Physical and Chemical Incompatibilities in Non-Sterile Compounding and Reconstitution

Physical Incompatibilities in Non-Sterile Compounding and Reconstitution

What is Physical Incompatibility?

Physical incompatibilities occur when two or more drugs or ingredients visibly change when mixed (e.g., clumping, color change, separation), but their chemical composition remains the same. These changes can affect dosing, appearance, or texture.

Physical incompatibilities happen when two or more ingredients in a mixture don’t work well together. This can cause changes you can see or feel, like:

Solids forming in liquids.
Ingredients separating into layers.
Changes in texture (too thick or too thin).
Color changes or bubbles forming.
Ingredients sticking to containers.

Types of Physical Incompatibilities

Here are the common types of physical incompatibilities that can happen when mixing or preparing medications.

1. Precipitation

Definition: The formation of solid particles in a liquid due to the insolubility of one or more components. This can occur due to pH changes, solubility limits, or incompatible excipients.
Example: Mixing calcium chloride and phosphate in a solution causes crystals to form.

2. Phase Separation (Emulsion Breakdown)

Definition: The separation of a two-phase system, such as an emulsion, into distinct layers (oil and water). This occurs due to poor emulsifier selection, improper mixing, or instability over time.
Example: A lotion or cream separating into an oily layer and a watery layer.

3. Caking/Sedimentation

Definition: The settling of solid particles in a suspension that forms a hard, compact layer at the bottom, making it difficult to resuspend. This happens due to inadequate suspending agents or improper particle size distribution.
Example: Amoxicillin suspension forming a thick layer at the bottom of the bottle.

4. Effervescence

Definition: The production of gas bubbles due to a chemical reaction, often caused by the combination of an acid and a carbonate or bicarbonate. This can lead to loss of product stability or container pressure build-up.
Example: Mixing citric acid and sodium bicarbonate makes fizzing bubbles.

5. Viscosity Changes (Thickening or Thinning)

Definition: An unintended increase or decrease in the thickness of a liquid or semi-solid formulation. This may result from incorrect excipient concentrations, temperature changes, or solvent evaporation.
Example: A gel getting too watery or an oral liquid getting too thick to pour.

6. Color Changes

Definition: An unintended alteration in the color of a preparation due to oxidation, pH shifts, or interactions with excipients. This can indicate chemical degradation or instability.
Example: Epinephrine turning pink when exposed to air or light.

7. Crystal Formation

Definition: Tiny solid crystals form in a liquid when ingredients separate out.The development of crystalline particles in a solution or suspension due to temperature fluctuations, supersaturation, or solvent evaporation, reducing drug uniformity and effectiveness.
Example: Sorbitol syrup forming sugar crystals if stored incorrectly.

8. Adsorption to Containers

Definition: The adhesion of drug molecules to the surface of packaging materials, such as plastic or glass, leading to reduced drug availability in the final preparation.
Example: Insulin sticking to plastic IV bags, leading to lower doses being given.

9. Hygroscopic Changes (Moisture Absorption)

Definition: The absorption of moisture from the air by certain drugs or excipients, leading to clumping, liquefaction, or degradation of the formulation.
Example: Powders like aspirin clumping together in humid conditions.

10. Cream or Ointment Separation

Definition: The leakage of liquid components from a cream or ointment due to phase instability, incorrect base selection, or inadequate mixing during preparation.
Example: A moisturizing cream releasing water droplets when stored in a warm place.

Resolving Physical Incompatibilities

Physical Incompatibility	Resolution Strategies
Precipitation	Adjust pH using buffers Use cosolvents (e.g., alcohol, glycerin) Select alternative soluble salts
Phase Separation (Emulsion Breakdown)	Use appropriate emulsifying agents Homogenize properly Store under recommended conditions
Caking/Sedimentation	Use proper suspending agents (e.g., xanthan gum, methylcellulose) Reduce particle size with trituration Shake well before use
Effervescence	Mix ingredients slowly Use controlled mixing conditions Store in vented or pressure-resistant containers
Viscosity Changes	Adjust concentration of viscosity modifiers Use appropriate thickening agents (e.g., hydrocolloids, gelling agents)
Color Changes	Protect from light and air exposure Store in amber-colored containers Use antioxidants (e.g., ascorbic acid, sodium bisulfite)
Crystal Formation	Store at appropriate temperatures Use proper solubilizing agents (e.g., surfactants) Ensure adequate solvent volume
Adsorption to Containers	Use appropriate container material (e.g., glass for insulin) Use compatible excipients to reduce adsorption
Hygroscopic Changes (Moisture Absorption)	Store in airtight containers Use desiccants Select non-hygroscopic excipients
Cream or Ointment Separation	Use correct emulsifiers and stabilizers Mix thoroughly during preparation Store under recommended temperature conditions

What is United States Pharmacopoeia (USP)

The USP stands for the United States Pharmacopeia. It is a nonprofit organization that sets the standards for the quality, safety, and effectiveness of medicines, food ingredients, and dietary supplements in the United States.

The USP:

Publishes official standards for drugs, their ingredients, and dosages.
Provides guidelines for drug manufacturing, compounding, and testing.
Ensures that medications are consistent, safe, and meet specific quality standards.

Physical incompatibilities are primarily discussed in the United States Pharmacopeia (USP) Volume under:

USP Chapter <795> – Pharmaceutical Compounding—Nonsterile Preparations This chapter provides guidelines for compounding non-sterile medications and addresses issues related to physical incompatibilities, such as precipitation, phase separation, and sedimentation in compounded formulations.

This volume outlines the standards for ensuring the stability, safety, and effectiveness of compounded drugs, including information on how to prevent or manage physical incompatibilities.

Chemical Incompatibilities in Non-Sterile Compounding and Reconstitution

Chemical instability occurs when a drug or formulation undergoes unintended molecular changes (e.g., degradation, oxidation, hydrolysis) due to interactions with other ingredients, environmental factors (light, heat), or pH shifts.

These changes alter the drug’s chemical structure, reducing potency, creating toxic byproducts, or rendering it ineffective. Key Characteristics:

Invisible Changes: Unlike physical incompatibilities, chemical instability may not be visibly detectable (e.g., no color change or precipitation).
Irreversible: Once degraded, the drug cannot revert to its original form.
Risk Factors: Exposure to moisture, oxygen, incompatible excipients, or incorrect pH.

Types of Chemical Incompatibilities

Here are some types of chemical incompatibilities that can happen when mixing or preparing medications:

1. Oxidation

Definition: When a substance reacts with oxygen and breaks down, losing its strength or effectiveness.
Example: Vitamin C turning yellow when exposed to air.

2. Hydrolysis

Definition: Breakdown of a drug caused by water, leading to loss of potency or effectiveness.
Example: Penicillin in a suspension breaking down when reconstituted with water.

3. Decomposition

Definition: A drug breaks down into different substances, which can be harmful or less effective.
Example: Nitroglycerin tablets losing their potency when exposed to light and air.

4. pH Incompatibility

Definition: When a drug is unstable at certain pH levels (acidic or basic) and changes or breaks down.
Example: Erythromycin becoming ineffective in acidic solutions.

5. Complexation

Definition: Two or more substances react and form a complex, which can make the drug less effective or harder to absorb.
Example: Tetracyclines binding with calcium or magnesium, reducing their absorption in the body.

6. Precipitation

Definition: When a substance becomes insoluble in a solution and forms solid particles.
Example: Mixing calcium and phosphate in a solution causes crystals to form.

7. Incompatibility with Excipients

Definition: A drug reacts with another ingredient (excipient) used in the formulation, causing a chemical change.
Example: Mixing certain drugs with alcohol-based solutions causing breakdown or reduced stability.

8. Light Sensitivity

Definition: A drug breaks down when exposed to light, causing it to lose its effectiveness.
Example: Methotrexate becoming unstable when exposed to sunlight.

Resolving Chemical Incompatibilities

Chemical Incompatibility	Resolution Strategies
Oxidation	Store in airtight containers to limit oxygen exposure. Use antioxidants (e.g., ascorbic acid, sodium bisulfite) to prevent oxidation. Use amber-colored containers to protect from light exposure.
Hydrolysis	Store in dry, cool conditions to avoid water exposure. Use excipients like alcohol or glycerin to reduce water contact. Reconstitute only when necessary, and use the mixture promptly.
Decomposition	Avoid exposure to light, air, and heat (store in cool, dark places). Use light-resistant packaging for sensitive drugs like nitroglycerin. Store drugs at their recommended temperature and avoid temperature fluctuations.
pH Incompatibility	Check the pH of both the drug and excipients before mixing. Adjust pH using buffers to maintain stability. Avoid mixing drugs that require different pH levels (e.g., acidic drugs with basic drugs).
Complexation	Avoid combining drugs that form complexes (e.g., tetracyclines and calcium). Administer drugs separately if they are known to form complexes.
Precipitation	Check solubility before combining and avoid exceeding solubility limits. Adjust pH or use cosolvents (e.g., glycerin, alcohol) to enhance solubility. Store preparations in appropriate conditions (e.g., keep liquids at recommended temperatures).
Incompatibility with Excipients	Use excipients that are known to be compatible with the drug. Avoid excipient combinations that could cause chemical reactions. Test small batches for compatibility before preparing large amounts.
Light Sensitivity	Store medications in dark, opaque containers to block light. Use packaging designed to protect light-sensitive drugs from exposure. Minimize exposure to light during compounding or reconstitution.