Preparation, characterization and evaluation of dissolution of nanoparticles made by precipitation in drug carrier pores

Poor water solubility, slow dissolution rate and stability are issues for the majority of upcoming and existing biologically active compounds. Drug dissolution is a key parameter that affects the bioavailability and onset of action of oral dosage forms. Low dissolution rates can occur because of small total surface area (of a drug) or poor solubility in the receiving aqueous medium. Decreasing the particle size from a micron to a nanometer scale can result in a significant increase in the surface area and related dissolution rate. Here, a method for developing nano-sized drug particles to improve dissolution of drugs with poor water solubility was developed. In addition, a method to test the nanoparticle dissolution behavior based on pulsatile microdialysis (PMD) was also developed.;This work primarily focused on a novel method of formulating nanoparticles, in which poorly soluble drugs were precipitated into the pores of carrier excipients. This study was done using porous spray-dried lactose monohydrate and the insoluble carrier syloid-244. The main test drug was ibuprofen, which has relatively poor solubility in water at pH 2. The formulations were prepared at various drug:carrier ratios, and then were characterized for the drug loading, dissolution profiles, thermal behavior, and drug particle size.;For most formulations, the ibuprofen loaded into the lactose showed bimodal precipitated particle size distributions, with almost half population was below 100 nm. The interpretation was less clear for ibuprofen-syloid formulations, since the carrier did not dissolve in water. The percentage of drug loading in formulations was found to be 2--10% (2--10 grams of drug per 100 grams of formulation) for ibuprofen-lactose formulations, and ranged from 4--38% in the ibuprofen-syloid formulations it is significant, as 4--38%. The melting temperature of both pore-confined ibuprofen was different from the bulk powder form. DSC curves of formulation showed depression in melting point of ibuprofen, which was sometimes insignificant for lactose nanoparticles batches but significant for syloid formulations.;Dissolution studies were done at 20°C and 37°C in pH 2 HCl (USP) buffer using ibuprofen-lactose and ibuprofen-syloid formulations, and pure ibuprofen. Dissolved ibuprofen concentrations were determined using PMD (3.8 uL probe volume, 11 uL sample volume, 9 second resting time and 100 uL/min flush rate). Direct samples were also taken from the dissolution medium and filtered with a 0.2 micron filter. The physical and experimental parameters of PMD were comprehensively studied in a wide variety of systems, including supersaturated donor solutions, to determine the optimal PMD experimental settings (probe length, flush rate, sample volume, resting time, number of probes used simultaneously, etc.). The donor concentration obtained from direct sampling and donor concentration calculated using PMD parameter was found significantly different. This was explicit the over estimation of direct filtered sampling.;The release rate of ibuprofen from nanoparticle formulations was much faster than that of the pure crystalline form, with some nanoparticle formulations showing nearly 400 fold increases in the initial dissolution rates compared to the pure drug. It was also found that the use of surfactant further increases the dissolution rate.;It was concluded that deposition of drugs in the pores of excipients is a potentially useful method to increase the dissolution of drugs with poor water solubility. In addition, to best characterize the dissolution/release properties of such formulations (and presumably, nanoparticle formulations in general), the adaptation of PMD presents advantages over existing methods of dissolution testing.