Manufacturing Methods of Suppositories

Pharmaceutics III

Manufacturing Methods of Suppositories

1- Hand rolling method:Classification of

Suppositories

Based on molding suppositories with fingers

after the formation of a plastic mass

In mortar add:-

1- A plastic-like mass is prepared by

triturating grated cocoa butter & active

ingredients in a mortar.

2- Pestle should be used to force the mass

together against the sides of the mortar. To

form plastic mass (It may be warmed very

gently temp below 30o C.

4- Cohesive mass is rolled into cylinder.

5- The total mass is weighed to record the

total weight. (the mass is divided into the

No. of the dose.)

6- The mass will quickly solidify & lose it

plasticity)

7- The cone & pointed cylinder are the

shapes that easily formed by hand rolling

procedure.

8- Wrapped & packed.

2-Compression method

Based on forcing suppository Base &

medicaments into special compression mold.

3-Fusion method

1-Based on melting the suppository base

(vehicle) & then disperse or dissolve the

drug in the melted base.

2- pour the mixture into mold. Allow it to

congeal.

3- remove from mold.

Quality Control Tests

QUALITY CONTROL procedures listed in

the US Pharmacopeia (USP30-NF25) for

manufactured suppositories include

identification, assay, and, in some cases,

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Pharmaceutics III

water content, residual solvent, dissolution,

and content uniformity

1- Appearance of suppository, include odor,

color, surface condition & shape.

2- Content uniformity : to ensure that each

individual supp. contains the labeled content

3-Weight variation: should be within 5%

4- Melting point/Melting Zone:

Macro-melting point test :- is a measure of

the time needed for the entire suppository to

melt when immersed in a constant-temp. at

37 C water bath.

Micro-melting point:- is the melting range

measured in capillary tubes for the base

only.

5-Breaking test (fragility test)

•Is the test that carried out to measure the brittleness or fragility of suppository.

Erweka hardness tester-is used to determine

the weight at which the suppository

collapse.

6- Dissolution rate

The in-vitro release pattern is measured.

The volume surrounding suppository is

constant & the drug content is measured at

different intervals

The time –versus drug concentration can be

obtained.

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Pharmaceutics III

7- Liquefaction time

Liquefaction testing provides information on

the behavior of a suppository when

subjected to a maximum temperature of

37◦C. The test commonly used is

Krowczynski’s method, which measures the time required for a suppository to liquefy

under pressures similar to those found in the

rectum in the presence of water at 37◦C. In general, liquefaction should take no longer

than about 30 minutes.

8- Melting and solidification time

There is a relationship between melting and

solidification that is important to

characterize. The release of the active

ingredient from the vehicle is related to the

melting point of the vehicle and the

solubility of the drug in the vehicle.

Suppositories undergo three changes in

phase during their “life.” First, they are melted and then solidified; upon

administration, they are again melted. An

understanding of these factors and their

relationships is critical for evaluating the

bioavailability of the final suppository

formulation. The higher the melting point,

the later the drug effects appear. If too high,

the drug effect does not appear.

Various methods are available to measure it,

including Shukoff’s method, the European Pharmacopoeia also describes a procedure.

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Pharmaceutics III

Sterile Products

Sterile Pharmaceutical Products

Parenterals

Ophthalmic preparations

Radiopharmaceutical preparations

They are sterile products intended for

administration by injection under or through

the skin or directly into body fluids, tissue or

organs

Sterile- free from any contaminating micro-

organism

Small Volume Parenterals or Large Volume

Parenterals

Physiology:- Located outside the alimentary

canal.

Disadvantage

Pain and discomfort

Incorrect drug dose ( impossible to

overcome the error

Restricted to hospital or specialized

personnel

ROUTE OF PARENTERAL

ADMINISTRATION

In pharmacology and toxicology, a route of

administration means the path by which a

drug, fluid, poison or other substance is

brought into contact with the body.

Parenteral by injection or infusion

1- Subcutaneous injections

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Pharmaceutics III

Injecting a fluid or a solid pellet into the

layer of loose connective and adipose tissue

directly underlying two outer layers (

epidermis and dermis) of the skin.

injections are used to administer vaccines

and medications,

A pellet may be injected to deliver long-

lasting doses of medication

Common drugs for this route are vaccines,

insulin, and epinepherine

Drugs by this route have a slow onset of

action than an IM or IV

Following administration, the site of

injection, the body temperature, age, degree

of massage at the injection site are factors

affecting drug distribution.

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Pharmaceutics III

The injection of a substance directly into a

relaxed muscle.

•It is used for particular forms of medication

that are administered in small amounts.

•Intramuscular injections are often given in the:

• Deltoid muscle in the shoulder (for rapid absorption of drug)

• ↑astus lateralis muscle of the thigh

• ↑entrogluteal and dorsogluteal muscles in the buttock

Deltoid muscle :- thick, flat triangular

muscle responsible for the round shape of

the shoulder.

Vastus lateralis

muscle

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Pharmaceutics III

Ventrogluteal muscles Dorsogluteal muscles

•IM injections are preferred to be isotonic

•Absorption is relatively rapid compared to

SC.

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Pharmaceutics III

•For SC or IM injection there is a delay in

the systemic effects of the drug (the drug

first has to pass through the epithelial cells

& the capillaries walls before entering into

the blood.

•This occurs by passive diffusion.

3- Intravenous injections - Volume varies

from less 1 ml- 500 ml.

• Giving of liquid substances directly into a

vein into blood for a faster effect.

•The word intravenous simply means "within a vein".

•IV rapidly increases the concentration of

the drug in the blood plasma, but the

concentration soon falls due to reversible

transfer of the drug from plasma into body

tissue (Process of drug distribution).

•That followed by irreversible excretion and

metabolism

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Pharmaceutics III

•IV products are usually aqueous or hydro-

alcoholic solutions

•O/W emulsion with controlled particle size

can be used

•Volume less than 10 ml is termed

intravenous BOLUS

•Advantage

•100 % bioavailability

•Rapid response

•Plasma concentration after 4 mins

•Constant blood level may be obtained

• Used for the administration of irritant or

caustic drugs due to:

•Rapid dilution by the circulating blood

•Insensitivity of venous wall to pain

•Disadvantage

•Sudden excessive drug concentration at a

target organ (drug shock)

• Once the dose is taken, anti-doting may be

impossible

•Thrombosis is possible if extreme sites are

used for injection

E.g ankle, wrist or when the drug is

potentially irritant

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Pharmaceutics III

IV infusion

Term IV infusion is used for volume more

than 10 ml.

•IV infusions administers a large volume of

fluid at a slow rate and ensures that the drug

enters the general circulation at a constant

rate.

•The drug plasma rises soon after the start of

infusion and achieves a steady state when

rate of drug addition equals the rate of drug

loss.

•Upon stopping infusion, elimination of the

drug from the body by metabolism and /or

excretion generally follow first order

(proportional to the drug concentration)

•The term also available for Large volume

parenteral (LVP) range 100-1000 ml.

IV admixture

•IV combination for LVP prior or during

administration (as a unit product) is known

as IV admixture.

•Used to provide continuous or prolonged

drug effect

Specialized Routes

•Intra-arterial : direct injection into an artery

(due to the fast flow of the blood in the

artery, the drug will rapidly disperse

throughout the blood system or to target the

drug to a specific organ or tissue that is

served by the artery)

• Intra-spinal: into spinal canal (aq. Solution

injected in a volume less than 20 ml into a

particular area of the spinal column)

•Intra-thecal: direct into cerebral spinal

fluid

Intra- articular: injection into a joint (aq.

Solution or suspension)

•Intra cardial : direct injection into the heart

( aqueous solution applied in emergency)

•Intra-pleural: inject into the pleural cavity

or a lung

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Pharmaceutics III

SPECIALIZED LVP AND STERILE

SOLUTIONS

Hyperalimentation: The administration of

Nutrients and Vitamins by intravenous

feeding, especially to individuals unable to

take in food through the alimentary tract

It is a medical procedure used for

individuals who cannot

get nutrients from food.

This is done mainly due to impaired

gastrointestinal (GI) conditions such as

severe malabsorption, progressed eating

disorders etc.

Dialysis is a process for removing waste and excess

water from the blood, and is used primarily

as an artificial replacement for lost kidney

function in people with renal failure.

A- Peritoneal dialysis solution

Sterile solutions injected (and continuously

withdrawn) into the abdominal cavity for

bathing the peritoneum for 30 -90 minutes

Used: to rapid removal of drugs or chemical

toxicity

To counteract acute renal failure (toxic or

metabolites diffuse into circulating fluids &

removed)

In peritoneal dialysis, a sterile solution

containing glucose (called dialysate) is run

through a tube into the peritoneal cavity, the

abdominal body cavity around the intestine,

where the peritoneal membrane acts as a

partially permeable membrane. The

peritoneal membrane or peritoneum is a

layer of tissue containing blood vessels that

lines and surrounds the peritoneal, or

abdominal, cavity and the internal

abdominal organs (stomach,

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Pharmaceutics III

Spleen, liver, and intestines). Diffusion and

osmosis drive waste products and excess

fluid through the peritoneum into the

dialysate until the dialysate approaches

equilibrium with the body's fluids. Then the

dialysate is drained, discarded, and replaced

with fresh dialysate.

This exchange is repeated 4-5 times per day;

automatic systems can run more frequent

exchange cycles overnight. Peritoneal

dialysis is less efficient than hemodialysis,

but because it is carried out for a longer

period of time the net effect in terms of

removal of waste products and of salt and

water are similar to hemodialysis. Peritoneal

dialysis is carried out at home by the patient,

often without help. This frees patients from

the routine of having to go to a dialysis

clinic on a fixed schedule multiple times per

week. Peritoneal dialysis can be performed

with little to no specialized equipment (other

than bags of fresh dialysate).

Ex: glucose solution containing the same

ionic contents of the extra-cellular fluids

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Pharmaceutics III

B- Haemodialysis solution

In hemodialysis, the patient's blood is

pumped through the blood compartment of a

dialyzer, exposing it to a partially permeable

membrane. The dialyzer is composed of

thousands of tiny synthetic hollow fibers.

The fiber wall acts as the semipermeable

membrane. Blood flows through the fibers,

dialysis solution flows around the outside of

the fibers, and water and wastes move

between these two solutions. The cleansed

blood is then returned via the circuit back to

the body. Ultrafiltration occurs by increasing

the hydrostatic pressure across the dialyzer

membrane. This usually is done by applying

a negative pressure to the dialysate

compartment of the dialyzer. This pressure

gradient causes water and dissolved solutes

to move from blood to dialysate, and allows

the removal of several litres of excess fluid

during a typical 4-hour treatment.

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Pharmaceutics III

Is an electrolytes solution simulating body

fluid and it is used for artificial kidney

apparatus

C- Irrigation solutions

Used to irrigate and clean body cavities

wounds.

They must be sterile, pyrogen free

Normal saline may be used as irrigative

solution

If designed (labeled) irrigative should not

used as parenteral

Injection Dosages

Small volume parenterals

- are sterile and Pyrogen free.

- are packed in volume up to 100 ml. as:-

Single- dose ampoules (glass thin walled

containers made of type I borosilicate glass

or may be plastic)

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Pharmaceutics III

Multiple- dose vials:- thick-walled glass &

the container is sealed with rubber closure

Prefilled syringes:- is aseptically filled into

sterile syringes. The packed solution has a

high level of sterility assurance & does not

contain an antimicrobial preservatives.

The product is available for immediate use.

(use is limited because. It is expensive)

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Pharmaceutics III

ADDITIVES

Substances added to the product to:-

•Provide efficacy

•Safe

•Elegant products

•Maintain pharmaceutical stability

•Ensure sterility

•Aid in parenteral administration

Antioxidants

Role of antioxidants

An antioxidant is a molecule that inhibits the

oxidation of other molecules. Oxidation is a

chemical reaction that transfers electrons or

hydrogen from a substance to an oxidizing

agent. Oxidation reactions can produce free

radicals. In turn, these radicals can start a

chain reaction. When the chain reaction

occurs in a cell, it can cause damage or

death to the cell. Antioxidants terminate

these chain reactions by removing free

radical intermediates, and inhibit other

oxidation reactions. They do this by being

oxidized themselves, so antioxidants are

often reducing agents such as this, ascorbic

acid, or polyphenols.

To prevent degradation active ingredients

and maintain product stability during shelf-

life.

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Pharmaceutics III

Stability of drugs that possess the low

oxidation potential are susceptible to

oxidative degradation. This can be prevented

by applying different techniques:-

The common antioxidant for aqueous

parenteral are:

Sodium Bi-sulfite,

Sodium metabisulfite

Ascorbic acid

Mechanisms of Action

They will preferentially oxidized instead of

the drug or block oxidative chain reaction

Displace the air by inert gas bubbled to

solution prior to filling and sealing in the

final products.

Eg. N2 and CO2

Addition of free radical scavengers to block

the oxidative chain reaction

Eg. Vit. E and Vit. C

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Pharmaceutics III

Antimicrobial (preservatives): have a

dual role

A- In multiple dose:

act as bacteriostatic

1- (inhibit the growth of any

microbes accidentally

introduced due to repeated doses

2- protect the product from

minor contamination

during formulation process

Required for all multiple-dose products

Not used for LVP (toxic effect)

Added to the most unit-dose solutions that

are terminally sterilized

(Terminal sterilization is the process of

sterilizing the final packaged product )

Preservative

Should be compatible with the drug &

excipients or injection components e.g

containers & closures

Effective in non-toxic concentration

Effective after formulation and near the

expiration date

Antimicrobial test should be evaluate the

antimicrobial activity of preservative in

the final packaged product

Buffers

Added to resist pH changes during storage

Requirements for ideal buffer

Have adequate buffer capacity to maintain

the pH of the product at stable value

Ideal pH of parenteral product is pH 7.4

At pH above 9 lead to necrosis

If below pH 3 pain in tissues

Doesn't cause drug degradation

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Pharmaceutics III

E.g. Citrate buffer increase the degradation

of Vit. B12

Doesn't affect the isotonicity and stability of

the product.

pH of many official preparations is

adjusted due to

1- To increase the stability of injection

2- minimize pain, irritation, necrosis

3- To provide unsuitable conditions for the

growth of microorganisms

4- To enhance physiological activity,

pH of product should be kept as

physiologically possible with acceptance

stability

5- control the drug solubility (as desired)

6- provide unsatisfactory conditions for

growth of micro-organism (M.O cant resist

low or high pH)

7- The pH of the product can be influenced

by product degradation, container, stopper,

diffusion of gases

The product, is buffered to obtain maxm.

solubility and resist change in pH.

Buffers for parenteral use either weak

acid and its salts or weak bases and its

salts

Sequestering agents (chelating agents)

Used to complex or inactivate e.g metals

copper, iron and zinc

Metal contamination related to: raw

materials, solvent e.g water

Rubber stoppers and containers

equipment

ex. Of chelating agents:

1- Ethylenediamine tetra acetic acid (EDTA)

2- salts of citric and tartaric acid

there activity increase in presence of

reducing agents

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Pharmaceutics III

Inert gases

Usually,

Applied to enhance the integrity of oxygen-

sensitive medications (increase stability)

to replace oxygen the main cause of

decomposition

Ex: nitrogen and CO2

For best results

Use boiling water to remove air

Purging the container with inert gases prior

to filling

Use glass-seal ampoules provide a barrier

for gas transmission

Use of butyl rubber stock better resistance to

gas permeation than other rubbers

Solubilizing agents and surfactants

Solubilizing agents

To increase drug solubility e.g lecithin,

PEG, glycerol, ethyl alcohol (steroids, fat-

soluble vit.)

Surfactants

SAA to increase dispersion of colloidal

particles, increase powder wettability and

prevent crystal growth for suspension

& provide acceptable syringability.

E.g Lecithin- Obtained from egg yolk, or

soya beans sources.

Osmotic pressure and tonicity adjustment

agents

Osmosis = passage of solvent molecules

through semipermiable membrane from

dilute to concentrated soln until equilibrium

Osmotic pressure = force or pressure

responsible for this process

Iso-osmotic (isosmotic ) solutions = have

the same osmotic pressure

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Pharmaceutics III

Iso-tonic solutions = solutions have the

same osmotic pressure as body fluids

(electrolytes concentrations)

Hyper tonic solutions = solutions have

higher O.P.

than body fluids.

Disadv.

1- allow water to move outwards from

RBCs through their semipermeable

membrane lead to shrink of cells (reversible

mechanism)

2- Drain fluids extensively from body tissue

and organs

Ex: hypertonic solution used for:

* NaCl solution used for abortion or emesis

by local action

* Wrong administration of large volume

hypertonic normal saline may cause

hemorrhage encephalopathy (drainage of

brain fluids) and renal failure (kidney

necrosis, and to pregnant females abortion.

Hypo-tonic solutions = solutions have lower

O.P. than body fluids.

Disadv.

1- allow water to move into RBCs through

their semipermeable membrane lead to swell

rapidly and brust (haemolysis) of cells

(irreversible mechanism)

2- not recommended in parenterals (can be

adjusted by NacL , KCl, glucose, mannitol)

Osmolarity of plasma = 306 milliosomole

“mosmol”/liter

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Pharmaceutics III

Parenterals deviate from this value cause:

Hemolysis of RBCs,

Tissue irritation

Pain on injection

Shrinking of RBCs

Large volume parenteral should be

isotonic

Small volume S.C, I.M, I.V may be

hypertonic

Large volume parenteral should be isotonic

(have osmolarity ranging from 260-

340mosmol/L)

ex: glucose 5% infusion (= 280 mosmol/L)

0.9% Sod. Chloride (308 mosmol/L)

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Pharmaceutics III

Vehicle

Aqueous

Non aqueous

•Should be pharmacologically inert, non toxic,

•compatible with blood, •maintain solubility of the drug

•Physically and chemically stable

•Unaffected by the pH changes.

•Not interfere with the therapeutic activity of injection

Water

Advantage

Ideal for most injections

Well tolerated

Safest

Easiest to administer

Help to provide uniform dose

More accurately measured

Easy visual inspection for particulate

contamination, chemical (ppt), color change

Disadvantage

May accelerate drug hydrolysis resulting in

an inert or toxic products (powder for

reconstitution)

Not suitable for poorly soluble drugs

Injection of distilled water may cause a rise

in body temp. (pyrogenic = fever producing)

Water free from this reaction = apyrogenic

Pyrogen

It is Lipid in nature and may be produced

by many organisms, yeast, gram –ve & gram

+ve bacteria, fungi & viruses (non volatile)

Non- microbial Pyrogens are :- some

steroids & plasma components as they

produce a pyrogenic response if injected

Endotoxins isolated from the outer

membrane of gram –ve bacteria are

composed of lipids that also produce

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Pharmaceutics III

significant physiological changes when

injected (pyrogenic effect)

They are fever-producing substances due to

their toxic effect

The most potent are associated with gram

negative bacteria

Source of pyrogen: solvent, medicament,

additives, apparatus, containers

Water is the greatest source of pyrogen in

parenterals

The contamination of LVP with pyrogen is

serious, owing to the large volumes that are

administered to seriously ill patients

Types of water in pharmacy are

1- Purified water, USP

is free of dissolved or solid impurities.

is intended for use in the preparation of

aqueous dosage forms, except those

intended for parenteral administration

(Injections)

Should be freshly boiled and cooled

immediately before use.

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Pharmaceutics III

2- Water for injection, USP:

Used for parenteral solutions which are to be

sterilized after their preparation.

It is obtained by sterilizing pyrogen-free

distilled water immediately after its

collection.

3- Sterile water for injection, USP:

water for injection which has been sterilized

and packaged in single dose containers not

greater than 1 – liter size.

it must be pyrogen-free

not contain an antimicrobial agent or other

added substance.

This water is intended to be used as a

solvent, vehicle, and diluent for already-

sterilized packaged injectable medications.

The one-liter bottles not administered

intravenously because they have no tonicity.

used for reconstitution of multiple dose

medication e.g antibiotics.

In use, the water is aseptically added to the

vial of medication to prepare the desired

injection.

4- Bacteriostatic water for injection:

sterile water for injection containing one or

more suitable antimicrobial agents (to

increase flexibility to multiple dose).

The container label must state the name and

proportion of the antimicrobial agent.

Sterile vehicle in the preparation of small

volumes of injectable preparations.

Bacteriostatic agent gives the flexibility for

multiple-dose vials. The preservative will

destroy the contaminant microorganism

Parenterals administered in large volumes is

restricted due to excessive toxic amounts of

antimicrobial agents that may be injected

along with the medication.

“ Generally, If volumes of greater than 5 ml of solvent are required, sterile water for

injection rather than bacteriostatic water for

injection is preferred”.

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Pharmaceutics III

Sodium chloride injection, USP

It is a sterile isotonic solution of sodium

chloride (155 m Eq/L= ionic content of

plasma) in water for injection.

It contains no antimicrobial agents.

used as a sterile vehicle in preparing

solutions or suspensions of drugs for

parenteral administration.

Sodium chloride injection is frequently used

as a catheter or IV infusion

Ringer’s injection, USP

A sterile soln of NaCl, KCl, CaCl2 (conc.

similar to body fluids).

Used as vehicle for drug or electrolytes

replenisher

Lactated ringer’s injection, USP

Lactated ringer’s injection, USPA sterile soln of NaCl, KCl, CaCl2 + sod. lactate

Used as vehicle for drug or electrolytes

replenisher

Non- aqueous solutions

If the drug is unstable in aqueous systems it

may be necessary to use an alternative (non-

aqueous solvent). To:

1- Increase drug stability

2-Improve solubility of poorly soluble drugs

A-Water miscible non aqueous

Ethyl alcohol (low conc to increase

solubility) e.g dioxin and phenytoin

injection BP

Propylene glycol (PG) (non toxic, rapidly

metabolized and excreted)

Glycerol and polyethylene glycol (PEG)

B-Water immiscible solvent

Mainly used to dissolve drugs that are

insoluble in water. Eg: steroids, hormones,

vitamins

Fixed oils of vegetable origin.

1- Almond Oil, (glycerides of oleic acid)

used as a solvent for oily phenol injections,

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Pharmaceutics III

2- Olive oil, sesame oil, maize oil,

cottonseed oil, Soya oil and castor oil are all

suitable for parenteral use.

N.B = mineral oils (paraffins) not used for

parenteral (not metabolized)

Dosage forms for parenteral use

A- solution

•Drug+ preservative + water

solution

sterile microfilteration 0.22 µm filter for

heat sensitive preparation

•For thermostable: terminally autoclave-

sterilized after filling (assure sterility and

package)

Parenteral Suspension

Ready-to-use injection

Reconstituted prior to administer

May contain 0.5- 5% solid (reach 30% with

antibiotics)

Particle size less than 5 µm

Should have good syringeability and

injectability

Bacteriostatic sodium chloride injection,

USP

It is a sterile isotonic solution of sodium

chloride (0.9%) in water for injection.

It contains one or more antimicrobial agents.

Not packed in container greater than 30 ml

Should be labeled “Not for use in new born” (toxicity)

Syringeability = handling characteristics of

suspension while withdrawing it from

container to a syringe + its clogging and

foaming tendency

Injectability = suspension characteristics

during injection

(required pressure for injection

Thixotropy = Preparation that is solid in

absence of shearing force become fluid if

shaken-

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Pharmaceutics III

- the original structure is resumed after few

mins. at rest

Advantage

•Suitable for insoluble drugs

•Increased stability

•Possible depot action

Disadvantage

•Difficult formulation and manufacturing

•Patient discomfort

•Difficult dose uniformity

•Needs more additives

1-Surfactant: needed for wetting

hydrophobic drug and prevent crystal

growth

e.g : lecithin, polysorbate --tween 80, 60

2-Suspending agent: to control

sedimentation rate ( viscosity ): gelatin, povidone, CMC

To hold suspended particles enough time for

accurate dose

Prevent reformation of particle clumps

3- pH adjustment : citric acid, sod. citrate

4- Antioxidant: ascorbic acid, sod. Bi sulfite,

or metabisulfite, sod. Formaldhyde, thiourea

5-Preservative: should be tested to

determine the most effective conc.

Preparation steps of Parenteral

suspension

•Sterilization and milling of active

ingredients

•Sterilization of vehicle

Or Dissolve all soluble components and

sterilize them by autoclave or sterile

filtration

•Add previously sterilized powder to the

sterile soln aseptically

•Aseptic wetting and dispersion of active

ingredients

•Aseptic milling of bulk suspension

•Aseptic filling of the bulk suspension in

suitable containers

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Pharmaceutics III

Methods for preparation of sterile drug

powder

Sterile re-crystalization

•Dissolve drug--- sterile by filtration

(0.022 um)

•Sterile anti-solvent --- then added to drug solution to allow drug to crystallize in

situ

-------- then filter aseptically

Spray drying

•Spray the drug soln. into dry chamber to

come in contact with hot sterile gas (air)

•Rapid evaporation ----- leaving sterile

uniform

drug powder

Adv.

•Suitable for heat sensitive drug powder

•Uniform particle size

•Low particulate contamination

•Low price and rapid process

Lyophilization

•Separation of solid substance from solution

by freezing.

(Evaporate the solvent by sublimation)

Adv.

Suitable for heat and oxygen sensitive drug

More rapid solubility (rapid re-constituation)

Reduced contamination

Disadv.

Expensive

Difficult to form crystalline powder

Low solvent content

Parenteral Emulsion

•Suitable for IV administration

•--- Dispersed droplets p.s = 0.5-1 um

•--- Stablized by surfactants (lecithin, tween

80, gelatin, serum albumin and CMC)

•Application

•A source of calories and essential fatty

acids

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Pharmaceutics III

•Vehicle for drugs showing more stability,

safety and efficacy in emulsion form.

•Ex: dexamethazone palmitate parenteral

emulsion 5-6 active >>> its solution form

•Diazepam emulsion showed lower

toxicity than solution.

•Physostigmine salicylate emulsion more

stable than its soluton

Disadv. of parenteral emulsion

1- Unstable product, difficult sterilization of

the product (heat influence stability &

impossible filtration)

2- rapid growth of M.O (not contain

preservative)

3-difficult manufacturing steps under aseptic

condition.

4- Unstable system upon storage (increase

globule size--- cause thrombosis if injected

IV)

5- Long term emulsion therapy may lead to

overloading syndrome (fever, anemia,

hepato-spleenomegaly.

Dry powder

•Unstable drugs presented in form of dry pd

for reconstitution prior to administration

with vehicle .

•If solution will be the final dosage form

should labeled “ for injection” or “sterile”

•If suspension “ sterile for suspension”

•Ex: “sterile ampicillin trihydrate for suspension”

Containers and package of parenterals

- Integral part of the product

(bec. Stability, potency,

safety)

Should reject any component of packaging

which is not safe , incompatible or affect

stability)

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Pharmaceutics III

1- Glass containers:

- multi-dose (vial)

Single –dose (Ampoule)

Large volume parenteral “L↑P” (now used in plastic forms)

Role of containers and closures that are

used for packing of parenterals

1- maintain the sterility of the packed

product

2- Withstand sterilization process

3- Allow withdrawal of the contents

Materials of parenteral containers

A- Glass 1- transparent and chemically inert,

2- excellent compatibility

3- Good product presentation,

4- good product identification

colored glass used to resist deterioration of the product by

light

Carbon& sulfur, iron & manganese (Amber)

Compd of cadmium and sulfur (yellow)

Cobalt oxide or cupric oxide (blue)

Iron oxide , manganese dioxide & chromium

dioxide (Green)

Types of glass

1- Type I Neural (neutral or borosilicate)

2- Type II (Soda glass with a surface

treatment)

3- Type III (Soda glass of limited alkalinity)

4- NP glass ( Soda glass for non parenteral

use)

Glass bottle are normally made of glass

type II

Plastics containers

1- Poly vinyl chloride “P↑C” collapsible bags are used to package

most infusion fluids.

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Pharmaceutics III

They are designed with port for the

attachment of administration set and an

additive port for addition of small-volume

parenteral fluids.

Resistant to impact

Flexible and collapse during fluid

administration & do not require an air inlet

system.

2- Semi- rigid polyethylene containers :-

These containers are intended for single use.

Rubber Closure

1- saturated elastomers

Copolymer of poly-isobutylene and poly-

isoprene

Ethylene propylene rubber

Ethylene propylene diene rubber

Silicone rubber

2- Unsaturated elastomers

Poly-isoprene

Poly butadiene

Styrene butadiene

Poly-chloroprene

Compatibility with the preparation

Leaching form stopper is the most common

leading to turbidity or precipitation

Reaction with preparation

Sorption of preservative or other ingredients

Methods of evaluation:

Microscopic examination of particulate

matter

Evaluation of solution by ultraviolet

Infrared, thin layer chromatography,…….

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Manufacturing Methods of Suppositories

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Transcript of Manufacturing Methods of Suppositories