Polymorphic Transformations:
Friend or Foe to Drug Formulators?
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Figure 1. Color Composite Image Created from PCA analysis. Shown with optical reflectance image. |
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Figure 2. Pure component Raman spectra determined from a PCA analysis.
 Click Here to Read Full Article:"Combining Raman Spectroscopy and Microscopy to Support Pharmaceutical Development." by Gary McGeorge, Ph.D., Bristol-Myers Squibb Company
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Characterizing polymorphic transitions of an active pharmaceutical ingredient (API) is crucial during drug development. An API’s crystalline form correlates with the drug product’s pharmacokinetic properties, thus affecting solubility, stability, dissolution rate and shelf life. Compatibility with specific excipients and compression properties of the drug are also affected by its polymorphic form.Polymorphs typically occur due to various conditions in the crystallization process such as the presence of impurities, or temperature- or solvent-induced rapid transitions. Ultimately, polymorph transformation or the unintended formation of hydrates, solvates or salts affects an API’s bioavailability in the drug product. Identifying the conditions when a polymorphic transformation occurs, as well as preserving the desired polymorph form, often present a challenge to drug researches and developers.
Thermodynamic stability directly impacts polymorph formation or transformation. Crystallization can be induced by nucleation, melt-mediation and solution-mediation while transformations may result from responses to external parameters such as temperature, light or pressure. Understanding phase transition mechanisms that define polymorph-dependant nucleation is crucial for the identification of new polymorphs, as well as the manufacturing of drug products that contain a stable polymorph of the API. Generally, in-situ analytical methods are employed to understand these processes that manifest metastable or amorphous forms that aren’t easily isolated for x-ray diffraction analysis.
Once identified, specific crystalline forms of the API can be protected as intellectual property. This is a common practice of innovator drug companies seeking legal protection from competitors, including other innovators and generic drug development companies. Many drugs receive regulatory approval for only a single crystal form, however, which opens the door for other more effective polymorphs to be discovered and patented.
Over the past several years, scientists at ChemImage Corporation have been conducting research on Raman Chemical Imaging’s (RCI) ability to identify and help control the polymorphic purity of pharmaceutical compounds. From ointments to polymers to tablets, RCI has shown great promise where other techniques like x-ray crystallography have fallen short.
One study focused on the transformation of amorphous to crystalline acetaminophen (APAP) using RCI. Here a full range of Raman spectra were collected and measured for amorphous and types I, II, and III APAP. These spectra were used to develop a multivariate calibration for application to Raman chemical images that were collected during a spontaneous transformation of the amorphous glass to crystalline APAP. Raman-detected differential scanning calorimetry confirmed the assignment of the exothermic transition of a super cooled liquid to type III transformation, which had not previously been understood nor reported in literature. The type III to type II transformation occurred at about 120°C.
Typically, drugs in creams and ointments may be introduced as one type of polymorph, but may change under specific conditions. Another study conducted by ChemImage examined the shelf-life stability of one such substance: ointments. Here, dispersive Raman and Liquid Crystal Tunable Filter spectra of the powder APIs were acquired using 532 nm laser excitation. The observed differences in band positions of the APIs established the basis for differentiating the spatial distribution of the API crystals in the final formulation from each other, as well as from other components. Comparison of the crystal spectra in each ointment sample to the API spectra enabled positive identification of crystals of particular habit, proving RCI’s ability to associate a precipitate’s morphology or crystal habit to a polymorphic form.
Once identified and understood, polymorphic transformations of drug products can be controlled. This information can benefit drug researchers and formulators by giving them valuable insight into the manufacturing process, as well as the ability to seek intellectual property rights. With its superior specificity and flexibility in drug delivery types, RCI is leading the way in polymorph characterization.
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