Precipitation of poorly soluble pharmaceutical compounds in the human gastrointestinal tract.

摘要

In vivo drug precipitation has been a major issue facing poorly soluble drugs, especially weak bases. This work aims to provide proper understanding of the crystallization kinetics of poorly soluble compounds under in vivo conditions, to develop new experimental and simulation techniques for measuring crystallization kinetics for low solubility drugs over a wide range of biorelevant conditions, and to incorporate supersaturation duration and crystallization kinetics along with other rate processes in an in silico oral absorption model. Dipyridamole is used as the model compound in this work.;Solubility experiments were performed in the intestinal pH range and in the absence and presence of bile salt sodium taurocholate above its critical micelle concentration. The results showed that bile salts act as solubilizing agents resulting in up to a 100 fold increase in total solubility in alkaline pH environments. This effect was primarily due to the solubilization of the free form of dipyridamole; the effect of bile on the ionized form of the drug was negligible. A solubility model taking account of the effect of pH and bile salts on all species was developed and validated against the experimental solubility data.;To perform the nucleation and growth experiments of dipyridamole, a solubility- supersolubility diagram was developed by determining the primary and secondary nucleation thresholds. The results showed that induction times for both primary and secondary nucleation decrease with increasing relative supersaturation. In the presence of seed crystals, induction times were much shorter. The metastable zone width was found to be nearly constant at all pH values.;The crystallization kinetic parameters for dipyridamole were obtained from nucleation and growth experiments performed in the intestinal pH range and in the presence of bile salts. Nucleation rates were obtained from the cumulative distribution functions of induction times. In the absence of NaTC, nucleation kinetic parameters were found to be independent of pH. An empirical power law expression containing global values for the nucleation order and coefficient for nucleation was developed. The effect of NaTC addition was complex; in the presence of 2.2 mM sodium taurocholate, nucleation was found to be retarded. However, when present at a 5 mM concentration, bile salts increased the nucleation rate possibly by acting as active sites for heterogeneous nucleation.;Growth kinetic parameters of dipyridamole were obtained indirectly from the desupersaturation curves by using population balance modeling. In the absence of bile salts, crystal growth was found to be mass transfer controlled and growth rates increased with decreasing pH. In the presence of bile salts, the growth mechanism was found to become a hybrid between mass transfer and surface integration controlled growth.;Finally, to investigate the overall impact of precipitation kinetics on the extent of the oral absorption of dipyridamole, the crystallization thermodynamic and kinetic parameters obtained experimentally were implemented in a novel in silico oral absorption model. The model compartmentalized the GI tract into many segments in series. Case studies were performed where crystal growth was modelled as the inverse of dissolution and compared to the case where the experimental crystallization kinetic parameters were used. Modeling crystal growth as the inverse of dissolution was found to overestimate the fractions of drug dissolved and absorbed. This study demonstrated the importance of correctly modeling crystallization kinetics on predicting bioavailability of poorly soluble drugs in oral dosage forms.