Pharmaceutical salts of small molecule drugs: opportunities and challenges

Posted: 28 October 2014 | | No comments yet

Over the past decades, pharmaceutical drug development has undergone some significant changes, a prominent example for this being the emergence of biomolecular drugs (New Biological Entities, NBEs) such as antibodies and peptides. However, classical small molecule drugs (New Chemical Entities, NCEs) are far from being a dying species, and in fact the number of NCE drugs approved by the US Food and Drug Administration (FDA) in the past few years has been higher with increasing trend compared to NBE drugs, which appear to stagnate at lower level in terms of new drug approvals1.

Pharmaceutical Salts

For NCE drugs, however, the introduction of High-Throughput (HT) combinatorial chemistry platforms as well as HT assay technologies has resulted in a pronounced increase in poorly water-soluble drugs, e.g. BCS class 2 and class 4 compounds2,3,4.

Hence, pharmaceutical development is nowadays frequently facing the challenge of tailoring poorly soluble lipophilic drugs to allow sufficiently high oral in-vivo absorption. This is even more demanding for early animal toxicological studies which typically require high doses being absorbed. Enabling formulation platforms are widely considered to mitigate this, and formulation scientists have a diverse tool-box available in this field, such as liquid formulation approaches, amorphous molecular dispersions, or particle size reduction technologies5,6. However, nearly all of these enabling formulation platforms require considerable development time and workload, which may be prohibitive especially for early-stage development timelines. Also, some of these approaches are limited in the applicability (e.g. particle size reduction is only useful if dissolution kinetics are the main limitation for oral absorption, but does not overcome solubility constraints itself). Moreover, one of the main liabilities of many enabling formulation products is the risk with respect to stability (physical form conversion issues in case of amorphous solid drug dispersions, enhanced chemical reactivity in solution state).

Alternatively, going one step back from formulation development activities, modification of drug substance (DS) solid-state properties may be considered as a more direct tool to overcome poor solubility…

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