White crystalline powder, inodourous,  bitter taste that rapidly diseappears because of anesthesia of oral mucosae. 

NAME AND STRUCTURE 

• Chemical Name: dl -1-(methylcyclopropyl)-N-(2,6-dimethylphenyl)-2- piperidinecarboxamide; dl-1-(methylcyclopropyl)-2',6'-pipecoloxylidide. >
• Chemical structure:

• Molecular formula and molecular weight: C₁₈H₂₆N₂O;  mol.weight: 286.42
• as hydrochloride: C₁₈H₂₆N₂O.HCl; mol.weight: 322.88

IQB-9302 base racemic [166181-63-1] 
IQB-9302 hydrochloride racemic [166546-89-0]    

SYNTHESIS (scheme) 

IQB-9302 is obtained in good yield from 2,6-dibromohexanoyl-2,6-dimethylaniline and aminomethylcyclopropane, heating the mixture for 16 hours in an adecuate organic solvent. IQB-9302 is obtained as free base by acidic extraction and washing. Yield 70%. 
Hydrochloride salt of IQB-9302 is obtained by reaction of the free base with HCl in isopropanol and recrystallization. 

SOLUBILITY 

Soluble in water  (88,4 mg/mL), DMSO and methanol. Soluble in hot ethanol. Insoluble in acetone, chloroform, ether, methylene chloride, etc. 

MELTING POINT 

 263.4º C (as HCl) (decomp.) 

THERMAL ANALYSIS

Thermal behaviour of samples of IQB-9302 was studied with a Thermogalen microscope fitted with the Kofler stage. Samples were studied between 30 and 300ºC at a heating rate of 2ºC/min. At room temperature the test material was constituted by needle-shaped crystals. With polarized light the sample appeared as coloured particles. In the range of 172-210ºC recrystallization by sublimation was detected. The new crystalline particles showed laminar aspect and were coloured even without polarised light.
Three batches of IQB-9302 were analyzed. All the samples melted in the interval 245-254ºC.

DIFFERENTIAL SCANNING CALORIMETRY 

Thermodynamic and calorimetric properties of IQB-9302 have been assessed by 
thermographic analysis performed on a Mettler TA3000 System. Neither hydrates or solvates, nor polymorphs are seen. Chemical purity of IQB-9302 ranged between 99 and 100%. On the base of DSC data,  lot 9454/R003 has been selected as standard for 
chemical analysis (see here purity of other batches).

THERMOGRAVIMETRY

Thermogravimetric curves were obtained using a Mettler TA 3000 thermogravimeter analyzer (TG50). Samples were placed into an alumina crucible and heated at a rate of 10º/min in the range of 30 to 300ºC. Data demonstrated the absence of solvates. Decomposition process occurs in one step.  Three batches gave identical TG curves

ULTRAVIOLET SPECTRUM 

Aqueous solution 100 mg/ml in distilled water   l_max = 262.4 nm  Abs= 0.120 
Acetonitrile/phosphate buffer 500 mg/ml 0.1 M, pH 5 (40:60)  l_max = 262.6 Abs = 0.646.
No shifts of l_max were seen when IQB-9302 was dissolved in either 01N HCl or 0,1. N NaOH. UV scans of three batches were identical, a proof that there is not batch-to-batch variability

INFRA-RED SPECTRUM 

Principal peaks at wavenumbers 3104, 2938 , 2606 and 1670 cm^-1 (KBr disk) . The IR spectra of three batches were practically identical thus demonstrating the absence of batch-to-batch variability

MNR SPECTRUM 

¹H-RMN. (DMSO-d₆) d in ppm: 
10.62 (s,1H); 9.84 (s, 1H); 7.08 (m, 3H); 4.27 (m,1H); 3.10 (m, 2H), 2.14 (m, 1H); 2.06 (m, 6H), 1.90-1.00 (m, 6H); 0.68 (t, 2H); 0.36 (t, 2H) 

X-RAY DIFFRACTION SPECTRUM 

The powder X-Ray diffraction spectra of several samples of IQB-9302.HCl were recorded using an automated Philips X-Pert X Ray diffractometer. Samples were irradiated with monochromatized CuK alfa radiation and analyses were caried out between 2 theta angles of 5 and 40º.
Characteristic diffraction lines are seen at angle values of 8.39, 11.640, 16.605, 17.730, 19.175, 21.455, 23.565, 25.390, 26.795 and 28.830. No differences in the X-ray diffraction spectra of five different batches of IQB-9302.HCl were observed thus confirming the absence of polymorphs.

HIGH PRESSURE LIQUID CHROMATOGRAPHY

Column. Hypersil ODS 5 mm (12 cm, f = 4.6 mm)
Eluent: Acetonitrile/phosphate buffer 0.1 M, pH 3.5 (30:70)
Flow: 1.0 ml/min
Detector: UV at l = 262 nm
Volume of injection: 20 ml
Sample concentration: 500 mg/ml in eluent
Rt = 4.3 
Purity (of batch 940531) = 99.3%  (See here purity of other batches)

THIN LAYER CHROMATOGRAPHY 

Plate: Kieselgel Merck 60F 354
Solvents: Diisopropyl ether, R_f = 0
             Ethanol, R_f= 0.76 
                Acetone/methylene chloride (95:5), R_f = 0

DISSOCIATION CONSTANT 

pKa:  7.99 ± 0.006

PARTITION COEFFICIENT

n-heptane/buffer pH 7.4 = 68
n-heptane/n-octanol =86
 

STABILITY OF RAW MATERIAL

Samples of IQB-9302 (as HCl) have been maintained for 4 years at room temperature under normal light and humidity with no apparent loss of activity. Additionally, the following tests have been done in order to accelerate degradation of the raw material:

1. In solution
 A1 - 1% solution in water 24 h at room temperature (shaking): Unchanged (100%)
 R1 - 1% solution in water 24 h under reflux. Practically unchanged  (99.13%)
 A2 - 1% solution in HCl 0.1N 24 h at room temperature (shaking).Unchanged (100%)
 R2 - 1% solution in HCl 0.1N 24 h under reflux. Practically unchanged  (99.13%)
 A3 - 1% solution in NaOH 0.1N 24 h at room temperature (shaking).Unchanged (100%)
 R3 - 1% solution in NaOH 0.1N 24 h under reflux.Unchanged (100%)
2. Stability of the solid
A1 - Under UV light:Unchanged (100%)
A2 - At 100º C for 2 months: small degradation 96.77% IQB-9302.HCl
A3 - Melted state (24 h): 11.01% IQB-9302.HCl; 67.37% 2,6-dimethylanilide.

DRUG MASTER FILE

A Drug Master File covering chemical synthesis, analytical methodology, impurities and other aspects of IQB-9302.HCl has been filled by LEBSA, manufacturer of the compound on the behalf of Laboratorios INIBSA