Understanding Dynamics of Polymorphic Conversion during the Tableting Process Using In Situ Mechanical Raman Spectroscopy

Abstract

The objective of this study is to achieve a fundamental understanding of polymorphic interconversion during the tableting process, including during compaction, dwell, decompression/unloading, and ejection using an in situ mechanical Raman spectroscopy. The fit-for-purpose in situ mechanical Raman spectroscopy developed herein can provide simultaneous measurement of Raman spectra and densification for the powder compacts. Chlorpropamide (CPA), an antidiabetic drug, was selected as a model pharmaceutical compound because of its mechanical shear-induced polymorphic conversions. The results confirm that CPA polymorph A (CPA-A) was transformed to CPA polymorph C (CPA-C) under different compaction stresses. We also observed that the converted polymorph CPA-C could be reverted to the CPA-A due to the elastic recovery of powder compacts as detected during dwelling and unloading. This study is the first depiction of the dynamics of CPA polymorphic interconversion during compression, dwell, unloading, and ejection. Mechanistically, this study illustrates a correlation between the change in the powder compact’s relative density and polymorphic interconversion of the drug substance in different solid-state forms. The present research suggests that the process-induced polymorph conversion is a complicated dynamic process, which could be affected by the compaction pressure, the elasticity/plasticity of the material, the level of elastic recovery, and the dissipation of residual stress. In summary, this study demonstrates that the in situ mechanical Raman spectroscopy approach enables the simultaneous detection of mechanical and chemical information of the powder compact throughout the tableting process.

Recent Advances in Nanomechanical Measurements and Their Application for Pharmaceutical Crystals

“…Raman spectroscopy has been extensively used as a nondestructive chemical analysis technique that can detect changes in the crystallinity, phase or polymorph transformations, molecular interactions, stress states, and molecular orientation in crystalline materials. ,,− Direct coupling of Raman spectroscopy with instrumented nanoindentation provides a comprehensive in situ nanomechanical characterization of the material and its direct correlation to the localized chemical composition or structure (Figure ). Combining these two technologies enables in situ analysis of mechanical properties and corresponding physiochemical changes of crystalline pharmaceutical materials.…”

“…Combining these two technologies enables in situ analysis of mechanical properties and corresponding physiochemical changes of crystalline pharmaceutical materials. The molecular vibrational states can be detected using Raman spectroscopy which gives a molecular fingerprint of the materials. − Simultaneously, a nanoindentation P – h curve serves as a fingerprint of the mechanical properties of the materials. Additionally, Raman mapping can also be done after nanomechanical tests to discover comprehensive information about the plastic deformation-assisted internal stress distribution inside the material during indentation. − A few studies are discussed below to highlight the application of the Raman spectroscopy coupled nanoindentation technique for pharmaceutical crystals.…”

Unusual In Situ Transformation of Metastable Co-Crystal Forms into a Stable Form, in Solution and Solid State, and the [2 + 2] Photochemical Reactivity in the Crystalline Forms

“…Polymorphic crystals of molecular solids (single component) are popularly well-known in the literature, and in fact, even lead to various judicial battles between the competitors of drug manufacturers in the pharmaceutical arena . However, the concomitant formation of co-crystals with different compositions of the same co-formers has not been realized, so far, and, thus, so accordingly no in situ interconversions are observed.…”

“…32−34 Polymorphic crystals of molecular solids (single component) are popularly well-known in the literature, and in fact, even lead to various judicial battles between the competitors of drug manufacturers in the pharmaceutical arena. 35 However, the concomitant formation of co-crystals with different compositions of the same co-formers has not been realized, so far, and, thus, so accordingly no in situ interconversions are observed. In our endeavors, thus, citric acid (CA), one of the highly praised biomolecules for its antacid and other bioproperties 36−38 and having three −COOH groups and one −OH group, which could in principle interact with multiple coformers through different types of intermolecular interactions, is crystalized with different N-donor compounds to explore the development of multicomposition co-crystals.…”

Impact of polymorphism on mechanical properties of molecular crystals: a study of p-amino and p-nitro benzoic acid with nanoindentation

“…"Pop-out" events are sudden burst towards lower penetration depth upon indentation pressure release and are characteristic of pressure-induced polymorphic transformation. 26,27 Here, their absence are suggesting that no polymorphic transformation occurred upon pressure released, which may suggest that no polymorphic transformation occurred at all upon indentation and that E and H values extracted correspond to the true values of the polymorphs. Table 1 shows the derived elastic modulus (using a Poisson ratio of 0.3 for pABA and pNBA, reported as a typical value for molecular single crystals 25 ) and hardness data obtained from indenting the polymorphs of these two systems together with other data on polymorphs retrieved from the literature.…”