Scopolamine base

The transdermal scopolamine system is a circular flat patch designed for continuous release of scopolamine following application to an area of intact skin on the head, behind the ear. Each system contains 1.5 mg of scopolamine base. Scopolamine is (alpha)-(hydroxymethyl)ben-zeneacetic acid 9-methyl-3-oxa-9-azatricyclo [3.3.1.0 2,4] non-7-yl ester. Scopolamine is a viscous liquid that has a molecular weight of 303.35 and a pKa of 7.55-7.81. The transdermal system is a film 0.2 mm thick and 2.5 cm2, with four layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are a... 

M. and M. Polonovski found that when scopolamine is treated with hydrogen peroxide, there is formed in addition to scopolamine iV-oxide [a]i, — 14° (H2O), [B. HBr, m.p. 153°] the quaternary base scopinium, isolated in the form of its bromide, m.p. 209-10°. The latter is reduced by sodium amalgam to a tertiary base, stereoisomeric with scopine and related to the latter as -tropine is to tropine and, therefore, named -SCOPINE. It yields crystalline salts B. HCl, m.p. 257-8°, aurichloride. 

In a one-liter separatory funnel, 94 g (0.215 mol) of scopolamine hydrobromide trihydrate was dissolved in 250 ml of water, made alkaline by shaking with 40 g (1 mol) of sodium hydroxide in 150 ml of water, and the free base immediately extracted with ether. As scopolamine is somewhat soluble in water, the aqueous layer was saturated with potassium carbonate and again extracted with ether. The combined ether extracts were dried over anhydrous magnesium sulfate and the ether removed by distillation, leaving 65 g (0.214 mol 100% yield) of nearly colorless oil. Then 100 g (1.05 mols) of cold methyl bromide was added to a chilled, 500-ml pressure flask containing the 65 g of scopolamine, the flask stoppered tightly with a clamp, and allowed to stand at room temperature for 96 hours. 

The salt was recrystallized from 550 ml of alcohol first crop, 70 g, MP 212° to 214°C second crop, 6 g, MP 195° to 200°C. The combined crops were again recrystallized from 500 ml of 3-A alcohol MP 210° to 212°C. The third recrystallization from 600 ml of alcohol yielded 64 g, MP 214° to 216°C, a 75% yield based on scopolamine hydrobromide trihydrate starting material. 

The more useful types of chirally active bonded phases are those based on the cyclodextrins. There are a number of different types available, some of which have both dispersive or polar groups bonded close to the chirally active sites to permit mixed interactions to occur. This emphasizes the basic entropic differences between the two isomers being separated. A range of such products is available from ASTEC Inc. and a separation of the d and / isomers of scopolamine and phenylephrine are shown in figure 4. The separations were carried out on a cyclodextrin bonded phase (CYCLOBOND 1 Ac) that had been acetylated to provide semi-polar interacting groups in close proximity to the chiral centers of the cyclodextrin. The column was 25 cm long, 4.6 mm in diameter and packed with silica based spherical bonded phase particles 5pm in diameter. Most of the columns supplied by ASTEC Inc. have these dimensions and, consequently, provide a... 

Saponins la 7,411,430 -, bioautographic determination la 109 Sarcosine Ia435 lbl24 Scandium cations, detection la 144 Scanner, optical trains la 30,39 S-Chamber (small chamber) la 126,127 SCHiFF s bases lb 52 Scintillators la 12 Scopolamine lb 231,252,255,323 Scopoletin lb 216-218,365 Screening process lb 45 Sebacic acid la 178,233,249,308 Sebuthylazine lb 418 Selectivity, enhancement by derivatiza-tion la 55... 

Indeed, it was shown that aposcopolamine was not formed by direct dehydration of scopolamine, but via the conjugate scopolamine O-sulfate generated by a sulfotransferase [127]. This explains the species differences observed, and indicates a mechanism of heterolytic C-0 bond cleavage made possible by the electron-withdrawing capacity of the sulfate moiety. The reaction is also facilitated by the acidity of the departing proton carried by the vicinal, stereogenic C-atom. This acidity also accounts for the facile base-catalyzed racemization of scopolamine and hyoscyamine [128]. 

Based on pooled data, Goodman calculated that 450 mg is the average lethal dose (LD50), about forty-five times the dose that produces delirium. One report in the literature documents a case of recovery from an oral dose of 1,000 mg of atropine. Also, at least one individual has survived 500 mg (from 100 to 150 times the delirium-producing dose) of the related but more potent drug scopolamine... 

Previously published clinical observations of daily atropine and scopolamine effects usually did not include precise recording time of onset and recovery from each dose. At least one journal report, however, did note that a certain degree of tolerance to atropine developed in the course of daily use for several months or years. This may or may not be based on a mechanism similar to the second-dose effect that we observed with BZ. Conceivably, this might have military implications if the target population had previously been exposed to an attack with BZ on one or more occasions. The practical significance of the slightly earlier onset and recovery, however (Fig. 12), seems to be relatively minor. 

Hyoscine crosses the blood-brain barrier more rapidly than atropine, therefore some of the side effects are more pronounced with hyoscine. These include drowsiness, blurred vision, dizziness, dry mouth, and difficulty with micturition, while confusion may occur in the elderly. Efficacy in PONV is only moderate, and it is now rarely used. It is, however, a well-proven remedy for motion sickness, and an effect on the vestibular apparatus may contribute to its action. Here, it is given in the form of the hydrobromide (scopolamine), 1 mg of which contains 0.7 mg of the laevo-hyoscine base. Commercially available seasickness tablets usually contain 0.3 mg and one or two are recommended for protection for short journeys. Side effects preclude the long-term use of hyoscine for travel sickness. 

Kennedy, R.S. et al., Differential effects of scopolamine and amphetamine on microcomputer-based performance tests, Aviat. Space Environ. Med., 61, 615, 1990. 

Major advances have been made in recent years in the development and optimization of chiral resolutions of derivatized CD-based CSPs [68]. It has been reported that CSPs based on CD derivatives were more enantioselective than CSPs obtained from native CDs [68]. An acetyl /CCD column exhibited enhanced separation for scopolamine in comparison to the native / -CD CSP in the reversed-phase mode [69]. The enantiomeric resolution of some drugs was compared on the native [l-CD and on CSPs based on (S)- and (i )-2-hydroxy-propyl /I-CD, and the best resolution was reported on the derivatized CSPs [44]. Five types of natural and chemically modified [>- or y-C D stationary phases were developed and used for the chiral resolution of dansyl amino acids. The best resolution of dansyl amino acids was provided by y-CD CSPs [70]. 

Direct analysis of the enantiomers in biological fluids is very important because it reduces both analysis time and sample preparation time. Indeed, when there is risk of the quick racemization of the enantiomer, direct analysis is essential. It has been observed that CD-based CSPs employ mobile phases that are generally compatible with biological samples, hence can be used for the direct analysis of the enantiomers in biological fluids [67,80]. Stalcup et al. [58] employed coupled column chromatography to isolate scopolamine from a plant extract and found that the extent of racemization depends on the isolation... 

Weak bases and their salts (nortriptyline hydrochloride, phenelzine sulfate, chloroquine phosphate, scopolamine hydrobromide, tamoxifen citrate, etc.) approximately 45%... 

Opium alkaloids such as codeine, thebaine, papaverine, and noscapine exhibit high solubility (0.09-0.9 mg/g) in supercritical fluids including CO N,0, CHF, [37]. However, in spite of their high solubilities, they were not extracted from plant material by pure CO, to the degree expected [29], possibly because these alkaloids exist as their salt forms in plant tissue. In this chapter, the examples that show the difference of the solubilities between alkaloidal free bases and salts are presented. For this comparison, the solubilities of the free bases of hyoscyamine (1), scopolamine (2), pseudoephedrine (6) were measured and compared with those of their hydrochloride salts (Figures 3 and 4). 

Figure 3. Solubilities of hyoscyamine (I) and scopolamine (2) free bases in supercritical CO, [39]. Reprinted from J. Chromatogr. A, 863, Y. H. Choi et al., Strategies for supercritical fluid extraction of hyoscyamine and scopolamine salts using basified modifiers, 47-55 (1999), with permission from Elsevier Science.

Although there were some differences on the effects of temperature and pressure according to each particular compound, the free bases of hyoscyamine (1), scopolamine (2), and pseudoephedrine (6) were all found to be highly soluble in supercritical CO,. However, the hydrochloride salts of these compounds were scarcely extracted by pure CO, under any conditions employed. These results were consistent with preliminary evidence indicating that these alkaloids are not extracted from plant materials by pure CO,. This means that the alkaloids in living cells in the plant are not in the form of their free bases but rather as water-soluble salts in the cell vacuole [40]. Therefore, it was necessary to develop a procedure to enhance the solubilities of alkaloidal salts in CO,. 

Generally, alkaloidal salts are insoluble in nonpolar solvents but their free bases are quite soluble in the solvents. Therefore, the basified modifier should be introduced into the SFE to solubilize alkaloids in CO,. For the evaluation of the effects of basified modifiers, diethylamine was added to methanol or water at a 10% (v/v) concentration level. Then, the basified modifiers were continuously incorporated into the extraction cell at concentrations of 1, 5, and 10 % (v/v). The effects of methanol basified with diethylamine as a modifier on the solubilities of hyoscyamine (1) and scopolamine (2) are shown in Figure 8. The addition of diethylamine (10% v/v) into methanol dramatically enhanced the solubilities of the alkaloidal hydrochloride salts compared with those of pure methanol alone. This may be due to the fact that methanol basified with diethylamine changed the salts to the free bases. 

In addition to the silica-based materials mentioned above, modem polymers are widely used for TTA and QTA sample preparation allowing SPE not impaired by undesirable silanol activities. HLB Oasis (Waters) is the tradename for a hydrophilic-lipophilic balance reversed-phase sorbent enabling lipophilic interaction to benzene moieties and hydrophilic interactions to pyrrolidone groups as present in the macroporous copolymer of poly(divinylbenzene-co-iV-vinylpyrrolidone). Elution of analytes is often performed with solvents containing MeOH or ACN. Applying this adsorbent TA such as atropine and scopolamine were extracted from human viscera [15], human serum [97-99], human urine [12] as well as from rat plasma and brain microdialysate [77], Furthermore, this hydrophilic-lipophilic balance phase was also suitable for extraction of the QTA trospium from human and rat plasma [77, 84] and methyl scopolamie from rat plasma [77] (Table 4). 

Supercritical fluid extraction (SEE) has become a method of choice for the extraction of plant material [14]. It represents an interesting alternative technique compared to conventional liquid-solid extraction, with lower solvent consumption and working temperature. The free bases of hyoscyamine and scopolamine are extractable with... 

Schiff s bases in gas chromatography, 188 Schiff s Reagent, 144 Schoenocuulon officinale, 1061 Scolaban, 409 Scoline, 998 Scoparium, 972 Scopolamine, 674 Scopolamine bromhydrate, 674 Scopolamine butylbromide, 675 Scopolamine hydrobromide, 674 Scopolamine methylbromide, 675... 

The combinatorial decoration or derivatization of existing natural products is a popular method for library creation. Among targets for such exercises are the alkaloids yohimbine and scopolamine, terpenoids and steroids, and the heterocyclic peptide antibiotic GE-2270A (Figure 11). In the latter case, combinatorial variation was instrumental in the discovery of a developmental candidate now in clinical trials at Vicuron. Pfizer, the world s largest pharmaceutical company, recently acquired Vicuron for the sum of 1.9 billion, a mark of approval for natural product-based combinatorial chemistry. 

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