The importance of drug solubility and analysis of enhancing technology

The importance of solubility oral administration is the most convenient and commonly used route of administration at present, because it is easy to administer, high compliance, low cost, less sterile restrictions, and flexible dosage form design Therefore, many generic pharmaceutical companies tend to produce bioequivalent oral drug products [1] However, the main challenge of oral dosage form design is its poor bioavailability Oral bioavailability depends on several factors, including water solubility, drug permeability, dissolution rate, first pass metabolism, pre systemic metabolism and susceptibility to efflux The most common reasons for low oral bioavailability are poor solubility and low permeability Solubility also plays an important role in other dosage forms such as parenteral preparations [2] Solubility is one of the important parameters to achieve the required concentration of drugs in the systemic circulation, so as to achieve the required pharmacological response [3] Poorly water soluble drugs usually require high doses to reach therapeutic plasma concentrations after oral administration Low water solubility is the main problem in the development of new chemical solid preparations and generic drugs Any absorbed drug must be in the form of an aqueous solution at the absorption site Water is the preferred solvent for liquid pharmaceutical preparations Most of the drugs are weak acid or weak alkaline, with poor water solubility More than 40% of the new chemicals developed in the pharmaceutical industry are almost insoluble in water These drugs with poor water solubility are absorbed slowly, resulting in poor bioavailability Solubility is a major challenge for formula scientists [4] It is one of the most challenging aspects in drug development to improve the solubility of drugs so as to improve their oral bioavailability, especially in the oral drug delivery system The poor solubility and low dissolution rate of low water-soluble drugs in gastrointestinal aqueous solution often lead to insufficient bioavailability Especially for class II (low solubility and high permeability) substances according to BCS, the bioavailability of BCS can be improved by increasing the solubility and dissolution rate of BCS in gastrointestinal tract As for BCS II drugs, the rate limiting step is the release of the drug from the dosage form, the solubility in gastric juice rather than absorption, so increasing the solubility in turn increases the bioavailability of BCS II drugs [1,3,4] Disadvantages of low solubility compounds include poor absorption and bioavailability, insufficient solubility of intravenous drugs, development challenges that lead to increased development costs and time, and transfer of burden to patients (frequent high dose administration) [2] Solubility improvement technology solubility improvement technology can be divided into physical modification, pharmaceutical chemical modification and other technologies Physical modification includes particle size reduction such as micronization and nano suspension, modification of crystal habit such as polycrystalline, amorphous and eutectic, drug dispersion in carrier such as eutectic mixture, solid dispersion, solid solution and low temperature technology Chemical modification includes the change of pH value, the use of bufier, derivatization, complexation and salt formation Other methods Other technologies include supercritical fluid technology, surfactant, solubilizer, cosolvent, hydrophilic and the use of new excipients For different drugs with poor water solubility, according to their characteristics, appropriate solubility improvement technologies can be selected (1) With the decrease of the particle size, the specific surface area of the drug increases, which leads to the larger interaction with the solvent, so as to achieve the purpose of increasing the solubility Traditional methods of particle size reduction, such as crushing and spray drying, rely on mechanical stress to decompose drugs However, the mechanical forces inherent in comminution, such as grinding and grinding, usually impose a large amount of physical stress on the drug product, resulting in degradation When dealing with thermal or unstable active compounds, the thermal stress that may occur during grinding and spray drying is also a matter of concern Traditional methods for almost insoluble drugs may not be able to increase the solubility to the required level Micronization is another conventional technology to reduce particle size Micronization increases the dissolution rate of the drug by increasing the specific surface area, but does not increase the equilibrium solubility Reducing the particle size of these drugs results in the increase of specific surface area and their dissolution rate Micronization is not suitable for drugs with high dose numbers because it does not change the saturation solubility of the drug [5] Figure 1 Finished product picture of micronization technology in the current market, the micronization process is mainly used in griseofulvin, progesterone, spironolactone Diosmin, fenofibrate and other drugs, and the micronization technology is widely used because of its simple and easy operation, which is a basic means to improve drug solubility at present For each drug, micronization can improve their digestion and absorption, so their bioavailability and clinical efficacy For example, the dissolution of micronized fenofibrate in 30 minute bioreactor increased more than 10 times (1.3% to 20%) [6,7] (2) The concept of solid dispersion solid dispersion was first proposed by Sekiguchi and Obi They studied the formation and solubility of eutectic melts of sulfonamides and water-soluble carriers in the early 1960s [8] Solid dispersion refers to a group of solid products composed of at least two different components, usually hydrophilic matrix and hydrophobic drugs In the current domestic market, the requirements for hydrophilic media are relatively strict The toxicity, interaction with main drugs and self stability of hydrophilic media are studied in depth Common hydrophilic carriers include polyvinylpyrrolidone (PVP), polyethylene glycol (PEGs), plasdones 630 The surfactants such as Tween-80, sodium docosate, myrj-52, pluronic-f68 and sodium dodecyl sulfate (SLS) also play an important role in the formulation of solid dispersion The solubility of celecoxib, flurantriazine and ritonavir can be improved by using appropriate hydrophilic carriers, such as solid dispersion of celecoxib with PVP and ritonavir with gelatin [9-11] (3) Nano suspension technology has become a promising candidate technology for the efficient delivery of hydrophobic drugs The technology is suitable for drugs that are difficult to dissolve in water and oil The particle size distribution of solid particles in nano suspension is usually less than 1 μ m, and the average particle size is between 200 and 600 nm [12] Various methods for preparing nanosuspensions include precipitation technology, media grinding, high-pressure homogenization in water, high-pressure homogenization in non-aqueous media, and combination of precipitation and high-pressure homogenization [13] (4) Another new solubilization technology in supercritical fluid (SCF) process is supercritical fluid (SCF) technology, which has been used more and more in recent years Supercritical fluid refers to the fluid whose temperature and pressure are higher than critical temperature (TC) and critical pressure (TP) It can have the properties of liquid and gas at the same time Once drug particles are dissolved in SCF (usually carbon dioxide), they can recrystallize at a greatly reduced particle size The flexibility and precision of SCF technology enable the micronization of drug particles in a very narrow range of particle size (usually submicron) At present, SCF technology has been proved to be able to produce nanoparticle suspension with a diameter of 5-200 nm (5) In order to improve the dissolution rate of drugs, low temperature technology has been developed Cryogenic technology can be defined by the type of injection device (capillary, rotary, pneumatic and ultrasonic nozzles), the location of the nozzle (above or below the liquid level), and the composition of cryogenic liquid (hydrofluorane, N2, AR, O2 and organic solvents) After low temperature treatment, dry powder can be obtained through spray drying, freeze-drying at atmospheric pressure, vacuum freeze-drying, freeze drying [14-16] and other drying processes However, due to the strict requirements of conditions and drug stability, the applicability of low temperature technology is still poor (6) Inclusion complex formation technology is applied to improve the water solubility, dissolution and bioavailability of insoluble drugs more precisely among many solubility enhancing technologies The most commonly used host molecule is cyclodextrin Cyclodextrin glycosyltransferase (CGT) can degrade starch to produce cyclodextrin (CDS) As shown in Figure 2, these are non reducing, crystalline, water-soluble and cyclic oligosaccharides, composed of glucose monomers arranged in a ring-shaped doughnut with a hydrophobic cavity and a hydrophilic outer surface The three natural CDs are β - cyclodextrin, β - cyclodextrin and β - cyclodextrin [17] According to the structure and properties of drug molecules, it can form 1:1 or 1:2 drug cyclodextrin complex, as shown in Figure 3 The following is a brief introduction of the preparation of low water-soluble drugs and cyclodextrin inclusion complex Fig 2, the representation of the hydrophobic cavity and the hydrophilic external surface of cyclodextrin Fig 3, micelle solubilization of 1:1 and 1:2 drug cyclodextrin complex (7) using surfactants to improve the dissolution performance of insoluble drugs may be the most basic, major and oldest method, and certainly the main flow method in the current market When the concentration of surfactant exceeds its critical micelle concentration (CMC, in the range of 0.05-0.10% of most surfactants), the formation of micelles will entrain the drug in the micelles This is known as micellization, which usually results in an increase in the solubility of insoluble drugs Surfactants also improve the wettability of solids and the rate of decomposition of solids into finer particles [18] The commonly used nonionic surfactants include polysorbate, polyoxyethyl castor oil, polyoxyethyl glyceride, lauryl macroglyceride and monofatty and bisfatty esters of low molecular weight polyethylene glycol Surfactants are also used to stabilize microemulsion and suspension [19] dissolved in drugs Examples of insoluble compounds solubilized by micelles are antidiabetic drugs, gliclazide, glibenclamide, glimepiride, glipizide, repaglinide, pioglitazone and rosiglitazone [20] (8) The specific surface area of crystal engineering dissolution drug depends on its particle size and the ability to be wetted by the lumen liquid Operation technology can produce highly heterogeneous, charged and cohesive particles, which may cause downstream processing and product performance problems Therefore, crystal engineering technology has been developed for controlled crystallization of drugs to produce high-purity powders with clear particle size distribution, crystallization habit, crystal morphology (crystal or amorphous), surface properties and surface energy [21] By controlling the crystallization conditions (using different solvents or changing the agitation or adding other ingredients to the crystallization drug solution), crystals with different arrangement can be prepared, which are called polymorphs This is also the most controversial technology in the market The most classic cases of drug polymorphs are Zhengda Tianqing and "adefovir dipivoxil crystal patent invalid" of Tianjin Pharmaceutical Research Institute Declaration case Therefore, the polymorphs of the same drug may change its physical and chemical properties, such as solubility, dissolution rate, melting point and stability A typical example of the importance of polymorphism to bioavailability is chloramphenicol palmitate suspension The results showed that stable polycrystalline chloramphenicol palmitate produced low serum level, while metastable polycrystalline produced higher serum level for the same dose of Administration [22] In another study, it was found that tablets made of oxytetracycline type a polymorphic form dissolved much more slowly than those of type B polymorphic form [23] The 30 min dissolution of a crystal is 55%, while that of B crystal is 95% The bulk engineering method also includes the preparation of hydrates and solvents to improve the dissolution rate For example, glibenclamide is separated into pentanol and toluene solvates, which show higher solubility and dissolution rate than the two nonsoluble polymorphic forms [24] Dissolution of hydrate