Preparation And Production Of Pharmaceutical Powder

Mixing of pharmaceutical powder is a unit operation that serves to make two or more components uniformly distributed in the powder bed. The mixing process is necessary to ensure that the active pharmaceutical ingredient (API) and other components are homogeneously distributed throughout the tablet.

Pharmaceutical powder

Powders do not mix spontaneously; therefore, effective mixing requires a thorough understanding of the materials to be mixed, as well as the science of mixing. Effective mixing of powders poses the greatest challenge when the amount of one of the components of the mix is relatively small compared to the other components.

Mechanisms Involved In The Mixing Of Pharmaceutical Powder

There are three main mechanisms involved in the mixing process, related to the different kinds of particle motion. These include:

1. Convection

2. Shear

3. Diffusion

Preparation Of Pharmaceutical Powder

1. Reduction of particle size of all ingredients to the same range to prevent stratification (separation of the large and small particles)

2. Sieving

3. Weighing each ingredient

4. Mixing

5. Packaging

During powdering, weighing and mixing, there is loss of powder which cannot be avoided. Therefore, while calculating the quantity of ingredients, calculate for one extra powder than required.

Read Also: Tablet production process

Size Reduction

For preparation of powder, each ingredient should be needed in finely ground form; hence manufacturers must use a number of procedures and equipment to reduce the particle size of powder ingredients. This process is called comminution. This is the process of reducing large solid units or substances into smaller unit mass, coarse particles or fine particles. It is also termed grinding or pulverization. Smaller particle size and increased surface area, leads to uniform distribution of the drug substance in a powder mixture or solid dosage form to ensure dose to dose content uniformity.

In extemporaneous compounding, there are three methods of comminution. The most common method used for particle size reduction in powder formulation is trituration.

Trituration

This involves placing the solid in a mortar and continually grinding the chemical between the mortar and the pestle using a firm, downward pressure. The powder must be frequently scraped from the sides of the mortar to ensure that all particles are evenly reduced and mixed.

Pulverization By Intervention

Pulverization by intervention method is used with hard crystalline powders that do not crush or triturate easily, or gummy-type substances. The first step is to use an "intervening" solvent (such as alcohol or acetone) that will dissolve the compound. The dissolved powder is then mixed in a mortar or spread on an ointment slab to enhance the evaporation of the solvent. As the solvent evaporates, the powder will recrystallize out of solution as fine particles.

Levigation

Levigation reduces the particle size by triturating it in a mortar or spatulating it on an ointment slab or pad with a small amount of a liquid in which the solid is not soluble. The solvent should be somewhat viscous such as mineral oil or glycerin. This method is also used to reduce the particle size of insoluble materials when compounding ointments and suspensions. A small mesh sieve can be used to determine the prevalent particle size of a powder after it has been reduced.

Read Also: Classification of pharmaceutical powder

Size reduction On Large Scales

1. Compression: positive pressure, e.g. nut crusher, ball mill

2. Impact: material is stationary and hit by an object, e.g. hammer mill

3. Shear: cutting force, e.g. scissors, colloid mills

4. Attrition: breaking the edges of the solid either by impact or particle collisions (fluid energy mill and roller mill)

Mixing Of Powders

Particle size reduction is followed by homogeneous mixing of all powder ingredients. Many times processes similar to those used for particle size reduction are used for obtaining homogeneous mixture. Powders that have been blended with a protectant to prevent the formation of an eutectic mixture must be mixed carefully with little or no pressure. The powders may be mixed by any one of the following methods:

1. Spatulation

2. Trituration

3. Geometric dilution

4. Sifting

5. Tumbling 

Spatulation

In this method, the powders are blended in small amounts by movement of a spatula on an ointment tile or on a small sheet of paper. The process is only suitable for small quantities of powder. Powders having potent substances or with a large quantity are not blended by this method, because the process does not ascertain a homogenous blending.

Solid substances that form eutectic mixtures are suitable for blending with spatulation because compacting of the powders results from these. Examples of substances that can be blended by this method are camphor, menthol, phenol, thymol, aspirin, etc.

Spatulation, or the mixing of particles with a spatula on an ointment slab, results in a light, well mixed powder without interfering with the protectant. Trituration

Trituration serves the dual purpose of reducing particle size and mixing powders. It is especially effective for mixing small quantities of potent drugs with larger amounts of diluents. In this method, the mixing of powders is done by the movement of a spatula throughout the powders on a sheet of paper or on a porcelain tile. The method is very useful in mixing.

Trituration is the continuous rubbing or grinding of the powder in a mortar with a pestle. This method is used when working with hard, fracturable powders.

It is used both to reduce particle size and mix powders. If particle size reduction is desired along with mixing of powders, a porcelain mortar with a rough inner surface is preferred to a glass mortar with a smooth working surface.

Read Also: Benefits and limitations of pharmaceutical powder

A glass mortar may be preferred for chemicals that may strain a porcelain surface and for simple mixture of substances without special need for comminution. A glass mortar cleans more readily after use.

Geometric Dilution

The method is used when potent substances are mixed with a large amount of diluent. The potent drug is placed upon an approximately equal amount of the dilute in a mortar and the substances are slightly mixed by trituration.

A second portion of diluent equal in volume to the powder mixture in the mortar is added and trituration is repeated. The process is continued, adding diluent equal in volume to the mixture in the mortar at each step, until all the diluent is incorporated.  

For example, if 100 mg of potent drug is required to be mixed with 900 mg of lactose, then according to geometric dilution, the following procedure should be followed: 100 mg of a potent drug + 100 mg of lactose = 200 mg of mixture. Then, 200 mg of the mixture + 200 mg of lactose = 400 mg of mixture. Followed with 400 mg of the mixture + 400 mg of lactose = 800 mg of mixture. Lastly, 800 mg of the mixture + remaining portion of lactose = 1000 mg of mixture.

Sifting

Powders are mixed by passing through sifters, which results in light and fluffy products. The process is not suitable for the incorporation of potent drugs into a powder mix.

The powders are mixed by passing through sifters. This process results in a light fluffy product and is generally not acceptable incorporation of potent drugs into a diluent base. 

Tumbling

Special motorized powder blenders are used in this process, whereby the powder is mixed by tumbling in a rotating chamber. The process is time consuming.

It is the process of mixing powders in a large container rotated by an electric motor. These blenders are widely employed in industry as large volume powder mixers. Hazardous substances can be effectively mixed by a process called tumbling. The powders are sealed in zipper-sealed bags or clear bottles with a lid and tumbled until they are well mixed. The addition of a coloring agent can assist in determining homogeneity in the mixture.

Pharmaceutical Powder Mixing Rule

1. When mixing powders with different particle sizes (granular salt and fine powders), reduce each powder separately to fine particles before mixing.

2. When mixing powders with different densities, put the light powder first and then put the heavier one on top of it.

3. When mixing small amounts of a drug to a large volume of bulk powder, use the principle of geometric dilution.

Packaging Of Powder

Powders may be wrapped in paper or dispensed in bulk powder in a wide mouth container.

Read Also: Tablet evaluation

White glazed paper is generally used for wrapping. The wrapping should be done on a clean tile or large sheet of glazed paper to protect the product.

Bulk powders for external use (sometimes called dusting powders) are often dispensed in a shaker-top container to facilitate topical application. They may also be dispensed in a wide-mouth jar or a plastic container with a flip-top lid. The jar or plastic container can be closed tightly to provide increased stability and protection from light and moisture, especially for compounds that contain volatile ingredients.

Package should contain a label as "For external use only”. Bulk powders intended for internal use should be dispensed in an amber colored, wide-mouth powder jar with a tight-fitting lid. They should be accompanied by an appropriately sized dosing spoon or cup and adequate directions for removing and administering a correct dose. Bulk powders for internal use should be labeled with the strength of the active ingredient per dose (e.g. potassium chloride 600 mg per tablespoonful).

Problems Encountered In Powder Formulation

1. Efflorescent powders

2. Hygroscopic powders and deliquescent powder

3. Incorporation of liquids

4. Incorporation of extracts

5. Incompatible salts

6. Expensive mixtures

Evaluation Of Powder

1. Content uniformity

2. Particle size and size distribution

3. Flow property

4. Angle of repose

5. Flow rate 

6. Density

7. Bulk density

8. Tapped density 

9. True density

10. Hausner’s ratio

11. Moisture content

12. Tensile and cohesive strength measurements

 13. Safety and efficacy

14. Stability