DocumentB

Design And Development of Alfuzosin HCl Floating Microspheres

An Introduction to Dissertation Submitted to

GUJARAT TECHNOLOGICAL UNIVERSITY, AHMEDABADIn Partial Fulfillment of the Requirement for the Degree of

MASTER OF PHARMACYIN

PHARMACEUTICS

DECEMBER 2012

Research Guide Student

Dr. M.R.Patel (M. Pharm, Ph.D) Ms. Shah Megha A (B. Pharm))

Associate Professor M.pharm, Department of PharmaceuticsH.O.D., Department of Pharmaceutics, Enrollment No:-112520808007Shri B.M.Shah College of Pharmaceutical Shri B.M.Shah College of Education and Research, Pharmaceutical Education and Research Modasa, Gujarat Modasa, Gujarat.

DEPARTMENT OF PHARMACEUTICS

Shri B. M. Shah College Of Pharmaceutical

Education & Research,

Modasa, GUJARAT,INDIA

CERTIFICATEThis is to certify that the Synopsis to the dissertation entitled “Design and Development of Alfuzosin HCl Floating Microspheres” is a bonafide work done by Ms. Shah Megha A, Enrollment No: 112520808007, in partial fulfillment of the requirement for the degree of Master of Pharmacy. I further certify that the Research/Literature work was carried out under my supervision and guidance at Department of Pharmaceutics and Pharmaceutical Technology, Shri B.M.Shah College of Pharmaceutical Education and Research, Modasa, Gujarat, during the academic year 2012- 2013, Semester- III.

Research Guide:

DR. M.R.Patel (M.Pharm, Ph.D.)

H.O.D.,Deaprtmaent of Pharmaceutics,Shri B.M.Shah College of Pharmaceutical Education and Research,

Modasa – 383315,Gujarat, India.

Forwarded by:

DR. N.M.Patel (M. Pharm., Ph.D.)

PrincipalShri B.M.Shah College of Pharmaceutical Education and Research,

Modasa – 383315,Gujarat,

India

INDEXSR NO. CONTENTS

PAGE NO.

1 AIM OF RESEARCH WORK 1

2 INTRODUCTION TO DOSAGE FORM 3

3 INTRODUCTION TO DRUG 19

4 LITERATURE REVIEW OF DOSAGE FORM 24

5 LITERATURE REVIEW OF DRUG 28

6 LIST OF MATERIALS AND EQUIPMENTS 29

7 FUTURE PLAN OF RESEARCH WORK 31

8 REFERENCES 32

B.M.C.P.E.R.MODASA Introduction to Dissertation

1. AIM OF RESEARCH WORK

1.1 Aim of Present Work:

AlfuzosinHClis an alpha-adrenergic blocker used to treat benign prostatic hyperplasia

(BPH). It works by relaxing the muscles in the prostate and bladder neck, making it

easier to urinate. The recommended dose of alfuzosin is 2.5mg in three divided dose per

day. It is generally given in 10 mg/day to 30mg/day. The biological half life of Alfuzosin

Hydrochloride is 10 hours. The bioavailability of Alfuzosin hydrochloride is only 49 %1.

Sustained drug delivery of Alfuzosin HCl can be given orally due to its absorption is

through gastrointestinal tract. But maximum absorption site of drug is in proximal part of

small intestine. So, most of the drug is absorbed in stomach and after that in colon there

is decrease in absorption occurs.

Administration of conventional tablet of Alfuzosin Hydrochloride has been reported to

exhibit fluctuation in plasma drug concentration which results in manifestation of side

effects or reduction in drug concentration at absorption site. But In Benign prostate

hyperplasia there is release of drug in sustained manner and also requires Steady state

plasma concentration. So, formulation of floating drug delivery satisfies these conditions.

Gastro retentive drug delivery system can be retained in stomach for prolonged time and

assist in increasing sustained delivery of drug that have narrow absorption window. There

are so many approaches offloating drug delivery like Hydro dynamically balanced

system, Gas generating system, Raft forming system, Low density system, High density

system and Bioadhesive system2.

Hence objective of study to formulate floating microspheres of Alfuzosin Hydrochloride

to improve bioavailability and also get steady state plasma concentration.

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1.2 RATIONALE:

Alfuzosin HCl is used in benign prostatic hyperplasia (BPH) and also used as

Anti hypertensive agent.

It is class 1 drug so rapidly absorbed after oral administration. Hence to reduce

solubility and controlled release formulation.

Alfuzosin HClhas bio-availability is only 49%. Andshort biological half life is 10

hours.

In BPH there is need of steady state plasma concentration throughout treatment.

Alfuzosin have Narrow absorption window in proximal part of small intestine.

In turn there is increase in bioavailability of alfuzosin HCl so reduce Dosing

frequency of drug and also achieve release of drug in controlled manner with

steady state plasma concentration.

Reduce dosing frequency and improve surface area to volume ratio by using

floating microspheres.

1.3 OBJECTIVE:

The aim of this research was to develop and optimize gastroretentive

microspheres of Alfuzosin HCl.

Screening of the polymers for total and proportional amount for desired drug

release.

Study the effect of different fillers on the release of the drug.

Optimization of drug to polymer ratio and polymer to polymer ratio.

To check compatibility of drug and excipients.

Optimize the formulation using a suitable experimental design.

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2. INTRODUCTION TO DOSAGE FORM

Historically, the oral delivery of drugs is by far themost preferable route of drug delivery

due to the easeof administration, patient compliance and flexibility informulation, etc.

From immediate release to site-specific delivery, oral dosage forms have

reallyprogressed. However, it is a well-accepted fact that itis difficult to predict the real in

vivo time of releasewith solid, oral controlled release dosage forms. Thus,drug absorption

in the gastrointestinal (GI) tract maybe very less in terms of percentage drug absorbed

and highly variable in certain circumstances 2

Drug Delivery system is becomingincreasingly sophisticated as pharmaceutical

scientistsacquire a better understanding of the physicochemicaland biological parameters

pertinent to theirperformances. Controlled Drug Delivery Systemprovides drug release at

a predetermined, predictableand controlled rate to achieve high therapeuticefficiency with

minimal toxicity.

Despite tremendousadvancement in drug delivery, oral route remains thepreferred route

for the administration of therapeuticagents and oral drug delivery is by far the

mostpreferable route of drug delivery because of low costof therapy and ease of

administration leads to highlevels of patient compliance as well as the fact

thatgastrointestinal physiology offers more flexibility indosage form design than most

other routes,consequently much effort has been put intodevelopment of strategies that

could improve patientcompliance through oral route.3

Gastric emptying of dosage forms is anextremely variable process and ability to prolong

andcontrol emptying time is a valuable asset for dosageforms, which reside in the

stomach for a longer periodof time than conventional dosage forms. Severaldifficulties

are faced in designing controlled releasesystems for better absorption and

enhancedbioavailability. One of such difficulties is the inabilityto confine the dosage

form in the desired area of thegastrointestinal tract. Drug absorption from

thegastrointestinal tract is a complex procedure and issubject to many variables. It is

widely acknowledgedthat the extent of gastrointestinal tract drug absorptionis related to

contact time with the small intestinalmucosa. Thus small transit time is an

importantparameter for drugs that are incompletely absorbed [3]The controlled gastric

retention of solid dosage formsmay be achieved by the mechanisms of

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mucoadhesion,flotation, sedimentation, expansion modified shapesystems or by the

simultaneous administration ofpharmacological agent that delay gastric emptying.This

review focuses on the principal mechanism offloatation to achieve gastric retention.

Current Approaches toGastroretentive Drug Delivery System 8

A. Floating drug delivery systems (FDDS): Floating FDDS is aneffective technology to

prolong the gastric residence time in order toimprove the bioavailability of the drug.

FDDS are low-densitysystems that have sufficient buoyancy to float over the

gastriccontents and remain in the stomach for a prolonged period. Floatingsystems can be

classified as effervescent and no effervescentsystem.

I) Effervescent systems

These buoyant delivery systems utilize matrices prepared withswellable polymers such as

Methocel or polysaccharides, e.g.,chitosan, and effervescent components, e.g., sodium

bicarbonate andcitric or tartaric acid or matrices containing chambers of liquid thatgasify

at body temperature.Gas can be introduced into the floating chamber by the

volatilizationof an organic solvent (e.g., ether or cyclopentane) or by the carbondioxide

produced as a result of an effervescent reaction betweenorganic acids and carbonate–

bicarbonate salts .Thematrices are fabricated so that upon arrival in the stomach,

carbondioxide is liberated by the acidity of the gastric contents and isentrapped in the

gellified hydrocolloid. This produces an upwardmotion of he dosage form and maintains

its buoyancy.

II) Noneffervescent systems

Noneffervescent systems incorporate a high level (20–75% w/w) ofone or more gel-

forming, highly swellable, cellulosic hydrocolloids(e.g., hydroxylethylcellulose,

hydroxypropylcellulose,hydroxylpropylmethylcellulose[HPMC],a carboxymethyl

cellulose), polysaccharides,ormatrix-formingpolymers(e.g., polycarbophil, polyacrylates,

and polystyrene) intotablets or capsules9. Upon coming into contact with gastric fluid,

these gel formers, polysaccharides, and polymers hydrate and form a colloidal gel barrier

that controls the rate of fluid penetration into th device and consequent drug release10-11.

The air trapped by theswollen polymer lowers the density of and confers buoyancy to the

dosage form.

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B) Bio Mucoadhesive systems

Bio Mucoadhesive systems bind to the gastric epithelial cell surface, ormucin, and

increase the GRT by increasing the intimacy andduration of contact between the dosage

form and the biologicalmembrane. The adherence of the delivery system to the gastric

wall increases residence time at a particular site, thereby improvingbioavailability12. A

bio mucoadhesive substance is a natural orsynthetic polymer capable of adhering to a

biological membrane or the mucus lining of the GIT (mucoadhesive polymer). On the

basis of binding of polymers to the mucin-epithelial surface can be subdivided into two

broad categories.

a. Hydration-mediated adhesion

Certain hydrophilic polymers tend to imbibe large amount of waterand become sticky,

thereby acquiring bioadhesive properties.

b. Bonding-mediated adhesion

mechanical bonding and chemical bonding. Chemical bonds may be either covalent

(primary) or ionic (secondary) in nature. Secondarychemical bonds consist of dispersive

interactions (i.e., Vander Waalsinteractions) and stronger specific interactions such as

hydrogen bonds. The hydrophilic functional groups responsible for forming hydrogen

bonds are the hydroxyl and carboxylic groups.

C) Receptor-mediated adhesion

Certain polymers can bind to specific receptor sites on the surface of cells, thereby

enhancing the gastric retention of dosage forms.Certain plant lectins such as tomato

lectins interact specifically withthe sugar groups present in mucus or on the glycocalyx.

D) Expandable, unfoldable and swellable Systems

Gastroretentivity of a pharmaceutical dosage form can be enhancedby increasing its size

above the diameter of the pylorus ifthe dosage form can attain the larger size than

pylorus, thegastroretentivity of that dosage form will be possible for long time.This large

size should be achieved fairly quickly; otherwise dosageform will be emptied through the

pylorus. Thus, configurationsrequired to develop an expandable system to prolong GRT

are:

I. A small configuration for oral intake,

II. An expanded gastroretentive form, and

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III. A final small form enabling evacuation following drug release from the device.

In addition they should be able enough to withstand peristalsis andmechanical

contractility of the stomach14.However, owing to significant individual variation, the

cut-off size cannot be determined exactly. Unfoldable systems are available invarious

shapes as shown in figure-4.The concept is to make a carrier, such as a capsule, which

extends in the stomach. Caldwell et al, proposed different geometric forms like

tetrahedron15, ring or planar membrane (4-lobed, disc or 4-limbed cross form) of

bioerodiblepolymer compressed within a capsule.

E) High-density systems

Gastric contents have a density close to water (¨1.004 g/cm3). When high density pellets

is given to the patient, it will sink to the bottomof the stomach and are entrapped in the

folds of the antrumand withstand the peristaltic waves of the stomach wall17.

Sedimentation has been employed as a retention mechanism for high densitysystems. A

density ~3g/cm3 seems necessary for significant

Factors Affecting Gastric Retention:

Gastric residence time of anoral dosage form is affected by several factors. To pass

through thepyloric valve into the small intestine the particle size should be inthe range of

1 to 2 mm6. The rate of gastric emptying and gastricretention of GRFDDS depends

mainly on-

A) Meals: The rate of gastric emptying depends mainly on nature ofmeal and caloric

content of meals.

Nature of meal: Feeding of indigestible polymers or fatty acid saltscan change

the motility pattern of the stomach to a fed state, thusdecreasing the gastric

emptying rate and prolonging drug release.

Caloric content of meal: GRT can be increased by four to 10 hourswith a meal

that is high in proteins and fats

B) Volume of GI fluid: The resting volume of the stomach is 25 to50 ml. When volume

is large, the emptying is faster. Fluids taken atbody temperature leave the stomach faster

than colder or warmerfluids.

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C) Dosage form related factors

Density: A buoyant dosage form having a density of less than that of the gastric

fluids floats. Since it is away from the pyloricsphincter, the dosage unit is retained

in the stomach for a prolonged period.

Size: Dosage form units with a diameter of more than 7.5mm are reported to have

an increase GRT compared with those with a diameter of 9.9mm. Small-size

tablets leave the stomach during the housekeeping waves.

Shape of dosage form: Tetrahedron and ringshaped deviceswith a flexural

modulus of 48 and 22.5 kilopounds per squareinch (KSI) are reported to have

better GRT ≈90% to 100%retention at 24 hours compared with other shapes.

Single or multiple unit formulation: Multiple unit formulationsshow a more

predictable release profile and insignificantimpairing of performance due to

failure of units, allow co-administration of units with different release profiles or

containing incompatible substances and permit a larger margin ofsafety against

dosage form failure compared with single unitdosage forms.

D) Fed Conditions

Fed or unfed state: Under fasting conditions, the GI motility ischaracterised by

periods of strong motor activity or the migratingmyoelectric complex (MMC) that

occurs every 1.5 to 2 hours.However, in the fed state, MMC is delayed and GRT

isconsiderably longer.

Frequency of feed: The GRT can increase by over 400 minutes when successive

meals are given compared with a single meal.due to the low frequency of MMC.

E) Patient related factors

Gender: Mean ambulatory GRT in males (3.4±0.6 hours) is lesscompared with

their age and racematched female counterparts(4.6±1.2 hours), regardless of the

weight, height and bodysurface.

Age: Elderly people, especially those over 70, have asignificantly longer GRT.

Posture: GRT can vary between supine and upright ambulatorystates of

thepatient.

Concomitant drug administration: Anticholinergics likeatropine and

propantheline, opiates like codeine and prokinetic agents like metoclopramide

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ADVANTAGES OF FLOATING DRUG DELIVERYSYSTEMS 9

The following advantages of the floating drug deliverysystems

The gastroretensive systems are advantageous for drugsabsorbed through the

stomach. E.g. Ferrous salts, antacids.

Acidic substances like aspirin cause irritation on thestomach wall when come in

contact with it. Hence HBSformulation may be useful for the administration of

aspirinand other similar drugs.

Administration of prolongs release floating dosage forms,tablet or capsules, will

result in dissolution of the drug in thegastric fluid. They dissolve in the gastric

fluid would beavailable for absorption in the small intestine after emptyingof the

stomach contents. It is therefore expected that a drugwill be fully absorbed from

floating dosage forms if itremains in the solution form even at the alkaline pH of

theintestine.

The gastroretensive systems are advantageous for drugsmeant for local action in

the stomach. E.g. antacids.

When there is a vigorous intestinal movement and a shorttransit time as might

occur in certain type of diarrhoea, poorabsorption is expected. Under such

circumstances it may beadvantageous to keep the drug in floating condition

instomach to get a relatively better response

2.1 FLOATING MICROSPHERES 10:

Novel drug delivery system aims to deliver the drug at a rate directed by the needs of the

body during the period of treatment, and channel the active entity to the site of action. At

present, no available drug delivery system behaves ideally achieving all the lofty goals,

but sincere attempts have been made to achieve them through novel approaches in drug

delivery. A number of novel drug delivery systems have emerged encompassing various

routes of administration, to achieve controlled and targeted drug delivery.1 Currently,

microencapsulation techniques are most widely used in the development and production

of improved drug- and food-delivery systems. These techniques frequently result in

products containing numerous variably coated particles. Microspheres of biodegradable

and nonbiodegradable polymers have been investigated for sustained release depending

upon the final application. Microsphere based drug delivery system has received

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Microparticle

Monocore Polycore

Microcapsule

Matrix Reservoir

Microsphere


considerable attention in recent years. The most important characteristic of microspheres

is the microphase separation morphology which endows it with a controlled variability in

degradation rate and also drug release.

A) CLASSIFICATION:

Generally, the micro particulate delivery systems are intended for oral and topical use.

The particles can be embedded within a polymeric or proteinic matrix network in either

as solid aggregated state or a molecular dispersion, resulting in the formulation of

microspheres. Alternatively, the particles can be coated by a solidified polymeric or

proteinic envelope, leading to the formation of microcapsules.

The ultimate objective of micro particulate-delivery systems is to control and extend the

release of the active ingredient from the coated particle without attempting to modify the

normal bio fate of the active molecules in the body after administration and absorption.

The organ distribution and elimination of these molecules will not be modified and will

depend only on their physicochemical properties. Thus, the principle of drug targeting is

to reduce the total amout of drug administered, and the cost of therapy while optimizing

its activity.

B) ADVANTAGES:

Sustained delivery: By encapsulating a drug in a polymer matrix, which limits access of the

biological fluid into the drug until the time of degradation, micro particles maintain the

bloodlevel of the drug within a therapeutic window for a prolonged period. Toxic side effects

can be minimized.

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Local delivery: Subcutaneously or intramuscularly applied microparticles can maintain a

therapeutically effective concentration at the site of action for a desirable duration. The local

delivery system obviates systemic drug administration for local therapeutic effects and can

reduce the related systemic side effects. This system has proven beneficial for delivery of

local anaesthetics.

Pulsatile delivery: While burst and pulsatile release is not considered desirable for the

sustained delivery application, this release pattern proves to be useful for delivery of

antibiotics and vaccines. Pulsatile release of antibiotics can alleviate evolution of the

bacterial resistance. In the vaccine delivery, initial burst followed by delayed release pulses

can mimic an initial and boost injection, respectively.

C) USES:

Taste and odour masking

Conversion of oil and other liquids, facilitating ease of handling.

Protection of the drugs from the environment.

Improvement of flow properties

Safe handling of toxic substances

Dispersion of water insoluble substances on aqueous media

Production of sustained release, controlled release and targeted medications.

Reduced dose dumping potential compared to large implantable devices

2. TYPES OF MICROSPHERE

Magnetic microspheres

Bioadhesive microspheres

Floating microspheres

Radioactive microspheres

Magnetic microspheres:

This kind of delivery system is very much important which localises the drug to the disease

Site. In this larger amount of freely circulating drug can be replaced by smaller amount of

magnetically targeted drug. Magnetic carriers receive magnetic responses to a magnetic field

from incorporated materials,

The different types are:

Therapeutic magnetic microspheres:They are used to deliver chemotherapeutic agent to

liver tumour. Proteins and peptides can also be targeted through this system.

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Diagnostic microspheres: These can be used for imaging liver metastases and also can be

used to distinguish bowel loops from other abdominal structures by forming nano size

particles supramagnetic iron oxides.

Bioadhesive microspheres:

Adhesion can be defined as sticking of drug to the membrane by using the sticking property

of the water soluble polymers. Adhesion of drug delivery device to the mucosal membrane

such as buccal, ocular, rectal, nasal, etc. can be termed as bioadhesion. These kinds of

microspheres exhibit a prolonged residence time at the site of application and causes intimate

contact with the absorption site and produces better therapeutic action.

Radioactive microspheres:

Radio emobilisation therapy microspheres sized from 10-30 nm which are larger than

capillaries and get tapped in first capillary bed when they come across. So they are injected to

the arteries that lead to tumour of interest. Hence radioactive microspheres deliver high

radiation dose to the targeted areas without damaging the normal surrounding tissues. It

differs from drug delivery systems, as radio activity is not released from microspheres but

acts from within a radioisotope-typical-distance and the different kinds of radioactive

microspheres are α emitters, β emitters and γ emitters.

Floating microspheres:

In floating types the bulk density is less than the gastric fluid so remains buoyant in stomach

without affected by gastric emptying. The drug is released slowly at the desired rate by

increasing gastric residence, if the system is floating on gastric content. Moreover it reduces

chances of striking, dose dumping and also it produces prolonged therapeutic effect, therefore

reduces dosing frequency.

3. METHODS OF PREPARATION OF MICROSPHERES (5)

Incorporation of solid, liquid or gases into one or more polymeric coatings can be done by

microencapsulation technique. The different methods used for various microspheres

preparation depends on particle size, route of administration, duration of drug release,

method of cross linking, evaporation time and co-precipitation, etc. The various methods of

Preparations are:

A. Emulsion Solvent Evaporation Technique

B. Emulsion Cross Linking Technique

C. Emulsion-Solvent Diffusion Technique

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D. Emulsification Heat Stabilizing Technique

E. Co-acervation Phase Separation Technique

a) Thermal Change

b) Non-Solvent Addition

c) Polymer Addition

d) Salt Addition

e) Polymer-Polymer Interaction

F. Spray Drying Technique

G. Polymerisation Technique

a) Normal polymerisation

b) Interfacial polymerisation

H. Ionic Gelation Technique

I. Hydroxyl Appetite (HAP) Microspheres In Sphere Morphology

J. Hot Melt Microencapsulation technique

A. Emulsion Solvent Evaporation Technique:

In this technique the drug is dissolved in polymer which is previously dissolved in

chloroform and the resulting solution is added drop wise to aqueous phase containing 0 .2 %

of PVP as emulsifying agent and agitated at 500 rpm, then the drug and polymer solution

Transformed into fine droplet which solidifies into rigid microspheres and then collected by

filtration,washed with demineralised water. Finally desiccated at room temperature for 24 hrs

B. Emulsion Cross Linking Technique

In this method, drug is dissolved in aqueous gelatine solution which is previously heated for

1 hr. at 40 C. The solution is added drop wise to liquid paraffin while stirring the mixture at⁰

1500 rpm for 10 min at 35 C, which results in w/o emulsion further stirring is done for 10⁰

min at 15 C. Then the microspheres are washed with acetone and isopropyl alcohol. Further⁰

air dried and dispersed in 5ml of aqueous glutaraldehyde saturated toluene solution at room

temperature for 3 hrs. for cross linking and treated with 100ml of 10Mm glycine solution

containing 0.1%w/v of tween 80 at 37 C for 10 min to block unreacted glutaraldehyde.⁰

C. Emulsion-Solvent Diffusion Technique

In order to improve the residence time in colon floating microparticles of drug is prepared

byemulsion solvent diffusion technique. The drug polymer mixture is dissolved in a mixture

of ethanol and dichloromethane (1:1) then the mixture is added drop wise to sodium lauryl

Megha A Shah 12


sulphate (SLS) solution. The solution is stirred with propeller type agitator at room

temperature at 150 rpm for 1 hr, washed and dried in a desiccator at room temperature.

D. Emulsification Heat Stabilizing Technique:

In this method, drug and polymer are dissolved in 20 ml of deionised water and 5 ml of egg

albumin solution and 0.1% of Tween‐80 are added stirred it for 30 min. The prepared

solution is used as aqueous phase. The oil phase is prepared by mixing 20 ml of sunflower oil

and 5ml of diethyl ether with 1% span‐80 (as emulsifier) and stirred it for 20 mins at 800‐1000 rpm on a magnetic stirrer. The primary emulsion is prepared by adding the oil phase

drop wise to the aqueous phase followed by stirring it for 30 mins at 800‐1000 rpm. The

prepared primary emulsion is added to pre‐heated (65 to 70 C) sunflower oil (80 ml) by⁰

using 21 No. needle and stirred at 1000‐1200 rpm for 2 hrs till the solidification of

microspheres takes place. The suspension then allowed to cool to room temperature with

continuous stirring using a magnetic stirrer. On cooling, 100 ml of anhydrous ether is added.

The suspension containing the microspheres is centrifuged for 15 mins and the settled

microspheres are washed three times with ether to remove traces of oil on microspheres

surfaces. The obtained microspheres are then vacuum dried in a desiccator overnight and

stored at 4 C in dark.⁰

E. Co-acervation Phase Separation Technique:

a)Thermal Change: Microspheres are formed by dissolving polymer (ethyl cellulose) in

cyclohexane with vigorous stirring at 80 C by heating. Then the drug is finely pulverized⁰

and added to the above solution with vigorous stirring. The phase separation is brought about

by reducing temperature using ice bath. The product is washed twice with cyclohexane and

air dried then passed through sieve (sieve no. 40) to obtain individual microcapsule.

b) Non Solvent Addition: Microspheres are formed by dissolving polymer (ethyl cellulose)

in toluene containing propyl-isobutylene in a closed beaker with stirring for 6 hrs. at 500 rpm

and the drug is dispersed in it. Stirring is continued for 15 mins., then phase separation is

brought about by petroleum benzene with continuous stirring. The microcapsules washed

with n-hexane and air dried for 2 hrs., and kept in an oven at 50 C for 4 hrs.⁰

c) Polymer Addition: Microspheres are formed by dissolving polymer (ethyl cellulose)

isdissolved in toluene, then1 part is added to 4 parts of crystalline methylene

bluehydrochloride. Co-acervation is accomplished by adding liquid polybuta-diene. Then the

Megha A Shah 13


polymer coating is solidified by adding a nonsolvent (hexane). The resulting product is

washed and air dried.

d) Salt Addition: Microspheres are formed by dissolving oil soluble vitamin in corn oil and

is emulsified by using pig skin gelatin under condition of temperature 50 C, coacervation is⁰

induced by adding sodium sulphate. The resultant microspheres product is collected and

washed with water, chilled below gelation temperature of gelatin and dried by using spray

drying.

e) Polymer-Polymer Interaction: In this process, aqueous solution of gum Arabica and

gelatin (isoelectic point 8.9) are prepared, the homogeneous polymer solutions are mixed

together in equal amount, diluted to about twice their volume with water, adjusted to pH 4.5

and warmed to 40- 45 C. the oppositely charged macromolecules interact at these conditions⁰

and undergo co-acervation. While maintaining the warm temperature, the liquid core material

(methyl salicylate) is added to polmer solution and stirred well. Then the mixture is cooled to

25 C and coating is rigidised by cooling the mixture to 10 C.⁰ ⁰

F. Spray Drying Technique

This method is used to prepare polymeric blended microspheres loaded with drug. It involves

dispersing the core material into liquefied coating material and then spraying the mixture in

the environment for solidification of coating followed by rapid evaporation of solvent.

Organic solution of poly epsilon-caprolactone (PCL) and cellulose acetate butyrate (CAB), in

different weight ratios with drug is prepared and sprayed in different experimental condition

achieving drug loaded microspheres. This is rapid but may loosecrystalinity due to fast

drying process.

G. Polymerization Techniques:

Mainly two techniques are used for the preparation of microsphere by polymerization

technique:

(a) Normal polymerization:

Normal polymerization classified as:

1. Bulk polymerization

2. Suspension/ pearl polymerization

3. Emulsion polymerization

Megha A Shah 14


1. In bulk polymerization, a monomer or a mixture of monomers along with the initiator or

catalyst is usually heated to initiate polymerization. Polymer obtained may be moulded as

microspheres. Drug loading may be done by adding the drug during the process of

polymerization. It is a pure polymer formation technique but it is very difficult to dissipate

the heat of reaction which affects the thermo labile active ingredients.

2. Suspension polymerizationis carried out at lower temperature and also referred to as pearl

polymerization in which the monomer mixture is heated with active drug as droplets

dispersion in continuous aqueous phase. Microsphere size obtained by suspension techniques

is less the 100 μm.

3. Emulsion polymerization differs from the suspension polymerization due to presence of

initiator in aqueous phase and also carried out at low temperature as suspension. External

phase normally water in last two techniques so through which heat can be easily dissipated.

The formation of higher polymer at faster rate is possible by these techniques but sometimes

association of polymer with the unreacted monomer and other additives can occur.

(b) Interfacial polymerization

It involves the reaction of various monomers at the interface between the two immiscible

liquid phases to form a film of polymer that essentially envelops the dispersed phase. In this

technique two reacting monomers are employed; one is dissolved in continuous phase while

other is dispersed in continuous phase (aqueous in nature) throughout which the second

monomer is emulsified. Two conditions arise because of the solubility of formed polymer in

the emulsion droplet. The formation is Monolithic, if the polymer is soluble in droplet and the

formation is Capsular type if the polymer is insoluble in droplet.

H. Ionic Gelation Technique:

In this technique polymer is dissolved in purified water to form a homogeneous polymer

Solution. The core material (drug) as fine powder passed through mesh no.120 is added to the

polymer solution and mixed to form a smooth viscous dispersion. This dispersion is added

drop wise into 10%w/v CaCl2 solution through a syringe with a needle of diameter 0.55mm.

The added droplets are retained in CaCl2 solution and allowed to cure for 20 minutes at 200

rpm to produce spherical rigid microsphere. Finally the microspheres are collected and dried

in an oven at a temperature 45 C for 12 hrs⁰

I. Hydroxyl Appetite (HAP) Microspheres in Sphere Morphology

In this method, initially HAP granules obtained by precipitation method followed by spray

Megha A Shah 15


drying process. Microspheres are prepared by oil-in-water emulsion followed by solvent

evaporation technique. Oil-in-water emulsion obtained by dispersing the organic phase

(dichloromethane solution containing 5% of EthyleneVinylAcetate and appropriate amount

of HAP) in the aqueous medium of the surfactant. While dispersing in aqueous phase, the

organic phase is transformed into tiny droplets and each droplet surrounded by surfactant

molecules. The protective layer thus formed on the surface which prevents the droplets from

coalescing and helps to stay individual droplets. While stirring, dichloromethane (DCM) is

slowly evaporated from the droplets and after the complete removal of DCM, the droplets

solidifies to become individual microspheres. The size of the droplets formed depends on

many factors like types and concentration of the stabilizing agents, type and speed of stirring

employed, etc, which in turn affects the size of the final microspheres formed.

J. Hot Melt Microencapsulation Technique

The polymer is first melted and then mixed with solid particles of the drug that has been

sieved to less than 50 μm. The mixture is suspended in a non-miscible solvent (like silicone

oil), continuously stirred, and heated to 5°C above the melting point of the polymer. Once the

emulsion is stabilized, it is cooled until the polymer particles solidify. The resulting

microspheres are washed by decantation with petroleum ether. The primary objective for

developing this method is to develop a microencapsulation process suitable for the water

labile polymers, e.g. polyanhydrides. Microspheres with diameter of 1-1000 μm can be

obtained and the size distribution can be easily controlled by altering the stirring rate. The

only disadvantage of this method is moderate temperature to which the drug is exposed.

EVALUATION OF FLOATING MICROSPHERES

2.1.1. Micro-meritic properties

Floating microspheres are characterized by their micromeritic properties such as angle of

repose, tapped density, compressibility index, true densityand flow properties. True density

is determined by liquid displacement method; tapped density and compressibility index

are calculated by measuring the change in volume using a bulk density apparatus; angle of

repose is determined by fixed funnel method. The hollow nature of microspheresis

confirmed by scanning electron microscopy. The compressibility index is calculated using

following formula:

I = Vb –Vt / Vb x 100

Megha A Shah 16


Where, Vb is the bulk volume and Vt is the tapped volume.

The value given below 15% indicates a powder which usually give rise to good flow

characteristics, whereas above 25% indicate poor flow ability.

2.1.2. Particle size and shape

Scanning electron microscopy (SEM) provides higher resolution in contrast to the light

microscopy(LM). The most widely used procedures to visualize microparticles are

conventional light microscopy (LM) and scanning electron microscopy (SEM). Both can

be used to determine the shape and outer structure of multi particulate. LM provides a

control over coating parameters in case of double walled microspheres. The

multiparticulate structures can be visualized before and after coating and the change can

be measured microscopically. SEM allows investigations of the multiparticulate surfaces

and after particles are cross sectioned, it can also be used for the investigation of double

walled systems. Conflocal fluorescence microscopyis used for the structure

characterization of multiple walled microspheres. Laser light scattering and multi size

coulter counter are other than instrumental methods, which can be used for the

characterization of size, shape and morphology of the multi particulates.

2.1.3. Floating behavior

Appropriate quantity of the floating microparticulates is placed in 100 ml of the simulated

gastric fluid (SGF, pH 2.0), the mixture isstirred with a magnetic stirrer. The layer of

buoyantmicroparticulate is pipetted and separated by filtration. Particles in the sinking

particulate layer are separated by filtration. Particles of both types are dried in a

desiccator until constant weight is achieved. Both the fractions of microspheres are

weighed and buoyancy is determined by the weight ratio of floating particles to the sum of

floating and sinking particles.

Buoyancy (%) = Wf / Wf + Ws

Where, Wf and Ws are the weights of the floating and settled microparticles.

Megha A Shah 17


2.1.4. Entrapment efficiency

The capture efficiency of the multi particulate or thepercent entrapment can be determined

by allowing washed multiparticulate to lyse. The lysate is then subjected to the

determination of active constituents as per monograph requirement. The percent

encapsulation efficiency is calculated using equation:

% Entrapment = Actual content/Theoretical content

x 100

2.1.5. In-vitro drug release studies

The release rate of floating microspheres is determined using United States

Pharmacopoeia (USP) XXIII basket type dissolution apparatus. A weighed amount of

floating microspheres equivalent to 50 mg drug is filled into a hard gelatin capsule (No. 0)

and placed in the basket of dissolution rate apparatus. 500 ml of the SGF containing

0.02% w/v of Tween 20 is used as the dissolution medium. The dissolution fluid is

maintained at 37 ± 1° at a rotation speed of 100 rpm. Perfect sink conditions prevailed

during the drug release study. 5ml samples are withdrawn at each 30 min interval, passed

through a 0.25 µm membrane filter (Millipore), and analyzed using LC/MS/MS method

to determine the concentration present in the dissolution medium. The initial volume of

the dissolution fluid is maintained by adding 5 ml of fresh dissolution fluid after each

withdrawal.

2.1.6. Fourier trans form –infrared spectroscopy: (FTIR)

FTIR is used to determine the degradation of the polymeric matrix of the carrier system,

and also interaction between drug and polymer system if present.

Megha A Shah 18


3. INTRODUCTION TO DRUG (12-15):

3.1 CHARACTERIZATION:

Alfuzosin hydrochloride is an alpha-adrenergic blocker used to treat benign prostatic

hyperplasia (BPH). It works by relaxing the muscles in the prostate and bladder neck,

making it easier to urinate.

Structure of Alfuzosin HCl:

IUPAC Name: (R,S)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)

methylamino]propyl]tetrahydro-2furancarboxamide

hydrochloride.

Empirical formula : C19H27N5O4

Molecular weight: 425.9gm/mol

Melting point: 240°C

Solubility : freely soluble in water, sparingly soluble in alcohol, and

practically insoluble in dichloromethane.

Category : Antihypertensive Agents

Adrenergic alpha-Antagonists

Storage : Preserve in tight containers. Protect from light and

humidity. And store at room temerature.

Megha A Shah 19


3.2 CLINICAL PHARMACOLOGY :

3.2.1 Mechanism of action:

Alfuzosin is a non-subtype specific alpha(1)-adrenergic blocking agent that exhibits

selectivity for alpha(1)-adrenergic receptors in the lower urinary tract. Inhibition of these

adrenoreceptors leads to the relaxation of smooth muscle in the bladder neck and

prostate, resulting in the improvement in urine flow and a reduction in symptoms in

benign prostate hyperplasia. Alfuzosin also inhibits the vasoconstrictor effect of

circulating and locally released catecholamines (epinephrine and norepinephrine),

resulting in peripheral vasodilation.

3.2.2 Pharmacodynamics:

Alfuzosin is a quinazoline-derivative alpha-adrenergic blocking agent used to treat

hypertension and benign prostatic hyperplasia. Accordingly, alfuzosin is a selective

inhibitor of the alpha(1) subtype of alpha adrenergic receptors. In the human prostate,

alfuzosin antagonizes phenylephrine (alpha(1) agonist)-induced contractions, in vitro, and

binds with high affinity to the alpha1a adrenoceptor, which is thought to be the

predominant functional type in the prostate. Studies in normal human subjects have

shown that alfuzosin competitively antagonized the pressor effects of phenylephrine (an

alpha(1) agonist) and the systolic pressor effect of norepinephrine. The antihypertensive

effect of alfuzosin results from a decrease in systemic vascular resistance and the parent

compound alfuzosin is primarily responsible for the antihypertensive activity.

3.2.3 Pharmacokinetics:

Absorption: AlfuzosinHCl is rapidly absorbed and quick on set of action. Absorption is

50% lower under fasting conditions.

Distribution: AlfuzosinHCl has protein binding 82-90%; volume of distibution is 3.2

L/kg.

Metabolism:

Hepatic.Alfuzosin undergoes extensive metabolism by the liver, with only 11% of the

administered dose excreted unchanged in the urine. Alfuzosin is metabolized by three

metabolic pathways: oxidation, O-demethylations, and N-dealkylation. The metabolites

are not pharmacologically active. CYP3A4 is the principal hepatic enzyme isoform

involved in its metabolism.

Megha A Shah 20


Elimination half life : 10 hours

3.3 SIDE EFFECTS:

Nervous system

Nervous system side effects are among the most commonly reported and include

dizziness (5.7%), headache (3%) and fatigue (2.7%).

Respiratory

Respiratory side effects have included upper respiratory tract infection (3%), bronchitis,

sinusitis and pharyngitis.

Cardiovascular

Cardiovascular side effects reported possibly due to orthostasis have included dizziness

(5.7%), hypotension or postural hypotension (0.4%) and syncope (0.2 %). In addition,

tachycardia, chest pain, and angina pectoris in patients with preexisting coronary artery

disease have been reported in post marketing experience.

OtherOther side effects have included pain and rash. In addition, flushing, edema, angioedema,

pruritus, and rhinitis have been reported in postmarketing experience.

GastrointestinalGastrointestinal side effects have included abdominal pain, dyspepsia, constipation and

nausea. Diarrhea has been reported in postmarketing experience.

GenitourinaryGenitourinary effects have included impotence and priapism.OcularOcular side effects including Intraoperative Floppy Iris Syndrome (IFIS) have been

observed in some patients undergoing phacoemulsification cataract surgery while being

treated with alpha-1 blockers.

Megha A Shah 21


3.4 PRECAUTIONS :

Before taking Alfuzosin hydrochloride, Apollo research medical teams if you are

allergic to it; or to other alpha blockers such as doxazosin, prazosin, terazosin; or

if you have any other allergies. This product may contain inactive ingredients,

which can cause allergic reactions or other problems. Talk to your pharmacist for

more details.

Before using this medication, tell your doctor or pharmacist your medical history,

especially of: other prostate gland problems (e.g., prostate cancer), heart problems

(e.g., angina, low blood pressure), kidney disease.

Alfuzosinhydrochloride, may cause a condition that affects the heart rhythm (QT

prolongation). QT prolongation can infrequently result in serious (rarely fatal)

fast/irregular heartbeat and other symptoms (such as severe dizziness, fainting)

that require immediate medical attention. The risk of QT prolongation may be

increased if you have certain medical conditions or are taking other drugs that

may affect the heart rhythm.

Before using Alfuzosin hydrochloride,, tell your doctor or pharmacist if you have

any of the following conditions: certain heart problems (heart failure, slow

heartbeat, QT prolongation in the EKG), family history of certain heart problems

(QT prolongation in the EKG, sudden cardiac death).

Low levels of potassium or magnesium in the blood may also increase your risk

of QT prolongation. This risk may increase if you use certain drugs (such as

diuretics/"water pills") or if you have conditions such as severe sweating,

diarrhea, or vomiting. Talk to your doctor about using Alfuzosin hydrochloride,

safely.

Megha A Shah 22


3.5 MARKETED FORMULATION:

Brand Name Composition Company

AFDURA tab Alfuzosinhcl 10mg SUN PHARMA

ALFOO tab Alfuzosinhcl 10mg DR. REDDY'S LAB

ALFUSIN tab Alfuzosinhcl 10mg CIPLA

ALFUSIN D tab Alfuzosinhcl 10mg,

dutasteride 0.5mg

CIPLA

FLOTRAL tab Alfuzosinhcl 10mg RANBAXY

FUAL tab Alfuzosinhcl 10mg ALKEM

FULFLO tab Alfuzosinhcl 10mg ALEMBIC

XEFLO tab Alfuzosinhcl 10mg SUN

Megha A Shah 23


4. INTRODUCTION TO DOSAGE FORM:

EUDRAGIT S 100Commercial form

EUDRAGIT® S 100 is Methacrylic Acid - Methyl Methacrylate Copolymer and

preferably used as a sustained release polymer.

Chemical structureEUDRAGIT® S 100 is an anionic copolymer based on methacrylic acid and methyl

methacrylate. The ratio of the free carboxyl groups to the ester groups is approx. 1:2.

Characters

DescriptionSolid substances. White powders with a faint characteristic odour

Solubility

1 g of EUDRAGIT® S 100 dissolves in 7 g methanol, ethanol, in aqueous isopropyl

alcohol and acetone (containing approx. 3 % water), as well as in 1 N sodium

hydroxide to give clear to slightly cloudy solutions. EUDRAGIT S 100 is practically

insoluble in ethyl acetate, methylene chloride, petroleum ether and water.

Molecular weight is approx. 135,000.

Particle size

At least 95 % less than 0.25 mm. The particle size is determined according to Ph. Eur. 2.1.4 or USP <811>.

Film formation

When the Test solution is poured onto a glass plate, a clear film forms upon

evaporation of the solvent.

Storage

Protect from warm temperatures (USP, General

Notices). Protect against moisture.

Megha A Shah 24


Viscosity / Apparent viscosity

EUDRAGIT® S 100: 50 - 200 mPa. The viscosity of the Test solution is determined by means of a Brookfield viscometer (spindle 1 / 30 rpm / 20 °C).EUDRAGIT® S 100: 22 - 52 mm2 / s according to JPE.

Density:- 0.831 - 0.852 g/cm3.

Identity testing

First identificationThe material must comply with the tests for "Assay" and "Viscosity / Apparent

viscosity."

Second identification

IR spectroscopy on a dry film approx. 15 µm thick. To obtain the film, a few drops

of the Test solution are placed on a crystal disc (KBr, NaCl) and dried in vacuo

for about 2 hours at 70 °C. The figure shows the characteristic bands of the C=O

vibrations of the carboxylic acid groups at 1,705 cm-1 and of the esterified

carboxyl groups at 1,730 cm-1, as well as further ester vibrations at 1,150 - 1,160,

1,190 - 1,195 and 1,250 - 1,275 cm-1. The wide absorption range of the associated

OH groups between 2,500 and 3,500 cm-1 is superimposed by CHX vibrations at

2,900 - 3,000 cm-1. Further CHX vibrations can be discerned at 1,385 - 1,390, 1,450

and 1,485 cm-1.

Megha A Shah 25


Hypromellose

Nonproprietary Names

BP: Hypromellose

JP: Hydroxypropylmethylcellulose

PhEur: Hypromellosum

Synonyms

Benecel MHPC; E464; hydroxypropyl methylcellulose; HPMC; Methocel;

methylcellulose propylene glycol ether; methyl hydroxypropylcellulose; Metolose;

Chemical Name and CAS Registry Number

Cellulose hydroxypropyl methyl ether [9004-65-3]

Empirical Formula and Molecular Weight

The PhEur 2005 describes hypromellose as a partly O-methylated and O-(2- hydroxyl

propylated) cellulose. It is available in several grades that vary in viscosity and extent of

substitution. Grades may be distinguished by appending a number indicative of the

apparent viscosity, in mPa s, of a 2% w/w aqueous solution at 20°C. Hypromellose

defined in the USP 28 specifies the substitution type by appending a four-digit number to

the non proprietary name: e.g., hypromellose 1828. The first two digits refer to the

approximate percentage content of the methoxy group (OCH3). The second two digits

refer to the approximate percentage content of the hydroxypropoxy group

(OCH2CH(OH)CH3),calculated on a dried basis. It contains methoxy and

hydroxypropoxy group. Molecular weight is approximately 10 000–1 500 000. The JP

2001 includes three separate monographs for hypromellose: hydroxyl propylmethyl

cellulose 2208, 2906, and 2910, respectively.

Structural Formula

where R is H, CH3, or CH3CH(OH)CH2

Megha A Shah 26


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

formulations.

In oral products, hypromellose is primarily used as a tablet binder,1 in film-coating,2–7

and as a matrix for use in extended-release tablet formulations.8–12 Concentrations

between 2% and 5% w/w may be used as a binder in either wet- or dry-granulation

processes. High-viscosity grades may be used to retard the release of drugs from a matrix

at levels of 10–80% w/w in tablets and capsules.

Depending upon the viscosity grade, concentrations of 2–20% w/w are used for film-

forming solutions to film-coat tablets. Lower-viscosity grades are used in aqueous film-

coating solutions, while higher-viscosity grades are used with organic solvents. Examples

of film coating materials that are commercially available include AnyCoat C, Spectracel,

and Pharmacoat.

Hypromellose is also used as a suspending and thickening agent in topical formulations.

Compared with methylcellulose, hypromellose produces aqueous solutions of greater

clarity, with fewer undispersed fibers present, and is therefore preferred in formulations

for ophthalmic use. Hypromellose at concentrations between 0.45–1.0% w/w may be

added as a thickening agent to vehicles for eye drops and artificial tear solutions.

Hypromellose is also used as an emulsifier, suspending agent, and stabilizing agent in

topical gels and ointments. As a protective colloid, it can prevent droplets and particles

from coalescing or agglomerating, thus inhibiting the formation of sediments.

In addition, hypromellose is used in the manufacture of capsules, as an adhesive in plastic

bandages, and as a wetting agent for hard contact lenses. It is also widely used in

cosmetics and food products.

8. Description

Hypromellose is an odorless and tasteless, white or creamy-white fibrous or granular

powder.

Megha A Shah 27


9. Typical Properties

Acidity/alkalinity:

pH = 5.5–8.0 for a 1% w/w aqueous solution.

Ash:

1.5–3.0%, depending upon the grade and viscosity.

Autoignition temperature:

360°C

Melting point:

browns at 190–200°C; chars at 225–230°C. Glass transition temperature is 170–180°C.

Moisture content

hypromellose absorbs moisture from the atmosphere; the amount of water absorbed

depends upon the initial moisture content and the temperature and relative humidity of

the surrounding air

Solubility:

soluble in cold water, forming a viscous colloidal solution; practically insoluble in

chloroform, ethanol (95%), and ether, but soluble in mixtures of ethanol and

dichloromethane, mixtures of methanol and dichloromethane, and mixtures of water and

alcohol. Certain grades of hypromellose are soluble in aqueous acetone solutions,

mixtures of dichloromethane and propan-2-ol, and other organic solvents.

Viscosity (dynamic):

A wide range of viscosity types are commercially available. Aqueous solutions are most

commonly prepared, although hypromellose may also be dissolved in aqueous alcohols

such as ethanol and propan-2-ol provided the alcohol content is less than 50% w/w.

Dichloromethane and ethanol mixtures may also be used to prepare viscous hypromellose

solutions. Solutions prepared using organic solvents tend to be more viscous; increasing

concentration also produces more viscous solutions.

To prepare an aqueous solution, it is recommended that hypromellose is dispersed and

thoroughly hydrated in about 20–30% of the required amount of water. The water should

be vigorously stirred and heated to 80–90°C, then the remaining hypromellose should be

added.Sufficient cold water should then be added to produce the required volume.

Megha A Shah 28


When a water-miscible organic solvent such as ethanol (95%), glycol, or mixtures of

ethanol and dichloromethane are used, the hypromellose should first be dispersed into the

organic solvent, at a ratio of 5–8 parts of solvent to 1 part of hypromellose. Cold water is

then added to produce the required volume.

Typical viscosity values for 2% (w/v) aqueous solutions of Methocel (Dow Chemical

Co.). Viscosities measured at 20°C

Methocel product Nominal viscosity (mPa s)

Methocel K100 Premium

LVEP

100

Methocel K4M Premium 4000

Methocel K15M Premium 15 000

Methocel K100M Premium 100 000

Methocel E4M Premium 4000

Methocel F50 Premium 50

Methocel E10M Premium CR 10 000

Methocel E3 Premium LV 3





Metolose 60SH 50, 4000, 10 000

Metolose 65SH 50, 400, 1500, 4000

Metolose 90SH 100, 400, 4000, 15 000

10. Stability and Storage Conditions

Hypromellose powder is a stable material, although it is hygroscopic after drying.

Solutions are stable at pH 3–11. Increasing temperature reduces the viscosity of solutions.

Hypromellose undergoes a reversible sol–gel transformation upon heating and cooling,

respectively. The gel point is 50–90°C, depending upon the grade and concentration of

material.

Megha A Shah 29


Aqueous solutions are comparatively enzyme-resistant, providing good viscosity stability

during long-term storage. However, aqueous solutions are liable to microbial spoilage

and should be preserved with an antimicrobial preservative: when hypromellose is used

as a viscosity-increasing agent in ophthalmic solutions, benzalkonium chloride is

commonly used as the preservative. Aqueous solutions may also be sterilized by

autoclaving; the coagulated polymer must be redispersed on cooling by shaking.

Hypromellose powder should be stored in a well-closed container, in a cool, dry place.

11. 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.

12. Method of Manufacture

A purified form of cellulose, obtained from cotton linters or wood pulp, is reacted with

sodium hydroxide solution to produce a swollen alkali cellulose that is chemically more

reactive than untreated cellulose. The alkali cellulose is then treated with chloromethane

and propylene oxide to produce methyl hydroxypropyl ethers of cellulose. The fibrous

reaction product is then purified and ground to a fine, uniform powder or granules.

13. Safety

Hypromellose is widely used as an excipient in oral and topical pharmaceutical

formulations.

It is also used extensively in cosmetics and food products.

Hypromellose is generally regarded as a nontoxic and nonirritant material, although

excessive oral consumption may have a laxative effect. The WHO has not specified an

acceptable daily intake for hypromellose since the levels consumed were not considered

to represent a hazard to health.

LD50 (mouse, IP): 5 g/kg

LD50 (rat, IP): 5.2 g/kg

14. Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material

handled. Hypromellose dust may be irritant to the eyes and eye protection is

Megha A Shah 30


recommended. Excessive dust generation should be avoided to minimize the risks of

explosion. Hypromellose is combustible.

15. Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA

Inactive Ingredients Guide (ophthalmic preparations; oral capsules, suspensions, syrups,

and tablets; topical and vaginal preparations). Included in nonparenteral medicines

licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal

Ingredients

Megha A Shah 31


5. LITERATURE REVIEW ON FLOATING MICROSPHERES :

Najmuddin M et al 17prepared floating microspheres of Ketoprofen by using Emulsion

solvent diffusion method using acrylic polymer like Eudragit L100 and Eudragit S100

with different drug:polymerratio.The formulation that contain drug :polymer (1:2) gives

excellent Micromericproperties,yield of microspheres, incorporation

efficiency,Invitrobuyoncy, and highest in vitro drug release in sustaind manner with

constant fashion over extended period of time for 12 hours.

KapoorDevesh et al 18 developed floating microspheres of Captopril by using Solvent

evaporation method using different ratio of HPMC K4M and stirring speed of stirrer are

taken as independent variables in factorial design. It was observed that increase in

polymer concentration gives better formulation.from study concluded that HPMC K4M

can give better drug entrapment efficiency with improved In vitro drug release.

GhandhiNishant S. et al 19 developed Microballons of Piogitazone using Eudragit S100.

The concentration of Eudragit S-100 had significant impact on drug entrapment

efficiency and particle size. Evaluation of formulations, chosen as optimal from grid

searches, indicated that the formulation that contain (Polymer: drug ratio 2.84:1 and

stirring speed: 393 rpm) fulfilled maximum requisites because of better drug entrapment

efficiency, sustained release of the drug and optimum particle size.

Sarrof Rama et al20 developed oral in situgel ofMetformin Hydrochloride using various

concentration of Sodium alginate and Calcium carbonate as gas generating agent. Sodium

alginate which forms a gel when it comes in contact with simulated gastric fluid. The

formulation (1.25% sodium alginate, 3.75% Metformin, 1.5% calcium carbonate, 2.5%

sodium citrate) showed optimum drug release and the release was 90 % in 8 hours.

J Josephine LJ et al 21prepared Stavudine loaded floating microspheres using polymer

Eudragit RS100 as rate controlling membrane. The floating microspheres prepared were

found to be spherical and free flowing. The formulated floating microspheres remained

buoyant for more than 12h.

Dubey Manish et al 22 prepare floating microspheres of Metformin Hydrochloride using

hydroxy propyl methyl cellulose (HPMC) and Eudragit RS100 polymers by emulsion

Megha A Shah 32


solvent evaporation technique. The kinetic study of prepared microspheresshowed

controlled drug release by matrix diffusion Process with zero order release rate kinetics

with good stability.

Jessyshaji et al 23 prepared floating pulsatile microsphers of Aceclofenacintende for

chronopharmacotherapy. The microspheres were prepared by using Eudragit S100 and

Eudragit L100 using emulsion solvent evaporation method. Prepared microspheres give

better buyoncy in stomach with improved lag time and after that it gives immediate drug

release by bursting effect.

KamathShwetha S. et al 24 prepared Floating microspheres of Rabeprazole sodium by

using HPMC K15M and Ethyl cellulose as a polymer. The prepared microspheres gives

better buyoncy, particle size of microspheres with high drug entrapment efficiency. From

study concluded that by using HPMC K15M gives better micrometric properties,

entrapment efficiency and In vitro drug release as compared to Ethyl cellulose.

DurgavaleAbhijeet A. et al 25 developed floating microspheres using Gas forming agent

and also HPMC K4M and Ethyl cellulose. The prepared microsphere exhibited

prolonged drug release (~ 12 hr) and remained buoyant for > 12 hr. Due to gas forming

agent like NaHCO3 and CaCO3 there is increase in drug entrapment efficiency during

process. In general, CaCO3 formed smaller and stronger floating beads than

NaHCO3.From study, It was demonstrated that although CaCO3 is a less effective gas-

forming agent than NaHCO3.

Paul Swati et al 26 prepared sodium alginate floating pellets of Metronidazole using

HPMC K4M and HPMC K100LV as polymer. By using Extrusion spherinization

prepared pellets gives better floating properties and improved bioavailability if srug.

From study concluded that increasing polymer concentration to an optimum level, the

release rate (23.18%) of metronidazole was satisfactory but further increase causes

decrease of metronidazole release.

Patel Gaurang et al 3studied Floaltingmicrosphers as a novel tool for H2 recepterbloker.

He applied different mieroencapsulation approaches and also concluded that multiple

unit dosage form give uniform drug release as well as high surface area to volume

Megha A Shah 33


ratio.compared to single unit dosage fom. Also Microspheres are applicable for both oral

as well as parentral route.

Virendra Kumar Dhakar et al 35developed floating, pulsatile, multiparticulate of

aceclofenac using polymer of low methoxylated pectin, sodium alginate and gellan gum

and combination of them. Cross-linked beads were prepared by using above polymers by

acid base reaction during ionotropic gelation..Drug loaded multiparticulates were

subjected to various characterization and evaluation parameters like entrapment

efficiency, buoyancy study, surface topography. From the above evaluation studies, low

methoxylated beads contain high entrapment efficiency with about 90% drug release.

Mowafaq M. Ghareebet al36 prepared floating beads of Cinnarizine by the emulsion–

gelation method usingdifferent concentrations of sodium alginate and calcium chloride

and their influence on beads uniformity, buoyancy, and in vitro drug release was studied.

The results indicated formula B7 contain 3% w/v sodium alginate, 15% v/v oil and 0.1

M calcium chloride, showed a higher similarity factor (f2 =70.1) of CNZ release in

comparison to release from standard gastroretentive sustained release floating cinnarizine

tablet with good floating over duration of more than 12 hours.

Shashikant D. Barhate et al 37Formulated and evaluated of controlled release

metronidazole floating alginate beads using natural polymersby ionotropic gelation

method for the treatment of H. pylori. The optimized coating composition was achieved

with 0.9% chitosan, 1.5% k-carragennan and 1.52% HPMC E5. In vitro dissolution study

of factorial batches showed zero-order drug release.

Tarique Khan et al 38formulated & evaluated floating tablet of diltiazem HCl using

different concentrations ofpolymer (sodium carboxy methyl cellulose or hydroxyl propyl

methyl cellulose K4M, K15M) & different concentration of effervescent agents. The

formulation D4 shows 99% drug release at the end of 12 h in vitro and floating lag time

was 30 sec and tablet remained buoyant throughout studies.

Shiva Kumar Yellanki et al 39prepared Floating Alginate Beads of Riboflavinusing

different weight ratios of gas‐forming agent and sodium alginate.The formulation C3

exhibited the optimum sustained release of Riboflavin over a period of at least 10 h., with

excellent floating properties.From above studies it is concluded that floating alginate

Megha A Shah 34


microbeads can be a suitable approach to improve oral bioavailability of drugshaving

narrow absorption window in stomach.

Masareddy RS et al 40 Developed Metformin Hcl Loaded Sodium Alginate Floating

Microcapsules Prepared by Ionotropic Gelation Technique with sodium bicarbonate as

gas forming agent,swellable polymers Hydroxy propyl Methylcellulose (HPMC E50),

Ethyl cellulose(EC) and calcium chloride gelling agent.All formulations possessed good

floating properties with total floating time more than 12 hrs ,spherical, good free flowing

high entrapment efficiency.

Megha A Shah 35


6. LITERATURE REVIEW ON ALFUZOSIN HCl :

LeelaManasa K et al 47 prepared Oro Dispersible tablet of Alfuzosin Hydrochloride by

direct compression and sublimation methods with a view to enhance patient compliance.

In these methods, varying concentrations of crospovidone, sodium starch glycolate and

croscarmellose sodium of 3.3, 6.6 and 10% w/w were used, along with camphor used as

subliming agent sublimation method In formulation containing 10% w/w Crospovidone

emerged as the overall best formulation (t50%1.79 and 1.21 minutes) based on drug

release characteristic in pH 6.8 phosphate buffer.

Chandana B et al 48prepared alfuzosin extended release (ER) tablets using

hydroxypropylmethyl cellulose (HPMC) and ethyl cellulose. Seven different

formulations were developed by wet granulation method using HPMC K100M and EC

7cps as polymers. All the formulations were evaluated for their micromeritic properties

such as compressibility index, Hauser’s ratio and flow properties. Dissolution studies of

showed that formulation F7 released 96% of drug at 20 h time interval. From the results,

it was shown that release followed first order kinetics.

Patil Sanjay B et al 49prepared sustained release floating pellets of alfuzosin

hydrochloride which has narrow absorption window in proximal intestine to improve

patient compliance and therapeutic efficacy in the treatment of benign prostatic

hyperplasia.The system was designed to provide drug loaded pellets coated with three

successive coatings over Celphere® (microcrystalline cellulose pellets) – drug layer,

effervescent layer (HPMC and sodium bicarbonate) and gas entrapped polymeric

membrane (Kollicoat® SR 30D).optimal formulation comprising of Kollicoat® SR 30D

(10%) and HPMC:sodium bicarbonate (1:4) was identified to provide desired values for

FLT of 4.16 min and percentage drug released at a 10 h (92.85%).

Megha A Shah 36


7. EXPERIMENT WORK

Materials Used In Present Investigations

Table 7.1 Materials used in present investigations

Excipients Source

Alfuzosin HCl (drug) Sun pharmaceutical pvt.ltd.

Eudragit S 100 Lesar chemicals,Ahmedabad.

Ethocel 20cps, 45cps Colorcon Asia Pvt. Ltd., Goa

HPMC K 100M Colorcon Asia Pvt. Ltd., Goa

Span 80 Chemdyes corporation

Tween 80 Finar chemicals ltd,Mumbai.

Dichloromethane Finar chemicals ltd,Mumbai.

Methanol Finar chemicals ltd,Mumbai.

Ethanol Finar chemicals ltd,Mumbai.

Liquid Paraffin Finar chemicals ltd,Mumbai.

Instruments Used In Present Investigations

Table 7.2 instruments used in present investigations

Instrument Supplier

UV-VIS double beam

Spectrophotometer

Shimadzu UV-1601, Kyoto,

Japan.

Analytical balance Shimadzu, Japan.

Overhead stirrer Remi Motors Ltd. Mumbai.

Dissolution test TDT-06T apparatus Electrolab, Mumbai, India.

FTIR Shimadzu, Japan.

7.1 PREFORMULATION STUDY

Preformulation can be defined as investigation of physical and chemical properties of

drug substance alone and when combined with excipients.

Megha A Shah 37


Preformulation studies are the first step in the rational development of dosage form of a

drug substance. The objectives of Preformulation studies are to develop a portfolio of

information about the drug substance, so that this information is useful to develop

formulation.

Preformulation studies are designed to identify those physicochemical properties and

excipients that may influence the formulation design, method of manufacture,

pharmacokinetic and biopharmaceutical properties of the resulting product.

The following test were performed for preformulation study:-

A.Physical State

C.Solubility

D.Melting Point

7.1.1Characterization of Alfuzosin HCl

Description: white to off-white crystalline powder

Identification: IR spectroscopy -Determined by infrared absorption spectrophotometry.Compare the spectrum with that obtained with the reference spectrum of Alfuzosin HCl.

45060075090010501200135015001650180019502400270030003300360039001/cm

10

20

30

40

50

60

70

80

%T

Alfuzocin

UV absorption spectroscopy – Standard Stock solution of Alfuzosin HCl was scanned for absorption between 200-400 nm by means of double beam UV visible spectrophotometer.

Alfuzosin HCl exhibited UV Absorption maxima at 244nm( λ max)0.1 N HCL.

Megha A Shah 38


Solubility:freely soluble in water, sparingly soluble in alcohol, and practically insoluble in dichloromethane.

Melting point:The melting point of Alfuzosin HCl was found out by capillary method using Thiele’s tube melting point apparatus and was compared with the literature survey.

Melting range: 235 to 240°C.

Figure 7.1: UV spectra of Alfuzosin HCl in 0.1N HCl.

7.1.2 Drug Excipient Compatibility Study

Drug- excipients interactions play a vital role in the release of drug from formulation. Fourier transform infrared spectroscopy has been used to study the physical and chemical interactions between drug and the excipients used. Fourier transform infrared (FTIR) spectra of Alfuzosin HCl, Eudragit S100, HPMC K100 M were recorded using KBr mixing method on FTIR instrument of the institute (FTIR-8400S, Shimadzu, Kyoto, Japan).

7.2 METHOD OF ANALYSIS OF DRUG

7.2.1 PREPARATION OF REAGENTS

Preparation of 0.1 N HCl

Megha A Shah 39


Measure accurately 8.5 ml of concentrated hydrochloric acid using 10 ml pipette. Dilute it up to 1000 ml with distilled water in 1000 ml volumetric flask.

Preparation of standard calibration curve for Alfuzosin HCl in 0.1 N HCl

Accurately weighed 100 mg Alfuzosin HCl was transferred to 100 ml volumetric flask and was dissolved in 20 ml 0.1N Hydrochloric acid. The volume was made up to the mark with 0.1N hydrochloric acid to prepare a stock solution of 1000 µg/ml (SS-1). From this SS-2 was prepared containing 100µg/ml. The above stock solution (SS-2) was further diluted with 0.1 N Hydrochloric acid to get the concentration of Alfuzosin HCl1,2,3,4,5,6 and 7 µg/ml.. The absorbance of the solutions was measured against 0.1 N HCl as a blank at 244 nm using double beam UV visible spectrophotometer. The graph of absorbance v/s concentration (mg/ml) was plotted and data was subjected to linear regression analysis in Microsoft Excel®. The results of standard curve preparation are shown in Table 7.1, and Figure 7.3.

Table 7.1: Standard curve of Alfuzosin HCl in 0.1 N HCl at 244nm.

Megha A Shah 40

Concentration(mg/ml)

Absorbance

0

1

2

3

4

5

6

7

0

0.148

0.274

0.383

0.490

0.626

0.718

0.820

Correlation coefficient = 0.996

Absorbance = = 0.116 × concentration + 0.026


Figure 7.2: Standard curve of Alfuzosin HCl in 0.1 N HCl at 244 nm.

7.3 PRELIMINARY SCREENING

7.3.1 Selection of polymer

Review of literature reveal that Ethyl cellulose ( 20 cps, 45 cps), Polymethacrylates

(Eudragits) like Eudragit S 100, Eudragit RS 100 and Methocel are used for the

formulation of Floating microspheres for sustained release of drug.

7.3.2 Preparation of preliminary batches of Alfuzosin HCL Floaing Microspheres:

Microspheres were prepared by Emulsion solvent evaporation method. Alfuzosin HCl

and Different polymers with drug to polymer ratio ( 1:2,1:3, 1:4, 1:5, 1:6, 1:9) are

dissolved in organic solvent like Dichloromethane : Eyhanol (1:1) or Dichloromethane :

methanol (1:2) to get dispersed phase. When solvent with dielectric constant 10 or above,

non polar Liquid paraffin is prepared as disperingmedium.mixture of drug and polymer

was poured in 200 ml Liquid paraffin containing Span 80 as droplet stabilizer and stirred

at 900 rpm for 3 hr. During this time solvent was completely removed by evaporation.

The solidified microspheres were filtered, washed five times with 20ml petroleum ether,

dried under vaccum at a room temperature for 12 hr.

FORMULATION FORMULATION BATCH CODE

Megha A Shah 41

0 1 2 3 4 5 6 7 80

0.10.20.30.40.50.60.70.80.9

f(x) = 0.116107142857143 x + 0.0259999999999999R² = 0.996853092251707

Concentration (µg/ml)

Abso

rban

ce


INGREDIENTS(mg) F1 F2 F3 F4 F5 F6 F7

Alfuzosin HCl 100 100 100 100 100 100 100

Ethocel 20 Cps 400 - - - - - -

Ethocel 45 Cps - 400 - - - - -

Eudragit RS - - 500 - - - -

Eudragit S 100 - - - 450 550 810

Methocel K 100M - - - 50 50 90

Dichloromethane (ml ) 10 10 10 5 5 5 5

Ethanol 10 10 10 - - - -

Methanol - - - 10 10 10 10

Span 80 - - 0.25% 0.25% 0.25% 0.25% 0.25%

Tween 80 0.25% 0.25%

Table 7.2: Formulation of preliminary batches

7.4 Evaluation parameter of Microspheres:

Particle Size Analysis:-

The size of microparticles of each batch was measured by using a calibrated micrometer

attached with a microscope and the average diameter was calculated.

Quantitative analysis of Alfuzosin HCl contents in hollow microspheres:- 50mg of hollow microspheres were taken and 50 ml of methanol was added on it and

after this 1 ml of solution was taken in a 10 ml of volumetric flask and volume was made

up to 10 ml using methanol. An absorbance of the solution was assayed by UV

spectrophotometer at wavelength 244 nm, using methanol as a blank. An amount of

Alfuzosin HCl was calculated from the calibration curve. The analysis was performed in

triplicate. The percent of production yield of the hollow microsphere, percent of drug

content, percent of theoretical content, and percentage of drug entrapment were

calculated from the following equation:-

Megha A Shah 42


% Yield = Total weight of microspheres x 100 Total weight of drug and Polymers

% Drug Loading = Quantity of drug present in microspheres x 100 Weight of micosphers

% drug entrapment efficiency = Quantity of drug encapsulated in microspheres x 100

Total quantity of drug utilized for encapsulation

Floating Ability :-

First 50 mg of the hollow microspheres were placed in 50 ml beaker. Second, 20 ml of

0.1 M HCL containing 0.02% Tween 20 were added and stirred with a magnetic stirrer at

37 ± 0.5 0C. Floating microspheres were collected after 24 hr. The experiments were

performed in triplicate and the percentage floating of the hollow microspheres was

calculated from the following equation:-

% floating of hollow microspheres = Weight of floating microspheres x 100

initial weight of hollow microspheres

In Vitro Dissolution Study

The release profile of the microspheres were studied in 0.1 N HCl (pH 1.2) using the USP

Type II Apparatus (Basket type) Method. An accurately weighed amount of microspheres

equivalent to 10 mg of Alfuzosin HCl was added to 900 ml of dissolution medium at

37±0.5ºC and stirred at 50 rpm.Samples of 5 ml were removed and replaced with fresh

medium at appropriate time intervals and assayed spectrophotometrically at 244 nm.

Megha A Shah 43


7.5 RESULTS AND DISCUSSION

7.5.1PREFORMULATION STUDY

7.5.1.1 Drug Excipient Compatibility Study

Drug- excipients interactions play a vital role in the release of drug from formulation. Fourier transform infrared spectroscopy has been used to study the physical and chemical interactions between drug and the excipients used.

Megha A Shah 44


7.6.2 PRELIMINARY SCREENING7.6.2.1 Selection of polymer

In present investigation attempt was made to prepare formulation of Alfuzosin HCl Microspheres using Ethyl cellulose ( 20 cps, 45 cps), Polymethacrylates (Eudragits) like Eudragit S 100 and Methocel K 100M usin Emulsion solvent evaporation method.

In preliminary study, different batches were prepared as per the composition given in Table 7.2. All the batches were evaluated for in vitro dissolution study as per the procedure given in section 7.4. Different other evaluation parameters were also studied.

Parameters FORMULATION BATCH CODE

F1 F2 F3 F4 F5 F6

Drug Loading (%) 19.22 14.22 14.6 13.66 8.6

Drug Entrapment Efficiency (%)

91.88 66.84 78.11 90.70 68.45

% Yield 95.6 94 89.66 94.85 79.6

Floating time 7 hr 8 hr 8 hr 10 hr 12 hr

Table 7.3: Evaluation parameters of F1 to F6 for preliminary screening

Table 7.10: Cumulative percentage drug release (CPR) from tablets for preliminary screening

TIME

(hr)

CPR

F1 F2 F3 F4 F5 F6

0 0.00 0.00 0.00 0.00 0.00 0.00

1 87.88 89.44 66.93 57.28 56.11 31.57

2 98.91 93.03 83.95 68.25 62.79 35.76

3 108.59 107.61 90.41 76.62 69.01 40.78

4 92.24 92.03 75.76 42.84

5 94.41 93.86 78.14 49.54

6 102.59 98.04 91.3 60

Megha A Shah 45


7 97.68 72.95

8 84.94

9 92.87

10 96.01

11 102.15

12

13

14

15

16

Megha A Shah 46


7. FUTURE PLAN OF RESEARCH WORK

Phase-I: Analytical Method Development

Phase-II: Preformulation Study

Physical characteristics of drug

Organoleptic evaluation

Solubility

Determination of solubility

Phase-III: Formulation and Development.

Screening of the polymers for total and proportional amount for

desired drug release.

Study the effect of different fillers on the release of the drug.

Optimization of drug to polymer ratio and polymer to polymer

ratio.

In process Quality control tests & properties of Formulation.

I. Particle size determination

II. Drug entrapment efficiency

III. Percent yield

Phase-IV: Compatibility Study

Drug-excipient compatibility will be check by comparing FTIR spectra or DSC

thermo gram of pure drug and FTIR spectra or DSC thermo gram of the physical

mixture of drug and excipient.

Phase-V: In-Vitro Drug release study

Phase-VI: stability study

Megha A Shah 47


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