Science-Watching: New Insights into Polyamorphism Could Influence How Drugs Are Formulated

[from the Royal Society of Chemistry’s Chemistry World, by Patrick de Jongh]

Results from a study combining experiments and simulations could overturn the assumption that amorphous forms of the same compound have the same molecular arrangement. The team behind the work claims to have prepared three amorphous forms of the diuretic drug hydrochlorothiazide and determined that they have distinct properties and distinct types of disorder. ‘If polyamorphism is proved in the future to be a universal—or at least not a very rare—phenomenon, then the pharmaceutical industry will need to make screens for polyamorphism and this will also be an opportunity for patenting,’ comments Inês Martins, from the University of Copenhagen in Denmark, who led the work with Thomas Rades.

Crystalline active pharmaceutical ingredients (APIs) often suffer from poor solubility. A common strategy to circumvent this problem is converting APIs into their amorphous form. This has been demonstrated for various APIs, including hydrochlorothiazide. However, the physical properties of polyamorphs are dependent on how they were prepared. Given there are no straightforward techniques to study how molecules interact and organise themselves in amorphous materials, the area is poorly understood.

Nevertheless, a team surrounding Rades and Martins set out to identify how amorphous forms of the same API, presenting different physicochemical properties, differ from each other. They decided to study hydrochlorothiazide as it was previously shown to have polyamorphs with glass transition temperatures above room temperature, which facilitates the preparation, isolation and analysis of its different polyamorphs. Starting from crystalline hydrochlorothiazide, they produced three polyamorphs: polyamorph I via spray-drying, polyamorph II via quench-cooling and polyamorph III by ball-milling. Thermal analysis revealed a significantly lower glass-transition temperature for polyamorph I (88.7°C), whereas polyamorphs II and III had similar glass-transition temperatures (117.5°C and 119.7°C, respectively). The polyamorphs also demonstrated very different shelf-life stabilities against crystallisation.

Subsequently, they studied polyamorphic interconversions by submitting the polyamorphs to the preparation conditions used for other polyamorphs. For example, polyamorph I (obtained by spray-drying) was subjected to quench–cooling or ball-milling. Identifying temperature as a critical parameter, they observed that polyamorph II could be obtained from polyamorphs I and III, but the reverse pathway was not possible. Meanwhile, they observed polyamorph I and polyamorph III interconvert. These results demonstrate polyamorph II is the most stable amorphous form.

Source: © Thomas Rades/University of Copenhagen
Researchers used a variety of techniques to elucidate the different polyamorphs that can be produced from crystalline hydrochlorothiazide and the polyamorphic interconversions that occur when a specific amorphous form is submitted to temperature or milling treatments

‘The problem out of the gate with polyamorphism as a concept is how to tell the difference between a well-defined metastable amorphous structure and an unrelaxed one that simply results from kinetically trapped defects introduced during processing. This is hard to define since the amorphous structure is statistical in any case,’ comments Simon Billinge, who studies the structure of disordered materials at Columbia University in the US. ‘They process the samples very differently. We know—from our own work—that this results in amorphous phases with very different stabilities against recrystallisation, for example, but is this polyamorphism? On the other hand, they find that the pair distribution functions of each of their “forms” are identical. There is no experimental evidence for a distinct structure. Taken together, the results do little to advance my understanding of polyamorphism.’

Distinct dihedral angle distributions

To get further information on how the polyamorphs are different on a molecular level, Martins and Rades turned to molecular dynamics simulations, comparing the dihedral angles around the sulfonamide groups in polyamorphs I and II. ‘Polyamorph I, which has a large number of the molecules with a dihedral angle similar to the one reported for crystalline hydrochlorothiazide, has a lower physical stability and faster structural relaxation time than polyamorph II, which has a broader dihedral angle distribution. Our findings indicate that a broader dihedral angle distribution seems to contribute to a better physical stability and slower structural relaxation,’ says Martins. They therefore hypothesise that having half the molecules with a conformation closer to crystalline hydrochlorothiazide and half of the molecules with a different conformation could help in establishing specific molecular arrangements that would favour the stability of the amorphous form.

The team also says the simulations corroborated its experimental results that polyamorph I can transform into polyamorph II, while the opposite conversion did not take place.

However, Billinge does not believe the computational studies provide conclusive evidence: ‘There is a detailed molecular dynamics analysis where different annealing conditions in the simulations give some slightly different statistics on the molecular conformations, but despite their claim, the resulting computed pair distribution functions do not look like the measured ones, so we have no way of knowing if the molecular dynamics is capturing what is happening in the real material. For amorphous materials, it is very difficult to equilibrate them in a molecular dynamics simulation, so you will be looking at artefacts of how the ensemble was created. Any claims to have found polyamorphism from molecular dynamics simulations by themselves are therefore questionable.’

Rades says their results can change the field of pharmaceutics: ‘We expect that other drug molecules may exhibit polyamorphism and the question would be which structural parameters would be different. In the case of hydrochlorothiazide, the dihedral angle distribution was found to be a parameter contributing for the formation of different polyamorphs. In other drugs, maybe the dihedral angle distribution (molecular conformations) could be different as well, but also maybe the type of intermolecular interactions can play a more important role in the formation of polyamorphs.’

The team now hope the pharmaceutical industry will look at amorphous systems differently and not assume that all amorphous forms of the same compound are the same. ‘Knowing this and considering that a certain polyamorph will have better physical stability, solubility or dissolution properties than another polyamorph, this will be an opportunity for the pharmaceutical industry to prepare tablets of a drug where the dose could be lower than tablets containing the crystalline form,’ concludes Rades.

New Ultrathin Capacitor Could Enable Energy-Efficient Microchips

Scientists turn century-old material into a thin film for next-gen memory and logic devices

[from Berkeley Lab, by Rachel Berkowitz]

Electron microscope images show the precise atom-by-atom structure of a barium titanate (BaTiO3) thin film sandwiched between layers of strontium ruthenate (SrRuO3) metal to make a tiny capacitor. (Credit: Lane Martin/Berkeley Lab)

The silicon-based computer chips that power our modern devices require vast amounts of energy to operate. Despite ever-improving computing efficiency, information technology is projected to consume around 25% of all primary energy produced by 2030. Researchers in the microelectronics and materials sciences communities are seeking ways to sustainably manage the global need for computing power.

The holy grail for reducing this digital demand is to develop microelectronics that operate at much lower voltages, which would require less energy and is a primary goal of efforts to move beyond today’s state-of-the-art CMOS (complementary metaloxide semiconductor) devices.

Non-silicon materials with enticing properties for memory and logic devices exist; but their common bulk form still requires large voltages to manipulate, making them incompatible with modern electronics. Designing thin-film alternatives that not only perform well at low operating voltages but can also be packed into microelectronic devices remains a challenge.

Now, a team of researchers at Lawrence Berkeley National Laboratory (Berkeley Lab) and UC Berkeley have identified one energy-efficient route—by synthesizing a thin-layer version of a well-known material whose properties are exactly what’s needed for next-generation devices.

First discovered more than 80 years ago, barium titanate (BaTiO3) found use in various capacitors for electronic circuits, ultrasonic generators, transducers, and even sonar.

Crystals of the material respond quickly to a small electric field, flip-flopping the orientation of the charged atoms that make up the material in a reversible but permanent manner even if the applied field is removed. This provides a way to switch between the proverbial “0” and “1” states in logic and memory storage devices—but still requires voltages larger than 1,000 millivolts (mV) for doing so.

Seeking to harness these properties for use in microchips, the Berkeley Lab-led team developed a pathway for creating films of BaTiO3 just 25 nanometers thin—less than a thousandth of a human hair’s width—whose orientation of charged atoms, or polarization, switches as quickly and efficiently as in the bulk version.

“We’ve known about BaTiO3 for the better part of a century and we’ve known how to make thin films of this material for over 40 years. But until now, nobody could make a film that could get close to the structure or performance that could be achieved in bulk,” said Lane Martin, a faculty scientist in the Materials Sciences Division (MSD) at Berkeley Lab and professor of materials science and engineering at UC Berkeley who led the work.

Historically, synthesis attempts have resulted in films that contain higher concentrations of “defects”—points where the structure differs from an idealized version of the material—as compared to bulk versions. Such a high concentration of defects negatively impacts the performance of thin films. Martin and colleagues developed an approach to growing the films that limits those defects. The findings were published in the journal Nature Materials.

To understand what it takes to produce the best, low-defect BaTiO3 thin films, the researchers turned to a process called pulsed-laser deposition. Firing a powerful beam of an ultraviolet laser light onto a ceramic target of BaTiO3 causes the material to transform into a plasma, which then transmits atoms from the target onto a surface to grow the film. “It’s a versatile tool where we can tweak a lot of knobs in the film’s growth and see which are most important for controlling the properties,” said Martin.

Martin and his colleagues showed that their method could achieve precise control over the deposited film’s structure, chemistry, thickness, and interfaces with metal electrodes. By chopping each deposited sample in half and looking at its structure atom by atom using tools at the National Center for Electron Microscopy at Berkeley Lab’s Molecular Foundry, the researchers revealed a version that precisely mimicked an extremely thin slice of the bulk.

“It’s fun to think that we can take these classic materials that we thought we knew everything about, and flip them on their head with new approaches to making and characterizing them,” said Martin.

Finally, by placing a film of BaTiO3 in between two metal layers, Martin and his team created tiny capacitors—the electronic components that rapidly store and release energy in a circuit. Applying voltages of 100 mV or less and measuring the current that emerges showed that the film’s polarization switched within two billionths of a second and could potentially be faster—competitive with what it takes for today’s computers to access memory or perform calculations.

The work follows the bigger goal of creating materials with small switching voltages, and examining how interfaces with the metal components necessary for devices impact such materials. “This is a good early victory in our pursuit of low-power electronics that go beyond what is possible with silicon-based electronics today,” said Martin.

“Unlike our new devices, the capacitors used in chips today don’t hold their data unless you keep applying a voltage,” said Martin. And current technologies generally work at 500 to 600 mV, while a thin film version could work at 50 to 100 mV or less. Together, these measurements demonstrate a successful optimization of voltage and polarization robustness—which tend to be a trade-off, especially in thin materials.

Next, the team plans to shrink the material down even thinner to make it compatible with real devices in computers and study how it behaves at those tiny dimensions. At the same time, they will work with collaborators at companies such as Intel Corp. to test the feasibility in first-generation electronic devices. “If you could make each logic operation in a computer a million times more efficient, think how much energy you save. That’s why we’re doing this,” said Martin.

This research was supported by the U.S. Department of Energy (DOE) Office of Science. The Molecular Foundry is a DOE Office of Science user facility at Berkeley Lab.