In relation to patient safety, it is essential that the drug is ”predictable” with respect to particle properties. Risk assessment should be based on particle size and crystalline structure, including evaluation of a minimum and maximum size. In fact the need for particle characterization is stated in several ICH guidelines (e.g. 6A, 8 and 9).
Once a pharmacologically active drug is synthesized it is just as important to make sure sufficient bioavailability of the drug at the site of action. Bioavailability depends upon particle size and crystal form as these properties determines the behaviour of the drug in vivo. A specification should be based on evaluation of a minimum and maximum size – and include ID of the polymorphic form and ”allowed” content of other crystal forms.
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– The dissolution profile changes. Changes in particle size or crystal form leads to changes in the dissolution rate of the product and thereby a risk of too high or low exposure in vivo.
– The product does not contain the desired amount of API – leading to a too high or low exposure in vivo. A change in particle size or morphology might affect the mixing properties during manufacturing leading to an inhomogeneous distribution of the API in the final product.
– The product contains impurities at a higher level than examined during development. A change in particle size or crystal form might affect the interactions of the API with the excipients or surrounding water, i.e. a “closer contact” and larger accessible surface for smaller particles could lead to unwanted reactions and/or degradation of the API.
Read more about why particle characterization is essential.
Why is setting correct particle specifications essential? What are the risks if you don’t consider particle characterization in your risk assessment?
Setting up limits
In the final product, the particle specifications should be based on scientifically well-founded rationales. You do not want to set the limits too narrow as it reduces freedom during manufacturing. On the other hand, you want to be sure that the changes in particles properties do not affect the patient safety.
To evaluate the effect of particle size one should, in the ideal world, produce particles of various sizes and analyse these with regard to all relevant properties. However, this is usually not possible, as controlling particle sizes during manufacturing is not straight forward – and the experimental work might be quite tedious. Instead a combination of experiments and calculations (with regard to dissolution and blending) could be used.
The risk of transformation of the crystal form should be based on results from a polymorph screening: How many crystal forms can be identified, and how is the relative stability, solubility or dissolution rate of each form? Read more about our analytical services.
Things to consider in risk assessment:
- Is the therapeutic window ”narrow” or ”broad”?
- Can particle size be controlled – and is it necessary?
- What is the impact on patient safety if particle size increases, e.g. 50%?
- Is there a minimum tolerated particle size?
- What is the maximal difference in solubility between different crystalline forms?
- How would stability be affected by a crystal transformation?
- Are the ”variations” significant compared to expected biological variations?
The crystal form/polymorphic form with the highest stability generally has the lowest dissolution rate. A transformation between different forms will affect the dissolution profile/bioavailability and the stability of the drug. Most often the most stable form is preferred in development.
Further, a quantification of the % crystallinity might be necessary. Read more about crystal forms and related methods to quantify the degree of crystallinity.
Smaller particles have higher dissolution rate and vice versa. Furthermore, special characteristics of the morphology might play a role for the properties. Thus, methods for examination of the surfaces should be used to obtain the full picture. Moreover, the overall effect of differences in particle size and morphology should be evaluated from dissolution experiments.
Be aware that changes in supplier or in production procedures might lead to quite large changes in particle size and/or morphology. Such changes should always be evaluated! Read more about particle size analysis and – determination.