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Particle morphology
Powder flow
Bulk density
pKa
Solid state complexity
Informatics assessment
Hygroscopicity
Melting point
Amorphization post size reduction
- Green: It is unlikely to entail excessive cost
- Orange: It is unlikely to increase cost and complexity of development
- Red: It is very likely to increase cost and complexity of development
- Blue: Knowledge gap
Key takeaways
Factors that might hinder development and suggested mitigation
Particle Morphology
Aspect ratio and particle size can both be manipulated by using seeding and better control of supersaturation during the crystallisation.
Significant reduction in size can occur during agitated drying so limiting agitation on drying should be investigated.
If the problem challenges the ability to manufacture, then an alternate solid state form might be investigated.
Powder flow
Poor API flow may cause problems during formulation manufacture. The tactics used to decrease aspect ratio and increase particle size are also generally applicable to improving powder flow.
Aspect ratio and particle size can both be manipulated by using seeding and better control of supersaturation during the crystallisation.
Significant reduction in size can occur during agitated drying so limiting agitation on drying should be investigated.
If the problem significantly challenges the ability to manufacture, then an alternate solid state form might be investigated.
Bulk density
Very low bulk density powders are likely to exhibit poor flow, be more difficult to formulate and present problems in transportation due to the larger number of containers required.
The tactics used to decrease aspect ratio and increase particle size are also generally applicable to improving bulk density:
Aspect ratio and particle size can both be manipulated by using seeding and better control of supersaturation during the crystallisation.
Significant reduction in size can occur during agitated drying so limiting agitation on drying should be investigated.
If the problem significantly challenges the ability to manufacture, then an alternate solid state form might be investigated.
pKa
APIs having basic sites with pKa of less than 5 are significantly more prone to dissociation.
Dissociation risks may be addressed by using excipients in the formulation to control microenvironmental pH. Also, alternate solid state forms may be less prone to dissociation than others.
Solid state complexity
If the API exhibits a complex solid state landscape then control of desired solid state form may be more difficult.
Investigate if the desired polymorph can be obtained reproducibly even though the solid state landscape is complex.
If control of solid state form is required (for example by following ICH Q6a decision tree) and this cannot be adequately controlled for the solid state form, then an alternate solid state form might be investigated.
Informatics assessment
Conduct more detailed polymorph or hydrate screens to confirm the findings of the computational informatics assessment.
Hygroscopicity
If the API picks up significant water and may form hydrates, this may impact biopharmaceutics, stability and manufacturability.
Selection of a non-hygroscopic or hydrating solid state form would address this problem. If this isn’t possible, then process controls for hygroscopicity will need to be explored if there is an impact on manufacturability stability or biopharmaceutics.
Melting point
Low melting point solids may undergo process induced melting during formulation.
Melting point could be manipulated by selecting an alternate solid state form or by selecting formulation unit operations that do not create frictional heat.
Amorphization post size reduction
High level amorphous content can be linked to poorer chemical and physical stability. Size reduction in wet media may be applied so long as filtration is not adversely impacted.
Particle conditioning in solvent vapour or water may be used to recrystallize amorphous content.
In extreme cases, an alternate solid state form may be investigated. Formulating particularly micronised powders can be difficult.
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