Biomedical subjects

Kenneth R Morris

Publications and source records attributed to Kenneth R Morris.

At least 19 recordsLinked to original sources

PubMed2006

Raman spectroscopy for tablet coating thickness quantification and coating characterization in the presence of strong fluorescent interference.

We report a novel approach to the measurement of colored tablet coating thickness, which employs Raman spectroscopy with univariate and multivariate data analysis. Our results suggest that Raman sensing can serve as a viable non-invasive means to quantify tablet coating thickness in the presence of a fluorescent ingredient in the coating formulation (food colorant Alphazurine FG or D&C Blue No. 4). This study comparatively tests the advantage of several data transformation approaches, including mean centering, standard normal variate, and Savitzky-Golay smoothed second derivative as means of improving predictive models in the presence of fluorescence. By application of the partial least squares (PLS) calibration algorithm to establish optimum covariance between transformed spectral data and measured tablet coating thicknesses, we have been able to create predictive models with calibration errors as small as 4 microm for a training set that spans colored coating thicknesses from 50 to 151 microm.

Algorithms↗

PubMed2006

Towards an understanding of the structurally based potential for mechanically activated disordering of small molecule organic crystals.

The potential for various small molecule organic crystals to undergo complete mechanically induced disordering is investigated. A model is proposed, which considers changes in free energy required for lattice incorporation of a critical dislocation density. Application requires knowledge of a few physical properties, namely the elastic shear modulus, Burgers vector magnitude, molar volume, melting temperature, and heat of fusion. The model was tested using seven compounds; acetaminophen, aspirin, gamma-indomethacin, salicylamide, sucrose, and two proprietary drug compounds, PFZ1 and PFZ2. Crystalline solids were subjected to high shear, controlled temperature comminution for various durations, after which the samples were examined using powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The results verified that acetaminophen, aspirin, and salicylamide, which were suggested by the model to be resistant to complete mechanical disordering, remained fully crystalline, even after 5 h of milling. Sucrose and gamma-indomethacin were both predicted to be susceptible to amorphization, which was confirmed by physical characterization. Single, 3-h grinding experiments were performed on two proprietary compounds, PFZ1 and PFZ2. The model indicated that each should be resistant to complete disordering, a trend held by PFZ1. Evidence of partial disordering of PFZ2 was unexpected and is discussed with respect to possible temperature effects.

Acetaminophen↗

PubMed2005

Hydrogen bonding interactions between adsorbed polymer molecules and crystal surface of acetaminophen.

The objective of this work was to investigate whether or not the hydrogen bonding interaction between polymer and crystal surface can be detected by the etching pattern changes in the presence of polymers. The (010) face of acetaminophen single crystal was used as a model solid surface. The etching patterns on the (010) face of acetaminophen crystal by water are in the directions of a- and c-axes, which are the same as the directions of the dominant attachment energies on the (010) face. In the presence of polymer, the hydrogen bonding interactions between adsorbed polymer and crystal surface can affect surface diffusion of acetaminophen molecules and change the etching patterns in the direction of a-axis, i.e., the direction of one hydrogen bond chain. Studies with 2-hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and poly(vinyl alcohol) (PVA) showed that polymers, which can form hydrogen bonds with acetaminophen crystal surface, can change etching patterns in the direction of a-axis. Study with Dextran suggested that if a polymer cannot form hydrogen bonds with crystal surface due to steric repulsion, it will not change the etching pattern in the direction of a-axis. Studies with poly(ethylene glycol) (PEG) and poly(propylene glycol) (PPG) further confirmed that only if a polymer can form hydrogen bonds with acetaminophen on crystal surface, the etching patterns in the direction of a-axis will be affected. The study results suggest that in the presence of polymers, the etching pattern change in the direction of hydrogen bond chain, the a-axis of acetaminophen crystals, can be used to indicate the existence of the hydrogen bonding interactions between adsorbed polymers and acetaminophen crystal surface.

Acetaminophen↗

PubMed2005

Kinetic study of the Maillard reaction between metoclopramide hydrochloride and lactose.

The purpose of this work is to study the apparent solid-state kinetics of the Maillard reaction of the colyophilized metoclopramide hydrochloride (MCP) and lactose system and to elucidate some of the effects of molecular mobility on the kinetic behavior of the amorphous mixture. Colyophilized MCP-lactose mixtures (1:9 molar ratio) were stored at temperatures ranging from 100 to 115 degrees C (above the glass transition temperature, Tg=99.7 degrees C). This temperature range, which corresponds to the change between the glass and liquid states of the lactose-MCP mixtures, is also the temperature region where molecular mobility represents a kinetic impediment of enough significance as to affect the observed order of the reaction. A pseudo second-order kinetic model was developed to fit the MCP loss data. The proposed model gives better fit to the degradation data than many of the commonly used kinetic models available in the literature. The second-order rate constant of the model follows Arrhenius kinetics and the activation energy was found to be 53.8 kcal mol(-1). The molecular mobility (relaxation time) of the mixture was calculated from the heating rate dependence of the DSC-determined glass transition temperature of the mixtures. From molecular mobility considerations alone, it is possible to accurately predict the temperature dependence of the reaction rate constant. These results support the hypothesis that the solid-state reaction is mobility controlled.

Freeze Drying↗

PubMed2005

Quantitative analysis of film coating in a pan coater based on in-line sensor measurements.

A method was developed that enables in-line analysis of film coating thickness on tablets during a pan coating operation. Real-time measurements were made using a diffuse-reflectance near-infrared (NIR) probe positioned inside the pan during the coating operation. Real-time spectra of replicate batches were used for modeling film growth. Univariate analysis provided a simple method for in-line monitoring of the coating process using NIR data. An empirical geometric 2-vector volumetric growth model was developed, which accounts for differential growth on the face and band regions of biconvex tablets. The thickness of the film coat was determined by monitoring the decrease of absorption bands characteristic of a component of the tablet core and monitoring the increase of bands characteristic of a component in the coating material. There was good correlation between values estimated from the NIR data and the measured tablet volumetric growth. In-line measurements allow the coating process to be stopped when a predetermined tablet coating thickness is achieved.

Tablets, Enteric-Coated↗

PubMed2005

Quantitative determination of polymorphic composition in intact compacts by parallel-beam X-ray powder diffractometry II. Data correction for analysis of phase transformations as a function of pressure.

An analytical, non-destructive method using parallel-beam transmission powder X-ray diffractometry (PXRD) is presented for in situ whole compact detection and quantification of solid-state phase transformations in powder compacts. Accurate quantification of analyte in intact compacts using PXRD requires a mathematical correction prior to interpolation of calibration data to account for sample differences that result as a function of pressure; namely, compact thickness and solid fraction. Chlorpropamide is examined as a model system, selected because of its susceptibility to polymorphic transformations when consolidated using moderately low pressures. The results indicate that quantification of the transformed phase of chlorpropamide without corrections for solid fraction and thickness, underestimates the extent of transformation by 2.4%. Although the magnitude of the correction for this particular system of polymorphs is small, more significant values are expected for other compounds, particularly those with sufficient compactibility to allow the formation of low solid fraction calibration samples.

Chlorpropamide↗

PubMed2005

A quantitative model to evaluate solubility relationship of polymorphs from their thermal properties.

PURPOSE: The objective of the study is to develop a model to estimate the solubility ratio of two polymorphic forms based on the calculation of the free energy difference of two forms at any temperature. This model can be used for compounds with low solubility (a few mole percent) in which infinite dilution can be approximated. METHODS: The model is derived using the melting temperature and heat of fusion for apparent monotropic systems, and the solid-solid transition temperature and heat of transition for apparent enantiotropic systems. A rigorous derivation also requires heat capacity (Cp) measurement of liquid and two solid forms. This model is validated by collecting thermal properties of polymorphs for several drugs using conventional or modulated differential scanning calorimetry. From these properties the solubility ratio of two polymorphs is evaluated using the model and compared with the experimental value at different temperatures. RESULTS: The predicted values using the full model agree well with the experimental ones. For the purpose of easy measurement, working equations without Cp terms are also applied. Ignoring Cp may result in an error of 10% or less, suggesting that the working equation is applicable in practice. Additional error may be generated for the apparent enantiotropic systems due to the inconsistency between the observed solid-solid transition temperature and the true thermodynamic transition temperature. This inconsistency allows the predicted solubility ratios (low melt/high melt) to be smaller. Therefore, a correction factor of 1.1 is recommended to reduce the error when the working equation is used to estimate the solubility ratio of an enantiotropic system. CONCLUSIONS: The study of the free energy changes of two crystalline forms of a drug allows for the development of a model that successfully predicts the solubility ratio at any temperature from their thermal properties. This model provides a thermodynamic foundation as to how the free energy difference of two polymorphs is reflected by their equilibrium solubilities. It also provides a quick and practical way of evaluating the relative solubility of two polymorphs from single differential scanning calorimetry runs.

Calorimetry, Differential Scanning↗

PubMed2005

Analysis of the acid-base reaction between solid indomethacin and sodium bicarbonate using infrared spectroscopy, X-ray powder diffraction, and solid-state nuclear magnetic resonance spectroscopy.

Indomethacin was used as a model compound to investigate acid-base reactions of solid materials, a common type of drug-excipient interaction. In a typical experiment, 500 mg of pure alpha-form indomethacin were mixed with 500 mg of sodium bicarbonate. The mixture was kept at 40 degrees C and at several relative humidities. The reaction was monitored by IR spectroscopy, X-ray powder diffraction, and solid-state NMR. At 40 degrees C and 80% RH, the reaction is nearly complete after 300 h. As observed by IR spectroscopy, the characteristic peaks of alpha-indomethacin disappear during the course of the reaction with the appearance of the characteristic peaks of the salt product, sodium indomethacin trihydrate. Solid-state NMR spectra and X-ray powder diffraction patterns of the reaction mixtures confirm the transformation of the mixtures to sodium indomethacin trihydrate; the reduced peak intensities in the diffraction patterns of the product relative to the initial mixtures indicate the formation of a microcrystalline product. A change in the reaction rate of sodium bicarbonate with alpha-indomethacin is observed when the mixtures are stored at different relative humidities. At 40 degrees C and 66% RH, the reaction of sodium bicarbonate with alpha-indomethacin is about 86% complete after 500 h. No detectable reaction was observed for sodium bicarbonate with the alpha form of indomethacin at 40 degrees C and 11% RH after 15 months. The combination of these solid-state characterization techniques is demonstrated to be essential to detect and monitor acid-base reactions in solid materials, which are impossible to monitor using solution-chemistry methods. The reaction kinetics at 66% RH fits the Jander equation very well, which is consistent with a diffusion-controlled mechanism.

Calibration↗

PubMed2005

Raman spectroscopic measurement of tablet-to-tablet coating variability.

We report new results suggesting the feasibility of Raman spectrometry as a tool by which to examine the variability of tablet coatings. Our experiments feature a probe that can operate with a revolving laser focus to average content and coating non-uniformity. Raman spectral changes are correlated with tablet exposure times in a pan coater by means of partial least squares (PLS) multivariate analysis. Statistical models are found to be improved by pre-processing schemes that emphasize spectral changes while minimizing the effects of background light scattering and fluorescence. These pre-processing techniques include multiplicative scatter correction (MSC) and standard normal variate (SNV) transformation, used in concert with Savitzky-Golay second derivative smoothing (SGSD). The two approaches give comparable results yielding R2 values for PLS calibration and cross-calibrated prediction variance regression of 0.999 and 0.997, respectively. Correlation results and model residual values demonstrate that Raman spectroscopy serves sensitively to reflect the coating thickness of the tablets studied.

Algorithms↗

PubMed2005

Determination of fluidized bed granulation end point using near-infrared spectroscopy and phenomenological analysis.

Simultaneous real-time monitoring of particle size and moisture content by near-infrared spectroscopy through a window into the bed of a fluidized bed granulator is used to determine the granulation end point. The moisture content and particle size determined by the near-infrared monitor correlates well with off-line moisture content and particle size measurements. The measured particle size is modeled using a population balance approach, and the moisture content is shown to follow accepted models during drying. Given a known formulation, with predefined parameters for peak moisture content, final moisture content, and final granule size, the near-infrared monitoring system can be used to control a fluidized bed granulation by determining when binder addition should be stopped and when drying of the granules is complete.

Chemistry, Pharmaceutical↗

PubMed2005

Real-time near-infrared monitoring of content uniformity, moisture content, compact density, tensile strength, and Young's modulus of roller compacted powder blends.

A method for real-time in-line near-infrared (NIR) monitoring of roller compaction is reported. Multivariate analysis using partial least square projections to latent structures (PLS) was used to relate the spectral data with key compact attributes: content uniformity, moisture content, relative density, tensile strength, and Young's modulus. NIR calibration curves were generated using the spectral data collected on simulated ribbons, that is, tablets prepared under uni-axial compression, and tested on the data collected on another set of simulated ribbons and by monitoring the ribbons as they exited the roller compactor. For all compact attributes, the NIR predicted values agreed well with the values measured using a reference method.

Acetaminophen↗

PubMed2005

Study on the interactions between polyvinylpyrrolidone (PVP) and acetaminophen crystals: partial dissolution pattern change.

The objective of the study was to investigate the interactions between polyvinylpyrrolidone (PVP) and acetaminophen crystal especially on crystal surface. The effects of PVP on the etching pattern change of the acetaminophen (010) face, solubility enhancement as well as the intrinsic dissolution rate (IDR) of acetaminophen crystals have been studied. The etching patterns of the acetaminophen (010) face in the presence of PVP have stable ledges in the direction of a-axis, but deviate from c-axis, which shows that the dissolution on the (010) face has been affected by the adsorbed PVP especially in the direction of c-axis through van der Waals interactions rather than hydrogen bonding interactions. Even though PVP(K30) can enhance the solubility of acetaminophen in concentration higher than 1 mg/mL, the IDR of acetaminophen in diluted PVP solutions was lower than in water. Because the viscosity of those diluted PVP(K30) solutions were the same as water viscosity, the lowered IDR of acetaminophen cannot be explained simply by the viscosity effects of PVP solutions. Overall, the study suggests that the PVP molecules adsorbed on the surface of acetaminophen crystals play an important role in etching pattern change as well as the intrinsic dissolution rate change.

Acetaminophen↗

PubMed2005

Effect of the variation in the ambient moisture on the compaction behavior of powder undergoing roller-compaction and on the characteristics of tablets produced from the post-milled granules.

Effect of variation in the ambient moisture levels on the compaction behavior of a 10% acetaminophen (APAP) powder blend in microcrystalline cellulose (MCC) powder was studied by comparing the physical and mechanical properties of ribbons prepared by roller compaction with those of simulated ribbons, i.e., tablets prepared under uni-axial compression. Relative density, moisture content, tensile strength, and Young's modulus were used as key compact properties for comparison. Moisture was found to facilitate the particle rearrangement of both, the APAP and the MCC particles, as well as the deformation of the MCC particles. The tensile strength of the simulated ribbons also showed an increase with increasing moisture content. An interesting observation was that the tensile strength of the roller compacted samples first increased and then decreased with increasing moisture content. Variation in the ambient moisture during roller compaction was also found to influence the characteristics of tablets produced from the granules obtained post-milling the ribbons. A method to study this influence is also reported.

Acetaminophen↗

PubMed2005

Influence of ambient moisture on the compaction behavior of microcrystalline cellulose powder undergoing uni-axial compression and roller-compaction: a comparative study using near-infrared spectroscopy.

This study evaluates the effect of variation in the ambient moisture on the compaction behavior of microcrystalline cellulose (MCC) powder. The study was conducted by comparing the physico-mechanical properties of, and the near infrared (NIR) spectra collected on, compacts prepared by roller compaction with those collected on simulated ribbons, that is, compacts prepared under uni-axial compression. Relative density, moisture content, tensile strength (TS), and Young modulus were used as key sample attributes for comparison. Samples prepared at constant roller compactor settings and feed mass showed constant density and a decrease in TS with increasing moisture content. Compacts prepared under uni-axial compression at constant pressure and compact mass showed the opposite effect, that is, density increased while TS remained almost constant with increasing moisture content. This suggests difference in the influence of moisture on the material under roller compaction, in which the roll gap (i.e., thickness and therefore density) remains almost constant, vs. under uni-axial compression, in which the thickness is free to change in response to the applied pressure. Key sample attributes were also related to the NIR spectra using multivariate data analysis by the partial least squares projection to latent structures (PLS). Good agreement was observed between the measured and the NIR-PLS predicted values for all key attributes for both, the roller compacted samples as well as the simulated ribbons.

Cellulose↗

PubMed2005

Effect of milling and compression on the solid-state Maillard reaction.

The effects of milling and compression on the solid-state Maillard reaction between metoclopramide hydrochloride and lactose were investigated. Anhydrous metoclopramide hydrochloride was milled for various times, and then mixed with amorphous lactose. The mixtures were stored at 105 degrees C and 0% RH. The reactivity of metoclopramide hydrochloride towards the Maillard reaction increased with milling time, as the result of increased surface area, formation of amorphous content, and creation of defects. Metoclopramide hydrochloride anhydrate and lactose were mixed and the mixtures were compressed into tablets under pressure varied from 70 to 350 MPa. Both tablets and mixtures were stored at 105 degrees C and 0% RH for 9 days. For all three types of lactose used, spray-dried anhydrous lactose, spray-dried lactose monohydrate, and amorphous lactose, tablets exhibited higher reaction rate toward the Maillard reaction than the powder mixtures. Tablets containing metoclopramide hydrochloride and amorphous lactose prepared at higher pressure showed higher reaction rates than those prepared at lower pressure. This is due to increased contact between reactants and an increased amount of water retained in the tablets.

Compressive Strength↗

PubMed2004

Physics of amorphous solids.

The physical state of a dosage form, crystalline versus amorphous, is critical in determining its solid-state physical and chemical properties. This minireview describes the physics associated with the preparation and storage of amorphous solids including a review of the common theories of the glass transition and relaxation processes.

Chemical Phenomena↗

PubMed2004

Modeling of adhesion in tablet compression. II. Compaction studies using a compaction simulator and an instrumented tablet press.

Adhesion problems are usually not identified until prolonged compression runs are studied near the end of the drug development process. During tablet manufacturing, adhesion problems encountered are usually addressed by statistically designed experiments based on experience. It would be a significant benefit for the pharmaceutical industry if adhesion problems could be identified early in drug development based on molecular considerations of the drug substance and/or prototype formulations. Drug substance-punch face interactions were reported in the first of the articles in this series, and focused on the elucidation of adhesion problems in tablet compression. It was hypothesized that the intermolecular interactions between drug molecules and the punch face was the first step (or criterion) in the adhesion process, and that the rank order of adhesion during tablet compression should correspond with the rank order of these energies of interaction. That is, the interaction between the molecular structure of the drug and the metal surface determines the primary interaction event or relative potential for adhesion, while the mechanical processes and/or lubrication effects may subsequently impact the extent of adhesion. Molecular simulations and atomic force microscopy were used to establish the rank order of the work of adhesion of a series of profen compounds. The results predicted that the relative degree of drug substance-punch face adhesion should decrease in the order of ketoprofen > ibuprofen > flurbiprofen. In this study, the authors investigated whether the rank order of the work of adhesion established on the molecular level and interparticulate level holds true in the tableting environment by measuring tablet take-off force, ejection force, and visual observation of the punch surfaces for both pure drug compacts and formulated tablets. The compaction simulator was used for pure profen compacts, while the instrumented tablet press for formulated tablets. Due to the inability to extract the adhesion force component from the total ejection force measurement, tablet ejection force was not used as a criterion to judge the adhesion behavior of the model compounds. The criteria used for judgement of punch face adhesion were tablet take-off force and visual observation of the punch faces. The rank order of adhesion for both pure drug and formulated tablets was determined to follow the order of ketoprofen > ibuprofen > flurbiprofen. The effect of run time on adhesion behavior was also investigated. Therefore, the rank order of the punch-face adhesion tendencies for the series of profen compounds was determined, and found to agree with the data from the predictive methods reported in the first article.

Adhesiveness↗

PubMed2004

Nondestructive measurements of the compact strength and the particle-size distribution after milling of roller compacted powders by near-infrared spectroscopy.

Compact strength and the particle-size distribution of milled roller compacted compacts were correlated to the slope of the best-fit line through near-infrared spectra for samples prepared under different roll speeds and feed rates. The above correlations were found to hold for compacts prepared from microcrystalline cellulose powder as well as from a typical direct compression pharmaceutical powder blend containing tolmetin sodium dihydrate, microcrystalline cellulose, and dicalcium phosphate dihydrate. Near-infrared spectra were also collected real time for the compacts prepared from the tolmetin powder blend. The real-time slope values for the spectra showed good agreement with the off-line data. The strength of compacts was determined using three-point beam bending method and the particle-size distribution of the milled compacts was determined using sieve analysis. The results suggest that the real-time values of the slope of the best-fit line through the near-infrared spectrum offers a robust, yet simple and fast quality control tool to monitor/control manufacturing and scale-up processes involving dry granulation by roller compaction.

Calcium Phosphates↗