Morphology Prediction And Control Of Calcium Bisphosphonates In The Crystallization Process And Their Molecular Simulations

Metal-organic coordination polymers are widely used in the biomedical field.Considering that calcium is the main metal element in inorganic components of bone and bisphosphonates are generally used in clinical treatment of bone metabolism related diseases,the calcium bisphosphonates with calcium as the central ion and bisphosphonates as the ligands are bound to have great application potential in the biomedical field.In the crystallization process of a calcium bisphosphonate,the crystal structure,morphology and other crystallographic indexes will have a great impact on its physical and chemical properties and bioavailability.The in-depth study on the structure and morphology of different calcium bisphosphonates has important theoretical significance and practical value.At present,the control method and mechanism of the structure and morphology of calcium bisphosphonates are not completely clear.The design and preparation of calcium bisphosphonates still highly depend on the high-throughput experimental screening.Therefore,it is necessary to understand the effect of crystallization environment on the structure and morphology of calcium bisphosphonates at the molecular level.Through the combination of experiment and simulation,taking the crystal structure as the starting point and from the perspective of crystal morphology,this paper pointed out the model and parameters suitable for the morphology prediction and control of calcium bisphosphonates,and further studied the influence of environmental conditions in the crystallization process of calcium bisphosphonate solution.1.Nine kinds of calcium bisphosphonate single crystals were prepared by reactive crystallization method of aqueous solution.The structure and morphology of the crystals were obtained.The coordination number of central calcium atom and the dimension of building unit were investigated,and the intermolecular interactions inside and outside the building unit were further analyzed.2.A large number of crystals by reactive crystallization method were prepared by changing the calcium source and the concentration of bisphosphonate solutions.The influence of p H value of the reaction solution on the crystal form of calcium bisphosphonates were explored.The structure and property of nine kinds of calcium bisphosphonates were revealed by using a variety of physical and chemical characterizations,then the rationality of the crystal structures was confirmed.3.The attachment energy model was used to simulate the crystal morphology of calcium bisphosphonates.The initial cell model was constructed.The atomic charge of crystalline water molecules was given.Different forcefield/charge rules suitable for various calcium bisphosphonates were found out.The reasonable number of water molecules in the solvent layer and the effects of hydrogen ion,sodium ion and chlorine ion were explored.4.The above model was used to verify the crystal morphology of calcium bisphosphonates,and correction coefficients was proposed to improve the accuracy of morphology simulation.The adsorption of solvent water on the crystal surface was given and the effect of water on different crystal surfaces was explained at the molecular level.The relation between the diffusion coefficient of water and the most important crystal surface of morphology was pointed out.The effect of supersaturation on the crystal morphology of calcium minodronate(one of calcium bisphosphonates)was proposed and verified.5.The same model was used to predict and verify the control effects of nine polar aprotic organic solvents and eight polar protic organic solvents on the crystal morphology of calcium minodronate.The relation between the change of morphology and the volume of organic solvents was quantitatively analyzed,and the difference of control effects of different organic solvents was explained at the molecular level.The relation between the properties of organic solvents and control effects was explored.To sum up,taking calcium bisphosphonates as the research object,this paper showed the synthesis and characterization of nine crystals,and used the attachment energy model combined with molecular dynamics to predict and verify the crystal morphology under different solvent conditions.The research results of this paper will provide some theoretical basis,data support and morphology control ideas for the application of calcium bisphosphonates in the biomedical field.