Evaluation of the inhibitory potential of HPMC, PVP and HPC polymers on nucleation and crystal growth†
Supersaturated drug delivery systems are generally developed for improving solubility and dissolution of poorly soluble drugs. Supersaturation is a high energy state with a tendency to precipitate. Polymers are often used as precipitation inhibitors that may act by inhibiting either nucleation or crystal growth, which are important steps of the crystallization process. Hence, proper understanding of the inhibitory potential of polymers on these critical processes is crucial for selection of appropriate polymers for development of supersaturated drug delivery systems. The current study aims to evaluate the inhibitory potential of polymers like HPMC, PVP and HPC on nucleation and crystal growth using a model drug nifedipine. Inhibition of nucleation and crystal growth was studied by measuring the induction time and precipitation initiation time, respectively. In addition, the extent of maintaining supersaturation was determined by defining a new term, the supersaturation holding capacity (SHC) of the polymers. Precipitates obtained were characterized by FTIR and DSC. The contribution of polymer properties on precipitation inhibition was analyzed by partial least square analysis. In the absence of polymer, nifedipine precipitates in 5 min. High viscosity grades of HPMC effectively inhibited nucleation which was reflected by 2–10 fold enhancements in induction time. In addition, they also inhibited the crystal growth which was reflected through 3–4 fold enhancements in SHC. PVP and HPC polymer grades were found to be less effective in nucleation inhibition. Experimental evaluation in addition to partial least square regression analysis highlights the importance of polymer properties (hydrogen bond acceptors, hydroxypropoxy content, methoxy content and viscosity) in precipitation inhibition which could aid in screening and selection of suitable polymers for systematic development of supersaturated drug delivery systems.