Introduction Page 1

1.0 INTRODUCTION

Oral drug delivery known for decades is the most widely utilized route for administration among all routes that have been explored for systemic delivery of different dosage forms. Popularity may be ease of administration as well as traditional belief that by oral administration the drug is well absorbed like food stuff ingested daily. Suspensions occupy a central role in drug development. Because Drug in suspension exhibits higher rate of bioavailability than other solid dosage forms. Bioavailability is in following order, Solution > Suspension > Capsule > Compressed Tablet > Coated tablet Oral suspensions are solid-liquid dispersions whose drug delivery attributes stand apart from those of solid and solution dosage forms. Among other positive features, they are readily swallowed and thus particularly useful in paediatric and geriatric medicines, and they allow the delivery of flexible and large doses of insoluble or marginally soluble drugs that can't be easily accommodated in a single capsule or tablet. However, several challenges attend with formulating orally administered suspensions. First, because of the substantial amount of interface between particles and liquid, an oral suspension is thermodynamically unstable even though its active and inactive ingredients may be chemically stable. The inherent properties of a solid-liquid dispersion system affect not only its physical stability but also its oral absorption. These properties include (1) The interfacial area associated with the suspended particles; (2) The polymorphic forms of the solids; and (3) The growth of large crystals at the expense of small ones due to Ostwald ripening.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 2 As particle sizes decrease and interfacial free energy increases, the dispersion systems naturally become increasingly unstable, resulting in aggregation, and particle sedimentation with or without caking. If a compound is polymorphous, the solid form of the drug may revert from a high energy state to a low one during the manufacture and storage of suspensions. For these reasons, the most stable crystal form is Preferable for preparing suspension dosage forms, but higher energy crystal forms may have bioavailability advantages1. We have evidence that stable oral suspensions can be developed using various higher energy polymorphs to gain their bioavailability advantages. Another concern is that orally administrated suspensions require acceptable organoleptic properties. Many existing therapeutic agents have repugnant tastes that lessen patient compliance, particularly in pediatric patients. Therefore, effective taste-masking technologies are highly desirable. The third concern is the preparation of placebo suspensions which are sometimes required for double-blind clinical trials. However, developing a placebo suspension that looks and tastes like the active suspension is more challenging than Preparing a placebo tablet or capsule. The manufacture of generic drug products must make provision for market competition and lower prices for the consumer, thereby making medicines more affordable and more accessible to the wider population. Generic drug product availability almost certainly influences the innovator drug product manufacturer to develop new drug products that have improved efficacy and/or safety features. Generic drug product development uses a different approach and strategy compared to that used to develop a brand name drug product containing a new chemical entity. Generic drug product manufacturers must formulate a drug product that will have the same therapeutic efficacy, safety, and performance characteristics as its brand name counterpart. In order to gain market approval, a generic drug product cannot be superior or better than the brand name drug product.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 3 TASTE MASKING The Unpleasant taste was the biggest barrier for completing treatment in pediatrics. The field of taste masking of active pharmaceutical ingredients (API) has been continuously evolving with varied technologies and new excipients. The flavor of a substance is attributed to its taste, sight, odor and qualities such as mouth feel. Taste refers to a perception arising from the stimulation of taste buds present on the surface of the tongue. Humans can distinguish among five components of taste: sourness, saltiness, sweetness, bitterness, and umami (savory). The sweet and the sour-taste receptors are concentrated on the tip and both edges of the tongue respectively, bitter taste is perceived by the receptors at the back of the tongue and umami taste receptors are located all over the tongue. Taste masking becomes a prerequisite for bitter drugs to improve the patient compliance especially in the pediatric and geriatric population TASTE MASKING TECHNOLOGIES Different taste masking technologies have been used to address the problem of patient compliance. Taste masking technologies are increasingly focussed on aggressively bitter tasting drugs like the macrolide antibiotics, non-steroidal antiinflammatory drugs and penicillins. Taste masking of water soluble bitter drugs, especially those with a high dose, is difficult to achieve by using sweeteners alone. As a consequence, more efficient techniques such as coating, microencapsulation and granulation have been used in combination with the sweeteners. The different types of technologies are as follows Coating Granulation Sweeteners Microencapsulation Taste Suppressants and Potentiators Solid Dispersions

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 4 Ion Exchange Resins Viscosity Enhancers Complex Formation pH Modifiers Adsorbates

A. Coating Coating is one of the most efficient and commonly used taste masking technologies. Here, it is classified based on the type of coating material, coating solvent system, and the number of coating layers. Hydrophobic polymers, lipids, sweeteners and hydrophilic polymers can be used as coating materials, either alone or in combination, as a single or multi-layer coat, to achieve the taste masking by aqueous or organic based coating process.Taste masked famotidine was formulated by using a combination of water soluble polymers like polyvinylpyrrolidone and insoluble polymers like cellulose acetate as the coating material. This polymeric solution gave a balance between taste masking and the desired in-vitro release. The application of reverse enteric coating by using a polymer synthesized from a hydrophobic monomer(cyclohexyl acrylate), a basic monomer(dimethyl aminoethyl methacrylate) and a hydrophilic monomer to mask the unpleasant taste of erythromycin. Hydrophobic polymers have been popularly used for coating bitter medicaments to achieve taste masking. However, hydrophilic polymers may also provide taste masking. For example, rotogranules containing ibuprofen, polyvinylpyrrolidone, sodium starch glycolate and sodiumlauryl sulfate were coated with hydrophilic polymers such as hydroxyethyl cellulose or a mixture of hydroxyethyl cellulose and hydroxypropyl methylcellulose to achieve taste masking. Sweeteners can be included in the coating solution for a better taste masking performance. Kokubo and Nishiyama(2006) described a similar approach to prepare the taste masked etoricoxib [6]. Kokubo et al.(2001) prepared aqueous based film

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 5 coating(containing 2% w/wmethylcellulose of viscosity 2.0-8.0 mm2/s and a sugar alcohol) to formulate taste masked coated particles . Taste masked pivoxil sulbactam formulation for syrup was prepared by melt granulating blend of pivoxil sulbactam and glyceryl palmitostearate at temperature 45 to 47oC followed by coating with colloidal silicon dioxide in a highspeed rotary mixer. B. Granulation Mixture of bitter medicaments and sweeteners, hydrophobic polymers, lipids or waxes can be processed by dry, wet and melt granulation techniques to prepare taste masked oral solid or liquid dosage forms. The melt granulation to achieve the taste masking of calcium-containing compounds like calcium carbonate. Melt granulation of a calcium-containing compound with a sugar alcohol as a binding agent resulted in granules with an acceptable taste and mouth feel. Dabre et al. (2007) developed taste masked pharmaceutical granules, which can be formulated as dry syrup, suspension, conventional chewable or dispersible tablet. Granulation of erythromycin with alginic acid was shown to enhance the mouth feel and acceptance of the bitter medicament. Granulation is a less expensive, rapid operation and an easily scalable taste masking technology. Polymers, flavors and waxes have been used as granulating agents to achieve the taste masking of bitter medicaments. Liquid and low melting point waxes such as glycerol palmitostearate, glyceryl behenate and hydrogenated castor oil are commonly used ingredients during the granulation to achieve taste masking. Sugar alcohols and flavors are also added in the blend to increase the efficiency of taste masking. Both pH dependent and independent water insoluble polymers, especially the swelling polymers such as MCC and polycarbophil have been employed. During granulation, particle coating may remain incomplete. However, a swelling matrix phenomenon can reduce the overall diffusion of the bitter active. Thus, swellable polymers can give a better taste masking in granulation compared to non swellable polymers. Cation exchange resins, like polacrillin potassium, have been used as a granulating agent to achieve taste masking.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 6 C. Sweeteners Sweeteners are commonly used in combination with other taste masking technologies. They can be mixed with bitter taste medicaments to improve the taste of the core material which is prepared for further coating or may be added to the coating liquid. Taste masked lamivudine (antiretroviral drug) was prepared by using lemon, orange and coffee flavors . Synthetic sweeteners such as sucralose are commonly used in most taste masked products. Newer sweeteners derived from plant parts have been evaluated for taste masking efficiency. For example, stevia was used to prepare the taste masked ibuprofen. Enlists the examples of sweetening agents, the amounts added and the benefits delivered by these taste masked formulations. Sweeteners have been commonly used for the taste masking of pharmaceuticals. Artificial sweeteners such as Sucralose, aspartame and saccharin have been used in combination with sugar alcohols such as lactitol, maltitol and sorbitol to decrease the after-taste perception of artificial sweeteners. Sucralose can be used with physiologically acceptable acids (e.g. citric acid) to increase the taste masking efficiency of the sweetener. Recently, sweeteners of plant sources such as stevia and glycyrrhizin have emerged as a viable alternative to the artificial sweeteners. Glycyrrhizin is extracted from glycyrrhiza root and is 50-60 times sweeter than sucrose.. Non sucrose component of sugar beet extract was used as an edible flavor improving agent. D. Microencapsulation Microencapsulation is a valuable technique applicable to protect materials from volatilizing, oxidation as well as to mask their unpleasant taste. Microencapsulation processes are commonly based on the principle of solvent extraction or evaporation. However, modifications of other techniques such as phase separation (coacervation) and spray drying are also utilized for microencapsulation. Spray congealing is another method of microencapsulation. Menjoge and Kulkarni (2006) described spray congealing of molten dispersion of clarithromycin, reverse enteric polymers and lipids to prepare taste masked microcapsules .Coating by enteric polymers in combination with water insoluble and gastrosoluble polymers or
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 7 inorganic or organic pore formers have been used for masking the unpleasant taste of medicaments. Combination of water soluble polymer like gelatin, and water insoluble coating polymer like ethyl cellulose was used to prepare taste masked microcapsules by the phase separation method. Enlists examples of taste masking excipients used for microencapsulation of drug particles and advantages of the taste masked formulations. Coating materials used in particulate coating are also commonly used for microencapsulation. pH independent water insoluble polymers have been used with enteric polymers, inorganic or organic pore formers to achieve taste masking by microencapsulation. Buffering agents are also included in suspending medium to increase taste masking efficiency of microcapsules in oral suspensions. Microencapsulation can be an advantageous taste masking strategy for suspensions due to the low particle size distribution of microcapsules that can remain suspended for a longer time. The technique can be efficiently used for applying higher coating levels. E. Taste Suppressants and Potentiators Most of the Linguagens bitter blockers (e.g. adenosine monophosphate) compete with bitter substances to bind with the G-protein coupled(GPCR) receptor sites . In general, the hydrophobic nature of these bitter substances contributes greatly to their binding and inter-action with the receptor sites. Lipoproteins are universal bitter taste blockers. Study on animal model showed that lipoproteins composed of phosphatidic acid and lactoglobulin inhibit the taste nerve responses to the bitter substances without affecting those due to the sugars, amino acids, salts or acids. Venkatesh and Palepu(2002) described the application of taste suppressants like phospholipid(BMI-60) in taste making of bitter medicaments. Neohesperidine phospholipids have bitter taste suppression characteristics by interacting chemically with the taste receptors. Cooling and warming agents suppress unpleasant taste of medicament by subjecting taste receptors to extreme sensations to overpower the bitter taste and confuse the brain. Mixture of cooling(e.g. eucalyptol) and warming agents(e.g. methyl salicylate) was used for taste masking of thymol. Potentiators

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 8 increase the perception of the taste of sweeteners and mask the unpleasant after taste. Potentiators such as thaumatine, neohesperidine dihydrochalcone(NHDC) and glycyrrhizin can increase the perception of sodium or calcium saccharinates, saccharin, aspartyl-pheny-lalanine, cesulfame, cyclamates, and stevioside. Thaumatine was used with sugar alcohols to achieve the taste masking of bromhexine. Describes examples of bitter taste blockers, suppressants and potentiators, their amounts used and the problems overcome. The recent trend of use of bitter taste blockers such as hydroxyflavanones, adenosine monophosphate and gammaaminobutanoic acid were found to be effective to achieve the taste masking of bitter drugs. Potentiators such as thaumatine and aldehydes can be used in combination with the sweeteners to potentiate the palatable taste and to avoid an unacceptable after-taste of sweeteners. A combination of cooling and warming agents was an effective alternative to achieve taste masking. F. Solid Dispersions Specific interactions between poorly soluble drugs and hydrophilic polymers can increase the solubility of the drug; likewise specific interactions between the drug and the hydrophobic polymers might decrease the solubility of a drug . Recently solid dispersions were introduced as a taste masking technology. Tsau and Damani(1994) disclosed a drug-polymer matrix composition to achieve the taste masking of dimenhydrinate. Amine or amido group of dimenhydrinate can have a physical and chemical interaction with the carboxylic acid and esters groups of copolymers such as shellac, zein and cellulose acetate phthalate. Cabrera (2005) developed the solid dispersion of quinolone and naphthyridonecarboxylic acids in an insoluble matrix to mask the taste of the active ingredient. Solid dispersion was prepared from the solution of quinolone and the natural hydrophobic polymer shellac by solvent evaporation. Solid dispersion of cephalosporins and cellulosic or methacrylic polymer was formulated to mask the unpleasant taste of the medicament. Additional excipients such as meglumine and magnesium silicate were added to increase the efficiency of taste masking. Enlists taste masked examples of polymer-drug combi-nation using solid dispersions. Hydrophobic polymers and long chain fatty acids have been used to achieve the taste masking by solid dispersion. This approach usually requires a higher
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 9 concentration of excipients compared to other taste masking techniques. Natural polymers such as shellac and zein, and enteric polymers like derivatives of acrylic acid polymers and phthalate are good choices to develop the taste masked solid dispersions. G. Ion Exchange Resins Ion exchange resins are high molecular weight polymers with cationic and anionic functional groups. Resins form insoluble resinates through weak ionic bonding with oppositely charged drugs and maintain low concentration of the free drug in a suspension. After ingestion, the resinate exchange the drug with the counter ion in gastrointestinal tract and the drug is eluted to be absorbed. Ion exchange resin like Amberlite was used to formulate taste masked fast dissolving orally consumable films of dextromethorphan. Describes examples of cation and anion exchange resins and the amount of excipients added to achieve taste masking of bitter drugs, which were selected based on the ionic characteristics of the drug. H. Viscosity Enhancers Suspending coated particles or microcapsules may not be efficient enough to achieve taste masking of highly bitter medicaments in liquid oral suspensions. Usage of viscosity enhancers in these cases would retard the migration of dissolved medicament from the surface of the solid particle to the suspending medium. Additionally, they can also decrease the contact between the bitter medicament and the taste receptors, thus improving the overall taste masking efficiency. Hypromellose was used as a viscosity modifier in taste masked azelastine suspension consisting of sucralose as the sweetening agent. Fredrickson and Reo(2004) developed taste masked multi-dose suspension of coated linezolid particles. Viscosity enhancers such as xanthan gum, microcrystalline cellulose, and sodium carboxymethylcellulose have been included in suspending vehicle to improve the taste masking efficiency. I. Complex Formation Complexing agents have been utilized to mask the objectionable taste of drugs. The mechanism of taste masking by complex formation has two theoretical possibilities. Either the cyclodextrins wraps the bad tasting molecule to inhibit its
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 10 interaction with the taste buds, or it interacts with the gatekeeper proteins of the taste buds. Cyclodextrin was used to achieve taste masking of levosulpiride by complex formation. Sweeteners such as acesulfame can form complex with medicaments to achieve taste masking. Andreas (2003) described complex of xanthine and acesulfame to achieve taste masking of the bitter medicament. J. pH Modifiers pH Modifying agents are capable of generating a specific pH

microenvironment in aqueous media that can facilitate in situ precipitation of the bitter drug substance in saliva thereby reducing the overall taste sensation for liquid dosage forms like suspension. Wyley (2004) described an application of pH modifying agent such as L-arginine for taste masking of bitter medicament. Larginine maintains alkaline pH of the suspending vehicle to promote in situ precipitation of des-quinolone in saliva. Redondo and Abanades (2003) developed taste masked liquid formulation of ibuprofen by using sodium saccharin and pH regulating agents. K. Adsorbates Adsorbates are commonly used with other taste masking technologies. The drug may be adsorbed or/and entrapped in the matrix of the porous component, which may result in a delayed release of the bitter active during the transit through the oral cavity thereby achieving taste masking. Kashid et al.(2007) developed a taste masked loperamide formulation with magnesium aluminum silicate by blending the drug and the adsorbate, and further granulating with hydrophobic polymers to achieve taste masking FACTORS AFFECTING SELECTION OF TASTE MASKING TECHNOLOGY A. Extent of Bitter Taste With aggressively bad tasting medicaments even a little exposure is sufficient to perceive the bad taste. For example, sweeteners could not achieve taste masking of oral formulation of ibuprofen due to its dominating taste [10].Coating is more efficient technology for aggressively bitter drugs even though coating imperfections,

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 11 if present, reduce the efficiency of the technique [103]. Similarly, microencapsulation of potent bitter active agents such as azithromycin is insufficient to provide taste masking of liquid oral suspensions [104]. Viscosity enhancers can complement the taste masking efficiency. Oral suspension containing viscosity enhancers can masquerade the objectionable taste, which arises from the leakage of drug from the coated medicaments or microcapsules. This approach was also used for the microencapsulated oxazolidinone particles to limit the transport of drug from the polymer coated drug particles to the vehicle [105]. Conventional taste masking techniques such as the use of sweeteners, amino acids and flavoring agents alone are often inadequate in masking the taste of highly bitter drugs such as quinine, celecoxib, etoricoxib, antibiotics like levofloxacin, ofloxacin, sparfloxacin, ciprofloxacin, cefuroxime axetil, erythromycin and clarithromycin [106]. B. Dose of Active Pharmaceuticals Dose of a drug may dictate whether a particular formulation strategy would be suitable to achieve taste masking. In pediatric formulations, the dose is small enough so as to allow the usage of flavoring agents to mask the taste of the medicine. For example, low dose palatable pediatric aspirin oral formulation was developed by adding sweeteners, but the same approach failed to address the problem of drugs like acetaminophen because of its high dose. In such cases, coating is preferred to achieve taste masking along with sweeteners to attain an acceptable final dosage form size [107]. C. Drug Particle Shape and Size Distribution Particle characteristics of the drug would affect the taste masking process efficiency. Core materials with irregular shapes and small particle size lead to poor taste masking efficiency and varying dissolution of coated particles [108]. Fines, abrasion and variable coating thickness can lead to situations wherein the taste mask coating is compromised. Multilayer coating using inner spacing layer to sequester the drug from taste masking layer helps to reduce or eliminate such coating imperfections. Taste masked granules of gatifloxacin and dextromethorphan were formulated by multilayer coating consisting of inner spacing layer followed by outer taste masking layer [10].
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 12 D. Dosage Forms It is estimated that 50% of the population have problem of swallowing tablets, especially the pediatric and geriatric population. Chewable tablets and liquid oral dosage forms have been used to address these problems. However, it is difficult to formulate some drugs in these dosage forms due. to their poor palatability [17]. For formulations which are swallowed unchewed capsules, coated tablets and slowly disintegrating hard tablets have been used as preferred taste masking technologies. Chewable tablets and liquid oral formulations are preferable in case of large dose drugs for an ease of intake. Taste masking technologies such as sweeteners, particulate coating, microencapsulation and granulation can be employed for chewable tablets and supported with technologies such as viscosity enhancers and pH modifiers to achieve taste masking in liquid oral formulations [19].Microencapsulation of the unpleasant tasting active agent with ethyl cellulose or a mixture of ethyl cellulose and hydroxypropyl cellulose or other cellulose derivatives has been used to provide chewable taste-masked dosage forms. However, this approach suffers from the disadvantage that the polymer coating releases the active agent in an inconsistent fashion and may not provide an immediate release. Moreover, coating is more suitable when the formulation is stored in a dry form. Viscosity enhancers or pH modifiers can be used in the suspending medium to achieve taste masking of suspended coated particles, especially for extremely bitter drugs like erythromycin and its derivatives during the shelf life of a reconstituted suspension. E. Drug Solubility Physicochemical properties of the drug play an important role in the selection of taste masking technology. For example, ondansetron has a relatively lower water solubility at higher pH, based on which a rapidly disintegrating taste masked composition of ondansetron was formulated by adding an alkalizing agent(sodium bicarbonate) to reduce the water solubility and the consequent taste perception [110]. Douglas and Evans(1994) described different approaches to achieve the taste masking of ranitidine base and its salts having different solubility profiles. The bitter taste associated with a poorly soluble form of ranitidine may be satisfactorily masked by lipid coating of the
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 13 drug substance. However, for water soluble forms of ranitidine(e.g. ranitidine hydrochloride), the degree of taste masking achieved by simple lipid coating of the drug substance may not be entirely satisfactory, particularly if the product is to be formulated in an aqueous medium. Thus ranitidine hydrochloride was first incorporated into the inner core of a polymeric binder, or a lipid or wax having a melting point higher than that of the outer lipid coating to achieve an efficient taste masking [9]. F. Ionic Characteristics of the Drug Ionic characteristics of drugs govern the selection of ion exchange resin polymers and the suitability of the drug candidate for this technology. For example, anionic polymers (e.g. alginic acid) are good candidates for cationic drugs like donepezil hydrochloride, and the cationic polymers are choice of excipients for anionic drugs like sildenafil [53, 94]. CURRENT & FUTURE DEVELOPMENTS The word medicine for a child is synonymous with bad taste. Oral pharmaceuticals have been continually adapted for making their bitter taste better, especially to the pediatric and the geriatric consumers. Taste masking is a viable strategy to improve the patient compliance, especially for bitter drugs, whereby, a gamut of methodologies may be adopted to deliver a palatable formulation. Taste masked products developed from innovative pharmaceutical technologies not only increase the commercial profits, but also create brand value for a company. Some of the branded products from patented taste masking technologies are Zantac and Pepcid. Such intellectual wealth acts as an impetus for emergence of the innovative low cost commercially viable taste masking technologies. Use of sweeteners is an age old and most popular tool for disguising bitterness, the present trend has been towards exploring intense sweeteners of natural origin that can hasten commercialization. Also, the combination of sweeteners with other taste masking technologies including microencapsulation, particulate coating, bitterness blockers, ion exchange resins and potentiators is found to be a more efficient strategy. Improvement in coating technology by use of multiple or spacer layers and a shift to aqueous based coating of
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 14 hydrophobic polymers are the newer trends. However, the technique requires specialized skills for optimization and scale up of the process. Granulation, a simpler technology finds more use of swelling polymers for efficient taste masking. Amongst the strategies employed, bitter taste blockers which specifically block the bitter taste but not the pleasant taste of any additive are being explored as universal taste masking alternatives. Presently, they are limited in number, and most of them not being GRAS (Generally Regarded As Safe) listed. With ongoing advancements,vusing a combination of various taste masking technologies, future looks promising for taste masking of bitter drugs.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 15

SUSPENSION
A Pharmaceutical suspension is a coarse dispersion in which internal phase is dispersed uniformly throughout the external phase. The internal phase consisting of insoluble solid particles having a specific range of size which is maintained uniformly through out the suspending vehicle with aid of single or combination of suspending agent. The external phase (suspending medium) is generally aqueous in some instance, may be an organic or oily liquid for non oral use.

CLASSIFICATION
Based On General Classes Oral suspension Externally applied suspension Parenteral suspension Based On Proportion of Solid Particles Dilute suspension (2 to10%w/v solid) Concentrated suspension (50%w/v solid) Based On Electro kinetic Nature of Solid Particles Flocculated suspension Deflocculated suspension Based On Size of Solid Particles
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 16 Collodal suspension (< 1 micron) Coarse suspension (>1 micron) Nano suspension (10 ng)

Features Desired In Pharmaceutical Suspensions

The suspended particles should not settle rapidly and sediment produced, must be easily re-suspended by the use of moderate amount of shaking. It should be easy to pour yet not watery and no grittiness. It should have pleasing odour, colour and palatability. Good syringe ability. It should be physically, chemically and microbiologically stable. Parenteral/Ophthalmic suspension should be sterilizable.

Advantages
Suspension can improve chemical stability of certain drug. E.g. Procaine penicillin G Drug in suspension exhibits higher rate of bioavailability than other dosage forms. Bioavailability is in following order, Solution > Suspension > Capsule > Compressed Tablet > Coated tablet Duration and onset of action can be controlled. E.g.Protamine Zinc-Insulin suspension

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 17 Suspension can mask the unpleasant/ bitter taste of drug. E.g. Chloramphenicol INNOVATIONS IN SUSPENSIONS

Taste Masked Pharmaceutical Suspensions

Un-palatability due to bad taste is a major concern in most of the dosage forms containing bitter drugs. In case of suspensions also taste masking is being applied to mask bitterness of drugs formulated. The taste masking approaches for suspensions can be summarized as Polymer Coating of Drugs The polymer coat allows the time for all of the particles to be swallowed before the threshold concentration is reached in the mouth and the taste is perceived. The polymers used for coating are Ethyl cellulose Eudragit RS 100 Eudragit RL 100 Eudragit RS 30 D Eudragit RL 30 D

Polymer coated drug powders are also used for preparation of reconstitutable powders that means dry powder drug products that are reconstituted as suspension in a liquid vehicle such as water before usage. These reconstitutable polymer coated powders are long shelf-life and once reconstituted have adequate taste masking.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 18

Some examples of taste masked suspensions are as follows Table -03 S.No 1 2 3 Name of the drug LEVOFLOXACIN ROXITHROMYCIN-I AND ROXITHROMYCIN-II DICLOFENAC Taste masking approach Polymer coating (Eudragit 100 : cellulose acetate, 60:40 or 70:30) Polymer coating with Eudragit RS 100 Polymer coating with Eudragit RS 100

Theory of Suspensions Sedimentation Behavior

Introduction Sedimentation means settling of particle or floccules occur under gravitational force in liquid dosage form. Theory of Sedimentation Velocity of sedimentation expressed by Stokes equation Vsed
=

(s o) g
18 o

2r2 (s-o) 9 o

Where, Vsed d r = = = sedimentation velocity in cm / sec Diameter of particle radius of particle

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 19 s = density of disperse phase o g o = = = density of disperse media acceleration due to gravity viscosity of disperse medium in poise

Stokes Equation Written in Other Form V' = V' = Vsed. = = V sed. n the rate of fall at the interface in cm/sec. velocity of sedimentation according to Stokes low represent the initial porosity of the system that is the initial volume fraction of the uniformly mixed suspension which varied to unity. n = measure of the hindering of the system & constant for each system

Limitation of Stokes Equation 2, 7 Stokes equation applies only to: Spherical particles in a very dilute suspension (0.5 to 2 gm per 100 ml). Particles which freely settle without interference with one another (without collision). Particles with no physical or chemical attraction or affinity with the dispersion medium. But most of pharmaceutical suspension formulation has conc. 5%, 10%, or higher percentage, so there occurs hindrance in particle settling.

Factors Affecting Sedimentation

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 20 Particle size diameter (d) Vd2 Sedimentation velocity (v) is directly proportional to the square of diameter of particle. Density difference between dispersed phase and dispersion media (s - o) V ( s - o) Generally, particle density is greater than dispersion medium but, in certain cases particle density is less than dispersed phase, so suspended particle floats & is difficult to distribute uniformly in the vehicle. If density of the dispersed phase and dispersion medium are equal, the rate of settling becomes zero. Viscosity of dispersion medium () V 1/ o Sedimentation velocity is inversely proportional to viscosity of dispersion medium. So increase in viscosity of medium, decreases settling, so the particles achieve good dispersion system but greater increase in viscosity gives rise to problems like pouring, syringibility and redispersibility of suspenoid. Advantages and Disadvantages due to viscosity of medium

Advantages
High viscosity inhibits the crystal growth. High viscosity prevents the transformation of metastable crystal to stable crystal. High viscosity enhances the physical stability.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 21

Disadvantages
High viscosity hinders the re-dispersibility of the sediments. High viscosity retards the absorption of the drug. High viscosity creates problems in handling of the material during manufacturing. Sedimentation Parameters Three important parameters are considered: Sedimentation volume (F) or height (H) for flocculated suspensions F = V u / VO -------------- (A) Where, Vu = final or ultimate volume of sediment VO = original volume of suspension before settling. Sedimentation volume is a ratio of the final or ultimate volume of sediment (Vu) to the original volume of sediment (VO) before settling. Some time F is represented as Vs and as expressed as percentage. Similarly when a measuring cylinder is used to measure the volume F= H u/ HO Where, Hu = Final or ultimate height of sediment H O = Original height of suspension before settling Sedimentation volume can have values ranging from less than 1 to greater than1;

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 22 F is normally less than 1. F=1, such product is said to be in flocculation equilibrium. And show no clear Supernatant on standing Sedimentation volume (F) for deflocculated suspension F = V/ VO Where, F=sedimentation volume of deflocculated suspension V = sediment volume of completely deflocculated suspension. (Sediment volume ultimate relatively small) VO= original volume of suspension. The sedimentation volume gives only a qualitative account of flocculation.

Fig -01
flocculated suspension initial state (F=1) State of suspension on storage of some time (F=0.4) Deflocculated suspension

Suspensions quantified by sedimentation volume (f)

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 23 Degree of flocculation () It is a very useful parameter for flocculation = F/F = Vu/Vo V/Vo = Vu/V = ultimate sediment volume of flocculated suspension Ultimate sediment volume of de flocculated suspension

Sedimentation velocity The velocity dx / dt of a particle in a unit centrifugal force can be expressed in terms of the Swedberg co-efficient S Under centrifugal force, particle passes from position x 1at time t1 to position x2at time t2.

The Sedimentation Behaviour of Flocculated and Deflocculated Suspensions:

Flocculated Suspensions

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 24 In flocculated suspension, formed flocs (loose aggregates) will cause increase in sedimentation rate due to increase in size of sedimenting particles. Hence, flocculated suspensions sediment more rapidly. Here, the sedimentation depends not only on the size of the flocs but also on the porosity of flocs. In flocculated suspension the loose structure of the rapidly sedimenting flocs tends to preserve in the sediment, which contains an appreciable amount of entrapped liquid. The volume of final sediment is thus relatively large and is easily redispersed by agitation.

Deflocculated suspensions In deflocculated suspension, individual particles are settling, so rate of sedimentation is slow which prevents entrapping of liquid medium which makes it difficult to re-disperse by agitation. This phenomenon also called cracking or claying. In deflocculated suspension larger particles settle fast and smaller remain in supernatant liquid so supernatant appears cloudy whereby in flocculated suspension, even the smallest particles are involved in flocs, so the supernatant does not appear cloudy. Sedimentation behavior of flocculated and deflocculated suspensions

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 25

Fig -02 Brownian movement (Drunken walk) Brownian movement of particle prevents sedimentation by keeping the dispersed material in random motion. Brownian movement depends on the density of dispersed phase and the density and viscosity of the disperse medium. The kinetic bombardment of the particles by the molecules of the suspending medium will keep the particles suspending, provided that their size is below critical radius (r). Brownian movement can be observed, if particle size is about 2 to 5 mm, when the density of particle & viscosity of medium are favorable.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 26 If the particles (up to about 2 micron in diameter) are observed under a microscope or the light scattered by colloidal particle is viewed using an ultra microscope, the erratic motion seen is referred to as Brownian motion. This typical motion viz., Brownian motion of the smallest particles in pharmaceutical suspension is usually eliminated by dispersing the sample in 50% glycerin solution having viscosity of about 5 cps.

The displacement or distance moved (Di) due to Brownian motion is given by equation:

Where, R =

Gas constant

T = Temp. In degree Kelvin N= = t = r = Avogadros number Viscosity of medium Time Radius of the particle

The radius of suspended particle which is increased Brownian motions become less & sedimentation becomes more important In this context, NSD i.e. No Sedimentation Diameter can be defined. It refers to the diameter of the particle, where no sedimentation occurs in the suspensions systems.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 27 The values of NSD depend on the density and viscosity values of any given system. Flocculating Agents Flocculating agents decreases zeta potential of the suspended charged particle and thus cause aggregation (floc formation) of the particles. Examples of flocculating agents are: Neutral electrolytes such as KCl, NaCl. Calcium salts Alum Sulfate, citrates, phosphates salts

Neutral electrolytes e.g. NaCl, KCl besides acting as flocculating agents, also decreases interfacial tension of the surfactant solution. If the particles are having less surface charge then monovalent ions are sufficient to cause flocculation e.g. steroidal drugs. For highly charged particles e.g. insoluble polymers and poly-electrolytes species, di or trivalent flocculating agents are used.

There are two important steps to formulate flocculated suspension The wetting of particles Controlled flocculation

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 28 The primary step in formulation is that adequate wetting of particles is ensured. Suitable amount of wetting agents solve this problem which is described under wetting agents. Careful control of flocculation is required to ensure that the product is easy to administer. Such control is usually is achieved by using optimum concentration of electrolytes, surface-active agents or polymers. Change in these concentrations may change suspension from flocculated to deflocculated state.

Important Characteristics of Flocculated Suspensions Particles in the suspension are in form of loose agglomerates. Flocs are collection of particles, so rate of sedimentation is high. The sediment is formed rapidly. The sediment is loosely packed. Particles are not bounded tightly to each other. Hard cake is not formed. The sediment is easily redispersed by small amount of agitation. The flocculated suspensions exhibit plastic or pseudo plastic behavior. The suspension is somewhat unsightly, due to rapid sedimentation and presence of an obvious clear supernatant region. The pressure distribution in this type of suspension is uniform at all places, i.e. the pressure at the top and bottom of the suspension is same. In this type of suspension, the viscosity is nearly same at different depth level. The purpose of uniform dose distribution is fulfilled by flocculated suspension. Important Characteristics of Deflocculated Suspensions

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 29 In this suspension particles exhibit as separate entities. Particle size is less as compared to flocculated particles. Particles settle separately and hence, rate of settling is very low. The sediment after some period of time becomes very closely packed, due to weight of upper layers of sedimenting materials. After sediment becomes closely packed, the repulsive forces between particles are overcome resulting in a non-dispersible cake. More concentrated deflocculated systems may exhibit dilatant behavior. This type of suspension has a pleasing appearance, since the particles are suspended relatively longer period of time. The supernatant liquid is cloudy even though majority of particles have been settled. As the formation of compact cake in deflocculated suspension, Brookfield viscometer shows increase in viscosity when the spindle moves to the bottom of the suspension. There is no clear-cut boundary between sediment and supernatant. Flocculation is necessary for stability of suspension, but however flocculation affects bioavailability of the suspension. In an experiment by Ramubhau D et al., sulfathiazole suspensions of both flocculated and deflocculated type were administered to healthy human volunteers. Determination of bioavailability was done by urinary free drug excretion. From flocculated suspensions, bioavailability was significantly lowered than deflocculated suspension. This study indicates the necessity of studying bioavailability for all flocculated drug suspensions.

Rheological Behaviour
Introduction

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 30 Rheology is defined as the study of flow and deformation of matter. The deformation of any pharmaceutical system can be arbitrarily divided into two types: 1) The spontaneous reversible deformation, called elasticity; and 2) Irreversible deformation, called flow. The second one is of great importance in any liquid dosage forms like suspensions, solutions, emulsions etc. Generally viscosity is measured as a part of rheological studies because it is easy to measure practically. Viscosity is the proportionality constant between the shear rate and shear stress, it is denoted by . = S/D Where, S = Shear stress & D = Shear rate Viscosity has units dynes-sec/cm 2 or g/cm-sec or poise in CGS system. SI unit of Viscosity is N-sec/m2 1 N-sec/m2 = 10 poise 1 poise is defined as the shearing stress required producing a velocity difference of 1cm/sec between two parallel layers of liquids of 1cm 2 area each and separated by 1 cm distance.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 31

Fig -03 Figure-03 showing the difference in velocity of layers As shown in the above figure, the velocity of the medium decreases as the medium comes closer to the boundary wall of the vessel through which it is flowing. There is one layer which is stationary, attached to the wall. The reason for this is the cohesive force between the wall and the flowing layers and inter-molecular cohesive forces. This inter-molecular force is known as viscosity of that medium. In simple words the viscosity is the opposing force to flow, it is characteristic of the medium. Formulation of Pharmaceutical Suspensions Introduction Suspension formulation requires many points to be discussed. A perfect suspension is one, which provides content uniformity. The formulator must encounter important problems regarding particle size distribution, specific surface area, inhibition of crystal growth and changes in the polymorphic form. The formulator must ensure that these and other properties should not change after long term storage and do not adversely affect the performance of suspension. Choice of pH, particle size, viscosity, flocculation, taste, color and odor are some of the most important factors that must be controlled at the time of formulation.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 32 The drug release from suspensions is mainly through dissolution .Suspension share many physico- chemical characteristic of tablet & capsules with respect to the process of dissolution. As tablets and capsules disintegrate into powders and form suspension in the biological fluids, it can be said that they share the dissolution process as a rate limiting step for absorption and bio-availability.

Wt1/3 = Wo1/3- K1/3 t Where Wt= particle weight at time t Wo = initial particle weight K1/3 = dissolution rate constant And under sink condition (Cs >>>>> Cb) K1/3 = (4/32)1/3 *DCs/h = solid density Above equation mostly useful for dissolution of macroscopic solid spheres in which the diffusion layer is considered constant and small compared with the size of the sphere. For multiparticulate system the square root relationship derived by Niebergall & Goyan Wt1/2 = Wo1/2- K1/2* t Under sink condition,
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 33 K1/2 = (3/2)1/2 *DCs/k K = proportionality constant between diffusion layer thickness and particle size. Square root relationship is based on the observation that a square root dependency on wt gave a steady dissolution rate constant for different particle size fractions of a particular solid. Higuchi & Hiestand explain the particulate dissolution system in which the size was much smaller than the diffusion layer thickness. Wt2/3 = Wo2/3- K2/3* t Under sink condition K2/3= (2*21/2/31/2)2/3 *DCs

Formulation Factors Governing Drug Release

Wetting Wetting of suspended particles by vehicle is must for proper dispersion. Air entrapment on the particle promotes particles that rise to the top of the dispersion medium, particle de-aggregation or other cause of instability. Poor wetting on drug particle leads poor dissolution of particles and so retard release of drug. Viscosity The total viscosity of the dispersion is the summation of the intrinsic viscosity of the dispersion medium and interaction of the particles of disperse phase. As per Stokes-Einstein equation,

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 34 D= KT/6r Intrinsic viscosity of medium affects the dissolution rate of particles because of the diffusion effect. On enhancement of viscosity the diffusion coefficient decreases, which gives rise to a proportionate decreases in rate of dissolution Effect of Suspending Agent Different suspending agents act by different way to suspend the drug for example suspension with the highest viscosity those made by xanthan gum and tragacanth powder shows inhibitory effects on the dissolution rate. The suspension of salicylic acid in 1 % w/v dispersion of sodium carboxymethycellulose and xanthan gum indicating effect of viscosity on hydrolysis of aspirin in GIT is not significant from a bioavailability point of view. EVALUATION OF SUSPENSIONS Appearance of Phases This test is done for the dispersed phase and dispersion medium. For preparation of dispersion phase for suspension usually purified water and syrup are used. The particle size distribution, clarity of syrup, the viscosity of gum dispersion, quality control of water is monitored to keep an eye on the product quality. Viscosity of Phases Stability of a suspension is solely dependent on the sedimentation rate of dispersed phase, which is dependent on the viscosity of the dispersion medium. So this test is carried out to ensure optimum viscosity of the medium so a stable, re dispersible suspension can be formed. The viscosity of the dispersion medium is measured before mixing with dispersed phase and also viscosity after mixing is determined using Brooke field viscometer. The calculated values are compared with the standard values and if any difference is found necessary corrective action are taken to get optimized viscosity.
Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 35 Particle Size of Dispersed Phase Optimum size of drug particle in the dispersed phase plays a vital role in stability of final suspension. So this test is carried out to microscopically analyze and find out particle size range of drug then it is compared with optimum particle size required. If any difference is found, stricter monitoring of micronisation step is ensured. PH Test PH of the phases of suspension also contributes to stability and characteristics of formulations. So pH of the different vehicles, phases of suspension ,before mixing and after mixing are monitored and recorded time to time to ensure optimum pH environment being maintained. Pourability This test is carried out on the phases of suspension after mixing to ensure that the final preparation is pourable and will not cause any problem during filling and during handling by patient. Final Product Assay For proper dosing of the dosage form it is necessary that the active ingredient is uniformly distributed throughout the dosage form. So samples are withdrawn from the dispersed phase after micronisation and after mixing with dispersion medium, assayed to find out degree of homogeneity. if any discrepancy is found out it is suitably corrected by monitoring the mixing step to ensure a reliable dosage formulation.

Sedimentation volume:

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Introduction Page 36 It is given by Ultimate volume of sediment F= Vu/Vo Original volume

If F >1, it is understood that the particles form a loose f1uff network in the vehicle, causing the final volume of sediment to swell which can be greater than original volume When F = 1, the product is said to be in a state of flocculation equilibrium, which is quite acceptable from a pharmaceutical standpoint.

Degree of flocculation - is given by Ultimate sediment volume of flocculated suspension = V/V Ultimate sediment volume of deflocculated suspension

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Literature Review 2.0 LITERATURE REVIEW

Page 37

Y.S.R. Krishnaiah, R.S. Karthikeyan, V. GouriSankar and V.Satyanarayana.,12 formulated Three-layer guar gum matrix tablet formulations for oral controlled delivery of highly soluble class III drug using guar gum as a carrier. Matrix tablet granules containing 30%, 40% or 50% of guar gum were prepared by the wet granulation technique using starch paste as a binder. The three-layer guar gum matrix tablet estimated using a HPLC method, provided the required release rate compare with the theoretical release rate for guar gum formulations meant for twice daily administration. The results indicated that guar gum, in the form of three-layer matrix tablets, is a potential carrier in the design of oral controlled drug delivery systems for highly water-soluble drugs. Gidwani, Suresh Kumar, Purushottam S., Tewari, Prashant Kumar.,13 designed sustained release matrix pharmaceutical compositions containing 60mg of class III drug constituting 8 to 50% by weight of the composition and hydrophobic polymers as a retardant by hot melt granulation at a temperature of 40C to 120C, which release drug in a sustained and reproducible manner over 24 hour. The Diluent comprises 10 to 70% by weight of the composition such as calcium carbonate. Binder comprises 2 to 10% consisting of gelatin and gum acacia. Glidant comprises 0.5 to 1.5% by weight of the composition consisting of colloidal silicone dioxide. Lubricant comprises 0.5 to 1.0% by weight of the composition selected from magnesium stearate. The tablets were film coated with 0.5 to 4.0% by weight of the tablet using cellulose derivatives. The dissolution was carried out in gastric simulated fluid pH 1.2 for the first hour and then in phosphate buffer pH 6.8 USP. Sweta et al.,14 developed Controlled release monolithic matrix pharmaceutical dosage form containing therapeutically effective amount of Class III drug, with rate controlling water swellable polymer such as Xanthan gum comprises 7% to 60% by weight of dosage form. And one hydrophobic material such as carnauba wax and stearic acid comprises 20% to 60% by weight of dosage form. Further comprising

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Literature Review

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pharmaceutically acceptable excipients selected from fillers, binders, lubricants, glidants, colouring agent, and flavoring agent. The in vitro release of drug is measured by a drug release test which utilizes the USP Apparatus I at 100 rpm with 500 ml of phosphate buffer at pH 6.8 and 37 C. Release rate is not less than about 75% after 16 hours. Tulsidutt et al., 15 designed sustained release matrix pharmaceutical compositions characterized by the absence of cellulose and/or their derivatives as release modifying agent containing, class III drug constituting 8 to 50% by weight of total composition formulated either water soluble material such as Polyethylene oxide, Sodium alginate, Calcium alginate and Xanthan Gum and water insoluble material such as stearic acid and polyvinyl acetate, or water swellable material such as guar gum, alginic acid. Purushottam s et al.,16 developed sustained release matrix compositions containing 60mg of Class III drug and hydrocolloid forming materials such as HPMC, HPC, Povidone, SCMC, Sodium alginate, Polyvinyl alcohol, Xanthan gum. Hydrophobic polymers as a retardant which release drug in a sustained and reproducible manner over a prolonged period of time to achieve the sustained effect of drug over a 24 hour period after oral administration. Alan E. Royce
17

reported Polyethylene oxide polymer is employed as a directly

compressible binder matrix for therapeutically active dosage forms. Advantageously, the polyethylene oxide has adjustable rate control effect on the release of medicament from the dosage form, enabling in particular the preparation of sustained release dosage form. Saleh M. Al-Saidan et al., 18 reported In Vitro and In Vivo Evaluation of Guar Gum Matrix Tablets for Oral Controlled Release of Water-soluble Diltiazem Hydrochloride, using various viscosity grades of guar gum prepared by wet granulation method and subjected to in vitro drug release studies. The drug release from all guar gum matrix tablets followed first-order kinetics. Guar gum matrix tablets showed no change in physical appearance, drug content, or in dissolution pattern after storage at 40oC/ 75% RH

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Literature Review

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for 6 months. When subjected to invivo pharmacokinetic evaluation in healthy volunteers, the tablets provided a slow and prolonged drug release. Based on the results of in vitro and in vivo studies it was concluded that that guar gum matrix tablets provided oral controlled release of water-soluble diltiazem hydrochloride. Shashank Bababhai Patel et al., 19 developed Once a day modified release oral dosage form using co-polymer of polyvinyl acetate. As the release-controlling agent containing highly water soluble active ingredient. D. Parekh et al., 20 designed oral controlled drug delivery for highly water-soluble drug, using various hydrophilic polymer (HPMC), waxy substances (Compritol ATO 888 and Precirol ATO 5) and a natural gum (Xanthan Gum) were used. Sung-Up Choi et al., 21 designed and evaluate a directly compressible hydrophilic poly(ethylene oxide) (PEO) matrix for the oral sustained delivery of dihydrocodeine bitartrate (DHCT). A direct compression method was used to prepare PEO matrices, and the amount of PEO in the matrices was varied to optimize in vitro DHCT release profiles. From the data obtained in this research, hydrophilic PEO matrices were found to be a novel sustained-release carrier for the oral delivery. Kewal K. Jain, MD.,
22

Drug Delivery Systems-Extended-Release Oral Drug

Delivery Technologies: Monolithic Matrix Systems, pg no: 223-224. Saptarshi Dutta et al., 23 developed modified release dosage form by replacing conventional administration of drugs by delivery system which would release effective quantities from a protected supply at a controlled rate over a long period of time. Ideally a drug to provide desired therapeutic action should arrive rapidly at the site of the action (receptor) in optimum concentration, remaining there for desired time, spare other site and get removed from the site, one of the most recent and interesting result of pharmaceutical research is the fact that absorption rate of release from the dosage form.

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Literature Review

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The product so formulated are designed as sustained action, sustained release, prolonged action, depot, retard action, delayed action, that products in most case are similar in appearance. Ian J. Hardy et al., 24 studied the mechanism and kinetics of drug release on the solubility of the active moiety and the swelling and erosion properties of the polymer, with a water soluble compound released predominantly by diffusion. A simple, cost effective and elegant solution for achieving a range of predictable release profiles from linear to bi-modal for a water soluble drug from HPMC matrices, through the inclusion of polyvinyl pyrrolidone (PVP). Mohammad Mahiuddin Talukdar et al.,
25

investigated the performance of

Xanthan gum (XG) and hydroxypropylmethyl cellulose (HPMC) as hydrophilic matrixforming agents in respect of compaction characteristics with its invitro drug release behaviour. The overall compaction characteristics were found to be quite similar to each other and were typical of polymer behaviour. But the flow characteristics were different, i.e., XG was more readily flowable than HPMC. The observed difference in drug release profiles between these two potential excipients were explored and explained by the difference in their hydrophilicity and subsequent hydration properties.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Literature Review 2.1 GENERAL LITERATURE REVIEW Samuel Levy, MD et al.,

26

Page 41

evaluate the potential benefit of oral highly soluble

drug (20 mg 3 times daily), an antianginal agent with a direct effect on ischemic myocardium, in combination with oral diltiazem (60 mg three times daily) beta blockers. David A. Fairman et al.,
27

reported the class III drug acts as an effective

antianginal clinical agent by modulating cardiac energy metabolism. It selectively inhibits long-chain 3-ketoacyl CoA thiolase (LC 3-KAT), there by reducing fatty acid oxidation resulting in clinical benefit. Evaristo Castedo et al.,
28

analyzed the ischemia-reperfusion injury due to free

radicals that occurs during heart transplantation and to determine the potential cytoprotective effect of highly soluble drug. Gabriele Fragasso et al.,
29

reported that the long-term addition of Class III drug

improves functional class and left ventricular function in patients with heart failure (HF). Gilbert Regnier et al., 30 reported that the Class III drug is useful for the treatment of ischeamic pathologies and peripheral vascular pathology. Onay-Besikci A et al., 31 reported that the highly soluble drug is an effective and well-tolerated antianginal drug that possesses protective properties against ischemiainduced heart injury. It consists of two major sections: (1) comprehensive and critical information about the pharmacological effects, mechanism of action, pharmacokinetics, side effects, and current usage of Class III drug, and (2) developments in analytical techniques for the determination of the drug in raw material, pharmaceutical dosage forms, and biological samples.

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Literature Review

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Krishnamoorthy G Ganesh M 32, developed Spectrophotometric determination of class III drug in bulk and solid dosage forms. Showing a maximum absorbance at 270nm. Beer's law was obeyed in the concentration range of 400- 700 g/ml. Thoppil SO et al., 33 developed a simple, selective, precise and stability-indicating high-performance thin-layer chromatographic method of analysis of highly soluble drug both as a bulk drug and in formulations. This method was utilized to analyze class III drug from conventional tablets and modified release tablets in the presence if commonly used excipients. M. Ganesh et al.,
34

developed a new validated spectrophotometric method for

determination of class III drug in Formulation and comparison with UV method. M.A. Naushad et al.,
35

developed and validated the HPLC method for the

analysis of class III drug in bulk drug and pharmaceutical dosage forms.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Literature Review

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Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Aim and Objective of the study

Page 44

3.0 AIM AND OBJECTIVE OF THE STUDY

The Highly soluble drug selected for the study is a 3-ketoacyl-coenzyme, a thiolase inhibitor with a cytoprotective effect, which by preserving the energy metabolisms of the cell exposed to the hypoxia or ischemic, avoids the collapse of the intracellular rate of adenosine triphosphate (ATP). Thus it ensures the functioning of the ion pumps and the sodium-potassium transmembrane flux and maintains the cellular homeostasis. Highly soluble drug is used therapeutically in the long term treatment of angina pectoris. It is freely soluble in water and has two pKa values of 4.32 and 8.95. This drug is administered orally in doses of 40 to 60mg daily in divided doses as an immediate release preparation. It is quickly absorbed and eliminated by the organism with plasma half life of around 6.0 1.4 hours and Tmax of around 1.8 0.7 hours. Since it has a shorter plasma half life, in practice 20mg preparation is given twice or thrice a day in order to ensure relatively constant plasma levels but due to the fact that it is absorbed quickly, these immediate release forms lead to maximum plasma levels immediately after administration and to a very low plasma level at the time of the next dose, resulting in great differences in peak and trough plasma levels at steady state. This drug is regarded as a safe drug in the long term treatment of chronic ischemic disorders. This compels the necessity of fabricating the immediate release dosage form into a modified release preparation for achieving regular and constant plasma levels, which is also favourable for compliance of the patient to his treatment.

OBJECTIVES OF STUDY
To provide a composition comprising a free flowing directly compressible vehicle which can be blended with a medicament and directly compressed to prepare a dosage form.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Aim and Objective of the study

Page 45

To provide a compositions which is characterized by the absence of cellulose and/or their derivatives as release modifying agents. To provide a process for preparation of modified release compositions. To provide a compositions which releases drug in a sustained and reproducible manner over a prolonged period of time achieving a sustaining effect of drug over 8-12 hours period after oral administration To provide composition of class III drug that demonstrate reliable release rate and facilitated in-vivo absorption for desired period of time. To provide MR composition which are useful for the treatment of angina pectoris and has better patient compliance.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Plan of work 4.0 PLAN OF WORK

Page 46

The present work was carried out to design and evaluate Modified release tablet of highly soluble drug, a cellular acting anti-ischemic agent. The Modified release tablets were prepared by direct compression technique using Polyethylene oxide, Xanthan Gum, Povidone K90, as drug retardant polymers, which control the release of drug, aimed to meet out the therapy for angina pectoris. The scheme of the entire work is listed as follows 1. 2. 3. 4. 5. Literature review Preformulation studies for highly soluble drug. Compatibility studies using IR spectral studies and forced degradation studies. Preparation of a modified release tablet containing polymers, by direct compression method. Evaluation of Blend 6. Angle of repose Bulk density and tapped density Compressibility index Hausners Ratio Drug content uniformity 7. Weight Variation Hardness Friability Thickness

Evaluation of tablets

Evaluation of in vitro release characteristics of all formulations using USP dissolution apparatus 2 (paddle).

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Plan of work 8. 9. 10.

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Checking the effect of pH (Multimedia dissolution) on the release pattern of a modified release tablet using USP dissolution apparatus. Comparison of the test formulation with the marketed product. Stability studies of optimized formulation following ICH guidelines.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Drug profile

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DRUG PROFILE
Category: Antibiotic Empirical Formula: C20H22N4O10S Molecular Weight: 510.48 g/mol Structure Formula:

Chemical Name: (1RS)-1-(acetyloxy)ethyl (6R,7R)-3-[ (carbamoyloxy)methyl]-7-[[(Z)-2(furan-2-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5- thia-1-azabicyclo[4.2.0]oct-2-ene2-carboxylate. Physiochemical Properties Appearance, odor and Color: A white or almost white powder. Melting Point: Cefuroxime axetil (CA) shows polymorphism of three forms: Crystalline form having a melting point of about 180 C., a substantially amorphous form having a

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Drug profile

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melting point of about 135 C. and a substantially amorphous form having a lower melting point in the range of about 70 to 95 C. Solubility: The amorphous Form is insoluble in water and in ether; slightly soluble in Dehydrated alcohol; freely soluble in acetone; soluble in chloroform, in ethyl acetate, and in methyl alcohol. The crystalline form is insoluble in water and in ether; slightly soluble in dehydrated alcohol; freely soluble in acetone; sparingly soluble in Chloroform, in ethyl acetate, and in methyl alcohol.

PHARMACODYNAMICS The model drug has in vitro activity against a broad range of gram-positive and gram-negative bacteria. The bactericidal action of Cefuroxime Axetil results from inhibition of cell wall synthesis. Cefuroxime Axetil kills bacteria by binding to the target sites in the bacterial cell membrane, the penicillin binding proteins (PBPs). This effects a change in the peptidoglycan by reducing the efficiency of cross-linking hence inducing cell-wall weakness; as a result the bacterial cell wall swells and ruptures. MECHANISM OF ACTION Model drug is a second-generation cephalosporin that contains the classic lactam ring structure. Bactericidal activity in vivo is resultant of its binding to essential target proteins, termed the penicillin-binding proteins, which are located in, the bacterial cell wall. Inhibition of these proteins leads to bacterial cell wall elongation and leakage, thus the bacteria are unable to divide and mature.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Drug profile ACTIONS AND SPECTRUM

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Based on spectrum of activity, classified as a second generation cephalosporin.a Generally no more active in vitro against susceptible gram-positive cocci than first generation cephalosporins, but has an expanded spectrum of activity against gramnegative bacteria compared with first generation drugs. Usually bactericidal. Like other -lactam antibiotics, antibacterial activity results from inhibition of bacterial cell wall synthesis. Spectrum of activity includes many gram-positive aerobic bacteria, some gram-negative aerobic bacteria, and some anaerobic bacteria; inactive against Chlamydia, fungi, and viruses. Gram-positive aerobes: Active in vitro and in clinical infections against Staphylococcus aureus, S. epidermidis, Streptococcus pneumoniae, S. pyogenes (group A -hemolytic streptococci), and other streptococci. Oxacillin-resistant (methicillin-resistant) staphylococci, Listeria monocytogenes, and most enterococci (e.g., Enterococcus faecalis) are resistant. Strains of staphylococci resistant to penicillinase-resistant penicillins (oxacillin-resistant staphylococci) should be considered resistant to cefuroxime and cefuroxime axetil, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.63 In addition, -lactamase-negative, ampicillin-resistant (BLNAR) strains of H. influenzae should be considered resistant to cefuroxime and cefuroxime axetil despite the fact that results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug. Gram-negative aerobes: Active in vitro and in clinical infections against Citrobacter, Enterobacter, Escherichia coli, Haemophilus influenzae (including ampicillin-resistant strains), H. parainfluenzae, Klebsiella (including K. pneumoniae), Moraxella catarrhalis (including ampicillin-resistant strains), Morganella morganii, Neisseria gonorrhoeae, N. meningitidis, Proteus mirabilis, Providencia rettgeri, Salmonella, and Shigella.a Some strains of Citrobacter, E. cloacae, and M. morganii are resistant.1 Acinetobacter

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Drug profile

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calcoaceticus, Legionella, Campylobacter, Pseudomonas, P. vulgaris, Serratia usually are resistant. Anaerobes: Active in vitro against Bacteroides (except B. fragilis), Clostridium (except C. difficile), Fusobacterium, Peptococcus, and Peptostreptococcus Biological Properties cLogP logP pKa Cmax T max Half-life (Mean) Pharmacokinetics Absorption After oral administration, Model drug is absorbed from the gastrointestinal tract and almost complete, 95% of the dose gets absorbed upon oral administration. The administration of food with model drug substantially increases its absorption 31, 35, and 34. The bioavailability was shown to increase from 36% to 52% when a 500 mg dose was taken in a fasting state Compared to being administered after food.35 the mechanism for this increased bioavailability is not completely understood. It has been proposed that food-induced cholecystokinin release which causes the gall bladder to contract and release bile may be responsible for improving absorption.36 Distribution Model drug, as cefuroxime, is approximately 30% protein bound and has a volume of distribution of about 15-20 per lit37. Distribution of this antibiotic into body : : : : : : 0.653999984264 -1.44000005722 2.5 750 mg 45 minutes 70 minutes

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fluids and tissues is variable, however, it does penetrate well (35-90%) into the tonsil tissue, sinus tissue, and bronchial mucosa.38 Metabolism Rapidly hydrolyzed by nonspecific esterase in the intestinal mucosa and blood to cefuroxime. Cefuroxime is subsequently distributed throughout the extra cellular fluids. The axetil moiety is metabolized to acetaldehyde and acetic acid Due to the rapid conversion it is not possible to detect model drug in the systemic Circulation31. Peak serum concentration achieved after a single 250 mg dose in the fed state is 4.7 mcg/ml and is reached after 2.1 h post-ingestion. Excretion Once de-esterified and released into systemic circulation, cefuroxime is not metabolized further, but is eliminated unchanged in the urine. In patients with normal renal function, the plasma elimination half-life after a dose of 500 mg of cefuroxime is 1.4. h. The elimination half-life increases as the renal function declines. In patients with creatinine Clearances <10 ml/min the elimination half-life extends to approximately 16.8 h.39 Based on these results, it is recommended that the dosing interval be extended in patients with renal dysfunction Dosage guide line for renal dysfunction

Estimated creatinine clearance 30 49 ml/min/1.73 m2 10 29 ml/min/1.73 m2 < 10 ml/min/1.73 m2

recommended dosage standard individual dose given Every 12 hr standard individual dose given Every 24 hr standard individual dose given Every 48 hr

Contraindications

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Drug profile Hypersensitivity to cephalosporins or penicillins Carnitine deficiency THERAPEUTIC INDICATION OF CEFUROXIME AXETIL Acute Otitis Media (AOM)

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Treatment of AOM caused by Streptococcus pneumoniae, Haemophilus influenzae (including -lactamase-producing strains), Moraxella catarrhalis (including lactamase-producing strains), or S. pyogenes.Not a drug of first choice; considered a preferred alternative to amoxicillin or amoxicillin and clavulanate when these drugs are ineffective or cannot be used (e.g., in patients with a history of non-type 1 hypersensitivity reactions to penicillin). Bone and Joint Infections Parenteral treatment of bone and joint infections caused by susceptible Staphylococcus aureus (including penicillinase-producing strains). Meningitis Parenteral treatment of meningitis caused by susceptible S. pneumoniae, H. influenzae (including ampicillin-resistant strains), Neisseria meningitidis, or S. aureus (including penicillinase-producing strains).Not a drug of choice for meningitis; treatment failures have been reported, especially in meningitis caused by H. influenzae. In addition, bacteriologic response to cefuroxime appears to be slower than that reported with ceftriaxone, which may increase the risk for hearing loss and neurologic sequelae. When a cephalosporin is indicated for the treatment of bacterial meningitis, a parenteral third generation cephalosporin (usually ceftriaxone or cefotaxime) generally recommended. Pharyngitis and Tonsillitis Treatment of pharyngitis and tonsillitis caused by S. pyogenes (group A hemolytic streptococci).Generally effective in eradicating S. pyogenes from the nasopharynx, but efficacy in prevention of subsequent rheumatic fever has not been established.CDC, AAP, IDSA, AHA, and others recommend oral penicillin V or IM penicillin G benzathine as treatments of choice; oral cephalosporins and oral macrolides

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Drug profile

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considered alternatives.Amoxicillin sometimes used instead of penicillin V, especially for young children. Respiratory Tract Infections Treatment of acute maxillary sinusitis caused by susceptible S. pneumoniae or H. influenzae (non--lactamase-producing strains only).Data insufficient to date to establish efficacy for treatment of acute maxillary sinusitis known or suspected to be caused by lactamase-producing strains of H. influenzae or M. catarrhalis. Treatment of secondary bacterial infections of acute bronchitis caused by susceptible S. pneumoniae, H. influenzae (non--lactamase-producing strains only), or H. parainfluenzae (non-lactamase-producing strains only). Treatment of acute exacerbations of chronic bronchitis caused by susceptible S. pneumoniae, H. influenzae (non--lactamase-producing strains only), or H. parainfluenzae (non--lactamase-producing strains only). Parenteral treatment of lower respiratory tract infections (including pneumonia) caused by susceptible S. pneumoniae, S. aureus (including penicillinase-producing strains), S. pyogenes (group A -hemolytic streptococci), H. influenzae (including ampicillin-resistant strains), Escherichia coli, or Klebsiella.1 Treatment of community-acquired pneumonia (CAP).Recommended by ATS and IDSA as an alternative for treatment of CAP caused by penicillin-susceptible S. pneumoniae.Also recommended as an alternative in certain combination regimens used for empiric treatment of CAP.Select regimen for empiric treatment of CAP based on most likely pathogens and local susceptibility patterns; after pathogen is identified, modify to provide more specific therapy (pathogen-directed therapy). For empiric outpatient treatment of CAP when risk factors for drug-resistant S. pneumoniae are present (e.g., comorbidities such as chronic heart, lung, liver, or renal disease, diabetes, alcoholism, malignancies, asplenia, immunosuppression; use of antiinfectives within the last 3 months), ATS and IDSA recommend monotherapy with a fluoroquinolone active against S. pneumoniae (moxifloxacin, gemifloxacin, levofloxacin) or, alternatively, a combination regimen that includes a -lactam active against S. pneumoniae (high-dose amoxicillin or fixed combination of amoxicillin and clavulanic

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Drug profile

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acid or, alternatively, ceftriaxone, cefpodoxime, or cefuroxime) given in conjunction with a macrolide (azithromycin, clarithromycin, erythromycin) or doxycycline.Cefuroxime and cefpodoxime may be less active against S. pneumoniae than amoxicillin or ceftriaxone. If a parenteral cephalosporin is used as an alternative to penicillin G or amoxicillin for treatment of CAP caused by penicillin-susceptible S. pneumoniae, ATS and IDSA recommend ceftriaxone, cefotaxime or cefuroxime; if an oral cephalosporin is used for treatment of these infections, ATS and IDSA recommend cefpodoxime, cefprozil, cefuroxime, cefdinir, or cefditoren. Septicemia Parenteral treatment of septicemia caused by susceptible S. aureus (including penicillinase-producing strains), S. pneumoniae, E. coli, H. influenzae (including ampicillin-resistant strains), or Klebsiella. In the treatment of known or suspected sepsis or the treatment of other serious infections when the causative organism is unknown, concomitant therapy with an amino glycoside may be indicated pending results of in vitro susceptibility tests. Skin and Skin Structure Infections Oral treatment of uncomplicated skin and skin structure infections caused by susceptible S. aureus (including -lactamase-producing strains) or S. pyogenes.Parenteral treatment of skin and skin structure infections caused by susceptible S. aureus (including -lactamase-producing strains), S. pyogenes, E. coli, Klebsiella, or Enterobacter. Urinary Tract Infections (UTIs) Oral treatment of uncomplicated UTIs caused by susceptible E. coli or K. pneumoniae.Parenteral treatment of UTIs caused by susceptible E. coli or K. pneumoniae. Gonorrhea and Associated Infections Oral or parenteral treatment of uncomplicated gonorrhea caused by susceptible N. gonorrhoeae.May be effective in urethral, endocervical, and rectal gonorrhea;not recommended for pharyngeal infections.Not a drug of choice for treatment of uncomplicated gonococcal infections;oral cefuroxime may be an alternative for uncomplicated urogenital and anorectal infections when IM ceftriaxone or oral cefixime cannot be used.Parenteral treatment of disseminated gonococcal infections caused by

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Drug profile

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susceptible N. gonorrhoeae. Not included in current CDC recommendations for disseminated gonococcal infections. Lyme Disease Treatment of early Lyme disease manifested as erythema migrans.IDSA, AAP, and other clinicians recommend oral doxycycline, oral amoxicillin, or oral cefuroxime axetil as first-line therapy for treatment of early localized or early disseminated Lyme disease associated with erythema migrans, in the absence of specific neurologic involvement or advanced atrioventricular (AV) heart block.Treatment of early neurologic Lyme disease in patients with cranial nerve palsy alone without evidence of meningitis (i.e., those with normal CSF examinations or those for whom CSF examination is deemed unnecessary because there are no clinical signs of meningitis).Parenteral anti-infectives (IV ceftriaxone, IV penicillin G sodium, or IV cefotaxime) recommended for treatment of early Lyme disease when there are acute neurologic manifestations such as meningitis or radiculopathy. Treatment of Lyme carditis.IDSA and others state that patients with AV heart block and/or myopericarditis associated with early Lyme disease may be treated with an oral regimen (doxycycline, amoxicillin, or cefuroxime axetil) or a parenteral regimen (IV ceftriaxone or, alternatively, IV cefotaxime or IV penicillin G sodium).A parenteral regimen usually recommended for initial treatment of hospitalized patients; an oral regimen can be used to complete therapy and for the treatment of outpatients.Treatment of borrelial lymphocytoma.Although experience is limited, IDSA states that available data indicate that borrelial lymphocytoma may be treated with an oral regimen (doxycycline, amoxicillin, or cefuroxime axetil). Treatment of uncomplicated Lyme arthritis without clinical evidence of neurologic disease.An oral regimen (doxycycline, amoxicillin, or cefuroxime axetil) can be used,but a parenteral regimen (IV ceftriaxone or, alternatively, IV cefotaxime or IV penicillin G sodium) should be used in those with Lyme arthritis and concomitant neurologic disease. Patients with persistent or recurrent joint swelling after a recommended oral regimen should receive retreatment with the oral regimen or a switch to a parenteral regimen.Some clinicians prefer retreatment with an oral regimen for those

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Drug profile

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whose arthritis substantively improved but did not completely resolve; these clinicians reserve parenteral regimens for those patients whose arthritis failed to improve or worsened.Allow several months for joint inflammation to resolve after initial treatment before an additional course of anti-infectives is given. Perioperative Prophylaxis Perioperative prophylaxis in patients undergoing noncardiac thoracic or orthopedic surgery. A preferred agent. Has been used for perioperative prophylaxis in patients undergoing cardiac surgery, GI surgery,or gynecologic or obstetric surgery (e.g., vaginal hysterectomy). Other drugs usually preferred. AVAILABILITY Oral suspension: 125 mg/5 ml Powder for injection: 750 mg, 1.5 g, 7.5 g Premixed containers: 750 mg/50 ml, 1.5 g/50 ml Tablets: 125 mg, 250 mg, 500 mg

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Excipient Profile 58

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EXCIPIENTS PROFILE
Stearic acid Synonyms Description Empirical Formula Solubility Acidum stearicum; cetylacetic acid; Crodacid; Cristal G; Cristal S; Dervacid Stearic acid is a hard, white or faintly yellow-colored, somewhat glossy, crystalline solid or a white or yellowish white powder.
C18H36O2

Freely soluble in benzene, carbon tetrachloride, chloroform, and ether; soluble in ethanol (95%), hexane, and propylene glycol; practically insoluble in water. Functional categories Density (bulk) Melting point Emulsifying agent; solubilizing agent; tablet and capsule lubricant. 0.537 g/cm3 6970 C Stearic acid is widely used in oral and topical pharmaceutical formulations. It is mainly used in oral formulations as a tablet and Applications capsule lubricant; although it may also be used as a binder or in combination with shellac as a tablet coating. It has also been suggested that stearic acid may be used in enteric tablet coatings and as a sustained-release drug carrier. Incompatibilities Stearic acid is incompatible with most metal hydroxides and may be incompatible with bases, reducing agents, and oxidizing agents. Stearic acid is a stable material; an antioxidant may also be added to it; The bulk material should be stored in a well closed container in a cool, dry place.

Stability and storage conditions

sucrose

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Excipient Profile 59 Synonyms

Page Beet sugar; cane sugar; a-D-glucopyranosyl-b-D-fructofuranoside; refined sugar; saccharose; saccharum; sugar white crystalline powder; it is odorless and has a sweet taste.

Description Empirical Formula Solubility

C12H22O11
Practically insoluble in water, soluble in ethanol (96%) and in light petroleum (50-70C). Confectionery base; coating agent; granulation aid; suspending agent; sweetening agent; tablet binder; tablet and capsule diluent; tablet filler; therapeutic agent; viscosity-increasing agent
0.93 g/cm3 (crystalline sucrose); 0.60 g/cm3 (powdered sucrose)
160186 C

Functional categories Density (bulk) Melting point

Sucrose is widely used in oral pharmaceutical formulations. Sucrose syrup, containing 5067% w/w sucrose, is used in Applications tableting as a binding agent for wet granulation. In the powdered form, sucrose serves as a dry binder (220% w/w) or as a bulking agent and sweetener in chewable tablets and lozenges. Powdered sucrose may be contaminated with traces of heavy Incompatibilities metals, which can lead to incompatibility with active ingredients, e.g. ascorbic acid. Sucrose has good stability at room temperature and at moderate Stability and storage relative humidity. It absorbs up to 1% moisture, which is released conditions upon heating at 90 C. The bulk material should be stored in a wellclosed container in a cool, dry place.

Xanthan Gum

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Excipient Profile 60 Synonym Description Molecular Formula Solubility Viscosity Functional category Grade Stability and storage condition

Page Corn sugar gum; polysaccharide B-1459; Rhodigel; Vanzan NF; Xantural. Xanthan gum occurs as a cream- or white-colored, odorless, free-flowing, fine powder. (C35H49O29)n Practically insoluble in ethanol and ether; soluble in cold or warm water 12001600 mPa s (12001600 cP) for a 1% w/v aqueous solution at 258C. Gelling agent; stabilizing agent; suspending agent; sustained-release agent; viscosity-increasing agent. Keltrol CG, Grindsted Xanthan 80, Vanzan NF Aqueous solutions are stable over a wide pH range (pH 312), although they demonstrate maximum stability at pH 410 and temperatures of 10608C. Xanthan gum is an anionic material and is not usually compatible with cationic surfactants, polymers, or preservatives, as precipitation occurs. Xanthan gum is used to prepare sustained-release matrix. Xanthan gum has also been used to produce

Incompatibilities

Application

directly compressed matrices that display a high degree of swelling due to water uptake, and a small amount of erosion due to polymer relaxation. The estimated acceptable daily intake for Xanthan

Safety

gum has been set by the WHO at up to 10 mg/kg body-weight.

Povidone Synonym Kollidon; Plasdone; poly [1-(2-oxo-1-pyrrolidinyl) ethylene]; polyvidone; polyvinylpyrrolidone; PVP; 1-vinyl-2-

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Excipient Profile 61 pyrrolidinone polymer. Description Molecular Formula Functional Category Solubility Melting point Density (bulk) Density (tapped) Stability and storage conditions

Page

Povidone occurs as a fine, white to creamy-white colored, odorless or almost odorless, hygroscopic powder. (C6H9NO)n Disintegrant; dissolution aid; suspending agent; tablet binder. Freely soluble in acids, chloroform, ethanol (95%), ketones, methanol, and water; practically insoluble in ether, hydrocarbons, and mineral oil. Softens at 150 0C. 0.290.39 g/cm3 0.390.54 g/cm3 Povidone may be stored under ordinary conditions without undergoing decomposition or degradation. However, since the powder is hygroscopic, it should be stored in an airtight container in a cool, dry place. It forms molecular adducts in solution with sulfathiazole,

Incompatibilities

sodium salicylate, salicylic acid, phenobarbital, tannin, and other compounds; When consumed orally, povidone may be regarded as essentially nontoxic since it is not absorbed from the

Safety

gastrointestinal tract or mucous membranes. Povidone additionally has no irritant effect on the skin and causes no sensitization. In tableting, povidone solutions are used as binders in wet granulation processes.

Application

neotame 3-(3,3-Dimethylbutylamino)-N-(a-carboxyphenethyl)succinamic Synonyms acid methyl ester; N-[N-(3,3-dimethylbutyl)-L-a-aspartyl]-Lphenylalanine 1-methyl ester; L-phenylalanine, N-[N-(3,3dimethylbutyl)- L-a-aspartyl]-1-methyl ester.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Excipient Profile 62 Description Empirical Formula Functional categories

Page Neotame occurs as an odorless, white to off-white powder. It has an intense sweet taste 700013 000 times sweeter than sucrose depending on the matrix. C20H30N2O5

Flavor enhancer; sweetening agent

pH Density (bulk) Melting point

5.07.0

8083 C Neotame is a water-soluble, nonnutritive, intense sweetening agent

Applications

used in beverages and foods. Neotame may be used in subsweetening quantities as a flavor enhancer, e.g. with mint or strawberry flavor. Neotame stability is affected by moisture, pH, and temperature. The bulk material should be stored in a well-closed container, in a cool, dry place; it is stable for up to 5 years at room temperature

Stability and storage conditions

Acesulfame Potassium Acesulfame K; ace K; acesulfamum kalicum; E950; 6-methyl-3,4Synonyms dihydro-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide potassium salt; potassium 6-methyl-2,2-dioxo-oxathiazin-4-olate; Sunett; Sweet One.

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Excipient Profile 63 Description Empirical Formula Solubility Functional categories Density (bulk) Melting point

Page Acesulfame potassium occurs as a colorless to white-colored, odorless, crystalline powder with an intensely sweet taste.
C4H4KNO4S

Soluble in water, very slightly soluble in acetone and in ethanol (96%). Sweetening agent.
1.04 g/cm3

250 C Acesulfame potassium is used as an intense sweetening agent in cosmetics, foods, beverage products, table-top sweeteners, vitamin

Applications

and pharmaceutical preparations, including powder mixes, tablets, and liquid products.It enhances flavor systems and can be used to mask some unpleasant taste characteristics. In the bulk form it shows no sign of decomposition at ambient temperature over many years. In aqueous solutions (pH 3.03.5 at 208C) no reduction in sweetness was observed over a period of approximately 2 years. Stability at elevated temperatures is good, although some decomposition was noted following storage at 408C for several months. The bulk material should be stored in a wellclosed container in a cool, dry place and protected from light.

Stability and storage conditions

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Materials and Instruments 64

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8.0 MATERIALS AND INSTRUMENTS

Table- 07: Material used S.No 1 2 3 4 5 6 7 8 9 10 Ingredients Highly bitter drug BP/Ph.Eur Stearic acid Ph.Eur Xanthan gum FF Ph.Eur Povidone K30 Ph.Eur Acesulfame potassium sunset Ph.Eur Neotame Ph.Eur Tutti-frutti IH Orange flavor IH Strawberry flavor IH Sucrose Ph.Eur Manufacturer Aurobindo Taurus chemicals limited C.P Kelco U.S Ink ISP Technologies Nutrinova Firmenich Firmenich Firmenich M.B. Sugars & Pharmaceuticals Table- 08: Instruments used S.No. 1 2 3 4 5 6 7 8 9 10 11 12 Name of Instrument Digital Weighing balance Vibratory Sifter Octagonal Blender Tablet Compression machine Vernier calipers Friability apparatus Hardness tester Moisture balance GPCJ 1.1 Six station dissolution test apparatus UV-Visible Spectrophotometer pH meter Manufacturer Essae digi Ganson / Anchor Ganson / Bectochem Cadmach Machinery pvt. Ltd Mitatoyo Electrolab Varian Essae Teroka Pam Glatt Electro Lab Shimadzu Mettler Toledo

Design and evaluation of a taste masked highly bitter cephalosporin dry powder for oral suspension

Preformulation studies 65

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9.0 PREFORMULATION STUDIES

Before formulation of drug substances into a dosage form, it is essential that drug polymer should be chemically and physically characterized. Preformulation studies gives the information needed to define the nature of the drug substance and provide a framework for the drug combination with pharmaceutical excipients in the fabrication of a dosage form. Compatibility studies by IR One of the requirements for the selection of suitable excipients or carrier for pharmaceutical formulation is its compatibility. Therefore in the present work a study was carried out by using infrared spectrophotometer to find out if there is any possible chemical interaction of highly bitter drug with Stearic acid, Xanthan gum ,Povidone K30 ,Acesulfame potassium ,Neotame ,Tutti-frutti ,Orange flavor ,Strawberry flavor ,Sucrose and used for the study.

Procedure Weighed amount of drug (3mg) was mixed with 100mg of potassium bromide (dried at 40-50oC). The mixture was taken and compressed under 10-ton pressure in a hydraulic press to form a transparent pellet. The pellet was scanned in IR spectrophotometer. Compatibility studies by force degradation studies The Binary mixtures of drug and excipients (1:1) were prepared, and packed in both closed vials and kept in accelerated environmental conditions (400/75% RH) for 1 month. At the end of 1 month period all the samples were observed for Physical observation, Assay and Impurity levels.

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Preformulation studies 66

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Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Methodology

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10.0 METHODOLOGY
10.1 Dry powder formulation methodology and Compositions Taste masking becomes a pre-requisite for bitter drugs to improve the patient compliance especially in the pediatric and geriatric population. Different taste masking technologies have been used to address the problem of patient compliance. Taste masking technologies are increasingly focused on aggressively bitter tasting drugs like the macrolide antibiotics, Cephalosporins, non-steroidal anti-inflammatory drugs and penicillins. Taste masking of water insoluble bitter drugs, especially those with a high dose, is difficult to achieve by using sweeteners alone. As a consequence, more efficient techniques such as coating, microencapsulation and granulation have also been used in combination with the sweeteners. In order to mask the taste of this highly bitter drug different technologies have been used and the details are as given below: Dry mixing Granulation (Non-Aqueous) Hot-Melt Granulation Spray drying Complexation Solid dispersion Dry granulation Dry granulation with combination of sweeteners and flavors The dry powder was filled in amber colored with a fill weight of 40g per bottle which is equivalent to 10 doses. Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Methodology S.No Ingredients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Model Drug Stearic acid Xanthan gum Povidone k-30 Acesulfame potassium Neotame Tutti-frutti Sucrose IPA Acetone Methylene chloride Glyceryl behinate Hydrogenated castor oil Eudragit Carbapol 934 KYRON T-114 TOTAL F001 153.48* 600 1 13 15 15 30 3175.64 2 4000

DRY MIXING F002 153.48* 800 10 10 15 15 30 2969.642 4000 F003 153.48* 1200 1 13 15 15 30 2583.642 4000

Page 68 GRANULATION (NON AQUEOUS) F004 153.48* 150 2 13 21 2.1 100 3561.54 qs 4000 F005 153.48* 150 2 13 21 2.1 100 3561.54 qs(120) 4000 F006 153.48* 150 2 13 21 2.1 100 3561.54 qs 4000 F007 153.48* 150 2 13 21 2.1 100 3561.54 Qs Qs 4000

10.2 Composition of formulation of modified release tablets of highly soluble drug

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Methodology S.No Ingredients

HOT MELT GRANULATION F008 153.48* 150 2 13 21 2.1 100 3561.54 4000 F009 153.48* 2 13 21 2.1 100 3561.54 150 4000 F010 153.48* 2 13 21 2.1 100 3561.54 150 4000

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Model Drug Stearic acid Xanthan gum Povidone k-30 Acesulfame potassium Neotame Tutti-frutti Sucrose IPA Acetone Methylene chloride Glyceryl behinate Hydrogenated castor oil Eudragit Carbapol 934 KYRON T-114 TOTAL

Page 69 SPARY COMPLEXATION SOLID DISPERSION DRYING F011 F012 F013 F14 153.48* 153.48* 153.48* 153.48* 150 2 13 21 2.1 100 3561.54 qs(220) 4000 2 13 21 2.7 100 3331.92 60% 375.90 4000 2 13 21 2.1 100 3683.42 qs 25 4000 2 13 21 2.7 100 3357.82 Qs 50 4000

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Methodology S.No Ingredients Single slug F015 F016 153.48* 153.48* 150 2 13 21 2.1 100 3561.54 4000 300 2 13 21 2.1 100 3311.54 4000

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Model Drug Stearic acid Xanthan gum Povidone k-30 Acesulfame potassium Neotame Tutti-frutti Sucrose Aerosil Acetone Methylene chloride Glyceryl behinate Hydrogenated castor oil orange flavor strawberry flavor Menthol TOTAL

Page 70 DRY GRANULATION Double slug Single slug (flavor) F017 F018 F019 F020 F021 153.48* 153.48* 153.48* 153.48* 153.48* 150 2 13 21 2.1 100 3561.54 4000 300 2 13 21 2.1 100 3311.54 4000 150 2 13 21 2.7 100 4000 150 2 13 21 2.1 100 4000 150 2 13 21 2.7 100 4000

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Methodology

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Table- 10: Application of ingredients in formulated tablet with its concentration used Used Concentration per tablet*

Inactive Ingredient* Core Ingredients Stearic acid Ph.Eur Xanthan gum FF Ph.Eur Povidone K30 Ph.Eur Acesulfame potassium sunset Ph.Eur Neotame Ph.Eur Tutti-frutti IH Orange flavor IH Strawberry flavor IH Sucrose Ph.Eur

Used as* Taste masking agent Suspending & viscosityincreasing agent Suspending agent. Sweetener Sweetener Flavoring agent Flavoring agent Flavoring agent Bulk sweetener

10.3 Preparation of a dry powder

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Methodology DRY MIXING (METHOD: 1) Sifting: Sift all the materials using Vibratory sifter. Divide the total quantity of stearic acid into 3 parts Cosift Model drug and Stearic acid through #60 mesh as follows, Cosift the part I of Stearic acid with total dispensed quantity of model drug through #60 mesh. Cosift the part II of Stearic acid with the above blend through #60 mesh. Cosift the PART III of Stearic acid with the above blend through #60 mesh.

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Co sift Xanthan Gum, Povidone (PVP K30), Tutti Frutti Aspartame and Acesulfame potassium with the above co sifted model drug and Stearic acid through #40 mesh in geometrical fashion and collect in separate triple polybag. Resift the above co sifted materials along with Sucrose (#60 mesh) through #40 mesh and collect in separate triple polybag. BLENDING: Transfer the Co sifted Blend to the blending area. Load the Co sifted Blend into the Octagonal blender and blend for 20 minutes.

Parameters of blend are as follows

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Methodology

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Parameter Description Average fill mass (net content) Uniformity of fill Mass

Specification White to off-white, flavored powder 40.00 g + 2% (39.2 g to 40.8 g) 40.00 g + 5% (38 g to 42 g) Not More Than 3.0%

Water Content (By KF)

FILLING & SEALING After proper blending fill the blend in bottles (100ml amber glass Bottle) and seal the bottle with white CRC 28mm cap and rubber stopper (bromobutyl 26mm grey). Parameters for Filling and Sealing Bottle CR Screw Cap Rubber stopper Fill weight / Bottle Cap Sealing

100ml amber glass Bottle Poly propylene white CRC 28 mm cap Rubber stopper Bromobutyl 26mm grey 40g 2% (39.2 g to 40.8 g) Leak test (water should not penetrate into the filled and sealed bottle)

Granulation (non aqueous) (Method 2) a) Weighing and Sieving: All the raw materials were passed through sieve no. 60 and weighed accurately as per the formulae. Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Methodology b) Granulation:

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The thoroughly mixed model drug and Stearic acid was kneaded for 10 mins with solvent till it forms dough mass. This mass was then passed through sieve no. 14 to form granules. C) Drying: The granules were spread on the tray and kept for drying at 400c for 30 min using hot air oven which inturn are passed through the sieve no. 60 to get uniform granules D ) Sifting: Sift above the materials through 60# using Vibratory sifter. Xanthan Gum, Povidone (PVP K30), Tutti Frutti ,Neotame and Acesulfame

potassium with the above through #40 mesh in geometrical fashion and collect in separate triple polybag Resift the above co sifted materials along with Sucrose (#60 mesh) through

#40 mesh and collect in separate triple polybag. E) BLENDING: Transfer the sifted Blend to the blending area. Load the Co sifted Blend into the Octagonal blender and blend for 20 minutes.

HOT MELT GRANULATION (METHOD 3) A ) Weighing and Sieving: Model drug weighed accurately as per the formulae and were passed through sieve no. 60 B) Granulation: Preparation of solution: Accurately weighed quantity of Stearic acid was taken and

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Methodology melted at 60c a clear solution is obtained.

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Preparation of granules: The thoroughly mixed drug powder was kneaded for 10 mins with solution till it forms dough mass. This mass was then passed through sieve no. 14 to form granules. C) Drying: The granules were spread on the tray and kept for drying at 400c for 30 min using hot air oven which in turn are passed through the sieve no. 60 to get uniform granules D) Sifting: Sift above the materials through 60# using Vibratory sifter. Xanthan Gum, Povidone (PVP K30), Tutti Frutti ,Neotame and Acesulfame

potassium with the above through #40 mesh in geometrical fashion and collect in separate triple polybag Resift the above co sifted materials along with Sucrose (#60 mesh) through

#40 mesh and collect in separate triple polybag E) BLENDING: Transfer the sifted Blend to the blending area Load the Co sifted Blend into the Octagonal blender and blend for 20 mins.

SPARY DRYING (METHOD 4) A ) Weighing and Sieving: Model drug and Stearic acid weighed accurately as per the formulae and were passed through sieve no. 60 B) Spray drying Drug and Stearic acid (1:1) were dissolved in methylene chloride (qs) The dispersion was subjected to spray drying using a spray dryer set at an inlet temperature of 45 C. and outlet temperature of 37 C. Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Methodology C) Drying:

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The powder was further dried at 30 to 40 C. for about 3 hours to remove residual solvent. D) Sifting: Sift above the materials through 60# using Vibratory sifter. Xanthan Gum, Povidone (PVP K30),Tutti Frutti ,Neotame and Acesulfame

potassium with the above through #40 mesh in geometrical fashion and collect in separate triple polybag Resift the above co sifted materials along with Sucrose (#60 mesh) through #40

mesh and collect in separate triple polybag E) BLENDING: Transfer the sifted Blend to the blending area Load the Co sifted Blend into the Octagonal blender and blend for 20 mins

COMPLEXATION (METHOD 5) Mixing Take 129 ml of purified water and 190 ml of acetone in a vessel Add 97.8gm of kyron T114 and 39.12 gm of drug which is sift through 60#

Add the material to above solution of step1 continues stirring and stir this solution for another 15 minutes

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Methodology

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Observe the ph 5.0-5.5 if required adjust the ph by 20% KOH solution and stir for 3 hour Drying

Load the complex into ss tray and keep them tray dryer

Adjust the temperature of tray dryer and continues drying Check the moisture content of complex it should show below 5.0%w/w. Sifting: Sift above the materials through 60# using Vibratory sifter. Xanthan Gum, Povidone (PVP K30), Tutti Frutti ,Neotame and Acesulfame potassium with the above through #40 mesh in geometrical fashion and collect in separate triple polybag Resift the above co sifted materials along with Sucrose (#60 mesh) through #40 mesh and collect in separate triple polybag.

BLENDING: Transfer the sifted Blend to the blending area. Load the Co sifted Blend into the Octagonal blender and blend for 20 minutes.

SOLID DISPERSION (METHOD 6) A ) Weighing and Sieving: Drug and polymer weighed accurately as per the formulae and were passed through sieve no. 60 B) Dispersion Drug and polymer were dissolved in solvent (qs). The dispersion was allowed to dry

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Methodology at room temperature and fine powder was obtained. C) Drying:

Page 78

The powder was further dried at 30 to 40 C. for about 3 hours to remove residual solvent. D) Sifting: Sift above the materials through 60# using Vibratory sifter. Xanthan Gum, Povidone (PVP K30),Tutti Frutti ,Neotame and Acesulfame

potassium with the above through #40 mesh in geometrical fashion and collect in separate triple polybag Resift the above co sifted materials along with Sucrose (#60 mesh) through

#40 mesh and collect in separate triple polybag E) BLENDING: Transfer the sifted Blend to the blending area Load the Co sifted Blend into the Octagonal blender and blend for 20 mins

. DRY GRANULATION (METHOD 7) A ) Weighing and Sieving: Drug, Stearic acid and aerosil weighed accurately as per the formulae and were passed through sieve no. 60 B) Mixing Drug, Stearic acid and aerosil mixed thoroughly by RMG to get uniform mix.

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Methodology c) Slug and Deslug

Page 79

The tablets were prepared using 16 mm round flat punch. The tablets were compressed by maintaining a constant hardness 40.5 kg/cm2. D) Milling And Sifting: The tablet were passed through 1.5 screen and passed through 60#. Xanthan Gum, Povidone (PVP K30),Tutti Frutti ,Neotame and Acesulfame

potassium with the above through #40 mesh in geometrical fashion and collect in separate triple polybag Resift the above co sifted materials along with Sucrose (#60 mesh) through #40

mesh and collect in separate triple polybag

BLENDING: Transfer the sifted Blend to the blending area Load the Co sifted Blend into the Octagonal blender and blend for 20 mins

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

7.0 EVALUATION OF SUSPENSION Evaluation of suspension includes 7.1 Evaluation of dry powder 7.2 Evaluation of reconstituted suspension 7.1 EVALUATION OF DRY POWDER Evaluation of dry powder for oral suspension was done by determination of a) BULK DENSITY & TAPPED DENSITY A quantity of 5g of the powder (W) from each formula was introduced into a 25 ml measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 2.5 cm at 2 sec intervals. The tapping was continued until no further change in volume was noted. The bulk density, and tapped density were calculated using the following formulas Bulk density = W / VO Tapped density = W / Vf Where, W = weight of the powder, VO = initial volume, Vf = final volume.

b) COMPRESSIBILITY INDEX Compressibility index is an important measure that can be obtained from the bulk and tapped densities. In theory, the less compressible a material the more flowable it is. A material having values of less than 12% is defined as the free flowing material. Compressibility index = 100 (VO Vf)

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

V0 Table 24 % Comp. Index 1-10 11-15 16-20 21-25 26-31 32-37 >38 Properties Excellent Good Fair Passable Poor Very poor Very very poor

c) ANGLE OF REPOSE In order to determine the flow property, the Angle of repose was determined. It is the maximum angle that can be obtained between the free standing surface of the powder heap and the horizontal plane. = tan -1 (h/r) Where, h = height r = radius = angle of repose Procedure: An accurately weighed sample was taken. A funnel was fixed in the stand in such a way that the tip of the funnel was at the height of 6 cm from the surface. The sample was passed through the funnel slowly to form a heap. The height and the circumference of the powder heap formed were measured. The radius was measured and the angle of repose was determined using the above formula. This was repeated five times for a sample. Table 25

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Flow Property Excellent Good Fair(aid not needed) Passable(may hang up) Poor(must agitate, vibrate) Very poor Very, very poor

Angle Of Repose(Degrees) 25-30 31-35 36-40 41-45 46-55 56-65 >66

d) AVERAGE FILL MASS: Procedure: Take 10 containers and individually weigh each container and its contents. Empty the container completely as possible and weigh. The difference between the mass represents the mass of the contents. Mass of 10 containers net Content ------------------------------------10

Averages fill mass, in gm

e) WATER CONTENT (By KF): Procedure: Transfer 35 to 45 mL methanol into the titration vessel, and titrate with KarlFischer reagent to the electrometric end point to consume any moisture that may be present. Transfer immediately about 100mg of dry powder accurately weighed, mixed, and again titrate with the reagent to the electrometric end point. Calculate the water content of the sample using KF factor. Perform ion duplicate and report the mean value. Calculation: Water Content (%): = Titre value x KF Factor ------------------------------Wt. of the sample, in mg

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

f) BLEND UNIFORMITY Blend uniformity test was carried out on the final formulation this test was carried out by determining the uniformity of blend at different time intervals based on average blend uniformity and % RSD the time interval for proper blending was determined OBSERVATIONS a) COMPRESSIBILITY INDEX Table 26 S.No 1 2 3 4 5 6 7 Formulation Code F001 F002 F003 F004 F005 F006 F007 Vo 28 32 31 31 28 29 30 V 24 27 27 26 24 25 26 Bulk Tapped Compressibility Density Density index 0.714 0.625 0.645 0.645 0.714 0.690 0.667 0.833 0.741 0.741 0.769 0.833 0.800 0.769 14.3 15.6 12.9 16.1 14.3 13.8 13.3

Vo volume before tapping V - Volume after tapping

c) Angle of repose Table 27 Formulation Code F001 F002 F003 Height (h) (Cms) 2.5 2.4 2.6 Radius (r) (Cms) 3.7 3.7 4.1 = tan 1 h/r 34 33 32

S.No. 1 2 3

h/r 0.68 0.65 0.63

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

4 5 6 7

F004 F005 F006 F007

2.3 2.7 2.3 2.7

3.2 4 3.5 4.2

0.72 0.68 0.66 0.64

36 34 33 33

d) AVERAGE FILL MASS Table 28 S.NO 1 2 3 4 5 6 7 Formulation code F001 F002 F003 F004 F005 F006 F008 Averages fill mass (42.5 g +/-2%) 42.05 43.10 42.40 41.90 42.18 42.70 42.60

e) WATER CONTENT Table 29 S.NO 1 2 3 4 5 6 7 Formulation code F001 F002 F003 F004 F005 F006 F007 Water content (NMT 3.0%) 0.20 0.18 0.16 0.13 0.17 0.16 0.15

f) Blend uniformity at different time intervals for final formulation (F007) Table 30

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Location U1 U2 U3 M1 M2 M3 L1 L2 L3 B0 AVG S.D R.S.D (NMT 5.0%)

limits At 10 min Model drug equivalent to 112.5 mg-137.5 mg of cefuroxime (90% to 110%) 99.2 100.2 98.1 100.8 99.9 106.2 98.3 100.6 97.4 105.5 100.6 3.0 3.0

Results in (%) At 15 min 101.9 99.9 98.1 98.5 102.8 99.2 96.8 99.5 100.6 98 99.5 1.8 1.9

At 20 min 102.8 101.3 100.2 101.4 99.2 100.6 99.5 98.9 99.1 98.9 100.2 1.3 1.3

Different sampling locations of octagonal blender are as follows.

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Octagonal blender Fig - 04

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

7.2 EVALUATION OF RE CONSTITUTED SUSPENSION: After re constitution of suspension it was stored at refrigerator (2-80C) and room temperature (37 20C) and evaluates the critical parameters of the suspension

a) RECONSTITUTION TIME: Procedure for reconstitution of suspension: Take the dry powder bottle and add small quantity of water (around10 mL) then shake well followed by make up to the mark with water and mix well. (For reconstitution around 16 mL will take for getting up the mark) Tap the bottle note down the initial time (t1) then shake gently to loosen the dry powder. Add half the required amount of water and shake vigorously. Slowly add the water up to the mark on the bottle. Again note down time (t2). Reconstitution time (T) = t2- t1 b) DESCRIPTION: Transfer 10 to 25ml of the sample to a dry Nesslers cylinder. Observe the color and clarity against white background.

c) DELIVERABLE VOLUME: Take 10 reconstituted suspension bottles and gently pour the contents of each container into a separate dry calibrated 100 mL graduated measuring cylinder. Allow each container to drain for a period not to exceed 30 minutes. Measure the volume of each mixture when free from air bubbles.

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

d) PH: Reconstitute the sample with water up to label mark. Wash the electrode with distilled water and wipe it with tissue paper. Transfer the sample solution into a beaker. Dip the electrode in sample solution and wait for 10 minutes then, measure the pH. Record the stabilized reading.

e) ASSAY (By HPLC Method):

WEIGHT PER ML CALCULATION Weight Per ml: Determine at 25C using specific gravity bottle Procedure: Take a clean dried empty specific gravity bottle with stopper and note down the weight (W1), fill the specific gravity bottle with distilled water, close the stopper note down the weight (W2). Then completely, empty and dry the specific gravity bottle, fill with suspension sample & note down the weight (W3).

Calculation: (W3- W1) Wt/mL = ---------------- x 0.99602 (W2- W1) = ___________ mg/mL

Weight of the Empty specific gravity Specific gravity bottle + water Specific gravity bottle + sample

= W1 mg = W2 mg = W3 mg

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

Procedure: Chromatographic system: Column Column temperature Flow rate Injection volume Detector Wave length Run Time : : : : : : Betasil C1: 250 mm4.6 mm; 5um 25C 2C 1.0 mL / minute 5 l. 278 nm About 45 minutes

Diluent-1: Methanol (100%) Diluent-2: Mix 900ml of methanol and 100ml of water. Buffer Solution: (0.2 M monobasic ammonium phosphate) Dissolve about 23g of monobasic ammonium phosphate in 1000ml of distilled water and mix well. Mobile phase: Mix 625ml of buffer and 375ml of methanol v/v then filter through 0.45m membrane filter and degassed. Standard Preparation: Weigh accurately about 60 mg of Model drug (equivalent to 50mg of Cefuroxime) working standard and transfer into a 50ml volumetric flask, then add 30ml of diluent-1, sonicate to dissolve then make up the volume with diluent-1, and mix well. Pipette out 5ml of the above solution into a 20ml volumetric flask and make up to mark with diluent-2, and mix well.

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

Test Preparation: Weigh accurately about 11800 mg of reconstitute suspension (equivalent to

250mg of Cefuroxime) in to a 100 mL volumetric flask, add 70mL of diluent-1, sonicate for 30minutes and make up to mark with diluent-1. Centrifuge the solution at 2000rpm. About 5 minutes. Pipette out 5ml of the above solution into 50ml with diluent-2.

Procedure: Separately inject equal volumes of about 5 l of diluent-2 as blank, five replicate injections of Standard preparation and two preparation of injections of test preparation into the chromatograph, record the chromatograms, and measure the responses for the peaks of Model drug diastereoisomers A and B.

System Suitability: (a) Tailing factor for the Model drug A peak from standard chromatogram should not be more than 2.0 (b) Tailing factor for the Model drug B peak from standard chromatogram should not be more than 2.0. (c) Resolution for Model drug diastereoisomers A and B Not Less Than 1.5 (d) Sum of theoretical plate count for Model drug diastereoisomers A and B not less than 4000 (e) The relative standard deviation of sum of the Model drug diastereo isomers A and B from replicate five injections of standard preparation should not be more than 2.0%.

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

Calculation: Calculate the quantity, in mg of Cefuroxime in 5 ml of the oral suspension sample taken by using the formula: AT WS 5 100 50 P 424.38 ---------x-------x------x--------x ---------x----------x------- ---- x 5 x Wt/ml AS 50 20 WT 5 100 510.48 Where, AT = the sum of the Model drug diastereoisomers A and B peak area obtained from the Test preparation of Cefuroxime. AS = the sum of the Model drug diastereoisomers A and B peak areas obtained from the Standard preparation Cefuroxime. WS = Weight of Model drug working standard taken in mg for standard Preparation. WT = Weight of test sample taken in mg for test preparation of Model drug. P = Purity of Model drug working standard as such basis in % Molecular weight of Cefuroxime = 424.38. Molecular weight of Model drug = 510.48. Wt/ml = Weight per ml of the Test Sample in mg/ml.

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

f) DISSOLUTION (By U.V Method) WEIGHT PER ML CALCULATION Weight Per ml: Determine at 25C using specific gravity bottle Procedure: Take a clean dried empty specific gravity bottle with stopper and note down the weight (W1), Fill the specific gravity bottle with distilled water; close the stopper note down the weight (W2). Then completely, empty and dry the specific gravity bottle, fill with suspension sample & note down the weight (W3). Calculation: (W3- W1) Wt/mL= ---------------- x 0.99602 (W2- W1) Weight of the Empty specific gravity Specific gravity bottle + water Specific gravity bottle + sample Dissolution Parameters: Medium Volume Apparatus RPM Time Temperature : : : : : : 0.07M pH 7.0 Phosphate Buffer 900mL USP Type-II (Paddle) 50 30 minutes. 37.0 0.5C = W1 mg = W2 mg = W3 mg = ___________ mg/mL

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

Dissolution Medium (0.07 M pH 7.0 phosphate buffer): Dissolve 3.7g of monobasic sodium phosphate and 5.7g of anhydrous dibasic sodium phosphate in 1000 mL of water, ensure that final pH of medium should maintain pH 7.0.

Standard Preparation: Weigh accurately about 33.5 mg of Model drug (equivalent to 27.8mg of Cefuroxime) working standard and transfer into a 100ml volumetric flask, then add 30ml of methanol dissolve then make up the volume with methanol Pipette out 1ml of the above solution into a 200ml volumetric flask and make up to mark with dissolution media

Test Preparation: Reconstitute the 6 samples; determine the weight per ml of these suspensions. Set the parameters of dissolution apparatus as mentioned above. Weigh and transfer the 5.0 mL constituted Model drug for oral suspension equivalent to 125 mg of cefuroxime (about 6.0 g of the Sample) from each bottle of six dissolution vessels and start the dissolution test. At the end of the specified time interval, withdraw about 10 ml of sample solution from each dissolution vessel, by using auto sampler 10 free flow filter.

Procedure Measure the standard solution absorption for five times at 280 nm using dissolution media as blank. Measure the time point of test preparation against dissolution media as a blank. System suitability The relative standard deviation of absorbance of paracetamol from five replicate scanning of standard solution should not be more than 2.0%

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

Calculation: Calculate the amount of Cefuroxime dissolved in dissolution medium % Labelled Amount = AT WS 1 900 200 ---------x----- ------x ---------x---------x ------ x AS 100 200 Wt 2 P 424.38 ---------- x ---------- x Wt per ml x 5 LC 510.48

Where, AT = absorbance obtained for Model drug from sample preparation AS = absorbance obtained for Model drug from standard preparation WS = Weight of Model drug working standard taken in mg for standard Preparation. Wt = Weight of test sample taken in mg for each dissolution bowel as CefuroximeAxetil. P = Purity of Model drug working standard as such basis in % Molecular weight of Cefuroxime = 424.38. Molecular weight of Model drug = 510.48. Wt/ml = Weight per ml of the Test Sample in mg/ml. LC = Label claim of Cefuroxime per 5ml of reconstitute suspension

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

g) RELATED SUBSTANCES (By HPLC Method) WEIGHT PER ML CALCULATION: Weight Per ml: Determine at 25C using specific gravity bottle Procedure: Take a clean dried empty specific gravity bottle with stopper and note down the weight (W1), fill the specific gravity bottle with distilled water, close the stopper note down the weight (W2). Then completely, empty and dry the specific gravity bottle, fill with suspension sample & note down the weight (W3). Calculation: (W3- W1) Wt/mL = ---------------- x 0.99602 (W2- W1) = __________ mg/mL

Weight of the Empty specific gravity Specific gravity bottle + water Specific gravity bottle + sample

= W1 mg = W2 mg = W3 mg

Chromatographic system: Column Column temperature Flow rate Injection volume Detector Wave length Diluted standard Run Time Test sample Run Time : Betasil C1: 250 mm4.6 mm; 5um : 25 C 2C : 1.0 mL / minute : 100 l. : 278 nm : About 60 minutes. : About 110 minutes

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

Diluent-1: Methanol (100%) Diluent-2: Mix 900 ml of methanol and 100 ml of Buffer. Diluent-3: Buffer (100%) Buffer Solution: (0.2 M monobasic ammonium phosphate) Dissolve about 23g of monobasic ammonium phosphate in 1000ml of distilled water and mix well. Mobile phase: Mix 700ml of buffer and 300ml of methanol v/v then filter through 0.45m membrane filter and degassed. Diluted Standard Preparation: Weigh accurately about 75mg of Model drug (equivalent to 62.5mg of Cefuroxime) working standard and transfer into a 50 ml volumetric flask, then add 30ml of Diluent-1, sonicate to dissolve then make up the volume with Diluent-1. Pipette out 5 ml of the above solution into a 100 ml volumetric flask and make up the volume with diluent-2. Pipette out 2 ml of the above solution into a 100ml volumetric flask and make up the volume with Diluent-3. Test Preparation: Weigh accurately about 11800 mg of reconstituted suspension (equivalent to 250mg of Cefuroxime) in to a 100 mL volumetric flask, add 50mL of diluent-1, sonicate for 30minutes and make up to mark with diluent-1. Centrifuge the solution at 2000 rpm about 5 minutes. Pipette out 5ml of the above solution into 50 ml with diluent-2. Pipette out 10ml of the above solution into 20ml with diluent-3. Filter the solution through hydrophilic PVDF 0.45 m membrane filter. Note: While sonicating the test sample need to maintain the temperature of the sonicator bath should be between 20 to 25C

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

Reference solution: Weigh accurately about 300 mg of Model drug (equivalent to 250mg of

Cefuroxime) in to a 100 mL volumetric flask, add 70mL of diluent-1, sonicate for 30minutes and make up to mark with diluent-1. Centrifuge the solution at 2000 rpm about 5 minutes. Pipette out 5ml of the above solution into 50 ml with diluent-2. Pipette out 5 ml of the above solution into 20ml with diluent-3. Filter the solution through using 0.45 m membrane filter (millex). Expose 5 ml of reference solution, in to ultraviolet light at 254 nm for 24 Hours to generate Delta3-isomers and Anti Isomer peaks. Identification of Impurities: Use the chromatogram obtained with reference solution to identify the pair of peaks due to Delta-3 and Anti Isomer impurities peaks.

Procedure: Separately inject equal volumes of about 100 l of diluent-3 as blank, two replicate injections of Standard preparation and one injections of test preparation into the chromatograph, record the chromatograms, and measure the responses for the peaks.

System Suitability Parameters for Model drug Sum of theoretical Plate Count for Model drug diastereoisomers A and B. Tailing factor for Model drug diastereoisomers A Tailing factor for Model drug diastereoisomers B Ratio of two peaks obtained from diluted standard for diastereomers A and B.

Limit 4000 NMT 2.0 NMT 2.0 Should be between 0.9 to 1.1

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

Resolution for Model drug diastereoisomers A and B. Resolution between Model drug diastereoisomers A and Delta-3 Isomer. Calculation: The percentage content of Cefuroxime impurities E-Isomer = AIET x WS1 x 5 x 2 x 100 x 50 x 20 x P x 5 x Wt /ml x 424.38x100 ADS 50 100 100 WT 5 10 100 LC 510.48 Delta-3-Isomer = AIDT x WS1 x 5 ADS 50 100 x 2 x 100 x 50 x 20 x P x 5 x Wt /ml x 424.38 x100 100 WT 5 10 100 LC 510.48 NLT 1.5 NLT 1.5

Cefuroxime Acid Impurity = AIDT1 x WS1 x 5 x 2 x 100 x 50 x 20 x P x 5 x Wt /ml x 424.38 x100 ADS 50 100 100 WT 5 10 100 LC 510.48 Cefuroxime Lactone Impurity = AIDT2 x WS1 x 5 x 2 x 100 x 50 x 20 x P x 5 x Wt /ml x 424.38 x100 ADS 50 100 100 WT 5 10 100 LC 510.48 Maximum individual unknown impurity = AIUIT x WS1 x 5 x 2 x 100 x 50 x 20 x P x 5 x Wt /ml x 424.38 x100 ADS 50 100 100 WT 5 10 100 LC 510.48 Total impurities = ATIT x WS1 x 5 x 2 x 100 x 50 x 20 x P x 5 x Wt /ml x 424.38 x 100 Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

ADS Where, AIET = Sum of Area of E-Isomer impurity peaks in test solution. AIDT = Area of Delta-3 Isomer impurity in test solution AIDT1 = Area of Cefuroxime Acid impurity in test solution AIDT2 = Area of Cefuroxime Lactone impurity in test solution AIUIT = Area of maximum individual unknown impurity in test solution. ATIT = Total area of all impurities after subtracting blank, Model drug diastereoisomers A and B and Placebo peaks. ADS = Sum of the Area of diluted standard diastereoisomers Model drug A and B. WS1 = Weight of working standard in mg. WT P LC = Weight of test sample in mg. = Purity of Model drug working standard as such basis in %. 50 100 100 WT 5 10 100 LC 510.48

= Label claim cefuroxime 125mg

Wt/ml= Weigh per ml of the Test Sample in mg Molecular weight of Cefuroxime = 424.38. Molecular weight of Model drug = 510.48.

RRTs of Impurities calculated with respective to Model drug A peak RT Table 31

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Evaluation of reconstituted suspension

Name of the impurities Cefuroxime Lactone Impurity Cefuroxime Acid Impurity Delta-3 Isomer E1 Isomer E2 Isomer RT 4.46 5.84 43.84 62.20 75.02 RRT 0.12 0.15 1.13 1.61 1.94

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Observations
OBSERVATIONS
b) DESCRIPTION Table 32
Description S.No 1 2 Batch no Innovator F001 On the day of reconstitution white coloured flavoured suspension Off white coloured flavoured suspension On 11 th day of reconstitution At 2-8c white coloured flavoured suspension Off white coloured flavoured suspension Off white coloured flavoured suspension Off white coloured flavoured suspension Off white coloured flavoured suspension Off white coloured flavoured suspension Off white coloured flavoured suspension Off white coloured flavoured suspension At 252c white coloured flavoured suspension Off white coloured flavoured suspension Off white coloured flavoured suspension Off white coloured flavoured suspension Off white coloured flavoured suspension Off white coloured flavoured suspension Off white coloured flavoured suspension Off white coloured flavoured suspension

F002

Off white coloured flavoured suspension

F003

Off white coloured flavoured suspension

F004

Off white coloured flavoured suspension

F005

Off white coloured flavoured suspension

F006

Off white coloured flavoured suspension

F007

Off white coloured flavoured suspension

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Observations

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Observations
a) RECONSTITUTION TIME Table 33 S.No 1 2 3 4 5 6 7 8 Batch no Innovator F001 F002 F003 F004 F005 F006 F007 Re constitution time About 5 min About 4min About 5min About 5min About 4min About 4min About 5min About 5min

c) DELIVERABLE VOLUME Table 34

S.No 1 2 3 4 5 6 7

Batch no F001 F002 F003 F004 F005 F006 F007

Deliverable volume(min) 48 49 50 50 50 50 50

d) PH Table 35 S.No Batch no On the day of re constitution PH On the 11 th day of reconstitution

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Observations
1 2 3 4 5 6 7 8 ASSAY Table 36 Assay (92.5%- 107.5%) On the 11 th day of reconstitution At 2-8c At 25 2c 125.13mg (100.1%) 124.75mg (99.80%) 125.38mg (100.3%) 124.63mg (99.7%) 125.25mg (100.2%) 124.88mg (99.9%) 125.88mg (100.7%) 125.25mg (100.2%) 125.75mg (100.6%) 125.13mg (100.1%) 126.00mg (100.8%) 125.38mg (100.3%) 125.63 mg (100.5%) 124.75mg (99.8%) 125.50 mg (100.4%) 124.75mg (99.8%) innovator F001 F002 F003 F004 F005 F006 F007 5.2 5.0 5.2 4.8 5.2 5.3 5.3 5.8 At 2-8c 5.0 4.8 5.1 4.5 5.1 5.1 5.0 5.2 At 25 2c 4.9 4.5 5.0 4.1 4.6 5.0 4.7 5.0

S.No 1 2 3 4 5 6 7 8

Batch no innovator F001 F002 F003 F004 F005 F006 F007

On the day of re constitution 125.38 mg (100.3%) 125.50 mg (100.4%) 125.63 mg (100.5%) 126.25 mg (101.0%) 126.13 mg (100.9%) 126.38 mg (101.1%) 125.88 mg (100.7%) 126.00 mg (100.8%)

f) DISSOLUTION
Dissolution Profile for formulated suspensions Table 37 % of labeled amount 30 min 82 82 79 73 88 80 81 f2 value 45 min 92 89 86 84 94 91 90 68 62 54 67 77 74

formulation Innovator F001 F002 F003 F004 F005 F006

15 min 79 71 70 68 85 74 73

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Observations
F007 76 82 93 86

120 100

% of drug release

80 60 40 20 0

10

20

30

40

50

time (in min)

F001

F002

F003

F004

F005

F006

F007

Comparison of innovator with final formulation

Table 38 formulation Innovator F007 % of labeled amount 30 min 82 82

15 min 79 76

45 min 92 93

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Observations
100 80 % of drug release 60 40 20 0
0 10 20 30 40 50

time(in min) Innovator F007

Similarity factor calculation

f1 = { [ t=1 n t Tt ] / [ t=1 n Rt ] } . 100 R f2 = 50. log { 1 + ( 1/n) t=1 n (Rt - Tt ) 2 ] 0.5 . 100

Table 39

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Observations
Time in min 0 15 30 45 Cumulative percentage RLD values TEST values 0 0 79 76 82 82 92 93 (R-T) 0.0 3.0 0.0 1.0 (R-T)2 0.0 9.0 0.0 1.0

F1 F2

2 86

(NMT 15) (NLT 50)

Comparison of dissolution Based on stearic acid concentration Table 40 Formulation F003(stearic acid 1200mg) F004(stearic acid 600mg) F008(stearic acid 850mg) % of labeled amount 15 min 30 min 45 min 68 73 84 85 88 94 76 82 93 f2 value 54 67 86

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Observations

120 100
% of drug release

80 60 40 20 0
0 10 20 30 40 50

time (in min) F003 F004 F007

Dissolution of final formulation at different time intervals of blending Table 41 BLENDING TIME 10min 15 min 20 min % of labeled amount 15min 70 72 76 30 min 76 78 80 45 min 82 84 91 56 62 80 f2 value

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Observations

100 80 60 40 20 0 0 10 20 30 40 50

% ofdrug release

time (in min) innovator At 10 min At 15 min At 20 min

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Observations
g) RELATED SUBSTANCES Table 42 Name of the impurities On the day of re constitution 0.135 ND 0.192 0.114 0.047 0.721 Impurity level in % Innovator On the 11th day of re constitution Stored at 2- 8oc Stored at (RT) 0.140 ND 0.281 0.124 0.205 0.799 0.160 ND 0.302 0.224 0.312 0.816 Reconstituted suspension (F007) On the day of re On the 11th day of re constitution Stored at 2- 8oc Stored at (RT) constitution 0.041 ND 0.106 0.182 0.035 0.413 0.170 ND 0.229 0.282 0.047 0.631 0.172 ND 0.267 0.311 0.053 0.726

acid Impurity lactone Impurity Delta-3 Isomer E- Isomers Maximum single un known impurity Total impurities

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Observations

On the day of reconstitution

0.25

% of impurity

0.2 0.15 0.1 0.05 0

Innovator Innovator
F007 F007

F007

Innovator Innovator
F007

Acid

Delta 3

E-isomer

Max sing

Impurity name Innovator F007

On the 11 th day of reconstitution(2-8c)

0.3 0.25

Innovator
F007 F007

F007

% of impurity

Innovator

0.2 0.15 0.1

Innovator

Innovator
F007

0.05 0 Acid Delta 3 E-isomer Max sing Im purity name Innovator F007

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Observations

On the 11 th day of reconstitution(RT)

0.4

Innovator
% of impurity
0.3 0.2 0.1 0 Acid

Innovator
F007

Innovator

Innovator

F007 F007

Delta 3

E-isomer

Max sing

Im purity nam e

Innovator

F007

Total impurities
1 0.8 Innovator F007 0.6 F007 0.4 0.2 0 Innovator F007

Innovator

% of impurity

Total Innovator Innovator F007 F007 Innovator F007

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Stability studies
Stability studies of the formulations Stability is an important parameter evaluated for the formulations to assess the stability of the drug in the formulation at the probable storage conditions. a blend of 100 bottles was prepared using final optimized formula (F7).blend was filled in 100ml amber glass bottle having poly propylene white CRC 28 mm cap with rubber stopper bromobutyl 26 mm grey and kept in stability chambers maintained at 25c /60% RH (3 month) 40c /75%RH (1, 2, 3 month) for evaluation with respect to assay and dissolution studies.

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Stability studies
Stability data at 40C 2C/75% RH 5% RH Table 43 Tests specification For dry powder Description White to off white flavored powder Water content Not more than 6.0% B) For Reconstituted Suspension On Day Of Reconstitution Description Off white to yellow colored flavored suspension PH Between 3.5-7.0 Assay (By HPLC) % Labeled amount between 90-110% Dissolution (in %) f2 value in between 50-100 Related Substances (in %) Cefuroxime Lactone Not more than 1.0% Cefuroxime Acid Not more than 1.0% E isomers Not more than 1.5% 3 isomers Not more than 2.0% Max. Single unknown Imp. Not more than 1.0% Total Impurities Not more than 7.0% For re constituted suspension on the 11 th day of reconstitution(at 2-8c) Description Off white to yellow colored flavored suspension PH For information only Assay (By HPLC) % Labeled amount between 90-110% Related Substances (in %) Cefuroxime Lactone Not more than 1.0% Cefuroxime Acid Not more than 1.0% E isomers Not more than 1.5% 3 isomers Not more than 2.0% Max. Single unknown Imp. Not more than 1.0% Initial Complies 0.16 Complies 5.88 100.8 86 ND 0.041 0.182 0.106 0.035 0.413 1st month Complies 0.15 Complies 5.72 100.6 82 ND 0.049 0.267 0.212 0.036 0.611 2nd months Complies 0.18 Complies 5.59 100.3 82 ND 0.145 0.277 0.267 0.052 0.691 3rd month Complies 0.16 Complies 5.20 99.8 77 ND 0.176 0.324 0.319 0.065 0.934

5.19 100.4 ND 0.170 0.282 0.229 0.047

5.15 100.3 ND 0.179 0.287 0.256 0.055

5.07 100.3 ND 0.192 0.295 0.286 0.057

5.05 99.8 ND 0.225 0.305 0.289 0.082

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Stability studies
Total Impurities Not more than 7.0% 0.631 82 99.8 5.0 ND 0.158 0.311 0.267 0.053 0.726 82 0.726 NP 99.7 4.9 ND 0.263 0.356 0.214 0.066 1.099 77 0.738 80 99.6 4.9 ND 0.267 0.376 0.291 0.068 1.162 75 1.076 76 99.5 4.8 ND 0.413 0.386 0.297 0.078 1.186 71

Dissolution (in %) f2 value in between 50-100 For re constituted suspension on the 11 th day of reconstitution(at RT) Assay (By HPLC) % Labeled amount between 90-110% PH For information only Related Substances (in %) Cefuroxime Lactone Not more than 1.0% Cefuroxime Acid Not more than 1.0% E isomers Not more than 1.5% 3 isomers Not more than 2.0% Max. Single unknown Imp. Not more than 1.0% Total Impurities Not more than 7.0% Dissolution (in %) f2 value in between 50-100 IMPURITY PROFILE
On the day of reconstitution

DISSOLUTION PROFILE
on the day of re constitution % of drug release
120 100 80 60 40 20 0 0 10 20 30 40 50

% Of impurity

0.8 0.6 0.4 0.2 0 Acid E- isomer Delta3 Max sing Total

Impurity name
Initial 1 st month 2 nd month 3 rd month

time ( in min) initial 1st month 2 nd month 3 rd month

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Stability studies

On the 11 th day of reconstitution at (2-8c)

on the 11 th day of re constitution(at 2-8c) % of drug release

100 80 60 40 20 0 0 10 20 30 40 50

1.2

% of impurity

1 0.8 0.6 0.4 0.2 0 Acid E- isomer Delta3 Max sing Total

Impurity name
Initial 1 st month 2 nd month 3 rd month

time (in min) initial 2 nd month 3 rd month

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Stability studies
On the 11 th day of reconstitution(RT)

on the 11 th day of re constitution(RT) % of drug release

100 80 60 40 20 0
0 10 20 30 40 50

1.4

% of impurity

1.2 1 0.8 0.6 0.4 0.2 0 Acid E isom er Delta3 M sing ax Total

time (in min) initial 1st month 3 rd month 2 nd month

Im putity nam e
Initial 1 st month 2 nd month 3 rd month

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Stability studies
Stability data at 25C 2C/60% RH 5% RH Table 44 Tests specification Description White to off white flavored powder Water content Not more than 6.0% B) For Reconstituted Suspension On Day Of Reconstitution Description Off white to yellow colored flavored suspension PH Between 3.5-7.0 Assay (By HPLC) % Labeled amount between 90-110% Dissolution (in %) f2 value in between 50-100 Related Substances (in %) Cefuroxime Lactone Not more than 1.0% Cefuroxime Acid Not more than 1.0% E isomers Not more than 1.5% 3 isomers Not more than 2.0% Max. Single unknown Imp. Not more than 1.0% Total Impurities Not more than 7.0% For re constituted suspension on the 11 th day of reconstitution(at 2-8c) Description Off white to yellow colored flavored suspension PH For information only Assay (By HPLC) % Labeled amount between 90-110% Related Substances (in %) Cefuroxime Lactone Not more than 1.0% Cefuroxime Acid Not more than 1.0% E isomers Not more than 1.5% 3 isomers Not more than 2.0% Max. Single unknown Imp. Not more than 1.0% Total Impurities Not more than 7.0% Design and Characterization of Modified release Matrix tablet of Highly soluble drug Initial Complies 0.16 Complies 5.88 100.8 86 ND 0.041 0.182 0.106 0.035 0.413 Complies 5.19 100.4 ND 0.170 0.282 0.229 0.047 0.631 3rd month Complies 0.16 Complies 5.43 100.6 81 ND 0.046 0.286 0.194 0.044 0.586 Complies 5.16 100.1 ND 0.186 0.295 0.246 0.054 0.804

Stability studies
Dissolution (in %) f2 value in between 50-100 For re constituted suspension on the 11 th day of reconstitution(at RT) Assay (By HPLC) % Labeled amount between 90-110% PH For information only Related Substances (in %) Cefuroxime Lactone Not more than 1.0% Cefuroxime Acid Not more than 1.0% E isomers Not more than 1.5% 3 isomers Not more than 2.0% Max. Single unknown Imp. Not more than 1.0% Total Impurities Not more than 7.0% Dissolution (in %) f2 value in between 50-100 DISSOLUTION PROFILE 82 99.8 5.0 ND 0.158 0.311 0.267 0.053 0.726 81 78 99.6 4.9 ND 0.258 0.363 0.279 0.068 1.102 76

IMPURITY PROFILE

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Stability studies
on the day of re constitution
100
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Acid E- isomer Delta3 Max sing Total

On the day of reconstitution

% of drug release

80 60 40 20 0 0 10 20 30 40 50

% of impurity

time (in min)

intial 3 rd month

Impurity name Initial 3 rd month

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Stability studies

on the 11 th day of re constitution (at 2-8c) % of drug release

On the 11 th day of reconstitution at(2-8c)

1

% of impurity

100 80 60 40 20 0 0 10 20 30 40 50

0.8 0.6 0.4 0.2 0 Acid E- isomer Delta3 Max sing Total

time (in min)

Impurity name Initial 3 rd month

initial

3 rd month

on the 11 th day of re constitution (RT) % ofdrug release

100

On the 11 th day of reconstitution(RT)

1.2

60 40 20 0

% of impurity

80

1 0.8 0.6 0.4 0.2 0 Acid E isom er D elta3 M sing ax Total

10

20

30

40

50

tim (in min) e initial 3 rd month

Impurity name Initial 3 rd month

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Result and Discussion 122

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11.0 RESULT AND DISCUSSION

Most of the conventional drug delivery system for treating the anginal was not much effective, as the drug do not reach the site of action in appropriate concentration. Thus an effective and safe therapy of this anginal disorder using specific drug delivery system was a challenging task to the pharmaceutical technologists. Modified release delivery systems was a technology by which we can achieve predictable and reproducible release rates, extended duration of activity for short half-life drugs, decreased toxicity, reduction of required dose, optimized therapy, and better patient compliance. Considerable attention was focused on hydrophilic polymers in the design of oral drug delivery systems because of their flexibility to obtain a desirable drug release profile, cost effectiveness and broad regulatory acceptance. The drug has been administered by oral route at doses of from 40 to 60 mg/day, in the form of tablets containing 20 mg of active ingredient in an immediate release form. Since the drug is rapidly absorbed and eliminated by the body, its plasma half-life being less than 6 hours, leading to administration of the active ingredient into 2 or 3 administration per day in order to ensure sufficient plasma levels. The dosage regimen most frequently required during the treatment is three tablets per day. Multiple daily administration bear the risk of being forgotten both by the patients leading to active life and by elderly patients already taking a number of medications Because of the rapid absorption and the 6 hour half life, such immediate release forms results in low levels in the blood by the time of the next administration. It is known to be important to maintain the effective myocardial protection throughout the 24 hours period and especially in the early morning when the consequences of ischemia are more serious, because complete coverage of the day is not achieved with the immediate release form. This led to the development of modified release form enabling perfect 24 hour coverage, Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Result and Discussion 123

Page

ensuring a sufficient level in the blood between two administrations whilst retaining a large plasma peak after each administration so as to maintain the efficacy of the drug, maintaining the energy metabolism of a cell exposed to hypoxia or ischemia and avoiding the lowering of the intracellular level of ATP. It also allows peripheral vasodilator effects to be avoided, while stabilizing blood flow rates and tensional effects This led to the formulation of a matrix tablet which enables the modified release of drug by oral route which composes of a hydrophilic matrix characterized in that the modified release is controlled by the use of a non-cellulosic derivative polymer This matrix tablet, administrable preferably twice a day, enables prolonged active ingredient release to be obtained whilst retaining a large plasma peak on each administration. It allows plasma levels greater than 70 g/l to be obtained in humans after each administration and a plasma level greater than or equal to 40 g/l to be maintained until the next administration, which was not the case with the immediate release tablet when administered 3 times per day. Among the hydrophilic polymers, cellulose derivatives such as methyl cellulose, hydroxyl propyl methyl cellulose and sodium carboxymethyl cellulose are generally considered to be stable and safe as release retardant excipients in the development of modified release dosage forms. But this present invention deals with the fabrication of matrices with noncellulosic polymer including water soluble/ swellable polysaccharides such as Xanthan gum and Polyethylene oxide for retarding the drug release to get the desired release profile matching with the innovator. Since semi synthetic polymers are quite expensive when compared with natural polymers such as Guar gum and Xanthan gum, the use of natural polymers were considered, as they are nontoxic and easily available. Poly (ethylene oxide) is also a non-ionic water-soluble resin, available in a variety of molecular weight grades ranging from 100,000 to 7,000,000 Daltons. The common grades of PEO which are used for extended-release applications include POLYOX WSR-205 NF, WSR-1105

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Result and Discussion 124

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NF, WSR N-12K NF, WSR N-60K NF, WSR-301 NF, WSR-303 NF and WSR Coagulant NF. They are the fastest hydrating water-soluble polymers amongst the hydrophilic polymers, which makes PEO products a suitable choice for applications where slower initial drug release is required The present study was to develop a modified release formulation of a class III highly soluble drug with hydrophilic polymers such as Xanthan gum & Polyethylene oxide which can retard the drug release up to 8-12 hrs. The formulation of modified release matrix tablet was prepared by direct compression technology using a combination of polymer with different concentration in order to match with the innovator release profile. Six formulations were designed with different combination of polymer to drug ratio to prepare the modified release matrix tablets. It was observed that the amount of polymer influences the drug release. In vitro release study results revealed that the release of drug was retarded with the proportional increase of the polymer concentration. Compatibility Studies By IR Spectra Drug excipient compatibility studies were carried out to check whether any compatibility related problems are associated between drug and excipients used in the formulations. The IR Spectrum of pure drug was compared with the IR spectrum of the drug with mixer of excipients. The IR spectrum of the formulation was matching with the IR spectrum of pure drug, which reveals that there is no interaction between the drug, excipients and polymer used in the tablets as there was no appearance or disappearance of any characteristics peaks. (Fig.08-14) By forced degradation studies: The Binary mixtures of drug and excipients were prepared and packed in closed

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Result and Discussion 125

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vials and kept in accelerated environmental conditions of 400/75% RH for 1 month. At the end of 1 month period all the samples were observed for physical observation and Impurity levels Table- 40 Compatibility data for Drug: Excipients Related Substances Highest Total unknown 0.009 0.03 0.014 0.102 0.011 0.012 0.052 0.017 0.023 0.019 0.043 0.022 0.076 0.052 0.285 0.072 0.064 0.057 0.192 0.031

S. No 1 2 3 4 5 6 7 8 9 10

Composition Details Drug Drug + Xanthan gum Drug + Anhydrous dicalcium phosphate Drug + Povidone K 90 Drug + Lactose monohydrate Drug + Polyethylene oxide Drug + Colloidal anhydrous silica Drug + Magnesium stearate Drug + Opadry II Pink 85G44092 Drug + Glycerine

Rati o 1:10 1:10 1:5 1:10 1:10 1:1 1:1 1:1

Overall, no noticeable change was observed in physical attributes (color, texture, etc) of the binary mixtures. Further, the total impurities in blends are compared to drug alone, corroborating the chemical compatibility between active substance and excipients attempted during the formulation development.

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Result and Discussion Page 126 IR Spectrum of API Fig- 4

IR Spectrum of API + Polyethylene Oxide Fig- 5

Fig: 6

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Result and Discussion Page 127 Fig- 6: IR Spectrum of API + Povidone K90

IR Spectrum of API + Povidone K90 Fig- 6

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Result and Discussion Page 128 IR Spectrum of API + Xanthan Gum Fig- 7

IR Spectrum of API + Polyethylene Oxide + Povidone K90 + Xanthan Gum IR Spectrum of API+ PEO+ Povidone K90+ Xanthan Gum Fig- 8

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Result and Discussion Page 129

IR Spectrum of Placebo Fig- 9

IR Spectrum of API + Placebo Fig- 10

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Result and Discussion Page 130

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Result and Discussion 131 Evaluation of Blend

Page

Based on Preformulation data, Xanthan Gum, Povidone K90, and Polyethylene oxide was taken as drug release retardants for formulation of matrix MR tablets of a highly water soluble drug. The tablets were formulated by direct compression technology using the above mentioned polymers to match the drug release with that of Innovator. The blended powders of different formulation were evaluated for angle of repose, loose bulk density (LBD), tapped bulk density (TBD), compressibility index, Hausners Ratio and drug content uniformity (Table- 20). The result of angle of repose in formulations F1, F4, F5 & F6 (35, 28, 33& 30) indicate good flow properties of the granules. In F2 & F3 (40 & 47) found to be poor flow. Compressibility Index indirectly measures the flowability of powder mass (Fiese and Hagen, 1986), the Compressibility Index value of all formulation was measured and found to be 17%, 19%, 23%, 17%, 26% & 22% for formulations F1, F2, F3, F4, F5 & F6 respectively. This result is an indication that the transport of blend from the hopper into the feed frame and for subsequent die filling could be better for the formulations F1, F2, F4 & F6 than F3 & F5 because it is known that the CI value below 15% indicates good to Excellent flowability of a material. The Hauser ratio, LBD and TBD ranged from 1.21 0.007 to 1.34 0.005, 0.4168 0.002 to 0.4546 0.004 and 0.5346 0.003 to 0.5963 0.005 respectively (Table- 20). The drug content in a weighed amount of powder blend of all MR formulations ranged from 98.27 0.88 to 98.57 0.84 (Table- 20). Formulation of modified release core tablets The modified release tablet was formulated to release the drug from 8hrs-12hrs by varying polymers and its concentration. In formulation F1, F2 & F3, Xanthan Gum was used in the ratio of 14%w/w, 24%w/w and 38%w/w of the total weight of the tablets (i.e.) 30mg, 50mg, & 80mg / tab respectively. The release of the drug from the formulation F1 was not satisfactory since the total drug was released within 2hrs. In F2 & F3, the concentration of Xanthan Gum was increased to prolong the drug release. But the drug release was prolonged for a period of 3hrs & 4hrs respectively. Since F1, F2 & F3 release profile was not matching with the

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Result and Discussion 132

Page

innovator product and further increasing the Xanthan gum concentration in the formulation may lead to reduction of flow property of blend and also possibility of microbial contamination, the polymer Xanthan gum was replaced with Polyethylene oxide, in order to retard the rate of release of drug.. In formulation F4, the Polyethylene oxide was used with a maximum amount of 73mg/tab based on IIG limit and was observed that the drug release was retarded to a extend of 6hrs only, which not matching with that of innovator. Moreover the tablets formulated only with PEO were found to have slight rough surface which may affect the appearance of tablets after coating. Hence Formulation F5 was designed with the combination of 2 polymers namely Xanthan gum & Polyethylene oxide in the ratio of 24% w/w & 34% w/w respectively to prolong the drug release. But the drug release was retarded for a period of more than 12hrs and was not matching with the proposed specification. Moreover since the quantity of Xanthan gum was more in the formulation, the impurity in the tablet formulated was found to exceed the limit as per ICH guidelines when kept at stability for a period of 1 month at 40oC/75% RH. Next trial F6 was formulated by decreasing the concentration of Xanthan gum from 24% to 14%w/w (i.e.) from 50mg/tab to 30mg/tab to match the dissolution profile with that of innovator and also to have a stable product, where the amount of Polyethylene oxide was kept constant with 73mg/tab. The physical parameters were found to be satisfactory & dissolution profile was found to be matching with innovator having f2 value of 71. Evaluation of modified release core tablets The matrix tablets of various batches formulated were evaluated for test such as uniformity of weight, hardness, thickness, friability and drug content. The weight variation tests were performed according to as per procedure given in British pharmacopoeia. The average percentage deviation of all tablet formulation was found to be (F1: -1.5 to +2.0; F2: -1.7 to +1.4; F3: -1.8 to +1.2; F4: -1.6 to +1.5; F5: -2.0 to +2.0; F6: -1.9 to +1.6 ) which was found to be within the pharmacopoeial limit of 7.5 % hence all formulation passed the test for uniformity of weight. The thickness of the matrix

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Result and Discussion 133

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tablet was found to be in the range of 4.1 to 4.4 mm. The hardness of all batches ranged from 9.4-12.2 Kp. Another measure of tablet strength is friability. The friability of all formulation ranged from (0.06 % to 0.34%) which was below 1% limit as per the British pharmacopoeia indicating that the friability is within the specification limit. All the tablet formulations showed acceptable pharmacotechnical properties and complied with the inhouse/BP specifications for weight variation, drug content, hardness and friability. Evaluation of Film coated Tablets After compression, the matrix tablets were film coated with a non-cellulosic polymer, namely Opadry II Pink 85G44092, containing PVA, for good appearance and to protect the tablet from environment. The film coated matrix tablets were evaluated for test such as uniformity of weight, hardness, thickness, friability and drug content. The average percentage deviation of all tablet formulation was found to be (F1: -1.5 to +1.5; F2: -1.4 to +1.1; F3: -1.3 to +1.5; F4: -0.9 to +1.5; F5: -1.3 to +2.5; F6: -1.8 to +1.4) within the pharmacopoeial limit. The thickness of the matrix tablet was found to be in the range of 4.2 to 4.5 mm. The hardness of all batches ranged from 10.5-15.3 Kp. Invitro evaluation of modified release film coated tablet The performance of modified release formulation has been reported to be greatly affected by physicochemical properties of polymer. The amount of polymer may influence the release of drug from the formulation. In vitro release study performed in 0.1N HCl with 900 ml, paddle, 50 rpm, reveals that the release of drug was retarded with the proportional increase of the polymer concentration. When the hydrophilic matrix tablets of Class III drug come into contact with the dissolution medium, they take up water and swell, forming a gel layer around the matrix. Then the dissolved drug diffuses out of the swollen hydrophilic matrix at a rate determined by the amount and viscosity of Xanthan gum and Polyethylene oxide in the tablet formulation. The hydrophilic polymer swells quickly & completely providing a stronger gel to prevent the immediate tablet disintegration and controlling the diffusion of the drug.

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Result and Discussion 134

Page

In vitro release study data indicate that duration of release of drug is dependent on the percentage of selected polymer used in the formulations. An increase in the polymer concentration not only causes increase in the viscosity of the gel but also leads to formation of gel layer with a longer diffusional path. This leads to a decrease in the diffusion of the drug and therefore a reduction in the drug release rate. Initially tablets prepared with drug to polymer ratio of 1:0.8 with Xanthan gum in formulation F1 released 100% of drug within 2 hrs. Hence the polymer concentration was increased in the further trials of F2 and F3 with drug to polymer ratio of 1: 1.4 and 1: 2 respectively, which released 100% drug at 3 & 4 hrs respectively, which states that the amount of polymer incorporated was not adequate to control the release of drug from the formulation. Hence in Formulation F4, the polymer Xanthan gum was replaced with another non cellulosic polymer namely Polyethylene oxide with drug to polymer ratio of 1: 2. But the rate of drug release was not matching with that of innovator, releasing (100 %) at the end of 6 hrs. Hence formulations F5 and F6 were designed with the combination of two polymers namely Xanthan gum & Polyethylene oxide in the ratio of 1.4: 2 & 1.08: 2 respectively. Formulation F5 was found to release the drug more than 12hrs which was not matching with the innovator as the release of drug was more retarded than the innovator release profile. Hence next trial F6 formulated showed a comparable release profile releasing the drug of 100% at 8hrs matching with innovator. Accelerated Stability study Reproducible batch with same qualitative and quantitative composition of F6, namely F7, F8 and F9 was charged for stability at 40C/75% RH for 3 months in PVC/PE/PVDC Alu clear blister of 1 x 10s. Sample were collected at an interval of 1 month, 2 month and 3 months and evaluated for impurity profile and dissolution in 0.1N HCl, USP- II paddle apparatus, 50rpm. The dissolution profile of F7, F8 and F9 charged at 40C/75%RH in 1M, 2M and 3M was found to be similar with that of dissolution profile of initial samples releasing not more than 45% at 1st hour and 45 to 65% at 2nd hour, 65 to 85% at 4th hour and not less than 85% at 8th hour respectively. Moreover the impurity

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Result and Discussion 135

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profile was observed to be well within the specification limit of less than 0.2% for known impurity and 0.2% for unknown maximum single impurity and 1.5% for total impurity. Hence the modified release tablets were found to be stable at the above condition for a period of 3 months.

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Summary and Conclusion

Page 136

12.0 SUMMARY AND CONCLUSION

The ultimate goal of Modified release drug delivery is to get optimal treatment with maximal safety. Compared with immediate release formulation Modified release formulation allow a longer dosing interval, which has the advantage of greater convenience and potentially improved compliance. This can be reasonably accomplished by development of models that is constructed from a non-immunogenic and biodegradable polymer backbone attached with exact functional group. The present work was carried out to design and evaluate Modified release tablet of highly soluble drug, a cellular acting anti-ischemic agent. The Modified release tablets were prepared by direct compression technique using Polyethylene oxide, Xanthan Gum, Povidone K90, as drug retardant polymers, which control the release of drug, aimed to meet out the therapy for angina pectoris. The types of excipient influenced the rate and extend of drug release from direct compression based matrix tablets. In formulation F1, F2 & F3, Xanthan gum was used as the only polymer to retard the drug release by gradually increasing the concentration in each trial. In these formulation the drug was retarded upto 2hr, 3hr & 4hr respectively, which was not matching with the innovator. Further increasing the Xanthan gum concentration leads to reduction of flow property of blend with the possibility of microbial contamination and increase in the impurity profile of the product. Hence the polymer, Xanthan gum was replaced with PEO, in order to retard the rate of release of drug to match the dissolution profile. In formulation F4, the PEO was used with a maximum amount of 7.3mg/tab based on IIG limit and was observed that the drug release was retarded to a extend of 6hrs only, which not matching with that of innovator. The tablets formulated only with PEO were found to have slight rough surface which may affect the appearance of tablets after coating. Hence Formulation F5 was designed with the combination of 2 polymers namely Xanthan gum & PEO in the ratio of 24% w/w & 34% w/w respectively to prolong the drug release. But the drug release was more retarded and was not matching with the proposed specification. Moreover since the quantity of Xanthan gum was more in the formulation,

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Summary and Conclusion

Page 137

the impurity in the tablet formulated was found to exceed the limit as per ICH guideline when kept at stability for a period of 1 month at 40oC/75%RH condition. Hence formulation F6 was formulated by decreasing the concentration of Xanthan gum from 24% to 14%w/w (i.e.) from 50mg/tab to 30mg/tab to match the dissolution profile with that of innovator and also to have a stable product. The amount of PEO was kept constant at 73mg/tab. The physical parameters were found to be satisfactory & dissolution profile was found to be matching with innovator having f2 value of 70. The product was also found to be stable at 40oC/75%RH for a period of 3 months. Powder blends were evaluated for tests such as bulk density, tapped density, compressibility index, Hausners Ratio and content uniformity before being punched as tablets, which ultimately showed that it was suitable for direct compression. Tablets were tested for weight variation, thickness, hardness and friability and were found to be satisfactory meeting the proposed specification. In vitro dissolution tests were performed and f2 values were calculated for optimized batches. Dissolution profile matched with innovator and f2 value was satisfactory. Dissolution study was conducted in 0.1N HCl and also in pH 4.5 acetate buffer, pH 6.8 phosphate buffer and in water to check the effect of pH on the dissolution profile of the product. The results have revealed that the rate of drug release was independent of pH. It was observed that the amount of polymer influences the drug release. In vitro release study results revealed that the release of drug was retarded with the proportional increase of the polymer concentration. When Xanthan gum was increased in the formulation the drug release was retarded but the tablets became soft when kept in stability leading to increase in the impurity level and also with a drop in the dissolution (faster dissolution). The use of polymer PEO alone in the formulation was not able to control the release of the drug with the IIG limits specified by the USFDA. Hence a combination of hydrophilic polymer namely Xanthan gum and PEO when used in an appropriate concentration controls the rate of drug release maintaining the impurity limit within the proposed specification. Moreover the stability result has also revealed that the product was stable upto 3 months in 40C/75%RH.

Design and Characterization of Modified release Matrix tablet of Highly soluble drug

Summary and Conclusion

Page 138

In conclusion, the present study indicated that the using a hydrophilic noncellulosic polymer in an appropriate combination in tablet could control the rate of drug release matching with that of the innovator. Success of the In vitro drug release studies recommends the product for further in vivo studies, which may improve patient compliance.

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References 139 REFERENCES

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1. S.J. Daharwal Gastro-Retentive Drugs: A Novel Approach towards Floating Therapy, Pharmainfo Vol. 5 Issue 1 2007. 2. British Pharmacopoeia 2009, 6th edition. 3. Sunil Kamboj et al., Matrix Tablets: An Important Tool for Oral Controlled-Release Dosage Forms, Pharmainfo, 2009 Vol. 7 Issue 6. 4. R.K.Khar, S.P.Vyas (2002) controlled drug delivered. Pg. no .1-50. 5. Brahmanker D.M. and Jaiswal S.B. in "Biopharmaceutics and Pharmacokinetics", "A Treatise," Vallabh Prakashan, 1st edn, 1995, pg.no.347-352. 6. Manish Shivadas Wani, Controlled Released System - A Review, Pharmainfo Vol. 6 Issue 1 2008. 7. Chien Y.W., Novel Drug Delivery Sysem (IInd Edn), Revised and expanded 1982, pg.no.139-140. 8. Chien Y.W., Novel Drug Delivery System (IInd Edn), Revised and expanded, 1992, pg.no.1-2. 9. Jain N.K., Controlled and Novel Drug Delivery CBS 1-2, 2002, pg.no.676-698. 10. Lee V.H., Robinson J.R, in, Sustained and Controlled Release Drug Delivery System, Marcel Dekker, New York, pg.no.71-121, 138-171. 11. Gilbert .s. banker Modern pharmaceutics 4rth edition pg. no.501-513.3.R.K.Khar, S.P.Vyas (2002) controlled drug delivered. Pg. no .1-50.

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