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Overcoming Poor Solubility in Formulation Development 

Overcoming poor solubility is an increasingly common challenge in pharmaceutical and formulation development. While low-solubility (BCS Class II and IV) drugs represent ~20% of already-established drug products, they represent ~40% of drugs in recent clinical trials. Many other promising APIs (active pharmaceutical ingredients) are abandoned in the early phases of development due to their poor solubility.   

For oral drug products, poorly soluble compounds often exhibit limited bioavailability and therapeutic efficacy in conventional (non-functionalized) formulations due to their slow or incomplete dissolution in the aqueous fluid in the gastrointestinal tract. Specialized formulations are typically required, with the following representing common strategies employed for liquid and solid dose forms: 

Liquid Oral Dose Forms 

• Cosolvents: Adding a water-miscible organic solvent (cosolvent) to an aqueous liquid formulation can enhance drug solubility by altering the solvent polarity and breaking down drug aggregates. Hence, instead of delivering the API as an aqueous suspension with delayed solubilization, it can be delivered in an aqueous-organic solution, i.e. already dissolved.
• Inclusion Complexes: Several types of molecules can form inclusion complexes at the molecular level with the drug, enhancing their solubility and bioavailability. Cyclodextrins and specific polymers can form such complexes, which are most readily formed and stabilized in solution delivery systems (again avoiding the solubilization delay from dosing suspensions). 

Solid Oral Dose Forms 

• Super-disintegrants: In oral solid dosage forms, super-disintegrants can promote rapid disintegration and, thereby, the dissolution of the tablet or capsule, enhancing the rate of drug solubilization. However, while fast disintegration of such dose forms is essential, it should be noted that this approach is often insufficient to ensure rapid and complete solubilization of the lowest solubility drugs.
• Solid Dispersion: Formulating the poorly soluble drug within a solid carrier matrix can improve solubility. There are many different types, each enhancing the dissolution of the drug when the formulation meets aqueous fluid. Two examples of these include:
  1. Solid solutions: API dispersed at the molecular level, allowing faster solubilization rates.  
  2. Amorphous precipitation within the carrier – amorphous compounds lack a highly-ordered crystal lattice, allowing for faster dissolution. 

In some cases, the carrier also serves as a precipitation inhibitor with additional bioavailability benefits (see Precipitation Inhibitors below).  Hot-melt extrusion and spray drying are examples of manufacturing processes that form solid dispersions. 

Both Solid and Liquid Oral Dose Forms 

• Salt Formation: Converting the drug into a more water-soluble salt form can improve its dissolution rate. This technique involves reacting the drug with an appropriate acid or alkali to generate a salt with enhanced water solubility. This technique can be performed as the final step in preparing the API or by adding suitable excipients to the formulation, i.e. in-situ salt formation. 
• pH Adjustment: Modifying the pH of the formulation or the surrounding environment can influence drug ionization and solubility. This approach is beneficial for weakly acidic or basic drugs. While this is most readily applied in oral liquid formulations, it is possible to achieve in solid formulations by the inclusion of a powdered acidifier or alkalizer – when exposed to aqueous fluid in the body; the dissolving pH modifier creates a micro-environmental (i.e. localized) pH change capable of accelerating the dissolution of the API particles. 
• Particle Size Reduction: Decreasing the particle size of the API through techniques like milling, micronization, or nanosizing can significantly enhance its dissolution rate and solubility. Smaller particles have a larger surface-area-to-volume ratio, thereby accelerating solubilization in contact with the aqueous fluid in the body. 
• Lipid-Based Formulations: Lipid-based formulations such as self-emulsifying drug delivery systems (SEDDS) or lipid nanoparticles can enhance the solubility and absorption of lipophilic drugs. Depending on the resultant mixture’s melting point, these can be liquid or semi-solid delivery systems. 
• Surfactants: Surfactants can be applied to enhance solubility/solubilization rates in both:
  1. Liquid formulations by, e.g. stabilizing colloidal dispersions or micellization of the drug, which can then dissolve/stay dissolved in the body 
  2. Solid formulations reduce the interfacial tension between the drug and the solvent, improving wetting and dissolution in contact with bodily fluids.  
• Precipitation Inhibitors: These are usually aqueous polymers that stabilize supersaturated solutions of the API in the aqueous bodily fluids. Typically, these do not promote solubilization of the API by themselves. However, in conjunction with the approaches above (that drive the API into solution), these increase bioavailability by holding the API in solution long enough in the small intestine to allow absorption into the blood before the API precipitates. 

It’s important to note that the best choice of solubilization strategy depends on many factors, for example:  

• The specific characteristics of the drug molecule, e.g. melting point, pKa, logP, hygroscopicity and chemical stability 
• The required dose (mg of API)  
• The as-delivered particle size of the API 
• The intended route of administration 
• The intended patient population and their needs & preferences 
• Regulatory requirements 
• Cost and equipment-availability considerations for the manufacturing process 

Thorough pre-formulation studies and robust testing are essential to ensure the selected approach effectively improves drug solubility and (thereby) bioavailability. 

Contact our experts now to learn more about overcoming poor solubility in formulation development.