Chapter-1

INTRODUCTION

1.1 Introduction to fast dispersible tablets:

Tablet is the most popular among all dosage forms existing today because of its convenience of self administration so oral drug delivery has been known for decades as the most widely utilized routes of administration among all the routes that has been explored for systemic 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 dosage forms. To solve this problem and improve patient compliance, fast dispersible tablets have emerged as an alternative to the conventional oral dosage forms.

In the present work, fast dispersible tablets of aceclofenac were designed with a view to enhance patient compliance by direct compression method. In the direct compression 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 were used 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 invitro dispersion time all formulations were tested for invitro drug release pattern in phosphate buffer.

Keywords: Crospovidone; Croscarmellose sodium; Sodium starch glycolate.

Oral administration is the most popular routes due to ease of ingestion, pain avoidance, versatility, and the most important patient compliance. Also solid oral delivery systems do not require sterile conditions and therefore less expensive to the manufacturer. Several novel technologies for fast dispersible have recently become available to address the physicchemical an d pharmacokinetic charecteristics of a drug while improving patient compliance.

The most desirable formulation for the use by the elderly is one that easy to swallow and easy to handle. Taking these requirements into consideration attempts have been made to develop a fast dispersible tablets. Since such a tablet disintegrate only a small amount of water in the oral cavity, it is easy to take care for any age patient, regardless of time. Recently many companies have researched and developed various types of fast disintegrating dosage form technologies with the potential to accommodate various physicochemical, pharmacokinetic, pharmacodynamic characteristic of drugs.

These tablets are called as fast dispersible tablets, quick disintegrating tablets, fast disintegrating tablets, fast dissolving tablets. However, of all the above terms,

United states of pharmacopoeia(USP) approved these dosage forms.

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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 who refuse to swallow such as pediatric, geriatric and psychiatric patients. No need of water to swallow the dosage form, which is highly convenient feature for patients who are traveling and 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 treatment of osteoarthriritis, rheumatoid arthritis, dental pain and other rheumatoid disorder. The major mechanism of action of NSAID’s is prostaglandins, prostacyclins and thromboxin are produced from archidonic acid by the enzyme cyclo-oxygenase which exits in a constutlive (cox -1) and an inducible (cox-2) isoforms ; the formers physiological housekeeping functions , while the later normaly present in minute quantities is induced by cytokines and other signal molecules at the site of inflammation.

AIM :-

The aim of present work was to show the effect of various super disintegrants on disintegration time and invitro drug release rate. In this study an attempt has been made to prepare fast dispersible tablets of drug using different super disintegrants following granulation and direct compression method.

The sodium starch glycolate, cross carmellose sodium and starch were used in different concentration 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 of NASAID and to investigate the effect of super disintegrants on the release profile of the drug from 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.

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1.3 Choice of Drug Candidate

Suitable 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.

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REVIEW OF LITERATURe

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Chapter -3

REVIEW OF LITERATURE

Sumanta et al12., formulated fast dispersible tablet of Aceclofenac by using

superdisintegrants such as crospovidone and sodium starch glycolate. Stability studies

indicated that tablets containing superdisintegrants were sensitive to high humidity conditions

and fast dispersible tablet of aceclofenac could be prepared by direct compression method.

Senoy et al13., fast dissolving tablets of diclofenac sodium was developed by using

direct compression after incorporating super disintegrants such as Cross linked Carboxy

Methyl Cellulose, Sodium Starch Glycolate and Cross linked povidone in different

concentrations and evaluated the effect of their concentrations on the characteristics of fast

dissolving tablets mainly in terms of disintegration time and dissolution rate. Tablets

containing cross linked Carboxy Methyl Cellulose showed better disintegrating character

along with rapid release.

Mallikarjuna et al14., developed fast dispersible tablet of aceclofenac by direct

compression method. In this method, they have studied effect of superdisintegrants such as

croscarmellose sodium, sodium starch glycolate and crospovidone. From the data obtained it

can be concluded that disintegration time and dissolution parameters decreased with increase

in the level of croscarmellose sodium and increased with increase in the level of sodium

starch glycolatein tablets and crospovidone dependent on the aggregate size in the dissolution

medium.

Anupamakalia et al15., developed fast dissolving tablets of oxcarbazepine to provide

immediate relief from epilepcy. Hence, the present investigation was undertaken with a view

to develop mouth-dissolving tablets of oxcarbazepine, which offers a new range of product

having desired characteristics and intended benefits. In this study, the mouth dissolving

tablets were prepared using two different technologies, direct compression method and solid

dispersion technology.

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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 drug

has also its poor bioavailability after oral administration. The rate of absorption or the extent

of bioavailability for such a poor soluble drug is controlled by rate of dissolution in GIT

fluids. Hence, to enhance the solubility of the drug a complex of carbamazepine was prepared

with β-cyclodextrin and this complex was compressed into tablets.

Suryakanta et al17., formulated a fast dissolving tablet of salbutamol sulphate to

improve the onset of action of bronchodilator for the treatment of asthma. The tablets were

prepared by direct compression method using superdisintegrants such as explotab,

microcrystalline cellulose, Ac-Di-Sol and ammonium bicarbonate. The prepared tablets were

evaluated for weight variation, thickness, friability, hardness, drug content, in vitro

disintegration and in vitro drug release. Among all the formulation ammonium bicarbonate

showed the least disintegration time.

Ganesh kumar et al18., prepared fast dissolving tablets of chlorpromazine HCl in the

oral cavity with enhanced dissolution rate. The tablets were prepared with five super

disintegrants eg: Sodium starch glycolate, Crospovidone, Croscarmellose, L-HPC,

Pregelatinised starch, The blend was examined for angle of repose, bulk density, tapped

density, compressibility index and Hausners ratio. The tablets were evaluated, It was

concluded that the fast dissolving tablets with proper hardness, rapidly disintegrating with

enhanced dissolution can be made using selected superdisintegrants.

Nilesh et al19., compared the effect of superdisintegrants and subliming agent on the

fast dissolving property of lansoprazole tablets. Orodispersible tablets of lansoprazole were

prepared using camphor and ammonium bicarbonate as subliming agent and sodium starch

glycollate, crosscarmellose sodium as superdisintegrants. Primarily powder blend and

granules were evaluated for preformulation parameters. The formulations were evaluated for

weight variation, hardness, friability, drug content, water absorption ratio, wetting time, in

vitro dispersion, in vitro disintegration and in vitro dissolution.

Ravi Kiran et al20., orodispersible tablets of piroxicam were prepared using two

different superdisintegrants namely crospovidone and sodium starch glycolate with two

concentrations (3% and 5%) and a control (without superdisintegrant) by direct compression

method. The final blend of the drug and excipients were evaluated for powder flow

properties, bulk density, tapped density, compressibility index and hausner’s ratio. All the

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formulations were evaluated for thickness, weight variation, disintegration time, hardness,

friability, drug content and water absorption ratio. Formulation F1 showed the lowest

disintegration time and more water absorption ratio. invitro dissolution studies revealed that

formulation F2 showed 93.70 % percent drug release at the end of 60 minutes. The short term

stability 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 and

45◦C±20◦C for 45 days.

3.1 DRUG PROFILE:

Aceclofenac is a new phenylacetic acid derivative provided with marked

antiinflammatory, antiarthritic, analgesic and antipyretic activities in animal experimental

models.

IUPAC Name Aceclofenac

Synonyms2-[2-[2-(2,6-Dichlorophenyl)aminophenyl]acetyl]oxyacetic acid

Molecular Structure

Molecular Formula C16H13Cl2NO4

Molecular Weight 354.19

CAS Registry Number 89796-99-6

 

Properties

Melting point 149-153 º

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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-inflammatory activities, similar to indomethacin and diclofenac due to its preferential cox-2 inhibitor, it has better safety than conventional NSAIDs with respect to the adverse effect on gastrointestinal and cardiovascular system.

INTRODUCTION

The pain is symptomatic of some form of dysfunction and resultant inflammatory processes in the body. A survey conducted for the WHO reported that one adult in five suffers from chronic non-malignant pain, which mostly occurs in the back, head, joints and limbs. More than 15% of the worldwide population suffers for instance from some form of osteoarthritis, and this incidence is even higher in the elderly. As the world population is grows older, this incidence will continue to rise.

The pain has been defined as a characteristic sensation arising from a noxious stimulus, which includes its neurophysiological aspect. Sherrington, in his classic definition has further included the reactive component of pain, i.e. the "psychical adjuvant of an imperative protective reflex". This indicates that pain also has a survival value for the species. There are two main classes of pain superficial and deep. Some pain receptors in the body are probably chemoreceptors, as a wide variety of compounds, including autacoids like bradykinin, and several of the prostaglandins, can elicit the pain. Drugs can alter the pain

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experience in three ways (Pain reception, perception, and reaction) the first that can be intercepted is peripheral pain reception at the nerve endings. This modality is susceptible to non-narcotic analgesic and local anesthesia. The second step, which can be modified, is pain perception at the level of the CNS. Both, narcotic and non-narcotic analgesics interfere with this 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 sensitizing nociceptors to the actions of other Mediators, occurring during acute and chronic inflammatory illness, prostaglandins are produced at the site of inflammation where it is believed 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 in initially the endoperoxide intermediate prostaglandin G2. The same enzymes also process peroxidase activity, which catalyzes the reduction of these prostaglandins to form PGH2. PGH 2 may then react with a number of enzymes sometimes called isomerases to become 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 of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis and other acute pain conditions. In general, they produce their anti-inflammatory and analgesic effects by inhibiting cyclooxygenase and this preventing the production of prostaglandins from arachidonic acid. It has been suggested that some NSAIDS inhibit leukotriene production via lipooxygenase inhibition.

3.2 Excipient profiles:

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An excipient is generally a pharmacologically inactive substance used as a carrier for the active ingredient  of a medication. In many cases, an "active" substance, may not be easily administered and absorbed by the human body; in such cases the substance in question may be dissolved into or mixed with an excipient. Excipients are also sometimes used to bulk up formulations that contain very potent active ingredients, to allow for convenient and accurate dosage. In addition to their use in the single-dosage quantity, excipients can be used in 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 may be used. For oral administration tablets and capsules are use

3.2.1 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 molecular

weight is typically 500 000-11 000 000. 

Very fine, white or off white, free flowing powder; odourless or almost odourless. Practically

insoluble in water, insoluble in most organic solvents. It consists of oval or spherical

granules, 30-100 µm in diameter with some less-spherical granules ranging from 10-35 µm in

diameter.

SSG is used as disintegrant for tablets, capsules and granules. The tablets mainly produced by

direct 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).

Characteristics

The effects of SSG as a disintegrating agent are caused by the rapid absorption of water and

enormous swelling properties of SSG particles. Undissolvable in water the swollen SSG

particles remain intact and consequently cause the rapid disruption of tablet in its

components. Hence, SSG improves the release and absorption of active ingredient. Even after

a long storage the effect of disintegration enhancement remains.

Usage of hydrophobic lubricants in the tablet formulation often reduces the disintegration time.

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3.2.2. Crosscarmellose :-

Croscarmellose sodium is an internally cross-linked sodium carboxymethylecellulose for use as a disintegrants in pharmaceutical formulations.

Croscarmellose sodium also resolves formulators' concerns over long-term functional stability, reduced effectiveness at high tablet hardness levels, and similar problems associated with other products developed to enhance drug dissolution. Croscarmellose sodium is a very commonly used pharmaceutical additive approved by the U.S FOOD AND DRUG ADMINISTRATION. Its purpose in most tablets - including dietary supplements - is to assist the tablet in disintegrating in the intestinal tract at the required location. If a tablet disintegrating agent is not included, the tablet could disintegrate too slowly, in the wrong part of the intestine or not at all, thereby reducing the efficacy and bioavailability of the active ingredients. . As a result, it provides superior drug dissolution and disintegration characteristics, thus improving formulas' subsequent bioavailability  by bringing the active ingredients 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 sodium carboxymethylcellulose. Excess sodium monochloroacetate slowly hydrolyzes to glycolic acid and the glycolic acid catalyzes the cross-linkage to form croscarmellose sodium. 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 disintegrant for Capsules, Tablets and Granules.

In tablet formulations, Croscarmellose sodium may be used in both direct-compression and wet-granulation processes. 

When used in wet granulations the Croscarmellose sodium is best added in both the wet and dry stages of the process (intra- and extra granularly) so that the wicking and swelling ability of thedisintegrant is best utilized. 

Concentrations of up to 5% w/w of Croscarmellose sodium may be used as a tablet disintegrant although normally 2% w/w is used in tablets prepared by direct compression and 3% w/w in tablets prepared by a wet-granulation process.

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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, place

3.2.3 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 of

any sample depends on the source of the talc and on the minerals found in the ore body from

which 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. It

comprises purified, de-polymerised, Micro Crystalline sub micron size colloidal particles. It

is produced by treating Alfa Cellulose obtained as a pulp from fibrous plants with minerals

acid. 

It is a white, odourless, tasteless, extra free flowing powder which is relatively free from organic and non-organic contaminants. It is metabolically inert, and has excellent water

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absorptive, swelling & dispersion properties, is insoluble in water, dilute acid, common organic solvents and oils. It is partially soluble in dilute alkali. 

Direct Compressible Grade of Micro Crystalline cellulose performs as an excipient to assist in the flow, lubrication and binding properties of the ingredients to be tableted and improves stability 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 Micro Crystalline Cellulose over non spray dried Micro Crystalline Cellulose. 

The conventional costly method of tableting through 6 process steps is replaced by 2 steps direct compression method of tableting. 

Detailed tests and investigations by various agencies for the use of Direct Compressible Grade Micro Crystalline Cellulose powder in tableting have shown: 

a. Excellent Compression & Hardnessb. No Sign of Lubrication Difficultiesc. Good Flowing Propertiesd. Reduces Friability & Weight Loss

3.2.5 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 pharmaceuticals directly 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 capsule diluent, excipient for chewable tablets, a tonicity agent, and as a vehicle (bulking agent) for lyophilized preparations. Mannitol is industrially derived from the sugar fructose, and is roughly half as sweet as sucrose. Mannitol has a cooling effect often used to mask bitter tastes, and may be used in gums and candies. Mannitol is also found naturally in many species, including plants, bacteria, and fungi.

3.2.6 Starch:

Maize, potato, rice and tapioca (cassava) starch were evaluated with respect to their

properties on direct compression. Rice starch showed much better compactibility as

compared to maize, potato and tapioca starch. Moreover, its binding capacity proved to be

almost insensitive to mixing with magnesium stearate.

Starch is also utilized in pharmaceuticals and cosmetics. Starch derivatives often have special functions in tablets: 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 starches

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swell heavily. This accelerates the disintegration the tablet and finally leads to the liberation of the effective substance. Further applications in pharmacy include starches for the production of hard and soft capsules as well 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 to the 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 systems

Further 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. Starches from different sources have been evaluated and used as excellent binders in either mucilage or the drypowdered form Although maize starch is the most frequently used excipient in tabletting, researchers have tried to develop botanical starches for use tablet excipient. Preliminary these starches following official and un-official protocols showed that they posses some of the desirable features of good excipient.

3.2.7 Magnesium stearate:

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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 has lubricating properties, preventing ingredients from sticking to manufacturing equipment during the compression of chemical powders into solid tablets; magnesium stearate is the most commonly used lubricant for tablets. Studies have shown that magnesium stearate may affect the release time of the active ingredients in tablets, etc., but not that it reduces the overall bioavailability of those ingredients. As a food additive or pharmaceutical excipient, its E number is E470b.

Magnesium stearate is also used to bind sugar in hard candies and is a common ingredient in baby formulas. In pure powder form, the substance can be adjust explosion hazard, although this issue is effectively insignificant beyond the manufacturing plants using it.

Magnesium stearate is manufactured from both animal and vegetable oils. Some nutritional supplements specify that the magnesium stearate used is sourced from vegetables.

Magnesium stearate is a major component of "bathtub rings." When produced by soap and hard water, magnesium stearate and calcium stearate both form a white solid insoluble in water, and are collectively known as soap scum.

Magnesium stearate is created by the reaction of sodium stearate with magnesium sulfate.

Formulations F1-F3

Ingredients (mg) F1 F2 F3Aceclofenac 100 100 100SSG 30 25CCS 30Starch 15 15 15Mg.sterate- 5 5 5Mannitol- 50 50 50MCC -- --- 25

SSG = Sodium starch glycolate

CCS = Cross carmellose sodium

MS = Magnesium stearate

Mcc=microcrystalline cellulose

SS = Sodium saccharin

F= Formulatio

Chapter - 4

Methods of formulation development15

4.1 Preformulation studies

Preformulation is defined as the phase of research and development process where physical, chemical and mechanical properties of a new drug substance are used alone and when combined with excipient inorder to develop stable ,safe and effective dosage form.A through understanding of physicochemical properties may ultimately provide a rationale for formulation design, or support the need for molecular modification or merely confirm that there is no significant barrier to the formulation development. A stage of development during which the physicochemical 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, surface properties, 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. Dilute 2.0 ml of the solution to 50.0 ml with methanol  R. Examined between 220 nm and 370 nm (2.2.25), the solution shows an absorption maximum at 275 nm. The specific absorbance at 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 a mixture, prepared immediately before use, of equal volumes of a 6 g/l solution of potassium ferricyanide R and a 9 g/l solution of ferric chloride R. Allow to stand protected from light for 5 min. Add 3 ml of a 10.0 g/l solution of hydrochloric acid R. Allow to stand protected from light for 15 min. A blue colour develops and a precipitate is formed.

Stability studies:

1.Chemical stability studies

Solid state stability Effect of moisture Effect of solid state form – amorphous vs. crystalline Excipient compatibility Effect of moisture

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Effect of processing

2.Degradation mechanism Hydrolysis Oxidation potential Effect of temperature

3.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 Considerations

4.2 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-

• Improving flow properties of the mix and hence the uniformity of the dose

• Increasing the bulk density of a product

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• Facilitating metering or volumetric dispensing

• Controlling the rate of drug release

• Decrease dust generation and reduce employee exposure to drug product

• Improving product appearance

What is Granulation..?

Granulation may be defined as a size enlargement process which converts fine or coarse particles into physically stronger and larger agglomerates having good flow property, better compression characteristics and uniformity. The art and science for process and production of granules is known as Granulation Technology.

Granulation Technology can be broadly classified into 2 types based upon the type of processing involved.

1. Wet granulation method and2. Dry granulation method.

4.2.1 Wet granulation method:

Wet granulation is a pharmaceutical unit operation whereby a liquid or binder solution is sprayed onto a powder blend to improve the flow, compressibility, and content uniformity of the blend, prior to tabletting.

Improvement of flow and compressibility can be important in extended/controlled release matrix formulations where polymers with fine particle size are typically utilized to ensure rapid, reproducible polymer by Wet Granulation

Wet granulation is the most widely used process of granulation in the pharmaceutical industry.

It involves addition of a liquid solution (with or without binder) to powders, to form a wet mass or it forms granules by adding the powder together with an adhesive, instead of by compaction . The wet mass is dried and then sized to obtained granules. The liquid added binds the moist powder particles by a combination of capillary and viscous forces in the wet state. More permanent bonds are formed during subsequent drying which leads to the formation of agglomerates.

Although the process is most widely used in the pharmaceutical industry, the conventional wet granulation process has following merits and demerits.

Merits and Demerits of conventional Wet Granulation Process

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Merits :-

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, which determines the wet agglomeration behaviour:

• Wetting and nucleation;

• Consolidation and growth and finally

• Breakage and attrition.

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Figure illustrates the granule growth phenomenon

These phenomena often take place simultaneously in the granulation equipment, making the investigation of the effect of an individual phenomenon on the agglomerate properties difficult. Wetting of the articles is necessary for nucleation, i.e. the formation of 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 delivery parameters and powder mixing.”

Since wet granulation method is the oldest and most convention method of making granules, all components involved in this process forms a three phase system made of:

• Dispersed solid • Granulation liquid and

• Air.

Cohesive Force that operates during the moist agglomeration process is mainly due to the liquid bridges that develop between the solid particles, even though

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intermolecular attractive forces, van der waals forces and electrostatic forces also play an initial role.

States of liquid content during wet granulation

When liquid is added to the drug powder during initial stage, liquid film is formed on powder surface. Discrete liquid bridges are then built at the point of contact. This state is termed as Pendular State, surface tension and the capillary provide the cohesive force during this stage, air is still present between the particles. As the liquid content increases air starts coalesce. The strength of the blend increases. In this so called Funicular State, the air does not built a coherent phase anymore. As water content increases further all inter-particle voids are filled.

Capillary pressure and interfacial forces at granule surface hold the particles at this stage called Capillary State. Granules attain its maximum strength at this stage. Further addition of liquid, forms solid particles, completely surrounded by the liquid, resulting in the droplet State. During this stage system consist only two phases, dispersed solid and liquid phase. When the granulation process is finished, the liquid is removed by drying, after that the granule is still kept together by different bonding mechanismsdration.

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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

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3.Tamp auger

4.Small quantity inlet funnel

5.Press rolllers with ribbon

6.Rotor with desired granules

PRODUCT QUALITY ASPECTS

Process Parameters: Force and Gap

The powder is compacted between two rolls by applying a force, which is the most important 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 an appropriate 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 will be compacted to a predefined ribbon thickness.A precise process control is essential to obtain equal granules properties from a homogenous ribbon. 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 fixed gap, the other one with a floating gap. Both consist of the three major units as explained above 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 area between 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 change according to the amount of powder provided. The force applied to the powder remains constant. This ensures that property fluctuations in the granules are reduced to a minimum.

Milling

With our integrated models, the ribbons are being milled right after compaction using a screen 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 too many fines. PAT (= Process Analytical Tool) The GERTEIS® roller compactors are able to control and measure all product quality relevant parameters (e.g. force, gap and roll speed) on-line in order to fulfill the requirements of 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

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batch variations, our machines are fitted with control systems to allow equal granule properties during manufacturing according to PAT.

APPLICATIONS

Improving Flow Ability

Dry granulation is used for increasing the bulk density of powders, whilst increasing the particle size, resulting in better flowing material, which is a prerequisite for manufacturing capsules and tablets on high speed production equipment.Furthermore, bonding the particles of various substances together during the compaction process reduces the tendency to segregation of powder particles of different substances. This results in an improvement of the homogeneity of the active ingredients (API) within the powder blend, causing an improvement of dose uniformity of such dosage forms.

Wet- & Dry Granulation

In contrast to wet granulation, dry granulation is a continuous process. This results in various economical advantages. Nowadays the throughput of common dry granulation systems can reach 400kg/h. Dry granulation systems require comparatively fewer investments into buildings or equipment. Coupled with lower maintenance costs, this results in a much higher overall 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 a basket.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 is runned for dissolution. Now collect the sample of 2ml for 10mins and it is filterd through sintered glass filter and now immediately replace 2ml of fresh buffer solution.Now 1ml of filtered solution is diluted to 100ml with distilled water.Repeat the same procedure for 20mins,30mins,40mins,50min,and 60mins and measure the released drug concentration by using uv/visible spectrometer at 274nm.

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