EA Review #1, NDA 20-358

Page 8

          m-chlorohippuric acid                                                24%

          m-chlorobenzoic acid                                                 <1%

          glucuronides of 17U67                                              10%

                  and/or 494U73

          unidentified polar metabolite 1                                 8%

          unidentified polar metabolite 2                                 11%

          unidentified polar metabolite 3                                 25%

It should be confirmed that the unidentified polar metabolites are more polar than the parent compound and contain the same backbone chemical structure.

DEFICIENT.

TIER 0 attributes: (See Attachment 3)

Water solubility of the drug substance was measured in 1976, prior to the availability of the FDA Technical Assistance Handbook.  The method is described on page 42, and involved just three (3) single determinations at three (3) different pH conditions, at an unspecified temperature.  The results have been recorded in the scientific literature and are thus considered adequate and scientifically valid.  The solubility in water is 1.3 M, five (5) orders of magnitude above the Tier 1 threshold.

A literature reference to the publication of the water solubility of the drug substance should be provided, together with any supportive data obtained or appearing since 1976.

DEFICIENT.

Hydrolysis was determined by a method described in pages 58-71, at pH 5.0, 7.4 and 9.0, using a range of buffer concentrations.  Hydrolysis rates (see Attachment 3) were several orders of magnitude below the Tier 0 threshold.

A reference for the method used should be provided and significant deviations from the EATAD 3.09 of the FDA’s Environmental Assessment Technical Assistance Handbook should be discussed.

DEFICIENT.

Dissociation constant was measured using a spectrophoto-metric titration.