The effect of polymeric excipients on the physical properties and performance of amorphous dispersions: Part I, free volume and glass transition.

PURPOSE: To investigate the structural effect of polymeric excipients on the behavior of free volume of drug-polymer dispersions in relation to glass transition. METHODS: Two drugs (indomethacin and ketoconazole) were selected to prepare amorphous dispersions with PVP, PVPVA, HPC, and HPMCAS through spray drying. The physical attributes of the dispersions were characterized using SEM and PXRD. The free volume (hole-size) of the dispersions along with drugs and polymers was measured using positron annihilation lifetime spectroscopy (PALS). Their glass transition temperatures (Tgs) were determined using DSC and DMA. FTIR spectra were recorded to identify hydrogen bonding in the dispersions. RESULTS: The chain structural difference-flexible (PVP and PVPVA) vs. inflexible (HPC and HPMCAS)-significantly impacts the free volume and Tgs of the dispersions as well as their deviation from ideality. Relative to Tg, free volume seems to be a better measure of hydrogen bonding interaction for the dispersions of PVP, HPC, and HPMCAS. The free volume of polymers and their dispersions in general appears to be related to their conformations in solution. CONCLUSIONS: Both the backbone chain rigidity of polymers as well as drug-polymer interaction can impact the free volume and glass transition behaviors of the dispersions.

Molecular basis of crystal morphology-dependent adhesion behavior of mefenamic acid during tableting.

PURPOSE: The molecular basis of crystal surface adhesion leading to sticking was investigated by exploring the correlation of crystal adhesion to oxidized iron coated atomic force microscope (AFM) tips and bulk powder sticking behavior during tableting of two morphologically different crystals of a model drug, mefenamic acid (MA), to differences in their surface functional group orientation and energy. METHODS: MA was recrystallized into two morphologies (plates and needles) of the same crystalline form. Crystal adhesion to oxidized iron coated AFM tips and bulk powder sticking to tablet punches was assessed using a direct compression formulation. Surface functional group orientation and energies on crystal faces were modeled using Accelrys Material Studio software. RESULTS: Needle-shaped morphology showed higher sticking tendency than plates despite similar particle size. This correlated with higher crystal surface adhesion of needle-shaped morphology to oxidized iron coated AFM probe tips, and greater surface energy and exposure of polar functional groups. CONCLUSIONS: Higher surface exposure of polar functional groups correlates with higher tendency to stick to metal surfaces and AFM tips, indicating involvement of specific polar interactions in the adhesion behavior. In addition, an AFM method is identified to prospectively assess the risk of sticking during the early stages of drug development.

Novel poly-DL-lactide-polycaprolactone copolymer based flexible drug delivery system for sustained release of ciprofloxacin.

This research evaluated 7525DLPCL for soft flexible drug delivery systems. The effect of ciprofloxacin hydrochloride (CIP) loading at three levels (10, 20, and 30%), on thermo-mechanical properties was studied. CIP release was monitored for 12 weeks. Addition of CIP to 7525DLPCL caused an increase in compressive modulus of 7525DLPCL. CIP release was found to be sigmoidal with two phenomena (apart from a minor burst) contributing to release-diffusion and later diffusion plus erosion. An increased burst was observed with greater CIP loading and the majority of CIP (> 70%) was released as an effect of diffusion plus erosion. Additional factors, like the effect of CIP particle size, had no significant effect on drug release. Change in the implant shape from a cylinder (5 mm diameter; 3 mm thickness) to disc (6 mm diameter, 0.5 mm thickness) also failed to show a significant impact on drug release. Erosion of 7525DLPCL is a major contributing factor towards this release and other factors like shape of implants and particle size of drug have little effect on CIP release. Such flexible drug delivery systems offer new avenues for long-term skeletal drug delivery of antibiotics for conditions like osteomyelitis or periodontitis.