Solid-State Screening: A Fit For Purpose Approach
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The selection of an appropriate solid form of your API is an important step in your development plan, as well as, a regulatory requirement.  A key question is what solid state research to carry out and at what stage in your development path.  Crystallics’ approach to solid state screening is based on a fit for purpose strategy which balances the importance of finding an appropriate solid form versus the cost of such a screen in relation to the development stage of your compound and the associated risk of the compound still failing.   In essence the focus for early screens at, say candidate selection, is to find a stable form for preclinical and early clinical work at a relatively low price.  As the compound progresses and is de-risked then additional screens are added to ensure that ultimately the most appropriate form is selected.

The issue with delaying all solid state screens until late in the development path of your compound is that you may end up with an unstable or sub-optimal form.  To rectify such an issue is expensive and time consuming. Crystallics’ fit for purpose solid state screening approach includes the following step by step screens which would be recommended at various stages of development.

The 10-day Salt Screen is aimed at ionizable compounds that are about to enter in preclinical research.  With as little as 500mg API a salt screen with 20 commonly used counter-ions is possible.  Basic physiochemical properties of the salts are collected and the most promising salts are scaled up for a comparable solubility and dissolution rate study together with the free form.  This screen enables you to quickly decide whether it is better to take a salt or the free form into development.

The Enabling Polymorph Screen is also for compounds that are entering the preclinical research phase.  It is important to start the pharmacokinetic and toxicology studies with a relative stable form.  Particular form changes that result in differences in the solubility and/or dissolution rate are to be avoided.  The Enabling Polymorph Screen is biased towards identifying stable forms through slurry conversions.  With as little as 250mg, 20 different crystallizations at one temperature are performed.  If 1,500mg of API are available, 30 different solvents (or mixtures) are used at two temperatures.  This set-up results in 90 different crystallizations.  Quantitative solubility of the API in all 30 solvents can be determined which your chemist colleagues will love.

Once the synthesis of your compound has become mature it is time to confirm the choice of your solid form with an Extensive Polymorph Screen.  Building on the solubility data collected from the Enabling Polymorph Screen a screen with diversity in crystallization modes and solvents is designed.  From cooling and evaporative crystallizations to slurry conversions in high boiling point solvents and vapor diffusions.  With almost 300 experiments, in rational selected solvents or solvent mixtures, divided over 15 different crystallization modes a near complete overview a potential polymorphs and pseudo-polymorphs will be obtained.  The acquired information will guide you to the “best” form to take into the final phases of development but also the knowledge is useful to strengthen the IP position on your API.

At Crystallics X-ray powder diffraction (XRPD) is the primary technique for characterization of solids.  Besides our proprietary High Throughput XRPD set-up we have all the necessary analytical equipment for a full physiochemical characterization of solids.  From high resolution XRPD with a hot/humidity stage to miniaturized (5mg) intrinsic dissolution rate testing.  Once you have decided on your final form we have the expertise and equipment in house to help you and your CMO to build a robust process that will deliver reproducible batches of your API.