Chemistry: analytical and immunological testing – Including chromatography
Reexamination Certificate
2001-02-13
2003-04-15
Ludlow, Jan (Department: 1743)
Chemistry: analytical and immunological testing
Including chromatography
C073S061520, C073S061560, C210S656000, C210S662000
Reexamination Certificate
active
06548307
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is related to an improved method for determination of logP
oct
values for drug candidates.
2. Related Art
The importance of octanol-water partition coeffiecients (logP
oct
) is underscored, for example, by the generally observed correlation between a high lipophilicity (logP
oct
>4.5) and a poor solubility.
1
Computed values for drug molecules are often inaccurate, depending on the software used, by as much as two logP
oct
units, for any given compound or class of compounds. Data analyses and alerts such as the Lipinski's “Rule-of-5”
2
would greatly benefit by the introduction of measured values, especially if they could be generated with high speed and accuracy. Thus, whenever possible, the computed values should be replaced by measured values, especially if the method requires only a very small amount of a new chemical entity, and can tolerate some impurities.
Lipophilicity of drug candidates is important since it is being used in the prediction of absorption, disposition and excretion.
3
It is generally held that very lipophilic compounds are “preferred” targets for metabolism, often leading to high clearance values and frequently correlates with a high plasma protein binding. A large volume of distribution, probably due to a high fraction of the compound bound to tissues, is often observed in the case of lipophilic compounds. Thus, a method that can accurately and rapidly yield logP
oct
values, is an important addition to the experimental tools available for physicochemical properties screening.
The classical shake-flask method, or variations of this method which have been described,
4
are neither rugged not rapid enough for medium to high-throughput applications, and they are generally sensitive to impurities, and less amenable to automation than are reverse phase high performance liquid chromatography (RP-HPLC) methods.
5
(RP-HPLC) retention data have been shown to correlate well with absolute and relative lipophilicity values but, they have also been criticized as not being a true “replacement” for shake-flask values.
4
Part of the criticism stems from the fact that many reports were limited in their scope, focusing either on fairly simple monofunctional solutes,
6-7
or classes of analogs
8
with a limited logP
oct
range. Furthermore, in several cases
4
, the slope of the logP
oct
vs. log k′ or log k′
w
, solvent was quite different from unity, casting doubts about the different balance of forces responsible for the two values. In these linear regression analyses, k′ represents the capacity factor of the solute at a given concentration of organic solvent, and k′
w
is the capacity factor extrapolated to 0% of the organic solvent. However we have found that, with a judicious choice of conditions, RP-HPLC methods might be defined, following Taylor
9
, as “being in a class of their own”.
Another factor of great importance,
5
is the reproducibility of the data from column to column, that is the reproducibility is likely to be dependent on packing chemistry and manufacturing of the columns. It might be argued that a pooling data from different columns will not be difficult, although “scaling standards” might be needed. However, tests of reproducibility of the method from column to column should be performed, independently of the above arguments.
The speed of the determination and the ability to handle diverse structures and lipophilicity values are, of course, of paramount importance in an industrial research setting. These aspects translate into the capability of screening, with fairly modest resources, a fairly large number of compounds, with a good degree of accuracy applicable across a wide range of lipophilicity values.
There is a long felt need for a method for determining logP
oct
which would be accurate, rapid and possess a good dynamic range, together with being applicable to a variety of drug-like molecules.
REFERENCES
1. Yalkowski, S. H.; Valvani, S. C. Solubility and Partitioning I: Solubility of Nonelectrolytes in Water. J. Pharm. Sci. 1980, 69, 912-922.
2. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development. Adv. Drug. Del. Rev. 1997, 23, 3-25.
3. Smith, D. A.; Jones, B. C.; Walker, D. K. Design of Drugs Involving the Concepts and Theories of Drug Metabolism and Pharmacokinetics. Med. Res. Rev. 1996, 16, 243-266.
4. Sangster, J. Octanol-Water Partition Coefficients: Fundamentals and Physical Chemistry. Wiley, New York, 1997; pp. 79-112.
5. van de Waterbeemd, H. M.; Kansy, M.; Wagner, B.; Fischer, H. Lipophilicity Measurements by Reversed-Phase High Performance Liquid Chromatography (RP-HPLC). In Lipophilicity in Drug Action and Toxicology, Ch. 5, Pliska, V., Testa, B., van de Waterbeemd, H., Eds.; VCH: Weinheim, 1996; pp 73-87
6. Pagliara, A.; Khamis, E.; Trinh, A.; Carrupt, P.-A.; Tsai, R.-S.; Testa, B. Structural Properties Governing Retention Mechanisms on RP-HPLC Stationary Phases used for Lipophilicity Measurements. J. Liq. Chromatogr. 1995, 18,1721-1745.
7. Minick, D. J.; Frenz, J. H.; Patrick, M. A.; Brent, D. A. A Comprehensive Method for Determining Hydrophobicity Constants by Reversed-Phase High-Performance Liquid Chromatography. J. Med. Chem. 1988, 31, 1923-1933
8. Morelock, M. M.; Choi, L. L.; Bell, G. L; Wright, J. L. Estimation and Correlation of Drug Water Solubility with Pharmacological Parameters Required for Biological Activity. J. Pharm. Sci. 1994, 83, 948-952.
9. Taylor, P. J. Hydrophobic Properties of Drugs. In Comprehensive Medicinal Chemistry, Hansch, C., Sammes, P. G., Taylor, J. B. Eds.; Pergamon Press: Oxford, 1990; pp 241-294.
10. The LC-ABZ column is considered to be “RP-18 like” and it is electrostatically coated to decrease the solute interactions with free silanols. Pagliara, A.; Khamis, E.; Trinh, A.; Carrupt, P.-A.; Tsai, R.-S.; Testa, B. Structural Properties Governing Retention Mechanisms on RP-HPLC Stationary Phases used for Lipophilicity Measurements. J. Liq. Chromatogr. 1995, 18,1721-1745.
11. Minick, D. J.; Brent, D. A.; Frenz, J. Modeling Octanol-Water Partition Coefficients by Reversed-Phase Liquid Chromatography. J. Chromatogr. 1989, 461, 177-191.
12. Melander, W.; Stoveken, J.; Horvath, C. Stationary Phase Effects in Reversed-Phase Chromatography. I. Comparison of Energetics of Retention on Alkyl-Silica Bonded Phases. J. Chromatogr. 1980, 199, 35-56.
13. Valko K.; Bevan, C.; Reynolds, D. Chromatographic Hydrophobicity Index by Fast-Gradient RP-HPLC: A High-Throughput Alternative to log P/logD. Anal. Chem. 1997, 69, 2022-2029.
14. Abraham, M. H.; Chadha, H. S.; Leitao, R. A. E.; Mitchell, R. C.; Lambert, W. J.; Kaliszan, R.; Nasal, A.; Haber, P. Determination of solute lipophilicity as logP (octanol) and logP (alkane) using poly(styrene-divinylbenzene) and immobilised artificial membrane stationary phases in reversed-phase high performance liquid chromatography. J. Cromatogr. A. 1997, 766, 35-47.
15. Abraham, M. H.; Chadha, H. S.; Whiting, G. S.; Mitchell, R. C. Hydrogen Bonding. 32. An Analysis of water-Octanol and Water-Alkane partitioning and the ElogP Parameter of Seiler. J. Pharm. Sci. 1994, 83, 1085-1100.
16. Slater, B.; McCormack, A.; Avdeef, A.; Comer, J. E. A. pH-Metric log P. 4. Comparison of Partition Coefficients Determined by HPLC and Potentiometric Methods to Literature Values. J. Pharm. Sci. 1994, 83, 1280-1283.
17. Jezequel, S. G. Fluconazole: Interspecies Scaling and Allometric Relationships of Pharmacokinetic Properties. J.Pharm.Pharmacol. 1994, 46, 196-199.
18. Fujita, T.; Iwasa, J.; Hansh, C. A new substituent constant, &pgr;, derived from partition coefficients. J. Am. Chem. Soc.1965, 86, 5175-5180.
19. Rotonda, M. I.; Amato, G.; Barbato, F.; Silipo, C.; Vittoria, A. Relationship between octanol-water partition data, chromatographic indices and their dependence on pH in a set of nonsteroidal anti-inflammatory drugs. Quant. Struct. Act. Relat. 1983, 2, 168-173.
20.
Lombardo Franco
Shalaeva Marina Y.
Tupper Karl A.
Ginsburg Paul H.
Ludlow Jan
Nissenbaum Israel
Pfizer Inc.
Richardson Peter C.
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