Physical factors influencing the aqueous dissolution rate of acetaminophen crystals doped with p-acetoxyacetanilide: evaluation by multiple linear regression

Abstract

A semi-empirical relationship between the aqueous intrinsic dissolution rate ( J),of acetaminophen, P, crystals and their length-to-width ratio ( l w ), uptake of p-acetoxyacetanilide, A ( X A), entropy of fusion ( ΔS f) and water content ( x w) has been developed by consideration of the following factors: (a) crystal anisotropy; (b) habit-related hydrodynamic conditions during dissolution; (c) crystal defects induced by A, water and/or crystallization conditions; and (d) non-stoichiometric hydrates. For the purpose of comparison, factors (a) and (b) may be represented approximately by l w , while factors (c) and (d), which are closely related, by ΔS f, x A and x w, respectively. Based on the Noyes-Whitney equation and solution thermodynamics, the following log-linear relationship is proposed: In J = n · ln( l w ) − p · ΔS f − q· ln x w + r · ln x A + s where n, p, q, r and s are empirical constants. This type of equation was tested against experimental data and examined statistically by multiple linear regression analysis. About 90% of the variation in J are ascribable to l w , ΔS f and x w , while the remaining 10% are due to errors and/or to other factors.