Elizabeth B. Vadas

Quantitative analysis of pharmaceutical products by laser-induced breakdown spectroscopy

Abstract In this paper, the capabilities of laser-induced breakdown spectroscopy (LIBS) for rapid analysis of multi-component pharmaceutical tablets are illustrated using several examples. The atomic line emission from an element present only in a particular component of the tablet (for instance, emission of phosphorus from the drug, or of magnesium from the lubricant) enables the quantitative analysis of that component. It is also demonstrated that simple schemes can significantly improve the analytical performance of LIBS in this context. In particular, internal standardization with a carbon line was found to enable the correction of a matrix effect, apart from improving the precision of measurement. Furthermore, an improvement in the linearity of calibration was observed when the plasma continuum emission was used as internal standard. Finally, in the case of drugs containing halogen species (e.g. F or Cl), producing the plasma in a helium atmosphere caused a seven to eight-fold increase of the signal-to-background ratio, thus improving sensitivity. These data illustrate the strengths of LIBS for fast at-line assessment of the reliability of pharmaceutical manufacturing processes.

Solid-State Phase Transitions Initiated by Water Vapor Sorption of Crystalline L-660,711, a Leukotriene D4 Receptor Antagonist

Significant water vapor sorption at room temperature by the crystalline and lyophilized forms of L-660,711, a potent, selective leukotriene D4 receptor antagonist, has been measured and shown to produce increasingly more nonflowing, semisolid masses with increasing relative humidity. Thermal analysis, SEM, powder X-ray diffraction, solid-state NMR, and thermomicroscopic measurements reveal that water vapor sorbed at room temperature converts the crystalline form to a noncrystalline form resembling the lyophilized sample. Evidence is presented to indicate that L-660,711 has surface active properties with a critical micellization concentration of approximately 1 × 10 −4M and an ability to form thermotropic and lyotropic mesomorphic phases when the crystal is heated above 80°C in the anhydrous state; it is lyophilized from aqueous solution, and it is exposed to relative humidities at and above 12%, at room temperature.

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.

Drug excipient interaction study of enalapril maleate using thermal analysis and scanning electron microscopy

Abstract A drug-excipient interaction between enalapril maleate and microcrystalline cellulose, previously known to cause increased rates of degradation, has been studied using primarily thermal analysis and scanning electron microscopy. Results indicated apparent reduced heats of fusion for the drug in the presence of the excipient. This was related to the drug-excipient ratio and surface contact. Degradation under DSC conditions was monitored by thermogravimetric analysis (TGA) and high pressure liquid chromatography (HPLC) and shown not to explain the observed reduction in the apparent heats of fusion. The most probable explanation was a weak interaction of the drug with the excipient surface which significantly altered the crystal structure and provided additional low energy sites for melting in a matrix with increasing amorphous content.

Safety of Chewable Tablets for Children

New emphasis on pediatric drug development makes the availability of safe, easy-to-use dosage formulations imperative for clinical practice. Chewable tablets are a widely used pediatric dosage form; however, a literature review on the safety of this formulation has not been published. We have, therefore, determined the safety of chewable tablets in the pediatric age group based on the published literature. A search of safety information on chewable tablets was performed from the published literature dating from January 1966 to January 1999. Search terms included tablet, chewable tablet, drug formulation, aspiration, choking, asphyxia, airway obstruction, and foreign body. Additional information was obtained from the Physicians Desk Reference, by purchasing products at a local drug store, from calls to manufacturers, and from the IMS Health National Prescription Audit Plus 7. Human, English-language studies of two types were included: clinical articles with any mention of chewable tablets, and aspiration case series. The results of this review showed that more than 60 chewable tablet formulations are approved for use in the United States. Medical issues, including foreign-body injuries, related to the chewable-tablet formulation were extremely rare. The advantages of chewable tablets include palatability, stability, precise dosing, portability, and ease of delivery. It is concluded that the available literature suggests that chewable tablets provide a safe, well-tolerated alternative to traditional pediatric drug formulations and offer significant advantages in children 2 years of age and older.

L-649,923 — The selection of an appropriate salt form and preparation of a stable oral formulation

Abstract L-649,923 is an orally active leukotriene D 4 antagonist and the salt of a γ-hydroxy acid. It was formulated as a physically and chemically stable compressed tablet dosage form. Because the free acid was inherently unstable, the physical and chemical properties of the sodium, calcium, ethylenediamine and benzathine salts were evaluated and the calcium salt selected as the most pharmaceutically acceptable form of the drug for formulation development. The principal route of degradation was through an intramolecular esterification to yield the γ-lactone. Degradation could be monitored by following the appearance of the γ-lactone with an HPLC assay. A mechanism of degradation was proposed resembling acid-catalyzed solution esterificatiom occuring in the sorbed moisture. This postulate was used as a predictive model. Formation of γ-lactone was minimized in a direct compression tablet formulation by reducing the amount of free acid in the drug substance, avoiding an aqueous granulating process, using excipients with low water content and adding sodium carbonate as an alkalizing agent.

Assessment of the physical stability of lyophilized MK-0591 by differential scanning calorimetry

Abstract MK-0591, a potent indirect leukotriene biosynthesis inhibitor, is poorly absorbed when administered orally as a crystalline sodium salt, primarily because of its low aqueous solubility (5 μg/mL). However, the lyophilized X-ray amorphous form with much higher aqueous solubility is very well absorbed and physically stable for long time periods. To better understand the physical stability of the amorphous state, conditions at which the compound will crystallize from the amorphous state were investigated in the context of its glass transition temperature. The physical stability of X-ray amorphous MK-0591 was evaluated by DSC with enhanced sensitivity using the crystallization exotherm at ca. 185°C (10°C/min) to detect crystallization in the solid matrix. No crystal formation was observed at 30°C for 6 months, 60°C for 6 months or 30°C at 75% RH for 6 months. This prolonged physical stability was attributable to two factors: its high glass transition temperature (ca. 125°C) and liquid crystal formation in aqueous solutions at concentrations greater than 60 mg/mL. Crystallization could not be induced after isothermally holding the X-ray amorphous MK-0591 at 120°C for 17 h. Seeding with crystalline MK-0591 (10%) also failed to induce crystallization at 50°C for 6 months or at 30°C at 75% RH for 6 months. Water plasticizes lyophilized MK-0591, lowering the Tg and inducing the onset of crystallization to 100°C. Crystallization at room temperature does not occur with equilibration at high relative humidites probably because of the additional stability imparted to the system by the formation of a lyotropic liquid crystalline phase. The behaviour of amorphous MK-0591, with its high Tg in the solid state and its liquid crystalline properties in concentrated aqueous solution, provided sufficient physical stability to permit its use in oral formulations.

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.

Formulation assessment of MK-886, a poorly water-soluble drug, in the beagle dog

Abstract MK-886 is an orally active leukotriene biosynthesis inhibitor which may have therapeutic benefits in inflammatory diseases. The compound is the sodium salt of an organic acid with low aqueous equilibrium solubility and potentially poor oral absorption characteristics. Since there is no adequate in vitro method of predicting oral bioavailability for such poorly water-soluble compounds, assessment of formulations was conducted in vivo. The beagle dog was chosen as an animal model to select a suitable dosage form with good absorption characteristics. Dosage form performance was evaluated by comparing the following pharmacokinetic parameters: area under the plasma concentration vs time curve (AUC), peak plasma concentration ( C max ) and the time required to reach this peak ( T max ). Since no intravenous formulation was available, oral absorption from the different solid and liquid soft gelatin capsule formulations was evaluated relative to the absorption from a reference oral solution of MK-886 in PEG 400. Oral absorption of MK-886 in PEG 400 solutions was independent of solution concentration within the 15-fold range of concentration tested and was not affected by encapsulating the solutions in a soft gelatin shell. Food or co-administration of an alkalizing agent had no effect on the absorption of MK-886 from the soft gelatin capsules. Solid oral dosage forms, both capsules and tablets, had similar absorption characteristics to those of the PEG 400 solutions when the drug was granulated with an aqueous solution of polyvinylpyrrolidone (PVP), a hydrophilic polymer. PVP-granulated solid oral dosage forms had superior absorption characteristics when compared with a dry filled capsule of ungranulated drug.