B.Tech Biotechnology
(July-December, 2014)
Submitted by
ANANDAN BANSAL
Roll No 701100003
Department of Biotechnology
Thapar University, Patiala
January, 2015
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
DBT
Institution Coordinator
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
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
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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From various analysis preformed, we conclude that the walls were sponge-like in
appearance and substantially permeable to both water and dissolved solutes. The rate of
release was a function of the wall thickness, level of leachable additives incorporated and
permeability of the polymer component of the walls, the total solubility of the core tablet, the
drug load, and the osmotic pressure difference across the wall. Release was insensitive to the
pH and degree of agitation in the receptor media. Release was primarily due to an osmotic
pump mechanism. Steady-state release rates were calculated from basic water and solute
permeability of the walls and correlated with actual device performance. The concept of
osmotically actuated drug delivery on an equivalent mass per unit surface area basis was
demonstrated and extended, as well, to multiparticulate dosage forms.
The release graphs obtained as result of dissolution test give us surety that CPOPT are much
better effective for drug release in body.
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INTRODUCTION
Conventional drug delivery systems have little control over their drug release and
almost no control over the effective concentration at the target site. This kind of dosing
pattern may result in constantly changing, unpredictable plasma concentrations. Drugs can be
delivered in a controlled pattern over a long period of time by the process of osmosis.
Osmotic devices are the most promising strategy based systems for controlled drug delivery.
They are the most reliable controlled drug delivery systems and could be employed as oral
drug delivery systems. The present review is concerned with the study of drug release
systems which are tablets coated with walls of controlled porosity. When these systems are
exposed to water, low levels of water soluble additive is leached from polymeric material i.e.
semi permeable membrane and drug releases in a controlled manner over an extended period
of time. Drug delivery from this system is not influenced by the different physiological
factors within the gut lumen and the release characteristics can be predicted easily from the
known properties of the drug and the dosage form.
The controlled-porosity osmotic pump tablet concept was developed as an oral drug
delivery system by Zentner et al (1985, 1991), Zentner and Rork (1990), Appel and
Zentner (1991), and Mc Celland et al. (1991). The controlled-porosity osmotic pump
tablet (CPOP) is a spray-coated or coated tablet with a semi permeable membrane (SPM)
containing leachable pore forming agents. They do not have any aperture to release the
drugs. Drug release is achieved through the pores, which are formed in the semi permeable
wall in situ during the operation. In this system, the drug, after dissolution inside the core, is
released from the osmotic pump tablet by hydrostatic pressure and diffusion through pores
created by the dissolution of pore formers incorporated in the membrane. The hydrostatic
pressure is created either by an osmotic agent or by the drug itself or by a tablet component,
after water is imbibed across the semi permeable membrane.
This membrane after formation of pores becomes permeable for both water and
solutes. A controlled-porosity osmotic wall can be described as having a sponge like
appearance. The pores can be continuous that have micro porous lamina, interconnected
through tortuous paths of regular and irregular shapes. Generally, materials (in a
concentration range of 5% to 95%) producing pores with a pore size from 10 -100 m can
be used.
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This system is generally applicable for only water-soluble drugs as poorly water
soluble drugs cannot dissolve adequately in the volume of water drawn into the OPT.
Recently this problem was overcome by adding agents like sulfobutyl ether- -cyclodextrin
(SBE)7m- -CD
or hydroxypropyl- -cyclodextrin
been
(HP- -CD)
developed
to
as solubilising and
prepare
the
porous
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.
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THEORY
Drug delivery system
Drug delivery is the method or process of administering a pharmaceutical compound
to achieve a therapeutic effect in humans or animals. For the treatment of human diseases,
nasal and pulmonary routes of drug delivery are gaining increasing importance. These routes
provide promising alternatives to parenteral drug delivery particularly for peptide and protein
therapeutics.
For this purpose, several drug delivery systems have been formulated and are being
investigated for nasal and pulmonary delivery. Nanoparticles composed of biodegradable
polymers show assurance in fulfilling the stringent requirements placed on these delivery
systems, such as ability to be transferred into an aerosol, stability against forces generated
during aerosolization, biocompatibility, targeting of specific sites or cell populations in the
lung, release of the drug in a predetermined manner, and degradation within an acceptable
period of time.
Development in Drug delivery systems
Development of new drug molecule is expensive and time consuming. Improving
safety efficacy ratio of old drugs has been attempted using different methods such as
individualizing drug therapy, dose titration, and therapeutic drug monitoring. Delivering drug
at controlled rate, slow delivery, targeted delivery are other very attractive methods and have
been pursued vigorously. It is interesting to note that considerable work and many
publications from USA, Europe are authored by Indian researchers.
Numerous animal and human investigations have provided an increased
understanding of the pharmacokinetic and pharmacodynamic principles that govern the action
and disposition of potent opioid analgesics, inhalation anaesthetic agents, sedative/hypnotics,
and muscle relaxants. These studies suggest that skin and buccal and nasal mucous
membranes may have use as alternate routes of analgesic and anaesthetic delivery. Similar
developments with other compounds have produced a plethora of new devices, concepts, and
techniques that have together been termed controlled-release technology (CRT). Some
examples of CRTs are transdermal and transmucosal controlled-release delivery systems, ml6
nasal and buccal aerosol sprays, drug-impregnated lozenges, encapsulated cells, oral soft
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gels, iontophoretic devices to administer drugs through skin, and a variety of programmable,
implanted drug-delivery devices. There are a number of factors stimulating interest in the
development of these new devices, concepts, and techniques.
Conventional drug administration methods, while widely utilized, have many
problems that may be potentially overcome by these methods. Equally important, these
advances may appear attractive relative to the costs of new drug development. Rising
research and development costs, alternative investment opportunities for drug firms, fewer
firms conducting pharmaceutical research, and erosion of effective patent life have resulted in
a decline in the introduction of new chemical entities since the late 1950s. Bringing a new
drug through discovery, clinical testing, development, and regulatory approval is currently
estimated to take a decade and cost well over $ 120 million. Novel drug delivery systems
may account for as much as 40% of US marketed drug products by 2000.
Why Controlled drug release?
New drug delivery systems have been developed or are being developed to overcome
the limitation of the conventional drug delivery systems to meet the need of the healthcare
profession. These systems can be characterised as controlled drug release systems and
targeted drug delivery systems.
The therapeutic benefits of these new systems include:
Increased convenience
Shorter hospitalizations
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Drug
b) Osmotic agent
c)
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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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.
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Isradipine
Salvianolic acid
Ibuprofen
Pseudoephedrine
Isosorbide mononitrate
Trimetazidine dihydrochloride
Indapamide
Testosterone
Polysorbate 80
Witepsolm h-35
Trimazosin
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Potassium chloride
Budesonide
Diltiazem hydrochloride
Polyvinyl acetate
Doxazosin
Chlorpheniramine maleate
Gliclazide
Dipyridamole
Famotidine
Prednisolone
Chitosan
Methylphenidate hcl
Venlafaxine
Metoprolol
Atenolol
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Preliminary examinations
Compound identity
Structure.
Therapeutic indications :
Probable human dose
Desired dosage forms
Bioavailability model
Competitive products
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
Purity
Designed to estimate the levels of all known & significant impurities & contaminates in
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4.
Particle size
This factor is very important to study activity of drug. Particle size can influence variety
of important factors:
Dissolution rate
Suspendability
Uniform distribution
Penetrability
Lack of grittiness
5.
Sieving
Microscopy
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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7.
Solubilisation
Solubilization is defined as the spontaneous passage of poorly water soluble solute
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
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Side effects
Some cases may lead to side effects for which get emergency medical help if you
have any of these signs of an allergic reaction to paracetamol: hives; difficulty breathing;
swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor
at once if you have a serious side effect such as:
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This evaluation is done using experiments based on various formulation parameters like:
Weight variation
Disintegration
Dissolution
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The USP has provided limits for the average weight of uncoated compressed tablets.
These are applicable when the tablet contains 50mg or more of the drug substance or when
the latter comprises 50% or more, by weight of the dosage form. Twenty tablets are weighed
individually and the average weight is calculated. The tablets physical parameters and
analysed which are usually measured by
Micrometer
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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Monsanto tester
Pfizer tester
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
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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.
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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.
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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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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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 improved disintegration since powder particles are not bonded together by a binder
Disadvantages
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.
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
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Disadvantages
The
greatest
disadvantage
of
wet
because
of
labour,
time,
any
incompatibility
between
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.
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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.
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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:
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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.
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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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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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drug
total
The total amount of drug mzero released at a constant rate increases with decreasing
drug solubility Sdrug. The osmotic pressure decreases for decreasing solubility and in
consequence the re- lease rate is slowed down. Hence, single compartment pumps depend on
the physical properties of the drug. This is a major limitation if the systems are planned to be
used with different drugs. However, there are several strategies to modulate drug solubility,
e.g. the use of solubilizers described in detail elsewhere.
Two compartment osmotic pumps store drug formulation and osmotic agent in two
separate compartments. During operation, the expansion of the agent compartment displaces
the content of the drug compartment. This class of osmotic pumps was described for the 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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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.
Acetone - Solvent
Ethanol - Solvent
Sorbitol Surfactant
Talc
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Apparatus
Butter paper
Dissolution tester
Filter paper
Friability Tester
Glass beakers
pH tester
Plastic pouches
Pouring Vessels
Sieves
Solubilizers
Spatula
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.
2.
A blank tablet is prepared to check hardness and other important factors before using the
drug.
3.
4.
5.
6.
Apparatus cleanup
7.
8.
9.
10. Comparison of both coated and uncoated tablets is done and result is derived.
1.
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.
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%
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.
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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.
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.
Phosphate buffer was made by adding 50ml 0.2M Potassium dihydrogen phosphate and
3.6 ml 0.2M NaOH
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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.
API characterization
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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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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.
in order.
2.
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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Coating of tablet
Each core tablet was coated with coating solution. The coating solution is prepared as
Release studies
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PFIZER TYPE
HARDNESS TESTER
Friability
Friability is the loss
of weight
of tablet
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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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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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.
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Value determined
0.440 0.050
0.712 0.025
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
16.4
17.2
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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.
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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.
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
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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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.
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