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Evaporation rates play a key role in evaporation crystallization and the drying of crystal products. Raman analysis was used to study the effect of the evaporation rate on the polymorphs of indomethacin at room temperature. The studied solvents were highly volatile ethanol, acetone, and ethyl acetate. The approach was based on a mass transfer model of evaporation, and experimental flux measurements were used for model evaluation. Evaporation rates from porous carriers were also investigated. The studied mesoporous silicon microparticles can be used in oral dosage forms of poorly soluble active pharmaceutical ingredients. Evaporation rates of dimethyl sulfoxide from a pure solvent, from indomethacin solutions, and from solutions containing microparticles were measured at 100 °C. An evaporation rate model of porous particles was used and the predicted results were compared with the experimental results obtained. [ABSTRACT FROM AUTHOR]

Abstract: The mean crystal size, the suspension density and the liquid concentration are the three most important process parameters to quantify the progress of industrial crystallization processes. It will be shown that these parameters can be in-line monitored simultaneously by means of an ultrasonic crystallization monitoring technique (UCM), which will be introduced here in a proof of concept. This process analytical technology (PAT) differs from the known ultrasonic attenuation spectroscopy (UAS). For the UCM the ultrasonic velocity and attenuation were correlated and related to characteristic events during a crystallization process measured at only one frequency (no spectra of frequencies as it is used for UAS). The results shown in this study prepare the ground to establish the UCM as a simple, less complex, robust, universal applicable, inexpensive and, therefore, a winning alternative PAT to monitor and control in-line the solid as well as the liquid phase in the industrial crystallization by means of only one measuring device with two sensors. [Copyright &y& Elsevier]

Attrition of crystals in industrial crystallization is the major source of secondary nucleation and has strong effects on product quality. This work describes attrition in industrial crystallizers using an empirical engineering model based on dimensionless groups describing crystal properties, suspension properties, and crystallizer geometry and operating conditions. Here the attrition rate of sodium chloride crystals in a small scale mixed-suspension crystallizer is studied, varying the following parameters: impeller speed, parent crystal size, suspension density, draft-tube impeller clearance, off-bottom impeller clearance, impeller type, and impeller material. It was found that the attrition rate depends on most of the variables investigated. The direction of the dependence is predictable based on intuitive modeling. An empirical power law model based on dimensionless groups predicted by Buckingham-Pi theory (using variables mentioned above) gives a good fit to the data. [ABSTRACT FROM AUTHOR]

Abstract: The coating of pharmaceutical compounds is a field of high interest. As most of the coating materials form an amorphous layer around the material, the studies on crystalline coatings are rare. In this work the progress in this domain should be summarized and innovative results concerning crystalline hollow needles as coating material are presented. Since the first reports on needles formed via a solvent-mediated phase transition from solvates to hydrates, the field could be widened to hydrate-to-anhydrate and anhydrate-to-hydrate transformations. Novel investigations on hollow theophylline monohydrate and carbamazepine dihydrate needles are presented. It is shown that the inclusion of substances into the hollow needle crystals is feasible by simple means, which enable an application in industry as coating for sensitive materials. [Copyright &y& Elsevier]

A significant hurdle in untargeted lipid/metabolomics research lies in the absence of reliable, cross-validated spectral libraries, leading to a considerable portion of LC-MS features being labeled as unknowns. Despite continuous advancement in annotation tools and libraries, it is important to safeguard, publish and share acquired data through public repositories. Embracing this trend of data sharing not only promotes efficient resource utilization but also paves the way for future repurposing and in-depth analysis; ultimately advancing our comprehension of Covid-19 and other diseases. In this work, we generated an extensive MS-dataset of 39 Covid-19 infected patients versus age- and gender-matched 39 healthy controls. We implemented state of the art acquisition techniques including IDA and SWATH-DIA to ensure a thorough insight in the lipidome and metabolome, ensuring a repurposable dataset., (© 2024. The Author(s).)

Amorphous solid dispersions (ASDs) can be used to enhance the solubility and bioavailability of poorly soluble drugs. An ASD is often a ternary system containing a drug, a surfactant, and a polymer. Recent work on binary ASDs has observed significant differences between surface and bulk compositions, with impacts on wettability and stability. Here we investigate a ternary ASD composed of the antifungal posaconazole, the surfactant Span 80, and a dispersion polymer (PVP or PVP/VA). The surfactant loading was fixed at the typical level of 5 wt %, and the drug/polymer ratio was varied. We observed strong surface enrichment of the surfactant and simultaneous depletion of the drug. This effect is already pronounced in the binary drug-surfactant system and is enhanced by the addition of the polymers. Between the two polymers, the more hydrophilic PVP causes a stronger enhancement of the surface enrichment effect. These results demonstrate the impact of component interactions on the surface composition of ASDs and the performance.

Warfarin, an oral anticoagulant, has been used for decades to prevent thromboembolic events. The complex interplay between CYP2C9 and VKORC1 genotypes on warfarin PK and PD properties is not fully understood in special sub-groups of patients. This study aimed to externally validate a population pharmacokinetic/pharmacodynamic (PK/PD) model for the effect of warfarin on international normalized ratio (INR) and to evaluate optimal dosing strategies based on the selected covariates in Caribbean Hispanic patients. INR, and CYP2C9 and VKORC1 genotypes from 138 patients were used to develop a population PK/PD model in NONMEM. The structural definition of a previously published PD model for INR was implemented. A numerical evaluation of the parameter-covariate relationship was performed. Simulations were conducted to determine optimal dosing strategies for each genotype combinations, focusing on achieving therapeutic INR levels. Findings revealed elevated IC 50 for G/G, G/A, and A/A VKORC1 haplotypes (11.76, 10.49, and 9.22 mg/L, respectively), in this population compared to previous reports. The model-guided dosing analysis recommended daily warfarin doses of 3-5 mg for most genotypes to maintain desired INR levels, although subjects with combination of CYP2C9 and VKORC1 genotypes * 2/* 2-, * 2/* 3- and * 2/* 5-A/A would require only 1 mg daily. This research underscores the potential of population PK/PD modeling to inform personalized warfarin dosing in populations typically underrepresented in clinical studies, potentially leading to improved treatment outcomes and patient safety. By integrating genetic factors and clinical data, this approach could pave the way for more effective and tailored anticoagulation therapy in diverse patient groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Compact composite probes were identified as a priority to alleviate space constraints in miniaturized unit operations and pharmaceutical manufacturing platforms. Therefore, in this proof of principle study, a compact composite sensor array (CCSA) combining ultraviolet and near infrared features at four different wavelengths (280, 340, 600, 860 nm) in a 380 × 30 mm housing (length x diameter, 7 mm diameter at the probe head), was evaluated for its capabilities to monitor in situ concentration of solutions and suspensions via multivariate analysis using partial least squares (PLS) regression models. Four model active pharmaceutical ingredients (APIs): warfarin sodium isopropanol solvate (WS), lidocaine hydrochloride monohydrate (LID), 6-mercaptopurine monohydrate (6-MP), and acetaminophen (ACM) in their aqueous solution and suspension formulation were used for the assessment. The results demonstrate that PLS models can be applied for the CCSA prototype to measure the API concentrations with similar accuracy (validation samples within the United States Pharmacopeia (USP) limits), compared to univariate CCSA models and multivariate models for an established Raman spectrometer. Specifically, the multivariate CCSA models applied to the suspensions of 6-MP and ACM demonstrate improved accuracy of 63% and 31%, respectively, compared to the univariate CCSA models [1]. On the other hand, the PLS models for the solutions WS and LID showed a reduced accuracy compared to the univariate models [1]., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Ixodes ricinus is the most relevant vector for tick-borne diseases in Austria and responsible for the transmission of Borrelia burgdorferi sensu lato (s. l.), which causes Lyme borreliosis in humans; however, also other bacteria and protozoa can be found in ticks and have the potential of infecting people and animals. In this study we collected ticks in popular recreational areas in the city of Vienna in the years 2019 and 2020 and analyzed them for the presence of such putative pathogenic microorganisms. By using reverse line blot (RLB) hybridization we detected DNA of B. burgdorferi s. l., Rickettsia spp., Babesia spp., Candidatus Neoehrlichia mikurensis (CNM) and Anaplasma phagocytophilum. Moreover, we also screened them for the relapsing fever spirochete Borrelia miyamotoi employing real-time PCR. The most frequently detected pathogens were B. burgdorferi s. l. in 28.6% of the ticks in 2019 and 21.3% of the ticks in 2020. The genus Rickettsia was detected in 13.8% of the ticks from 2019 and only in 4.6% from 2020. Babesia spp. were detected in 5.7% in 2019 and 4.2% in 2020. Furthermore, we detected CNM in 4.0% (2019) and 5.6% (2020), A. phagocytophilum in 0.5% (2019) and 1.3% (2020) and finally B. miyamotoi in 3.3% (2019) and 1.7% (2020). Collectively, we show that various microorganisms are prevalent in ticks collected in Vienna and identify hotspots for B. miyamotoi, which we have detected for the first time in the city., (© 2022. The Author(s).)

Few publications exist concerning polymorphic control during melt crystallization, particularly when employing heteronucleants. Here, the influence of a polymeric thin film (polyethylene terephthalate, PET) on the crystallization from melt of the polymorphic compound acetaminophen (ACM) in polyethylene glycol (PEG) was investigated. Molten ACM-PEG at different compositions was monitored using in situ Raman spectroscopy for nucleation induction time measurements and phase identification. Furthermore, X-ray diffraction (XRD) served to analyze the preferred orientation (PO) of the pastilles (solidified melt droplets) on PET-coated and uncoated substrates. The results indicate that PET-coated substrates qualitatively accelerate the nucleation of ACM form II (ACM II) in PEG compared to uncoated glass substrates. Additionally, the occurrence of ACM II in PEG was increased by an average of 10% when crystallized on PET-coated substrates compared to uncoated substrates. Overall, these results suggest that ACM can interact through hydrogen bonding with the PET-coated substrate, leading to faster nucleation. This investigation illustrates the effect of PET-coated substrates in the selective crystallization of ACM II in PEG as crystalline solid dispersions (CSDs). Ultimately, the results suggest the implementation of polymeric heteronucleants in melt crystallization processes, specifically, in advanced polymer-based formulation processes for the enhanced polymorphic form control of pharmaceutical compounds in CSDs., Competing Interests: The authors declare no competing financial interest.

Solvent-mediated polymorphic transformations (SMPTs) employing nonconventional solvents (polymer melts) is an underexplored research topic that limits the application of polymer-based formulation processes. Acetaminophen (ACM), a widely studied active pharmaceutical ingredient (API), is known to present SMPTs spontaneously (<30 s) in conventional solvents such as ethanol. In situ Raman spectroscopy was employed to monitor the induction time for the SMPT of ACM II to I in polyethylene glycol (PEG) melts of different molecular weights ( M w , 4000, 10 000, 20 000, 35 000 g/mol). The results presented here demonstrate that the induction time for the SMPT of ACM II to I in PEG melts is driven by its diffusivity through the polymer melts. Compared to conventional solvents ( i.e. , ethanol) the mass transfer (diffusion coefficient, D ) in melts is significantly hindered ( D ethanol = 4.84 × 10 -9 m 2 /s > D PEGs = 5.32 × 10 -11 -8.36 × 10 -14 m 2 /s). Ultimately, the study proves that the induction time for the SMPT can be tuned by understanding the dispersant's physicochemical properties ( i.e. , η) and, thus, the D of the solute in the dispersant. This allows one to kinetically access and stabilize metastable forms or delay their transformations under given process conditions.

Amorphous formulations, increasingly employed to deliver poorly soluble drugs, generally contain surfactants to improve wetting and dissolution. These surfactants are often liquids and can potentially increase the mobility of the drug and reduce its stability, but little is known about this effect. Here we investigate the effect of four common nonionic surfactants (Tween 80, Span 80, Triton X-100, and Poloxamer 407) on the crystallization of amorphous nifedipine (NIF). We find that the surfactants significantly enhance the rates of crystal nucleation and growth even at low concentrations, by up to 2 orders of magnitude at 10 wt %. The surfactants tested show similar enhancement effects independent of their structural details and hydrophilic-lipophilic balance (HLB), suggesting that surfactant adsorption at solid/liquid interfaces does not play a major role in crystal nucleation and growth. Importantly, the surfactants accelerate crystal nucleation and growth by a similar factor. This result mirrors the previous finding that a polymer dopant in a molecular glass-former causes similar slowdown of nucleation and growth. These results indicate that nucleation and growth in a deeply supercooled liquid are both mobility-limited, and a dopant mainly functions as a mobility modifier (enhancer or suppressor depending on the dopant). The common surfactants tested are all mobility enhancers and destabilize the amorphous drug, and this negative effect must be managed using stabilizers such as polymers. The effect of surfactants on nucleation can be predicted from the effect on crystal growth and the crystallization kinetics of the pure system, using the same principle previously established for drug-polymer systems. We show how the independently measured nucleation and growth rates enable predictions of the overall crystallization rates.

Crystal nucleation rates have been measured in the supercooled melts of two richly polymorphic glass-forming liquids: ROY and nifedipine (NIF). ROY or 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile is known for its crystals of red, orange, and yellow colors and many polymorphs of solved structures (12). Of the many polymorphs, ON (orange needles) nucleates the fastest with the runner up (Y04) trailing by a factor of 10 3 when compared under the same mobility-limited condition, while the other unobserved polymorphs are slower yet by at least 5 orders of magnitude. Similarly, of the six polymorphs of NIF, γ' nucleates the fastest, β' is slower by a factor of 10, and the rest are slower yet by at least 5 decades. In both systems, the faster-nucleating polymorphs are not built from the lowest-energy conformers, while they tend to have higher energies and lower densities and thus greater similarity to the liquid phase by these measures. The temperature ranges of this study covered the glass transition temperature T g of each system, and we find no evidence that the nucleation rate is sensitive to the passage of T g . At the lowest temperatures investigated, the rates of nucleation and growth are proportional to each other, indicating that a similar kinetic barrier controls both processes. The classical nucleation theory provides an accurate description of the observed nucleation rates if the crystal growth rate is used to describe the kinetic barrier for nucleation. The quantitative rates of both nucleation and growth for the competing polymorphs enable prediction of the overall rate of crystallization and its polymorphic outcome.

Recent advancements have demonstrated the feasibility of refrigerator-sized pharmaceutical manufacturing platforms (PMPs) for integrated end-to-end manufacturing of active pharmaceutical ingredients (APIs) into formulated drug products. Unlike typical laboratory- or industrial-scale setups, PMPs present unique requirements for process analytical technology (PAT) with respect to versatility, flexibility, and physical size to fit into the PMP space constraints. In this proof of principle study, a novel compact composite sensor array (CCSA) combining ultraviolet (UV) and near infrared (NIR) features at four different wavelengths (280, 340, 600, 860 nm) with temperature measuring capability in a 380 × 30 mm housing (length x diameter, 7 mm diameter at the probe head), were evaluated. The results indicate that the CCSA prototype is capable of measuring the solution and suspension concentrations in aqueous formulations of four model APIs (warfarin sodium isopropanol solvate, lidocaine hydrochloride monohydrate, 6-mercaptopurine monohydrate, acetaminophen) in situ and in real-time with similar accuracy as an established Raman spectrometer commonly applied for method development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

With McCrone's famous statement in mind, we set out to investigate the polymorphic behavior of a small-molecule dual inhibitor of Rac and Cdc42, currently undergoing preclinical trials. Herein, we report the existence of two polymorphs for 9-ethyl-3-(5-phenyl-1H-1,2,3-triazol-3-yl)-9H-carbazole (MBQ-167). These were characterized by differential scanning calorimetry, thermogravimetric analysis, Raman and Infrared spectroscopy, as well as powder and single crystal X-ray diffraction. The results obtained from the thermal analysis revealed that MBQ-167 form II undergoes an exothermic phase transition to form I, making this the thermodynamically stable form. An examination of the Burger-Ramberger rules for assigning thermodynamic relationships in polymorphic pairs indicate that this system is monotropic. The structure elucidation reveals that these forms crystallize in the orthorhombic (Pbca) and monoclinic (P2 1 /n) space groups. A conformational analysis shows that the metastable form (form II) presents the most planar conformation along the significant torsion angles identified. Hirshfeld surface analysis confirms that van der Waals contacts are the primary interactions and only subtle differences in short contacts help differentiate each form. These findings support the notion that polymorphism is prevalent in organic molecules and that one should invest time and money probing possible polymorphs, particularly in early development as in the case of MBQ-167., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We previously isolated and cultivated the novel Rickettsia raoultii strain Jongejan. This prompted us to ask whether this strain is unique or more widely present in Austria. To assess this issue, we retrospectively screened ticks collected from dogs in 2008. Of these collected ticks, we randomly selected 75 (47 females and 28 males) Dermacentor reticulatus , 44 (21 females, 7 males, and 16 nymphs) Haemaphysalis concinna , and 55 (52 females and 3 males) ticks of the Ixodes ricinus complex. Subsequently, these ticks were individually screened for the presence of tick-borne pathogens using the reverse line blot hybridization assay. In our current study, we detected DNA from the following microbes in D. reticulatus : Anaplasma phagocytophilum , Borrelia lusitaniae , Borrelia spielmanii , Borrelia valaisiana , and R. raoultii , all of which were R. raoultii strain Jongejan. In H. concinna , we found DNA of a Babesia sp., Rickettsia helvetica , and an organism closely related to Theileria capreoli . Lastly, I. ricinus was positive for Anaplasma phagocytophilum , Borrelia afzelii , Borrelia burgdorferi sensu stricto, Borrelia garinii / Borrelia bavariensis , B. lusitaniae , B. spielmanii , B. valaisiana , Candidatus Neoehrlichia mikurensis, Rickettsia helvetica , Rickettsia monacensis , and Theileria ( Babesia ) microti DNA. The detection of DNA of the Babesia sp. and an organism closely related to Theileria capreoli , both found in H. concinna ticks, is novel for Austria.

The purpose of this study was to determine the role of Tctex1 (DYNLT1, dynein light chain-1) in the pathophysiology of glioblastoma (GBM). To this end, we performed immunohistochemical analyses on tissues from GBM patients ( n = 202). Tctex1 was additionally overexpressed in two different GBM cell lines, which were then evaluated in regard to their proliferative and invasive properties. We found that Tctex1 levels were significantly higher in GBM compared to healthy adjacent brain tissues. Furthermore, high Tctex1 expression was significantly associated with the short overall- ( p = 0.002, log-rank) and progression-free ( p = 0.028, log-rank) survival of GBM patients and was an independent predictor of poor overall survival in multivariate Cox-regression models. In vitro, Tctex1 promoted the metabolic activity, anchorage-independent growth and proliferation of GBM cells. This phenomenon was previously shown to occur via the phosphorylation of retinoblastoma protein (phospho-RB). Here, we found a direct and significant correlation between the levels of Tctex1 and phospho-RB (Ser807/801) in tissues from GBM patients ( p = 0.007, Rho = 0.284, Spearman's rank). Finally, Tctex1 enhanced the invasiveness of GBM cells and the release of pro-invasive matrix metalloprotease 2 (MMP2). These findings indicate that Tctex1 promotes GBM progression and therefore might be a useful therapeutic target in this type of cancer.

MBQ-167 is a novel, small-molecule dual inhibitor of Rac and Cdc42, small GTPases that are involved in cytoskeletal organization, cell cycle progression, and cell migration. In an in vivo mouse model, MBQ-167 has been shown to significantly reduce mammary tumor growth and metastasis and is currently undergoing preclinical studies for the treatment of metastatic cancer. To date, no solubility data have been reported for this compound. For this reason, the present study aims to determine the solubility of this compound in eight neat solvents (acetonitrile, 1-butanol, 2-butanol, ethanol, ethyl acetate, methanol, 1-propanol, and 2-propanol) and two binary solvent mixtures [ethyl acetate (2) + heptane (3) and ethanol (2) + water (3)] between the temperatures of 278.15 and 333.15 K. The results obtained employing the polythermal method show that the solubility of MBQ-167 increases with an increase in temperature in all neat solvents used within this study. Moreover, in the two binary solvent mixtures, the solubility of this compound increases with increasing temperature and decreases with an increasing mass fraction of the antisolvent (heptane or water). The experimental solubility data were correlated using the modified Apelblat and λ h model equations. The predicted solubility data acquired from the Apelblat and λ h model equations correlate well with the experimental solubility data as indicated by the low ARD % (≤1.8304 and ≤6.5366, respectively). No solvent-mediated polymorphic phase transitions were observed while performing the solubility studies, and no other solid forms were detected after the recrystallization in the solvents and solvent mixtures. The solubility data determined here can offer pathways to develop pharmaceutical crystallization processes that can further the translation of MBQ-167 into a clinical setting., Competing Interests: The authors declare the following competing financial interest(s): Dr. Cornelis P. Vlaar is co-inventor on patents awarded to the University of Puerto Rico related to MBQ-167. In addition, he holds shares in MBQ Pharma, which has licensed these patents from the University of Puerto Rico. The other authors declare no competing financial interest.

The relapsing fever group Borrelia miyamotoi is an emerging tick-borne pathogen. Diagnosis of infection is currently mainly based on serological methods detecting antibodies against B. miyamotoi glycerophosphodiester phosphodiesterase (GlpQ). Here, we scrutinized the reliability of GlpQ as a diagnostic marker and compared the seroprevalence in different study populations and by applying various immunoblotting methods. Antibodies were detected in the sera of 7/53 hunters and in 1/11 sera of Lyme neuroborreliosis patients. Furthermore, 17/74 sera of persons with high concentrations of anti-Borrelia burgdorferi sensu lato (α-Bbsl) antibodies reacted strongly with B. miyamotoi GlpQ in immunoblots. The B. miyamotoi GlpQ seroprevalence was 7/50 in α-Bbsl negative persons. In healthy blood donors from commercial suppliers and from the Austrian Red Cross, seroprevalences were 5/14 and 10/35, respectively. Strikingly, two B. miyamotoi PCR-positive cases from Austria had negative GlpQ serology, indicating poor sensitivity. Finally, when we analyzed sera of dogs, we found α- B. miyamotoi GlpQ antibody seroprevalence in tick-free dogs ( n = 10) and in tick-exposed dogs ( n = 19) with 2/10 and 8/19, respectively. Thus, our results indicate that GlpQ-based B. miyamotoi serology holds neither specificity nor sensitivity.

Objectives The inter-individual variability of warfarin dosing has been linked to genetic polymorphisms. This study was aimed at performing genotype-driven pharmacokinetic (PK) simulations to predict warfarin levels in Puerto Ricans. Methods Analysis of each individual dataset was performed by one-compartmental modeling using WinNonlin®v6.4. The k e of warfarin given a cytochrome P450 2C9 (CYP2C9) genotype ranged from 0.0189 to 0.0075 h-1. K a and V d parameters were taken from literature. Data from 128 subjects were divided into two groups (i.e., wild-types and carriers) and statistical analyses of PK parameters were performed by unpaired t-tests. Results In the carrier group (n=64), 53 subjects were single-carriers and 11 double-carriers (i.e., *2/*2, *2/*3, *2/*5, *3/*5, and *3/*8). The mean peak concentration (Cmax) was higher for wild-type (0.36±0.12 vs. 0.32±0.14 mg/L). Likewise, the average clearance (CL) parameter was faster among non-carriers (0.22±0.03 vs. 0.17±0.05 L/h; p=0.0001), with also lower area under the curve (AUC) when compared to carriers (20.43±6.97 vs. 24.78±11.26 h mg/L; p=0.025). Statistical analysis revealed a significant difference between groups with regard to AUC and CL, but not for Cmax. This can be explained by the variation of k e across different genotypes. Conclusions The results provided useful information for warfarin dosing predictions that take into consideration important individual PK and genotyping data.

Solid dispersions embed active pharmaceutical ingredients in polymeric carriers to improve their solubility. Three solid dispersion preparation techniques are typically employed: solvent evaporation, solvent-fusion, and fusion methods. Although these are also widely recommended as preparative methods for phase diagram determination, few examples exist concerning their effect on the resulting polymorph, once the solid dispersion is produced. In this study, the influence of these methods on the polymorphic form obtained in crystalline solid dispersions (CSDs) composed of flufenamic acid (FFA) and poly(ethylene glycol) was investigated. The physical mixtures and CSDs were characterized by powder X-ray diffraction, infrared spectroscopy, and differential scanning calorimetry. The results reveal that the fusion method leads to concomitant polymorphs (mainly FFA I and III) in the CSDs. In contrast, the solvent evaporation and solvent-fusion methods lead to FFA III. Collectively, these results demonstrate that preparative methods have a significant influence on the phase diagrams determined (average relative deviation ≤8%), which are often used to justify the design space of manufacturing processes, including those deemed "continuous." Consequently, choosing a preparation method that results in the desired polymorph is crucial to ensure accurate determination of phase diagrams and critical quality attributes of formulations., Competing Interests: The authors declare no competing financial interest.

The solubility of warfarin sodium isopropanol solvate (WS·IPA), a widely used anticoagulant, was determined at temperatures ranging from 278.15 to 333.15 K in four pure solvents (acetone, ethanol, IPA, and water), five binary solvent mixtures (IPA + acetone, IPA + ethanol, IPA + water, IPA + heptane, and IPA + hexane), and five ternary solvent mixtures (IPA + acetone + heptane, IPA + acetone + hexane, IPA + ethanol + heptane, IPA + ethanol + hexane, and IPA + water + heptane) using the polythermal method. It was demonstrated that the solubility of WS·IPA increases with increasing temperature in the pure solvents and at constant solvent composition in the solvent mixtures. In addition, the solubility of WS·IPA in IPA increases with increasing content of acetone, ethanol, and water, which act as cosolvents, and decreases with increasing content of heptane and hexane, which act as antisolvents. The experimental solubility data of WS·IPA in pure solvents and binary and ternary solvent mixtures were correlated using the modified Apelblat and λ h model equations. The correlated solubility data agree with the experimental data based on the relative deviation and the average relative deviation (ARD %) values. Thus, the correlated and experimentally derived solubility data of WS·IPA provide a pathway to engineer advanced pharmaceutical crystallization processes for WS·IPA., Competing Interests: Notes The authors declare no competing financial interest.

Solubility measurements for polymorphic compounds are often accompanied by solvent-mediated phase transformations. In this study, solubility measurements from undersaturated solutions are employed to investigate the solubility of the two most stable polymorphs of flufenamic acid (FFA forms I and III), tolfenamic acid (TA forms I and II), and the only known form of niflumic acid (NA). The solubility was measured from 278.15 to 333.15 K in four alcohols of a homologous series (methanol, ethanol, 1-propanol, n -butanol) using the polythermal method. It was established that the solubility of these compounds increases with increasing temperature. The solubility curves of FFA forms I and III intersect at ~315.15 K (42 °C) in all four solvents, which represents the transition temperature of the enantiotropic pair. In the case of TA, the solubility of form II could not be reliably obtained in any of the solvents because of the fast solvent-mediated phase transformation. The solubility of the only known form of NA was also determined, and no other polymorphs of NA were observed. The experimental solubility data of FFA (forms I and III), TA (form I), and NA in these four solvents was correlated using the modified Apelblat and λh model equations. The correlated and experimentally determined solubility data obtained serves to (i) guide the accurate determination of the solubility for polymorphic compounds, (ii) assess the role of the solvent in mediating transformations, and (iii) provide a route to engineer advanced crystallization processes for these pharmaceutical compounds., Competing Interests: The authors declare no competing financial interest.