Biomedical subjects

Kenneth R Morris

Publications and source records attributed to Kenneth R Morris.

27 records · Page 2Linked to original sources

PubMed2004

Modeling and monitoring of polymorphic transformations during the drying phase of wet granulation.

PURPOSE: The purpose of this work was to monitor polymorphic transformations of glycine during the drying phase of a wet granulation and model the polymorphic conversions using a time-based reconciliation model. METHODS: Near-infrared spectroscopy (NIR) was used for quantitation of polymorphs, and X-ray powder diffraction (XRPD) was used for qualitative analysis of polymorphs. RESULTS: The data show that the faster the granulation was dried, the more kinetic trapping of the metastable alpha-glycine polymorph, as predicted by reconciliation of the time scales of both the drying rate and the rate of the solution-mediated conversion. CONCLUSIONS: By knowing basic properties of the drug substance (solubility of the polymorphic forms and the rate of the solution-mediated conversion), processing conditions, such as the drying rate, can be adjusted to anticipate and prevent potential polymorphic transformations.

Calibration↗

PubMed2003

Modeling of adhesion in tablet compression--I. Atomic force microscopy and molecular simulation.

Adhesion problems during tablet manufacturing have been observed to be dependent on many formulation and process factors including the run time on the tablet press. Consequently, problems due to sticking may only become apparent towards the end of the development process when a prolonged run on the tablet press is attempted for the first time. It would be beneficial to predict in a relative sense if a formulation or new chemical entity has the potential for adhesion problems early in the development process. It was hypothesized that favorable intermolecular interaction between the drug molecules and the punch face is the first step or criterion in the adhesion process. Therefore, the rank order of adhesion during tablet compression should follow the rank order of these energies of interaction. The adhesion phenomenon was investigated using molecular simulations and contact mode atomic force microscopy (AFM). Three model compounds were chosen from a family of "profen" compounds. Silicon nitride AFM tips were modified by coating a 20-nm iron layer on the surfaces by sputter coating. Profen flat surfaces were made by melting and recrystallization. The modified AFM probe and each profen surface were immersed in the corresponding profen saturated water during force measurements using AFM. The work of adhesion between iron and ibuprofen, ketoprofen, and flurbiprofen in vacuum were determined to be -184.1, -2469.3, -17.3 mJ. m(-2), respectively. The rank order of the work of adhesion between iron and profen compounds decreased in the order: ketoprofen > ibuprofen > flurbiprofen. The rank order of interaction between the drug molecules and the iron superlattice as predicted by molecular simulation using Cerius(2) is in agreement with the AFM measurements. It has been demonstrated that Atomic Force Microscopy is a powerful tool in studying the adhesion phenomena between organic drug compounds and metal surface. The study has provided insight into the adhesion problems occurring during tablet compression and a direction for continued study.

Adhesiveness↗

PubMed2003

Prediction of the relaxation behavior of amorphous pharmaceutical compounds. I. Master curves concept and practice.

Variability in the time to crystallization is a major technical and economic hurdle in using amorphous solids in dosage forms. It is hypothesized that amorphous solids "age", and that the older they are, the more relaxed they are and the higher the probability of crystallization. At present, there is no method that allows the "effective age" of an amorphous raw material to be assessed relative to its unrelaxed initial condition. A method has been developed that may satisfy this unmet need and provide a first step in subsequent investigation of the crystallization "event". This method consists of using master curves to enable the determination of the effective age ("aging") of an amorphous compound given normal excursions in storage conditions. The present study shows that master curves can be prepared for different storage conditions and subsequently be used to predict the relaxation or aging behavior of amorphous compounds with expected variations in storage conditions. Given the constraint that the system remain within the area enclosed by the equilibrium supercooled liquid line and the glass on the enthalpy-temperature diagram, experimental results using indomethacin and salicin as model compounds show that master curves can be used to predict aging behavior under nonisothermal conditions, with temperature excursions as large as 10 degrees C. The nonisothermal relaxation behavior can be modeled by combining the Kohlrausch-Williams-Watts (KWW) stretched exponential function, the relaxation function, and a shift factor. In addition, a model was developed that extends the range of applicability to time/temperature regions in which partial crystallization occurs.

Chemical Phenomena↗

PubMed2003

A statistical support for using spectroscopic methods to validate the content uniformity of solid dosage forms.

The advent of PAT, Process Analytical Technologies, offers the possibility of large scale monitoring of tablets as they come off the press. The most rapid techniques allowing the largest sample sizes are based on reflectance spectroscopy. As these techniques sample only a portion of the tablet, it is critical to prove that sampling a portion has a larger (and, therefore, more conservative) statistical variance than sampling the entire. Once demonstrated, a partial sampling technique, for example, a Near Infrared (NIR) sensor, should be able to provide a safe bracket for content uniformity evaluation. It is the purpose of this report to support the claim that the coefficient of variance (CV) from sampling a part of a dosage form cannot be smaller than the CV from sampling the whole dosage form. This hypothesis will be supported in this study by both a statistical proof and experimental data acquired from a model tablet system.

Chromatography, High Pressure Liquid↗

PubMed2003

Modeling of transmitted X-ray intensity variation with sample thickness and solid fraction in glycine compacts.

The previous paper in this series introduced an X-ray diffraction quantitation method for the polymorphic content in tablets made of pure components. Before the method could be transferred, further studies were required to explain the commonly observed X-ray intensity variation in analyzing compacts. The literature typically attributes the variation to partial amorphization under compression and/or to preferred orientation, without much viable explanation or compelling evidence. In this study, changes in intensity in compacts analyzed in transmission geometry were found to be primarily a function of sample thickness and solid fraction. A theoretical model was developed to describe the X-ray powder diffraction (XRPD) intensity as a function of solid fraction, mass absorption coefficient, and thickness. The model was tested on two sets of glycine compacts: one with varying thickness at constant solid fraction, and the other with various solid fractions at a given thickness. The results show that the model predicts the XRPD intensity at any given sample thickness and solid fraction. With this model, the intensity variation of compacts made under different compression conditions can be normalized, making the method transferable to various tablet geometries and facilitating the analysis over expected ranges of formulation and process variation.

Glycine↗

PubMed2003

In situ monitoring of wet granulation using online X-ray powder diffraction.

PURPOSE: Polymorphic transformations during the wet granulation of a metastable polymorph of flufenamic acid were monitored in situ using online X-ray powder diffraction. The resulting data were used in testing a proposed process induced transformation rate model, which allows the extent and occurrence of polymorphic transformations during wet granulation to be controlled by adjusting the granulation time. METHODS: A small-scale, top mixing granulator was designed for compatibility with novel X-ray powder diffraction equipment (available from X-Ray Optical Systems of East Greenbush, NY). RESULTS: The unique polycapillary optic and X-ray source allowed the transformation of the metastable to the stable polymorph to be followed during the granulation. Following a diffraction peak each for the metastable and stable forms demonstrated that polymorphic transformations during the wetting phase of granulation follow the trends predicted by the model. CONCLUSIONS: The advanced online monitoring may allow real-time control of the process by the adjustment of process parameters, such as granulation time, and clearly qualifies as a PAT (process analytical technology).

Flufenamic Acid↗

PubMed2002

Reactivity differences of indomethacin solid forms with ammonia gas.

The present study deals with the acid-base reaction of three solid-state forms of the nonsteroidal antiinflammatory drug indomethacin with ammonia gas. X-ray powder diffraction, optical microscopy, gravimetry, and spectroscopic methods were employed to establish the extent of the reaction as well as the lattice changes of the crystal forms. The glassy amorphous form readily reacts with ammonia gas to yield a corresponding amorphous ammonium salt. In addition, the metastable crystal form of indomethacin (the alpha-form) also reacts with ammonia gas, but produces the corresponding microcrystalline ammonium salt. This reaction is anisotropic and propagates along the a-axis of the crystals. The stable crystal form (the gamma-form), however, is inert to ammonia gas. Amorphous indomethacin can react with ammonia gas because it has more molecular mobility and free volume. The reactivity differences between the alpha- and gamma-forms are dictated by the arrangement of the molecules within the respective crystal lattices. The recently determined crystal structure of the metastable alpha-form of indomethacin (monoclinic P2(1) with Z = 6, V = 2501.8 A(3), D(c) = 1.42 g.cm(-3)) has three molecules of indomethacin in the asymmetric unit. Two molecules form a mutually hydrogen-bonded carboxylic acid dimer, while the carboxylic acid of the third molecule is hydrogen bonded to one of the amide carbonyls of the dimer. The carboxylic acid groups of the alpha-form are exposed on the [100] faces and are accessible to attack by ammonia gas. After one layer of molecules reacts, the reactive groups in the subsequent layer are accessible to the ammonia gas. This process proceeds along the a-axis until the ammonia gas has penetrated the entire crystal. In contrast to the alpha-form, the gamma-form has a centrosymmetric crystal structure in which the hydrogen-bonded carboxylic acid dimers are not accessible to ammonia gas because they are caged inside a hydrophobic shield comprising the remainder of the indomethacin molecule. In view of the significantly lower density of the stable gamma-form as compared to the metastable alpha-form (1.37 and 1.42 g cm(-3), respectively), it became apparent that the reactivity of the crystal forms depends exclusively on the molecular arrangement and not on the packing density of the indomethacin crystals.

Ammonia↗

PubMed2002

Quantitative determination of polymorphic composition in intact compacts by parallel-beam X-ray powder diffractometry.

This paper details the development of a method using parallel-beam X-ray powder diffractometry as a novel means of determining polymorphic composition in intact compacts. Two polymorphic systems, chlorpropamide and glycine, were selected. The polymorphic components were weighed, mixed, and compressed using a Carver press with 3/8-in. concave tooling. The compacts were then analyzed using parallel-beam X-ray powder diffractometry in transmission geometry. The data were processed using the profile-fitting module in the Shimadzu XRD-6000 software V 4.1 (for NT 4.0/98). The integrated intensity ratio of a selected peak for each crystal form was used for quantitation of each polymorph. Excellent linear correlation was observed for both polymorphic systems. The convex shape of the compact surface had no effect on the XRD patterns. Since parallel-beam X-ray diffractometry is not sensitive to the shape of the sample surface, it provides a simple method for quantifying polymorphs in intact compacts. Further work to extend this to formulated tablets is ongoing. The relatively larger variation in one of the peaks in the chlorpropamide study was found to be consistent with the computational analysis of the slip behavior of the stable polymorph. This method provides the first reported non-invasive X-ray diffraction pattern quantitation of crystal forms in intact compacts.

Chemistry, Pharmaceutical↗

PubMed2002

Accelerated fluid bed drying using NIR monitoring and phenomenological modeling: method assessment and formulation suitability.

The theory behind a fluidized bed fast-drying method is investigated as a potential timesaving process, which can reduce overall drying time compared to single-temperature cycles. The method teaches that for formulations in which heat transfer dominates the drying mechanism, an increase in temperature during the evaporative phase of drying decreases overall process time by 50%, without changing the physical properties of the active ingredient. The method is also examined in terms of its potential for cycle shortening for a given formulation. A combined expression for the overall drying profile has been developed and committed to a macro that facilitates the identification of phenomenological trends, which identify whether or not a process will benefit by using fast drying. The relationship and macro also allows prediction of time frames associated with a given set of dryer and formulation parameters.

Algorithms↗