Probing the Molecular and Macroscopic Structure of Solid Solutions by Dynamic Nuclear Polarization (DNP) Enhanced 13C and 15N Solid-State NMR Spectroscopy.

Crystallization is a widely used purification technique in the manufacture of active pharmaceutical ingredients (APIs) and precursor molecules. However, when impurities and desired compounds have similar molecular structures, separation by crystallization may become challenging. In such cases, some impurities may form crystalline solid solutions with the desired product during recrystallization. Understanding the molecular structure of these recrystallized solid solutions is crucial to devise methods for effective purification. Unfortunately, there are limited analytical techniques that provide insights into the molecular structure or spatial distribution of impurities that are incorporated within recrystallized products. In this study, we investigated model solid solutions formed by recrystallizing salicylic acid (SA) in the presence of anthranilic acid (AA). These two molecules are known to form crystalline solid solutions due to their similar molecular structures. To overcome challenges associated with the long 1H longitudinal relaxation times (T1(1H)) of SA and AA, we employed dynamic nuclear polarization (DNP) and 15N isotope enrichment to enable solid-state NMR experiments. Results of solid-state NMR experiments and DFT calculations revealed that SA and AA are homogeneously alloyed as a solid solution. Heteronuclear correlation (HETCOR) experiments and plane-wave DFT structural models provide further evidence of the molecular-level interactions between SA and AA. This research provides valuable insights into the molecular structure of recrystallized solid solutions, contributing to the development of effective purification strategies and an understanding of the physicochemical properties of solid solutions.

Artificial Intelligence-Based Organ Delineation for Radiation Treatment Planning of Prostate Cancer on Computed Tomography.

Purpose: Meticulous manual delineations of the prostate and the surrounding organs at risk are necessary for prostate cancer radiation therapy to avoid side effects to the latter. This process is time consuming and hampered by inter- and intraobserver variability, all of which could be alleviated by artificial intelligence (AI). This study aimed to evaluate the performance of AI compared with manual organ delineations on computed tomography (CT) scans for radiation treatment planning. Methods and Materials: Manual delineations of the prostate, urinary bladder, and rectum of 1530 patients with prostate cancer who received curative radiation therapy from 2006 to 2018 were included. Approximately 50% of those CT scans were used as a training set, 25% as a validation set, and 25% as a test set. Patients with hip prostheses were excluded because of metal artifacts. After training and fine-tuning with the validation set, automated delineations of the prostate and organs at risk were obtained for the test set. Sørensen-Dice similarity coefficient, mean surface distance, and Hausdorff distance were used to evaluate the agreement between the manual and automated delineations. Results: The median Sørensen-Dice similarity coefficient between the manual and AI delineations was 0.82, 0.95, and 0.88 for the prostate, urinary bladder, and rectum, respectively. The median mean surface distance and Hausdorff distance were 1.7 and 9.2 mm for the prostate, 0.7 and 6.7 mm for the urinary bladder, and 1.1 and 13.5 mm for the rectum, respectively. Conclusions: Automated CT-based organ delineation for prostate cancer radiation treatment planning is feasible and shows good agreement with manually performed contouring.

Terminal crystalline solid solutions, solubility enhancements and T-X phase diagram of salicylic acid - 4-hydroxybenzoic acid.

The binary T-X phase diagram of salicylic acid (SA) and 4-hydroxybenzoic acid (4HBA) has been constructed from 20 °C to melting, revealing a partially miscible system with an eutectic composition of 27.3 mol% 4HBA in SA. Terminal crystalline solid solutions were obtained at the extremes of the phase diagram with solid-state miscibility limits below 0.4% at 20 °C. The limited phase boundaries could be captured experimentally by both DSC analyses at around melting temperature and solid-liquid equilibria studies at 20 °C in two solvent systems. The NRTL model was applied to regress phase boundaries and generate the final binary T-X phase diagram. The NRTL model was also used to regress solubility data, and reproduce the ternary SA/4HBA/solvent phase diagram at 20 °C and 1 atm. 4HBA was obtained as two crystal forms, viz. anhydrate and monohydrate. It is shown how the monohydrate of 4HBA is less miscible with SA in the solid state than the anhydrous form of 4HBA. As compared to pure SA and 4HBA, the crystalline solid solutions exhibited significant changes in physical properties that are relevant for organic and pharmaceutical materials in the context of impurity effects. A lattice incorporation of just 0.2 mol% 4HBA in SA caused a 10% reduction in melting enthalpy and a 66% solubility increase in 40 wt% MeOH in H2O. The reasons for this thermodynamic effect are discussed.

Complex oiling-out behavior of procaine with stable and metastable liquid phases.

During the crystallization of a solute from solvent(s), spontaneous liquid-liquid phase separation (LLPS) might occur, under certain conditions. This phenomenon, colloquially referred to as "oiling-out" in the pharmaceutical industry, often leads to undesired outcomes, including undesired particle properties, encrustation, ineffective impurity rejection, and excessively long process time. Therefore, it is critical to understand the thermodynamic driving force and phase boundaries of this phenomenon, such that rational strategies can be developed to avoid oiling-out or minimize its negative impact. In this study, we systematically evaluated the oiling-out behavior of procaine, a low melting point drug, in the solvent systems heptane, and ethanol-heptane as a function of temperature and solvent composition. In the procaine-heptane binary system, we observed a region where the LLPS is metastable with respect to crystallization, which is most commonly observed in the crystallization of modern active pharmaceutical ingredients (APIs); however, we also identified a region of the phase diagram where the LLPS is stable with respect to crystallization, and therefore will persist indefinitely. In the procaine-ethanol-heptane ternary system we identified five different regions, including a homogeneous liquid (L) region, two solid-liquid (SLI and SLII) regions, a liquid-liquid (LILII) region, and a solid-liquid-liquid (SLILII) region. The binary and ternary phase diagrams were also predicted using a state-of-the-art thermodynamic model: the SAFT-γ-Mie equation of state, and the results were compared with experimental data. Our findings highlight the complexity of oiling-out behavior. This work also represents a combined modeling and experimental platform to identify phase boundaries that will enable rational selection of strategies to crystallize active pharmaceutical ingredients with oiling-out risks.

Enantiotropic inconstancy, crystalline solid solutions and co-crystal in the salicylic acid-anthranilic acid system.

The phase boundaries and thermodynamic properties of crystal phases in the salicylic acid (SA) - anthranilic acid (AA) system have been determined experimentally. The complete binary T-X diagram reveals a total of four crystalline phases, including a co-crystal and three crystalline solid solutions. The two eutectics were determined through triplicate DSC analyses at 33 compositions. By adding a liquid solvent and generating a ternary phase diagram, a methodology is introduced to determine the solid-state miscibility limits of the solid solutions at 20 and 55 °C. The crystalline solid solutions exhibit substantial differences in physical properties relative to the pure components, including solubility enhancements that are relevant for chemical processing and material properties. The thermodynamic relationships of the three polymorphs of AA have been resolved showing an enantiotropic transition temperature of 50-55 °C between Form I and III of pure AA. However, as a result of the solid solutions with SA, the enantiotropic transition temperature was suppressed by around 30 °C at the eutectoid. In addition, a co-existence envelope is formed, wherein the two AA polymorph solid solutions exist in equilibrium with one another over a wide range of temperatures and compositions.

Non-Invasive Evaluation of Intradiscal Deformation during Axial Loading of the Spine Using Deformation-Field Magnetic Resonance Imaging: A Potential Tool for Micro-Instability Measurements.

Degeneration alters the structural components of the disc and its mechanical behavior. Understanding this pathophysiological process is of great importance, as it may lead to back pain. However, non-invasive methods to characterize the disc mechanics in vivo are lacking. Here, a potential method for measurements of the intradiscal deformation under stress is presented. The method utilizes a standard MRI protocol, commercial loading equipment, and registration software. The lumbar spine (L1/L2-L5/S1) of 36 human subjects was imaged with and without axial loading of the spine. The resulting images were registered, and changes in the images during the registration were displayed pixel-by-pixel to visualize the internal deformation of the disc. The degeneration grade, disc height, disc angle and tilt angle were determined and correlated with the deformation using multivariate regression analysis. The largest deformation was found at the lower lumbar spine, and differences in regional behaviors between individual discs were found. Weak to moderate correlations between the deformation and different disc characteristics were found, where the degeneration grade and tilt angle were the main contributing factors. To conclude, the image-based method offers a potential tool to study the pathophysiological process of the disc.

Fatigue in Patients With Head and Neck Cancer Treated With Radiation Therapy: A Prospective Study of Patient-Reported Outcomes and Their Association With Radiation Dose to the Cerebellum.

Purpose: Although fatigue is a known side effect in patients with head and neck cancer (HNC) receiving radiation therapy, knowledge regarding long-term fatigue and dose-response relationships to organs at risk is scarce. The aim of this prospective study was to analyze patient-reported fatigue in patients with HNC receiving radiation therapy and to explore any possible association with organ-at-risk doses. Methods and Materials: Patients with HNC referred for curative radiation therapy were eligible for inclusion in the study. To assess patient-reported fatigue, quality of life questionnaires (European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-FA12) were distributed before treatment and 1, 3, 6, 12, 24, and 60 months after the start of treatment. Mean dose (Dmean) and near maximum dose (D2%) of the cerebellum and brain stem were evaluated in relation to baseline-adjusted fatigue scores at 3 months. Results: One hundred twenty-six patients treated with intensity modulated radiation therapy between 2008 and 2010 were available for final analysis. Female sex and age <60 years were associated with higher fatigue at baseline, whereas patients also treated with chemotherapy had reduced physical and emotional fatigue at 6 months. Physical fatigue (QLQ-FA12 scale) increased from baseline up to 3 months (29 vs 59; P < .0001) but showed no difference compared with baseline from 1 to 5 years. Emotional fatigue was significantly lower at 5 years compared with baseline (14 vs 28; P < .0001). Patients with cerebellum Dmean > 3.5 Gy had higher mean physical fatigue scores at 3 months (38 vs 27; P = .036). Conclusions: Although there is a significant increase in fatigue scores for patients with HNC up to 1 year after radiation therapy, this study showed a return to baseline levels at 5 years. A possible association was found between physical fatigue and a higher mean dose to the cerebellum.

Head and neck cancer patient positioning using synthetic CT data in MRI-only radiation therapy.

PURPOSE: The accuracy and precision of patient positioning is crucial in radiotherapy; however, there are no publications available using synthetic computed tomography (sCT) that evaluate rotations in head and neck (H&N) patients positioning or the effect of translation and rotation combined. The aim of this work was to evaluate the differences between using sCT with the CT for 2D- and 3D-patient positioning in a magnetic resonance imaging (MRI)-only workflow. METHODS: This study included 14 H&N cancer patients, with generated sCT data (MRI Planner v2.2) and the CT deformably registered to the MRI. Patient positioning was evaluated by comparing sCT against CT data: 3D cone beam CT (CBCT) was registered to the deformed CT (dCT) and sCT in six degrees of freedom (DoF) with a rigid auto-registration algorithm and bone threshold, and 2D deformed digital reconstructed radiographs (dDRR) and synthetic DRRs (sDRR) were manually registered to orthogonal projections in five DoF by six blinded observers. The difference in displacement in all DoF were calculated for dCT and sCT, as well as for dDRR and sDRR. The interobserver variation was evaluated by separate application of the paired dDRR and sDRR registration matrices to the original coordinates of the planning target volume (PTV) structures and calculation of the Euclidean distance between the corresponding points. The Dice similarity coefficient (DSC) was calculated between dDRR/sDRR-registered PTVs. RESULTS: The mean difference in patient positioning using CBCT was <0.7 mm and <0.3° and using orthogonal projections <0.4 mm and <0.2° in all directions. The maximum Euclidean distance was 5.1 mm, the corresponding mean (1SD) Euclidean distance and mean DSC were 3.5 ± 0.7 mm and 0.93, respectively. CONCLUSIONS: This study shows that the sCT-based patient positioning gives a comparable result with that based on CT images, allowing sCT to replace CT as reference for patient treatment positioning.

Synthetic computed tomography data allows for accurate absorbed dose calculations in a magnetic resonance imaging only workflow for head and neck radiotherapy.

BACKGROUND AND PURPOSE: Few studies on magnetic resonance imaging (MRI) only head and neck radiation treatment planning exist, and none using a generally available software. The aim of this study was to evaluate the accuracy of absorbed dose for head and neck synthetic computed tomography data (sCT) generated by a commercial convolutional neural network-based algorithm. MATERIALS AND METHODS: For 44 head and neck cancer patients, sCT were generated and the geometry was validated against computed tomography data (CT). The clinical CT based treatment plan was transferred to the sCT and recalculated without re-optimization, and differences in relative absorbed dose were determined for dose-volume-histogram (DVH) parameters and the 3D volume. RESULTS: For overall body, the results of the geometric validation were (Mean ± 1sd): Mean error -5 ± 10 HU, mean absolute error 67 ± 14 HU, Dice similarity coefficient 0.98 ± 0.05, and Hausdorff distance difference 4.2 ± 1.7 mm. Water equivalent depth difference for region Th1-C7, mid mandible and mid nose were -0.3 ± 3.4, 1.1 ± 2.0 and 0.7 ± 3.8 mm respectively. The maximum mean deviation in absorbed dose for all DVH parameters was 0.30% (0.12 Gy). The absorbed doses were considered equivalent (p-value < 0.001) and the mean 3D gamma passing rate was 99.4 (range: 95.7-99.9%). CONCLUSIONS: The convolutional neural network-based algorithm generates sCT which allows for accurate absorbed dose calculations for MRI-only head and neck radiation treatment planning. The sCT allows for statistically equivalent absorbed dose calculations compared to CT based radiotherapy.

Initial experience with introducing national guidelines for CT- and MRI-based delineation of organs at risk in radiotherapy.

A fundamental problem in radiotherapy is the variation of organ at risk (OAR) volumes. Here we present our initial experience in engaging a large Radiation Oncology (RO) community to agree on national guidelines for OAR delineations. Our project builds on associated standardization initiatives and invites professionals from all radiotherapy departments nationwide. Presently, one guideline (rectum) has successfully been agreed on by a majority vote. Reaching out to all relevant parties in a timely manner and motivating funding agencies to support the work represented early challenges. Population-based data and a scalable methodological approach are major strengths of the proposed strategy.

Motion induced interplay effects for VMAT radiotherapy.

The purpose of this study was to develop a method to simulate breathing motion induced interplay effects for volumetric modulated arc therapy (VMAT), to verify the proposed method with measurements, and to use the method to investigate how interplay effects vary with different patient- and machine specific parameters. VMAT treatment plans were created on a virtual phantom in a treatment planning system (TPS). Interplay effects were simulated by dividing each plan into smaller sub-arcs using an in-house developed software and shifting the isocenter for each sub-arc to simulate a sin6 breathing motion in the superior-inferior direction. The simulations were performed for both flattening-filter (FF) and flattening-filter free (FFF) plans and for different breathing amplitudes, period times, initial breathing phases, dose levels, plan complexities, CTV sizes, and collimator angles. The resulting sub-arcs were calculated in the TPS, generating a dose distribution including the effects of motion. The interplay effects were separated from dose blurring and the relative dose differences to 2% and 98% of the CTV volume (ΔD98% and ΔD2%) were calculated. To verify the simulation method, measurements were carried out, both static and during motion, using a quasi-3D phantom and a motion platform. The results of the verification measurements during motion were comparable to the results of the static measurements. Considerable interplay effects were observed for individual fractions, with the minimum ΔD98% and maximum ΔD2% being -16.7% and 16.2%, respectively. The extent of interplay effects was larger for FFF compared to FF and generally increased for higher breathing amplitudes, larger period times, lower dose levels, and more complex treatment plans. Also, the interplay effects varied considerably with the initial breathing phase, and larger variations were observed for smaller CTV sizes. In conclusion, a method to simulate motion induced interplay effects was developed and verified with measurements, which allowed for a large number of treatment scenarios to be investigated. The simulations showed large interplay effects for individual fractions and that the extent of interplay effects varied with the breathing pattern, FFF/FF, dose level, CTV size, collimator angle, and the complexity of the treatment plan.

MR-OPERA: A Multicenter/Multivendor Validation of Magnetic Resonance Imaging-Only Prostate Treatment Planning Using Synthetic Computed Tomography Images.

PURPOSE: To validate the dosimetric accuracy and clinical robustness of a commercially available software for magnetic resonance (MR) to synthetic computed tomography (sCT) conversion, in an MR imaging-only workflow for 170 prostate cancer patients. METHODS AND MATERIALS: The 4 participating centers had MriPlanner (Spectronic Medical), an atlas-based sCT generation software, installed as a cloud-based service. A T2-weighted MR sequence, covering the body contour, was added to the clinical protocol. The MR images were sent from the MR scanner workstation to the MriPlanner platform. The sCT was automatically returned to the treatment planning system. Four MR scanners and 2 magnetic field strengths were included in the study. For each patient, a CT-treatment plan was created and approved according to clinical practice. The sCT was rigidly registered to the CT, and the clinical treatment plan was recalculated on the sCT. The dose distributions from the CT plan and the sCT plan were compared according to a set of dose-volume histogram parameters and gamma evaluation. Treatment techniques included volumetric modulated arc therapy, intensity modulated radiation therapy, and conventional treatment using 2 treatment planning systems and different dose calculation algorithms. RESULTS: The overall (multicenter/multivendor) mean dose differences between sCT and CT dose distributions were below 0.3% for all evaluated organs and targets. Gamma evaluation showed a mean pass rate of 99.12% (0.63%, 1 SD) in the complete body volume and 99.97% (0.13%, 1 SD) in the planning target volume using a 2%/2-mm global gamma criteria. CONCLUSIONS: Results of the study show that the sCT conversion method can be used clinically, with minimal differences between sCT and CT dose distributions for target and relevant organs at risk. The small differences seen are consistent between centers, indicating that an MR imaging-only workflow using MriPlanner is robust for a variety of field strengths, vendors, and treatment techniques.

Technical Note: MRI only prostate radiotherapy planning using the statistical decomposition algorithm.

PURPOSE: In order to enable a magnetic resonance imaging (MRI) only workflow in radiotherapy treatment planning, methods are required for generating Hounsfield unit (HU) maps (i.e., synthetic computed tomography, sCT) for dose calculations, directly from MRI. The Statistical Decomposition Algorithm (SDA) is a method for automatically generating sCT images from a single MR image volume, based on automatic tissue classification in combination with a model trained using a multimodal template material. This study compares dose calculations between sCT generated by the SDA and conventional CT in the male pelvic region. METHODS: The study comprised ten prostate cancer patients, for whom a 3D T2 weighted MRI and a conventional planning CT were acquired. For each patient, sCT images were generated from the acquired MRI using the SDA. In order to decouple the effect of variations in patient geometry between imaging modalities from the effect of uncertainties in the SDA, the conventional CT was nonrigidly registered to the MRI to assure that their geometries were well aligned. For each patient, a volumetric modulated arc therapy plan was created for the registered CT (rCT) and recalculated for both the sCT and the conventional CT. The results were evaluated using several methods, including mean average error (MAE), a set of dose-volume histogram parameters, and a restrictive gamma criterion (2% local dose/1 mm). RESULTS: The MAE within the body contour was 36.5 ± 4.1 (1 s.d.) HU between sCT and rCT. Average mean absorbed dose difference to target was 0.0% ± 0.2% (1 s.d.) between sCT and rCT, whereas it was -0.3% ± 0.3% (1 s.d.) between CT and rCT. The average gamma pass rate was 99.9% for sCT vs rCT, whereas it was 90.3% for CT vs rCT. CONCLUSIONS: The SDA enables a highly accurate MRI only workflow in prostate radiotherapy planning. The dosimetric uncertainties originating from the SDA appear negligible and are notably lower than the uncertainties introduced by variations in patient geometry between imaging sessions.

Technical evaluation of a laser-based optical surface scanning system for prospective and retrospective breathing adapted computed tomography.

BACKGROUND: For breathing adapted radiotherapy, the same motion monitoring system can be used for imaging and triggering of the accelerator. PURPOSE: To evaluate a new technique for prospective gated computed tomography (CT) and four-dimensional CT (4DCT) using a laser based surface scanning system (Sentinel(™), C-RAD, Uppsala, Sweden). The system was compared to the AZ-733V respiratory gating system (Anzai Medical, Tokyo, Japan) and the Real-Time Position Management System (RPM(™)) (Varian Medical Systems, Palo Alto, CA, USA). MATERIAL AND METHODS: Temporal accuracy was evaluated using a moving phantom programmed to move a platform along trajectories following a sin(6)(ωt) function with amplitudes from 6 to 20 mm and periods from 2 to 5 s during 120 s while the motion was recorded. The recorded data was Fourier transformed and the peak area at the fundamental and harmonic frequencies compared to data generated using the same sinusoidal function. For verification of the 4DCT reconstruction process, the phantom was programmed to move along a sinusoidal trajectory. Ten phase series were reconstructed. The distance from the couch to the platform was measured in each image. By fitting the function sin(ωt-ϕ) to the values measured in the images corresponding to each slice, the phase of each image was verified. RESULTS AND CONCLUSION: In the recorded data, the peak area at the fundamental frequency covered on average 104 ± 4%, 102 ± 4% and 91 ± 27% of the peak area in the generated data for the Sentinel(™), RPM(™) and AZ-733V systems, respectively. All systems managed to resolve both harmonic frequencies. The second experiment showed that all images were sorted into the correct series using breathing data recorded by each system. The systems generated very similar results, however, it is preferable to use the same system both for imaging and treatment.

Ensuring the integrity of treatment parameters throughout the radiotherapy process.

BACKGROUND AND PURPOSE: Ensuring data integrity in radiotherapy is of major importance and a complex task. The aim of this study was to compare three different combinations of treatment planning and record and verify systems with respect to data integrity. MATERIALS AND METHODS: A software for comparison of treatment parameters in DICOM-RT files was developed using the MATLAB R2010a (MathWorks Inc.) environment. One hundred treatment plans were analyzed for each system combination. In the first step of the analysis, all parameters were compared and a normal condition for each system combination was identified. The second step focused on the discovery of potential special cause deviations, e.g. by applying tolerance levels. RESULTS: In total, 15% and 0.37% of all comparisons failed to meet the defined integrity demands in step 1 and step 2 of the analysis, respectively. Differences in the data integrity level between the systems were observed, ranging on average from 3.1 to 11.9 discrepancies per beam for the different RV-TPS combinations. CONCLUSIONS: The proposed method can be used to increase the safety for individual patients by ensuring that the intended treatment is delivered. The system combination with the highest level of data integrity was found to be the one which shares a single database.

Control chart analysis of data from a multicenter monitor unit verification study.

BACKGROUND AND PURPOSE: This study aims to investigate the process of monitor unit verification using control charts. Control charts is a key tool within statistical process control (SPC), through which process characteristics can be visualized, usually chronologically with statistically determined limits. MATERIAL AND METHODS: Our group has developed a monitor unit verification software that has been adopted at several Swedish institutions for pre-treatment verification of radiotherapy treatments. Deviations between point dose calculations using the treatment planning systems and using the independent monitor unit verification software from 9219 treatment plans and five different institutions were included in this multicenter study. The process of monitor unit verification was divided into subprocesses. Each subprocess was analyzed using probability plots and control charts. RESULTS: Differences in control chart parameters for the investigated subprocesses were found between different treatment sites and different institutions, as well as between different treatment techniques. 19 of 37 subprocesses met the clinical specification (± 5%), i.e. process capability index was equal to or above one. CONCLUSIONS: Control charts were found to be a useful tool for continuous analysis of data from the monitor unit verification software for patient specific quality control, as well as for comparisons between different institutions and treatment sites. The derived control chart limits were in agreement with AAPM TG114 guidelines on action levels.

Prediction of solubility curves and melting properties of organic and pharmaceutical compounds.

The relationships between solubility, temperature dependence of solubility, melting temperature and melting enthalpy are investigated for the purpose of finding relations that can significantly reduce the need for experimental work in the selection of the solvent for processing of organic fine chemicals and pharmaceuticals. The relationships are investigated theoretically and by evaluation of experimental data for 41 organic and pharmaceutical compounds comprising a total of 115 solubility curves in organic and aqueous solvents. The work considers (i) selection of the equation for correlation of solubility data based on thermodynamic considerations and ability to predict melting properties of the solute from solubility data, (ii) prediction of the temperature dependence of solubility, and (iii) prediction of solubility curves in new solvents. While it is a simple task to find an equation to obtain a decent fit of experimental solubility data, it is more challenging to find relations that are sufficiently sound thermodynamically to allow for extrapolation to the melting temperature. However, with a proper choice of equation it is shown that the melting temperature of the solute can readily be predicted from solubility data in organic solvents (average accuracy of -5K, standard deviation of 26K). Relationships are identified by which the entire solubility curve can be predicted of the compound in a new solvent using only the melting properties and a single solubility data point in that solvent.

Polymorphism and thermodynamics of m-hydroxybenzoic acid.

Solution and solid-state properties of m-hydroxybenzoic acid have been investigated. Two polymorphs were found where the monoclinic modification exhibits a higher stability than the orthorhombic form. The solubility of the monoclinic polymorph was determined between 10 and 50 degrees C in methanol, acetonitrile, acetic acid, acetone, water and ethyl acetate. The solubility of the orthorhombic polymorph was determined between 10 and 50 degrees C in acetonitrile, acetic acid, acetone and ethyl acetate. A thermodynamic analysis revealed a marked correlation between the molar solubility and the van't Hoff enthalpy of solution at constant temperature. In addition, in each solvent increased temperature resulted in increased van't Hoff enthalpy of solution. It is shown that the solubility data can be used to estimate melting properties for both polymorphs. The solubility ratio of the two forms and the DSC thermogram of the orthorhombic form strongly suggest that the system is monotropic. However, according to the polymorph rules of Burger and Ramberger, the estimated higher melting enthalpy and lower melting temperature of the orthorhombic form points towards an enantiotropic system. Hence, this system appears to be an exception to the Burger and Ramberger melting enthalpy rule, and the probable reason for this is found in the difference in the heat capacity of the two solid forms.

Phase equilibria and thermodynamics of p-hydroxybenzoic acid.

The prevalence of phases and associated solubilities of p-hydroxybenzoic acid have been investigated in methanol, acetonitrile, acetic acid, acetone, water, and ethyl acetate at temperatures from 10 to 50 degrees C. Thermodynamic data was acquired through determination of van't Hoff enthalpy of solution, enthalpy of fusion, and melting temperature. Indications of polymorphic enantiotropy were found primarily through solubility analysis and FTIR-ATR. A comprehensive thermodynamic investigation disclosed correlation between the van't Hoff enthalpy of solution and the solubility in different solvents. A higher solubility is linked to a lower van't Hoff enthalpy of solution. A thermodynamic analysis to discriminate between different solid phases is presented.

Analysis of solution nonideality of a pseudomorphic drug system through a comprehensive thermodynamic framework for the design of a crystallization process.

Solutions of a semipolar drug belonging to the alpha(V) beta(iii) integrin antagonist class of compounds were studied in a comprehensive thermodynamic framework. The solubility of two pseudomorphic forms (an anhydrate and a monohydrate) was measured at several temperatures and various solvent mixtures of acetonitrile and water. Both forms displayed a "bell"-shaped solubility behavior as a function of cosolvent composition. Thermodynamic framework used to analyze the data comprised van't Hoff and enthalpy-entropy compensation analyses. The two pseudomorphs exhibited linear temperature dependence from 25 to 65 degrees C at all solvent compositions (i.e., ideal behavior with temperature for fixed solvent composition). Plots of enthalpy of solublization and Gibbs free energy showed two distinct regions with contrasting thermodynamic, and consequently, underlying structural properties (indicating non-deal behavior with solvent composition for a fixed temperature). Solubility increased due to entropy effects in the acetonitrile rich region, whereas enthalpy effects dominated solublization in the water-rich region. Quantification of this phenomenon by plotting DeltaH versus DeltaG showed considerable nonlinearity, and that the two regions were separated by a significant discontinuity-a trend rarely seen before in the literature. The reason behind this behavior is believed to be due to the complex interactions in the solution of the drug in water acetonitrile solvent system. A very significant aspect of the comprehensive thermodynamic analysis is that it helped explain the puzzling feature of the data, which showed that the free energy of phase transformation between the two pseudomorphic forms for a given temperature was not independent of the solvent composition. The resulting explanation has major consequences for crystallization process development.