Suspensions

Suspensions

Suspensions are preparations containing finely divided drug particles (the suspensoid) distributed somewhat uniformly throughout a vehicle in which the drug exhibits a minimum degree of solubility.

Types of Suspensions:

  1. Ready-to-use suspensions: Already distributed through a liquid vehicle with or without stabilizers and other additives.

  2. Dry powder mixtures: Intended for suspension in liquid vehicles (usually purified water) and contain the drug and suitable suspending and dispersing agents.

  • Drugs that are unstable in aqueous solutions for extended periods are often supplied as dry powder mixtures for reconstitution at the time of dispensing (e.g., many antibiotic drugs). These are designated in the USP as "for Oral Suspension."

  • Prepared suspensions not requiring reconstitution are designated as "Oral Suspension."

Reasons for Preparing Suspensions

  1. Chemical Stability: Some drugs are chemically unstable in solution but stable when suspended.

  2. Ease of Swallowing: Liquid form is preferred over solid form for many patients, especially infants, children, and the elderly, due to ease of swallowing and flexibility in dosing.

  3. Taste Masking: Suspensions can mask the disagreeable taste of certain drugs by administering them as undissolved particles.

  • Insoluble forms of drugs are sometimes specifically developed to prepare palatable liquid dosage forms (e.g., erythromycin estolate, a less water-soluble ester form of erythromycin, is used to prepare Erythromycin Estolate Oral Suspension).

  • Using insoluble forms reduces taste-masking problems, allowing flavor selection based on taste preference.

Features Desired in a Pharmaceutical Suspension

In addition to therapeutic efficacy, chemical stability, permanency, and aesthetic appeal, pharmaceutical suspensions should have the following features:

  1. Settling and Redispersion: The suspension should settle slowly and be readily redispersed upon gentle shaking.

  2. Particle Size: The particle size of the suspensoid should remain fairly constant.

  3. Pourability: The suspension should pour readily and evenly from its container.

Sedimentation Rate of Particles

The factors influencing the settling rate of particles in a suspension are described by Stokes' Law.

Stokes Equation

dxdt=d2( p<em>s− p</em>o)g18η\frac{dx}{dt} = \frac{d^2 (\,p<em>s - \,p</em>o)g}{18 \eta}

Where:

  • dxdt\frac{dx}{dt} = Rate of settling

  • dd = Diameter of the particles

  •  ps\,p_s = Density of the particle

  •  po\,p_o = Density of the medium

  • gg = Gravitational constant

  • η\eta = Viscosity of the medium

Factors that can be adjusted to enhance physical stability:

  • Diameter of the particles

  • Density of the medium

  • Viscosity of the medium

Example Calculation

Given:

  • Powder density: 1.3 g/mL

  • Particle diameter: 2.5 μm

  • Viscosity of water: 1 cP = 0.01 poise

Settling rate in water:

dxdt=(2.5×10−4)2(1.3−1.0)(980)18×0.01=1.02×10−4 cm/s\frac{dx}{dt} = \frac{(2.5 \times 10^{-4})^2 (1.3 - 1.0) (980)}{18 \times 0.01} = 1.02 \times 10^{-4} \text{ cm/s}

If particle size is reduced to 0.25 μm:

dxdt=(2.5×10−5)2(1.3−1.0)(980)18×0.01=1.02×10−6 cm/s\frac{dx}{dt} = \frac{(2.5 \times 10^{-5})^2 (1.3 - 1.0) (980)}{18 \times 0.01} = 1.02 \times 10^{-6} \text{ cm/s}

A decrease in particle size by a factor of 10 results in a reduction in settling rate by a factor of 100.

Using glycerin as a dispersion medium:

  • Glycerin density: 1.25 g/mL

  • Glycerin viscosity: 400 cP = 4 poise

For 2.5 μm particles:

dxdt=(2.5×10−4)2(1.3−1.25)(980)18×4=4.25×10−8 cm/s\frac{dx}{dt} = \frac{(2.5 \times 10^{-4})^2 (1.3 - 1.25) (980)}{18 \times 4} = 4.25 \times 10^{-8} \text{ cm/s}

For 0.25 μm particles:

dxdt=(2.5×10−5)2(1.3−1.25)(980)18×4=4.25×10−10 cm/s\frac{dx}{dt} = \frac{(2.5 \times 10^{-5})^2 (1.3 - 1.25) (980)}{18 \times 4} = 4.25 \times 10^{-10} \text{ cm/s}

Condition

Rate of Settling (cm/s)

2.5 μm powder in water

1.02 x 10^-4

0.25 μm powder in water

1.02 x 10^-6

2.5 μm powder in glycerin

4.25 x 10^-8

0.25 μm powder in glycerin

4.25 x 10^-10

Changing the dispersion medium results in the greatest change in the rate of settling. Particle size reduction also contributes significantly to suspension stability.

Limitations of Stokes Equation

  • Stokes' equation is derived for uniform, perfectly spherical particles in a very dilute suspension settling without turbulence, collisions, or affinity for the dispersion medium.

  • Pharmaceutical suspensions usually contain irregularly shaped particles of various diameters, resulting in turbulence, collisions, and potential affinity for the suspension medium.

However, the basic concepts of the equation provide a valid indication of factors important to suspension and adjustments that can be made to decrease the rate of sedimentation.

  • The velocity of fall is greater for larger particles than for smaller particles.

  • Reducing particle size slows the rate of descent.

  • Greater particle density results in a greater rate of descent.

Vehicle Density

  • Aqueous vehicles are commonly used in oral suspensions, and particle density is generally greater than that of the vehicle.

  • If particles were less dense, they would float and be difficult to distribute uniformly.

Viscosity

  • Increasing the viscosity of the dispersion medium can reduce the sedimentation rate.

  • However, excessive viscosity is undesirable because it makes pouring difficult and hinders redispersion.

Solid Content

  • The viscosity of a suspension increases with the proportion of solid particles.

  • Viscosity is measured using a viscometer, such as a Brookfield viscometer.

Adjustments for Physical Stability

  • Physical stability is most appropriately adjusted by altering the dispersed phase (particle size, uniformity, and separation) rather than making significant changes to the dispersion medium.

Physical Features of the Dispersed Phase

Particle Size

  • The optimal particle diameter in pharmaceutical suspensions is 1 to 50 μm.

  • Particle size reduction is achieved by dry milling (micropulverization) before incorporating the dispersed phase into the dispersion medium.

  • Micropulverization uses high-speed attrition or impact mills to reduce powders to 10 to 50 μm.

  • Fluid energy grinding (jet milling or micronizing) is used for finer particles (under 10 μm).

    • This process employs high-velocity compressed airstreams to cause particle collisions and fragmentation.

  • Spray drying can also produce extremely small particles.

    • Involves spraying a drug solution into a cone-shaped apparatus and rapidly drying it with warm air.

    • The resulting dry powder is collected.

  • While pharmacists cannot achieve the same degree of particle size reduction as industrial methods using a mortar and pestle, many micronized drugs are commercially available (e.g., progesterone).

Effect of Particle Size on Stability

  • Reducing particle size is beneficial to suspension stability as it reduces the sedimentation rate.

  • However, excessively fine particles can form a compact cake upon settling, which resists breakup upon shaking.

Particle Shape

  • Symmetrical particle shapes (e.g., barrel-shaped) produce more stable suspensions than asymmetrical shapes (e.g., needle-shaped).

  • Needle-shaped particles can form a tenacious sediment cake that cannot be redistributed.

Flocculation

  • To avoid caking, agglomeration of particles into larger crystals or masses must be prevented.

  • Flocculation involves the intentional formation of loose aggregates (flocs) held together by weak particle-to-particle bonds.

    • Flocculated particles settle more rapidly than individual particles but are less prone to compaction.

    • Flocs settle to form a higher sediment volume and are easily redispersed with agitation.

  • Methods of preparing flocculated suspensions depend on the drug and desired product type.

    • Clays like diluted bentonite magma are commonly used as flocculating agents in oral suspensions.

    • In parenteral suspensions, altering the pH to the region of minimum drug solubility can induce flocculation.

    • Electrolytes can also act as flocculating agents by reducing the electrical barrier between particles.

    • Carefully determined concentrations of surfactants can induce flocculation and increase sedimentation volume.

Dispersion Medium

  • Rapid settling in flocculated suspensions can hinder accurate dosage measurement and produce an unsightly supernatant layer.

  • Suspending agents are added to the dispersion medium to lend it structure.

    • Examples include carboxymethylcellulose (CMC), methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, xanthan gum, and bentonite.

  • Testing is needed to ensure that suspending agents do not interfere with drug availability by binding to medicinal agents.

  • The amount of suspending agent must not make the suspension too viscous to agitate or pour.

  • Rheology is the study of flow characteristics.

  • Support of the suspensoid depends on its density, whether it is flocculated, and the amount of material requiring support.

  • The solid content of oral suspensions varies depending on the drug dose, product volume, and the ability of the dispersion medium to support the drug concentration while maintaining viscosity and flow.

  • Adult oral suspensions are often designed to deliver the drug dose in 5 mL (1 teaspoonful).

  • Paediatric suspensions are formulated to deliver the appropriate dose via calibrated drops or teaspoons.

Preparation of Suspensions

  • The pharmacist must understand the characteristics of both the dispersed phase and the dispersion medium.

  • Some drugs are easily wetted by the vehicle, while others clump or float on the vehicle.

  • Wetting agents (e.g., alcohol, glycerin, propylene glycol) are used to wet powders that are not easily penetrated by the vehicle.

    • They displace air in the crevices of the particles, dispersing the particles and allowing penetration of the dispersion medium.

  • In large-scale preparations, wetting agents are mixed with the particles using a colloid mill.

  • On a small scale, they are mixed with a mortar and pestle.

  • After wetting, the dispersion medium (containing soluble components like colorants, flavors, and preservatives) is added in portions and thoroughly blended before subsequent additions.

  • The mixing equipment is rinsed with a portion of the vehicle, which is then added to bring the suspension to its final volume and ensure the desired concentration of solid matter.

  • The final product is passed through a colloid mill or other blender to ensure uniformity.

  • Preservatives should be included in the formulation to protect against bacterial and mold contamination.

  • An example formula for an oral suspension:

    • Aluminum hydroxide compressed gel: 326.8 g (Suspensoid, antacid)

    • Sorbitol solution: 282.0 mL (Viscosity, sweetness)

    • Syrup: 93.0 mL (Viscosity, sweetness)

    • Glycerin: 25.0 mL

    • Methylparaben: 0.9 g (Preservative)

    • Propylparaben: 0.3 g (Preservative)

    • Flavor: qs

    • Purified water: to make 1,000.0 mL

  • The parabens are dissolved in a heated mixture of sorbitol solution, glycerin, syrup, and a portion of the water. After cooling, the aluminum hydroxide is added with stirring, followed by the flavor. Finally, purified water is added to reach the specified volume, and the suspension is homogenized using appropriate equipment.