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  • 1.
    Persson, Anita M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Evaluation of a Miniaturized Rotating Disk Apparatus for In Vitro Dissolution Rate Measurements in Aqueous Media: Correlation of In Vitro Dissolution Rate with Apparent Solubility2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The general aim of this thesis was to evaluate a newly designed and constructed miniaturized rotating disk apparatus for in vitro dissolution rate measurements of different drug substances from all of the classes in the Biopharmaceutical Classification System (BCS). The new equipment is based on a low volume flow-through cell of Plexiglas, a gold plated magnetic bar and a special designed press. The disk of drug substance (approx. 5 mg) is placed eccentrically in the bar. Rotation speeds were set with a graded magnetic stirrer. An external HPLC pump delivered a continuous flow of aqueous medium to the flow-through cell during dissolution testing.

    A reversed phase high-performance liquid chromatography system using diode array detection (RP-HPLC-DAD) was coupled online to the new equipment. The injections from the miniaturized rotating disk outlet into the quantifying HPLC system were controlled by a six-position switching valve. The injection volumes from the valve and the autosampler, used for the external standards, were statistically evaluated to match each other volumetrically. No analyses were longer than three minutes, using isocratic mode.

    A traditional USP rotating disk apparatus was used as a reference system and the two instruments were shown to be statistically dissimilar in the numerical dissolution rate values probably due to different hydrodynamics, but had approximately the same precision/repeatability. When correlating the logarithmic values of the in vitro dissolution rate (G) with the apparent solubility (S), using shake-flask methodology in the solubility studies, the two apparatuses gave the same correlation patterns. Further correlation studies were done where the media components were altered by the use of different buffer species or additives into the buffers, such as inorganic salts.

    Chemometric tools, e.g. orthogonal partial least squares (OPLS), were used to better evaluate the most influential factors for G and S in different media. The most significant factor for a model basic drug substance (terfenadine) was pH, followed by the ionic strength (I) and added sodium chloride in one of the media. However, the surfactants in the Fasted State Simulated Intestinal Fluid (FaSSIF-V2) were found to be insignificant for G and S in this study (using a 95% confidence interval).

    The new miniaturized apparatus is a promising prototype for in vitro dissolution rate measurements both for early screening purposes and in dissolution testing during drug development, but needs further instrumental improvements.

    List of papers
    1. Design and Characterization of a New Miniaturized Rotating Disk Equipment for In Vitro Dissolution Rate Studies
    Open this publication in new window or tab >>Design and Characterization of a New Miniaturized Rotating Disk Equipment for In Vitro Dissolution Rate Studies
    Show others...
    2008 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, no 8, p. 3344-3355Article in journal (Refereed) Published
    Abstract [en]

    A miniaturized apparatus for the determination of the apparent in vitro dissolution rate has been designed, constructed and characterized. The miniaturized apparatus was based on a low volume dissolution cell and a disk in a rotating magnetic bar. The disk tablet is pressed directly into the bar with a press designed and constructed for this purpose. It requires approximately 5 mg of substance. The disk was positioned eccentrically on the bar with an external flow of medium to increase the rate of solvent flow over the disk surface. Six different drug substances were used. The dissolution media were sodium phosphate buffer, pH 7.0, and ammonium acetate buffer, pH 6.8. All quantifications were made by integrating the dissolution cell with high-performance liquid chromatography (HPLC) using diode-array detection (DAD). The obtained results were compared with data from a conventional rotating disk equipment, where the disk was centrically mounted. The dissolution rates at 100 rpm seemed to be on an average of 2-3 times higher for the miniaturized apparatus (RSD 0.2-56%). The preliminary studies of this prototype indicate that the miniaturized rotating disk is a promising design for the qualitative estimation of dissolution rates of substances, for example during screening in early drug discovery.

    Place, publisher, year, edition, pages
    Wiley InterScience, 2008
    Keywords
    dissolution rate, in vitro models, physicochemical properties; analytical chemistry, HPLC (high-performance/pressure liquid chromatography), miniaturization
    National Category
    Medicinal Chemistry Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-17637 (URN)10.1002/jps.21235 (DOI)000258081100034 ()
    Available from: 2010-01-11 Created: 2009-10-08 Last updated: 2018-01-12Bibliographically approved
    2. Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part I. Comparison with a traditional USP rotating disk apparatus
    Open this publication in new window or tab >>Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part I. Comparison with a traditional USP rotating disk apparatus
    2009 (English)In: Drug Discoveries & Therapeutics, ISSN 1881-7831, Vol. 3, no 3, p. 104-113Article in journal (Refereed) Published
    Abstract [en]

    A correlation of the logarithmic values of the in vitro dissolution rate, G, and the apparent solubility, S, was evaluated in phosphate and ammonium acetate buffer at an initial pH of 7. The dissolution rates were determined with a newly designed and build miniaturized rotating disk equipment, as well as with a traditional rotating disk apparatus. The two apparatuses gave the same correlation pattern of logG and logS. Thirteen diverse drug substances from all of the classes in the Biopharmaceutics Classification System (BCS) were used for the correlation in the phosphate buffer system, with the results from the miniaturized apparatus only. A coefficient of determination, R2, of 0.982 was found if bases formulated as hydrochloride salts were excluded in the correlation. The miniaturized equipment is used for rapid screening of the dissolution rate, approximately 10 min for one run, and consumes small amounts of substance (about 5 mg) and dissolution media. All quantifications were performed by using reversed phase high-performance liquid chromatography (RPHPLC) with a diode array detector (DAD), integrated with the miniaturized rotating disk equipment.

    Place, publisher, year, edition, pages
    IACMHR and SDU-DDSC, 2009
    Keywords
    dissolution rate, solubility, in vitro models, correlation, HPLC (high-performance liquid chromatography)
    National Category
    Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-107740 (URN)
    Available from: 2010-01-11 Created: 2009-08-25 Last updated: 2018-01-13Bibliographically approved
    3. Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part II. Comparing different buffer media
    Open this publication in new window or tab >>Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part II. Comparing different buffer media
    2009 (English)In: Drug Discoveries & Therapeutics, ISSN 1881-7831, Vol. 3, no 3, p. 114-122Article in journal (Refereed) Published
    Abstract [en]

    A correlation of the logarithmic values of the in vitro dissolution rate, G, and apparent solubility, S, was made for seven different drug substances from all of the classes in the Biopharmaceutics Classification System (BCS), in four different phosphate buffers. The effect of inorganic salts added as sodium chloride, sodium nitrate, sodium phosphate and sodium sulfate in the buffer media was investigated for the correlation. Triethanolammonium acetate buffer was also included in the study of the correlation of logG vs. logS. The pH was 7.0 ± 0.1 in all of the buffers to mimic a pH condition in intestinal fluids. The dissolution rate was determined with a newly constructed miniaturized rotating disk equipment, which enables fast determinations and consumes only minute quantities of substance (about 5 mg). The solubility was determined by conventional shake-flask methodology, using 1.5 mL solution volumes. All quantifications were performed with reversed phase high-performance liquid chromatography (RP-HPLC) and diode array detection (DAD). The different inorganic anions seemed to affect the solubility more than the dissolution rate. The phosphate and nitrate ions decreased the solubility for amines compared to the chloride ion. The best correlations of logG and logS were however obtained with a triethanolammonium acetate buffer. The good correlation (R2 = 0.991) may be sufficient in initial screening of drug solubility, based on dissolution rates in aqueous buffer media.

    Place, publisher, year, edition, pages
    IACMHR and SDU-DDSC, 2009
    Keywords
    dissolution rate, solubility, in vitro models, correlation, HPLC (high-performance liquid chromatography)
    National Category
    Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-107746 (URN)
    Available from: 2010-01-11 Created: 2009-08-25 Last updated: 2018-01-13Bibliographically approved
    4. Multivariate data analysis of factors affecting the in vitro dissolution rate and the apparent solubility for a model basic drug substance in aqueous media
    Open this publication in new window or tab >>Multivariate data analysis of factors affecting the in vitro dissolution rate and the apparent solubility for a model basic drug substance in aqueous media
    2010 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 27, no 7, p. 1309-1317Article in journal (Refereed) Published
    Abstract [en]

    Purpose. To evaluate the usefulness of a miniaturized rotating disk equipment for the determination of factors influencing the in vitro dissolution rate, G, of a model basic drug substance (terfenadine) in different aqueous media, using experimental design and multivariate data analysis. The apparent solubility, S, was included in the chemometric study.

    Methods. The dissolution rate was determined with a miniaturized rotating disk apparatus and the solubility by shake-flask methodology. Media were based on acetate, phosphate or maleate buffers. The later used in fasted state simulated intestinal fluid (FaSSIF-V2). The chemometric analyses included fractional factorial design, principal component analysis (PCA) and orthogonal partial least squares (OPLS). Quantifications were made with a RP-HPLC-DAD system.

    Results. The most influential factor for both G and S of terfenadine in the different media was pH. Apart from the ionic strength and sodium chloride concentration in the acetate medium, the effects of the other variables were insignificant implying no wetting effect of the surfactants.

    Conclusions. The miniaturized rotating disk equipment was suitable to use, in conjunction with the chemometric analyses, in the evaluation of the factors affecting the in vitro dissolution rate. The apparent solubility was found to be influenced by the same factors as G.

    Keywords
    dissolution media, dissolution rate, solubility, chemometrics, miniaturized rotating disk equipment
    National Category
    Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-112089 (URN)10.1007/s11095-010-0111-0 (DOI)000278694400012 ()20358263 (PubMedID)
    Available from: 2010-01-08 Created: 2010-01-08 Last updated: 2018-01-12Bibliographically approved
  • 2.
    Persson, Anita M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Baumann, Kajsa
    Inst för kemi, Göteborgs universitet.
    Sundelöf, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindberg, Walter
    AstraZeneca, Mölndal.
    Sokolowski, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Design and Characterization of a New Miniaturized Rotating Disk Equipment for In Vitro Dissolution Rate Studies2008In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, no 8, p. 3344-3355Article in journal (Refereed)
    Abstract [en]

    A miniaturized apparatus for the determination of the apparent in vitro dissolution rate has been designed, constructed and characterized. The miniaturized apparatus was based on a low volume dissolution cell and a disk in a rotating magnetic bar. The disk tablet is pressed directly into the bar with a press designed and constructed for this purpose. It requires approximately 5 mg of substance. The disk was positioned eccentrically on the bar with an external flow of medium to increase the rate of solvent flow over the disk surface. Six different drug substances were used. The dissolution media were sodium phosphate buffer, pH 7.0, and ammonium acetate buffer, pH 6.8. All quantifications were made by integrating the dissolution cell with high-performance liquid chromatography (HPLC) using diode-array detection (DAD). The obtained results were compared with data from a conventional rotating disk equipment, where the disk was centrically mounted. The dissolution rates at 100 rpm seemed to be on an average of 2-3 times higher for the miniaturized apparatus (RSD 0.2-56%). The preliminary studies of this prototype indicate that the miniaturized rotating disk is a promising design for the qualitative estimation of dissolution rates of substances, for example during screening in early drug discovery.

  • 3.
    Persson, Anita M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Sokolowski, Anders
    AS Consulting, Uppsala.
    Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part II. Comparing different buffer media2009In: Drug Discoveries & Therapeutics, ISSN 1881-7831, Vol. 3, no 3, p. 114-122Article in journal (Refereed)
    Abstract [en]

    A correlation of the logarithmic values of the in vitro dissolution rate, G, and apparent solubility, S, was made for seven different drug substances from all of the classes in the Biopharmaceutics Classification System (BCS), in four different phosphate buffers. The effect of inorganic salts added as sodium chloride, sodium nitrate, sodium phosphate and sodium sulfate in the buffer media was investigated for the correlation. Triethanolammonium acetate buffer was also included in the study of the correlation of logG vs. logS. The pH was 7.0 ± 0.1 in all of the buffers to mimic a pH condition in intestinal fluids. The dissolution rate was determined with a newly constructed miniaturized rotating disk equipment, which enables fast determinations and consumes only minute quantities of substance (about 5 mg). The solubility was determined by conventional shake-flask methodology, using 1.5 mL solution volumes. All quantifications were performed with reversed phase high-performance liquid chromatography (RP-HPLC) and diode array detection (DAD). The different inorganic anions seemed to affect the solubility more than the dissolution rate. The phosphate and nitrate ions decreased the solubility for amines compared to the chloride ion. The best correlations of logG and logS were however obtained with a triethanolammonium acetate buffer. The good correlation (R2 = 0.991) may be sufficient in initial screening of drug solubility, based on dissolution rates in aqueous buffer media.

  • 4.
    Persson, Anita M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Sokolowski, Anders
    AS Consulting, Uppsala.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part I. Comparison with a traditional USP rotating disk apparatus2009In: Drug Discoveries & Therapeutics, ISSN 1881-7831, Vol. 3, no 3, p. 104-113Article in journal (Refereed)
    Abstract [en]

    A correlation of the logarithmic values of the in vitro dissolution rate, G, and the apparent solubility, S, was evaluated in phosphate and ammonium acetate buffer at an initial pH of 7. The dissolution rates were determined with a newly designed and build miniaturized rotating disk equipment, as well as with a traditional rotating disk apparatus. The two apparatuses gave the same correlation pattern of logG and logS. Thirteen diverse drug substances from all of the classes in the Biopharmaceutics Classification System (BCS) were used for the correlation in the phosphate buffer system, with the results from the miniaturized apparatus only. A coefficient of determination, R2, of 0.982 was found if bases formulated as hydrochloride salts were excluded in the correlation. The miniaturized equipment is used for rapid screening of the dissolution rate, approximately 10 min for one run, and consumes small amounts of substance (about 5 mg) and dissolution media. All quantifications were performed by using reversed phase high-performance liquid chromatography (RPHPLC) with a diode array detector (DAD), integrated with the miniaturized rotating disk equipment.

  • 5.
    Persson, Anita Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Rosén, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Multivariate data analysis of factors affecting the in vitro dissolution rate and the apparent solubility for a model basic drug substance in aqueous media2010In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 27, no 7, p. 1309-1317Article in journal (Refereed)
    Abstract [en]

    Purpose. To evaluate the usefulness of a miniaturized rotating disk equipment for the determination of factors influencing the in vitro dissolution rate, G, of a model basic drug substance (terfenadine) in different aqueous media, using experimental design and multivariate data analysis. The apparent solubility, S, was included in the chemometric study.

    Methods. The dissolution rate was determined with a miniaturized rotating disk apparatus and the solubility by shake-flask methodology. Media were based on acetate, phosphate or maleate buffers. The later used in fasted state simulated intestinal fluid (FaSSIF-V2). The chemometric analyses included fractional factorial design, principal component analysis (PCA) and orthogonal partial least squares (OPLS). Quantifications were made with a RP-HPLC-DAD system.

    Results. The most influential factor for both G and S of terfenadine in the different media was pH. Apart from the ionic strength and sodium chloride concentration in the acetate medium, the effects of the other variables were insignificant implying no wetting effect of the surfactants.

    Conclusions. The miniaturized rotating disk equipment was suitable to use, in conjunction with the chemometric analyses, in the evaluation of the factors affecting the in vitro dissolution rate. The apparent solubility was found to be influenced by the same factors as G.

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