Veronika Sladkova

Solid Forms of Tenofovir Disoproxil Fumarate, Their Mutual Conversion, and Stabilization of Form I in Formulation

Tenofovir disoproxil fumarate (TDF, form I) is an orally delivered pharmaceutical salt used for the treatment of HIV and chronic hepatitis, which acts as an inhibitor of nucleotide reverse transcriptase. There are many solid forms of TDF described in the literature; 2 of them were identified in the drug products: form I and form A. It seems that during formulation, the active pharmaceutical ingredient undergoes partial to total conversion of TDF form I to TDF form A. The goals of this study were to investigate when and why did the conversion occur and whether the conversion could be avoided and how. The influence of pH and possible interaction with excipients were studied. The conditions enabling using wet granulation in technology while preventing the undesired conversion were found. The stabilization was achieved either by replacement of used disintegrants or by acid addition to the current composition of formulation.

Ivabradine hydrochloride mandelic acid co-crystals: two peas in a pod

A pharmaceutical salt ivabradine hydrochloride (IVA HCl) is indicated for the symptomatic treatment of chronic stable angina pectoris and a chronic heart failure. It exhibits extensive polymorphism and cocrystallization could be a way to provide an alternative solid form. We performed a cocrystal screen, from which two hits were identified: ivabradine hydrochloride (S)-mandelic acid 1:1 (IClSM) and ivabradine hydrochloride (R)-mandelic acid 1:1 (IClRM). Both structures were successfully determined from single crystal X-ray diffraction data as cocrystals. The cocrystals were further characterized by common solid state techniques, such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), solid state NMR, IR and Raman spectroscopy, and dynamic vapor sorption (DVS). [1] To decide which of the newly prepared cocrystals was more stable and which could be thus selected for further development, the maturation experiments were designed. We let IVA HCl mature in various solvents in slurries with twice the excess of racemic mandelic acid, with the intention of crystallizing enantiomerically pure, preferred cocrystal. The resulting solids were mixtures of the cocrystals and were measured by XRPD both on flat Si holder and in a capillary (Bragg-Brentano and Debye-Scherrer configurations) and the phase quantification of the powder patterns was done by Rietveld refinement in Jana2006 and HighScore Plus software. However, the similarity of the two structures of IClSM and IClRM (similar unit cell parameters and overall crystal packing) resulted in the algorithm getting confused during the refinement. The limits of the Rietveld fit in this example are discussed.

Structural characterization of tenofovir disoproxil fumarate Form I using X-ray and electron diffraction and a study of its conversion to related solid forms

Tenofovir disoproxil fumarate (TDF) is an orally delivered pharmaceutical compound used for the treatment of HIV and chronic hepatitis, which acts as an inhibitor of nucleotide reverse transcriptase. There are many solid forms of TDF described in patent literature; two of them we identified in drug products: Form I and Form A. It seems that during formulation the active pharmaceutical ingredient (API) undergoes partial to total conversion of TDF Form I to TDF Form A. The aim of the study was to propose a formulation of tablet containing pure TDF Form I. However, we observed that TDF Form I converted either to TDF Form A or recently described TDF Form I-1. We investigated, when and why did the conversion occur and whether the conversion could be avoided, and how. The influence of pH and possible interaction with excipients were studied. The conditions enabling using wet granulation in technology while preventing the undesired conversion were found. The stabilization was achieved either by replacement of used disintegrants or pH adjustment by acid addition to the current composition of formulation. We also found that TDF Form I underwent the same non-reversible phase transformation to TDF Form I‐1 both upon heating, as well as upon exposure to humidity. The phenomenon was observed by temperature resolved X-ray powder diffraction (XRPD), solid state NMR spectroscopy and DSC. As neither structure of TDF Form I nor of TDF Form I-1 has been determined, we focused on structure solution by combining high quality XRPD, synchrotron single crystal XRD and electron diffraction. We were successful in indexing of the powder of TDF Form I, which was in agreement with the indexing of the microcrystals measured on synchrotron. Moreover, a structure of another tenofovir compound – tenofovir disoproxil phosphate, was successfully determined from single crystal XRD data. Acknowledgment: This work was supported by the Grant Agency of Czech Republic, Grant no. 106/16/10035S and received financial support from specific university research (MSMT No 20/2016). We acknowledge the ESRF for provision of synchrotron radiation facilities and we would like to thank J. Wright for assistance in using beamline ID11. Figure 1. TDF Form I converted either to TDF Form A upon slurrying in water or to recently described TDF Form I-1 upon heating or exposure to water.