Predictive Approach to Understand and Eliminate Tablet Breakage During Film Coating.

Pharmaceutical tablets can be susceptible to damage such as edge chipping or erosion of the core during the tablet coating process. The intersection of certain process parameters, equipment design, and tablet properties may induce more significant tablet damage such as complete tablet fracture. In this work, a hybrid predictive approach was developed using discrete element method (DEM) modeling and lab-based tablet impact experiments to identify conditions that may lead to tablet breakage events. The approach was extended to examine potential modifications to the coating equipment and process conditions in silico to mitigate the likelihood of tablet breakage during future batches. The approach is shown to enhance process understanding, identify optimal process conditions within development constraints, and de-risk the manufacture of future tablet coating batches.

Factors influencing crystal growth rates from undercooled liquids of pharmaceutical compounds.

Amorphous forms of drugs are increasingly being used to deliver poorly water-soluble compounds. Therefore, understanding the magnitude and origin of differences in crystallization kinetics is highly important. The goal of this study was to better understand the factors that influence crystal growth rates from pharmaceutically relevant undercooled liquids and to evaluate the range of growth rates observed. The crystal growth rates of 31 drugs were determined using an optical microscope in the temperature region between the glass transition temperature (Tg) and the melting temperature (Tm). Thermodynamic parameters such as Tm, melting enthalpy, and Tg were determined using a differential scanning calorimeter (DSC). Selected viscosity values for the undercooled liquid were taken from the literature. The growth rates of the different compounds were found to be very different from each other with a variation of about 5 orders of magnitude between the fastest growing compounds and the slowest growing compounds. A comparison of the physicochemical properties showed that compounds that had fast crystal growth rates had smaller molecular weights, higher melting temperatures, lower melt entropies, lower melt viscosities, and higher crystal densities. Variations in the growth rates of the compounds could be rationalized to a large extent by considering the thermodynamic driving force for crystallization, the viscosity, and the entropy difference between the melt and undercooled liquid. This study therefore provides important insight into factors that may compromise the stability of amorphous pharmaceuticals.

Evaluation of amorphous solid dispersion properties using thermal analysis techniques.

Amorphous solid dispersions are an increasingly important formulation approach to improve the dissolution rate and apparent solubility of poorly water soluble compounds. Due to their complex physicochemical properties, there is a need for multi-faceted analytical methods to enable comprehensive characterization, and thermal techniques are widely employed for this purpose. Key parameters of interest that can influence product performance include the glass transition temperature (T(g)), molecular mobility of the drug, miscibility between the drug and excipients, and the rate and extent of drug crystallization. It is important to evaluate the type of information pertaining to the aforementioned properties that can be extracted from thermal analytical measurements, in addition to considering any inherent assumptions or limitations of the various analytical approaches. Although differential scanning calorimetry (DSC) is the most widely used thermal analytical technique applied to the characterization of amorphous solid dispersions, there are many established and emerging techniques which have been shown to provide useful information. Comprehensive characterization of fundamental material descriptors will ultimately lead to the formulation of more robust solid dispersion products.

Role of viscosity in influencing the glass-forming ability of organic molecules from the undercooled melt state.

PURPOSE: Understanding the critical factors governing the crystallization tendency of organic compounds is vital when assessing the feasibility of an amorphous formulation to improve oral bioavailability. The objective of this study was to investigate potential links between viscosity and crystallization tendency for organic compounds from the undercooled melt state. METHODS: Steady shear rate viscosities of numerous compounds were measured using standard rheometry as a function of temperature through the undercooled melt regime. Data for each compound were fit to the Vogel-Tamman-Fulcher (VTF) equation; kinetic fragility via strength parameter (D) was determined. RESULTS: Compounds with high crystallization tendencies exhibited lower melt viscosities than compounds with low crystallization tendencies. A correlation was observed between rate of change in viscosity with temperature and crystallization tendency, with slowly crystallizing compounds exhibiting larger increases in viscosity as temperature decreased below T(m). Calculated strength parameters indicated all compounds were kinetically fragile liquids; thus, kinetic fragility may not accurately assess glass-forming ability from undercooled melt state. CONCLUSIONS: A link was observed between the viscosity of a compound through the undercooled melt regime and its resultant crystallization tendency, indicating viscosity is a critical parameter to fully understand crystallization tendency of organic compounds.

Evaluation and modeling of the eutectic composition of various drug-polyethylene glycol solid dispersions.

The purpose of this study was to gain a better understanding of which factors contribute to the eutectic composition of drug-polyethylene glycol (PEG) blends and to compare experimental values with predictions from the semi-empirical model developed by Lacoulonche et al. Eutectic compositions of various drug-PEG 3350 solid dispersions were predicted, assuming athermal mixing, and compared to experimentally determined eutectic points. The presence or absence of specific interactions between the drug and PEG 3350 were investigated using Fourier transform infrared (FT-IR) spectroscopy. The eutectic composition for haloperidol-PEG and loratadine-PEG solid dispersions was accurately predicted using the model, while predictions for aceclofenac-PEG and chlorpropamide-PEG were very different from those experimentally observed. Deviations in the model prediction from ideal behavior for the systems evaluated were confirmed to be due to the presence of specific interactions between the drug and polymer, as demonstrated by IR spectroscopy. Detailed analysis showed that the eutectic composition prediction from the model is interdependent on the crystal lattice energy of the drug compound (evaluated from the melting temperature and the heat of fusion) as well as the nature of the drug-polymer interactions. In conclusion, for compounds with melting points less than 200°C, the model is ideally suited for predicting the eutectic composition of systems where there is an absence of drug-polymer interactions.

A classification system to assess the crystallization tendency of organic molecules from undercooled melts.

Assessing the viability of an amorphous formulation strategy is of great importance in an era of drug discovery where a large percentage of new molecules have solubility limited dissolution rates, and disruption of the crystal lattice is a potential strategy to improve this process. The objective of the current study was to evaluate the glass forming ability (GFA) of a large data set of organic molecules and also to evaluate potential links between GFA and glass stability (GS). The crystallization tendency from the undercooled melt was evaluated for a group of 51 organic molecules and separated into three separate classes [class (I), class (II), class (III)] based upon the presence/absence of observable crystallization during a heating/cooling/heating cycle, as measured using differential scanning calorimetry (DSC). Class (I) molecules were further delineated based upon the observation of a crystalline [class (I-A)] or amorphous [class (I-B)] solid after quench cooling in liquid N(2). Principal component analysis (PCA) of various physiochemical descriptors suggested that molecules with low GFA tended to be low molecular weight (MW), rigid structures while class (III) molecules tended to be higher MW, more complex structures. For select compounds, it was observed that crystallization from the glassy state was much faster for compounds with a lower GFA. It is believed that nuclei are quenched into the glass during cooling for class (I-B) and (II) molecules, leading to more facile crystallization below T(g). In addition, these quenched in nuclei are also thought to be responsible for the recrystallization observed for these classes of molecules upon heating above T(g). In conclusion, the DSC screening method and classification scheme may be a useful tool to quickly assess the GFA and potential GS of new chemical entities during early drug development.

Crystallization tendency of active pharmaceutical ingredients following rapid solvent evaporation--classification and comparison with crystallization tendency from undercooled melts.

In this study, the crystallization behavior of a variety of compounds was studied following rapid solvent evaporation using spin coating. Initial screening to determine model compound suitability was performed using a structurally diverse set of 51 compounds in three different solvent systems [dichloromethane (DCM), a 1:1 (w/w) dichloromethane/ethanol mixture (MIX), and ethanol (EtOH)]. Of this starting set of 153 drug-solvent combinations, 93 (40 compounds) were selected for further evaluation based on solubility, chemical solution stability, and processability criteria. These systems were spin coated and their crystallization was monitored using polarized light microscopy (7 days, dry conditions). The crystallization behavior of the samples could be classified as rapid (Class I: 39 cases), intermediate (Class II: 23 cases), or slow (Class III: 31 cases). The solvent system employed influenced the classification outcome for only four of the compounds. The various compounds showed very diverse crystallization behavior. Upon comparison of classification results with those of a previous study, where cooling from the melt was used as a preparation technique, a good similarity was found whereby 68% of the cases were identically classified. Multivariate analysis was performed using a set of relevant physicochemical compound characteristics. It was found that a number of these parameters tended to differ between the different classes. These could be further interpreted in terms of the nature of the crystallization process. Additional multivariate analysis on the separate classes of compounds indicated some potential in predicting the crystallization tendency of a given compound.

Effect of molecular weight, temperature, and additives on the moisture sorption properties of polyethylene glycol.

Polyethylene glycol (PEG) is a hygroscopic polymer that undergoes the phenomenon of deliquescence once a critical relative humidity (RH(0)) is reached. The purpose of this study was to test the hypothesis that the deliquescence behavior of PEG will be affected by the polymer molecular weight, temperature, and the presence of additives. The deliquescence relative humidity for single component (RH(0)) and binary mixtures (RH(0,mix)) were measured using an automated gravimetric moisture analyzer at 25 and 40 degrees C. Changes in PEG crystallinity after exposure to moisture were qualitatively assessed using powder X-ray diffraction (PXRD). Optical microscopy was used to visually observe the deliquescence phenomenon. For single component systems, decreasing PEG MW and elevating the temperature resulted in a decrease in the observed RH(0). Physical mixtures of acetaminophen and anhydrous citric acid with both PEG 3350 and PEG 100,000 exhibited deliquescence (RH(0,mix)) at a relative humidity below that of either individual component. Qualitative changes in crystallinity were observed from the X-ray diffractograms for each PEG MW grade at high relative humidities, indicating that phase transformation (deliquescence) of the samples had occurred. In conclusion, it was found that the deliquescence behavior of PEG was affected by the polymer MW, temperature, and the presence of additives. This phenomenon may have important implications for the stability of PEG containing formulations.

Spontaneous crystallinity loss of drugs in the disordered regions of poly(ethylene oxide) in the presence of water.

The physical stability of active pharmaceutical ingredients (APIs) formulated in the crystalline state may be compromised in the presence of excipients. In the present study, it is shown that at high relative humidity, several model crystalline drugs compacted into a matrix of poly(ethylene oxide) (PEO) may dissolve into the disordered regions of the polymer. The purpose of this project is to identify both the physicochemical properties of the API and the polymer which may lead to such a transformation and the mechanism of transformation. Crystalline drugs and PEO were physically mixed, compressed into tablets, and stored in a dessicator at 94% RH. The physical state of the drug and the polymer were determined using Raman spectroscopy and X-ray powder diffraction. The solubility of each drug in PEG 400 was measured by ultraviolet spectroscopy, the thermal properties of each compound were measured using differential scanning calorimetry, and the amount of water sorbed into these systems from the vapor phase was determined by gravimetric analysis. A spontaneous loss of crystallinity was observed for many of the model drugs when stored at high relative humidity and in the presence of PEO. In the absence of PEO, no changes in the crystalline material were observed. However, the structure of PEO was dramatically altered when exposed to high relative humidity. Specifically, it was found that PEO undergoes a very slow deliquescence increasing the disordered fraction of the polymer which facilitates the "dissolution" of the crystalline drug into these disordered regions. The degree of transformation, estimated from Raman spectroscopy, was found to qualitatively correlate with the aqueous solubility of the compounds. It can be concluded that for the systems studied here, the phase stability of the polymer was compromised at high relative humidity and the polymer underwent deliquescence. The equilibrium phase of several of the crystalline drugs studied here was then altered as evidenced by a loss in crystallinity.