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Challenges with API Micronization Techniques for Use in Injectables and Medical Devices

Demand is steadily growing for pharmaceutical materials that contain micronized active drug substances (APIs) for inhalation and injectable delivery. Active pharmaceutical ingredients (APIs) are micronized for a number of reasons, generally performance-related. Neuland manufactures generic APIs like Salmeterol, Salbutamol and Ipratropium bromide, used in inhalation formulations, so we understand the challenges micronization can present.

micronizationFor injectable drugs and inhalants, particle size distribution typically should be in the range of 2-20 microns, with a steep distribution curve and minimum amount of fine and oversized particles. Depending on the complexity of the formulation, device or inhalation delivery system, the particle size can vary. However, the majority of particles must be between 0.5-8 microns.

With injectable drugs, the particle size is reduced to increase the solubility of the drug, (link to previous post) making it dissolve more quickly, and allowing effective doses to be injected in smaller amounts. Poorly-soluble APIs can be improved by micronization, as it increases surface area and speeds up dissolution. For other dosage forms, micronization can be used to improve homogeneity in addition to increasing solubility.

Micronization Defined

A particle size of less than 10 microns can be achieved in a number of ways, including controlled precipitation or using an external source of energy. A conventional method of reducing particle size is micronization, in which particles are reduced to a size of less than 10 microns.

Micronization typically refers to processes that use fluid energy to reduce particle size (e.g., jet milling), compaction using a ball or bead mill, or other non-conventional techniques. Each of these techniques has advantages and disadvantages.

For example, bead mills are suitable for heat sensitive materials, but also create some problems such as:

  • Low productivity
  • Reliance on large equipment and typically uses an external medium for grinding
  • Potential particulate contamination
  • And may require additional processing.

Non-Conventional Micronization
Something to keep in mind is that conventional micronization may not be suitable for all drug substances. In the last few years, several supercritical fluid-based techniques have been proposed to produce micron- and nano-sized particles. Three groups of processes used to produce fine and monodisperse powders are:

  • Rapid Expansion of Supercritical Solutions (RESS)
  • Supercritical Antisolvent (SAS)
  • Particles from Gas-Saturated Solutions (PGSS)

However, these techniques are not without their limitations. By relying on CO2, they are held back by its poor solvent power, high cost and the need to use significant amounts. Despite the number of mechanistic studies available, confusion remains concerning how each variable affects the particle morphology and properties.

Common Challenges of Micronization
API Drug Micronization
involves many challenges, risks and considerations. Some of the most common are:

  • The initial particle size of the API to be micronized – which plays a role in achieving the desired particle size.
  • Reducing particle size also carries the risk of altering the morphology of the drug molecule, resulting in different polymorphs, amorphous APIs, or a mixture of crystalline and amorphous APIs
  • Micronized material is charged and may lead to segregation, clumping, and other possible physical instabilities during long term storage or in the formulation if it is not well controlled.

API Micronization – Jet Mills Preferred for Inhalation

Jet mills (or fluidized jet mills) are the preferred method of micronizing an API for use in an inhalation dosage form. Jet milling micronizes drugs using compressed air or inert gas. The desired particle size is achieved by proper control of parameters.

Particle Size Distribution (PSD) Trials at Neuland

Given our experience with inhalation products, Neuland has developed strong micronization capabilities – providing customers with different particle size distributions (3-tier specifications ranging from 2- 5 microns) with a very narrow particle size range, something that can be difficult to accomplish. Another challenge we’ve been able to overcome is achieving bulk density and flowability – critical traits for medical devices.

To fine-tune our techniques, Neuland has conducted particle size distribution (PSD) trials using the Design of Experiment model in line with QbD requirements, achieving PSD targets at the outer limit of the specifications.  These experiments involved identifying, analyzing and fine-tuning a desired set of parameters to provide accurate, reproducible particle size distributions.

Selecting the appropriate technique for API micronization remains challenging. It is a complex process, reliant on an experienced team well-versed in the advantages and disadvantages of various drug micronization strategies.

Are there any particular API particle size strategies or techniques you’ve run across?

 

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