Sterile Dosage Forms

By
Prof. Ahmed BOSELA

Chapter I
PARENTERAL PRODUCTS

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

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 powderglassware-instruments.

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

 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.

3- Gas sterilization (for thermolabile)

Ethylene oxide or beta-propiolactone are used.
Ethylene oxide (inflammable) is mixed with inert gas as
Freon, or may be used as liquefied gas.
Conditions: 55 C - vacuum 27 inch Hg - 50-60% relative
humidity.
Mechanism: alkylating essential metabolites.
Application: dry powders- plastic materials.

 4- Sterilization by ionizing radiation (for thermolabile)

Advantages : low chemical reactivity-low measurable residue-few
variables.
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- Electron beam radiation: produced by electron accelerator.

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.

 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.

Parenteral Products

Advantages (reasons) of parenterals

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

 Disadvantages

1- Pain and discomfort.

2- Incorrect drug or dose is difficult counteract.
3- Restricted to hospital or specialized personnel.

 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.

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, not
muscle. Thus the deltoid muscle of the upper arm or midlateral muscle of
the thigh is preferred.

Deltoid

Gluteal

Lateral thigh

 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 large
superficial
Easily detectable

 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
prolonged therapy.
Physical and chemical incompatibilities or loss of sterility
should be avoided during preparation.

Calculations involving
IV admixture
Example1:
A medication order for a patient weighing 70 kg calls for 0.25 mg of
amphotericin 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 a
reconstituted 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 ml
50 mg
10 ml
17.5 mg
X
X= 3.5 ml

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.

 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
6g
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.

 Example 3
A medication order calls for 1000 ml infusion to be administered over
an 8-hour period. Using an IV administration set which delivers 10
drops 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

 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)

 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.

2- Hemodialysis :
The blood leaves the artery via a PE catheter and passes
through 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.

 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 depends
on:
- The nature of the drug and
- Route of administration.

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.

2- Chemical Modification:
Esters or salts of drugs may be utilized to increase :
- solubility
- stability
- enhance depot action
- decrease pain on injection.
Molecular modification may be also utilized such as prodrugs
Ex: Benzathine penicillin
Procaine penicillin
Chloramphenicol sod. Succinate.

 3- Polymorphism
It has direct effect on:
- solubility
- stability
- dissolution rate
- drug absorption.

4- pH
Profiles of pH versus stability and solubility are needed to predict
the optimum conditions for formulation, preparation and
storage.

B- Added Substances
1- Antioxidants
- Drugs with high oxidation potential are less sensitive to
oxidation.
- The oxidation potential of drugs could be increased by lowering
the pH of the medium.
- Oxidation reactions mediated by free radical mechanism are
protected by agents having lower oxidation potential
(Antioxidants) than the drug.
- Antioxidant should not interact with the drug, Ex. Epinephrine
stabilized by bisulphite forms inactive epinephrine sulphonate.
- When oxygen is directly involved (auto-oxidation) protection
may be afforded by replacing air from the system with inert gas
(Nitrogen or CO2).

 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.

 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 adsorb
antibacterials, 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.

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.

 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 and
their salts.
Ex. Acetate citrate Phosphate
Acceptable pH range:
For small volume IV :
3 10.5
Other parenteral routes : 4 - 9

4- Chelating agents:
They are added to complex and inactivate trace metals such
as copper, iron and zinc which catalyze oxidative degradation
of drugs.
Sources of metals: impurities solvents (water) rubber
stoppers containers equipments.
Ex. Of chelating agents: - EDTA derivatives
- Citric and tartaric acids

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.

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.

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 of
water(polarity).

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 nonionic 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.
57 : 43 water : dioxane

Drug
Solubility

% of water
10

20

30

40

50

60

70

80

90

100

Dielectric constant
Solubility profile of a drug versus dielectric constant in binary system of
water and dioxane

Example:
If a DEC of 60 was selected, a mixture of water (DEC = 80), PEG 400
(DEC= 12.5) and ethanol (DEC= 25.7) could be used. Selecting an amount
of ethanol necessary to dissolve the drug (e.g. 10%), the percentage of
PEG400 and water can be calculated as follows:
(10 ) (25.7) + (X) (80) + (90 x) (12.5) = (100) (60)
Calculating x which is the percentage of water required, the other
percentages can be calculated as follows:
Ethanol = 10%
PEG400 = 68.4%
water = 21.6%

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.

 The selected pH of the aqueous system depends on the

nature of the drug.
Most drugs are weak electrolytes, therefore they are
partially dissociated.
The ratio of dissociated to un-dissociated drug depends on
the pH. Therefore, solubility, stability and partition
coefficient will be influenced by the pH.
Weak acid drugs as barbiturates and sulfonamides are more
soluble at high pH, While
weak base drugs as antihistamines and akaloids are more
soluble at low pH.

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 dissolved
solids (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.

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-dose
packages.
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

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.

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.
Glass
Adv. : Economic inert good product identification.
Disadv. : Fragile heavy no satisfactory closures.

Types of glass:
Type I : Neutral or borosilicate glass (high thermal
and chemical resistance). Used for aqueous
and all parenteral products. Expensive.
Type II : Soda glass with surface treatment
(sulphurized). Good thermal and chemical
resistance. Used for aqueous and all
parenteral products.
Type III : Soda glass of limited alkalinity. Low
thermal and chemical resistance. Used only
for parenteral powders and non aqueous
products.
NP :
Soda glass. For non- parenteral use.

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.

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.

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 3035 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 is
needed in syringe plunger head.

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 to
prevent contamination and leakage.
4- Puncture resistance: The pressure required to insert the
needle through the closure.
5- Compression test: The closure material should have good
recovery 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 inert
gas. MVT can be decreased by increasing filler content.
7- Tackiness: The sticking of closures on autoclaving.

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
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 cleaned materials.

All lights and windows are flush mounted in walls and

ceilings for ease of cleaning and disinfection.
Separate entrance for personnel and equipment should be
provided through air locks which are kept at positive
pressure relative to less clean areas.

 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.

For sterile pharmaceutical preparations, clean room can be

classified to four grades as follows:
Grade A:
Local zone for high risk operations, e.g. filling, aseptic
connections.
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-airflow
workstation.

Airborne particulate classification for manufacture of sterile pharmaceutical

preparations

Grade

At rest

In operation

maximum permitted number of particles/m3

0.5 - 5.0 m

> 5 m

0.5 - 5.0 m

>5

3 500

3 500

3 500

350 000

2 000

350 000

2 000

3 500 000

20 000

3 500 000

20 000

not defined

not defined

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 density
or 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

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) during
filling.

Filling of powders:
Fine powder has slow and irregular flow ( air pockets and
electrostatic charges)
Small granular particles, with narrow size distribution, ( to
avoid 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 form
either tip-seal or pull-seal.
Excessive heating is not recommended due to expansion of air against
the 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
1- Parenteral Solutions
Dissolving the drug and preservative, adjusting the pH and
sterile filtering the solution through a 0.2 m membrane
filter.
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
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, rheological properties 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

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, sterile
crystallization or spray drying is added to the sterile vehicle
and aseptically filled.
2- The sterile drug (testosterone) solution in acetone is
prepared 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
It is not recommended to prepare emulsions for IV
administration because:
a) The emulsion droplet size should be less than
5 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 by
autoclaving.

4- Dry powder
It is prepared due to drug instability in aqueous solution.
Methods of preparation: Three methods
a) Sterile Crystallization: Sterile drug solution is added to sterile nonsolvent and the crystals are separated by filtration, dried and filled
aseptically.
Disadv. : - Density variation from batch to batch.
- Microbial and particulate contamination.
b) Lyophilization (freeze-drying): Sterile concentrated drug solution
is aseptically frozen at -50C (in trays or vials) , then vacuum dried
(sublimation). The dry cake is milled and filled aseptically (in case
of trays).
Excipients as NaCl, Sod. Phosphate and lactose may be added to
improve physical and chemical stability.

Adv. : - Suitable for heat and oxygen sensitive drugs.

- rapidly soluble, reduced particulate matter level
Disad. : - non-crystalline product.
- Limited solvent choice and expensive.
C) Spray drying : A sterile drug solution is sprayed into hot
sterile gas chamber. The solvent evaporates rapidly giving
dry hollow spherical powder. The powder is filled aseptically
into the final containers.
Adv. : - Suitable for heat sensitive drugs.
- uniform particle size and density and economic.
- low level of particulate matter.
Disad. : Limited solvent choice.

Parenteral Quality Contol

1- Sterility testing: A sample is transferred to test media, incubated
at specified temperature and microbial growth is detected.
2- Pyrogen testing: 3 healthy rabbits are injected in the ear vein (by
IV) with10ml/kg of tested solution. The temperature is followed
for 3 hrs.
- The temperature rise should not exceed 0.6 C for each rabbit
(otherwise the sample is rejected) and not more than 1.4 C for the
three rabbits.
- If the temperature rise of the three rabbits exceeded 1.4 C, the
test is repeated using 5 rabbits. The temperature rise should not
exceed 0.6 C for each rabbit, and not more than 3.7 C for the 8
rabbits.

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 against
0.01 M HCl using methyl red indicator
The consumed HCl is a measure for the glass alkalinity
dissolved in water.

Chapter II

RADIOPHARMACEUTICAL

RADIOPHARMACEUTICALS
Radiopharmaceuticals are dosage forms which incorporate a
radionuclide ( radioactive isotope ) .
Atomic structure:
A neutral atom consists of a positively charged nucleus
composed of protons 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

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 and

different mass number.
e.g. 1H1 (hydrogen)
2 H (deuterium)
1
and 3H1 ( tritium)

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

e.g. 3H1 and

H2

Isotones :
These are nuclide of different elements, possessing the same
number of neutrons.
e.g. 3H1 and

4H2

Radioactivity :
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 nuclei
are 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 from
radioactive nuclei. These are:
1- Alpha particles ( 42) :
An particle consists of two protons and two neutrons. Thus it is
identical 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)

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 1
km in air and about 25 cm in tissues

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
234 Th
4 He
92 (uranium)
90 (Thorium) +
2
2- Beta decay
It has two types:
a) Negatron decay: In this decay, a negatron and a neutrino (v) are
emitted: e.g.
32P
32S
v
15
16 + -1 +
It can be explained as follows:
A neutron is converted to a proton with the release of a negatron
and a neutrino is illustrated by the following particle reaction:
1n
1P +
0
1
-1 + v

The decay of phosphorus 32 of energy E1 to sulphur 32 of energy

E2 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 energy
of 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

neutrino are emitted as follows
11C
6

(carbon)

11B

(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 :
1P

1n
0

+ +1 + v

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:
7Be
4

(Berilium) +

0e
-1

7Li
3

(lithium) +

The following particle reaction occurs:

1P

0e
-1

1n
0 +

4- Isomeric transition:
In this reaction, an unstable nuclide. with a high energy decays
to a suitable isomeric nuclide of lower energy with the emission
of 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

Units of radioactivity :
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 of

the radionuclide
e.g. 50 mCi / g of 131 I

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:
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 may

produce 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:

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 constant
The 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 where
plotting log N versus time gives a straight line
with a slope = / 2.303 and
an intercept = log No

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.

Any bottle of a radiopharmaceutical should have a label

showing the following information:
1- The radioactive element e.g. Na I131
2- Manufacturing date e.g. 1 -4 - 2013
3- Activity at manufacturing date (Ao) e.g. 5.4 mCi / ml
4- t 0.5 or. e.g. 57 days or 0.012 day-1
5- Precautions which should be taken to avoid radioactive
hazards.

Problem:
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
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 2013
t 0.5 = 0.798 month
Solution:
Ao = 100 mCi / ml = 100,000 Ci / ml
= 0.693/ 0.798 = 0.868 month-1

Time = 2 months

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
1- Natural sources:
Naturally occurring radioisotopes are those that were formed
with 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 the
production of radioactive fission products like I131 . This process is
performed in a nuclear reactor.

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
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 the
production 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) .

 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.

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 :

a) Teletherapy sources 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 malignant
tumours.
It has been used in treatment of prostate and cervix uterine
carcinoma and bladder tumours.

b) Sodium phosphate ( 32 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 of
chronic granulocytic leukemia.
c) Sodium iodide (131I ):
In cases of hyperthyroidism, therapeutic doses of iodine-131
will 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;
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 doses
3- 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:

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 its
radioactivity is measured .

The blood volume is calculated from the measured

decrease in radioactivity of the injected sample upon its
dilution by the blood.

2- Isotope disappearance rate:

This technique is used for measuring half life of RBCs.
A blood sample is withdrawn and its RBCs are labeled
with 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 hemolytic
anemia . RBC half-life = 1 - 7 days.

3- Isotope transfer rate:

This technique is used to determine circulation time especially in
the extremities.
24Na is injected into one part of the vascular system and the time
required 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) Thyroid function is measured by determining the thyroid uptake
of 131 I after oral administration of Na 131 I
b) Liver function 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
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:
Na 131I 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:
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

1-Biological effects
a) Inactivation of essential enzymes
b) 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
These effects occur from about 2 months to many
years after exposure. They include:
Cataract, severe anemia, leukemia and cancer
4-Genetic effects
Radiation has 2 effects on reproductive cells:
a) Damage of chromosomes
b) Increase in frequency of gene mutation

Maximum permissible exposure

a) External exposure
The external exposure is calculated by the maximum
permissible dose (MPD) which differs according to the
organ to be exposed as follows:
1- MPD for critical organs like eyes = 5 rems / year
2- MPD for arms, feet and ankles =25 rems /year
3- MPD for skin and other organs = 10 rems / year

B) Internal exposure
The internal exposure is calculated by the maximum
permissible concentration (MPC) as follows:
1- MPC for critical organs = 5 rems /year
2- MPC for the skin and thyroid gland =30 rems / year
3- MPC for other organs =15 rems I year

Precautions for radioprotection

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 working
area 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 a
confined area.
7 - The radioactive material must be kept in double containers .

Chemical protective agents

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.

Chapter III

OPHTHALMIC PREPARATIONS

OPHTHALMIC PREPARATIONS
Ophthalmic preparations are sterile products
essentially free from foreign particles, suitably
compounded and packaged for installation into
the eye.
They may be in the form of Solutions,
Suspensions, Ointments or solid dosage forms

Absorption of drugs in the eye

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 is
only 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

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

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 penetrate
the three layers of the cornea ( lipid-rich epithelium, lipid-poor
stroma and lipid-rich endothelium) as shown in the figure.

Penetration of an alkaloid through the intact comes by

differential solubility

Pharmacologic Categories of Ophthalmic Drugs

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, are

used to treat inflammation of the eye, as allergic conjunctivitis.

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

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.

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. They
are intended to soothe, refresh, and remove redness due to minor
eye irritation.
Anti-histamines :as pheniramine maleate, are included in some
products to provide relief of itching due to pollen and ragweed.

Factors affecting ocular bioavailability:

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 drugprotein complex has a difficulty in penetrating the cornea.
lacrimal drainage: 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:

A- Drugs having lipophilic and hydrophilic characters are able to
penetrate the Cornea (corneal membrane contains both lipophilic
and 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

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 :
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:
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 antiinflammatory 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:

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
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:
The ointment vehicle is usually a mixture of mineral oil and
white petrolatum.
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
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
phenylmercuric acetate 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
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 white
boarder for visibility.

 The ocusert system provides a nearly steady zero-order

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 oneeighth 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
place. Replacement of contaminated unit
fresh one is very expensive

a.

FORMULATION AND PREPARATION OF OPHTHALMIC PRODUCTS

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 of
tear 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:

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 of
solution is not excessive and does not have a strong
resistance to neutralization (minimum buffer
capacity).

Tonicity adjustment:
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.
Sulfacetamide which is used in a concentration range of
10% - 30 % , while the isotonic solution should contain
only 3.5 % of the drug.
The tonicity adjusting ingredients usually used
include: NaCI - KCI Buffer salts - Dextrose - glycerin propylene glycol.

Viscosity - imparting agents

The USP permits the use of viscosity increasing agent to
prolong the contact time in the eye and thus enhance drug
absorption 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 a
concentration of 0.5 % depending on the pH and ionic
concentration of the product.

Preservatives and their choice

The limited choice of preservative agents is narrowed
when the requirements of chemical and physical
stability and compatibility are considered for a particular
formulation and package.
The choice of preservative is limited to only a few
chemicals that have been found over the years to be
safe and effective for this purpose.

a- Benzalkonium chloride:
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 penetration
enhancer for some drugs in addition to its preservative activity.

b- Organic mercurials :
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 . It has relatively slower activity, but acceptable stability at

room temperature when used in acidic solution around pH 5 or
below.
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

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 .-

In addition to its weak activity, it is volatile and

will lose activity via permeation through plastic
package.
It has limited water solubility, and can produce
burning 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:
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

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.

 The plastic bottle has the dispensing tip as an

integral part of the package, which can be designed
to deliver only one drop or stream of fluid for
irrigation.
The plastic bottle and dispensing tip are made of
low-density polyethylene (LDPE) resin which
provides the necessary flexibility and inertness.
In addition to stability studies on the product in
the containers, over a range of normal and
accelerated temperature, the plastic resin must pass
the biological and chemical tests for suitability.

 LDPE is compatible with a wide range of drugs and

formulation components, but the main disadvantage is:
its sorption and permeability 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 as
titanium 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.
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
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 I for 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.

Contact Lenses
Contact lenses are classified according to chemical
composition & physical properties into:
I. Hard contact lenses:
a. They are termed hard because they are made of a rigid
plastic resin, poly-methyl-methacrylate (PMMA).
b. They are 7-10 mm in diameter.
c. They only cover a part of the cornea
d. They float on the tear layer overlying the cornea.

Advantages:
1. Durable.
2. Provide dear, crisp vision for the patient.
Disadvantages:
1. They require a long adoption period as long as a week for
wearing comfort.
2. Some patients find them difficult to wear. because of their rigidity.
3. Are practically impermeable to O2 and moisture which impairs
corneal epithelial respiration.
4. May cause physical damage to epithelial tissue If placed
directly on the corneal surface.
To prevent direct contact, solutions are used that wet the surface of
the lens and provide a cushioning layer between the corneal
epithelium and the inner surface of the lens.

II. Soft contact lenses

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
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 hard
lenses.
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.
2- Extended-wear lenses 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 O2 permeable but
hydrophobic.
There are 2 types of RGP contact lens:
A- daily-wear
B- Super permeable extended-wear.

Advantages
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:

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 the
wearer than soft lenses.
2. They are more easily dislodged in eye than soft
lenses.

Chapter IV

AEROSOLS

AEROSOLS
Definition:
Colloidal systems, consisting of very finely subdivided
liquid or solid particles dispersed in and surrounded by a
gas.

Aerosols have been used for the symptomatic treatment

of 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 .
2- There is no danger of contamination of the product with
foreign materials

3- Protection from destructive effects of both air and moisture.

4- Sterility is maintained throughout the life of the product .

5- Accurate dosage form .

6- Dispensing of the product in the most desirable form; spray,
foam or semisolid preparation over an abraded area

7- Reduction or elimination of the irritation produced by the

application of topical preparation over an abraded area

8- It can be easily applied in a thin layer with no waste

a-Economy
b- May result in faster absorption and more efficient use
of medication.
9- The cooling effect of liquefied gas propellant may be
desirable in certain skin conditions.

Disadvantages:
1- Cost .
2- Disposal may be difficult.
3- Heat can develop high pressure.
4- Difficulty in formulation of emulsion and suspension aerosols.
5- Toxicity of propellants.
6- Catalytic effect of trace metals.
7- Interaction of aerosol components.

Components:
1- Propellants
2- Containers
4- Product concentrate

3- Valves and actuators

5- Protective caps

I- Propellants
The propellant is generally regarded as the heart of the aerosol
package. It is responsible for development of pressure within the
container, supplying the necessary force to expel the product
when the valve is opened.

Functions:
1- Apply the necessary force to expel the product.
2- Solvent and diluents .
3- Determine the characteristics of the product as it leaves the
container (in addition to the nature of formulation and the
valve design). .

Classifications of propellants:

A-Liquefied gases:
a- Fluorinated chlorinated hydrocarbons.
b- Hydro-chloro-fluorocarbons.
c- Hydro-chlorocarbons.
d- Hydrocarbons
e- Hydrocarbon ether
B-Compressed passes:
a - Nitrogen
b- Nitrous oxide
c- Carbon dioxide

A- Liquefied gas propellants:

Liquid gas propellants, mostly chlorinated, fluorinated hydrocarbons, have been used in refrigeration units for a number
of years.
They are used as propellants and as refrigerants due to their low
boiling points and high vapor pressures.

Since each propellant has a definite vapor pressure at a given

temperature, it may be possible to select a propellant to give the
desired pressure in an aerosol.
if a single propellant does not give the desired pressure, two of
these propellants can be blended to obtain a mixture which will
produce the desired pressure at a given temperature.

One advantage of liquefied propellants is the fact that as long as

there is some liquid propellant in the pressurized package, the
product will have a constant pressure at a given temperature.
Although the fluorinated hydrocarbons generally are considered
to be non-reactive, some of them are subjected to hydrolysis and
alcoholysis. Propellant 11 (Trichloro-monofluoro-methane) cannot
be used in packaging products that contain water or ethyl alcohol
because free hydrochloric acid may be formed causing corrosion
of metal containers.
Propellant 12 (Dichloro-difluoro-methane)
and 114 (Dichloro-tetrafluoro-ethane) are relatively stable in the
presence of water and alcohol.

B- Compressed gas propellants

The compressed gases that are used most frequently in preparing
aerosols are N2, CO2 and NO. Nitrogen is practically insoluble in
water, whereas the other two gases are slightly soluble.
Advantages of N2
1- The insolubility of N2 makes it possible to prepare aerosols so
that the dispensed products have the same consistency that they
had when they were placed in the package, an advantage in
aerosols of vitamin syrups, tooth pastes and some lotions and
ointments in which a foaming product would be objectionable.

2- Products packaged with N2 are not subjected to oxidation. The

gas is colorless, odorless and tasteless and is readily available at
low cost.

Disadvantage of N2 (as have also CO2 and NO, although

to a lesser degree).
Aerosols using N2 as the propellant must be packaged at a
higher pressure than aerosols prepared with liquefied gases
because there is a considerable pressure drop as the product is
dispensed from the container.
Compressed. gases, which are slightly soluble in water, have a
slight reserve in pressure because of the dissolved quantity of
gas. C O2, NO or mixtures of both are used to pressurize aerosols
from which it is desired to dispense the product as a foam.
When the product emerges from the opened valve into the
atmosphere, the dissolved gases expand and produce the foamy
product.

II- Containers:
Different materials are used for the manufacture of aerosol
containers. The materials must be inert, non-toxic and must
withstand pressure as high as 140 to 180 psi at 130 F'.
A. Metal:
1- Tin-plated steel:
The tin-plated steel container, the most widely accepted of the
metal containers, is fabricated from sheets of steel plates that
have been coated with a layer of tin. The thickness of the tin on
each side is dependent on the amount of tin used and is about
0.00006 inch on each surface.

Advantages:
1- Light
2- Relatively inexpensive.
3-For certain preparations (e.g hair lacquers) the tin
affords sufficient protection.

Disadvantages:
Addition of water or other corrosive ingredients or other
substances which will attack tin require a container having an
additional coating. This coating is usually organic in nature and
may consist of an oleoresin, phenolic, vinyl or epoxy coating.

2- Aluminum:

It may have a protective coating of phenolic, vinyl or epoxy resin

applied to the inner surface to protect them from the corrosive
effect of some aerosol constituents. It is used for most oral
aerosols.
Advantages:
1- Light weight.
2-lnert
3-Can be used without internal coating. Many containers are
available which have internal coating made from an epoxy-type
resin. Thus an added resistance toward reactivity is obtained.
4-Seamless i.e. there is no danger of leakage

Disadvantages:
It will react with certain solvents and other chemicals. For
example, anhydrous ethanol is extremely corrosive to
aluminum, so:
- Dissolving of aluminum.
- Liberation of hydrogen gas which results in increase of
pressure and subsequent rupture of the container.
This can be reduced or prevented by:
a- Coating aluminum.
b- Adding 2-3% water to the formula

B-Glass:

Advantages:
1- Excellent compatibility with pharmaceuticals

2- View the level of the contents remaining in the container

3- Greater freedom in design of the container

4-Plastic coated glass containers are employed mainly with

solution aerosols. They are not recommended for suspension
aerosol due to the visibility of suspended particles.

The plastic coating of glass bottles has the following functions:

A-Protect from flying glass in the event of glass scattering when
the container is broken.
B- The coating around the neck of the container serves to
absorb some of the shock from the crimping operation and
decreases the danger of breaking during this operation.
C- The coating also serves as an ultraviolet light absorber.
These plastic coatings are available in a clear finish or in various
colors.

C- Plastics:

Advantages:
I-Minimal breakage,
2-Absorb shock due to crimping.
3-Protect medicinal agents from UV lights
4-Clarity
5-Good chemical compatibility
6-Excellent impact-resistance

III- Valves:
The most basic part of any aerosol is the valve mechanism
through which the contents of the package are emitted.
The function of the aerosol valve is
1- To control the flow of the product from the container.
2- To allow the flow of the desired quantity of product from the
container when in use, and prevents the flow of product,
during storage.
3- The valve also affects the properties of the product as it flows
from the container, although the formulation itself plays a
part in these properties.

The valve should be capable of being easily opened and closed,

and deliver the specific amount in the desired form. Although
valves for aerosols depend on the particular use whether spray,
foam or solid stream, the majority fall into the following:

Classification of valves:
1- Continuous spray valve:

An aerosol valve consists of many different parts.

Various materials are used to manufacture the many
components of the valve.
A typical aerosol valve consists of the following parts:

a- Mounting cup
It is used to attach the valve to the container. For use with
containers having a one-inch opening, the cup is made from tin
plated steel or aluminum. Since the underside of the valve cup
is exposed to the contents of the container and to the effects of
O2 trapped in the head space, a single or double epoxy or vinyl
coating can be added to increase the resistance. For attachment
to container having an opening of less than 1 inch, the
mounting cup is referred to as a ferrule and is attached to the
outside of the container. This is made from a variety of different
metals, one of which is brass. Since the ferrule doesn't come
into contact with the formulation, there is less danger of
incompatibility.

b. Stem
The stem supports the actuator and delivers the formulation in
the proper form to the chamber of the actuator. One or more
orifices are set into the stem about 0.013 inch to 0.030 inch to
three orifices of 0.040 inch each. The stem is made from Nylon or
Delrin, although a metal such as brass can be utilized.
c. Gasket
The gasket placed with the stem, serves to prevent leakage of the
formulation when the valve is in closed position.
d. Spring
The spring holds the gasket in place and also in the mechanism by
which the actuator retracts when pressure is a released, thereby
returning the valve to the closed position

e-Housing
The housing is located below the mounting cup, serves
as a link between the dip tube and the stem and
actuator.
The housing contains an opening at the point of
attachment of the dip tube. Manufactured from Nylon
or Delrin and contains an opening ranging from about
0.013 inch to.0.080 inch. .""

f- Dip tube
The dip tube extends the housing down into the product
made from polyethylene or polypropylene. Both materials are
acceptable for use although the polypropylene tube is
generally more rigid.
The inside diameter of the commonly used dip tube is about
0.120 ineh to 0.125 inch, although capillary dip tubes are
about 0.050 inch and dip tubes for very viscous products may
be as large as 0.195 inch. Viscosity and the desired delivery
rate play an important role in the choice of a suitable dip
tube. Its function is
.1- Transports the liquid from the bottom of the container to
the dispensing valve at the top.
2- Prevents the propellant from escaping without dispensing
contents of the package.

g- Actuators:
They are buttons through which the user activates the valve
assembly for the emission of the product.
Functions:
1 - Provide a rapid and convenient means for releasing the
contents.
2- Allowing the product to be dispensed in the desired form e.g.
fine mist, spray, foam or solid stream.
The combination of the type and quantity of the propellant used
and the actuator design and dimension control the particle size
of the emitted product.
Large orifices (0.07 inch to 0.125 inch and greater) and less
propellants are used for products to be emitted as foams and
solid streams than those intended to be sprayed for misted.
3- Special actuator allows the dispensing of the product into the
mouth, nose, throat vagina, and eye

There are many different types of actuators:

i- Spray actuators:
Actuators for sprays are capable of dispersing the stream of
product concentrate and propellant into relatively small particles
by allowing the stream to pass through various openings (1 to 3
of 0.016 to 0.04 inch in diameter). Where there is a large
percentage of propellant mixture containing a sufficient quantity
of a low boiling propellant such as propellant 12, actuators having
relatively large orifices can be used. The combination of
propellant vaporization and actuator orifice and internal channels
can deliver the spray in the desired particle size range.

Spray actuators can be used with pharmaceuticals intended

for topical use such as spray - on bandages, antiseptics, local
anesthetics, and foot preparations. When these actuators are
used with aerosol products containing relatively low amounts
of propellants (50% or less), the product will be dispensed as
a stream rather than as spray, since the propellant is not
sufficient to fully disperse the product. For these products, a
mechanical breakup actuator is usually required. These
actuators are capable of "mechanically" breaking a stream
into fine particles by causing the stream to "swirl" through
various channels built into the actuator.

ii- Foam actuators:

These actuators consist of relatively large orifices which allow
the passage of the product into a relatively large chamber,
where it can expand and be dispensed through the large
orifice.

iii- Solid- stream actuator:

Semi-solid products as ointments generally require relatively
large openings similar to foam type -actuators to allow for the
passage of product through the valve stem and into the
actuator.
iv- Special actuators:
These are specially designed to deliver the medication to the
appropriate site of action - throat, nose, eye or vaginal tract.

2- Metering valves:
Metered valves are applicable to the dispensing of potent
medication. These valves deliver a measured quantity of aerosol
mixture at each actuation. Metering can be accomplished by
one of two methods.
The dip tube may contain a steel ball which operates between a
lower stop (merely a pin through the polyethylene tubes) and a
ball valve seat at the upper level. When the valve is actuated,
the fast flowing product carries the steel ball up in the tube until
the ball seats in the valve, at which time no more product can
flow up the dip tube. When the actuator is released, the steel
ball returns slowly to its lower position in the tube and is then
ready to deliver another quantity

Metering can be accomplished by the use of 2 valves separated

by a metering chamber or reservoir. Product is admitted to the
reservoir by opening the valve from the pressure packages and
simultaneously closing the valve on the dispensing end of the
reservoir. When the dose is to be taken, the dispensing valve is
opened and the other valve is closed simultaneously. The valves
are constructed to operate together on up and down strokes of
the valves controls. The volume of the reservoir determines the
quantity of spray per dose.

3- Standard valves:
The type of valve used most commonly is the standard valve
with an ordinary actuator button. These valves are suitable for
space and surface sprays in which the liquid propellant is a part
of the liquid phase. The actuator button for sprays usually has
an external orifice which is about 0.02 inch in diameter.
All spray valves have series of communicating passages which
serve as expansion chamber, the drop in pressure is sufficient
to cause the liquefied propellant to expand and boil. As the
material passes through successive orifices into other
passages, there are additional expansion and violent boiling
which serve to break the product up into small particles as it is
forced, along in the expanding gas stream.

4- Foam valves:
These valves are designed to deliver foamy or aerated
products. It may have only one expansion orifice which
connects directly into the actuator button without
intermediary obstruction. The actuator usually has a large
external orifice approximately 0.3 inch diameter. The
relatively large expansion chamber of the valve and the
actuator button allows the formation of foam within the
button so that the product is forced out in a foamy condition.

5- Powdered valves:
Standard valves can be used with many powder formulations,
especially if the powder is very fine and the concentration of
powder in the pressurized package is not too high. The most
serious difficulty experienced in preparing powder aerosols is the
accumulation of powder at the valve seat.
Valves with a high seating pressure and with the valve seat located
close to the orifice seem to be the most effective for powder
aerosols. If the valve is operated wide open, there is less
accumulation of powder at the valve than if the valve were only
partially opened in operation. Wide-open operation may result in
the discharge of a large plume of powder.

6- Compressed gas valves:

Valves intended for use in systems that employ
compressed gases may be provided with large orifices
and large diameter dip tubes to permit the passage of
thick, viscous preparations such as syrup and lotions.

IV- Product concentrate:

It is active ingredient of the aerosol combined with
the required adjuncts, such as antioxidants surface,
active agents and solvents to prepare a stable and
efficacious product

V- Protective caps:
Functions:

I-protect the valve assembly during storage and

transport.
2-decorative.
Protective caps are made of metal or polyethylene
or some other plastic materials.

Formulation of Pharmaceutical Aerosols

An aerosol formulation consists of two essential
components:
1. Product concentrate
2. Propellant.

The product concentrate consists of active ingredients

or a mixture of active ingredients and other necessary
agents such as solvents antioxidants, and surfactants.

However, since one must be familiar with the physicochemical

properties of surfactants, solvents, and suspending agents, it
follows that the formulator of aerosol preparations must be
thoroughly familiar with propellants and the effect the
propellant will have upon the finished product.
Propellants can be combined with active ingredients in many
different ways producing products having varying
characteristics. Depending on the type of aerosol system
utilized, the pharmaceutical aerosol may be dispensed as a fine
mist, wet spray, quick-breaking foam, stable foam, semi-solid,
or solid.
The type of system selected is dependent on many factors
including the following
(1) Physical, chemical, and pharmacological properties
of active ingredients, and
(2) Site of application.

Types of systems:
1- Formulation for solution system (Two-Phase System):
When the active ingredients are soluble in the propellant, no
other solvents are required.
Propellant 12 produces very fine particles. As other propellants
are added to propellant 12, the pressure of the system is
decreased giving larger sized particles. A lowering of vapor
pressure also is produced through the addition of less volatile
solvents such as ethyl alcohol, propylene glycol, ethyl acetate,
glycerin, acetone, and other similar solvents. Some amount of
propellant may vary from 5% to 50% of the entire formulation.
These sprays are useful for inhalation and also for topical
preparations, since they will tend to coat the affected area with a
film of active ingredients.
Example: Active ingredients up to '
10-15 %
Propellant 12/11 (50:50) up to
100%

2- Formulation for water - based system:

Relatively large amounts of water can be used to replace all or
part of the non aqueous solvents.
To obtain a spray, the formulation must consist of a dispersion of
active ingredients and other solvents in an emulsion system in
which the propellant is in the external phase.
In this way, when the product is dispensed, the propellant
vaporizes and disperses the active ingredients into minute
particles. Since propellant and water are not miscible, a three phase aerosol will be formed (propellant phase, water phase and
vapor phase).
Ethanol has been used as a cosolvent to solubilize some of the
propellant in the water.

3- Formulation for suspension or dispersion systems:

Such system involves a dispersion of active ingredients in

propellant or a mixture of propellants. In order to decrease the
rates of settling of the dispersed particles, various surfactants or
suspending agents have been added to the system.
Example:
Epinephrine bitartrate (1-5 um)
0.5%
Sorbitan trioleate
0.5%
Propellant 11
49.5%
Propellant 12
49.5%

The epinephrine bitartrate has a minimum solubility in the

propellant system, but is sufficiently soluble in the fluids in the
lungs to exert therapeutic activity. The stability of aerosol
dispersion can be increased by:
1- Control of moisture content.
2- Use of derivatives of active ingredients having minimum
solubility in propellant system.

3- Reduction of initial particle size to less than 50 m

4- Adjustment of density of propellant and / or suspension so
that they are equalized, and the
5- Use of dispersing agents.

4- Formulation for foam systems:

Foam aerosols consist of active ingredients, aqueous or non
aqueous vehicle, surfactant and propellant and are dispensed as
stable or quick - breaking foam, depending on the nature of the
ingredients and the formulation.

The liquefied propellant is emulsified and is generally found in the

internal phase.
a) Stable foam:
They can be formulated as follows:
Active ingredients
Oil- waxes
O/W surfactant
Water
75 95%
Propellant 12/114 (60-40)
5-25%

While the total propellant content may be as high as

25% in certain cases, it usually is about 8 to 10%.
As the amount of propellant 12 increases, stiffer and
dryer foam is produced.
Lower propellant concentrates yield wetter foams.
Propellant 114 is used as a replacement for propellant
11 in the presence of water since the latter will form
hydrochloric acid.

b) Non aqueous stable foams:

Non aqueous stable foam may be formulated through the use
of various glycols such as polyethylene glycol, which may be
formulated according to the following:
Glycol
86%
Emulsifying agent
4%
Propellant 12/114(40:60) 10%
The most effective emulsifying agent was formed from the
class of glycol esters such as propylene glycol mono-stearate.

Various medicinal agents can be incorporated into the above

base.

c) Quick-Breaking foams:
This system finds the propellant in the external phase. When
dispensed, the product is emitted as a foam which then
collapses into a liquid.
This type of system is especially applicable to topical
medication, which can be applied to limited or to large areas
without the active ingredients. Quick-breaking aerosol foams
may be formulated starting with:
Ethyl alcohol
46-66%
Surfactant
0.5-5%
Water
28-42%
Propellant
3 - 15%

d) Thermal foams:
Thermal foam systems operate on the principle that two
chemicals, contained in the same package but separated from
each other by non-permeable membranes, are dispensed at
the same time and given portion. When they are mixed in the
valve, an evolution of heat occurs warms the surrounding
media.
Greater importance than the production of warm foams is the
possibility of dispensing incompatible ingredients since they
need not to be mixed until just prior to use.
Drugs of limited stability when mixed with water, vitamins,
and effervescent preparation are just a few of the new
applications that may be possible.

Filling operations (packaging):

Two methods have been developed for the filling of aerosol
products.
The cold filling method requires the chilling of all components,
including concentrate and propellant, to temperatures of -30 or
40F, while the pressure filling method is carried out at room
temperature utilizing pressure equipment. The type of product
and size of container generally influence the method to be used.

For the most part, the pressure method is used to fill aerosol
pharmaceutical products.
Various factors determine the method to be used. The
pressure method generally is preferred to the cold method,
since:
there is less danger of contamination of the product with
moisture,
high production speeds can be achieved,
less propellant is lost, and the method is not limited, except
for certain type of metering valves which can only be
handled by the cold fill process or through use of an "under
the cap" filler and valve crimper. Some metered valves are
now available which are pressure-fillable.

Quality control for pharmaceutical aerosols:

Basically there is no difference between methods "used to
produce pharmaceutical aerosols and those used to produce
non pharmaceutical aerosols, but there are differences in the
standards and specifications for their production.
The standards 'of production for aerosol pharmaceuticals
resemble more closely those for non-aerosol pharmaceuticals.

Weight checking:
This is generally accomplished by periodically adding to the
filling line tared empty aerosol containers which, after being
filled with concentrate, are removed and then accurately
weighed. The same procedure is used to check the weight of the
propellant that is being added. When a propellant blend is being
utilized, checks must be made to ensure a proper blend of
propellants. As a further check, the finished container is
weighed in order to check the accuracy of the filling operation.

Leak testing:
A means of checking the crimping of the valve must be
available in order to prevent defective containers due to
leakage. For metal containers this is accomplished by
measuring the "crimp" dimensions and ensuring that they
meet specifications.
Final testing of the efficiency of the valve closure is
accomplished by passing the filled containers through the
water bath. Periodic checks are made of the temperature of
the water bath and these results are recorded.,

Spray testing:
Many pharmaceutical aerosols are 100% spray tested. This
serves to clear the dip tube of pure propellant (for pressure
filled products) and as a check for defects in the valve and of
the spray pattern. For metered valves, it serves to prime the
valve so that it is ready for use by the consumer.

Testing of pharmaceutical aerosols:

Aerosols are "pressurized packages" and many tests
are necessary in order to ensure proper performance
of the package and safety during use and storage.

Pharmaceutical aerosols can be evaluated by a series

of physical, chemical, and biological tests, including:

A. Flammability and combustibility.

1. Flashpoint.

2. Flame extension.

B. Physicochemical characteristics
1. Vapor pressure.
2. Density.
3. Moisture content.
4. Identification of propellant(s).
5. Concentrate-propellant ratio.

C- Performance.
1. Aerosol valve discharge rate.
2. Spray pattern.
3. Dosage with metered valves.
4- Net content
5. Foam stability
6- Particle size determination
7. Leakage.
D- Biological.
1. Therapeutic activity
2. Toxicity

1- Flame extension:
This test indicates the effect of an aerosol formulation on the
extension of an open flame.
The product is sprayed for about four seconds into a flame.
Depending on the nature of the formulation, the flame will be
extended, the exact length being measured with a ruler.
2- Flash point:
This is determined by use of the standard Tag Open Cup
Apparatus.
The aerosol product is chilled to a temperature of about -25F
and transferred to the test apparatus. The test liquid is allowed
to increase slowly in temperature, and the temperature at
which the vapors ignite is taken as the flash point.

3- Vapor pressure:
The pressure can be measured simply with a pressure gauge. It is
important that the pressure variation from container to
container be determined, since excessive variation indicates the
presence of air in the head space.
4- Density:
The density of an aerosol system may be accurately determined
through the use of a hydrometer or a pycnometer.
These methods, which have been used for the density of nonaerosols, have been modified to accommodate liquefied gas
preparations.

5- Moisture:
Many methods have been found useful for this purpose. The
karl- Fischer method has been accepted to a great extent.
6- Identification of propellants:
Gas chromatography and infrared spectrophotometry (IR) have
been used to identify the propellants and also to indicate the
proportion of each component in a blend.
7- Aerosol valve discharge rate:
This is determined by taking an aerosol product of known
weight and discharging the contents for a given period of time
using standard apparatus. By reweighing the container after the
time limit has expired the change in weight per time dispensed
is the discharge rate which can then be expressed as grams
/second or grams /minute.

8- Spray patterns:
A method for comparing spray patterns obtained from
different batches of material or through the use of different
valves is available.
The method is based on the spray on a piece of paper that has
been treated with a dye-talc mixture. Depending on the nature
of the aerosol, an oil-soluble or water-soluble dye is used.
The particles that strike the paper cause the dye to go into
solution and to be absorbed onto the paper. This will give
record of the spray which can then be used for comparison
purposes. To control the amount of material coming into
contact with the paper, the paper is attached to a rotating disk

9- Dosage with metered valves:

Several points must be considered:
1- Reproducibility of dosage each time a valve is depressed
2- Amount of medication actually recived by patient.
Reproducibility of dosage may be determined by assay
techniques whereby one or two doses are dispensed into a
material that will absorb the active ingredients. These solutions
can then be assayed and the amount of active ingredients
determined. Another method that can be used involves accurate
weighing of filled container followed by dispensing of several
doses. The container can then be reweighed, and the difference
in weight divided by the number of doses dispensed will give the
average dose. This must then be repeated and the results
compared.
Determination of the dosage received by a patient is a rather
difficult procedure, since all of the material dispensed is not
carried to the respiratory tract.

10- Net contents:

Several methods can be used to determine whether sufficient
product has been placed into each container. The tared cans
that have been placed onto the filling line are reweighed and
the difference in weight is equal to the net contents. The
other method is a destructive method and then dispensing
the contents. The contents are then weighed, with provision
being made for the amount retained in the container, other
modifications consist of opening the container and removing
as much of the product as possible. These tests are not
indicated in determining the actual net weight of each
container as related to the amount that can actually be
dispensed.

11- Foam stability:

Various methods have been suggested for the determination of
foam stability. The life of foam can range from a few seconds (for
some quick-breaking foams) to one hour or more depending on
the formulation.
Several methods have been used which include a visual
evaluation, time for a given mass to penetrate the foam, time for a
given rod that is inserted into the foam to fall, and the use of
rotational viscometers.

12- Therapeutic activity:

Various testing procedures are available to determine the
therapeutic activity of aerosols. With the exception of giving
consideration to the aerosol feature of the package, these
procedures are similar to existing tests used for non-aerosols.
The dosage .of the product will have to be determined for
inhalation aerosols and this must be related to particle size
distribution. Topical preparations are applied on the test areas in
the usual manner, and absorption of therapeutic ingredients can
be determined.

13- Toxicity:
Toxicity testing should include both topical and
inhalation effects. Aerosols applied topically may -be
irritating to the affected area and/or may cause a chilling
effect. The degree of chilling effect is dependent on the
type and amount of propellant present. There is no really
good test available at the present time, although the use
of thermistor probes attached to recording
thermometers have been used to indicate the change in
skin temperature when sprayed with an aerosol for a
given period of time.
Inhalation toxicity must also be considered even though
the product may be intended for topical administration.
This can be done by exposing test animals to vapors
sprayed from an aerosol container.

Thank you