preparation of a suspension
The following presentation outlines the procedure for preparing a suspension. The steps are:
- Wetting and Dispersion of the Active Ingredient.
- Stabilization of Dispersed Solid.
- Preparation of the Vehicle.
- Addition and Dispersion of Active Ingredient in Vehicle.
- Addition of Remaining Ingredients and Final Mixing.
Step 1. Wetting and dispersion of the Active Ingredient
Dry mill to achieve target particle size and particle size range. N.B. This milling may increase surface energy on the drug particles and hinder wetting and dispersion. It other solid-solid transformations.
Drug powder may be treated with a water miscible material such as glycerin to aid in wetting. Large quantities of drug may make this impractical.
Powder should be added to a low viscosity portion of the product, preferably plain water. This allows for most efficient mixing and homogenization. A surfactant is frequently added to the water to aid in wetting and displacement of air.
Step 2. Stabilization of the Dispersed Solid
- Electrical (Controlled flocculation). Addition of electrolytes to produce charges around each particle and allow for electrical repulsion to prohibit particle interactions. From a practical aspect, this is not effective except where particles are in the colloidal size range (i.e. < 1 mm). This should not be confused with the elctrical layer and double layer that are produced when ionic surfactants are adsorbed at the solid:liquid interface since the charges are bound by their attachment to the portions of the surfactant molecules making up less hydrophilic layer at the interface.
- Adsorption of a hydrophilic colloid: Such a material forms a layer around the particle. It is highly hydrated and the attractive forces between the hydrophilic colloid and water molecules are greater than the attractive forces between the solid particles, thus overcoming those forces and stabilizing the dispersion.
- Steric hindrance: Adsorption of a layer of non-ionic polymer onto the surface of the particle may physically block particle association either by the space occupied by folds in the chains or by mobile chain ends (usually the polyoxyethylene chains in non-ionic surfactants). A layer of finely divided solid particles like that which produces a comparable effect in emulsions is unlikely to form on a solid surface. The stabilizer therefore could be added as: a solution to the dispersed drug, or incorporated into the vehicle, or it may already be present as the surfactant which facilitated wetting.
Step 3. Stabilization of the Dispersed Solid
The vehicle will tend to stabilize the dispersion by limiting particle movement due to its high viscosity. Reaction of the vehicle to stress (such as shaking the bottle) gives rise to the following classifications:
- Newtonian: Viscosity is independent of applied stress.
- Plastic: There are weak interparticulate bonds in the system which must be broken before any flow can occur. Once those bonds are broken (at a point called the Yield Value), the material is Newtonian.
- Pseudoplastic: There may or may not be a Yield Value but regardless, there is a decrease in effective viscosity as the applied stress is increased.
- Thixotropic: There is an internal structure which is reversibly damaged upon application of external stress. It does reform in a time-dependent manner.
Agents which increase viscosity are generally hydrophilic high molecular weight water soluble compounds. The exception are those which, although hydrophilic, are wter insoluble. Polymers such as sodium carboxymethylcellulose and gums such as xanthan gum and tragacanth will form lumps if added to water improperly. Such lumps consists of a dry centre surrounded by a very high viscosity gel. Once formed they are difficult to break up and slow to dissolve. Because they are used in relatively small amount, it is often practical to disperse them in a water miscible liquid in which they are insoluble. A common technique is to make a paste of the material in glycerin, then carefully add this paste to water. It is also usual to allow this mixture to stand for up to 24 hours to ensure complete hydration of the polymer.
A variation of this method is a co-precipitate of sodium carboxymethylcellulose and microcrystalline cellulose where the good dispersion properties of the MCC are used to facilitate dispersion of the CMC. Clays are generally added directly to water as they do not form the same lumps as the polymers or gums. However, a period of standing is still required as they do hydrate over a period of several hours.
Additives such as sequestrants, preservatives, and buffers are generally added prior to the addition of the thickener and are frequently added at the solid dispersion stage.
Step 4. Addition and Dispersion of Active Ingredients in Vehicle
The dispersion of the active ingredient is added to the vehicle with low intensity mixing. The mixture is then homogenized to ensure uniform dispersion of the ingredients. Any high energy process which has a tendency to incorporate air into the suspension is done with care since:
- These mixtures contain surface active compounds which promote foaming, and
- The viscosity of the suspensions make it difficult to remove air bubbles from the suspensions.
Step 5. Addition of Remaining Ingredients and Final Mixing
Sensitive ingredients such as flavours are added after the high energy stages. Water is added to bring the suspension to its target volume. Frequently, because of the effect entrapped air will have on accuracy of volumes, mixing tanks are placed on load cells and, knowing the specific gravity of the final product, adjustment is to weight rather than volume.
A final homogenization may be carried out although with care. The suspension may then be allowed to stand to deaerate. With appropriate equipment, vacuum, is used to accelerate the deaeration.