Investigation On The Influence Mechanism Of Polymeric Excipients On The Crystallization Kinetics Of Poorly-Soluble Pharmaceuticals

As an ancient separation and purification technology,crystallization plays an important role in many industries such as pharmaceutical industry,inorganic salt industry,food industry and so on.In the pharmaceutical industry,there are huge differences in the in vivo dissolution rate,solubility,and bioavailability for the same pharmaceutical with different crystal forms,crystal habits,and particle size distribution.Therefore,it is very important to strengthen the investigations on the crystallization process and mechanism of pharmaceuticals.Especially for those poorly soluble pharmaceuticals,low solubility and dissolution rate,as well as the contradiction between increasing the dosage and toxic side effects greatly limited their clinical application.One of the effective approaches to improve the solubility of poorly solute pharmaceuticals is to prepare them into the amorphous state.But amorphous pharmaceuticals are thermodynamically metastable and easy to recrystallize.To solve this problem,polymer excipients are added to inhibit the crystallization of amorphous pharmaceuticals.However,the mechanism of polymer inhibiting the crystallization of amorphous drugs is still unclear.In pharmaceutical industry,suitable polymers are still screened out by means of try and error method,which greatly consumes human and material resources.Therefore,it is urgent to deepen the research on the mechanism of pharmaceutical crystallization,especially the crystallization mechanism of the multi-component system with polymer excipients.In view of the above problems,aspirin and mesalazine were selected as research objects to explore their crystal growth kinetics in binary systems and ternary systems.What’s more,the mechanism of polymer inhibiting the pharmaceutical crystallization was studied by the molecular simulation.Finally,the theoretical model was built to explore the mechanism of different factors influencing pharmaceutical crystallization based on the principle of non-equilibrium thermodynamics,which is expected to guide the selection of suitable polymer crystallization inhibitors.The main contents and research results of this paper are as follows:1.The effects of different factors on the crystallization kinetics of poorly soluble pharmaceuticals were explored.The isothermal crystallization curves of aspirin and mesalazine under different experimental conditions were measured.It was found that the crystallization rate of these two model pharmaceuticals decreased with the increase of the crystallization temperature,the decrease of the stirring speed and the increase of polymer content.The effect of PEGs with different molecular weights on the crystallization of aspirin and mesalazine was quite different.The crystallization inhibition ability of PVP and HPMC was much better than PEGs for these two pharmaceuticals.2.The mechanism of polymer inhibiting pharmaceutical crystallization was explained from the micro level.The interaction energy of different polymers with the important crystal surfaces of aspirin and mesalazine was explored by the molecular dynamics simulation.It can be seen that the stronger the interaction force between the polymer and the crystal surfaces,the better the crystallization inhibition effect.3.The chemical potential gradient model combined with the activity coefficient model was employed to investigate the crystallization mechanism of aspirin and mesalazine.It was shown that for these two pharmaceuticals,the chemical potential gradient model combined with the UNIQUAC equation can well calculate the crystal growth kinetics and predict the crystallization curves under different crystallization temperatures and stirring speeds.What’s more,the pharmaceutical crystallization rate is lower in the system with smaller crystal growth rate constant and lower crystallization driving force.Therefore,the selection of suitable polymer crystallization inhibitors can be guided from the perspective of reducing the crystal growth rate constant and crystallization driving force.