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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

Project: Control Porosity Osmotic Pump

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

Project: Control Porosity Osmotic Pump

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

Project: Control Porosity Osmotic Pump

INDEX
SUMMARY .1
INTRODUCTION3
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 SCOPE69
REFERENCES .......70

Project: Control Porosity Osmotic Pump

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 : Preformulation studies, excipient drug interaction studies, drug release curve, formulation
method, formulation technique, post formulation analysis, release studies, etc.

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Project: Control Porosity Osmotic Pump

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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Project: Control Porosity Osmotic Pump

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 -100 m can
be used.

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Project: Control Porosity Osmotic Pump

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

osmotic agents. Several approaches have

been

(HP- -CD)

developed

to

as solubilising and
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 drugs 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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Project: Control Porosity Osmotic Pump

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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Project: Control Porosity Osmotic Pump

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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Project: Control Porosity Osmotic Pump

Fig. 1 Steps involved in pharmaceutics therapy


management
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.

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Project: Control Porosity Osmotic Pump

Basic components required for controlled porosity osmotic pump:


a)

Drug

b) Osmotic agent
c)

Semi permeable membrane

d) Channelling agents or pore forming agents.

Fig. 2 Various layers inside a drug release capsule

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.

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Project: Control Porosity Osmotic Pump

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 (105 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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Project: Control Porosity Osmotic Pump

Fig. 3 Formation of pores in a drug tablet

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

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Project: Control Porosity Osmotic Pump

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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Project: Control Porosity Osmotic Pump

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 drugs 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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Project: Control Porosity Osmotic Pump

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:

5.

Sieving

Microscopy

Sedimentation rate method

Light energy diffraction

Laser holography

Cascade impaction

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 posses 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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Project: Control Porosity Osmotic Pump

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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Project: Control Porosity Osmotic Pump

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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Project: Control Porosity Osmotic Pump

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
tablets 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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Project: Control Porosity Osmotic Pump

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 manufacturers 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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Project: Control Porosity Osmotic Pump

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

Fig. 4 Layout of Roche friabilator

laboratories is the Roche friabilator (Fig. 5).

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Project: Control Porosity Osmotic Pump

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 invivo 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 (37C)
USP Dissolution Apparatus 2 - Paddle (37C)
USP Dissolution Apparatus 3 - Reciprocating Cylinder (37C)
USP Dissolution Apparatus 4 - Flow-Through Cell (37C)
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 ) and paddle (method ) 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 agents 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 Y (1_Y1)2 Y2 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 58 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 (055%, 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.

Fig. 6 A simple flowchart of


steps
involved
in
direct
compression method

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.

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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

Fig. 7 A simple flowchart of steps


involved in dry granulation

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

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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.

Fig. 8 A flowchart of steps


involved in wet granulation

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.

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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 ow across the semi-permeable membrane is directed to compensate differences in
solute concentrations.
This leads to a ow 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 ow of solvent. In equilibrium, the ow due
to the hydrostatic pressure difference balances the osmotic ow. The pressure difference
required to generate this balancing ow is equivalent to the difference of the osmotic
pressures of the two solutions.

Fig. 10 Diagram showing process of Osmosis and Reverse osmosis


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

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


osmotic pressure 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 mol1
K1), 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 being the degree of dissociation and 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 ow across the
semi-permeable membrane for actuation. In single compartment systems, the solvent inow
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 connement from the drug. The
compartment of the osmotic agent expands and accordingly displaces the liquid drug in a
neighbouring compartment. In general, the net ow rate of solvent can be described by the
following equation:

Where dV/dt stands for the volumetric net ow rate of solvent across the semipermeable 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 is its osmotic
reection coefficient. The osmotic pressure difference across the semi-permeable membrane
is . P stands for the hydrostatic pressure difference between the two sites of the semipermeable membrane.

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Theoretically, in the case of an osmotic agent in a sealed container, a hydrostatic pressure 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 ow through the release port. Consequently, the hydrostatic pressure
difference between the osmotic agent compartment and the outlet area is dened by the ow
resistance of the release port times the net ow 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 orice of osmotic pumps dm/dt, can be derived from the volume ow rate
of liquid drug solution dv/dt as:

Where C stands for the drug concentration of the dispensed solution. The reection
coefficient 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 . Additionally, the osmotic pressure of the
osmotic agent is several orders of magnitude larger than that of the surrounding medium.
Therefore, the term ( P) of can be substituted by the osmotic pressure 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 dened 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 rst 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:
drug
zero

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.

Fig. 11 Pores in semi permeable membrane for drug release

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 rst
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.

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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 specically
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.Vosm

osm

osm

osm

osm

drug

Where osm 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
osm

drug

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 fth 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 (NaCl =2.17 g/ cm3 vs. fructose =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 uids 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 RoseNelson 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:

2.

HPMC - 72-78%

Lactose - 23-27%

Magnesium stearate - 0.8-1.5%

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 (%)

250 mg

75

24

250 mg

72

26.5

1.5

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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Fig. 13 Spectrophotometry results for various


dilutions
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

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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 = 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 (o) = 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 (t) = 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 Carrs 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 Hausners 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 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.

Fig. 15 Process of Sieving


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.

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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 (DRSchlenger, 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 nylon
membrane filter. The filtrate was diluted suitably using 0.1 N hydrochloric acid and the drug
content was estimated by UV spectrophotometer at max 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 1015 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 45C 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

Absorbance

(g/ml)

(243 nm)

0.232

0.393

0.571

0.834

10

0.998

12

1.181

Calibration curve
1.4
y = 0.0985x + 0.0103
R = 0.9971

1.2
absorbance

1
0.8

Calibration curve

0.6
Linear (Calibration
curve)

0.4
0.2
0
0

10
conc. (ug/ml)

15

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.

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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.

Fig. 16 FT-IR plot


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.

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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 137C. 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

Hausners 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
Carrs index
(%)

Hausners ratio

0.629

15.21

1.43

0.494

0.648

14.69

1.54

0.421

0.678

12.25

1.35

BATCH

Angle of
repose

Bulk
density
(gm/cc3)

35.341.2

0.462

26.371.0

29.541.8

Tapped
density
(gm/cc3)

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.

Fig. 17 Release patterns at different % weight gain

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.

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Fig. 18 Release patterns at different pH


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. 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.

Fig. 20 Hixon Crowell drug release model


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:

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OBSERVATION DATA AND CALCULATED DATA OF UNCOATED TABLET


Time
(min)

Abs.

Conc.
(g/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.
(g/ml)

Conc.
(mg/ml)

CONC
*D.F.(10)

Conc.
Conc.
(mg/5ml) (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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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

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.

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Project: Control Porosity Osmotic Pump

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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