Formulation of Parenteral Sterile Products/preparation

Parenteral Product: Pharmaceutics

  • Parenteral drug products are the dosage forms intended for administration by a route that does not involve the gastrointestinal (GI) tract (thus, parenteral). Most of the parenteral drug products are injectable dosage forms that are intended for administration by injection using a syringe and a needle.
  • Parenteral preparations are sterile preparations containing one or more active ingredients intended for administration by injection,infusion or implantation into the body. They are packaged in either single-dose or multidose containers.
  • PPs may directly administer or may require to constituting or diluting prior to administration.
  • There are five main types of Parenteral Preparation
    1. Injection
    2. Infusion
    3. Powder for Injection
    4. Conc. solution for Injection
    5. Implants
Infusions

These parenteral preparations are composed of a sterile aqueous solution with water as its continuous phase. The preparations are free from bacterial endotoxins or pyrogens and are turned isotonic with blood. They do not contain any antimicrobial preservatives.

Powder for Injection

These are sterile solid compounds that are distributed in their final volume when the vial or container is shaken to form a clear particle-free solution.

Concentrated Solutions for Injections

The concentrated solutions are diluted with water for injection before they are administered through injection or through intravenous infusion.

Implants

These solid sterile preparations are implanted in the tissue in order to release the active ingredient for long periods. They are stored in sterile containers individually.

Parenteral dosage forms are preferred for one or more of the following reasons:

  • Low oral bioavailability and/or high variability in oral drug absorption.
  • Instability of the drug in the GI tract. For example, most protein drugs are highly unstable.
  •  Rapid onset of drug action is desired.
  • Ability to immediately stop drug administration is important. For example, most emergency room medications and anesthetics.
  •  High degree of flexibility in dosage adjustment with or without real-time patient physiological response is needed. For example, emer-gency medications such as analgesics, anticancer drugs, and fertility medications.
Unique characteristics of Parenteral Preparation/product
  • Must be sterile
  • Must be free from pyrogenic (endotoxin) contamination
  • Must be free from visible particulate matter
  • Isotonic to body fluid
  • Must be stable (chemically, physically, microbiologically) throughout the shelf life
  • Products must be compatible with diluents/additives, delivery systems & other co-administered products

Parenteral routes of administration

S.No.Route of AdministrationVolume
1Intradermal/intracutaneous0.1 to 0.2 mL
2S.C. (subcutaneous)/Hypodermis1 mL or less than 1 mL
3IM (Intramuscular)2 to 4 mL; Aq. Or oil suspension and oily solution can be administered by IM.
The irritant drug can NOT be administered via IM
4IV (intravenous)1 ml to 500 mL & more can be injected; if more than 15 mL solution given IV, Solution must be isotonic with blood; suspension & oily injection can not be injected; 100 % Bioavailability.
The irritant drug can be administered via IV (Irritant drug-diluted with blood)
5 Intra-spinal 10 mL; Must be Isotonic & Specific Gravity also same as Intra-spinal fluid.
Volume of Injection to be administered by IV, IM, SC & Intraspinal route

Intravenous route

The IV injections could be a bolus or an infusion. A bolus means the drug is injected into the vein over a short period of time. A bolus is used to administer a relatively small volume and is often written as IV push (IVP). An infusion refers to the introduction of larger volumes (100–1000 mL) of the drug over a longer period of time. A continuous infusion is used to administer a large volume of drugs at a constant rate.

IV infusion can be administered through peripheral veins, typically in the forearm or the peripherally inserted central catheter. The commonly administered IV infusion products include Lactated Ringers Injection USP; Sodium Chloride Injection USP (0.9%), which replenish fluids and electrolytes; and Dextrose Injection USP (5%), which provides fluid plus nutrition; and various combinations of dextrose and saline. Other solutions of essential amino acids or lipid emulsions are also used as infusions.

Intramuscular route

IM injections, drugs are injected into the striated muscle fibers that lie beneath the SC layer provide effects that are less rapid but generally longer lasting than those obtained from IV administration.

Aqueous or oleaginous solutions or suspensions of drugs may be administered intramuscularly. Drugs in aqueous solution are absorbed more rapidly than those in oleaginous preparations or in suspensions. An IM medication is injected deep into a large muscle mass, such as the upper arm, thigh, or buttocks. Up to 2 mL of the drug may be injected into the upper arm and 5 mL in the gluteal medial muscle of each buttock.

IM injections are often painful and nonreversible, that is, the administered drug cannot be withdrawn if needed.

Subcutaneous route

The SC route is used for small volume injections, typically 1 mL or less. SC injections are administered beneath the surface of the skin, between the dermis and muscle. Medications administered by this route are slowly absorbed and consequently have a slower onset of action than medications given by IV or IM routes.

Drugs often given by this route include epinephrine, insulin, heparin, scopolamine, and vaccines. Small injection volume often puts limitations on the drugs that can be administered by this route.

Other routes

Certain types of injections are intended for specific purposes. For example,

  • Intradermal administration involves injection just beneath the epidermis, within the dermal or skin layers. The usual site for intradermal injection is the anterior forearm. The volume of solution that can be administered intradermally is limited to 0.1 mL. The onset of action and the rate of absorption of the medication from this route are slow. This route is used for diagnostic agents, desensitization, testing for potential allergies, or immunization.
  • The intrathecal route involves drug administration into the cerebrospinal fluid (CSF). This route is needed if CSF is the desired site of drug action because most drugs do not reach the CSF from the systemic circulation. Drugs administered intrathecally include antineoplastics, antibiotics, anti-inflammatory, and diagnostic agents.
  • An intraarticular injection is made into the synovial cavity of a joint, usually to obtain a local therapeutic effect. For example, intraarticular injection of a corticosteroid provides an anti-inflammatory action in an arthritic joint.
  • An intraarterial injection is made directly into an artery that has been surgically isolated if it is necessary to deliver a high concentration of drug to a diseased organ, such as the kidney, with minimal distribution to other systemic locations.
  • An intraocular injection is made directly into the eye. For example, an injection into the vitreous humor provides access of the drug to the rear regions of the eye, such as the retina, which does not receive high drug concentration on topical administration.

Types of parenteral dosage forms

Small-volume parenteral versus large-volume parenteral

Injectable parenteral drug products are available as single or multiuse containers in different container–closure systems and volumes. Small-volume parenterals (SVPs) are available in volumes of less than 1 ml, and up to 50 ml. Large-volume parenterals (LVPs) are usually packaged in volumes up to 1000 mL.

SVPs include both unit-dose and single-dose and multidose containers. Unit dose containers are usually hermetically sealed ampoules that are intended to be discarded after a single injection. Multidose containers, on the other hand, are usually rubber-stoppered and sealed glass vials that are intended for multiple injections. The drug for each injection is withdrawn by inserting the needle through the rubber stopper, which self-seals after the needle is withdrawn.

SVPs for IV injection may not be isotonic because the large volume of blood rapidly dilutes them. However, hypertonic solutions tend to be tissue irritants. The pH of SVPs can also vary from the physiological pH because the blood buffering system rapidly readjusts the pH after a small volume injection. SVPs for single-dose administration may be free of antimicrobial preservatives, but multidose vials usually have the preservatives to ensure sterility over multiple uses over a certain period of time.

Injections versus infusions

Injection and infusion are the predominant methods of parenteral administration. Injection via different routes of administration usually utilizes an SVP. An infusion involves the IV administration of LVP over a prolonged period of time. Infusions are commonly used for fluid replacement, administration of drugs with a short plasma half-life, and/or dilution of a drug immediately before administration.

Formulation of Parenteral Preparation

  1. Vehicles
  2. Added Substance

1. Vehicles in Parenteral Preparation/product

  1. Aqueous Vehicle ( Pharmaceutical water)
  2. Non-Aqueous Vehicle
 Solvents/vehicles in Parenteral Products
Vehicle for Parenteral sterile product

Aqueous Vehicle ( Pharmaceutical water)

Find more about types of pharmaceutical water….

Potable water / Drinking water (500 CFU)

Type of WaterDescription (As per Indian Pharmacopoeia)
Purified water
CFU – 100
-Prepared by distillation reverse osmosis & the same time Ion-exchange.
-Used as a solvent in all pharmaceutical preparation except parenteral sterile preparation.
-Also used for all tests & assays of the IP, unless otherwise specified
-Hand washing (In the sterile production)
WFI
CFU-10/ml
pH 5-7
-Pyrogen free only ((not more than 0.25 IU of endotoxin per ml)
-Used as a solvent in parenteral preparation
Note: it is not intended to be sterile but should comply with the test for a limit of Endotoxin (Pyrosen free). i.e it is pyrogen-free but not sterilized as per IP.
-Not contain an added substance
SWFI
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– Sterilised & packed in a single-dose glass container of type I & II; maximum. of 1 (one) Litre capacity. i.e both pyrogen-free and sterilized
– Used as a solvent for powder or Injection.
-Not contain an added substance
BWFI
notes by The Pharmapedia
-Sterile WFI contains one or more suitable Bacteriostatic agents & packed in a single or multiple-dose glass container & Maximum 30 mL capacity.
-Contain added substance
Water BET(bacterial endotoxin test)it is WFI (Sterilised) & free from an endotoxin – used in the test for Bacterial Endotoxin (Pyrogen) Test.
Highly purified waterHigh Purity water is a Distilled water filtered through 0.45 m membrane & Conductivity not more than 0.15 S/cm @ 25 degrees centigrade.
Type of Pharmaceutical Water
Type of pharmaceutical Water
Type of Pharmaceutical Water

Non Aqueous Vehicle for parenteral Preparation

– Vegetable origin Oil

  • Fixed oil of vegetable origin.
  • Should be metabolized in the body
  • Should be liquid at room temp.
  • Not to be rancid rapid
  • Eg.  Corn oil, Seasam oil, almond oil, peanut oil, cotton seed oil etc
  • Oil subject to test:
  • Non-Aqueous vehilce is used in the preparation of progesterone, testosterone injection, fat soluble vitamin injection.

Lecithin – used as emulsifier agent in Non-Aqueous vehicles.

2. Additive/added substances in Parenteral Sterile Preparation/product

a. Antimicrobial Agents

b. Buffers

c. Anti-oxidants

d. Tonicity agents

e. Cryoprotectants & Lyoprotectants

Click here for all additives used in Pharmaceutical

a. Antimicrobial Agents in parenteral sterile product

  • Must be added to preparations contained in multiple dose container [30mL & max 10 withdrawal]
  • Used to prevent the growth of Microorganism
  • E.xample-
    • Phenyl mercuric nitrate 0.002 % [limit 0.01%]
    • Methyl paraben – 0.18%
    • Propyl paraben – 0.02%
    • Benzyl alcohol – 2% – also have local anesthetic property
    • Benzalkanium chloride & benzene thorium chloride – 0.01%
    • Phenol/cresol – 0.5%
    • Chlorobutanol – 0.5%
Antimicrobial agent
  • Mercurials are not used because of mercury toxicity.
  • Product without preservatives must be used immediately (within 3 hrs) after opening the package

b. Buffers in parenteral sterile product

Used to stabilize a solution against chemical-physical degradation that might occur if the pH changes. Eg. Acid salt of citrates, phosphates.

Buffers

c. Anti-oxidants used in parenteral sterile product

  1. Sodium bisulfite                                               
  2. BHT
  3. Sodium metasulfite
  4. BHA
  5. Ascorbic acid       
  6. Tochopherols
  7. EDTA

Displaying O2 in above the solution by purging N2  (inert gas)

Antioxidant agents

d. Tonicity agents used in parenteral sterile product

  • Used in Parenteral & Ophthalmic products.
  • 0.9% w/v NaCl solution Used to adjust tonicity of the solution
  • Injectable product to be isotonic with physiological fluids.
  • Isotonic preparation- use to minimize pain & tissue irritation at the site of application.
  • Eg. Electrolytes,NaCl or mono/disaccharide sugar

e. Cryoprotectant & Lyoprotactant

  • Used to protect Bio-pharmaceutical product from adverse effects during freeze-drying processing.
  • Eg. – Sugars (Non-reducing)- sucrose, Amino acids- glysine & lysine; Polymer – Liq PEG, dextran; Polyols – mannitol, sorbitol

Also, Read…

Containers and Closers for Parenteral Preparation

Evaluation of Parenteral sterile product


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