Abstract：OBJECTIVE To introduce the basic procedure and technical requirements of equilibrium solubility experiments and provide reference for design and conduct of equilibrium solubility experiments scheme. METHODS The concept and influence factors of solubility, principle and determination method of solubility experiments, equilibrium solubility project of world health organization were analyzed. RESULTS The influence factors of equilibrium solubility include composition of buffers, temperature, time of oscillation, time of sedimentation, techniques for separation of solid and liquid phases etc. CONCLUSION To ascertain the BCS classification of drugs, the first step is to determine the equilibrium solubility of drugs under physiological pH conditions. To date, there is no accepted standard method for the determination of equilibrium solubility. This paper introduces the basic procedure and technical requirements of equilibrium solubility experiments recommended by WHO, which would provide instructive and practical assists to conduct of equilibrium solubility experiments and standardize its application in BCS classification and biowaiver.
AMIDON G L, LENNEMAS H, SHAH V P, et al. A theoretical basis for a biopharmaceutic drug classification:the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res, 1995,12(3):413-420.
[2]
Food and Drug Administration. Guidance for industry:“Waiver of in invo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System”. . http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
[3]
European Medicines Agency. Note for guidance on the investigation of bioavailability and bioequivalence. . https://www.ema.europa.eu/documents/scientific-guideline/note-guidance-investigation-bioavailability-bioequivalence_en.pdf.
[4]
World Health Organization.Translated by JIN S H, NING B M. WHO Expert Committee on Specifications for Pharmaceutical Preparations Technical Report Series Fortieth Report(世界卫生组织药品标准专家委员会第40次技术报告).No.937. Beijing:China Medical Science and Technology Press, 2009:375-427.
[5]
China National Medical Products Administration. Human Bioequivalence Test Waiver Guidelines(Draft). . http://samr.cfda.gov.cn/WS01/CL0778/149640.html.
[6]
XU M D, WANG L, WANG T S, et al. Comparison of different biopharmaceutics classification systems (BCS) and discussion of its application. Chin Pharm J(中国药学杂志),2016,51(10):777-779.
[7]
GAO Y,GENG L D. Comparison and discussion of FDA, WHO and EMA guidelines on BCS-based biowaiver. Chin New Drugs J(中国新药杂志),2012,21(24):2861-2869.
[8]
BRITTAIN H G. Physical Characterization of Pharmaceutical Solids. New York:Marcel Dekker,1995:321-386.
[9]
EDIT B, JOHN E A C, KRISZTINA T N. Study of equilibrium solubility measurement by saturation shake-flask method using hydrochlorothiazide as model compound. J Pharm Biomed Anal, 2008, 46(2):335-341.
[10]
LI P, TABIBI S E, YALKOWSKY S H. Solubilization of flavopiridol by pH control combined with cosolvents, surfactants, or complexants. J Pharm Sci, 1999,88(9):945-947.
[11]
RAN Y, YALKOWSKY S H. Prediction of drug solubility by the general solubility equation(GSE). J Chem Inf Model, 2001,41(2):354-357.
[12]
WILLIAM L J, ERIN M D. Prediction of drug solubility from structure. Adv Drug Deliv Rev, 2002, 54(3):355-366.
[13]
World Health Organization. WHO expert committee on specifications for pharmaceutical preparations Technical Report Series Fifty-first Report No.1003. Geneva:WHO, 2017. https://www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/WHO_TRS_1003_full-version.pdf?ua=1.
[14]
STUART M, BOX K. Chasing equilibrium:measuring the intrinsic solubility of weak acids and bases. Anal Chem, 2005,77(4):983-990.
[15]
AVDEEF A. pH-metric solubility.1. solubility-pH profiles from bjerrum plots. gibbs buffer and pKa in the solid state. Pharm Pharmacol Commun, 1998,4(3):165-178.
[16]
AVDEEF A, BERGER C M, BROWNELL C. pH-Metric solubility.2:correlation between the acid-base titration and the saturation shake-flask solubility-pH methods. Pharm Res, 2000,17(1):85-89.
[17]
AVDEEF A, BERGER C M. pH-Metric solubility.3. dissolution titration template method for solubility determination. Eur J Pharm Sci, 2001,14(4):281-291.
[18]
MU S D, ZHENG G H, SONG C W, et al. Measurement of equilibrium solubility, oil-water partition coefficients and dissociation constant of chrysin. Chin J Pharm Anal(药物分析杂志),2018,38(6):997-1004.
[19]
QIN F H, CAI Y, YU J D. Determination of equilibrium solubility and apparent oil/water partition coefficients of rhein. Her Med(医药导报), 2018,37(1):88-91.
[20]
ZHANG T T, XU W, HU S L, et al. Determination of equilibrium solubility of silibinin in various medium and its apparent oil/water partition coefficient. Chin Pharm J(中国药学杂志), 2006,41(20):1569-1571.
[21]
APLEY M, CRIST G B, FELLNER V, et al. Determination of thermodynamic solubility of active pharmaceutical ingredients for veterinary species:a new USP general chapter. Dissolut Technol, 2017, 24(1):36-39.
[22]
World Health Organization. Stability testing of active pharmaceutical ingredients and finished pharmaceutical products. WHO expert committee on specifications for pharmaceutical preparations Technical Report Series Fifty-second Report No.1010. Geneva:WHO, 2018. http://apps.who.int/iris/bitstream/handle/10665/272452/9789241210195-eng.pdf?ua=1.
[23]
World Health Organization. Supplementary guidelines on good manufacturing practices:validation. WHO expert committee on specifications for pharmaceutical preparations Technical Report Series Fortieth Report No.937. Geneva:WHO, 2006. http://apps.who.int/iris/bitstream/handle/10665/43443/WHO_TRS_937_eng.pdf?sequence=1.
[24]
KOHSAKU K, KYOKO M, YASUO I. Impact of the amount of excess solids on apparent solubility. Pharm Res, 2005,22(9):1537-1543.
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