Simultaneous XRD-DSC identifies correct drug-polymer solubility and miscibility for enantiotropic solid forms.

Thermodynamic properties, including solubility and miscibility, which are highly correlated with amorphous solid dispersion physical stability were identified for the complex solid forms of bromopropamide using simultaneous X-ray diffraction (XRD)-differential scanning calorimetry (DSC). The most stable solid form of bromopropamide was crystallized and its crystal structure was solved. The crystallized material was characterized using simultaneous XRD-DSC measurements, which allowed dual analyses of a single sample.

Understanding the Influence of API Conformations on Amorphous Dispersion Formation Potential Predictions using the 3 Molecular Descriptor.

The 3 molecular descriptor (R-GETAWAY third-order autocorrelation index weighted by the atomic mass) has previously been shown to encode molecular attributes that appear to be physically and chemically relevant to grouping diverse active pharmaceutical ingredients (API) according to their potential to form persistent amorphous solid dispersions (ASDs) with polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA). The initial 3 dispersibility model was built by using a single three-dimensional (3D) conformation for each drug molecule. Since molecules in the amorphous state will adopt a distribution of conformations, molecular dynamics simulations were performed to sample conformations that are probable in the amorphous form, which resulted in a distribution of 3 values for each API.

Investigating and Comparing the Applicability of the R3m Molecular Descriptor and Solubility Parameter Estimation Approaches in Predicting Dispersion Formation Potential of APIs in a Random Co-Polymer Polyvinylpyrrolidone Vinyl Acetate and its Homopolymer.

Evaluation of different amorphous solid dispersion carrier matrices is enabled by active pharmaceutical ingredient (API) structure-based predictions. This study compares the utility of Hansen Solubility Parameters with the R3m molecular descriptor for identifying dispersion polymers based on the structure of the drug molecule. Twelve API-polymer combinations (4 APIs and 3 interrelated polymers) were used to test each approach.

Implications of Coexistent Halogen and Hydrogen Bonds in Amorphous Solid Dispersions on Drug Solubility, Miscibility, and Mobility.

Specific noncovalent drug-polymer interactions were analytically identified using Raman and Fourier transform infrared spectroscopy for amorphous solid dispersions (ASD) formed between either chlorpropamide or tolbutamide and polyvinylpyrrolidone vinyl acetate random copolymer (PVPVA). Spectral changes in the C-Cl stretching vibrations due to changes in the electronic environment of the Cl atom confirmed halogen bond formation in chlorpropamide-PVPVA ASDs, the extent of which was established to be inversely related to the concentration of the drug using 2D correlation spectroscopy analysis. Hydrogen bonding between the secondary amide of each drug and the pyrrolidone carbonyl of the copolymer was also confirmed in all dispersions.

Interpreting the Physicochemical Meaning of a Molecular Descriptor Which Is Predictive of Amorphous Solid Dispersion Formation in Polyvinylpyrrolidone Vinyl Acetate.

A molecular descriptor known as R3m (the R-GETAWAY ) was previously identified as capable of grouping members of an 18-compound library of organic molecules that successfully formed amorphous solid dispersions (ASDs) when co-solidified with the co-polymer polyvinylpyrrolidone vinyl acetate (PVPva) at two concentrations using two preparation methods. To clarify the physical meaning of this descriptor, the R3m calculation is examined in the context of the physicochemical mechanisms of dispersion formation. The R3m equation explicitly captures information about molecular topology, atomic leverage, and molecular geometry, features which might be expected to affect the formation of stabilizing non-covalent interactions with a carrier polymer, as well as the molecular mobility of the active pharmaceutical ingredient (API) molecule.

Understanding Deformation Behavior and Compression Speed Effect in Gabapentin Compacts.

Deformation mechanism and strain rate sensitivity of gabapentin powder was investigated in this work. Heckel analysis, specific surface area and indentation hardness measurements revealed an intermediate yield pressure and brittle fracture as the dominant type of deformation mechanism during consolidation. Strain rate sensitivity of gabapentin was studied by compressing it at 1 mm/min and 500 mm/min compression speeds.

Predicting Density of Amorphous Solid Materials Using Molecular Dynamics Simulation.

The true density of an amorphous solid is an important parameter for studying and modeling materials behavior. Experimental measurements of density using helium pycnometry are standard but may be prevented if the material is prone to rapid recrystallization, or preparation of gram quantities of reproducible pure component amorphous materials proves impossible. The density of an amorphous solid can be approximated by assuming it to be 95% of its respective crystallographic density; however, this can be inaccurate or impossible if the crystal structure is unknown.

Co-Processed Particles: An Approach to Transform Poor Tableting Properties.

The role of co-processing in improving tablet mechanical properties was investigated in this work. Gabapentin was used as the model compound owing to its poor tableting properties such as low tensile strength, strain rate sensitivity, high ejection force, and tablet capping. Gabapentin was blended with hydroxypropyl methylcellulose (Methocel) in a high shear mixer to obtain an interactive mixture consisting of finer hydroxypropyl methylcellulose particles adsorbed onto the surface of larger gabapentin particles.

Modeling and Prediction of Drug Dispersability in Polyvinylpyrrolidone-Vinyl Acetate Copolymer Using a Molecular Descriptor.

The expansion of a novel in silico model for the prediction of the dispersability of 18 model compounds with polyvinylpyrrolidone-vinyl acetate copolymer is described. The molecular descriptor R3m (atomic mass weighted 3rd-order autocorrelation index) is shown to be predictive of the formation of amorphous solid dispersions at 2 drug loadings (15% and 75% w/w) using 2 preparation methods (melt quenching and solvent evaporation using a rotary evaporator). Cosolidified samples were characterized using a suite of analytical techniques, which included differential scanning calorimetry, powder X-ray diffraction, pair distribution function analysis, polarized light microscopy, and hot stage microscopy.

Determination of Spatially Resolved Tablet Density and Hardness Using Near-Infrared Chemical Imaging (NIR-CI).

Near-infrared chemical imaging (NIR-CI) combines spectroscopy with digital imaging, enabling spatially resolved analysis and characterization of pharmaceutical samples. Hardness and relative density are critical quality attributes (CQA) that affect tablet performance. Intra-sample density or hardness variability can reveal deficiencies in formulation design or the tableting process.

Experimental Determination and Theoretical Calculation of the Eutectic Composition of Cefuroxime Axetil Diastereomers.

Cefuroxime axetil (CFA), an ester prodrug of cefuroxime exists as a pair of diastereoemers, namely isomer A and isomer B. To enable phase diagram construction, crystallization of the diastereomers of CFA from the commercially available amorphous drug substance was carried out. Isomer A was separated with a purity approaching 100% whereas the maximum purity of isomer B was 85% as confirmed by solution state proton NMR spectroscopy.

Full Out-of-Die Compressibility and Compactibility Profiles From Two Tablets.

In this study, a method is presented that can be used to generate full out-of-die compressibility and compactibility profiles using the data from only 2 tablets. For each material, one tablet was compacted at the maximum pressure of interest and a second tablet at a relatively low pressure. The in-die data collected during compaction to the maximum pressure of interest and the solid fraction change after ejection for both tablets were used to generate a profile equivalent to a complete out-of-die compressibility profile.

Improved Flux of Levodopa via Direct Deposition of Solid Microparticles on Nasal Tissue.

Epithelial flux and permeability across bovine olfactory tissue were compared when levodopa (L-DOPA) was loaded in different physical states. Aqueous solution of L-DOPA was prepared in Krebs-Ringer buffer (KRB), at a concentration (0.75 mg/mL) verified to be less than the saturation solubility at both 25 and 37°C.

Inter-grade and inter-batch variability of sodium alginate used in alginate-based matrix tablets.

The purpose of this study is to characterize the inter-grade and inter-batch variability of sodium alginate used in the formulation of matrix tablets. Four different grades and three batches of one grade of sodium alginate were used to prepare matrix tablets. Swelling, erosion, and drug release tests of sodium alginate matrix tablets were conducted in a USP dissolution apparatus.

Physical characterization of drug:polymer dispersion behavior in polyethylene glycol 4000 solid dispersions using a suite of complementary analytical techniques.

Fifteen model drugs were quenched from 3:1 (w/w) mixtures with polyethylene glycol 4000 (PEG4000). The resulting solids were characterized using powder X-ray diffraction (PXRD), analysis of pair distribution function-transformed PXRD data (where appropriate), hot-stage polarized light microscopy, and differential scanning calorimetry (DSC). Drug/polymer dispersion behavior was classified using the data from each technique, independent of the others, and limitations to single-method characterization of PEG-based systems are highlighted.

A material-sparing method for assessment of powder deformation characteristics using data collected during a single compression-decompression cycle.

Compressibility profiles, or functions of solid fraction versus applied pressure, are used to provide insight into the fundamental mechanical behavior of powders during compaction. These functions, collected during compression (in-die) or post ejection (out-of-die), indicate the amount of pressure that a given powder formulation requires to be compressed to a given density or thickness. To take advantage of the benefits offered by both methods, the data collected in-die during a single compression-decompression cycle will be used to generate the equivalent of a complete out-of-die compressibility profile that has been corrected for both elastic and viscoelastic recovery of the powder.

Characterization of strain rate sensitivity in pharmaceutical materials using indentation creep analysis.

Understanding how a material's response to stress changes as the stress is applied at different rates is important in predicting performance of pharmaceutical powders during tablet compression. Widely used methods for determining strain rate sensitivity (SRS) are empirically based and can often provide inconsistent or misleading results. Indentation creep data, collected during hardness tests on compacts formed from several common tableting excipients, were used to predict each material's relative sensitivity to changes in strain rate.

Characterizing compaction-induced thermodynamic changes in a common pharmaceutical excipient.

Work, heat, and internal energy change values were measured during compression of a common pharmaceutical tablet excipient, anhydrous lactose, using a compression calorimeter. Heat of solution measurements were used independently to measure the energy change caused by compaction. Both the compression calorimeter and the heat of solution measurements showed an increase in anhydrous lactose's energy state as a result of the net compression and decompression process.

A shared assignment to integrate pharmaceutics and pharmacy practice course concepts.

Objective: To demonstrate for first-year pharmacy students the relevance of pharmaceutics course content to pharmacy practice by implementing a joint, integrated assignment in both courses and assessing its impact.

Design: Medication errors and patient safety issues relevant to ophthalmic and otic formulations were selected as the assignment topic. A homework assignment based on a mock court case involving a patient who was given an inappropriate formulation because of a pharmacist's medication error was given to students.

Understanding deformation mechanisms during powder compaction using principal component analysis of compression data.

Principal component analysis (PCA) was applied to pharmaceutical powder compaction. A solid fraction parameter (SF(c/d)) and a mechanical work parameter (W(c/d)) representing irreversible compression behavior were determined as functions of applied load. Multivariate analysis of the compression data was carried out using PCA.

Relevance of rheological properties of sodium alginate in solution to calcium alginate gel properties.

The purpose of this study is to determine whether sodium alginate solutions' rheological parameters are meaningful relative to sodium alginate's use in the formulation of calcium alginate gels. Calcium alginate gels were prepared from six different grades of sodium alginate (FMC Biopolymer), one of which was available in ten batches. Cylindrical gel samples were prepared from each of the gels and subjected to compression to fracture on an Instron Universal Testing Machine, equipped with a 1-kN load cell, at a cross-head speed of 120 mm/min.

Interpreting deformation behavior in pharmaceutical materials using multiple consolidation models and compaction energetics.

Tableting behavior is often characterized using qualitative analyses of compactibility and compressibility measurements. More quantitative methods use consolidation models to estimate parameters indicative of the predominating deformation mechanism exhibited by a material. It will be shown that a concerted approach, using multiple consolidation models and mechanical energy analysis, presents a more reliable way of evaluating the relative plasticity of pharmaceutical materials and identifying complicating behaviors.

A structural investigation into the compaction behavior of pharmaceutical composites using powder X-ray diffraction and total scattering analysis.

Purpose: To use advanced powder X-ray diffraction (PXRD) to characterize the structure of anhydrous theophylline following compaction, alone, and as part of a binary mixture with either alpha-lactose monohydrate or microcrystalline cellulose.

Materials And Methods: Compacts formed from (1) pure theophylline and (2) each type of binary mixture were analyzed intact using PXRD. A novel mathematical technique was used to accurately separate multi-component diffraction patterns.

Using compression calorimetry to characterize powder compaction behavior of pharmaceutical materials.

The process by which pharmaceutical powders are compressed into cohesive compacts or tablets has been studied using a compression calorimeter. Relating the various thermodynamic results to relevant physical processes has been emphasized. Work, heat, and internal energy change values have been determined with the compression calorimeter for common pharmaceutical materials.