted by a drug molecule in contact with a biological system is the net result of the interaction s and extent of interactions with the c omplex biological environment. The degree as well as the rate of intera ction is governed by many parameters, many of which de­ pend on the physical and chemical properties associated with the drug molecule.