Study On The Interaction Among Co-amorphous Drugs By Terahertz-Raman Vibrational Spectrum

The application of poorly water-soluble drugs has always been a major problem in the promotion of new oral drugs.Studies have shown that about 40% of new drugs are poorly water-soluble drugs.Because of the nature of the drug's hydrophobicity,more than 50% of oral drugs have problems with the application of their dosage forms.There have been many preparation techniques to solve the problem of poor solubility,such as reducing the particle size,modifying the crystal,complexing with the cyclodextrin and using a soluble pro-drug.Among them,the rapid development of amorphous drug delivery systems has gradually become a powerful means to enhance the solubility of poorly water-soluble drugs.An amorphous drug refers to a drug that is in amorphous form.The same drugs can exist in various forms,and the crystalline form and the amorphous form are two common forms.The drug molecules in the crystal form are arranged in long-range order;the drug molecules in the amorphous form are disorderly arranged.When a crystalline drug is converted to an amorphous drug,it will tend to show higher water solubility.However,the pure amorphous drugs have many limitations in the application.The main drawback is that the physical stability of the amorphous drug is extremely poor,and it is easy to convert to the crystalline form.This is due to the high molecular energy and unstable thermodynamic condition of the material in the amorphous form.In view of the instability of the pure amorphous drug,research on how to improve the stability of amorphous drugs has become more and more popular.Recent studies have found that the stability can be greatly improved by preparing a single amorphous drug into a co-amorphous drug.A co-amorphous drug is a homogeneous amorphous single phase system formed from two or more low molecular weight components.It can be divided into the "drug-drug" combination and the "drug-excipient" combination.However,the reason of the co-amorphous drug is more stable has not been explained yet,and it is impossible that any two drug molecules can form a stable co-amorphous drug,so the selection of the co-amorphous drug component is very difficult.In order to solve these problems,the molecular interaction between three co-amorphous drugs was studied by Raman scattering spectroscopy and terahertz time-domain spectroscopy.And the related works are as follows:1.Preparation and characterization of the co-amorphous drugs: We prepared three types of cimetidine,naproxen,indomethacin pure amorphous drugs and three types of cimetidine-naproxen,cimetidine-indomethacin,naproxen – indomethacin co-amorphous by melt-quenching method.The above six amorphous drugs were characterized by powder X-ray diffraction technique,differential scanning calorimetry and polarized light microscopy,respectively.The test results showed that except for the pure naproxen amorphous drug,the other five(co-)amorphous drugs showed a good amorphous state.The XRD curve showed a typical "amorphous halo",and the apparent glass transition temperature was shown in the DSC curves.And the difference in brightness between the samples under the polarizing microscope is obvious.2.Evaluation of stability of the co-amorphous drugs: All amorphous drugs were stored at 4 ° C for 1 day,6 days,20 days,180 days,and then tested by powder X-ray diffraction technique.The amount of diffraction peak produced by the amorphous drug at time is explained by its stability.The experimental results showed that the stability of the co-amorphous drug was significantly better than that of the monomeric amorphous drug.It was also found that the amorphous naproxen,which had a very poor stability,had a great stability progress after being combined with cimetidine and even remained amorphous form after 180 days.Through the position of the diffraction peak,we also found that the reason of the deterioration of the co-amorphous drug was caused by the component which was less stable.3.Using vibrational spectroscopy to study the interaction between co-amorphous drugs: The crystal and amorphous form of several drugs were detected by Raman scattering spectroscopy.The results showed that the crystals of various drugs and the amorphous form of had clearly different scattering peaks and verified by principal component analysis.Comparing the Raman peak of the co-amorphous drug to its corresponding component,it can be found that some peaks appear offset,degenerate or disappear,which indicates that some new interactions has formed in the process.By analyzing these corresponding peaks,it was found that the interactions between different drugs were different,such as ?-? interaction,salt formation and hydrogen bond.At the same time,we also studied the crystallization process of amorphous indomethacin by Raman imaging technology.The terahertz time-domain spectroscopy technique was used to detect several crystals and amorphous drugs.The results showed that the absorption coefficient of the amorphous drug was significantly higher than the crystalline drug.In order to explain the relevant terahertz peak,we have further done quantum chemical calculation simulation and PED analysis.In summary,we prepared and characterized three kinds of co-amorphous drugs,and tested their stability and solubility,and further explained the intermolecular interactions in the co-amorphous form through vibrational spectroscopy.The intrinsic mechanism affecting the stability of co-amorphous drugs was elucidated.