Understanding the Influence of API Conformations on Amorphous Dispersion Formation Potential Predictions using the R3m Molecular Descriptor.

The R3m 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 R3m 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 R3m values for each API. Although different conformations displayed R3m values that differed by as much as 0.4, the median of each R3m distribution and the value predicted from the single 3D conformation were very similar for most structures studied. The variability in R3m resulting from the distribution of conformations was incorporated into a logistic regression model for the prediction of ASD formation in PVPVA, which resulted in a refinement of the classification boundary relative to the model that only incorporated a single conformation of 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. Co-solidified mixtures containing 75% API were prepared by melt-quenching. Phase behavior was evaluated and classified using differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, and hot stage microscopy. Observations of dispersion behavior were compared to predictions made using the Hansen Solubility Parameter and R3m. The solubility parameter approach misclassified the dispersion behavior of 1 API-polymer combination and also did not produce definite predictions in 3 out of 12 of the API-polymer combinations. In contrast, R3m classifications of dispersion behavior were correct in all but two cases, with one misclassification and one ambiguous prediction. The solubility parameters best classify dispersion behavior when specific drug-polymer intermolecular interactions are present, but may be less useful otherwise. Ultimately, these two methods are most effectively used together, as they are based on distinct features of the same molecular structure.

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. Implications of coexistent interactions were investigated for drug-polymer solubility, mixing free energy, and molecular mobility relative to tolbutamide, which only formed hydrogen bonds with PVPVA. Chlorpropamide had a higher solubility, a larger negative mixing free energy, and lower mobility in PVPVA relative to tolbutamide. These thermodynamic and kinetic differences demonstrate the significance of halogen bond formation even when hydrogen bonding is present.

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 third-order autocorrelation index weighted by the atomic mass) 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. Molecules with larger R3m values tend to have more atoms, especially the heavier ones that form stronger non-covalent interactions, generally, more irregular shapes, and more complicated topology. Accordingly, these molecules are more likely to remain dispersed within PVPva. Furthermore, multiple linear regression modeling of R3m and more interpretable descriptors supported these conclusions. Finally, the utility of the R3m descriptor for predicting the formation of ASDs in PVPva was tested by analyzing the commercially available products that contain amorphous APIs dispersed in the same polymer. All of these analyses support the conclusion that the information about the API geometry, size, shape, and topological connectivity captured by R3m relates to the ability of a molecule to interact with and remain dispersed within an amorphous PVPva matrix.

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. Gabapentin demonstrated an atypical strain rate sensitivity in compactibility profile (tensile strength vs. solid fraction). Compacts of gabapentin compressed at fast speed showed an increase in tensile strength when compared with those compressed at slow speed. To understand the effect of compression speed on gabapentin's compactibility, PXRD analysis, surface area analysis, indentation hardness measurements, and consolidation modeling were performed. PXRD analysis carried out on compacts revealed no effect of speed on the physical solid-state stability of gabapentin. Specific surface area of compacts made at fast speed was higher than that of compacts made at slow speed. Indentation measurements performed on gabapentin compacts showed higher values of hardness in the case compacts made at fast speed. It was identified that at the fast compression speed, gabapentin shows greater particle fragmentation and form compacts with smaller pores.

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. Molecular dynamic simulations were used to predict the density of 20 amorphous solid materials. The calculated density values for 10 amorphous solids were compared with densities that were experimentally determined using helium pycnometry. In these cases, the amorphous densities calculated using molecular dynamics had an average percent error of - 0.7% relative to the measured values, with a maximum error of - 3.48%. In contrast, comparisons of amorphous density approximated from crystallographic structures with pycnometrically measured values resulted in an average percent error of + 3.7%, with a maximum error of + 9.42%. These data suggest that the density of an amorphous solid can be accurately predicted using molecular dynamic simulations and allowed reliable calculation of density for the remaining 10 materials for which pycnometry could not be done.

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. Interactive mixture containing <1% by weight Methocel® was compressed on a material testing system (Instron®) to evaluate tablet mechanical properties. This co-processed gabapentin demonstrated improvement in tablet tensile strength and strain rate sensitivity which was attributed to improved particle bonding. In comparison, Methocel® 10% (w/w) low-shear mixture demonstrated strain rate sensitivity and lower tensile strength. Furthermore, Methocel® coating on gabapentin particles provided lubricity and decreased die-wall friction resulting in reduced tablet capping. This methodology has applications in improving mechanical properties of poorly compressible high-dose drugs without the use of high level of excipients. Furthermore, reduction in die-wall friction through particle surface coating could prove beneficial for formulations prone to overlubrication and slow dissolution owing to magnesium stearate.

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. Logistic regression was applied, where appropriate, to model the success and failure of compound dispersability in polyvinylpyrrolidone-vinyl acetate copolymer. R3m had combined prediction accuracy greater than 90% for tested samples. The usefulness of this descriptor appears to be associated with the presence of heavy atoms in the molecular structure of the active pharmaceutical ingredient, and their location with respect to the geometric center of the molecule. Given the higher electronegativity and atomic volume of these types of atoms, it is hypothesized that they may impact the molecular mobility of the active pharmaceutical ingredient, or increase the likelihood of forming nonbonding interactions with the carrier polymer.

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. This study was designed to develop NIR-CI methods to predict spatially resolved tablet density and hardness. The method was implemented using a two-step procedure. First, NIR-CI was used to develop a relative density/solid fraction (SF) prediction method for pure microcrystalline cellulose (MCC) compacts only. A partial least squares (PLS) model for predicting SF was generated by regressing the spectra of certain representative pixels selected from each image against the compact SF. Pixel selection was accomplished with a threshold based on the Euclidean distance from the median tablet spectrum. Second, micro-indentation was performed on the calibration compacts to obtain hardness values. A univariate model was developed by relating the empirical hardness values to the NIR-CI predicted SF at the micro-indented pixel locations: this model generated spatially resolved hardness predictions for the entire tablet surface.

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. The crystalline forms of isomer A and isomer B were confirmed as forms AI and BI, respectively, based on differential scanning calorimetry (DSC) analysis and powder X-ray diffraction. DSC analysis was used to observe the melting behavior of different diastereomer mixture compositions. The binary solid-liquid phase diagram for mixture compositions ranging from 0 to 85% w/w isomer B indicated the formation of a eutectic mixture having a melting temperature of 124.7 ± 0.4°C and a composition of 75% w/w (+/-5% wt.) isomer B. The eutectic composition was calculated using an index based on the van't Hoff equation for melting point depression and was found to be 75% isomer B and 25% isomer A. As CFA is present in commercial preparations as a mixture of diastereomers, the formation of a eutectic mixture between the diastereomers may impact the solubility and stability of the commercial product. Eutectic formation can be explained on the basis of the chemical similarity of diastereomers that favor miscibility in the liquid state.

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. After measuring the tensile strengths of each tablet, a compactibility profile was produced by fitting the out-of-die porosity and tensile strength data to the Ryshkewitch-Duckworth equation. This method generated accurate out-of-die compressibility and compactibility profiles for each of the materials studied. Not only is this technique computationally simple, but in cases where only small amounts of raw material are available, this method allows a detailed understanding of a material's mechanical behavior to be assessed.

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. Sodium metabisulfite was added to solution to minimize L-DOPA oxidation; chemical stability of aqueous L-DOPA was evaluated using HPLC-UV. Solid-state characterization of unprocessed, dry, crystalline L-DOPA powder was performed using TGA, DSC, PXRD, and optical microscopy to ensure that preparation of L-DOPA microparticles used for diffusion experiments did not elicit a phase change. Measurements of in vitro flux were made for all preparations, using freshly excised bovine olfactory mucosal membrane. Samples obtained from transport studies were analyzed by HPLC-UV. Tissue viability was measured before and after experiments using transdermal epithelial electrical resistance (TEER). The average steady-state flux (J ss ) of L-DOPA from solid microparticles directly deposited on nasal epithelial tissue was 6.08 ± 0.69 µg/cm2/min, approximately three times greater than the J ss measured for L-DOPA from solution (2.13 ± 0.97 µg/cm2/min). The average apparent permeability coefficient (P app ) of L-DOPA was calculated to be 4.73 × 10-5 cm/s. These findings suggest that nasal delivery of L-DOPA by administration of solid microparticles not only benefits from improved chemical and microbiological stability by avoiding the use of aqueous formulation vehicle but also does not compromise cumulative mass transport across the olfactory membrane.

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. Substantial differences in swelling and erosion behavior of sodium alginate matrix tablets were evident among different viscosity grades. Even different batches of the same grade exhibit substantial differences in the swelling and erosion behavior of their matrix tablets. The erosion behavior of sodium alginate matrix tablets can be partly explained by their rheological properties (both apparent viscosity and viscoelasticity) in solution. Sodium alginate with higher apparent viscosity and viscoelasticity in solution show slower erosion rate and higher swelling rate. Compacts prepared from grades or batches with higher viscosity and higher viscoelasticity show slower drug release. For grades or batches with similar apparent viscosities, apparent viscosities of sodium alginate solution at low concentration alone are not sufficient to predict the functionality of sodium alginate in matrix tablets. Viscoelastic properties of sodium alginate solutions at one high concentration corresponding to the polymer gel state, may be suitable indicia of the extended release behavior of sodium alginate matrix tablets.

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. The data from all characterization techniques were collectively used to classify dispersion behavior, which was compared with single-technique characterization. Of the 15 combinations, only six resulted in solids whose dispersion behavior was consistently described using each standalone technique. The other nine were misclassified using at least one standalone technique, mainly because the phase behavior was ambiguously interpreted when only the data from one technique were considered. The data indicated that a suite of complementary techniques provided better classifications of the phase behavior. Of all the quenched solids, only cimetidine was fully dispersed in PEG4000, suggesting that it solidified from a completely miscible mixture of molten drug and polymer that did not phase separate upon cooling. In contrast, ibuprofen and PEG4000 completely recrystallized during preparation, whereas the remaining 13 drugs were partially dispersed in PEG4000 at this composition.

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. This method has been found to be both a precise and accurate means of evaluating out-of-die compressibility for four common tableting excipients. Using this method, a comprehensive characterization of powder compaction behavior, specifically in relation to plastic/brittle, elastic and viscoelastic deformation, can be obtained. Not only is the method computationally simple, but it is also material-sparing. The ability to characterize powder compressibility using this approach can improve productivity and streamline tablet development studies.

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. Linear relationships between Ln(indentation hardness) and Ln(strain rate) were observed for all materials tested. The slope values taken from these relationships were compared to traditional strain rate sensitivity estimates based on in-die Heckel analysis. Overall, the results from the two methods were quite similar, but several advantages were evident in the creep data. The most notable advantage was the ability to characterize strain rate sensitivity derived from plastic behavior with little influence of elastic deformation. For example, two grades of corn starch had very similar creep behavior, but their yield pressures were affected very differently when the compaction rate was increased. This inconsistency was related to the difference in the viscoelastic recovery exhibited by these two materials. This new method promises to allow a better understanding of strain rate effects observed during tablet manufacturing.

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. Excellent agreement between the energy change measured by compression calorimetry (0.94 J/g) and the energy change measured by solution calorimetry (0.91 J/g) strongly supports the data and results generated by the compression calorimeter. Furthermore, specific volume and specific surface area measurements were used to investigate the nature of the measured energy increase. The results indicate that the vast majority of the stored energy is most likely associated with residual strain within the compacted particles.

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. The first principal component (PC1) showed loadings for the solid fraction and work values that agreed with changes in the relative significance of plastic deformation to consolidation at different pressures. The PC1 scores showed the same rank order as the relative plasticity ranking derived from the literature for common pharmaceutical materials. The utility of PC1 in understanding deformation was extended to binary mixtures using a subset of the original materials. Combinations of brittle and plastic materials were characterized using the PCA method. The relationships between PC1 scores and the weight fractions of the mixtures were typically linear showing ideal mixing in their deformation behaviors. The mixture consisting of two plastic materials was the only combination to show a consistent positive deviation from ideality. The application of PCA to solid fraction and mechanical work data appears to be an effective means of predicting deformation behavior during compaction of simple powder mixtures.

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. The scenario was followed by essay and calculation questions linking physical pharmacy concepts with patient safety recommendations. ASSESSMENT: Students' average score on the crossover assignment was 88.7%. Minute papers completed before and after the assignment showed improvement in student learning. Students' scores on examination questions related to the assignment topic were significantly higher than the previous year's students' performance on similar questions. In a survey conducted at the end of the semester, 91% of students indicated that the assignment helped them relate the covered topics to future practice, and 98% agreed that the assignment emphasized the importance of the pharmaceutics in professional practice. CONCLUSION: A crossover assignment was an effective means of demonstrating the connection between specific pharmaceutics concepts and practice applications to pharmacy students.

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. Among the grades with similar % G, (grades 1, 3, and 4), there is a significant correlation between deformation work (L(E)) and apparent viscosity (η(app)). However, the results for the partial correlation analysis for all six grades of sodium alginate show that L(E) is significantly correlated with % G, but not with the rheological properties of the sodium alginate solutions. Studies of the ten batches of one grade of sodium alginate show that η(app) of their solutions did not correlate with L(E) while tan δ was significantly, but minimally, correlated to L(E). These results suggest that other factors--polydispersity and the randomness of guluronic acid sequencing--are likely to influence the mechanical properties of the resultant gels. In summary, the rheological properties of solutions for different grades of sodium alginate are not indicative of the resultant gel properties. Inter-batch differences in the rheological behavior for one specific grade of sodium alginate were insufficient to predict the corresponding calcium alginate gel's mechanical properties.