Drug products, formulation development state selection

While the goal of the solid-state chemist is to select the thermodynamically stable form to be used in the development of a drug product that provides robust performance, stability, and manufacturability, it is important to consider the quote from Maria Kuhnert-Brandstatter (1975) Probably every substance is potentiaUy polymorphic. The only question is whether it is possible to adjust the external conditions in such a way that polymorphism can be realized or not. It is clear that the environmental conditions of an API solid form, at normal manufacturing and storage condition, are very different from the conditions that the API sohd form is exposed to in the drug product The formulation can alter the environment in such a way that the thermodynanucally stable form becomes metastable. This is a common occurrence when thermodynamically stable anhydrous forms are formulated to prepare an aqueous-based dosage form, in which a precipitation of a hydrate with lower solubility is observed [9]. 

Prior to developing a drug product, a number of experiments need to be conducted that will fully characterize the API. This information will then be used to help guide formulation development efforts. Each of the critical pieces of information that are needed for formulation development will be discussed below. These include a screening process where an ideal soHd-state salt form is selected and the generation of a suite of analytical methods necessary to probe the critical quality attributes of the new chemical entity, to support synthetic optimization scale-up, stability studies, and the release of material for GLP and experimental use. 

Public health is coupled with convenience of treatment more than recognized. The development of more convenient drugs and formulations (i.e., once-a-day extended release products, or those with reduced side effects) is often denigrated as non-innovative, but R D in this area can also have a substantive impact on public health. Patient compliance with pharmaceutical interventions is poor. In developed countries it is foimd that 40-70% of patients comply with recommended treatments for chronic diseases (18). In the United States, where most health care consumers have little appreciation of product costs, yet substantial control of product selection, the drive to more convenient and palatable drugs is certainly largest. But the resulting benefits to increased patient compliance, patient health and thus the public health overall underscore the value that even these seemly minor innovations can have. 

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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