Application Of Co-crystallization Technology On Estradiol And Celecoxib

Background and Objective: The world’s leading pharmaceutical companies have been facing the challenges to effectively deliver active pharmaceutical ingredients(APIs) with poorly aqueous solubility. Several solubility enhancement techniques have been developed. Among them, pharmaceutical co-crystals have attracted a lot of attention. This particular technology envolves crystal engineering principles and solid-state screening techniques. Pharmaceutical co-crystals present some unique properties, such as enhanced solubility/dissolution rate, increased physical/chemical stability, and mechanical properties. So far, however, the studies on pharmaceutical co-crystals include design, screening, synthesis and characterization are still in its infancy. In this thesis, co-crystals of estradiol(E2) and celecoxib(CEL) were investigated systematically based on design approach and the resulted co-crystals were fully characterized.Methods: Based on the review of pharmaceutical co-crystal and crystal engineering, co-crystals of E2 and CEL were designed and synthesized. All the co-crystals were thoroughly characterized. Furthermore, the physicochemical properties of the co-crystals were also researched and compared with the APIs. The main works carried out in this thesis were listed below:1. Screening of E2 co-crystals based on crystal engineering design approach.2. Preparation of E2 co-crystals by solution crystallization.3. Characterization of E2 co-crystals and determination of their dissolution rates.4. The bioavailability study of E2 co-crystals.5. Screening of CEL co-crystals based on crystal engineering design approach.6. Preparation of CEL co-crystals by solution crystallization.7. Characterization of CEL co-crystals and discussed of the desolvation mechanism and relative thermodynamic stabilities.Results:(1) E2 was co-crystalized with isonicotinamide(INA) and piperazine(PIP) through solution crystallization method(co-crystals 1 and 2).(2) A series of bipyridinyl derivatives were selected to co-crystallize with CEL, and nine co-crystals of CEL with 4,4’-Bipyridyl(BPY), 1,2-di(4-pyridyl)ethylene(DPE) and 1,2-bis(4-pyridyl)ethane(BPE) were synthesized by slow evaporation(co-crystals and solvated co-crystals).(3) Many reliable solid state characterization techniques, including single crystal X-ray diffraction(SCXRD), powder X-ray diffraction(XRPD), thermogravimetric analysis(TGA), differential scanning calorimetry(DSC) and Fourier-transform infrared spectroscopy(FT-IR) were used to characterize the co-crystals.(4) The properties of E2 co-crystals were studied systematically. The powder dissolution rates of the co-crystals and E2 were performed in deionized water, p H 2.0, 4.5 and 6.8 phosphate buffers at 37 °C. The results showed that dissolution rates of co-crystals 1 and 2 were as 4.0 and 2.0 times as that of E2, respectively. The bioavailabilities of E2 and co-crystal 1 in rats and dogs were investigatd. The results in rats showed that E2 co-crystal 1 can significantly improve the bioavailability of E2.(5) The desolvation experiment of CEL co-crystal solvates were studied. It illustrates that all solvates have similar crystal structures, but their desolvated co-crystals have significantly different hydrogen bonding patterns. The results showed that the third component has an important role in the formation of isomorphic crystals.Conclusion: E2 and CEL were selected as model compounds for the pharmaceutical co-crystal studies. The design, screening, structural analysis, characterization, and physicochemical properties of the co-crystals were investigated systematically. Two co-crystals of E2 and nine co-crystals of CEL were obtained. E2 co-crystal 1 have significantly improved dissolution rates and bioavailabilities when compared with E2. Thus, the co-crystal 1 is promising candidate for developing new solid-state modification for E2. The thermodynamic properties, desolvation mechanism and outcome of desolvation of CEL co-crystals were discussed.