DRUG DELIVERY SYSTEM

1. OCULAR DRUG DELIVERY SYSTEMS
Presented By – Payal Dnyaneshwar Borawake.
M. Pharm SEM-I
Guided By- Mrs. S.S. Mutha
(Asso. Prof. & HOD)
Department of Pharmaceutics
Pharmaceutics Department Of PharmaeutDepartment
Of Pharmaceutics(As
PDEA’s S.G.R.S. College Of Pharmacy , Saswad.
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2. CONTENTS
 Introduction
 Need of ocular drug delivery systems
 Anatomy and physiology of Eye
 Barriers of Drug permeation
 Methods to overcome barriers
 Ideal ocular drug delivery systems
 Classification of ocular drug delivery systems
 Evaluation
 References
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3. INTRODUCTION
 Definition:-They are specialized dosage forms designed to be instilled onto the
external surface of the eye (topical), administered inside (intraocular) or adjacent
(periocular) to the eye or used in conjunction with an ophthalmic device.
 Miotics e.g. pilocarpine HCl
 Mydriatics and cyclopegics e.g. Atropine
 Anti- inflammatories e.g. corticosteroid
 Anti-glaucoma drugs e.g. pilocarpine HCl
 Anesthetics e.g. Tetracaine.
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 Some drugs used in the eye are as follows:-

4.  There are many eye ailments which affects the eye and one can loss the eye sight also.
Therefore many ophthalmic drug delivery systems are needed.
 Conventional and non-conventional(newer) drug delivery systems are present. Most
commonly available preparation are eye drops and ointments(About 70% of formulations) in
market.
 These preparations when instilled into eye are rapidly drained away due to tear flow So only
small amount is available for therapeutic effect resulting in frequent dosing.
 To overcome these problems newer pharmaceutical formulations like Nanoparticles,
Microemulsions, Intophoresis, Ocular inserts,etc. have been developed to increase the
bioavailability of drug.
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5. Sclera - The eye's white outer protective coat
Cornea - The transparent, curved structure at the front of
the eye, allows light to enter in the eye.
Iris - The coloured part of the eye - blue, brown, green,
grey etc It lies between sclera and retina.
Pupil - The black part of the eye in the middle of the iris. It
constricts or dilates according to the amount of light passing
through it.
Lens - The transparent, biconvex disc closed in thin
transparent covering. It focuses incoming light onto retina.
Conjuctiva – The mucous membrane that begins at the edge
of cornea and lines inside surface of eyelid and sclera , serves
as lubricant of eye.
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ANATOMY AND PHYSIOLOGY OF EYE

6. ANATOMY AND PHYSIOLOGY OF EYE
Choroid - a large network of blood vessels(behind the retina) that
transport oxygen and other nutrients to the retinal pigment cells.
Optic disc - a small yellow oval structure in the retina, to which nerve
cell connections travel from all the rods and cones.
Aqueous humour - The transparent fluid that circulates
behind the cornea and in front of the lens.
Vitreous humour - The material (like transparent jelly) that
fills the eyeball between the lens and the retina.
Retina – The light-sensitive layer of millions of nerve cells.
The cells consist of two main groups, called rods and cones
due to their appearance under the microscope.
Macula - The small centre of the retina, responsible for
reading vision
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7. ADVANTAGES OF OCULAR DRUG DELIVERY SYSTEMS
 Provide sustained and controlled drug delivery.
 Increased ocular bioavailability of drug by increasing the corneal contact time.
 Targeting within the ocular globe so as to prevent the loss to other ocular tissues.
 Elimination of the protective barriers like drainage, lacrimation and conjunctival
absorption.
 To provide comfort, better compliance to the patient.
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8. LIMITATIONS OF OCULAR DRUG DELIVERY:
 Dosage form cannot be terminated during emergency.
 Interference with vision
 Difficulty in placement and removal.
 Occasional loss during sleep or while rubbing eyes.
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9. MECHANISM OF OCULAR ABSORPTION
 Non-corneal Absorption
-Penetration across sclera and conjuctiva
 Corneal Absorption
- Transcellular or paracellular pathway
- Rate limiting barrier, with pore size 60å,
only access to small molecules.
- Depends on oil/water partition
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10. DISTRIBUTION OF DRUG WITHIN OCULAR TISSUES AFTER
OPTHALMIC DRUG DELIVERY
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11. BARRIERS OF DRUG PERMEATION
 Spillage of drug by overflow
 Dilution of drug by tears turnover
 Nasolacrimal drainage
 Conjuctival absorption
 Enzymatic metabolism
 Cornea as a rate limiting barrier due to
anatomy of Cornea
 Outer :- Epithelium (Lipophilic)
 Middle :- Stroma (Hydrophilic)
 Inner :- Endothelium (Lipophilic)
xdPrecorneal constraints Corneal Constraints
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12. OTHER BARRIERS OF DRUG PERMEATION
■ Blood Ocular Barrier :-
- Inflammation breaks down this barrier allowing drugs and large molecules to penetrate into eye.
- It consist of :
a) Blood aqueous barrier – Ciliary epithelium and capillaries of iris
b) Blood retinal barrier – Capillaries of retina & tight junction between retinal epithelial cells
■ Physicochemical Properties Of drug
 Lipophilicity
 Solubility
 Molecular size and shape
 Charge and degree of ionization
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13. METHODS TO OVERCOME BARRIER
 Bioavailability Improvement :-
- Viscosity adjustment
- Prodrug
- Penetration Enhancers
 Controlled release drug delivery :-
- Vesicular system
- Recent formulation trends
- Particulate system
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14. IDEAL OCULAR DELIVERY SYSTEM
 Following characteristics are required to optimize ocular drug delivery system:-
i. Good corneal penetration.
ii. Prolong contact time with corneal tissue.
iii. Simplicity of instillation for the patient.
iv. Non irritative and comfortable form.
v. Appropriate rheological properties.
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15. OCULAR DELIVERY
SYSTEMS
CONVENTIONAL
VESICULAR
A
LIPOSOMES
NIOSOMES DISCOMES
PHARMACOSOME
•IMPLANTS
•INSERTS
•DENDRIMERS CONTROL RELEASE
•INTOPORESIS
•COLLAGEN SHIELD
•POLYMERIC SOLUTION
•CONTACT LENSES
•MICROONEEDLE
•MICROSUSPENSION
•NANOSUSPENSION
PARTICULATE
NANOPARTICLES
MICROSPHERES
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16. CONVENTIONAL TYPES
1- Solutions
2- Suspensions
3- Emulsions
4- Ointment
5- Gels
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17. FORMULATION OF OCULAR DRUG DELIVERY SYSTEMS
Dosage form Advantages Disadvantages
Solution Convenience Rapid precorneal elimination
Loss of drug by drainage
Suspensions Patient compliance
Best for drugs with slow dissolution
Drug properties decide performance
Loss of both solution and suspended
solid.
Emulsion Prolonged release of drug from vehicle
Increased pulse entry
Blurred vision
Patient non compliance
Ointment Improved drug stability
Increased tissue contact time
Sticking of eyelid
Poor patient compliance
Gels Comfortable
Less blurred vision than ointment
No rate control on diffusion
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18. SOLUTIONS
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 Ophthalmic solutions are sterile solutions, essentially free from foreign
particles, suitably compounded and packaged for instillation into the eye.
 Nearly all the major ophthalmic therapeutic agents are water soluble salts.
 The most commonly used salts are: hydrochloride,Phosphates, nitrates.
The selection of the appropriate salt depend on :
 Solubility
 ocular toxicity
 The effect of pH, tonicity, and buffer capacity
 The intensity of any burning sensation

19. AQUEOUS OPHTHALMIC SOLUTION MANUFACTURING
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1)Dissolution of the active ingredients and portion of the excipients into all portion of water.
2)Sterilization done by heat or by sterilizing Filtration through membrane filter media
into a sterile vessel.
3)Sterile solution is then mixed with the additional required Sterile components such as
viscosity –imparting agents, Preservatives.
4)Solution is brought to final Volume with additional sterile water.

20. EXAMPLES OF TOPICAL EYE DROPS
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 Atropine sulphate eye drops.
 Pilocarpine eye drops .
 Silver nitrate eye drops.
 Zinc sulphate eye drops.

21. SUSPENSIONS
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 If the drug is not sufficiently soluble, it can be formulated as a suspension.
 A suspension may also be desired to improve stability, Bioavailability ,and efficacy.
 The major topical ophthalmic suspensions are the steroid , anti-inflammatory agents.
 An ophthalmic suspension should use the drug in a microfine form; usually 95% or more of
the particles have a Diameter of 10µm or less.

22. MANUFACTURING OF SUSPENSIONS AND EXAMPLES
-Before bringing to the final volume with additional sterile water .
-The solid that is to be suspended is previously rendered sterile by Heat ,exposure to
ethylene oxide ,ionizing radiation (gamma ), sterile filtration.
■ Examples of suspensions:-
 Prednisolone acetate suspension.
 Besifloxacin suspension.
 Blephamide suspension
 Fluorometholone .
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23. INACTIVE INGREDIENTS IN TOPICAL DROPS:
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 The inactive ingredients in Ophthalmic solution and Suspension dosage forms are
necessary to perform one or more of the Following functions:
●Tonicity adjusting agents E.g. Nacl, Kcl
●Buffer and adjust pH E.g. Buffer system near to pH 7.4
●Stabilizers and antioxidants E.g. Na bisulfite, ascorbic acid
●Surfactants E.g. Polysorbates, tween 20 & 80
●Viscosity enhancers E.g. PVA , HPMC , Methyl cellulose

24. EMULSIONS
 Fine dispersion of minute droplets of one liquid into another liquid in which it is
immiscible.
 2 types of Emulsion:-
1) Oil in water
2) Water in oil
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oExample :-
Fluribrophen axetil + Castor oil have better bioavailability and less irritation

25. OINTMENT AND GELS
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 The ointment vehicles used in ophthalmology is mixture of Mineral oil and petrolatum base .
 The mineral oil is used to modify melting point and modify consistency.
 Petrolatum vehicle used as a ocular lubricate to treat dry Eye syndromes.
 They are mostly used as adjunctive night time therapy, While eye drops administered during the day
 It is suitable for moisture sensitive drugs and has longer Contact time than drops
 Preservatives used are Methyl paraben and propyl paraben

26. MANUFACTURING TECHNIQUE AND EXAMPLE
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 Ointment base sterilized by heat and filtered while molten.
 Then placed into a sterile steam jacket kettle to maintain the molten state under aseptic conditions.
 The previously sterilized active ingredient (s) and excipients are added aseptically.
 The entire ointment passed through a previously sterilized colloid mill for adequate dispersion of
the insoluble components .
 The product is compounded in an aseptic manner & filled into a previously sterilized container.
 Chloramphenicol ointment.
 Tetracycline ointment.
Examples:-

27. VESICULAR SYSTEMS
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Vesicular drug delivery system can be defined as highly ordered assemblies
consisting of one or more concentric bilayers formed as a result of self-assembling
of amphiphilic building blocks in presence of water.
It is important for targeted delivery of drugs because of their ability to localize the
activity of drug at the site or organ of action thereby lowering its concentration at the
other sites in body.
Various types :- 1.- Liposomes
2.- Niosomes
3.- Discosomes
4.- pharmacosomes

28. LIPOSOMES
Liposomes are biocompatible and biodegradable lipid
vesicles made up of natural lipids and about 25-10000nm
in diameter.
They have an intimate contact with the corneal and conjunctival surfaces and thus
increases the probability of ocular drug absorption.
 Limitations :-
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•Chemical instability,
•Oxidative degradation of phospholipids,
•cost and purity of natural phospholipids.

29. NIOSOMES AND DISCOSOMES
▲ Niosomes
Are non-ionic surfactant vesicles that have potential applications in the delivery of
hydrophobic or amphiphilic drugs

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▲Discomes
Formed by addition of specific amount of surfactant to vesicular dispersion may act as
potential drug delivery carriers as they released drug in a sustained manner at the ocular site.
▲Pharmacosomes:-
The amphiphilic prodrug is converted to pharmacosomes on dilution with water.

30. RECENT FORMULATION TRENDS
 Polymeric Solutions
 Phase Transition Systems
 Mucoadhesive / Bioadhesive Dosage Forms
 Collagen Shields
 Pseudolatices
 Ocular Penetration Enhancers
 Ocular Iontophoresis
 Particulate System : Microspheres, Nanoparticles
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31. POLYMERIC SOLUTIONS
 Addition of polymers to eye drop solutions increases corneal penetration of drug.
 Increases tear viscosity.
 Increases corneal contact time.
 Enhanced bioavailability
 Optimal viscosity - 12 to 15 cps
 Polymers used :-
1. PVA, PVP
2. Cellulose acetate pthalate
3. Methyl cellulose , HPMC , HEC
4. Chitosan
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32. PHASE TRANSITION SYSTEM
 Liquid dosage forms which shift to gel or solid phase when instilled into eye.
 Various polymers used as good sustain release material
 Temperature dependent phase transition system
E.g. Lutrol FC-127 and poloxamer 407
 Triggered transition system (pH)
E.g. Cellulose acetate pthalate(pH-4.5)
 Ion activated system
E.g. Gelrite – a low acetyl gellan gum gels clearly in presence of sodium
ions in tears. 32

33. BIOADHESIVES / MUCOADHESIVE DOSAGE FORMS
 Bioadhesive / Mucoadhesive systems can be either polymeric solution or microparticle suspensions.
 Polymers used are hydrocolloids with hydrophilic functional groups like carboxyl, Hydroxyl, amide.
 They retain in eye through adhesive bonds establish with mucin.
 Entanglement with mucin coat increases adhesive strength of polymer.
 Molecular weight increases, bioadhesiveness increases.
 pH, ionic strength of dosage form affect bioadhesion.
E.g. Polycarbophil shows strongest bioadhesion at acidic pH.
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34. COLLAGEN SHIELDS
 Collagen - Structural protein of bones, tendons, skin.
 Collagen corneal bandages used to healing corneal epithelium after surgery.
 Drug delivery:-
Shields are rehydrated in water solution of drug Drug absorbed by protein matrix
Shield dissolved in an eye, Drug is released.
 Convenient and attractive drug delivery device.
 Cross linking of collagen corneal shield , high drug concentration, increases
bioavailability.
E.g. Collagen shield soaked in ofloxacin & applied before surgery.
 Drawbacks:-
Anesthetization of cornea , Interference with vision , Patient discomfort
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35. PSEUDOLATICES
 New class of polymeric colloidal dispersion.
 Organic solution of polymers dispersed in an aqueous phase to form o/w type emulsion
by applying vaccum / by controlled temperature.
 Water is partially removed and sufficient quantity of water is adjusted to keep polymeric
phase dispersed.
 Such dispersions leaves intact non invasive polymer film which reserves drug.
 Advantages:-
-Prolong period of drug release
-Better ocular availability
-Less frequent dosing
-Patient compliance
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36. OCULAR PENETRATION ENHANCERS
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 Substances which increases permeability characteristics of cornea, modify integrity of corneal
epithelium are known as penetration enhancers.
 Classification:-
1) Calcium chelators – Looses tight junction between superficial epithelial cells and aids paracellular
transport. E.g. EDTA
2) Surfactants – sodium caprate
3) Bile acid & salts – Sodium deoxycholate
4) Preservatives - Benzalkonium chloride
5) Fatty acids – Caprylic acid

37. OCULAR IONTOPHORESIS
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 Iontophoresis is process in which direct current drives ions into cell or tissues.
 If the drug molecules carry a positive charge, they are driven into the tissues at the anode;
if negatively charged, at the cathode.
 Fast, Painless and safe dug delivery system.
 Types:-
◙ Trans corneal
◙ Trans scleral
 Applications:-
Anesthetic agents
Adrenergic agents
Antibiotics
Antifungals

38. PARTICULATE SYSTEM
 Drugs are bound to small particles which are then dispersed in aqueous vehicles.
 Microspheres and Nanoparticles good drug carriers enhances drug absorption and reduces
elimination.
 Due to small size , represents comfortable prolonged action drug delivery system.
 Nanoparticles:-
Size – 10-1000 nm,
Drug dispersed and encapsulated
Polymer used are biodegradable
 Microspheres :-
Spherical microparticles
Size – 1-1000 um
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39. ADVANCED OCULAR DRUG DELIVERY DEVICES
1) Matrix type drug delivery systems:-
 Hydrophilic Soft Contact lenses
 Soluble Ocular inserts
2) Capsular type drug delivery systems:-
 Ocusert and related devices
 Implantable silicon rubber device
3) Implantable Drug Delivery pumps:-
 Osmotic minipump and implantable infusion systems
4)Other delivery devices:-
 Ocufit and Lacrisert
 Minidisk ocular therapeutic systems
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40. MATRIX TYPE DRUG DELIVERY SYSTEMS
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1] Hydrophilic soft contact lenses :-
- Popular for correction of refractive errors of an eye.
- Made of hydrogels that absorb certain amount of aqueous solutions.
- Useful for drug delivery to anterior segment of eye.
- Polymers used for preparation of lenses (Hydroxyethylmethacrylate)
2] Soluble Ocular Inserts :-
-Soluble inserts consists of all monolytic polymeric devices that at the end of their release,
the device dissolve or erode.
-The system soften in 10-15 sec after introduction into the upper conjunctival sac, gradually
dissolves within 1h , while releasing the drug.
-Made of polymers
Natural – Collagen
Synthetic – HPC , MC , PVA , Ethyl Vinyl Acetate Copolymer.

41. CAPSULAR TYPE DRUG DELIVERY SYSTEMS
1] Ocusert & Related devices :
- Continous , controlled release , zero order kinetic achieved.
- 2 types of ocusert of pilocarpine drug i.e. Ocusert Pilo-20 , Ocusert Pilo-40.
- It consist of Pilocarpine-alginate core between 2 rate controlling ethylene vinyl
acetate copolymer membranes.
- When placed under upper or lower eyelid , drug molecule dissolved in lacrimal fluid released
through polymer membrane at predetermined rates.
2] Implantable silicone rubber devices :
- Device for hydrophobic drug, BCNU (1,3-Bis(2-chloroethyl)-1-nitrosourea).
- 2 sheets of rubber glued together at the edges.
- Tube of same material extends from device
- It releases drug at rate of 200-400ug/h for predetermined time. 41

42. IMPLANTABLE DRUG DELIVERY PUMPS
 Used for intravitreal drug delivery.
 Encapsulation of drugs in liposome or microspheres.
 Osmotic minipump – A drug pellet coated with PVA & EVA with polysulfone.
- ALZET : Constant drug delivery rate with duration of 2 weeks.
- Infusaid : infusion system
Pumping force generated by expanding fluid
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43. OTHER DRUG DELIVERY DEVICES
Ocufit & Lacrisert
Ocufit –
 Sustained release rod shaped device made of silicone elastomer.

 Diameter is 1.9 mm and length is 25-30mm.
 Fit the shape & size of conjuctival fornix.
Lacrisert -
 Cylindrical device made of cellulose.
 Used to treat dry eye syndrome.
 Long retention and sustained release features. 43

44. Minidisk Ocular Therapeutic Systems :-
 Monolytic polymeric device with diameter 4-5mm
 Shape like miniature contact lens, with convex and a concave face.
 Easily placed under upper or lower eyelid
Advantages
 No compromisation of comfort , vision.
 Does not interfere with oxygen permeability.
 Requires less time for insertion.
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45. EVALUATION TESTS
1) Sterility test :-
 In the Membrane filtration method :
- A solution of test product (1%) is prepared in isopropyl myristate.
- Allowed to penetrate through cellulose nitrate filter with pore size less than 0.45 μm.
- Membrane is then washed three times with sterile fluid
- Transferred aseptically into fluid thioglycolate (FTG)& soybean- casein digest medium(SBCD).
- The membrane is finally incubated for 14 days.
- Growth on FTG medium indicates anaerobic and aerobic bacteria
- Growth on SBCD medium indicates fungi and aerobic bacteria
- Absence of any growth in both these media establishes the sterility of the product.
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46. STERILITY TEST :-
 In the Direct - inoculation technique :
- 1 part of the product diluted with 10 parts of sterile fluid with the help of an emulsifier.
- Incubated in FTG and SBCD media for 14 days .
Selection of sample:-
 In both techniques, the number of test articles is based on the batch size of the product.
 If the batch size is less than 200 the containers, either 5% of the containers or 2
containers (whichever is greater) are used.
 If the batch size is more than 200, 10 containers are used for sterility testing .
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47. EVALUATION TESTS
2)Thickness of the film :
Measured by dial caliper at different points and mean is calculated.
3) Drug content uniformity :
Cast film cut at different places and tested for drug as per monograph.
4)Uniformity of weight :
In this , 3 patches are selected and weighed.
5) Percentage moisture absorption :
Ocular films weighed , placed in dessicator containing 100 ml saturated solution of aluminium
chloride and humidity maintained to 79.5%. After 3 days , films are reweighed and % moisture
absorbed is calculated
% Moisture absorbed = final weight – initial weight x 100
Initial weight 47

48. IN-VITRO EVALUATION METHODS
6) Bottle method :
- Dosage form placed in bottle containing dissolution medium which is maintained at specified
temperature & pH , then Bottle is shaken.
- Sample is taken out at appropriate intervals and analyzed for drug content.
7) Acclerated Stability Studies :
- Carried out to predict the breakdown that may occur over prolonged periods of storage at normal shelf
condition.
- Dosage form kept at elevated temp., humidity or intensity of light, or oxygen.
- After regular interval of time, sample taken and analyzed for drug content.
- From readings graphical data obtained and shelf life and expiry date are determined.
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49. REFERENCES
■ Controlled drug delivery, Concepts & advances by Suresh P. Vyas ,
Roop K. Khar.
■ Advances in controlled & novel drug delivery by N.K. Jain.
■ Pharmaceutical Dosage Forms and Drug Delivery by R.I. Mahato
■ www.slideshare.net
■ www.wikipedia.com
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