Atropine ionization

G. D. Reed, Identification of the controlled drugs propoxyphene, benzoylecgonine, and atropine by electron impact ionization capillary GC-MS, J. High Resolu. Chromatogr., 75 46 (1992). 

The octanol-water partition coefficient (Kow), characterizing distribution of a non-ionized compound between an octanol (o) and an immiscible aqueous (w) layer, may function as a measure of lipophilicity, that is often listed as its logarithmic value (log P). Therefore, log P may be used as a predictor of extractability in LLE. Table 1 presents log P values of TA calculated by the Molinspiration software [25] using SMILES notation for chemical structures. The SMILES concept is addressed in the next section [26], Conformity of calculated (calc.) and experimental (exp.) log P values is satisfying, as exemplarily shown for atropine (1.83 exp. [27] 1.77 calc.) and scopolamine (0.98 exp. [22] 1.05 calc.). 

John et al. added twice the volume of ACN to plasma samples thus generating a supernatant containing 66 % (v/v) ACN. Merely dilution with aqueous HPLC solvent A [0.1 % formic acid (FA)] was necessary prior to injection allowing quantitative analysis of R- and. S -hyoscyaminc [49] as well as atropine, cocaine, homatropine, ipratropium, littorine, iV-buty 1-scopolamine and scopolamine, simultaneously [50], Recoveries were greater than 85 % (Table 2). Despite this crude preparation procedure effects on ionization were negligible. 

The on-line coupling of CE with electrospray ionization mass spectrometry (CE-ESI-MS) allows high separation efficiency together with high sensitivity and selectivity as well as molecular structural information. A CE-UV-ESI-MS method was developed for the analysis of hoscyamine, scopolamine, and other tropane derivatives [131]. The differentiation of hyoscyamine from littorine, commonly encountered in plant material, was demonstrated using in-source collision-induced dissociation. The developed method was applied to the analysis of these alkaloids in Belladonna leaf extract and in Datura Candida x D. awreahairy root extract. Recently, CE coupled with electrochemiluminescence detection has been used for the determination of atropine and scopolamine in Flos daturae [132]. 

Antimuscarinics having a quaternary ammonium group are incompletely absorbed from the gut since these are completely ionized. The tertiary amine antimuscarinics are readily absorbed from the gut. The presence of food may reduce absorption. Quaternary ammonium antimuscarinics exhibit poor lipid solubility, do not cross the blood-brain barrier, and thus exhibit minimal central nervous system (CNS) effects. Also due to their poor lipid solubility they do not penetrate the eye and are unlikely to appear in the milk. Atropine and other tertiary amines are capable of crossing the CNS. Atropine is capable of crossing the placenta and has been stated to distribute into milk in small quantities. It is oxidized primarily in the liver. Atropine is apparently metabolized in the liver to tropic acid, tropine, and possibly esters of tropic acid and glucuronide conjugate. 

Atropine itself is a relatively strong base with a pfc, at 15-20° C. of about 10 (31), i.e., its mineral salts are about 99.9 % ionized at pH 7. However, when an atropine salt is applied locally to the eye, it mil be somewhat less well ionized, because the eye temperature will be near 37° C. and bases become weaker as the temperature rises, and because tears, which normally bathe the cornea, are slightly alkaline (pH 7-8), so that we shall probably not be far wrong in assuming that in the eye about 99% of atropine is present as atropinium cations. If un-ionized atropine base is able to penetrate cell membranes much more easily than the atropinium cation, and only 1 % is present as such, we should expect absorption to be slow, and, as already mentioned, atropine does not achieve its full effect in the human eye under an hour. In conformity with this idea, alkalization of atropine salt solutions increases both the speed and the intensity of their mydriatic activity. Thus, whereas a 1 10,000 solution of atropine sulfate produced no effect in a cat s eye in 10 min. and a barely perceptible dilatation in 50 min., a similar solution made 0.5 N with respect to sodium bicarbonate began to act in 10 min. and had produced full dilatation in 50 min. (32). The alkalinized solution was judged by indicators to have a pH of 8-9, so that the concentration of un-ionized atropine was probably increased about tenfold by the addition of sodium bicarbonate. 

Salts which are formed from a weak acid (or from a weak base) hydrolyse partly, in solution, to the acid (or base) from which they are derived and which are incompletely ionized. This situation is simpler than it may seem, because the degree of ionization in solution depends on only two factors, the pH and the The latter (which will be defined below) is a constant for any acid or base. Hence, if the pH is controlled, the degree of ionization depends only on the nature of the acid (or base) added, regardless of whether or not it has previously been neutralized. Thus the same ratio of atropine ions to atropine molecules will result from the addition of atropine hydrochloride, atropine sulfate, or free atropine to a bath that has been buffered at pH 7. If the pH of the bath is raised, the proportion of atropine ions to atropine molecules will decrease, but the new ratio will again be independent of the form in which the atropine was added. Because it is confusing to speak of Tree or non-ionized acids and bases, the term molecule , or neutral species is customarily used for all uncharged forms. 

The great majority of alkaloids, local anaesthetics, barbiturates, and neuroleptics have values between 6 and 8, so that both ionic and neutral species are present, in equilibrium, at physiological pH values. These substances will be considered in Sections 10.4 and 10.5. Among the alkaloids, atropine (piQ 10) (7.16) and tubocurarine (2.6) are atypical in having a higher degree of ionization. Tubocurarine is a quaternary amine and hence completely ionized at all pH values. Other quaternary amines used in medicine are ... 

---