Formulation studies - where should I begin?
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• Your next steps
• How much material you need
• Process workflow and timing
• Considerations to achieve success
Plan for
2 – 5 g of material
6 weeks to complete
Most organic compounds can exist in more than one crystal form. Each has a different stability, hygroscopicity, dissolution rate and apparent solubility. Polymorphism screening aims to identify all crystalline forms and determine which is most suitable for development, usually the one that is most thermodynamically stable.
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Polymorph screening aims to identify all the crystalline forms of a given compound and determine the most suitable form for development; this is usually the one shown to be the most thermodynamically stable.
Outcome
About
200 mg of material
4 weeks to complete
Evaluating up to five compounds in parallel, your potential candidates will be ranked according to ease of crystallization, hygroscopicity, solid form stability, and solubility and stability in dosing vehicles.
A parallel screening approach allows multiple lead compounds to be rapidly assessed against key developability criteria. This allows subsequent polymorphism and formulation studies to be focused on only the most promising candidates, reducing attrition rates.
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30 mg of material
1 week to complete
Expect crucial information about your compound’s suitability for development, including:
• crystallinity/fingerprint of the crystal form using X-ray powder diffraction (XRPD)
• understanding of thermally-induced form changes using differential scanning calorimetry (DSC)
• thermal stability and volatile content using thermogravimetric analysis (TGA)
• response to humidity using gravimetric vapour sorption (GVS)
Many compounds are produced in an amorphous form the first time they are made, with only larger batches being isolated in a less soluble crystalline form. Using sophisticated equipment to assess batch-to-batch variations in your solid form compound material, batch characterization aids interpretation of
in vivo results, where dosing different forms can result in vastly different PK profiles.
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2 – 5 g of material
6 weeks to complete
Crystalline salt forms of your API will be identified and evaluated for key developability criteria versus the known free base or free acid form.
If your molecule has an ionisable centre, salt formation can give you an opportunity to generate an alternative crystal form of your API. This can address issues with the free base/acid form and potentially mitigate issues associated with stability, solubility, dissolution rate or hygroscopicity. Salt forms can also be patented, extending IP protection around your candidate molecule.
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About
Outcome:
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Discovery phase studies routinely use both solution and suspension formulations for oral dosing.
If you can achieve the required solubility, solutions represent a quick and easy dosing option, though it’s important to understand any polymorphism associated with your compound to avoid overestimating its true thermodynamic solubility.
Suspensions, on the other hand, can better mimic table or powder-in-capsule dosing that might well be employed downstream. For these, it’s important to control crystal form and, to a lesser extent, particle size to avoid introducing additional variability to
in vivo experiments.
Our in-house formulation screening service rapidly evaluates the solubility and stability of novel APIs in dosing vehicles appropriate to the current stage of the project, as well identifying any issues that are likely to crop up during subsequent optimization for the clinic.
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Even if not the anticipated clinical administration route, intravenous (IV) dosed pharmacokinetic studies are essential during drug discovery programs to support a full understanding of intrinsic clearance. IV dosing is also perhaps the simplest method to achieve systemic exposure for early efficacy studies.
Depending on planned study parameters, various excipients and co-solvents can be used to achieve the required levels of solubility, as can varying the pH of the vehicle. When evaluating potential formulations, it’s important to understand the effect any polymorphism can have on solubility.
Our in-house formulation screening service rapidly evaluates the solubility and stability of novel APIs in dosing vehicles appropriate to the current stage of the project, as well identifying any issues that are likely to crop up during subsequent optimization for the clinic.
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Dosing directly to the lung, either as a nebulized solution or dry powder, is an attractive route of administration for treating respiratory diseases as your API is delivered exactly where it’s needed. For this approach, you can design molecules to be retained in the lung with low systemic exposure.
Alternatively, you can design molecules with physicochemical properties that allow the large surface area and highly-perfused nature of the lung to be used as a portal to systemic circulation, bypassing first-pass metabolism.
Dry powder formulations must be prepared from micronized (crystalline, non-hygroscopic) material. Blending potent micronized API with a lactose carrier achieves a dilution effect, enabling the effective delivery to the inner parts of the respiratory tract.
Nebulized administration of saline-based formulations is a common approach during discovery phase studies, as it circumvents the need for micronized material and allows rapid assessment of compounds without extensive investigation of solid form properties. It is still necessary, however, to assess a likely vehicle’s stability and solubility parameters.
Charles River has many years’ experience working with inhaled APIs, allowing us to rapidly evaluate novel compounds as to their suitability for dosing to the lung and to prepare prototype formulations for
in-vivo studies.
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While oral dosing is the most commonly desired route of administration, dosing topically can have advantages in some cases. By getting straight to the desired site of action, your API won’t be subjected to the low pH environment of the stomach and will avoid first pass metabolism. IV dosing can also present an attractive way of achieving systemic exposure, provided that the API can be solubilized in a suitable vehicle.
Whatever the anticipated dosing route, Charles River has experience quickly developing formulation approaches to allow rapid progression into key in-vivo studies.
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