Formulation, Development and Evaluation of Expectorant Extended Release Tablet

Paresh Patel

Institute of Pharmaceutical Science and Research Centre, Bhagwant University, Ajmer

*Corresponding Author E-mail:

ABSTRACT:

The formulation and development of extended released tablet of Guaifenesin was developed. The matrix tablet was formulated of drug. The preformulation study guaifenesin with polymer were studies and HPMC was used for formulation of matrix tablet. The granules formulated for making matrix tablet were evaluated for bulk density and tapped density. The compressed matrix tablet of guaifenesin, were evaluated for weight variation, thichness, hardness, content uniformity and in vitro released studies.

KEY WORDS: Guaifenesin, extended released tablet , HPMC.

INTRODUCTION:

For many decades, pharmaceuticals have primarily consisted of simple, fast-acting chemical compounds that are dispensed orally for the treatment of an acute disease or a chronic illness and have been mostly facilitated by drugs in various pharmaceutical dosage forms, including tablets, capsules, pills, suppositories, creams, ointments, liquids, aerosols, and injections. Even today these conventional dosage forms are the primary mode of drug administration for prescription and over the counter drug products. Conventional drug formulations typically provide a prompt release of drug in a bolus form. For drugs which get cleared rapidly from the body, achieving and maintaining the drug concentration within the therapeutically effective range requires a multiple dosing regimen, often more than once a day. Such an inconvenient dosing regimen leads to lack of patient compliance as well as a significant fluctuation in drug levels in the plasma.

Recently, several technical advancements have resulted in the development of new technologies capable of controlling the administration of a drug at a targeted site in the body in an optimal concentration-versus-time profile. The term “drug delivery” covers a very broad range of techniques used to get therapeutic agents into human body. These techniques are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity, and/or targeting the delivery of drug to a tissue as described in various articles.

Need for Controlled Drug Delivery System:

The ways in which drugs or new biological products are administered have gained increasing attention in the past few decades. Controlled release systems provide numerous benefits over the conventional dosage forms. Conventional dosage forms, which are still predominant for the pharmaceutical products, are not able to control either the rate of drug delivery or the target area of drug administration and provide an immediate or rapid drug release. This necessitates frequent administration in order to maintain a therapeutic level. As a result, drug concentrations in the blood and tissues fluctuate widely (Fig. 1). The concentration of drug is initially high, that can cause toxic and/or side effects, then quickly fall down below the minimum therapeutic level with time elapse. The duration of therapeutic efficacy is dependent upon the frequency of administration, the half-life of the drug, and release rate from the dosage form. In contrast, controlled release dosage forms are not only able to maintain therapeutic levels of drug with narrow fluctuations but they also make it possible to reduce the frequency of drug administration. Drug concentration profile in serum depends on the preparation technology, which may generate different release kinetics resulting in different pharmacological and pharmacokinetic responses in the blood or tissues. Controlled drug release formulations offer several advantages over conventional dosage forms (Fig. 2).

Some of the salient features of controlled release formulations are described below.

(1) The drug is released in a controlled fashion that is most suitable for the application. The control could be in terms of onset of release (delayed vs. immediate), duration of release, and release profile itself.

(2) The frequency of doses could be reduced thereby enhancing patient compliance.

(3) The drug could be released in a targeted region. This could be achieved either by tailoring the formulation to release the drug in that particular environment or by timed release of the drug. By targeting drug release, drug efficacy could be maximized.

(4) By targeting the drug to the desired site, systemic exposure of the drug could be reduced, thereby decreasing systemic side effects (especially for toxic drugs).

(5) The drug could be protected from the physiological environment for a longer duration of time. Thus the effective residence time of the drug could be extended.

However, controlled release products do not always provide positive effects for every type of formulation design. Negative effects outweigh benefits in the following circumstances ^(10,11)

(1) Dose dumping

(2) Less accurate dose adjustment

(3) Increased potential for first-pass metabolism

(4) Dependence on residence time in gastrointestinal (GI) tract

(5) Delayed onset

The limitations of controlled drug release formulations (CDRFs) technology making some drugs unsuitable for formulations are as follows ^(12,13):

(1) There is a risk of drug accumulation in the body if the administered drug has a long half-life, causing the drug to be eliminated at a slower rate than it is absorbed.

(2) Some drugs have a narrow therapeutic index, and thus, need to administer repeatedly to maintain the serum drug level within a narrow range. Such drugs may not be feasible for CDRF.

(3) If the GI tract limits the absorption rate of the drug, the effectiveness of the CDRF is limited (for oral controlled release).

(4) If a drug undergoes extensive first-pass clearance, its controlled release formulation may suffer from lower bioavailability.

(5) The cost of CDRF may be substantially higher than the conventional form.¹

An ideal dosage regimen in the drug therapy of any disease is the one which immediately attain the desired therapeutic concentration of drug in plasma (or at the site of action) and maintains it constant for the entire duration of treatment. This is possible through administration of conventional dosage form in a particular dose and at a particular frequency. The frequency of administration or the dosing interval of any drug depends upon its half life or mean residence time (MRT) and its therapeutic index. In most cases, the dosing interval is much shorter than the half life of the drug resulting in a number of limitations associated with such a conventional dosage form.²

There are two ways to overcome such situation:

1) Delivery of new, better and safer drug with long half lives and larger therapeutic indices

2) Effective and safer use of existing drug through concepts and techniques of controlled and targeted delivery systems.

The first approach has many disadvantages therefore resulted in increased interest in second approach.

Figure 1: Graph of plasma drug concentration versus time

An ideal controlled drug delivery system is one which delivers the drug at a predetermined rate, locally or systemically, for a specified period of time. Thus, unlike conventional immediate release systems, the rate of appearance of drug in the body with such a system is not controlled by absorption process but it is controlled by the rate of release of drug from the system itself.² There are several terms used interchangeably viz. controlled release, programmed release, sustained release, prolong release, timed release, slow release, extended release and other such dosage forms. However, controlled release systems differ from the sustained release systems. Sustained release systems simply prolong the drug release and hence plasma drug level for an extended period of time (i.e. not necessarily at a predetermined rate).³

Oral administration:

Oral administration of drugs has been the most common and preferred route for delivery of most therapeutic agents. It remains the preferred route of administration investigated in the discovery and development of new drug candidates and formulations. The popularity of the oral route is attributed to patient acceptance, ease of administration, accurate dosing, cost-effective manufacturing methods, and generally improved shelf-life of the product. For many drugs and therapeutic indications, conventional multiple dosing of immediate release formulations provides satisfactory clinical performance with an appropriate balance of efficacy and safety. The rationale for development of an extended-release formulation of a drug is to enhance its therapeutic benefits, minimizing its side effects while improving the management of the diseased condition.

Clinical advantages:

Reduction in frequency of drug administration

Improved patient compliance

Reduction in drug level fluctuation in blood

Reduction in total drug usage when compared with conventional therapy

Reduction in drug accumulation with chronic therapy

Reduction in drug toxicity (local/systemic)

Stabilization of medical condition (because of more uniform drug levels)

Improvement in bioavailability of some drugs because of spatial control

Economical to the health care providers and the patient

Commercial/industrial advantages:

Illustration of innovative/technological leadership

Product life-cycle extension

Product differentiation

Market expansion

Patent extension

Potential limitations:

Delay in onset of drug action Possibility of dose dumping in the case of a poor formulation strategy Increased potential for first pass metabolism Greater dependence on GI residence time of dosage form Possibility of less accurate dose adjustment in some cases Cost per unit dose is higher when compared with conventional doses Not all drugs are suitable for formulating into ER dosage form.⁴

Principle of controlled release drug delivery:

The conventional dosage forms release their active ingredients into an absorption pool immediately. This is illustrated in the following simple kinetic scheme.

Figure 2: Schematic representation of controlled release drug delivery principle

The absorption pool represents a solution of the drug at the site of absorption and the term Kr, Ka and Ke are first order rate-constant for drug release, absorption and overall elimination respectively. Immediate drug release from a conventional dosage form implies that Kr>>>>Ka. Alternatively speaking the absorption of drug across a biological membrane is the rate-limiting step. For non immediate release dosage forms, Kr<<<Ka i.e. the release of drug from the dosage form is the rate limiting step. This causes the above kinetic scheme to reduce to the following.

Essentially, the absorptive phase of the kinetic scheme become insignificant compared to the drug release phase. Thus, the effort to develop a non immediate release delivery system must be directed primarily at altering the release rate. The main objective in designing a controlled release delivery system is to deliver drug at predetermined rate necessary to achieve and maintain a constant drug blood level. This rate should be analogous to that achieved by continuous intravenous infusion where a drug is provided to the patient at a constant rate. This implies that the rate of delivery must be independent of the amount of drug remaining in the dosage form and constant over time. It means that the drug release from the dosage form should follows zero-order kinetics, as shown by the following equation:

Kr = Rate In = Rate Out = Ke Cd

Where,

Kr: Zero-order rate constant for drug release-Amount/time

Ke: First-order rate constant for overall drug elimination-time

Cd: Desired drug level in the body – Amount/volume, and

Vd: Volume space in which the drug is distributed-Liters

The value of Ke, Cd and Vd are obtained from appropriately designed single dose pharmacokinetic study. The equation can be used to calculate the zero order release rate constant. For many drugs, however, more complex elimination kinetics and other factors affecting their disposition are involved. This affects the nature of the release kinetics necessary to maintain a constant drug blood level. It is important to recognize that while zero-order release may be desirable theoretically, non zero-order release may be equivalent clinically to constant release in many cases.⁵

Classification:

Extended Release drug delivery system can be classified into following categories;

A. Rate programmed drug delivery system

B. Activation modulated drug delivery system.

C. Feedback modulated drug delivery system.

D. Site targeting drug delivery system.

All categories consist of the following common structure features;

1. Drug reservoir compartment.

2. Rate-controlling elements.

3. Energy source

According to the mechanism of drug release, extended release formulations are classified to:

Dissolution control release system

Diffusion Controlled Release systems

Diffusion – Dissolution controlled release system

Erosion control release system

Osmotic controlled release systems

Ion-Exchange control release system ⁶

Oral ER dosage forms fall into one of the following two technologies:

1. Hydrophilic, hydrophobic or inert matrix systems: These consist of a rate controlling polymer matrix through which the drug is dissolved or dispersed.

2. Reservoir (coated) systems where drug-containing core is enclosed within a polymer coatings. Depending on the polymer used, two types of reservoir systems are considered

(a) Simple diffusion/erosion systems where a drug-containing core is enclosed within hydrophilic and/or water-insoluble polymer coatings. Drug release is achieved by diffusion of the drug through the coating or after the erosion of the polymer coating.

(b) Osmotic systems where the drug core is contained within a semi- permeable polymer membrane with a mechanical/laser drilled hole for drug delivery. Drug release is achieved by osmotic pressure generated within the tablet core. Polymers commonly studied for fabrication of extended release monolithic matrices

Hydrophilic polymers:

(A) Cellulosic:

Methylcellulose

Hypromellose (Hydroxypropylmethylcellulose, HPMC)

Hydroxypropylcellulose (HPC)

Hydroxyethylcellulose (HEC)

Sodium carboxymethylcellulose (Na-CMC)

(B) Noncellulosic:

(1) gums/polysaccharides

Sodium alginate

Xanthan gum

Carrageenan

Ceratonia (locust bean gum)

Chitosan

Guar gum

Pectin

Cross-linked high amylose starch

(2) others

Polyethylene oxide

Homopolymers and copolymers of acrylic acid

(C) Water-insoluble and hydrophobic polymers

Ethylcellulose

Hypromellose acetate succinate

Cellulose acetate

Cellulose acetate propionate

Methycrylic acid copolymers

Poly(vinyl acetate)

(D) Fatty acids/alcohols/waxes

Bees’ wax

Carnauba wax

Candelilla wax

Paraffin waxes

Cetyl alcohol

Stearyl alcohol

Glyceryl behenate

Glyceryl monooleate, monosterate, palmitostearate

Hydrogenated vegetable oil

Hydrogenated palm oil

Hydrogenated cottonseed oil

Hydrogenated castor oil

Hydrogenated soybean oil

Factors influencing the drug release from matrix:⁷

1) Choice of matrix material.

2) Amount of drug incorporated in the matrix.

3) Viscosity of the hydrophilic material in aqueous system at a fixed concentration.

4) Drug: matrix ratio

5) Tablet hardness, porosity, and density variation.

6) Entrapped air in tablets.

7) Tablet shape and size.

8) Drug particle size.

9) Solubility of drug in aqueous phase

Patented technologies:

Several patented technologies are available for modified release drug delivery system, some of them are

1. Port technology

2. Flamel technology

3. Microchip technology for delivery of insulin

4. DUROS Technology

Port technology:⁸

Port stands for programmable oral release technologies that use a unique coated in capsulated system with opportunity to provide multiple program release of drug. Port technologies offer significant flexibility in obtaining unique and desirable release profile to maximize pharmacological and therapeutic effect.

Figure 3: Drug release mechanism from the Port tablet

Flamel micropump technology:⁹

Flamel micropump technology, a controlled release system which permits delayed and extended delivery of small molecule drugs.

Description:

Flamel micropump technology consists of a multiple microparticles per capsule or tablet. The 200-500 mm diameter size microform in the stomach and pass into the small intestine, where each micro particle release the drug by osmotic pump at a adjustable rate and over extended period of transit of time.

Figure 4: Flamel micropump technology

Microchip technologies for delivery of insulin:¹⁰

Researchers are working hard to develop an implantable insulin pump that can measure blood sugar levels and deliver the exact amount of insulin needed. This would make it possible to mimic the action of natural insulin delivery. Scientists are making progress with an implantable capsule that continuously produces insulin and release it to the blood stream. The capsules developers have also overcome biocompatibility problems using microchip technologies. They have succeed in creating a capsule that won’t be an attacked by destroyers of body’s immune system.

DUROS technology:¹¹

The DUROS technology is the miniature drug dispensing system that opposite like a miniature syringe and deliver minute quantity of concentrated form in a continuous and consistent manner over months or year. The system consists of an outer cylindrical titanium alloy reservoir. This reservoir has high impact strength and protects the drug molecules from enzymes, body mostres and cellular components that might deactivate the drug prepare to deliver.

Figure 5: DUROS technology

Factors influencing oral sustained release dosage form design:¹²

The design of controlled - release delivery systems is subject to several variables of considerable importance. Among these are the route of drug delivery, the type of delivery system, the disease being treated, the patient, the length of therapy and the properties of the drug. Each of these variables are interrelated and this imposes certain constrains upon choices for the route of delivery, the design of the delivery system and the length of therapy. Properties of drugs mainly physicochemical and biological properties are very important for designing a sustained release dosage form of the drug.

Effect of variables on extended-release matrix tablets:¹²

1.6.1. Effect of formulation variables:

• Drug particle size

• Drug solubility

• Polymer - particle size

• Polymer type

• Polymer amount

• Filler excipient

• pH modifiers

Effect of process variables:

• Compression force

• Tablet shape

• Tablet size

Criteria of drugs for CR formulations:

There are certain properties of the drug, which must be considered for the design of CR dosage forms.

• Solubility and permeability of drugs: High solubility and high permeability (best case for CR), Low solubility and low permeability (worst case for CR). Permeability coefficient: P< 0.5 x 10-6 mms-1 not suitable for CR dosage form.

• Location of major absorption sites or specificity at the site of absorption

• Biological half-life (between 2-6 hr to avoid accumulation in the body)

• Inactivation or metabolism of the drug in the body, including gut metabolism

• Effect of food and/or drugs likely to be used concurrently and physiological factors such as renal or hepatic function on the absorption, distribution, metabolism and excretion of the drug, Effect of age, sex and smoking.

• A drug with biological half-life of between 2-6 hr is preferred for inclusion in CR dosage form to avoid accumulation in the body. CR formulation of drugs with long half-life does not offer any advantage.

What is cough?¹³:

Cough is a sudden and often repetitively occurring reflex which helps to clear the large breathing passages from secretions, irritants, foreign particles and microbes. The cough reflex consists of three phases: an inhalation, a forced exhalation against a closed glottis, and a violent release of air from the lungs following opening of the glottis, usually accompanied by a distinctive sound. Coughing can happen voluntarily as well as involuntarily. Frequent coughing usually indicates the presence of a disease. Many viruses and bacteria benefit evolutionarily by causing the host to cough, which helps to spread the disease to new hosts. Most of the time, coughing is caused by a respiratory tract infection but can be triggered by choking, smoking, air pollution,[ asthma, gastroesophageal reflux disease, post-nasal drip, chronic bronchitis, lung tumors, heart failure and medications such as ACE inhibitors.

What are the signs and symptoms of cough?¹⁴

Common cough symptoms include:

A cough may be dry or produce mucus. The mucus may be think and white or thick and colored brown or yellow. In some cases, a cough may produce blood-streaked mucus. Commonly associated symptoms are fever, chest wall pain, wheezing, sinus congestion, and breathing difficulty.

(1) Fever : Fever is a common medical sign characterized by an elevation of temperature above the normal range of 36.5–37.5 °C (98–100 °F) due to an increase in the body temperature regulatory set-point.

(2) A wheeze (formally called "sibilant rhonchi" in medical terminology) is a continuous, coarse, whistling sound produced in the respiratory airways during breathing.

Factor influencing the delivery and expression of cough:

Host factors

1) Genetic

2) Obesity

3) Sex

Environmental factors:

1) Allergens

2) Infections (Predominantly viral)

3) Occupational sensitizers

4) Tobacco smoke

5) Outdoor/indoor Air Pollution

6) Diet.

Expectorant:¹⁵

Expectorants are drugs that loosen and clear mucus and phlegm from the respiratory tract.

Mechanism of action:

Expectorants mainly act by two ways:

(1) Direct stimulation

(2) Reflex stimulation

Final Result: Thinner mucus that is easier to remove:

(1) Direct stimulation: The secretary glands are stimulated directly to increase their production of respiratory tract fluids. Examples: Iodinated glycerol, Potassium iodide.

(2) Reflex stimulation: Agents causes irritation of the GI tract.

Loosening and thinning of respiratory tract secretions occur in response to this irritation. Examples: Guaiphenesin

Common expectorants:¹⁶

Following the standard convention of medicine, the capitalized brand name is followed by the lowercased generic name in parentheses.

(1) Anti-Tuss

(2) Glycodex

(3) Hytuss

(4) Mucinex

(5) Mucostop

(6) Ritussin

(7) Resil

(8) Tenntuss

(9) Tolyn

(10) Uni-Tussin

Review of literature:

In 2007, Draganoiu et al developed an extended release tablet of Guaifenesin using Carbopol® polymer by using inter and extra granular process. Carbopol® polymers can be processed by direct compression, wet or dry granulation or mixing process. They used Carbopol® 971P NF (powder grade) and Carbopol® 71G NF polymer.¹⁷

In 2008, Lakade et al developed sustained release tablet using hydrophilic and hydrophobic polymer which can release the drug upto 24 hrs in predetermined rate. They used Xanthan gum, Guar gum, HPMC, PVP, Ethyl cellulose as rate controlling polymer.¹⁸

In 2010, Kumar et al developed Guaifenesin bilayer tablet using superdisintegrant MCC and sodium starch glycolate for the fast release layer and metalose 90 SH and carbopol 934 for the sustaining layer. The granules were evaluated for the bulk density, tapped density, angle of repose, Carr’s index and Hausners ratio. The prepared bilayer tablets were evaluated for weight variation, hardness, friability, drug content and in vitro drug release.¹⁹

Kadam et al developed an extended release tablet of Guaifenesin using coprocessed excipient using wet granulation method. The drug release behavior of the system containing coprocessed excipient, physical admixture and each material separately was investigated. was used as method for coprocessing. The effect of coprocessed polymer variables such as concentration of polymer, different proportions of polymers, change of viscosity of one polymer used in a combination was studied on the developed formulations. The characterization of coprocessed was done by microscopy, DSC and IR spectroscopy for identification and comparison to confirm any change in the chemical and physical form of the polymers post coprocessing. Analytical method was developed and optimized formulation was evaluated for stability studies and drug release mechanism.²⁰

J. R. D. Gupta et al., 2009 Matrix type transdermal patches containing glibenclamide were prepared using three different polymers by solvent evaporation technique. Aluminium foil cup method was used as a substate. Polyethylene glycol (PEG) 400 was used as plastisizer and dimethyl sulfoxide (DMSO) was used as penetration enhancer. The physicochemical parameter like weight variation, thickness, folding endurance, drug content,% moisture loss were evaluated in vitro drug releases studies and skin permeation studies were carried out using Franz diffusion cell. Cumulative amount of released in 12 hours from the six formulations were 55.467, 52.633, 47.157, 53.394, 49.139 and 45.597% respectively. The corresponding values for cumulative amount of drug permeated for the said formulation were 43.013, 40.429, 37.793, 41.522, 37.450 and 34.656% respectively. On the basis of invitro drug release and skin permeation performance, formulation HP-1 was found to be better than other formulation and it was selected as the optimised formulation.

Evrim Atilay Takmaz et al., 2009 The purpose of this study was to investigate physicochemical characteristics and in vitro release of zidovudine from monolithic film of Eudragit RL 100 and ethyl cellulose. Films included 2.5% or 5% (w/w) zidovudine of the dry polymer weight was prepared in various ratios of polymers by solvent evaporation method from methanol/acetone solvent mixture. The release studies were carried out by vertical Franz cells (2.2 cm2 area, 20 ml receptor fluid). Ex vivo studies were done on Wistar rat skin within the films F6 (Eudragit RL100) and F7 (Eudragit RL100/Ethylcellulose, 1:1) consisting 5% (w/w) zidovudine in comparison with the same amount of free drug. Either iontophoresis (0.1 and 0.5 mA/cm2 direct currents, Ag/AgCl electrodes) or dimethyl sulfoxide (pretreatment of 1% and 5%, w/w, solutions) were used as enhancers. Films consisting of ethyl cellulose under the ratio of 50% (w/w) gave similar release profiles, and the highest in vitro cumulative released amount was achieved with F6 film which gave the closest results with the free drug. This result could be due to the high swelling capacity and recrystallization inhibition effect of RL 100 polymer which also influenced the film homogenization. All the films were fitted to Higuchi release kinetics. It was also observed that both 0.5-mA/cm2 current and 5% (w/w) dimethyl sulfoxide applications significantly increased the cumulative permeated amount of zidovudine after 8 h; however, the flux enhancement ratio was higher for 0.5-mA/cm2 current application, especially within F6 film. Thus, it was concluded that Eudragit RL100 film (F6) could be further evaluated for the transdermal application of zidovudine.

Yogeshwar G et al., 2009, The objective of the present investigation was to develop and evaluate microemulsion based gel for the vaginal delivery of fluconazole (FLZ). The solubility of FLZ in oils and surfactants was evaluated to identify components of the microemulsion. The ternary diagram was plotted to identify the area of microemulsion existence. Various gelling agents were evaluated for their potential to gel the FLZ microemulsion without affecting its structure. The bioadhesive potential and anti-fungal activity of the FLZ microemulsion basedgel (FLZ-MBG) was determined in comparison to the marketed clotrimazole gel (Candid V® gel) by in vitro methods. The vaginal irritation potential of the FLZ-MBG was evaluated in rabbits. The clinical efficacy of the FLZ-MBG and Candid V® gel was evaluated in females suffering from vaginal candidiasis. The FLZ microemulsion exhibited globule size of 24nm and polydispersity index of 0.98. Carbopol® ETD 2020 could successfully gel the FLZ microemulsion without disturbing the structure. The FLZ-MBG showed significantly higher (P < 0.05) in vitro bioadhesion and anti-fungal activity as compared to that of Candid V® gel. The FLZ-MBG did not show any signs of vaginal irritation in the rabbits. The small-scale clinical studies indicated that the FLZ-MBG shows faster onset of action than Candid V® gel although no difference was observed in the clinical efficacy.

Magdum Chandrakant S et al., 2009 A fluconazole w/o microemulsion was developed for topical application using isopropyl myristate as the oil phase. Pseudoternary phase diagrams were constructed to determine the microemulsion existence region using surfactant (tween 80) and co-surfactant (polyethylene glycol 400). Different formulations were prepared to evaluate the effect of oil content, surfactant/co-surfactant concentration on in-vitro permeation rates. In-vitro transdermal permeability of fluconazole from the microemulsions was evaluated using Keshary -Chien diffusion cells mounted with 0.45μ cellulose acetate membrane. The amount of fluconazole permeated was analyzed by HPLC. The permeability of the fluconazole incorporated into the micro emulsion systems was 2.5 - fold higher than that of the marketed formulation. These results indicate that the micro emulsion system studied is a promising tool for the percutaneous delivery of fluconazole. Vinay P et al., 2009 Overactive bladder is a chronic, and distressing medical condition characterized by urinary urgency and frequency, with or without urge incontinence, that often requires long term treatment to maintain control of symptoms. Tolterodine tartarate is an anti cholinergic drug used to treat overactive bladder. The suitability of drug with respect to lower dose, solubility, lower molecular weight and short half-life makes this drug as a suitable candidate for administration by transdermal route. A number of polymers such as HPMC, Carbopol-934P, and Ethyl cellulose were employed alone and in combination for the preparation of transdermal films. The films were casted using solvent casting technique. Solutions containing polymer at different concentrations (2%, 3%, 4%, w/w) and a plasticizer (propylene glycol) at various concentrations (20%, 30%, 40%, w/w) were prepared.

These solutions were then used to prepare films. Prepared films were then evaluated for various physicochemical properties like physical appearance, weight variation, thickness, drug content, folding endurance and percentage elongation, including in-vitro release study. Among the various polymers examined result show’s that the combination of HPMC: carbopol-934P (3:1) with 30% propylene glycol (PG), films formed were very flexible, with high folding endurance and uniform drug content. Further permeation study showed 68.72% and 81.12% release across the rat abdominal skin and cellophane membrane respectively for 12 hours. Thus it may be concluded that transdermal films are a promising drug delivery system for Tolterodine tartarate with more patient compliance in the treatment of overactive bladder. Kevin C. Garala et al., 2009 In the present work, monolithic matrix transdermal systems containing tramadol HCl were prepared using various ratios of the polymer blends of hydroxy propyl methyl cellulose (HPMC) and Eudragit S 100 (ES) with triethyl citrate as a plasticizer.

A 32 full factorial design was employed. The concentration of HPMC and ES were used as independent variables, while percentage drug release was selected as dependent variable. Physical evaluation was performed such as moisture content, moisture uptake, tensile strength, flatness and folding endurance. In-vitro diffusion studies were performed using cellulose acetate membrane (pore size 0.45 μ) in a Franz’s diffusion cell. The concentration of diffused drug was measured using UV-visible spectrophotometer (Jasco V-530) at λ max 272 nm. The experimental results shows that the transdermal drug delivery system (TDDS) containing ES in higher proportion gives sustained the release of drug. Hemangi J. Patel et al., 2009 Matrix type Transdermal drug delivery system of Amlodipine besilate, an antihypertensive drug were prepared using different polymers like Carbopol 934, 940, Hydroxy Propyl Methyl Cellulose and Eudragit L100 in varied ratios. The present study aims to formulate and evaluate Transdermal drug delivery for sustained release of Amlodipine besilate. Physicochemical parameters were characterized. The permeability studies indicate that the drug is suitable for Transdermal drug delivery. The patches were evaluated for various parameters like Thickness, Water-Vapor Permeability, Tensile Strength, Drug Content, Diffusion and Dissolution studies. The patches were further evaluated by DSC and SEM, to ensure uniform distribution of the drug and compatibility of drug with polymer. The Optimized formulation containing Carbopol 934: Eudragit L100 (3:7), with enhancer Hyaluronidase showed 84% drug release after 24 hours. Higuchi and Peppa’s models were used for optimizing the formulation.

Hemangi J. Patel et al., 2009 Ketotifen fumarate is almost completely absorbed from the gastro-intestinal tract following oral administration, but bioavailability is reported to be only about 50% due to hepatic first-pass metabolism. The present study aims to prepare Transdermal patch for Ketotifen fumarate as asthmatic drug. Preparation of standard curve for Ketotifen fumarate in solution of 20% w/v PEG 400 in normal saline. Preparation of transdermal patches of Ketotifen fumarate using polymers : Eudragit L-100 and Ethyl cellulose in combination with Hydroxypropyl methyl cellulose, plasticized with polyethylene glycol 400. The patches were evaluated for various parameters like Thickness, Water-Vapor Permeability, Tensile Strength, Drug Content, Diffusion and Dissolution studies. Prepared patches exhibited Zero Order Kinetics and the permeation profile was matrix diffusion type.

Soad A. Yehia et al., 2008 Two groups of fluconazole mucoadhesive buccal discs were prepared: (a) Fluconazole buccal discs prepared by direct compression containing bioadhesive polymers, namely, Carbopol 974p (Cp), sodium carboxymethyl cellulose (SCMC), or sodium alginate (SALG) in combination with HPMC (HPMC) or hydroxyethyl cellulose (HEC). (b) Fluconazole buccal discs prepared by freeze drying containing different polymer combinations (SCMC/HPMC, Cp/HPMC, SALG/HPMC, and chitosan/SALG). The prepared discs were evaluated by investigating their release pattern, swelling capacity, mucoadhesion properties, and in vitro adhesion time. In vivo evaluation of the buccal disc and in vivo residence times were also performed. Fluconazole salivary concentration after application of fluconazole buccal systems to four healthy volunteers was determined using microbiological assay and high-performance liquid chromatography. SCMC/HPMC buccal disc prepared by direct compression could be considered comparatively superior mucoadhesive disc regarding its in vitro adhesion time, in vivo residence time, and in vitro/in vivo release rates of the drug. Determination of the amount of drug released in saliva after application of the selected fluconazole disc confirmed the ability of the disc to deliver the drug over a period of approximately 5 h and to reduce side effects and possibility of drug interaction encountered during systemic therapy of fluconazole, which would be beneficial in the case of oral candidiasis.

Ashok R et al., 2008 the present investigation was aimed to evaluate the possibility of using different concentrations and polymeric grades of HPMC (K4M, K15M and K100M) for transdermal delivery of methotrexate, an immunosuppressant drug for rheumatoid arthritis. The matrix films were evaluated for their physicochemical characterization followed by in vitro and in vivo evaluation. Selected formulations were subjected for their in vivo studies on healthy rabbits following balanced incomplete block design. The relevance of difference in the in vitro dissolution rate profile and pharmacokinetic parameters (C_max, t_max, AUC(s), t1 / 2, Kel, and MRT) were e valuated statistically. The thickness and weight of the patch increased with the increase in polymeric grade and content. Fourier transform infrared spectroscopy and differential scanning calorimetry results confirm that there is no interaction between drug and polymer u sed. X-ray diffraction study reveals an amorphous state of drug in the matrix films.

The in vitro drug release followed Higuchi kinetics (r=0.972 997; p<0.001) as its coefficient of correlation values predominates over zero order and first order release kinetics. In vitro dissolution profiles and pharmacokinetic parameters showed a significant difference between test products (p< 0.01), but not within test products. A quantitatively good correlation was found between per cent of drug absorbed from the transdermal patches and AUC (s) .A significant in vitro/in vivo correlation was observed when percent drug released was correlated with serum drug concentration. Out of the various formulations made, the selected formulations are better in their in vitro dissolution and pharmacokinetic characteristics and thus hold potential for transdermal delivery. Ramesh Gannu et al., 2007 The matrix type TDDS of NTDP were prepared by solvent evaporation technique. Ten formulations (composed of Eudragit RL 100 and Hydroxypropylmethyl cellulose in the ratios of 5:0, 4:1, 3:2, 2:3, 1:4 in formulations A1, A2, A3, A4, A5 and Eudragit RS 100 and Hydroxypropylmethyl cellulose in the same ratios in formulation B1, B2, B3, B4, B5 respectively) were prepared. All formulations carried 6 % v/w of carvone as penetration enhancer and 15%v/w of propylene glycol as plasticizer in dichloromethane and methanol as solvent system. The prepared TDDS were evaluated for in vitro release, ex vivo permeation, moisture absorption, and moisture content and mechanical properties. The physicochemical interactions between nitrendipine and polymers were investigated by Fourier Transform Infrared (FTIR) Spectroscopy. The maximum drug release in 24 hrs for A series formulations was 89.29% (A4) and 86.17% for B series (B5), which are significantly (p < 0.01) different to the lowest values (57.58 for A1 and 50.64 for B1). Again formulations A4 (flux 23.51 μg/hr/cm2) and B5 (flux 22.98 μg/hr/cm2) showed maximum skin permeation in the respective series. The flux obtained with formulation A4 and B5 meets the required flux (19.10 μg/hr/cm2). The mechanical properties, tensile strength, elastic modulus (3.42 kg/mm2 for A4 and 4.25 kg/mm2 for B5) reveal that the formulations were found to be strong but not brittle. FTIR studies did not show any evidence of interaction between the drug and the polymers. Nitrendipine matrix type transdermal therapeutic systems could be prepared with the required flux having suitable mechanical properties.

Mohamed Aqil et al., 2003 The monolithic matrix type transdermal drug delivery system of metoprolol tartrate were prepared by the film casting on a mercury substrate and characterised in vitro by drug release studies, skin permeation studies and drug-excipients interaction analysis. Four formulations were developed, which differed in the ratio of matrix--forming polymers. Formulations MT-1, MT-2, MT-3 and MT-4 were composed of Eudragit RL-100 and polyvinyl pyrrolidone K-30 with the following ratios: 2:8, 4:6, 6:4 and 8:2, respectively. All the four formulations carried 10% (m/m) of metoprolol tartrate, 5% (m/m) of PEG-400 and 5% (m/m) of dimethyl sulfoxide in isopropyl alcohol:dichloromethane (40:60). Cumulative amounts of the drug released in 48 hours from the four formulations were 61.5, 75.4, 84.3 and 94.5%, respectively. The corresponding values for cumulative amounts of the permeated drug for the said formulations were 53.5, 62.5, 69.8 and 78.2%. On the basis of in vitro drug release and skin permeation performance, formulation MT-4 was found to be better than the other three formulations and it was selected as the optimized formulation.

M. Aqil et al., 2002 The monolithic matrix type transdermal drug delivery systems of pinacidil monohydrate (PM) were prepared by film casting technique on mercury substrate and characterised in vitro by drug release studies using paddle over disc assembly, skin permeation studies using Keshary and Chein diffusion cell on albino rat skin and drug-excipient interaction analysis. Four formulations were developed which differed in the ratio of matrix forming polymers, Eudragit RL-100 and PVP K-30, i.e. 8:2, 4:6, 2:8 and 6:4 and were coded as B-1, B-2, B-3 and B-4, respectively. All the four formulations carried 20% w/w of PM, 5% w/w of plasticiser, PEG-400 and 5% w/w of DMSO (based on total polymer weight) in isopropyl alcohol: dichloromethane (40:60) solvent system. Cumulative % of drug released in 48 h from the four formulations was 63.96, 55.95, 52.26 and 92.18%. The corresponding values for cumulative amount of drug permeated for the said formulations were 57.28, 50.35, 46.38 and 86.54%, respectively. On the basis of in vitro drug release and skin permeation performance, formulation B-4 was found to be better than the other three formulations and it was selected as the optimised formulation. The interaction studies carried out by comparing the results of assay, ultraviolet, infrared and TLC analyses for the pure drug, medicated and placebo formulations indicated no chemical interaction between the drug and excipients.

Ashok R et al., 2002 A matrix dispersion type transdermal delivery system of tramadol was designed and developed using different concentrations and polymeric grades of Hydroxypropyl Methylcellulose (HPMC K4M, K15M and K100M). Formulations were selected on the basis of their drug release content and release pattern. Films were evaluated for their physicochemical characteristics, followed by in vitro and in vivo evaluation. The possible drug-polymer interaction was studied by FTIR, DSC and X-RD studies. These were evaluated for in vitro dissolution characteristic using Cygnus' sandwich patch holder. The drug release followed Higuchi kinetics (r = 0.979-998; P < 0.001). In vivo evaluation was carried out on healthy rabbits of either sex, following balanced incomplete block design. The in vitro dissolution rate constant, dissolution half life and pharmacokinetic parameters generated from plasma (t_max, C_max, AUC(s), t1/2, Kel, and MRT) were evaluated statistically by two-way ANOVA. Statistically a good correlation was found between percent of drug absorbed from patches versus AUCs. Percent of drug dissolved at a given time versus plasma drug concentration correlated statistically. The results of this study indicate that the polymeric matrix type transdermal films of tramadol hold potential for transdermal delivery on the basis of their in vitro and pharmacokinetic results. Narasimha S Murthy et al., 2002 Transdermal formulations containing theophylline and salbutamol sulphate were formulated using hydroxy propyl methyl cellulose. Theophylline was loaded by adsorption with the aid of co-adsorbate, sodium chloride. The formulations were subjected to in vitro release studies and the dose of salbutamol and theophylline were optimized to yield the desired flux. The films were uniform and of 200±40 micron thickness. The in vitro flux of theophylline and salbutamol sulphate from the formulation was 1.22±0.4 mg/hr/sq.cm and 13.36±1.02 mcg/hr/sq.cm respectively. The formulation was subjected for pharmacodynamic studies in guinea pigs. The PCT of guinea pigs increased significantly after 4th hour the same was observed even after 24 hours. Pharmacokinetic studies were carried out in healthy human volunteers. Theophylline was analyzed in saliva and salbutamol in the blood plasma. The T_max of the drugs was 3 hours and appreciable concentrations of the drugs above their MEC could be analysed even after 12 hours. The half-lives of the drugs were significantly prolonged compared to tablets. There was no sign of erythema or oedema in volunteers on observation for a period of 7 days.

Verma P.R. et al 2000 To improve bioavailability and achieve a smoother plasma-concentration profile as compared with oral administration, a matrix-dispersion-type transdermal delivery system was designed and developed for propranolol using different ratios of HPMC (HPMC) K4M, K15M and K100M. Formulations were evaluated for in-vitro dissolution characteristics using a Cygnus’ sandwich-patch holder. Drug release followed Higuchi rather than zero-order or first-order kinetics. In-vivo evaluation was carried out on healthy volunteers (21±1•41 years; 60•89±5•35 kg) following the balanced incomplete block design. The dissolution rate constant (k) and data generated from plasma and urine (C_max, maximum plasma concentration; t_max, time to reach peak plasma concentration; AUC, area under the curve; ke, elimination rate constant; t½e, elimination half-life; ka, absorption rate constant; t½a, absorption half-life) were evaluated statistically by two-way analysis of variance. Statistically excellent correlation was found between the percentage of drug absorbed and C_max, AUC0–24 and AUC 0–∞. A highly significant difference (P<0•001) was observed when C_max and AUC0–∞ generated from plasma and urine were compared, but ke, t½e, ka and t½a did not differ significantly (P>0•1). We conclude that urinary excretion data may be used as a simpler alternative to blood level data in studying the kinetics of absorption and deriving the absorption parameters.

Girish K. Jain et al., 1996 Rapid permeation of verapamil hydrochloride (VHC1) across the skin using finite dose loading is documented. Transdermal drug delivery (TDD) systems of VHCI using hydrophilic polymers -- polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) and different concentrations of an enhancer, d-limonene were developed. In-vitro permeation profiles across the guinea-pig dorsal and human cadaver skins using a Keshary-Chien diffusion cell are reported. The permeation rate was enhanced and followed approximately zero order kinetics. Carol Braun Trapnell et al., Fluconazole significantly increased the plasma concentrations of both rifabutin and LM565. Mean increases in the area under the plasma concentration curve compared with the time curve over a 24-hour dosing interval were 82% (5442 ± 2404 ng • h/mL compared with 3025 ± 1117 ng • h/mL; P ≤ 0.05) for rifabutin and 216% (959 ± 529 ng • h/mL compared with 244 ± 141 ng • h/mL; P ≤ 0.05) for LM565. Fluconazole significantly increases the systemic exposure of both rifabutin and LM565.

This pharmacokinetic interaction offers a mechanism that may explain the changes reported in both the efficacy and toxicity of rifabutin with concomitant fluconazole therapy. Chemoprophylaxis for opportunistic infections associated with the human immunodeficiency virus (HIV) is increasingly common; clinical studies support the administration of drugs to prevent Pneumocystis carinii pneumonia, disseminated Mycobacterium avium complex infection, cytomegalovirus infection, and fungal infections. Because these agents are often administered concurrently in patients infected with HIV, many questions have been raised about the pharmacokinetic or pharmacodynamic consequences of the drug–drug interactions that may occur. Such interactions may also confound our understanding of the outcomes seen in large clinical trials. Two drugs that are often used concurrently in patients infected with HIV are rifabutin, for the prevention of M. avium complex bacteremia, and fluconazole, for the prevention of fungal infections. Rifabutin is an antimicrobial agent similar in structure to rifampin. Fluconazole, which is used to treat cryptococcal meningitis and oropharyngeal and esophageal candidiasis, has been reported to be effective for the primary prevention of deep and superficial fungal infections in HIV-infected patients whose CD4 lymphocyte counts are less than 50 cells/mm³.

Fluconazole and a related azole, ketoconazole, are potent inhibitors of hepatic microsomal enzymes, especially the cytochrome p450 3A group. Inhibition of these enzymes has, in turn, been shown to cause clinically significant increases in circulating levels of concomitant drugs that are metabolized by these enzymes. Our study was designed to assess a possible mechanism for the changes observed in the toxicity and efficacy of rifabutin with concomitant fluconazole therapy. We report the results of a steady-state pharmacokinetic and safety study of rifabutin and fluconazole during concurrent zidovudine therapy in HIV-infected persons. Ashok R et al., The present study aimed to develop hydroxypropyl methylcellulose based transdermal delivery of pentazocine. In formulations containing lower proportions of polymer, the drug released followed the Higuchi kinetics while, with an increase in polymer content, it followed the zero-order release kinetics. Release exponent (n) values imply that the release of pentazocine from matrices was non-Fickian. FT-IR, DSC and XRD studies indicated no interaction between drug and polymer. The in vitro dissolution rate constant, dissolution half-life and pharmacokinetic parameters (C_max, t_max, AUC(s), t1/2, Kel, and MRT) were evaluated statistically by two-way ANOVA. A significant difference was observed between but not within the tested products. Statistically, a good correlation was found between per cent of drug absorbed from patches vs. C_max and AUC(s). A good correlation was also observed when per cent drug released wascorrelated with the blood drug concentration obtained at the same time point. The results of this study indicate that the polymeric matrix films of pentazocine hold potential for transdermal drug delivery.

Rationale of research work:

Developing oral controlled release tablets for water soluble drugs with constant release rate has always been a challenge to the pharmaceutical technologist. Most of these water soluble drugs if not formulated properly, may readily release the drug at a faster rate and produce a toxic concentration of drug on oral administration. Hence it is a challenging task to formulate a suitable tablet dosage form for prolonged deliver y of water soluble drugs.²¹

The concentration of a drug in the blood fluctuates over successive doses of most conventional single unit oral dosage forms. The main reason for this is that the drug is released immediately after administration (i.e. burst release effect). This causes the drug blood concentration to rise quickly to a high value (“peak”) followed by a sudden decrease to a very low level (“trough”) as a result of drug elimination. One way of addressing this problem is by means of formulating dosage forms with sustained release profiles over an extended period of time. The ideal drug deliver y system would keep the drug blood plasma level constant over the entire treatment period after administration of a single dose. Guaifenesin is an expectorant. It is thought to act as an expectorant by increasing the volume and reducing the viscosity of secretions in the trachea and bronchi. Thus, it may increase the efficiency of the cough reflex and facilitate removal of the secretions. Guaifenesin is commercially available as Capsule, Elixir, Syrup and Solution which require two or three times a day dosing. It is also available in extended release dosage form. Fast acting dosage forms leads to patient noncompliance and fluctuation in plasma concentration. To overcome this extended release dosage form is better choice. It is desirable in the therapeutic and prophylactic treatment of diseases to provide the Guaifenesin in extended release form. Extended release dosage forms can increase patient compliance due to reduction in frequency of dosing. They may also reduce the severity and frequency of side effects as they typically maintain substantially constant plasma levels. Hence the current research work is carried out to develop pharmaceutical equivalent extended release dosage form in comparison with innovator product. The most commonly used method of modulating the drug release is to include it in a matrix system. Diffusion controlled polymeric matrix devices have been widely used as drug delivery systems owing to their flexibility to obtain a desirable drug release profile, less chance of dose dumping, cost effectiveness and broad regulatory acceptance. The controlled drug-delivery systems are useful to increase the retention time of the drug-delivery systems for more than conventional dosage forms.²²

Objectives:

Guaifenesin was currently being investigated in the treatment of cough. Extended release tablet will be designed as a

1) Matrix tablet or

2) Matrix tablet coated with modified release polymer or

3) Immediate release tablet coated with modified release polymer.

The formulation has been designed to ensure a gradual rise in blood levels of Guaifenesin. It is anticipated that it will provide smoother plasma levels compared with IR Expectorant formulations with minimized peak to trough variability over a 24 hr period and could, therefore, be associated with a reduced risk of adverse effects and improved tolerability.

Aim of research work:

To develop Pharmaceutically equivalent product with the innovator.”

Plan of work:

Literature survey.

Characteristic of active pharmaceutical ingredient and selection of excipients.

Preformulation studies.

Innovator characterization.

Analytical method development

Evaluation of powder blend (Granulometry study)

Bulk Density

Tapped Density

Carr’s index

Hausner’s ratio

Sieve analysis

Manufacturing of matrix tablets.

Evaluation of matrix tablets for,

Thickness

Hardness

Friability

Weight variation

Assay

In-vitro dissolution studies

Stability study of selected formulation.

Results.

Discussion.

Conclusion and summary.

EXPERIMENTAL WORK:

Materials Used:

Table 1:

Sr No.	Name of Chemical	Mfg. / Supplier	Function
1	Guaifenesin	Pan Drugs	API
2	Hydroxypropyl methylcellulose	Colorcon	Rate controlling polymer
3	Carbomer	Carbomer Inc.	Rate controlling polymer
4	Alginic acid	FMC Biopolymer	Rate controlling polymer
5	Colloidal Silicon Dioxide	Evonik Industries	Glidant
6	Povidone	Alembic Limited	Binder
7	Purified water	Alembic Limited	Solvent
8	Talc	Alembic Limited	Anti adherant
9	Magnesium stearate	Alembic Limited	Lubricant

Povidone (Plasdone K-30) was selected as the binder owing to its higher viscosity which helps in the formulation to give strong binding and further it also acts as a channel forming agent. Magnesium Stearate added to the formulation to make the compression process hassle free as this aid in flow of the granules.

Talc was added to the formulation to lubricate the blend prepared so it aid in the flow of the granules.

Linearity of Guaifenesin in pH 6.8 Buffer:

Instrumentation Conditions: Wavelength :

274 nm Preparation of Stock and Standard Solutions: A stock solution of Guaifenesin (100 µ g/ml) was prepared by accurately weighing approximately 10 mg of Guaifenesin into a 100 ml A-grade volumetric flask and making up to volume with double distilled water. Linearity: A calibration curve was constructed from ten non-zero samples covering the total range of 0-25 µ g/ml. The peak area was plotted versus the concentration in Table 3 and curve in Figure 6

Equipment Used:

Table 2:

Sr No.	Name of Equipment	Mfg. / Supplier
1	Weighing balance	Mettler Toledo
2	Mechanical stirrer	Remi motors ltd.
3	Rapid mixer granulator	Saral industries
4	Rapid dryer	Retsch
5	Halogen moisture balance	Mettler Toledo
6	Multi mill	Shakti engg.
7	Conta blender	Gansons
8	Compression machine	Cadmach
9	Vernier calipers(digital)	Mitutoyo
10	Hardness tester	Dr. schleuniger
11	Disintegration test apparatus	Electrolab
12	Friability tester	Electrolab
13	B.D and T.D. apparatus	Electrolab
14	Dissolution test apparatus	Vankel
15	H.P.L.C.	Shimadzu

Linearity in pH 6.8 Buffer:

Table 3:

Final Conc. In ppm	Absorbance
0	0.000
5	0.015
10	0.029
15	0.045
20	0.058
25	0.075

Linearity Curve:

y = 336.26 x + 0.058, R2 = 0.9996

Preformulation Study:²³

Pre-formulation is a branch of pharmaceutical sciences that utilizes biopharmaceutical principles in the determination of physicochemical properties of a drug substance. The goal of pre-formulation studies is to choose the correct form of the drug pre-requisite for formulation. Therefore, in pre-formulation substance, evaluate its physical properties and generate a thorough understanding of the material's stability under various conditions, leading to the optimal drug delivery system. The pre-formulation study focuses on the physicochemical parameters that could affect the development of efficacious dosage form. A thorough understanding of these properties may ultimately provide a rationale for formulation design. Also it will help in minimizing problems in later stages of drug development, reducing drug development costs and decreasing product's time to market.

Scope:

The use of pre-formulation parameters maximizes the chances in formulating an acceptable, safe, efficacious and stable product. Followings are the tests carried out for the preformulation study.

1) Organoleptic characteristics

2) Solubility of drug

3) Particle size and size distribution

4) Bulk density

5) Carr’s index

7) Hausner’s ratio

8) Compatibility study

Organoleptic characteristics:

The color, odour, and taste of the drug were characterized and recorded using descriptive terminology.

Particle size:

Particle size analysis is done analytical method or by sieve analysis. In sieve analysis standard sieves of different meshes were available as per the specifications of USP, sieves were arranged in a nest with courses at the top. This sieve set was fixed to the mechanical shaker apparatus and shaken for a certain period of times. The powder retain on each sieve was weighed and percentage of powder retained on each sieve was calculated using the initial weight taken. Particle size distribution data for Guaifenesin (Anhydrous) USP was recorded by the wet method using Malvern particle size analyzer and reported in the table 19.

Solubility of drug:

Drug is BCS Class III drug. Guaifenesin is pH dependent soluble compound. It is highly soluble in water, freely soluble in ethanol, soluble in chloroform, glycerol, propylene glycol, practically insoluble in petroleum ether. Add measured volumes of different media to 1 gm of API until it dissolve and produce saturated solution. Calculate the mg of API that goes into per ml of solvent or media. Solubility is carried out at temperature between 15-25°C and reported in the table 20.

Bulk density:

An accurately weighed quantity of powder, which was previously passed through sieve # 40 [USP] and carefully poured into graduated cylinder. Then after pouring the powder into the graduated cylinder the powder bed was made uniform without disturbing. Then the volume was measured directly from the graduation marks on the cylinder as ml. The volume measure was called as the bulk volume and the bulk density is calculated by following formula and reported in the table 21.

Bulk density = Weight of powder

Bulk volume

Tapped density:

After measuring the bulk volume the same measuring cylinder was set into tap density apparatus. The tap density apparatus was set to 250 taps drop per minute and operated for 500 taps. Volume was noted as (Va) and again tapped for 750 times and volume was noted as (Vb). If the difference between Va and Vb is not greater than 2% then Vb is consider as final tapped volume. The tapped density is calculated by the following formula and reported in the table 21.

Tapped density = Weight of powder

Tapped volume

Compressibility index (Carr’s index):

Compressibility index (C.I.) is an important measure that can be obtained from the bulk and tapped densities. Carr’s index of a material having values of less than 20% is defined as the free flowing material. It can be calculated as per given formula,

C.I. = 100 (Vb – Vt)

Vt

Vb = Bulk volume

Vt = Tapped volume

Hausner’s ratio:

Hausner’s ratio is an important character to determine the flow property of powder and granules. This can be calculation by the following formula,

Hausner’s Ratio= Tapped density

Bulk density

Table 4: Effect of Carr’s Index and Hausner’s Ratio on flow property

Carr’s Index (%)	Flow Character	Hausner’s Ratio
< 10	Excellent	1.00-1.11
11-15	Good	1.12-1.18
16-20	Fair	1.19-1.25
21-25	Passable	1.26-1.34
26-31	Poor	1.35-1.45
32-37	Very poor	1.46-1.59
>38	Very very poor	>1.60

Drug-excipients compatibility studies:

This study was conducted to determine the possible interaction between the API and excipients in 5: 1 ratio. Drug –Excipients mixtures were subjected to 40°C/75 % RH and 60°C for one month in glass vial pack. Samples were observed after every one- week time and noted for physical change. Samples were analyzed for Description, Related substances and water after 1 month time interval for 60°C and for 40°C/75%RH. Initial samples were additionally analyzed for DSC. DSC study data reveals that there is no interaction between Excipient and Guaifenesin anhydrous.

Procedure:

Guaifenesin and excipients are to be thoroughly mixed in predetermined ratio given in above table and passed through the sieve no.40. The blend was to be filled in transparent glass vials and are closed with gray rubber stoppers and sealed with aluminum seal and charged in to tress condition at room temperature, 60ºC and 40ºC. Similarly API shall also be kept at all condition as per the sample. Samples are to be withdrawn for analysis within two day of sampling date as per the compatibility study plan.

Physical observation:

Physical observation of sample was done at initial, second week and at fourth week for any color change or lumps formation and flow and reported in table 4.

Development of Guaifenesin extended-release tablets:

Guaifenesin anhydrous has a low bulk density and shows very poor flow properties. Hence, wet granulation technique was preferred as it improved the bulk density and made it easy to compress. As per the strategy, following trials were taken to develop Guaifenesin extended-release tablets. Development trials has been carried out in following steps. Selection of Polymer

Optimization of Polymer

Impact of Hardness

Stability Study

Selection of Polymer:

As we discussed earlier, our aim was to prepare matrix tablets using hydrophilic polymers. Polymers are selected based on the category like cellulosic, noncellulosic, other etc.

General procedure for preparation of tablets: Preparation of Drug Granular Blend:

Poly Vinyl Pyrrolidine (PVP) K90(5-6% ) was dissolved in Iso Propyl Alcohol (IPA) solution. Guaifenesin was granulated with IPA solution. Purified Water was added extragranular if required. Prepared granules were shifted through 30# sieve. The granulated blend was dried in rapid dryer at 40º C for 30 min. until LOD obtained was less than 3.0 % w/w.

Compression of tablets:

1) Granular blend of Guaifenesin, Hydroxypropyl methylcellulose (HPMC) was mixed in Rapid Mixer Granulator (RMG).

2) The mixed granules were passed through 30 # sieve by using Oscillating granulator or Multi mill and lubricated with talc and magnesium stearate in conta blender.

3) The lubricated granules were compressed using 19.0 X 8.8 mm oval shaped punch which bears the plain surface on the both sides.

Table 5: Drug-Excipient Compatibility Studies

Sr no.	Drug-Excipient combination	Drug-Excipient ratio
1	Guaifenesin anhydrous	NA
2	Guaifenesin anhydrous + Lactose Monohydrate	5:1
3	Guaifenesin anhydrous + Hydroxypropyl methylcellulose (Methocel K-4)	5:1
4	Guaifenesin anhydrous + Hydroxypropyl methylcellulose (Methocel K-15)	5:1
5	Guaifenesin anhydrous +Hydroxypropyl methylcellulose (Methocel K-100)	5:1
6	Guaifenesin anhydrous + Hydroxypropyl methylcellulose (Methocel E-10)	5:1
7	Guaifenesin anhydrous + Povidone K-30	5:1
8	Guaifenesin anhydrous+ Purified Talc	5:1
9	Guaifenesin anhydrous + Magnesium Stearate	5:1
10	Guaifenesin anhydrous + Colloidal Silicon Dioxide (Aerosil)	5:1

Table 6: Selection of polymer

Ingredients/Batch	A	B	C	D	E	F	G
(1) Granular Blend of Guaifenesin	601	601	601	601	601	601	601
(2) Polymer Selection
(a) HPMC K4 MCR	180
(b) HPMC K15 MCR		180
© HPMC K100 MCR			180
(d) HPMC K15-40 mg
(e) HPMC K15+40 mg
(f) Protanal 200 M + XG (50:50)				180
(g) Protanal 200 M + XG (50:50) + 0.5% CaSO4					181
(h) Keltone HVCR + XG (50:50)						180
(i) Keltone HVCR + XG (50:50) + 0.5% CaSO4							181
(3) Talc	6	6	6	6	6	6	6
(4) Mg Stearate	3	3	3	3	3	3	3
Total	790	790	790	790	791	790	791

Ingredients/Batch	H	I	J
(1) Granular Blend of Guaifenesin	601	601	601
(2) Polymer Selection
(b) HPMC K15 MCR	100	140	180
© HPMC K100 LV CR			40
(4) Talc	6	6	6
(5) Mg Stearate	3	3	3
Total	710	750	830

Table 7: Tooling details of Guaifenesin Extended-Release Tablets 600 mg

Upper Punch	19.0 X 8.8 mm oval shaped
Lower punch	19.0 X 8.8 mm oval shaped
Dies	19.0 X 8.8 mm oval shaped

Methods adopted for evaluation of granules:²³

Bulk density: Tapped density: Carr’s index: Hausner’s ratio:

Angle of repose: The angle of repose of API granules was determined by the funnel method. The accurately weight powder blend were taken in the funnel. The height of the funnel was adjusted in such a way the tip of the funnel just touched the apex of the powder blend. The powder blend was allowed to flow through the funnel freely on to the surface. The diameter of powder cone was measured and angle of repose was calculated using the following equation.

tan θ = h / r.

Where h = Height of funnel r = Radius of pile

Table 8: Effect of Angle of repose (θ) on Flow property

Effect of Angle of repose (θ) on Flow property
Angle of Repose (θ)	Type of Flow
< 20	Excellent
20-30	Good
30-34	Passable
>35	Very poor

Blend Uniformity:

As shown in below figure and table, samples (in duplicate) are withdrawn from 10 different locations after the lubrication stage to validate the mixing of the API with the excipients with the help of sampling rod. If RSD is < 5.0, for n = 10, indicates that all blends for compression are homogenous with respect to the distribution of API, indicating good mixing is achieved.

Methods adopted for evaluation of Drug X Extended release tablet:²³

4.7.1. Weight variation:

Every individual tablet in a batch should be in uniform weight and weight variation within permissible limits. Twenty (20) tablets from each batch were randomly selected and individually weighed in milligrams (mg) on

an analytical balance. The average weight, standard deviation and relative standard variation were reported in table 27.

Figure 7: Graphical representation for Octagonal blender

Tablet thickness:

The thickness in millimeters (mm) was measured individually for 10 pre weighed tablets by using Vernier Calipers. The average thickness, standard deviation and relative standard variation were reported in table 27.

Figure 8: Digital Vernier Calipers

Tablet hardness:

Tablet hardness was measured using a Dr. Schleuniger hardness tester. The crushing strength of the 10 tablets with known weight and thickness of each was recorded in kilopascals (kpa) and the average hardness, standard deviations and relative standard variation were reported in table 27.

Table 9: Sampling points for Blend Uniformity

Sampling points for Blend Uniformity
Sample Quantity	Sampling Position	Left Front	Left Rear	Right Rear	Right Front
From each sampling points in triplicate	Top	S1	S3	S5	S7
	Bottom	S2	S4	S6	S8
	Center	S9
	Center bottom	S10

Figure 9: Dr. Schleuniger hardness tester

Friability:

Twenty (20) tablets were selected from each batch and weighed. Each group of tablets was rotated at 25 rpm for 4 minutes (100 rotations) in the Electrolab tablet friabilitor. The tablets were then dedust and re-weighed to determine the loss in weight. Friability was then calculated as percent weight loss from the original tablets and reported in table 27.

Figure 10: Electrolab tablet friabilitor

Uniformity of dosage units:

This was assessed according to the USP requirements for content uniformity. The batch meets the USP requirements if the amount of the active ingredient in each of the 10 tested tablets lies within the range of 85% to 115% of the label claim and the RSD is less than or equal to 6%. According to the USP criteria, if one of these conditions is not met, an additional 20 tablets need to be tested. Not more that 1 unit of the 30 tested should be outside the range of 85% and 115% of the label claim and no unit outside the range of 75% to 125% of label claim. For all RSD should not exceed 7.8%.

In vitro drug release:

In vitro drug release was performed for the manufactured tablets according to the USP 32 “Dissolution procedure”, over a 10-hour period, using an automated Vankel dissolution system. A minimum of 3 tablets per batch were tested. The dissolution of Guaifenesin from the extended release tablets was monitored using an automated VK 7010 dissolution tester coupled to an automated VK 8000 sample collector. The USP 32 (apparatus II) method was used at 100 rpm. The media used 900 ml of pH of 6.8 buffer up to 10 hr and maintained at 37± 0.5°C. Sample should be collected at 1, 2, 4, 6, 8, 10 hr. Guaifenesin release from each tablet (in the dissolution samples) was determined by UV spectrometer at a wavelength of 274 nm.

Similarity value calculation:

Different dissolution profiles were compared to establish the effect of formulation or process variables on the drug release as well as comparison of the test formulations to the marketed product. The dissolution similarity was assessed using the FDA recommended approach (f2 similarity factor) (Food and Drug Administration 1997b).

The similarity factor is a logarithmic, reciprocal square root transformation of the sum of squared errors, and it serves as a measure of the similarity of two respective dissolution profiles:

Where:

n = number of sample points

Rt = percent of marketed product release profile

Tt = percent of test formulations release observed

FDA has set a public standard of f2 value between 50-100 to indicate similarity between two dissolution profiles. To use mean data, for extended release products, the coefficients of variation for mean dissolution profile of a single batch should be less than 10% (FDA, 1997b). The average difference at any dissolution sampling point should not be greater that 15% between the tested and the reference products, marketed product in this case, (FDA, 1997a).

Figure 11: Automated Vankel dissolution system

Table 10: Specification of Similarity factor value and its significance

Similarity factor (F2)	Significance
< 50	Test and reference profiles are dissimilar
50 – 100	Test and reference release profiles are similar
100	Test and reference release profiles are identical
> 100	The equation yields a negative value

Assay: ²⁷

Assay of Guaifenesin extended release tablet is carried out as per USP 32.

Benzoic acid solution- Dissolve a suitable quantity of benzoic acid in methanol to obtain a solution containing about 2 mg/ml.

Mobile phase-

Prepare a suitable filtered and degassed mixture of water, methanol and glacial acetic acid (60:40:1.5). Make adjustments if necessary.

Resolution solution-

Dissolve a suitable quantity of Guaifenesin in water, with shaking, to obtain a solution containing about 2 mg/ml. Transfer 2.0 ml of this solution and 5.0 ml of Benzoic acid solution to a 100 ml volumetric flask, add 40 ml of methanol, dilute with water to volume, and mix to obtain a solution containing about 40 µg of Guaifenesin and 100 µg of benzoic acid per ml.

Standard preparation-

Dissolved an accurately weighed quantity of Guaifenesin in water, with shaking, to obtain a solution having a known concentration of about 2 mg/ml. Transfer 2 ml of this solution to a 100 ml volumetric flask, add 45 ml of methanol, dilute with water to volume, and mix to obtain a Standard preparation having a known concentration of about 40 µg/ml.

Assay preparation-

Weigh and finely powder not less than 20 tablets. Transfer an accurately weighed portion of the powder, equivalent to about 200 mg of Guaifenesin, to a 100 ml volumetric flask, add about 60 ml of water, and shake for about 15 minutes. Dilute with water to volume, filter if necessary to obtain a clear solution and mix. Transfer 2 ml of this solution to a 100 ml volumetric flask, add 45 ml of methanol, dilute with water to volume and mix.

Chromatographic system-

Column: 4.6 mm × 25 cm.

Detector: 276 nm.

Flow rate: 2.0 ml/min.

Injection volume: Between 20µ L.

Temperature: 45°C.

Procedure-

Separately inject equal volumes (about 20 µl) of the standard preparation and the assay preparation into the chromatograph, and measure the peak responses for the major peaks. Calculate the quantity in mg by the formula: 5C (RU/RS), In which C is the concentration in mg/ml, of Guaifenesin in the standard preparation, and RU and RS are the response ratios of the Guaifenesin peak obtained from the assay preparation and the standard preparation, respectively.

Stability study:

Compressed tablets were packed in HDPE bottles along with purified cotton and sealed by heat induction sealer. Labeled them and stored in stability chamber in accelerated condition 40°C / 75% RH for 30 days. After defined period of time, samples were withdrawn and analyzed for physical appearance, hardness, % assay, and dissolution rate. “Significant Change” for a drug product is defined as:

1. More than 5% change in assay from its initial value.

2. Any degradation product’s exceeding its acceptance criteria.

3. Failure to meet acceptance criteria for appearance, physical attributes and Functionality test. (eg. Color, Hardness etc.)

Failure to meet the acceptance criteria for dissolution.

Manufacturing of Drug X extended release tablet:

Table 11: Formula for formulation of Guaifenesin extended release tablet

FORMULA	A	B	C	D	E	F	G
API granules	601	601	601	601	601	601	601
HPMC K-4	180	-	-	-	-	-	-
HPMC K-15	-	180	-	-	-	-	-
HPMC K-100	-	-	180	-	-	-	-
Protanal 200 M + Xanthan Gum (50:50)	-	-	-	180	-	-	-
Protanal 200 M + Xanthan Gum (50:50) + 0.5% CaSO4	-	-	-	-	181	-	-
Keltone HVCR + Xanthan Gum (50:50)	-	-	-	-	-	180	-
Keltone HVCR + Xanthan Gum (50:50) + 0.5% CaSO4	-	-	-	-	-	-	181
Talc	6	6	6	6	6	6	6
Magnesium Stearate	3	3	3	3	3	3	3
TOTAL	790	790	790	790	791	790	791

*Note: All the ingredients were taken in mg.

Table 12: Swelling Index Analysis I

Time (hr)	Batch
	Innovator	A	B	C	D	E	F	G
2	95.7	74.7	81.0	107.3	197.2	263.7	208.4	194.2
4	109.3	152.4	128.2	132.2	264.3	318.0	337.2	315.2
6	125.2	219.4	176.6	155.0	371.2	368.3	362.5	359.2
8	126.8	276.0	185.8	165.5	398.9	378.2	430.0	423.2

Figure 12: Flow chart of detailed manufacturing process

Above swelling index analysis shows almost same swelling index as compared to Innovator and B Batch. Now, we have to optimize B Batch with compared to Innovator Batch. We have to perform on dissolution of Batch A, B, C and Innovator for comparison.

Table 13: Dissolution Data Analysis

Time (hr)	% Drug Release
	Innovator	A	B	C
1	37	45	26	27
2	49	75	32	30
4	64	90	43	32
6	76	102	53	33
8	86	110	68	37
10	95	116	89	41

(2) Optimization of Polymer:

Table 14: Optimization of Polymer

FORMULA	H	I	J
API granules	600	600	600
HPMC K-15	100	140	180
HPMC K-100 LV	-	-	40
Talc	6	6	6
Magnesium Stearate	3	3	3
TOTAL	710	750	830

*NOTE: All the ingredients were taken in mg.

Table 15: Swelling Index Analysis II

Time (hr)	Batch
	Innovator	H	I	J
2	95.7	92.7	87.3	105.8
4	109.3	122.9	108.8	121.3
6	125.2	153.7	120.5	140.1
8	126.8	186.9	128.1	157.6

Above swelling index analysis shows almost same swelling index as compared to Innovator and I Batch. Now, we have to reproduce the batch I for the scale up batch K.

Impact of hardness:

Impact of hardness checked at 3 levels.

4-7 kPa

8-10 kPa

11-13 kPa

Hardness was checked at 3 levels and in all the 3 levels does not give impact on the dissolution profile. So, finally 8-10 kPa hardness was chosen for the scale up batch.

Stability study:

Batch I was the most suitable one and chosen for the scale up batch K. Aqueous coating was applied on scale up batch K for the taste mask, odour and appearance of the tablets and it was put under the accelerated stability condition of 40° + 2° C and 75 + 5% RH for 1 month in HDPE sealed bottle with aluminium foil followed by plastic cap.

Preparation of coating solution:

12% w/w Opadry Blue II® solution was prepared and stirring was carried out for 30 minutes and then filtered through muslin cloth. 25% extra coating solution was prepared to compensate losses. Coating was carried out using Ganscoater. The coating parameters were described in following table.

RESULTS:

Innovator characterization:

Table 16: Physical Characterization of Innovator Product

Parameters	Observations
Strengths	600 mg
Dosage form	Coated controlled-release tablet
Description	Each oval shaped white 600 mg tablet has plain surface on both sides.
Average weight	737.24 mg
Thickness in mm	4.59 – 4.60
Tablet hardness in kp	7.8-10.4
Tablet dimensions	18.98 × 8.77 mm
Inactive components (From SPC)	Hydroxy propyl methyl cellulose, Micro crystalline cellulose, Sodium carboxy methyl cellulose, Carbomer, Magnesium stearate
Packaging	Tablets in white opaque HDPE, Child resistant bottles containing 100 tablets along with Patient information leaflet.

Dissolution profile of reference product:

Dissolution profile of reference product was studied using following dissolution test parameters.

Medium: 900 ml of pH 6.8 phosphate buffer at 37 °C for 0 to 10 hr

Apparatus: Type II

Apparatus Speed: 100 rpm

Temperature: 37°C±0.5°C

Table 17: Dissolution profiles of reference product (600 mg)

Dissolution medium	Batch No.
	Time in hr.	% Drug release
pH 6.8 phosphate buffer	1	37
	2	49
	4	64
	6	76
	8	86
	10	95

Figure 13: In-Vitro release profile of Reference Product

Organoleptic characteristics.

The color, odor, and taste of the drug were characterized and recorded using descriptive terminology.

Table 18: Organoleptic characteristics API

Properties	Results
Description	Crystalline
Taste	Bitter
Odor	Odorless
Color	White powder

Particle size and size distribution:

Table 19: Particle size distribution of Drug Guaifenesin USP by Malvern

Drug FDGL02G USP
Size (µm)	Volume under %	Size (µm)	Volume under %
40	21.01	250	84.91
80	39.13	300	90.62
120	54.77	350	94.45
160	67.12	450	98.63
200	76.51	550	99.96

Solubility of drug:

Table 20: Solubility of API

Sr. No.	Media	Solubility
1	Water	8.8 mg/ml
2	0.1 N HCl	9.2 mg/ml
3	Phosphate buffer pH 6.8	8.7 mg/ml

Results of B.D., T.D., C.I., H.R.

Table 21: Result of preformulation parameters

Parameter	API
Bulk Density (gm/cm^3)	0.368 gm/cc
Tapped Density (gm/cm^3)	0.423 gm/cc
Compressibility Index (%)	10.36%
Hausner’s Ratio	1.12

Drug-excipients compatibility studies:

Physical observation:

Physical observation of sample was done at initial, second week and at fourth week for any color change or lumps formation and flow.

Figure 14: Particle size of API by analytical method

Table 22: Physical observation at 40°C/75%RH

Drug + Excipients	Ratio	40°C/75%RH
		Initial	2nd Week	4th Week
Drug FDGL02G anhydrous	NA	White	White	White
Drug FDGL02G anhydrous + Lactose Monohydrate	5:1	White	White	White
Drug FDGL02G anhydrous + Hydroxy Propyl Methyl Cellulose(Methocel K15)	5: 1	Off White	Off White	Off White
Drug FDGL02G anhydrous + Povidone (PVP K30)	5: 1	White	White	White
Drug FDGL02G anhydrous + Magnesium Stearate	5: 1	White	White	White
Drug FDGL02G anhydrous + Talc	5:1	Off White	Off White	Off White
Drug FDGL02G anhydrous + Colloidal Silicon Dioxode (Aerosil)	5: 1	White	White	White

Table 23: Physical observation at 60°C

Drug + Excipients	Ratio	60°C
		Initial	2nd Week	4th Week
Drug FDGL02G anhydrous	NA	White	White	White
Drug FDGL02G anhydrous + Lactose Monohydrate	5: 1	White	White	White
Drug FDGL02G anhydrous + Hydroxy Propyl Methyl Cellulose (Methocel K15)	5: 1	Off White	Off White	Off White
Drug FDGL02G anhydrous + Povidone (PVP K30)	5: 1	White	White	White
Drug FDGL02G anhydrous + Magnesium Stearate	5: 1	White	White	White
Drug FDGL02G anhydrous + Talc	5:1	Off White	Off White	Off White
Drug FDGL02G anhydrous + Colloidal Silicon Dioxode (Aerosil)	5: 1	White	White	White

Preformulation study of granules:

Table 24: Preformulation study of granules

The Preformulation studies of granules were carried out as per 4.6.

Sr No.	Parameter	Result
1	Bulk Density	0.576 gm/ml
2	Tapped Density	0.681 gm/ml
3	Compressibility index (%)	17.3
4	Hausner’s ratio	1.18
5	Angle of repose	21.9 ± 0.8°

Blend Uniformity:

Blend uniformity of lubricated granules was carried out according to 4.6.

Table 25: Results of blend uniformity of lubricated blend RPM: 22, blending time: 15 Minutes.

Sample location	Acceptance Criteria	Location					Mean	STD
		1	2	3	4	5
Top	NLT 90.00 % and NMT 110.00 % of label claim, RSD : NMT 5.00 %	101.4	99.1	101.4	100.3	100.8	100.3	0.92
Bottom		99.6	100.8	99.2	100.9	99.3

In-Vitro drug release study:

Table 26: In-Vitro drug release profile

Dissolution Profile
Dissolution Medium – pH 6.8 phosphate buffer
Time (hr)	Batch
	Innovator	A	B	C	H	I	J
1	37	45	26	27	42	36	37
2	49	75	32	30	62	48	52
4	64	90	43	32	78	64	69
6	76	102	53	33	91	77	84
8	86	110	68	37	99	87	98
10	95	116	89	41	105	96	108
Similarity Factor (f2)	-	32	38	21	46	93	54
Difference Factor (f1)	-	32	24	51	17	1	10

Figure 15: In-vitro release profile of batch I in comparisation with innovator

Post-formulation studies:

Table 27: Results of post formulation studies of formulated batches

Batch No.	I
LOD	2.55%
Average weight in mg	750 + 2%
Tablet hardness in kp	7.8-10.2
Thickness in mm	5.68-5.73
Friability	0.64%
Assay	95.68%
Dissolution	96%
F2 Value	93

DISCUSSION:

The purpose of the present study was to design, development, formulation and evaluation of an extended release tablet for an expectorant drug, Guaifenesin. Extended release tablet was prepared by wet granulation method using different polymers like Hydroxypropyl methylcellulose, Alginic acid, Sodium Alginate etc. Drug FDGL02G is highly water soluble drug (BCS class III), so it is very difficult to prepare an extended release tablet. Different approaches are available for formulation of such dosage form for particular drug molecules. Preformulation study of drug shows that the drug has more solubility in 0.1N HCl hence it is difficult to control the drug release in gastric fluid. But a satisfactory formulation has been developed by using HPMC K-15 for expectorant Drug Guaifenesin to extend the drug release for 10 hours using wet granulation process. Before the development of an extended release tablet various preformulation test is also carried out to determine Bulk density, Tapped density, Compressibility index, Hausner’s ratio, solubility, particle size and size distribution, drug-excipients compatibility [by physical observation]. From all those results we can say that the drug have higher water solubility, heavy in density [so wet granulation method is adopted for formulation], sufficient particle size and compatible with all other excipients.

Development was summarized as follows:

Initial batch A was taken in which matrix tablet of Drug Guaifenesin was prepared with HPMC K-4 as polymer, PVP K90 used as binder. Here percentage drug release was very fast, found to be up to 102% in 6 hr, therefore need to add certain type of release retarding agent. Swelling index shows 276% count in 8 hr, which is very higher with compared to Innovator product. Then batch B was taken with HPMC K-15 as polymer and PVP K90 used as binder. Here percentage drug release was slightly slow, found to be up to 89% in 10 hr. So need to improve release. Swelling index shows 185% count in 8 hr, which is nearer with compared to Innovator product. It is necessary to optimize the polymer concentration.

Then batch C was taken with HPMC K-100 as polymer and PVP K90 used as binder. Here percentage drug release was very slow, found to be up to 41% in 10 hr. So need to improve release. Swelling index shows 165% count in 8 hr, which is nearer with compared to Innovator product, but higher rate of swelling index seen at initial level. It is necessary to optimize the polymer concentration. Then batch D was taken with Protanal 200 and Xanthan Gum (50:50) as polymer and PVP K90 used as binder. Swelling index shows almost 400% count in 8 hr, which is three times with compared to Innovator product. So, dissolution was not performed as the swelling index was the main criteria for this research work.

Then batch E was taken with Protanal 200 and Xanthan Gum (50:50) and 0.5% CaSO4 as polymer and PVP K90 used as binder. Swelling index shows almost 378% count in 8 hr, which is three times with compared to Innovator product. So, dissolution was not performed as the swelling index was the main criteria for this research work. Then batch F was taken with Keltone HVCR and Xanthan Gum (50:50) as polymer and PVP K90 used as binder. Swelling index shows almost 430% count in 8 hr, which is very higher with compared to Innovator product. So, dissolution was not performed as the swelling index was the main criteria for this research work. Then batch G was taken with Keltone HVCR and Xanthan Gum (50:50) and and 0.5% CaSO4 as polymer and PVP K90 used as binder. Swelling index shows almost 423% count in 8 hr, which is very higher with compared to Innovator product. So, dissolution was not performed as the swelling index was the main criteria for this research work. So, from above all trials it has been observed that HPMC K15 was the suitable polymer for the preparation of extended release tablet. It is necessary to optimize the polymer concentration. Then batch H was taken with HPMC K-15 in half concentration as polymer and PVP K90 used as binder. Here percentage drug release was slightly higher, found to be up to 105% in 10 hr. So need to improve release. Swelling index shows 157% count in 8 hr, which is nearer with compared to Innovator product. It is necessary to optimize the polymer concentration.

Then batch I was taken with HPMC K-15 in 3/4th concentration as polymer and PVP K90 used as binder. Here percentage drug release was almost similar, found to be up to 96% in 10 hr. Swelling index shows 128% count in 8 hr, which is similar with compared to Innovator product. Then batch J was taken with HPMC K-15 and HPMC K-100 in combination as polymer and PVP K90 used as binder. Here percentage drug release was slightly similar, found to be up to 108% in 10 hr. Swelling index shows 128% count in 8 hr, which is similar with compared to Innovator product. From above all trials it has been observed that Batch I gives best results. Batch I is taken for Scale Up Batch and stability batch.

Batch K [Scale Up Batch] was taken with same formula as I. It was given almost similar kind of dissolution profile as we have obtained earlier. We also found the f2 value satisfactory for that finally this batch will charged for stability study. It is necessary to optimize the Formulation to get optimum level of release controlling polymer and release retardant polymer, to formulate extended release formulation of drug Guaifenesin. Some of the parameters to be monitored for this product include particle size distribution of drug substance, selection of polymer level, and environmental condition of processing and storage area. Thus After intensive research, an extended release formulation of an expectorant drug was successfully formulated which had attributes including:

Patent non-infringing

Improved patient compliance

Desired dissolution profile

Stable and Robust

Economical

Comparable to innovator

CONCLUSION:

An extended release tablets are also known as prolonged release or sustained release tablets, which are formulated in such a manner so as to make the contained active ingredient available over an extended period of time after ingestion. There are certain approaches which use to formulate an extended release dosage form like diffusion controlled, dissolution controlled, diffusion and dissolution controlled etc. In the present experiment matrix tablet of Drug Guaifenesin was prepared using several polymers like HPMC, Alginic acid , Sodium alginate and which follow diffusion controlled delivery principle. Here different polymers are used with different purpose like HPMC used as hydrophilic controlling release agent, PVP K90 used as a binder, Talc used as an anti-adherent and Magnesium stearate as lubricant. Before the development of an extended release tablet various preformulation test is also carried out to determine Bulk density, Tapped density, Compressibility index, Hausner’s ratio, solubility, particle size, drug- excipients compatibility [by physical observation,]. From all this results we can concluded that drug have higher water solubility, heavy in density [so wet granulation method is adopted for formulation], sufficient particle size and compatible with all other excipients.

Extended release tablet of Drug Guaifenesin was prepared with different polymers such as HPMC, PVP and Alginic acid and Sodium alginate in various ratios, also with different addition pattern, different fusion time and different hardness. All the formulations were subjected to various evaluation parameters i.e. weight variation, hardness, friability, diameter, assay, in- vitro release for 24 hr. From all these results, it was concluded that Batch I was the best formulation and release mechanism was diffusion controlled from all prepared batches. The formulation was also subjected to accelerated stability studies for 15 days in HDPE bottle sealed with heat induction sealer by storing at ICH storage conditions, at 40°C / 75% RH storage condition, it shows better stability at higher temperature. Thus, it can be concluded that Batch I formulation shows better results, comparable with innovator product and so it can be concluded that expectorant Drug Guaifenesin can be successfully formulated as an extended release tablets.

^REFERENCES:

1. Kumar N., Chaubal M., Domb A. J., Kumar R., Majeti N. V., Controlled Release Technology, Encyclopedia of Polymer Science and Technology.

2. Robinson J. R., Sustained and Controlled Release Drug Delivery System, Marcel Dekker, NewYork, 1987: 72-76, 302-309, 312-319.

3. Aulton M. E., Pharmaceutics, The Science of Dosage Form Design, Churchill Livingstone, United Kingdom, 2nd edition, 2002: 260-264.

4. Tiwari S. B., Rajabi A. R., Drug Delivery Systems, Extended Release Oral Drug Delivery Technologies, Monolithic Matrix Systems: 217-220.

5. Chien Y. W., Rate Controlled Drug Delivery Systems, Marcel Dekker, New York, 2005: 202-210.

6. Verma R. K., Krishna D.M., Garg S.L., Formulation aspects in the delivery of osmotically controlled oral drug delivery system, J. Controlled Release, 2002: 7-27.

7. Swarbrick J. K., Boylan J. C., Encyclopedia of Pharmaceutical Technology, Marcel Dekker, New York, 1990: 308-309, 319-325.

8. (8) http://www.pharmainfo.net/reviews/review-latest-advancement-patented-controlled-sustained-release-drug-delivery-system accessed on 11/07/2011.

9. http://www.flamel.com/ accessed on 13/08/2011.

10. http://www.lifeclinic.com/ accessed on 16/08/2011.

11. http://www.durect.com/pdf/duros_fact_sheet2001.pdf accessed on 20/08/2011.

12. Banker G.S., Rhodes C.T., Modern Pharmaceutics, Marcel Dekker, New York, 3rd edition, 2002: 577-580.

13. http://en.wikipedia.org/wiki/Cough accessed on 24/08/2011.

14. http://www.home-remedies.info/diseases/cough-symptoms.htm accessed on 31/08/2011.

15. http://www.scribd.com/doc/55978155/39/Expectorants-Mechanism-of-Action- cont%C2%B6d accessed on 11/09/2011.

16. http://www.drugbank.ca/drugs/DB00874 accessed on 19/09/2011.

17. (17) Draganoiu E., Stansbrey A., Giovannitti-Jensen A., Luo H., Wilber W., FDGL02G Extended Release Tablets Formulated with Carbopol® Polymers, Lubrizol Advanced Materials Inc.

18. (18) Lakade S. H., Bhalekar M. R., Formulation and Evaluation of Sustained Release Matrix Tablet of Anti-Anginal Drug, Influence of Combination of Hydrophobic and Hydrophlic Matrix Former, Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008.

19. Kumar B. V., Prasad G., Ganesh B., Swathi C., Rashmi A., Reddy G. A., Development and Evaluation of FDGL02G Bilayer Tablet, International Journal of Pharmaceutical Sciences and Nanotechnology, 3(3), October - December 2010.

20. Kadam V. J., Jadhav K. R., Patil A., Design and Development of Extended Release Tablet Formulation of FDGL02G using Coprocessed Excipient. Collet J. K., Moreton C.M., Pharmaceutics, The Science of Dosage Form Design, Churchill Livingstone, United Kingdom, 2nd edition, 2002: 289-305.

21. Juslin M. A., Turakka L. V., Pumakinen P. C., Controlled Release Tablets, Pharma Ind., 1980: 829-832. Liberman H. A., Lachman L., The Theory and Practice of Industrial

22. Pharmacy, 3rd edition, Verghese Publication House, 171-293.ICH topic 8 Pharmaceutical guidelines, Note for Guidence on Pharmaceutical Developments, (EMEA/CHMP167068/2004).

23. ICH Q1A (R2), Stability Testing Guidelines, Stability testing of a new drug product and new drug substance. Howard, John R. (Merseyside, GB) et al. United States Patent no.: 5049394.66. ICH Q1A (R2), Stability Testing Guidelines, Stability testing of a new drug product and new drug substance. 67. Howard, John R. (Merseyside, GB) et al. United States Patent no.: 5049394

Received on 12.05.2015 Accepted on 27.06.2015

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech. 2015; Vol. 5: Issue 4, Oct. - Dec., Pg 249-272

DOI: 10.5958/2231-5713.2015.00035.5