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API Granulation Equipment

Granulation

API making equipment must observe rigorous quality control standards across the entire manufacturing process. The pharmacodynamic properties of active pharmaceutical ingredients API make them highly sensitive to their environment, making API manufacturing and production a tightly regulated field.

Active pharmaceutical ingredients (API)

When you consider shifting pharmaceutical mixing processes from batch to continuous, accurate in-line continuous blending can be a real challenge.


<h2>In-line continuous blender with fast reactivity and minimum residue</h2>
The Modulomix from Hosokawa Micron is a continuous modular mixer and it has been designed to be compact with fast reactivity, minimum residue and rapid start-up and shutdown protocols, very useful in pharmaceutical applications.

It is a very compact blender because you will be able to combine the Modulomix modular mixer with PTS, LIW feeders, continuous blenders, PAT technologies and even downstream processing, like (wet) granulation and/or compact. It is adaptable due to it lets you have two different mixing environments in one single phase, multiple Modulomix mixers can be cascaded in series.

In-line continuous blender

Pharmaceutical granulators are often used with active substance mixtures to be processed into granulates, a process also known as compaction.


<h2>Dry granulation of pharmaceutical powders</h2>
With the Pharmapaktor® Serie (Pharmapaktors series L, K, and C 250) from Hosokawa Alpine, active substance mixtures are processed into granulate.

For this, the powder is first pressed into flakes/pellets. These are often crushed with a Flake Crusher into granulate.

Compaction (dry granulation) is understood to be the compression of powder between two synchronized, counter-rotating rollers. The powder is fed to the counter-rotating rollers in a regulated manner. Here, adhesive forces between the product particles are created under high pressure between the rollers.

For capsule or sachet filling the granulate must be de-dusted in a screening machine. The sieved fines can then be directly fed to the Pharmapaktor again

Pharmaceutical granulator

Fluid bed drying is a pharmaceutical process carried out to reduce the humidity and achieve the required moisture content in the granules or powders. It also applies binders or granulation liquid to facilitate the agglomeration of wet mass before further processing. When drying pharmaceutical granules, it is essential to avoid over-drying as this could result in significant wearing down, leading to product loss. To prevent losses and poor product quality, you need a fluid bed dryer to handle continuous operation.
<h2>An efficient, robust solution to dry pharmaceutical compounds</h2>
The Fluidized Bed Dryer from Romaco Tecpharm uses the drying process to reduce the moisture content in the granules. It can be configured as a dryer, granulator, and coater. It can thus dry wet granulate, top drive granulation, and bottom spray coating. It has a capacity from 30 L to 1,540 L, with other dimensions being available on request.

The fluid bed dryer for pharmaceutical solid dosage form is constructed with an in-wall design concept. It is equipped with a side-valve for automatic loading from the high shear mixer granulator. For the drying process, hot air is passed through a vacuum generated inside the machine. The wet solids rise from the bottom and are suspended in a current of air, remaining in a fluid state. The heat transfer and the low moisture content of the air in direct contact with the wet granule allow the evaporation of the water or solvents, reducing their humidity.

The equipment has a top spray that helps in carrying out the granulation. Next, the movement of the powder in a fluidized state is combined with the spraying of a binder solution. This combination allows increasing the particle sizing, generating a granulate. Finally, the coating process is carried out by combining the spraying of the coating suspension on the micro granules in a fluid bed movement.

Fluid bed dryer for pharmaceutical solid dosage form

It is rather difficult to successfully produce a pharmaceutical solid dosage forms with the desired properties such as size, morphology, hardness and friability. You need a solution that can transform fine heterogeneous powders into homogeneous blend of granules with bigger size and higher density in a short time and with repeatability. Wet granulation is carried out to convert fine and cohesive active ingredient and excipients, into more uniform, free-flowing granules that are optimised for downstream processing.
<h2>Achieve uniform particle size distribution for wet granulation</h2>
The High Shear Mixer Granulator from Romaco Tecpharm is configured to optimize the wet granulation process. It is used to turn a fine-powder heterogeneous mixture into a uniform granulation, with increased particle size and higher density.

The equipment offers you proper flow and compactness while having a shorter operational time. It can handle capacities ranging from 25 L to 1,400 L.The bottom impeller and the side chopper enables the intensive mixing in a short period of time. In addition, the equipment uses a synchronized system to avoid extrusion effect.

The high-shear granulator for drug formation processes the solid material down to the desired particle size, and the mixture is then pumped to the fluid bed dryer where the moisture is removed, leaving behind the granular product. During the process of wet granulation, the constituents of the oral solid dosage form blend are combined, along with agglutinative solution, to form granules with a homogenous composition.

Industrial high shear mixer granulator for drug formation

When making tablets, pharmaceutical manufacturers need to use a mechanical process, like a rolling press for compaction, to produce granules from powders susceptible to moisture and temperature. This method also applies to large-volume products where the compaction of powders requires consistent and precise control of the force applied to achieve uniform density.


<h3>Transforming dry particles into uniformly dense granules</h3>
The Dry Granulation BRC from Bohle, is a compacting system for fine solids and dry powders to form granules in pharmaceutical industries. The system is equipped with screw feeders that push the powders toward two rollers. The rollers apply precise compaction force to produce uniformly dense, ribbon-shaped products before crushing them down to the desired granule size through a cone-shaped rotary sieve mill. The granule size can be quickly adjusted using a different rotary sieve with a suitable profile. The system has a production range of less than 1kg/h up to 400 kg/h and has a hygienic design using integrated washer nozzles for an effective WIP process.

Continuous roller compactor for dry granulation of pharmaceuticals

Pharmaceutical industries employ several processes including drying, coating and granulation to create high-quality granules. Manufacturers can benefit from a single system that can complete all of these tasks simultaneously, increasing production yield without sacrificing the quality of the final product.


<h3>Coating, granulation, and drying granules by tangential fluid bed method</h3>
The Fluidized Bed System BFS from Bohle, is a system that can perform multiple processes such as coating, granulation, and drying to turn fine solids and dry powders into granules. The cone is equipped with a specially slotted air distributor plate which allows complete fluidization of particles while the tangential motion helps in achieving a uniform coating without the particles adhering to one another. Due to a relatively low fluidization height, the system does not require a high-volume expansion saving costs and production floor space.

The system can also be equipped with an online moisture measurement system using NIR technology to precisely identify moisture levels during the granulation and drying. The BFS has at least 6 filter elements that can be cleaned separately and ensure good uninterrupted airflow. To make it simple to use, the entire system is PLC controlled.

Fluidized bed system for the granulation and drying of pharmaceuticals

In pharmaceutical industries, where large-volume production is the norm, compactors or granulators are used to turn powdered materials into granules. As hydraulic systems are commonly utilized in these granulators, the compressibility is affected by the properties of the oil used. Certain oils can be compressed more than others and their properties degrade over time and are affected by temperature fluctuations.


<h2>Compacting dry powder into granules using an electromechanical roller drive</h2>
The Dry Granulator BRC 100 from L.B. Bohle, is a compacting system that turns powdered materials into granules for pharmaceutical industry applications. The system utilizes an electromechanical roller drive to provide precise control, consistent compressibility, and minimal material loss compared to hydraulic systems that rely on oil properties to drive the rollers.

This setup offers less maintenance as it does not require oil changes and an oil cooling system. The system has a flexible sieve setup allowing for the use of either a conical sieve or an oscillating sieve to obtain the desired granule size of the product coming out from the rollers. The granulator comes standard with integrated WIP (Washing in Place) nozzles for effective and easy cleaning. The entire system can be assembled or disassembled quickly, which helps improve maintenance and installation.

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Dry granulator for pharmaceutical powders

Pharmaceutical laboratories need compact equipment to handle and produce small amounts of granules from a mixture of wet and dry elements for R&amp;D applications. Furthermore, the granulation process requires short residence times in drying the products to easily identify and remove the defects without discarding the entire batch.


<h2>Automatic feeding, granulating, and quick drying of pharmaceutical  products</h2>
The QbCon 1 from L.B. Bohle is a continuous wet granulating and drying system for pharmaceutical laboratory scale applications. The system performs three processes: feeding, granulating, and drying. It features a twin screw granulator with a hinged barrel for easy access to its parts. The unit comes with a multi-position feeder and interchangeable ports, ensuring accurate gravimetric feeding of dry powder and using a pulsation-free pressurized feeder for granulation liquid.

The wet granules are gently dried by a moving fluid bed that provides short residence times and consistent product output. Its narrow residence time distribution allows easy traceability from the initial product to the final tablet or vice versa. The drying process parameters, such as airflow, temperature, and conveying speed, can be controlled and adjusted according to product requirements. The system allows for sampling wet and dry granulations without interrupting the ongoing processes. The system also has an innovative filter cleaning system to prevent clogging for longer hours of operation. The unit also features a complete WIP (Wash-in-Place) cleaning.

Continuous wet granulator and dryer for R&D

Producing the finest micro-emulsions and suspensions requires a mixing machine that generates extremely high shear.  Multi-staged rotor/stator dispersing machines work well for this purpose because of the high shear forces applied to the mixture at each rotor/stator stage.  A rotor /stator dispersing machine that also incorporates extremely fast rotation and resultant tip speeds for even greater shearing action will lead to the creation of super-fine emulsions and ensure the success of your process.
<h2>Top-of-the-line rotor/stator dispersion with utlra high shear for nano-scale particle emulsions and suspensions</h2>
The DISPAX-REACTOR® DRS from IKA is an inline ultra high shear dispersing machine used to achieve the finest micro-emulsions and suspensions. Extremely high shear rates (up to 190.000 1/s) combined with a fine generator geometry enable crushing of droplets and solids particles down to the nanoscale. The resulting product has long-term stability which reduces the need for emulsifying agents and thickeners. Because of the extremely high energy density, other dispersing aids can be reduced or possibly eliminated.

The DRS is usually equipped with a two-stage rotor-stator system (generators). The high tip speed of 40 m/s (10.000 fpm) often negates the need for a third stage. The ultra-fine dispersing machine, designed with the same high quality features as the ULTRA-TURRAX® UTL and the DISPAX-REACTOR® DR, is especially well suited for challenging pharmaceutical applications.  The units are designed for easy and reliable scalability and sizes are available with flow rates from 70 to 40.000 liters per hour.

Ultra-fine dispersing machine for emulsions and suspensions

Microtablets range between 1 and 4 millimeters, making the dosage form an excellent delivery system in polypharmacy. The size of the products makes them easier pills to swallow, but microtablets production brings a unique set of complexities.

Microtablets

When taking a tablet, it is usually the job of our stomach to break down the medication to make it ready to be absorbed into the bloodstream. However, some drugs are not meant to be dissolved in the stomach because the acidic pH of the stomach can disintegrate the drug, making it no longer effective. Using tablet coating equipment that applies a polymer barrier to the tablet makes it possible to protect it from stomach acidity.

Enteric Coated Tablets

Used in the pharmaceutical industry to produce tablets and capsules, among others, pharmaceutical granules are made to enhance the uniformity and flow of powder, increase the density of the blend and reduce dust and, therefore, toxic exposure. The choice of the granulation process, whether it is wet, dry, or direct compression, as well as the selection of appropriate pharmaceutical granulation equipment, depends on the specific drug being formulated.

Pharmaceutical granules

Built upon its world-leading laboratory equipment, IKA Process is a game changing manufacturer of dispersing machines, homogenizers, stirrers, jet flow agitators, and kneading machines.

In the pharmaceutical industry, change often moves at a snail’s pace due to stringent regulations, but it does happen.



Traditionally, API manufacturers relied on the dry milling process, which begins with crystallization or precipitation within a liquid medium, where crystals form and grow. These crystals are separated using a centrifuge, dried, and finally subjected to dry milling before tableting.

As APIs became more potent, dry handling became problematic due to dust generation, causing cleaning issues and product loss. Furthermore, stricter ATEX regulations for handling hazardous powders have expedited the demand for change.

It’s not as simple as just mixing dry ingredients together, and voila, you have your API. APIs are always, and I mean always, synthesized within a liquid medium to form solid crystals. If liquid is always a part of the equation, why not control the growth of those crystals already in the crystallization step?

And this is where wet milling came into play. This approach allows early particle size control during precipitation, enhancing pharmaceutical manufacturers’ control over the API’s final particle size and distribution.
<h2>“<em>The value of an idea lies in the using of it</em>.” – The benefit of early particle size reduction</h2>
We had a chance to speak with Werner Kanzinger, <a href="https://www.ikaprocess.com/en/Products/Process-plants-cph-18/?gclid=Cj0KCQjwmICoBhDxARIsABXkXlLSTjoDkEyEOxqysB6am7wNW99asG4jDKpXJpsQO5pzSj_wv8ZdyHYaAlsvEALw_wcB">IKA</a> Vice President, one of the first to use wet milling for API production. Creating new pharmaceuticals requires starting from scratch and developing principles in the R&amp;D world. To address this need, IKA introduced an innovative three-stage inline dispersing technology called the <a href="https://www.ikaprocess.com/en/Products/Pilot-plants-cph-40/magic-LAB-csb-MLAB/">Magic Lab</a>.

“<em>We knocked on every door in the R&amp;D world and were surprised how the technology was well-received. The industry recognized its</em><em> potential to simplify production through early-stage particle size reduction,” </em>Werner explains.

According to Werner: “<em>Even at a half-liter batch, APIs are very valuable and pricey. As production scales up to 1000 liters per batch, the cost can be over 1 million, and nobody wants to take any risk.”</em>

To serve the industry across diverse production scales, IKA replicated Magic Lab’s success on a larger scale, ensuring consistent milling outcomes without compromising quality.
<h2>No dust, no fuss - Wet milling is here to simplify your life by shortening your production time</h2>
In dry milling, solid materials undergo high-speed impact and shearing forces, generating airborne dust particles. This dust settles on equipment, necessitating extensive cleaning to prevent cross-contamination.

“A w<em>et mill is already designed to create a high-turbulence environment, which helps with dust reduction</em>,” Werner continues.

Additionally, wet mills are easier to clean than dry mills due to their smaller and less complex internals, requiring less time and effort. Operating already during the crystallization step, wet milling allows for localized energy application. This reduces energy consumption compared to drum mills.

“<em>IKA three-stage inline technology allows for complete drainage after use. The product flows from the top to the bottom through a three-stage rotor-stator, progressively reducing particle size from coarse to fine. Since it’s vertically installed, no product remains inside, making cleaning straightforward,</em>” Werner concludes.

Just remember, it is better to move forward at a snail’s pace than backward at any pace.

Wet milling: The revolution in the API production

Pharmaceutical

Biopharmaceuticals are drugs in which the active substance is manufactured or extracted from biological origin materials. They are usually produced in bioreactors by plant cells, microbial cells, yeast cultures, or mammalian cells. Also known as biomanufacturing, they are used to either treat or diagnose and prevent a patient’s medical condition or disease. Biopharmaceuticals are typically complex macromolecules administered by injection or infusions, and examples include vaccines, serums, and insulin.

Biopharmaceuticals

The most important part of a capsule is its contents. But if the shell is not carefully made, the dosage ingredients inside lose effectiveness. From molding to sizing, capsule manufacturing equipment forms perfectly-matching husks ready for filling. The simplicity of encapsulation revolutionized pharmaceuticals since it was introduced in the 19<sup>th</sup> century. However, capsules are changing to increase delivery efficiency and reduce the dependency on gelatin.

Capsules

<p class="filterable-grid__description">Liquid dosage forms are designed for easy absorption. The body quickly carries the active ingredients through the system and triggers the required response. But the greatest advantage of this medicinal type is its flexibility in formulation and dispensation. From lotions and syrups to drops and sprays, liquid solutions can be adapted to different administration routes including parenteral, topical, and oral. The fundamental liquid dosage manufacturing process involves dissolving or suspending solutes in a fluid. But that is not enough. A precise blend of excipients is needed to make the medicine go down.</p>

Liquid dosage forms

Pharmaceutical powders provide longer shelf life and better stability than liquid dosage forms. But the processing of pharmaceutical powders is crucial for growing segments besides pharmacy. Functional foods and cosmetics formulated with active ingredients and excipients depend on powdered forms to fulfill their promises.

Pharmaceutical powder

Pharmaceutical developments walk side by side with health advances to provide new medicines, treatments, and therapies that have increased life quality and extended life expectancy by years. Pharmaceutical manufacturing equipment helps deliver products to a great deal of the population, but there’s a significant share that doesn’t benefit from them yet. Over 2 billion people cannot get the medicines they need, according to the United Nations Industrial Development Organization, and local production might be a way to provide for these people.

Pharmaceuticals

The building blocks of matter have driven the imagination of philosophers, scientists, and artists for millennia. But, for manufacturers, these elements have a more concrete existence as powders. Powder processing technology conditions these primary materials to create a vast range of products, from chemicals and foods to pharmaceuticals and ceramics.

Powder

Among all dosage forms in use today, tablets constitute the most common one. They are pharmaceutical solid dosage forms containing active ingredients and excipients such as diluents, binders, glidants, and lubricants. Using tablet making equipment, these solid dosage forms are made by compression of granules or powder blends and then shaped by molding.

Tablets

Powder containment is the cornerstone of chemical and pharmaceutical manufacturing. Floating particles do not only represent efficiency loss but serious hazards too. Lack of tightness during the powder discharge process leads to cross-contamination and operational health risks.


<h3>Dock transfer systems squarely in place</h3>
The ASBV active/passive valve interface by Andocksysteme locks into position, minimizing exposure of material during powder discharge. The system has two split valves – one active, one passive – that can be easily and reliably centred on each other at a tolerance of ± 14 mm.

Once the units are docked, the valve discs open simultaneously, preventing exposure of the products during transfers. The dust-tight environment achieves contamination values lower than 1µg/m3.

The ASBV solution is fitted with EPDM seals and are optional with a wide range of materials, such as PTFE, offering top-range chemical resistance. All seals are made from FDA-approved materials and can handle a wide range of temperatures as well as explosion-proof executions.

Washing the ASBV interface is simple as the system can be connected to a WIP loop to flush out residual powders. These containment solutions serve applications with an exceptional performance and are easy to be integrated. Moreover, high quality parts and reduced complexity drives simple maintenance.

High containment split butterfly valve

Andocksysteme is a specialist in developing and engineering high-quality containment docking and solutions for bulk material.

The rise of high-potency ingredients (HPAPI) is taking medication into unchartered territory. Since the turn of the century, the pharmaceutical industry has developed a wave of targeted therapeutics formulated with more potent drugs in smaller doses.

Besides producing a more effective action against their biomedical targets, these innovative medicines are also lighter on excipients and provoke fewer side effects for patients. However, they do cause considerable side effects for manufacturers.


<h3>Higher potency can be too much of a good thing</h3>
HPAPI materials pose a risk of toxic exposure to operators. Process technology is designed to meet EHS guidelines, protecting handlers from hazardous substances. At the same time, it must also adhere to GMP standards to prevent contamination. However, the real danger lies at the inlets and outlets of the machines, as <a href="https://andocksysteme.de/en/" target="_blank" rel="noopener">Andocksysteme</a> Product Manager Duncan Ehrmann points out.

“It is all well and good when a mixer is blending chemicals, or a dryer is reducing moisture,” says Duncan. “But things get tricky while the materials are transferred from the mixer to the dryer.”

There is no such thing as a fully closed system; discharge will always release particles into the air. So, the challenge is to minimize that amount to the greatest extent possible.

The industry answer is the split butterfly valve principle, joining the ‘mouths’ of two systems and opening them synchronously. But engineering the concept into an actual pharma-grade interface is another story.
<h3>Big on seals, small on parts</h3>
Andocksysteme developed a valve solution that achieves contamination values lower than 1μg/m3. A primary contributor to this degree of containment is the minimalist construction of the interface. Designed with the bare minimum of separate parts, the valves significantly restrict roaming space for flowing powders.

"We designed  our technology with large seals  to cover the openings," explains Duncan, "A bigger seal exerts higher pressure, locking the active/passive valves tighter together.”

The state-of-the-art system meets the OEB 5 levels of protection required when handling ingredients with high pharmacological and toxic effects.

HPAPI particles move around a lot during processing. Their manufacturing cycles are long and winding, but high-containment valves hold them safely within that loop.

Closing the containment loop in HPAPI manufacturing

Conventional dryers are inefficient and can lead to significant mechanical and thermal stress on sensitive products. Non-uniform mixing can lead to lump formation and increased processing time. Vacuum dryer with eccentric agitator is designed to dry wet flowing powders from filtration and centrifuging processes.


<h2>Vacuum dry efficiently in an agitated paddle dryer</h2>
Planex® system from Italvacuum is a special horizontal vacuum paddle dryer with an eccentric agitator which revolves around its own axis while rotating tangentially to the drying chamber. It is ideal for drying wet feeds from filtration and centrifuging processes. Planex® is ideal for the production of active pharmaceutical ingredients (API), fine chemicals and intermediates. The efficient agitator action ensures perfect mixing and consumes three times less energy than conventional dryers. It also reduces the mechanical and thermal stress on the products which is important for delicate and temperature-sensitive applications. The tangential movement of the agitator prevents lump formation. Suitable for both crystalline and amorphous products, Planex® has a short cleaning downtime and complies with US FDA standards and cGMP regulations.

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Horizontal vacuum dryer with eccentric agitator

Italvacuum is specialised in vacuum drying technologies for the processing of wet feed materials to produce active pharmaceutical ingredients (API) or fine chemicals.

Without friction, we would not be able to walk, jot down notes, or slice a pie. Friction resists the relative motion of two objects that come in contact, generating grip between their surfaces.

But if you’re drying high-potency API, friction is the last thing you need. The force exerts mechanical and thermal stress on the ingredients that could destabilize the materials and compromise the quality of your end product.
<h3>A poor work of friction</h3>
High-potency <a href="https://making.com/active-pharmaceutical-ingredients-api">active pharmaceutical ingredients (API)</a> require thorough drying to ensure homogeneity in the production process. Once crystallized and isolated from organic solvents, the ingredients must be prepared into free-flowing materials ready for precision dosing, formulating, and formatting.

The drying step is a delicate process that converts the particles into workable materials without altering the chemical profiles developed during filtration. Vacuum drying is a cornerstone of this production stage. The method removes a high rate of bound moisture from materials at relatively low temperatures.

But the vacuum method solves one challenge and creates another. The agitator inside the drum spreads the ingredients over a broader area to expose trapped moisture to vaporization. Therefore, the blades on the agitator make direct contact with the surface of the HPAPI particles. This process creates friction at a millimetric level, producing heat.
<h3>It's a dryer, not a heater</h3>
Dario Penco, a technical engineer at <a href="https://www.italvacuum.com/en/" target="_blank" rel="noopener">Italvacuum</a>, says that adding thermal energy during the drying stage overheats the blend: “Subjecting sensitive materials to friction during the drying stage adds unnecessary heating and risks degrading the ingredients.”

The emergence of high-potency drugs has made this challenge even more pressing. The slightest distortions in the composition of the particles create a ripple effect across the manufacturing line.

Production engineering is developing new ways to overcome this hurdle and minimize friction occurring in a vacuum dryer. Novel design approaches to the blade profile reduce the physical contact with the materials and limit thermal stress significantly. Keeping temperatures at a constant ensures higher-quality pharmaceutical ingredients. And just like well-baked pizza, everyone wants a slice of that.

Lowering heat stresses on API by reducing friction

Find production technology for API Granulation, and connect directly with leading machine manufacturers worldwide