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INTRODUCTION Introduction of Extended-Release Tablets: - Extended-release tablets

are designed to slow the rate of release of the active ingredient(s) in the gastrointestinal
tract. Time release technology, also known as sustained-release (SR), sustained-action
(SA), extended release (ER, XR, or XL), time-release or timed-release, controlled release
(CR), modified release (MR), or continuous- release (CR), It also known as long – acting
medication and timed release medication.

Extended- release dosage forms cover a wide range of prolonged action preparations
that provide continuous release of their active ingredients for a specific period of time.
Extended-release medications have special coatings or ingredients that control how fast
the drug is released from the pill into your body. This may allow you to take certain
medications only once or twice a day, instead of more often.

Some extended-release medications have the letters "XL" or "LA" or "XR" in their name.
The mechanism used in pill tablets or capsules to dissolve slowly and release a drug
over time. Extended-release system allow for the drug to be released over prolonged
time periods. By extending the release profile of drug, the frequency of dosing can be
reduced.

The advantages of sustained-release tablets or capsules are that they can often be taken
less frequently than instant- release formulations of the same drug, and that they keep
steadier levels of the drug in the bloodstream. Extended - Release Tablets of
Antidiabetic:- Antidiabetic drug is a biguanide antihyperglycemic medication has been
proven to be safe and effective in patients with type–II diabetes with minimal risk of
hypoglycemia.
Unlike the mechanism of action of other oral agents used to treat type–II diabetes,
Metformin HCl (Antidiabetic drug) has been shown to reduce the rate of glucose
production through a reduction in hepatic gluconeogenesis. Additionally, Metformin
HCl improves peripheral sensitivity to insulin in the muscle and adipose tissue. Patients
treated with Metformin HCl generally do not gain weight and some may even lose
weight.

Indeed, Metformin HCl has become a cornerstone of treatment for patients with type-II
diabetes in the United States with use not only as monotherapy but also in combination
with other oral agents and/or insulin as needed to control hyperglycemia. Although
patients taking formulation of Metformin HCl significantly lowers fasting and
postprandial plasma glucose & A1C concentrations, they also had a higher prevalence
of GI side effects. The most commonly reported symptoms were diarrhea (53.2%
compared to 11.7% on placebo) and nausea/vomiting (25.5% compared to 8.3% on
placebo).

In a study , Approximately 20% of that taking extended- release formulation of

Metformin HCl reported diarrhea as the most common symptom, compared
to approximately 6-8% of those taking other oral agents. These side effects are usually
transient and dose related and can be minimized by taking the drug with meals and
slowly increasing the dose.

Persistent diarrhea resolves quickly if the drug is withdrawn. Type-II diabetes mellitus is
a chronic progressive disorder characterized by defective insulin secretion and increased
insulin resistance. It is widely accepted that it required intense and tight glycemic
control to prevent several cardiovascular complications.

Metformin Hcl is an orally administered biguanide, widely used in the management of

type -II diabetes, a common disease that combines defects of both insulin secretion and
insulin action. It is a hydrophilic drug which slowly and incompletely absorbed from the
gastrointestinal tract, the absolute bioavailability of a single 500 mg dose is reported to
be 50-60% has relatively short biological half-life of 1.5-4.5 hr.

An obstacle to more successful use of Metformin Hcl therapy is the high incidence of
concomitant gastrointestinal symptoms, such as abdominal discomfort, nausea and
diarrhea that especially occur during the initial weeks of treatment. Also the compound
has relatively short plasma elimination half-life of 1.5 to 4.5 hrs. ‘ER’ formulations that
would maintain plasma levels of drug for 8 to 12 hrs might be sufficient for once daily
dosing of Metformin Hcl.

‘ER’ products are needed for Metformin Hcl to prolong its duration of action and to
improve patient compliance. Metformin is highly water soluble anti-hyperglycemic
(anti-diabetic) agent used in the treatment of type II i.e. non-insulin-dependent diabetes
mellitus. Its relatively low (50-60 %) bioavailability together with short and variable
biological half-life (0.9-2.6

h) require repeated administrations of high doses to maintain effective plasma blood

concentrations, thus reducing patient compliance and/or enhancing the incidence of
side effects. Extended-release dosage form of Metformin Hcl would be expected to give
desired plasma blood concentration with patient compliance. Drug with high solubility
(greater than 1 gm/ml) along with high dose present a challenging task in developing
hydrophilic matrix tablet formulation.

Although HPMC has been researched and used matrix forming agent to modify the
release of insoluble drug formulations, only a scant report has been published on highly
soluble drugs using HPMC. In designing a successful hydrophilic matrix system, the
formulator must select a polymer that will wet, hydrate and swell to form a gelatinous
layer fast enough to prevent the disintegration of the tablet and to protect the interior
of the tablet content from dissolving during the initial wetting and hydration phases.

To achieve this, various synthetic and/or natural hydrophilic matrix forming polymers
have been employed. The polymers such as HPMC, hydroxypropyl cellulose (Klucel),
ethyl cellulose or carrageenan are
used to modify the drug release rate. HPMC, a semi-synthetic derivative of cellulose, is
the most frequently reported as a hydrophilic swellable matrix forming material in
pharmaceutical literature and has gained popularity in the formulation of modified drug
release products.

HPMC has good compression characteristics to form a solid compact upon compression
which makes it a good candidate for direct compression. It was also the intent of this
research to study the hydration rates of the matrix tablets and soluble and insoluble
additives on the drug release rate with view to understand the mechanism of drug
release from the hydrophilic swellable matrix compact systems.

Advantages of Extended- release Tablets There are main advantages are: - Sustained
blood levels Attenuation of adverse effects Better patient acceptance and compliance.
Reduced GI side effects. Reduced dosing frequency. Less fluctuation at plasma drug
levels. More uniform drug effect. Improved efficacy/safety ratio. Disadvantages Dose
dumping Reduced potential for accurate dose adjustment Need of additional patient
education Stability problem Designing extended-release drug delivery system: - Most of
the orally administered drugs, targeting is not a primary concern and it is usually
intended for drugs to penetrate to the general circulation and perfuse to other body
tissues. For this reason, most systems employed are of the sustained release variety.

It is assumed that increasing concentration at the absorption site will increase circulating
blood levels, which in turn, promotes greater concentration of drug at the site of action.
If toxicity is not an issue, therapeutic levels can thus be extended. In essence, drug
delivery by these systems usually depends on release from some type of dosage form,
permeation
through biological milieu and absorption through an epithelial membrane to the blood.
There are a variety of both physicochemical and biological factors that come into play in
the design of such system.

Figure no-1. Matrix System: - Rate controlling step: Diffusion of dissolved drug in matrix
Principle of controlled release drug delivery The conventional dosage forms release their
active ingredients in to an absorption pool immediately. This is illustrated in the
following simple kinetic scheme.
 __ The absorption pool represents a solution of the drug at the site of absorption and
the term Kr, Ka and Ke are first order rate – constant for drug release, absorption and
overall elimination respectively. Immediate drug release from a conventional dosage
form implies that K1 >>>> Ka. Alternatively speaking the absorption of drug across a
biological membrane is the rate – limiting step. For non-immediate release dosage
forms, Kr<<<<Kai.e.

the release of drug from the dosage form is the rate limiting step. This causes the above
kinetic scheme to reduce to the following. Essentially, the absorptive phase of the kinetic
scheme become insignificant Compared to the drug release phase. Thus, the effort to
develop a non-immediate release drug delivery system must be directed primarily at
altering the release rate.

The main objective in designing a controlled release delivery system is to deliver drug at
predetermined rate necessary to achieve and maintain a constant drug blood level. This
rate should be analogous to that achieved by continuous intravenous infusion where a
drug is provided to the patient at a constant rate. This implies that the rate of delivery
must be independent of the amount of drug remaining in the dosage form and constant
over time.

It means that the drug release from the dosage form should follows zero-order kinetics,
as shown by the following equation: Kr0 = Rate In = Rate Out = Ke Cd
Where, Kr0 = Zero-order rate constant for drug release – Amount/time Ke = First-order
rate constant for overall drug elimination-time Cd = Desired drug level in the body –
Amount/Volume, and Vd = Volume space in which the drug is distributed – Liters The
value of Ke, Cd and Vd are obtained from appropriately designed single dosage
pharmacokinetic study. The equation can be used to calculate the zero order release
rate constant.

For many drugs, however, more complex elimination kinetics and other factors affecting
their disposition are involved. This affects the nature of the release kinetics necessary to
maintain a constant drug blood level. It is important to recognize that while zero-order
release may be desirable theoretically, non-zero-order release may be equivalent
clinically to constant release in many cases. Criteria of Extended-release formulation If
the active compound has a long half-life (over 6 hours), it is sustained on its own.

If the pharmacological activity of the active compound is not related to its blood levels,
time releasing has no purpose If the absorption of the active compound involves an
active transport, the development of a time-release product may be problematic Finally,
if the active compound has a short half-life, it would require a large amount to maintain
a prolonged effective dose.

In this case, a broad therapeutic window is necessary to avoid toxicity; otherwise, the risk
is unwarranted and another mode of administration would be recommended. Disease:
Diabetes is a disease in which the body does not make any insulin or can't use the
insulin it does make as well as it should. Insulin is a hormone made in the body. It helps
glucose (sugar) from food enter the cells where it can be used to give the body energy.

Without insulin, glucose remains in the blood stream and cannot be used for energy by
the cells. Over time, having too much glucose in the blood can cause many health
problems. Diabetes is the leading cause of new blindness, kidney disease, and
amputation, and it contributes greatly to the state's and nation's number one killer,
cardiovascular disease (heart disease and stroke). People with diabetes are more likely to
die from flu or pneumonia.
Definition of Diabetes: Diabetes is a disorder of metabolism-the way our bodies use
digested food for energy. Most of the food we eat is broken down into glucose, the
form of sugar in the blood. Glucose is the body's main source of fuel. After digestion,
glucose enters the bloodstream. Then glucose goes to cells throughout the body where
it is used for energy.

However, a hormone called insulin must be present to allow glucose to enter the cells.
Insulin is a hormone produced by the pancreas, a large gland behind the stomach. In
people who do not have diabetes, the pancreas automatically produces the right
amount of insulin to move glucose from blood into the cells. However, diabetes
develops when the pancreas does not make enough insulin, or the cells in the muscles,
liver, and fat do not use insulin properly, or both.

As a result, the amount of glucose in the blood increases while the cells are starved of
energy. Over time, high blood glucose levels damage nerves and blood vessels, leading
to complications such as heart disease and stroke, the leading causes of death among
people with diabetes. Uncontrolled diabetes can eventually lead to other health
problems as well, such as vision loss, kidney failure, and amputations.

Figure no- 2: Diabetes can lead to heart and blood vessel disease Symptoms of
Diabetes: - Diabetes often goes undiagnosed because many of its symptoms seem
harmless or don't always appear right away. Recent studies show that early detection of
diabetes symptoms and treatment can decrease the chance of developing the
complications of diabetes.

Symptoms of diabetes includes increased thirst, increased hunger, having to urinate

more often – especially at night, feeling very tired, weight loss, Blurred vision, sores that
do not heal, tingling/numbness in the hands and feet People who are concerned that
they might have diabetes should talk to their doctor or health care provider to find out
how to get tested for diabetes.

A blood test called a fasting plasma glucose (FPG) or an oral glucose tolerance test
(OGTT), ordered by a doctor or health care provider can detect diabetes. Complications
(Problems) are Caused by Diabetes: If blood sugar consistently high, over time it can
affect the heart, eyes, kidneys, nerves, and other parts of the body. These problems are
called complications. Sometimes people with diabetes don't realize that they have the
disease until they begin to have other health problems.

For example, a doctor or health care provider may detect signs of diabetes damage even
though the patient does not know that he/she has the disease. Treatment of Diabetes:
-Diabetes is treated in two ways: - Combination of healthy diet and exercise Medication
with tablets and/or insulin Insulin injections increase the amount of insulin in your body
and bring down the blood sugar level. Insulin injections are used in Type 1 diabetes and
in some cases of Type-II.

These can be given once a day as a long-acting insulin, or as shorter acting injections
given more frequently through the day, and can be used in combination with tablet
treatment if necessary. There are different types of oral medication for treating Type-II
diabetes: Some increase the amount of insulin secreted by the pancreas Some increase
the action of insulin in the body Some delay the absorption of glucose from the
digestive system Some suppress a hormone called glucagon, which is secreted by the
pancreas and stops insulin from working.
Treatment for diabetes depends on the individual.

It starts the first-time patients gives an insulin injection or take diabetes tablet, and
continues through eating a well-balanced diet and starting an exercise programmed. To
help you get the most out of treatment, consult your GP or hospital healthcare team,
which should include a diabetes nurse specialist. Blood sugar levels: -Monitoring blood
sugar levels is an important aspect of treatment, especially in Type 1 diabetes where
levels can change markedly.

This can be done easily at home with a small blood glucose meter. Depending on the
reading, you may need to adjust your diet, the amount you exercise or your insulin
intake. Managing diabetes: -In the long term, diabetes is monitored through routine
checkups by your doctor and/or annual check-ups at the hospital on an outpatient
basis.

Their purpose is to determine if treatment is satisfactory and to look out for any
evidence of longer-term complications such as eye or kidney disease. Tests for these
complications are usually done at the annual check-up, while routine check-ups may be
carried out every three to six months.
REVIEW OF LITERATURE Review literature of extended – release tablets Shubham et al
2020, formulated and evaluated extended-release tablets of Carvedilol phosphate by
using sodium carboxy methylcellulose and HPMC K4M.they conclude sodium carboxy
methylcellulose and HPMC K4M can successfully be employed in oral controlled release
drug delivery system.

Modified release ability of the formulation is likely to increase its GI residence time, and
eventually improve the extent of bioavailability. Rajeswary et al 2019, formulated and
evaluated extended-release tablets of metformin hydrochloride and gliclazide layer that
contain different viscosity grades of HPMC.

They conclude the monolith diffusion-controlled bilayer tablets of metformin

hydrochloride and gliclazide offer improved patient compliance and convenience with
better postprandial hyperglycemic control with once-a-day dosing. Vuebaet al 2018,
prepared matrix tablets of Ibuprofen using hydrophilic matrix like methylcellulose (MC),
ethyl cellulose (EC), Hydroxypropyl cellulose (HPC), Hydroxypropylmethylcellulose
(HPMC). They conclude that dissolution from MC or HPC matrices are not controllable.

Kiortsiset al 2017, evaluated drug release from cellulosic (HPMC or HPC) and
hydrophobic component by wet granulation. They studied drug release from wet
granulation and physical mixture containing cellulosic polymer and hydrophobic
component. Ishikawa et al 2016, formulated extended-release tablet of Nifedipine using
Hydroxypropylmethylcellulose.

They conclude that the difference in release of drug from matrix depends on
concentrations of HPMC may be due to differences in the thickness of the HPMC gel
layer formed on the surface of the tablet. Cao et al. 2015, formulated extended-release
matrix tablet of Acetaminophen using Hydroxypropylmethylcellulose. They conclude
that the types and amounts of pharmaceutical excipients such as surfactant,
disintegrates and solubilizers in HPMC tablets were found to crucially control
Acetaminophen release characteristics. Review literature of Anti – diabetes extended –
release tablets: Basavaraj K Nanjwade et al.

2020, To develop and characterize an oral extended- release matrix tablet of

Antidiabetic drug hydrochloride using a combination of a
hydrophobic carrier and a hydrophilic polymer, and two types of formulation
techniques. The physicochemical characteristics of all the granules and tablets were
generally satisfactory. Optimization results indicate that the release rate of Antidiabetic
drug HCl was directly proportional to the levels of stearic acid (SA) and polyethylene
oxide (PEO) in the tablet formulations. Release rate was also dependent on the method
of granulation used.

Kinetic analysis showed that the formulation containing 30 %w/w of polymer exhibited
release similar to that of the commercial brand with a similarity factor (f2) of 81.1. Melt
granulation was more effective in extending drug release than direct compression.
Release mechanism followed most closely the Korsmeyer- Peppas model with a
correlation coefficient (r2). Vilas Sonagre et al.

2019, The matrix tablets are very effective in sustained release dose formulation. The
formulation of Antidiabetic drug hydrochloride sustained release matrix tablets by using
polymer, which is preferably used as an anti-diabetic and in case of type- II diabetes
mellitus. Matrix tablets were prepared using polymer with HPMC-K100 (Dow), in
different concentration by dry granulation technique.

The physical compatibility evaluation was performed in visual basic. The study implies
that the drug, polymer and other excipients are physically compatible with other as
there was no change of physical description. All the formulations were evaluated on the
basis of Pharmacopoeial specification. Shapes of the tablets were standard concave in
case of 500mg label claim.

Hardness, thickness, weight variation, dissolution was, carried out for all cases. Assay
was carried out only for those selected batches and the result was found to be 99.73%,
(Label claim 500mg). Stability studies of the selected formulated tablets were carried out
by keeping the tablets at room temperature and at 40°C ± 2°C / 75 ± 5% RH (stability
chamber) for 30days. All the parameters were within the limit after 30days.The
mechanism of drug release form matrix tablet is governed by diffusion and as the drug
is so highly soluble.

However, when considering in-vivo behavior of this system, the erosion rate will be
more important. Selected formulations were compared with the marketed product
(Riomet OD) in same strengths. Graham, Garry G. et al 2018, Antidiabetic drug is widely
used for the treatment of type-II diabetes mellitus.

It is a biguanide developed from galegine, a guanidine derivative found in Galega

officinalis (French lilac). Chemically, it is a hydrophilic base
which exists at physiological pH as the cationic species (>99.9%). Consequently,
itspassivediffusionthroughcellmembranesshouldbeverylimited.Themean?±?SD fractional
oral bioavailability (F) of Antidiabetic drug is 55?±?16%. It is absorbed predominately
from the small intestine.

Antidiabetic drug is excreted unchanged in urine. The elimination half-life (t½) of

Antidiabetic drug during multiple dosages in patients with good renal function is
approximately 5 hours. From published data on the pharmacokinetics of Antidiabetic
drug, the population mean of its clearances were calculated. Review literature of
excipients True L.

Rogers, Dave Wallicket al 2020, this three-part review has been developed following the
evaluation of literature where ethyl cellulose, methylcellulose or hypromellose was used
to make microcapsules. Parts 1 and 3 of the review are published as separate papers.
Part 1 covers the various materials used to formulate microcapsules, and Part 3 covers
the various end-use applications for microcapsules.

In the current paper, Part 2 covers the techniques used to make microcapsules.
Examples of techniques to be covered include temperature-induced phase separation,
emulsion solvent evaporation, solvent evaporation, film coating, non-solvent addition
and spray drying. It is hoped that formulators can use Part 2 to understand how to
formulate microcapsules using these encapsulating polymers.

Dumond P et al 2019, Carboxymethylcellulose (CMC) is used extensively in the

pharmaceutical and food industries on account of its various properties. Anaphylactic
reactions are rare. It has been reported principally after intra-auricular infiltration of
sustained-release corticosteroids containing CMC and, very rarely, after barium enema.

Gurtlerand R. Gurnyet al 2018, In the area of topical ocular administration, important

efforts concern the design and the conception of new ophthalmic drug delivery systems
able to prolong the residence time.

The use of inserts, which are solid devices to be placed in the cul-the-sac or on the
cornea represents one of the possibilities to reach increased residence time. These solid
ophthalmic devices present the advantage of avoiding a pulsed release due to multiple
applications. Kurt Christian Schuster et al 2017, The way to produce microcrystalline
cellulose (MCC) from native cellulose material or pulp by acid hydrolysis has been
known already for over 50 years.

MCC is purified partly depolymerized cellulose prepared by treating -

cellulose, obtained as a pulp from fibrous plant material, with mineralacid. Sajeev et al.
(2016), formulated various ethyl cellulose diclofenac sodium micro particles by thermal
change coacervation method and compressed these microparticles into sustained
release oral tablets. Micro particles and tablets were evaluated for physical properties
and dissolution profiles by paddle method in distilled water.

Micro particles were fine, spherical and free flowing. The release of drug sustained with
increase in polymer concentration and wall thickness of micro particles. The physical
properties of microparticles were evaluated according to compendial requirement. The
release data was best fit to the zero-order model. The rate of drug release was well
correlated with polymer concentration in micro particles.

The rate of drug release was well correlated with polymer concentration and tablet
weight. Good stability and producibility was observed for all the formulations. M.A.
Lamkin, F.L. Riley et al 2015, Silicon dioxide and silicate glass films are formed on silicon
nitride and silicon carbide ceramics during exposure to high- temperature oxidizing
atmospheres, and oxygen transport through the film is potentially a rate- controlling
step.

Recent published literature concerning oxygen permeation and diffusion through

amorphous and crystalline silicon dioxide, and silicate glasses, is reviewed. Data for
diffusion coefficients are collected to facilitate the assessment of probable dominant
oxygen transport mechanisms, and associated rates, under given sets of oxidation
conditions.
RESEARCH ENVISAGED Extended release pharmaceutical product became a very useful
tool in medical practice ,offering a wide range of actual and perceive advantages to the
patients.oral drug delivery is the most preferred route for the various drug molecules
among all other routes of drug delivery ,because ease of administration which lead to
better patient compliance .so extened release drug delivery system becomes a very
promising approch for those drugs that are given orally but having the shoter half-life
and high dosing frequency.

Oral time control drug release formulations have the interasting characteristic that a
drug is released from the formulation after a predetermined time before drug release
begins (the lag time). Recently, such time release formulations have been widly
investigated for several possible uses. Several studies have shown that time release
formulation can used to avoid pharmacokinetic drug- drug interaction between
administered madications, creating a time interval between their releases into the
gastrointestinal tract.

Metformin Hcl is an orally administered biguanide, widely used in the management of

type -II diabetes, a common disease that combines defects of both insulin secretion and
insulin action. It is a hydrophilic drug which slowly and incompletely absorbed from the
gastrointestinal tract, the absolute bioavailability of a single 500 mg dose is reported to
be 50-60% has relatively short biological half-life of 1.5-4.5 hr.

An obstacle to more successful use of Metformin Hcl therapy is the high incidence of
concomitant gastrointestinal symptoms, such as abdominal discomfort, nausea and
diarrhea that especially occur during the initial weeks of treatment. ER’ formulations that
would maintain plasma levels of drug for 8 to 12 hrs might be sufficient for once daily
dosing of Metformin Hcl.

‘ER’ products are needed for Metformin Hcl to prolong its duration of action and to
improve patient compliance. The purpose of the present study is to be optimized
formulation of extended- Release tablet of metformin as a model drug using polymer
Hypromellose (K 100M premium CR) in different ratio.
PLAN OF WORK Literature survey Preformulation studies of extended-release tablets of
metformin Hcl Formulation of extended-Release tablets of metformin Hcl Evaluation of
Extended-release tablets of metformin Hcl Stability studied of selected formulation
Comparison of prepared extended-release tablet of metformin Hcl with marketed
extended-release tablets. Results Discussion Conclusion and Summary
DRUG AND EXCIPIENTS PROFILE METFORMINE DRUG PROFILE Figure no: 3.

Structural formula Metformin drug profile PROPERTIES _INFORMATION _ _Molecular

formula _C4H11N5.Hcl _ _Molecular weight _165.6 _ _IUPAC name _N,N
Dimethylimidodicarbonimidic diamide _ _Category _Ant diabetic _ _Macroscopic
appearance _White crystalline powder _ _Half life _6.2 hours. Duration of action is 8-12
hours _ _Solubility _Freely soluble as Hcl salt, freely soluble in water, Soluble in ethanol,
practically insoluble in ether, chloroform & acetone _ _pH _6.68 _ _pKa _12.4

_ _Use _Oral hypoglycemic drug _ _

Description: - Metformin Hcl extended-release tablets are an oral antihyperglycemic
drug used in the management of type- II diabetes. Metformin Hcl (N, N
dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or
pharmacologically related to any other classes of oral antihyperglycemic agents.
Metformin Hcl is a white to off-white crystalline compound with a molecular formula of
C4H11N5 and a molecular weight of 165.63.

Metformin Hcl is freely soluble in water and is practically insoluble in acetone, ether, and
chloroform. The pKa of Metformin Hcl is 12.4. The pH of a 1% aqueous solution of
Metformin Hcl is 6.68. Metformin Hcl is a diabetes medicine sometimes used for
lowering insulin and blood sugar levels in women with polycystic ovary syndrome
(PCOS).

This helps regulate menstrual cycles, start ovulation, and lower the risk of miscarriage in
women with PCOS. Long-term use also lowers diabetes and heart disease risk Related to
high insulin levels. Mechanism of Action: -Metformin Hcl is an antihyperglycemic agent
which improves glucose tolerance in patients with type-II diabetes, lowering both basal
and postprandial plasma glucose. Its pharmacologic mechanisms of action are different
from other classes of oral antihyperglycemic agents.

Metformin Hcl decreases hepatic glucose production, decreases intestinal absorption of

glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and
utilization. Unlike sulfonylurea, Metformin Hcl does not produce hypoglycemia in either
patients with type-II diabetes or normal subjects (except in special circumstances) and
does not cause hyperinsulinemia.

With Metformin Hcl therapy, insulin secretion remains unchanged while fasting insulin
levels and day-long plasma insulin response may actually decrease. Pharmacokinetics
Parameters:- Absorption and Bioavailability: -The absolute bioavailability of a Metformin
Hcl 1000-mg tablet given under fasting conditions is approximately 50% to 60%.

Studies using single oral doses of Metformin Hcl 500 mg to 1500 mg, and 850 mg to
2550 mg, indicate that there is a lack of dose proportionality with increasing doses,
which is due to decreased absorption rather than an alteration in elimination. Food
decreases the extent of and slightly delays the absorption of Metformin Hcl, as shown
by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower
area under the plasma concentration versus time curve (AUC), and a 35- minute
prolongation of time to peak plasma concentration (Tmax) following administration of a
single 850-mg tablet of Metformin Hcl with food, compared to the same tablet strength
administered fasting.
The clinical relevance of these decreases is unknown.

Following a single oral dose of Metformin Hcl extended-release, Cmax is achieved with a
median value of 7 hours and a range of 4 hours to 8 hours. Peak plasma levels are
approximately 20% lower compared to the same dose of Metformin Hcl, however, the
extent of absorption (as measured by AUC) is similar to Metformin Hcl.

At steady state, the AUC and Cmax are less than dose proportional for Metformin Hcl
extended-release within the range of 500 mg to 2000 mg administered once daily. Peak
plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 µg/ml for 500, 1000, 1500, and
2000 mg once-daily doses, respectively. The extent of Metformin Hcl absorption (as
measured by AUC) from Metformin Hcl extended-release at a2000 mg once-daily dose
is similar to the same total daily dose administered as Metformin Hcl tablets 1000 mg
twice daily. After repeated administration of Metformin Hcl extended-release, Metformin
Hcl did not accumulate in plasma.

Within-subject variability in Cmax and AUC of Metformin Hcl from Metformin Hcl
extended-release is comparable to that with Metformin Hcl Although the extent of
Metformin Hcl absorption (as measured by AUC) from the Metformin Hcl
extended-release tablet increased by approximately 50% when given with food, there
was no effect of food on Cmax and Tmax of Metformin Hcl. Both high and low-fat meals
had the same effect on the pharmacokinetics of Metformin Hcl extended-release.

Distribution: -The apparent volume of distribution (V/F) of Metformin Hcl following

single oral doses of Metformin Hcl 850 mg averaged 654 ± 358 L. Metformin Hcl is
negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than
90% protein bound .Metformin Hcl partitions into erythrocytes, most likely as a function
of time.

At usual clinical doses and dosing schedules of Metformin Hcl, steady state plasma
concentrations of Metformin Hcl are reached within 24 to 48 hours and are generally <1
µg/ml. During controlled clinical trials of Metformin Hcl tablets, maximum Metformin
Hcl plasma levels did not exceed 5 µg/ml, even at maximum doses. Metabolism and
Elimination: -Intravenous single-dose studies in normal subjects demonstrate that
Metformin Hcl is excreted unchanged in the urine and does not undergo hepatic
metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal
clearance is approximately 3.5

times greater than creatinine clearance, which indicates that tubular secretion is the
major route of Metformin Hcl elimination. Following oral administration, approximately
90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with
a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination
half-life
is approximately 17.6 hours, suggesting that the erythrocyte mass may be a
compartment of distribution.

Side effects of Metformin Hcl:- The most common side effects of Metformin Hcl are
Nausea. Loss of appetite Diarrhea. Increased abdominal gas. A metallic taste.
EXCIPIENTS PROFILE: - Carboxymethylcellulose sodium Nonproprietary Names BP:
Carmellose sodium JP: Carmellose sodium PhEur: Carmellosumnatricum USP:
Carboxymethylcellulose sodium Synonyms Akucell, Aquasorb, Blanose, cellulose gum,
CMC sodium, E466, Finnfix, Nymcel, SCMC, sodium carboxymethylcellulose, sodium
cellulose glycolate, sodium CMC,Tylose CB.

Chemical Name Cellulose, carboxymethyl ether, sodium salt Empirical Formula and
Molecular Weight The USP 28 describes carboxymethylcellulose sodium as the sodium
salt of a polycarboxymethyl ether of cellulose. Typical molecular weight is 90 000–700
000. Functional Category Coating agent, stabilizing agent, suspending agent, tablet and
capsule disintegrant tablet binder, viscosity-increasing agent, water-absorbing agent.
Applications in Pharmaceutical Formulation Technology Carboxymethylcellulose sodium
is widely used in oral and topical pharmaceutical formulations, primarily for its viscosity
increasing properties. Viscous aqueous solutions are used to suspend powders intended
for either topical application or oral and parenteral administration.
Carboxymethylcellulose sodium may also be used as a tablet binder and disintegrant,
and to stabilize emulsions.

Higher concentrations, usually 3–6%, of the medium viscosity grade are used to produce
gels that can be used as the base for applications and pastes; glycols are often included
in such gels to prevent them drying out. Carboxymethylcellulose sodium is additionally
one of the main ingredients of self-adhesive stormy, wound care and dermatological
patches, where it is used as a mucoadhesive and to absorb wound exudates or Tran’s
epidermal water and sweat.

This mucoadhesive property is used in products designed to prevent post-surgical tissue

adhesions and to localize and modify the release kinetics of active ingredients applied to
mucous membranes; and for bone repair. Encapsulation with carboxymethylcellulose
sodium can affect drug protection and delivery. There have also been reports of its use
as a cytoprotective agent.

Carboxymethylcellulose sodium is also used in cosmetics, toiletries, surgical prosthetics,

and incontinence, personal hygiene, and food products. TableNo.–5.1 Use of
carboxymethylcellulose sodium _ _Use _Concentration (%) _ _Emulsifying agent _0.25 –
1.0 _ _Gel – forming agent _3.0 – 6.0 _ _Injections _0.05 – 0.75 _ _Oral solution _0.1 – 1.0 _
_Tablet binder _1.0 – 6.0 _ _ Description Carboxymethylcellulose sodium occurs as a
white to almost white, odorless, granular powder.

Typical Properties Density (bulk): 0.52 g/cm3 Density (tapped): 0.78 g/cm3 Dissociation
constant: pKa = 4.30 Melting point: browns at approximately 2270C, and chars at
approximately 2520C.
Moisture content: typically contains less than 10% water. However,
carboxymethylcellulose sodium is hygroscopic and absorbs significant amounts of water
at temperatures up to 370C at relative humidity of about 80%.

Solubility: practically insoluble in acetone, ethanol (95%), ether, and toluene. Easily
dispersed in water at all temperatures, forming clear, colloidal solutions. The aqueous
solubility varies with the degree of substitution (DS). Viscosity: various grades of
carboxymethylcellulose sodium are commercially available that have differing aqueous
viscosities; Aqueous 1% w/v solutions with viscosities of 5–13 000 mPa s (5–13 000 cP)
may be obtained. An increase in concentration results in an increase in aqueous solution
viscosity.

Prolonged heating at high temperatures will depolymerized the gum and permanently
decrease the viscosity. The viscosity of sodium carboxymethylcellulose solutions is fairly
stable over a pH range of 4–10. The optimum pH range is neutral. Stability and Storage
Conditions Carboxymethylcellulose sodium is a stable, though hygroscopic material.

Under high humidity conditions, carboxymethylcellulose sodium can absorb a large

quantity (>50%) of water in tablets, this has been associated with a decrease in tablet
hardness and an increase in disintegration time. Aqueous solutions are stable at pH
2–10; precipitation can occur below pH 2, and solution viscosity decreases rapidly above
pH 10.

Generally, solutions exhibit maximum viscosity and stability at pH 7–9.

Carboxymethylcellulose sodium may be sterilized in the dry state by maintaining it at a
temperature of 1600C for 1 hour. However, this process results in a significant decrease
in viscosity and some deterioration in the properties of solutions prepared from the
sterilized material.

Aqueous solutions may similarly be sterilized by heating, although this also results in
some reduction in viscosity. After autoclaving, viscosity is reduced by about 25%, but
this reduction is less marked than for solutions prepared from material sterilized in the
dry state. The extent of the reduction is dependent on the molecular weight and degree
of substitution; higher molecular weight grades generally undergo a greater percentage
reduction in viscosity , Sterilization of solutions by gamma irradiation also results in a
reduction in viscosity.

Aqueous solutions stored for prolonged periods should contain an antimicrobial

preservative. The bulk material should be stored in a well-closed container in a cool, dry
place. HYPROMELLOSE (HPMC) :-
Nonproprietary Names BP: Hypromellose JP: Hydroxypropylmethylcellulose PhEur:
Hypromellosum USPNF: Hypromellose Synonyms Benecel MHPC, E464 Hydroxypropyl
methylcellulose, HPMC, Methocel, methylcellulose propylene glucol ether, methyl
Hydroxypropylcellulos,Metolose,Tylopur.

Chemical Name and CAS Registry Number Cellulose hydroxypropyl methyl ether
[9004-65-3] Molecular Weight 10,000- 150, 00, 00 Structural formula of hypromellose
Functional Category Coating agent: - Film former, rate controlling polymer for sustained
release, stabilizing agent, suspending agent, tablet binder, viscosity-increasing agent
Applications in Pharmaceutical Formulation or Technology Hypromellose is widely used
in oral, ophthalmic, and topical pharmaceutical formulation.

In oral products, hypromellose is primarily used as a tablet binder, in film coating and as
a matrix for use in extended-release tablet formulation. Concentration between 2% and
5% w/w may be used as a binder in either wet- or dry-granulation processes.
Depending upon the viscosity grade, concentration of 2-20% w/w are used for film
coating solution to film-coat tablets.

Lower viscosity grade are used inaqueous film-coating solution, while higher viscosity
grade are used with organic solvent. Hypromellose is also used as a suspending and
thickening agent in topical formulations. Hypromellose at concentration between
0.45-1.0% w/w may be added as a thickening agent to vehicle for eye drops and artificial
tear solution.

Description Hypromellose is an odorless and tasteless, white or creamy white fibrous or

granular powder. Pharmacopoeial Specifications Hypromellose is official in JP, PhEur,
and USP. Incompatibilities Hypromellose is incompatible with some oxidizing agents.
Since it is nonionic, hypromellose will not complex with metallic salts or ionic organics to
form insoluble precipitates.

Comments Powdered or granular, surface treated grades of hypromellose are also

available that are dispersible in cold water. These are not recommended for oral use. A
Specification for hypromellose is contained in the Food Chemicals Codex (FCC)
MICROCRYSTALLINE CELLULOSE Nonproprietary Names BP: Microcrystalline cellulose
JP: Microcrystalline cellulose PhEur: Cellulosummicrocristallinum USPNF: Microcrystalline
cellulose
Synonyms Avicel PH, Celex, cellulose gel, Celphere, Ceolus KG, crystalline cellulose, E460,
Emcocel, Ethispheres, Fibrocel, Pharmacel, Tabulose,Vivapur.

Chemical Name and CAS Registry Number Cellulose [9004-34-6] Empirical Formula and
Molecular Weight (C6H10O5) n˜36 000 Where n˜ 220. Structural Formula Structural
Formula of Microcrystalline Cellulose Functional Category Adsorbent, suspending agent,
tablet and capsule diluent, tablet disintegrant. Applications in Pharmaceutical
Formulation or Technology Microcrystalline cellulose is widely used in pharmaceuticals,
primarily as a binder/diluent in oral tablet and capsule formulations where it is used in
both wet-granulation and direct compressionprocesses (TOBYN MJ ET AL,1996).

In addition to its use as a binder/diluent, microcrystalline cellulose also has some

lubricant and disintegrant properties that make it useful in tableting.
 Table No. – 5.2 Use of Microcrystalline Cellulose _ _Use _Concentration (%) _
_Adsorbent _20 – 90 _ _Antadherent _5 – 20 _ _Capsule binder / Diluent _20 – 90 _
_Tablet disintegrant _5 – 15 _ _Tablet binder / Diluent _20 – 90 _ _ Description
Microcrystalline cellulose is a purified, partially depolymerized cellulose that occurs as a
white, odorless, tasteless, crystalline powder composed of porous particles.

It is commercially available in different particle sizes and moisture grades that have
different properties and applications. Incompatibilities Microcrystalline cellulose is
incompatible with strong oxidizing agents. Ethyl Cellulose: - Nonproprietary Names BP:
Ethyl cellulose PhEur: Ethylcellulosum USPNF: Ethyl cellulose Synonyms Aquacoat ECD,
Aqualon,E462, Ethocel,Surelease.

Chemical Name and CAS Registry Number Cellulose ethyl ether [9004-57-3] Empirical
Formula and Molecular Weight
Ethyl cellulose with complete ethoxyl substitution (DS = 3) is C12H23O6 (C12H22O5)
nC12H23O5 where n can vary to provide a wide variety of molecular weights. Ethyl
cellulose, an ethyl ether of cellulose, is a long-chain polymer of anhydroglucose units
joined together by acetyl linkages.

Functional Category Coating agent, flavoring fixative, tablet binder, tablet filler,
viscosity-increasing agent. Applications in Pharmaceutical Formulation or Technology
Ethyl cellulose are widely used in oral and topical pharmaceutical formulations. The main
use of ethyl cellulose in oral formulations is as a hydrophobic coating agent for tablets
and granules.

Modified release tablet formulations may also be produced using ethyl cellulose as a
matrix former. Ethyl cellulose, dissolved in an organic solvent or solvent mixture, can be
used on its own to produce water-insoluble films. Higher-viscosity ethyl cellulose grades
tend to produce stronger and more durable films.

Ethyl cellulose films may be modified to alter their solubility, by the addition of
hypromellose or a plasticizer. An aqueous polymer dispersion (or latex) of ethyl cellulose
such as Aqua coat ECD (FMC Biopolymer) or Sure lease (Colorons) may also be used to
produce ethyl cellulose films without the need for organic solvents. Drug release
through ethyl cellulose-coated dosage forms can be controlled by diffusion through the
film coating.

This can be a slow process unless a large surface area (e.g., pellets or granules compared
with tablets) is utilized. In those instances, aqueous ethyl cellulose dispersions are
generally used to coat granules or pellets. Ethyl cellulose- coated beads and granules
have also demonstrated the ability to absorb pressure and hence protect the coating
from fracture during compression.

High-viscosity grades of ethyl cellulose are used in drug microencapsulation. Release of

a drug from an ethyl cellulose microcapsule is a function of the microcapsule wall
thickness and surface area. In tablet formulations, ethyl cellulose may additionally be
employed as a binder, the ethyl cellulose being blended dry or wet-granulated with a
solvent such as ethanol (95%). Ethyl cellulose produces hard tablets with low friability,
although they may demonstrate poor dissolution.

Ethyl cellulose has also been used as an agent for delivering therapeutic agents from
oral (e.g., dental) appliances. In topical formulations, ethyl cellulose is used as a
thickening agent in creams, lotions, or gels provided an appropriate solvent is used.
Ethyl cellulose has been studied as a stabilizer for emulsions. Ethyl cellulose is
additionally used in cosmetics and food Products. Table No.5.3

Uses of ethyl cellulose _ _Use _Concentration (%) _ _Microencapsulation _10.0-20.0 _

_Sustained-release tablet coating _3.0-20.0 _ _Tablet coating _1.0-3.0 _ _Tablet
granulation _1.0-3.0 _ _
Description Ethyl cellulose is a tasteless, free-flowing, and white to light tan
coloredpowder. Typical Properties Density (bulk): 0.4

g/cm3 Glass transition temperature: 129–133 0C Moisture content: ethyl cellulose

absorbs very little water from humid air or during immersion, and that small amount
evaporates readily. Stability and Storage Conditions Ethyl cellulose is a stable, slightly
hygroscopic material. It is chemically resistant to alkalis, both dilute and concentrated,
and to salt solutions, although it is more sensitive to acidic materials than are cellulose
esters. Ethyl cellulose is subject to oxidative degradation in the presence of sunlight or
UV light at elevated temperatures.

This may be prevented by the use of antioxidant and chemical additives that absorb
light in the 230–340nm range. Ethyl cellulose should be stored at a temperature not
exceeding 328C (908F) in a dry area away from all sources of heat. It should not be
stored next to peroxides or other oxidizing agents. Incompatibilities Incompatible with
paraffin wax and microcrystalline wax.

Comments Ethyl cellulose is compatible with the following plasticizers: dibutyl phthalate,
diethyl phthalate, dibutylsebacate, triethyl citrate, tributyl citrate, acetylated
monoglyceride, acetyl tributyl citrate, triacetin, dimethyl phthalate, benzyl benzoate,
butyl and glycol esters of fatty acids, refined mineral oils, oleic acid, stearic acid, ethyl
alcohol, stearyl alcohol, castor oi, corn oil, and camphor.

Ethyl cellulose has also been used as a backing membrane on mucoadhesive patches
intended for buccal administration. The membrane had high tensile strength, and
provided excellent unidirectional drug flow. (31) Studies have also suggested ethyl
cellulose for use in floating micro particles based on low-density foam powder, for
gastro retentive drug delivery systems.

A specification for ethyl cellulose is contained in the Food Chemicals Codex (FCC).
Colloidal Silicon Dioxide Nonproprietary Names BP: Colloidal anhydrous silica PhEur:
Silica colloidal anhydrica USPNF: Colloidal silicon dioxide Synonyms Aerosil, Cab-O-Sil,
Cab-O-Sil M-5P, colloidal silica, fumed silica, light anhydrous silicic acid, silicic
anhydride, silicon dioxide fumed, Wacker HDK.

Chemical Name and CAS Registry Number Silica [7631-86-9] Empirical Formula and
Molecular Weight SiO2 60.08 Structural Formula SiO2 Functional Category Adsorbent,
anticaking agent, emulsion stabilizer, glidant, suspending agent, tablet disintegrant,
thermal stabilizer, viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology: Colloidal silicon dioxide is

widely used in pharmaceuticals, cosmetics, and food products, its small particle size and
large specific surface area give it desirable flow characteristics that are exploited to
improve the flow properties of dry powders in a number of processes such as tableting.
Colloidal silicon dioxide is also used to stabilize emulsions and as a thixotropic
thickening and suspending agent in gels and semisolid preparations.

With other ingredients of similar refractive index, transparent gels may be formed. The
degree of viscosity increase depends on the polarity of the liquid (polar liquids generally
require a greater concentration of colloidal silicon dioxide than nonpolar liquids).
Viscosity is largely independent of temperature. However, changes to the pH of a
system may affect the viscosity.

In aerosols, other than those for

inhalation, colloidal silicon dioxide is used to promote particulate suspension, eliminate
hard settling, and minimize the clogging of spray nozzles. Colloidal silicon dioxide is also
used as a tablet disintegrant and as an adsorbent dispersing agent for liquids in
powders. Colloidal silicon dioxide is frequently added to suppository formulations
containing lipophilic excipients to increase viscosity, prevent sedimentation during
molding, and decrease the release rate.

Colloidal silicone dioxide is also used as an adsorbent during the preparation of wax
microspheres; as a thickening agent for topical preparations; and has been used to aid
the freeze-drying of Nano capsules and nano sphere suspensions. Table No. – 5.4 Use of
Silicon dioxide _ _Use _Concentration (%) _ _Aerosols _0.5–2.0 _ _Emulsion stabilizer
_1.0–5.0 _ _Glidant _0.1–0.5 _ _Suspending and thickening agent _2.0–10.0

_ _ Description: Colloidal silicon dioxide is a submicroscopic fumed silica with a particle

size of about 15 nm. It is a light, loose, bluish-white colored, odorless, tasteless,
non-gritty amorphous powder. Typical Properties: Acidity/alkalinity: pH = 3.5–4.4 (4%
w/v aqueous dispersion) Density (bulk): 0.029–0.042 g/cm3 Density (tapped): See Tables
III, IV and V. Flow ability: 35.52% (Carr compressibility index) Particle size distribution:
7–16 nm. Refractive index: 1.46 Solubility: practically insoluble in organic solvents, water,
and acids, except hydrofluoric acid; soluble in hot solutions of alkali hydroxide.

Forms a colloidal dispersion with water.

Specific gravity: 2.2 Stability and Storage Conditions: Colloidal silicon dioxide is
hygroscopic but adsorbs large quantities of water without liquefying. When used in
aqueous systems at a pH 0–7.5, colloidal silicon dioxide is effective in increasing the
viscosity of a system. However, at a pH greater than 7.5

the viscosity-increasing properties of colloidal silicon dioxide are reduced, and at a pH

greater than 10.7 this ability is lost entirely since the silicon dioxide dissolves to form
silicates. Colloidal silicon dioxide powder should be stored in a well-closed container.
Incompatibilities: Incompatible with diethylstilbestrol preparations. Comments: The
PhEur 2005 also contains a specification for hydrated colloidal silicone dioxide.

The incidence of microbial contamination of colloidal silicon dioxide is low.

MAGNESIUM STEARATE Synonyms: Magnesium salt, stearic acid, Empirical Formula:
C36H70MgO5 Molecular Weight: 591.34 Description: It is very fine, light white,
precipitated or milled powder of low density, having a faint odor of stearic acid and
characteristic taste.

It is greasy to touch and readily adheres to the skin. Functional category: Tablet and
capsule lubricant (0.25-5.0%w/w). Typical Properties Density: Bulk density- 0.159 g/cm³
Tapped density-0.286 g/cm³ Solubility: Practically insoluble in ethanol, water, slightly
soluble in warm benzene and warm ethanol (95%).

Stability and Storage Conditions Magnesium stearate is stable and should be stored in a
well-closed container in a cool, dry place
6. PREFORMULATION STUDY Preformulation study is the investigation of physical and
chemical properties of a drug substance alone and when combined with excipients. It is
the first step in the rational development of dosage forms. The first learning phase is pre
formulation.

A) PHYSO CHEMICAL PARAMETERS Description A detailed account of certain or salient

aspects, characteristics, or feature of a subject matter or something seen, here or
otherwise experienced or none. Solubility is a chemical property referring to the ability
for a given substance, the solute, to dissolve in a solvent. It is measured in terms of the
maximum amount of solute dissolved in a solvent at equilibrium.

PH It is the negative of the logarithm to base 10n of the concentration, measured in

units of moles per liter of hydrogen ions. More precisely it is the negative of the
logarithm to base 10 of the activity of the hydrogen ions. Melting point A melting point
is the temperature at which a solid substance assumes the liquid conditions.

At the melting point solid and the liquid phase exist in equilibrium. The melting point of
the substance depends on pressure and is usually specified standard pressure. Loss on
drying this is widely used test method to determine the moisture content of the sample
although it may refer to the loss of any volatile matter from the sample .therefore this
method does not usually refer to the molecularly bound water or water of crystallization.

Particle size determination Particle size analysis is the collective name of the technical
procedures or laboratory techniques, which determine the size range and or the average
or mean size of the particles in a power or liquid sample. Flow property measurement It
is very important parameter to measured, It affects the mass of uniformity of the dose, It
is usually predicted in the terms of angle of repose, bulk density, tapped density.

Angle of Repose The angle of repose of granular materials is the steepest angleof
descent or dip relative to the horizontal plane o which a material can pile without
slumbing. At this angle the material on the slope phase is on the verge of sliding. ? =
tan-1h/r
Where, _ ? = Angle of repose h = Height r = Radius
A funnel fixed at a height approximately of 2-4 cm over theplat form.

The loose powder slowly passed along the wall of funnel, till the cone of the powder
formed. Determine the angle of repose by measuring the height of the cone of
thepowder and the radius of the heap of the powder. Tapped density: -Tapped density
was determined in a bulk density testing apparatus (Konark instruments, India) by
placing the granules in the measuring cylinder and the total volume of granules was
noted before and after 100 tapings. Tapped density was calculated by using the formula.

Tapped density = Total weight of granules / Total volume of granules after 100 tapings
Average of three densities of granules were taken and tabulated. (n=3) Bulk density: -
Bulk density was determined (Konark instruments, India) by placing a fixed weight of
granules (100 G) blend in a measuring cylinder on bulk density testing unit (Konark
Instruments, India) and the total volume was noted. Bulk density was calculated by using
the formula.

Bulk density = Total weight of granules / Total volume of granules Average of three
densities of granules were taken and tabulated. (n=3) Compressibility: - Compressibility
index was determined by placing the granules in a measuring cylinder and the volume
(V0) was noted before tapping. After 100 tapping again volume (V) was noticed.
Compressibility index = (1- V/ V0) x 100 V0 = volume of granules before tapping.

V = volume of granules after 100 tapings. Average of three compressibility indices of

granules readings were taken. Hausner’sRatio: - it indicates the flow properties of the
mixed blend and is measured by the ratio of tapped density to the bulk density.
Hausner’s Ratio = Tapped density /bulk density.
Carr’sindex: -Carr’s index is an important measure that can be obtained from the bulk
and tapped densities.

It’s computed using the formula: Formula:- CI = (Tapped Density – Bulk Density) x 100
Tapped Density Materials and uses:- Table No.6.1- .Materials and uses Material _Use _
_Metformin _API _ _Hypromellose (K 100M premium CR) _Rate controlling polymer _
_Carmellose sodium(Blanose CMC 7H4XF Pharm) _Tablet Binder _ _Microcrystalline
cellulose (Avicel PH101) _Diluent _ _Ethyl cellulose (EC N22 Pharm) _Binder _ _Anhydrous
ethanol _Solvent _ _Colloidal anhydrous silica (Aerosil 200) _Lubricant _ _Magnesium
Stearate (Vegetable grade) _Anti-adherent agent _ _
Table No. – 6.2. List of equipments and suppliers Equipments _M.f.g.

and Supplier _ _Weight balance _Mettler Toledo _ _Mechanical stirrer _Remi motors Ltd.
_ _Rapid mixture granulator _Saral industries _ _Rapid dryer _Retsch _ _Halogen moisture
balance _Mettler Toledo _ _Multi mill _Shakti engg. _ _Vibrating Shifter _Ganson limited _
_Conta blender _Gansons _ _Sieve shaker _Cisa _ _Mesh _Cisa _ _Compression machine
_Cadmach.

_ _Vernier calipers (Digital) _Mitutoyo _ _Osculating granulator _Cadmech. _ _Hardness

tester _Dr. Schleuniger _ _Disintegration test apparatus _Electrolab. _ _Friability tester
_Electrolab. _ _Tapped density meter _Electrolab. _ _Dissolution test apparatus
_Electrolab. _ _H.P.L.C. _Waters _ _FT-IR Spectrophotometer _Perkin Elmer _ _
6.2

Formulation of extended-release tablets of metformin Hcl Method of Preparation: - Wet

granulation Wet granulation is a process of using a liquid binder to lightly agglomerate
the powder mixture. The amount of liquid has to be properly controlled, as over-wetting
will cause the granules to be too hard and under-wetting will cause them to be too soft
and friable.

Aqueous solutions have the advantage of being safer to deal with than solvent-based
systems but may not be suitable for drugs which are degraded by hydrolysis. Procedure:
Step 1: The active ingredient and excipients are weighed and mixed. Step 2: The wet
granulate is prepared by adding the liquid binder–adhesive to the powder blend and
mixing thoroughly.

Examples of binders/adhesive Ethyl cellulose dissolve in Anhydrous Ethanol to get clear

viscous solution. Step 3: Granulate properly Mixed powder with this binder. Step 4:
Drying the granulation. A conventional tray-dryer or fluid-bed dryer are most commonly
used (Drying Temperature are not more than 500c). Step 5: After the granules are dried,
they are passed through a screen of smaller size than the one used for the wet mass to
create granules of uniform size by mesh 18# and collect and milled and shift. Step 6:
Add shifted Colloidal anhydrous silica (Aerosil 200) to the sized granules and mix for 5
min.

To this add shifted Magnesium stearate and mix properly for 5 min. Step 7: Compress
lubricated blend to tablets with specified compression parameters. Low shear wet
granulation processes use very simple mixing equipment, and can take a considerable
time to achieve a uniformly mixed state. High shear wet granulation processes use
equipment that mixes the powder and liquid at a very fast rate, and thus speeds up the
manufacturing process.

Fluid bed granulation is a multiple-step wet granulation process performed in the same
vessel to pre-heat, granulate, and dry the powders. It is used because it allows close
control of the granulation process.
Tablet Punch:- Punch Diameter: 19.15mm X 09.35 mm , Die 19.15 X 09.35mm. Shape:
cylindrical, FORMULATION FORMULA: Table No. – 6.3

Formulation Table formula of Various batches _ _INGREDIEN TS _A–001 _A – 002 _A –

003 _A – 004 _A– 005 _A – 006 _ _Metformin HCl _500 _500 _500 _500 _500 _500 _
_Hypromellose (K 100M premium CR) _320 _300 _400 _350 _200 _350 _ _Carmellose
sodium _20 _10 _15 _15 _15 _10 _ _Microcrystalli ne cellulose (Avicel PH101) _70 _100 _30
_75 _199 _80 _ _Ethyl cellulose (EC N22 Pharm) _80 _80 _45 _50 _76 _50 _ _Colloidal
anhydrous silica (Aerosil 200) _5 _5 _5 _5 _5 _5 _ _Magnesium Stearate _5 _5 _5 _5 _5 _5 _
_Anhydrous Ethanol (90%) _ Q.s. _ Q.s. _ Q.s. _ Q.s. _ Q.s. _ Q.s. _ _Purified Water (10%)
_Q.s. _Q.s. _Q.s. _Q.s. _Q.s. _Q.s.

__
 INGREDIENTS _A– 007 _A – 008 _A – 009 _A -010 _A – 011 _A – 012 _ _Metformin HCl
_500 _500 _500 _500 _500 _500 _ _Hypromellose (K 100M premium CR) _320 _400 _300
_300 _300 _300 _ _Carmellose sodium _13 _10 _15 _15 _15 _15 _ _Microcrystalline
cellulose (Avicel PH101) _98 _40 _125 _125 _125 _125 _ _Ethyl cellulose (EC N22 Pharm)
_59 _40 _50 _50 _50 _50 _ _Colloidal anhydrous silica (Aerosil 200) _5 _5 _5 _5 _5 _5 _
_Magnesium Stearate _5 _5 _5 _5 _5 _5 _ _Anhydrous Ethanol (90%) _Q.s. _Q.s. _Q.s. _Q.s.
_Q.s. _Q.s. _ _Purified Water (10%) _Q.s. _Q.s. _Q.s. _Q.s. _Q.s. _Q.s.

_ _ Note: all ingredient quantity in milligram

POST COMPRESSION PARAMETERS:- The quantitative evaluation and assessment of a
tablets chemical, physical and bioavailability properties are important in the design of
tablets and to monitor product quality. These properties are important since chemical
breakdown or interaction between tablet components may alter the physical tablet
properties, and greatly effect the bioavailability of the tablet system. There are various
standards that have been set in the various pharmacopeias regarding the quality of
pharmaceutical tablets.

This includes the diameter, size, shape, thickness, weight, hardness, disintegration and
dissolution characters. The diameter and the shape depend 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. General appearance The general appearance of tablets, visual identity and
overall ‘elegance’ is essential for consumer acceptance, control of lot-to-lot uniformity
and general tablet uniformity and for monitoring the production process.

The control of general appearance involves measurement of attributes such as a tablet’s

size, shape, color, presence or absence of odour, taste, surface textures, physical flaws
and consistency. Size and Shape The type of tooling determines the shape and the
dimensions of compressed tablets during the compression process. At a constant
compressive load, tablets thickness varies with the changes in die fill, particles 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 good working condition. Thickness The thickness of individual tablet may be
measured with a micrometer, which permits accurate measurements and provides
information of the variation between the tablets. Tablet thickness should be control
within a ±5% variation of a standard value.

Any variations within a particular lot of tablets or between manufactures lots should not
be apparent to the unaided eye for consumer acceptance of the products. In addition
thickness must be controlled to facilitate packaging. The physical dimension of tablet
along with the density of the material in the tablet formulation and their proportions,
determine the weight of the tablet.
The size and the shape of the tablet can also influence the choice of the tablet machine
to use, the best particle size for granulation, production l ot size that can be made, the
best type of tabletting processing that can be use, packaging operations and the cost of
production. Weight variation This test is also known as uniformity of weight. This does
not apply to layer or enteric coated tablet.

Weight of individual 20 tablets was noted and their mean weight was calculated, and
the percentage deviation was calculated by using the formula. Percentage deviation =
X-X1 × 100 X Where, X = actual weight of the tablet X1= average weight of the tablet
Content uniformity The content uniformity test is used to ensure that every tablet
contain the amount of drug substance intended with little variation among tablet within
a batch due to increased awareness of physiological availability.

The content uniformity test has been included in the monograph of all coated and
uncoated tablets and all capsules intended for oral administration where the ranges of
size of the dosage form available include 50mg or smaller sizes. Tablet monograph with
a content uniformity requirements do not have weight variation requirements. For
content uniformity test respective samples of 30 tablets are selected are 10 are assigned
individually at least 9 must assay within 15% of the declared potency and none may
exceed ± 25%. Friability Friction and shock are the forces most often cause tablets to
chip, cap or break.

The friability test is closely related to tablet hardness and is designed to evaluate the
ability of the tablet to withstand abrasion in packaging, handling and shipping. It is
usually measured by use of Roche fribilator. A number of tablets are weigh and placed
in the apparatus their they are exposed to rolling and repeated shocks as they fall 6
inches in each turn within the apparatus.

After 4 minute of this treatment of 100 revelations the tablets are weighing and the
weight compared with the initial weight. The loss due to abrasion is a measure of the
tablet friability. The values expressed as percentage a maximum weight loss of not more
than 1% of the tablet being tested during the friability test is consider generally
acceptable and any broken or smashed tablet are not picked up. Normally, when
capping occurs friability values are not calculated.

A thick tablet may have fewer tendencies to cap whereas thin tablets of large diameter
often show expensive capping, thus indicate in that tablets with greater thickness have
reduced internal stress. Friability index = initial weight – final weight Initial weight
Hardness The resistance of tablet to capping, abrasion or breakage under conditions of
storage, transportation and handling before usage depends on its hardness it now
designated as either the Monsanto or stokes hardness tester .The instrument measure
the force required to break the tablets when the force generated by a coil spring is
applied diametrically to 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 specification; if it is too soft, it may not
be able to withstand the handling during subsequent processing. Such as coating or
packaging and shipping operation.

The force required to break the tablet is measured in kilograms and crushing strength of
4kg usually consider to the minimum for satisfactory tablets. Oral tablet normally have
the hardness 4- 10kg;However,hypodermic and chewable tablet are usually much
softer(3 kg) and some sustained release tablet are much harder(10-20kg).Tablet
hardness associated with other tablet properties such as densities and porosity.

Hardness generally increases with normal storage of tablet and depends on the shape,
chemical properties, binding agents and pressure applied during compression.
Dissolution is the process by which a solid solute enters a solution. In the
pharmaceutical industry it may be define as the amount of drug substance that goes in
to solution per unit time under standardized conditions of liquid/solid inter-phase,
temperature and solvent composition.

Dissolution behavior drug has a significant effect on pharmacological activity in fact a

direct
relationship between in vitro dissolution rate of many drugs and their solid dosage
forms may or may not disintegrate when they interact with gastro intestinal fluid
following oral administration depending on their design. Dissolution kinetics is
important in determining the bioavailability of a drug .A

variety of designs of apparatus for dissolution testing have been proposed and tested,
varying of simple beaker with stirrer to, complex system with lipid phases and lipid
barrier where an attempt is made to mimic the biological milieu. The choice of
apparatus to be used depends largely on the physiochemical properties of the dosage
forms.

The two types of methods are employed for performing the in vitro dissolution studies
Basket type Paddle type Basket type Basket method is used to evaluating the
formulations that tend to float by carrying out the dissolution study. Plotting can be due
to swelling of the formulation by taking some amount of dissolution medium. So, in this
method the formulation is entrapped inside the basket that will not allow the
formulation to float even if it swells and becomes lighter than the dissolution medium.
Paddle type Paddle method can be used for floating formulations and those
formulations that don’t float even after swelling.

The dissolution apparatus consists of a cylindrical vessel made of glass or inert

transparent material. The volume of the vessel generally used was 900ml.In the vessel
dissolution media was taken and the formulation to be evaluated had to be placed in it.
A shaft is present which is connected at one end to a motor and the other end to a
basket or paddle according to the method employed.

For basket method unless otherwise specified 40 mesh size for the basket was used. The
rpm of the shaft was 100 rpm for basket method and 50 rpm for paddle method .In
regular intervals of time samples were withdrawn from the vessel and analyzed for the
drug release up to each interval by UV visible spectrophotometer.

After withdrawing the sample it was replaced with same amount of dissolution medium
to maintain sink conditions. B. Drug excipients compatibility study Before making of
formulation the drug and the excipients compatibility is very important. It is necessary to
confirm that the drug does not react with the polymers and excipients under the
experimental conditions and affect the product shelf life.

Procedure Drug and excipients are mixed with the different ratio. These mixtures were
kept in 5ml white coloured vials. These vials are exposed to the room temperature and
40 0C /75%RH. 2-3gm of blend prepared which filled in 3 vials. Observations were made
at zero weeks, 1 month, the samples were withdrawn for analysis of appearance,
moisture content, assay and related substance.

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