INTRODUCTION:

Ambroxol hydrochloride is a metabolite of bromhexine and is official in the Martindale Extrapharmacopoeia¹. It is chemically described as trans-4-[(2-Amino-3,5-dibromobenzyl) amino]-cyclohexanol. It is widely used as an mucolytic agent prescribed in respiratory infections like bronchitis and bronchial asthma ². It has a short biological half life of 3 – 4 hours and is administered in a dose of 30mg 3-4 times a day ³. Therefore it is an ideal candidate for design as a Controlled release (CR) dosage form, which would result in prolonged clinical efficacy, reduced frequency of administration and lesser side effects.

Sustained or Controlled release delivery systems can achieve predictable and reproducible release rates, extended duration of activity for short half-life drugs,

decreased toxicity, reduction of required dose, optimized therapy, and better patient compliance ^4,5. With the aim of maximizing the bioavailability of conventional drugs with minimum side effects, new drug delivery systems continue to attract much attention⁶. In recent years, considerable attention has been focused on hydrophilic polymers in the design of oral controlled drug delivery systems because of their flexibility to obtain a desirable drug release profile, cost effectiveness and broad regulatory acceptance. Among the hydrophilic polymers, cellulose derivatives such as methyl cellulose, hydroxy propyl methyl cellulose and sodium carboxy methyl cellulose are generally considered to be stable and safe as release retardant excipients in the development of oral controlled release dosage forms. These semisynthetic polymers are quite expensive when compared with natural polymers such as guargum, xanthan gum and so forth. The natural polymers are nontoxic and easily available. A number of reports appear in the literature on the utility of guar gum or modified guargum in the design of oral sustained release tablets^7-11.

Guar gum is a nonionic polysaccharide derived from the seeds of Cyamopsis tetragonolobus, Family Leguminosae. It consists of linear chains of (1-4) b–D-mannopyranosyl units with alpa – D – galactopyranosyl units attached by 1-6 linkages. In pharmaceuticals, guar gum is used in solid dosage forms as a binder and disintegrant^12-14. A few reports appear on the use of guar gum, as a hydrophilic matrix for designing oral controlled release dosage forms^15-16. The efficiency of the hydrophilic matrix in controlling the drug release, in addition to other factors, is dependent on the viscosity of the hydrophilic polymer(s) incorporated in the formulation^17-18. Hence, in the present study various viscosity grades of guar gum were evaluated for the oral sustained drug release of ambroxol hydrochloride in the form of a matrix and to elucidate the release kinetics of ambroxol hydrochloride from three different proportions of various viscosity grades of guar gum.

MATERIALS AND METHODS:

Materials:

Ambroxol hydrochloride was a gift sample from Tablets India (P)Ltd., Chennai., Micro crystalline cellulose (Avicel, FMC Type pH-105), Starch, Magnesium stearate and Talc used were of USP/NF quality. Low–viscosity guar-gum (viscosity of 1% aqueous dispersion at 25° C is 86 cps; particle size ≤75µm), Medium viscosity guar gum (viscosity of 1% aqueous dispersion at 25° C is 4200 cps; particle size ≥75µm ), and High – viscosity guar gum (viscosity of 1% aqueous dispersion at 25° C is 5650 cps; particle size ≥75µm ), were the gift sample from M/s Sigma-Aldrich Corporation. All other ingredients used throughout the study were of analytical grade and were used as received.

Calculation of theoretical release profile of ambroxol hydrochloride from SR tablets:

The total dose of ambroxol hydrochloride for twice-daily SR formulation was calculated as per Robinson Erikson equation ¹⁹ using available pharmacokinetic data. Pharmacokinetic studies showed that a dose of 30mg of ambroxol hydrochloride produces expected therapeutic effect with in 2h with the half- life of 4h. Thus the elimination rate constant K=0.693 / t _½= 0.693 / 4 = 0.1732 mg / h. Hence the availability rate R = k D = 0.1732 x 30 = 5.2 mg / h, where D is the usual dose of the drug. The maintenance dose D_m= R_h= 5.2 x 11 = 57.2 mg, where h is the number of hours for which sustained action is desired. Thus, Total dose = D + Dm = 30 + 57.2 = 87.2 mg. D_corrected = D - Rtp = 30 - 5.2 x 2 = 19.6mg, where t_p is the time period required to achieve a peak plasma level. Therefore, Total dose corrected = D_corrected + Dm = 19.6 + 57.2 = 76.8mg (≈75mg). Hence an oral controlled release formulation of ambroxol hydrochloride should contain a total dose of 76.8mg (≈75mg) and should release 19.6 mg in first 1h like conventional tablets, and 5.2 mg / h upto 12h thereafter.

Fig.1: Comparison of In vitro release profiles of ambroxol hydrochloride from A-SR tablets and matrix tablets containing 30% wt/wt low-viscosity (F-III), 25 % wt/wt medium-viscosity (F-VI), 20% wt/wt high-viscosity (F-IX) guar gum and theoretical sustained release(TSR) dissolution profile.

Preparation of Ambroxol hydrochloride tablets:

Matrix tablets of Ambroxol hydrochloride using various viscosity grades of guar gum, in three different proportions were prepared by wet granulation method using 5% starch paste as the binder. Microcrystalline cellulose (MCC) was used as diluent. The compositions of different formulations used in the study are given in Table-1. In all the formulations, guar gum was sieved (<250 µm ) separately and mixed with ambroxol hydrochloride (<150 µm) and MCC (<250 µm). The powders were blended and granulated with 5% starch paste. The wet mass was passed through a mesh (1680 µm) and the granules were dried at 50° C for 2 hours. The dried granules were passed through a mesh (1190 µm) and these granules were lubricated with a mixture of talc and magnesium stearate (2:1). The lubricated granules were compressed at a compression force of 4500 to 5500 kg using 9-mm round, flat, and plain punches on a single-station tableting machine (M/s Cadmach Machinary Co Pvt Ltd, Ahmedabad, India). Prior to compression the granules were evaluated for several tests.

Evaluation of Granules:

The angle of repose was measured by using funnel method²⁰, which indicates the flowability of the granules. Loose bulk density (LBD) and tapped bulk density (TBD)²¹ were measured using the formulae: LBD= weight of the powder / volume of the packing. TBD = weight of the powder / tapped volume of the packing. Compressibility index²² of the granules was determined by using the formula CI (%) = [(TBD - LBD) / TBD] × 100. Total porosity ²³was determined by measuring the volume occupied by a selected weight of a powder (V_bulk) and the true volume of the granules. Drug content was determined as follows: An accurately weighed amount of powdered ambroxol granules (100mg) was extracted with 0.1N Hcl (pH 1.2) and the solution was filtered through 0.45µ membrane filter. The absorbance was measured at 248nm after suitable dilution.

Evaluation of Tablets:

The thickness of the tablet was determined using a Screw gauge (Mitutoyo, New Delhi, India). Five tablets from each batch were used, and average values were calculated. For Uniformity of weight, 20 tablets of each formulation were weighed and its average was determined according to the official method ²⁴. The drug content in each formulation was determined by pulverizing five tablets, and powder quantity equivalent to average weight of tablet was dissolved in 100ml 0.1N Hcl (pH 1.2) and shaken for 10 minutes to ensure complete solubility of drug. An aliquot was removed, filtered and analyzed after suitable dilution by double beam UV/Vis Spectrophotometer at 248 nm. For each formulation, the hardness and friability of 6 tablets were determined using the Monsanto hardness tester (Cadmach, Ahmedabad, India) and the Roche friabilator (Campell Electronics, Mumbai, India ), respectively.

In vitro drug release studies:

In vitro drug release studies were carried out using USP XXIV dissolution apparatus type II²⁵, with 900ml of dissolution medium maintained at 37±1° for 12 h, at 100 rpm, 0.1 N hydrochloric acid ( pH 1.2 ) was used as a dissolution medium for first 2h followed by pH 7.4 ± 0.2 phosphate buffer for further 10 h. 5ml of sample was withdrawn at predetermined time intervals replacing with an equal quantity of drug free dissolution fluid. The samples withdrawn were filtered through 0.45µ membrane filter, and drug content in each sample was analyzed after suitable dilution by UV/Vis Spectrophotometer at 248 nm, and cumulative percent drug release was calculated. The study was performed in triplicate and the calibration curve specifications were Y = 0.006 X ± 0.005 (r² = 0.9998, n =9). The commercial ambroxol SR tablets (A-SR) were used as the reference formulation, and were also subjected to in vitro drug release studies so as to choose the optimal amount of guar gum in the matrix tablets.

Kinetic treatment to dissolution data:

The rate and mechanism of release of ambroxol from the selected matrix tablets were analyzed by fitting the release data in to zero-order equation ²⁶, Q = Q₀-K_ot (1), where Q is the amount of drug released at time t and K _ois the release rate, First order equation, Ln Q=Ln Q₀–K₁t (2), where K₁is the release rate constant and Higuchi’s equation ²⁷, Q=K₂t^1/2 (3), where Q is the amount of drug released at time t and K₂is the diffusion rate constant. The release data were also analyzed as per korsemeyer – peppa’s equation ²⁸, M_t/ M_∞= Ktⁿ(4), where M_t is the total amount of drug release in time t, M_∞is the total amont of drug after an infinite time, K is a constant related to the structural and geometric properties of the drug delivery system (tablet) and ‘n’ is the release exponent related to the mechanism of the release. The ‘n’ values used for the elucidation of the drug release mechanism from the tablets were determined from log cumulative percentage of drug released versus log time plots (i.e., log M_t/ M_∞x 100) versus log t). A value of n = 0.5, indicates Case- I (Fickian) diffusion or square root of time kinetics, 0.5 < n < 1 anomalous ( non – fickian ) diffusion, n=1, Case-II transport and n > 1 super Case-II transport ²⁹.

Fig.2: Comparison of In vitro release profiles of ambroxol hydrochloride from formulated matrix tablets F-IX (20% wt/wt high-viscosity guar gum), Commercial SR tablets (A-SR) and theoretical sustained release (TSR) dissolution profile.

Stability studies:

Stability studies were conducted on ambroxol hydrochloride matrix tablets containing 20% wt/wt of high-viscosity guar gum ( F-IX) to assess their stability with respect to their physical appearance, drug content, and drug release characteristics after storing them at 40°C / relative humidity(RH) 75% for six months³⁰.

RESULTS AND DISCUSSION:

Since the guar gum was found to have poor flow properties, wet granulation method was used to improve the flow properties of guar gum ³¹. The granules of different formulations were evaluated for angle of repose, LBD, TBD, Compressibility index, total porosity and drug content (Table-2). The result of angle of repose (<30) indicate good flow properties of the granules²¹.This was further supported by lower compressibility index values (Table-2). Generally, compressibility index values upto 15% result in good to excellent flow properties²². Granule density, porosity and hardness are often interrelated properties. In addition, granule density may influence compressibility, tablet porosity, dissolution and other properties. The percentage porosity values of the granules ranged from 26.92% to 37.61%, indicating that the packing of the granules may range from close to loose packing and also further conforming that the particles are not of greatly different sizes. Generally, a percentage porosity value below 26% shows that the particles in the powders are of greatly different sizes and a value greater than 48% shows that particles in the powder are in the form of aggregates or flocculates²¹. The drug content in the weighed amount of granules of all formulations was found to be uniform. All these results indicate that the granules possessed satisfactory flow properties, compressibility and drug content.

Table-1: Formulae of Ambroxol hydrochloride (75mg) tablets containing 10%, 20% and 30% wt/wt Low-Viscosity, 10%, 20% and 25% wt/wt Medium-Viscosity, 10%, 15% and 20% wt/wt High-Viscosity guar gum.

Ingredients	Quantity present (mg) in
Ingredients	F-I	F-II	F-III	F-IV	F-V	F-VI	F-VII	F-VIII	F-IX
Ambroxol hydrochloride	75	75	75	75	75	75	75	75	75
Low-viscosity guar gum	25	50	75	-	-	-	-	-	-
Medium-viscosity guar gum	-	-	-	25	50	62.5	-	-	-
High-viscosity guar gum	-	-	-	-	-	-	25	37.5	50
Microcrystalline cellulose	130	105	80	130	105	92.5	130	117.5	105
Starch	12.5	12.5	12.5	12.5	12.5	12.5	12.5	12.5	12.5
Talc	5	5	5	5	5	5	5	5	5
Magnesium stearate	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5

Table-2: Properties of the granulation*

Tablets	Angle of repose	Loose Bulk density (g/ml)	Tapped Bulk density (g/ml)	Compressibility Index (%)	Total Porosity (%)	Drug Content (%)
F-I	25.40±0.02	0.439±0.04	0.586±0.03	13.28±0.02	27.34±0.02	96.53±0.04
F-II	22.10±0.02	0.504±0.03	0.554±0.02	12.25±0.03	29.67±0.02	96.68±0.04
F-III	21.20±0.02	0.521±0.04	0.578±0.04	12.82±0.02	27.92±0.03	97.53±0.03
F-IV	28.95±0.01	0.298±0.03	0.345±0.04	13.57±0.02	36.52±0.04	97.62±0.02
F-V	25.40±0.03	0.2839±0.03	0.335±0.06	12.59±0.03	36.71±0.02	95.62±0.04
F-VI	22.95±0.04	0.302±0.02	0.355±0.03	12.86±0.02	34.52±0.02	96.79±0.03
F-VII	24.86±0.02	0.291±0.04	0.336±0.03	13.54±0.04	37.34±0.04	95.60±0.02
F-VIII	25.20±0.02	0.304±0.03	0.352±0.02	13.08±0.02	31.25±0.02	96.53±0.03
F-IX	23.52±0.04	0.302±0.02	0.348±0.04	12.98±0.03	32.96±0.03	98.62±0.02

*All values are expressed as mean ± SD, n=5.

Table- 3: Properties of the Compressed Tablets

Tablets	*Thickness (mm)**	Deviation in Weight variation (%)	Drug Content* (%)	Hardness (kg/cm²)**	Friability* (%)**
F-I	3.61±0.04	2.867±0.04	98.60±0.02	4.2±0.20	0.74±0.03
F-II	3.67±0.04	2.895±0.03	98.60±0.03	4.3±0.23	0.82±0.03
F-III	3.62±0.03	2.962±0.02	99.23±0.02	4.6±0.14	0.72±0.05
F-IV	3.54±0.02	2.617±0.04	97.54±0.04	4.4±0.25	0.75±0.06
F-V	3.76±0.03	2.567±0.03	98.56±0.03	4.3±0.16	0.64±0.04
F-VI	3.60±0.04	2662±0.04	98.82±0.02	4.7±0.24	0.68±0.06
F-VII	3.62±0.02	2.867±0.02	97.60±0.04	4.5±0.20	0.76±0.05
F-VIII	3.71±0.04	2.841±0.03	98.20±0.02	4.6±0.18	0.73±0.03
F-IX	3.67±0.03	2.689±0.03	99.60±0.03	4.9±0.20	0.64±0.02

*All values are expressed as mean ± SE, n=5; **All values are expressed as mean ± SE, n=20; ***All values are expressed as mean ± SE, n=6

Table-4: Mathematical modeling and drug release mechanisms of Ambroxol hydrochloride from Matrix Tablets Containing 30 %wt/wt of Low-Viscosity (F- III), 25% wt/wt Medium-Viscosity(F-VI), or 20-% wt/wt High –Viscosity Guar gum(F-IX) and Commercial (A-SR) Tablets.

Formulation	Regression coefficient(r²)			Korsmeyer et al’s plots
Formulation	Zero order	First order	Higuchi equation	Slope (n)	Regression coefficient(r²)
F-III	0.9812	0.9957	0.9922	0.5886	0.9856
F-VI	0.9832	0.9982	0.9964	0.5890	0.9981
F-IX	0.9890	0.9988	0.9967	0.7181	0.9986
A-SR	0.9821	0.9942	0.9934	0.6291	0.9908

^*A-SR- Commercially available Ambroxol-SR tablet.

The formulated matrix tablets were subjected to various evaluation tests such as thickness, uniformity of weight, drug content, hardness, friability and in vitro dissolution. All the formulations showed uniform thickness. In a weight variation test, the pharmacopoeial limit for the percentage deviation for the tablets of more than 250mg is ± 5%. The average percentage deviation of all tablet formulations was found to be with in the above limit, and hence all formulations passed the test for uniformity of weight as per official requirements²⁴. Drug content was found to be uniform among different

batches of the tablets, and the percentage of the drug content was more than 95%. The formulation F-IX showed a comparatively high hardness value of 4.9 kg/cm². This could be due to the presence of high viscosity grade of guar gum in higher percentage, which is generally responsible for more hardness of the tablet. Tablet hardness is not an absolute indicator of strength³⁰. Another measure of tablet 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 for all the formulations was below 1% indicating that the friability is with in the prescribed limits²⁵. All the tablet formulations showed acceptable pharmacotechnical properties and complied with the in-house specifications for weight variation, drug content, hardness and friability (Table – 3).

The in vitro drug release studies of selected formulations from each viscosity grades F-III, F-VI, F-IX and Commercial ambroxol SR tablets (A-SR ) are shown in Fig - 1. Drug release from the matrix tablets was found to decrease with increase in drug polymer ratio. A matrix tablets containing 10% wt/wt and 20%wt/wt Low viscosity, 10% wt/wt and 20% wt/wt medium viscosity or 10% wt/wt and 15% wt/wt high viscosity guar gum were found disintegrated within 45 minutes of dissolution testing in pH 1.2 buffer. Whereas, matrix tablets containing 30% wt/wt (F-III) of low-viscosity, 25% wt/wt (F-VI) medium viscosity or 20% wt/wt (F-IX) high viscosity guar gum retained their shape for upto 12 hours of dissolution testing. The A-SR tablets were found swollen and retained their shape for upto 12 hours of testing. This indicates that the marketed sustained release tablets of ambroxol hydrochloride were formulated as matrix tablets with hydrophilic polymer(s) for controlling the drug release. All three guar gum matrix formulations F-III, F-VI and F-IX appear to control the release of ambroxol hydrochloride, but with a varying degree. When the guar gum matrix tablets of ambroxol hydrochloride come into contact with the dissolution medium, they take up water and swell, forming a gel layer around the matrix. Then the dissolved drug diffuses out of the swollen guar gum matrix at a rate determined by the amount and viscosity of guar gum in the tablet formulation. All the formulations, F-III, F-VI, F-IX and A-SR showed a biphasic release profile. There was a faster drug release from 0 to 2 hours, followed by a slow release from 2 to 12 hours. Such a biphasic release pattern may be beneficial in providing the initial therapeuitically effective plasma concentration followed by an extended plasma concentration. The drug present on the surface of the matrix tablet might have resulted in the initial fast release of the drug from the formulation.

The formulations F-VI and F-IX might be contributing their tough control of drug release owing to the higher viscosity of gum. It is expected that higher viscosity gums are required in lower quantity in providing a controlled release. But in the present study, low-viscosity guar gum (F-III) was able to provide controlled drug release as that of medium and high viscosity grade gums. This may be because of the difference in particle size of the various viscosity grades of guar gum used in the present study. The particle size of the low-viscosity guar gum was less than 75µm, whereas that of the medium and high viscosity guar gums used in the present study was more than 75µm. The finer low–viscosity guar gum might have swollen completely providing a stronger gel to control the diffusion of the drug.

The in vitro release studies demonstrated that the release of ambroxol from selected formulations containing 30% wt/wt (F-III) of low-viscosity, 25%wt/wt (F-VI) medium viscosity or 20%wt/wt (F-IX) high viscosity guar gum SR matrix tablets can generally be sustained upto 12 hours. The theoretical release profile calculation is important to evaluate the formulation with respect to release rates and to ascertain whether it releases the drug in a predetermined manner³². According to the theoretical release pattern (basis of calculation mentioned earlier), a twice daily ambroxol hydrochloride sustained release formulation should release 19.6mg in one hour and 5.2 mg per hour upto 12 hours. Formulation F-IX (20% wt/wt high viscosity guar gum) tablet gave release profile close to the theoretical sustained release needed for ambroxol hydrochloride (Figs- 1 and 2). The release from the formulation was also comparable to that of a commercially available SR tablet tested (Fig.2).

The regression coefficients obtained for first order kinetics were found to be higher (0.9942 to 0.9988) when compared with those of zero-order kinetics (0.9812 to 0.9890), indicating that drug released from all the formulations followed first-order kinetics(Table-4). Release of the drug from a matrix tablet containing hydrophilic polymers generally involves factors of diffusion. To evaluate drug release mechanism from the tablets, plots of percent released vs. square root of time as per Higuchi’s equation were constructed. These plots were found to be linear with all the formulations (R²: 0.9922 to 0.9967) indicating that the drug release from the tablets was diffusion controlled. To confirm the diffusion mechanism, the data were fit into Korsmeyer et al’s equation²⁸. The formulations F-III (30% wt/wt low viscosity guar gum) and F-VI (25 % wt/wt medium viscosity guar gum ) showed good linearity(R²: 0.9856 to 0.9981), with slope (n) vaues 0.5886 and 0.5890. Non- Fickian diffusion (0.5 < n < 1) is the dominant mechanism of drug relese with these formulations. As shown in table-4, the n values increased as the drug polymer ratio (by using different viscosity grades of guar gum) of the tablets increased. Formulation F-IX (20% wt/wt high viscosity guar gum) showed high linearity (R²value 0.9986), with a comparatively high slope (n) value of 0.7181. This ‘n’ however, appears to indicate a coupling of diffusion and erosion mechanisms- so-called anomalous diffusion. The relative complexity of this formulation and its components may indicate that the drug release is controlled by more than one process. Hence, diffusion coupled with erosion may be the mechanism of ambroxol hydrochloride release from F-IX.

At the end of the testing period, the matrix tablets were observed for changes in physical appearance, analyzed for drug content, and subjected to in vitro drug release studies. No visible changes in the appearance of the matrix tablets were observed at the end of the storage period. The drug content was found to be 98.6% ± 2.3%. At the end of 12 hours of dissolution testing, the amount of ambroxol hydrochloride released from F-IX matrix tablets before storage was 99% whereas that released from the F-IX formulation after storage was 99.8%. There was no significant difference in the mean amount of ambroxol hydrochloride released from F-IX matrix tablets after storing for 6 months at 40°C / 75% RH, indicating that the formulation could provide a minimum shelf–life of 2 years ³⁰. However, a detailed investigation is necessary to determine the exact shelf- life.

It may be concluded from the present study that slow, controlled and complete release of ambroxol over a period of 12h was obtained from matrix tablets (F-III, F-VI and F-IX) containing 30% wt/wt of low-viscosity, 25% wt/wt medium viscosity or 20% wt/wt high viscosity guar gum respectively. It is also evident from the results that the formulation F-IX containing 20% wt/wt high viscosity guar gum is a better system for twice-daily SR of ambroxol hydrochloride. Formulation F-III and F-VI exhibited Non-fickian diffusion mechanism of drug release and followed first order kinetics.. Whereas the mechanism of drug release from F-IX was diffusion coupled with erosion.

ACKNOWLEDGEMENTS:

The authors are thankful to The Management, Sankaralingam Bhuvaneswari College of Pharmacy, for providing necessary facilities to carryout this work.

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Received on 06.12.2008 Modified on 10.12.2008

Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008; Page 507-512