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Chapter-1                               INTRODUCTION1.1    Introduction to fast dispersible tablets:       Tablet is the m...
Exhibit low sensitive to environmental conditions as temperature and humidity.       Allow the manufacturer of tablets usi...
1.3 Choice of Drug CandidateSuitable drug candidate for fast dispersible tablet should posses:       No bitter taste.     ...
REVIEW OF LITERATURe                       4
Chapter -3                            REVIEW OF LITERATURE       Sumanta et al12., formulated fast dispersible tablet of A...
Raghavendrarao et al16., developed rapidly disintegrating tablets of carbamazepine,which is a bitter drug poor solubility ...
formulations were evaluated for thickness, weight variation, disintegration time, hardness,friability, drug content and wa...
PHARMACOKINETIC STUDY:             BIOAVAILABILITY:             PROTEIN BINDING:             ROUTES OF ADMINISTRATION:    ...
body are probably chemoreceptors, as a wide variety of compounds, including autacoids likebradykinin, and several of the p...
3.2 Excipient profiles:        An excipient is generally a pharmacologically inactive substance used as a carrier forthe a...
3.2.2. Crosscarmellose :-Croscarmellose sodium is an internally cross-linked sodium carboxymethylecellulose foruse as a di...
STABILITY AND STORAGE CONDITIONS :Croscarmellose sodium is a stable though hygroscopic material.Croscarmellose sodium shou...
Direct Compressible Grade of Micro Crystalline cellulose performs as an excipient to assistin the flow, lubrication and bi...
Starch is also utilized in pharmaceuticals and cosmetics. Starch derivatives often have special functions intablets: they ...
3.2.7 Magnesium stearate:        Magnesium stearate is often used as a diluent in the manufacture of medical tablets,capsu...
Chapter - 4              Methods of formulation development  4.1 Preformulation studies       Preformulation is defined as...
Solid state stability      Effect of moisture      Effect of solid state form – amorphous vs. crystalline      Excipient c...
• Improving flow properties of the mix and hence the uniformity of the dose           • Increasing the bulk density of a p...
Merits and Demerits of conventional Wet Granulation ProcessMerits :-                  a. It improves and flow properties a...
Figure illustrates the granule growth phenomenonThese phenomena often take place simultaneously in the granulation equipme...
intermolecular attractive forces, van der waals forces and electrostatic forces also play aninitial role.States of liquid ...
4.2.1.2 Dry granulation method:  In order to obtain the desired granules, the compaction process is followed by a milling ...
3.Tamp auger4.Small quantity inlet funnel5.Press rolllers with ribbon6.Rotor with desired granulesPRODUCT QUALITY ASPECTSP...
batch variations, our machines are fitted with control systems to allow equal granuleproperties during manufacturing accor...
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Introduction (2)

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Introduction (2)

  1. 1. Chapter-1 INTRODUCTION1.1 Introduction to fast dispersible tablets: Tablet is the most popular among all dosage forms existing today because of itsconvenience of self administration so oral drug delivery has been known for decades as themost widely utilized routes of administration among all the routes that has been explored forsystemic delivery of drugs via various pharmaceutical products of different dosage forms.Dysphagia is the common problem encountered in all age groups in concern to solid dosageforms. To solve this problem and improve patient compliance, fast dispersible tablets haveemerged as an alternative to the conventional oral dosage forms. In the present work, fast dispersible tablets of aceclofenac were designed witha view to enhance patient compliance by direct compression method. In the directcompression method, crospovidone (2-9% w/w),croscarmellose sodium (2-9% w/w),sodium starch glycolate(2-9% w/w) alone and in combination as super disintegrents wereused along with directly compressible microcrystalline cellulose to enhance mouth feel. The prepared batches of tablets where evaluated for hardness, friability, drug content,wetting time, water absorption ratio and invitro dispersion time. Based upon the invitrodispersion time all formulations were tested for invitro drug release pattern in phosphatebuffer.Keywords: Crospovidone; Croscarmellose sodium; Sodium starch glycolate. Oral administration is the most popular routes due to ease of ingestion, painavoidance, versatility, and the most important patient compliance. Also solid oral deliverysystems do not require sterile conditions and therefore less expensive to the manufacturer.Several novel technologies for fast dispersible have recently become available to address thephysicchemical an d pharmacokinetic charecteristics of a drug while improving patientcompliance. The most desirable formulation for the use by the elderly is one that easy to swallowand easy to handle. Taking these requirements into consideration attempts have been made todevelop a fast dispersible tablets. Since such a tablet disintegrate only a small amount ofwater in the oral cavity, it is easy to take care for any age patient, regardless of time. Recentlymany companies have researched and developed various types of fast disintegrating dosageform technologies with the potential to accommodate various physicochemical,pharmacokinetic, pharmacodynamic characteristic of drugs. These tablets are called as fast dispersible tablets, quick disintegrating tablets, fastdisintegrating tablets, fast dissolving tablets. However, of all the above terms, United states of pharmacopoeia(USP) approved these dosage forms. 1
  2. 2. Exhibit low sensitive to environmental conditions as temperature and humidity. Allow the manufacturer of tablets using convinential processing and packaging. Ease of administration to the patient who cannot swallow, such as the elderly,stroke victims, bedridden patients, patient affected by renal failure and patient whorefuse to swallow such as pediatric, geriatric and psychiatric patients. No need of water toswallow the dosage form, which is highly convenient feature for patients who are travelingand do not have immediate access to water. Rapid dissolution and absorption of the drug,which will produce quick onset of action. NSAID posses good anti inflammatory, analgesics and anti-pyretic, used for treatmentof osteoarthriritis, rheumatoid arthritis, dental pain and other rheumatoid disorder. The majormechanism of action of NSAID’s is prostaglandins, prostacyclins and thromboxin areproduced from archidonic acid by the enzyme cyclo-oxygenase which exits in a constutlive(cox -1) and an inducible (cox-2) isoforms ; the formers physiological housekeepingfunctions , while the later normaly present in minute quantities is induced by cytokines andother signal molecules at the site of inflammation.AIM :- The aim of present work was to show the effect of various super disintegrants ondisintegration time and invitro drug release rate. In this study an attempt has been made toprepare fast dispersible tablets of drug using different super disintegrants followinggranulation and direct compression method.The sodium starch glycolate, cross carmellose sodium and starch were used in differentconcentration according to the simplex lattice design as super disintegrants.The tablets were evaluated for diameter, thickness, hardness, friability, weight variation,wetting time, percentage of water absorption.1.2 OBJECTIVES OF THE STUDY In the present study, an attempt was made to develop fast dispersible Tablets ofNASAID and to investigate the effect of super disintegrants on the release profile of the drugfrom the tablets. In order to fulfill the aim, the following objectives have to be met:  Selection of suitable super disintegrants to develop the dosage form based on physicochemical properties of NASAID and excipients.  Selection of suitable technology for preparing fast dissolving tablets.  Screening of excipients for compatibility and efficacy for developing the formulation.  Evaluation of compressed products and identification of compression defects.  To evaluate the stability of the prepared formulations as per ICH guidelines. 2
  3. 3. 1.3 Choice of Drug CandidateSuitable drug candidate for fast dispersible tablet should posses: No bitter taste. Good stability in water and saliva. Dose should be low as possible.Unsuitable drug candidate for orally disintegrating tablet should include: Short half-life and frequent dosing. Drug having very bitter taste. Required controlled or sustained release. 3
  4. 4. REVIEW OF LITERATURe 4
  5. 5. Chapter -3 REVIEW OF LITERATURE Sumanta et al12., formulated fast dispersible tablet of Aceclofenac by usingsuperdisintegrants such as crospovidone and sodium starch glycolate. Stability studiesindicated that tablets containing superdisintegrants were sensitive to high humidity conditionsand fast dispersible tablet of aceclofenac could be prepared by direct compression method. Senoy et al13., fast dissolving tablets of diclofenac sodium was developed by usingdirect compression after incorporating super disintegrants such as Cross linked CarboxyMethyl Cellulose, Sodium Starch Glycolate and Cross linked povidone in differentconcentrations and evaluated the effect of their concentrations on the characteristics of fastdissolving tablets mainly in terms of disintegration time and dissolution rate. Tabletscontaining cross linked Carboxy Methyl Cellulose showed better disintegrating characteralong with rapid release. Mallikarjuna et al14., developed fast dispersible tablet of aceclofenac by directcompression method. In this method, they have studied effect of superdisintegrants such ascroscarmellose sodium, sodium starch glycolate and crospovidone. From the data obtained itcan be concluded that disintegration time and dissolution parameters decreased with increasein the level of croscarmellose sodium and increased with increase in the level of sodiumstarch glycolatein tablets and crospovidone dependent on the aggregate size in the dissolutionmedium. Anupamakalia et al15., developed fast dissolving tablets of oxcarbazepine to provideimmediate relief from epilepcy. Hence, the present investigation was undertaken with a viewto develop mouth-dissolving tablets of oxcarbazepine, which offers a new range of producthaving desired characteristics and intended benefits. In this study, the mouth dissolvingtablets were prepared using two different technologies, direct compression method and soliddispersion technology. 5
  6. 6. Raghavendrarao et al16., developed rapidly disintegrating tablets of carbamazepine,which is a bitter drug poor solubility in biological fluids is the major problem with this drughas also its poor bioavailability after oral administration. The rate of absorption or the extentof bioavailability for such a poor soluble drug is controlled by rate of dissolution in GITfluids. Hence, to enhance the solubility of the drug a complex of carbamazepine was preparedwith β-cyclodextrin and this complex was compressed into tablets. Suryakanta et al17., formulated a fast dissolving tablet of salbutamol sulphate toimprove the onset of action of bronchodilator for the treatment of asthma. The tablets wereprepared by direct compression method using superdisintegrants such as explotab,microcrystalline cellulose, Ac-Di-Sol and ammonium bicarbonate. The prepared tablets wereevaluated for weight variation, thickness, friability, hardness, drug content, in vitrodisintegration and in vitro drug release. Among all the formulation ammonium bicarbonateshowed the least disintegration time. Ganesh kumar et al18., prepared fast dissolving tablets of chlorpromazine HCl in theoral cavity with enhanced dissolution rate. The tablets were prepared with five superdisintegrants eg: Sodium starch glycolate, Crospovidone, Croscarmellose, L-HPC,Pregelatinised starch, The blend was examined for angle of repose, bulk density, tappeddensity, compressibility index and Hausners ratio. The tablets were evaluated, It wasconcluded that the fast dissolving tablets with proper hardness, rapidly disintegrating withenhanced dissolution can be made using selected superdisintegrants. Nilesh et al19., compared the effect of superdisintegrants and subliming agent on thefast dissolving property of lansoprazole tablets. Orodispersible tablets of lansoprazole wereprepared using camphor and ammonium bicarbonate as subliming agent and sodium starchglycollate, crosscarmellose sodium as superdisintegrants. Primarily powder blend andgranules were evaluated for preformulation parameters. The formulations were evaluated forweight variation, hardness, friability, drug content, water absorption ratio, wetting time, invitro dispersion, in vitro disintegration and in vitro dissolution. Ravi Kiran et al20., orodispersible tablets of piroxicam were prepared using twodifferent superdisintegrants namely crospovidone and sodium starch glycolate with twoconcentrations (3% and 5%) and a control (without superdisintegrant) by direct compressionmethod. The final blend of the drug and excipients were evaluated for powder flowproperties, bulk density, tapped density, compressibility index and hausner’s ratio. All the 6
  7. 7. formulations were evaluated for thickness, weight variation, disintegration time, hardness,friability, drug content and water absorption ratio. Formulation F1 showed the lowestdisintegration time and more water absorption ratio. invitro dissolution studies revealed thatformulation F2 showed 93.70 % percent drug release at the end of 60 minutes. The short termstability studies for the formulations showed no significant changes in disintegration time,drug content and percentage of drug released when stored at 40C±20◦C, 27°C ±2°C and45◦C±20◦C for 45 days.3.1 DRUG PROFILE: Aceclofenac is a new phenylacetic acid derivative provided with markedantiinflammatory, antiarthritic, analgesic and antipyretic activities in animal experimentalmodels.IUPAC Name Aceclofenac 2-[2-[2-(2,6-Dichlorophenyl)aminophenyl]acetyl]oxyaceticSynonyms acidMolecular StructureMolecular Formula C16H13Cl2NO4Molecular Weight 354.19CAS Registry Number 89796-99-6PropertiesMelting point 149-153 º 7
  8. 8. PHARMACOKINETIC STUDY: BIOAVAILABILITY: PROTEIN BINDING: ROUTES OF ADMINISTRATION: ABSORPTION DISTRIBUTION METABOLISM EXCRETION Pregnancy Category : Category N Aceclofenac has been shown to have potent analgesic and anti-inflammatoryactivities, similar to indomethacin and diclofenac due to its preferential cox-2 inhibitor, it hasbetter safety than conventional NSAIDs with respect to the adverse effect on gastrointestinaland cardiovascular system.INTRODUCTION The pain is symptomatic of some form of dysfunction and resultant inflammatoryprocesses in the body. A survey conducted for the WHO reported that one adult in fivesuffers from chronic non-malignant pain, which mostly occurs in the back, head, joints andlimbs. More than 15% of the worldwide population suffers for instance from some form ofosteoarthritis, and this incidence is even higher in the elderly. As the world population isgrows older, this incidence will continue to rise. The pain has been defined as a characteristic sensation arising from a noxiousstimulus, which includes its neurophysiological aspect. Sherrington, in his classic definitionhas further included the reactive component of pain, i.e. the "psychical adjuvant of animperative protective reflex". This indicates that pain also has a survival value for thespecies. There are two main classes of pain superficial and deep. Some pain receptors in the 8
  9. 9. body are probably chemoreceptors, as a wide variety of compounds, including autacoids likebradykinin, and several of the prostaglandins, can elicit the pain. Drugs can alter the painexperience in three ways (Pain reception, perception, and reaction) the first that can beintercepted is peripheral pain reception at the nerve endings. This modality is susceptible tonon-narcotic analgesic and local anesthesia. The second step, which can be modified, is painperception at the level of the CNS. Both, narcotic and non-narcotic analgesics interfere withthis level of pain integration. The third step, which can be influenced, is pain reaction.Mechanism of pain & Inflammation: Prostaglandins are implicated in the inflammatory response and are sensitizingnociceptors to the actions of other Mediators, occurring during acute and chronicinflammatory illness, prostaglandins are produced at the site of inflammation where it isbelieved that they mediate many of symptoms of inflammation such as oedema and pain. Arachidonic acid is released from cell membranes by phospholipases,cyclooxygenases catalyze the addition of molecular oxygen to arachidonic acid to form ininitially the endoperoxide intermediate prostaglandin G2. The same enzymes also processperoxidase activity, which catalyzes the reduction of these prostaglandins to formPGH2. PGH 2 may then react with a number of enzymes sometimes called isomerases tobecome one of the prostaglandins or thromboxanes.Role of Non-Steroidal Anti inflammatory drugs in pain (NSAIDs) Orally administered NSAIDS play an important role in symptomatic management ofosteoarthritis, rheumatoid arthritis and ankylosing spondylitis and other acute pain conditions.In general, they produce their anti-inflammatory and analgesic effects by inhibitingcyclooxygenase and this preventing the production of prostaglandins from arachidonic acid.It has been suggested that some NSAIDS inhibit leukotriene production via lipooxygenaseinhibition. 9
  10. 10. 3.2 Excipient profiles: An excipient is generally a pharmacologically inactive substance used as a carrier forthe active ingredient of a medication. In many cases, an "active" substance, may not beeasily administered and absorbed by the human body; in such cases the substance in questionmay be dissolved into or mixed with an excipient. Excipients are also sometimes used to bulkup formulations that contain very potent active ingredients, to allow for convenient andaccurate dosage. In addition to their use in the single-dosage quantity, excipients can be usedin the manufacturing process to aid in the handling of the active substance concerned.Depending on the route of administration, and form of medication, different excipients maybe used. For oral administration tablets and capsules are use3.2.1 Sodium starch glycolate : The superdisintegrantsPrimojel® (sodium starch glycolate) and Primellose®(croscarmellose sodium) are cross-linked and substituted polymers of glucose.Sodium starch glycolate is the sodium salt of a carboxymethyl ether of starch. The molecularweight is typically 500 000-11 000 000.Very fine, white or off white, free flowing powder; odourless or almost odourless. Practicallyinsoluble in water, insoluble in most organic solvents. It consists of oval or sphericalgranules, 30-100 µm in diameter with some less-spherical granules ranging from 10-35 µm indiameter.SSG is used as disintegrant for tablets, capsules and granules. The tablets mainly produced bydirect compression method and wet granulation method.SSG is recommended in a concentration of 2-8% of total weight.SSG is starch derivative which chemical and physical identities meet to the latest standards of(Ph.Eur.,USP-NF, BP).CharacteristicsThe effects of SSG as a disintegrating agent are caused by the rapid absorption of water andenormous swelling properties of SSG particles. Undissolvable in water the swollen SSGparticles remain intact and consequently cause the rapid disruption of tablet in itscomponents. Hence, SSG improves the release and absorption of active ingredient. Even aftera long storage the effect of disintegration enhancement remains.Usage of hydrophobic lubricants in the tablet formulation often reduces the disintegration time. 10
  11. 11. 3.2.2. Crosscarmellose :-Croscarmellose sodium is an internally cross-linked sodium carboxymethylecellulose foruse as a disintegrants in pharmaceutical formulations. Croscarmellose sodium also resolves formulators concerns over long-term functionalstability, reduced effectiveness at high tablet hardness levels, and similar problems associatedwith other products developed to enhance drug dissolution. Croscarmellose sodium is a verycommonly used pharmaceutical additive approved by the U.S FOOD AND DRUGADMINISTRATION. Its purpose in most tablets - including dietary supplements - is to assistthe tablet in disintegrating in the intestinal tract at the required location. If a tabletdisintegrating agent is not included, the tablet could disintegrate too slowly, in the wrong partof the intestine or not at all, thereby reducing the efficacy and bioavailability of the activeingredients. . As a result, it provides superior drug dissolution and disintegrationcharacteristics, thus improving formulas subsequent bioavailability by bringing the activeingredients into better contact with bodily fluids Croscarmellose sodium is made by first soaking crude cellulose in sodium hydroxide,and then reacting the cellulose with sodium monochloroacetate to form sodiumcarboxymethylcellulose. Excess sodium monochloroacetate slowly hydrolyzes to glycolicacid and the glycolic acid catalyzes the cross-linkage to form croscarmellosesodium. Chemically, croscarmellose sodium is the sodium salt of a cross-linked, partly O-(carboxymethylated) cellulose.APPLICATIONS : Croscarmellose sodium is used in oral pharmaceutical formulations as a disintegrantfor Capsules, Tablets and Granules.In tablet formulations, Croscarmellose sodium may be used in both direct-compression andwet-granulation processes.When used in wet granulations the Croscarmellose sodium is best added in both the wet anddry stages of the process (intra- and extra granularly) so that the wicking and swelling abilityof thedisintegrant is best utilized.Concentrations of up to 5% w/w of Croscarmellose sodium may be used as a tabletdisintegrant although normally 2% w/w is used in tablets prepared by direct compression and3% w/w in tablets prepared by a wet-granulation process. 11
  12. 12. STABILITY AND STORAGE CONDITIONS :Croscarmellose sodium is a stable though hygroscopic material.Croscarmellose sodium should be stored in a well-closed container in a cool, dry, place3.2.3 Talc Talc as a pure chemical compound is a hydrous magnesium silicate, [Mg6 (Si8O20)(OH4)], that exists in sheetlike crystalline forms or as fibers. The purity and physical form ofany sample depends on the source of the talc and on the minerals found in the ore body fromwhich it is refined.• The effectiveness of talc glidant activity is dependent upon particle size compatibility between the talc and other powders in the formulation.• Talc lubricant efficiency in plastic deforming binder/fillers increases with decreasing talc particle size and increasing talc surface area.• Talc improves direct compression tablet formulation disintegration behavior independent of particle size.• Talc can effectively be used in combination with magnesium stearate to restore disintegration and dissolution properties impaired by magnesium stearate.3.2.4 Microcrystalline cellulose: Micro Crystalline Cellulose is a mechanically disintegrated level of D.P. Cellulose. Itcomprises purified, de-polymerised, Micro Crystalline sub micron size colloidal particles. Itis produced by treating Alfa Cellulose obtained as a pulp from fibrous plants with mineralsacid. It is a white, odourless, tasteless, extra free flowing powder which is relatively freefrom organic and non-organic contaminants. It is metabolically inert, and has excellent waterabsorptive, swelling & dispersion properties, is insoluble in water, dilute acid, commonorganic solvents and oils. It is partially soluble in dilute alkali. 12
  13. 13. Direct Compressible Grade of Micro Crystalline cellulose performs as an excipient to assistin the flow, lubrication and binding properties of the ingredients to be tableted and improvesstability of durgs. Facilitate rapid disintegration of the tablet.It can be used in direct compression of most drugs and because of savings in material, capital,equipment and labour, it compensates the higher price of Direct Compressible MicroCrystalline Cellulose over non spray dried Micro Crystalline Cellulose.The conventional costly method of tableting through 6 process steps is replaced by 2 stepsdirect compression method of tableting.Detailed tests and investigations by various agencies for the use of Direct CompressibleGrade Micro Crystalline Cellulose powder in tableting have shown:a. Excellent Compression & Hardnessb. No Sign of Lubrication Difficultiesc. Good Flowing Propertiesd. Reduces Friability & Weight Loss3.2.5 Mannitol: Mannitol is a white, crystalline organic compound with the formula (C6H8(OH)6).Mannitol can also be used as a facilitating agent for the transportation of pharmaceuticalsdirectly into the brainMannitol is a polyol (sugar alcohol) and an isomer of sorbitol. Mannitol(C6H8(OH)6) is used in pharmaceutical products as a sweeting agent, tablet and capsulediluent, excipient for chewable tablets, a tonicity agent, and as a vehicle (bulking agent) forlyophilized preparations. Mannitol is industrially derived from the sugar fructose, and isroughly half as sweet as sucrose. Mannitol has a cooling effect often used to mask bittertastes, and may be used in gums and candies. Mannitol is also found naturally in manyspecies, including plants, bacteria, and fungi.3.2.6 Starch: Maize, potato, rice and tapioca (cassava) starch were evaluated with respect to theirproperties on direct compression. Rice starch showed much better compactibility ascompared to maize, potato and tapioca starch. Moreover, its binding capacity proved to bealmost insensitive to mixing with magnesium stearate. 13
  14. 14. Starch is also utilized in pharmaceuticals and cosmetics. Starch derivatives often have special functions intablets: they act as a disintegration aid.Specially modified starch derivatives give tablets good stability,provide low abrasion and stable consistency. In moistened condition, i.e. during oral intake the starchesswell heavily. This accelerates the disintegration the tablet and finally leads to the liberation of the effectivesubstance. Further applications in pharmacy include starches for the production of hard and soft capsules aswell as highly purified starch derivatives as basic material for the production of blood plasma substitutes.In the field of cosmetics, starch is added to creams, powders, and shower gels to impart special properties tothe products. They for instance generate a more comfortable and velvety feeling on the human skin.Furthermore, highly modified products are used as a lubricant for latex products (gloves and condoms).The following test procedures are available: Analytical characterisation of starch derivatives Production and testing of tablets Testing of tactility of cosmetic products Determination of cooking strength Checking stability of multiphase systemsFurther examples for the application of starch in special fields are: Flocculating aid for ceramics Flocculating agent for wastewater treatment Additives for drilling fluids Emulsifier for emulsion polymerisation Paints and varnishes Packaging material (foils and padding material) Binding agent for foundry Basic material for the production of chemicals Biopolymers Starch is one of the most widely used excipients in the manufacture of solid dosage forms. Starchesfrom different sources have been evaluated and used as excellent binders in either mucilage or thedrypowdered form Although maize starch is the most frequently used excipient in tabletting, researchershave tried to develop botanical starches for use tablet excipient. Preliminary these starches following officialand un-official protocols showed that they posses some of the desirable features of good excipient. 14
  15. 15. 3.2.7 Magnesium stearate: Magnesium stearate is often used as a diluent in the manufacture of medical tablets,capsules and powders. In this regard, the substance is also useful, because it haslubricating properties, preventing ingredients from sticking to manufacturing equipmentduring the compression of chemical powders into solid tablets; magnesium stearate is themost commonly used lubricant for tablets. Studies have shown that magnesium stearate mayaffect the release time of the active ingredients in tablets, etc., but not that it reduces theoverall bioavailability of those ingredients. As a food additive or pharmaceutical excipient, itsE number is E470b.Magnesium stearate is also used to bind sugar in hard candies and is a common ingredient inbaby formulas. In pure powder form, the substance can be adjust explosion hazard, althoughthis issue is effectively insignificant beyond the manufacturing plants using it.Magnesium stearate is manufactured from both animal and vegetable oils. Some nutritionalsupplements specify that the magnesium stearate used is sourced from vegetables.Magnesium stearate is a major component of "bathtub rings." When produced by soap andhard water, magnesium stearate and calcium stearate both form a white solid insoluble inwater, and are collectively known as soap scum.Magnesium stearate is created by the reaction of sodium stearate with magnesium sulfate.Formulations F1-F3Ingredients (mg) F1 F2 F3Aceclofenac 100 100 100SSG 30 25CCS 30Starch 15 15 15Mg.sterate- 5 5 5Mannitol- 50 50 50MCC -- --- 25SSG = Sodium starch glycolateCCS = Cross carmellose sodiumMS = Magnesium stearateMcc=microcrystalline celluloseSS = Sodium saccharinF= Formulatio 15
  16. 16. Chapter - 4 Methods of formulation development 4.1 Preformulation studies Preformulation is defined as the phase of research and development process wherephysical, chemical and mechanical properties of a new drug substance are used alone and whencombined with excipient inorder to develop stable ,safe and effective dosage form.A throughunderstanding of physicochemical properties may ultimately provide a rationale for formulationdesign, or support the need for molecular modification or merely confirm that there is nosignificant barrier to the formulation development. A stage of development during which thephysicochemical properties of drug substance are characterized. • Some commonly evaluated parameters: a. Solubility. b. Dissolution behaviour. c. Stability. d. Partition coefficient. e. Ionization constant (pKa). f. pH-Solubility Profile and Effect of Temperature. Solid state properties such as crystal forms/polymorphs, water sorption behavior, surfaceproperties, particle size and shape, and other mechanical properties.Solubility: Practically insoluble in water, freely soluble in acetone, soluble in alcohol.IDENTIFICATION Dissolve 50.0 mg in methanol R and dilute to 100.0 ml with the same solvent. Dilute2.0 ml of the solution to 50.0 ml with methanol R. Examined between 220 nm and 370nm (2.2.25), the solution shows an absorption maximum at 275 nm. The specific absorbanceat the maximum is 320 to 350. Dissolve about 10 mg in 10 ml of alcohol R. To 1 ml of the solution, add 0.2 ml of amixture, prepared immediately before use, of equal volumes of a 6 g/l solution of potassiumferricyanide R and a 9 g/l solution of ferric chloride R. Allow to stand protected from lightfor 5 min. Add 3 ml of a 10.0 g/l solution of hydrochloric acid R. Allow to stand protectedfrom light for 15 min. A blue colour develops and a precipitate is formed.Stability studies:1.Chemical stability studies 16
  17. 17. Solid state stability Effect of moisture Effect of solid state form – amorphous vs. crystalline Excipient compatibility Effect of moisture Effect of processing2.Degradation mechanism Hydrolysis Oxidation potential Effect of temperature3.Physical stability studies Effect of moisture on drug Solid solubility Characterization of hydrates/solvates Effect of processing Impact on chemical stability and bioavailability.4.Some Practical Considerations in Salt Screening and Selection Dosage Form Considerations IV vs. oral formulations High dose vs. low dose Excipient compatibility Interaction with other actives in potential combination formulations Salts and Other Solubilization Techniques Effect of Salts on Complexation Binding Constants Effect of Salts on Solublization by Surfactants Solubility of Salts in Non-aqueous Solvents Toxicological Considerations4.2 Formulation development 4.2.1 Granulation techniques Granulation process has been widely used in the pharmaceutical industry for the preparation of material for tabletting. Other process which involves the granule formation includes microencapsulation, multi-particulate system for modified release mechanism and to prepare granules to be used by patient directly. Primarily granules are prepared to improve flow and compression characteristics of the blend but there are many other reasons and some times multiple reasons for granulation such as- 17
  18. 18. • Improving flow properties of the mix and hence the uniformity of the dose • Increasing the bulk density of a product • Facilitating metering or volumetric dispensing • Controlling the rate of drug release • Decrease dust generation and reduce employee exposure to drug product • Improving product appearanceWhat is Granulation..? Granulation may be defined as a size enlargement process which converts fine orcoarse particles into physically stronger and larger agglomerates having good flow property,better compression characteristics and uniformity. The art and science for process andproduction of granules is known as Granulation Technology. Granulation Technology can be broadly classified into 2 types based upon the type ofprocessing involved. 1. Wet granulation method and 2. Dry granulation method.4.2.1 Wet granulation method: Wet granulation is a pharmaceutical unit operation whereby a liquid or binder solutionis sprayed onto a powder blend to improve the flow, compressibility, and content uniformityof the blend, prior to tabletting. Improvement of flow and compressibility can be important in extended/controlled releasematrix formulations where polymers with fine particle size are typically utilized to ensurerapid, reproducible polymer by Wet Granulation Wet granulation is the most widely used process of granulation in the pharmaceuticalindustry. It involves addition of a liquid solution (with or without binder) to powders, toform a wet mass or it forms granules by adding the powder together with anadhesive, instead of by compaction . The wet mass is dried and then sized to obtainedgranules. The liquid added binds the moist powder particles by a combination ofcapillary and viscous forces in the wet state. More permanent bonds are formed duringsubsequent drying which leads to the formation of agglomerates. Although the process is most widely used in the pharmaceutical industry, theconventional wet granulation process has following merits and demerits. 18
  19. 19. Merits and Demerits of conventional Wet Granulation ProcessMerits :- a. It improves and flow properties and expensive because of labour, compression characteristics and special equipment and increases density of granules. b. It reduces dust hazards. c. It prevents segregation of powders. d. It makes hydrophobic surfaces and hydrophilic. e. Better distribution of colour and processing steps involved in soluble drugs if added in binding add complexity.Demerits :- a. Process requires more space, time and energy requirement. b. Multiple the process. c. Loss of material during the various stages of processing. d. Moisture sensitive and drugs are poor candidates. e. Any incompatibility between the formulation component is aggravated during the processing.Process details: conventional wet granulation According to Iveson there are fundamentally only three stages of process, whichdetermines the wet agglomeration behaviour: • Wetting and nucleation; • Consolidation and growth and finally • Breakage and attrition. 19
  20. 20. Figure illustrates the granule growth phenomenonThese phenomena often take place simultaneously in the granulation equipment,making the investigation of the effect of an individual phenomenon on the agglomerateproperties difficult. Wetting of the articles is necessary for nucleation, i.e. the formationof initial agglomerates. As per Hapgood the nucleation rate is governed by following- • Wetting thermodynamics • Drop penetration kinetics and • Binder dispersion.“The binder dispersion in the powder mass depends on the liquid deliveryparameters and powder mixing.” Since wet granulation method is the oldest and most convention method ofmaking granules, all components involved in this process forms a three phase system madeof: • Dispersed solid • Granulation liquid and • Air. Cohesive Force that operates during the moist agglomeration process is mainlydue to the liquid bridges that develop between the solid particles, even though 20
  21. 21. intermolecular attractive forces, van der waals forces and electrostatic forces also play aninitial role.States of liquid content during wet granulation When liquid is added to the drug powder during initial stage, liquid film is formedon powder surface. Discrete liquid bridges are then built at the point of contact. Thisstate is termed as Pendular State, surface tension and the capillary provide the cohesiveforce during this stage, air is still present between the particles. As the liquid contentincreases air starts coalesce. The strength of the blend increases. In this so calledFunicular State, the air does not built a coherent phase anymore. As water contentincreases further all inter-particle voids are filled. Capillary pressure and interfacial forces at granule surface hold the particles at thisstage called Capillary State. Granules attain its maximum strength at this stage. Furtheraddition of liquid, forms solid particles, completely surrounded by the liquid, resultingin the droplet State. During this stage system consist only two phases, dispersed solidand liquid phase. When the granulation process is finished, the liquid is removed bydrying, after that the granule is still kept together by different bondingmechanismsdration. 21
  22. 22. 4.2.1.2 Dry granulation method: In order to obtain the desired granules, the compaction process is followed by a milling step. PROCESS BASICS Principally there are two methods to obtain the compacts when using dry granulation: slugging and roller compaction. Slugging If a tablet press is used for the compaction process, the term slugging is used. But since particles with a small particle size do not flow well into the die of a tablet press, the results are weight differences from one tablet (slug) to another. This in turn causes large fluctuations in the forces applied onto the individual slugs, with translates in variations of the slug’s mechanical strength. Therefore, the properties of these granulates obtained by milling the slugs cannot be controlled well either. This is one of the main reasons why slugging is hardly used any more as a dry granulation method. Roller Compaction A GERTEIS® Roller compactor generally consist of three major units:1. A feeding system, which conveys the powder to the compaction area between the rolls2. A compaction unit, where powder is compacted between two counter rotating rolls to a ribbon by applying a force3. A size reduction unit, for milling the ribbons to the desired particle size. 1.Inlet funnel with agitator 2.Feed auger 22
  23. 23. 3.Tamp auger4.Small quantity inlet funnel5.Press rolllers with ribbon6.Rotor with desired granulesPRODUCT QUALITY ASPECTSProcess Parameters: Force and Gap The powder is compacted between two rolls by applying a force, which is the mostimportant parameter in the dry granulation process. The applied force is expressed in kN/cm,being the force per cm roll width. Occasionally the press force is also indicated in bar. This,however, merely represents the pressure within the hydraulic system, and is in fact not anappropriate measuring unit for the force applied onto the powder.At a given force, depending on the amount of powder conveyed to the rolls, the powder willbe compacted to a predefined ribbon thickness.A precise process control is essential to obtain equal granules properties from a homogenousribbon. For more on that topic see section PAT below.Variable and Fixed Gap Roller Compactors Roller compactors can be divided into two categories: One is equipped with a fixedgap, the other one with a floating gap. Both consist of the three major units as explainedabove but differ in the way in which the smallest distance (gap) between the rolls is realized.When a fixed gap is installed, the amount of powder drawn in into the compaction areabetween the rolls is inconsistent, which results in different forces applied to the powder bed.Like in slugging, this will cause large fluctuations in the ribbon and granulate properties.With floating gap (e.g. GERTEIS®-Machines) the distance between the rolls changeaccording to the amount of powder provided. The force applied to the powder remainsconstant. This ensures that property fluctuations in the granules are reduced to a minimum.MillingWith our integrated models, the ribbons are being milled right after compaction using ascreen with a given mesh size, thus limiting the upper particle size.This milling process should be performed as gently as possible, so as to avoid creating toomany fines.PAT (= Process Analytical Tool)The GERTEIS® roller compactors are able to control and measure all product qualityrelevant parameters (e.g. force, gap and roll speed) on-line in order to fulfill the requirementsof the pharmaceutical industry for a well controlled and documented manufacturing process.All the parameters are calibrated and validated. Additionally, in order to cope with batch to 23
  24. 24. batch variations, our machines are fitted with control systems to allow equal granuleproperties during manufacturing according to PAT.APPLICATIONSImproving Flow Ability Dry granulation is used for increasing the bulk density of powders, whilst increasingthe particle size, resulting in better flowing material, which is a prerequisite formanufacturing capsules and tablets on high speed production equipment.Furthermore, bonding the particles of various substances together during the compactionprocess reduces the tendency to segregation of powder particles of different substances. Thisresults in an improvement of the homogeneity of the active ingredients (API) within thepowder blend, causing an improvement of dose uniformity of such dosage forms.Wet- & Dry GranulationIn contrast to wet granulation, dry granulation is a continuous process. This results in variouseconomical advantages. Nowadays the throughput of common dry granulation systems canreach 400kg/h. Dry granulation systems require comparatively fewer investments intobuildings or equipment. Coupled with lower maintenance costs, this results in a much higheroverall profit.5. Evaluation studies:5.1 INVITRO dissolution studies by using USP PADDLE apparatus: Preparation of phosphate buffer of ph 6.8: Weigh 27.22gms of monobasic potassium phosphate (KH2PO4) and dissolved in 100ml to get stock solution of 0.2m potassium dihydrogen phosphate.weighed 8gms of NaOH dissolved in 1000ml to get 0.2m NaOH solution. 50ml of monobasic potassium phosphate solution from stock solution was taken in a200ml volumetric flask, 22.4ml of NaOH solution from stock solution of 0.2m NaOH solution was added, and then water to volume was added. Procedure for dissolution study: After preparation of phosphate buffer it is transferred into 900ml into abasket.Now set rpm to 50 and now adjust the temperature to 37.5 degree centigrades.After reaching the desired temperature now drop the tablet into phosphate buffer and it isrunned for dissolution. Now collect the sample of 2ml for 10mins and it is filterd throughsintered glass filter and now immediately replace 2ml of fresh buffer solution.Now 1ml offiltered solution is diluted to 100ml with distilled water.Repeat the same procedure for20mins,30mins,40mins,50min,and 60mins and measure the released drug concentration byusing uv/visible spectrometer at 274nm. 24
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