Martin P. Redmon

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°C. On rescanning a sample heated to 120°C, no thermal events were distinguished in the temperature range 25°C to 150°C. Weight loss curves determined by thermogravimetric analysis showed a continuous, gradual weight loss of about 0.15% over the temperature range 30°C to 110°C, followed by a change in slope and more rapid weight loss beginning at 150°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°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 not form 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 and forms strong compacts, but is likely to be susceptible to capping on ejection from the die. This indicated the need for a plastically deformable excipient such as Avicel PH-101 in tablet formulations.

Development of a Lyophilized Formulation for (R,R)-Formoterol (L)-Tartrate

(R,R)-formoterol is a β-agonist for inhalation. Aqueous instability suggested the need for a reconstitutable lyophilized dosage form. The objective of these studies was to devise a stable, rapid-dissolving, therapeutically compatible dosage form. The effects of diluents and residual moisture on the stability of thermally stressed formoterol formulations were investigated. Drug and various excipients (acetate, lactose, and mannitol) were lyophilized and placed in humidity chambers (0 to 90% relative humidity) at 25 to 50°C. Stability was characterized by time-dependent changes using HPLC, pH, and XRD. Residual moistures were determined by Karl Fisher methods. Regression models were developed to quantify the effects of formulation and environmental variation on drug stability. Solid-state instability was observed as a function of high residual moisture and diluent type. Although the residual moistures in mannitol formulations were typically below 1%, the degradation rate (50°C) varied from 2 to 10 mcg/day, which was 1.3- to 20-fold high than observed for lactose formulations under the same relative humidity conditions. At high relative humidity, the presence of acetate significantly increased the degradation rate (p < 0.04). The critical residual moisture content for lactose formulations was 3%. The amount of lactose was optimized by evaluating the degradation over the temperature range 25 to 50°C. Mannitol and acetate were shown to be unsuitable excipients, and an optimal lactose amount was 50 mg for vials containing 50 mcg of drug.