In the development of innovative drugs, poorly soluble candidate drugs of BCSII and BCSIV account for nearly 90%. And statistics show that about 40% of currently marketed drugs are poorly soluble compounds. Due to the poor oral absorption and low bioavailability of poorly soluble drugs, it not only increases the difficulty of innovative drug development but also limits the speed of new drug project advancement. Therefore, solving the solubilization problem of poorly soluble drugs and increasing their exposure and bioavailability in the human body is one of the urgent problems to be solved.
The following introduces several commonly used formulation methods, such as cyclodextrin inclusion, adding solubilizers or co-solvents, using hydrotropic agents, synthesizing water-soluble prodrugs, preparing solid dispersions, preparing drug nanocrystals, using microemulsions, preparing liposomes and other methods.
Common Solubilization Methods for Poorly Soluble Drugs
Adjust pH Value:
Many drugs are weak acids or weak bases, and their solubility is affected by pH. By adjusting the pH of the solvent, the drug can be dissociated into ionic form, thereby increasing solubility. Commonly used buffers include citrate buffer, acetate buffer, and phosphate buffer (PBS). It should be noted that different routes of administration have different limits on pH.
Salt Formation:
Salt formation is a simple and cost-effective solubilization method. By making organic weak acid and weak base drugs into soluble salts, their solubility can be increased, thereby increasing the oral bioavailability of ionizable drugs. For example, the anticancer drug imatinib, the antihypertensive drug metoprolol, and the analgesic and anti-inflammatory drug diclofenac are all used to increase solubility through salt formation.
Polymorphism:
Drug solid crystals are solid substances in which drug molecules are orderly and repeatedly arranged in three-dimensional space. The same drug molecule can form many different crystal structures under different conditions, namely polymorphism. Different crystal forms of drugs have different physical and chemical properties, including solubility, dissolution rate, and melting point. By selecting the required metastable crystal form, the solubility of the drug can be increased. For example, drugs such as febuxostat, atorvastatin calcium, and axitinib have different solubility properties due to polymorphism.
Use Solubilizers and Co-solvents:
Solubilizer: Surfactants can increase the solubility of poorly soluble drugs in solvents and form solutions. Commonly used solubilizers include non-ionic surfactants, such as Tween 80.
Co-solvent: Adding a third substance (co-solvent) can form a soluble complex with the poorly soluble drug, thereby increasing the drug solubility. Commonly used co-solvents include ethanol, glycerol, and polyethylene glycol.
Cyclodextrin Inclusion:
Cyclodextrins have a unique molecular structure with a hydrophobic interior and a hydrophilic exterior, and unique cavity sizes, which enable them to encapsulate most clinical drug molecules. Therefore, they are widely used in drug preparations. Single natural cyclodextrins, especially β-cyclodextrin, have very low solubility in water and have a small range of applications. In order to improve the solubility of natural cyclodextrins and improve their encapsulation ability to drug molecules, some hydrophilic, hydrophobic, and ionic cyclodextrin derivatives have been synthesized. For example, methyl and hydroxypropyl groups are used to replace the hydroxyl groups on the sugar ring. These chemically modified cyclodextrins play an important role in the medical field due to their more flexible molecular cavity, greater water solubility and less toxicity.
Nanotechnology:
Nanocrystal Technology: Nanocrystal drugs refer to drug particles whose size is at the nanometer level. By definition, the size of nanocrystals is less than 1 μm. In practical applications, the size is usually between 200-500 nm. Nanocrystal drug preparations usually have very small particle sizes. This tiny size gives nanocrystal drugs some unique properties and advantages, such as enhanced drug solubility, increased surface area, improved bioavailability, and faster drug release rates, making them more suitable for DCS Ⅱa compounds. This technology also has some disadvantages, such as complex preparation process, difficult control, and high production costs. Commonly used preparation methods include high-pressure homogenization and wet milling.
Nanosuspension: Disperse the poorly soluble drug in a liquid medium to form a stable nanoscale suspension.
Liposomes: Liposomes are closed vesicles composed of phospholipids and cholesterol (lipid bilayers), and they also have great advantages as drug carriers. It has the advantages of enhancing targeting, improving stability, improving efficacy, and reducing drug toxicity and side effects. Polyethylene glycol-modified luteolin liposomes were prepared by film dispersion method using phospholipid, cholesterol and phosphatidylethanolamine-polyethylene glycol 2000 as carriers. The results showed that the prepared liposomes had high encapsulation efficiency, uniform particle size, and obvious sustained release effect. Compound huperzine A-astaxanthin liposomes were prepared by film dispersion-probe ultrasound method. Studies have shown that the composite liposomes prepared by this method have uniform particle size, high encapsulation rate, and good stability.
Solid Dispersion:
Dispersing the drug in a water-soluble carrier (such as a polymer) to form a solid dispersion can improve the drug’s solubility and dissolution rate. Commonly used preparation methods include spray drying and hot melt extrusion.
Amorphous Solid Dispersion (ASD): ASD production processes represented by spray drying and hot melt extrusion are important technologies for improving the solubility of poorly soluble drugs. The advantage of hot melt extrusion technology lies in its ability to introduce solvent-free and downstream processing to make extrudates into final preparations, and it can be produced continuously.
Other Technologies:
Nowadays, more and more new preparation technologies are being applied to the solubilization of poorly soluble drugs. Such as adding block copolymer solubilizers, osmotic pump technology, liquid-solid compression technology, etc.
Micronization Technology: Microemulsions and nanoemulsions are thermodynamically or kinetically stable oil-water mixed systems that can effectively solubilize poorly soluble drugs. Grinding the drug into a fine powder increases its surface area and increases the dissolution rate.
Liquid-Solid Compression Technology: The drug is dissolved or dispersed in a liquid carrier, and then adsorbed onto a solid carrier to form a compressible powder.
Block Polymer Micelle Technology: Using block polymers to form micelles, the drug is encapsulated in the hydrophobic core to improve solubility.
Although there are many ways to increase the solubility of poorly soluble drugs, how to comprehensively evaluate specific drugs based on their physical and chemical properties, clinical needs, and research costs, how to choose the appropriate solubilization method to improve their solubility and bioavailability, and ultimately improve the clinical efficacy of drugs, still requires in-depth exploration by drug researchers. I believe that with the widespread application of various new solubilization methods, poorly soluble drugs will have a better future!