Advances In Research On Polymorphic Forms Of Solid Drugs

The research and development of polymorphic forms of drugs has always been a research hotspot in the field of biopharmaceuticals. Different crystal states of drugs will have an important impact on drug solubility, dissolution rate, bioavailability and other aspects. It is also a key link in the quality and safety control of drug production. It provides a new development idea for drug research. By combing, analyzing and summarizing the relevant literature on drug polymorphism at home and abroad in the past 20 years, the research significance, preparation method and impact on clinical application of drug polymorphism are introduced.

Russian scientists Uller and Lebek first discovered two different crystal forms of benzamide compounds in 1832. Since then, drug polymorphs have entered the field of vision of pharmaceutical researchers. With the continuous update and progress of chemical analysis instruments, especially X-rays are used in the measurement of crystal structure, the research of drug polymorphism has achieved rapid development. The study of polymorphic forms of drugs started relatively late in my country. Around 1900, research on nimodipine found that its different crystalline forms had a significant impact on the clinical efficacy of the drug. Since then, domestic workers have begun to pay attention to drug polymorphism. In addition, patent infringement incidents about drug polymorphism often occur, which promotes the development of polymorphic drugs to a certain extent.

Part 1 Study The Significance Of Drug Polymorphism

When a solid drug is dissolved, due to different recrystallization conditions or cooling rates, the molecular stacking method and the arrangement order of molecules on the crystal lattice may change. Different crystal forms often exhibit different physical and chemical properties. For example, optical properties, bioavailability and dissolution rate, etc. The study of polymorphic drugs helps to improve the solubility and dissolution rate of drugs, ensure the stability of drugs during production, storage, and transportation, and improve the tabletability of drugs; at the same time, it can also determine the preparation process of crystal forms to ensure that the same batch The equivalence of secondary drugs. The greatest significance of research on polymorphic drugs is to screen out all crystal forms of the target drug as much as possible, and select one that is thermodynamically stable and has better solubility and dissolution rate, so as to maximize the efficacy of the drug.

Part 2 Preparation Method Of Drug Crystal Form

2.1 Recrystallization Method

1) Solvent evaporation method. Solvent evaporation method is the most simple and effective method for screening crystal forms. The target drug is dissolved in solvents of different polarities (the solvent can be a single solvent or a mixture of two or more solvents). As the solvent continues to volatilize, the crystal nuclei continue to grow, and the solution changes from a saturated state to a supersaturated state. The solute Slowly precipitate out. Due to different conditions such as solvent type, solution concentration and solvent volatilization rate, different crystal forms may be obtained. For example, the sulfadiuretic drug indopaan was prepared into four crystal forms in different mixed solvents.

2) cooling method. The cooling method is suitable for the solubility of drugs that are very sensitive to temperature changes. Dissolve the drug at a certain initial temperature (this temperature should not be too high to prevent damage to the chemical structure of the drug), and set a program for gradient cooling. The solubility of the drug decreases significantly as the temperature decreases, thus reaching a supersaturated state, and the solute is further precipitated.

2.2 Anti-Solvent Method

The anti-solvent method is also known as the precipitation method. The anti-solvent method needs to screen two target solvents, one is a good solvent and the other is a poor solvent. These two solvents will not undergo chemical changes, will not separate, and the solvents can dissolve each other, and the solubility of the drug in these two solvents is quite different. For example, the anti-hepatitis B virus drug adefovir dipivoxil (ADV) is completely dissolved in dichloromethane, and n-hexane is used as an anti-solvent to reduce its solubility, and a new crystal form was successfully prepared.

2.3 Crystal Transfer Method

1) Grinding and crystallization method. During the grinding of solid drugs, the particles gradually become smaller and the surface area continues to increase during the grinding process. The local high temperature of the grinding causes crystal dislocation or boundary deformation, and then crystal transformation occurs. For example, Shan-Yang Lin et al. found that the crystal transformation phenomenon occurred in the crystal forms I, II, III and IV when the antiepileptic drug gabapentin (GBP) was ground.

2) Heating crystal transformation method. The heating crystal transformation method is to heat up the drug and heat it to a certain temperature to achieve crystal transformation. The heating method is generally applicable to “pseudopolymorphism”. During the heating process, the drug molecule loses water or crystallizes to cause crystal transformation. For example, i-Hun An et al. studied antiviral drug adefovir dipivoxil (AD) two kinds of polycrystalline NF-I and NF-II, using thermogravimetric analyzer to heat up, NF-I undergoes crystal transformation.

3) Solution replacement crystal conversion method. The crystal form of the prepared solvate is suspended and stirred in a new solvent, and the solvent in the “pseudopolymorph” is replaced with a different solvent. Different crystal forms may be obtained due to different conditions such as stirring time, speed, and replacement solvent used. For example, WEI XU and others studied the second-line drug cabazitaxel for the treatment of prostate cancer. Its solvate was suspended and stirred in different target solvents (DMF, cyclohexane, n-hexane, ether) for 24 hours, and E ( DMF) could be obtained. , F (cyclohexane), G (n-hexane), and H (ethyl ether) four different solvates.

2.4 Sublimation Method

The sublimation method is a method in which the drug is vaporized by heating, and the vaporized drug molecules solidify into a solid when cooled. The drug molecules are placed in an evaporating dish, and the top of the evaporating dish is covered with a glass funnel. The heated and evaporated drug molecules are cooled and condensed into solids. For example, crystal form A of pyrimethamine, a drug for treating toxoplasmosis, can be transformed into crystal form B by sublimation.

2.5 Organic Vapor Adsorption Method

The organic vapor adsorption method is also called the gas phase diffusion method. Induction by organic vapor volatilization, inducing crystal transformation or forming a solvate. The prepared crystal forms are evenly spread out in a petri dish, and then the petri dish is placed on a floating support in a tank filled with various solvents, and nitrogen is used as a purge gas to remove the air in the tank, and then sealed; Put different solvents in the tank for induction, and slowly volatilize it under heating. Different crystal forms may be produced by inducing different crystal forms. For example, TDF-I in the antiviral drug tenofovir (TDF) was induced in ethanol, isopropanol, and toluene for 9 h to produce three different crystal forms of TDF I-EtOH, TDF I-IPA, and TDF I-toluene ; Two crystal forms of TDFI-ACN and cyclohexane-treated TDF I were produced after induction with acetonitrile and cyclohexane for 24 h.

2.6 Drying Method

Spray Drying And Freeze Drying Are Commonly Used To Prepare Amorphous Forms.

1) spray drying method. The spray-drying method disperses the drug-containing solution into fine particles. When the particles are in contact with hot air, the atomized solvent evaporates quickly, and the drug molecules have no time to arrange and appear in an amorphous form.

2) Freeze-drying method. The freeze-drying method uses the principle of ice crystal sublimation. The liquid medicine forms a solid at low temperature, and the solid directly sublimates the solvent into a gas without being liquefied. The solid medicine has no time to arrange in an orderly manner to obtain an amorphous form.

2.7 Other methods

Changes in the pH of the solution, addition of different polymers to the solvent, and changes in some excipients can change the rate of nucleation by laser-induced methods, thereby inducing crystal transformation. For example, the addition of trace metals to the hypoglycemic drug tolbutamide induces crystal transformation.

Part 3 Characterization Of Polymorphic Forms

3.1 Thermal Analysis Method

Through the program setting of the thermal analyzer, set the temperature range to observe the difference in the endothermic peak during the heating process to identify different crystal forms. In recent years, thermal analysis has become one of the routine characterization methods for polymorphic forms of drugs, which has the advantages of less sample amount, high sensitivity and good repeatability. Thermal analysis mainly includes differential scanning calorimetry (DSC) and thermogravimetry (TG).

1) Differential Scanning Calorimetry (DSC). Differential Scanning Calorimetry (DSC) uses temperature or time as the abscissa, and the endothermic or exothermic rate of the sample as the ordinate. For the analysis of the DSC curve, the crystalline state and the amorphous state are distinguished according to whether there is an endothermic peak. Judging the position, number and shape of the endothermic peaks through the DSC curve to determine whether it is the same crystal form.

2) Thermogravimetric analysis (TGA). Thermogravimetric analysis curve (TGA) is a curve with mass reduction percentage or mass reduction rate as the vertical axis and temperature or time as the horizontal axis. Through the program setting of the thermal analyzer, the relationship between temperature and mass is measured, and the TGA curve analysis is used to determine whether the drug contains solvates, crystallization products containing water, and phase change heat. TGA curves can distinguish “pseudopolymorphs” in crystalline drugs, and the content of solvates can be calculated through curve analysis.

3.2 Infrared Absorption Spectroscopy

Fourier transform infrared spectroscopy (FTIR) is more commonly used in infrared absorption spectroscopy, and infrared spectroscopy is often used as a preliminary screening method for the characterization of polymorphic forms of drugs. Different crystalline molecules have different covalent bond strengths, and in the infrared spectrum, it is shown that the characteristic peak positions, intensities and shapes of the fingerprint region and the functional group region are different.

3.3 X-Ray Diffraction Method

1) single crystal diffraction method (SCXRD). Single crystal X-ray diffraction is used to solve the crystal structure, and the crystal structure can be clearly seen through the single crystal solution software. The single crystal diffraction method is internationally recognized as the most reliable method for identifying crystal forms, but it requires that the tested substance can only be a single crystal, and many drugs cannot be prepared as a single crystal at present, so this method has certain limitations.

2) powder diffraction method (PXRD). Powder X-ray diffraction is used for phase analysis or analysis of ordered mesopores. Powder diffraction method is an earlier and more mature technology for identifying different crystal forms. It has high resolution and simple operation. It is the most effective method for detecting polymorphic forms of drugs, and it is also the most used method.

Part 4 Conclusion

With the rapid development of science and technology, many new active ingredients have also accelerated the development and utilization of new drugs. The main problems faced by many new drugs and generic drugs before they go on the market are poor water solubility, poor gastrointestinal absorption, low dissolution rate and poor stability, which lead to the efficacy of the drug far below expectations. The emergence of polymorphic forms of drugs provides a good choice for newly marketed drugs, and also provides a good choice for those already developed drugs that face low bioavailability and poor stability in clinical practice. The study of polymorphic forms of drugs has been included in the key technology and key research content of major new drug research and development in my country. However, there are obvious problems in the research of polymorphic forms of drugs in China. The focus is on the screening and characterization of new drug crystalline forms. In-depth research on the preservation, physical and chemical properties and biological activities of new crystal forms is lacking. As the technology continues to mature, problems in this area will gradually improve.