四色AV

The virtual 2020 Global Drug Bioavailability Enhancement Summit this past December showcased novel technologies and platforms aimed at addressing bioavailability and solubility challenges. These included techniques like elec颅trospinning, mesoporous silica technology, physiochemical optimization, amorphous nanoparticle engineering, and pharmacokinetic modeling. And the end goal is the same: Save time and money while accelerating formulation devel颅opment.

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This annual听Drug Development & Delivery听report introduces readers to some novel approaches to improving bioavailability and solubility that have one commonality: they treat each molecule as unique.

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四色AV: Emerging Platforms Address Extreme Compounds

The industry has a wide toolbox to address bioavailability and solubility issues. Promising technologies may require more time and studies, but provide the opportunity to deliver compounds that would be considered unviable in the recent past.

Multiple platforms have emerged in pharmaceutical development to ad颅dress bioavailability and solubility challenges. Amorphous solid disper颅sions by spray drying have become an industry standard, says Jo茫o Henriques, Scientist, Group Leader, Hov颅ione, R&D Drug Product Development. 鈥淭his growth is generating a wealth of data that not only provides confidence in the platform, but also creates the foundation for empirical driven for颅mulation approaches,鈥� he says. 鈥淭he use of prior data allows correlating molecular descriptors of low solubility molecules with formulations that have been successfully developed as solid dispersions. The correlations aid in preliminary prototype definition and evaluating of the likelihood of success of such a formulation approach.鈥�

In addition to statistical methods, the use of first-principle models that incorporate thermodynamics of mix颅ing, diffusion, and kinetics of solvent evaporation provide valuable infor颅mation for听in silico听screening and ex颅cluding non-viable formulations. 鈥淏oth strategies have their advantages and disadvantages and can be used complementary to each other as a valuable tool for formulators to define the best prototypes to screen and re颅duce development time and material consumption while delivering opti颅mized formulations that provide the required performance, are stable, and commercially viable,鈥� he explains.

While the formulation of most DCS2b compounds is presently a well-known and understood challenge, there remains a wide space for solu颅tions to address some extreme com颅pounds that either require significant amounts of stabilizers to maintain the amorphous form or that are not amenable to spray drying with reasonable cost of goods due to low sol颅ubility in organic solvents, he states. Alternative production methods of solid dispersions, such as co-precipi颅tation, can address the low organic solubility issue. 鈥淓merging platforms, such as impregnation with meso颅porous silica, present an opportunity for molecules that cannot be stabilized in the amorphous form with common stabilizers at reasonable ratios,鈥� says Mr. Henriques. 鈥淎PI-loaded silica has been shown to improve amorphous stability of compounds with a high tendency to recrystallize. Additional studies and clinical programs may help establish this technique as a stan颅dard alongside lipid formulations and solid dispersions in improving bioavailability and solubility.鈥�

鈥淥ne of the recurrent challenges we face is related to accelerated ap颅provals from the FDA with Fast Track and Breakthrough designations on low solubility compounds,鈥� says Mr. Henriques. 鈥淭his is common for oncol颅ogy programs that show promising early-stage results and may have re颅duced clinical study requirements.鈥�

Accelerated approvals put an in颅creased amount of pressure on all Chemistry, Manufacturing, and Con颅trol (CMC) activities, which must be compressed and de-risked, he says. The use of enabled formulations fur颅ther increases the complexity of this activity. 鈥淎dequate risk assessment and management tools are required because reformulations may compro颅mise all clinical timelines,鈥� says Mr. Henriques. 鈥淩ight-first-time formula颅tion in this case is a significant advan颅tage, and all formulation activities must have a strong sense of the man颅ufacturability and scalability early to ensure seamless transition from clini颅cal to commercial scales.鈥�

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