As a clinically common oral iron supplement, ferrous gluconate contains multiple hydroxyl groups (-OH) and carboxyl groups (-COOH) in its molecular structure. Additionally, Fe²⁺ easily forms coordination bonds with water molecules, resulting in strong hygroscopicity of the product. Hygroscopicity not only causes particle caking and reduced fluidity but also accelerates the oxidation of Fe²⁺ to Fe³⁺ (increased humidity raises oxygen solubility and promotes oxidation reactions), thereby decreasing bioavailability and generating irritating impurities. Therefore, it is necessary to establish a systematic moisture-proof solution based on the mechanism of hygroscopicity, combined with the barrier properties of packaging materials and the regulation of storage environments.
I. Hygroscopicity Mechanism and Influencing Factors
The hygroscopic process of ferrous gluconate is divided into two stages: "physical adsorption" and "chemical hygroscopicity." The core driving forces are directly related to material properties and environmental conditions:
1. Core of Hygroscopicity Mechanism
Physical adsorption: The surface of ferrous gluconate powder contains a large number of polar groups (hydroxyl and carboxyl groups), which easily form hydrogen bonds with water molecules in the air, leading to "monolayer adsorption." When the environmental humidity exceeds the critical value (i.e., critical relative humidity, CRH), the surface-adsorbed water further dissolves trace salt impurities in the powder (e.g., sodium sulfate and chlorides remaining from the synthesis process), resulting in "multilayer adsorption." This causes the powder to rapidly transition from a "dry state" to a "deliquescent state," manifested as particle adhesion and caking.
Chemical reactions associated with hygroscopicity: During hygroscopicity, water molecules act as a medium to accelerate the oxidation reaction of Fe²⁺—Fe²⁺ first combines with water to form [Fe(H₂O)₆]²⁺, then reacts with oxygen in the air to generate Fe(OH)₂, which is further oxidized to Fe(OH)₃ (and may eventually convert to Fe₂O₃). This process not only consumes active ingredients but also changes the product color from light green to yellowish-brown. Meanwhile, Fe(OH)₃ may form insoluble impurities with gluconate ions, increasing the risk of gastrointestinal irritation during oral administration.
2. Key Influencing Factors
Environmental humidity: The primary factor affecting hygroscopicity. Studies have shown that the CRH of ferrous gluconate is approximately 45%–50%: When environmental humidity < 45%, the hygroscopic rate is slow, with a moisture gain of < 0.5% within 24 hours; when humidity > 50%, the hygroscopic rate increases exponentially—at 60% humidity, the 24-hour moisture gain can reach 2.3%, and at 80% humidity, it even exceeds 5%, accompanied by obvious caking. If humidity > 70% and temperature rises simultaneously, partial crystal dissolution may occur, leading to a decrease in product purity.
Temperature: Temperature indirectly affects hygroscopicity by influencing the kinetic energy of water molecules and the oxidation rate of Fe²⁺. Under the same humidity conditions, when the temperature rises from 20°C to 30°C, the equilibrium moisture content of ferrous gluconate increases by approximately 15%–20%. On one hand, higher temperatures make it easier for water molecules to overcome the adsorption energy barrier on the powder surface, accelerating multilayer adsorption; on the other hand, increased temperature enhances the solubility of oxygen in water, promoting Fe²⁺ oxidation. The oxidation products (e.g., Fe³⁺ salts) have higher hygroscopicity than ferrous gluconate, further exacerbating the hygroscopic process.
Impurity content: Residual salt impurities from the synthesis process (e.g., sodium sulfate, chlorides) significantly reduce the CRH of ferrous gluconate. For example, when the sodium sulfate content increases from 0.1% to 0.5%, the CRH decreases from 48% to 42%. This is because salt impurities easily absorb water molecules to form a "salt solution film," disrupting the dry state of the powder surface and acting as a hygroscopic core. Additionally, the presence of Fe³⁺ impurities (e.g., iron(III) gluconate) also increases hygroscopicity, as Fe³⁺ in its molecular structure has stronger coordination ability and binds more easily to water molecules.
II. Selection of Packaging Materials Based on Hygroscopicity Control
The core function of packaging materials is to block external moisture and oxygen. Materials with appropriate barrier properties should be selected based on the dosage form of ferrous gluconate (e.g., active pharmaceutical ingredient/API, tablets, capsules) and storage period, while balancing cost and usability:
1. API Packaging: High-Barrier Composite Films and Rigid Containers
APIs require long-term storage (usually 6–12 months) and are prone to contact with the inner wall of packaging due to powder flow, demanding the highest barrier performance. The "aluminum-plastic composite film bag + vacuum packaging" combination is preferred: The composite film structure is recommended to be a three-layer "PET (polyethylene terephthalate)/AL (aluminum foil)/PE (polyethylene)" structure—
The PET layer provides mechanical strength to prevent film bag damage during transportation;
The AL layer acts as an absolute barrier, with a water vapor transmission rate (WVTR) as low as 0.1 g/(m²·24h) (under 23°C, 85% RH) and an oxygen transmission rate (OTR) close to 0, completely blocking external moisture and oxygen;
The PE layer serves as a heat-sealing layer to ensure the tightness of vacuum packaging.
During packaging, the API powder is first filled into the composite film bag, which is then evacuated to an absolute pressure of ≤ 5 kPa using a vacuum packaging machine, followed by heat-sealing (seal width ≥ 10 mm to avoid gaps). Meanwhile, 1–2 packs of desiccants (e.g., montmorillonite desiccants, dosage: 5%–10% of the API mass) are placed inside each bag to further absorb residual moisture in the packaging.
For long-term storage (> 12 months) or bulk transportation, rigid packaging of "stainless steel drum + inner aluminum-plastic composite bag" can be used: The stainless steel drum (material: 304 stainless steel, thickness ≥ 1.2 mm) provides impact resistance; the inner bag uses the aforementioned "PET/AL/PE" composite film, also vacuum-sealed with desiccants. The drum mouth is sealed with a screw cap + nitrile rubber gasket to ensure overall barrier performance, maintaining the humidity inside the packaging below 30% for a long time.
2. Preparation Packaging (Tablets/Capsules): Single-Dose or Small-Dose Barrier Packaging
Tablets and capsules need to avoid moisture absorption during storage (which may prolong disintegration time and reduce content) and meet the convenience of single-dose administration. Two types of packaging are recommended:
Aluminum-plastic blister packaging (PTP): Suitable for multi-dose preparations. The blister base material is a "PVC (polyvinyl chloride)/PVDC (polyvinylidene chloride)" composite film—PVC provides moldability, while the PVDC layer acts as a high barrier, with WVTR controlled below 0.5 g/(m²·24h) and OTR ≤ 1 cm³/(m²·24h·atm), effectively slowing moisture intrusion. The cover aluminum foil is an "AL/PE" composite aluminum foil (thickness ≥ 25 μm) to ensure heat-sealing strength (peel strength ≥ 3 N/15 mm) and prevent foil detachment during transportation.
Single-dose aluminum-plastic composite bags: Suitable for high-end preparations or scenarios requiring precise dosage control. Small-sized bags (capacity: 1–2 tablets/capsules) are made of three-layer "PET/AL/PE" composite film. Each bag is independently vacuum-sealed with a micro desiccant (e.g., fiber desiccant, dosage: ~0.1 g per bag), enabling "complete moisture isolation before administration," especially suitable for use in humid areas. Note that 100% tightness testing (e.g., negative pressure leak detection) is required for the seals of single-dose packaging to avoid moisture absorption due to sealing defects.
3. Auxiliary Packaging Materials: Desiccants and Humidity Indicator Cards
Regardless of the packaging type, auxiliary moisture-proof materials should be used to enhance hygroscopicity control:
Desiccant selection: Desiccants that do not interact with ferrous gluconate are preferred to avoid introducing impurities. Montmorillonite desiccants (moisture absorption rate ≥ 20%) are suitable for API packaging, featuring low cost and good stability; fiber desiccants (moisture absorption rate ≥ 30%, water-soluble) are suitable for preparation packaging—even if a small amount is accidentally mixed (e.g., when capsules break), they cause no harm to the human body, avoiding the risks of traditional silica gel desiccants (which may contain cobalt salt indicators with potential toxicity). Desiccants should be packaged in breathable materials (e.g., non-woven bags) to ensure moisture absorption efficiency, and the dosage should be calculated based on packaging volume (usually 1 g of desiccant per 100 mL of packaging volume).
Humidity indicator cards: A "45% RH/50% RH dual-point indicator card" is placed inside the packaging to visually monitor the humidity inside through color changes (e.g., from blue to pink). If the card indicates humidity > 45%, it suggests potential gaps in the packaging, requiring timely inspection to prevent quality degradation due to hidden moisture absorption.
III. Optimization and Management of Storage Conditions
Packaging materials need to be combined with suitable storage environments to minimize the impact of hygroscopicity. A system should be established from three aspects: "environmental parameter control," "storage operation specifications," and "quality monitoring":
1. Control of Core Storage Parameters
Humidity control: The humidity of the storage environment must be strictly lower than the CRH of ferrous gluconate, recommended to be 30%–40%. A "dehumidifier + humidity sensor" linkage system is adopted: The dehumidifier is a rotary type (dehumidification capacity ≥ 1 kg/h, suitable for storage rooms below 100 m²), and the humidity sensor has an accuracy of ≤ ±2% RH. An alarm threshold is set (audible and visual alarm triggered when humidity > 45%) to ensure stable humidity. For small-scale storage (e.g., laboratory samples), a constant temperature and humidity chamber can be used to directly control humidity at 35% ± 5%.
Temperature control: Temperature is controlled at 15–25°C, avoiding excessive temperature fluctuations (diurnal temperature difference ≤ 5°C). High-temperature and high-humidity environments synergistically exacerbate moisture absorption and oxidation, so products should not be stored near heat sources (e.g., heaters, air conditioning vents) or water sources (e.g., sinks, humidifiers). Real-time temperature monitoring is performed using temperature sensors, with an alarm triggered when temperature > 28°C.
Light-proof storage: Ultraviolet rays accelerate the oxidation of Fe²⁺ (photocatalytic oxidation), thereby indirectly intensifying hygroscopicity. Therefore, the storage environment should be light-proof (e.g., using light-shielding curtains, brown glass storage cabinets), and packaging materials should also have certain light-shielding properties (e.g., aluminum-plastic composite films, brown glass bottles) to prevent direct exposure of products to natural light or fluorescent lamps.
2. Storage Operation Specifications
Avoid packaging damage: Handle with care during transportation to prevent impact or compression of packaging (especially aluminum-plastic blister packaging, to avoid blister rupture). Use the product as soon as possible after opening the packaging (API packaging should be resealed within 24 hours after opening; preparation packaging should be used within the period specified in the instructions) to avoid prolonged exposure to air.
Partitioned storage: Store ferrous gluconate separately from materials that easily release moisture (e.g., glycerin, syrups), with a spacing of ≥ 1 m to prevent cross-moisture absorption. At the same time, avoid storing it in the same warehouse as strong oxidants (e.g., potassium permanganate, potassium chlorate) to prevent Fe²⁺ oxidation.
First-in, first-out (FIFO): Establish a FIFO storage management system, arranging products in the order of production batches to avoid long-term storage (API storage period ≤ 12 months; preparations follow the validity period in the instructions), reducing the cumulative effects of moisture absorption and oxidation.
3. Quality Monitoring During Storage
Regular quality sampling inspections of stored products are conducted to evaluate the impact of hygroscopicity:
Appearance inspection: Weekly sampling to observe product color (whether it changes from light green to yellowish-brown) and state (whether caking or adhesion occurs). If color darkening or slight caking is observed, further testing of humidity and content is required.
Moisture gain determination: Monthly random sampling of 3–5 packages to determine moisture gain in accordance with the "Guideline for Drug Hygroscopicity Test" in the Chinese Pharmacopoeia. If the moisture gain > 0.5%, investigate the storage environment humidity and packaging tightness.
Content and impurity testing: Every 3 months, sample and test the Fe²⁺ content (using potentiometric titration) and Fe³⁺ impurity content (using atomic absorption spectrophotometry). If the Fe²⁺ content decreases by > 5% or the Fe³⁺ content > 0.1%, immediately adjust storage conditions (e.g., enhance dehumidification, replace packaging) and evaluate whether the product still meets quality standards.
IV. Validation of Packaging and Storage Solutions
To ensure the effectiveness of the optimized solution, validation through "accelerated testing" and "long-term testing" is required to simulate the hygroscopicity control effect under extreme and actual storage conditions:
Accelerated testing: Place the product in a constant temperature and humidity chamber at 40°C and 75% RH for 6 months. Test the appearance, moisture gain, Fe²⁺ content, and Fe³⁺ impurities monthly. If after 6 months, the product shows no obvious caking, moisture gain ≤ 1.0%, Fe²⁺ content decrease ≤ 3%, and Fe³⁺ content ≤ 0.08%, the packaging and storage solution is deemed capable of coping with short-term extreme humid environments.
Long-term testing: Place the product in an environment at 25°C and 40% RH (simulating regular storage conditions) for 12 months, testing the above indicators every 3 months. If after 12 months, all product indicators still meet quality standards (moisture gain ≤ 0.5%, Fe²⁺ content decrease ≤ 2%), the solution is proven to have long-term stability and can be used in actual production and storage.
