Principles Behind Controlled Release Dosage Biology Essay

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Control release dosage form (CRDF) is the one which delivers the therapeutic agents at a predetermined rate for a specified period of time. The basic principle behind the generation of controlled release dosage is to modify the pharmacokinetic and pharmacodynamic properties of a drug in such a way that which help to improve utility of a drug by maximum decrease in side effects and cure or control the disease in shortest period of time by using very less quantity of drug administered by most easiest way.

CRDF maintain drug plasma level between a maximum safe level and minimum effective level over the long period of time. Thus it is safe and also helps to reduce the frequency of drug administration. Products of this type have been formulated for oral, injectable and topical use. [1]

Classification of CRDF

Depending upon the manner of drug release and methods of preparation, these systems can be classified into following three main types -

1] Physical Systems:

(I) Diffusion-controlled systems

(A) Monolithic systems

- Dissolved drug

- Dispersed drug

- Porous system

- Hydrogel

- Biodegradable

(B) Reservoir System

- Constant activity

- Non-constant activity

- Unsteady-state

(II) Ion exchange resin system

(III) Osmotically controlled systems

- Micro porous osmotic pumps

- Push / pull systems

(IV) Hydrodynamically balanced systems

(V) Other physical systems (geometry)

2] Chemical Systems:

(I) Immobilization of drugs

(II) Prodrugs

3] Biological Systems:

(I) Gene Therapy [2]

Mechanism of Action of CRDF

The discussion of current project was limited only to oral controlled release formulations. These formulations are devices or dosage forms that controls the release of drug at the site of absorption.

The mechanism of controlled release is governed by following systems -

I. Diffusion controlled release

II. Chemically controlled release

III. Osmotically controlled release

IV. Barrier coating controlled release

V. Prodrugs.

Two types of diffusion controlled release systems are available. The first one is Matrix system and other one is Reservoir system. Current project was based on diffusion controlled release by Matrix system. In this system drug is homogeneously mixed with polymer either as microsphere conventional tablets or as nanosphere. When these systems come in contact with the medium (body fluid), the drug is released by diffusion mechanism. Here cross-linking density plays a vital role and is often utilized to control the release characterisation. [3]

Applications of CRDF

It is used when traditional injectable and oral dosage forms cannot be useful. Uses include -

Drug delivery to specific sites.

Drug delivery at controlled rate.

Delivery of two or more agents with single formulation.

Advantages of CRDF

Improved patient compliance by reducing frequency of drug administration.

Maximum utilisation of drug.

More uniform pharmacological effect.

Decrease in fluctuation in blood plasma level.

Remarkable reduction in side effects.

Disadvantages of CRDF

Poor in vitro - in vivo correlation.

Reduced flexibility in adjusting dosage regimen for physicians because it is already fixed by the dosage form design.

This form is not useful if the drug is having narrow therapeutic index.

Expensive formulation. [4]


Trade Names- fusidin, fusiwal, fusigen

Structure -

Chemical Name -

16 - (Acetyloxy)-3, 11-dihydroxy-29-normmara-17(20), 24-dien-21-oic acid sodium salt.

Molecular Formula -


Molecular Weight - 538.70

Category - It belongs to Antibacterial class. [5]

General Description -

It is a Sodium salt of fusidic acid which was obtained from a strain of the fungus Fusidium coccineum. [6] It is steroidal antibiotic from antibacterial class and it is highly active against most of the gram positive bacteria like Streptococci, Staphylococci and Corynebacteria. Sodium Fusidate is inactive against most of the gram negative bacteria.

Use -

It is used for the treatment of bone and joint infections. Also it is used in infections of skin and soft tissues.

Actions -

Pharmacological and pharmacokinetics.

Mechanism of Action -

Sodium Fusidate inhibits bacterial protein synthesis by interfering with amino acid transfer from aminoacyl- tRNA to protein on ribosomes. It shows bacteriostatic and/or bactericidal action.

Absorption -

It is very well absorbed orally. Oral tablets have almost 91% bioavailability.

Protein Binding -

It shows extensive protein binding (97-99%).

Distribution -

Drug is well distributed.

Metabolism -

It includes hydrogen fusidic acid, dicarboxylic ester/acid, 3-keto fusidic aid, glycol metabolite and a glucuronide fusidic acid.

Excretion -

Metabolic products excreted in bile. Minimal excretion through urine. Fusidic acid is excreted through faeces (20%).

Side effects -

It shows GI tract disturbances, especially jaundice, thrombophlebitis or venospasm.

Storage -

It should be stored in a temperature between 15 to 250 C. [7]


Structure -

The number and sequence of Mannwrolate and Glucuronate residues (as shown above) vary in the naturally occurring alginate.

Molecular Formula - (C6H7NaO6) n [8]

Structure of an alginic acid is quite complex and it forms a water soluble salt by replacing some of the hydrogen molecules by sodium of the carboxyl groups. [9]

General Description -

Sodium alginate is a naturally occurring polymer. It is a sodium salt of an alginic acid which is derived from selected varieties of natural brown sea weed, also known as algae.

Traditionally it is obtain as a pink colour powder. It has a mint like odour which is helpful for its use as a dental material. Sodium alginate forms a soluble alginate with water.

Setting Process -

For a good setting, correct mixing ratio of a sodium alginate and water is very essential. ..................................

Sodium alginate is a linear polymer and when it is mixed with water it forms a soluble alginate by dispersed molecules in water which reacts with calcium salts. This way polymerisation occurs by cross-linking of chains. These molecules attach with each other to form a network of fibrils which encloses water and other by-products. Final structure is looks like a gel.

Strength of the gel depends on following factors -

Strength of the gel is directly proportional to the number of fibrils.

Correct mixing method is vital for proper strength of the gel.

Gel gets weak if mixing time is long.

Powder and water ratio.

Normally at room temperature gelation time is 3-4 minutes but at mouth temperature, which is 370 C, the setting process is little quick. [10]

Applications -

For impression material in dental industry.

In food Industry it plays versatile role, like, it is used for gelling, thickening, stabilizing and film forming properties.

As thickening agent in dyeing and printing industry. [11]


High Performance Liquid Chromatography (HPLC) was before known as High Pressure Liquid Chromatography. HPLC is a technique for the separation of many compounds. It is most widely used analytical separation technique than any other technique because of its high sensitivity and quick response. It is used for accurate quantitative determination; it is applicable for separating volatile and non volatile materials. HPLC detectors can work continuously and can detect very small amounts. It has widespread applicability to the substances that are of prime interest to industry and to the many fields of science. Such materials include amino acids, antibiotics, steroids, drugs, nucleic acids, hydrocarbons, proteins, metals, organic species and most of the inorganic substances.

Principle -

The principle of HPLC lies around the general principle of chromatography. The separation of compounds is achieved with respect to the time spent by the component in liquid stationary phase. The equilibrium between the component and stationary phase occurs by adsorption, partitioning or by ion exchange.

Resolution is the effective separation of components from its mixture into discrete band. The resolving power of chromatographic column is directly proportional to length of theoretical plates and inversely proportional to the height of the theoretical plate.

The relation is given by the following equation -

N = L / H

Where, N = number f theoretical plates

L = Length of chromatographic column

H = Height of theoretical plate

Theoretical plate is the place where the sample is in equilibrium with stationary phase and mobile phase. The stationary phase in HPLC refers to the solid support contained within the column over which the mobile phase flows continuously. The mobile phase in HPLC is the solvent being continuously applied to the column. It is a carrier for the sample solution. [12, 13]

HPLC Techniques -

I] Based on Modes of Chromatography

Normal phase mode

Reverse phase mode

II] Based on Separation Principle

Ion Exchange chromatography

Ion pair chromatography

Adsorption chromatography

Gel permeation or Gel filtration chromatography

Chiral phase chromatography

III] Based on Scale Operation

Analytical HPLC

Preparative HPLC

IV] Based on Elution Technique

Isocratic separation

Gradient separation

V] Based on Type of Analysis

Qualitative analysis

Quantitative analysis

Types of HPLC Instrument -

I] Mobile phase reservoirs:

It is made up of a glass or stainless steel which contains 200 to 1000 ml of a solvent. To remove the dissolved gases usually oxygen and nitrogen, reservoirs are often equipped with degassers.

II] Pumping system:

Introduction of pumping system in HPLC is an integral aspect for quick separation. It should produce high pressure and maintain constant flow of the solvent through the columns. The important features of an ideal pumping system are -

It should generate pressure up to 6000 psi.

It gives pulse-free output.

Maintain a constant flow rate of solvent in between 0.1 to 10 ml/min.

Three types of pumps are used for HPLC.

Reciprocating pumps -

It is most commonly used pump in commercial available HPLC system due to its god properties. In reciprocating pump solvent is hold in a small chamber and pumped by the back and forth motion of a motor-driven piston. The advantages related to these pumps include their constant flow rates, high output pressure and small internal volume which hold small volume of solvent. Only one disadvantage is that it produces a pulsed flow. The pulsed flow cause unstable baseline and increase in noise. To minimise the pulsed flow pulse dampener is used.

Displacement pump -

It is a large syringe like chamber. It displaces a fixed volume of solvent from pump to the column by a plunger driven by motor. It produces pulse free output. The disadvantage related to this pump system is that it has limited amount of sample capacity and is inconvenient when solvent change is necessary.

Pneumatic pump -

In these pumps solvent or mobile phase is held in a collapsible container. The mobile phase is forced out with constant pressure when pressure is applied by a compressed gas. The advantage related to these pumps is they are inexpensive and produces pulse free flow. It has disadvantage of limited solvent capacity and useful only when pressure is below 2000 psi.

III] Sample injection system:

Introduction of accurate volume of sample is crucial for better precision of the liquid chromatographic measurements because overloading of the sample causes band broadening. In HPLC sample introduction is done either by sampling loop or by auto sampler.


Sample loop -

This sample injection system is used for manual mode operation. The sample loop is rotated and the sample is mixed with mobile phase. Then without any disturbance in the flow rate this sample is introduced into the column. By sample loop introduction of the very less volume of sample is also possible like 0.5 to 5µl.

Auto sampler -

This injection system is useful for large number of samples. This is also reduces the human error during sampling. In an auto sampler samples are arranged either in circular or rectangular way.

IV] Chromatographic column:

Analytical columns -

It is an essential part of a HPLC system. The HPLC columns are available in various sizes and packing. Normally the analytical columns used in HPLC are 10-30 cm in length and 4-10mm in internal diameter. The most common particle size for column packing is 5 or 10µm.

Guard column -

Normally this column is introduced before the analytical column. Guard column is used to prevent analytical column from contaminants and particulate matter in solvents. Therefore it helps to increase the life of expensive analytical column.

Types of column packings -

Porous - It is consist of porous microparticles having diameter ranging from 3 to 10µm. Microparticles are generally composed of silica ion-exchange resin r an alumina.

Pellicular - It contains non porous, spherical, glass or polymer beads with typical diameter of 30 t 40 µm. A thin layer of silica or an ion exchange resin is deposited on these particles. Now days these type of packings are used commonly for guard columns not for analytical columns.

V] Detectors:

High sensitivity and stability of the detector system in HPLC is crucial due to quantity of material applied to the column is frequently very small.

Characteristics of an ideal HPLC detector are -

God stability and reproducibility.

Have a response that increase linearly with the amount of solute.

Have high sensitivity and predictable response.

High reliability and easy to use.

Similarity in response to all solutes.

Non-destructive of the solute.

Not contribute t extra-column peak broadening.

Types of detectors: -

HPLC detectors are classified in to two basic types.

Bulk Property detectors - These detectors respond to a bulk property of mobile phase like refractive index, dielectric constant or density.

Solute Property detectors - These types of detectors responds to some properties of solute such as UV absorbance, fluorescence or diffusion current.

Commonly used HPLC detectors -

Ultraviolet Absorbance detectors

Fluorescence detectors

Infra-red absorbance detectors.

Refractive-index detectors

Evaporative light scattering detectors.

Electrochemical detectors.

From all above detectors one of the most commonly used detectors is UV absorbance detector. It is very simple detector. Mercury lamp used as a source in UV absorption detectors. This detector is restricted to solutes which can absorb the wavelengths 250 nm, 313 nm, 334 nm and 365 nm. Species flows from the column detected by Deuterium or tungsten filament. The modern instrument generally contains filter wheels which detect various species rapidly as they are eluted. Some of the UV absorption detectors use monochromators.

Application of HPLC -

HPLC system shows vast applications in various fields like pharmaceutical, environmental and biochemical due to its high speed, better resolution and sensitivity.

Quality of the final product in most pharmaceutical industries is checked by using HPLC system.

In food industry it is used for residual testing of contaminants.

In the field of biochemistry mixture of amino acid is separated and qualitatively determined by using HPLC.

In chemical and biomedical research it is used to analyse the complex mixture.

Particularly reverse phase partition HPLC is useful for the separation of drugs and their metabolites, peptides, steroids, polyphenols and vitamins.

HPLC is used for calibration of standards and to determine release profile of drugs.[12,13]




Chemical and reagents used in the present project are as follows -



Sodium alginate

Kent Express.

Sodium Fusidate

Sigma-Aldrich, UK.


Fisher Scientific, UK.

Orthophosphoric acid

Fisher Scientific, UK.

Deionised water

Made in HPLC laboratory.

Table : List of chemical and solvents used


HPLC Instrument -

Agilent 1200 Series liquid chromatography system.

It is an isocratic system with a manual sampler.

G1365D multiwavelength detector with DE64255278 serial number.

Microvaccum degasser with quaternary pump.

Analytical Balance -

Mettler Toledo AB 104-S/FACT

Syring -

20µl manufactured by SGE Ltd., Australia.

Column -

Number: 00F-3033-EO


Size: 150 x 4.60 mm internal diameter, 5 micron particle size

Serial number: 81675

Beakers -

Volume: 50 ml and 100 ml.

Volumetric flask

Hot Air Oven

Glass Slides

Silicon Rubber Moulds



Weighing Boat


Filtration kit

Small plastic containers

Ceramic tile


Preparation of Mobile Phase (1000 ml) -

Mobile phase contains methanol 800 ml, 0.01 M Orthophosphoric acid and 200 ml deionised water.

0.01 m Orthophosphoric acid was made by adding 0.2 ml Orthophosphoric acid in to 200 ml of deionised water. Then this water was mixed with 800 ml methanol. All the solvents were of HPLC grade (e.g. Fisher Supplier UK) and the blended mobile phase degassed before use to avoid air bubbles.

Preparation of Standard stock solution -

Accurately weighed 100 mg of sodium Fusidate on a four digit analytical balance transferred carefully into 100 ml volumetric flask and made up volume with deionised water. This resultant solution is known as standard stock solution which contains sodium Fusidate 1000µg/ml. From this solution serial dilutions were made.

Formula used to make dilutions is -

C1V1 = C2V2

Where, C1 = concentration of stock solution.

C2 = concentration of dilution to be prepared.

V1 = Volume of unknown concentration to be calculated.

V2 = Volume of volumetric flask in which dilutions were made.

Volume of stock solution

Used (ml)

Deionised water (make up volume) ml





















Table : Dilution table

For calibration of the standard, above prepared dilution were analysed by using HPLC system. The standard calibration curve for sodium Fusidate was obtained by plotting concentration on X- axis and peak area on Y- axis.

Experimental conditions -

Flow rate should be 2ml/min.

Detection wavelength - 235 nm.

Column used - KROMASIL 50C18 00F-3033-EO

Mobile phase - Following solutions were prepared and degassed

Methanol (500 ml), deionised water (200 ml), Orthophosphoric acid (0.2 ml)

Experimental Procedure -

First prepared mobile phase was degassed by using degasser. Then it was transferred to mobile phase container and waste collecting bottle was emptied before turning the instrument on.

HPLC was turned on by switching on the pump, detector and sampler. An Aglient online process was turned on. This has allowed HPLC system working online or offline. This means it has given us flexibility to edit data or chromatographic conditions.