Communications Project

Document Type:Dissertation
Name:Phyllis R. Eckard
Title:The Investigation of Primary and Secondary Modifiers in the Extraction and Separation of Neutral and Ionic Pharmaceutical Compounds with Pure and Modified Carbon Dioxide
Degree:Doctor of Philosophy
Committee Chair: Larry T. Taylor
Committee Members:Neal Castagnoli, Jr.
James O. Glanville
Gary L. Long
Harold M. McNair
Gregory C. Slack
Keywords:Supercritical, Extraction, Chromatography, Pharmaceuticals, Trapping Capacity, Secondary Modifiers, Additives, Ion-Pairing, SFC, SFE, MEVACOR, Triphenylphosphinetrisulfonate, Pseudoephedrine Hydrochloride, Phospholipids
Date of defense:February 20, 1998
Availability:Release the entire work for Virginia Tech access only.
After one year release worldwide only with written permission of the student and the advisory committee chair.


A successful supercritical fluid extraction method includes removal of the analyte from the matrix into the bulk fluid as well as trapping or concentration of the analyte prior to analysis. In the first phase of this research, the trapping capacities of three solid­phase traps (glass beads, 50/50 (w/w) glass beads/octadecylsilica), 50/50 (w/w) Porapak Q®/glass beads) were determined as a function of trap composition for a mixture of components varying in polarity and volatility. The Porapak Q®/glass beads mixture was found to be the most successful solid­phase investigated exhibiting the highest trapping capacity. The use of the Porapak Q®/glass beads as a solid­phase trap was investigated in later extraction studies in this dissertation.

The extraction of highly polar, multifunctional analytes may not be completely successful with modified carbon dioxide, therefore, a secondary modifier (i.e. additive) may be added directly to the extraction fluid in hopes of improving the recoveries. In the second phase of this research, the effect of secondary modifiers in the subcritical fluid extraction of lovastatin from in­house prepared tablet powder mixtures and MEVACOR® tablets was investigated. The effect of in­line methanol­modifier percentage, additive type (acidic, basic, neutral) to the in­line methanol, and additive concentration on the extraction efficiency were examined. The extraction recoveries of lovastatin from MEVACOR® tablets were shown to be highly dependent on methanol concentration and additive type. Isopropylamine was shown to be the most successful additive investigated. An optimized and reproducible extraction method was developed.

The extraction of ionic compounds with carbon dioxide may be difficult due to the high polarity of the compounds. In the third phase of this research, the addition of ion­pairing additives to the matrix in hopes of forming an ion­pair complex of reduced analyte polarity was investigated. Therefore, a screening study consisting of a fractional­factorial design was performed in order to identify the factors which contribute most to the recovery of an anionic species, triphenylphosphinetrisulfonate (TPPTS), from a spiked­sand surface employing supercritical fluid extraction with carbon dioxide. The experimental parameters investigated were: type of ion­pairing additive (i.e. tetralkylammonium hydrogen sulfates) and its concentration, carbon dioxide density, extraction temperature, static extraction time, CO2 mass used, liquid CO2 flow rate, and the volume of methanol spiked into the matrix prior to extraction. Of the eight factors investigated, four factors were identified as significantly affecting the recovery of the anionic species. They were: 1) ion­pairing reagent added to the spiked sand surface and its concentration; 2) static extraction time; and 3) volume of methanol present in the extraction vessel. The experimental parameters and settings identified as influential by the statistical approach were later shown in concert to yield 100% recovery of TPPTS from the spiked­sand.

In the fourth phase, the extraction of a cationic species, pseudoephedrine hydrochloride, from spiked­sand and Suphedrine tablets, with pure and methanol­modified CO2 was examined. Once the extraction was shown to feasible, several strategies were compared in terms of their effectiveness in enhancing the analyte’s extractability. The first strategy involved the addition of ion­pairing additives. Several sodium salts of alkylsulfonic acids varying in lipophilicity and concentration were investigated. The addition of 1­heptanesulfonic acid, sodium salt, in methanol, in a 5:1 mole ratio of reagent to analyte was shown to be the most useful in recovering the drug from the spiked­sand. The second strategy considered the influence of acids and bases and other modifier compositions such as a methanol/water mixture with or without 1­heptanesulfonic acid, sodium salt, on the pseudoephedrine recovery. The recoveries obtained from the drug spiked­sand were shown to comparable in the presence of a methanol/water solution, a tetrabutylammonium hydroxide in methanol solution, and a methanol solution with 1­heptanesulfonic acid, sodium salt. Next the extraction of pseudoephedrine hydrochloride from Suphedrine tablets was performed with pure and modified CO2. Similar to the sand­spike studies, the effect of the addition of the ion­pairing reagent and other in­cell modifiers were examined. Once again, the recoveries obtained when the matrix was in the presence of a methanol/water mixture and a methanol solution containing 1­heptanesulfonic acid, sodium salt were similar. Finally, the identity of the extracted analyte was determined via IR analyses, and it was shown that pseudoephedrine hydrochloride was indeed extractable from the tablets with in­line modified CO2 in the absence of any in­cell modifier.

In the last phase of this research, a supercritical fluid chromatographic separation with evaporative light scattering detection was developed for the separation of five phospholipids varying in polarity and ionic characteristics. Several parameters were investigated and shown to be influential in the separation. They were: 1) stationary phase composition, 2) addition of an acidic additive and its concentration, 3) mobile phase ramp rate, and 4) column outlet pressure.

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