{"id":17015,"date":"2023-05-18T12:02:07","date_gmt":"2023-05-18T12:02:07","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/blog\/how-can-correct-form-analysis-de-risk-your-project-ahead-of-pre-clinical-tox\/"},"modified":"2023-05-18T12:02:07","modified_gmt":"2023-05-18T12:02:07","slug":"how-can-correct-form-analysis-de-risk-your-project-ahead-of-pre-clinical-tox","status":"publish","type":"blog","link":"https:\/\/www.sygnaturediscovery.com\/fr\/blog\/how-can-correct-form-analysis-de-risk-your-project-ahead-of-pre-clinical-tox\/","title":{"rendered":"De-risking Projects with Form Analysis: Pre-clinical Tox Insights"},"content":{"rendered":"

The form, formulation and DMPK parameters of a drug are intricately linked to exposure and therefore to efficacious dose. The solid form of a compound impacts many variables including solubility, bioavailability, tabletability, and physical\/chemical stability of the drug. The extent of absorption and hepatic clearance impact oral bioavailability and the rate of absorption relative to distribution and clearance determines half-life. Combined, these parameters determine the exposure for a given dose and dose frequency. Successful drugs need to balance these properties to achieve sufficient exposure for efficacy and to define therapeutic windows in toxicology studies.<\/p>\n

The problems customers face with non-linear PK<\/strong><\/h2>\n

Form analysis and formulation development need to be brought into the drug discovery process earlier, not left to the point where a candidate has been nominated. Form is often ignored but to do so can cause catastrophic failure down the line as in the case of Ritonavir<\/a> which was removed from the market when a second more stable polymorph was discovered.<\/p>\n

Formulations are considered often at the point where a significant bioavailability issue has been identified or where a compound exhibits non-linear PK and an enabling formulation is required to proceed through pre-clinical toxicology.<\/p>\n

Integrating the right teams to overcome these challenges<\/strong><\/h2>\n

Form and Formulation should integrate, scientifically and physically, with the DMPK and pharmacology departments. This enables clients to harness the know-how in DMPK to understand PK\/PD relationships and calculate the target exposure which drives the therapeutic effect.<\/p>\n

With an understanding of the target exposure for efficacy and pharmacokinetics, we can estimate the target absorbed dose and frequency, which are essential to know ahead of formulation development. We recommend the three teams \u2013 form and formulation, DMPK<\/a> and pharmacology \u2013 combining to generate and analyse the performance of the formulations.<\/p>\n

This integrated approach provides an upfront de-risking strategy as it is able to determine if there are any intrinsic DMPK liabilities with the compound(s) e.g. high clearance that formulation will not resolve before initiating a formulation project.<\/p>\n

Delivering value through the right technology<\/strong><\/h2>\n

Being technology agnostic is important when developing a formulation strategy. This allows the most appropriate technology to be applied to the molecule and the client\u2019s requirements, rather than \u2018shoe-horning\u2019 a compound into a single formulation methodology.<\/p>\n

This approach delivers value to the client by generating the best and financially most appropriate solution for the compound at the stage of development, whether the compound is heading into pre-clinical tox or moving from Phase I to Phase II.; Phase III to a marketed drug.<\/p>\n

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Karina Wojdat \u2013 Scientist 1, who is part of David\u2019s team, pictured setting up the spray drier.<\/p><\/div>\n

\u00a0<\/p>\n

Sygnature\u2019s current offering:<\/strong><\/span><\/p>\n

Solid form analysis<\/span><\/h4>\n

Typical projects undertake salt screening, polymorphism screening, crystalline landscape analysis, crystallisation development, and stability studies and utilise the following equipment:<\/p>\n