Compression-Induced Polymorphic Transformation in Tablets: Role of Shear Stress and Development of Mitigation Strategies

Abstract

a b s t r a c tOur goals were to evaluate the effects of (i) hydrostatic pressure alone and (ii) its combined effect with shear stress during compaction, on the polymorphic transformation (form C / A) of a model drug, chlorpropamide. The powder was either subjected to hydrostatic pressure in a pressure vessel or compressed in a tablet press, at pressures ranging from 25 to 150 MPa. The overall extent of phase transformation was determined by powder X-ray diffractometry, whereas 2D-X-ray diffractometry enabled quantification of the spatial distribution of phase composition in tablets. Irrespective of the pressure, the extent of transformation following compaction was higher than that because of hydrostatic pressure alone, the difference attributed to the contribution of shear stress experienced during compaction. At a compression pressure of 25 MPa, there was a pronounced gradient in the extent of phase transformation when monitored from radial tablet surface to core. This gradient decreased with increase in compression pressure. Four approaches were attempted to minimize the effect of compression-induced phase transformation: (a) site-specific lubrication, (b) use of a viscoelastic excipient, (c) ceramic-lined die, and (d) use of cavity tablet. The ceramic-lined die coupled with site-specific lubrication was most effective in minimizing the extent of compression-induced phase transformation.

Combined Effect of the Preparation Method and Compression on the Physical Stability and Dissolution Behavior of Melt-Quenched Amorphous Celecoxib

“…The finite element analysis revealed that under a 200 MPa compression pressure, these areas are expected to be up to 2–10 times more strained . Accordingly, this could explain the observed differences in the compressed celecoxib samples as the shear stress can facilitate nucleation and even direct solid-state transformations . It is also important to note that slow melt-quenched samples exhibited similar tendencies as illustrated in Figure S4.…”

Characterization Methods of Amorphous Form Stability in Solid Dispersion : A Review

“…XRD is an analytical method that can show specific molecular materials such as crystals, mesophases, amorphous, and mixtures. Not only in the form of powder, now XRD can also analyze intact tablet preparations (60). The appearance of the diffraction peak indicates the crystalline molecule, whereas the absence of the diffraction peak indicates that the molecule is amorphous (61).…”

Is it possible to predict the stability of a crystal structure under the influence of pressure? Quantum chemical study of ibuprofen crystals

“…2–5 Unfortunately, solids can undergo polymorphic transformations at any stage of production or storage under the influence of temperature, pressure, impurities, contamination or simply with time. 6–14 In general, crystal packing affects the properties of various functional materials, 15–18 but changes in the crystal structure of the API can lead to changes in biological activity from insignificant deviations to its complete loss and the impossibility to use the substance for therapeutic purposes. 6,19–21 Polymorphic transitions can be of the crystal–crystal or crystal–amorphous state types.…”