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Indian Journal of Chemical Technology
Vol.lO, July 2003, pp. 382-385
Precipitation and complex formation reactions based titrimetric and
spectrophotometric methods for the determination of
diphenhydramine hydrochloride
K Basavaiah* & V S Charan
Department of Chemistry, University of My sore, Mysore 570 006, India.
Received 4 April 2001; revised received 18 March 2003; accepted 28 March 2003
T.wo simp~e, accuraty and · s~lC?,Ctive method& for t,he-,determination of diphen~ydr;mtine in pharmaceutical grade sample
an<Un dosag~ forms are described. The ·titrimetiic method is J?ased o.n the.precipitation of the chloride content of the drug as
:AgCiwj th, a known exces.s q(si.lver nitrate ·and' b~ck titration Of ihe .residual silver nitrate with tlp.ocyanate using iron(ill) as
indicator. The reaction, stol.cbiometry and the ra!lge of determination have been eyaluated. The spectrophotof!!etric method
involves the displacem_e nt of thiocyanate of mercuric thiocyanate from the ionized chloride and the subsequent reaction of
the liberated thiocyanate with iron(ll) to form the familiar red coio\II'ed complex, Fe(SCN) 2+ which is measured spectroJbe Beer' s·law is obeyed over the range 5-45 J.Lg mL- 1 of diph~nhydrarni-ne HCl, the ·molar abphotometrically at 460
sorptjvity and Sandell se1_1sitivi~y- being 3.45 x 103 L moL' 1 cm- 1 and 84.5 ng cm-2, respectively at 460 nm. The reaction
variables have been optimized. The methods have bee!J found to be very_simple, cost-effective and reliable for three dosage
formS coniaining diphenhydramine hydrochJoride.
nm;.
Diphenhydramine hydrochloride (DPH), 2-(diphenylmethoxy) N, N-dimethyl ethylamine hydrochloride, is
a conventional antihistamine of the H 1 type (receptor
antagonist), which can block most of the reactions of
histamine in the body. Like man¥ other antihistamines, it has pronounced sedative properties. It also
has antiemetic, anticholinergic and local anaesthetic
properties.
Diphenhydramine is found in many pharmaceutical
preparations, it is usually given orally but it has also
been given in severe allergies by deep intramuscular
or slow intravenous injection. It is used in cough
mixtures, for the control of symptoms of parkinson's
disease, for prevention and treatment of nausea and
vomitting. It has also been given with methaqualone
as a hypnotic and a 2% water miscible cream has been
used for allergic dermatoses and bums 1.
The therapeutic importance of DPH has prompted
the development of many methods for its determination in body fluids and pharmaceutical preparations.
The alkalimetric titration method 2 suffers from interference from ephedrine. Non-aqueous titrimetric
methods 3-7 which are the methods of general applicability require scrupulously anhydrous medium. DPH
*For correspondence (E-mail:' [email protected]. in;
Fax: 0091-821-421263,0091-821- 516133)
has been determined by precipitating it with potassium iodobismuthate ion, filtering of the precipitate
and titrating the unreacted bismuth in the filtrate with
EDT A 8, the steps being complex and time-consuming.
Titration with sodium tetraphenylborate9 requires
carefully controlled pH.
Majority of the spectrophotometric methods suggested for DPH involve extractions of the chromogen
into the organic solvent before measuring the absorbance. They are based on reactions such as ion-pair
formation 10' 12 , charge-transfer complex formation 13 ' 14 ,
addition compound formation 15 ' 16 and ternary complex formation 17 -19 . They involve tedious extraction
step and suffer from such disadvantages as low sensitivity17-19, careful pH control 10-12 , insufficient accuracy
and precisiton, and/or longer extraction time. Methods
based on reduction 20 reaction and formation of mixed
aggregates with surfactants21 have also been reported.
Recently a flow injection method based on ion-pair
formation with bromocresol green has been described
by Prapatsom et al. 22 .
In the present investigations, precipitation reaction
and displacement followed by complex formation reactions involving the ionized chloride of DPH have
been utilised for micro titrimetric and sensitive spectrophotometric determination of DPH. The chloride
content of DPH is precipitated with a known excess of
Basavaiah & Charan: Titrimetric and spctrophotometric methods for determination of diphenhydramine hydrochloride
silver nitrate and the unreacted precipitant being back
titrated with potassium thiocyante using iron(III) as
indicator. The spectrophotometric procedure involves
the reaction of chloride with mercuric thiocyanate to
form soluble chloro mercurate(II) complex ion with
the liberation of thiocyanate ions which then react
with iron(III) to form red coloured complex which is
measured at 460 nm. The absorbance is proportional
to the thiocyanate ion concentration which in turn is
proportional to the chloride and DPH concentration ..
Experimental Procedure
The absorbance measurements were made on an
Elico model SL-171 digital spectrophotometer provided with 1-cm matched glass cells. All chemicals
used were of analytical reagent-grade. Double distilled water, second time distilled over alkaline potassium permanganate was used throughout. Silver nitrate (AR grade, Indian Drugs and Pharmaceuticals
Ltd, Hyderabad, Assay: 99.9%) solution (-0.04 M)
was standardized by using pure sample of NaCl 23
(Merck, Assay: 99%). Potassium thiocyanate (AR
grade, S.D. fine chem Ltd., Mumbai, Assay: 99%) (0.02 M) was standardized by Volhard method 24 .
Iron(III) (AR grade, S.D. Fine Chern Ltd., Mumbai,
Assay: 99%) indicator was prepared by dissolving
-10 g of iron(lll) alum in 1: 1 nitric acid (AR grade,
S.D. Fin_e Chern Ltd. , Mumbai, Assay: 69-71%) (100
mL) and boiling the solution to expel the oxides of
nitrogen. Iron(lll) nitrate (AR grade, BDH sample,
Mumbai, Assay: 98.5 %) reagent was prepared by dissolving 15.1 g of sample in 45 mL of 72% perchloric
acid (AR grade, S.D. Fine Chern Ltd., Mumbai, Assay: 70-72%) and diluting to 100 mL with water. A
saturated solution of mercuric thiocyanate (GR grade,
Loba Chemie, Assay: 99%) in methanol (AR grade,
S.D. fine chem Ltd., Mumbai, Assay: 99.5%) and 1:1
nitric acid were prepared in the usual way. Chloridefree nitrobenzene (AR grade, S.D. fine chem Ltd.,
Mumbai, Assay: 99%) was used for titrimetric work.
Pharmaceutical grade DPH was gifted by ParkeDavis, India Ltd., and was used as such. A stock standard solution containing 4 mg mL-1 DPH was prepared for titrimetry. This solution was diluted stepwise to provide a working solution of 100 )lg rnL·'.
Titrimetric method
To a 10 mL aliquot of solution containing 6-40 mg
of DPH, 2 mL of 1: 1 nitric acid were added followed
by 5 mL of 0.04 M silver nitrate solution by means of
a pipette. The contents were shaken for a minute, 2
Articles
mL of nitrobenzene were added and shaken vigorously until the silver chloride was coagulated. Then;
iron(lll) indicator (0.5 mL) was added, and the excess
of silver nitrat~ titrated with 0.02 M potassium thiocyanate to a permanent red colour end-point. A blank
was run in the same way with 10 mL of chloride free
water.
Spectrophotometric method
Into a series of 10 mL standard flasks were transferred 0.5, 1.0, 1.5 ..... 4.5 mL of 100 )lg mL- 1 of DPH
solution by means of a micro burette. A 1 mL volume
of iron(lll) reagent and 2 mL of mercuric thiocyanate
reagent solution were added and diluted to volume
with water. The absorbance of the solution was measured at 460 nm against the reagent blank after 5 min.
The increase in absorbance was plotted against the
drug concentration.
Formulations
Twenty tablets were finely powdered. An amount
of the powder equivalent to 200 mg of DPH was extracted with three 30 rnL portions of water and filtered
into a 100 mL standard flask. Washed the filter and
diluted to mark with water and subjected to analysis
using the general procedures. In respect of benadryl
syrup, 10 rnL containing 25 mg of DPH was used as
such for titrimetric analysis. For spectrophotometric
work the syrup was sequentially diluted to obtain 100
)lg rnL- 1 of DPH and subjected to analysis.
Results and Discussion
Optimisation of experimental variables
The stoichiometric study revealed that the reaction
between DPH and AgN0 3 proceeds in the molar ratio
of 1: 1 which is in conformity with the following reaction scheme :
DP. HCl
cr + Ag+
~
DPH+ + cr
~AgCI
(S)
A 0.5 mL of iron(lll) indicator and 2 mL 1: 1 nitric
acid were found to give satisfactory results. Since
AgCI is more soluble than AgSCN leading to low
values for chloride content and drug recovery, 2 mL
of nitrobenzene were added to eliminate this source of
error25 •
Fig. 1 shows the absorption spectra of the complex
and the reagent blank against the blank and water,
383
Articles
Indian J. Chern. Technol., July 2003
respectively. The absorption is maximum at 460 nm
which is in agreement with the earlier observations in
perchloric acid medium 26 •27 . Since the method is essentially the measurement of iron(III) thiocyanate
complex, variables that influence the sensitivity and
stability of the colour were optimised. Of the several
acids tested as the reaction medium, perchloric acid
was preferred because of high sensi tivity and stability
of the colour and lower blank absorbance.
Different sources of iron(Ill) may be used, such as
iron(III) nitrate 27 , iron(III) alum 28 and iron perchlorate29. Iron(III) nitrate was used since it gave better
sensitivity and because of high chloride content in
iron perchlorate. A 1 mL volume of the reagent solution was found optimum in a total volume of I 0 mL,
0.4
or--------------------,
A
0.3
.,
"'c:
-e•
~
and 2 mL of mercuric thiocyanate were found to yield
optimum absorbance. The colour formation was complete in 5 min and stable for a further period of 2 h.
Solvents such as water26 , ethanof7 and methanol 30
have been used _to prepare mercuric thiocyanate solution and in the present investigation methanolic solution was found to give a higher sensitivity.
Analytical parameters
Titrimetry was found to be applicable in the range
6-40 mg, outside which the results were deviant. The
relationship between the titration end-point and the
drug amount was examined by calculating the correlation coefficient value, r, via linear least squares
treatment and was found to be 0.9750 indicating that
the reaction between DPH and AgN0 3 occurs stoichiometrically in the ratio of 1:1 in 6-40 mg range.
Beer' s law is obeyed in the range 5-45 Jlg mL-1 of
DPH. The apparent molar absorptivity and Sandell
sensitivity were 3.45 x 103 L moL-1 cm· 1 and 84.5 ng
cm-2, respectively. The linear plot gave the regression
equation.
A=- 0.0098 + 0.0121 C
0.2
.0
<
Where, A, is the absorbance and C concentration in Jlg
mL- 1, and with a correlation coefficient of 0.9620
(n=10). The limit of detection was 0.74 Jlg mL-1 and
the limit of quantification 2.4/ Jlg nlL-1•
B
0.1
0+--.---r-~--r--~--.---r-~
400
420
440
460
480
500
520
540
560
Wavelength,nm
Fig. !-Absorbance spectra: A : 300 )lg DPH + 2 mL mercury
(II) thiocyanate+ l mL iron (Ill) nitrate per I 0 mL versus reagent
blank 8 : Reagent blank vers us water.
Accuracy ,a nd precision
To find out the accuracy and precision of the methods, seven replicate determinations in the same solution containing three different levels of DPH were
performed. The percentage recovery, the RSD and
range of error at 95% confidence level presented in
Table 1 indicate high accuracy and precision of the
methods.
Table !- Evaluation of accuracy and precision of the proposed methods
Drug
taken, mg
Drug
found *,
mg
Titrimetry
Error,%
Range of
error,%
Drug
taken, )lg
Drug
found*,
Spectrophotometry
RSD, %
Error,%
Range of
error,%
)lg
10
10.19
1.90
1.31
1.30
100
101.67
1.67
1.85
1.84
15
15.09
0.60
0.88
0.87
250
248.39
0.64
0.78
0.78
25
25 .25
1.00
0.74
0.73
300
300.90
1.30
1.09
1.08
30
29.75
0.83
0.10
0.10
400
401.65
0.41
0.88
0.87
*Values obtained for seven determinations.
384
RSD, %
Basavaiah & Charan: Titrimetric and spctrophotometric methods for determination of diphenhydramine hydrochloride
Articles
Table 2-Results of determination of DPH in tablets• and syrup• by the proposed methods
Method
Brand name
Benadryl capsules
Titrimetry
Benadryl syrup
Benadryl capsules
Spectrophotometry
Benadryl syrup
Label claim
mg
Found*,%
Proposed
method
SD
Reference
method
Student's
t-value
(2.77)
F-value
(6.39).
recover~±
25
50
12.5
101.73 ± 0.31
101.16 ± 0.44
99.10 ± 1.20
101.90 ± 0.68
101.90 ± 0.68
101.90 ± 0.68
0.51
2.05
2.02
4.81
2.39
3.11
25
50
12.5
100.24 ± 1.58
101.33 ± 0.73
101.40 ± 0.39
101.90 ± 0.68
101.90 ± 0.68
101.90 ± 0.68
2.15
1.27
1.44
5.40
1.15
3.04
*Average value of five determinations
• Marketed by Parke-Davis
•values in the parenthesis are the tabulated values at the 95% of confidence level.
Interferences
Bromide which interferes in titrimetry and sulphate, phosphate, ethyl and isopropyl alcohol, and
acetone which interfere in the spectrophotometric
procedure are not present in either the reagents employed or in the dosage forms used. Hence the methods are free from error due to them.
Application
The present methods have been successfully applied for the determination of DPH in capsules and
syrup. The results summarized in Table 2 suggest that
the methods can be economically used for the accurate analysis of formulations containing DPH. The
results also indicate that excipients like starch, talc,
lactose, sodium alginate and magnesium stearate do
not interfere in the determination.
Conclusions
The proposed methods are simple, fast and accurate. The time required for analysis in either method is
less than 15 min. There is no need for preliminary
separation of DPH from excipients.
Acknowledgements
The authors thank the Quality Control Manager of
M/s Parke Davis, India, for kindly providing pure
DPH as gift.
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