Image: AdobeStock – pixel robot
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Feb 24 2021 | 09:18 o’clock | from
New active ingredients are often extremely poorly soluble – brings Dr. Norbert Pöllinger, Head of Technology Development at Glatt Pharmaceutical Services, gets to the heart of the problem. Often this property is also combined with a taste that strains patient acceptance. And: The demands on the dosage form are also increasing. Where in the past the required amount of active ingredient was compressed into large tablets, systems such as oral liquids, micropellets, etc., are often required for the treatment of older people or children.
“Often, relatively large amounts of an active ingredient have to be administered, which have to be released and dissolved in the body with a defined profile in order to reach the relevant organs via the blood,” adds Norbert Pöllinger. Whenever the difference between the solubility of the active ingredient (API) and the amount to be absorbed is large, there is a need for action.
In practice, two general technologies are available: amorphous disperse systems (amorphous solid dispersions, ASD) and solid dispersions (solid dispersions). While the latter consists of a combination of an active ingredient with a solubilizer – usually a surfactant – amorphous solid dispersions can be produced by combining a crystalline active ingredient with a water-soluble polymer. In contrast to the crystalline API, the reaction of an amorphous solid dispersion with the gastrointestinal juice creates a supersaturated solution from which the active ingredient can be absorbed into the bloodstream.
Active ingredients are often dissolved together with the polymer polyvinylpyrrolidone (PVP) in a solvent such as ethanol. If the alcohol is then evaporated, the desired amorphous solid combination of active ingredient and polymer is created. And this is where the agony of choice begins: what is the best method for evaporation of the solvent? What are the advantages and disadvantages?
1: Technologies to increase the water solubility of active ingredients. Image: Smooth
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Different procedures for ASD
2: Principle of amorphous solid suspensions. Image: Smooth
Basically he has Pharmacists can choose between different technologies: Essentially, these are spray drying and fluidized bed granulation. The continuously operating spray-drying process usually produces a very fine powder that cannot easily be compressed into tablets. Usually an upstream dry compacting step is necessary first, after which the compacted material has to be comminuted again so that a uniform and defined grain size can be achieved for tableting. “We want to avoid this effort as much as possible,” explains Norbert Pöllinger and therefore recommends the fluidized bed granulation technology, which can be used to directly produce compressible granules: “Glatt has the top spray or bottom spray technology for this,” adds Pöllinger . The alcoholic solution of active ingredient and polymer is sprayed into the fluidized bed apparatus, the solvent evaporates and what remains is an amorphous product – also known as a co-precipitate. The technical term stands for the phenomenon that active ingredient and polymer are precipitated together in the fluidized bed.
“Theoretically,” says Pöllinger, “production in a single-pot high-shear granulator is also possible, but that takes a very long time and the granulate often breaks again.”
An important target when selecting the best fluidized bed granulation process is the bulk density of the granulate, which varies depending on the product. Because both the top spray process and the bottom spray alternative (Wurster process) often result in granules with a low bulk density – often only 0.3 to 0.4 g / ml.
There are also two other process variants that lead directly to higher bulk densities so that additional precompacting can be avoided: The tangential spray fluidized bed and the Twinpro combination process. In the former, the solution is sprayed tangentially under the bed at the location of the already greatest bulk density, namely directly above the fluidized bed floor.
In contrast, the Twinpro apparatus presented in 2018 combines the fluidized bed granulation and high-shear granulation processes. The agitator of the high-shear mixer compacts the granulate even more. “This new technology has particular potential when it comes to processing highly effective substances,” says Pöllinger with certainty. “The transfer of the moist granulate into the fluidized bed dryer, which is necessary with classic granulation lines, is necessary with the Twinpro technology, since high-shear granulation and fluidized bed drying take place in one device.”
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Produce pellets in a continuous process
3: Processes for the production of amorphous solid suspensions. Image: Smooth
Often the active ingredients should be processed into pellets. This is done by placing sugar or cellulose globules in a fluidized bed (Wurster process) and spraying the organic solution of active ingredient and polymer. In the process, an active ingredient layer is formed on the starter pellets that have been introduced, which has the same quality as the granules described, but lies as a layer on the pellets.
If an extremely high loading of pellets with the amorphous solid dispersion is required, matrix pellets are the form of choice: These are produced in the continuously operating fluidized bed processes Micropx and Procell. These technologies make it possible to produce pellets that are 100% made from the amorphous active ingredient-polymer matrix consist. “The technology developed by Glatt-Ingenieurtechnik has been in use in various industrial sectors for around two decades, but we now want to use the process more in the pharmaceutical sector,” explains Norbert Pöllinger.
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Solid dispersions: the surfactant as a solubilizer
4: Increase in solubility with solid dispersions. Image: Smooth
The two fluidized bed processes also form the basis for the second technology, with which water-insoluble active ingredients can be brought into solution: solid dispersions. These arise from the combination of an active ingredient with a solubilizer – a surfactant. Surfactants are made up of molecules with a fat-soluble (lipophilic) and a water-soluble (hydrophilic) end. When dissolved in water, surfactants form so-called micelles, in the lipophilic core of which the water-insoluble active ingredient molecule is solubilized.
A specific example is the production of the antibiotic clarithromycin in the form of micropellets, which are converted into a liquid form by adding water before ingestion. The extremely bitter active ingredient has a solubility of 0.3 mg / L at room temperature. The drug becomes effective when doses between 250 and 500 mg are administered and also absorbed into the blood in the body. In order to achieve the necessary solubility of clarithromycin and at the same time to mask the extremely bitter taste, the active ingredient is processed into micropellets in the solid dispersion process with a binder (PVP type) and the Solubilizer Poloxamer 188, which are coated twice: The first Layer serves as a seal, the second coating to mask the taste.
The 150 to 500 µm large pellets are produced using the continuously operating Micropx or Procell fluidized bed processes. The procedures just don’t stand out through the continuous operation, but also through the high product yield – in the example of the clarithromycin micropellets> 95%.
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Spray solidification of melts
5: Solubility of taste-masked clarithromycin micropellets. Image: Smooth
Solid dispersions can also be produced from melts. For example, the water solubility of an API could be increased from 13 mg / L to 200 mg / L. In this process, the surfactant and the active ingredient are melted, sprayed into the fluidized bed and solidify there. If the active ingredient cannot be melted, it is possible to add it as a powder to the fluidized bed and spray the melted surfactant on.
The examples show how complex the selection process is. Norbert Pöllinger: “Finding the best solution is not easy – the best way to do this is through an intensive exchange between pharmacist and machine supplier.”
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