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New insights into polymorphisms could influence drug development

Researchers have used a variety of methods in order to reveal the different polymorphs that can be prepared from a common crystalline material and the paths of conversion of one configuration to another depending on the temperature and the method of preparation

[Translation by Dr. Moshe Nachmani]

Researchers have used a variety of methods in order to reveal the different polymorphs that can be prepared from a common crystalline material and the paths of conversion from one configuration to another depending on the temperature and the method of preparation. [Source: Thomas Rades/University of Copenhagen]

Findings obtained from research that combines experiments and simulations could overturn the belief that amorphous formations of the same compound have the same molecular arrangement. The research team behind this study claims to have been able to synthesize three amorphous forms of the diuretic drug hydrochlorothiazide and determine that each of the forms has distinct properties and distinct types of disorder. "If in the future it is proven that polymorphism is a universal mechanism - or at least not very rare - then the pharmaceutical industry will have to carry out more research and in return will receive opportunities for patents", explains Inês Martins from the University of Copenhagen in Denmark, who led the research.

Active pharmaceutical ingredients (APIs) in crystalline form often exhibit poor solubility. A common approach to circumvent this problem is to convert the active pharmaceutical ingredients to their amorphous form. Such a case has been demonstrated for certain active pharmaceutical ingredients, including hydrochlorothiazide. However, the physical properties of polymorphs depend on how they are prepared. In view of the fact that there is no method by which it is possible to study the exact way in which the molecules react and self-organize in amorphous materials, the entire field is under-researched.

At the same time, the research team planned to examine how amorphous configurations of the same pharmaceutical active molecule exhibit different physicochemical properties and differ from each other. The researchers decided to study the substance hydrochlorothiazide due to the fact that the substance is known in several polymorphic configurations with glass transition temperatures above room temperature, a feature that facilitates the preparation, isolation and analysis of the various polymorphic configurations of this substance. The researchers started with crystalline hydrochlorothiazide, and prepared three polymorphs: polymorph I using spray-drying, polymorph II using quenching-cooling, and polymorph III using Ball grinding. Thermal analysis revealed a significantly lower glass transition temperature for polymorph I (88.7 mC), while polymorphs II and III had similar glass transition temperatures (117.5 and 119.7 mC, respectively). The polymorphs also exhibited very different levels of stability (in terms of shelf life) against formation.

Following these preliminary findings, the researchers investigated the interpolymorphic conversion between the different configurations by applying manufacturing conditions used for the preparation of another polymorph. For example, polymorph I, which was originally prepared by spray-drying, was also prepared by the other two methods - quenching-cooling and ball milling. Assuming that the temperature is a critical parameter, the researchers concluded that polymorph II could be obtained from polymorphs I and III, but the reverse route was not possible at all. At the same time, they demonstrated that polymorph I and polymorph III can be converted into each other. These findings support the conclusion that polymorph II is the most stable configuration.

"The main problem in the field of polymorphism is how to determine the difference between a metastable and well-defined amorphous structure and an unstable structure obtained as a result of kinetically trapped defects formed during preparation. This determination is difficult to define in light of the fact that the amorphous structure exists statistically in any case," comments Simon Billinge, a researcher from Columbia University in the US, who studied the structure of disordered materials. "The researchers processed the samples in a very different way. We know - from our research - that this gives rise to amorphous formations with very different levels of stability against re-formation, for example, but is this phenomenon indeed polymorphism? On the other hand, they found that the distribution functions of each of the configurations are identical. There is no experimental evidence for a separate structure. In conclusion, these findings do not advance my insights regarding polymorphism at all."

In order to get more information about the nature of the difference between the polymorphs at the molecular level, the researchers returned to molecular dynamics simulations, and compared the dihedral angles around the sulfonamide groups in polymorphs I and II. "Polymorph I, which had a high number of molecules with a dihedral angle, similar to what was reported for its crystalline material (hydrochlorothiazide), had a lower physical stability and a faster structural relaxation time than for polymorph II, which had a wider distribution of dihedral angles. Our findings indicate that a wider distribution of dihedral angles probably contributes to better physical stability and a slower structural relaxation time," said the lead researcher. Following these findings, the researchers estimate that half of the polymorphs are in an arrangement closer to that of the original crystal, and about half are in an arrangement different from that of the original crystal, a fact that can help determine a specific molecular arrangement that will favor the more stable polymorphic configuration.

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