FORMULATION & EVALUATION OF ANTI-DIABETIC EXTENDED RELAESE TABLET OF

METFORMIN

1. 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-

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release formulation of Metformin HCl reported diarrhea as the most common symptom,
compared

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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

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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
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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.

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Form Drug release PoolAbsorption area Elimination

Dosage Kr Absorption Ka Target Ke

The absorption pool represents a solution of the drug at the site of absorption and the term K r, 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 K 1 >>>> 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.

Dosage Kr Ta rget Ke

Form Drug release Area Elimination

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

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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
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die from flu or pneumonia.

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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

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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.

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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.

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2. 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

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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

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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 -
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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.

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3. 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.

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4. 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

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5. 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 White crystalline powder

appearance
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

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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:-

A. 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 (T max) following administration of a
single 850-mg tablet of Metformin Hcl with food, compared to the same tablet strength
administered fasting.

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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 C max 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 C max and
Tmax of Metformin Hcl. Both high and low-fat meals had the same effect on the pharmacokinetics
of Metformin Hcl extended-release.

B. 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.

C. 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
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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: -
1. Carboxymethylcellulose sodium

i. Nonproprietary Names
BP: Carmellose sodium

JP: Carmellose sodium

PhEur: Carmellosumnatricum

USP: Carboxymethylcellulose sodium

i. Synonyms
Akucell, Aquasorb, Blanose, cellulose gum, CMC sodium, E466, Finnfix, Nymcel, SCMC,
sodium carboxymethylcellulose, sodium cellulose glycolate, sodium CMC,Tylose CB.

ii. Chemical Name

Cellulose, carboxymethyl ether, sodium salt

iii. 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.

iv. Functional Category

Coating agent, stabilizing agent, suspending agent, tablet and capsule disintegrant tablet binder,
viscosity-increasing agent, water-absorbing agent.

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v. 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

i. Description Carboxymethylcellulose sodium occurs as a white to almost white, odorless,

granular powder.
ii. 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.

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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.

2. HYPROMELLOSE (HPMC) :-

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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.

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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)

3. MICROCRYSTALLINE

CELLULOSE Nonproprietary Names

BP: Microcrystalline cellulose

JP: Microcrystalline cellulose

PhEur: Cellulosummicrocristallinum

USPNF: Microcrystalline cellulose

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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.

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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.

4. 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-

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3]

Empirical Formula and Molecular Weight

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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

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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).

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5. 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
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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 2.0–10.0
agent

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.

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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.

6. 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

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Magnesium stearate is stable and should be stored in a well-closed container in a cool, dry place

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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.
Ө = tan-1h/r

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Where,
Ө = 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.

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 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
Tablet Binder
7H4XF Pharm)
Microcrystalline cellulose (Avicel
Diluent
PH101)
Ethyl cellulose (EC N22 Pharm) Binder
Anhydrous ethanol Solvent
Colloidal anhydrous silica (Aerosil 200) Lubricant
Magnesium Stearate (Vegetable grade) Anti-adherent agent

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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

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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.

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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 A–001 A – 002 A – 003 A – 004 A– 005 A – 006
TS
Metformin 500 500 500 500 500 500
HCl
Hypromellose 320 300 400 350 200 350
(K 100M
premium CR)
Carmellose 20 10 15 15 15 10
sodium
Microcrystalli 70 100 30 75 199 80
ne cellulose
(Avicel
PH101)
Ethyl 80 80 45 50 76 50
cellulose (EC
N22 Pharm)
Colloidal 5 5 5 5 5 5
anhydrous
silica (Aerosil
200)
Magnesium 5 5 5 5 5 5
Stearate
Anhydrous
Ethanol Q.s. Q.s. Q.s. Q.s. Q.s. Q.s.
(90%)
Purified
Water (10%) Q.s. Q.s. Q.s. Q.s. Q.s. Q.s.

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INGREDIENTS A– 007 A – 008 A – 009 A -010 A – 011 A – 012

Metformin HCl 500 500 500 500 500 500

Hypromellose (K 320 400 300 300 300 300

100M premium CR)
Carmellose sodium 13 10 15 15 15 15

Microcrystalline 98 40 125 125 125 125

cellulose (Avicel
PH101)
Ethyl cellulose (EC 59 40 50 50 50 50
N22 Pharm)
Colloidal anhydrous 5 5 5 5 5 5
silica (Aerosil 200)
Magnesium Stearate 5 5 5 5 5 5

Anhydrous Ethanol Q.s. Q.s. Q.s. Q.s. Q.s. Q.s.

(90%)
Purified Water Q.s. Q.s. Q.s. Q.s. Q.s. Q.s.
(10%)

Note: all ingredient quantity in milligram

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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.

1. 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.

2. 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.

3. 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.

4. 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

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5. 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%.

6. 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

7. 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.

8. 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

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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

1. Basket type

2. 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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