Modeling the Structure of Ketoprofen-Poly(vinylpyrrolidone) Amorphous Solid Dispersions with Empirical Potential Structure Refinements of X-ray Scattering Data.

The metastability of amorphous formulations poses barriers to their safe and widespread commercialization. The propensity of amorphous solid dispersions (ASDs) to crystallize is directly linked to their molecular structure. Amorphous structures are inherently complex and thus difficult to fully characterize by experiments, which makes structural simulations an attractive route for investigating which structural characteristics correlate with ASD stability. In this study, we use empirical potential structure refinement (EPSR) to create molecular models of ketoprofen-poly(vinylpyrrolidone) (KTP/PVP) ASDs with 0-75 wt % drug loading. The EPSR technique uses X-ray total scattering measurements as constraints, yielding models that are consistent with the X-ray data. We perform several simulations to assess the sensitivity of the EPSR approach to input parameters such as intramolecular bond rotations, PVP molecule length, and PVP tacticity. Even at low drug loading (25 wt %), ∼40% of KTP molecules participate in KTP-KTP hydrogen bonding. The extent of KTP-PVP hydrogen bonding does not decrease significantly at higher drug loadings. However, the models' relative uncertainties are too large to conclude whether ASDs' lower stabilities at high drug loadings are due to changes in drug-excipient hydrogen bonding or a decrease in steric hindrance of KTP molecules. This study illustrates how EPSR, combined with total scattering measurements, can be a powerful tool for investigating structural characteristics in amorphous formulations and developing ASDs with improved stability.

Accelerated Development of Pharmaceuticals Past, Present, and Future.

This paper reviews the accelerated development of pharmaceuticals, exploring past, present, and future perspectives. It provides a historical overview of early strategies used to expedite development, beginning with initiatives from the 1990s. The work of Gardner and Byrn in accelerated development analysis during this era is highlighted. The narrative progresses to the 2000s, discussing the emergence of PK/PD in accelerating pharmaceutical development. The paper further examines case studies in the accelerated development field, including the INDIGO and Chorus programs. It concludes with an analysis of the current state of the field, referencing the NIPTE conference, which focused on the industrial perspective of accelerated development. Additionally, the paper outlines strategies for the rapid development of Solid Lipid Nanoparticle manufacturing and vaccine production.

A Quality by Design Approach for Optimizing Solid Lipid Nanoparticles of Bedaquiline for Improved Product Performance.

Bedaquiline (BQ) solid lipid nanoparticles (SLNs), which have previously been formulated for parenteral administration, have a risk of patient non-compliance in treating tuberculosis. This research presents a strategy to develop BQ SLNs for oral delivery to improve patient adherence, The upper and lower levels for the formulation excipients were generated from screening experiments. Using 4 input factors (BQ, lecithin, Tween 80, and PEG), a full factorial design from 3 × 2x2 × 2 experiments was randomly arranged to investigate 3 response variables: Particle size distribution (PSD), polydispersity index (PdI), and zeta potential (ZP). High shear homogenization was used to mix the solvent and aqueous phases, with 15% sucrose as a cryoprotectant. The response variables were assessed using a zeta sizer while TEM micrographs confirmed the PSD data. Solid-state assessments were conducted using powdered X-ray diffraction and scanning electron microscopy (SEM) imaging. A comparative invitro assessment was used to determine drug release from an equivalent dose of BQ free base powder and BQ-SLN, both packed in hard gelatin capsules. The sonicated formulations obtained significant effects for PSD, PdI, and ZP. The p-values (0.0001 for PdI, 0.0091 for PSD) for BQ as an independent variable in the sonicated formulation were notably higher than those in the unsonicated formulation (0.1336 for PdI, 0.0117 for PSD). The SEM images were between 100 - 400 nm and delineated nanocrystals of BQ embedded in the lipid matrix. The SLN formulation provides higher drug levels over the drug's free base; a similarity factor (f2 = 18.3) was estimated from the dissolution profiles.

The Identification of Quality Risk Factors for Non-biological Complex Drugs and Epilepsy Drugs Using Statistical Analysis of Formulation-Based Recalls in the USA.

Pharmaceutical companies use the quality by design (QbD) approach to build high-quality drug products. A thorough understanding of risk factors is required to successfully employ QbD. In order to better understand risk factors that potentially impact drug product quality and inform future QbD approaches, we hypothesized root causes of drug product recalls based on publicly available data and a retroactive analysis of drug products recalled by the United States Food and Drug Administration (USFDA) from 2012 to 2018. We focused on two categories of drug products that pose unique regulatory challenges and an increased risk of shortage that could hinder the adequate supply of quality medicine to the patient. Knowing the significant risk factors from previous drug product recalls can help inform QbD and avoid future recalls. Quality recall reasons were studied individually to find risk factors associated with each recall category. Logistical regression statistical tests were done in R using a significance level of 0.05 to find correlations between a recalled product and its manufacturing information such as excipients and manufacturing steps. The results showed significant positive and negative correlations, such as products containing magnesium stearate are more likely to be recalled for impurities and degradation. This information could be used in the future to inform the design and manufacturing of drug products, ensuring consumers receive high-quality products with a low risk of recall.

Atomic-Level Drug Substance and Polymer Interaction in Posaconazole Amorphous Solid Dispersion from Solid-State NMR.

Despite the wide utilization of amorphous solid dispersions (ASDs) for formulating poorly water-soluble drugs, fundamental understanding of the structural basis behind their stability and dissolution behavior is limited. This is largely due to the lack of high-resolution structural tools for investigating multicomponent and amorphous systems in the solid state. In this study, we present what is likely the first publication quantifying the molecular interaction between the drug and polymer in ASDs at an angstrom level by utilizing 19F magic angle spinning (MAS) nuclear magnetic resonance (NMR) techniques. A variant of the 19F-13C rotational-echo and double-resonance (REDOR) technique was developed to quantify interatomic distances by implementing a supercycled symmetry-based recoupling schedule and synchronized simultaneous detection. We successfully deployed the technique to identify "head-to-head" and "head-to-tail" packing of crystalline posaconazole (POSA). To probe molecular interactions between POSA and hypromellose acetate succinate (HPMCAS) in the dispersion, as a major goal of this study, two-dimensional (2D) 1H-19F correlation experiments were performed. The approach facilitated observation of intermolecular hydrogen-to-fluorine contacts between the hydroxyl group of the polymer and the difluorophenyl group of the drug substance. Atomic distance measurement, utilizing the developed 19F-13C REDOR technique, revealed the close proximity of 13COH-19F at 4.3 Å. Numerical modeling analysis suggested a possible hydrogen bonding interaction between the polymer O-H group as an acceptor and POSA fluorine (O-H···F) or difluorophenyl ring (O-H···Ph) as a donor. These 19F MAS NMR techniques, including 2D 19F-1H heteronuclear correlation and 19F-13C atomic distance measurement, may shed light on the nature (i.e., type and strength) of drug-polymer interactions in ASDs and offer a new high-resolution analytical protocol for probing the microstructure of amorphous pharmaceutical materials.

Molecular packing of pharmaceuticals analyzed with paramagnetic relaxation enhancement and ultrafast magic angle pinning NMR.

Understanding the relationship between the structure and the physicochemical attributes of crystalline pharmaceuticals requires high-resolution molecular details. Solid-state nuclear magnetic resonance (ssNMR) spectroscopy is an indispensable tool for analyzing molecular structures, but often experiences challenges of low spectral resolution and sensitivity, particularly in the characterization of unlabeled pharmaceutical materials. Besides, the relatively long spin-lattice relaxation times in pharmaceutical crystals result in time-consuming data collections. In this study, we utilize ultrafast magic angle spinning (UF-MAS) of the sample at 60 and 110 kHz to enable proton and fluorine spectroscopies for probing the structural details of crystalline posaconazole. Paramagnetic relaxation enhancement (PRE), obtained by doping Cu(ii) ions into the crystalline lattice and coating on particle surface, is implemented to shorten the spin-lattice relaxation time for speeding up the ssNMR acquisition. Our results demonstrate a remarkably improved 1H and 19F resolution and sensitivity, which enables multi-dimensional 1H-1H and heteronuclear 1H-19F correlations. In combination with density functional theory (DFT) calculations of chemical shifts, molecular details of posaconazole are established in terms of 1H and 19F networks for identifying "head-to-tail" and "head-to-head" intermolecular packings, with presumably critical contacts that stabilize the crystalline structure. The PRE and UF-MAS techniques enable the high-resolution structure characterization of fluorinated drug molecules in pharmaceutical formulations at natural abundance.

An Analytic Investigation of the Drug Formulation-Based Recalls in the USA: See More Beyond the Literal.

High numbers of drug recalls persist despite the tremendous time and effort invested by pharmaceutical organizations and regulatory bodies such as the Food and Drug Administration (FDA) to ensure the quality of safe and effective medicines for the patient. It is imperative to better understand the underlying risk factors of drug formulation-based recalls to best protect the patient from poor quality drugs. Increased knowledge of underlying factors of formulation risk can also help inform the future design and development of drugs. In this study, we used a text mining technique with Python to parse the data and examine drug recalls from the aspect of administration route, dosage form, release mechanism, market type, pharmacologic class, and excipients. Observational analysis of the recalls revealed both high- and low-risk factors for the formulation-based recalls. Higher risk, or an increased probability of a formulation-based recall, was associated with factors such as extended release mechanism, capsule dosage form, oral route of administration, and an increased number of excipients, while lower risk of formulation-based recalls was associated with other factors including the new drug application market type, immediate release mechanism, and solution dosage form. In addition, the factors did not work independently, and we observed interactions among variables. For example, the release mechanism modified the effect of market type, administration route, and dosage form. This study will help inform the future design of quality drug products by pharmaceutical organizations and assist risk-based oversight by regulatory organizations, such as FDA, to ensure patient safety.

Physical Barrier Type Abuse-Deterrent Formulations: Mechanistic Understanding of Sintering-Induced Microstructural Changes in Polyethylene Oxide Placebo Tablets.

The main goal of the presented work was to understand changes in the microstructure of tablets, as well as the properties of its main component viz. polyethylene oxide (PEO) as a function of sintering. Key polymer variables and sintering conditions were investigated, and sintering-induced increase in tablet tensile strength was evaluated. For the current study, binary-component placebo tablets comprised of varying ratios of PEO and anhydrous dibasic calcium phosphate (DCP) were prepared at two levels of tablet solid fraction. The prepared tablets were sintered in an oven at 80°C at different time points ranging from 10 to 900 min and were evaluated for pore size, tablet expansion (%), and PEO crystallinity. The results showed that for efficient sintering and a significant increase in the tablet tensile strength, a minimum of 50% w/w PEO was required. Moreover, all microstructural changes in tablets were found to occur within 60 min of sintering, with no significant changes occurring thereafter. Sintering also resulted in a decrease in PEO crystallinity, causing changes in polymer ductility. These changes in PEO ductility resulted in tablets with higher tensile strength. Formulation variables such as PEO level and PEO particle size distribution were found to be important influencers of the sintering process. Additionally, tablets with high initial solid fraction and sintering duration of 60 min were found to be optimal conditions for efficient sintering of PEO-based compacts. Finally, prolonged sintering times were not found to provide any additional benefits in terms of abuse-deterrent properties.

Pediatric Formulations: Knowledge Gaps Limiting the Expedited Preclinical to Clinical Translation in Children.

Traditionally, drug discovery and development research have been primarily focused on the mitigation of disease treatment for the general adult population, often overlooking the medical needs of pediatric patients. While remarkable progress toward the discovery of better medicines has been made, the pharmacological differences between children and adults are often neglected as part of the translation process. In fact, until recently, children have been considered therapeutic orphans due to the lack of significant drug discovery, formulation development, and dosage form design specifically tailored for pediatric patients. Perhaps the least understood is the significant physiological changes that occur during the maturation process from birth to adulthood. It requires careful considerations to achieve age-specific-desired therapeutic outcomes with minimal toxicity. This introduces considerable risk into the preclinical and clinical testing of new medicaments, which until recently, was avoided based on the conventional approach where a demonstration of safe and efficacious use in adults over several years potentially would minimize the chance of adverse juvenile responses. However, the lack of appropriate drug products for children has led to off-label use of adult medicines with potential life-threatening adverse reactions and health complications. Recent developments and future considerations regarding pediatric drug discovery and development using a patient-centric approach in the context of ontogenic biopharmaceutical considerations are discussed below.

Predictive and Accelerated Formulation Design Using Synchrotron Methods.

Predictive formulation design and accelerated formulation design can lead to the discovery of useful formulations to support drug clinical studies and successful drug approval. Predictive formulation design can also lead to discovery of a path for commercialization, especially for poorly soluble drugs, when the target product profile is well defined and a "learning before doing" approach is implemented. One of the key components of predictive/accelerated formulation design is to understand and leverage the material properties of drug substance including solubility, BCS classification, polymorphs, salt formation, amorphous form, amorphous complex, and stability. In addition, utilizing synchrotron-based PDF (pair distribution function) analysis can provide important structural information for the formulation. This knowledge allows control of physical and chemical stability of the designed product. Finally, formulation design should link to process development following Quality by Design principles, and solid-state chemistry should play a critical role in many of the steps required to achieve Quality by Design, which can lead to successful product development.

Investigating the Physicochemical Stability of Highly Purified Darunavir Ethanolate Extracted from PREZISTA® Tablets.

Understanding physicochemical stability of darunavir ethanolate is expected to be of critical importance for the development and manufacturing of high-quality darunavir-related pharmaceutical products. However, there are no enabling monographs for darunavir to illustrate its solid-state chemistry, impurity profile, and assay methods. In addition, the US Pharmacopeia reference standard of darunavir is still not commercially available. It has been also challenging to find reliable vendors to obtain highly purified darunavir ethanolate crystals to conduct the physicochemical stability testing. In the present research, we developed a straightforward and cost-effective approach to extract and purify darunavir ethanolate from PREZISTA® tablets using reverse-engineering and crystallization. Using these highly purified crystals, we thoroughly evaluated the potential risks of degradation and form conversions of darunavir ethanolate at stressed conditions to define the manufacturing and packaging specifications for darunavir-related products. Amorphization was observed under thermal storage caused by desolvation of darunavir ethanolate. The ethanolate-to-hydrate conversion of darunavir was observed at high relative humidity conditions. Moreover, acid/base-induced degradations of darunavir have been investigated herein to determine the possible drug-excipient compatibility issues in formulations. Furthermore, it is of particular interests to allow the production of high-quality darunavir-ritonavir fixed dose combinations for marketing in Africa. Thus, a validated HPLC method was developed according to ICH guideline to simultaneously quantify assays of darunavir and ritonavir in a single injection. In summary, the findings of this study provide important information for pharmaceutical scientists to design and develop reliable formulations and processings for darunavir-related products with improved stability.

Impact of Supramolecular Aggregation on the Crystallization Kinetics of Organic Compounds from the Supercooled Liquid State.

Despite numerous challenges in their theoretical description and practical implementation, amorphous drugs are of growing importance to the pharmaceutical industry. One such challenge is to gain molecular level understanding of the propensity of a molecule to form and remain as a glassy solid. In this study, a series of structurally similar diarylamine compounds was examined to elucidate the role of supramolecular aggregation on crystallization kinetics from supercooled liquid state. The structural similarity of the compounds makes it easier to isolate the molecular features that affect crystallization kinetics and glass forming ability of these compounds. To examine the role of hydrogen-bonded aggregation and motifs on crystallization kinetics, a combination of thermal and spectroscopic techniques was employed. Using variable temperature FTIR, Raman, and solid-state NMR spectroscopies, the presence of hydrogen bonding in the melt and glassy state was examined and correlated with observed phase transition behaviors. Spectroscopic results revealed that the formation of hydrogen-bonded aggregates involving carboxylic acid and pyridine nitrogen (acid-pyridine aggregates) between neighboring molecules in the melt state impedes crystallization, while the presence of carboxylic acid dimers (acid-acid dimers) in the melt favors crystallization. This study suggests that glass formation of small molecules is influenced by the type of intermolecular interactions present in the melt state and the kinetics associated with the molecules to assemble into a crystalline lattice. For the compounds that form acid-pyridine aggregates, the formation of energy degenerate chains, produced due to conformational flexibility of the molecules, presents a kinetic barrier to crystallization. The poor crystallization tendency of these aggregates stems from the highly directional hydrogen-bonding interactions needed to form the acid-pyridine chains. Conversely, for the compounds that form acid-acid dimers, the nondirectional van der Waals forces needed to construct a nucleus promote rapid assembly and crystallization.

Stability of pharmaceutical salts in solid oral dosage forms.

Using pharmaceutical salts in solid dosage forms can raise stability concerns, especially salt dissociation which can adversely affect the product performance. Therefore, a thorough understanding of the salt instability encountered in solid-state formulations is imperative to ensure the product quality. The present article uses the fundamental theory of acid base, ionic equilibrium, relationship of pH and solubility as a starting point to illustrate and interpret the salt formation and salt disproportionation in pharmaceutical systems. The criteria of selecting the optimal salt form and the underlying theory of salt formation and disproportionation are reviewed in detail. Factors influencing salt stability in solid dosage forms are scrutinized and discussed with the case studies. In addition, both commonly used and innovative strategies for preventing salt dissociations in formulation, on storage and during manufacturing will be suggested herein. This article will provide formulation scientists and manufacturing engineers an insight into the mechanisms of salt disproportionation and salt formation, which can help them to avoid and solve the instability issues of pharmaceutical salts in the product design.

Structural Properties, Order-Disorder Phenomena, and Phase Stability of Orotic Acid Crystal Forms.

Orotic acid (OTA) is reported to exist in the anhydrous (AH), monohydrate (Hy1), and dimethyl sulfoxide monosolvate (SDMSO) forms. In this study we investigate the (de)hydration/desolvation behavior, aiming at an understanding of the elusive structural features of anhydrous OTA by a combination of experimental and computational techniques, namely, thermal analytical methods, gravimetric moisture (de)sorption studies, water activity measurements, X-ray powder diffraction, spectroscopy (vibrational, solid-state NMR), crystal energy landscape, and chemical shift calculations. The Hy1 is a highly stable hydrate, which dissociates above 135 °C and loses only a small part of the water when stored over desiccants (25 °C) for more than one year. In Hy1, orotic acid and water molecules are linked by strong hydrogen bonds in nearly perfectly planar arranged stacked layers. The layers are spaced by 3.1 Å and not linked via hydrogen bonds. Upon dehydration the X-ray powder diffraction and solid-state NMR peaks become broader, indicating some disorder in the anhydrous form. The Hy1 stacking reflection (122) is maintained, suggesting that the OTA molecules are still arranged in stacked layers in the dehydration product. Desolvation of SDMSO, a nonlayer structure, results in the same AH phase as observed upon dehydrating Hy1. Depending on the desolvation conditions, different levels of order-disorder of layers present in anhydrous OTA are observed, which is also suggested by the computed low energy crystal structures. These structures provide models for stacking faults as intergrowth of different layers is possible. The variability in anhydrate crystals is of practical concern as it affects the moisture dependent stability of AH with respect to hydration.

Impact of Metallic Stearates on Disproportionation of Hydrochloride Salts of Weak Bases in Solid-State Formulations.

Excipient-induced salt disproportionation (conversion from salt form to free form) in the solid state during storage or manufacturing is a severe formulation issue that can negatively influence product performance. However, the role of excipient properties on salt disproportionation and mechanisms of proton transfer between salt and excipients are still unclear. Moreover, knowledge about the formation of disproportionation products and the consequent impact of these reactions products on the disproportionation process is still inadequate. In the present study, three commonly used lubricants (sodium stearate, calcium stearate, and magnesium stearate) were mixed with a hydrochloride salt as binary mixtures to examine their different capabilities for inducing salt disproportionation at a stressed storage condition (40 °C/65% RH). The overall objective of this research is to explore factors influencing the kinetics and extent of disproportionation including surface area, alkalinity, hygroscopicity, formation of new species, etc. In addition, we also aim to clarify the reaction mechanism and proton transfer between the model salt and stearates to provide insight into the in situ formed reaction products. We found that the properties of stearates significantly affect the disproportionation process in the initial stage of storage, while properties of the reaction products negatively affect the hygroscopicity of the powder mixture promoting disproportionation during longer-term storage. In addition, lubrication difference among three stearates was evaluated by performing compaction studies. The findings of this study provide an improved understanding of the proton transfer mechanism between the ionized form of an active pharmaceutical ingredient and excipients in solid dosage forms. It also provides pragmatic information for formulation scientists to select appropriate lubricants and other excipients, and to design robust formulations.

Solid-State Spectroscopic Investigation of Molecular Interactions between Clofazimine and Hypromellose Phthalate in Amorphous Solid Dispersions.

It has been technically challenging to specify the detailed molecular interactions and binding motif between drugs and polymeric inhibitors in the solid state. To further investigate drug-polymer interactions from a molecular perspective, a solid dispersion of clofazimine (CLF) and hypromellose phthalate (HPMCP), with reported superior amorphous drug loading capacity and physical stability, was selected as a model system. The CLF-HPMCP interactions in solid dispersions were investigated by various solid state spectroscopic methods including ultraviolet-visible (UV-vis), infrared (IR), and solid-state NMR (ssNMR) spectroscopy. Significant spectral changes suggest that protonated CLF is ionically bonded to the carboxylate from the phthalyl substituents of HPMCP. In addition, multivariate analysis of spectra was applied to optimize the concentration of polymeric inhibitor used to formulate the amorphous solid dispersions. Most interestingly, proton transfer between CLF and carboxylic acid was experimentally investigated from 2D 1H-1H homonuclear double quantum NMR spectra by utilizing the ultrafast magic-angle spinning (MAS) technique. The molecular interaction pattern and the critical bonding structure in CLF-HPMCP dispersions were further delineated by successfully correlating ssNMR findings with quantum chemistry calculations. These high-resolution investigations provide critical structural information on active pharmaceutical ingredient-polymer interaction, which can be useful for rational selection of appropriate polymeric carriers, which are effective crystallization inhibitors for amorphous drugs.

Investigating the Interaction Pattern and Structural Elements of a Drug-Polymer Complex at the Molecular Level.

Strong associations between drug and polymeric carriers are expected to contribute to higher drug loading capacities and better physical stability of amorphous solid dispersions. However, molecular details of the interaction patterns and underlying mechanisms are still unclear. In the present study, a series of amorphous solid dispersions of clofazimine (CLF), an antileprosy drug, were prepared with different polymers by applying the solvent evaporation method. When using hypromellose phthalate (HPMCP) as the carrier, the amorphous solid dispersion system exhibits not only superior drug loading capacity (63% w/w) but also color change due to strong drug-polymer association. In order to further explain these experimental observations, the interaction between CLF and HPMCP was investigated in a nonpolar volatile solvent system (chloroform) prior to forming the solid dispersion. We observed significant UV/vis and (1)H NMR spectral changes suggesting the protonation of CLF and formation of ion pairs between CLF and HPMCP in chloroform. Furthermore, nuclear Overhauser effect spectroscopy (NOESY) and diffusion order spectroscopy (DOSY) were employed to evaluate the strength of associations between drug and polymers, as well as the molecular mobility of CLF. Finally, by correlating the experimental values with quantum chemistry calculations, we demonstrate that the protonated CLF is binding to the carboxylate group of HPMCP as an ion pair and propose a possible structural model of the drug-polymer complex. Understanding the drug and carrier interaction patterns from a molecular perspective is critical for the rational design of new amorphous solid dispersions.

Relaxation Kinetic Study of Eudragit® NM30D Film Based on Complex Modulus Formalism.

This study is aimed at resolving and characterizing the primary (α) and secondary relaxations (ß) in Eudragit® NM30D film based on apparent activation energies derived from complex modulus formalism using dielectric analysis (DEA). The glass transition (T g) of the film was determined using differential scanning calorimetry (DSC). The α relaxation corresponding to T g and the ß relaxations occurring below T g were probed using DEA. The occurrence of α and ß relaxations in Eudragit® NM30D film was elucidated using the complex modulus of the dielectric response employing loss modulus and permittivity data. Activation energies of these relaxations and the fundamental frequency so determined support the assignment of the relaxation pattern in the Eudragit® NM30D film. DEA methodology of the complex modulus formalism is a useful tool for differentiating the α and ß relaxation kinetics in Eudragits® not easily studied using traditional thermal methods such as DSC. The kinetics associated with α and ß relaxations so determined will provide formulation design support for solid orals that incorporate Eudragit® polymers. As mobility changes can affect stability and diffusion, the dipolar α and ß relaxations revealed through DEA analysis may enable a better correlation to functionality of Eudragit® based pharmaceutical dosage forms.

Molecular structure of ketoprofen-polyvinylpyrrolidone solid dispersions prepared by different amorphization methods.

Amorphous solid dispersions (ASDs) are a widely studied formulation approach for improving the bioavailability of poorly water-soluble pharmaceuticals. Yet, a complete understanding remains lacking for how specific processing methods may influence ASDs' molecular structure. We prepare ketoprofen/polyvinylpyrrolidone (KTP/PVP) ASDs, ranging from 0-75 wt% KTP, using five different amorphization techniques: melt quenching, rotary evaporation with vacuum drying, spray drying, and acoustic levitation with either a premixed solution or in situ mixing of separate co-sprayed solutions. The co-spray levitation approach enables on-demand compositional changes in a containerless processing environment, while requiring minimal pharmaceutical material (∼1 mg). The structure of all ASDs are then compared using high-energy X-ray total scattering. X-ray pair distribution functions are similar for most ASDs of a given composition (Rx = 0.4-2.5%), which is consistent with them having similar intramolecular structure. More notably, differences in the X-ray structure factors for the various amorphization routes indicate differing extents of molecular mixing, a direct indication of their relative stability against crystallization. Melt quenching, spray drying, and levitation of premixed solutions exhibit some degree of molecular mixing, while the co-sprayed levitation samples have molecular arrangements like those of KTP/PVP physical mixtures. These findings illustrate how X-ray total scattering can be used to benchmark amorphous forms prepared by different techniques.

Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of Bedaquiline.

Bedaquiline has been approved as a combination therapy to treat multi-drug-resistant tuberculosis in adults ≥ 18 years old. The citrate, fumarate, phosphate, and tartrate salts have obtained patents, but the structures for these moieties have not been extensively described in the literature; only the powder X-ray patterns have been published. To expand the knowledge of the bedaquiline structure, this study provides detailed information for the synthesis, elucidation, characterization, and stability of four additional new potential molecular entities, namely, benzoate, hydrochloride (HCl), nicotinate, and malonate salts. The salts were formed using a 1:1 ratio of the counter ions (acids) to a 30 mg equivalent of the bedaquiline free base. The principles of the International Conference on Harmonization Q6 were used to characterize the new salts and their stability-indicating parameters were evaluated at 0, 3, and 6 months under accelerated conditions of 40 °C and 75% relative humidity. The benzoate salt exhibited the lowest tendency to lose its chemical potency. Aside from the HCl salt, the others retained their chemical structure, displaying long-term stability. All salts were non-hygroscopic and the hydrated benzoate and nicotinate salts were stable to dehydration. Regarding their chemical potencies, thermal analysis, chemical stability, and water sorption potential, the salts were ranked as follows: benzoate > malonate > nicotinate > HCl.