1, molecular structure of drug
The solubility of drugs in solvents is the result of the interaction between drug molecules and solvent molecules. According to the principle of "similar compatibility", the polarity of drugs has a great influence on solubility, and the structure of drugs determines the polarity of drugs.
Step 2: Solvent
Solvent is an important factor affecting the solubility of drugs. By reducing the attraction between drug molecules or ions, drug molecules or ions are solvated and dissolved. Polar solvents can solvate and dissolve salt drugs and polar drugs; Polar groups in weaker drug molecules form hydrogen bonds with water and dissolve; Nonpolar solvent molecules and nonpolar drug molecules form an induced dipole-induced dipole combination; Non-polar solvent molecules and semi-polar drug molecules form induced dipole-permanent dipole binding. Usually, the solvation of drugs will affect the solubility of drugs in solvents.
3. Temperature
The effect of temperature on solubility depends on whether the dissolution process is endothermic or exothermic. If solid drugs need to absorb heat when dissolving, their solubility will usually increase with the increase of temperature. The dissolution of most drugs is an endothermic process, so its solubility increases with the increase of temperature. But the dissolution of calcium hydroxide and other substances is just the opposite.
4. Particle size
Generally speaking, the solubility of drugs has nothing to do with the size of drug particles. However, for drugs with poor solubility, at a certain temperature, their solubility and dissolution rate are directly proportional to their surface area, that is, the solubility of small particles is large and the solubility of large particles is small. But this small particle must be less than 1μm, and the solubility will change obviously. When the particle size is less than 0.0 1μm, if it is further reduced, the solubility will not be improved, but will be reduced, because the change of particle charge has a greater influence on the solubility than the reduction of particle size.
5. Crystal form
Drugs with the same chemical structure get crystals with different lattice arrangements due to different crystallization conditions such as solvent, temperature and cooling rate, which is the so-called polymorphic phenomenon. Polymorphism exists widely in organic drugs. Different crystal forms of drugs lead to different lattice energy, and their melting point, dissolution rate and solubility are also different. Lattice energy's smallest crystal form is the most stable, which is called stable form, and it has small solubility and dissolution rate. Lattice energy in other crystal forms is greater than lattice energy in stable form, which is called metastable state. Their melting point and density are low, and their solubility and dissolution rate are higher than those of stable forms. Drugs without crystal structure are generally called amorphous. Compared with the crystalline type, the solubility and dissolution rate are higher than those of the crystalline type, because there is no lattice constraint and the free energy is large. For example, tasteless chloramphenicol type B and amorphous are effective, but crystal forms A and C are ineffective; The solubility of three crystal forms of vitamin B2 in water is: 60 mg/L for type I, 80 mg/L for type II, and 0/20 mg/L for type III; The solubility of the amorphous form of neomycin in acidic aqueous solution is 10 times that of the crystalline form.
6, solvates
In the process of drug crystallization, the crystal lattice is changed due to the addition of solvent molecules, and the obtained crystal is called solvate. If the solvent is water, it is called hydrate. The melting point, solubility and dissolution rate of solvates and nonsolvents are different. In most cases, solubility and dissolution rate are determined by hydrate.
7.ph value
Most drugs are organic weak acids, weak bases and their salts. The solubility of these drugs in water is greatly influenced by pH, and the solubility of weakly acidic drugs increases with the increase of solution pH; The solubility of weakly basic drugs increases with the decrease of pH value of solution. However, amphoteric compounds have the smallest solubility at isoelectric point = pH
8, the same ion effect
If the dissociative form or salt form of a drug is the component that limits its solubility, its relative ion concentration in solution is the decisive factor that affects the solubility of the drug. Generally, in the saturated solution of insoluble salts, when compounds containing the same ions are added, the solubility decreases, which is the same ion effect. For example, the solubility of many hydrochloride drugs in physiological saline or dilute hydrochloric acid is lower than that in water.
9. Others
For example, if a non-electrolyte (such as ethanol) is added to the electrolyte solution, the solubility of the electrolyte will decrease due to the decrease of the polarity of the solution; When electrolyte (such as ammonium sulfate) is added to the non-electrolyte, the weak bond between the non-electrolyte and water is destroyed due to the strong hydrophilicity of the electrolyte, and the solubility is reduced. In addition, when there are other substances besides drugs and solvents in the solution, the solubility of poorly soluble drugs is often affected. Therefore, in the process of dissolution, it is advisable to dissolve the insoluble drugs in the prescription in the solvent first.