Polymorphic purity, salt

Characterization of the reference standard for purity, impurities, physical-chemical properties related to bioavailability Rationale for selection of polymorphic and salt form, if applicable Batch profile—toxicology and clinical batches... 

Each initial salt needs to be studied for polymorphic purity, and the presence of solvates. Ideally, only one polymorphic form will be present. This polymorphic purity will be measured by one of the solid-state technique s) listed in Section II.D. Initial screening will typically be conducted with less labor intensive and less expensive methods such as differential scanning calorimetry (DSC) and TGA. 

The aim of this section is to provide a generic step by step methodology for the design of a final purification process for a non-salt form API using crystallization. The process objective is to consistently manufacture API of the desired purity and polymorphic form, within the constraints of a typical batch production facility. A brief outline of the analytical techniques that may be required is presented in section 4.6. 

In addition to potency, purity, and stability considerations of the API, the product development department is especially interested in the chemical and physical form (free acid or base, salts, esters, amides, polymorphs, solvates, particle size and shape) of the API. Time spent early in the cycle in establishing these particular factors often aids and/or simplifies the subsequent product and process development program. 

Toxicology batches (drug candidate) Meeting deadline is primary concern, to reach go/no go decision points during API development. Note that animals may be grown in advance of such studies. Invest time to determine and prepare desired final form (salt, polymorph). Prepare high-quality material, but not ultra-pure. If tox studies are conducted on material of an unrealistically high purity, subsequent tox studies will be needed to qualify batches of lower quality. 

Additional preformulation and physicochemical characterization of the candidate compound are performed and stress stability studies may be initiated. Ideally, the optimal solid-state (polymorphic) and chemical (salt) form of the molecule are identified as part of clinical candidate selection. Selection of the most stable and bio-available chemical and physical forms will expedite subsequent development. The methods for testing the drug substance are refined and additional methods may be developed, including tests for physical, chemical, and chiral purity. Analytical characterization becomes extremely critical where significant formulation intervention is required such as amorphous formulations for BCS 2/4 compounds, inhalation products, or highly concentrated formulations for monoclonal antibodies. 

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