Sophie-Dorothee Clas

Crystallization inhibition in solid dispersions of MK-0591 and poly(vinylpyrrolidone) polymers

The effects of poly(vinylpyrrolidone) (PVP) molecular weight, composition, and content on the crystallization of a model drug, MK-0591 (Form I), were investigated. Solid dispersions of crystalline MK-0591 with PVP homopolymers of different molecular weights (2500-1 x 10(6) g/mol) and with a copolymer containing poly(vinyl acetate) (PVA), (PVP/VA, 60:40, 5.8 x 10(4) g/mol) were prepared by the solvent method. MK-0591 in the solid dispersions was found to be X-ray amorphous. One glass transition temperature (T(g)) was observed suggesting drug-polymer miscibility. The T(g) values were higher than predicted by the Gordon-Taylor equation, indicating drug-polymer interactions. The extent of crystallization inhibition increased with PVP molecular weight and, for a comparable PVP molecular weight, the homopolymer was more effective in the crystallization inhibition of the drug than the copolymer. The first onset temperature of crystallization (T(c)(obs)) increased with polymer content. The T(c)(obs) values (normalized to polymer content) were a function of the difference between the T(g) of the polymer and drug. For PVP K-90, K-30, and K-17 dispersions, the T(c)(obs) values increased proportionally to the T(g) of the dispersions. However, for PVP K-12 and PVP/VA, the increase in T(c)(obs) values corresponded to a small decrease in the T(g) values of the dispersions. This result suggests that additional factors other than the reduction in mobility affect the crystallization behavior of MK-0591 in the solid dispersions, such as specific interactions. By Fourier transform-infrared spectroscopy, changes in the carbonyl-stretching band of PVP in the solid dispersions were observed. The existence of an ion-dipole interaction between COO(-)Na(+) of the drug and the cyclic amide group of PVP was postulated.

Differential scanning calorimetry: applications in drug development.

Differential scanning calorimetry (DSC) is frequently the pharmaceutical thermal analysis technique of choice because of its ability to provide detailed information about both the physical and energetic properties of a substance. This review provides an up-to-date overview of the applications of DSC in the drug development process. It should serve as a broad introduction to those starting work in this area, and also as a valuable reference for those already practising in this field.

Micro-scale measurement of the mechanical properties of compressed pharmaceutical powders. 1: The elasticity and fracture behavior of microcrystalline cellulose.

The feasibility of using very small compacts ( approximately 8.0 x 4.5 x 0.4 mm; approximately 20 mg) to determine the elasticity and fracture behavior of compressed pharmaceutical powders using the three-point beam-bending technique was evaluated. Compacts of microcrystalline cellulose with a range of porosities were tested using a thermomechanical analyzer and values for the Youngs modulus and critical stress intensity factor at zero porosity (E(0) and K(IC0)) were determined by extrapolation. The value of E(0) measured at ambient relative humidity on un-notched beams was found to be in close agreement with that reported for much larger samples, and the value of K(IC0) for the small notched compacts was at the lower limit of the accepted range of values for microcrystalline cellulose. The fracture toughness (R) and total energy of fracture (U) for the notched specimens were also determined and used to estimate the apparent surface energies for crack initiation (gamma(i)) and for total fracture (gamma(f)). To further probe the utility of the micro-scale mechanical testing techniques, the effects of humidity on the various mechanical properties of the small microcrystalline compacts were examined and it was found that E(0), K(IC0), R(0), gamma(i0) and gamma(f0) each decreased as the surrounding humidity (and water content of the samples) increased.

Evaluation of Disintegration Testing of Different Fast Dissolving Tablets Using the Texture Analyzer

The in vitro disintegration behavior of fast dissolving systems manufactured by the main commercialized technologies was studied using the texture analyzer (TA) instrument. Quantitative parameters were employed to characterize the effect of the major test variables on the disintegration profiles. The average disintegration profiles of the products were compared using the test conditions that minimized these effects and at the same time mimicked the in vivo situation in the patients mouth. The differences in the disintegration mechanisms of the fast dissolving systems were reflected in the shape of their disintegration profiles and in the parameters derived from the profiles. The differences were explained in relation to the technology and/or formulation characteristics involved in the manufacture of each product. The in vitro disintegration times obtained under the simulated in vivo conditions were correlated with the reported in vivo disintegration times.

Quantification of crystallinity in blends of lyophilized and crystalline MK-0591 using x-ray powder diffraction

Abstract X-ray powder diffraction was used to determine the percent crystallinity in blends of crystalline and X-ray amorphous MK-0591, a potent indirect leukotriene biosynthesis inhibitor. A linear calibration curve was obtained. Preliminary studies using powder blends of MK-0591 with pregelatinized starch, microcrystalline cellulose, and magnesium stearate demonstrated the feasibility of using this method to determine (or quantify) the percent crystallinity of MK-0591 in tablet formulations.

Thermal, mechanical and functional properties of cellulose acetate phthalate (CAP) coatings obtained from neutralized aqueous solutions

Abstract This study investigated the thermal, mechanical and functional properties of cellulose acetate phthalate (CAP) film coatings obtained from neutralized aqueous solutions. A novel salt forming agent, 2-amino-2-methyl-l-propanol (MAP), was used for the neutralization and dissolution of CAP in water. Triethylcitrate (TEC) was used as the plasticizer at 10–35% levels. Thermal and mechanical properties of free films plasticized with 10–35% TEC were evaluated by thermogravimetric analysis (TGA), thermal mechanical analysis (TMA) and dynamic mechanical spectroscopy (DMS). The physical stability of CAP/MAP films stored at 40 and 50°C was compared to ammoniated CAP films with respect to dissolution times in pH 6.8 buffer. Plasticized CAP/MAP films were also sprayed at three weight gains (6, 8 and 10%) onto acetylsalicylic acid (ASA) tablets (650 mg) using pan coating technology. The functional properties of the films were assessed for enteric integrity in 0.1 N HCI, drug release in pH 6.8 phosphate buffer and water permeability. Results have shown that CAP/MAP films plasticized with 25–35% TEC released ≤1% ASA after 2 h in 0.1 N HCl and > 95% after 1 h in buffer, thereby demonstrating their excellent functional properties. These films had high permeability to water/acid which makes them unsuitable for acid-labile drugs, since water/HCl would penetrate rapidly into the tablet core and degrade the drug. Neither the T g nor E ′ values differed significantly for films that showed satisfactory functional properties. Films were stiff and brittle with E ′ values in the range of 2–3 × 10 9 Pa and T g values of 108–112°C. TEC appeared to have limited solubility in the CAP/MAP polymer with reduced plasticization effects at concentrations higher than 20–25%. CAP/MAP free films were found to be superior to ammoniated CAP films with respect to extent of aging when stored at 40°C. The results clearly showed the potential use of plasticized CAP/MAP films as an enteric film former for pharmaceutical products.

Chemistry-enabled drug delivery (prodrugs): recent progress and challenges.

Prodrugs can be used to enhance the properties of an active pharmaceutical ingredient or drug, generally by improving solubility and/or permeability of the compound. However, discovery teams duly spend considerable time and resources on structure-activity optimization and formulation-enabled drug delivery technologies to achieve the target exposures and biopharmaceutical properties, when early implementation of prodrugs could lead to an improved drug molecule. The goal of this review is to provide an overview of the achievements during the past few years in developing prodrugs and highlighting the challenges of following this approach.

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.

Discovery of MK‐8970: An Acetal Carbonate Prodrug of Raltegravir with Enhanced Colonic Absorption

Developing new antiretroviral therapies for HIV‐1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethyl (1‐((4‐((4‐fluorobenzyl)carbamoyl)‐1‐methyl‐2‐(2‐(5‐methyl‐ 1,3,4‐oxadiazole‐2‐carboxamido)propan‐2‐yl)‐6‐oxo‐1,6‐dihydropyrimidin‐5‐yl)oxy)ethyl) carbonate (MK‐8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand‐transfer inhibitor approved for the treatment of HIV infection with twice‐daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK‐8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug–drug interaction profile of raltegravir.

Detection of a Minor Amorphous Phase in Crystalline Etoricoxib by Dynamic Mechanical Analysis: Comparison with Raman Spectroscopy and Modulated Differential Scanning Calorimetry

Detection and quantification of the amorphous phase of etoricoxib bulk drug substances, a selective cycloogenase-2 inhibitor used for the treatment of osteoarthritis, rheumatoid arthritis, and dental pain, was carried out using modulated differential scanning calorimetry (MDSC), dynamic mechanical analysis (DMA), and Raman spectroscopy. Detection of amorphous content in pharmaceutical powders by DMA is a special application of dynamic mechanical spectroscopy. DMA was found to be a sensitive technique, able to detect the presence of an amorphous phase in a crystalline phase at concentrations as low as 0.5%. The limit of detection (LOD) determined for DMA was 2.5%. In comparison, Raman spectroscopy and MDSC had LOD values of 2% and 5% amorphous, respectively.