over 70%
such is the estimated percentage of drug candidates in the development stage that are poorly soluble to this day. In fact, 40% of commercialized products are also considered poorly soluble. Many developments are unfortunately put to a stop because of the drug’s solubility hurdle. While there are ways to directly modify the API itself, acting on the formulation could also improve the drug’s solubility. More dissolved API means more API available in the bloodstream and therefore a more potent effect. The following graph depicts how the release profile of the API can be influenced by increasing its solubility:
Solubility: 1 < 2 < 3 < 4
Solid solutions and dispersions, Coprecipitates
The release of sparingly soluble drugs can be optimized and / or accelerated when they are embedded in a drug / polymer matrix.
Depending on the solubility of the drug substance, a solid solution can be achieved. Sparingly soluble, crystalline APIs are transformed into amorphous co-precipitates, which are a specific type of solid solution. The resulting supersaturated solutions lead then to enhanced bioavailability.
We are specialized and use this approach in spray granulation and one-step process, but also pellets.
Adsorbates
A fine-particulate API (micronized or nanomilled) is adsorbed on substances providing a large surface area. The combination of extremely fine drug particle size and availability from a large surface area allows to optimise drug release and bioavailability.
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Solubilisates
Drugs solubilised in emulsions, micelles or mixed micelles are transferred into a solid dosage form by adsorbing the solubilisate onto a powder or blend of powders providing a large surface area. Surfactants and co-solvents can help the drug dissolution in water-based environments.
• Surfactants: These molecules have two ends—one that likes water (hydrophilic) and one that likes oil (lipophilic). When added to a drug formulation, surfactants surround the drug particles and form tiny droplets (micelles or emulsions). This process reduces the surface tension between the drug and the surrounding liquid, making it easier for the drug to dissolve in water. As a result, more of the drug can be absorbed by the body, improving its bioavailability.
• Co-solvents: These are substances like ethanol or polyethylene glycol that mix with both water and oils. They help dissolve drugs that are poorly soluble in water by creating a more favorable environment for the drug to stay dissolved. By improving the solubility of the drug in the GI fluids, co-solvents ensure that more of the drug is available for absorption.
SMEDDS
(Self-Microemulsifying Drug Delivery Systems), SNEDDS (Self-Nanoemulsifying Drug Delivery Systems), and SEDDS (Self-Emulsifying Drug Delivery Systems) are examples of such advanced formulations.
• SMEDDS: Forms a microemulsion when mixed with digestive fluids, creating very small droplets that enhance drug absorption.
• SNEDDS: Similar to SMEDDS but creates even smaller, nano-sized droplets, further boosting solubility and bioavailability.
• SEDDS: Forms an emulsion (larger droplets than SMEDDS or SNEDDS) to improve the solubility and uptake of drugs.
Formulating SMEDDS, SNEDDS, and SEDDS involves a careful selection of oils, surfactants, and cosurfactants or solvents to create systems that can spontaneously form emulsions or nanoemulsions when they come into contact with aqueous environments like the gastrointestinal (GI) fluids.
pH adjustment
pH adjustment is a common strategy to enhance the solubility and bioavailability of drugs by altering the ionization state of the molecule by creating a micro-environment around it. Many drugs are either weak acids or weak bases, and their solubility can be influenced by the pH of the surrounding environment.
• Weak Acids: They are more soluble in a basic environment because they ionize at higher pH levels. By increasing the pH, weak acids dissolve better, enhancing their solubility and absorption in the GI tract.
• Weak Bases: These are more soluble in acidic conditions because they ionize at lower pH levels. By lowering the pH, weak bases can become more soluble and more readily absorbed.
By adjusting the pH of a formulation to a level where the drug ionizes and becomes more soluble, the drug’s bioavailability is improved, leading to better therapeutic outcomes.
To achieve a better solubility, at GPS, we work with several different techniques. Learn more about how we could help you by contacting us at pharmaceuticalservices@glatt.com