API Milling methods

Teva api’s Personal Touch Delivers Ideal Particle Sizes

 By Yasmeen Yeshayahoo, Teva api R&D Solid State Technology Manager; Zohar De-Valenca, Sr. Manager T&SA; Itai Shalom, Associate Director, Solid State Tech, Teva api R&D



The physical properties of APIs and particle size distribution (PSD) are critical to manufacturing drug products that will work most effectively for the patient. Producing robust API particles that meet the manufacturer’s exact specifications requires proper crystallization and milling.  How do we at Teva api determine what API particle size will work best? When customers approach us with a project, they have a general idea of what they need. Experience has taught us that every situation is unique, so we take a personalized approach to each project using our industry-leading expertise, sophisticated milling equipment, and close collaboration between different units in our organization to deliver optimal results. 

R&D Article Products

At the beginning of any project – whether R&D development or manufacturing at scale – customers typically ask the API supplier to mill an API to a specific particle size. As the API supplier, understanding the logic behind this request is a key stage in supplying an API that will fulfill the customer’s needs. Since every API is different very strong technology and scientific understanding is needed.


TAPI API milling capabilities


A personalized approach to deliver an optimal product


To ensure each customer’s specifications are met properly, Teva api takes a step back and asks some questions so we thoroughly understand what they need to accomplish:

  • What will the final dosage form be?
  • Why did they request a particular particle size?
  • What formulation process are they using?
  • What is the analytical method used to measure the particle size? Will they agree to use Teva apis PSD method?


Our R&D teams are experts on the latest milling techniques and have a full understanding of how a particle’s physical properties can affect their process. Our scientists may be able to recommend a different solution that would result in a more successful outcome. 


For example, inhalation products require very small particles for absorption, a very narrow distribution and specific surface properties. If the particles are too coarse they won’t enter the lungs, and if they are too small they won’t be absorbed. Teva api support  customers needed particle size distribution to achieve their desired results, and we have the facilities necessary to produce particle sizes, no matter how small or how range-specific.


Throughout the years, we’ve refined our process to make sure our customers get the full benefit of our industry expertise, advanced milling equipment and personalized customer experience. Unlike many competitors, Teva api is performing almost all milling activities in-house except of a minor percentage (less than 2%) that is being  done by 3rd party for special projects We have our own milling facilities around the globe (in Europe, Asia, Israel, and Central America) operated by highly-skilled technicians who can deliver optimal results. Our sites are equipped with the most advanced technology on the market today, which can mill APIs from the de-lumping stage all the way to nanoparticles. In many cases final crystallization is modified to ensure specific PSD before milling. It can then be reduced to meet PSD and specifications for other physical properties. If necessary, Teva api experts from multiple sites around the world will team up to develop a solution for a customer’s unique need. 


API milling by TAPI


Teva api is equipped to handle your milling need


Four categories of milling cover an extremely wide range of particle sizing, from a few microns up to 1,000 microns. Teva api offers all four categories, and we have the capability to produce small quantity samples in R&D or bulk product on a large scale for commercial production. Each category has the distinct ability to mill particles to the specific sizes required to meet customer specifications and ensure effectiveness of the final formula that includes them. 

The categories are:


  1. De-lumping: breaks up lumps and aggregates them into roughly uniform size
  2. Aggressive milling: in the 30-100 µm range and usually achieved by impact mills
  3. Micronization: in the 5-30 µm range and usually done via straightforward micronization
  4. Ultra-Micronization and Nano milling: less than 5 µm and achieved by micronization with special equipment  (e.g., special micronizers, cryogenic, wet milling)

 API milling chart by TAPI

Examples of milling technologies used in particle size ranges.


R&D and production experience to understand and meet specific needs


All the cutting-edge technology in the world is useless to a customer without the supplier’s expertise on how and when to use it, which is why we’ve implemented several initiatives to ensure we meet our customer specifications:

  • Our particle size teams can provide information and guidance about APIs being produced
  • R&D supports locally-based teams, including monthly meetings with experts from different areas of the company worldwide to raise important issues, discuss new technology options and stay up to date with activities across the company
  • Our teams are trained to anticipate customer questions and be ready to deliver answers
  • We are always innovating - always on the lookout for new technologies for both milling and crystallization while using advanced computational tools    
  • We collaborate closely with customers to learn as much as we can about their projects and procedures to support them from early development (R&D to R&D) to product delivery


Our experts go to these extra lengths to deliver API particle sizes that will work for the manufacturer and ultimately, the patient. For example there was a scenario where, despite the best efforts of everyone involved, the resulting tablets broke apart too easily. Because of the close collaboration between Teva api and the customer, we were able to identify and measure the root cause. By changing the API’s crystallization procedure and tailoring the right milling system, we were able to improve the tablet’s strength. 


In another instance, a customer required an API which have  high permeable and high solubility for direct capsulation. The primary challenge arose in API formulation – the API must be free flowing since 75 percent of the capsule is the API. Teva api researchers developed a controlled and robust crystallization process to eliminate nucleation and encourage crystal growth. We developed a very gentle milling process to eliminate fine particles and produced more than 100 lots with very small STDV in particle size distribution bulk properties and flowability. We were able to achieve equivalent results in 3 liter, 100 liter, and at 4 m3 scale.

TAPI API milling expertise


Personalized attention is a matter of pride at Teva api


One of the key reasons customers choose Teva api is the high level of personal attention that each receives. Teva api does everything with the customer point of view as its guide, no matter how complicated their needs might be. 


Combining the API milling expertise, full production capabilities and a personal touch means Teva api has a deep understanding of exactly what the customer needs before anything goes to R&D or manufacturing, and throughout these processes. This approach saves time, aggravation – and money. And, most importantly, our customers are able to meet market demand for drug products worldwide.


Yasmeen Yeshayahoo is Teva api’s R&D Solid State Technology Manager, part of Teva api Global R&D, and has been with the company for almost five years. She is located in Israel and has a master’s degree in Chemical Engineering from Technion - Israel Institute of Technology.

Zohar De-Valenca is Senior Manager TSA, Technologistic Team at Teva api. He has been with the company for five years working in Israel. He started out as a Solid Process Engineer with expertise in developing powder grinding processes, mechanical processes and particle flow processes.

Itai Shalom is Associate Director, Solid State Technology, Teva apiGlobal R&D, and has been with the company for 15 years. Itai is located in Israel and has more than 14 years of powder technology expertise. He started as team leader in production, served as a facility manager and has a BSC in Chemical Engineering and a master’s degree in Environmental Engineering. 



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