Pyridostigmine bromide

a ch3

Fig. 2.22

CI b

Drug type: anti-cholinergic.

Functional groups:

• A Salt of strongly basic quaternary ammonium ion. Quaternary ammonium ions are charged at all pH values.

• B Carbamate group, the nitrogen is neutral as in an amide but the carbamate group is less stable than an amide having a stability similar to that of a phenolic ester.

Compounds containing a quaternary ammonium group: atracarium besylate, bretylium tosylate, clindium bromide, glycopyrronium bromide.

Predominant form of guanethidine at pH 7.0; charge on A is delocalised over all three nitrogens

^^^ Additional problems

1. Calculate the pH of the following solutions assuming that the concentration and the activity of the solutions are the same:

(ii) 0.1 M chloroacetic acid (Ka = 1.4 x 10~3). (in) 0.1 M phosphoric acid (First Ka 7.5 x 10 3).

(iv) 0.1 M fumaric acid {Ka 9.3 x 10" and 3.4 x 105).

(v) 0.1 M di-isopropylamine base (Kb = 9.09 x 10").

101 (|a) '0zl (a) -'wl (a!) '-9S'l (!!!) i£6'l (!!) ie'l (!) -SJ3MSUV

2. Calculate the pH of the following salt solutions:

(i) 0.1 M sodium formate (Ka formic acid = 1.77 x 10")

(ii) 0.1 M sodium fusidate (Ka fusidic acid = 4.0 x 10-«).

(iii) 0.1 M ephedrine hydrochloride (Ka of ephedrine = 2.5 x 10"°).

3. Calculate what volumes of the salt solutions specified which would be required to prepare 1 I of the following buffers:

(i) 0.1 M phosphoric acid/0.1 M sodium dihydrogen phosphate pH 2.5 (pKa H3P042.13)

(ii) 0.1 M sodium dihydrogen phosphate/0.1 M disodium hydrogen phosphate pH 8.0 (pKa H2P04 7.21).

(iii) 0.1 M sodium bicarbonate/0.1 M sodium carbonate pH 9.5 (pKa HC03 10.32). ■|W S UEL/ILU S'898 (!!!) :|W S098/|w S'6EL (!!) -'|w 10£/|W 66Z (!) -SJaMSuy

4. Indicate the percentage of ionisation of the functional groups specified in the following drugs at pH 7.0 (Fig. 2.23).

cr n

n ch3

Theophylline

B pKa 9.2 chch2ch2n(ch3)2

Chlorpheniramine

%1?'66 8 %60'6 V auiaiej.iuaijdjomD .'(u3ßoJi]u 3|p!3e) %gs'l 3uj||/il)doam :sjsMsuy

5. Calculate the percentage of the following compounds that would be extracted under the conditions specified:

(i) A solution of basic drug pKa 9.2 in an oral liquid is mixed with a buffer having a pH of 7.2 and is extracted with an equal volume of chloroform (the partition coefficient of the un-ionised base into chloroform is 500).

(ii) an acidic drug with a pKa 4.2 is extracted from a solution of pH 4.5 with an equal volume of chloroform (the partition coefficient of the un-ionised acid into chloroform is 300).

6. Extracts containing benzylpenicillin were prepared for analysis in buffer at pH 6.5 at 25°C, the rate constant for the hydrolysis of benzylpenicillin under these conditions is 1.7 x 10~7 s. What is the maximum length of time the solutions can be stored before analysis so that no more than 1% decomposition occurs.

7. Determine the absolute configurations of the chiral centres in menthol and phenbutrazate. List the configurations of the pairs of enantiomeric diastereoisomers of menthol (Fig. 2.24).

Menthol

Phenbutrazate

■|oqiuaw joj se aiezejinquai|d utszuusEuzsi 'yinzm/siszsi -siuzuuuiszsi 'szszyi/utuzsi wiuaiAi SE SZ SL aiezejjnquaijd -HZ HZ SI |oqiua|/\| :sj3msuv

References

1. J.B. Stenlake. Foundations of Molecular Pharmacology. Athlone Press (1979).

2. A.T. Florence and D. Attwood. Physicochemical Principals of Pharmacy. 2nd Edn, Macmillan Press (1988).

3. E.J. Ariens. Trends Pharmacol. Sei. 7, 200-205 (1986).

4. P.A. Lehmann. Trends Pharmacol. Sei. 7, 281-285 (1986).

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