RESUMEN
Two anhydrous polymorphs of the novel antiviral medicine nirmatrelvir were discovered during the development of Paxlovid, Pfizer's oral Covid-19 treatment. A comprehensive experimental and computational approach was necessary to distinguish the two closely related polymorphs, herein identified as Forms 1 and 4. This approach paired experimental methods, including powder X-ray diffraction and single-crystal X-ray diffraction, solid-state experimental methods, thermal analysis, solid-state nuclear magnetic resonance and Raman spectroscopy with computational investigations comprising crystal structure prediction, Gibbs free energy calculations, and molecular dynamics simulations of the polymorphic transition. Forms 1 and 4 were ultimately determined to be enantiotropically related polymorphs with Form 1 being the stable form above the transition temperature of â¼17 °C and designated as the nominated form for drug development. The work described in this paper shows the importance of using highly specialized orthogonal approaches to elucidate the subtle differences in structure and properties of similar solid-state forms. This synergistic approach allowed for unprecedented speed in bringing Paxlovid to patients in record time amidst the pandemic.
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Antivirales , Tratamiento Farmacológico de COVID-19 , Cristalización , Simulación de Dinámica Molecular , Difracción de Rayos X , Antivirales/química , Difracción de Rayos X/métodos , Cristalografía por Rayos X/métodos , Espectroscopía de Resonancia Magnética/métodos , Espectrometría Raman/métodos , SARS-CoV-2/efectos de los fármacos , Temperatura de TransiciónRESUMEN
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.
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Titanium dioxide (TiO2) is used primarily as an opacifier in solid dosage forms and is present in the majority of tablet and capsule dosage forms on the market. The IQ* TiO2 Working Group has previously shown that titanium dioxide has unique properties which are necessary for its function in these formulations and noted that, as the potential replacements lack the semi-conductor properties, high refractive index and whiteness of E171, it might be hard to replicate these properties with alternative materials. In this paper we detail the results of readiness surveys and practical assessments that have been conducted with alternative materials by IQ member companies. A range of technical challenges and regulatory hurdles were identified which mean that, in the short term, it may be difficult to replace titanium dioxide with the currently available alternative materials while readily achieving the same drug product quality attributes, especially for some of the marketed formulations that titanium dioxide is currently used for. We note the higher technical complexity, due to the variability, color fading and identified scale up risk, of E171 free film coatings and the likely impact on development costs and timelines. We also highlight several regulatory hurdles that would have to be overcome if a titanium dioxide replacement was required for some markets but was not mandated by others.
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Nanopartículas , Titanio , Tamaño de la Partícula , Aditivos AlimentariosRESUMEN
Pharmaceutical products represent a meaningful target for sustainability improvement and emissions reduction. It is proposed here that rethinking the standard, and often linear, approach to the synthesis of Active Pharmaceutical Ingredients (API) and subsequent formulation and drug product processing will deliver transformational sustainability opportunities. The greatest potential arguably involves API that have challenging physico-chemical properties. These can require the addition of excipients that can significantly exceed the weight of the API in the final dosage unit, require multiple manufacturing steps to achieve materials amenable to delivering final dosage units, and need highly protective packaging for final product stability. Co-processed API are defined as materials generated via addition of non-covalently bonded, non-active components during drug substance manufacturing steps, differing from salts, solvates and co-crystals. They are an impactful example of provocative re-thinking of historical regulatory and quality precedents, blurring drug substance and drug product operations, with sustainability opportunities. Successful examples utilizing co-processed API can modify properties with use of less excipient, while simultaneously reducing processing requirements by delivering material amenable to continuous manufacturing. There are also opportunities for co-processed API to reduce the need for highly protective packaging. This commentary will detail the array of sustainability impacts that can be delivered, inclusive of business, regulatory, and quality considerations, with discussion on potential routes to more comprehensively commercialize co-processed API technologies.
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Química Farmacéutica , Industria Farmacéutica , Tecnología Farmacéutica , Embalaje de Medicamentos , Excipientes/química , Preparaciones FarmacéuticasRESUMEN
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.
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Química Farmacéutica , Excipientes , Excipientes/químicaRESUMEN
Titanium dioxide (in the form of E171) is a ubiquitous excipient in tablets and capsules for oral use. In the coating of a tablet or in the shell of a capsule the material disperses visible and UV light so that the contents are protected from the effects of light, and the patient or caregiver cannot see the contents within. It facilitates elegant methods of identification for oral solid dosage forms, thus aiding in the battle against counterfeit products. Titanium dioxide ensures homogeneity of appearance from batch to batch fostering patient confidence. The ability of commercial titanium dioxide to disperse light is a function of the natural properties of the anatase polymorph of titanium dioxide, and the manufacturing processes used to produce the material utilized in pharmaceuticals. In some jurisdictions E171 is being considered for removal from pharmaceutical products, as a consequence of it being delisted as an approved colorant for foods. At the time of writing, in the view of the authors, no system or material which could address both current and future toxicological concerns of Regulators and the functional needs of the pharmaceutical industry and patients has been identified. This takes into account the assessment of materials such as calcium carbonate, talc, isomalt, starch and calcium phosphates. In this paper an IQ Consortium team outlines the properties of titanium dioxide and criteria to which new replacement materials should be held.
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Excipientes , Talco , Carbonato de Calcio , Aditivos Alimentarios/química , Humanos , Almidón , Comprimidos , Titanio/químicaRESUMEN
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.
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Alcoholes Grasos , Poloxámero , Anciano , Niño , Excipientes , Humanos , Poloxámero/química , SolubilidadRESUMEN
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.
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Polvos/química , Tecnología Farmacéutica/métodos , Química Farmacéutica/métodos , Fricción , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
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.
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Preparaciones Farmacéuticas/química , Cristalización , Modelos Químicos , Conformación Molecular , Conformación Proteica , Proteínas/química , TemperaturaRESUMEN
Pharmaceutical powders are very prone to electrostatic charging by colliding and sliding contacts. In pharmaceutical formulation processes, particle charging is often a nuisance and can cause problems in the manufacture of products, such as affecting powder flow, fill, and dose uniformity. For a fundamental understanding of the powder triboelectrification, it is essential to study charge transfer under well-defined conditions. Hence, all experiments in the present study were conducted in a V-blender located inside a glove box with a controlled humidity of 20%. To understand tribocharging, different contact surfaces, namely aluminum, Teflon, poly methyl methacrylate, and nylon were used along with 2 pharmaceutical excipients and 2 drug substances. For the pharmaceutical materials, the work function values were estimated using MOPAC, a semiempirical molecular orbital package which has been previously used for the solid-state studies and molecular structure predictions. For a mechanistic understanding of tribocharging, a discrete element model incorporating charge transfer and electrostatic forces was developed. An effort was made to correlate tribocharging of pharmaceutical powders to properties such as cohesive energy density and surface energy. The multiscale model used is restricted as it considers only spherical particles with smooth surfaces. It should be used judiciously for other experimental assemblies because it does not represent a full validation of a tightly integrated model.
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Composición de Medicamentos/instrumentación , Polvos/química , Simulación por Computador , Diseño de Equipo , Excipientes/química , Humedad , Lactosa/química , Modelos Químicos , Preparaciones Farmacéuticas/química , Electricidad Estática , Propiedades de SuperficieRESUMEN
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.
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Excipientes/química , Química Farmacéutica/métodos , Electrones , Fricción , Polvos/química , Electricidad Estática , Tecnología Farmacéutica/métodosRESUMEN
The objectives of this study were to measure the apparent surface acidity of common excipients and to correlate the acidity with the chemical stability of an acid-sensitive active pharmaceutical ingredient (API) in binary API-excipient powder mixtures. The acidity of 26 solid excipients was determined by two methods, (i) by measuring the pH of their suspensions or solutions and (ii) the pH equivalent (pHeq) measured via ionization of probe molecules deposited on the surface of the excipients. The chemical stability of an API, atorvastatin calcium (AC), in mixtures with the excipients was evaluated by monitoring the appearance of an acid-induced degradant, atorvastatin lactone, under accelerated storage conditions. The extent of lactone formation in AC-excipient mixtures was presented as a function of either solution/suspension pH or pHeq. No lactone formation was observed in mixtures with excipients having pHeq > 6, while the lactone levels were pronounced (> 0.6% after 6 weeks at 50°C/20% RH) with excipients exhibiting pHeq < 3. The three pHeq regions (> 6, 3-6, and < 3) were consistent with the reported solution pH-stability profile of AC. In contrast to the pHeq scale, lactone formation did not show any clear trend when plotted as a function of the suspension/solution pH. Two mechanisms to explain the discrepancy between the suspension/solution pH and the chemical stability data were discussed. Acidic excipients, which are expected to be incompatible with an acid-sensitive API, were identified based on pHeq measurements. The incompatibility prediction was confirmed in the chemical stability tests using AC as an example of an acid-sensitive API.
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Atorvastatina/química , Excipientes/química , Química Farmacéutica/métodos , Estabilidad de Medicamentos , Concentración de Iones de Hidrógeno , Soluciones Farmacéuticas/química , Polvos/química , Suspensiones/químicaRESUMEN
The mechanical properties of a solid dosage, defined by its granular micro-structure and geometry, play a key role in its dissolution profile and performance. An ultrasonic method for extracting the viscoelastic material properties and granular structure of drug tablet compacts is introduced and its utility is demonstrated for tablet compacts made of microcrystalline cellulose (MCC), lactose monohydrate, and sodium starch glycolate as well as magnesium stearate as lubricant. The approach is based on the effect of viscoelasticity and internal micro-structures on the frequency-dependent attenuation of an ultrasonic wave propagating in a granular medium. The models for viscoelastic (a two-parameter Zener model) and scattering attenuation (Rayleigh model) mechanisms are employed. The material parameters including viscoelastic and scattering parameters (average Young's modulus, stress and strain relaxation time constants, and the Rayleigh scattering material parameter) and grain size distribution with a known distribution profile are extracted by an optimization algorithm based on the least square method. The results also indicate good agreement between experimentally and computationally determined phase and group velocities in compacted samples. It is found that the effects of both attenuation mechanisms are present and the extracted grain size distribution parameters are in good agreement with the optically determined values.
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Excipientes/química , Tecnología Farmacéutica/métodos , Ultrasonido , Algoritmos , Celulosa/química , Química Farmacéutica , Módulo de Elasticidad , Elasticidad , Lactosa/química , Análisis de los Mínimos Cuadrados , Lubricantes/química , Modelos Químicos , Estructura Molecular , Tamaño de la Partícula , Dispersión de Radiación , Almidón/análogos & derivados , Almidón/química , Ácidos Esteáricos/química , Estrés Mecánico , Comprimidos , Tecnología Farmacéutica/instrumentación , Transductores , Ultrasonido/instrumentación , ViscosidadRESUMEN
Responses from the second Product Quality Research Institute (PQRI) Blend Uniformity Working Group (BUWG) survey of industry have been reanalyzed to identify potential links between formulation and processing variables and the measured uniformity of blends and unit dosage forms. As expected, the variability of the blend potency and tablet potency data increased with a decrease in the loading of the active pharmaceutical ingredient (API). There was also an inverse relationship between the nominal strength of the unit dose and the blend uniformity data. The data from the PQRI industry survey do not support the commonly held viewpoint that granulation processes are necessary to create and sustain tablet and capsule formulations with a high degree of API uniformity. There was no correlation between the blend or tablet potency variability and the type of process used to manufacture the product. Although it is commonly believed that direct compression processes should be avoided for low API loading formulations because of blend and tablet content uniformity concerns, the data for direct compression processes reported by the respondents to the PQRI survey suggest that such processes are being used routinely to manufacture solid dosage forms of acceptable quality even when the drug loading is quite low.
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Composición de Medicamentos/métodos , Cápsulas/química , Excipientes/química , Preparaciones Farmacéuticas/química , Control de Calidad , Comprimidos/químicaRESUMEN
The mechanical properties of a drug tablet can affect its performance (e.g., dissolution profile and its physical robustness. An ultrasonic system for real-time in-die tablet mechanical property monitoring during compaction has been demonstrated. The reported set-up is a proof of concept compaction monitoring system which includes an ultrasonic transducer mounted inside the upper punch of the compaction apparatus. This upper punch is utilized to acquire ultrasonic pressure wave phase velocity waveforms and extract the time-of-flight of pressure waves travelling within the compact at a number of compaction force levels during compaction. The reflection coefficients for the waves reflecting from punch tip-powder bed interface are extracted from the acquired waveforms. The reflection coefficient decreases with an increase in compaction force, indicating solidification. The data acquisition methods give an average apparent Young's moduli in the range of 8-20 GPa extracted during the compaction and release/decompression phases in real-time. A monitoring system employing such methods is capable of determining material properties and the integrity of the tablet during compaction. As compared to the millisecond time-scale dwell time of a typical commercial compaction press, the micro-second pulse duration and ToF of an acoustic pulse are sufficiently fast for real-time monitoring.
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Acústica , Sistemas de Computación , Composición de Medicamentos/instrumentación , Comprimidos/química , Celulosa/química , Módulo de Elasticidad , Excipientes/química , Lactosa/química , Control de Calidad , Tecnología Farmacéutica/instrumentaciónRESUMEN
We analyze the scaling properties of the Hertz-Kuwabara-Kono (HKK) model, which is commonly used in numerical simulations to describe the collision of macroscopic noncohesive viscoelastic spherical particles. Parameters describing the elastic and viscous properties of the material, its density, and the size of the colliding particles affect the restitution coefficient É and collision time τ only via appropriate rescaling but do not change the shape of É(v) and τ(v) curves, where v is the impact velocity. We have measured the restitution coefficient experimentally for relatively large (1 cm) particles of microcrystalline cellulose to deduce material parameters and then to predict collision properties for smaller microcrystalline cellulose (MCC) particles by assuming the scaling properties of the HKK model. In particular, we demonstrate that the HKK model predicts the restitution coefficient of microscopic particles of about 100 µm to be considerably smaller than that of the macroscopic particles. In fact, the energy dissipation is so large that only completely inelastic collisions occur for weakly attractive particles. We propose a straightforward self-consistent extension to the Johnson-Kendall-Roberts (JKR) model to include dissipative forces and discuss the implications of our findings for the behavior of experimental powder systems.