Ionization molecules

A laser pulse is used to knock material from the surface of a solid sample the laser pulse creates a microplasma that ionizes molecules in the sample. 

The mass spectral fragmentations of 9,10-dimethoxy-2,3,4,6,7,ll/)-hexa-hydro-l//-pyrimido[6,l-n]isoquinolin-2-ones 140 and -2,4-diones 141, under electron ionization (at 70 eV) were examined by metastable ion analysis, a collosion-induced dissociation technique and exact mass measurement (97RCM1879). Methyl substituent on N(3) in 140 (R = Me) had a larger effect on both the fragmentation and on the peak intensities, than a methyl substituent on C(6) (R = Me). The ionized molecules of 140 (R = H) were rather stable, whereas 4-phenyl substitution on C(4) of 140 (R = Ph) promoted the fragmentations of the molecular ions. The hexahydro-1//-pyrimido[6,l-n]isoquinoline-2,4-diones 141 were more stable, than the hexahydro-l//-pyrimido[6,l-n]isoquinolin-2-ones 140, and the molecular ions formed base peaks. 

Electrospray ionization mass spectrometry (ESI-MS) is an analytical method for mass determination of ionized molecules. It is a commonly used method for soft ionization of peptides and proteins in quadmpole, ion-trap, or time-of-flight mass spectrometers. The ionization is performed by application of a high voltage to a stream of liquid emitted from a capillaty. The highly charged droplets are shrunk and the resulting peptide or protein ions are sampled and separated by the mass spectrometer. 

Tandem mass spectrometry (MS/MS) is a method for obtaining sequence and structural information by measurement of the mass-to-charge ratios of ionized molecules before and after dissociation reactions within a mass spectrometer which consists essentially of two mass spectrometers in tandem. In the first step, precursor ions are selected for further fragmentation by energy impact and interaction with a collision gas. The generated product ions can be analyzed by a second scan step. MS/MS measurements of peptides can be performed using electrospray or matrix-assisted laser desorption/ionization in combination with triple quadruple, ion trap, quadrupole-TOF (time-of-flight), TOF-TOF or ion cyclotron resonance MS. Tandem... 

The photoelectron spectrum of methane shows two bands, at 23 and 14 eV, and not the single band we would expect from the equivalency of the four C—H bonds. The reason is that ordinary sp hybridization is not adequate to explain phenomena involving ionized molecules (such as the CH4" radical ion, which is left behind when an electron is ejected from methane). For these phenomena it is... 

The thermosphere is the outermost part of the atmosphere, above an altitude of about 85 km. Here, molecules of nitrogen and oxygen absorb X-ray radiation coming from the sun. These photons have enough energy to ionize molecules and to break chemical bonds. Here are two examples ... 

It has been shown that in some compounds the active species is the non-ionized molecule while the ion is inactive (benzoic acid, phenols, nitrophenols, salicylic acid, acetic acid). Thus, conditions of pH which favour the formation of the ions of these compounds will also reduce their activity. The effect of pH on the ability of acetic acid and phenol to inhibit the growth of a mould is shown in Fig. 11.4. 

In other cases the activity ofthe drug is due to the ionized molecule. For example, with the antibacterial acridine dyestuffs it is the cation which is the active agent and factors favouring ionization, all other things being equal, enhance their antibacterial activity (see Chapter 12). 

For ionizable molecules, the membrane permeability, P (Pc in cellular models), depends on pH of the bulk aqueous solution. The maximum possible Pm is designated Pq, the intrinsic permeabiUty of the uncharged species. For monoprotic weak acids and bases, the relationship between P and Pq may be stated in terms of the fraction of the uncharged species,, as Pm= Pofo, i-e. ... 

We have not yet introduced the influence of the presence of point charges on the lipophilicity of a chemical. Nevertheless, Sections 12.1.1.2 and 12.1.1.3 do warn that the lipophilic behavior of an ionized molecule might be very different from that of its parent neutral compound. Indeed, in order to investigate the balance of forces governing the lipophiUcity of ionized species we must do without Abraham s equations, since they do not exist when ions are considered. Recently, Abraham et al. also demonstrated what had long been perceived intuitively - descriptors for ions are not the same as those for nonelectrolytes [12]. 

On the subject of applications of such experimental parameters, the questions of whether an ionized molecule may or may not partition into octanol and whether bulk-phase partitioning is in turn adequate to describe bilayer partitioning are important and pertinent ones, and are addressed in Section 16.3. 

C. N. Partitioning of ionizing molecules between aqueous buffers and phospholipid vesicles. J. Pharm. Sci. 1995, 84, 1180-1183. 

A state of dynamic equilibrium exists between the ionized and the non-ionized molecules (XY (non-ionized molecule) X+ (cation) + Y (anion)). The process of electrolytic dissociation is reversible. 

If Ia is the ionization potential of the atom of an element, Im that of its diatomic molecule, D the heat of dissociation of the neutral molecule, and Df that of the ionized molecule, it can easily be shown11 that... 

In solutions saturated (i.e., excess solid present) at some pH, the plot of log Co versus pH for an ionizable molecule is extraordinarily simple in form it is a combination of straight segments, joined at points of discontinuity indicating the boundary between the saturated state and the state of complete dissolution. The pH of these junction points is dependent on the dose used in the calculation, and the maximum value of log Co is always equal to log. Sb in a saturated solution. [26] Figure 2.2 illustrates this idea using ketoprofen as an example of an acid, verapamil as a base, and piroxicam as an ampholyte. In the three cases, the assumed concentrations in the calculation were set to the respective doses [26], For an acid, log Co (dashed curve in Fig. 2.2a) is a horizontal line (log Co = log So) in the saturated solution (at low pH), and decreases with a slope of —1 in the pH domain where the solute is dissolved completely. For a base (Fig. 2.2b) the plot of log Co versus pH is also a horizontal line at high pH in a saturated solution and is a line with a slope of +1 for pH values less than the pH of the onset of precipitation. 

The distribution ratio D is used only in the context of ionizable molecules [229,270-276]. Otherwise, D and P are the same. The partition coefficient P, defined in Eq. (4.2), refers to the concentration ratio of a single species. In contrast,... 

Ionizable molecules embedded in the surfaces of lipids, such as octanol (see Fig. 2.8), liposomes (see Fig. 5.2), or micelles, will have their apparent pKa values shifted. With neutral lipids, the pKa of an acid increases and the pKa of a base decreases. This is due to the effect of the decreased dielectric constant in the interfacial zone, as we have already discussed in various sections. 

The protonation reactions for ionizable molecules have been defined in Section 3.1. When a solute molecule, HA (or B), is in equilibrium with its precipitated form, HA(s) (or B(s)), the process is denoted by the equilibrium expression... 

Two sensibly priced commercial databases for solubility exist [366,507], An article in the journal Analytical Profiles of Drug Substances carries solubility data [496]. Abraham and Le [508] published a list of intrinsic aqueous solubilities of 665 compounds, with many ionizable molecules. It is difficult to tell from published lists what the quality of the data for ionizable molecules is. Sometimes, it is not clear what the listed number stands for. For example, Sw, water solubility, can mean several different things either intrinsic value, or value determined at a particular pH (using buffers), or value measured by saturating distilled water with excess compound. In the most critical applications using ionizable molecules, it may be necessary to scour the original publications in order to be confident of the quality of reported values. 

Figure 6.6 Empirical relationship between intrinsic solubility of ionizable molecules and their octanol water log P [pION]. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]...

The procedure takes as input parameters the measured (or calculated) pKa and the measured (or calculated) octanol-water partition coefficient, log P. The latter parameter is used to estimate the intrinsic solubility So, using the Hansch-type expression [38], log So = 1.17 — 1.38 log P, or an improved version for ionizable molecules of moderate lipophilicity (Fig. 6.6) ... 

The system reported by Avdeef and co-workers [25-28,556-560] is an extension of the Roche approach, with several novel features described, including a way to assess membrane retention [25-28,556,557] and a way to quantify the effects of iso-pH [558] and gradient pH [559] conditions applied to ionizable molecules. A highly pure synthetic phospholipid, dioleoylphosphatidylcholine (DOPC), was initially used to coat the filters (2% wt/vol DOPC in dodecane). Other lipid mixtures were subsequently developed, and are described in detail in this chapter. 

The effective permeability of ionizable molecules depends on pH, and the shapes of the permeability-pH profiles can be theoretically predicted when the pKa of the molecule is known, the pH partition hypothesis are valid, and the resistance of... 

The membrane permeabilities Pm may be converted to intrinsic permeabilities P(h when the pKa is taken into consideration. An ionizable molecule exhibits its intrinsic permeability when it is in its uncharged form and there is no water layer resistance. The relationship between Pm and P0 is like that between the pH-dependent apparent partition coefficient (log Kd) and the true partition coefficient (log Kp), respectively. This relationship can be rationalized by the mass balance. Take, for example, the case of a monoprotic acid, HA. The total substance concentration is... 

The method preferred in our laboratory for determining the UWL permeability is based on the pH dependence of effective permeabilities of ionizable molecules [Eq. (7.52)]. Nonionizable molecules cannot be directly analyzed this way. However, an approximate method may be devised, based on the assumption that the UWL depends on the aqueous diffusivity of the molecule, and furthermore, that the diffusivity depends on the molecular weight of the molecule. The thickness of the unstirred water layer can be determined from ionizable molecules, and applied to nonionizable substances, using the (symmetric) relationship Pu = Daq/ 2/iaq. Fortunately, empirical methods for estimating values of Daq exist. From the Stokes-Einstein equation, applied to spherical molecules, diffusivity is expected to depend on the inverse square root of the molecular weight. A plot of log Daq versus log MW should be linear, with a slope of —0.5. Figure 7.37 shows such a log-log plot for 55 molecules, with measured diffusivities taken from several... 

It is difficult to prove that quaternary ammonium compounds can cross lipid bilayers using cell uptake experiments, since several mechanisms may be operative, and separating contributions from each may be very difficult [1]. It may be an advantage to use PAMPA to investigate transport properties of permanently ionized molecules. Of all the molecules whose permeabilities were measured under iso-pH conditions in 2% DOPC/dodecane, verapamil, propranolol, and especially quinine seem to partially violate the pH partition hypothesis, as shown in Figs. 7.47a-c. In Fig. 7.47c, the solid line with slope of +1 indicates the expected effective permeability if the pH partition hypothesis were strictly adhered to. As can be seen at pH 4... 

When molecules have the insoluble BCS classification, the expected absorption profile is exemplified in Fig. 2.2. The upper horizontal line (solid) in Fig. 2.2, representing log Pq, can be determined by the methods described in Chapter 7. The slope 0, 1 segments curve (dashed), representing log Co, the concentration of the uncharged form of an ionizable molecule, can be determined by the methods described in the Chapter 6. The summation of log P0 and log C0 curves produces the log flux-pH profile. Such plots indicate under what pH conditions the absorption should be at its highest potential. 

---