The study of technological properties and biopharmaceutical solubility of phenyltetrahydroquinolinedione derivative with TRPA1-antagonistic activity


N.V. Pyatigorskaya, N.S. Nikolenko, A.D. Kravchenko
Sechenov First Moscow State Medical University (Sechenov University), st. Trubetskaya, 8, bldg. 2, Moscow, 119991, Russian Federation

Introduction. In accordance with the principles described in ICH Q8 guideline, the critical characteristics of the components of a dosage form that can affect its quality should be studied before the serial production of a drug. Such parameters include technological properties and biopharmaceutical solubility of an active pharmaceutical ingredient. Objective: to investigate the technological properties and biopharmaceutical solubility of the original substance of a phenyltetrahydroquinolinedione derivative – TRPA1 antagonist in order to develop a solid dosage form based on it. Material and methods. Flowability and angle of repose were determined using an Erweka GTL flow tester. The bulk volume before and after compaction was determined using an ETD-1020 bulk density tester. Equilibrium biopharmaceutical solubility was determined using dissolution tester DT 626/1000 HH. The dissolved quantity of the substance was determined using Agilent 8453 UV spectrophotometer. Results. The flowability was 18.68±1.15 g/s (25 mm funnel); the angle of repose was 46.37±2.04°, the compressibility index and the Hausner ratio were 31.83±1,33% and 1.47±0,09 units, respectively. The calculated therapeutic dose did not completely dissolve in 250 ml of the medium at any pH value. The biopharmaceutical solubility at pH 1.2 was 26.64±1.36 µg/ml, at pH 4.5 – 2.72±0.15 µg/ml, at pH 6.8 – 3.8±0.21 µg/ml. Conclusion. According to the results the following conclusions can be made: it is necessary to use the granulation method or to use the excipients for direct compression; the dissolution profile of the substance allows us to attribute it to class II or IV of the biopharmaceutical classification system, so the development of the dosage form of this substance should be aimed at increasing its solubility or solubility and permeability.

pharmaceutical development
TRPA1 antagonist

  1. ICH guideline Q8 (R2) on pharmaceutical development. [Electronic resource]. Access mode: [Accessed 07 Feb., 2022].
  2. Бесхмельницына Е.А., Покровский М.В., Должиков А.А. и др. Исследование анальгетической и противовоспалительной активности нового неопиоидного анальгетика на основе селективного ингибитора ионных каналов TRPA1. Кубанский научный медицинский вестник. 2019; 26 (1): 77–87. [Beskhmel'nitsyna E.A., Pokrovskii M.V., Dolzhikov A.A. et al. Study of the Analgesic and Anti-Inflammatory Activity of a New Non-Opioid Analgesic Based on a Selective Inhibitor of TRPA1 Ion Channels. Kubanskii nauchnyi meditsinskii vestnik. 2019; 26 (1): 77–87. DOI: 10.25207/1608-6228-2019-26-1-77-87 (in Russian)]
  3. Chaurasia G. A review on pharmaceutical preformulation studies in formulation and development of new drug molecules. International J. of Pharmaceutical Science and research. 2016; 7 (6): 2313–20. DOI: 10.13040/IJPSR.0975-8232.7(6).2313-20
  4. Benet L.Z. The Role of BCS (Biopharmaceutics Classification System) and BDDCS (Biopharmaceutics Drug Disposition Classification System) in Drug Development. J. of Pharmaceutical Sciences. 2013; 102 (1): 34–42. DOI: 10.1002/jps.23359
  5. Yasir M., Asif M., Kumar A. et al. Biopharmaceutical classification system. International J. of PharmTech Research. 2010; 2 (3): 1681–90
  6. Chavda H.V., Patel C.N., Anand I.S. Biopharmaceutics classification system. Systematic Reviews in Pharmacy. 2010; 1 (1): 62–9. DOI: 10.4103/0975-8453.59514
  7. Шохин И.Е., Раменская Г.В., Кулинич Ю.И. и др. Определение равновесной биофармацевтической растворимости на примере пироксикама. Биофармацевтический журнал. 2011; 3 (3): 39–42. [Shokhin. I.E., Ramenskaya G.V., Kulinich Yu.I. еt al. Equilibrium biopharmaceutical solubility determination of piroxicam substance. Biofarmatsevticheskii zhurnal. 2011; 3 (3): 39–42 (in Russian)].
  8. Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. [Electronic resource]. Available at: [accessed 14 March 2022]
  9. ICH M9 on biopharmaceutics classification system based biowaivers. [Electronic resource]. Access mode: [accessed 14 March 2022]
  10. Кравченко А.Д. Обоснование начальной дозы нового антагониста TRPA1 – производного фенилтетрагидрохинолиндиона для клинических исследований. Инновационные исследования: теоретические основы и практическое применение: сборник статей по итогам Всероссийской научно-практической конференции. Уфа, 2021; 62–5. [Kravchenko A.D. Justification of the initial dose of a new TRPA1 antagonist, a phenyltetrahydroquinolinedione derivative, for clinical trials. Innovatsionnye issledovaniya: teoreticheskie osnovy i prakticheskoe primenenie: sbornik statei po itogam Vserossiiskoi nauchno-prakticheskoi konferentsii. Ufa, 2021; 62–5 (in Russian)]
  11. Kravchenko A.D., Pyatigorskaya N.V., Brkich G.E. et al. Synthesis, molecular docking, ADMET study and in vitro pharmacological research of 7-(2-chlorophenyl)-4-(4-methylthiazol-5-yl)-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-dione as a promising non-opioid analgesic drug. Research Results in Pharmacology. 2021; 8 (1): 1–11. DOI: 10.3897/rrpharmacology.8.8050