Tale of Two Polymorphs: Investigating the Structural Differences and Dynamic Relationship between Nirmatrelvir Solid Forms (Paxlovid).

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 ∼17 °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.

Surface acidity and solid-state compatibility of excipients with an acid-sensitive API: case study of atorvastatin calcium.

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.

A Commentary on Co-Processed API as a Promising Approach to Improve Sustainability for the Pharmaceutical Industry.

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.

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.

Titanium Dioxide (E171 Grade) and the Search For Replacement Opacifiers and Colorants: Supplier Readiness Survey, Case Studies and Regulatory Perspective.

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.

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 Role of Titanium Dioxide (E171) and the Requirements for Replacement Materials in Oral Solid Dosage Forms: An IQ Consortium Working Group Review.

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.

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.

Quantification of Tribocharging of Pharmaceutical Powders in V-Blenders: Experiments, Multiscale Modeling, and Simulations.

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.

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.