Parenteral Preparations Overview

Parenteral Preparations

• Parenteral preparations are administered by injection or infusion into the body tissues or blood
• Classification of parenterals includes volume-based and pharmaceutical classification
• Volume-based classification includes small volume and large volume parenteral solutions
• Pharmaceutical classification includes solutions, suspensions, emulsions, and dry powder

Solutions

• Most injectable products are solutions that are typically aqueous
• Solutions may be mixtures of water with glycols, alcohol or other non-aqueous solvents
• Viscosity and surface tension of most solutions are similar to water; however, some solutions (e.g., streptomycin sulfate injection, ascorbic acid injection) are viscous
• Parenteral solutions are usually filtered through 0.22µm membrane filters to achieve sterility and remove particulate matter
• Thermostable drug solutions should be terminally autoclave sterilized after filling to ensure sterility

Suspensions

• Suspensions are one of the most difficult parenteral dosage forms
• For insoluble drugs, particle size ranges from 5 - 10 µm
• Suspensions given via IM route and characterized by prolonged depot effect
• Drug dissolution rate in tissue fluids decreases, resulting in a decrease in absorption rate (sustained effect)
• Formulation requires balancing various factors for ease of resuspension and ejection through 18-21 gauge needles
• Factors for suspension formulation include particle size distribution, zeta potential, rheological properties, and wettability & surface tension

Emulsions

• Parenteral emulsions have several uses, including emulsions of allergens (SC), sustained-release depot preparations (IM), and rarely IV emulsions
• Parenteral emulsions should have a droplet size less than 1µm to prevent embolism
• Limited selection of stabilizers and emulsifiers limits emulsion formulations due to autoclave sterilization and injection constraints
• Unwanted physiological effects, such as pyrogenic reactions and hemolysis are a concern in emulsion formulations

Lipid Emulsions

• Lipid emulsions are a class of IV emulsions
• Fats are transported in the bloodstream as small droplets (0.5-1µm), having a central triglyceride core and outer phospholipid layer
• IV fat emulsions typically contain 10-20% oil
• These emulsions provide essential fatty acids and calories for total parenteral nutrition (TPN)
• Common components include soybean oil, safflower oil, cottonseed oil, egg phospholipids, soybean phospholipids, and soybean lecithin

Dry Powder

• Some drugs are unstable in aqueous solutions and are formulated as dry powders
• Dry powders are reconstituted with water immediately before administration
• The pharmacist must be aware of the final reconstitution volume
• Reconstituted product is typically an aqueous solution, but can also be an aqueous suspension (e.g., ampicillin trihydrate, spectinomycin hydrochloride)
• Most common form of sterile powder is freeze-dried or lyophilized powder

Advantages of Freeze Drying

• Water is removed at low temperatures, avoiding damage to heat-sensitive drugs
• Proper freeze drying creates a high surface area for rapid and complete reconstitution
• Freeze-dried dosage forms allow for precise filling of solutions into vials
• Minimizes dust containment and worker exposure to hazardous drugs

Limitations of Freeze Drying

• Some drugs (e.g., proteins, liposomal products, vaccines) can be damaged by freeze-drying
• Stability of the drug in the solid (crystalline or amorphous) state can be an issue if freeze drying produces an unstable amorphous solid
• Freeze drying can be an expensive drying procedure

Controlled Drug Delivery in Parenteral Preparations

• Controlled drug delivery is achieved by decreasing drug dissolution rates in tissue fluids, leading to decreased absorption rates and a sustained effect
• Increasing particle size (e.g., in suspensions) and increasing viscosity (e.g., with oil solutions, suspensions, or viscosity-imparting agents) can also achieve controlled drug delivery
• Implants (SC) for potent hormones, use of less soluble salts (e.g., insulin-Zn), and use of crystalline rather than amorphous forms (e.g., insulin lente) are additional methods

Insulin Lente

• Insulin zinc suspension
• Intermediate-acting porcine or human insulin with zinc salt added
• Solid phase of the suspension contains a ratio of 7:3 crystalline to amorphous insulin

Specification of Parenterals

• Key specifications include sterility, absence of pyrogens, clarity, pH, and tonicity

Sterility

• Sterility means the absence of all living microorganisms and their spores
• Sterilization methods depend on the preparation and ingredients
• Sterility testing is crucial to ensure effectiveness
• Preservatives are added to maintain sterility

Methods of Sterilization

• Typical methods include moist heat sterilization, dry heat sterilization, ionizing radiation sterilization, gaseous sterilization (ethylene oxide), and filtration

Preservation

• Antimicrobial agents are added to multi-dose vials to protect the injection from contamination
• Preservatives are usually not added to LVPs (single-dose containers) as they are discarded after use, but there are exceptions
• Preservative use may be avoided if the drug has inherent antimicrobial effect
• An ideal preservative must be effective against a wide range of bacteria, nontoxic at the used concentration, stable, and compatible with injection components.

Clarity

• Parenteral solutions must be clear and completely free of foreign particles (e.g., dust, glass, fiber) to prevent foreign body reactions (muscle granuloma or embolism).

Pyrogens

• Pyrogens are organic metabolic products from microbial contamination causing fever and other reactions in patients
• Caused by contamination with Gram-negative bacteria endotoxins (lipopolysaccharides).
• Injection of pyrogens can cause toxic effects, such as fever, chills, pain, malaise, shock, and death

Methods of Depyrogenation

• Common methods for removing pyrogens include distillation for water depyrogenation and rinsing with pyrogen-free water (for equipment) and using dry heat for thermostable equipment

pH

• The pH of blood is ~7.4, maintained by major buffer systems (carbonic acid/bicarbonate, phosphoric acid/phosphate, protein)
• Ideal pH for parenteral preparations is 7.4, however, some drugs require different pH values for stability.
• Drug solubility can depend on solution pH

Non-Neutral Parenterals

• Formulated at suitable pH for stability and solubility
• Use buffers to prevent degradation and avoid significant disturbance to body's buffer systems
• Frequent buffer systems include acetates, phosphates, and citrates

Non-Neutral LVPs

• IV infusions should avoid buffering systems to minimize toxicity
• Large volumes need large amounts of buffer which can be difficult to neutralize; hence are avoided in IV solutions
• Non-neutral IV solutions must be injected slowly to prevent major changes in blood pH due to the large volumes

Tonicity

• Isotonic solutions have the same osmotic pressure as blood plasma
• Hypertonic solutions (higher osmotic pressure than blood) can cause crenation and pain, while hypotonic solutions (lower osmotic pressure than blood) can cause lysis and hemolysis
• Tonicity adjustment to parenterals is common

Tonicity Adjustment

• Hypertonic solutions can be made isotonic through dilution
• Hypertonic solutions for IM or SC injections can still be mildly painful, so injected slowly into large veins
• In some cases, deliberately prescribed hypertonic IV infusions can be essential to patients with acute hyponatremia to raise blood sodium concentration back to normal range.

Formulation of Parenteral Products

• Successful parenteral administration depends on maintaining adequate drug concentration in the desired area of action
• Active drugs, solvents, containers, and additives are all considered during parenteral formulation

Active Drug

• No absorption step; drug absorption from the injection site is essential
• Drug solubility is crucial to injection, along with consideration of drug precipitation issues at the injection site

Prodrugs

• Chemical modifications can make drugs more stable, alter solubility, improve depot action or reduce pain
• Conversion is either within the body of reconstituted after reconstitution - an example is dry powder

Polymorphism

• Polymorphism is the existence of multiple crystal forms of a drug
• Affects solubility and dissolution rates; important to parenteral formulations

Solvents and Vehicles for Injection

• Aqueous solvents are preferred, but non-aqueous vehicles may be necessary for drugs with limited water solubility or susceptibility to hydrolysis by water

Aqueous Vehicles

• Water for injection is the most common aqueous vehicle
• It undergoes rigorous purifying process, must be sterile and pyrogen-free, packaged in single-dose containers (maximum 1 L)
• May contain antimicrobial agents (bacteriostatic) or additives depending on the preparation

Other Aqueous Vehicles

• Sodium chloride injection (sterile isotonic solution, no antimicrobial agents), Bacteriostatic sodium chloride injection (sterile isotonic solution, with antimicrobial), Ringer's Injection (sterile solution with sodium chloride, potassium chloride, calcium chloride), Lactated Ringer's injection (similar to Ringer's, but includes sodium lactate )

Non-Aqueous Vehicles

• Preferred for drugs poorly soluble in water
• Must be nonirritating, nontoxic, stable at various pH levels, have appropriate viscosity for ease of injection, and meet temperature and sterilization standards
• Primarily oil-based: including water miscible oils (water soluble), that assist in maintaining stability, and serving as stabilizers (e.g. diazepam)

Oils

• Used for sustained-release products, often with steroids
• Oil-based injections are common for IM administration but not IV.
• Oils must be clear at storage temperature, and contain no mineral oil or paraffin
• Oils must meet stability and clarity requirements.

This quiz explores the fundamentals of parenteral preparations, their classification, and key properties. Participants will learn about volume-based and pharmaceutical classifications as well as the characteristics of solutions and suspensions. Test your knowledge on the various types of injectable products and their preparation methods.