Compression-Induced Crystallization of Amorphous Indomethacin in Tablets: Characterization of Spatial Heterogeneity by Two-Dimensional X-ray Diffractometry

Abstract

Tablets of amorphous indomethacin were compressed at 10, 25, 50, or 100 MPa using either an unlubricated or a lubricated die and stored individually at 35 °C in sealed Mylar pouches. At selected time points, tablets were analyzed by two-dimensional X-ray diffractometry (2D-XRD), which enabled us to profile the extent of drug crystallization in tablets, in both the radial and axial directions. To evaluate the role of lubricant, magnesium stearate was used as "internal" and/or "external" lubricant. Indomethacin crystallization propensity increased as a function of compression pressure, with 100 MPa pressure causing crystallization immediately after compression (detected using synchrotron radiation). However, the drug crystallization was not uniform throughout the tablets. In unlubricated systems, pronounced crystallization at the radial surface could be attributed to die wall friction. The tablet core remained substantially amorphous, irrespective of the compression pressure. Lubrication of the die wall with magnesium stearate, as external lubricant, dramatically decreased drug crystallization at the radial surface. The spatial heterogeneity in drug crystallization, as a function of formulation composition and compression pressure, was systematically investigated. When formulating amorphous systems as tablets, the potential for compression induced crystallization warrants careful consideration. Very low levels of crystallization on the tablet surface, while profoundly affecting product performance (decrease in dissolution rate), may not be readily detected by conventional analytical techniques. Early detection of crystallization could be pivotal in the successful design of a dosage form where, in order to obtain the desired bioavailability, the drug may be in a high energy state. Specialized X-ray diffractometric techniques (2D; use of high intensity synchrotron radiation) enabled detection of very low levels of drug crystallization and revealed the heterogeneity in crystallization within the tablet.

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

“…36 We had earlier observed a pronounced decrease in compression-induced crystallization on the radial surface by external (i.e., site-specific) lubrication of the die wall. 10 A similar effect was observed in the polymorphic transformation of CPM, when the die wall and punch tip faces were prelubricated with MgSt. The effect of the type of lubrication on the transformation profile in tablets compressed at 25 or 150 MPa is shown in Figure 4.…”

“…A similar effect of compression was observed in indomethacin, wherein compression caused amorphous / crystalline transition. 10 Site-specific lubrication, while reducing the effect of compression, could not prevent phase transformation on the tablet surface. We therefore took a multipronged approach to minimize radial surface-die wall friction, and thereby attenuate the effect of compression.…”

“…8 On the other hand, compression of amorphous drugs such as indomethacin, sucrose, celecoxib caused its crystallization. [9][10][11] Crystallization was most pronounced on the radial tablet surface, which comes in contact with die wall and was attributed to die wall friction. 10 There are also several examples of compression-induced crystalline / crystalline (i.e., polymorphic) transformations.…”

“…[9][10][11] Crystallization was most pronounced on the radial tablet surface, which comes in contact with die wall and was attributed to die wall friction. 10 There are also several examples of compression-induced crystalline / crystalline (i.e., polymorphic) transformations. Caffeine form I, when formulated with excipients and compressed at 70-170 MPa, transformed to the stable form II.…”

Comparison of pharmaceutical formulations: ATR-FTIR spectroscopic imaging to study drug-carrier interactions

“…reducing the crystallinity to form an amorphous state (Kaushal et al, 2004;Newman et al, 2012;Song et al, 2015). Potential caveats of using these approaches exist for example, the amorphous form is in a thermodynamically unfavourable state so conversion to a more stable (or meta-stable) crystalline form can occur (Patterson et al, 2005;Thakral et al, 2015). It is also possible for the ionised species to undergo disproportionation, where the salt form converts back to its original acid or base structure (Ewing et al, 2015;Guerrieri and Taylor, 2009).…”