Roch Thibert

Polymorphic properties of micronized carbamazepine produced by RESS.

Carbamazepine microparticles were produced by the rapid expansion of supercritical carbon dioxide solutions (RESS) method. The characteristics of the resulting particles were studied by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and image analysis. X-ray diffractograms and SEM photomicrographs revealed that the crystalline nature of the produced carbamazepine microparticles depended on operating pressure and temperature conditions. Different polymorphs were obtained under various operating conditions. Under certain temperature (below 40 degrees C) and pressure (below 240 bar) conditions, it was possible to form primarily the carbamazepine polymorph stipulated by US Pharmacopeia. A significant reduction was observed in the particle size and size distribution range of carbamazepine produced by RESS. The processed particles had a mean diameter smaller than 3 microm and a size distribution range between 0.5 and 2.5 microm compared to unprocessed starting material with a mean diameter of approximately 85 microm and a size distribution range between 15 and 336 microm. Thus, this study demonstrates that the polymorphic characteristics of carbamazepine microparticles produced by the RESS method can be controlled by varying operating pressure and temperature parameters.

New methods characterizing avalanche behavior to determine powder flow

AbstractPurpose. To characterize the avalanche behavior of different powders and to compare the results of the strange-attractor and novel characterization approaches. Methods. The following nine different materials were tested: three lactoses, maltodextrin, two microcrystalline celluloses, sodium chloride, sucrose, and glass beads. Morphology, size, and size distribution, true density, bulk and tap density, angle of repose, flow index, and avalanching behavior were quantified for each excipient by scanning electron microscopy, laser time-of-flight analysis, helium pycnometer, graduated cylinder, fixed-height funnel, Flodex (Hanson Research Corp., Chatsworth, California) method, and AeroFlow (TSI, Inc., St. Paul, Minnesota), respectively. Environmental factors were controlled, and the avalanches were studied at various speeds. Results. The strange-attractor graph obtained at 1 rotation per 120 s showed that it was difficult to appreciate the flowability differences among 3-mm glass beads, lactose 100, and lactose 325. However, plotting the raw data as a relationship of the time between each avalanche and the inverse of speed revealed a characteristic linear slope for each sample. Furthermore, a new flowability index based on the SD calculated from the raw data gave results that were consistent with Carrs index. A cohesive index also can be determined by avalanche behavior, and it reflects the stability of the rapid particular rearrangements of powder. Conclusion. A novel method of evaluating avalanche measurements makes it possible to better characterize powder flowability and to predict powder behavior under working conditions.

Determination of the Viscosity of an Amorphous Drug Using Thermomechanical Analysis (TMA)

AbstractPurpose. To evaluate thermomechanical analysis (TMA) as a technique for determining the viscosity of amorphous pharmaceutical materials. This property of amorphous drugs and excipients is related to their average rate of molecular mobility and thus to their physical and chemical stability. Methods. Indomethacin was selected as a model amorphous drug whose viscosity has previously been reported in the literature. A Seiko TMA 120C thermomechanical analyzer was utilized in isothermal penetration mode to determine the viscosity of the amorphous drug over the maximum possible range of temperatures. Results. Using a cylindrical penetration geometry it was possible to accurately determine the viscosity of amorphous indomethacin samples by TMA over the temperature range from 35 to 75°C. The results were consistent with those reported in the literature using a controlled strain rheometer over the range 44−75°C. The limiting lower experimental temperature for the TMA technique was extended to significantly below the calorimetric glass transition temperature (Tg ≈ 42°C), thus allowing a direct experimental determination of the viscosity at Tg to be made. Conclusions. Thermomechanical analysis can be used to accurately determine the viscosity of amorphous pharmaceutical materials at temperatures near and above their calorimetric glass transition temperatures.

Characterization of the self-association properties of a leukotriene D4 receptor antagonist, MK-0476

Abstract The development of a liquid dosage form requires a comprehensive understanding of physicochemical properties unique to solutions. The objective of this study was to investigate the behaviour of MK-0476, a potent leukotriene D4 receptor antagonist, using determination of solubility characteristics, surface tension measurements, static and dynamic light scattering, and near-UV spectroscopy. More specifically, the self-association behaviour of aqueous solutions of MK-0476 was investigated as a function of ionic strength, pH and temperature. The observed pH-solubility profile deviated markedly from the expected profile suggesting a self-association behaviour. The ionic strength influenced the solubility and surface activity. The critical micelle concentration (cmc) determined by tensiometry at pH 10.0 decreased from 162 μM to 14μM with increasing ionic strength, and a linear relationship between logarithm of cmc and the logarithm of the total counterion concentration was obtained. The cmc determined from surface tension measurements was marginally affected by pH in the range of 8.8 to 10.8 in a constant ionic strength (μ = 0.05) glycine-KOH buffer. Results from surface tension measurements showed that temperature had no effect on the self-association phenomenon in the range 25°-37°C. Light scattering data indicated that at low ionic strength and basic pH, micelles of an average hydrodynamic radius of 1.6 nm exist. The addition of 150 mM of NaCl increased micelle size to approximately 40 nm. The radius of gyration of these aggregates measured by the angular dissymmetry method were larger than the hydrodynamic radii calculated from dynamic light scattering measurements, indicating an elongated shape. Understanding the surface active behaviour of MK-0476 and establishing the critical parameters affecting its self association provided valuable insight towards the development of a liquid dosage form.

Clickhaler® dry powder inhaler: focussed in vitro proof of principle evaluation of a new chemical entity for asthma

A new chemical entity (NCE) was evaluated in the Clickhaler (Innovata Biomed Ltd.) dry powder inhaler, a reservoir-based multidose delivery system. The standard device metering system was modified to handle higher doses (nominally 20 mm(3) of lactose based blend). The micronized drug was formulated at 12.5% w/w in lactose monohydrate (Pharmatose 325M, DMV) equivalent to a nominal dose of approximately 1 mg. Delivered shot weight (mg of blend) and emitted dose (microg drug) averaged 7.4 mg and 905 microg, respectively, and were consistent (within +/-20 to 25% of mean) through the life of the inhaler. The fine particle fraction (FPF) (Andersen cascade impactor) was typically 60%. A short stability study (i.e. 3 months at room temperature, 53 or 75% RH, unpacked) showed that the in vitro performance was maintained. The results of these studies provide in vitro proof of principle for this novel drug/device combination.

Development of a discriminating in vitro dissolution method for a poorly soluble NO-donating selective cyclooxygenase-2 inhibitor.

A discriminating dissolution method using a USP apparatus 2 dissolution tester was developed for a nitric oxide donating selective COX-2 inhibitor to support phase I and II formulation development, clinical supplies release and stability testing of an immediate release oral tablet. The BCS class II compound showed very low aqueous solubility and required the use of surfactant-containing (sodium lauryl sulfate (SLS)) dissolution medium in order to achieve an appropriate release profile. The dissolution method utilized 900 mL of 2% SLS (w/v). Samples were withdrawn at five specified time-points over 60 min, at a paddle speed of 75 rpm. Analysis of samples was performed using a validated HPLC method. Despite the use of high levels of SLS, the ability to discriminate variations in physical properties such as drug particle size, granule particle size and tablet compression force was demonstrated. In order to confirm the relationship between these physical parameters and the tablet in vivo release profile, oral dosing of the formulations in fasted beagle dogs was performed to determine if the changes observed in the dissolution profiles were biorelevant. The results of the dissolution and corresponding in vivo experiments helped identify the critical processing parameters likely to influence product bioavailability.