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Solid-State of Organic Pharmaceutical Compounds

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Materials Chemistry".

Deadline for manuscript submissions: closed (15 April 2022) | Viewed by 21220

Special Issue Editor

Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal
Interests: molecular dynamics; nucleation; polymorphism; active pharmaceutical ingredients; crystallization; calorimetry; instrumentation; ionic liquids
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The crystal phase plays a crucial role in the properties of active pharmaceutical ingredients (API), since different solid forms of the same compound often exhibit different physical properties (e.g., fusion temperature, solubility, stability, crystal morphology, and dissolution rate). The ability to control the solid phase of materials was, therefore, recognized as an effective method to tune the properties of APIs, attracting attention in the scientific community in recent decades. The current Special Issue aims to provide a view of the most recent advances in solid-state studies. The topics of interest include the study of polymorphism, solvates, and co-crystals; the investigation of the nucleation and growth of crystals from solution; the crystallization of materials with well-defined size and morphology; chiral separation; solubility studies; and the development of theoretical approaches for the predictions of properties of crystallized materials (e.g., crystal phase and solubility).

Dr. Carlos Eduardo Sabino Bernardes
Guest Editor

Manuscript Submission Information

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Keywords

  • Crystallization
  • Polymorphism
  • Nucleation
  • Solvatomorphism
  • Co-crystallization
  • Solubility
  • Solid phase stability

Published Papers (8 papers)

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Research

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21 pages, 8330 KiB  
Article
Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening
Molecules 2021, 26(21), 6721; https://doi.org/10.3390/molecules26216721 - 06 Nov 2021
Cited by 2 | Viewed by 2157
Abstract
In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for 2,4-diaminopyrimidine (DAP), which is the pharmacophore of these active pharmaceutical ingredients (API). The isomeric pyridinecarboxamides and two xanthines, theophylline (THEO) and [...] Read more.
In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for 2,4-diaminopyrimidine (DAP), which is the pharmacophore of these active pharmaceutical ingredients (API). The isomeric pyridinecarboxamides and two xanthines, theophylline (THEO) and caffeine (CAF), were used as co-formers in the same experimental conditions, in order to evaluate the potential for the pharmacophore to be used as a guide in the screening process. In silico co-crystal screening was carried out using BIOVIA COSMOquick and experimental screening was performed by mechanochemistry and supported by (solid + liquid) binary phase diagrams, infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). The in silico prediction of low propensities for DAP, TMP and PMA to co-crystallize with pyridinecarboxamides was confirmed: a successful outcome was only observed for DAP + nicotinamide. Successful synthesis of multicomponent solid forms was achieved for all three target molecules with theophylline, with DAP co-crystals revealing a greater variety of stoichiometries. The crystalline structures of a (1:2) TMP:THEO co-crystal and of a (1:2:1) DAP:THEO:ethyl acetate solvate were solved. This work demonstrated the possible use of the pharmacophore of DHFR inhibitors as a guide for co-crystal screening, recognizing some similar trends in the outcome of association in the solid state and in the molecular aggregation in the co-crystals, characterized by the same supramolecular synthons. Full article
(This article belongs to the Special Issue Solid-State of Organic Pharmaceutical Compounds)
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17 pages, 3091 KiB  
Article
First and Second Dissociation Enthalpies in Bi-Component Crystals Consisting of Maleic Acid and L-Phenylalanine
Molecules 2021, 26(18), 5714; https://doi.org/10.3390/molecules26185714 - 21 Sep 2021
Cited by 3 | Viewed by 1538
Abstract
The energetics of the stepwise dissociation of a A:B2 bi-component crystal, according to A:B2(cr) → A:B(cr) + B(cr) and A:B(cr) → A(cr) + B(cr), was investigated using MA:Phe2 and MA:Phe (MA = maleic acid; Phe = L-phenylalanine) as model [...] Read more.
The energetics of the stepwise dissociation of a A:B2 bi-component crystal, according to A:B2(cr) → A:B(cr) + B(cr) and A:B(cr) → A(cr) + B(cr), was investigated using MA:Phe2 and MA:Phe (MA = maleic acid; Phe = L-phenylalanine) as model systems. The enthalpy changes associated with these sequential processes and with the overall dissociation reaction A:B2(cr) → A(cr) + 2B(cr) were determined by solution calorimetry. It was found that they are all positive, indicating that there is a lattice enthalpy gain when MA:Phe2 is formed, either from the individual precursors or by adding Phe to MA:Phe. Single-crystal X-ray diffraction (SCXRD) analysis showed that MA:Phe2 is best described as a protic salt containing a maleate anion (MA) and two non-equivalent L-phenylalanine units, both linked to MA by NH···O hydrogen bonds (H-bond): one of these units is protonated (HPhe+) and the other zwitterionic (Phe±). Only MA and HPhe+ molecules are present in the MA:Phe lattice. In this case, however, NH···O and OH···O H-bonds are formed between each MA unit and two HPhe+ molecules. Despite these structural differences, the enthalpy cost for the removal of the zwitterionic Phe± unit from the MA:Phe2 lattice to yield MA:Phe is only 0.9 ± 0.4 kJ mol−1 higher than that for the dissociation of MA:Phe, which requires a proton transfer from HPhe+ to MA and the rearrangement of L-phenylalanine to the zwitterionic, Phe±, form. Finally, a comparison of the dissociation energetics and structures of MA:Phe and of the previously reported glycine maleate (MA:Gly) analogue indicated that parameters, such as the packing coefficient, density, hydrogen bonds formed, or fusion temperature, are not necessarily good descriptors of dissociation enthalpy or lattice enthalpy trends when bi-component crystals with different molecular composition are being compared, even if the stoichiometry is the same. Full article
(This article belongs to the Special Issue Solid-State of Organic Pharmaceutical Compounds)
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14 pages, 3140 KiB  
Article
Solvatomorphism of Moxidectin
Molecules 2021, 26(16), 4869; https://doi.org/10.3390/molecules26164869 - 11 Aug 2021
Cited by 1 | Viewed by 1570
Abstract
The solvatomorphism of the anthelmintic drug moxidectin is investigated, and a new solvatomorph with nitromethane is reported. Moreover, the hitherto unknown crystal structures of the solvatomorphs with ethanol and 2-propanol are reported and discussed. The thermal characterization of these solvatomorphs through variable-temperature powder [...] Read more.
The solvatomorphism of the anthelmintic drug moxidectin is investigated, and a new solvatomorph with nitromethane is reported. Moreover, the hitherto unknown crystal structures of the solvatomorphs with ethanol and 2-propanol are reported and discussed. The thermal characterization of these solvatomorphs through variable-temperature powder X-ray diffraction analysis (VT-PXRD) is also described, providing new insights into the crystallochemistry of this active pharmaceutical ingredient. Full article
(This article belongs to the Special Issue Solid-State of Organic Pharmaceutical Compounds)
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13 pages, 2063 KiB  
Article
Diagnosis of Agglomeration and Crystallinity of Active Pharmaceutical Ingredients in Over the Counter Headache Medication by Electrospray Laser Desorption Ionization Mass Spectrometry Imaging
Molecules 2021, 26(3), 610; https://doi.org/10.3390/molecules26030610 - 25 Jan 2021
Cited by 2 | Viewed by 2414
Abstract
Agglomeration of active pharmaceutical ingredients (API) in tablets can lead to decreased bioavailability in some enabling formulations. In a previous study, we determined that crystalline APIs can be detected as agglomeration in tablets formulated with amorphous acetaminophen tablets. Multiple method advancements are presented [...] Read more.
Agglomeration of active pharmaceutical ingredients (API) in tablets can lead to decreased bioavailability in some enabling formulations. In a previous study, we determined that crystalline APIs can be detected as agglomeration in tablets formulated with amorphous acetaminophen tablets. Multiple method advancements are presented to better resolve agglomeration caused by crystallinity in standard tablets. In this study, we also evaluate three “budget” over-the-counter headache medications (subsequently labeled as brands A, B, and C) for agglomeration of the three APIs in the formulation: Acetaminophen, aspirin, and caffeine. Electrospray laser desorption ionization mass spectrometry imaging (ELDI-MSI) was used to diagnose agglomeration in the tablets by creating molecular images and observing the spatial distributions of the APIs. Brand A had virtually no agglomeration or clustering of the active ingredients. Brand B had extensive clustering of aspirin and caffeine, but acetaminophen was observed in near equal abundance across the tablet. Brand C also had extensive clustering of aspirin and caffeine, and minor clustering of acetaminophen. These results show that agglomeration with active ingredients in over-the-counter tablets can be simultaneously detected using ELDI-MS imaging. Full article
(This article belongs to the Special Issue Solid-State of Organic Pharmaceutical Compounds)
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12 pages, 4178 KiB  
Article
Investigation of Solubility Behavior of Canagliflozin Hydrate Crystals Combining Crystallographic and Hirshfeld Surface Calculations
Molecules 2021, 26(2), 298; https://doi.org/10.3390/molecules26020298 - 08 Jan 2021
Cited by 5 | Viewed by 1890
Abstract
Canagliflozin (CG) was a highly effective, selective and reversible inhibitor of sodium-dependent glucose co-transporter 2 developed for the treatment of type 2 diabetes mellitus. The crystal structure of CG monohydrate (CG-H2O) was reported for the first time while CG hemihydrate (CG-Hemi) [...] Read more.
Canagliflozin (CG) was a highly effective, selective and reversible inhibitor of sodium-dependent glucose co-transporter 2 developed for the treatment of type 2 diabetes mellitus. The crystal structure of CG monohydrate (CG-H2O) was reported for the first time while CG hemihydrate (CG-Hemi) had been reported in our previous research. Solubility and dissolution rate results showed that the solubility of CG-Hemi was 1.4 times higher than that of CG-H2O in water and hydrochloric acid solution, and the dissolution rates of CG-Hemi were more than 3 folds than CG-H2O in both solutions. Hirshfeld surface analysis showed that CG-H2O had stronger intermolecular forces than CG-Hemi, and water molecules in CG-H2O participated three hydrogen bonds, forming hydrogen bond networks. These crystal structure features might make it more difficult for solvent molecules to dissolve CG-H2O than CG-Hemi. All these analyses might explain why the dissolution performance of CG-Hemi was better than CG-H2O. This work provided an approach to predict the dissolution performance of the drug based on its crystal structure. Full article
(This article belongs to the Special Issue Solid-State of Organic Pharmaceutical Compounds)
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22 pages, 3245 KiB  
Article
Preparation and Solid-State Characterization of Eltrombopag Crystal Phases
Molecules 2021, 26(1), 65; https://doi.org/10.3390/molecules26010065 - 25 Dec 2020
Cited by 3 | Viewed by 2853
Abstract
Eltrombopag, of C25H22N4O4 chemical formula, is a drug used against thrombocytopenia, marketed worldwide under different tradenames in the form of its bis-olamine salt. The free acid (CAS no. 496775-61-2) is an intermediate species used for the [...] Read more.
Eltrombopag, of C25H22N4O4 chemical formula, is a drug used against thrombocytopenia, marketed worldwide under different tradenames in the form of its bis-olamine salt. The free acid (CAS no. 496775-61-2) is an intermediate species used for the final drug isolation and is reported to crystallize in more than 20 distinct crystal forms, including a large number of hydrates and solvates. Their identification, and, ultimately, their quantification in industrial lots require the usage of accurately measured X-ray powder diffraction pattern, as well as the assessment of the metrical features (crystal symmetry and lattice parameters), nowadays accessible by powerful crystallographic software. Here, the complete indexing of 13 monophasic samples, prepared using literature or newly tailored crystallization methods, jointly to simultaneous thermogravimetric and calorimetric analyses and to variable temperature X-ray diffraction studies, provide a clear picture of the stability fields of the different crystal phases and their mutual interconversion processes, leading, in a few cases, to new and unexpected crystalline polymorphs or solvates of the pristine unsolvated Form I. Full article
(This article belongs to the Special Issue Solid-State of Organic Pharmaceutical Compounds)
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15 pages, 3366 KiB  
Article
Assembling the Puzzle of Taxifolin Polymorphism
Molecules 2020, 25(22), 5437; https://doi.org/10.3390/molecules25225437 - 20 Nov 2020
Cited by 12 | Viewed by 2629
Abstract
A large amount of the current literature dedicated to solid states of active pharmaceutical ingredients (APIs) pays special attention to polymorphism of flavonoids. Taxifolin (also known as dihydroquercetin) is an example of a typical flavonoid. Some new forms of taxifolin have been reported [...] Read more.
A large amount of the current literature dedicated to solid states of active pharmaceutical ingredients (APIs) pays special attention to polymorphism of flavonoids. Taxifolin (also known as dihydroquercetin) is an example of a typical flavonoid. Some new forms of taxifolin have been reported previously, however it is still unclear whether they represent polymorphic modifications. In this paper, we tried to answer the question about the taxifolin polymorphism. Taxifolin microtubes and taxifolin microspheres were synthesized from raw taxifolin API using several methods of crystal engineering. All forms were described with the help of spectral methods, scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), and thermal analysis (TA). SEM reveals that the morphology of the solid phase is very specific for each sample. Although XRPD patterns of raw taxifolin and microtubes look similar, their TA profiles differ significantly. At the same time, raw taxifolin and microspheres have nearly identical thermograms, while XRPD shows that the former is a crystalline and the latter is an amorphous substance. Only the use of complex analyses allowed us to put the puzzle together and to confirm the polymorphism of taxifolin. This article demonstrates that taxifolin microtubes are a pseudopolymorphic modification of raw taxifolin. Full article
(This article belongs to the Special Issue Solid-State of Organic Pharmaceutical Compounds)
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Review

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18 pages, 384 KiB  
Review
Thermal Stability of Amorphous Solid Dispersions
Molecules 2021, 26(1), 238; https://doi.org/10.3390/molecules26010238 - 05 Jan 2021
Cited by 18 | Viewed by 5154
Abstract
Amorphous solid dispersion drug delivery systems (ASD DDS) were proved to be efficient for the enhancement of solubility and bioavailability of poorly water-soluble drugs. One of the major keys for successful preparation of ASD is the selection of appropriate excipients, mostly polymers, which [...] Read more.
Amorphous solid dispersion drug delivery systems (ASD DDS) were proved to be efficient for the enhancement of solubility and bioavailability of poorly water-soluble drugs. One of the major keys for successful preparation of ASD is the selection of appropriate excipients, mostly polymers, which have a crucial role in improving drug solubility and its physical stability. Even though, excipients should be chemically inert, there is some evidence that polymers can affect the thermal stability of active pharmaceutical ingredients (API). The thermal stability of a drug is closely related to the shelf-life of pharmaceutical products and therefore it is a matter of high pharmaceutical relevance. An overview of thermal stability of amorphous solids is provided in this paper. Evaluation of thermal stability of amorphous solid dispersion is perceived from the physicochemical perspective, from a kinetic (motions) and thermodynamic (energy) point of view, focusing on activation energy and fragility, as well all other relevant parameters for ASD design, with a glance on computational kinetic analysis of solid-state decomposition. Full article
(This article belongs to the Special Issue Solid-State of Organic Pharmaceutical Compounds)
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