How to solve the caking of API in the drug storage process?
Caking of API during storage is a common physical stability problem, which may be caused by a variety of factors. The following are the possible causes and detailed analysis:
1. Hygroscopicity (Hygroscopicity) Mechanism: If the active pharmaceutical ingredient is hygroscopic, it will absorb moisture from the air and form a "liquid bridge" (a liquid film of water) on the surface of the particles. When the ambient humidity decreases, the water evaporates and the residual solute (such as the drug itself or excipients) recrystallizes, bonding the particles into hard blocks. Typical drugs: antibiotics (such as amoxicillin), vitamins (such as vitamin C), certain inorganic salts (such as sodium chloride). Verification method: The moisture absorption curve was determined by dynamic moisture adsorption analysis (DVS).
2. Temperature fluctuation Mechanism: When the temperature rises, the drug may partially dissolve or soften; when the temperature drops, it is re-cured, and repeated cycles lead to inter-particle adhesion. Case: Low melting point drugs (such as ibuprofen, with a melting point of about 75℃) may soften and stick when stored at high temperatures. Solution: Control the storage temperature in a constant cool condition (such as below 25℃).
3. Crystal phase transformation (Polymorphism) Mechanism: Amorphous (Amorphous) drugs are easy to absorb moisture or crystallize due to the disorder of molecular arrangement and high free energy, forming more stable crystalline state, which may form lumps in the process. Typical case: ritonavir (Ritonavir) was previously ineffective due to crystal transformation. Control measures: X-ray diffraction (XRPD) is used to monitor the stability of crystal form, and thermodynamically stable crystal form is preferred.
4. Electrostatic action Mechanism: In a dry environment, the powder particles generate static electricity due to friction, and the agglomeration is caused by the adsorption of opposite charges. After long-term storage, the powder will be lumped. High risk scenarios: fine powder with poor fluidity (such as particle size <50μm), non-polar drugs (such as steroids). Solution: Add antistatic agent (such as silica), or use conductive packaging materials.
5. Mechanical pressure Mechanism: When the large package is stacked, the lower layer of active pharmaceutical ingredients are under continuous pressure, and the contact area between particles increases, which may lead to plastic deformation or cold welding (Cold Welding). Typical manifestations: Clumps are often found at the bottom of the package or in the pressure area near the edge. Improvement measures: use small size packaging, or use rigid containers to reduce pressure.
6. Microbial contamination Mechanism: If the active pharmaceutical ingredient contains a small amount of nutrient source (such as starch, sugar), and the humidity is high, microbial metabolism may secrete sticky metabolites (such as polysaccharides), promoting clumping. Risk factors: water activity (Aw>0.6), natural source drugs that are not strictly sterilized (such as plant extracts). Control method: strictly control the moisture content (such as drying to moisture <1%), and add preservatives when necessary.
7. Insufficient packaging seal Effect: High permeability of packaging (such as ordinary polyethylene bag) will lead to the infiltration of external moisture, aggravating the hygroscopic lump. Improvement plan: use aluminum-plastic composite film, aluminum-coated bag and other moisture-proof packaging, and fill in desiccant (such as silica gel).
8. Drug properties Viscous ingredients: Sugars and polymer excipients (such as hydroxypropyl methylcellulose) may cause adhesion due to molecular chain migration. Low glass transition temperature (Tg): When the Tg of amorphous drugs is low (such as Tg<50℃), molecular motion is easy to occur at room temperature, resulting in a decrease in physical stability.
Troubleshooting and solution suggestions
1. Analysis of lump properties: The morphology of the clumps was observed under a microscope (e.g., whether they contained crystals or fibrous structures). Measure the moisture content, crystal type (XRPD) and thermal properties (DSC) before and after the lump.
2. Optimize storage conditions: Control humidity (e.g., <40% RH, use dehumidifier or desiccant). Avoid temperature fluctuations (it is recommended to store in a cool storage).
3. Process improvement: Add a flow aid (such as colloidal silica) to reduce static electricity. Increase the particle size and reduce the specific surface area by granulation (wet/dry granulation).
4. Packaging upgrade: Use moisture-proof, anti-static packaging materials, vacuum sealing or nitrogen protection. If further analysis is required, it is recommended to provide specific drug name, storage conditions (temperature and humidity, packaging form) and lump characteristics (hardness, whether it can be crushed), so as to make targeted diagnosis.
