Influence of the Composition of Water/Ethanol Mixtures on the Solubility and Recrystallization of Nevirapine

Abstract

When anhydrous nevirapine was recrystallized from ethanol that contained increasing amounts of water, it was found that the amount of water affected not only the solubility but also the solvent inclusion and crystal habit of the precipitated material. This led to the crystallization of a previously unknown nevirapine hemiethanolate from solutions that contained less than 5% water. Adding more than 10% water led to the isolation of the known hemihydrate, and a further increase in water-content caused precipitation of the anhydrous form. It was shown not only that discontinuities in the solubility profile indicate transition from one crystal form to another but also that they occurred at the junction between two distinct crystal forms or crystal habits. A possible explanation for these observations was found in the relationship between the solubility of nevirapine, the solubility parameter of the solvent mixtures, and the change in water activity.

Channel inclusion of primary alcohols in isostructural solvates of the antiretroviral nevirapine: an X-ray and thermal analysis study

“…More recently, in a different context that focused on the influence of composition of ethanol-water mixtures on the crystallization of nevirapine [3], we have documented the isolation of a new solvate, namely nevirapineÁ(ethanol) 0.5 1.…”

Polymorphism and Solvatomorphism 2010

“…123 A previously unknown hemiethanolate was obtained when the water content was less than 5% and adding more than 10% water yielded the known hemihydrate, and higher amounts of water led to isolation of the anhydrate form. The known polymorphism associated with the monohydrates of nitrofurantoin has been further investigated, providing a more detailed discussion of the hydrogen bonding networks in the two crystal forms.…”

Recrystallization of Active Pharmaceutical Ingredients

“…The nature of the crystallization solvent can affect crystal habit, regardless of change in polymorphism (Stieger et al, 2010a). The interaction of the solvent at the different crystalsolution interfaces may lead to altered roundness of growing crystal faces and/or edges, changes in crystal growth kinetics, and enhancement or inhibition of crystal growth at certain faces (Figure 7), thereby changing the crystal habit (Stoica et al, 2004;Tiwary, 2006).…”

“…Antisolvent crystallization is performed by dissolving the API in the solvent and then gradually adding an antisolvent. This results in a decrease of solute solubility and an increase in supersaturation -much like cooling crystallization (Nonoyama et al, 2006;Stieger et al, 2010a;Zhou et al, 2006). Reverse addition is a variation of antisolvent recrystallization whereby the API solution is added to the antisolvent.…”

“…The resulting rapid increase in supersaturation leads to swift nucleation and the precipitation of very fine particles (Tung et al, 2009). The composition of the crystallization medium can affect both the crystal form and crystal habit of the product (Stieger et al, 2010a …”