Reduced Crystallization Temperature Methodology for Polymer Selection in Amorphous Solid Dispersions: Stability Perspective.

API-polymer interactions, used to select the right polymeric matrix with an aim to stabilize an amorphous dispersion, are routinely studied using spectroscopic and/or calorimetric techniques (i.e., melting point depression). An alternate selection tool has been explored to rank order polymers for formation of stable amorphous dispersions as a pragmatic method for polymer selection. Reduced crystallization temperature of API, a parameter introduced by Zhou et al.,1 was utilized in this study for rank ordering interactions in API-polymeric systems. The trends in reduced crystallization temperature monitored over polymer concentration range of up to 20% polymer loading were utilized to calculate "crystallization parameter" or CP for two model systems (nifedipine and BI ABC). The rank order of CP, i.e., a measure of API-polymer interaction, for nifedipine followed the order PVP > PVP-VA > Soluplus > HPMCAS > PV Ac > PAA. This rank ordering was correlated to published results of molecular interactions and physical stability for nifedipine. A different rank ordering was observed for BI ABC: PAA > PVP > HPMCAS > Soluplus > PVPV-VA > PVAc. Interactions for BI ABC were not as differentiated when compared to nifedipine based on CP trends. BI ABC dispersions at drug loadings between 40 and 60% were physically stable for prolonged periods under ICH conditions as well as accelerated stress. We propose that large CP differences among polymers could be predictive of stability outcomes. Acceptable stability at pharmaceutically relevant drug loadings would suggest that the relative influence of downstream processes, such as polymer solubility in various solvents, process suitability and selection, and more importantly supersaturation potential, should be higher compared to stability considerations while developing compounds like BI ABC.

Implementation of mechanistic modeling and global sensitivity analysis (GSA) for design, optimization, and scale-up of a roller compaction process.

The pharmaceutical industry has been shifting towards the application of mechanistic modeling to improve process robustness, enable scale-up, and reduce time to market. Modeling approaches have been well-developed for processes such as roller compaction, a continuous dry granulation process. Several mechanistic models/approaches have been documented with limited application to high drug-loaded formulations. In this study, the Johanson model was employed to optimize roller compaction processing and guide its scale-up for a high drug loaded formulation. The model was calibrated using a pilot-scale Minipactor and was validated for a commercial-scale Macropactor. Global sensitivity analysis (GSA) was implemented to determine the impact of process parameter variations (roll force, gap, speed) on a quality attribute [solid fraction (SF)]. The throughput method, which estimates SF values of ribbons using granule production rate, was also studied. The model predicted SF values for all 14 Macropactor batches within ± 0.04 SF. The throughput method estimated SF with ± 0.06 SF for 7 out of 11 batches. GSA confirmed that roll force had the largest impact on SF. This case study represents a process modeling approach to build quality into the products/processes and expands the use of mechanistic modeling during drug product development.

Origin of two modes of non-isothermal crystallization of glasses produced by milling.

PURPOSE: To mechanistically explain the origin of two distinct non-isothermal crystallization modes, single-peak (unimodal) and two-peak (bimodal), of organic glasses. METHODS: Glasses of ten organic molecules were prepared by melt-quenching and cryogenic milling of crystals. Non-isothermal crystallization of glasses was monitored using differential scanning calorimetry and powder X-ray diffractometry. RESULTS: The non-isothermal crystallization of glass, generated by milling, is either unimodal or bimodal, while that of melt-quenched glass without being milled is always unimodal. The mode of crystallization of amorphous phase depends on the relative position of the crystallization onset (T ( c )) with respect to glass transition temperature (T ( g )), and can be explained by a surface crystallization model. Bimodal crystallization event is observed when T ( c ) is below or near T ( g ), due to the fast crystallization onset at milled glass surfaces. Unimodal crystallization is observed when T ( c ) is well above T ( g ). We have verified this model by intentionally inducing flip between the two crystallization modes for several compounds through manipulating glass surface area and T ( c ). CONCLUSIONS: The two modes of crystallization of organic glasses is a result of the combined effects of faster surface crystallization and variation in specific surface area by milling.

Reduced pressure ice fog technique for controlled ice nucleation during freeze-drying.

A method to achieve controlled ice nucleation during the freeze-drying process using an ice fog technique was demonstrated in an earlier report. However, the time required for nucleation was about 5 min, even though only one shelf was used, which resulted in Ostwald ripening (annealing) in some of the vials that nucleated earlier than the others. As a result, the ice structure was not optimally uniform in all the vials. The objective of the present study is to introduce a simple variation of the ice fog method whereby a reduced pressure in the chamber is utilized to allow more rapid and uniform freezing which is also potentially easier to scale up. Experiments were conducted on a lab scale freeze dryer with sucrose as model compound at different concentration, product load, and fill volume. Product resistance during primary drying was measured using manometric temperature measurement. Specific surface area of the freeze-dried cake was also determined. No difference was observed either in average product resistance or specific surface area for the different experimental conditions studied, indicating that with use of the reduced pressure ice fog technique, the solutions nucleated at very nearly the same temperature (-10 degrees C). The striking feature of the "Reduced Pressure Ice Fog Technique" is the rapid ice nucleation (less than a minute) under conditions where the earlier procedure required about 5 min; hence, effects of variable Ostwald ripening were not an issue.

Role of thermodynamic, molecular, and kinetic factors in crystallization from the amorphous state.

Though there is an advantage in using the higher solubility amorphous state in cases where low solubility limits absorption, physical instability poses a significant barrier limiting its use in solid oral dosage forms. Unlike chemical instability, where useful accelerated stability testing protocols are common, no methodology has been established to predict physical instability. Therefore, an understanding of the factors affecting crystallization from the amorphous state is not only important from a scientific perspective but also has practical applications. Crystallization from the amorphous matrix has been linked to the molecular mobility in the amorphous matrix and recent research has focused on developing the link between these two fundamental properties of glass forming materials. Although researchers have been actively working in this area for some time, there is no current review describing the present state of understanding of crystallization from the amorphous state. The purpose of this review therefore is to examine the roles of different factors such as molecular mobility, thermodynamic factors, and the implication of different processing condition, in crystallization from the amorphous state. We believe an increased understanding of the relative contributions of molecular mobility and processing conditions are vital to increased usage of the amorphous state in solid oral dosage forms.

Prediction of onset of crystallization from experimental relaxation times. II. Comparison between predicted and experimental onset times.

UNLABELLED: Given a good correlation between onsets of crystallization and mobility above T(g), one might be able to predict crystallization onsets at a temperature of interest far below T(g) from this correlation and measurement of mobility at a temperature below T(g). Such predictions require that: (a) correlation between crystallization onset and mobility is the same above and below T(g), and (b) techniques used to measure mobility above and below T(g) measure the same kind of mobility [(b) demonstrated previously using dielectric and calorimetric techniques]. The objective of present work is to determine whether crystallization onset times couple with relaxation times determined above T(g), and if so to verify predictions made below T(g) (from data above T(g)) with experimental data. Model compounds were indomethacin, ketoconazole, flopropione, nifedipine, and felodipine. Onsets of crystallization measured above T(g) were coupled with dielectric mobility for indomethacin, felodipine, and flopropione. Prediction of crystallization onset times for temperatures below T(g) matched well with experimental data for indomethacin (25 degrees C, 35 degrees C: Predicted 473, 95 h; EXPERIMENTAL: 624 +/- 158, 139 +/- 49 h) and flopropione (35 degrees C, 40 degrees C; Predicted 115, 58 h; EXPERIMENTAL: 96 +/- 30, 59 +/- 10 h). The data suggests that coupling between crystallization onsets and molecular mobility at temperatures above T(g) may be exploited to develop stability testing protocol for crystallization from amorphous state.

Prediction of the onset of crystallization of amorphous sucrose below the calorimetric glass transition temperature from correlations with mobility.

The objective of the present work is to determine if crystallization onset observed for an amorphous solid correlate with relaxation time at temperatures above and below the calorimetric glass transition (T(g)). Crystallization onset of spray-dried and freeze-dried amorphous sucrose were measured calorimetrically. Relaxation times measured in two temperature ranges by different techniques (isothermal calorimetry, dielectric spectroscopy) followed the expected modified Vogel-Tammann-Fulcher (VTF) behavior when extrapolated to a temperature near T(g). However, the change in slope was more conspicuous for freeze-dried sucrose, indicating that amorphous materials generated using different techniques differ in their mobilities for temperatures below T(g). Dielectric relaxation time values obtained above T(g) were well correlated to onset of crystallization. The model predicted 21 days for crystallization onset for spray-dried samples stored 7 K below T(g), compared to the experimentally observed crystallization onset of 17 days. Onset times versus temperature for freeze-dried sucrose, however, show a change in slope on approaching T(g), with the onsets somewhat decoupling from measured mobility for temperatures below T(g). Molecular mobility in amorphous materials at temperatures both above and below T(g) can be correlated to macroscopic physical change such as crystallization, but prediction of crystallization onset from relaxation time is only qualitatively correct at temperatures well below T(g).

Heat and mass transfer scale-up issues during freeze drying: II. Control and characterization of the degree of supercooling.

This study aims to investigate the effect of the ice nucleation temperature on the primary drying process using an ice fog technique for temperature-controlled nucleation. In order to facilitate scale up of the freeze-drying process, this research seeks to find a correlation of the product resistance and the degree of supercooling with the specific surface area of the product. Freeze-drying experiments were performed using 5% wt/vol solutions of sucrose, dextran, hydroxyethyl starch (HES), and mannitol. Temperature-controlled nucleation was achieved using the ice fog technique where cold nitrogen gas was introduced into the chamber to form an "ice fog," thereby facilitating nucleation of samples at the temperature of interest. Manometric temperature measurement (MTM) was used during primary drying to evaluate the product resistance as a function of cake thickness. Specific surface areas (SSA) of the freeze-dried cakes were determined. The ice fog technique was refined to successfully control the ice nucleation temperature of solutions within 1 degrees C. A significant increase in product resistance was produced by a decrease in nucleation temperature. The SSA was found to increase with decreasing nucleation temperature, and the product resistance increased with increasing SSA. The ice fog technique can be refined into a viable method for nucleation temperature control. The SSA of the product correlates well with the degree of supercooling and with the resistance of the product to mass transfer (ie, flow of water vapor through the dry layer). Using this correlation and SSA measurements, one could predict scale-up drying differences and accordingly alter the freeze-drying process so as to bring about equivalence of product temperature history during lyophilization.

Effect of heating rate and kinetic model selection on activation energy of nonisothermal crystallization of amorphous felodipine.

The nonisothermal crystallization kinetics of amorphous materials is routinely analyzed by statistically fitting the crystallization data to kinetic models. In this work, we systematically evaluate how the model-dependent crystallization kinetics is impacted by variations in the heating rate and the selection of the kinetic model, two key factors that can lead to significant differences in the crystallization activation energy (Ea ) of an amorphous material. Using amorphous felodipine, we show that the Ea decreases with increase in the heating rate, irrespective of the kinetic model evaluated in this work. The model that best describes the crystallization phenomenon cannot be identified readily through the statistical fitting approach because several kinetic models yield comparable R(2) . Here, we propose an alternate paired model-fitting model-free (PMFMF) approach for identifying the most suitable kinetic model, where Ea obtained from model-dependent kinetics is compared with those obtained from model-free kinetics. The most suitable kinetic model is identified as the one that yields Ea values comparable with the model-free kinetics. Through this PMFMF approach, nucleation and growth is identified as the main mechanism that controls the crystallization kinetics of felodipine. Using this PMFMF approach, we further demonstrate that crystallization mechanism from amorphous phase varies with heating rate.

Prediction of onset of crystallization in amorphous pharmaceutical systems: phenobarbital, nifedipine/PVP, and phenobarbital/PVP.

The aim of this work is to determine if a stability testing protocol based on the correlations between crystallization onset and relaxation time above the glass transition temperature (T(g)) can be used to predict the crystallization onsets in amorphous pharmaceutical systems well below their T(g). This procedure assumes that the coupling between crystallization onset and molecular mobility is the same above and below T(g). The stability testing protocol has been applied to phenobarbital, phenobarbital/polyvinylpyrrolidone (PVP) (95/5, w/w), and nifedipine/PVP (95/5, w/w). Crystallization onsets have been detected by polarized light microscopy examination of amorphous films; molecular mobility has been determined by dielectric relaxation spectroscopy above T(g) and by both isothermal calorimetry and modulated differential scanning calorimetry below T(g). We find that small amounts of PVP significantly retard re-crystallization. This dramatic effect of PVP is not related to mobility, so this approach applies, at best, to extrapolation of high temperature data on a given formulation to low temperatures. Variation in molecular mobility at these concentrations of PVP is not the dominant factor in determining variation in propensity for re-crystallization from glassy systems; we suggest surface interactions between PVP and nuclei and/or small crystals slowing growth control variation in crystallization kinetics between formulations.

Correlation between molecular mobility and crystal growth of amorphous phenobarbital and phenobarbital with polyvinylpyrrolidone and L-proline.

The aim of the present study is to determine if the correlation between molecular mobility and crystallization growth rates exists over a broad temperature range from temperatures below the glass transition (T(g)) to temperatures above the glass transition. Phenobarbital and solid dispersions of phenobarbital with PVP and L-proline were studied in this research. Relaxation times below and above the T(g) were measured. Crystallization was followed in a hot-stage microscope and crystal growth rates were measured by observing radial growth of a single crystal. Arrhenius type temperature dependences were found both in relaxation times and crystal growth rates over studied temperature ranges, in all cases studied except in the case of pure phenobarbital, where a change of slope was observed for the crystal growth rate for the temperature range below T(g). For all cases, molecular mobility was correlated with crystal growth rate, for the temperature range studied, with a coupling coefficient of 0.38 for phenobarbital, and 0.23 and 0.28 for solid dispersions with PVP and proline respectively. By establishing the coupling between molecular mobility and crystal growth rate, predictive models can be created to estimate the stability of amorphous materials both, for pure form as well as for solid dispersions.

Role of mechanical stress in crystallization and relaxation behavior of amorphous indomethacin.

Even within an amorphous state, high energy sites can be generated due to sample handling and variations in preparation techniques can result in variation in these high energy sites. Such small handling variations may result in changes in physical properties and physical stability. The aim of this work is to characterize the differences in crystallization tendencies of amorphous Indomethacin arising from minor variations in sample handling. Amorphous Indomethacin was prepared by three variations on melt quenching using liquid nitrogen. Crystallization was studied by annealing the samples at various temperatures above T(g) and then using DSC to observe the melt of the polymorph crystallized during annealing. The "No stress" samples showed only T(g) whereas other samples showed three events: T(g), crystallization and melting. Even at high temperatures (90 degrees C), crystallization was not reproducible in the "No Stress" sample. However, crystallization at 90 degrees C was reproducible and immediate in samples with mechanical stress. At lower temperatures, differences were observed in extent of crystallization and in polymorph formed, which demonstrated the introduction of nuclei due to sample handling. Differences were also observed in relaxation kinetics of the different sample preparations. However, at 35 degrees C the relaxation kinetics were similar but with crystallization behavior being different.

Different measures of molecular mobility: comparison between calorimetric and thermally stimulated current relaxation times below Tg and correlation with dielectric relaxation times above Tg.

Stability of the amorphous state has been linked to molecular mobility of the matrix; however different techniques may capture different mobility substates. Our previous work suggested that two calorimetric techniques, Isothermal Microcalorimetry (TAM) and MDSC, measured different aspects of mobility with TAM measuring, in part, some faster modes of relaxation in addition to the modes mobilized at T(g). The aim of this work is to compare the relaxation times obtained using Thermally Stimulated Depolarization Current Spectroscopy (TSDC) with calorimetric mobility measured below T(g) and to determine if all measures of relaxation times below T(g) are consistent with relaxation times obtained above T(g) using Dielectric Spectroscopy (DRS). Model compounds were indomethacin, ketoconazole, nifedipine, flopropione, felodipine. For all compounds, relaxation times obtained using Thermal Windowing-TSDC technique below T(g) correlated well with relaxation times (tau) obtained above T(g) by DRS. At any given temperature below T(g), relaxation times measured depended upon the technique used and were in the following order TSDC < TAM < MDSC (tau). TSDC captures some faster relaxations not measured by calorimetric techniques, and therefore, different techniques give different measures of relaxation times below T(g). This information is important in understanding the relationships between mobility in the glassy solid and pharmaceutical stability.

Predictions of onset of crystallization from experimental relaxation times I-correlation of molecular mobility from temperatures above the glass transition to temperatures below the glass transition.

PURPOSE: Predicting onsets of crystallization at temperatures below T (g), from data above T (g), would require that the correlation between crystallization onset and mobility is same above and below T (g), and the techniques being used to measure mobility above and below T (g) are measuring essentially the same kind of mobility. The aim of this work is to determine if the relaxation times obtained using different techniques (DSC, TAM) below T (g) correlate with relaxation time obtained above T (g) using dielectric spectroscopy. METHODS: Model compounds for this work were chosen based on their varied DeltaH (f), DeltaC (p)(T (g)) and H-bonding in crystalline state vs. amorphous state. Relaxation times above T (g) were determined by the simultaneous fit of real and imaginary permittivity to the Cole-Davidson model. Tau and beta below T (g) were determined using isothermal microcalorimetry (TAM) or MDSC. MDSC was used to calculate Kauzmann temperature and strength of the glass using established relationships. RESULTS: Indomethacin, nifedipine and flopropione showed Arrhenius temperature dependence throughout the entire temperature range and extrapolation of tau ( beta ) measured above T (g) by dielectric relaxation agreed with tau ( beta ) measured below T (g) by TAM/MDSC. Ketoconazole, however, showed the expected VTF behavior. For at least two compounds compared (indomethacin and ketoconazole), relaxation times measured by TAM and MDSC did not agree, with TAM giving significantly lower values of tau ( beta ), but TAM and MDSC relaxation times appeared to extrapolate to a common value at T (g). CONCLUSIONS: It was found that, for all cases studied, relaxation time constants determined above and below T (g) did appear to extrapolate to the same value around T (g) indicating that molecular mobility measured above and below T (g) using different techniques is highly correlated.

The nonsteady state modeling of freeze drying: in-process product temperature and moisture content mapping and pharmaceutical product quality applications.

INTRODUCTION: Theoretical models of the freeze-drying process are potentially useful to guide the design of a freeze-drying process as well as to obtain information not readily accessible by direct experimentation, such as moisture distribution and glass transition temperature, Tg, within a vial during processing. Previous models were either restricted to the steady state and/or to one-dimensional problems. While such models are useful, the restrictions seriously limit applications of the theory. An earlier work from these laboratories presented a nonsteady state, two-dimensional model (which becomes a three-dimensional model with an axis of symmetry) of sublimation and desorption that is quite versatile and allows the user to investigate a wide variety of heat and mass transfer problems in both primary and secondary drying. The earlier treatment focused on the mathematical details of the finite element formulation of the problem and on validation of the calculations. The objective of the current study is to provide the physical rational for the choice of boundary conditions, to validate the model by comparison of calculated results with experimental data, and to discuss several representative pharmaceutical applications. To validate the model and evaluate its utility in studying distribution of moisture and glass transition temperature in a representative product, calculations for a sucrose-based formulation were performed, and selected results were compared with experimental data. THEORETICAL MODEL: The model is based on a set of coupled differential equations resulting from constraints imposed by conservation of energy and mass, where numerical results are obtained using finite element analysis. Use of the model proceeds via a "modular software package" supported by Technalysis Inc. (Passage/ Freeze Drying). This package allows the user to define the problem by inputing shelf temperature, chamber pressure, container properties, product properties, and numerical analysis parameters required for the finite element analysis. Most input data are either available in the literature or may be easily estimated. Product resistance to water vapor flow, mass transfer coefficients describing secondary drying, and container heat transfer coefficients must normally be measured. Each element (i.e., each small subsystem of the product) may be assigned different values of product resistance to accurately describe the nonlinear resistance behavior often shown by real products. During primary drying, the chamber pressure and shelf temperature may be varied in steps. During secondary drying, the change in gas composition from pure water to mostly inert gas is calculated by the model from the instantaneous water vapor flux and the input pumping capacity of the freeze dryer. RESULTS: Comparison of the theoretical results with the experiment data for a 3% sucrose formulation is generally satisfactory. Primary drying times agree within two hours, and the product temperature vs. time curves in primary drying agree within about +/-1 degrees C. The residual moisture vs. time curve is predicted by the theory within the likely experimental error, and the lack of large variation in moisture within the vial (i.e., top vs. side vs. bottom) is also correctly predicted by theory. The theoretical calculations also provide the time variation of "Tg-T" during both primary and secondary drying, where T is product temperature and Tg is the glass transition temperature of the product phase. The calculations demonstrate that with a secondary drying protocol using a rapid ramp of shelf temperature, the product temperature does rise above Tg during early secondary drying, perhaps being a factor in the phenomenon known as "cake shrinkage." CONCLUSION: The theoretical results of in-process product temperature, primary drying time, and moisture content mapping and history are consistent with the experimental results, suggesting the theoretical model should be useful in process development and "trouble-shooting" applications.