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Experimental Solubility, Thermodynamic/Computational Validations, and GastroPlus-Based In Silico Prediction for Subcutaneous Delivery of Rifampicin

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Abstract

We focused to explore a suitable solvent for rifampicin (RIF) recommended for subcutaneous (sub-Q) delivery [ethylene glycol (EG), propylene glycol (PG), tween 20, polyethylene glycol-400 (PEG400), oleic acid (OA), N-methyl-2-pyrrolidone (NMP), cremophor-EL (CEL), ethyl oleate (EO), methanol, and glycerol] followed by computational validations and in-silico prediction using GastroPlus. The experimental solubility was conducted over temperature ranges T = 298.2–318.2 K) and fixed pressure (p = 0.1 MPa) followed by validation employing computational models (Apelblat, and vanʼt Hoff). Moreover, the HSPiP solubility software provided the Hansen solubility parameters. At T = 318.2K, the estimated maximum solubility (in term of mole fraction) values of the drug were in order of NMP (11.9 × 10-2) ˃ methanol (6.8 × 10-2) ˃ PEG400 (4.8 × 10-2) ˃ tween 20 (3.4 × 10-2). The drug dissolution was endothermic process and entropy driven as evident from “apparent thermodynamic analysis”. The activity coefficients confirmed facilitated RIF–NMP interactions for increased solubility among them. Eventually, GastroPlus predicted the impact of critical input parameters on major pharmacokinetics responses after sub-Q delivery as compared to oral delivery. Thus, NMP may be the best solvent for sub-Q delivery of RIF to treat skin tuberculosis (local and systemic) and cutaneous related disease at explored concentration.

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Abbreviations

RIF:

rifampicin

OA:

oleic acid

EO:

ethyl oleate

PG:

propylene glycol

EG:

ethylene glycol

RMSD:

root mean square deviation

CEL:

cremophor-EL

PEG400:

polyethylene glycol 400

UPLC:

ultra performance liquid chromatography

DSC:

differential scanning calorimeter

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Acknowledgement

“The authors would like to thank the Deanship of Scientific Research at King Saud University for supporting this study through research group project number (RG-1441-443)”.

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Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia

    Wael A. Mahdi, Afzal Hussain, Mohammad A. Altamimi, Sultan Alshehri & Sarah I. Bukhari

  2. Department of Medical Laboratory Technology, University Polytechnic, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India

    Mohd Neyaz Ahsan

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  1. Wael A. Mahdi
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Contributions

Wael A. Mahdi: conceptualization and funding acquisition, Afzal Hussain: methodology and writing—original draft and review, Mohammad A. Altamimi: software and data curation, Sultan Alshehri: data curation, Sarah I Bukhari: formal review, Mohd. Neyaz Ahsan: software and analysis.

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Correspondence to Afzal Hussain.

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Mahdi, W.A., Hussain, A., Altamimi, M.A. et al. Experimental Solubility, Thermodynamic/Computational Validations, and GastroPlus-Based In Silico Prediction for Subcutaneous Delivery of Rifampicin. AAPS PharmSciTech 22, 116 (2021). https://doi.org/10.1208/s12249-021-01987-y

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