Nitrendipine Anti-solvent Crystallization Mechanism And Particle Size Dependence Of Oral Bioavailability

This thesis focuses on the anti-solvent crystallization and particle size dependence of the dissolution and oral absorption of poorly water soluble drug.Nitrendipine was selected as the model drug.Crystal growth mechanism in the anti-solvent crystallization process was investigated and provided an indepth insight into crystal growth in water solution containing polymers.Based on this mechanism,stable nitrendipine nanocrystal suspension was prepared.Nitrendipine crystals with different particle sizes were prepared and the effects of particle size on the drug dissolution and oral absorption were investigated.Firstly,the crystal growth of nitrendipine was investigated in aqueous solution containing polymers.A new crystal structure of nitrendipine was discovered,and its formation mechanism was investigated.The effects of process parameters on the size and morphology of the crystals were studied.The process parameters included the polymers and their concentration in aqueous phase,the temperature,the PEG 200 content and drug concentration in the organic phase.Monodispersed micro-spherical crystals were obtained when PVA and PEG 200 were present in the system,and the temperature was 2?.The particle size of nitrendipine spherical crystals was affected by the PVA concentration in the aqueous phase and the PEG 200 content in organic phase.A higher concentration of PVA and PEG 200 resulted in relatively smaller crystals.The growth mechanism of nitrendipine spherical crystals was also investigated.At the very beginning of the precipitation,a large number of amorphous nanoparticles were formed.Then,these nanoparticles aggregated to form a core for subsequent growth.These amorphous nanoparticles tended to be transformed into a crystalline form.Once the crystalline was achieved,there was rapid growth on the surface of the aggregates with the amorphous particles acting as a reservoir allowing the formation of star-like particles.These star-like particles were constructed from small needle-like distinct crystalline units arranged radially around a core,and served as templates for the formation of spherical crystals.Finally,spherical crystals were formed by filing the gap between the needle-like distinct crystalline units of star-like templates.These findings provide a new insight into spherulitic crystallization of active pharmaceutical ingredients.Secondly,the solvent-mediated amorphous/crystalline transformation of nitrendipine in aqueous solution containing polymers was investigated using Raman spectroscopy and X-ray powder diffraction techniques(XRPD).Moreover,the nucleation and crystal growth rates were quantitatively determined by image analysis with videos recorded under polarized light microscopy.The transformation of amorphous nitrendipine nanoparticles to its crystalline phase took place through the dissolution of amorphous nanoparticles and followed by growth of crystalline phase where the amorphous nanoparticles acted as a reservoir.By analyzing the crystal growth videos,the rates of nucleation and crystal growth were decreased with an increase in concentration of PEG 200 from 0%to 75%;and PVA concentration from 0.1%to 1%.However,a further increase in PVA concentration to 2%did not show a significant decrease in nucleation and crystal growth rate.The induction time of nucleation was greatly increased by an increase of PEG200 content.The drug concentration in organic phase also affected the nucleation rate and crystal growth rate.When the drug concentration was 30mg/ml,the nucleation rate was significant higher than that of 10mg/ml(P=0.05),however,it had no significant difference with 100mg/ml(P=0.38).There was no difference between 10mg/ml and 30mg/ml(P=0.93)in nucleation rate,however,it slowed down when the drug concentration increased to 100mg/ml(P=0.04).The drug concentration had no effect on the induction time.Amorphous/crystalline transformation of nitrendipine in polymer solution was investigated effectively using polarized light micrographs,Raman spectroscopy and XRPD.Image analysis in combination with XRPD and spectroscopic techniques can provide an indepth insight into solid state transformation of pharmaceuticals during processing.It is difficult to obtain stable nanocrystal suspension using conventional anti-solvent crystallization method due to the amorphous/crystalline transformation,resulting in significant growth of formed nanoparticles.The metastable amorphous nanoparticles were treated by sonication and,this facilitated the low energy crystalline modification.The nanosuspensions were prepared by the precipitation-ultrasonication method.The effects of five important process parameters,i.e.the concentration of PVA in the anti-solvent,the concentration of nitrendipine in the organic phase,the precipitation temperature,the power input and the time length of ultrasonication on the particle size of nanosuspensions were investigated systematically.The optimal values for the nanosuspension were 0.15%PVA,30 mg/ml drug in organic phase,3?precipitation temperature,400 W sonication for 15 min.The particle size and zeta potential of nanocrystals were 209±9 nm and-13.9±1.9 mV,respectively.The prepared nanosuspension can be stabilized for more than six months at 4?.Finally,six types of nitrendipine crystal suspensions with different particle sizes(200 nm,620 nm,2.7 ?m,4.1 ?m,20.2 ?m,36.6 ?m)were prepared either by the precipitation-ultrasonication or the antisolvent precipitation method.The effects of crystal size on the dissolution and oral absorption of nitrendipine in rats were investigated.The dissolution test was investigated in there dissolution mediums and simulated using a Noyes-Whitney type equation.The dissolution of nitrendipine was greatly increased by a reduction in particle size.The dissolution test in FaSSIF can discriminate the differences in dissolution rates of various particle sizes and the simulated results were in agreement with the observed dissolution curves.Thus,FaSSIF can be used to predict differences.in in vivo absorption.The in vivo study demonstrated that the reduction in drug particle size from 36.6(raw crystals)?m to 200 nm correlated well with incremental improvements in oral absorption.The absolute bioavailability of a nanosuspension with a particle size of 200 nm was 61.4%,and the AUC0?12 and Cmax values were approximately 6.2-fold and 8.7-fold greater than that of raw crystals,respectively,and its bioavailability was 5-fold higher than that of commercial product.Nanocrystals were found to be an efficient method of improving the oral bioavailability of nitrendipine.