The solid form of an active pharmaceutical ingredient (API) influences the drug's solubility, stability, and compatibility
with other components in a formulation. API manufacturers are tasked with screening, detecting, and characterizing various
physical forms, such as polymorphs, solvates, amorphous materials, and partially disordered materials. Applying solid-state
chemistry, however, can be a time-consuming and difficult job, and several recent developments point to ways to facilitate
the search for the optimal solid form.
(IMAGE: JASON REED / GETTY IMAGES)
The task at hand
"It is important to apply the most appropriate means of characterizing or identifying all physical forms," says Seenu Srinivasan,
PhD, global vice-president and chief scientific officer of CMC pharmaceutical development services at Covance. "On choosing
the preferred physical form, a robust crystallization or preparation process needs to be developed, preferably using solvents
that are safe, available in large quantities, and are environmentally friendly. Generally, the thermodynamically most stable
form is preferred for development. However, in some cases, it may be necessary to progress metastable crystalline forms, solvates,
hydrates, or even amorphous materials."
He adds that co-crystals, where more than one molecular entity is incorporated into the crystalline unit cell, can be considered
as well. "The latter approach is useful for pharmaceutically engineering the properties of a drug substance when no ionizable
moieties are present in the parent molecule," he says. Even when the product is not administered as a solid dose, the physical
form of the drug substance should be characterized as fully as possible to ensure that there is no interbatch variability,
which may in turn affect, for example, reconstitution time or chemical stability. "We have seen many examples where very subtle
variations in physical properties of different batches of an API can have profound effects on its behavior," he says.
Patricia Van Arnum
Decisions to be made
The optimal physical form is based on several factors, which may be influenced by the target product profile, including bioavailability,
physical and chemical stability, desired dissolution properties, the impurity profile of the API, drug-substance hygroscopicity,
morphology, size distribution, compaction properties, and ability to formulate. "The higher ranking of these criteria for
a particular API is used in the decision to choose a free molecule, salt form, or co-crystal," explains Laurent Lafferrere,
PhD, head of CMC development services in Porcheville, France, at Covance.
Identifying polymorphs, where a drug substance exists in two or more crystalline phases, is crucial. Polymorph stability is
evaluated experimentally by monitoring the phase transition of the different polymorphs in different crystallization media
and at different temperatures by using in-situ monitoring probes and analytical solid-state methods, explains Lafferrere. These data are used to manufacture the desired
polymorph and to control it through the various manufacturing steps. Polymorphs can undergo phase transitions when exposed
to a range of manufacturing processes, such as drying, milling, micronization, wet granulation, spray drying, and compaction.
Exposure to environmental conditions, such as humidity and temperature, also can induce polymorph transition. The extent of
transition depends on the relative stability of the polymorphs, kinetic barriers to phase transition, and applied stress.
The physical stability of polymorphs may be monotropic or enantiotropic, where the relative thermodynamic stability between
the two forms can be inverted with temperature. Additional considerations are made when the physical form of the drug-substance
may be modified in the formulation process, such as in hot-melt, lyophilization, solubilization, or suspension in a semisolid
matrix, says Lafferrere. Also, drug substance–excipient interactions are considered when stabilizing particular physical and
other process parameters that may affect the performance or quality of the final product.