Poor solubility remains a major challenge in formulation development. As the number of new chemical entities that are poorly
soluble keeps increasing, formulation scientists are faced with the important task of addressing these solubility issues so
that more compounds can be translated into clinically useful medicines. A popular approach to this problem is to use polymers
as solubilizing excipients. Pharmaceutical Technology brought together a panel of industry experts for a special forum to discuss solubilizing polymers and the related formulation
strategies for poorly soluble drugs. Participants include Michael Morgen, PhD, director of new technology at Bend Research;
Brian Koblinski, strategic marketing manager at Dow Wolff Cellulosics; and Firouz Asgarzadeh, PhD, director of technical services,
North America, pharma polymers & services at Evonik Corporation.
Chemical classes and physicochemical properties
PharmTech: Various polymers/copolymers can be used in solubility enhancement. What would you identify as key chemical classes for these
excipients and the related properties that contribute to their function as a solubilizer? In what formulation types are they
Morgen (Bend Research): Cellulosics, poly(vinylpyrrolidone) (PVP) and its copolymers, acrylates, and poly(ethylene oxide) (PEO) and its copolymers
are some of the key classes of polymers that have been investigated as solubilizing excipients for oral formulations. Effective
solubilizing polymers tend to be amphiphilic in nature, meaning they have both hydrophobic and hydrophilic sites that enable
them to interact favorably with low-solubility (i.e., hydrophobic) compounds and yet disperse and dissolve in aqueous environments
such as the gastrointestinal (GI) tract. The specific interactions of the polymer with itself, the API, and the aqueous medium
can result in a range of solubilizing structures, including micelles, colloids, and ionic complexes.
Solubilizing polymers are used in many types of formulations, depending on the route of administration, dose, API properties,
and specific delivery challenges associated with the particular development program. For oral delivery, solid amorphous dispersions
can be an enabling formulation approach for improving the bioavailability of Biopharmaceutics Classification System (BCS)
Class II and IV compounds. Two common processes for making such dispersions are spray-drying and hot-melt extrusion (HME).
Spray-drying can be used to form a monolithic dispersion particle or alternatively, the dispersion can be deposited onto a
solid support to increase surface area and dissolution rate. Two-phase physical mixtures of polymer and crystalline API in
a solid dosage form can be used to solubilize the API. For early scoping studies, liquid solutions of polymer (e.g., PEO)
and the API may be valuable. In each case, the choice of formulation type and the manufacturing process will depend on the
requirements of the specific drug-development program.
Koblinski (Dow): Cellulose-based polymers, such as hypromellose (HPMC) and hydroxypropyl methyl cellulose acetate succinate (HPMCAS, also
known as hypromellose acetate succinate) have high utility in solid dispersions. Their safety and low drug reactivity make
them an ideal candidate for most drugs. Spray-dried dispersions (SDDs) and HME are the most common technologies for solubilization
used with cellulosic polymers. Cellulosic polymers maintain stable solid dispersions, inhibit API crystallization, and can
promote supersaturation of the drug. Options in viscosity and substitution levels both with HPMC and HPMCAS help a formulator
to optimize performance in solubility enhancement as well as in material processibility, which includes postprocessing SDDs
and HME formulations into traditional dosage forms such as tablets and capsules.
Asgarzadeh (Evonik): The chemical structure and physicochemical properties of APIs and polymers play a major role in the formation of polymer-API
solid solutions. Poly(meth)acrylates, cellulosic polymers and PVP are extensively used in solid dispersion formulation development.
Each class of polymers contains specific chemical bonds that can interact with specific groups on APIs. HME, SDD, and coprecipitation
techniques transform poorly-soluble crystalline drugs into an amorphous, metastable, higher-state-of-energy structure dispersed
in a polymer matrix that is more easily solubilized, leading to enhanced solubility. Strong hydrogen bonding and ionic interactions
between the amorphous API and the polymer would inhibit or retard the recrystallization of the API even with polymers that
have low glass-transition temperatures (Tg's). Because there is a myriad of API structures with different physicochemical
characteristics, there is not one class of polymers that would be considered better solubilizers than others. It is essential
to select appropriate polymers for screening studies based on a good understanding of both the polymer and drug structures
and the possible interactions they may have.