Pilocarpic acid

Pilocarpine dissolves in dilute soda solution, and the rotation is thereby reduced, due to the formation of the sodium salt of pilocarpic acid, CiiHigOgNa, of which pilocarpine is the lactone. Amorphous barium and copper salts have been prepared. Pilocarpine in dilute sulphuric acid gives with hydrogen peroxide, followed by potassium dichromate, a bluish-violet colour soluble in benzene. For the identification of the alkaloid Wagenaar recommends precipitation with gold chloride solution. 

Fig. 7.13. HO -Catalyzed ring opening of pilocarpine (7.76) and isopilocarpine (7.77) to pilocarpic acid and isopilocarpic acid, respectively, and proton-catalyzed lactonization of the two acids to the respective lactone. Note that pilocarpine and isopilocarpine interconvert by a base-catalyzed reaction of epimerization (Reaction a).

The reverse reaction of lactonization of pilocarpic acid is proton-catalyzed and, hence, favored at low pH. Thus, the pilocarpine/pilocarpic acid ratio was 1.0, 1.6, 2.7, 4.0, 5.1, and 6.7 at pH values of 6.0, 5.6, 5.2, 4.8, 4.4, and 4.0, respectively [161]. Interestingly, the lactonization of isopilocarpic acid is ca. 17-fold faster than the lactonization of pilocarpic acid, since the second-order rate constants of proton-catalyzed lactonization at 25° were 0.96 and 0.055 M-1 min-1 for isopilocarpine and pilocarpine, respectively [162], A lack of planarity in the lactone ring of pilocarpine, and a more lac-tone-like planarity in isopilocarpine, appear to account for this difference in reactivity between the two epimers. 

A complex example of activation, aimed at improving ocular delivery, has been reported for prodrugs of pilocarpine (8.87, Fig. 8.6) [123][124], The prodrugs are, in fact, lipophilic diesters of pilocarpic acid (8.86, Fig. 8.6). The first step is enzymatic O-acyl hydrolysis to remove the acyl carrier (Fig. 8.6, Reaction a). In a second step, intramolecular nucleophilic attack leads to loss of the alcohol carrier and ring closure to pilocarpine (Fig. 8.6, Reaction b). 

Inactivation of pilocarpine is thought to occur at neuronal synapses and probably in plasma. Pilocarpine and its minimally active or inactive degradation products, including pilocarpic acid, are excreted in the urine. 

Bundgaard, H., Falch, E., Larsen, C., and Mikkelson, T. J. Pilocarpine prodrugs I. Synthesis, physicochemical properties and kinetics of lactonization of pilocarpic acid esters. J. Pharm. Sci. 75 36-43, 1986. 

HPLC Water Cyano Spherisorb, 25°C Aq. 0.1% TEA (pH 2.5) 220 nm Resolved from pilocarpine, pilocarpic acid, and isopiiocarpic acid [532)... 

A. Gomez-Gomar, M. Gonzalez-Aubert, and J. Costa-Segarva, HPLC method of pilocarpine, isopilocarpine, pilocarpic acid and isopipocarpic acid, J. Pharm. Biomed. Anal., 7 1729 (1989). 

T. Jarvinen, P. Suhonen, H. Naumanen, A. Urtti, and P. Peura, Determination of physicochmical properties, stability in aqueous solutions and serum hydrolysis of pilocarpic acid diesters, J. Pharm. Biomed. Anal., 9 737 (1991). 

Jarvinen and co-workers [136] synthesized unique O, 0 -(xylylene)bispilocarpic acid esters containing two pilocarpic acid monoesters linked with one moiety. The found that prodrug showed a two- to seven-fold higher corneal permeability than pilocarpine itself despite the high molecular weight. 

The kinetics of the hydroxide ion-catalyzed epimerization of pilocarpine to isopilocarpine and of its hydrolysis to pilocarpic acid have been studied (56). Both forms of degradation lead to loss of pharmacological activity. The importance of possible inactivation by epimerization during thermal sterilization of ophthalmic preparations of pilocarpine was pointed out. It was also considered that some epimerization would always occur during the extraction of pilocarpine from Jaborandi leaves, and that isopilocarpine might, therefore, be an artifact and not a genuine plant alkaloid (55). 

Figure 12.11 Sample chromatogram for separation of pilocarpine (P), isojnlocarpine (I) and pilocarpic acid (A). A phenyl-bonded silica was used with mobile phase of acetonitrile-aqueous buffer (3 90 v/v), (pH 2.5).

Pilocarpine is widely used in ophtalmology in eye-drops. However, in solution it may undergo epimerization to isopilocarpine, and even hydrolysis to pilocarpic acid. In both cases loss of pharmacological activity is the result. Therefore, the analysis of ophtalmic solutions for pilocarpine and its decomposition products have been the subject of several investigations. 

Column Lichrosorb RP18 10 um (300x4 mm ID), mobile phase 6% potassium dihydrogen phosphate in water - methanol (97 3)(pH 2.5), flow rate 1.5 ml/min, detection with differential re-fractometer. Peaks 1, pilocarpine 2, isopilocarpine 3, pilocarpic acid 4, isopilocarpic acid. 

To improve the ocular bioavailability and prolong the duration of action, various pilocarpic acid mono- and diesters were evaluated as prodrugs for pilocarpine. As shown in Scheme 24, the pilocarpic acid monoesters (138) undergo a quantitative... 

FIGURE 36.22 Double esters derived from pilocarpic acid are readily converted to pilocarpine under conditions simulating those occurring in vivo ... 

Figure 13.41. Two-step activation of pilocarpine prodrugs (215). The prodrugs are diesters of pilocarpic acid (46). Enzymatic hydrolysis (reaction a) cleaves the acyl carrier group. The product is a monoester of pilocarpic that undergoes cyclization to pilocarpine (47) upon intramolecular nucleophilic attack (cyclization) and elimination of the alcohol carrier (reaction b).

Stability in aqueous solutions. This stability problem was solved by forming double prodrug pilocarpic acid esters. Because of their blocked hydroxyl group, these compounds are unable to undergo cyclizationto pilocarpine in the absence of hydro lytic enzymes. 

Scheme 67. Cyclization of pilocarpic acid and isopilocarpic acid to pilocarpine and isopilccarpine, respectively.

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