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When considering oral drug delivery, a major factor for the failure of new chemical entities from entering the market is that they are practically insoluble with reduced bioavailability compromising their pharmacological effects.
The reward in the selection of the amorphous state of a new drug substance has been proposed in Amorphous Drug Substances: Solid-State Opportunities and Considerations, Part 1. Attention moves to the development traits for the compound and subsequent drug product.
It is desirable to identify and develop a crystalline version of a drug substance from the perspective of API production, drug product formulation and manufacture, having established that satisfactory solubility, bioavailability and stability are achieved.
For a drug compound crystallinity is a highly desirable solid-state attribute to achieve as this can simplify process development activities, drug product investigations and manufacture. Compound crystallinity does not necessarily guarantee suitability as a drug substance for a drug product.
Attention is rightly directed to establishing the desired attributes of the final material or drug substance which have been determined from the solid state investigations and the crystallisation process to enable development.
One of the first parameters to establish of a newly discovered solid drug substance or API is the aqueous solubility. Solubility equilibria and permeability are important solid state characteristics of any API as a drug substance and also in the drug product.
The crystallisation process used to produce your new discovered therapeutic molecule defines the attributes of the solid isolated. Chemical purity, composition, crystallographic form, particle habit and size are the characteristics that can be controlled by the crystallisation used to generate the material. This operation produces API for evaluation in vitro, in vivo and also feeds the formulation development that culminates in the production of the drug product which the patient handles.
Establishing if your newly discovered drug substance solid is polymorphic is a regulatory requirement as part of new drug approval submission. This is captured as part of the chemistry, manufacturing and controls (CMC) section of an NDA for a drug substance, together with a whole host of topics.
The ability to produce a salt of a drug substance with counter ions relies on the new chemical entity, NCE, or API containing functionalities which allow proton transfer to take place. Alternatively, cocrystal formation utilises hydrogen bonding and Van der Waals interactions between suitable moieties in the drug substance and a conformer.
You have identified and selected the structure of your compound from medicinal chemistry investigations as a therapeutic agent and is a new chemical entity, NCE, and have also generated material with which you are collecting pharmacokinetic and toxicological information to support your drug compound.
For a newly discovered solid chemical entity as an API, one of the characteristics to establish is the aqueous solubility. Another property which is also used to define a drug substance is the melting point. For a substance to melt, energy is required; this process is described as endothermic. This is a thermodynamic property of the solid and is termed the enthalpy.
A concern from a regulatory stance, BP and Ph. Er., with progressing a potential drug molecule sulfonate salt into clinical and drug development is the formation and presence of mutagenic alkyl sulfonate impurities produced when the salt formation or salt recrystallisation was conducted in alcohol solvents.
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