OUTSOURCING
Key strategies central to overcoming poor API solubility
Noel Hamill, an investigator with the Physical Sciences Group at Almac, discusses various fit-for-purpose and cost-effective routes to enable rapid progression of new drugs into clinical development.
T
he number of novel drug candidates with solubility-limited bioavailability is increasing and this presents an industry-wide challenge to effective and efficient drug development. The widespread use of high throughput screening in drug discovery and the tendency towards targets with more lipophilic binding sites are factors that have contributed significantly to poor solubility of new active pharmaceutical ingredients (APIs).1 Rather than seeking a re-design of the molecule through the medicinal chemistry route, solid-state chemistry and preformulation development are a fit-for-purpose and cost-effective means of enabling rapid progression into the clinical phases.
Improving drug solubility To date, the most common means of improving drug solubility has been salt formation, with around half of all drugs in the FDA Orange Book marketed as salts.2 Salts can increase solubility by several orders of magnitude compared to the un-ionised API, albeit over a specific pH range. Although salt screening is recognised as an essential part of
drug development, it is often restricted to a lower-priority activity for the medicinal chemist, development chemist or formulator to accomplish alongside other tasks. For those who have not had experience in this area, screening can be narrow in scope and ‘risk averse’, with the first crystalline ‘hits’ generally accepted as a successful outcome. For example, hydrochloride is not automatically the best choice for a basic molecule, as the dissolution rate and bioavailability may be retarded as a result of the common ion effect. Restricting the screening to ions that have been previously used in marketed drugs does not necessarily mitigate risk either; just because hydrobromic acid and
ethylenediamine were (and are) readily used in organic chemistry labs does not mean that they would be acceptable to today’s regulators.
It is true that while the methodology for salt screening is not difficult, the understanding of salt formation, toxicology and solid-state characterisation is essential to create the best opportunity for drug improvement and avoid incorrect (or costly) selection of the ‘wrong’ form of an API. To this end, a tailored scientific
investigation is preferable to a generic high throughput experimental screen, as several iterations with different conditions may be necessary to coax the first good-quality crystals to nucleate.
Changing the salt form during the clinical phase of a drug should be avoided because this is regarded as a change in the drug substance from a regulatory point of view, which results in costly repeated toxicological (‘tox’) bridging studies. This implies that most effort on salt formation is applied during the synthesis of the preclinical ‘tox’ batch. For small and virtual pharma and biotech companies, using an integrated supplier like Almac for project management of synthesis, screening, form selection and ‘tox’ studies in parallel (known as rapidd™) can reduce risk and minimise spend by eliminating the extended time and loss of information from technology transfer.
The main drawback with salts is that, by necessity, the API must be an acid or base of sufficient strength to enable a stable salt to form and, therefore, for a weak acid or base, only a few non-toxic, pharmaceutically acceptable counter-ions may be available for screening. This is not the case for cocrystals, which are stoichiometric mixtures held together by hydrogen bonds, as there is no requirement for ionisable moieties and allows a much wider range of excipients to be screened. Although known about for a long time as ‘molecular complexes’ or ‘addition compounds’, cocrystals have only recently attracted attention as a tool for rescuing insoluble drug candidates from rejection. As the drug is not ionised, there is an enhancement in the ‘kinetic’ solubility, not a fundamental change in the thermodynamic equilibrium solubility afforded by salts at certain pH. Nonetheless, the solubility advantage can be substantial, with up to a 150-fold increase reported for carbamazepine cocrystals.3
Fig 1. The formation of cocrystals: flufenamic acid/nicotinamide cocrystal structure. 24 sp2 Inter-Active September/October 2012
Whereas salt formation is predictable to
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