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M J Pikal

Publications and source records attributed to M J Pikal.

30 records · Page 2Linked to original sources
PubMed1984

Effect of nitroglycerin-soluble additives on the stability of molded nitroglycerin tablets.

Nitroglycerin vapor pressures at 25 degrees C were determined for additive-nitroglycerin systems over the additive-nitroglycerin weight ratio range of 0.5 to 3.0 for 16 additives exhibiting solubility in nitroglycerin. The effects of the additives on nitroglycerin chemical stability at 25 degrees C and 50 degrees C were also studied. Tablet stability characteristics, i.e., content uniformity, open-dish stability, and chemical decomposition were evaluated for selected tablet formulations. Most additives lowered the vapor pressure of nitroglycerin sufficiently to stabilize content uniformity when used at additive-nitroglycerin weight ratios near 1. Higher additive levels are needed for significant potency stabilization in open-dish stability tests, but these levels normally decrease the chemical stability of nitroglycerin. However, stabilization of content uniformity, a twofold reduction of potency loss in an open-dish stability test, and chemical stability are possible with at least three of the additives studied.

Absorption↗
PubMed1983

Physical chemistry of freeze-drying: measurement of sublimation rates for frozen aqueous solutions by a microbalance technique.

The sublimation rate of frozen solutions was studied as a function of freezing rate, thickness of dried product (l), temperature, residual air pressure, and solute concentration. Data are presented for pure water, aqueous potassium chloride, aqueous povidone, and aqueous dobutamine hydrochloride-mannitol (System I). The resistance of the dried product to water vapor flow (Rp) was evaluated from the sublimation rate and the sample temperature. The primary experimental technique was based on freeze-drying a cylindrical microsample isothermally, with the sample suspended from one arm of a vacuum microbalance. Methodology to evaluate resistance data from vial freeze-drying experiments is also described. In separate experiments, samples in the form of a thin (15-microns) film were visually observed through a microscope during freeze-drying. Freeze-drying of most samples appeared to occur by water vapor escaping through open channels created by prior sublimation of ice. Contrary to the usual theoretical model, Rp is neither independent of temperature nor directly proportional to l. Rather, Rp decreases with increasing temperature and the l dependence is normally of the form Rp = (A0 + A1l)/(1 + A2l), where Ai (i = 0, 1, 2) are constants. In several cases, Rp is very large near l = 0, decreases sharply at l congruent to 0.1 cm, and obeys the above equation where l greater than 0.2 cm, a result suggesting an amorphous surface skin which cracks on desorption of water. The temperature dependence of Rp suggests that, as the sample temperature approaches the eutectic (or collapse) temperature, hydrodynamic surface flow of adsorbed water is an important flow mechanism.

Air Pressure↗
PubMed1978

Quantitative crystallinity determinations for beta-lactam antibiotics by solution calorimetry: correlations with stability.

The solution calorimetry method is based on the observation that amorphous forms are normally significantly higher in energy than are crystalline forms. The utility and validity of the calorimetric method were investigated for cephalothin sodium, cefazolin sodium, cefamandole nafate, and cefamandole sodium. Amorphous, partially crystalline, and crystalline forms were prepared and characterized by X-ray diffraction (powder), by solution calorimetry, and, for cephalothin sodium, by the thermal decomposition rate at 50 degrees. Qualitatively, there was a good correlation between calorimetric crystallinity and the (less precise) crystallinity derived from X-ray data. The energy and structure of the amorphous state depend on the history of the sample; even samples of the same crystalline polymorph, containing no amorphous phase, may differ in energy. Thus, the absolute value of the crystallinity (X-ray or calorimetric) depends on the choice of amorphous and crystalline standards. The heat of solution is a precise (+/- 1%) and unambiguous measure of the relative crystallinity; and provided amorphous and crystalline standards are appropriately chosen, the calorimetric crystallinity correlates well with chemical stability.

Absorption↗
PubMed1977

Polymer sorption of nitroglycerin and stability of molded nitroglycerin tablets in unit-dose packaging.

The sorption of nitroglycerin by thermoplastic polymers and the stability of molded nitroglycerin tablets in strip packaging were studied. The polymers investigated varied greatly in their affinity for nitroglycerin, the order of decreasing affinity being: vinyls greater than low density polyethylene greater than ionomers greater than high density polyethylene. With the proper choice of packaging, molded nitroglycerin tablets stabilized with povidone maintained acceptable potency for up to 2 years at 26 degrees when strip packaged in unit doses. Chemical decomposition (hydrolysis) of nitroglycerin also was investigated. Povidone accelerated the decomposition of nitroglycerin; at high temperature, decomposition was a significant factor in tablet stability for tablets containing povidone.

Adsorption↗
PubMed1977

Thermal decomposition of amorphous beta-lactam antibacterials.

Thermal decomposition rates for amorphous samples of penicillin G potassium, cephalothin sodium, cefamandole sodium, and cefamandole nafate were determined as a function of water content and temperature. Even when rigorously dry, amorphous cephalosporins were at least one order of magnitude less stable than the corresponding unsolvated crystalline form. Absorbed water generally increased both the number of decomposition products and the net decomposition rate. Reaction kinetics were usually apparent first order, but an anomalously high effective reaction order was observed in several systems. Nonlinear Arrhenius plots were observed, and a qualitative model based on molecular relaxation in glayses is proposed. Although decomposition rates at 25 degrees were small for dry samples, even slight decomposition produced visually detectable changes. Thus, the unsolvated crystalline form was noticeably more stable, even at 25 degrees.

Anti-Bacterial Agents↗
PubMed1976

Vapor pressure of nitroglycerin in sublingual molded tablets: implications for stability.

To understand nitroglycerin intertablet migration, vapor pressures of nitroglycerin in tablets were measured using a modified gravimetric Knudsen effusion technique. To supplement the vapor pressure data, adsorption isotherms at 296 degrees K were determined, and tablets were studied by scanning electron microscopy. For conventional tablets (i.e., tablets without stabilizing additives such as polyethylene glycol 400), the nitroglycerin vapor pressure in a tablet is within about 10% of that for pure liquid nitroglycerin, provided the potency is greater than 0.3 mg. Significant capillary condensation in tablets at relative vapor pressures close to unity is demonstrated. Stabilizing additives lower the vapor pressure of nitroglycerin, the magnitude of the effect depending on both the nature of the additive and the additive-nitroglycerin weight ratio. The mechanism of intertablet migration involves capillary condensation. Vapor pressure reduction of about 15%, achieved through the use of an additive, appears sufficient to prevent significant intertablet migration.

Adsorption↗
PubMed1976

Knudsen vapor pressure measurements on pure materials and solutions dispersed in porous media: molded nitroglycerin tablets.

The gravimetric Knudsen method for vapor pressure measurement may be subject to serious systematic errors when the sample: (a) consists of the volatile component dispersed in an inert porous matrix and/or (b) contains a dissolved polymeric solute. Vaporization of water present as an impurity in the matrix may result in an appreciable "background" mass loss, and "nonequilibrium effects" may be present; i.e., The vapor of interest may be unable to escape from the sample rapidly enough to maintain the equilibrium vapor pressure in the Knudsen cell. Methods for eliminating the interference due to background effects are described, and a theoretical analysis of nonequilibrium effects is presented. The essential validity of the theories for nonequilibrium effects and the effectiveness of the methods for circumventing background effects were verified by experimental studies with molded nitroglycerin tablets. With nitroglycerin tablets, accurate Knudsen vapor pressure data may be obtained using the modified procedures and data analysis presented in this report.

Chemical Phenomena↗
PubMedDate not supplied

Process control in freeze drying: determination of the end point of sublimation drying by an electronic moisture sensor.

The end point of sublimation drying, or primary drying, is an important control point in the freeze drying process. Traditionally, the end of sublimation drying is determined by product temperature response, the rapid rise in product temperature after the temperature sensor loses thermal contact with ice being taken as evidence of the complete removal of ice from that container. However, the product temperature is measured by temperature sensors placed in a relatively small number of vials, and product in these vials can behave differently than the batch as a whole. There is clearly a need for an alternate method for end point detection which depends on a property of the batch as a whole. The partial pressure of water vapor in the drying chamber could serve as such a property. During sublimation drying, the partial pressure of water vapor in the drying chamber is high (close to the total pressure), but when the rapid evolution of water vapor ceases with the conclusion of sublimation drying, the partial pressure of water sharply decreases. In this research, an electronic moisture sensor is employed to monitor the partial pressure of water during the freeze drying process. The moisture sensor response provides a convenient and reliable method for determination of the end point of sublimation drying for the batch as a whole. The moisture sensor method has sufficient sensitivity to detect the presence of as few as 0.3% of the vials in a batch having residual ice.(ABSTRACT TRUNCATED AT 250 WORDS)

Freeze Drying↗
PubMedDate not supplied

Evaluation of manometric temperature measurement as a method of monitoring product temperature during lyophilization.

The objective of this study was to evaluate manometric temperature measurement as a non-invasive method of monitoring product temperature during the primary drying phase of lyophilization. This method is based on analysis of the transient response of the chamber pressure when the flow of water vapor from the chamber to the condenser is momentarily interrupted. Manometric temperature measurements (MTM) were compared to product temperature data measured by thermocouples during the lyophilization of water, mannitol, lactose and potassium chloride solutions. The transient pressure response was mathematically modeled by assuming that four mechanisms contribute to the pressure rise: 1) direct sublimation of ice through the dried product layer at a constant temperature, 2) an increase in the temperature at the sublimation interface due to equilibration of the temperature gradient across the frozen layer, 3) an increase in the ice temperature due to continued heating of the frozen matrix during the measurement, and 4) leaks in the chamber. Experimental transient pressure response data were fitted to an equation consisting of the sum of these terms containing three variables corresponding to the vapor pressure of ice, product resistance to vapor flow, and the vial heat transfer coefficient. Excellent fit between the mathematical model and the experimental data was observed, and the value of the variables was calculated from the measured transient pressure response by a least squares method. The product temperature measured by MTM, which measures the temperature at the sublimation interface, was compared with product temperature measured by thermocouples placed in the bottom center of the vials. Manometrically measured temperatures were consistently lower than the thermocouple measurements by about 2 degrees C, this difference being largely accounted for by the temperature gradient across the frozen layer. The resistance of the dried product to mass transfer calculated from MTM was found to agree reasonably well with values measured by a direct vial technique. Product resistance was observed to increase with increasing solute concentration, and to increase continuously as the depth of the dried product layer increases for mannitol and potassium chloride. For lactose, product resistance increases continuously with thickness up to the onset of collapse, at which point the product resistance becomes essentially independent of depth. Scanning electron microscopy was used to explain this observation based on changes in morphology of the solid. The vial heat transfer coefficients obtained from regression analysis were on the order of 10(-3)-10(-4) cal.sec-1. degrees C-1; however, the scatter in the vial heat transfer coefficient data prevents the method from being used for accurate measurement of the vial heat transfer coefficient. The results of the study show that the manometric method shows promise as a process development tool and as an alternative method of in-process product temperature measurement during primary drying.

Freeze Drying↗
PubMedDate not supplied

Intravial distribution of moisture during the secondary drying stage of freeze drying.

Particularly for proteins that may be damaged by overdrying, the distribution of residual moisture in the dried product may be as important as the mean water content. Protein at the top of the cake could be "overdried" even though the mean water content was optimal. Theoretical studies suggest that, particularly for large fill depths, the residual moisture near the top of the cake is much lower than the moisture near the bottom, at least during and immediately after freeze drying. This work is an experimental study of the distribution of moisture within a vial as a function of time in secondary drying (mean residual water content of about 3%-6%) for dextran, human serum albumin, and bovine somatotropin. A core sample of the dried product was taken and sectioned into "top," "middle," and "bottom" sections. These three "core sections" and the remaining "outer" section (i.e., near the vial wall) were assayed for moisture. In general, the moisture content in the top section is less than the moisture content in the bottom section, but the "outer" section is consistently found to be lowest in moisture content. This observation suggests that drying was faster along the walls of the vial than in the core region, resulting in a highly curved ice-vapor interface. It is proposed that faster drying along the vial walls is a result of the observed product shrinkage during drying which provides a low resistance pathway for vapor escape along the vial wall. Product temperature measurements support the above speculation.

Freeze Drying↗