A clear understanding of a drug’s chemical properties will lead to a better formulation design.
Before a formulation is developed around an active pharmaceutical ingredient (API), that API itself must be clearly understood. A careful analysis of the solubility, stability and other chemical properties of a newly discovered API will significantly streamline the formulation process, by helping identify potential problem areas, and suggesting solutions to those issues.
A preformulation analysis of a solid-state API may reveal additional crystalline variations (polymorphs) which can exhibit unique chemical traits, and may be developed into lucrative intellectual property in their own right. Even if the API is not crystalline, preformulation studies often reveal unexpected attributes that may increase a drug’s commercial value.
The following article presents a brief survey of preformulation studies, including key concerns in each area of analysis.
The API’s stability and solubility profiles should be clearly and thoroughly established.
Every complex chemical degrades when heated above certain temperatures, when exposed to light of certain wavelengths, when placed under oxidative stress, or when introduced to a highly acidic or basic environment. One of the key tasks in a preformulation analysis is to determine the API’s resilience to these conditions, and the precise points at which its chemical stucture breaks down. A precise characterization of the API’s stability parameters is critical for success in subsequent stages of the drug development process, such as the selection of excipients and delivery mechanisms.
Since an API must exhibit some degree of acqueous solubility in order to exert an effect (and since many drugs are in fact delivered in solution form), solubility testing forms a crucial part of the preformulation process. A characterization of the API’s solubility in water often serves as the first step in solubility analysis; subsequent steps may test solubility in chemical environments that simulate conditions in certain bodily systems, such as the blood or gastric media.
Methods of solubility analysis can take a variety of forms. The API’s dissolution behavior may be monitored, its membrabne permeability may be tested, and its pH and acid dissolution constants (pKa values) should be determined. Once these parameters have been established, the API’s solubility profile can be altered by chemical modification into a salt or ester form, or by techniques such as amorphous solid dispersion and pH adjustment.
A range of additional attributes may also impact the API’s pharmacokinetic properties.
The solubility and stability of an API (as well as its other traits) are the result of a complex interplay of chemical factors. For example, the stability and shelf life of a solid-state API are often determined by their tendency to adsorb free moisture. Since many excipients contribute some amount of free water to a formulation, it is crucial to establish the amount of moisture adsorbed by an anhydrous sample of the API, via techniques like gravimetric or gas chromatography.
A clear characterization of the API’s bulk density will also prove crucial in determining the size of its dosage form during the formulation stage. The bulk density of a solid-state API can vary according to a number of factors, including the crystallization process, as well as the milling and slugging techniques used. By the same token, the API’s bulk density can be adjusted to suit the final formulation by modifying any of these techniques.
Color, odor and taste are also reflections of pharmacokinetic processes. While these might not seem to stand out as key attributes of a newly discovered API, they can all impact a drug’s marketability, and will need to be taken into account when selecting excipients. If color varies by batch, some manufacturing steps may need to be adjusted, in order to achieve more uniform coloring. Pungent odors and unpalatable tastes may require balancing excipients, such as herbal scents to offset chemical smells, or sweet syrups to balance bitterness.
Solid-state APIs should be screened for polymorphs, which may have unexpected properties.
Different crystallization techniques yield different polymorphic variations of an API. In some cases, even a single technique may yield multiple polymorphs, each exhibiting different chemical traits.
Polymorphic variation can alter crystal caking, color, hardness, solubility, density, and grittiness. Variations can also alter an API’s melting properties, causing some batches to melt prematurely, or to fail to melt upon administration.
Thus, screening and characterization of polymorphs is an essential step in the preformulation stage for any solid-state API. In fact, the study of polymorphism serves as a major focus for the pharmaceutical industry, because many newly discovered polymorphs can be patented as unique intellectual property, even if they originate from an API already patented by another developer. If the discoverer of a new polymorph can demonstrate that the variation represents a unique discovery with useful value, this often constitutes sufficient proof for a patent on the polymorph.
Some contract manufacturing organizations (CMOs) now specialize in polymorph screening, supplementing conventional techniques like X-ray Powder Diffraction (XPRD) with more advanced methods such as nuclear magnetic resonance (NMR) spectroscopy. Leading-edge labs have also implemented automated screening systems, which can detect polymorphs much more rapidly than human experts, on a timeline of days rather than months. A few have even developed computer simulation tools that can predict which crystallization techniques will produce polymorphs with the desired chemical properties.
An API’s solubility, stability, bulk density, and other properties all impact the selection of excipients, as well as the design of delivery systems. Characterizing these properties as early as possible in the drug development process helps streamline sourcing of needed raw materials, optimize the design of manufacturing pipelines, and bring new drugs to market in the most efficient way possible.