Liquid Formulation Strategies

Solubility is a prerequisite for ensuring bioavailability and the desired therapeutic effect. With an estimated 70–90% of drugs currently in development being poorly water soluble, finding adequate solutions to overcome this challenge is increasingly important and urgent.

• The solubility and stability of small molecules can be addressed with a variety of techniques including formulation and API processing.
• API processing is performed in early phases of drug development and leverages strategies such as salt and cocrystal formation to improve API properties, including enhanced solubility.
• Among the most versatile excipients used in liquid formulations are cyclodextrins and surfactants.
  • Surfactants stabilize emulsions or suspensions and can also enhance solubility. New approaches are available such as self-emulsifying drug delivery systems.
  • Cyclodextrins can be used to improveboth API solubility and stability.
    
  • In addition to its application as a counter ion in salts, meglumine can be also used as functional excipient to enhance API solubility, improve API stability, and adjust pH value.

Parenteral preparations are high-risk formulations. Because of their route of administration, the potential of contaminations to cause harm is higher compared to other routes of administration such as oral or topical delivery. 

• Strict regulations apply and the final drug manufacturer must take precautionary measures to minimize risk throughout the production, select appropriate raw materials, and reduce bioburden levels.
• Excipients can be used to optimize processes, protect, support, and improve stability and bioavailability, modulate release of the API, and enhance effectiveness of the drug. For injectable applications, considerations how to minimize excipient risks are very important.

Formulating ophthalmic drugs presents unique challenges. Multiple factors must be appropriately balanced including tonicity, pH, and viscosity are necessary to ensure safety, tolerability, and efficacy of the medication. In parallel, low bioburden must be ensured throughout the shelf-life and usage period.

• Excipients play an important role in ophthalmic dosage forms, having a direct impact on critical process parameters and critical quality attributes. Polymers are particularly well-suited for ophthalmic dosage forms, offering several important benefits.
• Polyvinyl alcohol (PVA) offers many advantages for ophthalmic formulations. This excipient  can be used for different applications such as retention in the eye cavity and solubility, and is compatible with a range of other excipients.

Pharmaceutical formulations, especially liquid and semi-solid formulations, are susceptible to unwanted microbial contamination. If preventive measures are not taken, this will severely impact product shelf life and patent safety. Preservatives may be used to protect formulations from contamination as well as ensure the necessary shelf life. 

• Selecting the best preservative for a specific formulation requires consideration of many factors. 
• Benzalkonium chloride is frequently used as a preservative due to its wide anti-microbial and broad pH range activity. It is used in ophthalmic formulations as well as transmucosal, otic, topical, and inhalation indications. 
• Benzyl alcohol is a preservative used in injections, topical, oral and otic applications. It is also used as a stabilizer and because of its anesthetic properties it can be used to reduce pain on injection. 
• Methylparaben is commonly used as a preservative in combination with propyl-paraben or propyl 4-hydroxybenzoate. Paraben salts, such as methylparaben sodium salt, have better water solubility and as such, may be preferred in formulations. 
• Benzoic acid and sodium benzoates are used for low-risk pharmaceutical and food applications. Sodium benzoate has much higher water solubility and as a result, is used in a  large number of products including a high percentage of oral liquid preparations.

Manufacturing processes must be designed to bring new therapies to market faster and more cost effectively. A key to workflow efficiency is avoiding process interruptions, quality deviations and operator safety risks.

• Caking and clumping of chemicals, dust formation, and laborious weighing processes reduce efficiency. Solutions such as granulated raw materials, which are free-flowing and have reduced caking behavior, can improve processability, accelerate production, and increase operator safety. 
• Innovative packaging such as right-size weighing, single-use powder transfer bags, and specialty solutions for hygroscopic salts can simplify processes and streamline manufacturing. 

An unpleasant or bitter tasting oral liquid formulation will result in poor patient compliance, especially among pediatric patients. Enhancing the taste of these formulations requires consideration of many factors including sweetness potency, flavor, mouthfeel, and aftertaste, as well as ensuring safety and stability.

• Masking the bitterness of APIs and improving the sweetness profile of the formulation is a highly effective approach to increase acceptance of the final dosage form 

Folates are an essential B vitamin used to promote health and well-being. The stability of folate, including its synthetic form folic acid, however, is compromised by oxidation which presents a challenge for liquid formulations of the vitamin.

• Arcofolin^® is a proprietary L-5-methyltetrahydrofolate that has long-term stability in solution. It is directly bioavailable in its active form, more rapidly absorbed, and doesn’t mask a B12 deficiency.