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Predicting the Polymorphs of Primidone and Progesterone

The Polymorph Predictor was used to predict the different forms for primidone and progesterone, both of which have two known polymorphs.

The molecular structures for primidone (left) and progesterone (right). Click on each for a more detailed picture .

The Polymorph Predictor can be applied successfully not only to smaller molecules, such as acetic acid and aspirin, but to larger molecules as well, such as primidone and progesterone.

Primidone is an anticonvulsant which exists in two polymorphic forms, A and B. The molecule can easily form hydrogen bonds, which is evident in both polymorphs. Form A has two types of hydrogen bonds: one type that forms dimers, and another type that links the dimers into sheets of molecules. Form B has only hydrogen bonds that form sheets of molecules.

Progesterone is a steroid that is used to treat abnormalities of the menstrual cycle and pregnancy. The compound exists in two forms (alpha and beta) that are readily interconverted. Hydrogen bonds are not a factor in the packing arrangement since progesterone lacks hydrogen bond donors.

Researchers at Zeneca used C 2 ·Polymorph to successfully predict both polymorphs of both primidone and progesterone. Experimental powder data was used to identify the correctly predicted structures. Rietveld refinement was subsequently performed to achieve better agreement with the known crystal structures.

The crystal structures for primidone form A (left) and form B (right). Click on each for a more detailed picture.
The crystal structures for progesterone alpha form (left) and beta form (right). Click on each for a more detailed picture.

References

  1. Payne R.S., Roberts R.J., Rowe R.C., Docherty R., International Journal of Pharmaceutics , 177 231-245 1999.

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