Research On The Polymorphism Of 7-ethyl-10- Hydroxy Camptothecin And Olmesartan Medoxomil

The various solid forms generally present distinguished physicochemical properties, and are closely related to the product’s performance, including its bioavailability, manufacturability, and shelf life. Increasing numbers of polymorphs have been recorded over the past decades, proving the growing interest in polymorphism in pharmaceutical researchers. It has become an important part of the drug research and development process and cannot be ignored in drug quality control. In this work, we study the polymorphous of anticancer drug 7 - ethyl - 10 - hydroxy camptothecin (SN38) and anti-hypertensive drug olmesartan medoxomil (OLM):(i) three pseudopolymorphs of SN38 were obtained. The crystal structures of the three forms were characterized by single crystal X-ray diffraction technique. This study also provides a comprehensive understanding of the vapour induced crystalline transformation in three solvate forms of SN38. Besides, the effect of isonicotinamide on the crystallization of SN38 DMF solvate was examined from the viewpoints of nucleation kinetics.(ⅱ) Moreover, four reported forms of OLM were successfully obtained. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analyses (TGA), Fourier transform infrared (FT-IR) techniques were used to achieve a complete solid state characterization of the four forms. We also investigate the solubility and stability of the four forms of OLM. The main contents are as follows:(1)In this work, one previously known polymorph (monohydrate) and two new pseudopolymorphs (methanol solvate and DMF solvate) of an anticancer drug, SN38 were obtained. The crystal structures of the three forms were characterized by single crystal X-ray diffraction technique for the first time. The three forms were characterized by solid-state techniques such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analyses (TGA), Fourier transform infrared (FT-IR) spectra and Raman spectroscopy (RS). The crystal structure data revealed that the monohydrate exhibits 3D H-bond network. The dense structure of the monohydrate is responsible for the most stable form.In methanol solvate, the adjacent OIMC (one-dimensional isostructural molecule chains) subunits are further connected with one methanol molecule through two hydrogen bond to generate an infinite 2D sheet. On the contrary, the DMF solvate is the most unstable form among the three forms of SN38 due to a fragile lattice formed by 1D H-bonding chains.(2)Solvent vapours induced crystalline transformation in three solvate forms of SN38. Investigations of transformations induced by solvent vapours for three phases of SN38 have been investigated. Combined with the single crystal structure, we got further insights regarding the transformation mechanisms, (a) The dense structure of the methanol solvate of SN38 is responsible for the better stability. And SN38 molecules in the methanol solvate still could interact with water molecules by forming hydrogen bonds with residue hydrogen sites. As the humidity is increased above 10% R.H., the sample uptakes significant amount of water vapour rapidly. This is often an indication of hydrate formation. During the desorption process, the methanol solvate hydrate loses its water molecules and then recover when the humidity is decreaed below 10% R.H.; As the humidity is increased above 20% R.H., the DMF solvate, which has a fragile lattice, quickly transforms into the monohydrate. (b)The methanol solvate and the DMF solvate have the similarity of crystal structures (in terms of hydrogen bonding units), solvent exchange process occurring through the solvent channel, with the intermediate state preserving this channel and the basic hydrogen bonding unit. So the rate of transformation from the methanol solvate to the DMF solvate is higher than the rate of transformation of monohydrate to the DMF solvate. (c) The rate of transformation from the monohydrate to the methanol solvate is higher than the rate of transformation from the monohydrate to the DMF solvate. The boiling point of DMF is higher than methanol. Under the same experimental conditions, the higher concentration of methanol vapor in the closed system is responsible for the higher rate of transformation from the monohydrate to the methanol solvate. So it will take much more time to transform the monohydrate to the DMF solvate. A complete understanding of transformation among three solvates of SN38 is vital for the successful development, processing, packing, and storage of formulations.(3)A parallel synthesis platform (CrystalSCAN, HEL Limited, UK) was used to determine the nucleation induction time of SN38 DMF solvate crystal at different supersaturations. And the effect of isonicotinamide on the nucleation kinetics of SN38 DMF solvate was quantitatively examined. It was found that ISO can inhibit the SN38 DMF solvate nucleation and strongly disturb the interaction between the nucleating phase and the substrate. This effect can increase the interfacial free energy and nucleation barrier, resulting in a reduction in the total nucleation number. On the other hand, the ISO will promote nucleation by facilitating the kink kinetics in terms of inducing the pre-ordering of fluid molecules at the interface. Our analysis shows that this promotion effect is dominant compared with the inhibition effect caused by ISO. In this case, better and fewer crystals could be obtained.(4) The reported Form A, Form B, Form R and amorphous of OLM were successfully obtained. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analyses (TGA), Fourier transform infrared (FT-IR) techniques were used to achieve a complete solid state characterization of the four forms. The thermodynamic, humidity stability and solubility of the four forms were also investigated. The results show that the four forms can remain their initial crystal form at 40 ℃/75% RH for 12 weeks, and the solubility values of the Form R, Form B and amorphous are apparently higher than Form A. Therefore, the three forms could be excellent candidates with significant advantages for pharmaceutical formulations.