According to the stacking state of the drug molecule, the drug state includes amorphous drugs in addition to the crystalline drug. Crystal drug molecules show an orderly long range and short range. The polycrystalline type phenomenon of crystal drugs is created due to the difference of molecular accumulation mode. However, the undetermined form is long-range disorder and short-range order. Because of the short-range disorder of the stacked drug molecules, it is in a thermodynamically unstable state and has a high surface free energy. According to the basic principle of thermodynamics, the high energy state should be transformed to the low energy state, so that the drug amorphous form is easy to transfer to the drug crystal state, which also causes difficulties for the development of amorphous drugs.

 Of course, its disordered stacking state also improves the wettability of the drug, breaking the lattice energy between the crystal drugs, which can improve the solubility of the insoluble drug in the solvent. The increase in solubility will in turn affect the dissolution rate of the insoluble drug preparation. The improvement of dissolution will affect the release and absorption of drugs, indirectly improve the exposure of insoluble drugs in the human body, and improve the efficacy of drugs. However, although the amorphism form of insoluble drugs improves the dissolution, special attention should be paid to the stability of the amorphous dissolution process. Because with the drug amorphous dissolution, hydration also occurs. After the drug amorphous contact with the solvent, the glass conversion temperature of the amorphous form will decrease, which will also cause the amorphous form to easily convert to the crystal state, and once the transcrystal occurs, the dissolution will also decrease. At the same time, the hydration of drug amorphous will also make the drug amorphous in the dissolution medium, form a gel, prevent the dissolution of amorphous powder.

 For example, the amorphologies of simvastatin (simvastatin, SIM), carvedilol, CAR), and irbesartan (irbesartan, IRB) were prepared by melting cooling method, and gel formation resulted in the dissolution of these three amorphous drugs significantly lower than their crystalline state. Geling of drug undetermined form does not necessarily indicate the occurrence of transcrystal, which needs to be differentiated, if necessary, can be treated.

 Compared with crystal drugs, it is thermodynamically unstable, surface free energy, high solubility and dissolution rate, and relatively high wet lead, which are more polar groups in drug molecules. The polar groups in drug molecules are easy to bind with water through hydrogen bonding, which increases the moisture icity of drug. The improvement of the moisture ability of the drug also increases its instability. Water molecules have plasticizing effect, which can reduce the problem of drug amorphism and improve the possibility of transcrystal. According to relevant studies, indomexacin can be converted into different drug crystal patterns under different humidity conditions. Therefore, in the development of drug amorphous shape, we need to pay attention to its stability under different humidity conditions.

Just like the polycrystalline form of crystalline drugs, the drug amorphous form also has the amorphous polymorphism phenomenon. Because of the differences in preparation methods, the molecular arrangement, thermodynamic and kinetic differences in amorphism are caused, thus forming the polymorphic phenomenon of drug amorphism. The difference between amorphous polymorphism can be determined by means of powder X-ray diffraction, thermal analysis (such as DSC) and spectral molecules. Because of the difference between the physical and chemical properties of drugs, it is necessary to study the preparation methods and preparation parameters to effectively control the amorphism. Common preparation methods, small-scale common methods include solvent method, grinding method, melting cooling method, large-scale use of hot melt extrusion method.

Schematic of typical extruder system

For each drug amorphism, there are two forms, the supercooled liquid and the glassy state. The glassy state is an unbalanced state of drug amorphism, in which drug amorphism has certain hard fragility, high viscosity and slow molecular motion. Compared with the supercooled liquid, the amorphous shape is more stable in this state. The boundary of the above two states is known as the glass conversion temperature (Tg). When the temperature is lower than the glass conversion temperature, the drug amorphous is in the glass state, the molecular movement is slow, and the transcrystal probability decreases; when the temperature is higher than the glass conversion temperature, the drug amorphous is in too cold liquid, the molecular movement is fast, and easy to transcrystallization. The glass conversion temperature is an important index used to measure the amorphous stability of drugs. However, due to the complexity of the transcrystal mechanism, some cases occur even when the temperature is under the glass conversion temperature. Because of "medicine" and "discussion", also can not be overgeneralized.

 Compared with crystal drugs, the drug amorphism is indeed poor because of its high energy state, but because of its high energy characteristics also gives an answer to the dissolution of insoluble drugs. Drug amorphous molecules are more disordered, high free energy, small particle size, large specific surface area and easy to moisten, all of which are conducive to the dissolution of insoluble drugs. However, when the drug is amorphous and prepared into a preparation, the preparation meets the dissolution medium, and everything leads to uncontrollable development. As: Fengling ferry first meet, see Yang Guo mistake for life. Early it is beautiful, but later it is really cruel. Following the Oswald distribution rule, the amorphous drug will first change into substability in the solvent, then into a crystal, and eventually dissolve poorly.

 Of course, preparation scientists cannot give up trying to solve the chronic problem of dissolving poorly soluble drugs. To increase the stability of the drug in the medium, scientists have proposed the "spring-parachute" theory. The amorphism of the high-energy state increases the dissolution rate, just like a spring, a fly. In order to avoid amorphous transcrystallization in the medium, some excipients, such as PVP, PEG, HPMC and other polymers, were added to the amorphous preparation. The addition of these polymers, through the formation of non-covalent force with amorphous molecules, hinders the reorganization of the amorphous molecules, and suppresses the glass transition temperature of the polymer, which increases the amorphous temperature and increases the chemical potential energy of the drug, thus increasing the energy barrier of the amorphism. Polymers are like parachutes, guarding the stability of the drug-less form. Turning the impossible into possible and turning decadent into magic is the way for science and innovation.

Although drugs in the form of crystal as the carrier of drug molecules and drug is the mainstream of small molecule solid preparation development, but when drug lattice can be too high, serious limit drug dissolution, even if the drug morphology because it belongs to the thermodynamics, high surface free energy, easy to wet, there is one or that instability and preparation method is unusual, it can still be as we improve insoluble drug solubility, dissolution rate, and improve drug exposure in the body, improve the curative effect of good choice.

With the surge of innovative drug development, the properties of candidate compounds are needless to say much. Take the first step early, perhaps is a big step towards the development of the research and development company, how about the weight, and how should, please say with the spring breeze!

reference documentation:

1.Technical review and prospect of drug solid-state dispersion

2.Hot-Melt Extrusion: from Theory to Application inPharmaceutical Formulation

3.Theory and application of crystal-type drug research and development

4.gelation of small molecule amorphous drugs