INTRODUCTION:

Bromhexine Hydrochloride is chemically named 2-amino-3,5- dibromo-N-cyclohexyl- N-methyl benzenemethanamine hydrochloride 412.59g/ml, is a mucolytic agent used in the treatment of respiratory disorders associated with excessive mucus. The drug is official in USP¹, IP², BP³ and EP⁴. Literature survey reveals HPLC^5-11, spectrophotometric^12-24, release study of drug²⁵ miscellaneous^26-27. Simple, rapid and reliable non aqueous titration method is developed for the determination of bromhexine hydrochloride. This method can be used for the routine analysis. In the proposed methods optimization and validation of this method are also reported.

Structure of Bromhexine hydrochloride

EXPERIMENTAL:

Instrumentation:

An potentiometric titrator was used (Lab- India-Auto titrator, 9.5) for assay method development and validation. A Shimadzu analytical balance with 0.01 mg was used.

Reagents and chemical:

Reference standard of bromhexine hydrochloride was obtained from reputed firm with certificate of analysis.

Potassium hydrogen phthalate, perchloric acid, mercury acetate and glacial acetic acid of A. R. grade were used.

General procedure

Standardization of 0.1 N perchloric acid

About 0.350mg of potassium hydrogen phthalate (previously powdered lightly, dried at 120^oC for 2 hours) was weighed accurately into clean and dry titration jar. It was dissolved in 50ml of glacial acetic acid. It was titrated with 0.1 N perchloric acid by using auto titrator. Blank determination was performed out for necessary correction. The titration was performed in duplicate.

One ml of 0.1 N HClO₄ is equivalent to 0.2042 gm of potassium hydrogen phthalate (C₈H₅KO₄)

Normality of perchloric acid = ---------------------

B.R. x 0.2042

Where

W is weight of potassium hydrogen phthalate in g.

B.R. is burette reading in ml.

Quantitative determination of Bromhexine hydrochloride

About 0.100 g. of bromhexine hydrochloride test sample was weighted accurately into a clean and dried titration jar. It was dissolved in 60 ml. of anhydrous glacial acetic acid. It was heated to dissolve bromhexine hydrochloride and 15 ml of 5% (w/v) mercuric acetate was added.

It was titrated with 0.1N perchloric acid potentiometrically.

Blank determination was also carried out for necessary correction.

One ml of 1 N perchloric acid is equivalent to 0.2063 g. of bromhexine hydrochloride

% (Percentage) Bromhexine hydrochloride on the dried basis was calculated as below.

B.R. x N x 0.2063 x 100

% Assay =-----------------------------------------------

Where

B.R. is burette reading in ml at the potentiometric end point.

N is actual normality of 0.1 N perchloric acid.

W is weight of the sample taken in g.

RESULT AND DISCUSSION:

Determination of bromhexine hydrochloride

The objective of this work was to determine accurately the content of terbutaline sulphate. The assay of bromhexine hydrochloride (on the dried basis) of various batches of test sample was analyzed using the above method. It was in the range of 99.38 to 99.76 %.

Analytical method validation

The method precision was checked after analyzing six different preparations of homogeneous test sample of bromhexine hydrochloride. The % RSD of results obtained was found to be 0.3176. It confirms good precision of the method. The results are presented in table 1.

Linearity

For the establishment of method linearity, five different weights of bromhexine hydrochloride test samples corresponding to 50 % , 100 % 150% , 200% and 250% of the about weight (0.100 g.) were taken and analyzed for % (percentage) of bromhexine hydrochloride content. The results are in table 2.

Table no. 1: Method of precision

Sr. No	Weight of Bromhexine hydrochloride	Burette reading in ml	Normality of perchloric acid	% assay
1	0.05	2.4	0.1008	99.81
2	0.0502	2.405	0.1008	99.62
3	0.0501	2.4	0.1008	99.61
4	0.0499	2.4	0.1008	100.01
5	0.0504	2.405	0.1008	99.23
6	0.0503	2.4	0.1008	99.22
			Mean	99.58
			Std. deviation	0.3163
			RSD	0.3176

Table no.2: Linearity

Sr. No.	Weight of Bromhexine hydrochloride in gm	Burette reading	Normality of Perchloric acid	% assay
1	0.05	2.4	0.1009	99.91
2	0.1004	4.8	0.1009	99.51
3	0.1506	7.2	0.1009	99.51
4	0.2002	9.6	0.1009	99.81
5	0.2503	12	0.1009	99.79
			Mean	99.71
			Std. deviation	0.1836
			RSD	0.1841

The potentiometric titration was conducted once at each level. Linearity curve Figure no .1 was drawn by plotting test sample weight in gram on x axis and titre values on y axis.

Fig. no.1: Linearity curve

The values of correlation coefficient, slope and intercept are given in table 3.

Table no.3: Regression values

Parameter	Values
Slope	48
Intercept	- 7E-15
Coefficient of co-relation	0.9999

Accuracy and recovery:

Accuracy was determined at five different levels i.e., 50 %, 100 %, 150 %,200% and 250 % of the nominal concentration. (0.100 g.) The titration was conducted in triplicate at each level and the titre value was recorded. The tire value obtained in linearity study was considered as true value during the calculation of percentage (%) recovery. The percentage recovery is calculated using following equation.

Titre value x 100

Percentage recovery = ---------------------------

True titre value

The percentage range recovery of Bromhexine hydrochloride was in 99.38 to 99.76 %. It confirms the accuracy of the proposed method. (Table 4).

Ruggedness:

The ruggedness of the method is defined as degree of reproducibility of results obtained by analysis of bromhexine hydrochloride sample under variety of normal test conditions such as different laboratories, different analysts and different lots of reagents. Quantitative determination of bromhexine hydrochloride was conducted potentiometrically on one laboratory. It was again tested in another laboratory using different instrument by different analyst. The assays obtained in two different laboratories were well in agreement. It proved ruggedness of the proposed method.

Table no 4: Accuracy and Precision

S. No.	Weight of Bromhexine hydrochloride added	Weight of Bromhexine hydrochloride found	% Assay	Mean % assay
1	0.05	0.0499	99.81	99.55
	0.0503	0.0500	99.42
	0.0502	0.0499	99.41
2	0.1003	0.0998	99.51	99.38
	0.1007	0.0998	99.12
	0.1004	0.0999	99.52
3	0.1505	0.1497	99.48	99.55
	0.1502	0.1498	99.75
	0.1506	0.1497	99.41
4	0.2004	0.1996	99.61	99.63
	0.2001	0.1996	99.76
	0.2006	0.1996	99.51
5	0.2502	0.2495	99.73	99.76
	0.2505	0.2505	100.03
	0.2507	0.2495	99.53

CONCLUSION:

The proposed method of non-aqueous potentiometric titration was found to be precise, accurate and rugged. The values of percentage recovery and standard deviation showed sensitivity. The method was completely validated. It showed satisfactory data for all the parameters of validation. Hence it can be applied for routine quality control application.

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Received on 02.05.2020 Modified on 21.05.2020

Asian J. Research Chem. 2020; 13(4):249-252.

DOI: 10.5958/0974-4150.2020.00048.6