dosage form i

8/9/2019 Dosage Form I

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Chapter I

PARENTERAL PRODUCTS


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Sterilization

The complete destruction or elimination of microbial life.

Efficiency of sterilization technique depends on:

- Length and degree of exposure to sterilization

source.

- Type of microorganisms.

- Number of microorganisms.


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Methods of sterilization

1- Dry heat sterilization

Suitable for thermostable substances.

2 hrs at 180C or 45 min at 260 C including lag time.

Lag time depends on:- Oven size

- Heat circulation -

- loading capacity.

Application: Fixed oils-petrolatum-Heat stable powder-

glassware-instruments.


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2- Moist heat sterilization (autoclave)

Effective 121 C and 15 pounds pressure for 20 min.

Cannot destroy pyrogens. More effective than dry heat due to:

a- Coagulation of cell protein at lower temperature.

b- Steam has a higher thermal capacity than hot air.

Application: Aqueous solutions-surgical dressings-

glassware-instruments.

Not applicable in: oils-fats-powders damaged by steam.


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Bulk solution takes more time for sterilization than

the same volume when subdivided.

Cooling cycle of autoclave can be shortened by:

a- Spraying with gradually cooling water.

b- Pulses of cooling air.


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3- Gas sterilization (for thermolabile)

Ethylene oxide or beta-propiolactone are used.

Ethylene oxide (inflammable) is mixed with inert gas asFreon, or may be used as liquefied gas.

Conditions: 55 C - vacuum 27 inch Hg - 50-60% relativehumidity.

Mechanism: alkylating essential metabolites.

Application: dry powders- plastic materials.


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4- Sterilization by ionizing radiation (for thermolabile)

Advantages : low chemical reactivity-low measurable residue-fewvariables.

a- Gamma radiation: - decay from cobalt 60.

- Provides continuous process. Conditions: 2.5 M.Rad.Adequate dose delivery complete and

uniform Coverage of product adequate penetration.

Application: Sutures- plastics- dry powder drugs as vitamins,

antibiotics.

b- Electronbeam radiation: produced by electron accelerator.


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5- Sterilization by filtration (for thermolabile)

It should not change the composition of the solution.

Filters are membrane type and act through sieving. (Millipore).

Filters are hydrophobic plastic polymers (cellulose acetate, PVC).

Membranes are rendered hydrophilic by addition of surfactant

during manufacture. Pore size of the filters is 0.2 micron. (series may be used).

Depth filter (pre-filter) may be used for high particle content.


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Testing of filters (for pore size and integrity)

a- Bubble point test: pressure required to pass gas through

wet filter is measured which is inversely proportional to the

diameter of the pores.

b- Microbial challenge test: filtration of solution of high No.

of small microorganisms , then testing the

fi growth on culture.


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Parenteral Products

Advantages (reasons) of parenterals

1- Delivery of adequate drug conc. to diseased tissue (intra-

ventricular).

2- Guarantee drug compliance (monthly IM long acting penicillin).

3- Direct control of onset time, tissue conc. and elimination.

4- For drugs which cannot be taken orally (Insulin- some

penicillins).

5- When oral route is not available.( comatose anesthetic use)

6- Provide local effect (local anesthetics- ant-inflammatory). 7- Rapid correction of fluid and electrolyte imbalance.


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Disadvantages

1- Pain and discomfort.

2- Incorrect drug or dose is difficult counteract.

3- Restricted to hospital or specialized personnel.


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Routes of parenteral administration

1- Subcutaneous (SC) :

Injection of up to 1 ml into fat layer under skin. (insulin-vaccines )

Slower onset and lower absorption rate than IM and IV.

Site of injection: Abdomen, legs and arms.
http://upload.wikimedia.org/wikipedia/commons/f/fa/Mantoux_tuberculin_skin_test.jpghttp://upload.wikimedia.org/wikipedia/commons/f/fa/Mantoux_tuberculin_skin_test.jpg


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2- Intramuscular(IM):

- Injected into deltoid, gluteal or lateral thigh. Up to 5 ml.

-Slower than IV. Solutions, suspensions and emulsions ( o/w and w/o)can be injected.

-Depot of drug is formed in the muscle (onset time is 1-2 hr).

-Drug release from the depot depends on:

Rheology of product-Drug conc.-tonicity of product-physical properties

of drug.

- In adults the upper outer quadrant of the gluteus maximus is the most

frequently used site for IM injections.

- In infants, the gluteal area is small and composed primarily of fat, notmuscle. Thus the deltoid muscle of the upper arm or midlateral muscle of

the thigh is preferred.


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Deltoid Gluteal Lateral thigh


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3- Intravenous :

Advantages:

a- Rapid response and maximum bioavailability.

b- Avoid tissue irritation (cytotoxic drugs).

Disadvantages : very difficult antidoting due to rapid absorption.

The veins suited in front of the elbow are

usually selected for IV injection, because

they are largesuperficial

Easily detectable


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Volume: 1-100 ml. only aqueous or hydroalcoholic.

Large volume parenterals (LVP) are used to:

- Supply electrolytes and nutrients,- To restore blood volume,

- To prevent tissue dehydration and

- To dilute toxic materials.

IV admixture

Addition of drug or more to LVP to provide continuous and

prolongedtherapy.

Physical and chemical incompatibilities or loss of sterility

should be avoided during preparation.
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Calculations involving

IV admixture Example1:

A medication order for a patient weighing 70 kg calls for 0.25 mg ofamphotericin B per kg of body weight to be added to 500 ml of 5 %dextrose injection. If the amphotericin B is to be obtained from areconstituted injection that contains 50 mg per 10 ml, how many

milliliters should be added to the dextrose injection?

Solution

Total quantity needed for the patient:

0.25 x 70 = 17.5 mg

Reconstituted solution contain 50 mg per 10 ml50 mg 10 ml

17.5 mg X

X= 3.5 ml
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Example 2

Prepare the following intravenous infusion

15 mEq of potassium ions and 20 mEq of sodium ions in 500 ml of 5 %

dextrose injection. Using an injection of potassium chloride containing 6

g per 30 ml and saline solution.
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Solution

15 mEq of K+ will be supplied by 15 mEq of KCl

And 20 mEq of Na+ will supplied by 20 mEq of NaCl

1 mEq of KCl = 74.5 mg

15 mEq of Kcl = 1117.5 mg or 1.118 g

6 g 30 ml

1.118 g X

X= 5.59 ml

1 mEq of NaCl = 58.5 mg

20 mEq of NaCl = 1170 mg or 1.17 g

0.9 g 100 ml

1.17 g X

X = 130 ml.
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Example 3

A medication order calls for 1000 ml infusion to be administered overan 8-hour period. Using an IV administration set which delivers 10drops per ml, how many drops per minute should be delivered to the

patient?

Solution:

Volume of fluid = 1000 ml

8 hour = 480 minutes

1000/ 480 = 2.1 ml per min

2.1 ml/min x 10 (drops per ml) = 21 drops/minute
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4- Specialized LVP and sterile solutions

A) Hyperalimentation solution

LVP containing large amounts of nutrients (carbohydrate-amino

acids-vit.)

Administered through superior vena cava by catheter, for patients

unable to feed orally (comatose-esophageal obstruction-GI

disease)


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B) Dialysis solutions

1- Peritoneal dialysis solutions:

Sterile solutions are injected into abdominal cavity for 30-90 min.

, and then withdrawn, for the purpose of:

- removing toxic substances from the body.- to aid and accelerate the normal excretion function of the

kidney.


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2- Hemodialysis :

The blood leaves the artery via a PE catheter and passesthrough a disposable dialyzing membrane unit, which is

bathed in electrolyte solution simulating body fluids. After

cycling the blood through the dialyzer, it enters the body

through a vein.

C) Irrigating solutions

They are intended to irrigate, flush and aid in cleansing

cavities and wounds.


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Design of parenteral products

It depends on:

I- Nature of the drug :

- Its solubility in water .

- Its stability in aqueous solutions.

II- Therapeutic considerations:

Onset and duration of action of the drug which dependson:

- The nature of the drug and

- Route of administration.


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A- The Active Drug

Physico-chemical properties of drug includes:

1- Crystallinity and particle size distribution

Crystallization process variables (such as temperature, rate of

mixing and stirring, pH, solvent conc. and purity) will affect:

- Crystal form

- Crystal size and shape

- Size distribution

- Degree of crystallinity

- State of aggregation.


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3- Polymorphism

It has direct effect on:

- solubility

- stability

- dissolution rate

- drug absorption.

4- pHProfiles of pH versus stability and solubility are needed to predictthe optimum conditions for formulation, preparation andstorage.


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B- Added Substances

1- Antioxidants

- Drugs with high oxidation potential are less sensitive tooxidation.

- The oxidation potential of drugs could be increased by loweringthe pH of the medium.

- Oxidation reactions mediated by free radical mechanism areprotected by agents having lower oxidation potential(Antioxidants) than the drug.

- Antioxidant should not interact with the drug, Ex. Epinephrinestabilized by bisulphite forms inactive epinephrine sulphonate.

- When oxygen is directly involved (auto-oxidation) protectionmay be afforded by replacing air from the system with inert gas(Nitrogen or CO2).


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Antioxidant conc depends on :

- Drug reactivity.

- Type of container (glass seal or rubber stopper).

- Single or multiple dose use.

- Container head space.

Examples of antioxidants :bisulfites metabisulfites sulfites.

ascorbic acid monothioglycerol.


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2- Antibacterial agents

They are generally required for:

a) All multiple-dose parenerals.b) Unit-dose products which are not terminally sterilized.

They should be compatible with all ingredients in the product.

Their activity may be reduced in presence of macro-molecules due to

binding, Ex. Surfactants. Plastics and rubber closures may also adsorbantibacterials, reducing its activity.

They have dual role in the formulation:

1- They inhibit microbial growth accidentally introduced during

withdrawal of dose in multiple dose preparations

2- They have antimicrobial effect during filling under aseptic

conditions.

They are excluded in LVP. due to toxicity.


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3- Buffers

They are added to resist change of pH that may occur during storage

due to:

1- Product degradation.

2- Container and stopper effect.

3- Diffusion of gases through the closure or container.

4- Effect of gases in the head space.

The buffer system should have adequate buffer capacity to maintain

the pH during storage while permitting the body fluids to adjust the

pH easily to 7.4 Suitable buffer system can be selected from the knowledge of pH

profile of the drug for both solubility and stability.


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Buffer system may affect drug stability,

Ex. Degradation of Vitamin B1 with citrate buffer

Phosphate buffer increases the rate of

hydrolysis of Phenethicillin.

Buffers are weak acids and their salts or weak bases andtheir salts.

Ex. Acetate citrate Phosphate

Acceptable pH range:

For small volume IV : 3 10.5

Other parenteral routes : 4 - 9


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5- Inert gases:

To improve stability of oxygen-sensitive drugs.

Dissolved oxygen may be removed from water by boiling ,

then air is displaced with N2 or CO2.

glass seal provides the best resistance to gas permeation.

6- Solubilizing agents:

Surfactants are used in parenteral:

Suspensions as wetting agent and to improve syringeability

Emulsions as emulsifying agent.

Solutions as solubilizing agent (in steroids).The most safe surfactant is the non-ionic type.


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7- Tonicity adjustment agents:

LVP given by IV route should be isotonic.

Hypotonic leads to hemolysis of RBCs.

While :

hypertonic leads to crenation of RBCs.

Dextrose sod. Chloride pot. Chloride are commonly used.


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C- Solvent system:

The majority of parenterals are aqueous solutions.

Advantages of solutions:

- Provide uniform doses.- Accurately measured.

- Visually inspected for ppt. or colour change.

But it is not possible to formulate drugs in completely aqueous

system because of :- limited aqueous solubility(due to high polarity of H2O)

- limited stability.

Solubility of drugs in aqueous system can be improved by

addition organic co-solvents as ethanol, propylene glycol,glycerol or PEG 400 by lowering Dielectric constant ofwater(polarity).


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Selection of the vehicle depends on:a) Polarity of cosolvent:

Cosolvents with high dielectric constants e.g. ethanol and glycerin mix well with

water and dissolve ionic compounds, while those with low dielectric constants

e.g. chloroform, benzene and oils are not water miscible and dssolve non-ionic compounds.

The solubility profile of the drug as afunction of dielectric constantshould be

done in binary solvent system, from which the dielectric constant of

maximum solubility could be determined.

Drug

Solubility

10 20 30 40 50 60 70 80 90 100

Dielectric constant

% of water

Solubility profile of a drug versus dielectric constant in binary system of

water and dioxane

57 : 43 water : dioxane


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b) Effect of molecular structure

- Crystals composed of asymmetric molecules tend to be more

soluble than those of highly symmetric molecules.

- Drugs with polymorphic transformation e.g. Chloramphenicol,

Progesterone and Sulphathiazole have different arrangement of

molecules in the crystalline state resulting in different dissolution rates

and different bioavailability.


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The selected pH of the aqueous system depends on thenature of the drug.

Most drugs are weak electrolytes, therefore they arepartially dissociated.

The ratio of dissociated to un-dissociated drug depends onthe pH. Therefore, solubility, stability and partitioncoefficient will be influenced by the pH.

Weak acid drugs as barbiturates and sulfonamides are moresoluble at high pH, While

weak base drugs as antihistamines and akaloids are moresoluble at low pH.

1 A hi l


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1- Aqueous vehicles:

Water for injection (WFI):

- It is non-sterile, pyrogen free. Stored in large tanks.

- Inorganic compounds are removed by distillation, reverse osmosis,deionization.

- Purity specifications limit Cl-, Ca++, SO4, NH3, CO2 and dissolvedsolids (10 ppm).

- Membrane and depth filters are used to remove particulate

contaminants and microorganisms.- Charcoal beds may be used to remove organic materials.

It is used in preparation of parenterals.

Sterile water for injection USP:

Sterile, pyrogen free and packaged as 1 litre container.Used as a solvent or diluent for sterile preparations.

It cannot be administered as LVP as it is not isotonic.


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Bacterostatic water for injection USP:

Sterile WFI containing antimicrobial agent.

Packed in vials not more than 30 ml, used in preparation of

sterile small volume parenterals, especially multiple-dosepackages.

Not used for preparation of LVP due to probable toxicity of

antimicrobial in large doses.

Sodium chloride injection USP (Saline)

Sterile isotonic solution of sod.chloride (0.9%) in WFI.

Used in LVP and in preparation of parenteral solutions or

suspensions.

Bacterstatic sodium chloride injection USP


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2- Non-aqueous (Oils) and mixed vehicles

They are necessary to:

a) Stabilize drugs e.g. barbiturates (hydrolyze by H2O).

b) Improve solubility e.g. Digoxin.

Ex. Of non-aqueous vehicles: Fixed oils as corn oil,

cottonseed oil, peanut oil and sesame oil.

Fixed oils are injected only by IM route.

Used to prepare steroid hormones. Benzyl benzoate is added

to improve steroid solubility in the oil.

Mixed solvents are used to improve drug solubility and

stability.

Mixed solvent systems may be irritating or toxic when

present in high percentage.


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D- The container and container components:

Container components are considered as integral part of the

product, affecting its stability and safety.

Selection of container material is based on:

- Maintenance of microbiological purity.

- Product stability.

- Suitability to production operation and inspection.

- Resistance to breakage and leakage.

- Convenience of clinical use.

GlassAdv. : Economic inert good product identification.

Disadv. : Fragile heavy no satisfactory closures.


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Pl ti


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Plastics:

They are compounds of high M.Wt. that can be molded to shape.

Plastic material may contain additives such as:

Plasticizer Stabilizer Antioxidant- Antistatic Plastics commonly used in parenterals include:

Polyethylene: used in manufacture of syringes.

Polypropylene: autoclavable - manufacture of syringes.

Polyvinyl chloride (PVC): in manufacture of IV bags.

Nylon: hard- manufacture of filters in blood sets.

Factors involved in selecting plastic material:

Vapor transmission sterilization quality texture clarity

inertness leaching biologic safety.

Ad f l i b l i


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Advantages of plastic bags over glass containers:

1- No venting is required due to responding to normal outside

pressure, so contamination is eliminated.

2- Non-breakable, lighter and consume less space.

3- They have less particulate matter than glass.

Advantages of glass containers over plastic bags:

1- Complete mixing occurs more likely in glass containers.

2- Addition of drugs by puncture of plastic bag with needle may

cause contamination.

3- Drug may be adsorbed by plastic materials, affecting its

concentration in the product.

R bb l


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Rubber closures:

The main polymers used in manufacture of rubber are

saturated and unsaturated elastomers. Additives may be

included to improve rubber quality such as:Plasticizers- fillers- accelerators- activators..

To maintain batch to batch uniformity, the following control

tests are necessary.

A- Physical properties

1- Durometer: is a measure for rubber hardness. Values of 30-

35 is soft, 35-45 is medium and above 45 is hard. High

durometer means increased coring, reduced resealability

and increased resistance to puncture. High durometer isneeded in syringe plunger head.

2 C i i th t t f ll ti l f th t


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2- Coring: is the cut out of a small particle from the stopper as

the needle is inserted. It is influenced by rubber type and

thickness.

3- Resealability: Stopper must reseal after needle insertion toprevent contamination and leakage.

4- Puncture resistance: The pressure required to insert the

needle through the closure.

5- Compression test: The closure material should have goodrecovery after compression to assure good sealing with the

glass finish.

6- Moisture vapor transmission (MVT) : is important for

hygroscopic, lyophilized and products with over-head inertgas. MVT can be decreased by increasing filler content.

7- Tackiness: The sticking of closures on autoclaving.

B) C tibilit ith ti


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B) Compatibility with preparation:

Two main problems are involved:

1- Leaching of ingredients from the stopper (as waxes) and

reaction with the ingredients of the preparation (detected

by examination of turbidity of the product)

2- The adsorption of ingredients from the preparation (as

preservatives) by the closure (detected by evaluation of the

extracts of the closures).

Parenteral Production


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Parenteral Production

A) Facilities:

The plant floor should be designed in a series of zones to

provide barriers for contamination.

Walls, ceilings and floors should be constructed of hard,smooth, non-flaking and easily cleanedmaterials.

All lights and windows are flush mounted in walls andceilings for ease of cleaning and disinfection.

Separate entrance for personnel and equipment should beprovided through air locks which are kept at positive

pressure relative to less clean areas.


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Fresh outside air must be first filtered to remove particulate


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Fresh outside air must be first filtered to remove particulate

matter, then HEPA (High Efficiency Particulate Air) filters are

used to remove microorganisms and submicron particles

(purity up to 99.7%). The requirements proposed by GMP include:

- Particle count per cubic foot of air must not exceed

100000 in size range 0.5 um (class 100000) and

class 100 at filling and sealing area.

- A temperature of 22 3 C.

- A relative humidity range of 30 50 %

- At least 20 air exchange per hour.

A laminar air flow units provide environmental control for

aseptic area.


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For sterile pharmaceutical preparations, clean room can beclassified to four grades as follows:

Grade A:

Local zone for high risk operations, e.g. filling, asepticconnections.

Grade B: Background environment to grade A (in case of aseptic

preparation).

Grade C and Grade D:

Clean areas for less critical operations.

Normally such conditions are provided by a laminar-airflowworkstation.


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Grade At rest In operation

maximum p ermitted number of part icles/m3

0.5 - 5.0 m > 5 m 0.5 - 5.0 m > 5

A 3 500 0 3 500 0

B 3 500 0 350 000 2 000

C 350 000 2 000 3 500 000 20 000

D 3 500 000 20 000 not defined not defined

Airborne particulate classification for manufacture of sterile pharmaceutical

preparations

B- Processing


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B- Processing

1- Cleaning of equipment and containers.

2- Compounding the product.

3- Filtration of solutions: Solutions are filtered for:- Clarification from particles of size down to 3 m.

- Sterilization by removal of particles down to 0.3 m.

4- Filling procedures:

Liquids are more easily filled than solids.

Low density liquids are more easily filled than high densityor sticky liquids.

The size of delivery tube is governed by :

- the opening of the container.- The viscosity and density of liquid.

- The speed of delivery.

A retraction device is fitted to the filling machine to remove


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A retraction device is fitted to the filling machine to remove

the hanging drop during filling to prevent wetting the neck

of the container which may cause breakage during sealing.

LVPs are filled by gravity as they do not need precision

( containing no potent drugs).

Pressure pump fillers ( semi-automatic) : for liquids.

Vacuum pump fillers (Automatic) : for powders.

Emulsions and suspensions require steam-jacketed (to

decrease product viscosity) and constantly stirred reservoir

(to prevent sedimentation of suspended particles) duringfilling.

Filling of powders:


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Filling of powders:

Fine powder has slow and irregular flow ( air pockets andelectrostatic charges)

Small granular particles, with narrow size distribution, ( toavoid segregation) are more flowable.

5- Sealing:

Containers should be sealed in aseptic area near filling

Ampoules are sealed by melting a portion of the glass neck to formeither tip-seal or pull-seal.

Excessive heating is not recommended due to expansion of air againstthe soft glass forming fragile bubbles at the point of seal.

Fracture of the wet ampoule neck may occur during sealing.

Sealing of vials and bottles Rubber closures must fit container opening and secured by aluminum

caps having a centre that is torn away at the time of use.

C- Preparation of parenterals


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C- Preparation of parenterals

1- Parenteral Solutions

Dissolving the drug and preservative, adjusting the pH and

sterile filtering the solution through a 0.2 m membranefilter.

Pre-filtration through a coarser filter may be necessary to

maintain adequate flow and prevent blocking.

The sterile filtrate is aseptically filled in the final containers.

Whenever possible, it is preferable to terminally sterilize the

product by autoclaving if the drug is thermostable.

2- Parenteral Suspensions


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2- Parenteral Suspensions

Suspensions require a balance of ease of filling and storage

without caking and ease of passage through syringe

(syringeability and injectability). Therefore, it is necessary to control particle size, particle size

distribution, rheologicalproperties and wettability.

A formula for parenteral suspension should contain:

- Active ingredient suspended in aqueous vehicle containing preservative.- A suspending agent as Aluminum monostearate, gelatin, mannitol,

povidone or sorbitol.

- Surfactants as wetting agent and to prevent crystal growth such as

Tween 80 and lecithin.

- Buffer for adjusting pH as citrate buffer.

Methods of preparation: Two methods


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Methods of preparation: Two methods

1-The aqueous vehicle containing the soluble ingredients is

sterilized by heat or filtration. The sterile drug powder

(procain penicillin G) prepared by freeze-drying, sterilecrystallization or spray drying is added to the sterile vehicle

and aseptically filled.

2- The sterile drug (testosterone) solution in acetone isprepared and aseptically added to the sterile aqueous

vehicle, leading to crystallization of the drug. The crystals are

allowed to settle and the supernatant is siphoned off. The

crystals are washed several times with sterile aqueous

vehicle and finally adjusted to volume, then filled aseptically

in the final containers.

3- Parenteral Emulsions


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3 Parenteral Emulsions

It is not recommended to prepare emulsions for IV

administration because:

a) The emulsion droplet size should be less than5 m (to prevent blood emboli) which is difficult.

b) Selection of emulsifiers and stabilizers is limited.

Among the few examples of parenteral emulsions in the

market is 10% Soybean oil (o/w) for IV parenteral nutrition(TPN). It contains Eggyolk phospholipid as emulsifier and

glycerin as stabilizer.

Oil soluble vitamins (E) is available as o/w IM emulsion.

The parenteral emulsions are usually sterilized byautoclaving.


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3- Leaker testing:


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3 Leaker testing:

The tested ampoules are immersed in 1% methylene blue,

vacuum is applied for 15 min., then released rapidly.

Defective ampoules show blue colour.

4- Alkalinity testing:

The tested ampoules are either filled with or crushed and

immersed in distilled water, autoclaved and titrated against0.01 M HCl using methyl red indicator

The consumed HCl is a measure for the glass alkalinity

dissolved in water.


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RADIOPHARMACEUTICAL

Chapter II

RADIOPHARMACEUTICALS


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RADIOPHARMACEUTICALS

Radiopharmaceuticals are dosage forms which incorporate a

radionuclide ( radioactive isotope ) .

Atomic structure:

A neutral atom consists of a positively charged nucleus

composed ofprotons and neutrons and surrounded by negative

electrons.

Atomic number (Z) = number of Protons = number of electrons.

Mass number (A) = number of protons + number of neutrons.

The nucleus with its protons and neutrons is called nuclide

which is given the symbol z XA


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Isotopes:

These are nuclides of the same chemical element,possessing the same number of protons but with

different number of neutrons.

Therefore isotopes have the same atomic number anddifferent mass number.

e.g. 1H1 (hydrogen)2 H1 (deuterium)

and 3H1 ( tritium)

Isobars:


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Isobars:These are nuclides of different elements, possessing the same

mass number

e.g. 3H1 and3 H2

Isotones :

These are nuclide of different elements, possessing the samenumber of neutrons.

e.g. 3H1 and4H2

Radioactivity :


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y

It is the process in which unstable nuclei with excess energy are

changing spontaneously and emitting energy in the form of

particles, electromagnetic waves or both. Such radioactive nucleiare called "radioisotopes" and the process of nuclear

transformation is called "radioactive decay"

Types of radiation from radioisotopes:

Three types of radiation are emitted most frequently fromradioactive nuclei. These are:

1- Alpha particles ( 42) :

An particle consists of two protons and two neutrons. Thus it isidentical to the helium nucleus 4H2 It has a penetration power of about 5 cm in air and less than 0.1

mm in tissues.

2-Beta particles (+1 and 1)


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2 Beta particles ( +1 and -1)

These have two kinds,

positron (+1 ) and negatron (-1).

They have a penetration power of about 3 cm in air

and about 1 mm in tissues.

3-Gamma radiation ( y ) :

Gamma radiation is electromagnetic waves having a

high penetration power which can reach up to about 1km in air and about 25 cm in tissues

Types of radioactive decay:


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Types of radioactive decay:

1- Alpha decay:

It occurs in heavy nuclide having atomic numbers > 82 . In this

decay alpha particle is emitted as follows:238U 92 (uranium)234 Th 90 (Thorium) +

4 He 2

2- Beta decay

It has two types:

a) Negatron decay: In this decay, a negatron and a neutrino (v) are

emitted: e.g.32P15

32S16 + -1 + v

It can be explained as follows:

A neutron is converted to a proton with the release of a negatronand a neutrino is illustrated by the following particle reaction:

1n01P1 + -1 + v


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The decay of phosphorus 32 of energy E1 to sulphur 32 of energyE2 is represented by an energy level diagram as as shown in the

figure. Such decay is associated with the release of energy equal to

E. where E = E 1 - E2.

The energy released (E) was found to be greater than the energyof the particle and therefore. a new particle, the neutrino was

postulated to account for the balance of the energy so that the sum

of the energies of the beta particle and its associated neutrino is

equal to E .

b) Positron decay: In this decay a positron and a


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b) Positron decay: In this decay. a positron and a

neutrino are emitted as follows

11C6 (carbon)11B5 (boron) + +1 + v

Here, a proton is converted to a neutron with the

release of a positron and a neutrino. A neutrino is also

required here to account for the balance of the energy.

The corresponding particle reaction is :

1

P11

n0 + +1 + v

3 Electron capture decay:


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3- Electron capture decay:

Here, the nucleus capture an orbital electron and a

proton is converted to a neutron with the release of

gamma rays as follows:

7

Be4 (Berilium) +0

e-17

Li3 (lithium) + y

The following particle reaction occurs:

1P1 + 0e-1 1n0 + y

4- Isomeric transition:


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4 Isomeric transition:

In this reaction, an unstable nuclide. with a high energy decays

to a suitable isomeric nuclide of lower energy with the emissionof gamma rays.

Here, protons and neutrons are rearranged within the nucleus

leading to change in energy level of the nuclide.

The more excited isomeric state is called metastable state which

is indicated by adding the letter" m " to the mass number

e.g. metastable technetium 99m Tc

99m Tc 99Tc + y

Units of radioactivity :


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y

A) Activity units

1- Curie (Ci) : it is the quantity of a radionuclide that is decaying at

a rate of 3.7 x 1010 disintegrations per second (dps) .

1curie =3.7 x 1010 dps

2- 1 millicurie (mCi) =3.7 x 10 7 dps

3- 1 microcurie (Ci) = 3.7 x 10 4 dps

* Specific activity: it is the radioactivity contained in 1 g or 1 ml ofthe radionuclide e.g. 50 mCi / g of 131 I

B) Dose units :


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B) Dose units :

1- Exposure dose:

Exposure dose is measured in Roentgen.

Roentgen :It is the quantity of X - or gamma radiation which

will produce one unit of charge of either sign in 1 cm3

of air

Thus the roentgen is a unit of exposure dose to X - or gamma

radiation which is the commonly used in radiotherapy. The

roentgen is not a unit of or radiation which is rarely used

2 Absorbed dose:

b b d d i d i " d " " "


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Absorbed dose is measured in " rad " or "Gray"

Rad : It is the dose of ionizing radiation that results in

absorption of an energy of 100 ergs / g of material.

An exposure of 1 roentgen delivers an absorbed dose of

approximately 1 rad.

Equal absorbed doses of different types of radiation mayproduce different biological effects. Therefore each kind of

radiation has what is called quality factor " Q" ,which is a number

representing the relative biological effectiveness of a particular

kind of radiation. For example, "Q" for alpha particle = 20 and "Q"for neutron = 10 .

The absorbed dose in " rad" multiplied by the quality factor "Q" is

called radiation equivalent dose "rem".

Rate of radioactive decay:

R f di i d i d fi d h b f f h


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Rate of radioactive decay is defined as the number of atoms of the

nuclide disintegrating per unit time. It may be expressed by the

following equation:

dN / dt = - N and in the logarithmic form

log N = log No - t /2.303

Where : N = Number of radioactive atoms present at time t

No = Number of radioactive atoms present at zero time

= decay constantThe rate of decay is also called" activity" and its equation may be

written as ;

Log A = log Ao - t/ 2.303

The decay of radioactive atoms is a first order reaction whereplotting log N versus time gives a straight line

with a slope = / 2.303 and

an intercept = log No


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The half - life of a radioactive nuclide is the time required for

one half of a given number of atoms to decay. It can be

obtained from the following equation:

t 0.5 = 0.693 /

The half - life can vary from a fraction of second up to millions

of years.


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Problem:


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A patient requires 500 Ci of radioactive iodine on 25 - 5 - 2013 ,

how many ml are required from the previously mentioned bottle

of Na 1131

Solution:

Ao = 5.4 mCi / ml = 5.4 X 1000 Ci / ml

Time from 1-4-2013 to 24-5-2013 = 55 days

log A = log Ao - t /2.303

= log ( 5.4 X 1000) - 0.012 X 55/2.303

A = 2786.12 Ci / ml

500 Ci X ml

X ( number of ml required) = 500 / 2786.12 = 0.18 ml

Problem:

On 1 12 2013 a radiopharmacist was asked to prepare a gold (AU198) injection


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On 1 -12- 2013 , a radiopharmacist was asked to prepare a gold (AU198) injection

containing 500 Ci / 2ml . how can he proceed to prepare such injection if he has a

gold bottle with the following data :

Ao = 100 mCi / ml Manufacturing date = 1 - 10 2013t 0.5 = 0.798 month

Solution:

Ao = 100 mCi / ml = 100,000 Ci / ml Time = 2 months

= 0.693/ 0.798 = 0.868 month-1

log A = log Ao - t/2.303

= log 100000 - 0.868 X 2/ 2.303 = 4.246

A = 17620 Ci / ml

17620 Ci 1 ml

500 Ci X ml

X = 0.028 ml

The pharmacist takes 0.028 ml and complete to 2 mf with water for injection to

obtain an injection containing 500 Ci / 2ml

Sources of radioisotopes


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p

1- Natural sources:

Naturally occurring radioisotopes are those that were formedwith the earth and decay so slowly that they are still present

today e.g. Uranium-238 , and potassium-40 . They disintegrate

through a series of decay processes until stable nuclear

configuration are reached.

2- Artificial sources:

a) By fission :

Certain heavy radionuclide like U238 can be caused to fission by

introduction of a neutron into the nucleus leading to theproduction of radioactive fission products like I131 . This process is

performed in a nuclear reactor.

b)

By activation:


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b) By activation:

Many radioactive nuclides are prepared by neutron activation

by placing a suitable target element in a nuclear reactor where

it is bombarded by neutrons. For example, radioactive

Phosphorus (32p) can be prepared by neutron bombardment of

the stable phosphorus (31p) or sulphur ( 32S ).

c) By acceleration (Cyclotron produced isotopes):Certain radioisotopes are produced by accelerating charged

particles like protons, deutrons or alpha particles in an

accelerator by applying a high voltage.

The highly energetic accelerated particles are caused to

bombard a target element. I123 is an example of this type. It is

obtained by proton bombardment of I127

Radioisotope generator


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p g

These are used to produce short half-life radioisotopes from

long half-life ones. Short half-life radioisotopes are used in internally administered

radio pharmaceuticals to minimize the radiation dose received by

the patient.

A radioisotope generator is an ion exchange column containing

a resin or alumina upon which has been adsorbed a long-lived

parent radionuclide.

Radioactive decay of the long-lived parent nuclide results in theproduction of a short-lived radioactive daughter nuclide which is

eluted from the column by means of an appropriate eluent (in

which the parent nuclide is insoluble) .


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An example is the technetium-99 generator in which the

parent radionuclide molybdenum-99 is adsorbed on an

alumina column.

Radioactive decay of molybdenum-99 produces

technetium-99 which is eluted from the column with sterile,

pyrogen free saline solution.


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APPLICATIONS OF RADIOISOTOPES


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APPLICATIONS OF RADIOISOTOPES

A radiopharmaceutical is a preparation intended for

therapeutic or diagnostic purposes, containing a radionuclide

in the form of an element , a simple salt or a complex and

may exist in the form of a solid, liquid or gas. They have the

following applications :

A - Therapeutic applications:

For therapy, isotopes are used as radiation sources either

externally or internally.

1- External radiation sources :


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a) Teletherapysources e.g. Cobalt-60 and Cesium-137 have been

used for the treatment of lesions.

b) Surface sources e.g. Phosphorus-32 and Strontium-90

2- Internal radiation sources :

a) Gold (198Au ):introduced as a colloidal gold suspension into the cavities

containing the serous fluid. it will be localized on the surface of

the cavity as large aggregates or precipitate e.g. in the treatment

of peritoneal and pleural effusion associated with malignanttumours.

It has been used in treatment of prostate and cervix uterine

carcinoma and bladder tumours.

b) Sodium phosphate ( 32 P ):


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b) Sodium phosphate ( P ):

may be used to decrease the rate of formation of

erythrocytes, where the isotope is concentrated in the

cancerous tissues. It may be also utilized in the treatment ofchronic granulocytic leukemia.

c) Sodium iodide (131I ):

In cases of hyperthyroidism, therapeutic doses of iodine-131will destroy thyroid tissues by means of radiation produced

within the gland. This procedure is better than X-ray

treatment since there is less radiation danger to the

surrounding tissues.

B- Diagnostic applications;

F di i i t d di ti t t


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For diagnosis, isotopes are used as radioactive tracers not as

radioactive sources. Differences between radioactive tracers and

sources are shown in the following table :__________________________________________________________________

adioactive sources Radioactive tracers

_______________________________________________________

1- Pharmacologically active Pharmacologically inactive

2- Administered in large doses Administered in very small doses3- They are long half-life isotopes Short half-life isotopes

e.g. 60CO, 137Ci , 90Sr e.g. 57Co , 51Cr, 24Na

_______________________________________________________

Diagnostic applications involve the following techniques:


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g pp g q

1 Isotope dilution:

This technique is used for measuring blood volume.

Radioiodinated human serum albumin is injected IV and

after 10 min a blood sample is withdrawn and itsradioactivity is measured .

The blood volume is calculated from the measured

decrease in radioactivity of the injected sample upon itsdilution by the blood.

2- Isotope disappearance rate:


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This technique is used for measuring half life of RBCs.

A blood sample is withdrawn and its RBCs are labeledwith 51Cr and then re-injected .

The rate of disappearance of the labeled cells can be

determined by measuring radioactivity of blood

samples taken every 2 or 3 days for at least 2 weeks.

The normal RBC half-life = 30 - 33 days. In hemolyticanemia . RBC half-life = 1 - 7 days.

3- Isotope transfer rate:

Thi h i i d d i i l i i i ll i


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This technique is used to determine circulation time especially in

the extremities.24

Na is injected into one part of the vascular system and the timerequired for its arrival at another part is determined.

4- Isotope uptake:

The concentration of a particular isotope in an organ can be used

as a measure of the function of that organ e.g.a) Thyroidfunction is measured by determining the thyroid uptake

of 131 I after oral administration of Na 131 I

b) Liverfunction is measured by determining the liver uptake of

131I after intravenous injection of rose bengal with 131 I .c) Renal function is measured by determining the renal uptake of

131 I after intravenous injection of iodopyracet with 131l or

iodohippurate with 131 I

5- Scanning technique:

By this technique tissues and organs can be visualized to detect


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By this technique, tissues and organs can be visualized to detect

abnormalities in their function.

Scanning technique consists of the following steps:

- Administration of a radionuclide.

- Concentration of the radionuclide in a certain organ or tissue.

- Making an image of the organ or tissue.

The following are examples of radioisotopes used in such

technique:

Na131

I is used for scanning of thyroid gland. Rose bengal 131I is used for scanning of liver.

Sodium iodohippurate 131 I is used for scanning of kidney.

RBCs labeled with 51Cr is used for scanning of spleen.

C- Pharmaceutical applications:


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Radioactive isotopes are used in the field of

biopharmaceutics and pharmacokinetics for the

determination of :

Dissolution rate and disintegration time of solid

dosage forms.

Rate of absorption, distribution, metabolism and

excretion of drugs in body.

Harmful effects of radiation


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1-Biological effects

a) Inactivation of essential enzymesb) Coagulation of proteins

c) Damage of nucleic acids

d) Release of histamine like substances

2-Skin effects

a) Short exposure to intense radiation produces

erythema

b) Long exposure to low radiation causes brittleness and

dryness of the skin, loss of hair and burns

3 Somatic effects


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3- Somatic effects

These effects occur from about 2 months to many

years after exposure. They include:

Cataract, severe anemia, leukemia and cancer

4-Genetic effectsRadiation has 2 effects on reproductive cells:

a) Damage of chromosomes

b) Increase in frequency of gene mutation

Maximum permissible exposure


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a) External exposure

The external exposure is calculated by the maximumpermissible dose (MPD) which differs according to the

organ to be exposed as follows:

1- MPD for critical organs like eyes = 5 rems / year2- MPD for arms, feet and ankles =25 rems /year

3- MPD for skin and other organs = 10 rems / year


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Precautions for radioprotection

h d d l k h f ll


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Each individual must keep the following precautions:

1- Keep the exposure as low as possible

2- Keep the isotope laboratory clean and neat and the workingarea should be free from equipment not required for the process

3- Keep the finger nails short and clean and avoid working with

the skin broken and avoid eating or smoking in the isotope

laboratory

4- Wear the prescribed monitoring equipment (pocket

dosimeter ).

5- Wear protective clothing, gloves and respiratory protective

devices.

6- Use pipette filling devices and perform the work within aconfined area.

7 - The radioactive material must be kept in double containers .

Chemical protective agents


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p g

1- Injection or ingestion of compounds containing

sulfhydryl group e.g. certain amino acids.

2- Administration of a large dose of a non radioactive

compound of similar composition as the radionuclide to

allow in-vivo exchange between the two compounds.

3- The use of a blocking dose or a dose which enhance

excretion of the nuclide e.g. high dose of 32 P is treated

by large dose of stable P and Ca ions.


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OPHTHALMIC PREPARATIONS

Ophthalmic preparations are sterile products

essentially free from foreign particles, suitably

compounded and packaged for installation intothe eye.

They may be in the form of Solutions,Suspensions, Ointments or solid dosage forms

Absorption of drugs in the eye


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When a quantity of topical ophthalmic dosage form is applied to

the eye, several factors affect the availability of the drug :

1- Normal application of two drops (100l) on a tear volume of

30 I , means that 70% of the administered volume can be

expelled from the eye by overflow since the capacity of the eye isonly 30 I.

If blinking occurs, the residual volume of 10 I indicates that 90%

of the administered volume will be expelled.

2- Drainage of the administered drop via the naso-lcrimal


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2 Drainage of the administered drop via the naso lcrimal

system into the gastrointestinal tract begins immediately

upon installation.

3- A third mechanism competing for drug absorption into the

eye is the superficial absorption of the drug into conjunctiva

with rapid removal from the ocular tissues by the peripheral

bloodstream.

4- In competition with the three foregoing forms of drug

l f th l ti i th t l b ti


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removal from the ocular tissues, is the trans-corneal absorption

of the drug.

For topically administered drug, to traverse the intact cornea

and to appear in the aqueous humor, it must possess dual or

differential solubility.

This differential solubility characteristic, depending upon the pH

of the environment, causes the drug molecule to exist in

equilibrium with its ionized form.

The non-ionized and ionized forms of the drug can penetratethe three layers of the cornea ( lipid-rich epithelium, lipid-poor

stroma and lipid-rich endothelium) as shown in the figure.


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Penetration of an alkaloid through the intact comes by

differential solubility

Pharmacologic Categories of Ophthalmic Drugs


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Topical anesthetics: as tetracaine, are employed to provide

pain relief preoperatively, postoperatively, for ophthalmic

trauma, and during ophthalmic examination.

Antibiotic / Antimicrobial Agents: as gentamicin, are used

systemically and locally to combat ophthalmic infection.

Antifungal Agents: as amphotericin B, are used topically

against fungal endophthalmitis and fungal keratitis.

Steroidal anti-inflammatory Agents: as dexamethasone, areused to treat inflammation of the eye, as allergic conjunctivitis.

Non-steroidal anti-inflammatory agents: as diclofenac, are used

to relief ocular inflammation


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to relief ocular inflammation.

Antiviral Agents: as vidarabine, are used against viral infections,

as that caused by herpes simplex virus.

Astringents: as Zinc sulfate, are used in the treatment of

conjunctivitis.

Beta-Adrenergic Blocking Agents: as timolol maleate, are used

topically in the treatment of elevated intraocular pressure (lOP)

and chronic open angle glaucoma.

Miotics: as pilocarpine, are used in the treatment of glaucoma,

Mydriatics allow examination of the fundus through the dilation

of the pupil (atropine).

Cycloplegics are long acting mydriatics.


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Protectants / Artificial Tears: as carboxymethyl cellulose

solutions employed as artificial tears or as a contact lens fluids to

lubricate the surface of the eye.

Vasoconstrictors / Decongestants: as oxymetazoline

When applied topically to the mucous membranes of the eye

cause transient constriction of the conjunctival blood vessels. Theyare intended to soothe, refresh, and remove redness due to minor

eye irritation.

Anti-histamines :as pheniramine maleate, are included in someproducts to provide relief of itching due to pollen and ragweed.

Factors affecting ocular bioavailability:


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I. Physiologic factors which include:

Protein binding:

Normally, tears contain 0.6 - 2.0% of albumin and globulins, and

in disease states, these protein levels are raised. Large size drug-

protein complex has a difficulty in penetrating the cornea.

lacrimaldrainage: Due to lacrimal drainage, a brief time is

available for a drug to remain in the eye leading to a

considerable decrease in absorption.

Drug metabolism:

Like other biological fluids, tears contain lysozyme enzymes

capable of the metabolic degradation of drugs.

II. Physicochemical characteristics of drug and product formulation:


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A- Drugs having lipophilicand hydrophiliccharacters are able to

penetrate the Cornea (corneal membrane contains both lipophilicand hydrophilic layers).

B- Ophthalmic suspensions, gels, and ointments mix less readily

with lacrimal fluids than low-viscosity solutions with the

consequent longer contact with ocular tissue and enhanced

bioavailability.

Types of ophthalmic products


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1- Ophthalmic Solutions

It is the most common means of administering drugs to the eye.

All ingredients are completely soluble and there is little physical

interference with vision.

The main disadvantage of solutions is the short contact time

with the absorbing surface

The selection of the appropriate drug salt depends on :

- Its solubility - therapeutic concentration- ocular toxicity - buffer capacity

- effect on pH and tonicity

- its discomfort reactions (stinging or

burning sensation).

An example for the effect of drug salt on the product properties

is the Epinephrine solution :


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is the Epinephrine solution :

a- The bitartrate forms solution has a pH range of 3-4 ,but has a

high buffer capacity causing considerable stinging due to the free

carboxyl group.

b- The borate salt has lower buffer capacity, a more nearly

physiological pH and only mild stinging, but less stable.

c- The hydrochloride salt combines better stability than borate

and acceptable pH and stinging.

Therefore, Epinephrine hydrochloride is the salt of choice.

2- Ophthalmic 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,

bioavailabilitv, or efficacy.

The major topical ophthalmic suspensions are the steroid anti-inflammatory agents: Prednisolone acetate and Dexamethazone.

Water soluble salts of prednisolone phosphate and

dexamethazone phosphate are available however, they have a

lower potency and are poorly absorbed.

An ophthalmic suspension should use the drug in a microfine

form, usually 90 % or more of the particles having a diameter of 10

m or less , to avoid irritation of the sensitive ocular tissues and to

ensure uniform dosage delivery,

3- Sterile powders for reconstitution:


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Several ophthalmic drugs are prepared as sterile powders for

reconstitution before dispensing to the patient. These include

Chloramphenicol, Epinephrine and Tetracycline hydrochloride.

The sterile powder is usually manufactured by lyophilization and

is packaged separately from the diluent, and a sterile dropper is

provided.

In powder form, these drugs are more stable (longer shelf-life)

than solution form.

Each product has an expiration date for the

reconstituted solution which should be explained to


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reconstituted solution which should be explained to

the patient with the proper storage conditions and

method of usage.

The sterile powders may contain:

Inert bulking agent such as Mannitol.

Co-drying agent as potassium acetate is used to

improve stability of the extremely moisture sensitive

drugs such as Echothiophate iodide ( choline estrase

inhibitor for treatment of glaucoma ).

4- Ophthalmic Ointments:


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The ointment vehicle is usually a mixture of mineral oil and

whitepetrolatum.

The main advantages of the petrolatum-based ointments are:

1- Their inertness and anhydrous nature which make them

suitable vehicles for moisture-sensitive drugs.

2- They offer longer contact time and greater drug bioavailability.

The main disadvantages of ophthalmic ointments are:

1- greater dosage variability than solution.

2- Blurring of vision ( therefore used at nighttime ).

The anhydrous petrolatum base may be made more miscible

with water through the use of an anhydrous liquid lanolin


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with water through the use of an anhydrous liquid lanolin

derivative. Drugs can be incorporated into this type of base in

aqueous solution.

Ophthalmic ointments are usually manufactured from

sterilized ingredients under aseptic conditions, and should

meet the requirements of the official sterility tests.

Preservatives such as chlorobutanol,parabens , and

phenylmercuricacetate and nitrate are commonly used

(especially chlorobutanol ).

The drug is added to the ointment base either as a solution or

as a micronized powder. The finished ointment must be free

from large particles.

5- Ocular Inserts (Ocuserts) :

They are drug containing devices that deliver one or more drugs at


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They are drug-containing devices that deliver one or more drugs at

a programmed rate, for a prescribed period of time to provide

continuous control of drug therapy.

Pilocarpine ocusert is an example of this type of solid dosage form.

It consists of three parts:

1- The drug reservoir mixed with a carrier material (alginic acid) .

2- A rate controller, ethylene/vinyl acetate copolymer

membrane

3- The platform consists of annular ring of the membrane

impregnated with titanium dioxide that forms whiteboarder for visibility.

The ocusert system provides a nearly steady zero-order

delivery rate of pilocarpine from the unit for 7 days when placed


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delivery rate of pilocarpine from the unit for 7 days when placed

in the aqueous tear environment of the eye.

Advantages:

1- The ocusert exposes the patient to only one- fourth to one-

eighth the amount of pilocarpine compared to drop therapy. This

could lead to reduced local side effects and toxicity.

2- It provides a continuous around-the-clock control of

intraocular pressure (lOP).

3- It provides more patient convenience and improved

compliance, as the dose is administered only once per week.

4- It is a good alternative for patients sensitive to preservatives.

Disadvantage:

The patient must check periodically to see that the unit is still in


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place. Replacement of contaminated unit

fresh one is very expensive

a.


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FORMULATION AND PREPARATION OF OPHTHALMIC PRODUCTS


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Ophthalmic solutions are formulated to be sterile isotonic and

buffered for stability and comfort. A viscosity imparting agent

may or may not be present. Solutions must be free from foreign

particles.

The proper pH (optimum drug stability), buffer and buffer

capacity should offer drug stability and comfort of the eye ( pH oftear is about 7.4 ). Therefore, buffer capacity should be sufficient

to maintain pH but minimized to the point where tear fluid can

overcome capacity and readjust the pH to 7.4 immediately after

instillation in the eye.

Buffering and pH adjustment:


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Ideally, an ophthalmic product should have a pH of

7.4 ( physiological pH of tear fluid ).

But the tear fluid has some buffer capacity which can

adjust the pH of the instilled product if the volume ofsolution is not excessive and does not have a strong

resistance to neutralization (minimum buffer

capacity).

Tonicity adjustment:


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An ophthalmic solution is considered isotonic when

it has an osmotic pressure equal to that of tear fluid(equal to that of 0.9 % sod. chloride solution).

In formulation of ophthalmic preparation, it is more

important to consider the sterility, stability,and

preservation rather than isotonicity.

It was found that the eye can tolerate solutions

equivalent to 0.5 % 1.8 % sod. chloride.

In some cases, the therapeutic concentration of the

drug necessitates using hypertonic preparation ,ex. Sod.


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drug necessitates using hypertonic preparation ,ex. Sod.

Sulfacetamide which is used in a concentration range of

10% - 30 % , while the isotonic solution should containonly 3.5 % of the drug.

The tonicity adjusting ingredients usually used

include: NaCI - KCI Buffer salts - Dextrose - glycerin -

propylene glycol.

Viscosity - imparting agents


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The USP permits the use of viscosity increasing agent to

prolong the contact time in the eye and thus enhance drugabsorption and bioavailability.

A secondary benefit of the polymer solution is a lubricating

effect.

The major commercial viscous polymers used are Polyvinyl

alcohol ( Liquifilim) and hydroxvpropylmethylcellulose ( Isopto ) .

The first polymer has viscosity of 4 - 6 cp at a concentration of

1.4 % , while the second has a viscosity of 10- 30 cp at aconcentration of 0.5 % depending on the pH and ionic

concentration of the product.

Preservatives and their choice


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The limited choice of preservative agents is narrowed

when the requirements of chemical and physicalstability and compatibility are considered for a particular

formulation and package.

The choice of preservative is limited to only a fewchemicals that have been found over the years to be

safe and effective for this purpose.

a- Benzalkonium chloride:


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It is the most widely used preservative, generally used in

combination with disodium edetate .

It is rapidly acting and stable over wide range of pH even at

hot storage conditions.

It has pronounced surface active properties, but incompatible

with nitrates, salicylates , anionic soaps and fluorescein.

The usual concentration range used in eye drops is 0.004 -

0.02 % ( 0.01 % ). A 0.03 % solution is used as a penetrationenhancer for some drugs in addition to its preservative activity.

b- Organic mercurials :


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When benzalkonium chloride cannot be used, one of the

organic mercurials , Phenymercuric nitrate (PMN),Phenylmercuric

acetate (PMA) or Thimerosal is used.

They are relatively weak and slow in their antimicrobial activity.

They are restricted to use in neutral to alkaline or slightly acidic

solutions.

Phenylmercuric ions are incompatible with halide ions forming

salts of lower solubility and effectiveness. Thimerosal has greater

solubility and is more stable than phenylmercuric compounds.

The usual concentration ranges are 0.002 - 0.004 %for PMN and

PMA, and 0.005 - 0.02 % ( but usually 0.01 % ) for thimerosal

c- Chlorobutanol.-


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It has relatively slower activity, but acceptable stability at

room temperature when used in acidic solution around pH 5 orbelow.

If autoclaved at pH 5 , it will decompose about 30% resulting in

HCl and the pH will further decrease by time.

The use of chlorobutanol necessitates the use of glass

package, because being volatile it will permeate the

polyethylene plastic containers.

It is used in a concentration of 0.5 % .

d- Methyl and Propylparabens .-

They are esters of para hydroxybenzoic acid used mainly to


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They are esters of para-hydroxybenzoic acid used mainly to

prevent mold growth, but in higher concentrations ( weak

antimicrobial activity).

They have low water solubility causing stinging and burning

sensation in the eye.

They bind to a number of nonionic surfactants and polymers,

reducing their bioactivity.

They are used as combinations, in a concentration of 0.03 - 0.1

% for methyl ester and 0.01 - 0.02 % for propyl ester.

e- Phenylethyl alcohol.-


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y y

In addition to its weak activity, it is volatile andwill lose activity via permeation through plastic

package.

It has limited water solubility, and can produceburning and stinging sensation in the eye.

It is recommended to be used in combination

with other preservatives in a concentration of 0.5

%

Other additives

a- Antioxidants:

S di bi lfi bi lfi i i d i i


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Sodium bisulfite or metabisulfite is permitted in concentration

up to 0.3 % especially for preparations containing epinephrine.

Other antioxidants have been developed such as ascorbic acid

and acetylcysteine , sodium bisulfite and 8-hydroxyquinoline.

b-Surfactants: The use of surfactants in ophthalmic preparations is restricted.

Nonionic surfactants , the least toxic class, are used in low

concentrations to achieve solution clarity.

Nonionic surfactants may react with some antimicrobials

lowering their effect.

Cationic surfactants such as benzalkonium chloride are mainly

used for their preservative effect.

PACKAGING OF OPHTHALMIC PRODUCTS

E d k d l t i l ti d b ttl A f


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Eye drops are packaged almost in plastic dropper bottles. A few

products still remain in glass dropper bottles because of special

stability considerations.

The main advantages of plastic bottles are:

1- Convenience of usage by the patient.

2- Decreased contamination.

3- Lower weight and cost.


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LDPE is compatible with a wide range of drugs and

formulation components, but the main disadvantage is:


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its sorption andpermeability characteristics.

The sorption and permeability can be detected by the stability

studies. If the permeating component is preservative such as

chlorobutanol or phenylethyl alcohol , a safe and reasonable

excess of the permeable component may be added to balance

the loss over the shelf- life.

LDPE resins are translucent and, if the drug is light -sensitive,

additional package protection may be required. This may be

achieved by using a resin containing an opaquing agent such astitanium dioxide ,by placing an opaque sleeve over the

container, or by placing the bottle in a cardboard carton.

LDPE resin used for the bottle and the dispensing tip cannot be

autoclaved and they are thus gas sterilized usually with ethylene

oxide-freon mixture.


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oxide freon mixture.

They are then aerated and degassed for several days before use.

The caps are usually made of a harder resin than the bottles,

such as polystyrene, and are also gas sterilized and aerated

before use.

A special plastic ophthalmic packages are made of special

grade of polypropylene such that the entire package when filled

and sealed can be sterilized by autoclaving.

The glass dropper bottle is still used for products which are

extremely sensitive to oxygen or contain permeable


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components that are not sufficiently stable in plastic.

Powders for reconstitution also utilize glass containers due

to their heat transfer characteristics, which are necessary

during the freeze-drying process.

The glass should be type Ifor maximum compatibility with

the heat or steam autoclave sterilization. Amber glass is used

for light -sensitive drugs. A sterile dropper is made of glass or

LDPE plastic pipette and a rubber dropper bulb.

The pharmacist should instruct the patient on precautions to

prevent contamination during usage.


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II. Soft contact lenses


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1. They are made of a hydrophilic transparent plastic

hydroxy-ethyl-methacrylate (HEMA), with small

amounts of cross-linking agents that provide a

hydrogel network.

2. They are 13 to 15 mm in diameter.

3. They cover the entire cornea.

Advantages:

1. They contain 30 - 80% water which enable enhanced


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permeability to oxygen and offer greater comfort to patient

than hard lenses.

2. Because of their size and coverage, they are less likely than

hard lenses to dislodge spontaneously.

3. They are less likely to permit irritating foreign particles (e.g.

dust or pollen) to lodge beneath them.

Disadvantages:

1. Do not provide the same high level of visual acuity as hardlenses.

2. Are less durable than hard lenses.

There are 2 types of soft contact lens:

1- Daily-wear lenses must be removed at night before the wearer

goes to Sleep


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goes to Sleep.

2- Extended-wearlenses are designed to be worn >24 hrs with

some approved for up to 30 days of continuous wear.

However, lenses should not be retained in eye > 4 - 7 days without

removal for cleaning & disinfection to avoid eye infection.

Disposable soft lenses do not require cleaning and disinfection for

the recommended period of use. They are discarded and replaced

with a new pair.

III- Rigid gas permeable (RGP) lenses

They are constructed of materials that are O permeable but


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They are constructed of materials that are O2 permeable but

hydrophobic.

There are 2 types of RGP contact lens:

A- daily-wear

B- Super permeable extended-wear.

Advantages


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They take advantages of both soft and hard lenses.

Compared to hard lenses, RGP lenses:

1. Permit greater movement of O2 through the lens.2. Retain the durability and ease of handling.

3. Provide greater wearing comfort.

Compared to soft lenses, RGP lenses:


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1. Provide strength, durability and longer life span",

and relatively easy care regimens.

2. Are easy to handle during insertion and removal.

3. Are more resistant to absorption of environmental

contaminants.4. Provide superior visual acuity.

Disadvantages

1. They require a greater adoption period for thewearer than soft lenses.

2. They are more easily dislodged in eye than soft

lenses.

Chapter IV


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AEROSOLS


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AEROSOLS

Definition:


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Colloidal systems, consisting of very finely subdividedliquid or solid particles dispersed in and surrounded by a

gas.

Aerosols have been used for the symptomatic treatmentof asthma as well as for the treatment of migraine.

Topical aerosols have been used to treat dermatological

manifestations.

Advantages:

1- Convenient and easy to use .


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2- There is no danger of contamination of the product withfore

dosage form i

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