Patient Acceptability and Preferences for Solid Oral Dosage Form Drug Product Attributes: A Scoping Review.

Background: There is no consistent framework for patient-centric drug product design, despite the common understanding that drug product acceptability and preferences influence adherence and, therefore, drug product effectiveness. The aim of this review was to assess current understanding of patient acceptability and preferences for solid oral dosage form (SODF) drug product attributes, and the potential impact of these attributes on patient behaviors and outcomes. Patients and Methods: A scoping review was conducted. Embase, Ovid MEDLINE®, and PubMed® were searched for full-text articles published between January 2013 and May 2023. Following screening and assessment against predefined inclusion criteria, data were analyzed thematically. Results: Nineteen studies were included. Four overarching domains of drug product attributes were identified and summarized in a framework: appearance, swallowability, palatability, and handling. Each domain was informed by specific drug product attributes: texture, form, size, shape, color, marking, taste, mouthfeel, and smell. The most frequently studied domains were swallowability and appearance, while the most studied attributes were size, shape, and texture. Smell, marking, and mouthfeel were the least studied attributes. Texture intersected all domains, while form, shape, and size intersected appearance, swallowability, and handling. Swallowability and size appeared to be the key domain and attribute, respectively, to consider when designing drug products. Few studies explored the impact of drug product attributes on behaviors and outcomes. Conclusion: While existing studies of drug product attributes have focused on appearance and swallowability, this review highlighted the importance of two less well-understood domains-palatability and handling-in understanding patients' acceptability and preferences for SODF drug products. The framework provides a tool to facilitate patient-centric design of drug products, organizing and categorizing physical drug product attributes into four overarching domains (appearance, swallowability, palatability, and handling), encouraging researchers to comprehensively assess the impact of drug product attributes on patient acceptability, preferences, and outcomes.

Medicines come in a variety of types and forms. These include tablets and capsules. Factors, such as the size and shape of tablets, can affect how people take medicines. However, patients are rarely involved in designing the medicines that they take. In this study, researchers summarized 19 studies published between 2013 and 2023. They wanted to understand how different factors, like size and shape, affect patients' preferences, ability, and willingness to take medicines. Researchers focused on the "physical" aspects of medicines and found 4 common themes: 1) what they look like (appearance), 2) how easy they are to swallow (swallowability), 3) how they taste and feel in the mouth (palatability), and 4) how easy they are to handle (handling). Eight factors were also found: color, markings, shape, size, smell, taste, texture, and how a medicine feels in the mouth (mouthfeel). Most studies focused on what medicines look like and how easy they are to swallow. The factors that researchers mostly looked at were the size, shape, and texture of medicines. The design of medicines can impact patients of different ages, though there may be specific needs for certain groups of patients, including children, older adults, and people with certain diseases. Patient input should become a part of future medicines design to ensure their acceptability.

Excipient Taxonomy for the 21st Century.

The performance of pharmaceutical dosage forms relies heavily on the characteristics of the excipients that are incorporated into the drug product during the manufacturing process. Therefore, it is imperative that formulators are able to accurately and completely specify the key chemical and physical properties of those excipients. Current approaches to describing excipients are outdated and inadequate for the needs of the 21st century and in this article we highlight the benefits of a more systematic and comprehensive approach to specifying and controlling excipient properties. We hope that this will prompt the users, suppliers, and manufacturers of excipients to take a careful look at current approaches and develop tangible proposals for attaining an enhanced future state.

Binary isobaric phase diagrams of stearyl alcohol-poloxamer 407 formulations in the molten and solid state.

Multiparticulate formulations allow for the design of specialized pharmaceutical dosage forms that cater to the needs of a wide range of patient demographics, such as pediatric and geriatric populations, by affording control over the release rate and facilitating the formulation of fixed-dose combination drugs. Melt spray-congealing (MSC) is a method for preparing multiparticulate dosage forms from a suspension or solid solution of active pharamaceutical ingredients (API) and a molten carrier matrix. Stearyl alcohol and poloxamer 407 mixtures are widely used as carrier matrices in MSC microsphere formulations. In this report, the phase equilibria of stearyl alcohol-poloxamer 407 mixtures were investigated by generating binary phase diagrams of composition, i.e. weight/weight percent of poloxamer 407 in stearyl alcohol, and temperature in the molten form and the solid state. The phase equilibria of the molten state were characterized by 1H NMR measurements. The miscibility curves of stearyl alcohol-poloxamer 407 molten mixtures revealed that stearyl alcohol and poloxamer 407 are not miscible in all proportions and that miscibility substantially increases with temperature. The phase equilibria of the solid state were characterized by DSC and PXRD experiments. The phase diagrams of the solid state indicate that stearyl alcohol and poloxamer 407 crystallize and melt separately and, thus, do not form a eutectic or a single phase. The phases equilibria of the bulk mixtures were compared to the phases observed in placebo MSC microspheres and it was determined that the microspheres consist of a mixture of thermodynamically stable and metastable stearyl alcohol crystals immediately after manufacture.

The Wall Friction Properties of Pharmaceutical Powders, Blends, and Granulations.

Data from wall friction testing and physical property characterization of over 100 pharmaceutical powders, blends, and granulations have been analyzed. The analyses focused on data for stainless steel surfaces with the most common finishes for pharmaceutical powder processing equipment, either a 2B cold rolled mill finish or an electropolished 2B surface. Active pharmaceutical ingredients exhibited the highest friction against these surfaces, whereas active granulations exhibited the least friction. The typical (median) wall friction angle for an active blend on 2B stainless steel was 22° versus 18° for an active granulation. Typical wall friction values on electropolished 2B surfaces were about 17° and 12° for active blends and granulations, respectively. Blends typically exhibited larger wall friction angles than the granulations suggesting that simple blends will usually require hoppers or bins with steeper walls to achieve mass flow. Lower wall friction angles were consistently observed against the smoother electropolished 2B surface, and, thus, the wall surface finish should be considered when designing bins and hoppers for use with pharmaceutical powders. The wall friction angles of blends and granulations did not show any definite trend as the percentage of active pharmaceutical ingredient increased.

Evaluation of dynamic image analysis for characterizing pharmaceutical excipient particles.

The capability of the newly developed dynamic image analysis instrument QicPic equipped with the high-speed dry-powder-dispersing device was investigated systematically using various MCC particles. Instrument cross-validation was conducted by comparing the particle size distribution of spherical particles obtained with the QicPic and with a conventional laser diffraction instrument (HELOS). While good agreement was observed with spherical particles, significant differences were found when analyzing rod-shaped Ceolus KG-1000 particles, revealing the intrinsic difference in operating principles between these two techniques. Particle shape distributions of several spherical and rod-shaped samples obtained with the QicPic were compared to scanning electron micrographs (SEMs), and semi-quantitative agreement was obtained. The particle size and particle shape of a series of binary particulate systems composed of both spherical (CP-102) and rod-shaped (KG-1000) particles of varying mass ratios were analyzed using the QicPic. The particle size and shape distributions of these binary mixtures were also computed using the distributions of the pure components weighted by their respective mass fractions. Comparisons between the measured and computed distributions appeared to indicate that the QicPic overestimated the amount of KG-1000 particles present in all the mixtures. Further analysis revealed that the observed discrepancy might be caused by a particle porosity effect.

Use of prediction methods to estimate true density of active pharmaceutical ingredients.

True density is a fundamental and important property of active pharmaceutical ingredients (APIs). Using prediction methods to estimate the API true density can be very beneficial in pharmaceutical research and development, especially when experimental measurements cannot be made due to lack of material or sample handling restrictions. In this paper, two empirical prediction methods developed by Girolami and Immirzi and Perini were used to estimate the true density of APIs, and the estimation results were compared with experimentally measured values by helium pycnometry. The Girolami method is simple and can be used for both liquids and solids. For the tested APIs, the Girolami method had a maximum error of -12.7% and an average percent error of -3.0% with a 95% CI of (-3.8, -2.3%). The Immirzi and Perini method is more involved and is mainly used for solid crystals. In general, it gives better predictions than the Girolami method. For the tested APIs, the Immirzi and Perini method had a maximum error of 9.6% and an average percent error of 0.9% with a 95% CI of (0.3, 1.6%).

Predicting the Crystallization Propensity of Drug-Like Molecules.

Predicting the crystallization propensity of drug-like molecules is one of the most significant challenges facing pharmaceutical scientists today. Despite the importance of being able to understand what structural features of a molecule (polarity, molecular size, etc.) and which experimental conditions (temperature, concentration, etc.) permit a molecule to crystallize, there has been very little published work focused on this topic. This commentary provides a short overview of recent progress in this area and points to potential experimental and computational approaches that might be used in the future.

Towards an understanding of the structurally based potential for mechanically activated disordering of small molecule organic crystals.

The potential for various small molecule organic crystals to undergo complete mechanically induced disordering is investigated. A model is proposed, which considers changes in free energy required for lattice incorporation of a critical dislocation density. Application requires knowledge of a few physical properties, namely the elastic shear modulus, Burgers vector magnitude, molar volume, melting temperature, and heat of fusion. The model was tested using seven compounds; acetaminophen, aspirin, gamma-indomethacin, salicylamide, sucrose, and two proprietary drug compounds, PFZ1 and PFZ2. Crystalline solids were subjected to high shear, controlled temperature comminution for various durations, after which the samples were examined using powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The results verified that acetaminophen, aspirin, and salicylamide, which were suggested by the model to be resistant to complete mechanical disordering, remained fully crystalline, even after 5 h of milling. Sucrose and gamma-indomethacin were both predicted to be susceptible to amorphization, which was confirmed by physical characterization. Single, 3-h grinding experiments were performed on two proprietary compounds, PFZ1 and PFZ2. The model indicated that each should be resistant to complete disordering, a trend held by PFZ1. Evidence of partial disordering of PFZ2 was unexpected and is discussed with respect to possible temperature effects.

Mechanical property anisotropy of pharmaceutical excipient compacts.

The mechanical property anisotropy of compacts made from six commercially available pharmaceutical excipient powders was evaluated. Uni-axially compressed cubic compacts of each excipient were subjected to pendulum impact testing and transverse tensile testing in several orientations. The pendulum impact test was used to measure the dynamic indentation hardness of each compact face (side, top, and bottom). Transverse tensile testing was utilized to determine the compact axial and radial tensile strength values. The indentation hardness (top>bottom>side) and tensile strength tests (radial>axial) revealed mechanical property anisotropy in all the compacts. The extent of mechanical property anisotropy was quantified by using dimensionless ratios and was found to be significantly different for each material. In general, compacts with a higher degree of compact mechanical anisotropy also exhibited a higher brittle fracture index (BFI). This suggests that the macroscopic flaws intentionally made in the compact for the BFI measurement were similar to the flaws induced in highly anisotropic materials during uni-axial compaction. These results are consistent with the practical observation that brittle materials are more likely to exhibit failure in a plane normal to the compaction axis, i.e. experience tablet capping and lamination phenomena.

Effect of pressure up to 5.5GPa on dry powder samples of chlorpropamide form-A.

The effect of pressure up to 5.5GPa on a dry powder sample of chlorpropamide (4-chloro-N-((propylamino)-carbonyl)-benzenesulfonamide), form-A (sp. gr. P2(1)2(1)2(1), a=9.066A, b=5.218A, c=26.604A), was studied in situ in a Merrill-Bassett diamond anvil cell using high-resolution X-ray powder diffraction (a synchrotron radiation source at SNBL ESRF, Grenoble). No evidence of the polymorphic transformation of chlorpropamide form-A to form-C was observed. The A-C polymorphic transition on tabletting previously reported by is therefore likely to be due to local heating effects. Similarly, the phase transitions of form-A reported by to be induced by pressure applied to a sample in its saturated ethanol solution (at 0.9 and at 2.0GPa) would appear to be solvent-mediated. In the dry sample, a phase transition may be supposed to occur at pressures above 4GPa, but this requires further studies.

The influence of measurement conditions on the Hammett acidity function of solid pharmaceutical excipients.

In this work the Hammett acidity function has been measured to assess the relative acidity of excipients used in the preparation of pharmaceutical solid dosage forms. A systematic series of experiments is reported which illustrates how the selection of the measurement conditions can influence the results of such determinations. Although the technique is somewhat empirical and relies on several key assumptions it is shown that very consistent results can be achieved by carefully controlling the measurement conditions. It is also shown that by taking this approach laboratory-to-laboratory variation can be reduced to a negligible level and the influences of subtle changes in the acidity of pharmaceutical excipients due to intrinsic variations in their physical properties or due to different processing histories can be detected and quantified.

A simple predictive model for the tensile strength of binary tablets.

The tensile strength of tablets of single-component powders, such as microcrystalline cellulose (MCC), hydroxypropylmethyl cellulose (HPMC) and starch, and binary mixtures of these powder were measured at various relative densities. It was found that the tensile strength of tablets of powder blends was primarily dependent upon relative density but was independent of the tablet dimensions and compaction kinematics. It was found that the logarithm of tensile strength was proportional to the relative density. A simple model, based upon Ryshkewitch-Duckworth equation that was originally proposed for porous materials, has been developed in order to predict the relationship between the tensile strength and relative density of binary tablets based on the properties of the constituent single-component powders. The validity of the model has been verified with experimental results for various binary mixtures. It has demonstrated that the proposed model can well predict the tensile strength of binary mixtures based upon the properties of single-component powders, such as true density, and the concentrations.

A combined experimental and numerical approach to explore tribocharging of pharmaceutical excipients in a hopper chute assembly.

Electrostatic charging via contact electrification or tribocharging refers to the process of charge transfer between two solid surfaces when they are brought into contact with each other and separated. Charging of continuous particulate flows on solid surfaces is poorly understood and has often been empirical. This study aims toward understanding the tribocharging of pharmaceutical excipients using a simplified geometry of unidirectional flow in a hopper-chute assembly. Assuming electron transfer to be the dominant mechanism of electrification, a triboelectric series was generated using work functions estimated from quantum chemical calculations. A 3D-DEM model has been developed employing charge transfer and electrostatic forces. Using numerical simulations, the charge accumulation for an assemblage of particles during flow was determined under different conditions. To theoretically analyze the process of charging, parametric studies affecting powder flow have been investigated. A higher specific charge was observed at larger friction coefficients and lower restitution coefficients. The results obtained from the simulation model reinforce the collisional nature of triboelectrification. The simulation results revealed similar trends to experimental observations. However, to enable a priori prediction the model needs to be tested for additional materials or extended to other process operations.

Improving the prediction of exceptionally poor tableting performance: an investigation into Hiestand's "special case".

The mechanical and flow properties of selected pharmaceutical powdered excipients and drug substances were evaluated to investigate their behavior as extremely poor tableting, or "special case," materials. The compaction stress, dynamic indentation hardness, and tensile strength of compacts compressed to 15% porosity and their powder's effective angle of internal friction were measured using the tableting indices technology and a simple shear cell, respectively. It has been previously demonstrated that compacts of special case materials exhibit a dynamic indentation hardness greater than the stress required to form the compact under slow compression conditions. In addition, new data suggest that special case materials also exhibit low compact dynamic indentation hardness, low compact tensile strength, and low powder effective angle of internal friction. These findings support the theory that the particles of such materials preferentially rearrange rather than deform under compressive conditions because bonding between them is weak. The added special case indicator measurements can be used to clearly identify exceptionally poor tableting powders during the selection of components for solid dosage formulations. Careful consideration of the data will provide guidance to the proper use of the bonding indices equations.

Modeling of transmitted X-ray intensity variation with sample thickness and solid fraction in glycine compacts.

The previous paper in this series introduced an X-ray diffraction quantitation method for the polymorphic content in tablets made of pure components. Before the method could be transferred, further studies were required to explain the commonly observed X-ray intensity variation in analyzing compacts. The literature typically attributes the variation to partial amorphization under compression and/or to preferred orientation, without much viable explanation or compelling evidence. In this study, changes in intensity in compacts analyzed in transmission geometry were found to be primarily a function of sample thickness and solid fraction. A theoretical model was developed to describe the X-ray powder diffraction (XRPD) intensity as a function of solid fraction, mass absorption coefficient, and thickness. The model was tested on two sets of glycine compacts: one with varying thickness at constant solid fraction, and the other with various solid fractions at a given thickness. The results show that the model predicts the XRPD intensity at any given sample thickness and solid fraction. With this model, the intensity variation of compacts made under different compression conditions can be normalized, making the method transferable to various tablet geometries and facilitating the analysis over expected ranges of formulation and process variation.

Simulation of roller compaction using a laboratory scale compaction simulator.

A method for simulation of the roller compaction process using a laboratory scale compaction simulator was developed. The simulation was evaluated using microcrystalline cellulose as model material and ribbon solid fraction and tensile strength as key ribbon properties. When compacted to the same solid fractions, real and simulated ribbons exhibited similar compression behavior and equivalent mechanical properties (tensile strengths). Thus, simulated and real ribbons are expected to result in equivalent granulations. Although the simulation cannot account for some roller compaction aspects (non-homogeneous ribbon density and material bypass) it enables prediction of the effects that critical parameters such as roll speed, pressure and radius have on the properties of ribbons using a fraction of material required by conventional roller compaction equipment. Furthermore, constant ribbon solid fraction and/or tensile strength may be utilized as scale up and transfer factors for the roller compaction process. The improved material efficiency and product transfer methods could enable formulation of tablet dosage forms earlier in drug product development.

The powder flow and compact mechanical properties of sucrose and three high-intensity sweeteners used in chewable tablets.

The physical, flow, and mechanical properties of four common pharmaceutical sweeteners were measured to assess their relative manufacturability in solid dosage formulations. Sucrose, acesulfame potassium (Sunett), saccharin sodium, and aspartame were evaluated to determine significant differences in particle shape, size distribution, and true density. Powder flow and cohesivity as well as compact mechanical properties such as ductility, elasticity, and tensile strength were measured and found to be noticeably different. Among these sweeteners, sucrose and acesulfame potassium demonstrated excellent flowability and marginal mechanical property performance relative to over 100 commonly used pharmaceutical excipients evaluated in the authors' laboratory. Saccharin sodium and aspartame demonstrated poor flowability and superior compact strength relative to sucrose and acesulfame, despite their noticeably higher brittleness. These data suggest that careful selection of an appropriate sweetener is warranted in obtaining desirable process and tableting robustness, particularly if sweetener loading is high. Detailed descriptions of each material property and recommendations for sweetener selection in formulation development are included.

Comparison of the mechanical properties of the crystalline and amorphous forms of a drug substance.

PURPOSE: To better understand the influence of long-range molecular order on the processing characteristics of an active pharmaceutical ingredient (API). METHODS: Crystalline and amorphous samples of a model drug substance were isolated and their "true" density, crystallinity, melting point, glass transition temperature, particle size distribution, and powder flow characteristics determined. Compacts of a standard porosity were manufactured from each form and their dynamic indentation hardness, quasi-static indentation hardness, tensile strength and "compromised tensile strength" determined. X-ray powder diffraction was used to confirm that no changes were induced by compact formation or testing. RESULTS: The crystalline and amorphous forms of the drug substance had relatively high melting and glass transition temperatures (approximately 271 and 142 degrees C, respectively) and were physically and chemically stable under the conditions of the testing laboratory. Consistent with this there was no evidence of crystallinity in the amorphous samples or vice versa before, during or after testing. The two API lots were effectively equivalent in their particulate properties (e.g. particle size distribution), although differences in their particle morphologies were observed which influenced powder flow behavior. The compacts of the bulk drug samples exhibited moderate ductility, elasticity, and strength, and high brittleness, in keeping with many other drug substance samples. A significantly greater compression stress was required to form the compacts of the crystalline material, and these sample materials were more ductile, less brittle and less elastic than those made from the amorphous API. There were no major differences in the tensile strength or the viscoelasticity of the compacts made from the crystalline and amorphous samples. CONCLUSIONS: The mechanical properties of compacted amorphous and crystalline samples of a drug substance have been measured and the contributions due to the molecular ordering of the crystalline form proposed. Small but significant differences in the mechanical properties were noted which could potentially affect the processing performance of API.

Development of a robust procedure for assessing powder flow using a commercial avalanche testing instrument.

The objectives of this work were to develop a robust procedure for assessing powder flow using a commercial avalanche testing instrument and to define the limits of its performance. To achieve this a series of powdered pharmaceutical excipients with a wide range of flow properties was characterized using such an instrument (Aeroflow, TSI Inc., St. Paul, MN, USA). The experimental conditions (e.g., sample size, rotation speed) were rationally selected and systematically evaluated so that an optimal standard-operating-procedure could be identified. To evaluate the inherent variability of the proposed methodology samples were tested at multiple sites, using different instruments and operators. The ranking of the flow properties of the powders obtained was also compared with that obtained using a conventional shear-cell test. As a result of these experiments a quick, simple, and rugged procedure for determining the flow properties of pharmaceutical powders in their dilated state was developed. This procedure gave comparable results when performed at four different testing sites and was able to reproducibly rank the flow properties of a series of common pharmaceutical excipient powders. The limits of the test method to discriminate between different powder samples were determined, and a positive correlation with the results of a benchmark method (the simplified shear cell) was obtained.