Surface chemistry controls the selective nucleation of crystal polymorphs of a pharmaceutical drug
Reliable batch-to-batch formation is crucial for crystalline, active pharmaceutical ingredients as two different polymorphs of the same drug may function very differently in the body. Sendhil Poornachary from the A*STAR Institute of Chemical and Engineering Sciences and colleagues now report that the surface chemistry of modified glass substrates can influence the nucleation and formation of specific polymorphs of the drug, carbamazepine, within a certain concentration range of supersaturated solutions1.
The isolation of a specific polymorph is usually achieved by controlling homogeneous crystal nucleation. However, heterogeneous nucleation — which relies on the presence of a nucleating surface — is more ‘thermodynamically favorable’, meaning less energy is required. The most common heterogeneous method is to add seed crystals to a solution, but problems such as inconsistencies in seed crystal properties and cross-nucleation between crystal polymorphs may result in unwanted polymorphs.
Poornachary and team show that modified glass surfaces can selectively nucleate two different polymorphic forms of carbamazepine, an anticonvulsant and mood-stabilizing drug. “This concept of template-induced crystallization shows promise for improving batch-to-batch reproducibility with respect to the crystal form obtained,” says Poornachary.
The researchers produced cyano-, mercapto- and fluoro-functionalized glass vials by altering the interior surface using a silanization method, and then observed crystallization of the drug from supersaturated ethanol solutions. The two polymorphs were easily distinguished; either needle-shaped crystals corresponding to the metastable form II or tetrahedral-shaped crystals of the more energetically stable form III (see image).
The researchers found that at an initial drug concentration of 60 milligrams per milliliter, the metastable form II crystals were preferentially formed on the cyano-surface with no evidence of the crystals transforming to the more stable polymorph even after 24 hours. The mercapto- and fluoro-surfaces, however, preferentially nucleated form III with a small amount of metastable form II. In control vials, both polymorphs crystallized in tandem and transformed to the stable form within 24 hours. The time taken for the first crystals to appear was similar for all three modified surfaces, and significantly faster than in the control vials.
“We plan to improve our fundamental understanding of this template-induced crystallization process through molecular modeling and simulation,” says Poornachary.
The researchers envisage that better knowledge of the molecular packing arrangements in the crystal polymorphs — along with an enhanced understanding of crystal nucleation — may enable the design of template substrates with specific chemistries, eventually improving polymorphic selectivity for a variety of active pharmaceutical ingredients.
“We are also exploring scale-up of the template-induced crystallization approach using functionalized seed crystals and template particles,” added Poornachary.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Chemical and Engineering Sciences
Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München
Second research flight into zero gravity
21.10.2016 | Universität Zürich
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.
In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...
'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.
Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
21.10.2016 | Health and Medicine
21.10.2016 | Information Technology
21.10.2016 | Materials Sciences