Process for the precipitation and isolation of 6,6-dimethyl-3-aza-bicyclo [3.1.0] hexane-amide compounds by controlled precipitation and pharmaceutical formulations containing same

1. A granular pharmaceutical formulation comprising 50 wt. % API, 14 wt. % lactose monohydrate (intragranular), 5 wt. % intragranular microcrystalline cellulose, 5 wt. % extragranular microcrystalline cellulose, 3 wt. % intragranular croscarmellose sodium, 3 wt. % extragranular croscarmellose sodium, 15 wt. % pregelatinized starch (intragranular), 3 wt. % sodium lauryl sulfate (intragranular), and 2 wt. % magnesium stearate (extragranular), wherein

said API is an agglomerated particulate comprising a compound of Formula B,

said agglomerated particulate having a median bulk surface area of from about 5 m 2 /g to about 12 m 2 /g, an agglomerated particulate particle size of from about 1 micron to about 2.5 microns, an agglomerated particulate particle size distribution of from about 1 micron to about 50 microns, a bulk density of from about 0.15 g/ml to about 0.19 g/ml and a softening point of from about 20° C. to about 50° C.,

said agglomerated particulate is prepared by a process comprising combining a 0° C. stream of a solution comprising methyltertiarybutyl ether (MTBE) having dissolved therein 166 mg/ml of the compound of 3-[2-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-6,6-diMethyl-3-aza-bicyclo [3.1.0]hexane-2-carboxylic acid (2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethyl)-amide (the compound of Formula B), with a -20° C. stream of heptane wherein the solution stream is provided under conditions yielding a Reynolds number of 10650, the heptane stream is supplied under conditions yielding a Reynolds number of 23,650 and the solution stream is combined at substantially a 90 degree angle to the anti-solvent stream, thereby providing a slurry comprising precipitated particles of the compound of Formula B, collecting said slurry and distilling supernatant liquid from the collected slurry at subatmospheric pressure and at a temperature that forms an agglomerated particulate having a softening point of greater than about 25° C., and

the compound of Formula B has the following structural formula:

2. A capsule comprising the granular pharmaceutical formulation of claim 1 , having on average the following dissolution profile when tested using a USPII dissolution testing apparatus Paddle Stirrer filled with 900 mL of dissolution medium consisting of 0.5% sodium lauryl sulfate solution buffered with pH 6.8 sodium phosphate buffer at 37° C. and with the paddles set at 50 RPM :

Post DropTime:

% API Dissolved

10 minutes

80

20 minutes

90

30 minutes

93

45 minutes

96

60 minutes

98.

3. A dosage form comprising an amount of the granular pharmaceutical formulation of claim 1 containing 800 mg of API which dosage form provides a Cmax of 2106 ng/ml at about 3.0 hours and an AUC of 7029 ng.hr/ml when administered to a human.

4. A dosage form comprising an amount of the granular pharmaceutical formulation of claim 1 containing 800 mg of API which dosage form does not prolong the QT interval relative to a placebo when administered to a human.