In most developing countries, the prevalence of malnutrition and micronutrient deficiencies is high among infants and young children aged 6 to 23 months. As they grow older, the energy and nutrient contribution from complementary food becomes increasingly important for meeting daily requirements. If daily food is not meeting the whole requirements then supplements should be taken to avoid deficiencies, which may cause diseases.
Iron is one of the essential metals required by the body. We normally get iron from nutritious foods. Folic acid supplementation is additionally required to reduce the risk of neural tube defects. Furthermore, emerging evidence suggests that folic acid-containing supplements are associated with reducing the risk of malformations and certain paediatric cancers. Ferrous fumarate and folic acid (combination) tablets are used to treat anaemia that is caused by an iron deficiency.
Ferrous fumarate has an iron content of 32.87% and is poorly soluble in water, soluble in dilute acid (such as gastric acid) and is well absorbed as ferrous sulphate. In infants, iron absorption from ferrous fumarate is significantly higher than iron absorbed from ferric pyrophosphate.
Ferrous fumarate tablets have been manufactured alone or in combination with folic acid, usually ferrous fumarate 150–200 mg and folic acid 0.1–0.5 mg. The manufacturing methods used for tablet formulation (wet-granulation methods) are time consuming and multistep processes. However, the direct-compression method allows tablets to be compressed directly from mixtures of the drug and excipient without any preliminary treatment.
A simple formula is composed of an active ingredient, diluent, binding agent and a lubricant. The direct-compression method has advantages over other manufacturing processes for tablets and provides high efficiency. Direct compression is simple and more economical by reducing the total time and manufacturing requirements. In contrast, wet granulation not only increases the cycle time but also has certain limits imposed by thermolability and moisture sensitivity of the active pharmaceutical ingredients.
Therefore, the pharmaceutical industry is now focusing more on the direct-compression process. The unnecessary exposure of any drug to moisture and heat has to be avoided at all times. Tablets produced by the direct-compression method give lower microbial levels than those prepared by the wet-granulation method.
Microcrystalline cellulose (avicel) is widely used in pharmaceuticals primarily as a binder/diluent in oral tablet and capsule formulations in both wet-granulation and direct-compression processes. In addition to its use as a binder/diluent, microcrystalline cellulose also has some lubricant and disintegrant properties that make it useful in tablet processing. Avicel is self-lubricating and adds strength to tablets. For best results in pharmaceutical formulations, it should be used at a concentration of 5-20%.
Ferrous fumarate is a poorly flowable active pharmaceutical agent and causes friction with the punches and dies in the compression machine. The use of lubricating agent(s) is the way to overcome the friction problems with the compression machine. Talcum and magnesium stearate were selected as lubricating agents. Talcum is used as a lubricant and glidant at concentrations of 1-10%. Magnesium stearate is another very important lubricant, glidant and anti-adherent. However, Magnesium stearate is hygroscopic and may retard the dissolution characteristics of the product. It can also increase tablet friability, therefore, magnesium stearate should be used in the lowest concentration possible (0.25–2%). The blending time with magnesium stearate should also be carefully controlled.
In the pharmaceutical industry, hardness of the tablets is an important parameter because pharmaceutical tablets must have sufficient ability to survive the handling forces during packaging and shipping. However, if the hardness exceeds a certain limit, it increases the disintegration time, which ultimately affects the bioavailability. Friability is another important parameter that is related to hardness. The allowed limit of friability is not more than 1% of weight loss.
Complete disintegration is the state in which any residue of the tablet, except fragments of insoluble coating remaining on the screen, is a soft mass having no palpable firm core. Sodium lauryl sulphate is a good disintegrating agent in the manufacturing of ferrous fumarate and folic acid (Combination) tablets.
Several formulations have been developed, including DC granules (Direct compression granules) of ferrous fumarate for the direct-compression method. DC granules have good compressibility characteristics because they are mixtures of ferrous fumarate with pre-gelatinised starch, gelatin and PVP or carboxymethyl cellulose; however, they are not pure ferrous fumarate according to official monographs. Moreover, mixing problems with folic acid may arise due to the difference in particle size.
An optimised formulation using a direct-compression method was found to be the best for use by the pharmaceutical industry because this method is time saving, cost effective and increases production capacity.