Co-crystals, Salts or Mixtures of Both? The Case of Tenofovir Alafenamide Fumarates.

Hannes Lengauer,Damjan Šterk,Arthur Pichler,Franc Perdih,Damjan Makuc,Janez Plavec,Zdenko Časar,Tina Trdan Lušin

doi:10.3390/pharmaceutics12040342

Abstract

Tenofovir alafenamide fumarate (TAF) is the newest prodrug of tenofovir that constitutes several drug products used for the treatment of HIV/AIDS. Although the solid-state properties of its predecessor tenofovir disoproxil fumarate have been investigated and described in the literature, there are no data in the scientific literature on the solid state properties of TAF. In our report, we describe the preparation of two novel polymorphs II and III of tenofovir alafenamide monofumarate (TA MF2 and TA MF3). The solid-state structure of these compounds was investigated in parallel to the previously known tenofovir alafenamide monofumarate form I (TA MF1) and tenofovir alafenamide hemifumarate (TA HF). Interestingly, the single-crystal X-ray diffraction of TA HF revealed that this derivative exists as a co-crystal form. In addition, we prepared a crystalline tenofovir alafenamide free base (TA) and its hydrochloride salt (TA HCl), which enabled us to determine the structure of TA MF derivatives using 15N-ssNMR (15N-solid state nuclear magnetic resonance). Surprisingly, we observed that TA MF1 exists as a mixed ionization state complex or pure salt, while TA MF2 and TA MF3 can be obtained as pure co-crystal forms.

Highlights

HIV/AIDS remains one of the important causes of death globally and the leading cause of death in low-income countries [1]
For the purpose of the tenofovir alafenamide and tenofovir alafenamide hydrochloride synthesis, tenofovir alafenamide hemifumarate was purchased from Jiangsu Cdymax Pharmaceuticals Co., Ltd. (Qidong, China)
All solution nuclear magnetic resonance (NMR) spectra were recorded at 298 K on a Varian VNMR400 NMR spectrometer (Varian Inc., Palo Alto, CA, USA) equipped with an AutoX DB double resonance probe operating at a 1H resonance frequency of 400 MHz and a 13C resonance frequency of 100 MHz. 1H NMR chemical shifts and 13C NMR chemical shifts are quoted in parts per million downfield from tetramethylsilane (TMS), and coupling constants (J) are quoted in Hertz (Hz)

Summary

Introduction

HIV/AIDS remains one of the important causes of death globally and the leading cause of death in low-income countries [1]. It was estimated that nearly 38 million people were living with HIV in 2018 and that 770,000 died because of AIDS globally in 2018 [2]. There are several therapeutic classes of drugs available for the treatment of HIV infection [3–5]. Tenofovir alafenamide fumarate (known as TAF) [6–8] is a novel prodrug derivative of the well-known nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir (TFV) [9–11], which was initially developed for the treatment of HIV infection as tenofovir disoproxil fumarate (TDF) in the late 1990s [12–14] and marketed under the tradename Viread® since 2001 [15]. TAF, as a new type of TFV prodrug, was approved as a mono therapy (Vemlidy®) in November 2016 for the treatment of chronic hepatitis B virus infection [16–20] in adults with compensated liver disease by the U.S Food & Drug Administration (FDA).

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Results

Conclusion