Modification of acetaminophen crystals. III. Influence of initial supersaturation during solution-phase growth on crystal properties in the presence and absence of p-acetoxyacetanilide

Abstract

Acetaminophen (paracetamol, P) has been crystallized from aqueous solutions at various initial supersaturations (5.34–16.88 g dm −3) with 0 or 500 mg dm −3 p-acetoxyacetanilide (A) and its physical properties examined. In the absence of A, an increase in the initial supersaturation, σ (i.e. the initial concentration of P minus the solubility of P), does not appear to change the crystal habit (polyhedral prisms), but substantially increases the water content (by a factor of 8), decreases the enthalpy of fusion, ΔH f, melting point, T m, and entropy of fusion, Δs f, (by 6–14, 0.3–1.4 and 6–13 % respectively) and reduces the intrinsic dissolution rate of the crystals to constant values for σ between 6.63 and 14.32 g dm −3. On the other hand, when 500 mg dm −3 A are added to the solution, increasing the initial supersaturation broadens the crystal habit progressively, lowers and raises the water content, increases and decreases the ΔH f, T m and ΔS f, reduces the uptake of A to approximately constant mole fractions around 0.0013, and enhances and then reduces the intrinsic dissolution rate of the crystals to values about 50% greater than that of the polyhedral prisms grown in the absence of A. The above observations demonstrate the pharmaceutical significance of supersaturation during crystallization as a modulator of the physical properties and aqueous dissolution rate of the P crystals.