Suspensions Lecture Notes

Suspensions Part 2

Learning Outcomes

• Discuss approaches to formulation of suspensions
• Discuss the typical ingredients found in different types of pharmaceutical suspensions

Formulation of Suspensions

• Particles are the starting point.
• Wetting and dispersion medium are added.
• This leads to a uniform dispersion of deflocculated particles.
• Two pathways from here:
  • Deflocculated Suspension:
    • Incorporate a structured vehicle resulting in the final product.
  • Flocculated Suspension:
    • Add a flocculating agent to get a flocculated suspension.
    • Incorporate a structured vehicle to get a flocculated suspension in a structured vehicle as the final product.
    • Another option is to proceed with the flocculated suspension as a final product.

Structured Vehicle

• Aqueous solutions of polymeric materials are used.
• Examples include methylcellulose, carboxymethylcellulose, bentonite, and carbomers.
• Hydrocolloids are typically negatively charged in solution.
• These act as viscosity-increasing suspending agents.
• The concentration used depends on the consistency required.

Controlled Flocculation

• A deflocculated, wetted dispersion of powder is flocculated using a flocculating agent.
• The goal is to control the amount of flocculating agent to achieve maximum sedimentation volume.
• Reflection point: What are 3 types of agents we can use as flocculating agents? How do they produce flocculation?

Formulation Excipients

• Flavors, sweeteners, and colors are added for palatability.
• Antimicrobial preservatives are necessary to prevent microbial growth.
• Buffers maintain the pH of the suspension.
• Chemical stabilizers prevent degradation of the drug.
• Density and viscosity modifiers/suspending agents improve physical stability.
• Wetting agents aid in dispersing the drug particles.
• Flocculation modifiers control the flocculation process.

Flavors, Sweeteners, and Colors

• Added to make the suspension palatable, especially for children.
• The intensity of taste is less than in solutions due to only a small amount being in solution, but taste still needs consideration.
• Suspensions are often used for children because they prefer sweet and fruity tastes.
• Bitter drugs are best masked by bitter tastes like grapefruit.
• The effect of colors and flavors on the physical behavior of suspensions is likely limited due to the small amounts added.

Sweeteners

• Sucrose was commonly used but has concerns related to dental caries and diabetes glucose control.
• Artificial sweeteners are sweeter than sugar, so less is required; examples include sodium saccharin, potassium acesulfame, and aspartame.
• They may affect the electrical double layer.
• Aspartame breaks down to phenylalanine, requiring caution in patients with phenylketonuria.

Sweeteners - Details

• Saccharides:
  • Sucrose: Up to 80% concentration is used.
• Polyols:
  • Mannitol: Has a cooling effect, is considered noncaloric, fairly expensive, and can cause diarrhea.
  • Sorbitol: Half as sweet as sucrose, considered noncaloric, and can cause diarrhea.
• Synthetic:
  • Sodium Saccharin: 500 times as sweet as sucrose and inexpensive.
  • Aspartame: Has good acid stability.

Antimicrobial Preservatives

• Water necessitates the use of preservatives such as sorbic acid, benzoic acid, parabens, sucrose, and benzalkonium chloride.
• Sucrose has preservative action at >= 67% w/v.
• Ideally, preservatives do not interfere with DLVO behavior.
• Preservatives can affect the density and viscosity of the system, which can impact sedimentation.

Antimicrobial Preservatives - Benzalkonium Chloride (BZK)

• Typically used in aqueous eye drop formulations at 0.01% w/w.
• It's a cationic surfactant that dissociates to produce $Cl^-$ ions and a long-chain ionized surfactant moiety.
• BZK could affect DLVO behavior.
• It's not a "pure" product; batches have molecules with varying hydrocarbon chain lengths.
• Variability between batches may affect flocculation behavior.

Preservatives - Sorbic Acid and Benzoic Acid

• Most effective in their unionized form.
• They do not typically affect flocculation behavior.
• The $pK_a$ for sorbic acid is 4.8, and for benzoic acid is 4.2.
• They are likely to be partially ionized at the usual pH of oral formulations.
• Potassium sorbate and sodium benzoate are often used, which can introduce ions that may affect the diffuse layer and, consequently, flocculation.

Preservatives - Parabens

• Do not ionize at pH conditions expected in pharmaceutical formulations.
• Unlikely to interfere with flocculation.

Typical Preservatives and Concentration Ranges

• Alcohols:
  • Ethanol: >20%
  • Propylene Glycol: 15-30%
  • Benzyl Alcohol: 0.5-3%
• Quaternary Amines:
  • Benzalkonium Chloride: 0.004-0.02%
• Acids:
  • Sorbic Acid: 0.05-0.2%
  • Benzoic Acid: 0.1-0.5%
• Parabens:
  • Methylparaben: 0.2%
  • Propylparaben: 0.05%

Buffers

• Mixtures of a weak acid or base and one of its salts.
• Designed to maintain the pH of the aqueous vehicle within narrow limits.
• May be needed to maintain a specific pH range for a particular administration route or to suppress drug solubility.
• Ionic nature means buffers contribute charges to the formulation and may affect flocculation.
• They may also affect the ionization state of other components, such as preservatives.

Chemical Stabilizers

• Antioxidants (e.g., ascorbic acid, sodium metabisulfite) and chelating agents (e.g., EDTA or disodium edetate) are used.

Viscosity Modifiers

• Also known as suspending agents.
• Reduce sedimentation by increasing the viscosity of the medium.
• A balance is needed between viscosity at rest and the ability to pour the liquid for dose measurement.
• Examples include:
  • Cellulose-based materials (e.g., methylcellulose, carboxymethylcellulose, hydroxypropylcellulose).
  • Alginic acid.
  • Clays.
  • Gums (acacia, tragacanth).

Typical Suspending Agents

• Cellulose Derivatives:
  • Methylcellulose: Pseudoplastic/plastic rheologic behavior, neutral ionic charge, 1-5% concentration range.
  • Hydroxypropyl Methylcellulose: Pseudoplastic rheologic behavior, neutral ionic charge, 0.3-2% concentration range.
  • Sodium Carboxymethylcellulose: Pseudoplastic rheologic behavior, anionic ionic charge, 1-2% concentration range.
  • Microcrystalline Cellulose with Sodium Carboxymethylcellulose: Plastic/thixotropic rheologic behavior, anionic ionic charge, 0.5-2% concentration range.
• Clays:
  • Bentonite: Plastic/thixotropic rheologic behavior, anionic ionic charge, 1-6% concentration range.
  • Magnesium Aluminum Silicate: Plastic/thixotropic rheologic behavior, anionic ionic charge, 0.5-5% concentration range.
• Polymers:
  • Carbomer: Plastic rheologic behavior, anionic ionic charge, 0.1-0.4% concentration range.
  • Povidone: Newtonian/Pseudoplastic rheologic behavior, neutral ionic charge, 5-10% concentration range.
• Gums:
  • Xanthan gum: Plastic/thixotropic rheologic behavior, anionic ionic charge, 0.3-3% concentration range.
  • Carrageenan: Newtonian/Pseudoplastic rheologic behavior, anionic ionic charge, 1-2% concentration range.

Wetting Agents

• Improve the flow of the vehicle over the particle surface.
• Enhance the homogeneous distribution of particles throughout the formulation.
• Reduce interfacial tension between the solid particles and the liquid medium.
• Typically surfactants used below their critical micelle concentration (CMC).
• Can affect the charge on the particle surface and DLVO behavior.

Flocculation Modifiers

• Ions present in solution affect surface charge, Stern potential, and zeta potential.
• Types include ionic modifiers, surfactants, and polymers.
• NaCl may be added as a flocculation modifier; the effect depends on the ionic strength of the ion.
• Multivalent ions such as $CaCl_2$ will have a greater effect than monovalent salts (e.g., NaCl).

Injectable Suspensions

• Can use aqueous or non-aqueous dispersion medium.
• Some are available as powders that are re-dispersed just prior to injection.
• Administer suspensions intramuscularly (IM) or subcutaneously (SC), but NOT intravenously (IV)!!!
• Must be sterile, pyrogen-free, capable of being administered by syringe, isotonic, and non-irritating.
• Usually contain 0.5-5% solid with a particle size <5µm.
• Procaine penicillin is an example with a higher concentration of solid (30%).

Procaine Penicillin

• Solubility of procaine penicillin is 1g in 250mL water.
• The injection contains 1.5g in 3.4mL.
• Administered intramuscularly (IM).
• The drug slowly dissolves from crystals, giving peak levels in 2 hours.
• Administered as a once-daily injection for 2-5 days.

Solvent Systems

• Aqueous or non-aqueous solvents can be used.
• Water is preferred for parenteral formulations.
• Sometimes water is mixed with other water-miscible solvents such as ethanol, glycerin, or propylene glycol.
• Care is needed, as some solvents can cause muscle damage or lysis of red blood cells.

Non-Aqueous Solvents

• Water-immiscible solvents used in suspension injection formulations include fixed oils, ethyl oleate, isopropyl myristate, and benzyl benzoate.
• Fixed oils must be fluid at room temperature and vegetable in origin.
• Often need to add an antioxidant when using fixed oils.
• Examples include sesame oil, peanut oil, and castor oil.

Manufacture of Injectable Suspensions

• Sterilization and aseptic milling of active ingredients.
• Sterilization of the vehicle.
• Aseptic wetting and dispersion of active ingredients.
• Aseptic mixing of bulk suspensions.
• Aseptic filling of bulk suspension into suitable sterile containers.

Re-Constitutable Oral Suspensions

• Commonly used for antibiotics.
• Reconstituted and used over a short period (e.g., 14 days).
• Desired attributes:
  • The powder blend must be a uniform mixture of appropriate concentrations of each ingredient.
  • During reconstitution, the powder must re-disperse easily and quickly in the aqueous vehicle.
  • Must be easily redispersed and poured by the patient to provide an accurate, uniform dose.
  • The final product must have acceptable appearance, odor, and taste.

Types of Ingredients in Re-Constitutable Oral Suspensions

• Suspending agents.
• Wetting agents.
• Sweeteners.
• Preservatives.
• Flavors and colors.
• Solid diluent.
• Anticaking agents.
• Flocculating agent.
• Antioxidant.
• Buffer.

Suspending Agents in Re-Constitutable Oral Suspensions

• Should be easily dispersed by vigorous shaking during reconstitution.
• Not recommended: agar, carbomer, methylcellulose.
• Recommended: acacia, tragacanth, xanthan gum, povidone, silicon dioxide colloidal, Na-CMC.

Sweeteners in Re-Constitutable Oral Suspensions

• A significant component as drugs frequently taste bitter.
• Increased viscosity from sweeteners aids in suspending particles.
• Sucrose can act as both a sweetener and viscosity enhancer, as well as a diluent for the dry mixture.
• Other sweeteners: dextrose, mannitol, aspartame, sodium saccharin.

Wetting Agents in Re-Constitutable Oral Suspensions

• Use the lowest concentration to avoid foaming and taste problems.
• Polysorbate 80 is commonly used; it is nonionic and chemically compatible with cationic and anionic excipients and drugs.
• Sodium lauryl sulfate (anionic) is also used.

Other Agents in Re-Constitutable Oral Suspensions

• Flocculating agents are not commonly used because suspensions are redispersed frequently enough to prevent caking.
• Buffers are used to maintain optimum pH; sodium citrate is commonly used.

Other Agents - Preservatives and Anticaking Agents

• Suspending agents and sweeteners are good growth media for microorganisms; sucrose at high concentration can help prevent microbial growth.
• Anticaking agents such as amorphous silica prevent poor powder flow and caking of dry powder mixtures due to moisture uptake.
• As a desiccant, amorphous silica removes moisture from the dry mixture and helps maintain flow properties; it also provides some thermal insulation and is chemically inert.

Extemporaneous Preparation of Suspensions

• Must obtain uniform, small particles of the drug, often achieved by grinding in a mortar.
• Thoroughly wet the powder before mixing with the vehicle.
• Hydrophilic materials are best wetted with a water-miscible liquid (glycerin).
• Hydrophobic materials are often wetted with a surfactant, using only the minimum required.
• The drug and wetting agent form a thick paste, then the vehicle is added with constant stirring.

Extemporaneous Preparation Considerations

• Often made from tablets (consider if the tablet should be crushed).
• Grind tablets to ensure uniform particle size.
• Common suspending agents are Compound Tragacanth Powder or carboxymethylcellulose suspension APF.
• Must also consider sweetening, flavoring, and preservation.

Suspending Agents and Vehicles for Compounding Suspensions