Dissolution and Partitioning Behavior of Hydrophobic Ion-Paired Compounds C. S. Lengsfeld, 2 D. Pitera, 1 M. Manning, 3 and T. W. Randolph 1,4 Received June 15, 2002; accepted July 2, 2002 Purpose. This study was conducted to determine the effects of coun- terion hydrophobicity on organic/aqueous partition coefficients for hydrophobic ion paired (HIP) complexes. Furthermore, the coupled dissolution and reverse ion-exchange kinetics for dissolution of HIP complexes into aqueous electrolyte solutions were measured and mathematically modeled. Methods. HIP complexes of model drugs tacrine and l-phenylephrine were formed using linear sodium alkylsulfates and bis (2-ethylhexyl sodium sulfosuccinate). Equilibrium partition coefficients between chloroform and aqueous solutions for the complexes and the kinetics of dissolution of the complexes in buffered aqueous solutions were measured. Results. The chloroform/aqueous partition coefficients for l - phenylephrine/bis (2-ethylhexyl sodium sulfosuccinate) complexes decrease with increasing molar surface tension increment of salts added to the aqueous solution. The logarithm of the partition coef- ficient for a homologous series of alkyl sulfate complexes decreases as the hydrophilic-lipophilic balance number increases. Dissolution of HIP complexes in deionized water shows first order kinetics, whereas dissolution in aqueous electrolyte solutions shows biphasic kinetics. A kinetic model explains these dissolution rates. Conclusions. Solubility and dissolution rates for HIP complexes de- pend on the hydrophobic-lipophilic balance number of the organic counter ion as well as on the electrolyte composition of aqueous solutions. Reverse ion-exchange kinetics are sufficiently slow to allow HIP complexes to be considered simple prodrugs. KEY WORDS: hydrophobic ion pairs; prodrug; dissolution; solubility. INTRODUCTION Hydrophobic ion pairing (HIP) is a technique whereby ionic pharmaceutical compounds and proteins can be directly solubilized in organic solvents (1–6). HIP consists of exchang- ing small, hydrophilic counterions on the molecule for large hydrophobic organic ions, producing complexes whose solu- bility in low-dielectric organic solvents is increased by orders of magnitude compared with that of the parent molecule. This technique makes it possible to obtain true homogeneous so- lutions of ionic compounds in neat organic solvents, with the only requirement being an accessible charge on the molecule. It should be emphasized that HIP is a general process, be- cause nearly any solvent may be used. HIP can be used to increase bioavailability of ionic drugs (7–13). In contrast to their enhanced solubilities in organic sol- vents, HIP complexes exhibit reduced solubilities in aqueous media. However, when HIP compounds are dissolved in aqueous electrolyte solutions, reverse ion exchange can occur as small hydrophilic counterions are substituted for the hy- drophobic organic ions, resulting in the reformation of the parent drug, with a concomitant increase in drug solubility. HIP complexes may thus be thought of as a simple prodrug that may exhibit sustained-release profiles whose kinetics are determined by the rates of dissolution of the HIP complex and subsequent reverse ion exchange. Little is known about the factors that influence the solubility of HIP complexes or their dissolution and reverse ion-pairing behavior (1–3,14). In this study, we examine the solubility and reverse ion- exchange kinetics for two model drugs, l-phenylephrine hy- drochloride and tacrine hydrochloride. EXPERIMENTAL APPROACH Materials Sodium chloride, sodium nitrate, dibasic sodium phos- phate, sodium sulfate, and chloroform were purchased from Fisher Scientific. Sodium octylsulfate, sodium dodecylsulfate, sodium tetradecylsulfate, sodium octadecysulfate, and tacrine hydrochloride were from Aldrich and l-phenylephrine hydro- chloride and sodium bis (2-ethylhexyl) sulfosuccinate (AOT) were from Sigma. All chemicals were used as received. Phosphate buffered saline solutions (PBS) contained 200 mL deionized water, 1600 mg NaCl, 40 mg KCl, 48 mg KH 2 PO 4 , 288 mg Na 2 HPO 4 at a pH of 7.4. Measurement of Water/Chloroform Partition Coefficients To examine the effect of anions on partitioning, stock solutions containing 2-mg/mL (9.8 mM) l-phenylephrine hy- drochloride in aqueous 0.2-M salt (NaNO 3 , NaCl, Na 2 HPO 4 , NaH 2 PO 4 , or Na 2 SO 4 ) were prepared. Separate aqueous stock solutions of AOT were prepared, also at 9.8 mM. Equal volumes of the two solutions were combined, resulting in spontaneous formation of the ion-paired complexes. The pH of solutions containing l-phenylephrine/AOT complexes with no added salt was 6.7. The pH did not change upon addition of 0.2 M NaNO 3 , NaCl, or Na 2 SO 4 . pH values for l- phenylephrine/AOT complex solutions containing 0.2 M Na 2 HPO 4 or NaH 2 PO 4 were 9.6 and 5.2, respectively. To examine the effect of changing pH, a solution containing l- phenylephrine/AOT complex and a mixture of NaH 2 PO 4 and Na 2 HPO 4 (0.2 M total phosphate) was prepared to obtain a pH of 6.7. To examine the effect of organic counterion hydropho- bicity on partitioning, separate 9.8 mM aqueous stock solu- tions of hydrophobic organic ions (sodium octylsulfate, so- dium dodecylsulfate, sodium tetradecylsulfate, sodium octa- decylsulfate, or AOT) were prepared and added to equal 1 University of Colorado at Boulder, Department of Chemical Engi- neering, Engineering Center ECCH-111, Boulder, Colorado 80309. 2 University of Denver, Department of Engineering, 2390 S. York Street, Denver, Colorado 80208. 3 University of Colorado Health Science Center, School of Pharmacy, Denver, Colorado 80262. 4 To whom correspondence should be addressed. University of Colorado at Boulder, Department of Chemical Engineering, Engi- neering Center ECCH-111, Boulder, Colorado 80309. (e-mail randolph@pressure.colorado.edu) Pharmaceutical Research, Vol. 19, No. 10, October 2002 (© 2002) Research Paper 1572 0724-8741/02/1000-1572/0 © 2002 Plenum Publishing Corporation