As a commonly used oral iron supplement, the core function of ferrous gluconate is to replenish divalent iron (Fe²⁺) in the human body for improving iron-deficiency anemia. Its bioavailability directly determines the efficiency with which iron is absorbed by the intestines and enters the bloodstream. As a key physical property of solid drugs, crystal form exerts a significant regulatory effect on the bioavailability of ferrous gluconate by influencing solubility, dissolution rate, stability, and intestinal mucosal permeability. The specific mechanisms and patterns of this influence are analyzed as follows:
I. Impact of Crystal Form on the Solubility and Dissolution Rate of Ferrous Gluconate
The prerequisite for the absorption of oral iron supplements is that the drug dissolves in gastrointestinal digestive juices and is released in ionic form (Fe²⁺), and crystal form is the core factor determining the efficiency of this process. Ferrous gluconate exists in an amorphous form and multiple crystal forms (e.g., α-form, β-form). Differences in the crystal structure (such as molecular packing mode, lattice energy, and hydrogen bond strength) between different crystal forms directly lead to variations in their solubility and dissolution rate.
Amorphous ferrous gluconate lacks regular crystal arrangement, resulting in weak intermolecular forces and extremely low lattice energy. It can quickly disperse and dissolve in water or gastrointestinal environments, with a significantly higher concentration at dissolution equilibrium than crystalline products. Moreover, it does not need to overcome the energy barrier for crystal lattice destruction, so its dissolution rate can be several times that of crystalline products. This "rapid dissolution - high concentration gradient" characteristic enables the rapid establishment of an Fe²⁺ concentration difference at the intestinal absorption site (mainly the duodenum and upper jejunum), providing a sufficient source of ions for subsequent active transport absorption and thus laying the foundation for improved bioavailability.
In contrast, crystalline ferrous gluconate (especially the stable crystal form) has molecules packed in a dense and ordered manner, with strong intermolecular interactions such as hydrogen bonds and van der Waals forces, resulting in high lattice energy. During the dissolution process, energy must first be consumed to break the lattice structure, leading to a slow dissolution rate and a low saturated concentration after dissolution. The dissolution rate of some stable crystal forms in simulated gastric fluid (pH 1.2) or simulated intestinal fluid (pH 6.8) may be less than 80% (meeting pharmacopoeia standards but lower than that of the amorphous form). If the dissolution rate is lower than the drug emptying rate caused by intestinal peristalsis, undissolved solid particles will be excreted with intestinal contents, directly reducing the amount of Fe²⁺ absorbed and resulting in decreased bioavailability.
II. Impact of Crystal Form on the Stability of Ferrous Gluconate (Indirect Effect on Bioavailability)
Fe²⁺ in ferrous gluconate has strong reducibility and is easily oxidized to physiologically inactive ferric iron (Fe³⁺) by oxygen, gastric acid (or oxidizing components in food) in the gastrointestinal tract. Fe³⁺ is not only difficult for the human body to absorb but may also form insoluble precipitates with tannic acid and phytic acid in the intestines, further reducing iron utilization. Crystal form indirectly affects the oxidative stability of Fe²⁺ by changing the microscopic morphology and surface properties of ferrous gluconate, thereby influencing bioavailability.
On one hand, although amorphous ferrous gluconate has excellent solubility, its high surface energy and disordered molecular arrangement make Fe²⁺ more likely to come into contact with oxidizing substances when exposed to air or gastrointestinal environments, resulting in a higher oxidation rate than crystalline products. If stored improperly or retained in the gastrointestinal tract for a long time, part of Fe²⁺ will be oxidized to Fe³⁺ in advance, reducing the actual amount of absorbable active Fe²⁺ and potentially weakening the bioavailability advantage.
On the other hand, specific crystal forms (e.g., the β-form optimized through processes) have a dense crystal structure and smooth surface, which can reduce the contact area between Fe²⁺ and external oxidizing substances to a certain extent. At the same time, the ordered lattice structure can reduce the reactivity of molecules and delay the oxidation process of Fe²⁺. For example, in in vitro experiments simulating the gastrointestinal environment, the Fe²⁺ retention rate of β-form ferrous gluconate within 2 hours is 15%–20% higher than that of the amorphous form, meaning more Fe²⁺ can maintain an active state until reaching the absorption site, thus ensuring the stability of bioavailability. In addition, some crystal forms may form a "crystal encapsulation" structure to reduce the direct reaction between Fe²⁺ and gastric acid (avoiding decreased stability caused by excessive protonation), further reducing oxidative loss.
III. Potential Impact of Crystal Form on the Intestinal Mucosal Permeability of Ferrous Gluconate
The absorption of Fe²⁺ in the intestines mainly relies on the "divalent metal transporter 1 (DMT1)" on the surface of intestinal mucosal epithelial cells for active transport. The crystal form of ferrous gluconate may indirectly regulate its permeability by affecting the dispersibility and adsorption of the drug on the surface of the intestinal mucosa, thereby influencing bioavailability.
The Fe²⁺ ions or small-molecule aggregates formed after the dissolution of amorphous ferrous gluconate have higher surface activity and are more likely to bind to the mucus layer on the surface of intestinal mucosal epithelial cells, forming a local "high-concentration microenvironment." This increases the contact probability with DMT1 and improves transport efficiency. At the same time, the rapid dissolution characteristic of the amorphous form can prevent the agglomeration of drug particles in the intestines (crystalline products, if dissolved slowly, tend to form large aggregates due to interparticle attraction), reducing physical shielding of the intestinal mucosa and ensuring the normal transport of Fe²⁺ by DMT1.
However, if some crystalline forms of ferrous gluconate have large particle sizes or tend to form flocculent precipitates after dissolution, they may form a "physical barrier layer" on the surface of the intestinal mucosa. This not only reduces the contact efficiency between Fe²⁺ and DMT1 but may also affect the normal permeability of the intestinal mucosa. For example, some overly stable crystal forms dissolve slowly, and undissolved solid particles may adsorb on the mucosal surface, interfering with the normal absorption function of epithelial cells, reducing the transport rate of Fe²⁺, and ultimately manifesting as decreased bioavailability.
IV. Crystal Form Selection and Bioavailability Balance in Practical Applications
From the perspective of bioavailability optimization, the selection of the crystal form of ferrous gluconate requires balancing "solubility - stability - permeability":
Although the amorphous form has significant advantages in solubility and permeability, formulation technologies (e.g., microcapsule coating, addition of antioxidants) are needed to improve its oxidative stability and avoid premature loss of Fe²⁺.
Crystalline products (e.g., β-form) have better stability, but processes such as particle size control (micronization) and crystal form modification (reducing lattice energy) are required to improve the dissolution rate to match the needs of the intestinal absorption window.
For example, some oral ferrous gluconate preparations in clinical application currently adopt an "amorphous - crystalline composite system": the amorphous form ensures rapid dissolution and a high concentration gradient, while a small amount of stable crystalline form delays oxidation and maintains the effective Fe²⁺ concentration. Ultimately, the bioavailability is increased by 10%–30% compared with a single crystal form, while avoiding the problems of unstable storage of the amorphous form or insufficient dissolution of the crystalline form. This practice further proves that crystal form does not affect bioavailability in isolation but acts as a key variable regulating the iron-supplementing efficiency of ferrous gluconate through the synergistic effect of multiple links.
