Factors for Selecting Pharmaceutical Particle Size

Factors for Selecting Pharmaceutical Particle Size

Selecting the right pharmaceutical particle size reduction service is critical for ensuring product efficacy, regulatory compliance, and cost efficiency. The process requires precise control over droplet size during atomization, which directly impacts powder characteristics like solubility, flowability, and active ingredient concentration. Partnering with a service provider that offers end-to-end support, advanced technology, and proven expertise can significantly enhance product performance and market competitiveness.

Pharmaceutical manufacturers face increasing pressure to optimize powder formulations while meeting stringent regulatory standards. The right particle size reduction partner can help achieve these goals by providing access to cutting-edge equipment, such as dynamic atomization systems, and ensuring compliance with FDA, GMP, and other certifications. This introduction explores key factors in selecting a service provider, the impact of different particle engineering technologies, and analytical methods for verifying particle size distribution.

We’ll examine how to evaluate potential partners based on their technology, experience, and quality systems, as well as the benefits of advanced atomization techniques. You’ll gain insights into improving powder solubility, reducing active ingredient usage, and ensuring regulatory compliance—all while maintaining cost efficiency and product quality.

By Hendrik Grobler, Stephen Enloe, Ulli Lindau and Will West | Advanced Powder Dynamics

TL;DR – Quick Summary

Selecting the right particle size reduction service for pharmaceutical powders is crucial for product quality and regulatory compliance.

End-to-End Partnership: Evaluate partners based on their end-to-end partnership approach, including robust onboarding and product development processes.

Latest Technology Access: Ensure the service provider has access to the latest technology, including liquid handling, batching, mixing, blending, and drying equipment.

Compliance Certifications: Consider their experience and proven results, as well as compliance with FDA registration, GMP certification, and other organic and religious certifications.

Dynamic Atomization Benefits: Dynamic atomization technology offers precise control over droplet size, resulting in a lighter, fluffier powder with enhanced solubility and reduced active ingredient usage, potentially lowering costs.

Particle Size Measurement: Reliable analytical methods for measuring particle size distribution include on-site labs equipped with particle size analyzers, density measurement tools, and algorithms for flowability and compressibility.

Pro tip: When evaluating particle size reduction services, request case studies and data on their success rates and customer testimonials to ensure they can meet your specific requirements.

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Key Factors for Selecting Particle Size Reduction Services

Hendrik: Yeah, that is very impressive. So going on from that question, which was a great answer, we’ll go to the next question here, which is, what factors should I consider when selecting particle size reduction service for pharmaceutical grade powders? There’s quite a few here. So I will start with what I think is the most important one, and that is your partner’s end-to-end partnership approach. Can they take you through the whole process, depending on what your specific requirements are? Do they have a robust onboarding process? Do they have a robust product development process? That focuses on your objectives and can achieve those objectives in a timely manner. Those are the most important factors. Additional to that, I would say, do they have access to the latest technology? And that includes the liquid handling side of your product. Do they have the batching equipment? Do they have the mixing equipment? Do they have the blending equipment? Then do they have the… The dryer technology itself to dry and atomize and produce in specification product for you? And then thirdly, on the dry product handling size, do they have the applicable packaging materials and packaging requirements that complies to your requirements? I would say then additional to that is do they have the experience and experience. Expertise with proven results that they can show you what they have achieved in the past with regards to specific products and with specific requirements with regards to that particle size reduction. Those are the important things to consider. You’re looking for a partner that can take you through the whole process, guide you through the process, be very transparent and very open into.

What they have achieved and what they cannot have achieved and how they are going to approach or handle those challenges. Lastly, very important is do they have the required quality systems in place and do they have the required regulation in place? FDA registration, GMP certification, and then the other organic. Religious certifications like kosher, halal, and then also organic certification.

Stephen: Mm-hmm. Anything to add from Will or Uli on that one?

Will: Yeah, I would just say that, you know, most of our production and factory work is more on the food, beverage, nutraceutical, medical food side of the line. From the Tesseract point of view, our patents and our delivery system, all that applicability extends well into the pharmaceutical side. The rules that Hendrik outlined, they remain the same, you know, on both sides of the equation. And ultimately, it really is about making sure that there’s alignment between what the market needs and what happens on the front end of the process and in the engineering side. Because ultimately, consumers behave in very similar ways and the end product has to be engineered in a way that’s going to meet with the consumer expectations on both sides. And so I think we see that. Every day, every week, no matter which type of customer we’re working with and partnering with. And so regardless of what industry our partner sits in, they usually use the same rules.

Impact of Particle Engineering Technologies on Morphology

Stephen: So moving on from that question, great answers guys. We have our sixth question of the day, which is how do different particle engineering technologies affect the final particle morphology and performance characteristics?

Hendrik: Again, we mentioned some of these technologies earlier. At the end of the day, the most important factors to consider is the ability to have precise control over forming a droplet. Droplet size in atomization technology is critical with regards to what kind of powder you will create at the end of the day. How do you manage that? You have to the technology with minimal shear, no heat scorching, no mechanical shear, and those things combined with the ability to have exact control over your atomization energy. So that is the spray pattern, the amount of force that you put into your atomization to create that specific droplet size. Additional to that, your technology should. Be supported by the latest control system, the software that you apply to manage and to control the energy that you put into the atomization. If you have that and you have the latest technology with regards to atomization itself, you can have precise control over the droplet size, and that will give you the particle in the product at the end of the day that you require.

Will: Yeah, I would add here also that you get, for example, with the dynamic atomization option that Hendrik’s describing, a very light fluffy powder. It’s absolutely beautiful compared to the outcome that sometimes are experienced with other methodologies. But there’s also the question of other technologies beyond simply the drawing platform, as I’ll call it. For example, we talked a while ago about cyclodextrin approach. One of the interesting things about cyclodextrin is that the way you formulate with cyclodextrin is you look at the molar weight of the active ingredient and you develop a formula where the outcome of the powder is a combination of the active ingredient and the cyclodextrin and you can look at the combination based on the molar weights and the active ingredient ends up being a minority of that powder. It does two things. Among others, but first and foremost it makes a highly, highly soluble powder. And so if one of the things you’re trying to achieve is solubility, which is very often a primary goal of the client, looking at a cyclodextrin inclusion is one technology to consider in addition to the drawing platform. And sometimes if that’s the primary goal,. Then simply establishing that you want to use a cyclodextrin technology will necessitate a certain drawing platform like dynamic atomization because that’s the only way to get the water activity down to an acceptable level, meaning removing it from the interior of the cyclodextrin cavity. The second thing that happens with the cyclodextrin approach is that you actually reduce. The amount of the active ingredient that gets used in the final powder, which can have some economic advantages.

For example, if you have an active ingredient that is extremely expensive, it means that in the final output of your powder on a per kilogram basis, you’ve actually reduced the cost of the raw material that’s going into that powder. Now, you’ve offset that by the cost of the cyclodextrin and the cost of the work doing the drawing, but in the long run, you have very likely created a superior output that has some enhanced margin in the market and differentiated yourself from the competition. So you may have leapfrogged your competition, you may have distanced yourself, you may have created new skews, you may have accelerated the… Uptake of your product in the market, which of course leads to incremental revenue at incremental margin. And so your return can be nothing short of, you know, visibly very attractive in the short, medium and long run. But at the same time, people have to realize in the finance, the product development, engineering, you know, and CEO suites that in fact what they’ve done is they’ve made a very, very minor. Investment sometimes close to neutral to achieve these things. And that’s often surprising to them because they typically believe that adding a cyclodextrin inclusion step only comes with cost and an additional phase in the supply chain when in fact it can be quite simple and very cost effective.

Stephen: Yeah, that’s interesting that even just the way that you started the conversation about that question with the powder itself being much lighter, much fluffier, more… Intentional of a product to create basically and then that was my first thought was what you ended up getting right into was how much of that is actual product now at the end of the day how much is the active ingredient it’s really interesting how that ends up working out.

Will: Yeah, if it’s going to perform better for consumers, the market will reward them for that.

Stephen: Yeah, exactly. And at the end of the day, I mean, you’re not just making a product. You’re not just making something that just lives on a shelf and is supposed to live on a shelf for forever. You’re making something that actually serves a consumer. And the better product that you make that serves that consumer, the better product you’ll have to work with to market on the side of Oulie. But the better product you’ll have to deal with in terms of longevity with your clientele and everything.

Will: Yeah, it’s ironic. We make products with substantially longer shelf life and then the clients can’t keep the product on the shelf.

Ulli: I do want to add something here because I do think that it’s important to keep in mind that dynamic atomization and spray drying in general not only applies of course to nutraceuticals and supplements and food and beverage, although those are, you know, some of the prime applications, but they also extend to what we call non-regulated industries, which are polymers. Particle engineering for ceramics customers. So there is a large universe out there where powders are used and where actually very large quantities of powders are used that need significant shelf life when you think about, for example, the construction industry, when you think about the concrete or cement industry, when you think about anything that has to do with agriculture. Be it fertilization, be it moisture retention in the soil, or reducing the number of foreign substances that you bring onto the crops. So there are, when we think about our consumers or our customers, there is the final customer who can be. Just a private citizen like all of us are, or they can be organizations that supply the cattle industry with better food, better feed stuff for the cattle. So just to make sure that we keep in mind the whole breadth and width of the applications of all of these technologies.

Will: Absolutely. That’s a fantastic point from Uli. In fact, I would say that we have customers right now who come to us with one to three SKUs that they’re looking to upgrade, sometimes move forward in the value chain. And after two conversations, which happened in parallel, one being the product refinement and product development conversation on the technical side with Hendrik and the team. And another being more of a strategic and business development conversation, which we all participate in. They end up seeing how there are openings in the landscape for them to develop new SKUs, sometimes small portfolios of SKUs to enhance their overall business and generate completely new revenue streams and expand the margin. Within those existing SKUs that they brought to us, but also create incremental margin from the new revenue streams for their overall business portfolio. It’s quite fascinating. And what we’re finding is that for our business in the APD category, what we’re becoming is something of a hub, just generating connections among the clients we have. Inbound and older clients making contacts with these organizations who need to be able to place these new products and partner with organizations who can take help them take advantage of geographic relationships and partnerships to you know to make the most of the intellectual property and the new SKUs that they’re able to to create and so with the right technical input. And the right product engineering, there’s tremendous opportunities to advance what they’re doing just with the fact that there are multiple intersections here on our engineering platform, on the manufacturing side, plus the ability to deliver through cyclodextrins and the full delivery system we have for all of these applications in all of these markets. It opens a completely new world.

Whereas historically people thought of drying as do I use spray drying or not? And if so, which of the commodity spray dryers do I use? And it was usually based on a difference of a penny or two per kilogram.

Stephen: Yeah, that’s really interesting. And it makes total sense why there would almost be like a certain level of a partnership marketplace or kind of community that gets built around because as you guys are innovating certain aspects of the technology and expanding what people are able to do with it, it would make sense that those partners would, or those people or organizations would end up having a clear ability to partner with other. Other companies that are doing similar aspects. So moving on to the next question here. We have, what analytical methods are most reliable for measuring particle size distribution and ensuring consistent product quality? Because we’ve talked a lot about, I think, both of those aspects today. So how do you guys go about measuring that? And what are the industry standards comparatively to what you guys are doing also?

Hendrik: So what Uli just mentioned, across all of these different market segments, whether it’s industrial products like polymers or minerals, or it’s in the food market or in a dietary supplement and nutraceutical markets, one thing that’s consistent and an absolute requirement is consistency. The same powder every single time, regardless of the scale. And there are across the board. Very specific items that customers look for. They look at moisture content, flowability, density, particle size distribution, even sometimes things like color. The technology should be able to achieve the same product with all of these same characteristics every single time. And the CMO needs to be able to prove that they can do that. So a requirement is to have. An on-site lab where you can do in-process testing to show that, you can produce the same product every single time. There are many external factors that could influence these aspects even while you’re running the product. Ambient temperature, humidity, operators sometimes that can have an influence, minor drive settings. Drive condition changes that they do and regardless of that, whether they change the throughput or they change drive settings, you still have to achieve that powder with those consistent property requirements. So you have to have a lab that have at least the equipment where you can measure moisture content, you can measure water activity, particle size distribution. Density and then flowability. We use a particle size analyzer for particle size distribution. We have equipment to measure density. And then we have algorithms to measure flowability and compressibility.

Will: You know, there are lot of labs, a lot of analytical, lot of analytically skilled organizations out there, Stephen, who can do the range of fundamental tests. What I find a lot more interesting is the differences in which these platforms create the particles that are being analyzed. And so… When you sample particles to have them analyzed, the particles that you sample are probably gonna have some variation. If you take them from one part of a drum post-production versus a different part of a drum post-production, what are the chances that you’re going to sample particles that are outside of a portion of the bell curve in one spot of the drum? And inside a portion of the bell curve in another part of the drum. Well, it’s really based upon how consistent are those particles coming off the production line. If they’re inconsistent, there’s a really good chance that if you pull from two different spots in your powder, you’re going to get two different kinds of particles. Right? So that’s obvious. So if we back up one step further, what I find really illustrative is. The way that these particles are actually produced in the lines. We mentioned before that with dynamic atomization, we’re basically producing this powder in a blink, literally a blink of an eye, which is about four tenths of a second. So you can imagine this powder, this product’s going in less than half a second later, it’s done and it’s coming out of the dryer. So imagine. The opposite of that was spray drying. Powder goes in, it’s in there for 25, 30 seconds, it’s roughly 450 degrees, it’s floating around. Is it coming out at the right time?

Some of it’s coming out a little bit sooner, some of it’s staying a little bit longer. That’s when you get into problems with morphology. Some things are overcooked, they get crusty, they have all of these things that go on with morphology when some things are in… You know, too long, some things are in not enough. That’s when some things come out and they’ve got too much moisture, too little moisture. So powders that are in for 28 seconds versus ones that are in 34 seconds, they’re all gonna be different in every aspect of the particle. And so back to the layman’s explanation, if I have something that I put in the microwave for one half of a second, it’s very likely gonna turn out the same way. Every other item I put in the microwave for one half of a second turned out versus if I have to make cakes and all day long I’m baking cakes in the oven and I’m putting them in there and over and over again I’m making a cake those cakes are just not going to turn out the same if I have to leave them in there a long time we all know there’s a lot of things that that just can go wrong when you’re trying to create something the longer you have to to bake it at lower heat.

Stephen: Yeah, think most people can understand that. Even just as a kid you understand that. You bake a bunch of batches of cookies. And some of them turn out good and some of don’t. The way that you have very eloquently described the process of.

Will: And that’s exactly the problem.

Stephen: That traditional spray drying kind of chamber and timing and all of that, it makes total sense why it would lend itself to a lot of differences within different particles from that same exact batch.

Will: Yeah, well, and I think you’ve even given us the perfect metaphor. I mean, I have two teenagers and they make chocolate chip cookies. And the first thing that happens when the tray comes out of the oven is they both fight over the one perfect cookie because some of them are puffed to the certain, you know, perfect height. Others, they fall a little bit. And all those cookies were in for exactly the same time. So they’ve taken most of the variables out of it. I can guarantee you they didn’t, they didn’t, you know,. Measure the ingredients and make the cookies from scratch. They came out of the out of the pre-made You know cookie section at the store So all the ingredients were the same everything else But even being in the oven pre-made cookies same amount of time same temperature same pan There are differences and so the exact same thing happens with all of these powders when you put things in for an extended amount of time and so If you sent all of those cookies.

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