Report on Control porosity osmotic pressure pumps

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PROJECT SEMESTER REPORT B.Tech Biotechnology (July-December, 2014) FORMULATION AND IN-VITRO CHARACTERIZATION OF CONTROL POROSITY OSMOTIC PRESSURE PUMP Submitted by ANANDAN BANSAL Roll No 701100003 Under the Guidance of Mr. S.P. RATHOD Department of Biotechnology Thapar University, Patiala January, 2015

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Report on Control porosity osmotic pressure pumps

Transcript of Report on Control porosity osmotic pressure pumps

Page 1: Report on Control porosity osmotic pressure pumps

PROJECT SEMESTER REPORT

B.Tech Biotechnology

(July-December, 2014)

FORMULATION AND IN-VITRO

CHARACTERIZATION OF

CONTROL POROSITY OSMOTIC PRESSURE PUMP

Submitted by

ANANDAN BANSAL

Roll No 701100003

Under the Guidance of

Mr. S.P. RATHOD

Department of Biotechnology

Thapar University, Patiala

January, 2015

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DECLARATION

I, hereby declare that the project work entitled “Formulation and In-vitro characterization

of Control porosity osmotic pressure pump tablets” in partial fulfillment of the

requirement for the award of degree of B.Tech (Biotechnology), Department of

Biotechnology, Thapar University, Patiala, is an authentic record of my own work carried out

during the period of June to December, 2014 under the guidance of Mr. S.P. Rathod of MS

University of Baroda.

Anandan Bansal

Date: 06 January 2015 701100003

This is to certify that the above statement made by the student is true to the best of our

knowledge.

Faculty Coordinator Mr. S.P. Rathod

DBT Associate professor, MS University

Thapar University, Patiala Institution Coordinator

Dr. Dinesh Goyal

Professor and Head, DBT

Thapar University, Patiala

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ACKNOWLEDGEMENT

I am using this opportunity to express my gratitude to everyone who supported me

throughout this project. I am thankful for the aspiring guidance, invaluably constructive

criticism and friendly advice of everyone during the project work. I am sincerely grateful to

them for sharing their knowledge various queries related to the project.

I express my warm thanks to Mr. S.P Rathod for their support and guidance at MS University

of baroda. I wish to express my gratitude to Dr. Praveen and Mr. Neerav for their guidance,

friendship and continual support all the way through this project. I wish to thank Mr. Dhaval

Patel for his support and inspiration throughout the project.

I want to thank especially Er. Sanjeev Ratti, passout from Thapar university itself, who

arranged everything in Vadodara from training to residence. He gave us full support to work

and live in Gujarat.

I want to thank Dr. Dinesh Goyal, HOD of Department of Biotechnology for his support. I

also want to express my gratitude to Dr. Manoj Baranwal and Mrs. M Vasundhara for there

support and help in completion of this project.

I wish to thank my parents for always supporting me and for all their love, affection,

encouragement and blessings that kept me strong. I also thank those who could not find a

separate name but helped me directly or indirectly.

Thank you

Anandan Bansal

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INDEX

SUMMARY ……………………………………………………………………………….1

INTRODUCTION…………………………………………………………………………3

THEORY..………………………………………………………………………………….5

CPOPT….……………………………………………………………………………7

PRE FORMULATION STUDIES .………………………………………………...11

PARACETAMOL …………………………………………………………….…....15

POST FORMULATION STUDIES ………………………………………………..16

REVIEW OF LITERATURE ……………………………………………………………..25

AVAILABLE CPOP TABLETS …………………………………………………...25

TABLET FORMULATION METHODS…………………………………………..28

EXCIPIENTS……………………………………………………………………….33

TABLET COATING ……………………………………………………………….37

PRINCIPLE ………………………………………………………………………………39

MATERIAL ……………………………………………………………………………….45

METHOD ………………………………………………………………………………...47

RESULTS AND DISCUSSION………………………………………………………….59

CONCLUSION…………………………………………………………………………...68

FUTURE SCOPE…………………………………………………………………………69

REFERENCES ...………………………………………………………………………....70

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SUMMARY

In view of developing “New drug delivery systems” for efficient absorption of drug

in the body, A concept of using osmotic pressure was developed. Control Porosity Osmotic

pressure Pump Tablets (CPOPT) are developed for this case which ensures a longer zero

order release time thus ensuring much more effectiveness. Whereas conventional drug

delivery systems had little control over their drug release and almost no control over the

effective concentration at the target site.

Conventional practice of dosing pattern may result in constantly changing,

unpredictable plasma concentrations. Drugs can be delivered in a controlled pattern over a

long period of time by the process of osmosis. Osmotic devices are the most promising

strategy based systems for controlled drug delivery. They are the most reliable controlled

drug delivery systems and could be employed as oral drug delivery systems.

The present review is concerned with the study of drug release systems which are

tablets coated with walls of controlled porosity. When these systems are exposed to water,

low levels of water soluble additive is leached from polymeric material i.e. semi permeable

membrane and drug releases in a controlled manner over an extended period of time. Drug

delivery from this system is not influenced by the different physiological factors within the

gut lumen and the release characteristics can be predicted easily from the known properties of

the drug and the dosage form.

In this project, Paracetamol tablets were coated with osmotically active agent “A

chemical polymer – Cellulose acetate”. This polymer makes a porous polymer layer around

drug tablet. This pores release drug in systematic and controlled manner and allow orifice

mechanism. Thus drug is released in zero order for a longer duration as it releases slowly into

the blood.

During formulation of tablet, there are different steps followed which are : Pre-

formulation studies, excipient drug interaction studies, drug release curve, formulation

method, formulation technique, post formulation analysis, release studies, etc.

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From various analysis preformed, we conclude that the walls were sponge-like in

appearance and substantially permeable to both water and dissolved solutes. The rate of

release was a function of the wall thickness, level of leachable additives incorporated and

permeability of the polymer component of the walls, the total solubility of the core tablet, the

drug load, and the osmotic pressure difference across the wall. Release was insensitive to the

pH and degree of agitation in the receptor media. Release was primarily due to an osmotic

pump mechanism. Steady-state release rates were calculated from basic water and solute

permeability of the walls and correlated with actual device performance. The concept of

osmotically actuated drug delivery on an equivalent mass per unit surface area basis was

demonstrated and extended, as well, to multiparticulate dosage forms.

The release graphs obtained as result of dissolution test give us surety that CPOPT are much

better effective for drug release in body.

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INTRODUCTION

Conventional drug delivery systems have little control over their drug release and

almost no control over the effective concentration at the target site. This kind of dosing

pattern may result in constantly changing, unpredictable plasma concentrations. Drugs can be

delivered in a controlled pattern over a long period of time by the process of osmosis.

Osmotic devices are the most promising strategy based systems for controlled drug delivery.

They are the most reliable controlled drug delivery systems and could be employed as oral

drug delivery systems. The present review is concerned with the study of drug release

systems which are tablets coated with walls of controlled porosity. When these systems are

exposed to water, low levels of water soluble additive is leached from polymeric material i.e.

semi permeable membrane and drug releases in a controlled manner over an extended period

of time. Drug delivery from this system is not influenced by the different physiological

factors within the gut lumen and the release characteristics can be predicted easily from the

known properties of the drug and the dosage form.

The controlled-porosity osmotic pump tablet concept was developed as an oral drug

delivery system by Zentner et al (1985, 1991), Zentner and Rork (1990), Appel and

Zentner (1991), and Mc Celland et al. (1991). The controlled-porosity osmotic pump

tablet (CPOP) is a spray-coated or coated tablet with a semi permeable membrane (SPM)

containing leachable pore forming agents. They do not have any aperture to release the

drugs. Drug release is achieved through the pores, which are formed in the semi permeable

wall in situ during the operation. In this system, the drug, after dissolution inside the core, is

released from the osmotic pump tablet by hydrostatic pressure and diffusion through pores

created by the dissolution of pore formers incorporated in the membrane. The hydrostatic

pressure is created either by an osmotic agent or by the drug itself or by a tablet component,

after water is imbibed across the semi permeable membrane.

This membrane after formation of pores becomes permeable for both water and

solutes. A controlled-porosity osmotic wall can be described as having a sponge like

appearance. The pores can be continuous that have micro porous lamina, interconnected

through tortuous paths of regular and irregular shapes. Generally, materials (in a

concentration range of 5% to 95%) producing pores with a pore size from 10 Å -100 m can

be used.

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This system is generally applicable for only water-soluble drugs as poorly water

soluble drugs cannot dissolve adequately in the volume of water drawn into the OPT.

Recently this problem was overcome by adding agents like sulfobutyl ether- -cyclodextrin

(SBE)7m- -CD or hydroxypropyl- -cyclodextrin (HP- -CD) as solubilising and

osmotic agents. Several approaches have been developed to prepare the porous

membrane by spray coating using polymer solutions containing dissolved or suspended

water-soluble materials. The rate of drug release can also be varied by having different

amounts of osmogens in the system to form different concentrations of channelling agents for

delivery of the drug from the device. Incorporation of the cyclodextrin-drug complex has also

been used as an approach for the delivery of poorly water-soluble drugs from the osmotic

systems, especially controlled-porosity osmotic pump tablets.

ADVANTAGES

The OPT can be so designed that delivery of its drug would follow zero order

kinetics and thus better control over the drug’s in vivo performance is possible.

The drug release from the osmotically controlled drug delivery systems are independent

of the gastric pH and hydrodynamic conditions, which is mainly attributed to the unique

properties of the SPM employed in the coating of osmotic formulations.

The delivery rate of drug from these systems is highly predictable and can be

programmed by modulating the terms.

It is possible to attain better release rates than those obtained with conventional diffusion

based drug delivery systems.

Drug release from the OCODDSs exhibits significant in vitro-in vivo correlation

[IVIVC] within specific limits.

DISADVANTAGES

Drug release from the osmotic systems is affected to some extent by the presence of

food.

Retrieval of therapy is not possible in the case of unexpected adverse events.

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THEORY

Drug delivery system

Drug delivery is the method or process of administering a pharmaceutical compound

to achieve a therapeutic effect in humans or animals. For the treatment of human diseases,

nasal and pulmonary routes of drug delivery are gaining increasing importance. These routes

provide promising alternatives to parenteral drug delivery particularly for peptide and protein

therapeutics.

For this purpose, several drug delivery systems have been formulated and are being

investigated for nasal and pulmonary delivery. Nanoparticles composed of biodegradable

polymers show assurance in fulfilling the stringent requirements placed on these delivery

systems, such as ability to be transferred into an aerosol, stability against forces generated

during aerosolization, biocompatibility, targeting of specific sites or cell populations in the

lung, release of the drug in a predetermined manner, and degradation within an acceptable

period of time.

Development in Drug delivery systems

Development of new drug molecule is expensive and time consuming. Improving

safety efficacy ratio of “old” drugs has been attempted using different methods such as

individualizing drug therapy, dose titration, and therapeutic drug monitoring. Delivering drug

at controlled rate, slow delivery, targeted delivery are other very attractive methods and have

been pursued vigorously. It is interesting to note that considerable work and many

publications from USA, Europe are authored by Indian researchers.

Numerous animal and human investigations have provided an increased

understanding of the pharmacokinetic and pharmacodynamic principles that govern the action

and disposition of potent opioid analgesics, inhalation anaesthetic agents, sedative/hypnotics,

and muscle relaxants. These studies suggest that skin and buccal and nasal mucous

membranes may have use as alternate routes of analgesic and anaesthetic delivery. Similar

developments with other compounds have produced a plethora of new devices, concepts, and

techniques that have together been termed controlled-release technology (CRT). Some

examples of CRTs are transdermal and transmucosal controlled-release delivery systems, ml6

nasal and buccal aerosol sprays, drug-impregnated lozenges, encapsulated cells, oral soft

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gels, iontophoretic devices to administer drugs through skin, and a variety of programmable,

implanted drug-delivery devices. There are a number of factors stimulating interest in the

development of these new devices, concepts, and techniques.

Conventional drug administration methods, while widely utilized, have many

problems that may be potentially overcome by these methods. Equally important, these

advances may appear attractive relative to the costs of new drug development. Rising

research and development costs, alternative investment opportunities for drug firms, fewer

firms conducting pharmaceutical research, and erosion of effective patent life have resulted in

a decline in the introduction of new chemical entities since the late 1950s. Bringing a new

drug through discovery, clinical testing, development, and regulatory approval is currently

estimated to take a decade and cost well over $ 120 million. Novel drug delivery systems

may account for as much as 40% of US marketed drug products by 2000.

Why Controlled drug release?

New drug delivery systems have been developed or are being developed to overcome

the limitation of the conventional drug delivery systems to meet the need of the healthcare

profession. These systems can be characterised as controlled drug release systems and

targeted drug delivery systems.

The therapeutic benefits of these new systems include:

Increased efficacy of the drug

Site specific delivery

Decreased toxicity/side effects

Increased convenience

Shorter hospitalizations

Viable treatments for previously incurable diseases

Potential for prophylactic applications

Lower healthcare costs - both short and long term

Better patient compliance.

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Controlled osmotic release – Control Porosity Osmotic Pump

Conventional drug delivery systems have little control over their drug release and

almost no control over the effective concentration at the target site. This kind of dosing

pattern may result in constantly changing, unpredictable plasma concentrations. Drugs can be

delivered in a controlled pattern over a long period of time by the process of osmosis.

Osmotic devices are the most promising strategy based systems for controlled drug delivery.

They are the most reliable controlled drug delivery systems and could be employed as oral

drug delivery systems. The present review is concerned with the study of drug release

systems which are tablets coated with walls of controlled porosity. When these systems are

exposed to water, low levels of water soluble additive is leached from polymeric material i.e.

semi permeable membrane and drug releases in a controlled manner over an extended period

of time. Drug delivery from this system is not influenced by the different physiological

factors within the gut lumen and the release characteristics can be predicted easily from the

known properties of the drug and the dosage form.

Fig. 1 Steps involved in pharmaceutics therapy

management

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Basic components required for controlled porosity osmotic pump:

a) Drug

b) Osmotic agent

c) Semi permeable membrane

d) Channelling agents or pore forming agents.

Osmotic agent

Polymeric osmogens are mainly used in the fabrication of osmotically controlled

drug delivery systems and other modified devices for controlled release of relatively

insoluble drugs. Osmotic pressures for concentrated solution of soluble solutes commonly

used in controlled release formulations are extremely high, ranging from 30 atm for sodium

phosphate up to 500 atm for a lactose-fructose mixture. These osmotic pressures can

produce high water flows across semi permeable membranes.

Fig. 2 Various layers inside a drug release capsule

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Semi permeable Membrane

The membrane should be stable to both outside and inside environments of the device.

The membrane must be sufficiently rigid so as to retain its dimensional integrity during the

operational lifetime of the device. The membrane should also be relatively impermeable to

the contents of dispenser so that osmogen is not lost by diffusion across the membrane.

Finally, the membrane must be biocompatible. Some good examples for polymeric materials

that form membranes are cellulose esters like cellulose acetate, cellulose acetate butyrate,

cellulose triacetate, ethyl cellulose and Eudragits.

Ideal properties of semi permeable membrane

The material must possess sufficient wet strength (10-5 Psi) and wet modules so (10-

5 Psi) as to retain its dimensional integrity during the operational lifetime of the

device.

The membrane must exhibit sufficient water permeability so as to attain water flux

rates (dv/dt) in the desired range. The water vapour transmission rates can be used to

estimate water flux rates.

The reflection coefficient of the osmotic agents should approach the limiting value of

unity. But polymer membranes must be more permeable to water.

Channelling agents/ leachable pore forming agents

These are the water-soluble components which play an important role in the

controlled drug delivery systems. When the dissolution medium comes into contact with the

semi permeable membrane it dissolves the channelling agent and forms pores on the semi

permeable barrier.

Then the dissolution fluid enters the osmotic system and releases the drug in a

controlled manner over a long period of time by the process of osmosis. Some examples of

channelling agents are polyethylene glycol (PEG) 1450, -mannitol, bovine serum albumin

(BSA), diethylphthalate, dibutylphthalate and sorbitol.

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Some successful DRUG candidates for CPOP tablets

Isradipine

Salvianolic acid

Ibuprofen

Pseudoephedrine

Isosorbide mononitrate

Trimetazidine dihydrochloride

Indapamide

Testosterone

Polysorbate 80

Witepsolm h-35

Trimazosin

Polyvinylacetate e polyvinyl pyrrolidon

Fig. 3 Formation of pores in a drug tablet

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Potassium chloride

Budesonide

Diltiazem hydrochloride

Polyvinyl acetate

Doxazosin

Chlorpheniramine maleate

Gliclazide

Dipyridamole

Famotidine

Prednisolone

Chitosan

Methylphenidate hcl

Venlafaxine

Metoprolol

Atenolol

PRE FORMULATION STUDIES

Preformulation is branch of Pharmaceutical science that utilizes biopharmaceutical

principles in the determination of physicochemical properties of the drug substance.

Preformulation study means investigation of physic-chemical properties of the new drug

compound that could affect drug performance and development of an efficacious dosage

form.

Prior to the development of any dosage form new drug, it is essential that certain

fundamental physical & chemical properties of drug powder are determined. This information

may dictate many of subsequent event & approaches in formulation development.

Why is this done?

To establish the necessary physicochemical parameters of new drug substances

To determine kinetic rate profile.

To establish physical characteristics.

To establish compatibility with common excipients.

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Preliminary examinations

Compound identity

Formula and molecular weight

Structure.

Therapeutic indications :

Probable human dose

Desired dosage forms

Bioavailability model

Competitive products

Factors examined for characteristics

1. Colour

Colour is generally a function of a drug’s inherent chemical structure relating to a certain

level of unsaturation. Colour intensity relates to the extent of conjugated unsaturation as well

as the presence of chromophores. Some compound may appear to have color although

structurally saturated.

2. Odour

The substance may exhibit an inherent odour characteristic of major functional groups

present. Odour greatly affects the flavour of a preparation or food stuff.

3. Purity

Designed to estimate the levels of all known & significant impurities & contaminates in

the drug substance under evaluation.

Study performed in an analytical research & development group. It is another parameter

which allows for comparison with subsequent batches. Thin layer chromatography is a wide

ranging applicability & is an excellent tool for characterizing the purity. HPLC, paper

chromatography & gas chromatography are also useful. More quantitative information can be

obtained by using quantitative differential scanning colorimetry.

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4. Particle size

This factor is very important to study activity of drug. Particle size can influence variety

of important factors:

Dissolution rate

Suspendability

Uniform distribution

Penetrability

Lack of grittiness

Techniques to determine particle size:

Sieving

Microscopy

Sedimentation rate method

Light energy diffraction

Laser holography

Cascade impaction

5. Flow properties

Powder flow properties can be affected by change in particle size, shape & density. The

flow properties depends upon force of friction and cohesion between one particle to another.

Fine particle posse’s poor flow by filling void spaces between larger particles causing

packing & densification of particles. Measurement is done of free flowing powder by

compressibility also known as Carr's index.

6. Surface area

Particle size & surface area are inversely related to each other. Smaller is the drug

particle, greater the surface area. Specific surface is defined as the surface area per unit

weight (Sw) or unit volume (Sv) of the material.

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7. Solubilisation

Solubilization is defined as the spontaneous passage of poorly water soluble solute

molecules into an aqueous solution of a soap or detergent in which a thermodynamically

stable solution is formed. It is the process by which apparent solubility of an otherwise

sparingly soluble substance is increased by the presence of surfactant micelles.

When surfactants are added to the liquid at low concentration they tend to orient at the

air-liquid interface. On further addition of surfactant the interface becomes completely

occupied and excess molecules are forced into the bulk of liquid. At very high concentration

surfactant molecules in the bulk of liquid begin to form micelles and this concentration is

known as Critical Micelle Concentration (CMC).

8. PH solubility profile

The solubility of acidic or basic drug will show difference in solubility with changes in

pH. pH solubility profile of a drug can be established by running the equilibrium solubility

experiment within pH range of 3-4.

9. Temperature variation

The heat of solution ‘Hs’ , represents the heat released or absorbed when a mole of solute

is dissolved in large quantity of solvent.

10. Complexation

For the Complexation occur both drug and ligand molecule should be able to donate or

accept electrons. The solubility of compound is the sum of solubility of the compound and its

complex.

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PARACETAMOL – The drug candidate for CPOPT

For this project, Paracetamol drug was chosen as drug candidate and modified to

make Control Porosity Osmotic Pump Tablet (CPOPT). Paracetamol, also known as

acetaminophen, is classified as a mild analgesic. It is commonly used for the relief

of headaches and other minor aches and pains and is a major ingredient in

numerous cold and flu remedies. In combination with opioid analgesics, paracetamol can also

be used in the management of more severe pain such as post-surgical pain and

providing palliative care in advanced cancer patients. Though paracetamol is used to treat

inflammatory pain, it is not generally classified as an NSAID because it exhibits only weak

anti-inflammatory activity.

Paracetamol has a very low solubility in nonpolar and chlorinated hydrocarbons such

as toluene and carbon tetrachloride whereas the solubility is very high in solvents of medium

polarity such as N, N-dimethylformamide, dimethyl sulfoxide, and diethylamine.

Paracetamol is soluble in alcohols, but the solubility decreases with an increase in the length

of the carbon chain in the n-alcohol homologous series (methanol to 1-octanol). The

solubility of paracetamol in water is much lower than in other polar solvents such as the

alcohols. The ideal solubility of paracetamol is calculated, and the activity coefficient in the

saturated solutions is estimated.

Dosage information - Usual Pediatric Dose for Fever

<=1 month: 10 to 15 mg/kg/dose every 6 to 8 hours as needed.

>1 month to 12 years: 10 to 15 mg/kg/dose every 4 to 6 hours as needed (Maximum: 5 doses

in 24 hours)

>=12 years: 325 to 650 mg every 4 to 6 hours or 1000 mg every 6 to 8 hours.

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Side effects

Some cases may lead to side effects for which get emergency medical help if you

have any of these signs of an allergic reaction to paracetamol: hives; difficulty breathing;

swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor

at once if you have a serious side effect such as:

Low fever with nausea, stomach pain, and loss of appetite

Dark urine, clay-colour stools

Jaundice (yellowing of the skin or eyes).

POST FORMULATION EVALUATION STUDIES

After formulation of drug tablets, evaluation is done to ensure drug dosage,

dissolution in body, concentrations at different time intervals, material strength, friability etc.

There are various standards that have been set in the various pharmacopoeias regarding the

quality of pharmaceutical tablets. These include the diameter, size, shape, thickness, weight,

hardness, disintegration and dissolution characters. The diameters and shape depends on the

die and punches selected for the compression of tablets.

The remaining specifications assure that tablets do not vary from one production lot to

another. The following standards or quality control tests should be carried out on compressed

tablets. The general appearance of tablets, its visual identity and overall ‘elegance’ is

essential for consumer acceptance, control of lot-to-lot uniformity and general tablet to tablet

uniformity and for monitoring the production process.

The control of general appearance involves measurement of attributes such as a

tablet’s size, shape, color, presence or absence of odour, taste, surface textures, physical

flaws and consistency. The mechanical strength of a tablet provides a measure of the bonding

potential of the material concerned and this information is useful in the selection of

Excipients. An excessively strong bond may prevent rapid disintegration and subsequent

dissolution of a drug. Weak bonding characteristics may limit the selection and/or proportion

of excipients, such as lubricants, that would be added to the formulation.

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This evaluation is done using experiments based on various formulation parameters like:

Size and shape

Hardness and friability

Weight variation

Disintegration

Dissolution

SIZE AND SHAPE

The shape and dimensions of compressed tablets are determined by the type of tooling

during the compression process. At a constant compressive load, tablets thickness varies with

changes in die fill, particle size distribution and packing of the powder mix being compressed

and with tablet weight, while with a constant die fill; thickness varies with variation in

compressive load. Tablet thickness is consistent from batch to batch or within a batch only if

the tablet granulation or powder blend is adequately consistent in particle size and particle

size distribution, if the punch tooling is of consistent length, and if the tablet press is clean

and in good working condition.

The thickness of individual tablets may be measured with a micrometer, which

permits accurate measurements and provides information of the variation between tablets.

Tablet thickness should be controlled within a ±5% variation of a standard value. Any

variation in thickness within a particular lot of tablets or between manufacturer’s lots should

not be apparent to the unaided eye for consumer acceptance of the product. In addition,

thickness must be controlled to facilitate packaging.

The physical dimensions of the tablet along with the density of the material in the

tablet formulation and their proportions, determine the weight of the tablet. The size and

shape of the tablet can also influence the choice of tablet machine to use, the best particle size

for granulation, production lot size that can be made, the best type of tableting processing that

can be used, packaging operations, and the cost of production.

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The USP has provided limits for the average weight of uncoated compressed tablets.

These are applicable when the tablet contains 50mg or more of the drug substance or when

the latter comprises 50% or more, by weight of the dosage form. Twenty tablets are weighed

individually and the average weight is calculated. The tablets physical parameters and

analysed which are usually measured by

Micrometer

Sliding calliper scale

Tablet thickness should be controlled within ± 5% variation of standard value to

ensure no capping problem. If parameters go out of safety limit, there are chances of

improper distribution of drug in body or even no absorption in body blood.

HARDNESS

The resistance of tablets to capping, abrasion or breakage under conditions of storage,

transportation and handling before usage depends on its hardness. The small and

portable hardness tester was manufactured and introduced by Monsanto in the Mid 1930s. It

is now designated as either the Monsanto or Stokes hardness tester. The instrument measures

the force required to break the tablet when the force generated by a coil spring is applied

diametrically to the tablet.

The Strong Cobb Pfizer and Schleuniger apparatus which were later introduced

measures the diametrically applied force required to break the tablet.

Hardness, which is now more appropriately called crushing strength determinations are made

during tablet production and are used to determine the need for pressure adjustment on tablet

machine. If the tablet is too hard, it may not disintegrate in the required period of time to

meet the dissolution specifications; if it is too soft, it may not be able to withstand the

handling during subsequent processing such as coating or packaging and shipping operations.

The tablet is formulated using different apparatus of hardening and different methods

of formation like wet granulation, dry granulation or direct compression. So to ensure safe

harness limits, testing is done so that hardness falls in required range. Range depends on pH,

drug composition, where it is to be absorbed etc.

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To test harness, following instruments are usually used:

Monsanto tester

Strong & Cobb tester

Pfizer tester

Erweka tester – kilogram

Schleuniger tester

FRIABILITY

Measuring the hardness of a tablet is not a reliable indicator for tablet strength as some

formulations when compressed into very hard tablets tend to 'cap' or lose their crown portions

on attrition. Such tablets tend to powder, chip and fragment.

They not only lack elegance and consumer acceptance but also spoil the areas of

manufacturing such as coating and packaging.

In friability test the tablets are prone to abrasion hence enabling us to check for the tablet

strength under application of force in

different manner.

The friability test is carried out in an

instrument called a friabilator. A friability

testing apparatus should stimulate the

conditions that the product will be exposed

to during the process of production. This

test is a method to determine physical

strength of uncoated tablets upon exposure

to mechanical shock and attrition.

The commonly used friabilator in

laboratories is the Roche friabilator (Fig. 5). Fig. 4 Layout of Roche friabilator

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Standard procedure for testing is:

Pre weighed tablet sample placed in friabilator

Operated 100 revolution (25 rpm for 4 min)

Dropping tablet a distance 6 inch

Tablet are then dusted and reweighed

There is a general specification used in this case. Conventional compressed tablet that

lose less than 0.5 to 1% of their weight are generally acceptable.

DISINTEGRATION

For a drug to be absorbed from a solid dosage form after oral administration, it must

first be in solution, and the first important step toward this condition is usually the break-up

of the tablet; a process known as disintegration. The disintegration test is a measure of the

time required under a given set of conditions for a group of tablets to disintegrate into

particles which will pass through a 10 mesh screen. Generally, the test is useful as a quality

assurance tool for conventional dosage forms. The disintegration test is carried out using the

disintegration tester which consists of a basket rack holding 6 plastic tubes, open at the top

and bottom, the bottom of the tube is covered by a 10-mesh screen. The basket is immersed

in a bath of suitable liquid held at 37 o C, preferably in a 1L beaker.

Types of disintegration apparatus:

Disintegration apparatus for solid dosage forms ( Tablets, capsules etc) and

Disintegration apparatus for semisolid dosage forms ( Suppositories and peccaries ) The USP

device to test for disintegration time consists of six glass tubes each of three inches length,

open at the top, and held against a 10 mesh screen at the bottom end of the basket rack

assembly. To test for the disintegration time, a single tablet is placed in each tube, and the

basket rack is positioned in a 1-L beaker containing water or simulated gastric fluid, or

stimulated intestinal fluid.

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The temperature of the system is maintained at 37+/-2oc and the tablets remain 2.5

cm below the surface of the liquid on their upward movement and descend not closer than 2.5

cm from the bottom of the beaker.

A standard motor-driven device is used to move the basket assembly containing the

tablets up and down through a distance of 5 to 6 cm at a frequency of 28 to 32 cycles per

minute. Perforated plastic discs may also be used in the test. These discs are placed on top of

the tablets. The discs are useful for preventing the tablets from coming out of the assembly. If

the tablets are to be declared as USP compliant, they must disintegrate and all particles must

pass through the 10-mesh screen in the specified time. Most of the tablets have a maximum

disintegration time of 30 minutes, but uncoated tablets have disintegration times as low as 5

min.

DISSOLUTION TEST

Dissolution is the process by which a solid solute enters a solution. In the

pharmaceutical industry, it may be defined as the amount of drug substance that goes into

solution per unit time under standardized conditions of liquid/solid interface, temperature and

solvent composition. Dissolution is considered one of the most important quality control tests

performed on pharmaceutical dosage forms and is now developing into a tool for predicting

bioavailability, and in some cases, replacing clinical studies to determine bioequivalence.

Dissolution behaviour of drugs has a significant effect on their pharmacological activity. In

fact, a direct relationship between in vitro dissolution rate of many drugs and their

bioavailability has been demonstrated and is generally referred to as In-vitro – in-

vivo correlation, IVIVC.

Solid dosage forms may or may not disintegrate when they interact with

gastrointestinal fluid following oral administration depending on their design (Figure 1). For

disintegrating solid oral dosage forms, disintegration usually plays a vital role in the

dissolution process since it determines to a large extent the area of contact between the solid

and liquid. However it is well known that considerable dissolution of the drug can take place

before complete disintegration of the dosage form, a phenomenon which depends largely on

the mechanism of disintegration and certain physicochemical properties of the drug, such as

its solubility. This could be important when considering the motility of the drug or dosage

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form, and the release of the drug at specific sites, in the gastrointestinal tract. Thus,

correlations have been established between disintegration times and dissolution rates for

various pharmaceutical tablets.

There are four dissolution apparatuses standardized and specified. They are:

• USP Dissolution Apparatus 1 - Basket (37°C)

• USP Dissolution Apparatus 2 - Paddle (37°C)

• USP Dissolution Apparatus 3 - Reciprocating Cylinder (37°C)

• USP Dissolution Apparatus 4 - Flow-Through Cell (37°C)

USP Dissolution Apparatus 1 – Basket type

The most commonly used methods for evaluating dissolution first appeared in the

13th edition of the U.S. Pharmacopeia in early 1970. These methods are known as the USP

basket (method Ι) and paddle (method ΙΙ) methods and are referred to as “closed-system”

methods because a fixed volume of dissolution medium is used.

In practice a rotating basket method provides a steady stirring motion in a large vessel

with 500 to 1000 mL of fluid that is immersed in a temperature –controlled water bath.

Basket method is very simple, robust, and easily standardized. The USP basket method is the

method of choice for dissolution testing of immediate-release oral solid dosage forms.

USP Dissolution Apparatus 2 – Paddle type

An apparatus described by Levy and Hayes may be considered the forerunner of the

beaker method. It consisted of a 400 ml beaker and a three-blade, centrally placed

polyethylene stirrer (5 cm diameter) rotated at 59 rpm in 250 ml of dissolution fluid (0.1N

HCl). The tablet was placed down the side of the beaker and samples were removed

periodically. In this a paddle replaces the basket as the source of agitation. As with the basket

apparatus, the shaft should position no more than 2mm at any point from the vertical axis of

the vessel and rotate without significant wobble.

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The apparatus is useful for tablets, capsules and suspensions. Like USP Apparatus 1

solids (mostly floating), monodisperse (tablets) and polydisperse (encapsulated beads) drug

products are commonly tested using USP Apparatus 2. But floating dosage forms require

sinker which could be considered as a disadvantage of the apparatus. Moreover cone

formation and positioning of tablet during the test is sometimes hard to maintain.

Fig. 5 Dissolution test apparatus

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USP Dissolution Apparatus 3 – Reciprocating Cylinder

The assembly of USP apparatus 3 consists of a set of cylindrical, flat-bottomed glass

outer vessels; a set of glass reciprocating inner cylinders; and stainless steel fittings and

screens that are made of suitable material and that are designed to fit the tops and bottoms of

the reciprocating cylinders. Operation involves programming the agitation rate, in dpm, of the

up and down for the inner tube inside the outer tube. On the up stroke, the bottom mesh in the

inner tube moves upward to contact the product and on the down stroke the product leaves

the mesh and floats freely within the inner tube. Thus the action produced carries the product

being tested through a moving medium.

USP Dissolution Apparatus 4 – Flow Through Cell type

USP Apparatus 4 can be operated under different conditions such as open or closed

system mode, different flow rates and temperatures. The diversity of available cell types

allows the application of this apparatus for testing of a wide range of dosage forms including

tablets, powders, suppositories or hard and soft gelatin capsules. It is the method of choice for

extended release and poorly soluble products.

USP Apparatus 4 requires the sampling pump to be on continuously throughout the

analysis, as the dissolution rate is directly proportional to the flow rate of the medium that is

pumped into the flow through cell. Sampling for this technique therefore requires that

continuous collection or measurement of the eluted sample be maintained.

As the dissolution time increases, large sample storage may be required, which may

not be practical. Fraction collectors have a finite number of positions that are reduced as the

volume of samples to be collected increases, which can limit the number of time points that

can be collected. Sample splitters can also be used to divert the sample sequentially between

collection and waste, thus reducing the volume of sample to be collected.

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REVIEW OF LITERATURE

To study formulation and analysis of Control porosity osmotic pump tablets, I

reviewed research papers for already available CPOP tablets, excipients, and tablet

formulation methods.

1. Some drug candidates already available under CPOP tablets:

1.1 Ibuprofen

Ibuprofen tablets were prepared and sodium chloride and polyethylene glycol 6000

were used as osmotic agents. The tablets were coated with a mixture of cellulose acetate and

polyethylene glycol 400 by the use of a modified fluidized bed apparatus. Delivery orifices

on the coated tablets are produced using a micro drill. The tablets were tested for dissolution

rate using the USP paddle method. Finally, it was observed that the release rate of ibuprofen

was influenced by the concentration of osmotic agent’s sodium chloride and polyethylene

glycol 6000.

An estimated amount of active material was compressed without any additional

substance and coated with a solution of cellulose acetate in acetone (4% w/w). Since the

coating material was too hard and fragile, however, PEG 400 (2% w/w) was added as a

plasticizer. Scanning electron microscope (SEM) photographs demonstrate the structures of

both coating materials after contact with water. As seen in these pictures, the structure seems

to have a more elastic and porous condition with the addition of PEG. Therefore, the solution

of cellulose acetate containing PEG 400 was used to coating all tablets in the study. The

coated tablets with the IP code, that contain no orifice, were subjected to a dissolution rate

test in order to detect whether the active material passes through the film by diffusion. Since

no active material was released through the tablets during first 150 min, and it was

determined that only 1.66% of the active material was released by the end of 180 min, it was

concluded that diffusion from the membrane did not influence the release of active material.

1.2 Trimetazidine dihydrochloride

This was done to develop and optimize Trimetazidine dihydrochloride (TM)

controlled porosity osmotic pump (CPOP) tablets of directly compressed cores.A23 full

factorial design was used to study the influence of three factors namely: PEG400 (10 % and

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25 % based on coating polymer weight), coating level (10% and 20%of tablet core weight)

and hole diameter (0 ‘‘no hole’’ and 1 mm). Other variables such as tablet cores, coating

mixture of ethyl cellulose (4%) and dibutylphthalate (2%) in 95% ethanol and pan coating

conditions were kept constant. The responses studied (Yi) were cumulative percentage

released after 2 h and regression coefficient of release data fitted to zero order equation

(RSQzero), forY1,Y2,Y3, andY4, respectively. Polynomial equations were used to study the

influence of different factors on each response individually. Response surface methodology

and multiple response optimizations were used to search for an optimized formula. Response

variables for the optimized formula were restricted to 10% 6 Y1 6 20%, 40% 6 Y2 6 60%,

80% 6 Y3 6 100%, and Y4>0.9. The statistical analysis of the results revealed that PEG400

had positive effects on Q%2h, Q%6h and Q%12h, hole diameter had positive effects on all

responses and coating level had positive effect on Q%6h, Q%12h and negative effect on

RSQzero. Full three factor interaction (3FI) equations were used for representation of all

responses except Q%2h which was represented by reduced (3FI) equation. Upon exploring

the experimental space, no formula in the tested range could satisfy the required constraints.

Thus, direct compression of TM cores was not suitable for formation of CPOP tablets.

Preliminary trials of CPOP tablets with wet granulated cores were promising with an intact

membrane for 12 h and high RSQzero. Further improvement of these formulations to

optimize TM release will be done in further studies.

1.3 Salvianolic acid

CPOPT for Salvianolic acid (SA) were prepared and optimized with experimental

design methods including anartificial neutral network (ANN) method. Three causal factors,

i.e., drug, osmotic pressure promoting agent rate, PEG400 content in coating solution and

coating weight, were evaluated based on their effects on drug release rate. The linear

correlation coefficient of the accumulative amount of drug release and the time of 12h, r

(Y1), and the sum of the absolute value between measured and projected values, Y2, were

used as outputs to optimize the formulation. The weight expression Y¼ (1_Y1)2 þY2 2 was

used in the calculation. Furthermore, the ANN and uniform design have similar optimization

results, but ANN projected the outputs better than the uniform design. This paper showed that

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the release rate of Salvianolic acid B and that of the total Salvianolic acid was consistent in

the optimized formulation.

Controlled release formulations of Salvianolic acid were developed based on osmotic

technology. The effect of three different formulation variables was evaluated for the

optimization of drug release profile. The mixture of lactose: sucrose ratio 1:1 was chosen as

osmogens, and the amounts of osmogens tablet core were shown to have an impact on the

release of Salvianolic acid. When the osmogens were excessive, the saturated osmotic

pressure was too high to control the drug release. Although no significant difference was

observed in drug release rate with the hardness of core tablets as a variable, the tablets with

low hardness can cause abrasion of tablet core and crush during the coating process. The

release rate of Salvianolic acid was found to be inversely proportional to the concentration of

the plasticizer. The Salvianolic acid release rate increased as the pore- forming substance in

the coated membrane increased. The Salvianolic acid release rate from a micro porous

membrane was affected by and is inversely proportional to overall coating weight.

1.4 Pseudoephedrine

Unlike the elementary osmotic pump (EOP) which consists of an osmotic core with the drug

surrounded by a semi permeable membrane drilled with a delivery orifice, controlled porosity

of the membrane is accomplished by the use of different channelling agents in the coating.

The usual dose of pseudoephedrine is 60 mg to be taken three or four times daily. It

has a short plasma half life of 5–8 h. Hence, pseudoephedrine was chosen as a model drug

with an aim to develop a controlled release system for a period of 12 h. Sodium bicarbonate

was used as the osmogen. The effect of different ratios of drug: osmogent on the in-vitro

release was studied. Cellulose acetate (CA) was used as the semi permeable membrane.

Different channelling agents tried were diethylphthalate (DEP), dibutylphthalate (DBP),

dibutylsebacate (DBS) and polyethylene glycol 400 (PEG 400). The effect of polymer

loading on in-vitro drug release was studied. It was found that drug release rate increased

with the amount of

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This could be retarded by the proper choice of channelling agent in order to achieve

the desired zero order release profile. Also the lag time seen with tablets coated using

diethylphthalate as channelling agent was reduced by using a hydrophilic plasticizer like

polyethylene glycol 400 in combination with diethylphthalate. This system was found to

deliver pseudoephedrine at a zero order rate for 12 h. The effect of pH on drug release was

also studied. The optimized formulations were subjected to stability studies as per ICH

guidelines at different temperature and humidity conditions.

1.5 Isosorbide mononitrate

Extended release formulations of isosorbide mononitrate (IMN), based on osmotic

technology, and were developed. Target release profile was selected and different variables

were optimized to achieve the same. Formulation variables like type (PVP, PEG-4000, and

HPMC) and level of pore former (0–55%, w/w of polymer), percent weight gain were found

to affect the drug release from the developed formulations. Drug release was inversely

proportional to the membrane weight but directly related to the initial level of pore former in

the membrane. Burst strength of the exhausted shells was inversely proportional to the level

of pore former, but directly affected by the membrane weight. Satisfactory burst strength

(more than 320 g) was obtained when PVP was used as pore.

The release from the developed formulations was independent of pH and agitational

intensity, but dependent on the osmotic pressure of the release media. Results of SEM studies

showed the formation of pores in the membrane from where the drug release occurred. The

formulations were found to be stable after 3 months of accelerated stability studies.

Prediction of steady-state levels showed the plasma concentrations of IMN to be within the

desired range.

2. Tablet formulation methods

2.1 Direct compression

Direct compression is a popular choice because it provides the shortest, most effective

and least complex way to produce tablets. The manufacturer can blend an API with the

excipient and the lubricant, followed by compression, which makes the product easy to

process. No additional processing steps are required.

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Moisture or heat sensitive ingredients, which would be contraindicated in wet

granulation, can also be used in this type of process. However, it does require a very critical

selection of excipients in comparison to granulation processes because the raw materials must

demonstrate good flow ability and compressibility for successful operation. Both high and

low doses of API present a challenge in this respect. Most APIs tend to have poor

compressibility, which affects the quality of tablets if the formulation calls for a large

proportion of API. At the same time, there can also be problems when low amounts of actives

need to be incorporated into tablets because it is difficult to accurately blend a small amount

of active in a large amount of excipient to achieve the desired uniformity and homogeneity.

For instance, segregation of the different components can occur. This means there is

not a uniform distribution of tablet ingredients being fed to the press, and thus batch to batch

consistency of the manufactured tablet cannot be assured. One of the principal risk factors for

segregation is the wide particle size distribution in direct compression formulations, in which

active ingredients tend to be at the fine end of the range. Where there is a wide range of

particle sizes, there is an increased likelihood of sifting, where the smaller particles 'slip

through' the bigger ones.

Other bulk powder properties are also

important for successful tableting, such as good flow

ability, and all of these factors combine to place a

high requirement on the excipients used for direct

compression.

Manufacturing steps for direct compression

I) Milling of drug and excipients.

ii) Mixing of drug and excipients.

iii) Tablet compression.

2.2 Granulation

If a powder blend's properties do not suit direct compression tableting, manufacturers

will turn to granulation processes to create the desired flow ability and low dust ability. These

characteristics are required to minimise tablet weight variations, and ensure high density for

high tablet filling weight and high moldability for hard tablet manufacture.

Fig. 6 A simple flowchart of

steps involved in direct

compression method

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Granulation narrows the particle size distribution of a tablet formulation's bulk

powder, eliminating segregation problems. This in turn ensures superior compressibility in

the tableting process, permitting higher quantities of API to be used and ensuring good active

distribution in the tablet. However, granulation is a more time-consuming technique

compared with direct compression and there is also a risk of product cross-contamination and

product loss during the different processing steps (granulation, drying, sieving). All of these

factors can increase costs compared with direct compression. Dry granulation is more flexible

than direct compression. Compared with wet granulation, however, it has a shorter, more

cost-effective manufacturing process. Because it does not entail heat or moisture, dry

granulation is especially suitable for active ingredients that are sensitive to solvents, or labile

to moisture and elevated temperatures. We now discuss both types of granulation as:

Dry granulation

Wet granulation

Dry granulation

In dry granulation process the powder mixture is compressed without the use of heat

and solvent. It is the least desirable of all methods of granulation. The two basic procedures

are to form a compact of material by compression and then to mill the compact to obtain a

granules. Two methods are used for dry granulation. The more widely used method is

slugging, where the powder is precompressed and the resulting tablet or slug are milled to

yield the granules. The other method is to precompress the powder with pressure rolls using a

machine such as Chilosonator.

Advantages

For moisture sensitive material

For heat sensitive material

For improved disintegration since powder particles are not bonded together by a binder

Disadvantages

It requires a specialized heavy duty tablet press to form slug

It does not permit uniform colour distribution as can be

Achieved with wet granulation where the dye can be incorporated into binder liquid.

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The process tends to create more dust than wet granulation, increasing the potential

contamination.

Steps in dry granulation

i) Milling of drugs and excipients

ii) Mixing of milled powders

iii) Compression into large, hard tablets to make slug

iv) Screening of slugs

v) Mixing with lubricant and disintegrating agent

vi) Tablet compression

Wet granulation

The most widely used process of agglomeration in pharmaceutical industry is wet

granulation. Wet granulation process simply involves wet massing of the powder blend with a

granulating liquid, wet sizing and drying.

Advantages

Highly smooth and soluble drug tablets can be formulated

Fig. 7 A simple flowchart of steps

involved in dry granulation

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Bioavalability increases in this technique

Disadvantages

The greatest disadvantage of wet

granulation is its cost. It is an expensive

process because of labour, time,

equipment, energy and space requirements.

Loss of material during various stages of

processing

Stability may be major concern for

moisture sensitive or thermo labile drugs

Multiple processing steps add complexity

and make validation and control difficult

An inherent limitation of wet granulation is

that any incompatibility between

formulation components is aggravated.

Important steps involved in the wet

granulation

i) Mixing of the drug(s) and excipients

ii) Preparation of binder solution

iii) Mixing of binder solution with powder

mixture to form wet mass.

iv) Coarse screening of wet mass.

v) Drying of moist granules.

vi) Screening of dry granules through a suitable sieve (14-20 # screen).

vii) Mixing of screened granules with disintegrant, glidant, and lubricant.

Fig. 8 A flowchart of steps

involved in wet granulation

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3. Excipients and other additives

Excipients

Excipient means any component other than the active pharmaceutical ingredient(s)

intentionally added to the formulation of a dosage form. Many guidelines exist to aid in

selection of non toxic excipients such as IIG (Inactive Ingredient Guide), GRAS (Generally

Regarded As Safe), Handbook of Pharmaceutical Excipients and others.

While selecting excipients for any formulation following things should be considered

wherever possible: keep the excipients to a minimum in number minimize the quantity of

each excipient and multifunctional excipients may be given preference over unifunctional

excipients.

Excipients play a crucial role in design of the delivery system, determining its quality

and performance. Excipients though usually regarded as nontoxic there are examples of

known excipient induced toxicities which include renal failure and death from diethylene

glycol, osmotic diarrhoea caused by ingested mannitol, hypersensitivity reactions from

lanolin and cardiotoxicity induced by propylene glycol.

Diluents

In order to facilitate tablet handling during manufacture and to achieve targeted

content uniformity, the tablet size should be kept above 2-3 mm and weight of tablet above

50 mg. Many potent drugs have low dose (for e.g. diazepam, clonidine hydrochloride) in such

cases diluents provide the required bulk of the tablet when the drug dosage itself is

inadequate to produce tablets of adequate weight and size.

Usually the range of diluents may vary from 5-80%. Diluents are also synonymously

known as fillers. Diluents should not react with the drug substance and moreover it should

not have any effect on the functions of other excipients, it should not have any physiological

or pharmacological activity of its own, it should have consistent physical and chemical

characteristics, it should neither promote nor contribute to segregation of the granulation or

powder blend to which they are added, it should be able to be milled (size reduced).

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If necessary in order to match the particle size distribution of the active

pharmaceutical ingredient, it should neither support microbiological growth in the dosage

form nor contribute to any microbiological load, it should neither adversely affect the

dissolution of the product nor interfere with the bioavailability of active pharmaceutical

ingredient, it should preferably be colourless or nearly so.

Binders

Binder is one of an important excipient to be added in tablet formulation. In simpler

words, binders or adhesives are the substances that promote cohesiveness. It is utilized for

converting powder into granules through a process known as Granulation. Granulation is the

unit operation by which small powdery particles are agglomerated into larger entities called

granules. The uniformity of the particle size, hardness, disintegration and compressibility of

the granulation depends on type and quantity of binder added to formulation.

As for example hard granulations results due to stronger binder or a highly

concentrated binder solution which require excessive compression force during tableting. On

the other hand, fragile granulations results due to insufficient quantity of binder which

segregates easily.

Larger quantities of granulating liquid produce a narrower particle size range and

coarser and hard granules i.e. The proportion of fine granulates particle decreases. Therefore

the optimum quantity of liquid needed to get a given particle size should be known in order to

keep a batch to batch variations to a minimum.

Disintegrants

Bioavailability of a drug depends in absorption of the drug, which is affected by

solubility of the drug in gastrointestinal fluid and permeability of the drug across

gastrointestinal membrane. The drugs solubility mainly depends on physical – chemical

characteristics of the drug. However, the rate of drug dissolution is greatly influenced by

disintegration of the tablet.

The drug will dissolve at a slower rate from a non-disintegrating tablet due to

exposure of limited surface area to the fluid. The disintegration test is an official test and

hence a batch of tablet must meet the stated requirements of disintegration.

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Disintegrant, an important excipient of the tablet formulation, are always added to

tablet to induce breakup of tablet when it comes in contact with aqueous fluid and this

process of desegregation of constituent particles before the drug dissolution occurs, is known

as disintegration process and excipients which induce this process are known as disintegrant.

The objectives behind addition of disintegrant are to increase surface area of the tablet

fragments and to overcome cohesive forces that keep particles together in a tablet.

Lubricants

Lubricants are the agents that act by reducing friction by interposing an intermediate

layer between the tablet constituents and the die wall during compression and ejection. Solid

lubricants, act by boundary mechanism, results from the adherence of the polar portions of

molecules with long carbon chains to the metal surfaces to the die wall. Magnesium stearate

is an example of boundary lubricant. Other is hydrodynamic mechanism i.e. fluid lubrication

where two moving surfaces are separated by a finite and continuous layer of fluid lubricant.

Since adherence of solid lubricants to the die wall is more than that of fluid lubricants, solid

lubricants are more effective and more frequently used.

Since primarily lubricants are required to act at the tooling or material interface,

lubricants should be incorporated in the final mixing step, after granulation is complete.

When hydrophobic lubricants are added to a granulation, they form a coat around the

individual particles (granules), which may cause an increase in the disintegration time and a

decrease in the drug dissolution rate. Presence of lubricants may results in a less cohesive and

mechanically weaker tablet because it may interfere with the particle - particle bonding.

Further, the amount of lubricant increases as the particle size of the granulation

decreases but its concentration should not exceed to 1% for producing maximum flow rate.

Usual excipients used in CPOPT along with approximate conc. range used:

Hydrophilic and hydrophobic polymers

Cellulose acetate 2-15% w/w

SMCC Silicified cellulose 90mg

Ethyl cellulose 4-10%

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Hydroxypropyl methylcellulose HPMC 2%

Solubilizing agent

PVP 10-20 wt%

PEG400 4-35% of coat (40-60mg

PEG6000 5-50%

Osmogens

NaCl 5-50%

Sucrose 20-30%

Lactose 35%

Sucrose 20-30%

Surfactants

Sorbitol 20-30%

Coating agents

Magnesium stearate 2-5%

Coating solvent

Acetone 800mL

Ethanol 38%

Water

Isopropyl alcohol 200mL

Plasticizer

Dibutylphthalate 2-10% w/w

Diethylphthalate 2-5%

Pore forming agent

Calcium nitrate

Potassium sulphate

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4. TABLET COATING

Coated tablets are defined as "tablets covered with one or more layers of mixture of

various substances such as natural or synthetic resins ,gums ,inactive and insoluble filler,

sugar, plasticizer, polyhydric alcohol ,waxes ,authorized colouring material and sometimes

flavouring material .

Coating may also contain active ingredient. Substances used for coating are usually

applied as solution or suspension under conditions where vehicle evaporates.

Principle of coating

The principle of tablet coating is relatively simple. Tablet coating is the application of

coating composition to moving bed of tablets with concurrent use of heated air to facilitate

evaporation of solvent.

Basic principles involves :

Insulation which influences the release pattern as little as possible and does not markedly

change the appearance.

Modified release with specific requirement and release mechanism adapted to body

function in the digestive tract

Colour coating which provides insulation or is combined with modified release coating.

Fig. 9 Spray coating of tablets

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Types of coating

Sugar coating

Compressed tablets may be coated with coloured or uncoloured sugar layer. The

coating is water soluble and quickly dissolves after swallowing. The sugar-coat protects the

enclosed drug from the environment and provides a barrier to objectionable taste or order.

The sugar coat also enhances the appearance of the compressed tablet and permit imprinting

manufacturing's information. Sugar coating provides a combination of insulation, taste

masking, smoothing the tablet core, colouring and modified release. The disadvantages of

sugar coating are the time and expertise required in the coating process and thus increases

size, weight and shipping costs.

Film Coating

Film coating is more favoured over sugar coating. Film coating is deposition of a thin

film of polymer surrounding the tablet core. Conventional pan equipments may be used but

now a day's more sophisticated equipments are employed to have a high degree of

automation and coating time. The polymer is solubilised into solvent. Other additives like

plasticizers and pigments are added. Resulting solution is sprayed onto a rotated tablet bed.

The drying conditions cause removal of the solvent, giving thin deposition of coating material

around each tablet core.

Enteric coating

This type of coating is used to protect tablet core from disintegration in the acid

environment of the stomach for one or more of the following reasons:

To prevent degradation of acid sensitive API

To prevent irritation of stomach by certain drugs like sodium salicylate

Delivery of API into intestine

To provide a delayed release component for repeat action tablet.

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PRINCIPLE

Osmosis is one of the fundamental phenomena in biology enabling for instance cells

and plants to adjust water balance. An osmotic flow is generated when two solutions of

different solute concentrations are separated by a semi-permeable membrane rejecting the

solute on the one hand but allowing passage of the solvent molecules on the other hand. The

osmotic flow across the semi-permeable membrane is directed to compensate differences in

solute concentrations.

This leads to a flow of solvent from the region of low solute concentration (high

chemical potential) to the region of higher solute concentration (low chemical potential). As a

consequence it results in a hydrostatic pressure difference across the semi-permeable

membrane causing in turn an oppositely directed flow of solvent. In equilibrium, the flow due

to the hydrostatic pressure difference balances the osmotic flow. The pressure difference

required to generate this balancing flow is equivalent to the difference of the osmotic

pressures of the two solutions.

There are several theories to predict the osmotic pressure of a solution. However, the

Van't Hoff equation applicable to ideal diluted mixtures is the most commonly accepted and

best known theory. According to the Van't Hoff equation, the osmotic pressure of a solution

Fig. 10 Diagram showing process of Osmosis and Reverse osmosis

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is proportional to solute concentration and temperature. By knowing these parameters, the

osmotic pressure π can be easily calculated:

where n is the number of moles of solute (mol), V is the volume of solution (L), C stands for

the corresponding solute concentration (mol/L), R is the molar gas constant (8314 J mol−1

K−1), and T the absolute temperature (K). The Van't Hoff factor i represent the number of

moles of solute actually dissolved in a solution per mole of added solid solute, i.e. i equals

one if the solute does not dissociate (e.g. non-electrolytes in water) or becomes larger than

one in case dissociation occurs. In the latter, the number of solute molecules increases, as it is

the case for most ionic compounds. With α being the degree of dissociation and υ the number

of ions, a solute can dissociate into i molecules according to the following equation:

In most cases, water is used as solvent. All pumps exploit the solvent flow across the

semi-permeable membrane for actuation. In single compartment systems, the solvent inflow

through the membrane into the device dissolves the drug which is used as an osmotic agent

and displaces the saturated drug solution through an outlet. In two compartment systems, the

solvent dissolves an osmotic agent stored in a separate confinement from the drug. The

compartment of the osmotic agent expands and accordingly displaces the liquid drug in a

neighbouring compartment. In general, the net flow rate of solvent can be described by the

following equation:

Where dV/dt stands for the volumetric net flow rate of solvent across the semi-

permeable membrane, K is the permeability of the semi- permeable membrane with respect to

the solvent, A is the surface area of the semi-permeable membrane, and σ is its osmotic

reflection coefficient. The osmotic pressure difference across the semi-permeable membrane

is Δπ. P stands for the hydrostatic pressure difference between the two sites of the semi-

permeable membrane.

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Theoretically, in the case of an osmotic agent in a sealed container, a hydrostatic pres-

sure equivalent to the osmotic pressure can build up over time. In applications for drug

release, an open release port is necessary which limits the hydrostatic pressure due to the

continuous drug flow through the release port. Consequently, the hydrostatic pressure

difference between the osmotic agent compartment and the outlet area is defined by the flow

resistance of the release port times the net flow of solvent across the semi-permeable

membrane.

The effective drug release rate, i.e. the mass of drug molecules re-leased over time

through the outlet orifice of osmotic pumps dm/dt, can be derived from the volume flow rate

of liquid drug solution dv/dt as:

Where C stands for the drug concentration of the dispensed solution. The reflection

coefficient σ describes the leakage of solute through semi-permeable membranes and is

ideally equal to one. For commonly used membranes, this parameter is close to one.

Typically, dP is negligibly small compared to Δπ. Additionally, the osmotic pressure of the

osmotic agent is several orders of magnitude larger than that of the surrounding medium.

Therefore, the term (σ·Δπ− P) of can be substituted by the osmotic pressure π of the osmotic

agent. After substitution of the resulting expression into, the following relationship is

obtained:

Osmotic pumps consist of three building blocks: osmotic agent, solvent, and drug.

This can be used to categorize osmotic pumps into three different groups. Single

compartment pumps defined a rest category. The drug itself is employed as osmotic agent and

accordingly only one compartment separating the drug from the solvent is required.

Consequently, the concentration C of the dissolved drug equals the concentration of the

osmotic agent. Thereby, the solubility of the drug itself is one of the most important

parameters affecting the release rate. This pump type was first described by Theeuwes in

1975 as the elementary osmotic pump.

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Constant zero-order release kinetics can be maintained as long as the drug solution in

the compartment remains saturated. When the solid drug is completely dissolved, the release

rate is determined by the depleting concentration of the solution and declines parabolic in

time. The amount of drug mzero which can be released with zero order kinetics from the total

stored amount of drug mtotal can be determined as:

zero drug

drug

total

The total amount of drug mzero released at a constant rate increases with decreasing

drug solubility Sdrug. The osmotic pressure decreases for decreasing solubility and in

consequence the re- lease rate is slowed down. Hence, single compartment pumps depend on

the physical properties of the drug. This is a major limitation if the systems are planned to be

used with different drugs. However, there are several strategies to modulate drug solubility,

e.g. the use of solubilizers described in detail elsewhere.

Two compartment osmotic pumps store drug formulation and osmotic agent in two

separate compartments. During operation, the expansion of the agent compartment displaces

the content of the drug compartment. This class of osmotic pumps was described for the first

time by Theeuwes and Yum in 1976. Due to the separation of osmotic agent and drug, the

special feature of those pumps is a drug release rate independent of the osmotic pressure of

the drug.

Fig. 11 Pores in semi permeable membrane for drug release

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Thus, any drug solution or suspension, aqueous or non-aqueous in nature, contained

in the drug compartment can be released. In addition, the stability of the drug solution can be

tailored by selecting the optimal solvent independent of the osmotic agent. This is specifically

important for implantable systems, where the drug formulation must not degrade at body

temperature during long-term applications lasting up to years, e.g. for protein or peptide

delivery. Suspensions of drug solids and non-aqueous solvents are less prone to hydrolytic

degradation reactions because of the absence of water. However, the solvent is also released

to the body and has to be considered, even if the amounts are small. A list of investigated

non-aqueous drug solvents for osmotic pumps is provided in.

The main drawbacks of the two compartment approaches are the reduced drug storage

capacity per volume compared to single compartment pumps as well as the more complicated

technological de- sign. In order to achieve a constant release rate with this type of pump, the

osmotic agent solution must remain in a saturated state during the entire operational time.

Consequently, the stored amount of solid agent mosm should not be completely dissolved

before the volume of the drug compartment Vdrug is completely displaced and end of

operation is reached. This can be expressed by the following two relations before and after

operation:

osm osm.Vosm

osm osm osm drug

Where ρosm is the density of the osmotic driving agent and Vosm is its initial

compartment volume. To ensure constant release rate, the critical volume ratio of both

compartments can be derived by combining which results in

osm

drug

osm

osm osm

Consequently, the critical mass of osmotic agent mosm required to entirely dispense

the volume Vdrug is given by

osm drug osm

osm

osm

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The osmotic actuator unit can be properly designed in terms of volume and loading of

the osmotic agent chamber. To build pumps of small size or to load pumps of similar size

with more drug solutes, a low ratio Vosm/Vdrug is advantageous. For example, sodium

chloride (NaCl) and fructose generate similar osmotic pressures which are about 36 MPa.

Nevertheless, using NaCl as osmotic agent requires only a fifth of the osmotic agent volume

compared to fructose. This is because (i) the solubility of NaCl is lower than that of fructose

(SNaCl =36.1 g/100 g H2O vs. Sfructose =79.0 g/100 g H2O) and (ii) the density of NaCl is

higher than that of fructose (ρNaCl =2.17 g/ cm3 vs. ρfructose =1.59 g/cm3). Therefore, the

ratio Vosm/Vdrug is lower in case of NaCl requiring less volume Vosm of osmotic agent

needed to displace a given volume Vdrug of the drug chamber. Generally, salts are preferred

as osmotic agents in two-compartment systems instead of non-electrolytic compounds.

While single and two compartment pumps are driven by water from body fluids used

as solvent, multi-compartment systems have at least one additional enclosed water

compartment separated from the osmotic agent by the semi-permeable membrane. Since a

dedicated liquid environment is not required, such pumps can be operated under “dry”

conditions, e.g. as part of extracorporeal systems The Rose–Nelson pump featuring three

compartments was developed in 1955 for pharmaceutical research and is generally

recognized as the pioneering device of this most sophisticated osmotic pump type. As multi

compartment pumps differ in the attached water compartment from two compartment pumps,

the general operation principles apply also to this pump type.

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MATERIALS REQUIRED

All the chemicals, drug (paracetamol), excipients, apparatus etc. were provided by

university as per scholar apparatus. All items were drawn in defined quantity which was done

under supervision of PhD scholar. No item was purchased from market or industry.

Chemicals and excipients

Acetone - Solvent

Cellulose acetate – Coating polymer

Distilled water – Solvent and various other purposes

Ethanol - Solvent

Hydroxypropyl methylcellulose (HPMC) – Most used excipient

Isopropyl alcohol - Solvent and various other purposes

Lactose – Osmogen excipient

Magnesium stearate – Coating agent

NaCl – Osmogen excipient

Paracetamol – Drug candidate

PEG400 – Solubilizing agent

Sorbitol – Surfactant

Sucrose – Osmogen excipient

Sucrose – Osmogen excipient

Talc

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Apparatus

Butter paper

Dissolution tester

Filter paper

Friability Tester

Glass beakers

Mortar and pestle

pH tester

Plastic pouches

Pouring Vessels

Sieves

Solubilizers

Spatula

Stirrers – Glass and magnetic

Tablet compression machine

Tissue roll

Weighing balance

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METHODOLOGY

After learning from previous research papers and theory about Drug delivery systems,

Controlled drug release and other studies, we were ready to formulate our own tablet with

Paracetamol as drug candidate. All the steps were optimised for best results which gave us

positive result.

The main steps in procedure are given as following:

1. List of excipients is prepared which can be used in tablet formulation.

2. A blank tablet is prepared to check hardness and other important factors before using the

drug.

3. Drug amount selection is done as per regulations.

4. Drug absorption curve is derived using spectrophotometric technique.

5. Pre formulation studies are done to check compatibility.

6. Apparatus cleanup

7. Tablet core preparation and compression

8. Coating of tablet with Polymer - Cellulose acetate to make CPOPT

9. Release pattern of coated tablet and uncoated tablet is derived

10. Comparison of both coated and uncoated tablets is done and result is derived.

1. Excipients for tablet formulation

Specific excipients have to be added along the active drug component to aid handling

of the active substance by facilitating powder flow ability or non-stick properties, in addition

to aiding in vitro stability such as prevention of denaturation over the expected shelf life.

The selection of appropriate excipients depends upon the route of administration and the

dosage form, as well as the active ingredient and other factors.

Following substances were gathered to be used as excipients:

Hydroxypropyl Methyl cellulose (HPMC)

Lactose

Magnesium stearate

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These substances are added in different compositions based on the drug candidate. A

general composition (w/w) for these substances is:

HPMC - 72-78%

Lactose - 23-27%

Magnesium stearate - 0.8-1.5%

2. Blank tablet preparation

A blank tablet is a composition where drug candidate in not included. This is prepared

to verify compression machine, check hardness testing factors, measure hardness with

different compositions, check which tablet formulation method is best suitable for us etc

This tablet was prepared by all 3 methods of preparation that are Direct compression,

Dry granulation and Wet granulation. We found that Direct compression and wet granulation

technique are both good for us and thus can be used further to prepare tablet with drug

candidate included.

Fig. 12 Weighing of blank tablet

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We tried 3 compositions of blank tablet by varying excipients to choose best one:

S.No Total weight of

tablet HPMC (%) Lactose (%)

Magnesium

stearate (%)

1 250 mg 75 24 1

2 250 mg 72 26.5 1.5

3 250 mg 74 24.8 1.2

Out of these 3 compositions, Composition number 3 was chosen for further calculations. This

composition gave us best hardening and texture properties as desired for proper absorption

and effectiveness in body.

3. Drug amount input

Paracetamol is given is different dosage forms. The composition of each tablet is

decided according to target age group. For Normal adults 250-500 mg dosage is given every

4 hours for better effectiveness. Thus each 350-400 mg tablet has 250 mg paracetamol drug.

4. Drug caliberation curve

The amount of paracetamol released at different time intervals has to be noted so as to

study how much drug should be given for effectiveness.

Procedure

Phosphate buffer was made by adding 50ml 0.2M Potassium dihydrogen phosphate and

3.6 ml 0.2M NaOH

pH of this buffer was made to 5.8

10 mg drug was added to 100 ml PBS 5.8 buffer.

Dilutions were made as 5, 10, 15, 20, 25 and 30ug/ml.

Absorbance was taken for each dilution using spectrophotometer.

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5. Pre formulation studies

Preformulation is defined as that phase of research and development process where

physical, chemical and mechanical properties of a drug substance are characterized alone and

when combined with excipients, in order to develop stable, safe and effective dosage form.

The objective of preformulation studies is to develop a portfolio of information about

the drug substance to serve as a set of parameters against which detailed formulation design

can be carried out. A thorough understanding of physicochemical properties may ultimately

confirm that no significant barriers are present for the formulation development.

The following pre formulation studies were performed.

• Drug - Excipient compatibility study

• API characterization

Fig. 13 Spectrophotometry results for various

dilutions

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Drug- Excipient Compatibility Studies

FT-IR Study

The pure drug (Paracetamol) and osmogents were subjected to IR studies alone and in

combination. Pure drug/combination of drug-osmogent was mixed with 100 mg of potassium

bromide. Thorough grinding in smooth mortar can effect mixing. The mixtures were then

placed in the sample holder of the instrument. These were analyzed by FT- IR to study the

interference of osmogents for drug analysis.

Selection of Excipients

Based on the literature review and compatibility study of API with various inactive

ingredients, all excipients were found to be physically compatible with the API.

API Characterization Melting point

The melting point of the drug sample was determined by open capillaries using

melting point apparatus.

Flow properties

Angle of repose

Fixed funnel method was used to determine angle of repose. A funnel was fixed to a

clamp with its tip at a given height (h), above a flat horizontal surface on which a graph paper

was placed. Powder was carefully poured through a funnel till the apex of the conical pile just

touches the tip of funnel. The angle of repose was then calculated using the formula,

Tan Ө = h/r

Where, h= the height of the powder cone

r= the radius of the powder cone

Bulk density

Bulk density or apparent density is defined as the ratio of mass of powder to the bulk

volume. The pre-sieved blend equivalent to 25g was accurately weighed and filled in a 100

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ml graduated cylinder and the unsettled volume, V was noted. The bulk density was

calculated by the formula

Bulk density (ρo) = M/Vo(g/cc)

Where, M = Mass of powder (g)

V = Apparent unstirred volume (cc)

Tapped density

Tapped density was determined by using Electrolab USP Apparatus. The pre-sieved

blend equivalent to 25 g was filled in 100 ml graduated cylinder. The mechanical tapping of

the cylinder was carried out using tapped density tester at a nominal rate of 300 drops per

minute for 500 times initially and the tapped volume V was noted. Tapping was preceded

further for an additional tapping of 750 times and tapped volume Vb was noted. The

difference between two tapped volume was less than 2%, so Vb was considered as a tapped

volume The tapped density was calculated by the formula:

Tapped density (ρt) = M/Vf(g/cc)

Where, M = weight of blend (g)

Vf = Tapped volume (cc)

Compressibility Index

Compressibility Index is a measure of flow property of a powder to be compressed as

such they are measured for relative importance of inter- particulate interactions. The packing

ability of drug was evaluated from change in volume, which is due to rearrangement of

packing occurring during tapping. It is indicated as Carr’s compressibility index (CI). The

bulk volume and tapped volume was measured and compressibility index was calculated

using the formula.

Compressibility index (%) = (Vo – Vf) / Vo X 100

Where, Vo = Bulk volume and Vf = Tapped volume

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Hausner ratio

Hausner ratio gives an idea regarding the flow of the blend. It is the ratio of tapped

density to the apparent density.

HR = Tapped density / Apparent density

If Hausner’s ratio is < 1.25: good flow of granules

>1.5: poor flow of granules

between 1.25-1.5: flow can be improved by addition of glidants.

Solubility studies

Solubility of drug was determined in buffers of different pH 1.2, 6.8, 7.4, by placing

excess of drug in 50 ml volumetric flask containing 10 ml of buffers. Volumetric flasks were

subjected to sonication for 20 min. The samples were filtered through 0.45 μ filters. The

aliquots of these solutions are suitably diluted and analyzed using spectrophotometer.

Fig. 14 A sonicator

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6. Apparatus cleanup

Before starting any formulations, tablet hardness machine, its components, work

table, work area, pestle and mortar etc are cleaned and sterilized. Sterilizing and anti septic

solvents are used to clean apparatus and work bench is sterilized using UV rays. Sterility has

to be insured as drugs are to be consumed by humans which can react otherwise.

7. Tablet core preparation and compression

Core tablets of Paracetamol were prepared by wet granulation method and direct

compression method also.

1. Direct compression method

All components are mixed and compressed direct. Magnesium stearate is added at last

in order.

2. Wet granulation method

All the ingredients except API paracetamol and magnesium stearate were accurately

weighted and mixed in mortar with a pestle for 10 minutes to get the uniform mix. The dry

blend was granulated with sufficient quantity of isopropyl alcohol.

Fig. 15 Process of Sieving

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The powder mass was dried at 60 °C in hot air oven for 6 h and passed through sieve

no.20. The dried granules were mixed with magnesium stearate for 3 min. The blended

powder was compressed in to round tablets. Using single punch machine fitted with a

concave 9 mm punch and die set, tablets of 350 mg were obtained. The target tablet hardness

was adjusted to be in the range of 50 to 60 Newton using a tablet hardness tester (DR-

Schlenger, Pharmaton, United States).

8. Coating of tablet

Each core tablet was coated with coating solution. The coating solution is prepared as -

Cellulose acetate – 3% w/v

Sorbitol – 15 % w/w of cellulose acetate

It was made to 100 ml using Acetone:Methanol in 80:20. The coating process was

carried out on a batch of 50 tablets in a conventional laboratory coating pan (Scientific

Instrument, India) having an outer diameter of 10 cm. Rotation speed was maintained at 20

rpm and hot air inlet temperature was kept at 38-40 °C.

The manual coating procedure based on intermittent spraying and coating procedure

was used with spray rate of 3 mL/min. The coating process of the core tablets was continued

until an increase of about 8 % in the tablet weight was obtained. In all cases, coated tablets

were dried at 50 °C for 6 h before further evaluation.

9. Release studies

Evaluation of core tablet

Weight variation test:

Twenty tablets were randomly selected from each batch and individually weighed.

The average weight and standard deviation of twenty tablets were calculated. The batch

passes the test for weight variation if the % deviation is within the permissible limits (+ 5%).

% Deviation = Individual weight – Average weight / Average weight x 100

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Hardness test

Hardness (diametric crushing strength) is a force required to break a tablet across the

diameter. “Hardness factor”, the average of the six determinations, was determined and

reported. Hardness indicates the strength of tablet. The force is measured in kg/cm2.

Hardness is measured using Monsanto hardness tester or Pfizer type tester.

PFIZER TYPE

HARDNESS TESTER

Friability

Friability is the loss of weight of tablet in the container/package, due to

removal of fine particles from the surface. The permitted friability limit is 1.0 %.A sample of

10 whole tablets were taken and placed in a Roche friabilator and rotated for 100 times at 25

rpm and tablets were removed dedusted and weighed again.

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Thickness

Three samples were selected randomly from each batch and thickness was measured

using Vernier calipers.

Drug content

Twenty tablets were randomly selected, average weight was calculated and powdered

in a mortar. Powder equivalent to 100 mg of drug was weighed accurately and transferred to

100 ml volumetric flask, added 50 ml of 0.1 N hydrochloric acid and sonicated for 20 min.

Then, the volume was made up to mark. The solution was filtered through 0.45 μ nylon

membrane filter. The filtrate was diluted suitably using 0.1 N hydrochloric acid and the drug

content was estimated by UV spectrophotometer at λmax of 274 nm against blank and

reported. The content uniformity should be not less than 90% and not more than 110% of the

labelled value.

Evaluation of Coated Tablets

Percentage weight gain

10 core tablets were randomly selected subjected to coating. The initial weight of 10

uncoated tablets was recorded. After period of coating, spraying of coating solution was

stopped and allowed to dry for 10–15 min, in the coating pan at 45 °C to remove the majority

of solvent moisture. The weight of 10 coated tablets was recorded.

The percent weight gain was calculated. Samples were collected for predetermined

weight gain (approximately). The sample of coated tablets was subjected for overnight drying

in tray drier 45ºC to remove complete solvent. The dried tablets were weighed again and %

weight gain was calculated accurately.

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In-vitro Drug Release

Apparatus: USP-type II dissolution apparatus (paddle type)

Medium: 0.1N HCl pH 1.2

Phosphate buffer pH 6.8

Volume of medium: 500 ml

Apparatus: USP II (Paddle) apparatus RPM: 50

Temperature: 37+ 0.50c

Sample points: 1 hour

Sample volume: 5 ml

Replacement volume: 5 ml

Collected samples were analyzed at 274 nm using 0.1 N hydrochloric acid as blank

for the first 2 h samples and at 274 nm using phosphate buffer pH 6.8 as a blank for rest of

the samples. The percentage cumulative drug release (% CDR) was calculated.

Drug Release Kinetics

To study the release kinetics, data obtained from in vitro drug release studies were

plotted in various kinetic models: Zero Order as cumulative percentage of drug unreleased vs.

time, First Order as log cumulative percentage of drug remaining vs. time, Hixson-Crowell

Cube Root Law Model as the cube root of the percentage of drug remaining in the matrix vs.

time, and Higuchi Model as the square root of time vs. % drug release.

10. Comparison of both coated and uncoated tablets

Our project is to develop CPOPT so to see difference of change in release, release

kinetics of both coated and uncoated tablet is compared and result will show us the

difference.

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RESULTS AND DISCUSSION

Drug calibration curve

The amount of paracetamol released at different concentrations was noted. The absorbance

was taken at 243 nm for all dilutions and graph was plotted as follows:

S. no Concentration

(µg/ml)

Absorbance

(243 nm)

1 0 0

2 2 0.232

3 4 0.393

4 6 0.571

5 8 0.834

6 10 0.998

7 12 1.181

From graph, R2 was calculated to be 0.9971 which is very close to value 1. This value

shows very efficient correlation between Concentration and absorbance thus showing perfect

calibration.

y = 0.0985x + 0.0103R² = 0.9971

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 5 10 15

ab

sorb

ance

conc. (ug/ml)

Calibration curve

Calibration curve

Linear (Calibration curve)

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Pre-formulation studies

FT-IR studies

FT-IR studies were carried out to confirm the compatibility of the excipients with the

drug used in the formulation. The FT-IR scans for the pure drug and for mixtures of drug and

different excipients.

Thus from the above Fig. 16, it was observed that there is no significant change in the

peaks of drug-excipient mixtures in comparison to pure drug. It indicates that there is no

incompatibility of excipients with the drug.

Fig. 16 FT-IR plot

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API characterization

Melting point

The melting point of the drug sample was found to be 135 with reference to the

literature it was found to be 137ºC. The drug sample showed compliance with the data given

in merck index, which reflects its quality and purity.

Flow properties

The flow properties of the pure drug were determined and the data is reported in the

table below. From the Table, it is observed that the drug showed poor flow properties and

poor compressibility characteristics.

TABLE : FLOW PROPERTIES OF THE DRUG

Parameter Value determined

Bulk density (gm/cc) 0.440 ± 0.050

Tapped density (gm/cc) 0.712 ± 0.025

Compressibility index (%) 38 ± 0.065

Hausner’s ratio 1.618

Solubility studies

The solubility of drug was determined in the water and in different buffer solutions of

pH 1.2 to 6.8 and results were tabulated in the table below.

TABLE: SOLUBILITY STUDY OF THE DRUG

Media Solubility (mg/ml)

Purified water 15

0.1 N HCl, pH 1.2 16.4

Phosphate buffer, pH 6.8 17.2

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Pre compressibility study

TABLE: EVALUATION OF PRE COMPRESSION PARAMETERS OF

FORMULATIONS

BATCH Angle of

repose

Bulk

density

(gm/cc3)

Tapped

density

(gm/cc3)

Carr’s index

(%)

Hausner’s ratio

1 35.34±1.2 0.462 0.629 15.21 1.43

2 26.37±1.0 0.494 0.648 14.69 1.54

3 29.54±1.8 0.421 0.678 12.25 1.35

Release studies

Evaluation of core tablet

Physicochemical properties

The mean values of hardness, friability, thickness, weight and drug content of

prepared matrix tablets and core tablet of porous osmotic pump tablets is recorded in the table

below.

Table: Physicochemical parameters of developed core tablets of porous osmotic pump

These are mean values of 3 batches which were formulated during my project. All the

physical properties were adjusted to be into a certain limits to ensure best efficiency and thus

produce best results.

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Effect of Various Parameters on Drug Release

In-vitro drug release profile at different % weight gain

Core tablets of Paracetamol were coated so as to get tablets with different weight gain

(6, 8, 10 % w/w). Release profile of drug from these formulations is shown in Figure 32 . It is

clearly evident that drug release decreases with an increase in weight gain of the coating

membrane. No bursting of tablet was observed during the dissolution in any formulation.

In-vitro drug release profile at different pH

The in-vitro drug dissolution studies of marketed product and optimized formulation

was carried out in different pH media 0.1N HCl, pH 6.8, and in 7.4. The marketed product

showed the 95.2% drug release in 12 hours and followed first order where as the optimized

formulation F6 shows the 95.36% drug release in 12 hours and fallowed zero order release

from these results it is confirmed that optimized formulation is better than the marketed

product.

Fig. 17 Release patterns at different % weight gain

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Kinetics of In-vitro Drug Release

The optimized coated formulations followed Zero order release kinetics. The in-vitro

release data were processed as per and Hixson-Crowell Cube root models. The equations

were generated through statistical procedures and reported.

Fig. 18 Release patterns at different pH

Fig. 19 Higuchi drug release model

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R2 values are compared for Hixson - Crowell Cube root model with optimized

formulation and osmotic mechanism can be understood.

In-vitro drug release – Release studies

The % Cumulative Drug Release of both coated and uncoated tablets are compared.

Based on these comparison, we can derive result. The absorbance values were taken at 243

nm for uncoated tablets first. And %CDR was calculated using various formula algorithm.

Following data was collected:

Fig. 20 Hixon Crowell drug release model

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OBSERVATION DATA AND CALCULATED DATA OF UNCOATED TABLET

Time

(min)

Abs. Conc.

(µg/ml)

Conc.

(mg/ml)

CONC

*D.F.(10)

Conc.

(mg/5ml)

Conc.

(mg/900ml)

% DR

30 0.09 1.259 0.0013 0.0126 0.063 11.329 11.3287

60 0.174 2.434 0.0024 0.0243 0.122 21.902 21.9021

90 0.26 3.636 0.0036 0.0364 0.182 32.727 32.7273

120 0.376 5.259 0.0053 0.0526 0.263 47.329 47.3287

150 0.456 6.378 0.0064 0.0638 0.319 57.399 57.3986

180 0.568 7.944 0.0079 0.0794 0.397 71.497 71.4965

Now, CPOPT was taken, and similarly data was derived using absorbance at 243 nm.

Same calculations were done to calculate % DR.

OBSERVATION DATA AND CALCULATED DATA OF CPOPT TABLET

Time

(min)

Abs. Conc.

(µg/ml)

Conc.

(mg/ml)

CONC

*D.F.(10)

Conc.

(mg/5ml)

Conc.

(mg/900ml)

% DR

30 0.132 1.846 0.0018 0.0185 0.092 16.615 16.6154

60 0.269 3.762 0.0038 0.0376 0.188 33.860 33.8601

90 0.344 4.811 0.0048 0.0481 0.241 43.301 43.3007

120 0.468 6.545 0.0065 0.0655 0.327 58.909 58.9091

150 0.602 8.420 0.0084 0.0842 0.421 75.776 75.7762

180 0.662 9.259 0.0093 0.0926 0.463 83.329 83.3287

Comparison was done using 2 line graph method. The data of %DR of both coated

and uncoated tablets was taken and the plot was drawn as follows:

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From the plot, The CPOPT has more Drug release in same time. So as we go on

increasing time interval, %CDR of Control porosity osmotic pump is extensively more than

simple drug tablet which gives us longer zero order release and hence more effective time

duration in the body. The dosage intervals thus get reduced and chances of over dose

decrease. Drug is released in body in very controlled way thus insuring very effective Drug

delivery system.

Time (min) %DR CPOPT %DR UNCOATED

30 16.61538 11.3286

60 33.86014 21.9021

90 43.3007 32.7272

120 58.909 47.3286

150 75.7762 57.3986

Fig. 21 Comparative plot of % drug release of coated and uncoated tablets

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CONCLUSION

Controlled release formulations of Paracetamol were developed based on osmotic

technology. The effect of different formulation variables was studied to optimize release

profile. Solubility of active pharmaceutical ingredient is the key factor in development of

osmotic dosage form. It is difficult to formulate the osmotic tablet of drugs having low

solubility. Solubility of drug is required to increase to get desired profile. Level of

solubilizers affected the release from the developed formulations. As the concentration of

Paracetamol increased, release rate was increased. Effect of sodium chloride concentration,

pore former concentration and weight gain of tablets on dissolution was also checked.

Concentration of sodium chloride, pore former increases, dissolution rate of

paracetamol also increases. But increase in the tablet weight gain is inversely proportional to

the dissolution release rate. Drug release from the developed formulations was found to be

dependent on the percent increase in weight after coating, but independent of pH and the

agitation intensity of the release media, suggesting that the release will be fairly independent

of pH and hydrodynamic conditions of the body. The release from the optimized formulations

was independent of pH and agitation intensity of the release media, assuring the release from

the tablet was independent of pH and hydrodynamic conditions of the body. Paracetamol

release from the developed formulation was inversely proportional to the osmotic pressure of

the release media, confirming osmotic pumping to be the major mechanism of drug release.

Also, the release appeared to be independent of the type of cellulose acetate

derivatives used as coating polymers. Membranes were found to develop porous surfaces

after coming in contact with the aqueous environment; the number of pores depends on the

initial concentration of pore former in the coating membrane. The observed independent

variables were found to be very close to predicted values of optimized formulation which

demonstrates the feasibility of the optimization procedure in successful development of

porous osmotic pump tablets containing Paracetamol by using sodium chloride (100mg) as

osmotic agent and 20% w/w (with 80% w/w cellulose acetate) of PEG 400 as pore former.

Stability studies revealed that optimized formulation is stable.

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FUTURE SCOPE

New drug delivery systems are developed continuously for overcoming instability

issues and different problems. Control osmotic pressure pumps are based on Osmotic

Technology thus overcoming lot many problems. More and more alterations can be done for

different drugs with different solubility. Excipient compositions, plasticizers, solvents,

membrane compounds can be altered for required Drug components.

Future scope lies in triggering based on ph or osmotic pressure. Future possibility for

improvement in pH triggered controlled porosity osmotic pump tablet and drug delivery are

very bright, but they are still relatively new technologies. Several drug delivery technologies

that can be leveraged on improving drug therapy form controlled porosity osmotic pump

tablets have yet to be fully realized. In future the conventional dosage forms can be well

replaced by CPOPT because of the greater advantages over the other conventional dosage

forms and more patient compliance.

Fig. 22 A Nano drug carrier used in New drug delivery system.

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