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Molecules 2017, 22(7), 1182; doi:10.3390/molecules22071182

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

College of Pharmacy, CHA University, Sungnam 13844, Korea
Department of Chemistry and Energy Systems Research, Ajou University, Suwon 16499, Korea
R&D center, J2H Biotech, Ansan 15426, Korea
Both authors equally contributed to this work.
Authors to whom correspondence should be addressed.
Received: 28 May 2017 / Revised: 6 July 2017 / Accepted: 11 July 2017 / Published: 14 July 2017
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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. View Full-Text
Keywords: Tenofovir disoproxil; crystal structure; stability; solubility; active pharmaceutical ingredients Tenofovir disoproxil; crystal structure; stability; solubility; active pharmaceutical ingredients

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An, J.-H.; Kiyonga, A.N.; Yoon, W.; Ryu, H.C.; Kim, J.-S.; Kang, C.; Park, M.; Yun, H.; Jung, K. Crystal Structure Analysis of the First Discovered Stability-Enhanced Solid State of Tenofovir Disoproxil Free Base Using Single Crystal X-ray Diffraction. Molecules 2017, 22, 1182.

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