By: Candice Tang, MSc.
The following post first appeared on the Xtalks blog.
Statins are the most commonly used group of drugs to treat lipid disorders. They not only help lower cholesterol, but they are associated with anti-inflammatory and antioxidant activity. According to the Centers for Disease Prevention and Control (CDC), lipid-lowering drugs were the most common type of drug used among US and Canadian patients aged 60–79.
Statins are a challenging active pharmaceutical ingredient (API) to work with, as they can assume more than two different crystalline structures (polymorphs), each of which affects its physical properties and pharmacological activity.
Consider atorvastatin calcium, one of the most widely prescribed drugs in the world. There are at least 70 known polymorphic forms of atorvastatin, but the majority of them are a thermodynamically stable crystalline form used in oral drugs. These forms tend to have low solubility, reducing their absolute bioavailability to only 14 percent. Low bioavailability is common among other statins, presenting a challenge to drug makers to create a shelf-stable, bioavailable dosage form.
The solid form of an API is important to consider in the drug development process. With the right tools, scientists can determine which polymorph would be the most appropriate for their application.
To learn more about solid form selection in drug development, Xtalks spoke with Dr. Steef Boerrigter, a senior research scientist at Curia and an expert at materials science. He has extensive experience with experimental screening technologies for polymorphs, salts and cocrystals and has developed computational methods for virtual coformer screening. He shared his insights on the importance of solubility versus stability, the different common polymorphs in pharmaceutical drug development, regulations driving solid form selection and different screening modalities in an on-demand webinar.
Xtalks: Give me an overview of why solid form selection is important in drug development.
Dr. Steef Boerrigter (SB): The energetics of the solid state affects, most importantly, the solubility behavior of drugs when they are administered orally. The release profile is determined by the dissolution rate which, in turn, is determined by the solubility of a drug. The energetics also effect the long-term stability of the drug substance. Solid form selection is finding the balance between these two aspects.
Xtalks: What are the common types of solid forms used in pharmaceutical drug development?
SB: The most common type of polymorphism is when we have the same molecule crystallize into different crystal lattices – a single component system. This is what we refer to as neat polymorphs or neat polymorphism. The second class is where we have different types of molecules (coformers) co-crystallizing with the active pharmaceutical ingredient (API). These are multi-component systems. When this is a solvent, we refer to that polymorph as a solvate or a solvated form. Solvates, as such, are almost never used as a drug substance because of the toxicity of solvents. However, when we replace the solvent with a non-toxic coformer, we call it a cocrystal. The use of cocrystals is becoming more and more popular.
Next, we have salts, where, due to the acid-base properties of the API and coformer, the multi-component system contains ionic species. Classically, the option to pick different salt formers for the same API has been the primary handle to manipulate the solid state properties, and is still the most commonly used. Salts are typically crystalline.
Another rising class is where materials are amorphous, which is non-crystalline. Making a material amorphous can make it highly soluble but can also diminish its shelf-life. To mitigate that problem, amorphous API are typically stabilized in a dispersion system.
Xtalks: What are the different advantages, if any, of having multiple different solid forms of one API?
SB: A drug substance may have stable neat polymorphs or it may not. When we have multiple competing polymorphs, it may actually be regarded as an inconvenience rather than an advantage because you need to make sure that you don’t accidentally make the wrong polymorph during production. At the same time, it may also be an opportunity to play around with some of the properties. For instance, one polymorph may be less hygroscopic than another; one polymorph may grow as needles causing filtration problems, whereas another may not have that problem, and so on. Then there is the solubility advantage I mentioned before, although it must be said that the difference is often minimal. When a great boost in the dissolution rate is needed, it is advantageous to be able to use cocrystal or dispersion technology.
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