Pseudopolymorphs and Intrinsic Dissolution of Nevirapine

Abstract

Nevirapine (C 15 H 14 N 4 O) is a lipophilic drug of low aqueous solubility used in AIDS treatment. Three different crystal forms of this non-nucleoside reverse transcriptase inhibitor were obtained after recrystallization procedures. Physical characterization was evaluated with DSC, TG, IR spectroscopy, and X-ray diffraction methods. Two new pseudopolymorphs have been characterized: nevirapine hemihydrate and nevirapine hemiethyl acetate. The pseudopolymorph identified as the hemiethyl acetate is disordered. It is converted to the hemihydrate form at room temperature. The crystal structures of the hemihydrate and hemiethyl acetate forms have been determined. The hemihydrate crystallizes in space group P2 1 /n, while the ethyl acetate form is in space group P1 h. Polymorphs and pseudopolymorphs of a drug may exhibit different chemical and physical properties, which can affect dissolution, besides manufacturing, stability, and bioavailability. For this reason, an investigation on the behavior of the two nevirapine pseudopolymorphs through the dissolution test has been described. The disk intrinsic dissolution rate of the solvent-free form has been found to be 1.5-fold greater than the hemihydrate form in 0.01 mol L -1 HCl and in 0.1 mol L -1 HCl, which can be explained by solubility results.

Solvated Crystalline Forms of Nevirapine: Thermoanalytical and Spectroscopic Studies

“…This is equivalent to the loss of 0.5 mol of ethanol per mole of the host compound. This is in contrast to the results reported by Pereira et al (24) where no desolvation has been observed after recrystallization from 95% ethanol using water as antisolvent. The boiling point of the solvent (78.4°C) is much lower than the desolvation temperature, suggesting that the solvent molecule is entrapped into the interstitial spaces or it is tightly bound.…”

“…It is a well-known antiretroviral agent belonging to nonnucleoside reverse transcriptase inhibitor and is used in the treatment of AIDS. The drug belongs to class II of the Biopharmaceutics Classification System with a pK a of 2.8 and is practically insoluble in water (solubility ∼0.1 mg/ml), and consequently, dissolution of the drug has been considered to be the rate-limiting step for absorption (21)(22)(23)(24). The amide function (-CONH) in the drug makes it a potential candidate for crystal polymorphism or pseudopolymorphism upon interaction with various solvents, thereby displaying unique physicochemical properties (25).…”

“…The alternate solid forms may have improved solubility and dissolution properties. Nevirapine has been reported in three polymorphic forms (26,27) and as some solvates or hydrates (24,28,29). However, not much information is available on the thermal properties.…”

Discriminatory Dissolution Test for Tablets Containing a- and b-Thalidomide Polymorphs

“…One of the best ways to analyze the discriminatory power of the method is to test the formulations with drugs that have different characteristics (particle size, crystalline form, density). If the result presents a significant difference in the variables, then the method can be considered discriminatory for the critical production variables (9,18).…”

Crystal Forms of Anti-HIV Drugs: Role of Recrystallization

“…However, many other experiments to investigate the existence of any other thermodynamically more stable form at room temperature, led to appearance of different solvatomorphs of nevirapine with varying stoichiometries depending upon the solvents selected. The first report on preparation of different solvatomorph by Pereira et al appeared in 2007 (Pereira et al, 2007). Six different solvates of nevirapine with different morphology were obtained by saturating the solvent systems with drug at room temperature and cooling in refrigerator.…”