Crystal Structure Analysis of the First Discovered Stability-Enhanced Solid State of Tenofovir Disoproxil Free Base Using Single Crystal X-ray Diffraction

Abstract

Tenofovir disoproxil (TD), an anti-virus drug, is currently marketed under its most stable form, Form-I of Tenofovir disoproxil fumarate (TDF). However, studies regarding the properties of TD free base crystal as a promising drug as well as its crystal structure have not yet been reported. This assumption was made because TD free base is not directly produced in a solid form during the manufacturing process. TD free base is first obtained in an oil form, and is then synthesized into TDF crystal. In this regard, the present study was conducted to investigate both the potentiality of TD free base to be an active pharmaceutical ingredient (API) and its crystal structure. Here, TD free base solid was produced by means of drowning-out crystallization. Next, single crystal X-ray diffraction (SXD) was employed to determine the crystal structure. Powder X-ray diffraction (PXRD) and a differential scanning calorimetry (DSC) analysis were performed to evaluate the crystal’s properties. Furthermore, experiments were carried out at 15%, 35%, 55%, 75%, and 95% relative humidity (RH) for 12 h using a hygroscopic tester to determine and to compare the hygroscopicity and stability of TD free base with TDF crystal. Additionally, experiments were conducted under accelerated (40 °C, RH 75%) and stress storage (60 °C, RH 75%) conditions for 30 days to investigate the changes in purity and the formation of dimer. In this work, we report that TD free base possesses lower hygroscopicity, and thus does not generate dimer impurity from hydrolysis. Primarily, this is attributed to the fact that TD free base is not an easily ionized salt but comprises neutral hydrophobic molecules. According to the structural properties, the improved hygroscopic property of the TD free base crystal was due to the decrease of crystal polarity owing to the intermolecular H-bonds present in TD free base rings. In addition, the solubility investigation study carried out in aqueous solution and at gastrointestinal pH revealed a similarity in TDF and TD free base solubility under the mentioned conditions. Accordingly, we could confirm the potentiality of TD free base as an active pharmaceutical ingredient.

The Selection of a Pharmaceutical Salt—The Effect of the Acidity of the Counterion on Its Solubility and Potential Biopharmaceutical Performance

“…It is not uncommon that the free base dissociated from a salt in aqueous medium is not a crystalline solid form, but rather a gel or oil. 15,24 Therefore, it was unsurprising that the solids from the sample vials of both benzoate and besylate salt in 0.1 NaOH were not crystalline.…”

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

“…Interestingly, although there are several literature reports on the solid-state properties of TDF [94][95][96][97][98][99], to the best of our knowledge, TAF solid-state chemistry has not yet been described in the scientific literature. The patent literature discloses tenofovir alafenamide monofumarate form I (TA MF1) [100], as well as tenofovir alafenamide hemifumarate (TA HF) [101], which is considered to be the more thermodynamically stable form.…”

Pharmacokinetic Feasibility of Stability-Enhanced Solid-State (SESS) Tenofovir Disoproxil Free Base Crystal

“…The TEV (PMPA; purity 98.00%), synthesized stability-enhanced solid state TD free base crystal (SESS-TD crystal; purity 99.93%), and TDF (i.e., TDF form-I; purity 98.37%) ( Figure 1 ) were provided by Dr. Kiwon Jung (CHA University and Oncobix Co., Ltd., Gyeonggi-do, Republic of Korea) [ 11 ]. The physicochemical properties of the SESS-TD crystal are described in Table 1 .…”