Top-Down Synthesis of a Lamivudine-Zidovudine Nano Co-Crystal

Bwalya A Witika,Roderick B Walker,Vincent J Smith

doi:10.3390/cryst11010033

Abstract

Lamivudine (3TC) and zidovudine (AZT) are antiretroviral agents used to manage HIV/AIDS infection. A wet media milling top-down approach was used to develop and produce nano co-crystals of 3TC and AZT. Micro co-crystals were prepared by solvent evaporation and subsequently milled in the presence of two surfactants, viz., sodium lauryl sulfate (SLS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000). Optimisation was undertaken using design of experiments (DoE) and response surface methodology (RSM) to establish and identify parameters that may affect the manufacturing of nano co-crystals. The impact of SLS and TPGS 1000 concentration, milling time, and number of units of milling medium on the manufacturing of nano co-crystals, was investigated. The critical quality attributes (CQA) monitored were particle size (PS), Zeta potential (ZP), and polydispersity index (PDI). Powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, transmission electron microscopy, energy dispersive X-ray spectroscopy scanning electron microscopy, and cytotoxicity assays were used for additional characterization of the optimised nano co-crystal. The mean PS, PDI, and ZP of the optimised top-down nanocrystal were 271.0 ± 92.0 nm, 0.467 ± 0.073, and −41.9 ± 3.94 mV, respectively. In conclusion, a simple, inexpensive, rapid, and precise method of nano co-crystal manufacturing was developed, validated, and optimised using DoE and RSM, and the final product exhibited the target CQA.

Highlights

HIV/AIDS remains one of the most widespread diseases in the world with an estimated 37 million people living with HIV at the end of 2018, and approximately 1.8 million new infections are reported, annually [1]
TPGS 1000 and sodium lauryl sulfate (SLS) were included in the formulation to impart steric and electrostatic stabilisation properties to the nano co-crystal (NCC), respectively
The particle size (PS) was directly affected by the combined antagonistic effect of the number of milling balls and milling time, indicating that increasing the number of milling balls required a reduction in milling time to achieve the target PS

Summary

Introduction

HIV/AIDS remains one of the most widespread diseases in the world with an estimated 37 million people living with HIV at the end of 2018, and approximately 1.8 million new infections are reported, annually [1]. The only effective regimen for HIV treatment is highly active antiretroviral treatment (HAART), which requires the use of more than one class of antiretroviral (ARV) compound [3]. Lamivudine (3TC) and zidovudine (AZT) are ARVs used in combination with other molecules for the suppression of HIV to halt progression of HIV to AIDS [4,5,6]. The bioavailability of AZT is relatively poor due to low solubility, while hepatic first-pass metabolism of AZT necessitates frequent dosing to achieve therapeutic levels, often resulting in poor adherence to therapy, subsequently leading to poor clinical outcomes [7,8,9].

Methods

Results

Conclusion