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Polymorph Screening
A number of currently
marketed
pharmaceutical products have more than one crystalline form. A compound
that exists in more than one crystalline form is considered to be
polymorphic. While polymorphs are the same in terms of chemical
composition, their physiochemical properties can vary significantly.
These differing physiochemical properties can dramatically a compound's
efficacy due to changes in properties such as dissolution rate,
solubility, and bioavailability. Knowing this, pharmaceutical companies
are moving towards more structured polymorph screens for new chemical
entities. These screens are being performed earlier in the drug
development process in order to maximize the chances that the most
stable physical form is carried into the clinic. Regulatory bodies now
also require demonstration of polymorph identification in submissions.
Lastly, polymorph screening of compounds in late development is often
valuable in terms of maximizing the intellectual property investment a
pharmaceutical company has made, and offers opportunities to extend a
patent portfolio.
Polymorph screening
involves
re-crystallizing a compound from a variety of organic solvents while
often varying environmental conditions, such as rate of cooling,
solution concentration (i.e. extent of supersaturation), rate of
stirring (or absence of stirring), etc. Depending on the specific
approach taken, and the amount of compound available for a screen,
anywhere from 10's to 100's of unique combinatorial conditions are
created and analyzed for the resulting polymorphic form.
Salt Selection
A significant number
of current
therapeutics are delivered as salt forms (as opposed to the free base
form). There are some estimates that place the percentage of salt-form
medicines as high as 50%. Increasingly, pharmaceutical companies desire
to conduct salt selection screening earlier in the drug development
process in order to maximize their understanding of the chemical
"landscape" for a given molecular entity. Because critical
physico-chemical properties are heavily influenced by the salt form of
a compound (e.g. melting point, morphology, hygroscopicity, powder
flowability, etc.) establishing the knowledge of how the salt form
performs in a drug product is critical in taking the best form of a
compound into the clinic.
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Typical salt
selection screens
involve re-crystallizing a particular compound from a variety of
counter-ion solutions, as well as varying crystallization solvents and
conditions. Depending on the specific approach taken, and the amount of
compound available for a screen, anywhere from 10's to 100's of unique
combinatorial conditions are created and analyzed for the resulting
salt form.
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