Preformulation studies on the S-isomer of oxybutynin hydrochloride, an Improved Chemical Entity (ICE).
(S)-Oxybutynin HCl (S-OXY) is a white crystalline solid powder with an acicular particle morphology. Differential scanning calorimetry (DSC) thermograms revealed one characteristic endotherm at 116.2 degrees C. On rescanning a sample heated to 120 degrees C, no thermal events were distinguished in the temperature range 25 degrees C to 150 degrees C. Weight loss curves determined by thermogravimetric analysis showed a continuous, gradual weight loss of about 0.15% over the temperature range 30 degrees C to 110 degrees C, followed by a change in slope and more rapid weight loss beginning at 150 degrees C. Observation by hot-stage microscopy confirmed the melting endotherm observed by DSC. Equilibrium moisture uptake studies indicated low water vapor uptake at low relative humidities (<52.8%). At relative humidities of 75.3% and 84.3%, S-OXY first deliquesced and then converted to a lower melting point crystal form. X-ray powder diffraction (XRPD) data supported the DSC findings. S-OXY underwent degradation by ester hydrolysis at alkaline pHs. The kinetics of this reaction were studied at 25 degrees C in carbonate-bicarbonate buffers. Observed rate constants of 0.008 h(-1) and 0.0552 h(-1) were determined at pH 9.69 and 10.25, respectively. The pKa of S-OXY was 7.75. The aqueous solubility of S-OXY was described as a function of pH and the free-base solubility. The mean partition coefficient log P was 3.33 using 1-octanol. The surface tensions of aqueous solutions of S-OXY decreased with increasing concentration, but no concentration-independent region was observed, indicating that S-OXY does notform micelles in aqueous solution. The dissolution rate of S-OXY from a compressed disk in 0.1 N HCl was rapid, whereas it was considerably slower at pH 7.4. Addition of 1% hexadecyltrimethylammonium bromide (CTAB) at pH 7.4 significantly improved the dissolution rate. S-OXY displayed very poor flow properties when compared to standard pharmaceutical excipients. XRPD results indicated that S-OXY exhibited a loss in crystallinity following ball milling. Hiestand tableting indices indicated that S-OXY has good bonding properties andforms strong compacts, but is likely to be susceptible to capping on ejection from the die. This indicated the needfor a plastically deformable excipient such as Avicel PH-101 in tablet formulations.
Luner
P E
PE
Pharmaceutics Division, College of Pharmacy, University of Iowa, Iowa City 52242, USA.
Kirsch
L E
LE
Majuru
S
S
Oh
E
E
Joshi
A B
AB
Wurster
D E
DE
Redmon
M P
MP
D002152:Calorimetry, Differential Scanning; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D018680:Cholinergic Antagonists / Q000737:chemistry*; D005079:Excipients; D006813:Humidity; D006863:Hydrogen-Ion Concentration; D007536:Isomerism; D007700:Kinetics; D008333:Mandelic Acids / Q000737:chemistry*; D013696:Temperature; D014835:Volatilization; D014961:X-Ray Diffraction
D018680:Cholinergic Antagonists; D005079:Excipients; D008333:Mandelic Acids; C005419:oxybutynin