Tag: molecule

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.

Knot Theory and the Strangeness of Reality

The subfield of “knot theory” in math as a kind of geometry of “twistiness” gives us a deep “meta-intelligent” signal or lesson.

Meta-intelligent means “perspective-challenging” with or without full details of any subfield itself.

Consider this overview or comment on “knot theory” now:

“In mathematical knot theory, you throw everything out that’s related to mechanics,” Dunkel (MIT math professor) says. “You don’t care about whether you have a stiff versus soft fiber—it’s the same knot from a mathematician’s point of view. But we wanted to see if we could add something to the mathematical modeling of knots that accounts for their mechanical properties, to be able to say why one knot is stronger than another.”

But you immediately think: in the real world knots are not only twisted up in mathematically definable ways but are in fact actual shoelaces, neckties, ropes, etc, that have chemical and molecular properties before you describe their twist-and-tighten or slide-and-grip “shapes.”

Which is the real: the math or the “ropiness” of the ropes or the “laciness” of the laces?

The relationship between things and numbers is elusive.

Mathematicians have long been intrigued by knots, so much so that physical knots have inspired an entire subfield of topology known as knot theory—the study of theoretical knots whose ends, unlike actual knots, are joined to form a continuous pattern.

In knot theory, mathematicians seek to describe a knot in mathematical terms, along with all the ways that it can be twisted or deformed while still retaining its topology, or general geometry.

MIT mathematicians and engineers have developed a mathematical model that predicts how stable a knot is, based on several key properties, including the number of crossings involved and the direction in which the rope segments twist as the knot is pulled tight.

“These subtle differences between knots critically determine whether a knot is strong or not,” says Jörn Dunkel, associate professor of mathematics at MIT. “With this model, you should be able to look at two knots that are almost identical, and be able to say which is the better one.”

“Empirical knowledge refined over centuries has crystallized out what the best knots are,” adds Mathias Kolle, the Rockwell International Career Development Associate Professor at MIT. “And now the model shows why.”

As per usual in science, one is dazzled by the ingenuity of the quest and the formulations but puzzled by the larger implications since we can never decide whether math “made” us or we “made” (i.e., invented) math.

Education and Ambiguity Awareness: A Polyvalent World

Sleepwalkers and sleepwalking are both destructive and constructive and show us the ambiguity in all phenomena.

The World War I chronicle of Professor Christopher Clark, The Sleepwalkers, from 2012, is described this way:

On the morning of June 28, 1914, when Archduke Franz Ferdinand and his wife, Sophie Chotek, arrived at Sarajevo railway station, Europe was at peace. Thirty-seven days later, it was at war. The conflict that resulted would kill more than fifteen million people, destroy three empires, and permanently alter world history.

The Sleepwalkers reveals in gripping detail how the crisis leading to World War I unfolded. Drawing on fresh sources, it traces the paths to war in a minute-by-minute, action-packed narrative that cuts among the key decision centers in Vienna, Berlin, St. Petersburg, Paris, London, and Belgrade.

Distinguished historian Christopher Clark examines the decades of history that informed the events of 1914 and details the mutual misunderstandings and unintended signals that drove the crisis forward in a few short weeks.

How did the Balkans—a peripheral region far from Europe’s centers of power and wealth—come to be the center of a drama of such magnitude? How had European nations organized themselves into opposing alliances, and how did these nations manage to carry out foreign policy as a result? Clark reveals a Europe racked by chronic problems—a fractured world of instability and militancy that was, fatefully, saddled with a conspicuously ineffectual set of political leaders. These rulers, who prided themselves on their modernity and rationalism, stumbled through crisis after crisis and finally convinced themselves that war was the only answer.

On the other hand, the great science writer and intellectual Arthur Koestler (died in 1983) in his own book, The Sleepwalkers, (originally, 1959) argues that the revolution in cosmology associated with the names of Copernicus, Kepler, Galileo, et al depended on visionary thinking, a kind of “sleepwalking.”

Lastly, the classic novel, The Sleepwalkers by Hermann Broch (died in 1851) condemns sleepwalking as the basis of Europe and Germany’s descent into nightmare.

Important works by Broch are The Sleepwalkers (German: “Die Schlafwandler,” 1932) and The Guiltless (German: “Die Schuldlosen,” 1950). The Sleepwalkers is a trilogy, where Broch takes “the degeneration of values” as his theme. Various generations are depicted as sleepwalking through their times and eras without any ability to “see past” their time, place, era. They were “sleepwalking.” This made them liable to demagogic deceptions and recruitment.

On the other hand, the experience and story of Kekulé (died 1896) and his scientific discoveries prodded by dreams and reveries and sleepwalking give us a story that argues against seeing sleepwalking as always negative:
Kekulé’s dream and “good kinds of sleepwalking.”

Friedrich August Kekulé, later Friedrich August Kekule von Stradonitz (7 September 1829 – 13 July 1896), was a German organic chemist. From the 1850s until his death, Kekulé was one of the most prominent chemists in Europe, especially in theoretical chemistry. He was the principal founder of the theory of chemical structure.

The new understanding of benzene (C6H6), and hence of all aromatic compounds, proved to be so important for both pure and applied chemistry after 1865 that in 1890 the German Chemical Society organized an elaborate appreciation in Kekulé’s honor, celebrating the twenty-fifth anniversary of his first benzene paper.

Here Kekulé spoke of the creation of the theory.

He said that he had discovered the ring shape of the benzene molecule after having a reverie or day-dream of a snake seizing its own tail (this is an ancient symbol known as the ouroboros).

Kekulé’s story of “dreaming up” the structure of benzene (C6H6) gives us another historical example of Arthur Koestler-type “good sleepwalking” ie visionary dreams and reveries that really enhance “objective” concrete scientific analysis and not only art works.

It is educational to see the inner ambiguity of words and phenomena (such as sleepwalking) because this duality and “polyvalence” applies to many cases.