Biomedical subjects

Lynne S Taylor

Publications and source records attributed to Lynne S Taylor.

At least 19 recordsLinked to original sources

PubMed2006

Effect of small levels of impurities on the water vapor sorption behavior of ranitidine HCl.

PURPOSE: Deliquescence is the process by which a solid undergoes dissolution by sorbing moisture from its surroundings when a characteristic relative humidity, RH0, is reached. For mixtures of two or more deliquescent solids, RH0 will generally be lowered. The goal of this research was to investigate the effect of small amounts of impurities or degradants on RH0 for a model deliquescent pharmaceutical salt. MATERIALS AND METHODS: The model salt chosen for this work was ranitidine HCl, which has two polymorphic forms. Moisture sorption profiles for each polymorph and samples of different purities were obtained using a gravimetric water vapor sorption balance. RESULTS: Polymorphs of a similar purity yielded virtually identical moisture sorption profiles. In contrast, samples containing higher levels of impurities had both enhanced moisture sorption below RH0 and a lowered value of RH0. CONCLUSIONS: It was concluded that small levels of degradants and/or impurities can drastically affect the moisture sorption profile of a deliquescent material, both through affecting the deliquescence relative humidity and by altering the overall interaction of the substance with moisture. Such changes in behavior may have significant effects on both active pharmaceutical ingredient and drug product stability during both processing and storage.

Adsorption↗

PubMed2006

Theoretical and practical approaches for prediction of drug-polymer miscibility and solubility.

PURPOSE: Crystallization of drugs formulated in the amorphous form may lead to reduced apparent solubility, decreased rate of dissolution and bioavailability and compromise the physical integrity of the solid dosage form. The purpose of this work was to develop thermodynamic approaches, both practical and theoretical, that will yield a better understanding of which factors are most important for determining the ability of polymers to stabilize amorphous active pharmaceutical ingredients (API). MATERIALS AND METHODS: Lattice based solution models were used to examine miscibility criteria in API-polymer blends. Different methods were used to estimate the Flory-Huggins interaction parameter for model API-polymer systems consisting of felodipine or nifedipine with poly(vinylpyrrolidone) (PVP). These were melting point depression and determination of solubility parameters using group contribution theory. The temperature and enthalpy of fusion of crystalline API alone and the fusion temperature of the API in the presence of the polymer were measured by differential scanning calorimetry. The resultant thermal data were used to estimate the reduced driving force for crystallization and the solubility of the API in the polymer. RESULTS: Flory-Huggins theory predicts that, for typical API-polymer systems, the entropy of mixing is always favorable and should be relatively constant. Due to the favorable entropy of mixing, miscibility can still be achieved in systems with a certain extent of unfavorable enthalpic interactions. For the model systems, interaction parameters derived from melting point depression were negative indicating that mixing was exothermic. Using these interaction parameters and Flory-Huggins theory, miscibility was predicted for all compositions, in agreement with experimental data. A model was developed to estimate the solubility of the API in the polymer. The estimated solubility of the model APIs in PVP is low suggesting that kinetic rather than thermodynamic stabilization plays a significant role in inhibiting crystallization. CONCLUSIONS: The thermodynamics of API-polymer systems can be modeled using solution based theories. Such models can contribute towards providing an understanding of the compatibility between API and polymer and the mechanisms of physical stabilization in such systems.

Algorithms↗

PubMed2006

A comparison of the physical stability of amorphous felodipine and nifedipine systems.

PURPOSE: The objective of this study was to investigate thermodynamic and kinetic factors contributing to differences in the isothermal nucleation rates of two structurally related calcium channel blockers, nifedipine and felodipine, both alone and in the presence of poly(vinylpyrrolidone) (PVP). MATERIALS AND METHODS: Thin films of amorphous systems were cast onto glass slides and the nucleation rate was determined using optical microscopy. Enthalpy, entropy, and free energy of crystallization of the pure compounds were measured using differential scanning calorimetery (DSC). Molecular mobility and glass transition temperature of each amorphous system were characterized using DSC and hydrogen bonding patterns were analyzed with infrared spectroscopy. The composition dependence of the thermodynamic activity of the amorphous drug in the presence of the polymer was estimated using Flory-Huggins lattice theory. RESULTS: Nifedipine crystallized more readily than felodipine from the metastable amorphous form both alone and in the presence of PVP despite having a similar glass transition temperature and molecular mobility. Nifedipine was found to have a larger enthalpic driving force for crystallization and a lower activation energy for nucleation. CONCLUSIONS: The properties of the metastable form alone did not explain the greater propensity for nifedipine crystallization. When considering the physical stability of amorphous systems, it is important to also consider the properties of the crystalline counterpart.

Calcium Channel Blockers↗

PubMed2006

Hyphenation of Raman spectroscopy with gravimetric analysis to interrogate water-solid interactions in pharmaceutical systems.

A moisture sorption gravimetric analyzer has been combined with a Raman spectrometer to better understand the various modes of water-solid interactions relevant to pharmaceutical systems. A commercial automated moisture sorption balance was modified to allow non-contact monitoring of the sample properties by interfacing a Raman probe with the sample holder. This hybrid instrument allows for gravimetric and spectroscopic changes to be monitored simultaneously. The utility of this instrument was demonstrated by investigating different types of water-solid interactions including stoichiometric and non-stoichiometric hydrate formation, deliquescence, amorphous-crystalline transformation, and capillary condensation. In each of the model systems, sulfaguanidine, cromolyn sodium, ranitidine HCl, amorphous sucrose and silica gel, spectroscopic changes were observed during the time course of the moisture sorption profile. Analysis of spectroscopic data provided information about the origin of the observed changes in moisture content as a function of relative humidity. Furthermore, multivariate data analysis techniques were employed as a means of processing the spectroscopic data. Principle components analysis was found to be useful to aid in data processing, handling and interpretation of the spectral changes that occurred during the time course of the moisture sorption profile.

Adsorption↗

PubMed2006

Role of deliquescence lowering in enhancing chemical reactivity in physical mixtures.

Mixtures of deliquescent solids are susceptible to deliquescence lowering, where water vapor condensation occurs in mixtures at a lower critical relative humidity (RH(0mix)) than individual component critical relative humidities (RH(0)s). The purpose of this study was to evaluate the effect of deliquescence lowering on chemical reactivity. Sucrose, citric acid and their physical mixtures were characterized using vapor sorption analysis to determine RH(0) and RH(0mix). Acid-catalyzed sucrose hydrolysis kinetics was determined using polarimetric analysis. Physical mixtures of sucrose and citric acid crystals were prepared and stored at various relative humidities at 22 degrees C. For these physical mixtures, sucrose hydrolysis was found to occur only when the environmental RH exceeded RH(0mix). Degradation kinetics correlated with the storage RH, being fastest at higher RH. In addition, a lag period was initially observed, which was most prominent for samples stored close to RH(0mix). With exposure to RHs below RH(0mix), no sucrose degradation was detected over the experimental time period. In conclusion, mixtures of deliquescent solids showed increased water sorption at lower RHs, which caused solid dissolution and subsequently led to an increase in the chemical reactivity.

Adsorption↗

PubMed2006

Physical stability of crystal hydrates and their anhydrates in the presence of excipients.

There are few studies in the literature that deal with the effect of excipients on the kinetics of vapor phase induced hydrate-anhydrate phase transformations. The main purpose of this study was to probe the phase stability of hydrate-anhydrate systems in the presence of hygroscopic and nonhygroscopic excipients following exposure to either dehydrating or hydrating conditions. Physical mixtures and compacts of model hydrate formers (theophylline and carbamazepine) and excipients (mannitol, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP) K12 and K90) were stored at 22 degrees C and varying relative humidities. Raman spectroscopy was used to monitor the kinetics of transformation between hydrate and anhydrate. In general, excipients were found either to have no effect or to promote dehydration. For hydrate formation, excipients could accelerate, retard, or have no influence on hydration kinetics. MCC was found to have only minimal effects on either the dehydration or hydration kinetics of model compounds, whereas mannitol enhanced dehydration but had little effect on hydration. Different PVP grades showed a variety effects: PVPK12 greatly enhanced the dehydration of both theophylline monohydrate (MT) and carbamazepine dihydrate (DC). PVPK90 also enhanced the dehydration of DC, but had a negligible effect on MT. For hydrate formation, PVPK12 was found to have a retarding effect on theophylline anhydrous (AT) transformation, but enhanced the conversion of carbamazepine anhydrous (AC) to DC, PVPK90 also retarded the hydration of AT, but had no effect on AC. Optical microscopy and X-ray powder diffraction studies suggested that PVP (in particular K12), when stored at high RH, was able to result in the partial dissolution of the active pharmaceutical ingredient and hence changed the hydration process from a solid state to a solution-mediated transformation. In summary, the effect of excipients on the kinetics of dehydration and hydration is complex and needs be rationalized in terms of several excipient properties including physical state, chemical composition, and the possibility of specific API-excipient interactions. It is concluded that a multitude of factors will dictate, and often complicate, the final effect of excipients on the phase transformation kinetics of hydrate formers.

Carbamazepine↗

PubMed2006

Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine.

The ability of various polymers to inhibit the crystallization of amorphous felodipine was studied in amorphous molecular dispersions. Spin-coated films of felodipine with poly(vinylpyrrolidone) (PVP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and hydroxypropylmethylcellulose (HPMC) were prepared and used for measurement of the nucleation rate and to probe drug-polymer intermolecular interactions. Bulk solid dispersions were prepared by a solvent evaporation method and characterized using thermal analysis. It was found that each polymer was able to significantly decrease the nucleation rate of amorphous felodipine even at low concentrations (3-25% w/w). Each polymer was found to affect the nucleation rate to a similar extent at an equivalent weight fraction. For HPMC and HPMCAS, thermal analysis indicated that the glass transition temperature (T(g)) of the solid dispersions were not significantly different from that of felodipine alone, whereas an increase in T(g) was observed for the PVP containing solid dispersions. Infrared spectroscopic studies indicated that hydrogen bonding interactions were formed between felodipine and each of the polymers. These interactions were stronger between felodipine and PVP than for the other polymers. It was speculated that, at the concentrations employed, the polymers reduce the nucleation rate through increasing the kinetic barrier to nucleation.

Calorimetry, Differential Scanning↗

PubMed2006

Deliquescence-induced caking in binary powder blends.

In this study, moisture-induced caking of deliquescent crystalline powder blends was investigated. Physical mixtures of sugars and citric acid anhydrous showed significant cake formation when cycled above and below the mixture critical relative humidity. It was found that combinations of glucose and citric acid underwent efflorescence to form crystalline solid bridges while fructose and citric acid cakes contained amorphous material. In conclusion, the reduced deliquescence point in deliquescent solid mixtures was found to cause caking.

Carbohydrates↗

PubMed2006

On-line content uniformity determination of tablets using low-resolution Raman spectroscopy.

Analytical techniques for rapid and nondestructive content uniformity determination of pharmaceutical solid dosage forms have been studied for several years in an effort to replace the traditional wet chemistry procedures, which are labor intensive and time consuming. Both Raman spectroscopy and near-infrared spectroscopy have been used for this purpose, and predictability errors are approaching those of the traditional techniques. In this study, a low-resolution Raman spectrometer was utilized to demonstrate the feasibility of both rapid at-line and on-line determination of tablet content uniformity. Additionally, sampling statistics were reviewed in an effort to determine how many tablets should be assayed for specific batch sizes. A good correlation was observed between assay values determined by high-performance liquid chromatography and Raman analysis. Due to rapid acquisition times for the Raman data, it was possible to analyze far more samples than with wet chemistry methods, leading to a better statistical description of variation within the batch. For at-line experiments, the sampling volume was increased by rotating the laser beam during the acquisition period. For the on-line experiments, the sampling volume was increased by sampling from a stream of tablets moving underneath the Raman probe on a conveyor system. Finally, an approach is proposed for monitoring content uniformity immediately following the compaction process. In conclusion, Raman spectroscopy has potential as a rapid, nondestructive technique for at- or on-line determination of tablet content uniformity.

Algorithms↗

PubMed2006

Analysis of the effect of particle size on polymorphic quantitation by Raman spectroscopy.

Raman spectroscopy has been widely used to monitor various aspects of the crystallization process. Although it has long been known that particle size can influence Raman signal, relatively little research has been conducted in this area, in particular for mixtures of organic materials. The aim of this study was to investigate the effect of particle size on quantification of polymorphic mixtures. Several sets of calibration samples containing different particle size fractions were prepared and Raman spectra were collected with different probes. Calibration models were built using both univariate and multivariate analysis. It was found that, for a single component system, Raman intensity decreased with increasing particle size. For mixtures, calibration models generated from the same particle size distribution as the sample yielded relatively good predictions of the actual sample composition. However, if the particle sizes of the calibration and unknown samples were different, prediction errors resulted. For extreme differences in particle sizes, prediction errors of up to 20% were observed. Prediction errors could be minimized by changing the sampling optics employed.

Journal Article↗

PubMed2005

Use of in-line near-infrared spectroscopy in combination with chemometrics for improved understanding of pharmaceutical processes.

High shear granulation is a complex unit operation with several interacting process parameters. No generally accepted real-time in-line tools are available to gain insight into this process, and in practice, a highly experienced process formulator and operator are needed to develop a wet granulated solid dosage form. In this study, the use of in-line near-infrared (NIR) spectroscopy as a process analytical tool for high shear granulation was investigated. In combination with principal component-based methods, process analysis of three separate phases of high shear wet granulation (mixing, spraying, and wet massing) was facilitated. Critical information, both chemical and physical, was collected during processing. Chemical information included the homogeneity of the formulation and the amount of water in wet mass. In addition, physical information related to the particle size of granules was extracted. Principal component loadings were fully interpreted to validate the conclusions drawn from scores and predictions. Thus NIR spectroscopy could be used to determine the end points of the three subphases of high shear wet granulation and, as such, provide a fast in-line quality control tool.

Cellulose↗

PubMed2005

In-line monitoring of hydrate formation during wet granulation using Raman spectroscopy.

Process-induced transformations are very important to control during pharmaceutical manufacturing because they may change the properties of the active pharmaceutical ingredient in the drug product, compromising therapeutic efficacy. One process that may facilitate a process-induced transformation is high-shear wet granulation. In this study, the feasibility of Raman spectroscopy for in-line monitoring of the transformation of theophylline anhydrous to theophylline monohydrate during high-shear wet granulation has been evaluated. The midpoint of conversion occurred 3 min after the binder solution was added. The effects of several processing parameters were also examined, including mixing speed and monohydrate seeding. Mixing speed had the greatest effect on the transformation, where an increase in mixing speed shortened the onset time and increased the rate of transformation. In contrast, seeding with monohydrate or changing the way in which the binder was incorporated into the granules did not affect the transformation profile. The transformation kinetics observed during wet granulation were compared with those generated by a simple model describing the solvent-mediated transformation of theophylline in solution. In conclusion, these studies show that Raman spectroscopy can be used for in-line monitoring of solid-state transformations during wet granulation. In addition, for this particular compound, a simple solvent-mediated transformation model has been shown to be useful for estimating the time scale for hydrate formation during high-shear wet granulation.

Algorithms↗

PubMed2005

Deliquescence in binary mixtures.

PURPOSE: Deliquescence is a first-order phase transformation from solid to solution and occurs at a specific relative humidity (RH) that is characteristic to the solid. The goal of this research was to investigate the reduction in critical relative humidity (RH0) in binary solid mixtures of deliquescent active pharmaceutical ingredients (APIs) and deliquescent excipients. METHODS: The RH where deliquescence is induced, RH0, was measured using a gravimetric water vapor sorption balance. Values were obtained for model deliquescent APIs and excipients as well as for their binary mixtures. Model APIs included ranitidine HCl and diphenhydramine HCI, and sucrose and sodium chloride were examples of excipients investigated. To probe the thermodynamics of this phenomenon, water activity (a(w)) of various saturated solutions of API and excipient systems was measured using a water activity meter. Optical microscopy was used to observe visually the phenomenon under investigation. The Ross equation was used to estimate RH0mix, and predicted values were compared with experimental results. RESULTS: There was close agreement between RH0 measurements (single-component RH0, and RH0mix) and a(w) measurements of the corresponding saturated solutions. In addition, RH0mix values were always lower than RH0 for the API and excipients alone. In general, experimentally observed RH0mix values were higher than those predicted using the Ross equation. CONCLUSIONS: Mixtures of deliquescent API and deliquescent excipient are more hygroscopic (i.e., have lower RH0) than either the API or the excipient alone. This might have significant effects on API and drug product stability.

Humidity↗

PubMed2005

Comparison of sampling techniques for in-line monitoring using Raman spectroscopy.

Raman spectroscopy is currently of interest as a process monitoring tool for pharmaceutical unit operations. In this study, the performance characteristics of Raman spectrometers with different sampling optics have been investigated in the context of process monitoring, with emphasis being placed on assessing homogeneity in powder blends and following changes in solid-state form during wet granulation. A novel large spot non-contact Raman sampling device was compared with a traditional small spot size non-contact sampling device and an immersion probe. The large spot non-contact optics provided significant advantages over the standard systems both as a result of the enhanced sampling volume and because of the greater robustness of the system to fluctuations in the sampling distance during the wet granulation process.

Computer Systems↗

PubMed2005

Improved understanding of factors contributing to quantification of anhydrate/hydrate powder mixtures.

Different spectroscopic approaches have proved to be excellent analytical tools for monitoring process-induced transformations of active pharmaceutical ingredients during pharmaceutical unit operations. In order to use these tools effectively, it is necessary to build calibration models that describe the relationship between the amount of each solid-state form of interest and the spectroscopic signal. In this study, near-infrared (NIR) and Raman spectroscopic methods have been evaluated for the quantification of hydrate and anhydrate forms in pharmaceutical powders. Process type spectrometers were used to collect the data and the role of the sampling procedure was examined. Multivariate regression models were compared with traditional univariate calibrations and special emphasis was placed on data treatment prior to multivariate modeling by partial least squares (PLS). It was found that the measured sample volume greatly affected the performance of the model whereby the calibrations were significantly improved by utilizing a larger sampling area. In addition, multivariate regression did not always improve the predictability of the data compared to univariate analysis. The data treatment prior to multivariate modeling had a significant influence on the quality of predictions with standard normal variate transformation generally proving to be the best preprocessing method. When the appropriate sampling techniques and data analysis methods were utilized, both NIR and Raman spectroscopy were found to be suitable methods for the quantification of anhydrate/hydrate in powder systems, and thus the method of choice will depend on the conditions in the process under investigation.

Computer Systems↗

PubMed2003

Atomic force microscopy analysis and confocal Raman microimaging of coated pellets.

Polymer-coated pellets with different coating thicknesses have been studied regarding coating morphology and drug release properties with atomic force microscopy (AFM) and confocal Raman microscopy. The results were compared with those from scanning electron microscopy (SEM) and drug release profiles, which have been measured previously for these systems and found to vary depending on coating thickness. Results from AFM studies indicated that these pellets differ in the amount of crystalline material on the surface of the coating. The amount was found to be highest on the pellet with the thinnest coating. Confocal Raman microscopy studies confirmed that the active component (remoxipride hydrochloride monohydrate) is present at or close to the surface and that the amount is higher for the thinnest coating. AFM studies in aqueous media showed that the crystalline material on the surface was almost instantaneously dissolved and released into the liquid. AFM has proven to be a powerful tool in the study of the surface of dry formulations and in the study of the controlled release mechanism of a pharmaceutical in a liquid cell. The method can be combined with Raman, giving the added possibility to identify the chemical composition in selected small areas of the coating surface.

Crystallization↗

PubMed2003

Airborne chemistry coupled to Raman spectroscopy.

In this paper, the use of airborne chemistry (acoustically levitated drops) in combination with Raman spectroscopy is explored. We report herein the first Raman studies of crystallization processes in levitated drops and the first demonstration of surface-enhanced Raman scattering (SERS) detection in this medium. Crystallization studies on the model compounds benzamide and indomethacin resulted in the formation of two crystal modifications for each compound, suggesting that this methodology may be useful for investigation of polymorphs. SERS detection resulted in a signal enhancement of 27 000 for benzoic acid and 11 000 for rhodamine 6-G. The preliminary results presented here clearly indicate that several important applications of the combination between Raman spectroscopy and acoustic drop levitation can be expected in the future.

Journal Article↗

PubMed2002

Infrared imaging of laser-induced heating during Raman spectroscopy of pharmaceutical solids.

Raman spectroscopy is finding increasing popularity as an analytical technique for the analysis of pharmaceutical powders and solid dosage forms. It is well known that illumination by the high intensity lasers used in Raman spectrometers can result in sample heating, however, the extent of the problem has not been assessed for pharmaceutically relevant materials. Using direct thermal imaging of compressed powders, the extent of heating for microcrystalline cellulose (MCC), vanillin, ibuprofen and stearic acid was measured as a function of laser intensity. MCC was found to be the most susceptible to sample heating while ibuprofen was least sensitive. At high laser powers (1.5 W), samples were heated by between 38 and 60 degrees C while at more moderate laser powers (0.7 W) the degree of heating was between 20 and 30 degrees C. The kinetics of the heating process were mathematically modeled for MCC and the derived constants were used to predict the rotation speed necessary to prevent a solid state transition in a heat sensitive compound, theophylline monohydrate. Experimental measurements at different rotation speeds verified that the estimated rotation speed reduced sample heating by the desired amount. In conclusion, the extent of heating is clearly of some concern for pharmaceutical materials but can be substantially reduced by sample rotation.

Hot Temperature↗