Joseph R. Hardimon Global Director of Research Jost Chemical Company
The use of mineral salts in food, nutritional and pharmaceutical formulations, while common practice, can present some difficulties in production of final dosage tablet and capsule applications.
Typically, tablets and capsules contain many ingredients (active and excipient) to deliver appropriate dosages of minerals. To meet homogeneity goals prior to tableting or capsule filling, ingredients must be appropriately blended—often requiring similar particle size distribution and Hausner ratio, to guarantee uniform blending and mineral/ active content. Logically, the more components in a blend will constitute a larger margin of error. While producing capsules is typically not as difficult as producing a tablet, formulators will primarily need to focus on mineral loading, product flowability and bulk density to appropriately fill and seal.
Formulators that manufacture tablets will want to minimize the use of excipients whenever possible to simplify formulations and to provide cleaner labels. This can often be achieved by choosing mineral salts with superior tableting characteristics. How well a mineral salt will perform in a formulation and tablet press can be pre-determined by evaluating compression using Carr indices and incorporating Hausner ratios to gauge product flow properties and preblending homogeneity goals. Powder bulk density, combined with mineral loading, is critical in selecting the proper compounds for your tablet.
Using multiple components to achieve dosages of a variety of minerals can be tricky because not all mineral salts possess the same physical properties. Some salts may have excellent compression profiles, while others do not. Powder flow characteristics can greatly differ as well. Often, tablet and capsule manufacturers need to add excipients to enhance homogeneity, flowability, compression profiles, and mineral loadings. This can lead to difficulty achieving appropriate active loading while minimizing tablet and capsule size.
Mitigation of taste, especially in chewable tablets, is often typically solved through incorporation of flavor-masking chemicals, sugars, and acidulants. Again, these may lead to blend homogeneity issues and will definitely contribute to larger tablet and capsule sizes.
To help minimize the use of multiple components in a blend to be delivered by tablet or capsules, three novel co-salts have been developed and brought to market. These novel co-salts effectively deliver minerals without the need for excessive excipients, flow-aids, or flavor masking, providing fewer complex formulations, easier-to-achieve homogeneity targets and cleaner labels.
These novel co-salts have been specifically developed to provide better compression, flowability, and taste profiles that are typically problematic in tablets and capsules as well as meeting the increasing awareness and demand for nutritional supplementation.
All three of these novel co-salts are mineral chelates, which can be readily verified for identity, purity, and potency. Chelated minerals are often a preferred choice by nutritionists because their complex structures better survive passage through the stomach to the small intestine.
It is common to find higher levels of vagrant heavy metals in mineral products because minerals are found in natural ore deposits. This can make sourcing mineral salts with low heavy metal levels extremely difficult. (Jost Chemical has a proprietary process to manufacture low heavy metal mineral salts that meet and typically exceed the heavy metal requirements of ICH Q3, California Prop 65, USP Elemental Impurities, and The European Regulation No. 629/2008 (amending 1881/2006)).
These salts should be fully reacted. The process for manufacturing fully reacted pure salts involves the reaction of an acid and a base in an aqueous solution and the precipitation of a salt compound, leaving no unreacted raw material in the finished products. The use of mineral salts containing unreacted compounds can lead to formulation stability problems, inaccurate ingredient declarations on the finished product label, post-blending issues, tablet issues, and Human consumption / Digestion / Absorption issues.
These novel co-salts have all received FDA NDI (New Dietary Ingredient) approval.
Calcium Magnesium Citrate Co-Salt
Calcium magnesium citrate contains calcium and magnesium in a 2:1 Ca:Mg molar ratio. Isolation and characterization by EDTA titration, FTIR, ICP/MS and XRD have indicated the co-salt has a chemical formula of Ca2Mg(C6H5O7)2 · 5H2O possessing a molecular weight of 572.7 g/mol as shown in Figure 1.
Calcium magnesium citrate product in powder form will prove beneficial to formulators that desire aqueous suspensions of Ca and Mg with excellent mouth feel and unmatched suspension stability. It has been reported that dry blends of calcium citrate and magnesium citrate micronized powders when combined and slurried in water (20 – 30% w/w) display extensive thickening, solidification and/or hardening. The two citrate salts react in the aqueous phase and precipitate a unique compound whose suspension is extremely thixotropic. This resulting mixture does not remain fluid and completely solidifies over time, providing difficult if not impossible dosing from the finished goods container. The solidification process is generally slow; however, experimental data demonstrates rapid acceleration of this reaction when heat (sterilization) is applied to the system.
Granular calcium magnesium citrate will be the most beneficial to formulators that require a directly compressible source for tablet manufacturing. Also noteworthy is the superior compression profile of the granular calcium magnesium citrate compared to a dry blend of calcium citrate and magnesium citrate as shown in Figure 2.
Nutritionally, calcium magnesium citrate co-salt closely matches the RDI (Recommended Dietary Intake) of calcium and magnesium in a single dose. The RDI for Ca is 1000mg/day while that of Mg is 400mg/day. Because of their respective molecular weights, this ratio of calcium to magnesium is very close to the correct RDI ratio. For example, a 7143mg dose of this product delivers 1000mg of calcium and 303mg of magnesium.
Magnesium Citrate Glycinate Co-Salt
A novel concept has been developed in di-valent metal citrate glycinate co-salts, including magnesium citrate glycinate (US 11,148,990 B2), which incorporates an equal molar ratio of citric acid and glycine, completely neutralized with the divalent metal (such as magnesium) in a metal to ligand ratio of 1:1. This new co-salt mitigates issues regarding poor compressibility and low magnesium loading. It also improves aqueous solubility and poor organoleptic properties associated with the use of divalent metal citrate and bis-glycinate salts, such as magnesium citrate and magnesium bis-glycinate salts, either independently or together. Bis-Glycinate salts taste rather unfavorably and often are used in conjunction with flavor masking agents to achieve a palatable end product. An internal taste-testing panel has confirmed that the taste profile of the di-magnesium citrate glycinate co-salt is far superior to the individual magnesium bis-glycinate.
Di-magnesium citrate glycinate co-salt has a molecular formula of Mg2C8H9NO9 – X H2O. Di-magnesium citrate glycinate co-salt has a molecular weight of 311.8 g/mol and magnesium content of 15.6% on the anhydrous basis shown in Figure 3. The cosalt typically is found to contain between 0.0 – 20.0% water, depending on extent of drying.
Use of divalent metal citrate and glycinate salts, such as magnesium citrate and magnesium bis-glycinates salt, either independently or blended, often yield attributes or performance that are less than desirable. Magnesium citrate, for example, tends to exhibit poor aqueous solubility and can be difficult to compress in tableting applications due to low compressibility. Magnesium bis-glycinate has decent aqueous solubility, however, magnesium bis-glycinate salt exhibits poor compressibility and has a very unpleasant taste profile, which can limit its use in foods, beverages, and other oral applications.
SEM imagery of Di-magnesium citrate glycinate co-salt (Figure 4) demonstrates the amorphous nature of this product. The amorphous nature lends to favorable tableting characteristics; unlike the polycrystalline crystallites found in magnesium bisglycinate or triclinic plates found in magnesium citrate tribasic.
The compressibility of di-magnesium citrate glycinate was evaluated using an instrumented Carver press. Approximately 1.6 g, 5 mm-thick tablets were compressed using the 0.4”x0.9” rectangular tooling. No excipients were used. The sides of the tooling were slightly dusted with magnesium stearate to facilitate tablet ejection and eliminate sticking. The tablets were subjected to a three-point bend stress using the TA.XT2-Plus texture analyzer. Flexural strength and young modulus of the compact were measured. In addition, compact density was calculated from the weight and size measurements of the tablets.
Individual salts, magnesium citrate tribasic and magnesium bisglycinate were tested alongside magnesium citrate glycinate co-salt. However, these materials were characterized by inadequate compressibility and no cohesive tablets were obtained under the current experimental conditions. Dimagnesium citrate glycinate co-salt is compressible in the range of compression pressures from approximately 50 MPa to approximately 150 MPa (Figure 5). The individual citrate and glycine salts failed to tablet as mentioned earlier.
Zinc Ascorbate Glycinate
Zinc ascorbate glycinate co-salt (US 11,524,971 B2) incorporates an equal molar ratio of ascorbic acid and glycine, completely neutralized with zinc in a metal to ligand ratio of 1:2. This new co-salt delivers zinc, ascorbic acid (vitamin C) and glycine in a single water-soluble dosage unit without the need for blending or combining multiple components, making it ideal for simplified formulations and labels. Zinc ascorbate glycinate co-salt, when prepared correctly, has a molecular formula of ZnC8H9NO8 – X H2O, has a molecular weight of 314.6 g/mol and zinc content of 20.8% on the anhydrous basis. The co-salt typically is found to contain between 0.0 – 20.0% water, depending on extent of drying.
Many studies show that zinc supplementation can lessen the severity of the common cold and is beneficial to the human immune system. Glycine is believed to be beneficial in reducing oxidative stress through production of glutathione in the body.
Further, glycine is used by the body to produce creatine, a substance shown to increase muscle size, strength, and power. Glycine has also been studied for its beneficial effects on bone health, brain function and neurological conditions like Parkinson’s and Alzheimer’s disease.
Glycine is a major constituent of collagen, which is known to promote skin health, relief of joint pain and prevention of bone loss. Other studies show that glycine may also benefit sleep quality and mental cognition. The benefits of ascorbic acid (vitamin C) are well known and documented.
SEM imagery of zinc ascorbate glycinate co-salt demonstrates the amorphous nature of this product as well. The amorphous nature of this product provides excellent tableting characteristics; unlike the rod crystallites found in zinc bisglycinate and polycrystalline crystallites found in zinc ascorbate (Figure 7).