Lecithin, soy

Industrial lecithins from a variety of sources ate utilized (Tables 2 and 3). The main sources include vegetable oils (eg, soy bean, cottonseed, corn, sunflower, tapeseed) and animal tissues (egg and bovine brain). However, egg lecithin and in particular soy lecithin (Table 4) ate by fat the most important in terms of quantities produced. So much so that the term soy lecithin and commercial lecithin ate often used synonymously. 

Cmde soy lecithin is obtained as a by-product during the degumming process of soy oil. The phosphoms-containing compounds are removed to improve the stabiHty of the oil. 

Fig. 3. Discontinuous deoiling of soy lecithin. 1, Acetone storage tank 2, lecithin storage tank 3, mixer 4, separation tank 5, filter/decanter 6, dryer 7, classifier 8, oil misceUa tank 9, evaporator 10, oil extract tank 11, condenser and 12, acetone storage tank.

Somewhere in the middle are soy lecithin and sorbitan mono-laurate, which make good foam stabilizers in whipped cream and similar products. 

Figure 7.17 shows the asymmetry ratios of a series of compounds (acids, bases, and neutrals) determined at iso-pH 7.4, under the influence of sink conditions created not by pH, but by anionic surfactant added to the acceptor wells (discuss later in the chapter). The membrane barrier was constructed from 20% soy lecithin in dodecane. All molecules show an upward dependence on lipophilicity, as estimated by octanol-water apparent partition coefficients, log KdaA). The bases are extensively cationic at pH 7.4, as well as being lipophilic, and so display the highest responses to the sink condition. They are driven to interact with the surfactant by both hydrophobic and electrostatic forces. The anionic acids are largely indifferent... 

Hydrogen bonding and electrostatic interactions between the sample molecules and the phospholipid bilayer membranes are thought to play a key role in the transport of such solute molecules. When dilute 2% phospholipid in alkane is used in the artificial membrane [25,556], the effect of hydrogen bonding and electrostatic effects may be underestimated. We thus explored the effects of higher phospholipid content in alkane solutions. Egg and soy lecithins were selected for this purpose, since multicomponent mixtures such as model 11.0 are very costly, even at levels of 2% wt/vol in dodecane. The costs of components in 74% wt/vol (see below) levels would have been prohibitive. 

Most of the permeabilities of the bases decrease steadily as the phospholipid fraction increases. There are some significant exceptions. Metoprolol, which is only moderately permeable in the DOPC lipid, becomes appreciably permeable in 10% soy lecithin. But at the 68% soy level, this molecule also shows reduced transport. 

TABLE 7.12 Soy Lecithin in Dodecane PAMPA Models (No Sink), pH 7.4a... 

Figure 7.31 Soy lecithin permeabilities at various concentrations in dodecane, with and without sink (a) bases (b) acids (c) neutrals.

Figures 7.31a-c clearly show that after some critical soy content in dodecane, Pe values decrease with increasing soy, for both sink and sinkless conditions. [This is not due to a neglect of membrane retention, as partly may be the case in Fig. 7.23 permeabilities here have been calculated with Eq. (7.21).] Section 7.6 discusses the Kubinyi bilinear model (Fig. 7.19d) in terms of a three-compartment system water, oil of moderate lipophilicity, and oil of high lipophilicity. Since lipo-some(phospholipid)-water partition coefficients (Chapter 5) are generally higher than alkane-water partition coefficients (Chapter 4) for drug-like molecules, soy lecithin may be assumed to be more lipophilic than dodecane. It appears that the increase in soy concentration in dodecane can be treated by the Kubinyi analysis. In the original analysis [23], two different lipid phases are selected at a fixed ratio (e.g., Fig. 7.20), and different molecules are picked over a range of lipophilicities.

The negative-charge lipid content in the egg lecithins is not as high as that found in BBM and especially BBB lipids (Table 7.1). Furthermore, the negative-charge content in the egg lecithin is about one-fourth that in the soy lecithin. This is clearly evident in the membrane retention parameters for the bases at the 10% lecithin levels (models 12.0 or 14.0 in Table 7.8 vs. model 16.0 in Table 7.12), as they are 20-30% lower for the lipophilic bases in egg, compared to soy. 

For acids, the membrane retention actually increases in the case of egg lecithin, compared to soy lecithin. This may be due to decreased repulsions between the negatively charged sample and negatively charged phospholipid, allowing H-bond-ing and hydrophobic forces to more fully realize in the less negatively charged egg lecithin membranes. The neutral molecules display about the same transport properties in soy and egg lecithin, in line with the absence of direct electrostatic effects. These differences between egg and soy lecithins make soy lecithin the preferred basis for further model development. 

Since soy lecithin ( 20% extract from Avanti) was selected as a basis for absorption modeling, and since 37 % of its content is unspecified, it is important to at least establish that there are no titratable substituents near physiological pH. Asymmetric triglycerides, the suspected unspecified components, are not expected to ionize. Suspensions of multilamellar vesicles of soy lecithin were prepared and titrated across the physiological pH range, in both directions. The versatile Bjerrum plots (Chapter 3) were used to display the titration data in Fig. 7.33. (Please note the extremely expanded scale for %.) It is clear that there are no ionizable groups... 

Figure 7.33 Bjerrum plot for titration of a suspension of 1 mM soy lecithin.

Iso-pH Permeability Measurements using Soy Lecithin-Dodecane-Impregnated Filters... 

The above iso-pH measurements are based on the 2% DOPC/dodecane system (model 1.0 over pH 3-10 range). Another membrane model was also explored by us. Table 7.16 lists iso-pH effective permeability measurements using the soy lecithin (20% wt/vol in dodecane) membrane PAMPA (models 17.1, 24.1, and 25.1) The negative membrane charge, the multicomponent phospholipid mixture, and the acceptor sink condition (Table 7.1) result in different intrinsic permeabilities for the probe molecules. Figure 7.40 shows the relationship between the 2% DOPC and the 20% soy iso-pH PAMPA systems for ketoprofen. Since the intrinsic permeability of ketoprofen in the soy lecithin membrane is about 20 times greater than in DOPC membrane, the flat diffusion-limited transport region of the log Pe... 

Figure 7.40 Permeability-pH profiles for ketoprofen under iso-pH conditions for two different PAMPA models unfilled circles = 2% DOPC/dodecane, filled circles = 20% soy lecithin/dodecane. [Reprinted from Avdeef, A., in van de Waterbeemd, H. Lennemas, H. Artursson, P. (Eds.). Drug Bioavailability. Estimation of Solubility, Permeability, Absorption and Bioavailability. Wiley-VCH Weinheim, 2003 (in press), with permission from Wiley-VCH Verlag GmbH.]...

Figure 7.41 Gradient pH profiles for three weak bases with double-sink conditions, 20% wt/vol soy lecithin in dodecane (a) verapamil (pKa 9.07) (b) propranolol (pKa 9.53) (c) metoprolol (pKa 9.56).

DOUBLE-SINK (Soy Lecithin 20% wt/vol in Dodecane, SINK in Acceptor)... 

Figure 7.43 Gradient pH profiles for two nonionizable molecules double-sink conditions, 20% wt/vol soy lecithin in dodecane.

The 20% soy lecithin (Table 7.17) and the 2% DOPC (Table 7.15) intrinsic permeabilities may be compared in a Collander equation, as shown in Fig. 7.44. The slope of the regression line, soy versus DOPC, is greater than unity. This indicates that the soy membrane is more lipophilic than the DOPC membrane. Intrinsic permeabilities are generally higher in the soy system. Three molecules were significant outliers in the regression metoprolol, quinine, and piroxicam. Metoprolol and quinine are less permeable in the DOPC system than expected, based on their apparent relative lipophilicities and in vivo absorptions [593]. In contrast, piroxicam is more permeable in DOPC than expected based on its relative lipophilicity. With these outliers removed from the regression calculation, the statistics were impressive at r2 0.97. 

TABLE 7.17 Intrinsic Permeabilities and the Unstirred Water Layer Permeabilities Determined from Gradient-pH Dependence of Effective Permeabilities 20% Soy Lecithin in Dodecane, Sink in Acceptor... 

TABLE 7.18 Interpolated Apparent and Membrane Permeabilities Determined from Double-Sink Conditions 20% Soy Lecithin in Dodecane... 

Figure 7.44 Collander relationship between intrinsic permeabilities of 20% soy lecithin versus 2% DOPC PAMPA models.

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