Investigation of Drug–Excipient Interactions in Lapatinib Amorphous Solid Dispersions Using Solid-State NMR Spectroscopy

Abstract

This study investigated the presence of specific drug-excipient interactions in amorphous solid dispersions of lapatinib (LB) and four commonly used pharmaceutical polymers, including Soluplus, polyvinylpyrrolidone vinyl acetate (PVPVA), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and hydroxypropylmethylcellulose phthalate (HPMCP). Based on predicted pKa differences, LB was hypothesized to exhibit a specific ionic interaction with HPMCP, and possibly with HPMCAS, while Soluplus and PVPVA were studied as controls without ionizable functionality. Thermal studies showed a single glass transition (Tg) for each dispersion, in close agreement with predicted values for Soluplus, PVPVA, and HPMCAS systems. However, the Tg values of LB-HPMCP solid dispersions were markedly higher than predicted values, indicating a strong intermolecular interaction between LB and HPMCP. (15)N solid-state NMR provided direct spectroscopic evidence for protonation of LB (i.e., salt formation) within the HPMCP solid dispersions. (1)H T1 and (1)H T1ρ relaxation studies of the dispersions supported the ionic interaction hypothesis, and indicated multiple phases in the cases of excess drug or polymer. In addition, the dissolution and stability behavior of each system was examined. Both acidic polymers, HPMCAS and HPMCP, effectively inhibited the crystallization of LB on accelerated stability, likely owing to beneficial strong intermolecular hydrogen and/or specific ionic bonds with the acidic polymers. Soluplus and PVPVA showed poor physical properties on stability and subsequently poor crystallization inhibition.

Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin

“…40 Therefore, these formulations could be considered as amorphous polymeric drug salts. Amorphous drug-polymer salts have also been produced by 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 20 Weuts et al, 41 Song et al 42 and Maniruzzaman et al 43 In each case an ionic interaction between the COOH groups of the polymers and amino groups of the drugs was detected. Conventional DSC, using a heating rate of 10 o C/min, resulted in DSC thermograms that proved difficult to interpret for these samples (Figure 4a).…”

Acid–Base Interactions of Polystyrene Sulfonic Acid in Amorphous Solid Dispersions Using a Combined UV/FTIR/XPS/ssNMR Study

“…16 This technique was therefore also of interest to examine the potential acid−base interactions in PSSA solid dispersions. 15 N solid-state NMR spectra of LB, GB, and amorphous solid dispersions in PSSA are shown in Figures 8 and 9.…”

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

“…Acid-base interactions between drug-excipient play an important role in the physical stabilization of amorphous systems242526. An important small molecule tyrosine kinase inhibitor used in breast cancer therapy, lapatinib (LP), has been chosen as model.…”

“…An important small molecule tyrosine kinase inhibitor used in breast cancer therapy, lapatinib (LP), has been chosen as model. It is a weak base with a secondary amine group (pKa = 7.26) and it was recently reported to form a strong intermolecular ionic interaction with acidic polymers2526, promoting the formation of highly stable amorphous solid dispersions.…”