Oral drug absorption enhancement by chitosan and its derivatives.

Chitosan is a non-toxic, biocompatible polymer that has found a number of applications in drug delivery including that of absorption enhancer of hydrophilic macromolecular drugs. Chitosan, when protonated (pH<6.5), is able to increase the paracellular permeability of peptide drugs across mucosal epithelia. Chitosan derivatives have been evaluated to overcome chitosan's limited solubility and effectiveness as absorption enhancer at neutral pH values such as those found in the intestinal tract. Trimethyl chitosan chloride (TMC) has been synthesized at different degrees of quaternization. This quaternized polymer forms complexes with anionic macromolecules and gels or solutions with cationic or neutral compounds in aqueous environments and neutral pH values. TMC has been shown to considerably increase the permeation and/or absorption of neutral and cationic peptide analogs across intestinal epithelia. The mechanism by which TMC enhances intestinal permeability is similar to that of protonated chitosan. It reversibly interacts with components of the tight junctions, leading to widening of the paracellular routes. Mono-carboxymethylated chitosan (MCC) is a polyampholytic polymer, able to form visco-elastic gels in aqueous environments or with anionic macromolecules at neutral pH values. MCC appears to be less potent compared to the quaternized derivative. Nevertheless, MCC was found to increase the permeation and absorption of low molecular weight heparin (LMWH; an anionic polysaccharide) across intestinal epithelia. Neither chitosan derivative provokes damage of the cell membrane, and therefore they do not alter the viability of intestinal epithelial cells.     

Investigation of Solubility and Dissolution of a Free Base and Two Different Salt Forms as a Function of pH

No HeadingPurpose. To evaluate the effect of pH on solubility and dissolution rates of a model weak base, haloperidol, and two different salt forms, hydrochloride and mesylate.Methods. pH-solubility profiles were determined by using haloperidol base, haloperidol hydrochloride, and haloperidol mesylate as starting materials; concentrated or diluted HCl or NaOH solutions were added to aqueous suspensions of solids to adjust pH to desired values. Intrinsic dissolution rates were determined using intrinsic dissolution apparatus under various pH-stat conditions. Further, approximation of diffusion layer pH was estimated from that of 10% w/w slurries of drug substances in dissolution media, which were used to correlate with intrinsic dissolution rates of haloperidol and its salt forms under different pHs.Results. pH-solubility profiles of haloperidol base and its HCl salt were similar, while when the mesylate salt was used as starting material, it exhibited a higher solubility between pH 2 and 5. The higher solubility of the mesylate salt at pH 2–5 is attributed to its higher solubility product (K_sp) than that of the hydrochloride salt. The pH-solubility profiles indicated a pH_max (pH of maximum solubility) of 5, indicating that the free base would exist as the solid phase above this pH and a salt would be formed below this pH. Below pH 1.5, all solubilities were comparable due to a conversion of haloperidol base or the mesylate salt to the HCl salt form when HCl was used as the acidifying agent. These were confirmed by monitoring the solid phase by differential scanning calorimeter. When their dissolution rates are tested, dissolution rates of the mesylate salt were much higher than those of the free base or the HCl salt, except at very low pH (<2). Dissolution rates of free base and HCl salt also differed from each other, where that of HCl salt exhibits higher dissolution rates at higher pHs. A direct correlation of dissolution rate with solubility at diffusion layer pH at the surface of dissolving solid was established for haloperidol, its hydrochloride, and mesylate salts.Conclusions. Using pH-solubility and pH-dissolution rate interrelationships, it has been established that diffusion layer pH could be used to explain the observed rank order in dissolution rates for different salt forms. A non-hydrochloride salt, such as a mesylate salt, may provide advantages over a hydrochloride salt due to its high solubility and lack of common ion effect unless at very low pH.     

Chitosan and its derivatives as intestinal absorption enhancers

Chitosan is a non-toxic, biocompatible polymer that has found a number of applications in drug delivery including that of absorption enhancer of hydrophilic macromolecular drugs. Chitosan, when protonated (pH<6.5), is able to increase the paracellular permeability of peptide drugs across mucosal epithelia. Chitosan derivatives have been evaluated to overcome chitosan's limited solubility and effectiveness as absorption enhancer at neutral pH values such as those found in the intestinal tract. Trimethyl chitosan chloride (TMC) has been synthesized at different degrees of quaternization. This quaternized polymer forms complexes with anionic macromolecules and gels or solutions with cationic or neutral compounds in aqueous environments and neutral pH values. TMC has been shown to considerably increase the permeation of neutral and cationic peptide analogs across Caco-2 intestinal epithelia. The mechanism by which TMC is enhancing the intestinal permeability is similar to that of protonated chitosan. It reversibly interacts with components of the tight junctions, leading to widening of the paracellular routes. This chitosan derivative does not provoke damage of the cell membrane, and does not alter the viability of intestinal epithelial cells. Co-administrations of TMC with peptide drugs were found to substantially increase the bioavailability of the peptide in both rats and juvenile pigs compared with administrations without the polymer.     

Preformulation study of pelrinone hydrochloride

Pelrinone HCl is essentially nonhygroscopic. The pH-solubility profile exhibits a U-shaped curve, while the octanol-water partition coefficient-pH profile shows a bell-shaped curve. Two ionizable functions, with a pKa1 value of 4.71 and a pKa2 value of 8.94, produce the cationic and anionic forms, respectively. A weak ionic strength effect on solubility of the compound is observed: at pH 3.9 (0.1 M acetate buffer), the solubility increases with increasing ionic strength, while at pH 7.5 (Tris HCl buffer), the solubility decreases with increasing ionic strength. No gross incompatibility of the compound is seen with the 13 excipients selected, except povidone. The solubility phase diagram, X-ray diffraction pattern, and IR spectroscopy demonstrate the presence of polymorphs. The compound in solution is stable at various pH conditions under 500-foot-candle (ft-c) light at room temperature and at 80 degrees C for 64 d. In the solid state, no decomposition is observed at 80 degrees C and on exposure to 500-ft-c light for at least 112 d.     

Physicochemical characterization of ricobendazole: I. Solubility, lipophilicity, and ionization characteristics

The physicochemical properties of ricobendazole (RBZ) were characterized using conventional methods. Solubility in some pharmaceutical solvents, pH-solubility, ionization properties, and lipophilicity are described. The solubility of RBZ in water is 62 mug/mL and very poor in common pharmaceutical solvents, for example, oils (<0.25 mg/mL in all the tested oils) or ethanol (1.2 mg/mL) and propylene glycol (2.6 mg/mL), and slightly higher in dipolar solvents, DMSO (16.5 mg/mL). U-shaped pH-solubility profile in aqueous solutions indicates RBZ is an ampholyte. pK(a) values measured by absorbance spectroscopy and pH solubility methods were 3.45 and 3.76 for the basic group and 9.82 and 9.53 for the non-basic nitrogen, respectively. Combination of low pH and surfactant/co-solvent mixtures also improved solubility. RBZ formed a 1:1 complex with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) with a binding constant (K(1:1)) of 311/M1. Apparent partition coefficients of RBZ were 14.3-15.2 at pH 6-9 and reduced at higher or lower pH. In conclusion, traditional organic co-solvents, pH-adjustment or complexation (with HP-beta-CD) approaches are unlikely to yield sufficient solubility for formulation of RBZ solutions for subcutaneous injection and novel approaches should be considered.     

The composite solubility versus pH profile and its role in intestinal absorption prediction

The purpose of this study was to examine absorption of basic drugs as a function of the composite solubility curve and intestinally relevant pH by using a gastrointestinal tract (GIT) absorption simulation based on the advanced compartmental absorption and transit model. Absorption simulations were carried out for virtual monobasic drugs having a range of pKa, log D, and dose values as a function of presumed solubility and permeability. Results were normally expressed as the combination that resulted in 25% absorption. Absorption of basic drugs was found to be a function of the whole solubility/pH relationship rather than a single solubility value at pH 7. In addition, the parameter spaces of greatest sensitivity were identified. We compared 3 theoretical scenarios: the GIT pH range overlapping (1) only the salt solubility curve, (2) the salt and base solubility curves, or (3) only the base curve. Experimental solubilities of 32 compounds were determined at pHs of 2.2 and 7.4, and they nearly all fitted into 2 of the postulated scenarios. Typically, base solubilities can be simulated in silico, but salt solubilities at low pH can only be measured. We concluded that quality absorption simulations of candidate drugs in most cases require experimental solubility determination at 2 pHs, to permit calculation of the whole solubility/pH profile.     

Bupivacaine salts of diflunisal and other aromatic hydroxycarboxylic acids: aqueous solubility and release characteristics from solutions and suspensions using a rotating dialysis cell model.

In the search for poorly soluble bupivacaine salts potentially enabling prolonged postoperative pain relief after local joint administration in the form of suspensions the solubility of bupivacaine salts of diflunisal and other aromatic hydroxycarboxylic acids were investigated together with the release characteristics of selected 1:1 salts from solutions and suspensions using a rotating dialysis cell model. The poorest soluble bupivacaine salts were obtained from the aromatic ortho-hydroxycarboxylic acids diflunisal, 5-iodosalicylic acid, and salicylic acid (aqueous solubilities: 0.6-1.9 mM at 37 degrees C). Diffusant appearance rates in the acceptor phase upon instillation of solutions of various salts in the donor cell applied to first-order kinetics. Calculated permeability coefficients for bupivacaine and the counterions diflunisal, 5-iodosalicylic acid, and mandelic acid were found to be correlated with the molecular size of the diffusants. Release experiments at physiological pH involving suspensions of the bupivacaine-diflunisal salt revealed that at each sampling point the diflunisal concentration exceeded that of bupivacaine in the acceptor phase. However, after an initial lag period, a steady state situation was attained resulting in equal and constant fluxes of the two diffusants controlled by the permeability coefficients in combination with the solubility product of the salt. Due to the fact that the saturation solubility of the bupivacaine-salicylic acid salt in water exceeded that of bupivacaine at pH 7.4, suspensions of the latter salt were unable to provide simultaneous release of the cationic and anionic species at pH 7.4. The release profiles were characterised by a rapid release of salicylate accompanied by a much slower appearance of bupivacaine in the acceptor phase caused by precipitation of bupivacaine base from the solution upon dissolution of the salt in the donor cell.     

Solubility of doxycycline in aqueous solution.

The solubility of doxycyline monohydrate and doxycycline hydrochloride dihydrate was investigated in aqueous solution. The hydrochloride dihydrate salt was isolated and identified from solutions initially containing doxycycline hyclate in water. The pKa' = 3.09 (mu = 0.1 and 25 degrees) for protonation of doxycycline was determined spectrophotometrically. The pH-solubility profiles were determined for doxycycline monohydrate in water and in 1.0 M NaNO3-HNO3 and NaCl-HCl. The pH-solubility profile at 25 degrees for doxycycline in aqueous hydrochloric acid without added salt reached a sharp maximum fo 50 mg/ml at pH 2.16. Added chloride ion strongly suppressed the solubility of the hydrochloride dihydrate salt. The apparent solubility product was not constant but decreased as the concentration of added salt increased. A theoretical model was developed involving dimerization of doxycycline and applied to the experimental data. The dimerization constant, Kd = 24 M-1, and true solubility product, K0sp = 1.8 X 10(-3) M2, were calculated. The effect of concentration on NMR and visible spectra indicated that dimerization resulted from intermolecular hydrogen bonding of the phenolic beta-diketone portion of the molecule.     

Simultaneous effect of cyclodextrin complexation, pH, and hydrophilic polymers on naproxen solubilization

The effect of pH variation on complexation and solubilization of naproxen (pK(a) 4.2) with natural betaCyclodextrin (betaCyD) and various neutral, cationic and anionic betaCyD-derivatives has been investigated. The combined effect of pH variation and hydrophilic polymer addition on CyD solubilizing and complexing efficiency has also been determined. Phase-solubility analysis in buffered aqueous solutions (pH from 1.1 to 6.5) was used to study the interaction of the drug with each CyD, in the presence or not of the water-soluble polymer. A clear influence of the substituent type was observed, the methylderivative being the most efficient agent; on the contrary, unexpectedly, no influence of the CyD charge in the interaction with the ionizable drug was detected. As expected, total drug solubility increased with increasing pH; however, the solubility increment with respect to drug alone obtained by CyD complexation progressively decreased, with a parallel reduction of the complex stability, attributed to the reduced affinity of charged drug for the hydrophobic CyD cavity. The addition of the polymer in part counterbalanced the destabilizing effect obtained with increasing pH, by improving the CyD complexation power towards naproxen. In particular, the presence of PVP allowed an increase of the complex stability constant with hydroxypropyl betaCyD up to 60% with respect to the corresponding drug-CyD binary system. Therefore, the combined strategy of pH control and polymer addition to the CyD complexing medium can be successfully exploited to improve naproxen solubilization and reduce the amount of CyD needed. The construction of theoretical drug solubility curves as a function of pH for any given CyD and polymer concentration enables selection of the best experimental conditions for obtaining the desired drug solubility value.     

Solubility of E2050 at various pH: a case in which apparent solubility is affected by the amount of excess solid

The solubility of E2050, supplied as a dihydrochloride salt, in aqueous solutions at different pHs was studied. Two pK(a)s controlling the equilibrium between the various protonated species were determined. The solubility-pH profile of E2050 is expected to be high in acidic solutions because protonated species are formed and to be low in alkaline conditions due to the formation of hydrophobic free base. The solubility is also affected by chloride ion, a common ion for this drug substance. Two solubility products (K(sp)) were determined corresponding to the solubility of di-HCl salt and mono-HCl salt. Based on the pK(a)s (3.10 and 7.71), the solubility products with chloride (2.92 and 3.77 as corresponding pK(sp)), and the solubility of free base (2 x 10(-5) M), the solubility in solutions with different pH and different levels of chloride ion can be predicted. The prediction of the solubility change during the dilution of E2050 parenteral formulations by saline was also demonstrated. Furthermore, the present study presents an interesting example in which an apparent solubility can be different if varying (excess) amounts of salt are added to the solution. In this case, excess chloride ion suppresses the solubility in the pH region where mono-HCl salt controls the solubility.     

Effect of the amphoteric properties of salbutamol on its release rate through a polypropylene control membrane.

The permeation of salbutamol from aqueous vehicles with different pH values through the Celgard 2500 polypropylene membrane was studied, the goal being to assess the effect of the amphoteric properties of the drug on its release by the membrane. Permeation rates were generally low, which was related to the fact that purely aqueous vehicles were not imbibed into the pores of the membrane and therefore permeation took place through the amorphous polypropylene domains. Permeability coefficients were not proportional to the fraction of uncharged drug at different bulk pH values, indicating that either a pH gradient between the bulk and the membrane surface exists and/or charged drug species can permeate the hydrophobic membrane. Calculated hypothetical pH values of the membrane surface, assuming permeation of the uncharged drug only, failed to provide a consistent explanation of the experimental permeabilities. Permeability coefficients of the different ionization forms of the drug assuming no pH gradient were calculated from a system of linear equations, each one of them corresponding to a specific bulk pH. These were for the anionic and the cationic species one to two orders of magnitude smaller than for the combined uncharged and zwitterionic species. It is possible that both, a pH difference between bulk and membrane surface and permeation of ionized molecules were simultaneously responsible for the observed permeation rates.     

Increased target specificity of anti-HER2 genospheres by modification of surface charge and degree of PEGylation

Genospheres are cationic lipid-nucleic acid nanoparticles prepared by the assembly of the lipids and nucleic acids from an aqueous/organic liquid monophase that independently dissolves the components, where the resultant particles are homogeneously sized (70-110 nm), with efficiently incorporated and protected DNA. In the present study, we demonstrate pH-dependent modulation of the Genosphere surface charge using pH-titratable lipids. By incorporation of the lipids with titratable anionic or imidazole headgroups, Genospheres with neutral or anionic surface charge at neutral pH were produced and compared for cellular uptake and transfection of a reporter gene (luciferase) in culture of breast cancer cells. The extent of particle-cell association was also studied by fluorescent microscopy and quantified by cytofluorometery. The effects of Genosphere surface modification with poly(ethylene glycol) (molecular weight 2000) at low (0.5 mol %) and high (5 mol %) grafting densities, as well as the effects of HER2-receptor-directed targeting by an internalizable anti-HER2 scFv F5, linked via PEG spacer, were also studied. Inclusion in the Genosphere formulation of pH-titratable lipids CHEMS (cholesteryl hemisuccinate), CHIM (1-(3-(cholesteryloxycarbonylamino)propyl)imidazole), or DSGG (1,2-distearoyl-sn-glycero-3-hemiglutarate) rendered the particles surface-charge neutral or slightly anionic at neutral pH, and cationic at mildly acidic pH, as shown by zeta-potential measurements. In HER2-targeted systems, transfection activity and target specificity with HER2-overexpressing SKBR-3 breast cancer cells were dependent on Genosphere surface charge and PEGylation. The highest target specificity correlated with low cationic charge at neutral pH, while incorporation of 5 mol % PEG-lipid had only minor effects on Genosphere-cell association, internalization, and transfection activity. The implications of this work for potential in vivo applications are discussed.     

Nanoparticle surface charges alter blood-brain barrier integrity and permeability

PURPOSE: The blood-brain barrier (BBB) presents both a physical and electrostatic barrier to limit brain permeation of therapeutics. Previous work has demonstrated that nanoparticles (NPs) overcome the physical barrier, but there is little known regarding the effect of NP surface charge on BBB function. Therefore, this work evaluated: (1) effect of neutral, anionic and cationic charged NPs on BBB integrity and (2) NP brain permeability. Methods: Emulsifying wax NPs were prepared from warm oil-in-water microemulsion precursors using neutral, anionic or cationic surfactants to provide the corresponding NP surface charge. NPs were characterized by particle size and zeta potential. BBB integrity and NP brain permeability were evaluated by in situ rat brain perfusion. RESULTS: Neutral NPs and low concentrations of anionic NPs were found to have no effect on BBB integrity, whereas, high concentrations of anionic NPs and cationic NPs disrupted the BBB. The brain uptake rates of anionic NPs at lower concentrations were superior to neutral or cationic formulations at the same concentrations. CONCLUSIONS: (1) Neutral NPs and low concentration anionic NPs can be utilized as colloidal drug carriers to brain, (2) cationic NPs have an immediate toxic effect at the BBB and (3) NP surface charges must be considered for toxicity and brain distribution profiles.     

Relationship between immobilized artificial membrane chromatographic retention and human oral absorption of structurally diverse drugs

Capacity factors are determined for a set of drugs for which human oral absorption (HOA) data are available, using immobilized artificial membrane (IAM) chromatography. The compound set represented acidic, basic, neutral and amphoteric drugs from various structure classes and having low to high human oral absorption. Effect of mobile phase pH on retention was investigated to determine the optimal condition for better correlation with HOA. The retention (capacity factor, k'(IAM) of each drug was measured by reverse phase HPLC using an IAM.PC.DD2 (1 cm x 3 mm i.d., 12 microm) column with an eluent of acetonitrile - 0.01 M phosphate buffer at pH 4.5-7.4. The pH dependent k'(IAM) was in accordance with pH partition theory. Using non-linear regression analysis the obtained log k'(IAM) values were compared with published data on HOA in order to establish correlation. The better correlation with HOA was observed when the highest log k'(IAM) value selected among pH 4.5-7.4 (R(2)=0.8566) for each drug rather than obtained at more traditional pH 7.4 (R(2)=0.7403). Finally, it was confirmed by Cook's D outlier test that there was no influential observation in the model that affect the relationship between IAM capacity factor and HOA. The assay conditions were optimized and validated to make it suitable for routine analysis and for compound characterization in early discovery where permeability may be an issue.     

Determining the Effect of pH on the Partitioning of Neutral,Cationic and Anionic Chemicals to Artificial Sebum: New Physicochemical Insight and QSPR Model

Purpose

Sebum is an important shunt pathway for transdermal permeation and targeted delivery, but there have been limited studies on its permeation properties. Here we report a measurement and modelling study of solute partition to artificial sebum.

Methods

Equilibrium experiments were carried out for the sebum-water partition coefficients of 23 neutral, cationic and anionic compounds at different pH.

Results

Sebum-water partition coefficients not only depend on the hydrophobicity of the chemical but also on pH. As pH increases from 4.2 to 7.4, the partition of cationic chemicals to sebum increased rapidly. This appears to be due to increased electrostatic attraction between the cationic chemical and the fatty acids in sebum. Whereas for anionic chemicals, their sebum partition coefficients are negligibly small, which might result from their electrostatic repulsion to fatty acids. Increase in pH also resulted in a slight decrease of sebum partition of neutral chemicals.

Conclusions

Based on the observed pH impact on the sebum-water partition of neutral, cationic and anionic compounds, a new quantitative structure-property relationship (QSPR) model has been proposed. This mathematical model considers the hydrophobic interaction and electrostatic interaction as the main mechanisms for the partition of neutral, cationic and anionic chemicals to sebum.

     

Unusual solubility and dissolution behavior of pharmaceutical hydrochloride salts in chloride-containing media

The pH-solubility profiles of 3 pharmaceutical hydrochloride salts were determined in sodium acetate-hydrochloric acid buffer. Unusual pH-solubility profiles containing maxima at pH 4–6 were observed for phenazopyridine hydrochloride, cyproheptadine hydrochloride and bromhexine hydrochloride. The decrease in solubility at lower pH values was attributed to the common ion effect of chloride on the solubility product equilibrium of the hydrochloride salts. The dissolution behavior of the free bases and that of the hydrochloride salts of these drugs were compared in dilute hydrochloric acid solution, in pH range from 1.0 to 3.0. The apparent dissolution rates and solubilities of these hydrochlorides were less than those of the respective free base forms in the pH range of the stomach (pH 1.0–2.0). These results substantiated further the contention that the salt formation does not always result in an enhancement of solubility characteristics.     

Transbuccal Delivery of Acyclovir: I. In Vitro Determination of Routes of Buccal Transport

Purpose. To determine the major routes of buccal transport of acyclovir and to examine the effects of pH and permeation enhancer on drug permeation. Methods. Permeation of acyclovir across porcine buccal mucosa was studied by using side-by-side flow through diffusion cells at 37°C. The permeability of acyclovir was determined at pH range of 3.3 to 8.8. Permeability of different ionic species was calculated by fitting the permeation data to a mathematical model. Acyclovir was quantified using HPLC. Results. Higher steady state fluxes were observed at pH 3.3 and 8.8. The partition coefficient (1-octanol/buffer) and the solubility of acyclovir showed the same pH dependent profile as that of drug permeation. In the presence of sodium glycocholate (NaGC) (2–100 mM), the permeability of acyclovir across buccal mucosa was increased 2 to 9 times. This enhancement was independent of pH and reached a plateau above the critical micelle concentration of NaGC. The permeabilities of anionic, cationic, and zwitterionic species were 3.83 × 10^–5, 4.33 × 10^–5, and 6.24 × 10^–6cm/sec, respectively. Conclusions. The in vitropermeability of acyclovir across porcine buccal mucosa and the octanol-water partitioning of the drug were pH dependent. A model of the paracellular permeation of the anionic, cationic, and zwitterionic forms of acyclovir is consistent with these data. The paracellular route was the primary route of buccal transport of acyclovir, and the enhancement of transbuccal transport of acyclovir by sodium glycocholate (NaGC) appeared to operate via this paracellular route.     

Nanoparticle Surface Charges Alter Blood–Brain Barrier Integrity and Permeability

Purpose: The blood–brain barrier (BBB) presents both a physical and electrostatic barrier to limit brain permeation of therapeutics. Previous work has demonstrated that nanoparticles (NPs) overcome the physical barrier, but there is little known regarding the effect of NP surface charge on BBB function. Therefore, this work evaluated: (1) effect of neutral, anionic and cationic charged NPs on BBB integrity and (2) NP brain permeability.

Methods: Emulsifying wax NPs were prepared from warm oil-in-water microemulsion precursors using neutral, anionic or cationic surfactants to provide the corresponding NP surface charge. NPs were characterized by particle size and zeta potential. BBB integrity and NP brain permeability were evaluated by in situ rat brain perfusion.

Results: Neutral NPs and low concentrations of anionic NPs were found to have no effect on BBB integrity, whereas, high concentrations of anionic NPs and cationic NPs disrupted the BBB. The brain uptake rates of anionic NPs at lower concentrations were superior to neutral or cationic formulations at the same concentrations.

Conclusions: (1) Neutral NPs and low concentration anionic NPs can be utilized as colloidal drug carriers to brain, (2) cationic NPs have an immediate toxic effect at the BBB and (3) NP surface charges must be considered for toxicity and brain distribution profiles.     

Release of polyionizable compounds from submicrometer oil-in-water emulsions.

A novel, general, theoretical equation that describes the release of polyionizable compounds from submicrometer emulsions was derived and evaluated. The model accounts for simultaneous partitioning, interfacial activity, and adsorption to surfactant for n independent drug species and j surfactant species in a single emulsion system. Under the appropriate conditions, this model collapses to a previously described model for submicrometer emulsions. The model was tested for submicrometer emulsions containing a model dibasic compound (quinine sulfate). Drug release behavior was observed at pH 3.00, 5.07, and 7.50 in the presence and absence of an anionic surfactant (sodium lauryl sulfate). At each pH, the proposed theory describes the observed release behavior. At all pHs studied, a substantial amount of quinine was adsorbed to the surface of the oil droplet. Presumably, this behavior was largely the result of electrostatic attraction between ionized drug and sodium lauryl sulfate at the oil-water interface. Adsorption constants were evaluated for complexation of cationic and dicationic species of quinine to sodium lauryl sulfate, and the adsorption constant of the cationic species was larger, presumably because of the ionic nature of the surfactant.