Kinetic determination of propranolol in tablets by oxidation with ceric sulphate

Journal ofPharmaceurrcal & Vol 7, No 3, pp 279-286,1989 Prmted m Great Bntam

0731-7085/89 $3 00 + 0 00 @ 1989 PergamonPress plc

Analysis

Kinetic determination of propranolol in tablets by oxidation with ceric sulphate SALAH M SULTAN,*_F SAAD A ALTAMRAH,$ ABDULLAH M AZIZ ALRAHMAN,f IBRAHIM Z ALZAMILS and MOHAMMED 0 KARRARS

t Chemistry Department, King Fahd Unwerslty, KFUPM Box 2026, Dhahran 31261, Saudi Arabia $ Department of Chemistry, College of Science, King Saud Unwerslty, Rlyadh 11451, P 0 Box

2455, Saudi Arabia

Abstract A simple and accurate kinetic method for the determmatlon of propranolol has been developed Cermm(IV) sulphate (0 5 M) 1s used to oxidize propranolol m 2 M sulphunc acid at room temperature to the ketone form that absorbs light at a A,,, of 525 nm The fixed-concentration method 1s used by recording the exact time, t(s), taken for the reaction to reach a fixed absorbance of 0 100 The unknown concentration, c(M), of propranolol 1s calculated from the equation

l/t = 0 0 000217 + 0 03 c The method has been applied to the determination of propranolol m propnetary tablets and the results were compared with those obtamed by the B P and other standard methods Keywords

Kinetics, fixed-absorbance

method, propranolol

determmahon

Introduction

Propranolol hydrochloride, 1-(lsopropylammo)-3-(1-naphthyloxy)-Zpropanol hydrochloride, 1s commonly used as a P-adrenerglc blocking agent that mhlblts the effect of catecholammes released m the heart It is prescribed for its antihypertensive, antianxiety, antlconvulsant , antlangmal and antlarrhythmlc effects [l-3], it has also been proposed for use m dlsfunctlonal labour and migraine [4, 51 Various methods for the determmatlon of propranolol have been described, mcludmg fluorlmetry [6, 71, spectrophotometry [8, 91 and commonly chromatography [lo-181 The B P [19] monograph described a method for the determination of propranolol m non-aqueous media, the drug was dissolved m methanol m a standard flask and the resulting solution was determined spectrophotometncally at 290 nm Recently, Sultan [l] determmed propranolol kmetlcally by the fixed-time method by oxldatlon with potassmm dlchromate m 5 M sulphurlc acid and heating the reactants at 90°C for 20 mm, the absorbance (A) of the resulting product of chrommm(II1) was measured at 590 nm The propranolol concentration (c) was calculated from the equation A = *To whomcorrespondence

0 000857 + 0 000564 c

should be addressed

279

280

SALAH M SULTAN et al

In the present paper, propranolol 1s determined by the fixed-concentration method, the drug 1s reacted with cermm(IV) m 2 M sulphurlc acid at room temperature When the fixed preselected absorbance at 525 nm of the oxldlzed form of propranolol 1s attamed, the time 1s recorded and the unknown concentration of propranolol 1s calculated from the correspondmg equation of the cahbratlon graph Experimental Reagents and samples

Chemicals of analytical or pharmaceutical with high punty water Cenum(ZV)

solutlon

grade were employed throughout,

A stock solution of 0 01 M Ce(SO&

was prepared

together

m 05M

sulphurlc acid Sulphunc

and

A stock solution (10 M) was prepared m the usual way

Propranolol standard solution (1 mg ml-‘) This was prepared by dlssolvmg 500 mg of propranolol hydrochloride (kmdly supphed by ICI, batch ref No 8297/85 and 99 8%, m/m purity) m about 200 ml of warm water, the solution was stirred for 5 mm, cooled to room temperature and diluted to volume m a 500-ml standard flask Propranolol tablets, (1 mg ml-l) Ten tablets were weighed accurately and crushed mto fme powder A quantity of this powder, equivalent to 500 mg of propranolol, was weighed accurately and dissolved m about 50 ml of hot chloroform, the solution was stirred for 5 mm, filtered through a Whatman No 41 filter-paper and evaporated to dryness The residue was dissolved m about 200 ml of hot dlstllled water for 5 mm, cooled and made up to volume with water m a 500-ml standard flask Apparatus

A Beckman Model 35 spectrophotometer connected to a Beckman Model 24-25 ACC recorder was used for all spectrophotometrlc measurements Matched sets of cells (w 21O/UV 10 00 mm) were used Results and Discussion Optlmlzatlon and kmetlcs

The oxldatlon of propranolol with cermm(IV) was explored thus confn-mmg mformatlon on its reactlon mechamsm and extending knowledge on its chemical behavlour, this was done with the aim of fmdmg an alternative and simple method for its determination by kmetlc methods of analysis under the true condltlons of the reactlon Cenum(IV) was found to react slowly with propranolol producing a brown-red colour that absorbs at a A,,, of 525 nm, the formation of which 1s the basis of this method, the coloured product 1s beheved to be the oxldlzed form of propranolol, produced when oxldlzed anodlcally [20] The rate of formation of this product 1s followed spectrophotometrically and found to be dependent upon aadlty, temperature and concentrations of reactants The rate of the reaction was found to increase as sulphurlc acid concentration was

KINETIC DETERMINATION

281

OF PROPRANOLOL

increased The rate of reactlon was moderate at 1 5-2 5 M sulphunc acid, 1 e It was too fast to record measurements above this range and too slow to follow below this range Thus 2 M sulphunc aad was found to be acceptable Slmllarly, a rise m temperature accelerated the reaction but the solution became turbid and a fme precipitate settled as the temperature was increased To avoid this comphcatlon, the reaction was conducted at 25”C, at which temperature the reaction rate was measurable Obviously, a higher concentration of cenum(IV) than that of propranolol 1s mandatory so that the rate of its change could be constant when compared with that of the latter It was found that 0 001 M of cermm(IV) 1s the hmltmg concentration above which the absorbance of the cermm(IV) overlaps that of the product The mfluence of change of propranolol concentration on the reaction rate 1s illustrated m Fig 1 which clearly indicates that the rate increases slgmflcantly as the propranolol concentration increases Therefore, the concentration range of propranolol determlnation 1s limited by the smtable preselected fixed absorbance that intersects and falls wlthm the measuring rates In the present expenments propranolol can be determined m the range 70-200 kg ml-’ It 1s concluded that the optimum condltlons for the determmatlon of propranolol m the range 70-200 kg ml-’ are 2 M sulphurlc acid, 0 001 M cermm(IV) sulphate, and room temperature (25°C) Under such condltlons the concentration of propranolol 1s at least l/lo of those of cermm(IV) and that of sulphurlc acid, hence the reactlon would follow pseudo-zeroorder kmetlcs with respect to both cermm(IV) and sulphurlc aad The rate m this case would be directly proportional to propranolol concentration and would follow a pseudofirst-order rate equation Rate = z where k’ 1s the pseudo-first-order propranolol

= k’[propranolol]“,

(1)

rate constant and IZ1s the reactlon order with respect to

The effect of propranolol concentration on the reaction rate Graphs 1-6 represent propranolol concentrations of 80,100,120,140,160 and 180 kg III-‘, respectively

01

’

5

I IO

I 15

I

I

I

I

20

25

30

35

Time(mm)

SALAH M SULTAN et al

282

From Fig 1 it 1s clear that the reaction takes place m two steps the first step 1s very fast and the second one 1s slow and rate determining From the rates of the second step and by regression of a plot of loglo of absorbance versus time (s), a straght line 1s obtained with a correlation coefficient (r) = 0 99 and slope (k’) = s-l mdlcatmg that the kinetics of the reaction, with respect to propranolol (n), are first order The constancy of the values of k’ for different propranolol concentrations 1s given m Table 1 thus confu-mmg a first-order reaction Proposed mechanrsm Previous mvestlgatlons [l, 201 showed that the N-alkylethanolamme group 1s the common active site of the propranolol molecule From the results for the reaction of propranolol with cermm m excess, the observation of two steps m the reaction could be explained by the occurrence of two consecutive steps m the oxldatlon of the hydroxyl function In the first step, a radical 1s formed by releasing one hydrogen atom m a reversible fast reaction In the second step, a ketone 1s formed and hydrogen 1s released, this represents the slow rate-determmmg step The phenomenon that the reaction rate 1s accelerated by an increase m sulphurlc acid concentration and retarded by a decrease m sulphurlc acid concentration, could be explained by the release of the free protons m both steps of the reaction to form the ketone The followmg scheme represents the proposed mechanism and 1s m full agreement with results of previous studies [l, 201

i (1)

i

CH’

i

C.(lV)

R-0-C-C-C-N-CH II H

OH

II H

H

-

I

CH,

i

i:“’

i

R-0-C-&--C-N-CH+ I

I

I

I

H+

I

CH3 (II) R-O-C-;-C-N

I

I

I

I

I

H

OH

H

H

CH

Ce(IV)_

CHa

i

LiH3

i

R-0-C-C-C-N-CH

I 0II HI

H

I

H

I

CH3

+H+

KINETIC DETERMINATION

283

OF PROPRANOLOL

Table 1 Values of the reaction rate constant (k’) for the

reaction at vanous concentrations of propranolol and at constant concentrations of 2 M sulphunc acid and 0 001 M cenum(IV) sulphate at 25°C Propranolol (pg ml-‘)

k’

70 80 100 120 140 150 170 180 200

4 19 4 37 4 41 4 21 4 33 4 46 4 51 4 39 4 29

(s-l) x x x x x x x x x

1o-5 10-5 10-5 10-s low 10-s low 10-s 1O-5

where R 1s the residue of the propranolol benzene rings

molecule

and represents

two conjugate

Appraisal of the kmetrc method

Rates were measured by recording absorbance-time graphs (Fig 1) for the reaction at constant concentrations of 2 M sulphurlc acid and 0 001 M cenum(IV) sulphate at 25°C but with different concentrations of propranolol These graphs were treated by the furedconcentration method m which a value of absorbance 1s preselected and time 1s measured The fixed absorbance 1s preselected so that it intersects graphs of the widest range of concentration possible At a fixed absorbance, equation (1) could be rearranged as follows l/t = k’[propranolol]

(2)

In this method, an absorbance of 0 100 was found to be suitable m that it covers a wide range of 70-200 Fg ml-’ of propranolol Therefore the reciprocal of time t (s) versus propranolol concentration (M) (Table 2) was plotted by a computer and the followmg equation of the cahbratlon graph was obtained l/t = 0 000217 + 0 03c, r = 0 995, Table 2

Values of reciprocal of time (s-l) calculated at a fixed absorbance of 0 100 for &fferent concentrations of propranolol at constant concentrations of 2 M sulphunc acid and 0 001 M cenum(IV) sulphate at 25°C l/t(s_‘)

Propranolol (M)

75 120 180 240 900

1 33 8 33 5 56 4 17 1 11

x x x x x

1o-2 1O-3 lo-’ 10-3 1o-3

(3)

284

SALAH M SULTAN et al

0

e~

=. 0 O 0

+1 +1 -H +1

-H

+] +1 -H

-H +1

+1+1+1+1

+1

+1+1+1

+1+1

+1 ,.~

87

E

8

m

0

E

g

0

e~ ..D

Z~ O

0 O

<

t~

a8 <

e~

=O 3 u,l

O

O o

d:

.1¢-

KINETIC DETERMINATION

285

OF PROPRANOLOL

where c 1s the mltlal concentration of propranolol (M) The mltlal rate, the rate constant and the fixed-time methods [21, 221 were applied, but were not fruitful Appllcatlons and comparrson with other methods

The method was applied to the determination of propranolol m proprietary tablets by using equation (3) The same batches of tablets, hsted m Table 3, were analysed by the B P method [19] and the results obtained by both methods were statlstlcally compared by calculating the Student t-test values From the results, It 1s clear that the t-test values do not exceed the theoretical value of 2 78 for the 95% confidence level mdlcatmg no slgmflcant difference between the two methods Exclplents m the dosage forms tested, did not cause any mterference In addition the presence of chloride (m the drug) did not interfere This was checked by analysmg a chloride-free drug sample prepared by converting propranolol hydrochlonde mto the sulphate usmg a column charged with Amberhte IRA 400 (Cl) anion-exchange resin and washed first with 0 04 M sodium sulphate (analytical grade) and finally with water The new method 1s more specific than the B P method [19] and other UV spectrophotometrlc methods [6-91 m which the reaction takes place m non-aqueous media The proposed method 1s rapid and simple and allowed the determmatlon of more proprietary tablets than did the fixed-time method which requu-es heating the reactants at 90°C for 20 mm In addltlon, the method does not need tedious extraction procedures as those used m the chromatographlc methods [lo-181 Recommended

procedure

To an appropriate amount of propranolol m a 50-ml standard flask add 5 ml of cenum(IV) stock solution and 7 5 ml of the stock solution of sulphurlc acid then make up to volume with water Start a stopwatch and shake the flask gently Transfer some of the reaction solution mto the photocell and follow the absorbance at 525 nm against the reagent blank treated slmllarly Record precisely the time when the absorbance exactly reaches 0 100 Fmally, calculate the unknown concentration of propranolol by substltutmg mto the followmg equation l/t = 0 000217 + 0 03c, where t = time (s) and c = concentration

of propranolol

(M)

- We thank the Imperlal Chemical Industnes ICI, Pharmaceutical Dlvlslon, Macclesfleld, Cheshire, England, for the gift of a pure analytlcal sample of propranolol hydrochlonde

Acknowledgement

References [l] S M Sultan, Analyst 113 (1988) In press [2] J Harner, T Grandjean, L Molendey and G Gowton, Br Med J 2-6,720 (1965) [3] D G N Shand, Engl J Med 293, 280-285 (1975) [4] A Mltram, M Oettmger, E G Alunder, M Sharf and A Klem, Br J Obstet Gynaecol (1975) [5] R B Weber and 0 M Remmuth, Neurology 22, 366-370 (1972) [6] J W Black, W A M Duncan and R G Shanks, Br J Pharmac 25, 577-583 (1965) [7] K Kraml and W T Robinson, CIzn Chrm Acra 24, 171-175 (1978) [8] D M Shmgbal and J S Prabhudesal Zndum Drugs 21, 304-306 (1984) [9] N M Sanghavl and N G Jlvam, Tulanra 27, 591-596 (1980)

82, 651-656

286

SALAH M SULTAN el al

[lo] J D Ramsey and R J Flanagan, J Chromatogr 240,423-450 (1982) [ll] E Dnale, K M Baker, S R Baregg, W D Watkms, C A adsey, A Fngero and P L Morselh, J Chromatogr 24,347-351 (1973) [12] L P Hacket and L Dusa, J Clan 7’ox~c 15, 63-66 (1979) [13] J F Pntchard, D W Schenk and A H Hayes, .I Chromatogr 162, 47-50 (1979) [14] T Walle, Pharmacologrst 17, 262-270 (1975) [15] A S Chnstophersen and K E Rasmussen, J Chromatogr 57, 246-250 (1982) [16] H Yosinda, I Manta, T Masqima and H Imal, Chem Pharm Bull 30, 2287-2290 (1982) [17] K Kawaslnma, A Levy and S Specter, 1 Pharmac Exp Ther 196, 517-522 (1976) [18] H Ehrsson, J Pharmc 28, 622-625 (1976) [19] Bntrsh Pharmacopoera, p 815 H M Stationery Office, London (1980) [20] E Bishop and W Hussein, Analyst 109, 65-71 (1984) [21] K B Yatnmlnski, Zknetzc Methods of Analym Pergamon Press, Oxford (1966) [22] H A Lrutmen and W E Harris, Chemrcal Analysrs, 2nd edn McGraw-Hill, Tokyo (1975) [Recerved for review 22 October 19873