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.

Wetting characteristics of media emulating gastric fluids.

A variety of dissolution media have been used to simulate the physiological environment of the gastric region. The objective of this study was to formulate and examine the wetting properties of dispersions composed of the dominant surface active species found in the stomach at physiologically relevant concentrations. Systems representing the fed and fasted states were studied and compared to other media that have been considered for use as simulated gastric fluids. Dilute bile salt/phospholipid solutions and bile salt-lipid emulsions were formulated on the basis of available physiologic data to represent the fasted and fed states, respectively. Wetting was evaluated through the determination of the surface tension and contact angle of the various solutions using poly(methyl methacrylate) (PMMA) as a model surface. Additional surfactant solutions and other biorelevant media were also tested. Data were evaluated in terms of contact angle, surface tension and the thermodynamic stages of wetting. The results indicate that solutions patterned after the composition of the GI tract have significantly different wetting properties relative to the fed and fasted states. The surfactant solutions tested were significantly better wetting agents for the surface than the physiologically representative formulations. The implications for the formulation of surfactant-based biorelevant media are discussed.

Wetting behavior of bile salt-lipid dispersions and dissolution media patterned after intestinal fluids.

The wetting properties of bile salt-lipid solutions and dispersions patterned after the contents of the upper intestine in the fed and fasted states were evaluated using poly(methyl methacrylate) (PMMA) as a model substrate. The surface tension of the solutions and their contact angles on PMMA were measured. Media compositions for the intestinal fed and fasted states were estimated on the basis of physiologic data. The effect of various individual lipids and media composition was also evaluated relative to the adhesional, immersional, and spreading stages of wetting. In micellar systems, both the type and concentration of lipid present in the bile salt solution had an influence on wetting. The wetting of media patterned after gastrointestinal contents showed marked differences with respect to the fed or fasted state compositions. For the fed state compositions, alteration of the solution pH from 7.5 to 5.0 resulted in a significant change in wetting. The surface tension of the medium representative of the fasted state was 15 mN/m higher than that of the fed state. The wetting properties of the physiologically representative media formulated in this study were markedly different compared with other media proposed in the literature. Analysis of the wetting behavior of individual lipids as a function of concentration in bile salt solutions showed that they adsorb in a manner that progressively reduces the expected wetting of the surface. The results have implications for the design and formulation of both biorelevant and surfactant-based dissolution media.

Low-level determination of polymorph composition in physical mixtures by near-infrared reflectance spectroscopy.

Near-infrared reflectance spectroscopy (NIRS) was employed to quantify sulfathiazole (STZ) forms I and III in binary physical mixtures in which one form was the dominant component. Physical mixtures of the polymorph pair were made by weight, ranging from 0 to 5% STZ form I mixed with STZ form III, and near-infrared spectra of the powder samples contained in glass vials were obtained over the wavelength region of 1100 to 2500 nm. A calibration plot was constructed by plotting STZ form I weight percent against a ratio of second-derivative values of log (1/R') (where R' is the relative reflectance) versus wavelength. The coefficients of determination, R(2), were > 0.9983 and standard errors were low for these calibration models. The instrument reproducibility, method error, and limits of detection (LOD) and quantification (LOQ) of the method were assessed. The LOD and LOQ were determined from the standard deviation of the response of the 0% analyte sample (0% STZ form I containing 100% STZ form III). The LOQ was subsequently validated with independently prepared samples. The results show that polymorphs can be quantified in binary physical mixtures in the 0.3% polymorph composition range. These studies indicate that NIRS is a precise and accurate quantitative tool for determination of polymorphs in the solid state, is comparable to other characterization techniques, and is more convenient to use than many other methods.

Determination of indomethacin crystallinity in the presence of excipients using diffuse reflectance near-infrared spectroscopy.

Studies were conducted to investigate the use of near-infrared spectroscopy for determining the crystallinity of indomethacin in multi-component physical mixtures. Three calibration sets of amorphous/crystalline indomethacin physical mixtures were prepared over the composition range of 0-100% crystallinity. Each of the three calibration sets was diluted step-wise with increasing amounts of a single excipient (Avicel, alpha-lactose monohydrate, or sodium chloride). Near-infrared spectra were obtained after each round of dilutions using diffuse reflectance sampling on samples contained in glass vials. After a second derivative transformation, standard curves were constructed by plotting percent indomethacin crystallinity against the ratio of responses at two wavelengths. At dilution levels up to 75% Avicel or lactose, the calibration models demonstrated high coefficients of determination and low standard errors. Dilution with sodium chloride did not produce comparable results and it was necessary to use partial least-squares regression to achieve a similar level of error. These findings were confirmed with separate validation sets. An investigation of instrument error showed that the impact of instrument variability on quantification generally increased as a function of the dilution level.

Quantitative analysis of polymorphs in binary and multi-component powder mixtures by near-infrared reflectance spectroscopy.

Near-infrared reflectance spectroscopy was employed to quantify polymorphs in binary and multi-component powder mixtures. Sulfamethoxazole (SMZ) forms I and II were used as model polymorphs for this study. The instrument reproducibility, method error, precision, and limits of detection and quantification of the method were assessed. Physical mixtures of the polymorph pair were made by weight, ranging from 0 to 100% SMZ form I in II. Near-infrared spectra of the powder samples contained in glass vials were obtained over the wavelength region of 1100-2500 nm. A calibration plot was constructed by plotting SMZ form I weight percent against a ratio of second derivative values of log(1/R') (where R' is the relative reflectance) versus wavelength. The coefficients of determination, R(2), were generally greater than 0.9997 and standard errors were low for all the systems. Instrument error was assessed by analyzing a sample 10 times without perturbation. Method error was assessed in the same manner except the sample was re-mixed between analyses. A precision study was conducted by analyzing aliquots from a larger homogeneous sample. Limits of detection (LOD) and quantification (LOQ) were determined from the standard deviation of the response of the blank samples (100% SMZ form II, undiluted or diluted with 60% lactose). These limits were subsequently validated with independent samples. The results show that polymorphs can be quantified in binary and multi-component mixtures in the 2% polymorph composition range. These studies indicate that NIRS is a precise and accurate quantitative tool for determination of polymorphs in the solid-state, is comparable to other characterization techniques, and is more convenient to use than many other methods.

Application of diffuse reflectance near-infrared spectroscopy for determination of crystallinity.

Studies were conducted to investigate the use of near-infrared spectroscopy (NIRS) for determining degree of crystallinity. Physical mixtures of amorphous/crystalline indomethacin and amorphous/crystalline sucrose were prepared over several composition ranges. Spectra were obtained on powder samples contained in glass vials using diffuse reflectance sampling. Parallel studies were conducted using X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) for comparison. NIRS standard curves were constructed by plotting crystalline weight percent against the ratio of responses at two wavelengths or by partial least squares regression. NIRS standard curves demonstrated higher coefficients of determination and lower standard errors than either XRPD or DSC. Validation standards confirmed the accuracy of NIRS over XRPD. Method error analysis demonstrated comparable accuracy for NIRS and XRPD, with NIRS showing slightly better precision in repeated crystallinity determinations for a 50% crystalline sucrose sample. Interpretive analysis of the NIRS spectra was performed using neutron scattering and polarized Raman spectroscopy data obtained from the literature. Results indicated that the NIRS differences between crystalline and amorphous sucrose may be attributed to the disruption of regular vibrational modes when crystalline sucrose is rendered amorphous.

Quantifying crystalline form composition in binary powder mixtures using near-infrared reflectance spectroscopy.

The objectives of this study were to assess the utility of near-infrared reflectance spectroscopy (NIRS) in differentiating crystalline forms of pharmaceutical materials and determine the accuracy of this technique in quantifying crystalline forms of solids in binary mixtures. Various crystalline forms of sulfamethoxazole, sulfathiazole, lactose, and ampicillin, independently characterized with other methods, were analyzed qualitatively and quantitatively. The observed differences in near-infrared (NIR) spectra of crystalline form pairs were interpretable on the basis of the features of their crystalline and molecular structures and mid-infrared spectra. NIR spectra of binary physical mixtures of crystalline form pairs were obtained directly through glass vials over the wavelength range of 1100-2500 nm. The calibration lines were constructed using an inverted least-squares regression method. The ratio of the response of the second derivative of the reflectance spectra at two wavelengths was plotted versus crystal form composition. The correlation coefficients for plots of predicted versus theoretical composition were generally greater than 0.99 and standard errors were all low. Parallel studies comparing the NIRS method to a quantitative x-ray powder diffraction method using sulfamethoxazole and sulfathiazole confirmed the accuracy of the results. Additional NIRS studies were conducted in the 0-10% composition range with ampicillin and sulfamethoxazole. These results indicated that prediction down to the 1% level was possible. This study demonstrates that NIRS can be used as a quantitative physical characterization method, is comparable in accuracy to other techniques, and is capable of detecting low levels of one crystal form in the presence of another.

Wetting properties of bile salt solutions and dissolution media.

The objective of this study was to determine the extent to which specific bile salt solutions and compendial dissolution media differ in their ability to wet a model surface. Solutions were examined in the concentration range of bile salts found in the gastrointestinal tract and at pH values approximating those of the stomach and small intestine. Wetting was evaluated from measurement of the surface tension of the solutions and contact angles of sessile drops on poly(methyl methacrylate). Compendial dissolution media had higher surface tensions and contact angles than bile salt solutions at 10 mM. Individual bile salts at 10 mM varied in surface tension lowering and contact angles. The contact angle-concentration profiles achieved plateau values at 2.5 mM. Dewetting was observed at low bile salt concentrations at pH 7.5. Calculated adhesion tension and interfacial tension were consistent with this behavior. The effect was attributed to the influence of the substrate surface charge on the orientation of the adsorbed bile salt molecule. Adhesion tension profiles showed that from low (<0.5 mM) to moderate (2 mM) concentrations preferential bile salt adsorption to the liquid-vapor interface occurred, but at higher values (>2 mM) the preference shifted toward the solid-liquid interface. These results have implications in the design of physiologically based dissolution media.

Diffuse reflectance near-infrared spectroscopy as a nondestructive analytical technique for polymer implants.

A near-infrared spectroscopic method to quantify drugs or excipients within polymeric matrixes is proposed. Cylindrical implants were fabricated by a melt-mold technique containing various ratios of poly(epsilon-caprolactone) (PCL) and poly(ethylene glycol) (PEG) and various loadings of lomefloxacin HCl with a constant ratio (70:30 w/w) of PCL/PEG. Near-infrared (NIR) spectra were obtained on intact sections of larger implants using a Foss NIRSystems Model 5000 monochrometer equipped with a Rapid Content Analyzer. Spectral data were treated with second derivative transformation followed by linear regression and PLS to obtain correlation with lomefloxacin or PEG content. Lomefloxacin content was separately determined by UV analysis (287 nm) using a validated extraction procedure. The NIR method was tested by comparing predicted loadings of test implants with either theoretical values based on weight (PEG) or with UV analysis results (lomefloxacin). Second derivative spectral values at particular wavelength ratios (PEG, 2064 nm/1698 nm; lomefloxacin, 2172 nm/2226 nm and 1824 nm/1862 nm) yielded linear results for PEG or lomefloxacin content. PEG content determined by NIR spectroscopy was in excellent agreement with theoretical content. Lomefloxacin content determined by NIR spectroscopy was also in excellent agreement with UV analysis. NIR analysis is interpreted through the use of corresponding mid-infrared spectral data.

Surface free energy of ethylcellulose films and the influence of plasticizers.

The surface free energy parameters of ethylcellulose (EC) films were determined using the Lifshitz-van der Waals/acid-base approach and the influence of plasticizers on their surface energetics was assessed. Films were prepared by dip-coating glass slides in organic solvents containing EC and the advancing angles of drops of pure liquids on the EC films were measured with a contact angle goniometer using the captive drop technique. EC has lower surface free energy than cellulose. The acid-base (AB) term made only a slight contribution to the total surface free energy and the surfaces exhibited predominantly monopolar electron-donicity. The addition of plasticizer (dibutyl sebacate or dibutyl phthalate) resulted in a small decrease in the total surface free energy. The effects of film forming variables, including solvent system, concentration and post-formation treatment (annealing), on the surface free energy parameters of EC films were also investigated. These data were then used to analyze how the surface energetics affect the interaction of the EC films with other surfaces based on interfacial tension, work of adhesion and spreading coefficient calculations. Lifshitz-van der Waals (LW) interactions provided the major contribution to the work of adhesion for EC with all of the solid substrates analyzed. However, the AB interactions contributed significantly to the work of adhesion for EC with 'bipolar' substrates and to the spreading coefficients of EC over substrates. The consideration of work of adhesion and spreading coefficient based on surface free energy parameters may have potential use in evaluating factors affecting film adhesion and, furthermore, in optimizing pharmaceutical film coating processes.

The effects of bile salts and lipids on the physicochemical behavior of gemfibrozil.

Physicochemical effects caused by intestinal fluids on drugs in the gastrointestinal (GI) tract can be a contributing factor in food induced changes in bioavailability. To identify physicochemical properties of gemfibrozil that may be altered by endogenous and dietary lipids, in vitro studies were conducted in model systems approximating the conditions of the upper GI tract. Factors examined include pH, solubility in bile salt micellar and mixed micellar systems with monoolein and lecithin, effect of fatty acids, dissolution, wetting, and partitioning in triglyceride dispersions. Gemfibrozil was solubilized by glycocholate solutions in a manner typical of other lipids and a three-fold increase in solubility was observed over physiologic concentrations. Addition of increasing amounts of swelling amphiphiles (monoolein, lecithin) to glycocholate solutions resulted in a linear increase in solubility. Fatty acid salts had no effect on gemfibrozil solubilization by micellar solutions. The dissolution rate of gemfibrozil increased slightly in the presence of glycocholate relative to buffer, however, addition of monoolein increased the dissolution rate three-fold. In triglyceride dispersions of mixtures of lipids, monoolein increased the fraction of drug in the micellar subphase, whereas fatty acid reduced it. The results indicate that in the conditions of the fed state gemfibrozil solubility and dissolution could be substantially increased relative to the conditions in the fasted state.

Description and simulation of a multiple mixing tank model to predict the effect of bile sequestrants on bile salt excretion.

A nonlinear, multicompartment mixing tank model based on human physiologic parameters from the literature and in vitro bile salt sequestrant binding parameters was integrated numerically to simulate bile salt excretion. The model focuses on the transit of bile salts and resin, bile salt binding, and bile salt reabsorption as a means of gaining insight into the functioning of bile sequestrants in the gastrointestinal tract and the effect of reabsorption of bile salts on the sequestering process. The series of compartments through the ileal region were tested over a range of parameter values, and the results were compared with bile salt output from ileostomy patient data to validate the model without resin. In simulations incorporating resin with a reversible binding scheme, fecal bile salt output was 2.37 (+/- 0.6) x 10(-3) mol/day compared with 2.64 (+/- 1.1) x 10(-3) mol/day for human data. Assuming irreversible bile salt binding resulted in predictions of fecal bile salt excretion greater than three times physiologic values. The results of these simulations support the hypothesis that the lack of efficacy of bile sequestrants is due to the displacement of bound bile salts from the sequestrant as a consequence of anion competition and bile salt reabsorption. Gastric emptying effects and the timing of resin doses have also been investigated with the model.

Equilibrium and kinetic factors influencing bile sequestrant efficacy.

In vitro bile salt binding equilibria and kinetic studies were performed with cholestyramine to determine how these factors influence bile sequestrant efficacy in vivo. Chloride ion at physiologic concentrations caused more than a twofold reduction in glycocholate (GCH) binding, compared to binding in the absence of salt, over a range of GCH concentrations and was also observed to displace bound GCH. In addition, chloride ion displaced from cholestyramine as a result of bile salt binding was measured using a chloride selective electrode, and the results show that bile salt binding is due to ion exchange. Comparison of the results of the equilibrium binding experiments to human data shows that the effect of anion binding competition alone cannot account for the lack of efficacy of cholestyramine. Consideration of other effects, such as additional binding competition or poor availability for binding, based on data from the literature, shows that adequate bile salt binding potential exists and that these interferences are not major factors influencing resin efficacy. In kinetic studies, both binding uptake of GCH and displacement of GCH from cholestyramine by chloride ion were relatively rapid, indicating that cholestyramine should equilibrate rapidly with bile salts in the GI tract. Based on these findings, it is suggested that the low efficacy of cholestyramine is a result mainly of its relatively poor ability to prevent bile salt reabsorption in the ileum.