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Title: Designing ADME formulations with matching exposures to amorphous solid dosage forms

Aditya Tatavarti

Merck Research Laboratories, USA

Biography

Dr. Tatavarti is a Principal Scientist in the Oral Formulation Science and Technology group at Merck Research Laboratories. He has more than 14 yrs. of industry experience with expertise in the areas of immediate and modified release, solubility enhancement and differentiated complex dosage form development. He is the author/co-author of more than 25 published manuscripts, patent applications and abstracts. He holds a PhD in pharmaceutical sciences from the University of Maryland and conducted doctoral research in the area of microenvironmental pH modulation in controlled release systems. Since joining Merck, he has worked across various indications, but has dedicated majority of his time towards designing and advancing complex delivery systems, in the NCE and PVE space, for HIV and Oncology indications. He led the formulation development for approved HIV products, PIFELTRO and DELSTRIGO. He is also a subject matter expert on extrustion-spheronization, pediatric formulations and encapsulation.

Abstract

Amorphous solid dispersion (ASD) based formulations have been frequently used to improve the bioavailability of poorly soluble drugs. However, common processes to produce ASDs are not feasible for absorption, distribution, metabolism and excretion (ADME) studies with radio-labeled active pharmaceutical ingredients (API) due to contamination concerns. Hence, simple liquid or solid formulations are routinely used to support the ADME studies, though bridging the bioperformance gap between simple formulations that are amenable for use with radioactive API, and amorphous solid dispersion clinical formulations generated through processes such as spray drying and hot melt extrusion can be quite challenging. The challenge is to not only design solid or liquid formulations that would effectively solubilize the API but also inhibit rapid in vitro and in vivo precipitation and recrystallization. This abstract captures two different strategies for developing ADME formulations, one where an ampiphilic polymer, hypromellose acetate succinate (HPMCAS-L) impregnated in a liquid vehicle, polyethylene glycol (PEG-400) provided not only inhibition of crystallization but also resulted in nanoparticle formation that was critical to bioperformance. It was found that the bioavailability of the formulation can be compromised by the presence of undissolved crystalline seeds, and the inclusion of HPMCAS-L can mitigate this effect, as well as potentially facilitate nanoparticle formation.  In a second case study, where the compound of interest is insoluble in liquid vehicles, a unique pentahydrate sodium salt was utilized in combination with an HPMC capsule and a dose adjustment strategy to provide comparable exposures to the amorphous solid dispersion clinical formulation. The HPMC polymer from the capsule acted as an inhibitor of precipitation and aided in the overal path forward for the ADME study. As such, two distinct methodologies were successfully employed to enable ADME studies of two different compounds with unique physiochemical characteristics.
Audience take away:
• Understanding the challenges with desiging ADME formulations
• Methodologies for desiging ADME formulations
• Understanding impact of polymeric crystallization inhibitors and nanoformers on exposure
• The talk will help the audience in adopting these methodologies for ADME studies in their respective jobs