Sterile dosage forms

By Amna Matly
 Introduction

 Sterile products are the dosage forms of therapeutic

agents that are free of viable microorganisms.
 Principally, these include parenteral, ophthalmic and
irrigating preparations.
 These parenteral products are unique among dosage
forms of drugs because they are injected through the
skin or mucous membrane into internal body
compartments.
 They must be free from microbial contamination and
toxic components ,as well as possess an exceptionally
high level of purity. Although parenteral are comes
under category of sterile products but all sterile
products can’t say as parenterals.
 The human eye is a remarkable organ and the ability to see is
one of our most treasured possessions. Thus the highest
standards are necessary in the compounding of ophthalmic
preparations and the greatest care is required in their use. It is
necessary that all ophthalmic preparations are sterile and
essentially free from foreign particle.
 5

 All products must be sterile.

 All products must be free from pyrogenic (endotoxin)
contamination.
 Injectable solutions must be free from visible particulate matter.
this includes reconstituted sterile powders.
 Products should be isotonic, although strictness of isotonicity
depends on the route of administration. Products administered into
the cerebrospinal fluid must be isotonic
 6

 An immediate physiological response can be achieved if

necessary, which can be of prime consideration in clinical
condition such as cardiac arrest, asthma and shock .
 Parenteral therapy is required for drugs that are not effective
orally or that are destroyed by digestive secretions such as insulin
other hormones and antibiotics.
 Drug for uncooperative, nauseous or unconscious patients must be
administered by injection.
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 When desirable, parenteral therapy gives the

physician control of the drug since the patient must return
for continued treatment, also in some cases the
patient cannot be relied upon to take oral administration.
 Parenteral administration can results in local effect for
drugs when desired as in dentistry and anesthesiology.
Disadvantages:
8

 Once injected cannot be controlled (retreat).

 Injections may cause pain at the site of injection.
 Only trained person is required.
 If given by wrong route, difficult to control adverse effect.
 Difficult to save patient if overdose.
 Sensitivity or allergic reaction at the site of injection.
 Requires strict control of sterility & non pyrogenicity than other
formulation.
 9

•Based on types of packaging

1)Single dose units: ampoules, infusions and prefilled
disposable syringes
2)Multiple dose units: multiple dose vials

•Based on the production and control

a)Small volume parenterals: volume < 100 ml
b)Large volume parenterals: volume ≥ 100 ml
•Based on clinical use
10 a)Solutions for irrigation
b)Ophthalmic solution
c)Dialysis solution
d)Diagnostic agent
e)Allergenic extracts
f)Implants

•Based on physical state of product

a)Sterile solutions
b)Sterile suspensions
c)Sterile emulsions
 11 Small volume parenterals:
Volume of these parenterals varies from fractions of Milli liter to
several hundred milliliters i.e. 1ml to 500ml.
Example: Injections :- Furosemide, Heparin, Cimetidine, Iron
dextran etc.

Large volume parenterals:

Volume of these parenterals varies from 500ml and above. they are
administered as single dose injections at a slow rate.
Example: Infusion Fluids, Total parenteral nutrition solutions,
patient controlled analgesia, dialysis fluids etc.
 Components of parenteral products
12

Parenteral drugs are formulated as solutions,

suspensions,emulsions, liposome, microspheres, nanosystems,
and powders to be reconstituted as solutions.
 Vehicles
 Stabilizers
 Buffering agents
 Tonicity factors
 Solubilizers
 Wetting, suspending, emulsifying agents
 Antimicrobial compounds
 Solvents systems
13

 The drug is generally present in an injection in low concentration.

 The vehicle provides the highest proportion of the formulation

and should not be toxic nor have any therapeutic activity.

 The first choice of solvent is obviously water.

 However, although the drug may be freely soluble, it may be

unstable in aqueous solution.
 VEHICLES
14 Water for injection:
a.It is most frequently used in the large scale manufacturer of
injections.
b.Water of suitable quality for compounding and rinsing product
contact surfaces may be prepared either by distillation method or
reverse osmosis, to separate adequately various liquid, gas, and
solid contaminants and undissociated substances such as pyrogens
present in the absence of ions from water.
c.It is not required to be sterilized and pyrogen free.
d.It is intended to be used within 24 hours after collection.
e.The water should be collected in sterile and pyrogen free
containers.
f.It contains total solid contents not more than 1 mg/100 ml.
 Non-aqueous vehicles
15

 Water-miscible co-solvents, such as glycerin and propylene glycol are used as

vehicle in small-volume parenteral fluids.

 They are used to increase the solubility of drugs and to stabilize drugs degraded

by hydrolysis.

 Metabolizable oils are used to dissolve drugs that are insoluble in water. E.g.

Steroids, hormones and vitamins are dissolved in vegetable oils.

 These formulations are administered by intramuscular injection.

 Antioxidants
16
 Many drugs in aqueous solutions are easily degraded by oxidation. Small-volume

parenteral products of these drugs often contain an antioxidant.

 Bisulphites and metabisulphites are commonly used antioxidants in aqueous injections.

 Antioxidants must be carefully selected for use in injections to avoid interaction with

the drug.

 Antioxidants have a lower oxidation potential than the drug and so are either

preferentially oxidized or block oxidative chain reactions.

 Antibacterial
17

 Antibacterials may be divided into two groups according to their speed of

action and residue production:

 The first group contains those that act rapidly to destroy bacteria, but quickly

disappear. E.g. alcohols, chlorine, peroxides, and aldehydes.

 The second group consists mostly of newer compounds that leave long-acting

residues on the surface to be disinfected and thus have a prolonged action. E.g.
triclocarban, and benzalkonium chloride.
 Buffers
18
 The ideal pH of parenteral products is pH 7.4.

 If the pH is above pH 9, tissue necrosis may result, whilst below pH 3 pain

and phlebitis in tissues can occur.
 Buffers are included in injections to maintain the pH of the packaged
product.
 pH changes can arise through interaction between the product and the
container.
 Acetate, citrate and phosphate buffers are commonly used in parenteral
products.
 Chelating agents
19

 Chelating agents such as disodium edetate may be

included to chelate the metal ions and thus enhance
stability.
 It is seen that disodium edetate is a very useful adjuvant to
ophthalmic preparations at concentrations of up to 0.1 %
w/v to enhance antibacterial activity and chemical
stability.
 Inert gases
20

 An inert gas is a gas which does not undergo chemical reactions

under a set of given conditions.
 Inert gases are used generally to avoid unwanted chemical
reactions degrading a sample.
 The term inert gas is context-dependent because nitrogen gas and
several of the noble gases can be made to react under certain
conditions.
 Purified nitrogen and argon gases are most commonly used as
inert gases.
 Surfactants
21

 Certain compounds, because of their chemical structure, have

a tendency to accumulate at the boundary between two phases,
such compounds are termed surfactants.
 The adsorption at the various interfaces between solids, liquids
and gases results in changes in the nature of the interface
which are of considerable importance in pharmacy.
 Surfactants are generally classified according to the nature of
the hydrophilic group.
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Containers and closures
Large-volume parenteral fluids are packed into:
 Glass bottles
 PVC collapsible bags
 Semi-rigid polythene containers
The containers and closures that are used for packaging parenteral
products must;
 Maintain the sterility of the packed fluids
 Withstand sterilization
 Be compatible with the packed fluid
 Allow withdrawal of the contents
 Containers
23

 Parenteral preparations are usually supplied in glass

ampoules, bottles or vials, plastic bottles or bags, and
prefilled syringes, which are coloured in the case of light-
sensitive substances.
 Containers should be made from material that is sufficiently
transparent to permit the visual inspection of the contents.
 They should not adversely affect the quality of the
preparation, allow diffusion of any kind into or across the
material of the container.
 Closures
24

 Closures for parenteral preparation containers should be equipped

with a firm seal to prevent entry of microorganisms and other
contaminants.

 They should not be made of components that react with the

contents, nor should they allow foreign substances to diffuse into
the preparation.

 Plastic materials or elastomers of which the closure is composed

should be sufficiently firm and elastic to allow the passage of a
needle with the least possible shedding of particles.
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Routes of parenteral administration

 Intravenous injections and infusions

 Subcutaneous injections
 Intramuscular injections
 Intradermal injections
 Intra-arterial injections
 Intracardic injections
 Intraspinal injections
 Intra-articular injections
26

Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 2014/06/10

 Intravenous (IV):
27
 Into the vein
1 to 1000 ml
1 inch ,19 to 20 gauge needle with injection rate 1ml/
10 sec. for volume upto 5 ml & 1 ml/ 20 sec. for
volume more than 5 ml.

Given:
 Aqueous solutions
 Hydro alcoholic solutions
 Emulsions

 Liposome
  IV infusion of large volume fluids (100- 1000 ml)
28

has become increasingly popular. This technique is

called as Venoclysis.
 This is used to supply electrolytes & nutrients to
restore blood volume & to prevent tissue
dehydration.
 Combination of parenteral dosage forms for
administration as a unit product is known as an IV
admixture.

29 Subcutaneous (SC):
 The injection is given under the skin
 Need to be isotonic
 Upto 2 ml is given
 Using ½ to 1 inch 23 gauge needle or smaller needle

 Given:
 Vaccines

 Insulin

 Scopolamine

 Epinephrine
30  Intramuscular (IM):
 Striated muscle fibre
 0.5 to 2 ml sometimes upto 4 ml
 1 to 1.5 inch & 19 to 22 gauge needle is used
 Preferably isotonic
 Principle sites:
 Gluteal (buttocks)
 Deltoid (upper arms)
 Vastus lateralis (lateral thigh)
 Given:
 Solutions
 Emulsions
 Oils
 Suspension
31  Intradermal:

 Also called as diagnostic testing

 0.05 ml
½ inch, 25 to 26 gauge needle
 Should be isotonic

 Given:

 Diagnostic agents
32
 Intra-arterial (IA):
 Direct into the artery
2 to 20 ml
 20 to 22 gauge
 Solutions & emulsions can be administered

 Given:
 Radio opaque media
 Antineoplastic

 Antibiotics
33
 Intrathecal:
 Also called intra-spinal
 Directly given into the spinal cord
1 to 4 ml
 24 to 28 gauge
 Must be isotonic

 Given:
 LA

 Analgesics

 Neuroleptics
  Intraarticular:
34
 Given directly into the joints
2 to 20 ml
5 inch 22 gauge
 Must be isotonic

 Given:
 Morphine

 LA

 Steroids

 NSAID’s

 Antibiotics
  Intra-arterial (IA):
35
 Direct into the artery
2 to 20 ml
 20 to 22 gauge
 Solutions & emulsions can be administered

 Given:
 Radio opaque media
 Antineoplastic

 Antibiotics
 Intrathecal:
36
Also called intra-spinal
Directly given into the spinal cord
1 to 4 ml
24 to 28 gauge
Must be isotonic
Given:
LA
Analgesics
Neuroleptics
  Intraarticular:

 Given directly into the joints

37

2 to 20 ml
5 inch 22 gauge
 Must be isotonic

 Given:

 Morphine

 LA

 Steroids

 NSAID’s

 Antibiotics
38
Intrapleural:
Given directly into the pleural cavity or lung
Used for fluid withdrawal
2 to 30 ml
2 to 5 inch, 16 to 22 gauge needle
Given:
LA
Narcotics
Chemotherapeutic agents
39
Intracardial:
Directly given into the heart
0.2 to 1 ml
5 inch , 22 gauge needle
Given:
Cardiotonics
Calcium salts as a calcium channel blockers
40
Formulation of parenterals (solution)

 Aqueous solutions
 High viscosity solutions
 For compound with mol. wt. more than 750
 For water solution drugs
 Gelling agents or viscosity enhancers are used

 Complex formulations
 Drug forms dissociable complex with macromolecule
 Fixed amount of drug gets complexed
 Given by I.M. route
 Formulation of parenterals (solution)
 41Oil solutions

 Drug release is controlled by controlling partitioning of drug

out of oil into surrounding into aqueous medium

 For I.M. administration only

 No. of oils are limited

 LVP usually contains one or more electrolytes

 Potassium chloride is the most common additive

 Other salts of potassium, magnesium, or sodium can be added

 Additives to I. V. solutions can also be multivitamins or trace elements

 Solution
42

 The vehicles most commonly used for IV infusions

are:
 Dextrose in water
 NS solution
 Dextrose in saline solution

 The two main types of IV solutions are:

 small-volume parenterals (SVPs) of 50 or 100 mL
 large-volume parenterals (LVPs) of more than 100 mL
 Suspension
43

 Suspension for injection contain less than 5% of drug solids with a

mean particle diameter within the range 5-10m.

 During the manufacture of suspension for injection, the

components are prepared and sterilized separately, then aseptically

combined.

 The final product cannot be filter sterilized owing to the presence

of particles in the formulation.

 Powders for use in sterile suspensions can be sterilized by gas

44
Suspensions
 Aqueous suspensions
 Given by I.M. or S.C. routes
 Concentration of solids should be 0.5 to 5 %
 Particle size should be < 10 μm
 Drug is continuously dissolving to replenish the lost.
 For oil soluble drugs
 Only crystalline and stable polymorphic drugs are given by
this form
 Viscosity builders can be used.
 E.g., Crystalline zinc insulin
 Suspensions
45

 Oil suspensions

 Given by I.M. route.

 Process of drug availability consists of dissolution of drug particles

followed by partitioning of drug from oil solution to aqueous
medium.

 More prolong dug action as compared to oil solution and aqueous

suspension.

 E.g., Penicillin G procaine in vegetable oil

 Emulsions
46

 Can be given by I.M., S.C., or I.V. routes

 O/w systems are not used due to large interfacial area and rapid

partitioning.

 W/o emulsions are used for water soluble drugs.

 Multiple emulsions are used generally such as w/o/w and

o/w/o since an additional reservoir is presented to the drug for

partitioning which can effectively retard its release rate.
 Emulsions
47

 Release of water soluble drugs can be retarded by

presenting it as oil suspension and vice versa.

Water soluble drug

e.g., 5-Fluorouracil

Oil soluble drug

e.g., lipidol

Aqueous phase

Oil phase
48
Dry powders

 Dry sterile powder is aseptically added to a

sterile vial.
 The dry drug powder is reconstituted with a
sterile vehicle before use.
 Powders for injections are solid substances,
distributed in their final containers and which,
when shaken with the prescribed volume of the
appropriate sterile liquid, rapidly form either
clear and practically particle-free solutions or
uniform suspensions.

2014/06/10
Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.
 Sterilization
49

 Products to a process whereby all viable life forms are either

killed or removed.
 The sterilization process is usually the final stage in the
preparation of the product.
 The methods of sterilization in regular use include exposure to:
saturated steam under pressure, dry heat, ionizing radiation,
ethylene oxide or passage through a bacteria retaining filter.
 When possible, exposure to saturated steam under pressure is the
sterilization method of choice.
 Radiopharmaceuticals
50

• Radiopharmacy is concerned with the manufacture of

radioactive medicines known as radiopharmaceuticals.

• These have two main applications in medicine:

1. As an aid to the diagnosis of disease (diagnostic

radiopharmaceuticals)

2. In the treatment of disease (therapeutic

radiopharmaceuticals)
51

• Diagnostic radiopharmaceuticals may be classified into two types:

1. Radiopharmaceuticals used in tracer techniques for measuring

physiological parameters (e.g. Cr-EDTA
51

[Ethylenediaminetetraacetic acid] for measuring glomerular

filtration rate)

2. Radiopharmaceuticals for diagnostic imaging (e.g. 99m

Tc-methylene
diphosphonate (MDP) used in bone scanning).
 Radiation protection
52

• There are three basic principles to radiation protection:

1. Shielding: By placing shielding around the radioactive

source the radiation dose rate may be reduced.

2. Distance: The radiation dose from a radioactive course is

inversely proportional to the square of the distance.

3. Time: Minimizing the time spent handling a radioactive

source will reduce the radiation dose.
 53
Ophthalmic preparations
 Eye drops including solutions and suspensions of active
medicaments for instillation into the conjunctival sac.
 Eye lotions for irrigating and cleansing the eye surface, or for
impregnating eye dressings.
 Eye ointments, creams and gels containing active ingredients for
application to the lid margins and/or conjunctival sac.
 Contact lens solutions to facilitate the wearing and care of contact
lenses.
 Parenteral products for intracorneal, intravitreous or retrobulbar
injection
 Ophthalmic inserts placed in the conjunctival sac and designed to
release active ingredient over a prolonged period
 Packaging of ophthalmic products
54

 Contact lens solutions are usually packed in plastic containers.

 It is imperative that the low concentrations of antimicrobials

present in these products are not reduced to ineffective levels
due to sorption effects with the plastic.

 Contact lens storage cases are also of importance to the contact

lens wearer.

 It is important that these containers are kept in a hygienic

conditions.
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