Thursday, April 15, 2021

Stability Considerations for Pharmaceutical Suspensions

by | September 22, 2020 0

A suspension is a heterogeneous system consisting of two phases. The dispersed or internal phase is made up of particulate matter that is essentially insoluble in but uniformly dispersed throughout, the continuous or external phase, which is generally a liquid.

The formulation of suspensions for oral administration requires consideration of the physical properties of both the therapeutic agent and the excipients required to ensure that the formulation is physically stable and suitable for administration to patients.

The factors to be considered during the formulation of pharmaceutical suspensions can be broadly classified into

  1. Stability considerations
  2. Rheological considerations
  3. Theoretical considerations

Apart from the above, other important formulation considerations for suspensions include

  1. Dose of the active pharmaceutical ingredient (API)
  2. Route of administration
  3. Patient population
  4. Physicochemical characteristics of the API (e.g. solubility)
  5. Biopharmaceutical properties of the API
  6. The physicochemical properties of the other components of the formulation

In this article, we will discuss stability considerations for pharmaceutical suspensions. Rheological considerations and theoretical considerations for pharmaceutical suspensions will be discussed in separate articles.

Stability Considerations for Pharmaceutical Suspensions

General chemical stability considerations apply to suspensions as much as to any other formulation. The drug must remain chemically stable over the intended shelf-life of the product. Physical stability is equally important for suspension formulations.

To obtain a suspension that is chemically and physically stable, the following have to be taken into consideration.

  1. Settling/Sedimentation rate of the suspended particles
  2. Limitations of Stokes’ Law
  3. Sedimentation in flocculated and deflocculated systems
  4. Controlled flocculation
  5. Effects of particle size on suspension stability
  6. Crystal growth
  7. Use of structured vehicles

1. Settling/Sedimentation rate of the suspended particles

Settling or sedimentation is a very important issue in suspension stability. It is a general trend to reduce the rate of settling, although an inordinately slow rate of settling in a deflocculated suspension may cause the particles to settle as compact residue at the bottom of the container.

Sedimentation of particles in a suspension is governed by a variety of factors:

  1. particle size
  2. density of the particles
  3. density of the vehicle and
  4. viscosity of the vehicle

The relationship between the velocity of sedimentation of particles, the diameter of the particle, the acceleration of gravity, density of the suspended particle, density and viscosity of the vehicle in a suspension can be determined by using the Stokes’ law which is mathematically stated as

V = d21 – ρ2) g / 18 η

Where:

V = velocity of sedimentation, d = diameter of the particle, g = acceleration of gravity, ρ1 = density of the particle, ρ2 = density of the vehicle, η = viscosity of the vehicle.

From the above equation (Stoke’s equation), the velocity of sedimentation of particles in a suspension has a direct relationship with particle diameter and the difference of the densities of both the particles and the vehicle.

The velocity of sedimentation can be reduced by decreasing the particle size and also by minimizing the difference between the densities of the particles and the vehicle. Since the density of the particles is constant for a particular substance and cannot be changed, the changing of the density of the vehicle close to the density of the particle would minimize the difference between the densities of the particles and the vehicle.

The density of the vehicle of a suspension can be increased by adding polyethylene glycol, polyvinyl pyrrolidone, glycerin, sorbitol, and sugar either alone or in combination.

2. Limitations of Stokes’ Law

Stokes’ law is a generalized equation that describes how certain factors affect the rate of settling in dispersed systems. The implication is that, as the average particle size of suspended particles is increased, there is a dramatic effect on the resultant rate of sedimentation.

Stokes’ law is based upon several assumptions, which may not always hold true for pharmaceutical suspensions. The law is valid for diluted pharmaceutical suspensions that are composed of no more than 2% solids. In a diluted suspension, the solid particles settle without interference from one another in what is termed free settling. In a concentrated suspension, this interference may occur and may hinder the settling results.

Particle shape and size are also important in Stokes’ equation. This equation assumes spherical and monodisperse particles, which may not be encountered in real systems. The limitations to Stoke’s law include:

  • Negative density difference in Stoke’s equation
  • High content of dispersed solids
  • Dielectric constant
  • Brownian movement

Read more on the limitations of Stoke’s law

3. Sedimentation in flocculated and deflocculated systems

Flocculated suspensions as discussed in the theoretical considerations show rapid sedimentation creating loose sediment; whereas, deflocculated suspensions show slow, but compact, sedimentation. A deflocculated system has an advantage in that their sedimentation rate is slow, thereby allowing uniform dosing. However, if settling occurs, the sediment can be compact and difficult to redisperse.

On the other hand, flocculated suspensions are stilted because the particles separate quickly. Rapid sedimentation may cause inaccurate dosing but redispersion can occur, even after long storage since the sediment is loose. An intermediate condition known as controlled flocculation can be created to obtain the most acceptable product.

The extent of flocculation of a system can be redefined by the extent of sedimentation by using two commonly important sedimentation parameters;

1.  The sedimentation volume, F, which is the ratio of the equilibrium volume of the sediment, Vu to the total volume of the suspension, Vo used for that purpose with the value of F normally ranging from 0 to 1. The above statement can be stated mathematically as

F = Vu / Vo

If the sedimentation volume is 0.8, 80% volume of the suspension is occupied by the loose flocs as the sediment. The F value of a deflocculated suspension is usually relatively small, about 0.2. A pharmaceutical suspension with F value 1 is the ideal system and such a system is said to be flocculated. There is no sedimentation or caking in such a system and it is also aesthetically elegant since there is no visible clear supernatant.

A pharmaceutical suspension with F value 1 can also be said to be in flocculation equilibrium. It is possible to have F values greater than 1 when the ultimate volume of the sediment is greater than the original volume of the suspension.

2. The degree of flocculation, β. This is a more applicable parameter for flocculation and it is the sedimentation volume of the flocculated suspension, F, to the sedimentation volume of the suspension when it is deflocculated, F. This is expressed mathematically as

β = F / F

The sedimentation volume of the deflocculated suspension can be shown by the following equation

F = V / Vo

Where

F = sedimentation volume of the deflocculated system
Vo = ultimate volume of the sediment

The degree of flocculation is a more useful parameter because it compares the suspension under investigation to a standard: the deflocculated state of the system.

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