Paul E. Luner

Characterization of the surface free energy of cellulose ether films

Abstract The objective of this study was to determine the surface free energy components of aqueous-based cellulose ether films and compare these values with those of other cellulose polymers. The surface free energy parameters were calculated from the contact angles of sessile drops of apolar and polar liquids on cellulose ether films cast on glass slides using the Lifshitz–van der Waals/acid–base (LW/AB) approach according to the method of van Oss, Chaudhury and Good. The cellulose ethers studied were hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), hydroxypropyl cellulose (HPC) and hydroxyethyl cellulose (HEC). The total surface free energy of these cellulose ethers ranged from 42 to 50 mJ m−2. The contribution of the acid–base (AB) component of surface free energy to the total surface free energy of the polymers ranged from 4 to 12%, which was considerably lower than that of cellulose. The cellulose ethers demonstrated near monopolarity and had dominant electron donor (Lewis-base) character. The overall trend in the values of the thermodynamic terms derived from the surface free energy parameters as indicators of hydrophilicity and hydration were in good agreement with the relative bulk solubility and hydration behavior of the polymers. Independent estimates of the AB character of the polymers from work of adhesion terms calculated from the liquid wetting data agreed with those obtained from the surface free energy parameters. Calculation of the work of adhesion with substrates of varying surface free energy parameters indicated that acid–base interactions made a major contribution to the total work of adhesion between cellulose ethers and bipolar surfaces. Although no direct correlation could be established between the surface free energy parameters and the type of substitution on the cellulose backbone for the cellulose ethers, the values of the terms derived from the LW/AB approach were consistent with those of cellulose and ethylcellulose. The LW/AB approach provides a reasonably consistent method for estimating the surface properties of cellulose ethers and the resulting surface free energy parameters are shown to relate to the interfacial properties of the polymers.

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 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.

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.

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.

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.

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, α-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.

Influence of formulation composition and processing on the content uniformity of low-dose tablets manufactured at kilogram scale

The purpose of this study was to investigate the impact of processing, API loading, and formulation composition on the content uniformity of low-dose tablets made using direct compression (DC) and roller compaction (RC) methods at 1 kg scale. Blends of 1:1 microcrystalline cellulose/lactose or 1:1 microcrystalline cellulose/dicalcium phosphate anhydrous with active pharmaceutical ingredient (API) at loadings of 0.2, 1 and 5% were processed either by DC or RC. A statistical analysis showed that DC produced comparable content uniformity results to RC. Microcrystalline cellulose/lactose formulations had improved average potency compared to microcrystalline cellulose/dicalcium phosphate anhydrous formulations for both DC and RC. The impact of segregation in the DC blends and adhesion to equipment surfaces was assessed to aid in understanding potency trends. DC may be as suitable as RC for low-dose regime (e.g. < 1 mg) when manufacturing clinical supplies at small scale provided the API has a suitable particle size and potency loss to equipment is negligible.