As a pharmaceutical product formulator, you may have wondered what Disodium Edetate (also known as Sodium EDTA) is and how you can use it in your products. Given its ubiquity in pharmaceutical and other processing industries, these are not trivial questions, so kudos for wanting to familiarize yourself with its applications and limitations.

In simple terms, it is ethylenediaminetetraacetate as the disodium salt. It occurs as a white crystalline, odorless powder with a slightly acidic taste. According to the European Pharmacopoeia the pharmaceutical-grade material is required to contain NLT 99.0% and NMT 101.0% of C₁₀H₁₄N₂Na₂O₈, calculated on a dried basis.

Chemical and physical particulars

Chemical Name: Ethylenediaminetetracetic acid, disodium salt

CAS Registry Number: [139-33-3]

Molecular weight: 336.2

Chemical formula and structure: [CH₂N(CH₂CO₂H]₂]₂ Na₂

Acidity/alkalinity: pH 4.3 – 4.7 (1% w/v solution)

Solubility: Soluble in water (1 in 11 parts)

Current Regulatory Status

Currently listed in the Ph.Eur, USP-NF, BP and JP. It is also GRAS listed and included in the FDA Inactive Ingredients Database (Inhalations, Injections, Ophthalmic preparations, Oral capsules, Solutions, Suspensions, Syrups and Tablets, Rectal, Topical and Vaginal preparations).

Dsodium edetate is poorly absorbed from the gastrointestinal tract and associated with few adverse effects when used as an excipient. In larger doses, however, disodium edetate (and other edetates) cause calcium depletion (hypocalcemia), especially when used over an extended period of time.

However, this material should he used with caution in patients with renal impairment, tuberculosis, and impaired cardiac function. The WHO has set an estimated acceptable daily intake in foodstuffs of up to 2.5 mg/kg body-weight.

Uses in Pharmaceutical Formulations

Disodium edetate is used in topical, oral, ophthalmic and parenteral pharmaceutical formulations as well as in cosmetic and food products as a chelating and sequestering agent of heavy metal cations. The typical concentrations are between 0.005 and 0.1% w/v.

Chelation and sequestration of metal cations helps to stabilise, clarify and protect a formulation in many different ways. For instance, Edetate enhances the action of preservatives and stabilizes antioxidants; stabilises and protects polymeric thickeners, colorants, flavours and fragrances; and prolongs action of antioxidants such Tocopherol and ascorbate, for instance, in fats and oils.

Therefore, add edetate disodium (or other suitable edentates) to products that have a flavour, fragrance, colorant, polymeric thickener e.g carbomer, hyaluronic acid and hydrocolloid gums, preservatives, antioxidants, antibiotics, local anaesthetics and certain vaccines.

Disodium edetate is also used therapeutically as an anticoagulant due to its ability to chelate calcium and prevent the coagulation of blood in vitro.

Useful Tips and Comments

Edetate salts are more stable than EDTA. However, disodium edetate dihydrate loses water of crystallization when heated to 120^o C.

Disodium edetate is hygroscopic and is unstable when exposed to moisture. The stability of the metal—edetate complex is dependent on the metal ion involved and the pH.

Disodium edetate is incompatible with strong oxidizing agents, strong bases and metal ions.

Manufacturers/Suppliers

Merck (Titriplex® II – EMPROVE® EXPERT PhEur, BP, USP, JP)

For a full description of this material, navigate to Disodium Edatate Monograph page.

References

[1] R.K. Evans, D.K. Nawrocki, L.A. Isopi, D.M. Williams, D.R. Casimiro, S. Chin, M. Chen, D.M. Zhu, J.W. Shiver, D.B. Volkin, Development of stable liquid formulations for adenovirus-based vaccines, J Pharm Sci, 93 (2004) 2458-2475.

[2] R.S. Lanigan, T.A. Yamarik, Final report on the safety assessment of EDTA, calcium disodium EDTA, diammonium EDTA, dipotassium EDTA, disodium EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium EDTA, HEDTA, and trisodium HEDTA, International journal of toxicology, 21 Suppl 2 (2002) 95-142.

[3] J. Wahr, J. Vender, H.C. Gilbert, B. Spiess, J.C. Horrow, R. Maddi, Effect of propofol with and without EDTA on haemodynamics and calcium and magnesium homeostasis during and after cardiac surgery, Intensive care medicine, 26 Suppl 4 (2000) S443-451.

Propylene glycol alginate is a propylene glycol ester of alginic acid. Alginic acid is a naturally-occurring anionic polysaccharide obtained from algae. It is composed of a mixture of mannuronic acid and guloronic acid residues.

Propylene glycol alginate is a whitish fibrous powder, that is practically odourless and tasteless. It exhibits both cold and hot water solubility. It is available in different grades, corresponding to difference in viscosity: standard grades and high esterification grades.

The general chemical structure of Propylene glycol alginate is shown below:

Generalised Chemical Structure of Propylene glycol alginate

Current Regulatory Status

Propylene glycol alginate is listed in the USP-NF and approved for use in food in Europe (E405). A specification for propylene glycol alginate is contained in the Food Chemicals Codex (FCC) and the Japanese Pharmaceutical Excipients (JPE).

Propylene glycol alginate is included in the FDA Inactive Ingredients Database (oral preparations) and generally regarded as safe, nontoxic and non-irritant material, although excessive oral consumption may be harmful.

Applications in Pharmaceutical Formulations

Propylene glycol alginate is supplied in two types: standard and high esterification. Within each type are several grades having viscosities ranging from 50 to 600 mPa s.

The principal use of propylene glycol alginate is as a viscosity-increasing agent and thickener in topical and oral emulsions and suspensions. Higher viscosity grades are ideal for this application and are selected for the same reasons as sodium alginate but unlike sodium alginate propylene glycol alginate remains soluble at low pH and does not gel in the presence of polyvalent cations (e.g calcium).

Propylene glycol alginate exhibits surface active effects, enabling it to additionally function as an emulsion stabiliser, which distinguishes it from sodium alginate.

Propylene glycol alginate is also used as a binder and disintegrant in oral granules and tablets and can help enhance the rate of dissolution.

Owing to its mucoadhesive properties, propylene glycol alginate can be used to formulate lozenges, buccal, sublingual, nasal, ocular and other dosage forms that require extended residence times on mucosal surfaces.

Typical Uses of Propylene glycol alginate:

Useful Tips and Comments

Propylene glycol alginate solutions are most stable at pH 3 – 6. In alkaline solutions, propylene glycol alginate is rapidly saponified. Please note that alginate solutions are susceptible to microbial spoilage and should be preserved with an antimicrobial preservative. Sterilization processes (e.g autoclaving) can adversely affect the viscosity of propylene glycol alginate solutions.

Manufacturers/Suppliers

KIMICA

References

[1] W. Schmid, K.M. Picker-Freyer, Tableting and tablet properties of alginates: Characterisation and potential for Soft Tableting, European Journal of Pharmaceutics and Biopharmaceutics, 72 (2009) 165-172.

[2] Z. Shariatinia, Chapter 2 – Pharmaceutical applications of natural polysaccharides, in: M.S. Hasnain, A.K. Nayak (Eds.) Natural Polysaccharides in Drug Delivery and Biomedical Applications, Academic Press2019, pp. 15-57.

[3] J.N. BeMiller, 9 – Hydrocolloids, in: E.K. Arendt, F. Dal Bello (Eds.) Gluten-Free Cereal Products and Beverages, Academic Press, San Diego, 2008, pp. 203-215.

What is a Poloxamer?

Poloxamers are also known as polyethylene- propylene glycol copolymer or polyoxvethylene-polyoxypropylene copolymer. They are a series of block copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO).

All poloxamers are chemically similar in composition, differing only in the relative amounts of propylene and ethylene oxides added during manufacture. The presence of PEO and PPO blocks in a single polymer chain imparts to the molecule amphiphilic properties whose self-assembling properties display a wide range of phase behaviour.

Several different types of poloxamers are commercially available whose physical and surface-active properties vary over a wide range. Pharmacopoeial grades generally occur as white, waxy, granules or as solids. They are practically odourless and tasteless.

Poloxamers are listed in pharmacopoeia and generally regarded as nontoxic and non-irritant. Included in the FDA Inactive Ingredients Database (IV injections; inhalations, ophthalmic preparations; oral powders. solutions, suspensions, and syrups; topical preparations).

The general chemical structure of Poloxamers is shown below:

Generalised Chemical Structure of Poloxamer

Key Physicochemical Properties of Poloxamers

How are Poloxamers Used in Formulations?

The main uses of poloxamers is as dispersing agents, emulsifying agents, solubilizing agents, tablet lubricants, wetting agents and foaming agents.

As nonionic polyoxyethylene-polyoxypropylene copolymers, poloxamers are used as emulsifying or solubilizing agents. They are used as emulsifying agents in intravenous fat emulsions and as solubilizing and stabilizing agents to maintain clarity of elixirs and syrups.

Poloxamers can also be used as wetting agents; in ointments, suppository bases, and gels; and in tablet binders and coatings. Poloxamer 188 has also been used as an emulsifying agent for fluorocarbons used as artificial blood substitutes, and in the preparation of solid-dispersion systems. More recently, poloxamers have found use in drug-delivery systems.

Therapeutically, poloxamer 188 is administered orally as a wetting agent and stool lubricant in the treatment of constipation; it is usually used in combination with a laxative such as dantron. Poloxamers may also be used therapeutically as wetting agents in eye-drop formulations, in the treatment of kidney stones, and as skin-wound cleansers.

Any Useful Tips?

Naming of poloxamers can be bewildering but typically, the nonproprietary name – poloxamer – is followed by a number: the first two digits of which, when multiplied by 100, correspond to the approximate average molecular weight of the polyoxypropylene portion of the copolymer and the third digit, when multiplied by 100, corresponds to the percentage by weight of the polyoxyethylene portion.

Similarly, with many of the trade names used for poloxamers e.g. Kolliphor 188, the first digit arbitrarily represents the molecular weight of the polyoxypropylene portion and the second digit represents the weight percent of the oxyethylene portion. The letters L, ‘P’, and ‘F’, stand for the physical form of the poloxamer: liquid, paste, or flakes.

Although the USP-NF contains specifications for five poloxamer grades, many more different poloxamers are commercially available that vary in their molecular weight and the proportion of oxyethylene present in the polymer.

Some poloxamers (e.g Poloxamer 188) are incompatible with parabens.

Poloxamers are used in the cosmetics field as oil-in-water emulsifiers, cleansers for mild facial products, and dispersing agents.

References

[1] R.G. Strickley, Solubilizing Excipients in Oral and Injectable Formulations, Pharmaceutical Research, 21 (2004) 201-230.

[2] G. Dumortier, J.L. Grossiord, F. Agnely, J.C. Chaumeil, A Review of Poloxamer 407 Pharmaceutical and Pharmacological Characteristics, Pharmaceutical Research, 23 (2006) 2709-2728.

[3] A.M. Bodratti, P. Alexandridis, Formulation of Poloxamers for Drug Delivery, Journal of Functional Biomaterials, 9 (2018).

What is Gellan Gum?

Gellan gum is a water soluble anionic hydrocolloid produced by the microorganism Sphingomonas elodea. This microorganism was discovered in 1978 in the United States by scientists at Merck following a concerted effort to find naturally occurring hydrocolloids.

Gellan gum is supplied as a free-flowing white powder. For commercial grades, gellan gum is manufactured by fermentation of a carbohydrate. In its native state, Gellan gum has acyl groups in its structure. Treatment with alkali removes acyl groups completely

Physicochemical Properties of Gellan Gum

Chemical Structure

Gellan gum is a straight chain polymer consisting of D-glucose, L-rhamnose and D-glucuronic acid units. In its native or high acyl grade, acetate and glycerate substituents are present on one of the glucose residues. The low acyl grade there is no acyl substituents. Note that the presence of acyl groups has a strong bearing on gel properties of Gellan gum.

Differences between High Acyl and Low Acyl Gellan Gum

Where can you use Gellan gum?

Gellan gum is a useful and effective gelling agent in pharmaceutical and food products. It offers the following benefits:

• It is effective at low concentrations
• Provides a wide range of viscosities and textures
• Gels on cooling
• Forms fluid gels, which are solutions with a weak gel structure. These systems are extremely versatile for suspending drug substances without settling
• Can be used in combination with other hydrocolloids

Uses of Gellan gum in pharmaceutical products

Regulatory status

Approved for use in foods in Europe, USA, Japan, China and India. Gellan gum is also approved for use in non-food, cosmetics and pharmaceutical formulations in the USA, Canada, Australia, Brazil and China. Pharmaceutical use in EU falls under E418 (Directive EC/95/2). Gellan gum is manufactured in accordance with applicable food GMPs and complies with purity criteria defined in the current USP-NF monograph.

References

KELCOGEL® Gellan gum book, 5^th Edition, CP Kelco, San Diego, USA

Mahdi M H et al., 2014. Evaluation of Gellan gum fluid gels as modified reléase oral liquids. International Journal of Pharmaceutics, 475; 335 – 343.

Kubo W et al., 2003. Oral sustained delivery of paracetamol from in-situ gelling Gellan and sodium alginate formulations. International Journal of Pharmaceutics, 258 (1-2); 335 – 343; 55-64

What is AEROPERL® 300 Pharma Mesoporous Silica?

AEROPERL® 300 Pharma is a mesoporous silica obtained by granulating colloidal silicon dioxide. Mesoporous silicas are of great interest in the pharmaceutical industry due to their unique properties, such as ordered pore structures, very high internal surface areas and availability in a variety of shapes and morphologies (spheres, rods and powders).

Scanning electron micrograph of AEROPERL® 300 Pharma

Physicochemical Properties AEROPERL® 300 Pharma Mesoporous Silica

How is AEROPERL® 300 Pharma Mesoporous Silica used in Formulations?

Improving the Bioavailability of Poorly Water Soluble Drug Molecules

For poorly soluble active pharmaceutical ingredients (BCS II and IV) increasing the effective surface area in contact with the dissolution medium can enhance the rate of drug dissolution and improve bioavailability. This can be achieved by loading the drug substance in the form of small crystallites onto AEROPERL® 300 Pharma surface. Alternatively, the drug substance can be dissolved into a lipid carrier which is then adsorbed onto the mesoporous silica surface. Both these approaches result into a homogeneous and reproducible drug-loading and release.

Conversion of Liquid Lipid Formulations into Powders

Owing to its porous and highly adsorptive properties, AEROPERL® 300 Pharma can be used to change lipid formulations into powders. It is possible to use the material as a carrier and load it with up to 150% of its own weight with an oil without compromising its powder flow properties. This is undertaken via a simple blending process without the need for specialised equipment.

The high capillary forces draw the liquid into the pores. Moreover, this is a purely physical phenomenon, meaning that polarity of the lipid does not impact on adsorption – so provided the oil has reasonable viscosity, it will be adsorbed.

Inorganic Solid Dispersions via Solvent Evaporation Technique

AEROPERL® 300 Pharma has been investigated as an inorganic dispersion material for poorly soluble active pharmaceutical ingredients (API) in order to increase their dissolution rates. The API is first dispersed in a suitable solvent such as acetone, which is then added to AEROPERL® 300 Pharma. The acetone is then evaporated off resulting into adsorption of the API onto the surface of the mesoporous silica.

Enzyme Encapsulation into Mesoporous Silica for Biocatalysis

Owing to their pore size, pore structure and particle morphology mesoporous silica materials are of interest to many applications requiring enzymes to be immobilized or supported in situ. Immobilization of enzymes can result in enhanced stability, ease recovery and re-use, and allow the enzyme to be used in non-aqueous solvents where the enzyme is insoluble.

AEROPERL® 300 Pharma is ideally suited as a support material due to it mechanical and chemical stability as well as high surface area. It is also comparatively low cost and exhibits low non-specific protein adsorption properties. This means that adsorption of the enzyme is least likely to compromise the enzyme conformation or activity.

Moisture Activated Dry Granulation (MADG)

MADG is an approach to granulation carried out in a high shear granulator similar to conventional wet granulation except that the amount of water used is limited and there is no heat-based drying step. MADG starts with the addition of small quantities of water to a powder mix comprising the active ingredient(s), binder and other excipients, which is then blended under high shear to achieve agglomeration. The mesoporous silica, as the moisture absorbing excipient, is then added to the mixture to absorb excess moisture and to ‘dry’ the granules.

AEROPERL® 300 Pharma mesoporus silica offers an innovative approach to wet granulation processing. Studies have shown that AEROPERL® 300 Pharma serves as an efficient moisture absorber due to its high surface area and pore volume. The added moisture is bound effectively to create a stable, functional dry granular powder that can be readily processed via tabletting, capsule filling or dosing into sachets.

References

Ahern, R.J.; Hanrahan, J.P.; Tobin, J.M.: Ryan, K. B.; ,Crean, A.M.; European Journal of Pharmaceutical Sciences, 2013 50 400

Abdallah, N.H.; Schlumpberger, M.; Gaffney, D.A.; Hanrahan, J.P.; Tobin, J.M.; Magner, E.M.; J. Mol. Cat B: Enzymatic, 2014 108 82

What is Benzalkonium Chloride?

Benzalkonium chloride, also known as BKC, BAK or Alkyl dimethyl benzyl ammonium chloride, is a quaternary ammonium salt and a cationic surfactant with broad antimicrobial activity against bacterial, yeasts, fungi and viruses. It is a mixture of alkybenzydimethylammonium chloride, the alkly groups having lengths of 8 to 18. The general chemical structure of Benzalkonium chloride is shown below:

n = 8, 10, 12, 14, 16, 18

Physicochemical Properties of Benzalkonium Chloride

Physical form

How is Benzalkonium Chloride Used in Formulations?

Benzalkonium chloride is widely used in inhalations, IM injections, nasal, ophthalmic, and topical preparations as an antimicrobial preservative, antiseptic, disinfectant, solubilizing and wetting agent. It is used in similarly to other cationic surfactants, such as cetrimide.

In ophthalmic preparations, benzalkonium chloride is the preservative of choice and one of the most widely used preservatives, at concentrations of 0.01-0.02% w/v.

Antimicrobial activity can be enhanced, particularly against strains of Pseudomonas, benzalkonium chloride, through combination with other preservatives or excipients, such as 0.1% w/v Disodium edetate, phenylethanol or chlorhexidine.

In nasal formulations, benzalkonium chloride is used at a concentration of 0.002-0.02% w/v. Levels of 0.01% w/v have also been utilized in small-volume parenteral products.

Benzalkonium chloride can also be added to topical medical devices, antiseptic wipes and cosmetics as an alternative to parabens. It produces significantly less stinging or burning compared with isopropyl alcohol and hydrogen peroxide when used in topical products.

Any Comments and Useful Tips?

Benzalkonium chloride solutions are active against a wide range of bacteria, yeasts, and fungi. Activity is more marked against Gram-positive than Gram- negative bacteria but minimal against bacterial endospores and acid-fast bacteria. The antimicrobial activity of Benzalkonium Chloride is greatly dependent on the alkyl composition of the mixture.

Note that benzalkonium chloride has been associated with ototoxicity when applied to the ear. Prolonged contact with the skin may cause irritation and hypersensitivity. Benzalkonium Chloride is also known to cause bronchoconstriction in some asthmatics when used in nebulizer solutions.

Benzalkonium chloride is not suitable for use as a preservative in solutions used for storing and washing hydrophilic soft contact lenses, as the Benzalkonium Chloride can bind to the lenses and may later produce ocular toxicity when the lenses are worn.

Local irritation of the throat, oesophagus, stomach, and intestine can occur following contact with strong solutions (>0.1% w/v).

References

[1] F.G. Casablancas, Novo Nordisk Pharmatech A/S.

[2] H.S. Bean, Preservatives for pharmaceuticals, J. Soc. Cosmet. Chem, 23 (1972) 703-720.

[3] B.B. Tarbox., et al., Benzalkonium chloride. A potential disinfecting irrigation solution for orthopaedic wounds, Clinical orthopaedics and related research, (1998) 255-261.

[4] C. Boukarim, S. Abou Jaoude, R. Bahnam, R. Barada, S. Kyriacos, Preservatives in liquid pharmaceutical preparations, J Appl Res, 9 (2009) 14-17.