The aim of this study was to examine solubility-pH behavior of desipramine structural analogues:
imipramine and amitriptyline hydrochlorides. Appearance of aggregates (trimer, around pH 4 in imipramine case), which lead to slow sedimentation, and oil forms make solubility determination extremely challenging. Oils which are more soluble than crystalline forms are formed in alkaline solutions (above pH 7.8 in imipramine case). Sometimes in such cases, pH adjustment in that pH region can be unpredictable. Furthermore, oil sticks to electrode making pH measurement difficult,
especially in amitryptiline case. Concentration was measured using HPLC with UV/Vis
detection. Different techniques were used for solid phase characterization. Solid phase
characterization is particularly important in complicated systems like this

Avdeef, Alex

Marković, Olivera

Pešić, Miloš P.

Verbić, Tatjana

Central Repository of the Institute of Chemistry, Technology and Metallurgy (CER)

      8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery  & Fifth World Conference on ADMET and DMPK            Book of Abstracts            Split, Croatia, September 9-11, 2019                     8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery  & Fifth World Conference on ADMET and DMPK Split, Croatia, September 9-11, 2019 Book of Abstracts  Published by  International Association of Physical Chemists E-mail: office@iapchem.org, URL: http://www.iapchem.org   For Publisher Zoran Mandić  Editor Zoran Mandić  Design, Page Making and Computer Layout  Aleksandar Dekanski   On Line version only          The Scientific and Organizing Committee: Alex Avdeef, In-ADME Research, USA Christel Bergström, Uppsala University, Sweden Biserka Cetina-Čižmek, PLIVA, Croatia Zoran Mandić, University of Zagreb, Croatia - conference chair Abu Serajuddin, St. John’s University, USA Kiyohiko Sugano, Ritsumeikan University, Japan Kin Tam, University of Macau, Macau - conference co-chair Klara Valko, Bio-Mimetic Chromatography, UK Tatjana Verbić, University of Belgrade, Serbia        Organization of IAPC-8 Meeting is supported by        Sponsors and Exhibitors              8th IAPC Meeting September 9 - 11, 2019, Split, Croatia  51 P 16 pH-Dependent solubility profiles of imipramine and amitriptyline hydrochlorides Olivera S. Marković, Miloš P. Pešić1, Alex Avdeef2, Tatjana Ž. Verbić1,  Department of Chemistry, IChTM, University of Belgrade, Belgrade, Serbia 1University of Belgrade – Faculty of Chemistry, Belgrade, Serbia 2in-ADME Research, New York, USA tatjanad@chem.bg.ac.rs  Amphiphilic tricyclic bases are surface-active, sparingly-soluble drugs, which can exhibit complicated aqueous solution chemistry. New pH-Ramp Shake-Flask method was previously applied to desipramine hydrochloride solubility studies and described in the literature [1]. Solubility was measured using state-of-the-art experimental design, recommended in the white paper on equilibrium solubility measurements [2]. The aim of this study was to examine solubility-pH behavior of desipramine structural analogues: imipramine and amitriptyline hydrochlorides (Figure 1). Imipramine and amitriptyline are tricyclic antidepressants, which are used in the treatment of mental illnesses. pH-Ramp Shake-Flask method was applied.      Figure 1. Structures of desipramine, imipramine, and amitryptiline hydrochlorides, respectively.  Appearance of aggregates (trimer, around pH 4 in imipramine case), which lead to slow sedimentation, and oil forms make solubility determination extremely challenging. Oils which are more soluble than crystalline forms are formed in alkaline solutions (above pH 7.8 in imipramine case). Sometimes in such cases, pH adjustment in that pH region can be unpredictable. Furthermore, oil sticks to electrode making pH measurement difficult, especially in amitryptiline case. Concentration was measured using HPLC with UV/Vis detection. Different techniques were used for solid phase characterization. Solid phase characterization is particularly important in complicated systems like this.  Acknowledgement: Ministry of Education, Science and Technological Development of Serbia supported this work (Grant No. 172008 and 172035).  References: 1. O.S. Marković, M.P. Pešić, A.V. Shah, A.T.M. Serajuddin, T.Ž. Verbić, A. Avdeef, Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates, Eur. J. Pharm. Sci. 133 (2019) 264–274. 2. A. Avdeef, E. Fuguet, A. Llinas, C. Rafols, E. Bosch, G. Volgyi, T. Verbić, E. Boldyreva, K. Takacs-Novak, Equilibrium solubility measurement of ionizable drugs consensus recommendations for improving data quality, ADMET&DMPK 4 (2016) 117–178.   

pH-Dependent solubility profiles of imipramine and amitriptyline hydrochlorides

Amphiphilic tricyclic bases are surface-active, sparingly-soluble drugs, which can exhibit 
complicated aqueous solution chemistry. New pH-Ramp Shake-Flask method was 
previously applied to desipramine hydrochloride solubility studies and described in the 
literature [1]. Solubility was measured using state-of-the-art experimental design, 
recommended in the white paper on equilibrium solubility measurements [2]. The aim of 
this study was to examine solubility-pH behavior of desipramine structural analogues: 
imipramine and amitriptyline hydrochlorides (Figure 1). Imipramine and amitriptyline are 
tricyclic antidepressants, which are used in the treatment of mental illnesses. pH-Ramp 
Shake-Flask method was applied. Appearance of aggregates (trimer, around pH 4 in imipramine case), which lead to slow 
sedimentation, and oil forms make solubility determination extremely challenging. Oils 
which are more soluble than crystalline forms are formed in alkaline solutions (above pH 
7.8 in imipramine case). Sometimes in such cases, pH adjustment in that pH region can be 
unpredictable. Furthermore, oil sticks to electrode making pH measurement difficult, 
especially in amitryptiline case. Concentration was measured using HPLC with UV/Vis 
detection. Different techniques were used for solid phase characterization. Solid phase 
characterization is particularly important in complicated systems like this

Marković, Olivera S.

Faculty of Chemistry Repository - Cherry

      8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery  & Fifth World Conference on ADMET and DMPK            Book of Abstracts            Split, Croatia, September 9-11, 2019                     8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery  & Fifth World Conference on ADMET and DMPK Split, Croatia, September 9-11, 2019 Book of Abstracts  Published by  International Association of Physical Chemists E-mail: office@iapchem.org, URL: http://www.iapchem.org   For Publisher Zoran Mandić  Editor Zoran Mandić  Design, Page Making and Computer Layout  Aleksandar Dekanski   On Line version only          The Scientific and Organizing Committee: Alex Avdeef, In-ADME Research, USA Christel Bergström, Uppsala University, Sweden Biserka Cetina-Čižmek, PLIVA, Croatia Zoran Mandić, University of Zagreb, Croatia - conference chair Abu Serajuddin, St. John’s University, USA Kiyohiko Sugano, Ritsumeikan University, Japan Kin Tam, University of Macau, Macau - conference co-chair Klara Valko, Bio-Mimetic Chromatography, UK Tatjana Verbić, University of Belgrade, Serbia        Organization of IAPC-8 Meeting is supported by        Sponsors and Exhibitors                           Poster Presentations    8th IAPC Meeting September 9 - 11, 2019, Split, Croatia  51 P 16 pH-Dependent solubility profiles of imipramine and amitriptyline hydrochlorides Olivera S. Marković, Miloš P. Pešić1, Alex Avdeef2, Tatjana Ž. Verbić1,  Department of Chemistry, IChTM, University of Belgrade, Belgrade, Serbia 1University of Belgrade – Faculty of Chemistry, Belgrade, Serbia 2in-ADME Research, New York, USA tatjanad@chem.bg.ac.rs  Amphiphilic tricyclic bases are surface-active, sparingly-soluble drugs, which can exhibit complicated aqueous solution chemistry. New pH-Ramp Shake-Flask method was previously applied to desipramine hydrochloride solubility studies and described in the literature [1]. Solubility was measured using state-of-the-art experimental design, recommended in the white paper on equilibrium solubility measurements [2]. The aim of this study was to examine solubility-pH behavior of desipramine structural analogues: imipramine and amitriptyline hydrochlorides (Figure 1). Imipramine and amitriptyline are tricyclic antidepressants, which are used in the treatment of mental illnesses. pH-Ramp Shake-Flask method was applied.      Figure 1. Structures of desipramine, imipramine, and amitryptiline hydrochlorides, respectively.  Appearance of aggregates (trimer, around pH 4 in imipramine case), which lead to slow sedimentation, and oil forms make solubility determination extremely challenging. Oils which are more soluble than crystalline forms are formed in alkaline solutions (above pH 7.8 in imipramine case). Sometimes in such cases, pH adjustment in that pH region can be unpredictable. Furthermore, oil sticks to electrode making pH measurement difficult, especially in amitryptiline case. Concentration was measured using HPLC with UV/Vis detection. Different techniques were used for solid phase characterization. Solid phase characterization is particularly important in complicated systems like this.  Acknowledgement: Ministry of Education, Science and Technological Development of Serbia supported this work (Grant No. 172008 and 172035).  References: 1. O.S. Marković, M.P. Pešić, A.V. Shah, A.T.M. Serajuddin, T.Ž. Verbić, A. Avdeef, Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates, Eur. J. Pharm. Sci. 133 (2019) 264–274. 2. A. Avdeef, E. Fuguet, A. Llinas, C. Rafols, E. Bosch, G. Volgyi, T. Verbić, E. Boldyreva, K. Takacs-Novak, Equilibrium solubility measurement of ionizable drugs consensus recommendations for improving data quality, ADMET&DMPK 4 (2016) 117–178.   

pH-Dependent  solubility profiles of imipramine and amitriptyline hydrochlorides

http://cherry.chem.bg.ac.rs/bitstream/id/32742/bitstream_32742.pdf

pH-Dependent solubility profiles of imipramine and amitriptyline hydrochlorides

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