Use Cocrystal Technology To Improve The Physical Properties And Stability Of Hydroxytyrosol

Cocrystal technology is a new type of technology which have been used in the new drug development.It has shown great potential in improving the physicochemical properties as well as pharmacokinetic properties of drugs.Pharmaceutical cocrystal is a kind of supramolecular compound which formed by the active pharmaceutical ingredient and other physiologically acceptable ligands in a fixed stoichiometric ratio connected through hydrogen bonds and other non-covalent bonds.It can change the physical and chemical properties of drugs without damaging the structural integrity of API,thus affecting its physiological activity.Changing the solid form of API by preparing cocrystals is an important means to improve physical and chemical properties of drugs such as solubility,permeability,hygroscopicity,bioavailability,melting point and stability.In recent years,researchers have widely used crystal engineering to improve the melting point and physicochemical properties of drugs through cocrystals.Hydroxytyrosol is a natural polyphenolic compound with strong antioxidant activity,which regarded as one of the most powerful antioxidants.It has antiinflammatory,vasodilating and antimicrobial effects,thus has potential medical prospects.However,HT has very poor physical and chemical properties,such as low melting point,strong hygroscopicity,and being a viscous oily liquid after absorbing 2-3% water,HT also presents poor chemical stability,which makes it difficult to prepare solid preparations.At present,the encapsulation technology is widely used to prepare solid powder to protect the stability and activity of the oil compound.However,due to the amphiphilic properties of HT,the encapsulated efficiency is low.The commercial HT encapsulated powder exists some problems,such as low loading capacity,strong hygroscopicity,and poor stability.This research aims to improve the physicochemical properties of HT through cocrystal technology.Cocrystals of HT were designed based on the easily oxidized phenolic hydroxyl group,specifically carboxylic anion-phenolic hydroxyl synthon,amide-phenolic hydroxyl synthon and carboxylic acid-phenolic hydroxyl synthon were selected to prepare cocrystals.Four cocrystals were prepared through mechanochemical grinding method and solution method.These four cocrystals were carried out systematically solid-state characterizations,and found that they all have good physical and chemical properties,such as high melting point and low hygroscopicity.Different from the oil liquid HT,the four cocrystals are all solid powders,which proved that the cocrystal technology can improve the physical properties of HT through improve the melting point.We also studied the stability of two different crystal forms of hydroxytyrosol-isoniacinamide cocrystal from different aspects,such as single crystal structure analysis,Hirshfeld surface analysis,thermoanalysis and crystal transformation experiments.The results show that Form II is stable at room temperature while Form I is metastable,and the transform relationship between Form II and Form I is monotropic.The results of illumination stability experiment,high temperature stability experiment and high humidity stability experiment show that high temperature and high humidity can affect the chemical stability of HT and commercial HT encapsulated powder,while the cocrystals have obvious advantages of high melting point,low hygroscopicity and great stability under high temperature and high humidity conditions.The accelerated stability experiments of HT cocrystals and commercial HT encapsulated powder show that the cocrystal technology can significantly improve the chemical stability of HT.This research proves that cocrystal technology is an effective means to improve the melting point of drugs and improve the hygroscopicity of drugs as well as solve the stability problems of drugs.