"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."
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.