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Sterile Dosage Forms

Nahla S. Barakat, Ph.D King Saud University College of Pharmacy

Dept. of Pharmaceutics 1432-1431

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The course topics

Reference: Sterile dosage forms, preparation, clinical application. Salvatore Turco. 1996

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Sterile products: Sterile dosage form refers to a product of a general group of

pharmaceuticals having in common the characteristic of sterility, i.e., freedom from living microorganism

The sterile dosage forms in general use:

- Injections - Infusion fluids

- Radiopharmaceuticals - Sterile solids

- Sterile suspensions

-Ophthalmic solutions, suspensions, and ointments

-Solution for irrigation

- Diagnostic agents

- Peritoneal dialysis solutionsons

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Parenteral products are dosage forms intended for

administration by injection, infusion or implantation.

Major routes of Parenteral administration:

Intradermal Subcutaneous

Intramuscular Intravenous

Intra-arterial Intraspinal

Intra-articular Intracardiac

Hypodermoclysis

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Intradermal (23)

Intravenous (21)

Intramuscular (20)

Subcutaneous (21)

Intra arterial (20-22)

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Official Types of Injections:

1. Solutions of Medicinal

Example: Codeine Phosphate Injection

Insulin Injection

2. Dry solids or liquid concentrate does not contain diluents etc.

Example: Sterile Ampicillin Sodium

3. If diluents present, referred to as.....for injection

Example: Methicillin Sodium for injection

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4. Suspensions "Sterile....Suspension" Example: Sterile Dexamethasone Acetate Suspension

5.Dry solids, which upon the addition of suitable vehicles yield preparations containing in all respects to the requirements for sterile suspensions.

Title: Sterile....for Suspension Example: Sterile Ampicillin for Suspension

6. Injectable Emulsions: Example: Propofol injection

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• Formulation of Parenteral: 1. Therapeutic agents2. Vehicles

i. Waterii. Water miscible vehiclesiii. Non- aqueous vehicles

3. Added substances (Additives)i. Antimicrobialsii. Antioxidantsiii. Buffersiv. Bulking agentsv. Chelating agentsvi. Protectantsvii.Solubilizing agentsviii.Surfactants ix. Tonicity- adjusting agents

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IV Component Abbreviation

2.5% dextrose in water D2.5W

5% dextrose in water D5W

5% dextrose and lactated Ringer’s solution D5RL or D5LR

10% dextrose in water D10W

5% dextrose and normal saline D5NS

2.5% dextrose and 0.45% normal saline D2.5½ NS

5% dextrose and 0.45% normal saline D5 ½ NS

Commonly Used IV AbbreviationsFluids

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IV Component Abbreviation

Normal saline NS

0.45% normal saline 0.45%NS or ½ NS

lactated Ringer’s solution RL or LR

sterile water for injection SWFI

bacteriostatic water for injection BWFI

sterile water for irrigation SW for irrigation

normal saline for irrigation NS for irrigation

Commonly Used IV Abbreviations:Fluids

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IV Component Abbreviation

potassium chloride KCl

potassium phosphate K phos or KPO4

potassium acetate K acet

sodium phosphate Na phos or NaPO4

sodium chloride NaCl

Commonly Used IV Abbreviations:Electrolytes

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IV Component Abbreviation

multivitamin for injection MVI

trace elements TE

zinc (a trace element) Zn

selenium (a trace element) Se

Commonly Used IV Abbreviations:Additives

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Liquid drugs are supplied in prefilled syringe, heat-sealed ampoules, vials sealed with rubber closure.

• Ampoules are intended for single dose only, do not provide dose flexibility.

A 5 micron filter needle should be used when drawing the contents of an ampoule into a syringe since glass particles may have fallen inside the ampoule when the top was snapped off.

It is useful to wrap an alcohol wipe or small piece of gauze around the top of the ampoule before breaking it.

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2

1

3

• Vials may be designed for single-dose or multi-dose use (contain preservative). Glass or plastic container

Advantages: The product is easier to remove from vials than form ampoules. The vials can hold multiple doses. Eliminate the risk of glass particles contamination during opening. Some drugs are not stable in liquid form and so are put into the

powder form and reconstituted before use.

Disadvantages: The rubber stopper can become cored

causing a small bit of rubber to enter the solution. Possible error in dose calculation Increased waste Increased microbial contamination

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12

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• Can be used to package a sterile powder with its vehicle.

• The top chamber contain sterile water for injection, is separated from the

bottom chamber holding the sterile powder by a rubber plug located at the

constriction of the container.

• External pressure is applied to the outer rubber closure to dislodge the

inner closure and mix the contents of the components. Ex.: Solu-Cortef,

kefzol.

• A convenient way to separate unstable drug from the diluent

Mix-O-Vial (Upjohn)

Double chambered vials

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Prefilled disposable cartridge or syringes:

• Are designed for maximum convenience. The injection is

filled into a glass cartridge with needle attached and

administered with a reusable stainless steel or plastic holder.

• The other type of prefilled syringe consists of a glass tube

closed at both ends with rubber stoppers. The prefilled tube is

placed into a specially designed syringe that has needle

attached to it.

• After using this type of prefilled syringe, all of the pieces are

discarded.

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Advantages:

Ease of administration,

reduction of medication error,

increase assurance of sterility,

good control of drugs (narcotics),

adequate labeling save nurses' time.

Emergency drugs as:

Sodium bicarbonate, epinephrine,

Ca chloride, lidocaine, atropine are available for

use as IV in this type of prefilled syringe.

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Syringe tips:i- Luer-Lok Tip

ii- Luer-Slip Tip

iii- Eccentric Tip

iv- Catheter Tip

i

ii

iv

iii

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Intravenous Access Devices

Syringes: are devices for injection, withdrawing fluids.

Syringes consist of glass or plastic barrel

with a tight-fitting plunger and tip

provides the point of

attachment for a needle.

The barrel is graduated in milliliters.

Glass reusable, glass disposable, plastic disposable.

Syringe volume: 1-60 ml

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• Insulin syringe is graduated in units of insulin (40,

80, 100 unit/ml)

• Tuberculin syringes have capacity of 1 ml, a volume

of 0.05 ml can be measured with accuracy.

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The Needle:

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Different bevels: are slanting edges cut into needle tips

Regular bevel: used for IM and SC

Short bevel: used for IV and intraspinal

True short bevel: used for intradermal administration

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• Various needle lengths are available: range from 1/4 to 6

inches (in).

• The choice depends on the site of administration, the depth of

penetration into the body.

• Compounding parenteral 1 1/4 in

• IM 1-2 in

• I.D , SQ 1/4 - ⅝ in

• IV infusion 11/4 - 2 1/2 in

• Intracardiac 3 1/2 in

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• Needle gauge: is the outside diameter of the needle

shaft.

• Gauge in common range from 13-to 27.

• The choice of gauge depends on the viscosity of the fluid to

be injected or withdrawn.

• Intradermal require 24-26 G

• S.Q require 24-25 G (insulin)

• IM require 19-22 G

• Compounding Parenteral 18-20 G

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The French catheter scale or "French units" (F) is commonly

used to measure the outside diameter of needles, catheters,

and other cylindrical medical instruments.

In the French system, the diameter in millimeters of the

catheter can be determined by dividing the French size by 3.

D(mm) = F/3 or F = D(mm) * 3

For example,

if the French size is 9, the diameter is 3 mm.

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IV SetsAn IV administration set is a sterile, pyrogen-free disposable

device used to deliver IV fluids to patients

The set may be sterilized before use by means of radiation or

ethylene oxide

The set come in sterile packaging and a sealed plastic wrap

Sets carry expiration dates

Sets carry the following legend:

“Federal law restricts this device to sale by or on the order of

a physician.”

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Each unit is supplied in packaging that ensures the maintenance of

sterility

Flanges and other rigid parts of an IV set are molded from tough

plastic

Most of the length of the tubing is molded from a polyvinyl chloride

(PVC)

PVC sets should not be used for

nitroglycerin, which is absorbed by the tubing

IV fat emulsions, which may leach out of the tubing

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The length of sets varies from 6-inch extensions up to 110- to

120-inch sets used in surgery

the priming of tubing depends on the length of the set

Standard sets have a lumen diameter of 0.28 cm

varying the size of the lumen diameter achieves different flow

rates

regulation of flow rates is critical in neonates and infants

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Intravenous administration set: Plastic spike to pierce the rubber closure or plastic seal on the IV

container A drip chamber to trap air and permit adjustment of flow rate 150-450 cm length polyvinyl chloride tubing terminating in A gum-rubber injection port ending with rigid needle or catheter

adapter An adjustable clamp (screw or roller type) on the tubing to regulate

flow Air-inlet filters designed as part of the administration set (used with

glass container that have no air tubes ).

• The most convenient site is often the arm, especially the veins on the back of the hand, or the median cubital vein at the elbow, but any identifiable vein can be used.

• Often it is necessary to use a tourniquet which restricts the venous drainage of the limb and makes the vein bulge.

• Once the needle is in place, it is common to draw back slightly on the syringe to aspirate blood, thus verifying that the needle is really in a vein. The tourniquet should be removed before injecting to prevent extravasation of the medication.

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Different Types of IV Containers

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Preparing IV solutions

• Preparation should always be done under the supervision of a licensed pharmacist

• Medication that is prepared by the technician must be reviewed and approved by the pharmacist

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• Begin any IV preparation by washing your hands thoroughly using a germicidal agent such as chlorhexidine gluconate or povidone-iodine

• All jewelry should be removed from the hands and wrists before scrubbing and while making a sterile product

• Wear gloves during procedures • Laminar airflow hoods are normally kept running• The exterior surfaces of the hood should be disinfectant

weekly with 70% isopropyl alcohol.• Before making the product, thoroughly clean all interior

working surfaces using sterile gauze• Prefilters in the laminar -airflow hood will be cleaned

monthly.

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• Eating, drinking, talking, or coughing is prohibited in the laminar airflow hood

• Working in the laminar flow hood should be free from interruptions

• Gather all the necessary materials for the operation and make sure they are:

– not expired

– free from particulate matter such as dust

– check for leaks by squeezing plastic solution containers

• Only essential objects and materials necessary for product preparation should be placed in the airflow hood.

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• Work in the center of the work area within the laminar airflow hood

– at least six inches inside the edge of the hood

– make sure nothing obstructs the flow of air from the high-efficiency particulate air (HEPA) filter over the preparation area

– nothing should pass behind a sterile object and the HEPA filter.

– Minimize hand movements within the hood.

– Swab all surfaces require puncture with 70% isopropyl alcohol or betadine solution.

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• Follow proper procedure for handling sterile devices and medication containers

• Remember that the plunger and tip of the syringe are sterile and must not be touched

• For greatest accuracy, use the smallest syringe that can hold the desired amount of solution

– syringe should not be larger than twice the volume to be measured

– Examine all formulations before removing them from the hood

– Place all syringes and needles in puncture-proof containers

• Peripheral IV injection

• This is the most common intravenous access method in both hospitals and pre-hospital services.

• A peripheral IV line consists of a short catheter (a few centimeters long) inserted through the skin into a peripheral vein (any vein that is not inside the chest or abdomen). Arms and hand veins are typically used.

• The scalp veins are sometimes used in infants

• This is usually preferred for drugs that don’t irritate the veins

• Patients require short-term IV therapy

• Administration of isotonic solutions.

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Venflon intravenous cannula

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Parts of I.V. cannula

• Special consideration:The size of cannula effects four factor;

• Needle guage

• External diameter of cannula i.e. its catheter

• Length of catheter

• Flow rate i.e. ml/min

• As the gauge number increases the cannula size decreases (14 largest and 24 smallest)

• Larger the gauge number is (24G) smaller the cannula/diameter is (0.7mm)

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Butterfly catheter — a metal needle with flexible plastic ‘wings’ and a

short length of tubing. The ‘wings’ assist in placement and facilitate

fixation with tape.

Central IV lines• Central IV lines flow through a catheter with its tip within a

large vein, usually the superior vena cava or inferior vena cava, or within the right atrium of the heart.

This has several advantages over a peripheral IV:

• It can deliver fluids and medications that would be overly irritating to peripheral veins because of their concentration or chemical composition. These include some chemotherapy drugs and total parenteral nutrition.

• It is used when patients require long-term IV therapy.

• Multiple medications can be delivered at once.

• Medications reach the heart immediately, and are quickly distributed to the rest of the body.

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• Central IV lines carry risks of bleeding, infection, gangrene,

thromboembolism and gas embolism.

• They are often more difficult to insert correctly as the veins

are not usually palpable and rely on an experienced clinician

knowing the appropriate landmarks and/or using an ultrasound

probe to safely locate and enter the vein.

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Methods of IV administration

Injection Infusion

Intermittent Continuous

Piggyback

Volume control set

Manufactured reconstituted

Mini-infusion

Partial fill

prefilled piggyback

Frozen

Liquids

• Methods of IV administration

• Continuous drip infusion: is the slow primary-line infusion of an IV preparation to maintain a therapeutic drug level or provide fluid and electrolyte replacement. This method achieve continuous, constant blood levels of the drug.

• In many instances, drug therapy is accomplished initially by IV push and then maintained slowly and constantly by IV infusion.

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• Intermittent infusion: allows drug administration at specific intervals (e.g., every 4 h). has a "high" infusion rate, alternating with a low programmable infusion rate to keep the cannula open.

• The timings are programmable. This mode is often used to administer antibiotics, or other drugs that can irritate a blood vessel.

• Total parenteral nutrition usually requires an infusion curve similar to normal mealtimes.

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• Direct IV push (Bolus): The drug solution is administered in a short time directly into a vein. The injection time is a matter of minutes and varies with different drugs .

• Many drugs are given by IV push and are diluted further with the vehicle to reduce the irritability on the vein.

• Not all drugs may be pushed IV

• Phenytoin and diazepam injections must be given by IV push

• They much be pushed at a specified rate that is slow enough to prevent toxicity.

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• A piggyback is a small-volume parenteral admixture that is attached to an existing IV line

• The piggybacked solution is infused into the tubing of the running IV– usually over a short time, from 30 minutes to 1 hour

• Some IV piggybacks are prepared in 250 mL solution because they contain a medication that is irritating to the veins

• In some cases, syringes are used instead of piggyback containers to deliver medication into a running IV

Benefits of intermittent infusion:

The method is suitable for patients who don not require administration of large amounts of IV fluids. It permits greater patient ambulation, as the intermittent infusion injection devices do not require continuous attachment to an IV bottle or bag.

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Preparing a Label for an IV Admixture

Labels for IV admixtures should bear the following information:– patient’s name and identification number– room number– fluid and amount– drug name and strength (if appropriate)– infusion period– flow rate (e.g., 100 mL/hr or infuse over 30 min)– expiration date and time – additional information as required by the institution or by

state or federal guidelines

• Pumps are electronic devices used to administer parenteral infusions when the use of gravity flow alone might lead to inaccurate dosing or risk patient safety.

• Pumps are used to administer parenteral nutrition, chemotherapy, cardiac medications and blood products.

• Types of pump• There are two basic classes of pumps. • Large volume pumps can pump nutrient solutions large

enough to feed a patient.• Small-volume pumps infuse hormones, such as insulin, or

other medicines, such as opiates.• Within these classes, some pumps are designed to be

portable, others are designed to be used in a hospital.

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Benefits of pumps:

• They maintain a constant, accurate flow rate• They detect infiltration, occlusions and air• Pumps decrease the time of a nurse spends

dispensing medications

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Types of pumps:

• 1- Volumetric pump: are used for intermittent infusion of medications such as antibiotics, also used for continuous infusion of IV fluid, Parenteral nutrition

• 2- Syringe pump: are used to administer intermittent or continuous infusion of medication in concentrated form

• 3- Mobile infusion pump: is small device designed for ambulatory and home patients, used for chemotherapy, and opiate medications

• 4- Implantable pump: are infusion device surgically placed under the skin to provide a continuous release of medication, typically an opiate, this type has a lower index of infection

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5-patient-controlled analgesia (PCA), in which repeated small doses of opioid analgesics are delivered on demand, with the device coded to stop administration before a dose that may cause hazardous respiratory depression is reached.