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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.

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.

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.

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.

The solubility of 5-ffuorouracil (5-FU), a widely used chemotherapeutic agent to treat solid tumors, which include colorectal, head and neck, breast, and lung cancer, was determined at temperatures ranging from 278.15 to 333.15 K in 11 pure solvents and binary water + ethanol solvent mixtures using the polythermal method. It was demonstrated that the solubility of 5-FU increases with increasing temperature in the pure solvents and at constant solvent composition in the solvent mixtures. Moreover, the solubility of 5-FU in the solvent mixtures exceeds its solubility in pure water and ethanol. The experimental solubility data of 5-FU in the pure solvents and solvent mixtures were correlated using the modified Apelblat and λh model equations. The predicted solubility data obtained agree with the experimental data based on the calculated relative deviation (RD) and the average relative deviation (ARD%) values. The selected solvents are categorized as either Class 2 or 3 (less toxic and lower risk to human health) solvents, and hence the correlated and experimentally derived solubility data of 5-FU presented provide a pathway to develop and engineer enhanced pharmaceutical processes and products based on this compound., Competing Interests: The authors declare no competing financial interest.

The inadvertent occurrence of polymorphic phase transformations in active pharmaceutical ingredients (APIs) during hot melt extrusion (HME) processes has been claimed to limit the application of this technique. Hence, the control of polymorphism would need to be addressed if there is any prospect of HME to be successfully implemented as an alternative solid dosage formulation strategy in integrated, continuous end-to-end pharmaceutical manufacturing settings. This work demonstrates that flufenamic acid (FFA), one of the most polymorphic APIs known, thus far, can be processed using temperature-simulated HME with polyethylene glycol (PEG) as polymeric carrier. At temperatures above the transition point of FFA forms III and I (42 °C), the induction time of the polymorphic phase transformation is longer than the average reported residence time in conventional HME processes (5 min). Moreover, it was demonstrated that thorough understanding of the thermodynamic and kinetic design space for the PEG-FFA system leads to polymorphic control in the produced crystalline solid dispersions. Ultimately, this investigation helps to gain fundamental understanding of the processing needs of crystalline solid dispersions, which will lead to the broader application of HME as a continuous manufacturing strategy for drug products containing APIs prone to polymorphism, representing about 80% of all APIs.

Organic compounds contribute to a major fraction of atmospheric aerosols and have significant impacts on climate and human health. However, because of their chemical complexity, their measurement remains a major challenge for analytical instrumentation. Here we present the development and characterization of a new soft ionization technique that allows mass spectrometric real-time detection of organic compounds in aerosols. The aerosol flowing atmospheric-pressure afterglow (AeroFAPA) ion source is based on a helium glow discharge plasma, which generates excited helium species and primary reagent ions. Ionization of the analytes occurs in the afterglow region after thermal desorption and produces mainly intact quasimolecular ions, facilitating the interpretation of the acquired mass spectra. We illustrate that changes in aerosol composition and concentration are detected on the time scale of seconds and in the ng m(-3) range. Additionally, the successful application of AeroFAPA-MS during a field study in a mixed forest region is presented. In general, the observed compounds are in agreement with previous offline studies; however, the acquisition of chemical information and compound identification is much faster. The results demonstrate that AeroFAPA-MS is a suitable tool for organic aerosol analysis and reveal the potential of this technique to enable new insights into aerosol formation, growth, and transformation in the atmosphere.