Kinetic estimation of solid state transition during isothermal and grinding processes among efavirenz polymorphs

Abstract

Investigation into the solid-state transition among drug polymorphs has been more intense lately. Many factors induce the transformation of polymorphs during manufacturing processes. Efavirenz (EFV), an AIDS therapy drug, has more than 23 polymorphs, but very little information has been reported on them. This study aimed to perform a characterisation of EFV polymorph properties and to predict the kinetics and mechanism of the polymorphic transformation of EFV during manufacturing processes. The bimorphism study was conducted by Differential Scanning Calorimetry (DSC) thermal analysis. The phase transition kinetics of the polymorphs was monitored by X-ray powder diffraction and the quantification of concomitant polymorphs was examined using Rietveld refinement with MAUD ver. 2.7 as a software aid. To predict the solid-state transition, correlation coefficients of solid-state kinetic models were fitted to the experimental data. The results show that Form I and Form II of EFV were thermodynamically shown to be monotropy related. By fitting the experimental data, it was found that isothermal treatment had the best model fit with the phase boundary reaction in the two-dimensional model (G2). Accordingly, by employing mechanical treatment (grinding), it was predicted that the transition mechanism is a second-ordered reaction (R2). The activation energy of the transition during isothermal treatment calculated by the Arrhenius plot was found to be 23.051 kJ mol À1 ; the half-lif of Form II at ambient temperature was 428.05 min (~7.1 h).

Peningkatan Disolusi dan Stabilitas Efavirenz Menggunakan Beberapa Metode Dispersi Padat

“…Bentuk kristalin cenderung lebih stabil dibandingkan amorf, namun kelarutannya lebih rendah dibandingkan amorf [6]. Diantara obat-obatan yang memiliki sifat polimorf, contohnya adalah Efavirenz [6][7][8][9]. Efavirenz (EFV) adalah penghambat transkriptase balik non-nukleosida (NNRTI) yang sering digunakan sebagai terapi lini pertama untuk pengobatan infeksi HIV [10].…”

“…Efavirenz merupakan obat terapi AIDS yang memiliki lebih dari 23 polimorf [9]. Efavirenz bersifat sangat hidrofobik dengan gugus fungsi seperti -Cl, CF3, siklopropana, dan gugus alkil, namun memiliki gugus NH yang dapat terprotonasi, tetapi berikatan dengan C=O yang menjadikannya "enol" konjugasi yang diperpanjang [19].…”

“…Efavirenz memiliki perbedaan kelarutan dan stabilitas dalam berbagai bentuk polimorfik [6][7][8]. Perbedaan kelarutan dan stabilitas tersebut dikaitkan pada sifat termodinamika polimorf (monotropi) dan modifikasi morfologi [6][7][8][9]. Polimorf stabil lebih disukai secara termodinamika di zona mobilitas rendah, sedangkan bentuk metastabil lebih disukai secara kinetik ketika mobilitas molekul obat cukup tinggi [17].…”

“…Efavirenz kristal dapat menjadi bentuk amorf dengan pelelehan pada suhu 140°C [6]. Rekristalisasi efavirenz dengan pelarut organik yang berbeda juga akan menghasilkan polimorf dengan morfologi dan sifat yang berbeda [8,9]. Transformasi efavirenz bentuk amorf ke bentuk kristal cepat terjadi pada proses penggilingan setelah 10 menit, dan pada efek pemanasan sekitar 80°C [6,21].…”

In Vitro Solubility and Release Profile Correlation with pKa Value of Efavirenz Polymorphs

“…In these equations, C t is the amount of drug dissolved at time t; C0 is the initial amount of drug in the solution (usually t = 0); Q is the amount of drug released over time t per unit area A; D is the diffusivity of the drug molecules (diffusion coefficient) in the matrix substance; k is the release order rate constant; and kH is the Higuchi dissolution rate constant (43).…”