Preparation of Flocculated and Deflocculated Suspensions, Stability Problems and Methods to Overcome : Pharmaceutical Guidelines -->

Editable Pharmaceutical Documents in MS-Word Format


Preparation of Flocculated and Deflocculated Suspensions, Stability Problems and Methods to Overcome

Methods of preparation of flocculated and deflocculated suspensions, Stability problems, Settling in suspensions, Formulation of suspensions.
Suspensions of pharmaceuticals consist of two phases of uniform dispersion throughout the external portion of the internal phase. Particulate matter in the internal phase is essentially insoluble but can be uniformly dispersed with a single or combination of suspending agents throughout the continuous phase. It is generally non-oral and generally aqueous, though the medium can be organic or oily.

Pharmaceutical suspensions are among the most common dosage forms. It's beneficial to administer insoluble or poorly soluble drugs in suspension dosage form and to mask unpleasant or bitter tastes associated with the drugs and other ingredients. Young or elderly patients will find it easy to swallow; the drug will not degrade due to hydrolysis, oxidation, or microbial activity; and the drug can be injected into muscles easily. A formulation scientist's main objective during suspension formulation is to control the separation process and, as a result, make the formulation more stable. The internal phase of the molecule will separate during storage for this reason. If after agitation (shaking), a pharmaceutical suspension is homogeneously dispersed over a prolonged period, such that a precise dose is removed for administration, then it is considered stable.

There are several steps involved in manufacturing pharmaceutical suspensions. A small particle typically in the micrometer range should be obtained as a first step.

Suspensions for pharmaceuticals are typically prepared either through direct incorporation of dispersion methods. The controlled flocculation method can also be employed to formulate suspensions.

Methods of preparation of flocculated and deflocculated suspensions

Direct incorporation/ dispersion method

  1. In the proper volume of diluent (vehicle), dissolve the soluble components.
  2. By mixing, the solid therapeutic agent is dispersed into the vehicle, before being corrected for volume.
Formulating a vehicle that is as wet and dispersible as possible will facilitate easy wetting and dispersing of the solid phase. This can be achieved by using wetting agents and suspending agents.

An important factor in the manufacture of the formulation is the mixing rate used in dispersing solid therapeutic agents. Flocculated suspensions may be manipulated with high-speed mixing since the system is pseudoplastic (shear thinning). High-speed mixing, however, can cause the product to become sticky (called dilatant flow) if the formulation was poorly designed and has poor flocculation properties.

Precipitation method

By precipitation method, suspensions are prepared as follows:
  1. Dispersion of the active substance (or part of the active substance) in the vehicle is followed by precipitation after the addition of counterions. The salt that forms is insoluble (such systems are frequently flocculated, and therefore low shear rates).
  2. It is then added to the suspension of the drug to dissolve the excipients in the vehicle, or the portion of the vehicle, whichever is the case.
  3. This stage may involve the formulation being sheared at high rates to guarantee homogeneity.
  4. The formula is then corrected for volume by adding the appropriate mass of diluent.
There is a potential problem with this method of formulation of suspensions due to the possible formation of ionic by-products during precipitation. Concentrations higher than this should be washed with an aqueous solvent if they are too high.

Controlled flocculation

The structure is imparted to suspensions by flocculation with little increase in viscosity. The following steps are involved in the flocculation process:
  1. The final volume of the aqueous vehicle is approximately half that of the wetting agent.
  2. Micronized drug is evenly distributed across the surface of the delivery vehicle at the desired concentration.
  3. Powder must be allowed to be wetted undisturbed to make a wet slurry, then it must be passed through a sieve or a colloid mill to remove the poorly wet powder.
  4. Until the slurry concentration of the drug reaches the flocculation endpoint, agitation is performed and a flocculating agent is added. Samples are placed in a graduated cylinder, the vehicle is added in equal quantities, and the cylinder is gently shaken with no disturbance allowed for the endpoint to be determined. A sample with the highest sediment volume to total suspension volume, as well as a clear supernatant and good drainage, is considered to have reached the proper endpoint.
  5. Once the remaining formulation adjuvants (preservatives, colorants, flavorings, buffers, etc.) have been added, the slurry is added to the liquid vehicle to form the final volume.

Stability problems

Factors that affect stability in suspension are as follows:

Temperature - Fluctuations in temperature are another factor that negatively impacts the stability and performance of pharmaceutical suspensions. Caking and claying may occur as a result of temperature fluctuations.

Settling in suspensions

Brownian movement

It prevents sedimentation when particles move according to Brownian laws. A particle in a pharmaceutical suspension is not usually moving as Brownian motion, because
  • Larger particle size. Brownian movement occurs when particles have a diameter of about 2 to 5 mm (depending on how dense the particles are and how thick the suspension is).
  • medium with a higher viscosity.


According to Stoke's law, particle sedimentation is expressed as follows:

Stock's law applies in the following cases:
  1. The particles in the suspension are largely irregular, but the particles are spherical.
  2. Free and independent particle settling occurs.
When particle concentrations are 0.5 - 2 % (w/v), there is no interference between the particles during sedimentation - thus free settling occurs.

There is a high concentration of solids in pharmaceutical suspensions, mostly between 5 and 10 percent. Interactions between the particles during the fall invalidate the settling process.Stoke's law no longer holds. Because particles settle independently, Stoke's law applies to systems with dislocated particles. Although this law is useful qualitatively in identifying factors that can be employed in the formulation of suspensions, it is not exhaustive.

1. Particle size

Rate of sedimentation ∞ (Diameter of the particle)2

This means that a suspension that is smaller in particle size will be more stable. When particle-particle interaction occurs, it results in floccules or coagulates, increasing sedimentation. By wet milling the final suspension or by dry milling before the suspension, the particles are finely ground.

2. The viscosity of the medium

Stoke's law states the following:

Rate of sedimentation ∞ 1 / (Viscosity of the medium)

Suspension should have an optimal viscosity. If you add suspending or thickening agents, the viscosity of your solution can be increased. Choosing products with high viscosity comes with advantages and disadvantages.

3. Density

Rate of sedimentation ∞ (density of solid – density of liquid medium)

Solid particles settle at a slower rate than liquid particles when the densities of solid particles and liquid are different. As opposed to solid particles, liquid particles can have their density altered by altering their composition because the absolute density of solid particles cannot be altered. In addition to sorbitol, polyvinylpyrrolidone, polyethylene glycol, glycerine, sugar, or a combination of these, non-ionic substances can also be added to the mixture. As soon as the particles are denser than the continuous medium, they settle downward, which is the sedimentation process. The movement of particles upward from a liquid medium depends on the particle density - creaming is the result of this.

Formulation of suspensions

Ideally, the product should
  • There is no problem letting the flow out
  • Each dose is uniformly distributed concerning particle size.
It is common to employ two approaches to meet both of these requirements,
  1. Maintaining suspension of deflocculated particles with the use of a structured vehicle. Vehicles are constructed of pseudoplastic and plastics, and hence there is a lot of reason to associate thixotropy with these types of flows. Structured vehicles work by trapping particles, so ideally no settling happens. Some amount of sedimentation will likely occur, however. In addition to facilitating redispersion, these vehicles feature property that causes their shear thinning.
  2. With flocculation, flocs are produced that, although they settle rapidly, can be re-dispersed with little effort.

Wetting of particles

In-vehicle manufacture, a powder that is insoluble in water must first be dispersed in a vehicle. In large-scale operations, it can be necessary to dust powders over the liquid surface to add them to the vehicle. A thin layer of air, minute amounts of grease, and other contaminants often make it difficult to disperse powders. Hydrophilic powders, such as sulfur, charcoal, and magnesium stearate, are not easily wetted by water and show a large contact angle. Hydrophilic powders are those that readily hydrate when free from contaminants attached to them. Such materials include zinc oxide, magnesium carbonate, talc, etc.

Methods to overcome stability problem

Ensure that particle suspension is uniform and discrete

The dispersion of particles over a large distance is determined by several factors, and these factors can be classified as either kinetic or thermodynamic. Brownian motion causes particles in a suspension to move or gravity causes them to move. The kinetic stability is improved when such movement is slowed down, aggregation is inhibited, and sedimentation is decreased. Stability operates at a more fundamental level. It is influenced by steric and electrostatic effects. Changes in the particle's size or shape can alter the particle's electrostatic charge.

Flocculants Form Easily When Shaken into Loose Flocculants

In situations where particles are not able to be held in a discrete suspended state, it might be preferable to intentionally induce flocculation to prevent their tightly bonded state. A floc is formed when particles are bound together by weak van der Waals forces, resulting in a loose porous structure that can soak up liquids efficiently. This means that there will be a large volume of sediment, and the drug can easily be redispersed by gentle shaking or agitation, as necessary to restore uniformity. Although flocculated particles settle more quickly than discrete ones, they form a lattice that resists complete settling. As a result, cake formation and compaction are less likely.

The Continuous Phase of Network Gel Induction

To give such a system yield stress, a network structure may be introduced into the continuous phase of suspensions where gravitational forces dominate. To give such a system yield stress, a network structure may be introduced into the continuous phase of suspensions where gravitational forces dominate. Therefore, the particles in such suspensions will remain stationary and suspended with no breaches in the network, providing the stress applied does not exceed the yield stress. Gelling the continuous phase via the addition of suitable additives is one method of creating such structures.

A Measurement System that Supports the Formulation Process

To successfully implement one of these strategies, it is beneficial to measure the suspension's physical and chemical properties. Formulations need to take into account particle size, rheology, and zeta potential data.

Particle size
Changing the particle size of a suspension is one of the simplest modifications to make. Formulators may not be free to experiment with this feature, however, since it could harm bioavailability.

Stability is directly related to the ease with which a uniform suspended phase can be maintained. When particles are suspended at submicron scales, Brownian motion keeps them in a dispersed state. In large particles, gravitation takes hold more strongly if the density difference between the dispersed phase and continuous phase is significant. By calculating the ratio of gravitational forces to Brownian forces, equation 1.1 can be used to predict sedimentation likelihood.

a^4 Δρg / kB T       …...... (1.1)

This formula computes the particle radius as a function of the density difference between dispersed and continuous phases, gravity acceleration as g, Boltzmann constant as kB, and temperature as T.

A suspended particle that falls under gravity experiences a velocity that is directly proportional to its size. Therefore, keeping suspended drug particles small reduces the likelihood of sedimentation thereby ensuring the dispersion of the drug. If particles settle even though they are fine, this may result in rigid aggregates that are not easily broken up and have a difficult time dispersion. In addition to laser diffraction, dynamic light scattering (DLS) is an instrument that can detect particle size.

Both are fully automated, offer rapid measurement, and are highly repeatable and reproducible. DLS is most frequently used to study samples that contain particles in the submicron region, possibly as small as 0.3 nm. Laser diffraction is most suitable for materials with a range of nanometre to millimeter sizes. Therefore, these techniques provide a comprehensive view of the size range relevant for pharmaceutical suspensions.

Stokes' law states that the sedimentation velocity increases with greater viscosity of the continuous phase as well as with increased particle size of a dilute suspension. When particles of the same size are suspended, doubling their suspension viscosity can consequently halve their sedimentation rate. As a result of interactions between neighboring particles, settling behavior in concentrated suspensions can be more complex, and high particle loading leads to an increase in density and viscosity. It is possible to measure viscosity using a viscometer or preferable a rotational rheometer. Rotational rheometers, unlike viscometers, are capable of measuring over a wide range of conditions, such as low shear, which is what the suspension is experiencing at rest, and high shear, which is what the suspension experiences when shaken. Additionally, rotational rheometers are useful for assessing yield stress, as well as for investigating suspensions' underlying structure as well as supporting further stability development.

Zeta potential
The zeta potential provides information on electrostatic and charges repulsion/attraction between particles, besides between particles and their associated double layers, as well as between particles and their environment. As zeta potential can extract insights into how to enhance the properties of formulations susceptible to thermodynamic instability as opposed to kinetic instability, zeta potential can be an effective means of enhancing the properties of such a system.

Those who have discovered that the larger the negative or positive zeta potential, the more particles self-repel, while those with a smaller value indicate more flocculation. In general, stability is defined by a zeta potential greater or less than 30 mV, with suspensions with zeta potentials that are positive or negative indicating stability.

We measure the Zeta potential using the Electrophoretic Light Scattering (ELS) method. A particle whose charge, or more accurately its zeta potential, is positive will migrate towards the oppositely charged electrode with a velocity or mobility that is directly related to its zeta potential when an electric field is applied. A particle whose charge, or more accurately its zeta potential, is positive will migrate towards the oppositely charged electrode with a velocity or mobility that is directly related to its zeta potential when an electric field is applied. DLS systems with high specifications, such as the Zeta Sizer Nano from Malvern Instruments, include all components needed for ELS analysis, and can thus measure both size and zeta potential, the latter of which makes them more useful in formulation studies.
Get subject wise pdf documentsView Here

Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
.moc.enilediugamrahp@ofni :liamENeed Help: Ask Question

No comments: Read Comment Policy ▼

Post a Comment

Please don't spam. Comments having links would not be published.

Popular Categories

QA SOPs QC SOPs Micro SOPs HVAC Production SOPs Stores SOPs Checklists Maintenance SOPs HPLC Sterile GLP Validation Protocols Water System GDP Regulatory Maintenance Calibration Warning Letters Education B.Pharmacy
Download COVID-19 SOP for Home

Follow Pharmaguideline



Editable Pharmaceutical Documents in MS-Word Format. Ready to use SOPs, Protocols, Master Plans, Manuals and more...




Pharmaceutical Updates

✔ Worldwide Regulatory Updates
✔ Pharmaceutical News Updates
✔ Interview Questions and Answers
✔ All Guidelines in One Place


Recent Posts