Formulation and Development of Sustained Release Matrix Tablets of Ambroxol hydrochloride by QBD Approach

 

Shubham P. Bhadane, Rajendra K. Surawase

Loknete, Dr. J. D. Pawar, College of Pharmacy, Manur,

Shivaji Nagar, Kalwan, Tal. Kalwan, Dist. Nashik. 423501.

 

ABSTRACT:

Ambroxol hydrochloride is a potent mucolytic agent capable of inducing bronchial secretions used in the treatment of respiratory disorders linked to thick or viscous mucus. The Sustained release matrix tablets containing 75 mg Ambroxol hydrochloride were developed using different drug: polymer ratios. Sustained release matrix tablets were prepared by direct compression method. evaluated for loose bulk density, tapped bulk density, compressibility index and angle of repose, shows satisfactory results. The prepared tablets were further evaluated for uniformity of weight, hardness, friability, thickness, content uniformity, In-vitro dissolution, drug-excipients interactions, swelling index study also carried out. The FT-IR studies revealed that there was no chemical interaction between drug and excipients. In-vitro release studies were carried out using USP type II (paddle method) dissolution apparatus at 50 rpm. The absorbance of these solutions was identified at 250 nm using a UV Spectrophotometer. Among all formulations, the preparation of the F4 batch showed the highest percent drug release at 98.56% after 12 hours. end of 12 h. The stability studies were carried out according to ICH guideline, which indicates that the selected formulations were stable.

 

 

 

INTRODUCTION:

Sustained-release capsules and tablets often only need to be taken once or twice daily, as opposed to their traditional equivalents, which may need to be taken up to four times daily to have the same beneficial effects. In sustained-release products, the medicine is released right away, producing the intended therapeutic impact, and then more drug is released gradually over time to prolong the effect. Release solutions that guarantee that the drug's plasma level is maintained often do away with the necessity for nighttime dosing, which is not only helpful to patients but also ensures their wellbeing.¹

 

 

A common category of diseases known as chronic bronchopulmonary illnesses are marked by aberrant mucus secretion and poor mucus transport. They are treated with strong antibiotics, antituberculosis medications, and antifungal medicines because they are frequently linked to infectious microorganisms. Mucolytic drugs are helpful as supplemental treatment for respiratory tract conditions, resulting in a slight improvement in lung function and symptom management. When treating symptoms of chronic bronchitis, mucolytics and antibiotics have been shown to work well together. Additionally, mucolytics serve as scavengers of reactive oxygen species that the body over expresses, particularly during oxidative stress periods when they can seriously harm cell structures.^2,3

 

Ambroxol (trans-4-(2-amino-3,5-dibromobenzyl)-aminocyclohexanol) is an active metabolite of bromhexine that has been used to increase surfactant secretion in the lungs and as mucolytic to breakdown acid mucopolysaccharide fibers making the sputum thinner and less viscous, thus more easily removed by coughing.⁴

 

Additionally, ambroxol has been shown to suppress coughing and reduce inflammation by blocking the release of mediators that are implicated in the etiology of allergic inflammation. As therefore, it is widely used to treat pulmonary alveolar proteinosis, newborn respiratory distress syndrome, bronchial asthma, and chronic bronchitis. With a half-life of only 3.4 hours, it is quickly eliminated after oral administration and is quickly absorbed after that. For maximum therapeutic efficacy, three doses per day are necessary.^5,6

 

MATRIX SYSTEM:

The matrix tablet, a controlled drug method of administration releases as the drug continually using both dissolution-controlled and diffusion the processes. The medications' release, which is regulated by their varying solubility qualities, the medication is disseminated in hard, non-swellable hydrophobic materials, a rigid hydrophobic matrix, or plastic materials. In order to create a tablet having a matrix of the medication placed in it release as the retardant, a direct compression of a mixture of drug release, retardant material, and additives is among the most straightforward techniques to develop sustained release dosage forms. Granulating a solution is a possibility medicine that are release combination of suppressant before compressing.^7,8

 

MATERIAL AND EQUIPMENT:

Materials:

Ambroxol hydrochloride was obtained as a gift sample from basic international, vadodara. HPMC K100, HPMC K30 and HPMC K4 (Polymer) are purchases from Fine chemical industries, Mumbai. Lactose (diluent), Talc (Glidant), Magnesium Stearate (Lubricant) were purchases from Modern Chemical Industries Sinnar.

 

Equipment:

There are various instruments used for research work, including a UV-visible spectrophotometer (Equiptronics, model EQ-826/EQ-824) and a tablet compression machine (Cemach Machineries Ltd. Modelno. 8 station D tooling) and also used Fourier Transform Infrared Spectrophotometer (Bruker), Electronic precision balance (Wenser PGB220), Bulk Density and Tapped Density Apparatus (Electro lab ETD-1020), Tablet Friability Test Apparatus (Veego VFT-1), Hardness Tester (Monsanto 31-1), Disintegration Apparatus (Electro Lab, India USP-TDT-081), Dissolution Apparatus (Electro Lab, India USP-ED-2L), DSC Apparatus.

 

METHODS:

Preparation of Sustained Release Matrix Tablets:

Ambroxol hydrochloride tablets were prepared by direct compression method. Accurately weighed quantities of polymer of HPMC K4, HPMC K30 and HPMC K100 and Lactose were taken in a mortar and mixed geometrically, to this required quantity of Ambroxol was added and mixed slightly with pestle. The powder is passed through sieve no. 40 and mixed with the drug blend which is also passed through sieve no 40. The whole mixture was collected in a plastic bag and mixed for 3 minutes. To this Magnesium stearate was added and mixed for 5 minutes, later Talc was added and mixed for 2 minutes. The mixture equivalent total 250mg was compressed into tablets with 8 mm round concave punches at a hardness of 6 kg/ cm².

 

EXPERIMENTAL DESIGN:

Experimental design is a systematic and scientific approach to study the relationship and interaction between independent and dependent variables. 2³ full factorial design was implied for optimizing the formulations. The selected design offers adequate degree of freedom to determine main effects of individual factors as well as factor interactions.⁹

 

Three independent variables (factors), concentration of HPMC K100 (A), HPMC K30 (B), and HPMC K4 were chosen and assessed at two different levels: low (-1) and high (+1). considered as independent factors of Swelling index, and drug release were selected as dependent variables (responses). The range of factor was selected, in order to find out its impact on the responses or dependent variables. Data were analyzed using Design Expert® (version 8.0.7.1) software available from Stat-Ease Inc., Minneapolis, MN. Table no.1 provides the details of.¹⁰

 

Table 1: Composition of independent variables and their levels for the preparation of Ambroxol hydrochloride matrix tablet

 

Table 2: 2³ full factorial design for formulation designed using Stat-Ease Design-Expert® soft-ware (version 8.0.7.1)

Ingredient	F1	F2	F3	F4	F5	F6	F7	F8
Ambroxol Hcl	75	75	75	75	75	75	75	75
HPMC K100	25	25	12.50	25	25	12.50	12.50	12.50
HPMC K30	12.50	25	25	25	12.50	25	12.50	12.50
HPMC K4	25	12.50	25	25	12.50	12.50	25	12.50
Mg. Stearate	4	4	4	4	4	4	4	4
Talc	4	4	4	4	4	4	4	4
Lactose	Upto 250 mg	Upto 250 mg	Upto 250 mg	Upto 250 mg	Upto 250 mg	Upto 250 mg	Upto 250 mg	Upto 250 mg

 

Evaluation:

Pre-compression parameters

1.     Bulk density:

It is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring the weight powder (passed through standard sieve # 20) into a measuring cylinder and initial weight was noted. This initial volume is called the bulk volume.¹¹

 

Bulk density BD = (M/V) g/cc

 

2.     Tapped Density:

It is the ratio of total mass of the powder to the tapped volume of the powder. Volume was measured by tapping the powder for 750 times and the tapped volume.¹²

 

Tapped density Td = Mass/Tapped volume

 

3.     Hausner’s Ratio:

Hausner’s ratio is an index of ease of powder flow; it is calculated by following formula.¹³

 

Hausner’s ratio = Tapped density/Bulk density

 

4.     Carr’s Index

Tapped and bulk density measurements can be used to estimate the Carr’s index of a material. Carr’s index was determined by¹⁴

                   Tapped density – Bulk density

C.I (%) = ---------------------------------------x 100

                           Tapped density

 

5. Angle of Repose:

It is defined as maximum angle possible between the surface of the pile of powder and the horizontal plane.¹⁵

 

θ = tan ^-1 (h/r)

 

Post-Compression Parameters

1.     Weight Variation:

10 tablets were selected randomly from the lot and weighted individually to check for weight variation. The individual weighed is then compared with average weight for the weight variations.¹⁶ [Table-3].

2.     Hardness:

The strength of tablet is expressed as tensile strength (kg/cm²). The tablet crushing load, which is the force required to break a tablet into pieces by compression. It was measured using a tablet hardness tester (Monsanto hardness tester). Three tablets from each formulation batch were tested randomly and the average readings were noted.¹⁷ [table 3].

 

3.     Friability:

Friability of the tablets was determined using Roche Friabilator. This device consists of a plastic chamber that is set to revolve around 25 rpm for 4 min dropping the tablets at a distance of 6 inches with each revolution. Pre weighed sample of 10 tablets was placed in the friabilator and were subjected to 100 revolutions and reweighed. The friability (F %) is given by the following formula.¹⁸

 

F (%) = (1 – W0 / W) × 100

 

Where, W0 is weight of the tablets before the test

             W is the weight of the tablets after test.

 

4.     Swelling studies:

One tablet from each formulation was weighed and kept in Petri dish containing 20 ml of phosphate buffer of pH 6.8. At the end of specified time intervals tablets were withdrawn from Petri dish and excess buffer blotted with tissue paper and weighed. The % weight gain by the tablet was calculated by following formula.¹⁹

 

R = wa – wb/ wb × 100

Where, wa = weight of tablet after absorption

             wb = weight of tablet before absorption.¹⁹

 

5.     In vitro dissolution studies:

The dissolving tests on the Ambroxol Hydrochloride SR tablets were performed using the USP disintegration testing equipment II (paddle type). The in-vitro dissolution experiment employed acidic medium 0.1 N HCL for the first two hours. The dissolving media was then 900ml of a buffer with phosphates pH 6.8 at 37°C and 50 rpm. 5 ml of the sample were taken out of the dissolving apparatus every hour for a total of twelve hours. The same amount of medium was used to replace the samples. The absorbance of these solutions was identified at 250 nm using a UV Spectrophotometer. Calculating the drug concentration released at various time intervals was done using the usual graph. To determine the pattern of drug release, drug release was estimated from this percentage and plotted against the function of time. The drug's release rates were calculated.^20,21

 

RESULT AND DISCUSSIONS:

Determination of λ max of Ambroxol Hydrochloride

To provide the concentration of 5-25 g/ml needed for the standard calibration curve, 0.5, 1.0, 1.5, 2.0, and 2.5 ml of the 100 g/ml solution were pipetted into a 10 ml volumetric flask, and the remaining volume was filled with Methanol. At its greatest wavelength, the absorbance of each solution was measured. In a UV Spectrophotometer, the sample was scanned from 200 to 400 nm against a blank solution of Methanol to find out the wavelength that corresponded to the solution's highest absorbance.

 

 

Fig no. 1: λ max of Ambroxol Hydrochloride in Methanol

 

 

Figure no 2: Calibration Curve of Ambroxol Hydrochloride in Methanol

 

Drug- excipient compatibility study

A.   Fourier Transform Infrared Spectroscopy (FTIR)

The IR spectrum of the Ambroxol Hydrochloride was recorded by KBr (Potassium Bromide) disk method. The IR spectra of the pure Ambroxol Hydrochlorideshow the functional group as per the structure. The interpretation of the peak obtained in the IR spectra along with their corresponding functional group are at frequency 1059.15 is C-N stretching, 1587.02 is C=C stretching, 2890.39 is C-H Stretching and 3332.25 is O-H stretching

 

 

Figure no 3: FTIR Spectra of Ambroxol Hydrochloride

 

B.    Differential Scanning Calorimetry of Drug and All Excipients

The DSC curve of Ambroxol Hydrochloride shows sharp endothermic peak at 237.66°C at 19.14 min. and the DSC of Ambroxol Hydrochloride and all Excipients shows the they are compatibles.

 

 

Figure no 4: DSC Thermogram of Drug and Polymers

Table No. 3 Preformulation parameters pre compressional blend

Formulation code	Bulk density (gm/ml)	Tapped density	Hausner ratio	Carr’s index (%)	Angle of repose (θ)
F1	0.40 ±0.04	0.46 ±0.12	1.16	13.03 ±5.56	33.02 ±3.62
F2	0.37 ±.0.02	0.41 ±0.16	1.12	11.05 ±4.78	35.52 ±3.76
F3	0.39 ±0.06	0.48 ±0.08	1.23	18.75 ±4.72	31.78 ±3.94
F4	0.40 ±0.04	0.45 ±0.16	1.12	11.11 ±3.98	28.81 ±3.42
F5	0.38 ±0.06	0.45 ±0.02	1.19	15.55 ±5.78	31.58 ±3.97
F6	0.43 ±0.12	0.45 ±0.08	1.16	14.00 ±5.36	30.54 ±4.72
F7	0.38 ±0.06	0.48 ±0.08	1.28	20.83 ±4.24	33.02 ±3.96
F8	0.37 ±0.06	0.45 ±0.06	1.21	17.77 ±3.70	37.23 ±4.82

 

Table 4: Post Compression evaluation for Ambroxol Hydrochloride Tablet

Formulation code	Weight Variation (mg)	Diameter (mm)	Thickness (mm)	Hardness (kg/cm2)	Friability (%)
F1	253 ±1.38	8.00	4.76 ±0.19	5.54 ±0.25	0.80 ±0.02
F2	251.5 ±1.12	8.00	5.06 ±0.84	5.98 ±0.96	1.20 ±0.06
F3	251.5 ±1.44	8.00	5.06 ±0.92	5.98 ±0.88	1.20 ±0.04
F4	251 ±1.16	8.00	5.03 ±0.62	6.14 ±1.48	0.80 ±0.02
F5	251.5 ±1.48	8.00	5.06 ±0.78	5.98 ±0.74	1.20 ±0.08
F6	253 ±2.32	8.00	5.29 ±0.66	6.23 ±1.06	0.40 ±0.06
F7	253.5 ±2.16	8.00	5.44 ±0.84	6.43 ±1.43	0.32 ±0.02
F8	250 ±0.82	8.00	5.04 ±0.72	6.1 ±0.98	0.56 ±0.06

 

Discussion:

The bulk densities for all formulations were between 0.37 and 0.42 grams/ml, while the tap densities were between 0.41 and 0.48 grams/ml. All of the formulations' angles of repose fell between 28.81° and 40.69°, which is in the outstanding or good range and indicates the outstanding flowability required for optimum particle flow. The range of values of 8.69 to 26.00% for the powder blend's Carr's index was determined to be excellent or within acceptable bounds, indicating good or reasonable flowability for the correct flow of powder mix. The Hausners ratios was discovered to be between 1.09 and 1.36. All of these outcomes suggested.

 

Discussion:

The weight variance for all formulations was between 250 and 256.50 mg, while the diameter variation was between 8.00 mm. All of the formulas' tablet thicknesses were determined to be between 4.65 and 5.44 mm, which is a respectable range. A value of 5.54 to 6.66 kg/cm2, which is excellent or within the acceptable range, was determined to be the hardness of the tablets for all formulations. Friability was determined to be between 0.32 to 1.20%.

 

Swelling Index of Ambroxol Hydrochloride Tablet:

 

Figure no. 5: Swelling Index of F1-F7

 

Discussion:

Form the above study of swelling index of batch F1-F8 is study. All of the formulation tablet swelling index were determined 85.20%, which is within a good range.

 

Table No. 5 Characterization of Swelling index

Time (Hrs)	F1	F2	F3	F4	F5	F6	F7	F8
1	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00
2	23.78	40.30	34.20	29.20	23.78	33.33	35.21	36.20
3	44.38	54.63	42.33	47.63	44.38	45.55	61.00	45.23
4	51.30	62.15	55.20	58.60	51.30	57.33	65.21	54.30
5	64.50	68.63	60.46	62.33	64.50	59.63	68.56	63.46
6	75.40	71.54	70.53	75.45	75.40	67.60	64.12	72.53
7	82.20	77.20	75.65	85.20	82.20	75.40	74.20	71.75

 

Table No. 6 In-Vitro% Drug Release of Ambroxol Hydrochloride

Time (Hrs.)	Dissolution Medium	F1	F2	F3	F4	F5	F6	F7	F8
0	0.1N HCl	00	00	00	00	00	00	00	00
1		13.32±4.62	18.96±4.71	27.50±5.12	17.9±3.29	14.7±4.57	15.14±5.11	18.45±3.42	27.86±3.67
2		27.99±5.94	26.79±4.22	34.06±2.23	31.41±4.60	17.9±3.29	23.06±4.77	26.66±4.74	35.59±4.82
3	Phosphate Buffer 6.8 pH	35.64±4.87	37.11±3.91	39.06±4.46	35.86±3.44	30.61±4.52	30.79±3.53	34.20±2.18	42.18±3.91
4		43.24±6.31	45.92±3.43	46.27±2.60	41.91±2.86	36.57±3.87	41.11±3.82	43.47±4.83	49.02±3.49
5		52.34±4.78	54.85±2.54	60.3±3.65	45.47±3.72	46.21±5.65	48.93±2.46	51.96±5.79	56.58±2.83
6		59.76±1.55	62.55±4.63	72.77±2.28	54.72±4.32	57.92±4.39	56.85±3.81	60.19±3.93	64.85±3.54
7		67.88±2.55	70.15±5.25	84.42±2.62	65.21±7.64	66.45±4.33	63.7±4.52	72.70±2.17	73.12±2.55
8		78.37±2.74	79.95±3.21	88.69±2.32	75.70±4.60	78.64±2.49	70.04±2.37	81.17±4.78	83.71±2.78
9		83.90±3.45	85.36±4.53	98.20±2.54	82.64±6.64	83.62±3.96	77.04±1.08	89.00±3.85	91.44±5.57
10		92.83±2.66	98.36±4.63	-	87.26±6.26	88.78±3.85	83.08±2.85	95.00±4.63	-
11		96.78 ±3.90	-	-	90.56 ±5.46	97.67 ±4.54	90.56±3.66	-	-
12		-	-	-	98.56±4.62	-	95.89±4.83	-	-

 

 

Figure no 6: In Vitro %CDR Batch F1 to F8

 

Table no. 7 Evaluation parameter of optimized Batch (F4)

Sr. No.	Parameter	Result
1.	Weight Variation(mg)	251 ±1.16
2.	Diameter (mm)	8.00
3.	Thickness (mm)	5.03 ±062
4.	Hardness (kg/cm2)	6.14 ±1.48
5.	Friability (%)	0.80 ±0.02
6.	Swelling Index %	85.20
7.	% Drug Release (%)	98.56 ±4.62 (In 12Hrs)

 

ANALYSIS OF DATA:

To investigate the influence of 3 factors, full factorial design was used; polynomial equation was deduced to study the impact of independent variables upon the responses i.e., Swelling index and % drug release. Inference on results is obtained by regression equations after considering the magnitude of the coefficient and the sign of coefficient indicates the type of response. Positive sign in the polynomial equation infers that the response increases with increase in the value and negative sign shows the decrease in response with increase in the value. The kind of response when two factors were changed simultaneously is given by interaction terms.

 

A. Full model for Y1 (% Swelling Index)

Final Equation in Terms of Coded Factors

Swelling Index = +77.98+3.73*A+0.39*B+1.34 *C0.89*A*B+0.66*A*C+0.72*B*C+127 A2-0.012*B2-2.74*C2

 

It was observed that the independent variables viz. A (HPMC K100) B (HPMC K30), had a Positive effect on Swelling index but C (HPMC K4) has Negative effect as shown in fig. no. 7,8

 

3D Response Surface Plot:

·       Effect of HPMC K100, HPMC K30 and HPMC K4 on drug release Time of Ambroxol Hydrochloride in 3D response surface plot confirmed. From the figure response curve of Y1 (% Drug release),

·       It is observed that as concentration of HPMC K100 increases from 12.50mg to 25mg, HPMC K30 increases from 12.50mg to 25mg and HPMC K4 increases from 12.50mg to 25mg drug release increases significantly.

 

 

Figure no: 7 Contour plot for Y1 (Swelling index)

 

 

Figure no:8. Effect of independent variables on Swelling index 3D surface plot

 

Full model for Y2 % CDR:

% CDR =+96.49+1.36 *A+1.26 *B+0.65 *C-0.65 *A*B-0.82 *A*C-0.020 *B*C+0.29 A2-0.020*B2-0.40*C2

It was found that the independent variables, viz. A (HPMV K100) B (HPMC K30), had a Negative effect on friability, but C (HPMC K4) has Positive effect as shown in fig no.9,10

 

 

Figure no:9 Contour plot for Y2 (%CDR)

3D Response Surface Plot % CDR

·       Curved Y2 (% CDR) Effect HPMC K100, HPMC K30 and HPMC K4 on drug release Time of Ambroxol Hydrochloride in 3D response surface plot confirmed. From the figure response curve of Y2 (% Drug release),

·       It is observed that as concentration of HPMC K100 increases from 12.50 mg to 25 mg, HPMC K30 increases from 12.50 mg to 25 mg and HPMC K4 increases from 12.50 mg to 25 mg drug release increases significantly.

 

 

Figure no :10 Effect of independent variables on % CDR 3D surface plot

 

STABILITY STUDY:

Table no. 8 stability study of optimized formulation (F4)

 

DISCUSSION:

According to the standard ICH guideline, the optimized formulation for a stability study must be stored at a temperature of 40°C ± 2°C and a relative humidity of 75% RH ± 5% RH for a minimum of one month. After a one month of period visual appearance is white and slightly change in drug content (%) i.e. 98.03%.

 

CONCLUSION:

In this present study an attempt has been made SR matrix tablet Ambroxol hydrochloride by using direct compression method. HPMC K100, HPMC K30 and HPMC K4 were used as carrier in different ratios for preparation of SR formulation. Since all the formulations procedure were simple, inexpensive and show better drug release and from the results obtained, following conclusion can be made; The following conclusions can be drawn from the result obtained. Pre-formulation parameters such as melting point and solubility of the drug were evaluated. The result found to be satisfactory and all the values obtained comply within pharmacopeia limit. Result obtained from FTIR studies confirmed that there was no any chemical interaction or no incompatibility between Ambroxol Hydrochloride and excipients

ACKNOWLEDGEMENT:

Special thanks to my guide, Dr. Rajendra K. Surawase Loknete Dr. J. D. Pawar College of Pharmacy, Manur, Kalwan. for their guidance and invaluable feedback throughout the research work. I extend my appreciation to my family and friends for their unwavering support and understanding.

 

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Received on 08.07.2024      Revised on 20.01.2025 Accepted on 27.05.2025      Published on 25.07.2025 Available online from July 31, 2025 Res.  J. Pharma. Dosage Forms and Tech.2025; 17(3):183-190. DOI: 10.52711/0975-4377.2025.00026 ©AandV Publications All Right Reserved
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