INTRODUCTION:

The preformulation studies are carried out before preparation and characterization of pharmaceutical dosage form¹. The studies prior to the formulation are broadly known as preformulation studies and these studies should focus on those physicochemical properties of compounds that could affect drug performance and development of an efficacious dosage form. In the simplest case, these preformulation investigations may merely confirm that here are no significant barriers to the development of dosage form or delivery systems. Hence, before preparation and characterization of pharmaceutical dosage form containing therapeutic moiety, preformulation studies must be done to characterize the physicochemical properties of the drug that could affect the development of efficacious dosage form. Athorough understanding of these properties provides a rationale for formulation design. This time preformulation has been conducted to design medicated chewing gum².

Chewable tablets and Chewing gum permits more rapid therapeutic action compared to per-oral dosage form³. Intraoral drug delivery overcomes hepatic first pass metabolism and promotes rapid systemic delivery with improved bioavailability with selected drugs having the required physicochemical and biopharmaceutical characteristics⁴.

Chewable tablets and chewing gum for use in children with full dentition have been very well received by the patients. In children chewing gum is considered as more preferred method of drug administration compared with oral liquids and tablets⁵. Today chewing gum is convenient drug delivery system which is appropriate for a wide range of active substance, especially for diseases like cough, bronchitis and other respiratory track diseases.⁶

DRUG PROFILE:^7,8

Ambroxol HCl (trans-4-[(2-Amino-3,5-dibromobenzyl) amino] cyclohexanol HCl N-(trans-p-hydroxycyclohexyl)-(2-amino 3, 5-dibromobenzyl) HCl, Chemically named as–N-desmethyl metabolite of bromhexine (C₁₃H₁₈Br₂N₂O) having molecular weight of 416.6, pH4.5-6.0 and pKa – 8.2.

Structure –

Pharmacology of drug:

Ambroxol belongs to category of mucolytic agent. Applicable for use inProductive cough, Acute and chronic inflammatory Disorder of upper and lower respiratory tract associated with viscid mucus including acute and chronic Bronchitis, Asthmatic bronchitis, bronchial asthma with thick expectoration, chronic pneumonia. Contraindicated in Gastric Ulceration, Hypersensitivity. Precaution to be taken during first trimester of pregnancy, not taken simultaneously with antitussive.Adverse effects observed are epigastric pain, stomach overfill feeling, allergic response like Eruption, Urticaria. Ambroxol should not be taken simultaneously with Antitussive (eg. Codeine) because phlegm which has been liquified by Ambroxol might not be expectorated. Rapid oral absorption, bitter in taste. ⁹

PREFORMULATION METHODOLOGY:

Physicalappearance¹⁰

The sample of Ambroxol HCl was analyzed for physical appearance.

Identification

The procured sample of Ambroxol HCl was identified by using melting point, FTIR Spectra and UV absorption maxima study.

Melting Point

It is one of the parameters to judge the purity of crude drugs. In case of pure chemical or photochemical, melting points are very sharp and constant. The melting point of ambroxol HCl was determined by capillary method with melting point apparatus i.e. (Bea-54 Biocraft Scientific Systems (P) Ltd).

A small quantity of powder was transferred into a capillary tube and the tube was placed in the melting point determining apparatus. Readings were taken in triplet The temperature was gradually increased automatically. Read the temperature (by using a thermometer) at which powder started to melt and when all the powder melted.

3.2.2. Solubility study

Preformulation studies focus on drug-solvent systems that occur during the delivery of drug candidates. Solubility may be defined as the spontaneous interaction of two or more substances to form a homogenous molecular dispersion. The solubility of Ambroxol HCl was tested in various common solvents. A definite quantity (10mg) of drug was dissolved in 10ml of each investigated solvents at room temperature.

Determination of absorption maxima (λ_max)

The absorption maxima (λ max) of drug were determined by Systronic 2202 PC based UV visible double spectrophotometer. The absorption maximum was determined by dissolving 100 mg of drug Ambroxol HCl in 0.05M H₂SO₄ and volume was made up to 100 ml with 0.05M H₂SO₄ in volumetric flask. From this stock solution 1 ml of solution was transferred into 10ml volumetric flask and the volume was made up with 0.05M H₂SO₄. This solution was scanned in the range of 200-400 nm by UV Visible double beam spectrometer

Preparation of standard curve in 0.05M H₂SO₄

Accurately weighed quantity of Ambroxol HCl (10mg) was dissolved in 0.05M H₂SO₄and volume was made upto100ml with 0.05M H₂SO₄in volumetric flask. From this solution 10 ml solution was taken and volume was made up to 100 ml with 0.05M H₂SO₄ in volumetric flask. From this stock solution different dilutions were prepared in the concentration range of 10, 20, 30, 40 and 50µg /ml absorbance was measured at two absorption maxima245 nm and 310nm.

Preparation of standard curve in Phosphate buffer 6.8

Accurately weighed quantity of Ambroxol HCl (10mg) was dissolved in phosphate buffer 6.8and volume was made upto100ml with phosphate buffer 6.8 in volumetric flask. From this solution 10 ml solution was taken and volume was made up to 100 ml with phosphate buffer 6.8 in volumetric flask. From this stock solution different dilutions were prepared in the concentration range of 10, 20,30, 40, and 50µg /ml absorbance was measured at two absorption maxima 245 nm and 310nm.

FTIR Spectroscopy

The infrared spectrum of the Ambroxol HCl was obtained by KBr pellet technique using Shimadzu 8400S FTIR Spectrophotometer. The sample was placed into a pellet before measuring the infrared absorption spectra. To prepare the pellets, a few milligrams of the sample were ground together in a mortar with about100 times quantity of Potassium Bromide (KBr)¹¹. The finely ground powder was introduced into a stainless steel die. The powder was then pressed in the die between polished stainless steel anvils at a pressure of about 8t/in².

RESULTS:

Physical appearance of the received Ambroxol HCl complied with Pharmacopoeial standards. It was white or slightly yellowish crystalline powder.

_M_e_l_t_{ing point of Ambroxol
HCl was found to be}235.66ºC.

The solubility was observed only by the visual inspection. Ambroxol found to be soluble in distilled water, ethanol and methanol. Insoluble in cyclohexene and methylene chloride.

Two absorption maxima observed at 245 and 310 nm. Represented in graph 1

Graph 1: Absorption maxima (λ_max) of Ambroxol HCl in 0.05M H₂SO₄

Calibration curve prepared in 0.05M H₂SO₄and in Phosphate buffer 6.8. Results displayed in graph 2, 3, 4.

The infrared spectrum of drug is presented in Table 1 with their characteristic peaks and absorptions in graph 5.

Graph 2: Calibration curve of Ambroxol HCl in 0.05M sulphuric acid at 245

Graph 3: Calibration curve of Ambroxol HCl in 0.05M sulphuric acid at 310

Graph 4: Calibration curve of Ambroxol HCl in Phosphate buffer 6.8 at 245 nm

Graph 5 : FTIR Spectra of Ambroxol HCl (Shimadzu, 8400)

Table 2: Interpretation of IR spectra of Ambroxol HCl

Wave number (cm^-1)	Characteristic absorption
1595-1545	C=C stretching, aromatic
3350-3250	Aromatic primary amine, NH stretch
3400-3345	Intermolecular hydrogen bonded OH, Stretch
700-600	Bromo compound, C-Br stretch

REFERENCES:

1. Lachman L, Lieberman A H and Kanig L. Joseph, “The Theory and Practice of Industrial Pharmacy”, 3^rd edition, Varghese Publishing House, Bombay, India, 1991, Pg no. 171-173.

2. Raviolo MA, Briñón MC. Preformulation Studies of Zidovudine Derivatives: Acid Dissociation Constants, Differential Scanning Calorimetry, Thermogravimetry, X-Ray Powder Diffractometry and Aqueous Stability Studies. Sci Pharm. 2011 Sep; 79(3):479-491.

3. Parmar Vilcy William and Thosar Millind, A Comprehensive Review on Medicated Chewing Gum, International Journal of Research in Pharmaceutical and Biomedical Sciences, 2012:3(2): 894-906.

4. Rama Bukka et al, Preparation and evaluation of Intraoral Drug Delivery system for Rasagiline mesylate, International Journal of Pharmaceutical Sciences and Drug Research, 2010,2(4):294.

5. Gavaskar B, Venkataramana D and Rao Y Madhusudan, “Medicated Chewing Gum A Novel Approach to improve Patient Compliance”, International Journal of Research in Pharmaceutical and Biome Sciences 2011:2:23-32.

6. Naik Heema and Gupta Stuti, “Medicated Chewing Gum Updated Review”, International Journal of Pharmaceutical Research and Development, 2011:2: 66-76.

7. “The Merc Index” An Encyclopedia of Chemicals, Drugs and Biologicals, 13^th Edition, Published by Merck Research Laboratores, Division of Merc and Co INC Whitehouse Station, 2001, Page no. 983.

8. Technical Monograph No.4, IDMA-APA Guideline, Pharmaceutical Preformulation Analytical Studies.

9. Tripathi K.D, “Essential of Medical Pharmacology”, 6^th Edition, Jaypee Brothers Medical Publishers Pvt Ltd, New Delhi, India, Reprint 2009, page no. 213-216.

10. “Indian Pharmacopoeia”, Vol-2, Published by the Indian Pharmacopoeia Commission Ghaziabad, 2007, page no.701

11. William Kemp, Organic Spectroscopy, Infrared Spectroscopy, 3rd Edn, PALGRAVE, New York: 43, (199).

Received on 25.06.2013 Modified on 16.07.2013

Asian J. Research Chem. 6(9): September 2013; Page 868-870