Design and In Vitro Studies of Ambroxol Hydrochloride Sustained Release Matrix Tablets.

Shanmugam. S., Sandhiya. K. M.*, Ayyappan. T, Sundaramoorthy. K. and Vetrichelvan. T.

Department of Pharmaceutics, Adhiparasakthi College of Pharmacy, Melmaruvathur-603 319, Tamilnadu, India.

ABSTRACT:

In the present investigation, an attempt was made to formulate the oral sustained release matrix tablets of Ambroxol HCl in order to improve efficacy, reduce the frequency of administration, and better patient compliance. Ambroxol Hydrochloride is a potent mucolytic agent capable of inducing bronchial secretions used in the treatment of respiratory disorders. Differential scanning calorimetric analysis confirmed the absence of any drug polymer interaction. Matrix tablets of Ambroxol Hydrochloride were formulated employing hydrophilic polymers HPMC K100M, Carbopol 934P and hydrophobic polymer Ethyl cellulose as release retardant polymers. The powder blend was evaluated for micromeritic properties. The sustained release matrix tablets were prepared by direct compression technique. The tablets were evaluated for thickness, diameter, weight variation test, hardness, friability, and drug content. The in vitro drug release characteristics were studied in simulated gastric fluid (2 hours) and intestinal fluid for a period of 6hours using USP type II dissolution apparatus (total 8hours). The results of dissolution studies indicated that formulation F3 (drug to polymer 1:1.06), the most successful of the study and exhibited satisfactory drug release in the initial hours and the total release was very close to the theoretical release profile. Matrix tablet containing HPMC K 100M (F3) formulation were found to show good initial release (14.8% in 2 hrs) and extended the release (90% in 11 hrs). The n value for F3 obtained from Korsmeyer – peppas model confirmed that the drug release was anomalous diffusion mechanism.

KEYWORDS: Ambroxol HCl, Hydroxypropyl methylcellulose, Carbopol 934P, Ethyl cellulose.

INTRODUCTION:

Oral administration of drugs has been known for decades as the most common and preferred route for delivery of most therapeutic agents via various pharmaceutical products of different dosage forms. The popularity of oral route is attributed to patient acceptance, ease of administration, accurate dosing, cost effective manufacturing methods, as well as traditional belief that by oral administration the drug is as well absorbed and to the fact that gastrointestinal physiology offers more flexibility in dosage form design than most other tablets¹.

Sustained release drug delivery aimed at controlling the rate of release as well as maintains desire drug level in the blood that is therapeutically effective and non toxic for extended period of time, thus achieving better patient compliance and allowing a reduction of both the total dose of drug administered and the incidence of adverse side effects. It provides prolonged but not necessarily uniform release of the drug.

The rationale for development of a sustained release formulation of a drug is to enhance its therapeutic benefits, minimizing its side effect while improving the management of the diseased condition².

Ambroxol is a metabolite of bromhexine with similar actions and uses. It is chemically described as-4-[(2-amino-3, 5-dibromobenzyl) amino]-cyclohexanol. Ambroxol hydrochloride is an expectorant improver and a mucolytic agent used in the treatment of respiratory disorders such as, bronchial asthma, chronic bronchitis characterized by the production of excess or thick mucus. Ambroxol hydrochloride has also been reported to have a cough suppressing effect and an inflammatory action. It has been successfully used for decades in the form of its hydrochloride as a secretion releasing expectorant in a variety of respiratory disorders. Its short biological half life (4 hrs) that calls for frequent daily dosing (3 to 4 times) and therapeutic use in chronic respiratory diseases necessitates its formulation in to sustained release dosage forms³.

MATERIAL AND METHODS:

Ambroxol Hydrochloride was received as a gift sample from Kaushik Pharmaceuticals, Chennai).HPMC K100M, microcrystalline cellulose (AVICEL PH 101), were procured from Milton drugs Pvt. Ltd., (Pondicherry, India). Carbopol 934P, ethyl cellulose, Aerosil, Magnesium stearate was purchased from Loba chemie pvt.Ltd, (Mumbai, India).

Differential scanning calorimetry (DSC):

The DSC analysis of pure drug, drug+ HPMC K100M, Drug+ Carbopol 934P and Drug+ Ethyl cellulose were carried out using a Shimadzu DSC 60, (Japan) to evaluate any possible drug-polymer interaction. The 2 mg sample were heated in a hermetically sealed aluminum pans in the temperature range of 40-300ºC at heating rate of 10ºC /min under nitrogen flow of 20 ml/min^4,5.

Micromeritic properties:

The tablet blend were evaluated for their bulk density, tapped density, compressibility index, angle of repose and Hausner ratio. The tapping method was used to determine the bulk density, tapped density, percent compressibility index and Hausner ratio.

Compressibility index = [ρ_t-ρ_b / ρ_t] ×100

Hausner ratio= ρ_t/ ρ_b

Where ρ_t = tapped density

ρ_b = initial bulk density of tablet blend.

Angle of repose θ of the tablet blend measures the resistance to particle flow and was determined by fixed funnel method⁶.

PREPARATION OF MATRIX TABLETS:

The composition of different formulations of Ambroxol hydrochloride matrix tablets is shown in Table 1.Matrix tablets containing 75mg of Ambroxol Hcl along with various amount of polymers such as HPMC K100M, EC, Carbopol and other inactive ingredients were mixed and tablet were prepared by direct compression technique. In the first step, active and inactive ingredients (except Magnesium stearate) weighed accurately and were screened through a 40-mesh sieve. Required materials except lubricant were then combined and passed through 40-mesh sieve. Mixing of powders was performed by geometric dilution method in polythene bag. In the screened powder following the addition of given amount of lubricant powder was again mixed. Before compression, the surfaces of the die and punch were lubricated with Magnesium stearate, and then desired amount of blend was directly compressed (11mm diameter, biconcave punches) using a single punch tablet compression machine (Cad mach, Ahmedabad, India). All the preparations were stored in airtight containers at room temperature for further study^7-8.

IN VITRO DRUG RELEASE STUDIES:

The release rate of Ambroxol Hcl from matrix tablets was determined using United States Pharmacopeia (USP) Dissolution Testing Apparatus II (paddle method; Veego Scientific VDA-8DR, Mumbai, India). The dissolution test was performed using 900 ml of pH 1.2 for the first 2 hrs and phosphate buffer pH 6.8 from 2-8hrs at 37 ± 0.5°C and 100 rpm. A sample (2ml) of the solution was withdrawn from the dissolution apparatus hourly and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45μ membrane filter and diluted suitably; Absorbance of these solutions was measured at 244.5 nm using a Shimadzu-1700 Pharmaspec UV-VISIBLE spectrophotometer. For each formulation, the experiments were carried out in triplicate ^[9-10].

DRUG RELEASE KINETICS:

For finding out the mechanism of drug release from tablets, the dissolution data obtained from the above experiments were treated with the different release kinetic equations.

Zero order release equation: Q = K0 t

First order equation: Q = Kf t

Higuchi‘s square root of time equation: Q = KH t ½

Korsmeyer and Peppas equation: F = (Mt / M) = Km tn

RESULTS AND DISSCUSSION:

The method employed for compression in this was direct compression for which the powder blend should possess good flow and compacting properties. The prepared powder blend of the different formulations was evaluated for angle of repose, loose bulk density, tapped bulk density, compressibility index, and Hausner ratio. The prepared matrix tablets were evaluated for thickness, weight variation, hardness, friability, drug content, in vitro drug dissolution studies and stability studies. All the studies were performed in triplicate, and results are expressed as mean ± SD.

TABLE 1: Formulation of sustained release matrix tablets of ambroxol hydrochloride

S.NO	Ingredients (mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9
1.	Ambroxol HCl	75	75	75	75	75	75	75	75	75
2.	HPMC K100M	40	60	80	_	_	_	_	_	_
3.	Carbopol 934 P	_	_	_	40	60	80	_	_	_
4.	Ethyl cellulose	_	_	_	_	_	_	40	60	80
5.	PVP K-30	20	20	20	20	20	20	20	20	20
6.	Microcrystalline cellulose	255	235	215	255	235	215	255	235	215
7.	Aerosil	3	3	3	3	3	3	3	3	3
8.	Magnesium stearate	7	7	7	7	7	7	7	7	7

TABLE 2: Physico-chemical characterization of ambroxol HCl matrix tablets

Formulation Code	Thickness (mm)*	Weight Variation (%)	Hardness (kg/cm^2)*	Friability (%)	Drug content (%)^#
F1	4.34±0.06	0.721±0.52	7.42±0.53	0.1	100.63±0.57
F2	4.38±0.04	0.516±0.33	7.38±0.21	0.2	100.67±0.07
F3	4.24±0.05	0.673±0.74	8.16±0.21	0.07	100.76±0.12
F4	4.27±0.04	0.685±0.39	7.72.±0.39	0.0	100.79±0.22
F5	4.30±0.75	0.284±0.31	8.05±0.15	0.02	100.32±0.44
F6	4.24±0.09	0.631±0.48	7.15±0.24	0.22	100.31±0.30
F7	4.39±0.04	0.227±0.37	8.05±0.15	0.14	100.76±0.56
F8	4.41±0.05	0.405±0.25	8.02±0.23	0.05	99.90±0.15
F9	4.44±0.07	0.466±0.33	8.10±0.35	0.02	99.93±0.91

*All the values are expressed as mean± SE, n=10; ^#All the values are expressed as mean± SE, n=3.

TABLE 3: Different kinetic models for ambroxol HCl matrix tablets (F1 TO F9)

Code	Zero order		First order		Higuchi		Peppas		Best fit model
	R^2	K0 (mg/h^−1)	R^2	K1 (h^−1)	R^2	K (mg h^−1/2)	R^2	n
F1	0.9983	10.482	0.9636	0.182	0.9261	27.968	0.9985	0.651	Peppas
F2	0.9886	10.465	0.9791	0.176	0.9265	24.451	0.9902	0.673	Peppas
F3	0.9934	08.297	0.9526	0.123	0.9060	19.219	0.9943	0.693	Peppas
F4	0.9985	10.538	0.9619	0.184	0.9264	24.550	0.9986	0.614	Peppas
F5	0.9908	10.606	0.9760	0.182	0.9241	24.746	0.9918	0.612	Peppas
F6	0.9861	08.744	0.9287	0.137	0.8851	20.125	0.9890	0.582	Peppas
F7	0.9966	10.694	0.9607	0.189	0.9252	24.916	0.9940	0.548	Zero order
F8	0.9972	10.070	0.9682	0.168	0.9217	23.428	0.9951	0.582	Zero order
F9	0.9927	10.174	0.9746	0.169	0.9193	23.680	0.9940	0.573	peppas

CHARACTERIZATION OF POWDER BLEND:

The powder blend prepared for compression of Matrix tablets were evaluated for their flow properties. Angle of repose was in the range of 26.11±0.48 to 29.52^°±0.55 which indicates good flow of all formulations. The bulk density of the powder formulation was in the range of 0.348±0.00 to 0.365±0.00 g/ ml; the tapped density was in the range of 0.405±0.00 to 0.445±0.00 g/ ml, which indicates that the powder was not bulky. The Carr’s index was found to be in the range of 12.45±0.00 to 14.63±0.00, which indicates good flow of the powder for all formulation. Hausner ratio was found to be in the range of 1.14±0.00 to 1.23±0.00, these values indicate that the prepared blend exhibited good flow properties. Differential scanning calorimetry studies showed that there is no any drug polymer interaction.

EVALUATION OF MATRIX TABLETS:

The results of physicochemical characterizations are shown in Table 2. The thickness of matrix tablets was measured by vernier caliper and was ranged between 4.24±0.09and 4.44±0.07 mm for all formulation. The weight variation for different formulations (F1 to F9) was found to be 0.227±0.37% to 0.721 ±0.52%, showing satisfactory results as per Indian Pharmacopoeia (IP) limit. The hardness of tablet is indicative of crushing strength to withstand handling during packaging and transportation. The hardness of the matrix tablets was measured by Monsanto tester and was controlled between 7.15±0.24 and 8.16±0.21 kg/cm². Another measure of a tablet's strength is friability. Conventional compressed tablets that lose less than 1% of their weight are generally considered acceptable. In the present study, the percentage friability of formulation was below 1%, indicating that the friability was within the prescribed limits, which is an indication of good mechanical resistance of the tablet. Good uniformity in drug content was found among the formulations, and percentage of drug content was more than 95%. All the tablet formulations showed acceptable pharmacotechnical properties.

IN VITRO DRUG RELEASE STUDY:

The In vitro dissolution studies of all the formulations of matrix tablets of Ambroxol HCl were carried out in pH 1.2, pH 6.8 buffer solution. The study was performed for 8 hours, and percentage drug release was calculated at 1 hours time intervals. The results of in- vitro dissolution studies of all formulations were shown in Figures 2 to 4.The drug release from formulation F1 to F3 containing HPMC K100M at three different concentration levels of 10%, 15%, 20% were found to be 81.544±0.03, 76.635±0.03 and 70.732±0.011 respectively. The drug release from formulation F4 to F6 containing Carbopol 934P at three concentration level of 10%, 15%, 20% were found to be 82.261±0.15,78.706±0.12,75.792±0.07 respectively. The drug release from formulation F7 to F9 containing Ethyl cellulose at three different concentration levels of 10%,15%,20% were found to be 84.155±0.07,79.706±0.04 and 77.095±0.01 respectively at the end of 8 hrs (2 hrs in 0.1N Hcl and 6 hrs in Ph 6.8).

When % drug release plotted vs. time showed in figures (1, 2 and 3) for F1 to F3, F4 to F6 and F7 to F9 and it was observed that, for three of the polymers used, an increase in polymer concentration induce a decrease in the release rate. The drug release rate from HPMC K100M matrix (F1toF3) was found to be less as compared to Carbopol 934P and Ethyl cellulose. This might be due to hydration of matrix and its property to form a thick gel layer, which retard the drug release from the tablet. Whereas formulation containing Carbopol 934P (F4 to F6) gave higher drug release as compared to formulation containing HPMC K100M (F1toF3). This is due to less degree of swelling of Carbopol 934P in acidic media as compared with Carbopol 934P, the dissolution medium can penetrate fast and deep in to the glossy core and the drug is released faster. Formulation containing Ethyl cellulose (F7 to F9) gave higher drug release as compared to formulation containing HPMC K100M (F1to F3) and Carbopol 934P (F4 to F6) which may be due to quick hydration of polymer matrix, after which matrix might get started to erode. The release of drug depends not only on the nature of matrix but also upon the drug polymer ratio. The formulation F3 which consisted of the drug: polymer HPMC K100M ratio of 1:1.0.66, gave satisfactory release profile in a sustained manner for 8 hrs among all formulations.

Figure 1: In-Vitro drug release of formulation F1 to F3

In-vitro drug release profile for formulations F1 (); F2 () and F3 ().

Figure 2: In- Vitro drug release of formulation F4 to F6

In-Vitro drug release profile for formulations F4 (); F5 () and F6 ().

Figure 3: In- Vitro drug release of formulation F7 to F9

In-Vitro drug release profile for formulations F7 (); F8 () and F9 ().

Based on the in- vitro drug release data the t_50%, t_90% parameters were calculated. It was found that as the concentration of HPMC K100M increases, the values of t50 and t90 increased. This polymer has been well known to retard the drug release by swelling in aqueous media. HPMC is mixed alkyl hydroxyl alkyl cellulose ether containing methoxyl and hydroxypropyl groups. The hydration rate of HPMC depends on the nature of the substituent. Specifically, the hydration rate of HPMC increases with an increase in the hydroxypropyl content. The solubility of HPMC is pH independent. In the present study, HPMC K100 was used because it forms a strong viscous gel on contact with aqueous media, which may be useful in controlled delivery of highly water-soluble drugs. Thus, a polymer’s ability to retard the drug release rate is related to its viscosity. From this data, the formulation F3 (HPMC K100M) showed the maximum retardation of drug release (11 hours to release the 90% of drug) and it shows anomalous diffusion mechanism, for these reasons, it was considered that the formulation F3 was best formulation among all the nine formulations.

KINETIC ANALYSIS OF DISSOULTION DATA:

The linear regression analysis is given in Table 3. The kinetic data of formulationsF1to F6 and F9 showed good fit in the Korsmeyer-Peppas model (R²: 0.9890 to 0.9991) when compared with other kinetics model (first order, zero order, Higuchi). Formulation F7 and F8 showed high linearity with the zero order kinetics (R²: 0.9962, 0.9972). Drug release data was also fitted to peppas model, which showed the slope (n) value (0.582 to 0.693) in case of formulations F1 to F9 .From the release exponent in the Korsmeyer-Peppas model, it can be suggested that the mechanism that led to the release of Ambroxol HCL was an anomalous non-Fickian diffusion transport, which indicates that the drug release occurred through diffusion in the hydrated matrix and polymer relaxation.

CONCLUSION:

This study deals with the investigation carried out with the objective of developing oral sustained release formulation of Ambroxol Hcl using x HPMC K100M, Carbopol 934P Ethyl cellulose. Preparation of matrix tablet by direct compression technique was found to be more successful in sustaining the release of drug. Based on the in- vitro drug release data the formulation F3 it was concluded as best formulation. Although all the polymers studied could slow down the release of Ambroxol HCl from the matrices, HPMC showed the best results. This is due to swelling and gel able properties of hydrophilic polymer matrix which form protective barrier to influx of water and efflux of drug solution. Formulation F3 showed sustained drug release t_90% value as 11 hours. The kinetics of drug release for optimized formulation was explained by peppas equation. The drug release from the tablets was sufficiently sustained and anomalous diffusion mechanism of the drug from tablets was confirmed. In conclusion the present study demonstrated the successful preparation of stable once daily sustained release matrix tablet of Ambroxol hydrochloride.

ACKNOWLEDGEMENTS:

The authors are sincerely thankful to Adhiparasakthi College of Pharmacy, Melmaruvathur for providing us necessary facilities and moral support to carry out this research work. I sincerely express my gratitude to Kaushik Pharmaceuticals, (Chennai, India) for providing Ambroxol HCl as a gift sample and Milton drugs Pvt. Ltd., (Pondicherry, India) for providing HPMC K100M, , micro crystalline cellulose.

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Received on 24.11.2010

Accepted on 03.12.2010

© A&V Publication all right reserved

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(2): March-April 2011, 48-52