Hydrophobic Ion Pairing of Small Molecules: How to Minimize Premature Drug Release from SEDDS and Reach the Absorption Membrane in Intact Form

Abstract

The present work aimed to form hydrophobic ion pairs (HIPs) of a small molecule remaining inside the oily droplets of SEDDS to a high extent. HIPs of ethacridine and various surfactants classified by functional groups of phosphates, sulfates, and sulfonates were formed and precipitation efficiency, log D_{n-octanol/water}, and solubility in different excipients were investigated. Most lipophilic HIPs were incorporated into SEDDS and evaluated regarding drug release. Docusate HIPs showed the highest increase in lipophilicity with a precipitation efficiency of 100%, a log D_{n-octanol/water} of 2.66 and a solubility of 132 mg/mL in n-octanol, 123 mg/mL in oleyl alcohol, and 40 mg/mL in medium chain triglycerides. Docusate HIPs were incorporated into three SEDDS of increasing lipophilicity (F1 < F2 < F3) based on medium chain triglycerides, oleyl alcohol, Kolliphor EL, and Tween 80 (F1: 1 + 5 + 2 + 2; F2: 3 + 3 + 2 + 2; F3: 5 + 1 + 4 + 0). Highest achievable payloads ranged from 74.49 mg/mL (F3) to 97.13 mg/mL (F1) and log D_SEDDS/RM increased by at least 7.5 units (4.99, F1). Drug release studies via the diffusion membrane method confirmed minor release of docusate HIPs from all SEDDS (<2.7% within 4 h). In conclusion, highly lipophilic HIPs remain inside the oily phase of SEDDS and likely reach the absorption membrane in intact form.

Keywords: drug release; ethacridine; hydrophobic ion pairing; oral drug delivery; self-emulsifying drug delivery systems; small molecule.

Figure 1

Possible mechanisms of interaction between ethacridine and surfactants using the example of sodium dodecylbenzene sulfonate as counterion.

Figure 2

Precipitation efficiency [%] of ethacridine ion-paired with different surfactants classified by functional groups of phosphates (A), sulfates (B), and sulfonates (C). Indicated values are means (n ≥ 3) ± SD.

Figure 3

Log D_{n-octanol/water} of ethacridine after hydrophobic ion pairing with different surfactants classified by functional groups of phosphates (A), sulfates (B), and sulfonates (C) compared to non-ion paired ethacridine used as reference (D). Indicated values are means (n ≥ 3) ± SD.

Figure 4

Solubility in medium chain triglycerides (MCT, Labrafac lipophile WL 1349), oleyl alcohol (OA), and n-octanol (OCT) of ethacridine after hydrophobic ion pairing with different surfactants classified by functional groups of phosphates (A), sulfates (B), and sulfonates (C) compared to non-ion paired ethacridine used as reference (D). Indicated values are means (n ≥ 3) ± SD.

Figure 5

Maximum solubility of non-ion paired ethacridine (◊) used as reference and ethacridine-docusate HIPs (⧫) in SEDDS formulations F1, F2, and F3. Log D values between SEDDS formulation F1, F2, F3 and 25 mM HEPES pH 6.8 used as release medium (RM) of ethacridine (hatched bars) as well as ethacridine-docusate HIPs (solid bars). Difference in Log D_SEDDS/RM between ethacridine and ethacridine-docusate HIPs shown as Δ Log D. Indicated values are means (n ≥ 3) ± SD (*p < 0.05, ***p < 0.001).

Figure 6

(A) Ethacridine [μg] released from SEDDS formulation F1, F2, and F3 compared to reference R1, R2, and R3 (dissolution of ethacridine in release medium at concentrations providing a 100% drug release (0.97 mg/mL for F1, 0.90 mg/mL for F2, and 0.74 mg/mL for F3) and subsequent addition of blank SEDDS preconcentrate for emulsification). (B) Ethacridine [%] released from SEDDS formulation F1, F2, and F3. Released ethacridine of reference emulsions after 48 h served as 100% value. 1 mL of emulsion was dialyzed against 9 mL of release medium (RM, 25 mM HEPES pH 6.8) at 37 °C under shaking at 300 rpm. Indicated values are means (n = 3) ± SD (**p < 0.01, ***p < 0.001).