Ira S. Buckner

Co-proccessed excipients with enhanced direct compression functionality for improved tableting performance

It is necessary to have excipients with excellent functional properties to compensate for the poor mechanical properties and low aqueous solubility of the emerging active ingredients. Therefore, around 80% of the current drugs are not suitable for direct compression and more advanced excipients are required. Further, conventional grades of excipients cannot accommodate the technologically advanced high speed rotary tablet presses which require a powder with excellent flow, good compressibility, compactibility, particle size distribution and homogeneity of the ingredients. Co-processed excipients have been created to enhance the functional properties of the excipients and reduce their drawbacks. Co-processing is defined as the combination of two or more excipients by a physical process. Co-processed excipients are adequate for direct compression since they become multifunctional and thus, their dilution potential is high eliminating the need for many excipients in a formulation. In some cases, they are able to hold up to 50% of the drug in a formulation rendering compacts of good tableting properties. This study describes and discusses the functionality enhancement of commercial and investigational excipients through co-processing.

Use of Compaction Energetics for Understanding Particle Deformation Mechanism

A primary goal of the current work was to examine the potential use of compaction energetics as a tool to predict particle deformation mechanism. Three deformation models, namely, those developed by Heckel, Walker, and Gurnham, were first used to evaluate the deformation mechanisms of 11 commonly used excipients. To complement the information gained from the deformation models, the mechanical energy used in tablet formation was then examined. It has been found that the sum of the work in the compression and decompression phases (plastic work) is a relatively good indicator of a materials plasticity. Conclusions based on this indicator regarding deformation mechanism for the different diluents used were in good agreement with those obtained from the different deformation models studied.

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.

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

Understanding how a materials 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 materials 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.

A Structural Investigation into the Compaction Behavior of Pharmaceutical Composites Using Powder X-ray Diffraction and Total Scattering Analysis

PurposeTo 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 α-lactose monohydrate or microcrystalline cellulose.Materials and MethodsCompacts 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. The pair distribution function (PDF) of isolated theophylline diffraction data was employed to assess structural differences induced by consolidation and evaluated by principal components analysis (PCA).ResultsChanges induced in PXRD patterns by increasing compaction pressure were amplified by the PDF. Simulated data suggest PDF dampening is attributable to molecular deviations from average crystalline position. Samples compacted at different pressures were identified and differentiated using PCA. Samples compacted at common pressures exhibited similar inter-atomic correlations, where excipient concentration factored in the analyses involving lactose.ConclusionsPractical real-space structural analysis of PXRD data by PDF was accomplished for intact, compacted crystalline drug with and without excipient. PCA was used to compare multiple PDFs and successfully differentiated pattern changes consistent with compaction-induced disordering of theophylline as a single component and in the presence of another material.

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. A framework of equations has been proposed relating the physical processes of friction, reversible deformation, irreversible deformation, and inter-particle bonding to the compression calorimetry values. The results indicate that irreversible deformation dominated many of the thermodynamic values, especially the net internal energy change following the compression-decompression cycle. The relationships between the net work and the net heat from the complete cycle were very clear indicators of predominating deformation mechanisms. Likewise, the ratio of energy stored as internal energy to the initial work input distinguished the materials according to their brittle or plastic deformation tendencies.

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.

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. Force versus displacement data for compact formation, porosity versus pressure and tensile strength data for ejected compacts were collected with a single instrument. The porosity and tensile strength data were analyzed using two relatively new models and the results were compared to three more classical models. Additionally, the mechanical work measurements were used to interpret the consolidation model predictions. Although the individual models are susceptible to a number of errors, complications and invalid assumptions, confidence can be gained when diverse models provide similar predictions. Disagreement between the model predictions can be taken as a sign of atypical behavior that should be further investigated by looking at the material’s mechanical energetics. Finally, the use of work energy associated with compression and decompression as an initial measure of plasticity is supported.

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 pharmacists 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 years 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.

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.