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

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.

On the Single-Crystal Structure of Tenofovir Alafenamide Mono-Fumarate: A Metastable Phase Featuring a Mixture of Co-Crystal and Salt

“…The product outcome with ∆pK a values between 0-3 remains hard to predict. Our present case is further complicated by two pK a values (pK a1 = 3.0, pK a2 = 4.4) for fumaric acid and two pK a values (pK a1 = 4.2, pK a2 = 9.8) for TAF [13]. We therefore invoked Fourier-transform infrared (FT-IR) spectra in combination with single-crystal X-ray diffraction results to study the structural features of 2.…”

“…In current medical practice, inhibiting the retroviral process is a major approach to suppressing the replication of viruses to minimize liver damage when modulating immune system dysfunction in HIV [9]. In this regard, tenofovir (TF, Figure 1) is a nucleotide reverse transcriptase inhibitor, which is Accordingly, TF derivatives, particularly tenofovir disoproxil (TDF, Figure 1), in combination with the other drugs cobicistat, elvitegravir, emtricitabine, and rilpivirine, have been extensively exploited as prodrugs of TF for the treatment of HIV-1 infections [11,13]. Compared to the native TF, TDF is designed to improve TF permeability, allowing a systemic drug delivery via oral administration.…”

“…[4,14] Besides, TAF is readily transformed into TF within lymphocytes, providing improved intracellular drug accumulation in HIV target cells. Furthermore, TAF is more stable in blood when compared to TDF and efficiently delivers tenofovir to cells with lower dosages, and it possesses a greater antiviral activity and better distribution into lymphoid tissues with a lower incidence of Accordingly, TF derivatives, particularly tenofovir disoproxil (TDF, Figure 1), in combination with the other drugs cobicistat, elvitegravir, emtricitabine, and rilpivirine, have been extensively exploited as prodrugs of TF for the treatment of HIV-1 infections [11,13]. Compared to the native TF, TDF is designed to improve TF permeability, allowing a systemic drug delivery via oral administration.…”

“…In a very recent report, TAF and TAF hemifumarate (1; TAF:fumarate = 2:1) have been prepared and structurally authenticated by single-crystal X-ray diffraction studies, with 1 also being confirmed as TAF and fumaric acid co-crystal [13]. However, when TAF was precipitated as monofumarate (TAF:fumarate = 1:1), three polymorphic forms existed, as revealed by powder X-ray diffraction (PXRD) [13]. The 15 N solid-state nuclear magnetic resonance (NMR) of one of these forms also indicated that it contained ca.…”

Supramolecular Diversity of Oxabicyclo[2.2.2]octenes Formed between Substituted 2H-Pyran-2-ones and Vinyl-Moiety-Containing Dienophiles

“…X-ray diffraction analysis confirmed that the cycloaddition yielded a mixture of both stereoisomers that we were able to separate and based on the NMR data for these two compounds, the structures of other cycloadducts were established as well. However, we were intrigued by the possibility of further investigating the structures of some of the other cycloadducts of the type 3 and 4 in the solid state, as nowadays novel studies regularly underpin the importance of various intermolecular interactions [42][43][44][45], not just hydrogen bonds. Therefore, we prepared suitable crystals of six primary cycloadducts of the type 3 and one cyclohexadiene product 4 and embarked on thorough X-ray crystallographic investigation, including their crystal packing and supramolecular architectures.…”