Local Structure of Ion Pair Interaction in Lapatinib Amorphous Dispersions characterized by Synchrotron X-Ray diffraction and Pair Distribution Function Analysis

Gabriel L B De Araujo,Chris J Benmore,Stephen R Byrn

doi:10.1038/srep46367

Gabriel L B De Araujo, Chris J Benmore + Show 1 more

Open Access

https://doi.org/10.1038/srep46367

Copy DOI

Abstract

For many years, the idea of analyzing atom-atom contacts in amorphous drug-polymer systems has been of major interest, because this method has always had the potential to differentiate between amorphous systems with domains and amorphous systems which are molecular mixtures. In this study, local structure of ionic and noninonic interactions were studied by High-Energy X-ray Diffraction and Pair Distribution Function (PDF) analysis in amorphous solid dispersions of lapatinib in hypromellose phthalate (HPMCP) and hypromellose (HPMC-E3). The strategy of extracting lapatinib intermolecular drug interactions from the total PDF x-ray pattern was successfully applied allowing the detection of distinct nearest neighbor contacts for the HPMC-E3 rich preparations showing that lapatinib molecules do not cluster in the same way as observed in HPMC-P, where ionic interactions are present. Orientational correlations up to nearest neighbor molecules at about 4.3 Å were observed for polymer rich samples; both observations showed strong correlation to the stability of the systems. Finally, the superior physical stability of 1:3 LP:HPMCP was consistent with the absence of significant intermolecular interactions in (∆) in the range of 3.0 to 6.0 Å, which are attributed to C-C, C-N and C-O nearest neighbor contacts present in drug-drug interactions.

Highlights

Decrease in the number of peaks and in Weakening intermolecular packing, corresponding to the loss of its periodicity when comparing systems structural order[13,14,15,36]
The Pair Distribution Function (PDF) results indicated a complete miscibility with a good agreement with the number of glass transitions found; in the second system, the PDF indicated potential phase separation not detected by differential scanning calorimetry (DSC), suggesting that the system was a solid nanosuspension with nanometer sized amorphous domains lower than 30 nm
In the present work we report the potential application of PDF analysis and high-energy X-ray diffraction as a tool to study acid-base interactions and drug-excipient interactions in amorphous systems

Summary

Introduction

Decrease in the number of peaks and in Weakening intermolecular packing, corresponding to the loss of its periodicity when comparing systems structural order[13,14,15,36]. Differences in PDF patterns during grinding indicated the existence of an intermediary nanocrystalline phase during the amorphization process of crystalline form II, not observed for crystalline form I10,22. Billinge and co-workers using a Qmáx = 20 Å−1 obtained a real-space resolution of 0.31 Å in the study of amorphous indomethacin and carbamazepine samples, being able to better identify differences in the molecular packing[11]. The high resolution allowed the differentiation of significant intermolecular and intramolecular interactions in the range of 5–15 Å; for e.g. a shift in a peak was observed at 3.78 Å to 3.94 Å was identified due to changes in the orientation of the phenyl ring of clotrimazole caused by the vitrification process[14]

Methods

Results

Conclusion