Stabilization of a Metastable Polymorph of 4-Methyl-2-nitroacetanilide by Isomorphic Additives

Abstract

4-Methyl-2-nitroacetanilide (1) crystallizes in white (1W), amber (1A), and yellow (1Y) modifications. The isomorphic molecules 4-chloro-2-nitroacetanilide (2) and 2-nitro-4-trifluoromethylacetanilide (3) were synthesized, and their effects on the crystallization of 1 were studied. The percentages of an additive incorporated into the 1W, 1A, and 1Y crystal lattices were determined by HPLC. Compound 2 is incorporated as a solid solution in 1A up to levels of 30% (w/w), whereas the incorporation efficiency of 3 is much lower at the same doping level. From these results it can be assumed that 2 causes less disruption to the host lattices than does 3. At the same doping level of an additive, 1A incorporates the additive at a greater level than 1W or 1Y. As the incorporation level of an additive increases, both the solution and solid-state transformation rate from 1A to either 1W or 1Y decreases. Structural comparison of the 1W, 1A, and 1Y crystal lattices indicates that the additives may be least disruptive to the 1A lattice, therefore explaining the greater incorporation efficiency of an additive in 1A.

Stabilization of Metastable Flufenamic Acid by Inclusion of Mefenamic Acid: Solid Solution or Epilayer?

“…The growth of the stable phase can be seen to gradually traverse through the crystal by the advance of the yellow front. As opposed to what was reported for 4‐methyl‐2‐nitroacetanilide,13 the shape of the crystal did not change during the transformation, which McCrone classified as the formation of a pseudomorph 18. The area in transformation is indicated by the black lines.…”

“…An interesting yet little pursued avenue is the stabilization of the metastable phase by creating solid solutions by incorporation of a structurally related compound 13. It was argued that the incorporation of additives can change the relative stability between the metastable phase and the stable phase thus reducing the driving force for a transformation to the stable form.…”

Polymorphism of 1,3,5‐Trinitrobenzene Induced by a Trisindane Additive

“…1f, g Another clear example is provided by Davey and co‐workers5 who selected trimesic acid and trans ‐glutaconic acid as inhibitors of the stable β‐polymorph of L ‐glutamic acid leading to the metastable α‐polymorph. He, Stowell, and co‐workers6 designed isomorphous additives that induced crystallization of a metastable form of 4‐methyl‐2‐nitroacetanilide. The phenomenon has been reviewed 7.…”

Phase Transformation in Conformational Polymorphs of Nimesulide

“…Nimesulide is known to undergo polymorphic modification from Form II to Form I during formulation. 6 Despite the commercial importance of this drug, there is only cocrystallization additive [10][11][12][13][14] in EtOH solvent, rodshaped diffraction-quality single crystals of Form I appeared concomitantly with Form II, but the former was of better quality. The pure Form I was generated by using solvent crystallization, slurry grinding, [15][16][17][18] and solvent-drop grinding (see Experimental section for details).…”