Most drugs exhibit polymorphism. The pharmaceutical implications of this phenomenon have received a good deal of attention from both academia and the industry given that polymorphism can have significant effects on drug stability, bioavailability and manufacturability. The challenge for formulation scientists, therefore, is to develop the most thermodynamically stable polymorph of the drug to ensure reproducible bioavailability of the product over its shelf life under various storage conditions (1).
In some instances, particularly for poorly soluble drugs, the amorphous or metastable crystalline form is preferred and justified by the higher dissolution rate needed for rapid absorption and so that sufficient therapeutic concentrations can be achieved. It is, however, important that the risks associated with these less stable forms are properly evaluated to ensure that the largest possible form change would have no detrimental effect on product quality and bioavailability; and/or a change would not occur under all reasonable storage conditions; and/or analytical methodology and sampling procedures are in place to detect problems before dosage forms with compromised quality and bioavailability reach the end users (1).
Pharmaceutical scientists have been exploring the use of metastable polymorphs with the most stable form; however, the most stable form often has poor solubility, low dissolution rate and insufficient bioavailability apart from manufacturing difficulties and IP issues. A team of researchers from the University of Bradford, UK, recently developed a solvent-free, continuous method using high-temperature extrusion to produce the metastable form of the antimalarial drug, artemisinin. The technique is similar to hot-melt extrusion but operates below the melting point of the API (2). “This is the first commercial application of high-temperature extrusion to control polymorphic transformation,” Professor Anant Paradkar, director of the University’s Centre for Pharmaceutical Engineering Science, who led the research, told Pharmaceutical Technology.
Artemisinin is known to have two polymorphic forms: orthorhombic and triclinic. The commercially available orthorhombic form is more thermodynamically stable but suffers from low water solubility, which results in poor bioavailability. Consequently, large amounts of the drug have to be administered to achieve sufficient therapeutic concentrations. The metastable triclinic form, on the other hand, is more soluble, and therefore, has a higher dissolution rate with better bioavailability profiles (3).
According to Professor Anant Paradkar, previous attempts have been made to produce the triclinic form of artemisinin but these methods involve the use of solvents. “The triclinic form is unstable in the presence of even small traces of solvents, making it problematic to manufacture,” explained Professor Paradkar. “Very often, you will find that the presence of solvents causes the triclinic form to transform into the more thermodynamically stable orthorhombic form.” Producing metastable crystals in a solvent-free environment is, therefore, a potential solution and Professor Paradkar and his team explored the application of high-temperature extrusion to produce the metastable triclinic form of artermisinin.
High-temperature extrusion applies mechanical shear stress that can disrupt the crystalline structure of the drug, increase the surface area and result in solid deformation. The elevated temperature can produce local melting of a crystal or melting at the interface between crystals and solid-state transformation may occur in the melt phase before solidification (2).
According to the report published in the Royal Society of Chemistry journal, CrystEngComm, the researchers were able to demonstrate that the triclinic form obtained by high-temperature extrusion is more stable than triclinic crystals made using solvent-based techniques (2). “The triclinic form produced using this solvent-free technique has remained stable for two years,” Professor Paradkar told Pharmaceutical Technology. “It is four times more soluble than the orthorhombic form, with a two-fold increase in bioavailability.”
More importantly, Paradkar believes that this method is capable of being scaled-up for high throughput. “The method is not specific to artemisinin, but can be applied to many other pharmaceutical drugs, not only making drugs that are more effective in smaller doses, but making drug manufacture more cost-effective,” said Paradkar.
1. D. Singhal and W. Curatolo, Adv. Drug Deliv. Rev. 56 (3) 335-347 (2004).
2. C. Kulkarni et al., CrystEngComm 15 (32) 6297-6300 (2013).
3. H. Qu et al., Chem. Eng. Technol. 33 (5) 791-796 (2010).