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Overview of drug solubilizer excipients, emulsifiers & lipid based vehicles, like vitamin E TPGS, used in topical & oral pharmaceutical formulations.

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Overview of drug solubilizer excipients, emulsifiers & lipid based vehicles, like vitamin E TPGS, used in topical & oral pharmaceutical formulations.

Q1. What are pharmaceutical solubilizing agents?

Solubilizer agents, such as surfactants, are solubilizer excipients added to pharmaceutical formulations in order to increase the solubility of poorly soluble drugs, thereby increasing the bioavailability of the corresponding active pharmaceutical ingredient (API). Solubility is defined as the extent to which a given solute can dissolve in a pharmaceutical solvent, to form a saturated, homogeneous solution at a fixed temperature. 

The solubility of poorly water-soluble drugs is way below the desired threshold, which lowers their absorption in the gastrointestinal tract. Furthermore, poorly water soluble drugs have reduced drug efficiencies as compared to pharmaceutical formulations with appropriate solubility profiles and may cause undesirable side effects upon administration. 

Drug formulators are trying to better understand the mechanism of action of poorly soluble drugs, both before and after the active pharmaceutical ingredient (API) is released from the dosage form to cope with these issues. However, studying the transformation of such formulations in a complex gastrointestinal environment is riddled with challenges. 

The method to increase the solubility of poorly water soluble drugs in pharmaceutical solvents is known as solubilization. Solubilization is the process that enables solubility enhancement of poorly soluble drugs by preparing isotropic, thermodynamically stable solutions via the addition of solubilizer excipients (also called solubilizing agents) to solutions. Solubilization progresses in the following step:

Step 1: Breaking interionic or intermolecular bonds of solutes.

Step 2: Separation of pharmaceutical solvents into freed up spaces to accommodate solutes. 

Step 3: Interactions between pharmaceutical solvents and solutes (ions or molecules).

 

Methods of solubility enhancement employed in the pharmaceutical industry include: 

- Addition of co-solvents

- pH/temperature modifications 

- Particle size reduction

- Addition of surfactants 

- Complexation 

- Solid dispersion techniques 

- Solid state manipulations

- Pharmaceutical solvent deposition

- And various other processes.

 

Commonly used solubilizer agents for oral dosage forms and paediatric pharmaceutical formulations are listed below: 

- Alcohols such as ethanol

- Sugars such as sorbitol

- Polyethylene glycols such as PEG-400

- Propylene glycol

- Cyclodextrins 

- Sodium Lauryl Sulphates

- And copious other solubilizer agents.

Q2. What is the role of solubilizers in pharmaceutical drug delivery?

Oral ingestion is the most convenient route of drug delivery and oral dosage forms are the most commonly employed pharmaceutical formulations due to ease of administration, high patient compliance, flexibility in the design of dosage forms, and cost effectiveness. However, the major challenge with the design of oral dosage forms lies within their poor bioavailability

Oral bioavailability depends on several factors including aqueous solubility, drug permeability, dissolution rate, presystemic metabolism, and susceptibility to efflux mechanisms. The low solubility and dissolution rate of poorly water soluble drugs in aqueous gastrointestinal fluids often result in insufficient bioavailability of the corresponding APIs.

An insufficient solubility profile is one of the key factors responsible for reduced API (active pharmaceutical ingredient) bioavailability. Solubilizers or solubilizing agents enhance the bioavailability of oral dosage forms by increasing the solubility of poorly soluble drugs. These surface-active properties of solubilizing agents triggered the interest of drug formulation developers before it ultimately became a fixture in the toolbox of pharmaceutical drug delivery innovators.

Some commonly used solubilizer agents for pharmaceutical dosage forms are ethanol, sorbitol, polyethylene glycols, cyclodextrins, sodium lauryl sulphates, polysorbates , propylene glycol, etc. Furthermore, solubilizer excipients and co-solvents play a major role for the bioavailability enhancement of other dosage forms like parenteral formulations

Solubilizing agents may also act as emulsifiers or emulsifying agents in the formulation of emulsion and self emulsifying drug delivery systems (SEEDS). Emulsifiers are used in pharmaceutical formulations to get stable emulsions to achieve the physico-chemical characteristics required for optimal delivery of API and absorption enhancement. Solubilizers such as polysorbates are used to solubilize oils in water and can be used in various topical formulations such as sprays, emulsion, creams, lotions, etc. 

Q3. How are solubilizing agents classified?

Solubilizer excipients or solubilizing agents used in oral formulations are classified into the following types, explored below. 

1. Water Soluble Organic Lipids

- E.g. Propylene glycol, glycerin, ethanol, etc. 

Lipid-based drug delivery systems (LBDDS) are one of the emerging technologies designed to address challenges like the solubility and bioavailability of poorly soluble drugs. Lipids act as vehicles for drug delivery and are combined with one or more surfactants and hydrophilic co-solvents to achieve solubility enhancement

2. Non-ionic Surfactants 

- E.g. Sorbitan monooleate, vitamin E TPGS (tocophersolan), etc.

Non-ionic surfactants are very useful as absorption enhancers as they improve the dissolution rate and permeability of drugs. Surfactants reduce surface tension and form colloidal aggregates called micelles; solubility increases as concentration of micelles (CMC) increases. 

3. Water-insoluble Lipids

- E.g. Olive oil, peppermint oil, castor oil, etc.

Water insoluble lipids are insoluble in polar pharmaceutical solvents like water but highly soluble in the non-polar or weakly polar organic solvents, including ether, chloroform, benzene, and acetone. Water insoluble lipids, thus increase absorption and achieve solubility enhancement in non-polar pharmaceutical solvents also known as fat solvents. 

4. Organic Liquids/Semi-solids

- E.g. Beeswax, d-alpha-tocopherol, etc.

Organic liquids and semi-solids are solubilizing agents or vehicles used to enhance the solubility of solids in the gastrointestinal tract. These lipid based drug delivery vehicles are employed in solid dispersion and solid state manipulation techniques of solubility enhancement

5. Cyclodextrins

- E.g. alpha-cyclodextrin, beta-cyclodextrin, etc. 

Cyclodextrins are used as solubilizing agents or complexing agents to increase the solubility, and consequently the stability, of poorly soluble drugs in aqueous solutions. They further reduce side effects and irritation in gastrointestinal systems, achieve odor and taste-masking, prevent drug drug or drug additive interactions, etc. 

6. Phospholipids 

- E.g. Hydrogenated soy phosphatidylcholine, l-alpha-dimyristoyl phosphatidylglycerol, etc. 

Phospholipids are solubilizer agents/vehicles that are used in complexation techniques of solubilization. Drug-phospholipid complexes are considered ideal for oral delivery as they are biodegradable and non-toxic, which enable them to be employed as solubilizer excipients, emulsifying agents, and as matrix forming pharmaceutical excipients that increase the permeability and solubility of poorly water soluble drugs

Q4. How do solubilizer excipients facilitate solubility enhancement and emulsion formulation?

Solubilization enhancement is used in pharmaceutical drug delivery to increase the solubility, defined as the maximum concentration of solute that can be dissolved in a given amount of solvent, of formulations. It is achieved by manipulating factors that affect solubilization such as temperature, pressure, and particle size or by using solubilizer excipients (solubilizer agents).

- Temperature: Generally an increase in temperature results in an increase in the solubility of oral formulations. However, the opposite can also be true in case of gaseous formulations

  • Endothermic Processes: Solubility increases as temperature increases.
  • Exothermic Processes: Solubility increases as temperature decreases (for gaseous pharmaceutical formulations)

- Pressure: While changes in pressure have minimal or no effect on the solubility of solids and liquids, an increase in the pressure of gaseous solutes can facilitate solubility enhancement

- Particle Size: Solubility increases as particle size decreases which leads to an increase in surface energy, however, there has to be a substantial reduction in size (<1 micrometer) for solubility enhancement to occur. Particle size reduction is usually achieved via micronization and nanoization technologies. 

 

Poorly water soluble drug formulations are a major issue for the pharmaceutical industry. For solubility enhancement, there are various solubilizer excipients such as surfactants, lipids, cyclodextrins, etc. which can increase the bioavailability of active pharmaceutical ingredients (APIs) by increasing their solubility. Advanced solubility enhancing pharmaceutical excipients can accelerate the time it takes to bring pharmaceutical formulations to market. In aqueous-based solutions, solubilizers are used to modify the polarity of water to allow an increase in the solubility of a nonpolar drug.

In addition to solubility enhancement, some solubilizer excipients (for e.g. vitamin E TPGS/Tocophersolan) may also function as emulsifiers by enabling the formation of emulsion formulations. Emulsifying agents are soluble in both oil and water as one end of the molecule is attracted to water (hydrophilic) and the other end is attracted to fats/oils (lipophilic). 

When a solubilizer is added to an oil and water product, one end of the molecule dissolves in water and the other dissolves in oil to form emulsion formulations, forcing these molecules to be near each other without separating, thereby acting as an emulsifier or an emulsifying agent . This push and pull of emulsifiers in oil and water keeps different substances suspended in a solution.

Surface active agents or emulsifying agents are added to emulsions to stabilize the dispersed and continuous phase by increasing the electrostatic repulsion or steric repulsion between them. Emulsifiers thus act on the interface and increase the kinetic stability of emulsions so that the size of the droplets do not change significantly with time.

Emulsion formulation is an essential process and is applied in the food industry to make butter, margarine, mayonnaise, etc. Many cosmetic and pharmaceutical dosage forms come in emulsion preparations, and chemical synthesis of glues, paints, and other polymer dispersions also utilizes emulsion formulation

Q5. What are the different types of pharmaceutical solubilizers available in the market?

Poorly soluble drugs are a major issue for the pharmaceutical industry. By using solubility enhancement excipients pharmaceutical formulators can increase the bioavailability of active pharmaceutical ingredients (API). Advanced solubility enhancement excipients can help companies bring products to market faster.

There are various pharmaceutical companies that offer solubilizer excipients, including, but not limited to:

- PMC Isochem
(E.g. Vitamin E TPGS)

PMC Isochem offers Vitamin E TPGS or Tocophersolan, a water soluble derivative of natural Vitamin E, which is a multirole pharmaceutical excipient that functions as a solubilizer, plasticizer, vehicle for lipid based pharmaceutical formulations, binder, and as an emulsifier. Tocophersolan (Vitamin E-TPGS) has been approved by the FDA as a safe adjuvant and subsequently has been widely used in drug delivery systems

- Gattefossé
(E.g. CapryolTM 90, Gelucire® 44/14, Labrasol® ALF, Labrasol®, etc.)

Gattefossé is a leading provider of lipid excipients and formulation solutions to healthcare industries worldwide. Their functional solubilizer excipients are designed to meet the most pressing formulation challenges in drug development; Poor solubility, permeability, and bioavailability, with lipid-based drug delivery systems consisting of single or multiple excipients.

- BASF North America
(E.g. Kolliphor EL, Kollidon VA 64, Soluplus, Kolliphor RH40, Kolliphor ELP, Kollisolv P 124, etc.)

Solubilization is an essential process that ideally results in crystal clear systems. The major challenge it poses is matching the lipophilic substance and the medium with the solubilizer. BASF’s comprehensive solubilizer portfolio allows customers to solubilize a wide range of lipophilic substances in different media, including water, alcohol and surfactant systems.

- ABITEC
(E.g. Captex 350 Glycerol Tricaprylate/Caprate/Laurate, Captex 200P, Caprol Polyglycerol Esters, etc.)

ABITEC develops and manufactures lipid-based excipients to enhance the bioavailability of poorly water-soluble and poorly permeable Active Pharmaceutical Ingredients (APIs) for the pharmaceutical industry.

- Roquette Pharma    
(E.g. CRYSMEB, Glucono-Delta-Lactone, KLEPTOSE® 10, CLEARGUM® CO A1, etc.)

For several decades, formulators have trusted Roquette to help them overcome the challenge of API insolubility. Roquette offers versatile solubility enhancers that adapt to the demands of a formulations’ characteristics. Engineered to deliver functional reliability, their solutions deliver repeatable dissolution profiles batch after batch. No matter the drug characteristics or process strategy, they provide a range of products suited to enhance API solubility in oral dosage forms.


- SPI pharma
(E.g. Advantose 100)

SPI Pharma produces Advantose 100 solubilizer excipients. Advantose® 100 is a spray-dried maltose powder that provides excellent flow, solubility, & tableting properties for oral dosage formulations. Maltose is well known for its safety & mouthfeel qualities, especially in chewable tablets & lozenges. It is often used to achieve taste masking for tablets with undesirable taste profiles. 

 

Applications:

Vitamin E TPGS (Tocophersolan) is used as a solubilizer, emulsifying agent, plasticizer, stabilizer, and vehicle for lipid-based formulations.

Ingredient(s): Tocophersolan

Dosage Form: Capsule, Cream / Lotion / Ointment, Injectable / Parenteral, Ophthalmic Solution, Nasal Solution, Tablet

Category: Solubilizers

Route of Administration (Grade): Oral, Parenteral, Nasal, Ophthalmic, Topical
Pharmacopoeia Reference: USP 40 – NF 35

Technical Specifications: Specific Gravity: 1.06 at 50°C to 1.03 at 90°C; Solubility In Water: -20% at 20°C; Viscosity: 390cP at 50°C; Available in mol. wt. of 1500 g/mol, 200 g/mol, 2000 g/mol, 300 g/mol, 400 g/mol, 4000 g/mol.