Cough                                                             

When a patient visits a general care physician or an allergy or respiratory specialist clinic, one of the most common symptoms they report with is a cough (1-2). Expert judgment is used to define chronic cough because there are no clear clinical criteria to differentiate between acute and chronic cough. In reality despite intensive medical intervention, persistent cough is frequently a chronic and onerous illness that lasts for years or even decades for a significant portion of patients (3-5).  Chronic cough is a common symptom of many pulmonary and some extrapulmonary illnesses and disorders, which makes diagnosis and therapy difficult. Furthermore, 40% of individuals with chronic cough who are referred for specialized examination either have a persistent cough even after receiving the best therapy possible for illnesses linked to chronic cough (known as refractory chronic cough) or have no recognized explanation for their chronic cough (known as unexplained chronic cough)(6).The prevalent belief is that adult chronic cough, regardless of aetiology, is a hypersensitivity condition that manifests as coughing frequently in response to low levels of thermal, mechanical, or chemical exposure(7).

The significant burden of persistent chronic cough has prompted recognition of adult cough hypersensitivity as a separate clinical entity, with distinct mechanisms involving both peripheral and central neural pathways contributing to this hypersensitivity. These mechanisms have fuelled advancements in the development of cough suppressant (antitussive) drugs (8). Acute cough was defined as a cough that had started within the last two weeks and persisted for eight weeks. Any frequency of cough episodes was acceptable. Current asthma was identified as long as it met the following criteria: wheezing within the last year, dyspnea during wheezing, and wheezing without respiratory tract infections (9). Chronic rhinosinusitis was identified as long as there was nasal blockage or nasal discharge (anterior or posterior nasal drip), as well as facial pain/pressure or reduction/loss of smell for longer than three months (10).

Chewable Tablet                                           

Chewable pills that must be broken up and gnawed on in between teeth before consumption. Both people who detest swallowing and youngsters who have trouble swallowing are prescribed these medications. Chewable pills are known for their smooth disintegration, agreeable taste, and lack of bitter or unpleasant aftertaste. (11) These tablets are meant to dissolve in the mouth at a reasonable rate, either with or without real chewing. To create a sturdy solid dosage form, developing a tablet formulation successfully requires careful component selection. Achieving a satisfactory level of manufacturing performance in tablet formulation might depend on selecting the right excipient for a certain task, such as lubrication or disintegration.  In order to hide the disagreeable tastes and make pediatric dosage easier, chewable tablet formulations frequently incorporate both synthetic and naturally occurring sweeteners as functional excipients. (12-13) Precisely when they are chewed, the tablets should dissolve in the mouth and release their contents, minimizing the amount of time that passes before they are absorbed from the stomach. (14) Chewable tablets are frequently used when the goal of the active component is to operate locally instead than systemically. A pill that is edible and can be consumed with little to no water is said to be chewable. Direct compression or the wet granulation method are typically used in the manufacturing of chewable tablets. The incorporation of micronized and submicron forms of physiologically and therapeutically active chemicals into tablet formulations is becoming more common as a means of using these forms' increased absorption properties. (15)

Advantages of chewable tablets: 

Chewable tablets are not meant to be swallowed whole; instead, they are typically chewed in the mouth before being swallowed. The major goal of a chewable tablet is to give the right amount of medication in a unit dose form that is simple to give to young patients or elderly people who have trouble swallowing tablets whole. Chewable tablets offer the following particular benefits:

• Greater bioavailability by avoiding disintegration, which causes dissolution to rise.
• Better patient acceptability, particularly in paediatrics’, thanks to palatable flavour.
• Patient convenience; swallowing requires no water.
• May be used in place of liquid dose forms in situations requiring a quick start of action.
• Product uniqueness as seen from a marketing angle.
• It is challenging to swallow the dose form due to its bulk. Chewable tablets have benefits over it in some situations.                                                                                                                    
• faster the drug absorption
• When a pill is masticated before swallowed, its size decreases, increasing the medicinal agent's effectiveness. (16-17)

Ambroxol hydrochloride

One drug that treats respiratory tract conditions is ambroxol HCL, which is categorized as an expectorant. This medication, which is mucoactive, thins and loosens mucus in the airways to facilitate coughing. The hydrochloride salt of ambroxol, a synthetic variation of vasicine, a naturally occurring substance that was taken from the Adhatoda vasica plant, is known as ambroxol HCL. Treatment for bronchial asthma and chronic bronchitis involves the administration of ambroxol hydrochloride, a mucolytic and expectorant enhancer. There have also been reports of ambroxol hydrochloride's anti-inflammatory and cough-suppressive properties. The lungs' release of surfactants has been increased by ambroxol hydrochloride. For therapeutic medicines to have systemic effects, oral medication delivery is the most desirable and recommended mode of administration. Asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), and upper respiratory tract infections are among the respiratory disorders for which ambroxol HCL is frequently used in treatment. It is frequently used in conjunction with other treatments to offer complete relief from respiratory symptoms. It comes in a variety of formats, such as pills, syrup, and injection. Ambroxol HCL is an excellent drug for treating respiratory conditions overall as it effectively reduces symptoms and enhances lung function.

Drug Profile of Ambroxol Hcl

• Molecular Structure: -

       
           
       
Figure 1: Molecular structure of Ambroxol Hcl

Synonym: - Ambroxol Hydrochloride, Mucosolvan, Mucosol

Molecular Formula: - C13H19Br2ClN2O

Molecular Weight: - 414.56 g/mol

Melting point: - 233-234.5°C

Solubility: - 0.0185 mg/mL

Category: - Mucolytic Agent

Description: - Ambroxol HCL is a medication that belongs to the group of mucolytics. It is used to treat respiratory diseases associated with excessive mucus production like Cough.

• Mechanism of Action: -: Ambroxol hydrochloride exerts its therapeutic effects by:

• Stimulating the production and secretion of pulmonary surfactant, a substance                                             that help maintain the elasticity of lung tissue and reduces surface tension in the airways.
• Enhancing the activity of ciliary epithelial cells in the respiratory tract, which helps to   facilitate the movement of mucus and foreign particles out of the airways.
• Modulating the rheological properties of mucus, making it less viscous and easier to

       expel from the lungs.

• Pharmacokinetics and Pharmacodynamics

· Absorption: Ambroxol is well absorbed from the gastrointestinal tract after oral administration. Peak plasma concentrations typically occur within 1-3 hours after ingestion.

· Distribution: Ambroxol has a moderate volume of distribution, indicating that it distributes fairly widely throughout the body's tissues. It crosses the blood-brain barrier to a limited extent.

· Metabolism: Ambroxol undergoes extensive first-pass metabolism in the liver. The primary metabolic pathway involves conjugation with glucuronic acid to form inactive metabolites, which are then excreted in the urine.

·  Route of Elimination: The elimination half-life of ambroxol is relatively short, typically around 7-12 hours in healthy individuals. It is primarily excreted via the kidneys, with approximately 90% of the administered dose eliminated in the urine within 24 hours.

· Half-life: In patients with impaired renal function, the elimination half-life of ambroxol may be prolonged, necessitating dosage adjustment to prevent drug accumulation.

· Drug Interactions: Ambroxol is not known to have significant interactions with other drugs that affect its pharmacokinetics. However, caution should be exercised when co-administering with other medications that are extensively metabolized by the liver or excreted renally.

Uses: -

Ambroxol hydrochloride is used primarily as a mucolytic agent to treat respiratory conditions associated with excessive mucus production. Here are some common uses of ambroxol hydrochloride:

· Acute and Chronic Bronchitis: Ambroxol hydrochloride is frequently prescribed for the treatment of acute and chronic bronchitis, which are characterized by inflammation of the bronchial tubes and excessive mucus production. By thinning and loosening mucus in the airways, ambroxol helps to alleviate coughing and facilitate the clearance of mucus from the respiratory tract.

· Chronic Obstructive Pulmonary Disease (COPD): Ambroxol hydrochloride may be used as an adjunctive therapy for patients with COPD, including chronic bronchitis and emphysema. It helps to reduce the viscosity of mucus, making it easier to expectorate and improving airflow in the lungs.

· Asthma: While ambroxol hydrochloride is not typically used as a primary treatment for asthma, it may be used as an adjunctive therapy in some cases to help alleviate symptoms such as coughing and mucus production.

· Respiratory Tract Infections: Ambroxol hydrochloride may be used to alleviate symptoms associated with respiratory tract infections, such as the common cold or influenza. It helps to loosen and expel mucus from the respiratory tract, making breathing easier and relieving coughing.

MATERIAL AND METHOD

Materials:

Ambroxol hydrochloride (HCl) as the primary active ingredient and purchased from Research-Lab Fine Chem Industries, Mumbai and. along that the excipients: Fillers/Binders etc are collected Such as lactose, starch, sodium saccharine, poly vinyl pyrrolidone, sodium starch glycolate, Magnesium stearate or stearic acid

Methods:

Weigh out the required amounts of ambroxol HCl, fillers, binders, disintegrants, and other excipients as per the formulation. Mix these ingredients thoroughly in a suitable mixer to ensure uniform distribution. Granulation. Dry granulation or wet granulation may be employed depending on the formulation requirements and the properties of the ingredients used. The granulated blend is then compressed into tablets using a suitable tablet press equipped with chewable tablet tooling. Compression force and dwell time are optimized to achieve tablets of appropriate hardness and disintegration properties. Coating (if applicable):After compression, tablets may undergo a coating process for improved appearance, taste-masking, or to provide enteric properties. Packaging: Finally, the chewable tablets are packaged in blister packs or bottles, ensuring they are protected from moisture and environmental factors.

Experimental Work

Preformulation studies:

To guarantee the creation of a stable, therapeutically effective, and safe dosage form, preformulation studies are required.

Organoleptic Properties

Appearance: Assess the tablet's visual characteristics such as shape, size, color, and surface texture. Ambroxol HCl chewable tablets are often formulated to be visually appealing and easily distinguishable from other medications.

Odor: Evaluate the smell of the tablets, which should ideally be neutral or pleasant to enhance patient acceptability. Offensive odors may indicate chemical degradation or interaction with excipients.

Taste: Determine the taste of the tablets since chewable formulations are meant to be consumed orally. Ambroxol HCl itself has a slightly bitter taste, which may need to be masked or mitigated with flavors and sweeteners to improve palatability.

Texture: Assess the tactile properties such as smoothness, roughness, hardness, and mouthfeel of the tablets during chewing. This aspect is crucial for patient compliance and comfort.

Solubility study

Choose a range of solvents with different polarities, including water, aqueous buffers (e.g., phosphate buffer), organic solvents (e.g., ethanol), and simulated gastric fluid (SGF) or simulated intestinal fluid (SIF).

Melting Point:

Apply heat to one end of a capillary tube and rotate it constantly for two to three minutes to shut the tube. Use finely powdered Ambroxol hcl. Dip the capillary tube’s open end into the finely ground Ambroxol hcl.. To fill the capillary tube with compound to a length of approximately 1-2 cm, gently tap it on the table. Put the capillary tube with the powdered Ambroxol hcl.  inside the melting point device. To measure the sample’s temperature precisely, make sure the thermometer is positioned appropriately. Gradually raise the sample’s temperature and record the point at which it begins to melt. Note the temperature range between the sample’s beginning to melt and its complete liquid state.

UV-visible spectroscopy:

• Wavelength Range: Measure the absorption spectrum of ambroxol HCl typically in the UV range (200-400 nm) and potentially extending into the visible range (400-800 nm). Identification: Determine the characteristic absorption peaks or bands specific to ambroxol HCl. This helps in identifying the drug substance and assessing its purity.
• Calibration Curve: Constrct a calibration curve using known concentrations of ambroxol HCl to correlate absorbance readings with concentration levels. Purity Assessment: Impurity Detection: Use UV-visible spectroscopy to detect and quantify impurities in ambroxol HCl samples. Impurities may appear as additional peaks or changes in baseline absorbance.

Fourier transform infrared spectroscopy (FT-IR):

Prepare a thin film or a small amount (about 1-2 mg) of Ambroxol HCL powder. If using a tablet or capsule, crush it into a fine powder. Ensure the FTIR instrument is calibrated and optimized for the analysis. Select the appropriate spectral range (e.g., 4000-600 cm-1). Place the sample in the FTIR instrument's sample compartment. Use a suitable sampling technique (e.g., transmission, reflectance, or attenuated total reflectance (ATR)). Collect the FTIR spectrum. Apply any necessary corrections (e.g., baseline correction, smoothing). Normalize the spectrum (if necessary). Compare the obtained spectrum to a reference spectrum or a database. Identify the functional groups and structural features of Ambroxol HCL. Record the spectrum and results in a laboratory notebook or report. Include relevant information (e.g., sample preparation, instrument settings, data processing).

Drug excipients Compatibility study:

The Fourier Transform Infrared Spectrometry (FTIS) method was employed in testing drug 17xcipients compatibility using Bruker Alpha II spectrophotometer, ranging from 4000 to 400 cm^-1. For analysis purpose, a drug and polymer were mixed before putting onto the sample holder whereby it became solid to facilitate analysis.

Spectroscopical analysis:

Determination of Lambda max by UV Spectroscopy:

Ambroxol hcl lambda max was calculated by dissolving 10 mg of the medication in 100 ml of ethanol, then diluting the solution to create a strength of 100 ?g/ml using the same solvent. The maximum wavelength was then ascertained by scanning it in the 400–200 nm range with ethanol serving as a blank using a UV–visible spectrophotometer (Shimadzu UV-1900i UV–Vis Spectrophotometer).

Preparation of Calibration curve:

Calibration curve of Ambroxol Hcl was prepared with the help of UV spectroscopy Calibration curve of Ambroxol Hcl was prepared in ethanol.

Calibration curve:

Preparation of solution:

Ambroxol Hcl (10 mg) was precisely weighed and added to a 100 ml volumetric flask. A solution containing 100 ?g/ml was obtained by dissolving the medication and diluting it with ethanol until it reached the desired level.

Preparation of working solution:

A precise 10 ml volumetric flask was used to extract appropriate aliquots (0.2, 0.4, 0.6, 0.8, 1, and 1.2 ml) from the Ambroxol Hcl stock solution. The final concentration of the solution was diluted with ethanol until it reached the desired range of 2–12 ?g/ml, and it was then scanned at Lambda max. Using ethanol as a blank, the absorbance of various Ambroxol Hcl solutions was measured at their Lambda maximum.

Formulation study

Formulation of Ambroxol Hcl Tablet:

Chewable Ambroxol pills were made using the direct compression technique. The super disintegrant, sodium starch glycolate, was chosen for this investigation based on its availability in the laboratory. Each component was precisely weighed and then put through a standard sieve (sieve no. 60). For 20 minutes, the necessary amount of medication and excipient were fully combined in a polybag using the geometric addition method. Three batches (F1-F3) of ambroxol hcl tablets were obtained, with an average of 350 mg and a relative density (solid fraction) of less than 1 for all the batches of ambroxol chewable tablets. The obtained powder blend was then compressed with a 4.5 tons compression force using a rotary tablet machine-8 station with a 9 mm flat punch.

Evaluation of Ambroxol Hcl Chewable Tablet

Organoleptic Properties:

A tiny portion of the medication sample was put in a watch glass, and its physical properties such as color and odor, size, shape were visually observed.

Weight Variation: Select 20 tablets and randomly check weight of each tablet to ensure uniformity.

Hardness:

Measure the resistance of tablets to scratching or crushing. Formula: Hardness (kg/cm?2;) = (Force (kg) x 10) / (Surface Area (cm?2;) x Thickness (cm))

Disintegration Time:

Determine how long it takes for the tablet to break apart in water.

Dissolution:

Measure the amount of Ambroxol HCL released from the tablet in a specified time.

Friability: Evaluate the tablet's resistance to abrasion and friability.

Formula: Friability (%) = (W1 - W2) / W1 x 100

Where, W1 is the initial weight of the tablets

             W2 is the weight of the tablets after testing

RESULTS AND DISCUSSION:

Preformulation studies:

Melting point:

The reported melting point of Ambroxol hcl was in the range of 233⁰C-237⁰C. The observed melting point of the was found at 236⁰C by using Thieles tube method. It confirms that the given powdered drug is pure in nature and it complies that powder is ambroxol hcl.

       
           
       
Table No. 2. Melting Point of Drug

FT-IR:

IR spectra of Ambroxol hcl, shown as follows

Drug-excipients compatibility study was done by using FT-IR spectra, from this graph it was prove that there is no change in the IR spectra of physical mixture of drug and excipients.

Spectroscopic studies:

Determination of Lambda max by UV Spectroscopy:

The absorption spectrum of Ambroxol hcl was acquired from a solution of 100 µg/ml concentration in ethanol, revealing an absorbance peak at 243 nm.

       
           
       
Figure. 7. UV absorption spectrum of Ambroxol hcl with ethanol.

Calibration Curve of Ambroxol hcl with ethanol:

The graph of Concentration Vs Absorbance for pure Ambroxol hcl was found to be in the concentration of range 2-10 µg/ml.

       
           
       
Figure 8. Calibration Curve of Ambroxol hcl with ethanol

       
           
       
Table No.3. Calibration Curve Of Ambroxol hcl with ethanol

       
           
       
Figure 9. Graph of calibration curve of Ambroxol hcl in ethano

       
           
       
Table No. 4. Various constant for Calibration Curve Of Ambroxol hcl in ethanol.

Characterization of Ambroxol hcl

Dissolution test

Performing dissolution testing on three batches of Ambroxol HCl chewable tablets is essential to assess batch-to-batch consistency in drug release characteristics. Here’s how you can conduct and compare dissolution testing across these batches:

Disintegration test

The purpose of the disintegration test, which is typically to evaluate the time required for the tablets to disintegrate into small particles in a specified medium.

• Disintegration medium (e.g., pH, temperature)
• Disintegration apparatus used (e.g., USP apparatus)
• Record the disintegration time (in seconds or minutes) for each tested tablet.
• Present these results in a table format for clarity.

= (Sum of 20 tablets' disintegration times) / 20

= (2450 seconds) / 20

= 122.5 seconds

Weight variation test

Briefly summarize the purpose of the weight variation test, which is typically to assess the uniformity of tablet weight within a batch.

       
           
       
Table 7. individual weight of  Ambroxol HCl Chewable Tablet

= (Sum of 20 tablets' weights) / 20

= (7504 mg) / 20

= 375 mg

Friability testing

Friability testing assesses the ability of chewable tablets to withstand mechanical stress during handling and transportation. Performing this test on three batches of Ambroxol HCl chewable tablets helps ensure consistency in tablet durability across different manufacturing runs. The percentage weight loss due to friability should not exceed a specified limit (typically ?1% for chewable tablets).

       
           
       
Table 8: -. % of weight loss due to friability