An Insight into Thermodynamic Relationship Between Polymorphic Forms of Efavirenz

Abstract

-Purpose:The aim of the work is to study the crystallization of efavirenz to understand the preferential formation of various polymorphic forms, to establish their identity, to study the transformation between the polymorphic forms on heating and to determine their free energy. Methods: Slow crystallization from different solvents under controlled conditions was employed to prepare various crystalline forms. The TGA and DSC were used to study their thermal behavior and inter-conversion of these forms. The calorimetrically determined enthalpies of solution and solubility data are utilized to determine the transition temperatures. Results: Six polymorphic forms of efavirenz are identified and characterized completely. The TGA scans of all the forms did not show any mass loss indicating absence of hydrate or solvate. The thermally induced transformations are observed in the DSC scans of five forms II-VI indicating them to be metastable which are converted to stable higher melting forms. The melting temperature and enthalpy of fusion of lower melting (Form L ) and higher melting forms (Form H ) reveal that four of these polymorphic pairs are monotropically related. The enthalpies of solution of Form L are found to be more exothermic as compared to corresponding Form H . The transition temperature (T t ) determined using enthalpy of solution and solubility data was found to be higher than the melting of both the forms except for polymorphic pair VI L /VI H . The effect of ΔC p on transition temperature is also reported. Conclusions: The form I is found to be thermodymanically most stable but least soluble. The forms II-V are metastable and are converted irreversibly to stable forms. The enthalpy of fusion rule and virtual transition temperature provided complementary evidence for the existence of monotropy in these polymorphic pairs. However, enantiotropy is demonstrated in VI L /VL H pair and is well established in our study. Novelty: The present study reveals the thermodynamic aspects of various isolated polymorphic forms of efavirenz. Solution calorimetry along with other techniques is used to study the transformation of one form to another. The emphasis is laid on determination of transition temperature of various polymorphic pairs which has not been reported earlier.

Development of a Discriminative Intrinsic Dissolution Method for Efavirenz

“…The mean onset and endset temperatures were around 138.7 °C and 140.5 °C, respectively (ΔH = 44.6 J/g). Additional peaks indicative of polymorphic transitions were not observed and confirmed results obtained from XRD, indicating that the evaluated samples contained only polymorph I (35,36).…”

“…The XRD analyses of the compacts showed no changes in the crystalline structure of the drug after application of the compressive force, since the XRD patterns obtained with 30 s and 1 min of compression corresponded to the crystalline form I patterns of efavirenz and to the diffractograms (Figure 1) obtained before the application of compressive force (35,36). The compacts increased in hardness when prepared in the range of 100-1000 psi for 30 s, which indicates that the compacts became harder when subjected to increasing compression forces of up to 300 psi.…”

“…Form I is the most stable polymorph of efavirenz and is commonly used in pharmaceutical formulations (35,36). The DSC thermogram (Figure 2) shows that the endothermic melting curves of efavirenz batches were between 138 and 141 °C.…”

Conjugation of Hot-Melt Extrusion with High-Pressure Homogenization: a Novel Method of Continuously Preparing Nanocrystal Solid Dispersions

“…EFZ is a poorly water-soluble (9.2 μg/mL, pH 8.7, 25°C) lipophilic (log P=5.4) drug with a crystalline state. The melting temperature (T m ) of EFZ is around 140°C (39). To maintain the crystalline state of EFZ, the HME operating temperature must be kept below 140°C.…”

Polymorphism: The Phenomenon Affecting the Performance of Drugs

“…Thermal properties of polymorphs are an important aspect and are generally fetched by DSC and TGA [66][67][68]. Thermal properties of polymorphs are an important aspect and are generally fetched by DSC and TGA [66][67][68].…”