Active Pharmaceutical Ingredient Powders

Why lumping and flowability are an industry pain that is difficult to resolve… and why Teva api is determined to do something about it

Active Pharmaceutical Ingredients have several important physical powder properties including hygroscopicity, compactability, flowability and lumping.

Powders are complex materials… they could even be accused of having personalities…

  • Not flowing
  • Sticky
  • Not loose
  • Sensitive
  • (Flowing) Not spontaneously

See how Teva api’s R&D experts can help you with flowability and lumping.

Several pharmaceutical processes including storage of powder, transportation, blending and compaction are influenced by powder behavior. Powder behavior issues such as flowability and lumping have been major challenges for the pharmaceutical industry, which works mainly with powders. These phenomena are complex, poorly understood and handled, and require prior experience and advanced analytical tools in order to be understood and resolved.

Flowability in Active Pharmaceutical Ingredients

Flowability – is the ability of powder to move in a specific system. The powders are lined up from “free flowing” powder to “non-flowing” powder.

Flowability of a powder refers to the specific relevant system. The same powder can flow with no issues in one system but will face difficulties in a different pharma equipment.

Flowability is a complex factor influenced by multi physical properties. Therefore the key to improve flowability will rarely be a small change in one production parameter and will not be characterized by a single analytical test.

Combinations of analytical tests (such as: angle of repose, compressibility index and Hausner ratio, flow through an orifice, shear cell methods) and deep evaluation of:

  • Material features (electrostatic charge, cohesion and hygroscopicity)
  • Production parameters (drying, milling processes)
  • Environment conditions (humidity, moisture content and storage container)
  • Pharma equipment that the powder should flow through

Will provide that starting point for improving the way the powder moves in pharma equipment.

The analytical tool can be useful in order to evaluate “better flowing” material, can distinguish between batches and allow you to have fine-tuning on your production parameters in order to comply with pharma requests and formulation instrumentation.

Lumping in Active Pharmaceutical Ingredients

Lumping can occur during storage: small aggregates accumulating over time within the powder, in extreme cases the entire powder takes on the shape of the container.

Lumping can also occur during drying: during solvent removal, lumps requiring “pre-milling” are created and in some specific cases, the lumps are too large to be milled by conventional means.

Lumps formation in the API is studied already in the early R&D stage. Several aspects of the Active Pharmaceutical Ingredient are considered in order to predict lumps formation: solubility, hygroscopicity, package information, particle size (milled, micronized) and solvents used in the last process step. Using multiple analytical tools such as microscopy, contact angle, PSD, lumping prediction in small scale, surface area, bulk and tapped density, angle of repose and more, Teva api is able to predict and control lumping in our APIs.

Lumping can be characterized by many analytical tools such as: microscopy and surface area (SSA)

Solving lumping issues, a case study

Tackles lumping is an Active Pharmaceutical Ingredient that has been produced by Teva api for more than 20 years and was known as lumped material. The solution to this lumping came from our customer’s formulation equipment that had separated all the lumps. A request from another customer raised the need of Teva api to evaluate the root cause and find a lasting solution to the phenomenon. One known technique to prevent lumps forming is to change the drying procedure. In this particular case, being the material highly hygroscopic, it was discovered that the discharge of the material from the drier needs to happen at a temperature very close to room temperature to prevent water absorption during cooling which could bring to the formation of water bridges.

After taking this precaution the lumping formation was reduced, but still some small lumps were observed in the material.

Further analyses led us to discover that residual solvent from the crystallization process can also contribute to the creation of lumps.

Residual solvent that was trapped in the wet part of the powder (part of the powder that was not well stirred or left in the corners of the dryer) was contributing to these smaller lumps. So additional drying was needed for that layer.

Another way to prevent lumping involves the packaging of the powders, this solution is recommended in cases of soluble material in water or in organic solvent.

All grades of particle size of this material had a tendency to lump over time. Extended drying and cooling prior to unloading solved the issue for the large and medium grades.

The fine grade material (micronized grade) would often lump even at the end of milling. Along with extended drying and cold unloading, packaging with N2 has prevented lumping for at least 6 months after packing.

This complex problem is a challenge we accept on behalf of our customers

With our years of experience in the improvement of powder flowability and the prevention of lumping, Teva api is the industry leader. Teva api is constantly looking at new techniques, procedures and products that improve our customer’s end product experiences and their satisfaction with our Active Pharmaceutical Ingredients. By working in close cooperation with our customers we are ensuring that the properties of our powders match our customer’s expectation.

About the author

Maytal Piran is Dir Global Solid State Characterization. She leads the solid state global team of product managers and researchers, specializing in API crystal forms, particle & powder properties.