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Pharmaceutical solid state 36

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Reviews & perspectives
Frontiers in Chemistry

Review examines cocrystal performance and barriers to clinical translation

Muhammad Inam; Muhammad Hayat; Abuzar Osman

A Frontiers in Chemistry review examines pharmaceutical cocrystals as a way to modify dissolution and related biopharmaceutical properties without changing an API's chemical identity. The abstract distinguishes solubility-limited BCS II drugs from permeability-limited BCS IV drugs. It highlights gastrointestinal instability, manufacturing reproducibility, coformer selection, and limited pharmacokinetic evidence. Much of the reported performance evidence remains preclinical.

Pharmaceutical solid stateFormulation Development & Manufacturing
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DOI: 10.3389/fchem.2026.1965408

Methods
AAPS Open

Compaction density reveals reversible urea polymorph changes under pressure

Gerrit Vreeman; Changquan Calvin Sun

An AAPS Open study used a compaction simulator to track reversible density changes in urea between 600 and 900 MPa, consistent with its known form I-to-III transformation. The original abstract proposes in-die density monitoring as a material-sparing screen for pressure-induced phase changes. Applicability depends on a sufficiently large density difference; urea is the demonstrated model compound.

Pharmaceutical solid stateFormulation Development & Manufacturing
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DOI: 10.1186/s41120-026-00206-x

Original research
RSC Advances

40 years later: completion of the structural characterization of the anxiolytic drug buspirone HCl and solid-form landscape expansion

Delbert S. Botes; Mikaela I. Aleman; Alyssa M. Anderson; Pierre Le Maguerès; Kristin M. Hutchins

Electron diffraction established the previously unresolved structure of buspirone hydrochloride Form 2. The study also prepared 15 multicomponent solids, including cocrystals, an ionic cocrystal, and salts, and compared conformations and thermal behavior. This expands structural knowledge of a long-marketed drug and provides a solid-form exploration example without demonstrating improved clinical performance for the newly prepared materials.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1039/d6ra07954g

Original research
Journal of Applied Crystallography

Cryo-EM–microcrystal electron diffraction structural elucidation of cefadroxil: nanocrystallographic and neurotherapeutic insights into a β-lactam antibiotic

Saleem Iqbal; Bairong Shen

The authors reported a cryo-MicroED structure of cefadroxil, characterizing its molecular geometry, stereochemistry, and intermolecular packing. The crystallographic model also supported complementary molecular-dynamics analysis. This is a structural case study of an established beta-lactam antibiotic; the accompanying computational work should not be interpreted as clinical evidence of a new neurotherapeutic benefit or a general performance guarantee.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1107/s1600576726003250

Original research
Communications Chemistry

Predicting the ritonavir crisis by revisiting the polymorph landscape with crystal structure prediction and form 4 structure solution

Luca Iuzzolino; Andrew W. Kelly; Mohammad T. Chaudhry; Cristian Jandl; Danny Stam; Alfred Y. Lee

Revisiting ritonavir’s polymorph landscape, the authors examined whether crystal structure prediction could have flagged the risk posed by the less soluble Form 2. They also solved the previously unresolved Form 4 structure using 3D electron diffraction, modeling, and powder X-ray diffraction, finding disorder and thermodynamic instability. The retrospective analysis informs risk assessment rather than guaranteeing future polymorph prediction.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1038/s42004-025-01814-6

Original research
ChemMedChem

Discovery of Oxyacanthine Dihydrochloride Monohydrate Polymorphs from Obfuscated Samples by Microcrystal Electron Diffraction

Jieye Lin; Orel Paz; Johan Unge; Tamir Gonen

MicroED identified two polymorphic structures of oxyacanthine dihydrochloride monohydrate in samples mislabeled as berbamine dihydrochloride. The forms differed principally in the conformation of a tetrahydroisoquinoline ring. Structural, energetic, and packing analyses suggested a thermodynamic preference between them. The study demonstrates how crystallographic analysis can expose both identity problems and polymorphism in complex natural-product samples.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1002/cmdc.202500601

Original research
Crystal Growth & Design

Crystal Structure Determination of Inseparable Polymorphic Mixtures by 3D ED/MicroED

Keiyo Nakai; Kuniyoshi Miki; Takashi Kikuchi; Hiroyasu Sato; Keigo Takahira; Robert Bücker; Akito Sasaki; Atsushi Kaga; Ryo Anzai; Mitsuhisa Yamano

3D ED/MicroED determined casopitant mesylate Forms 1 and 3 from one batch of fine powder containing an inseparable polymorphic mixture. Their structures differed through a small packing shift, explaining their very similar powder X-ray diffraction patterns. The work demonstrates how selecting individual microcrystals can resolve structurally similar phases that remain difficult to separate or distinguish in bulk measurements.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1021/acs.cgd.5c01477

Original research
Chemical and Pharmaceutical Bulletin

Combination of Microcrystal Electron Diffraction and Solid-State NMR for the Structural Determination of Indomethacin–Nicotinamide Co-crystals

Hidetomo Yokoo; Tatsuo Koide; Tamaki Miyazaki; Yoshitaka Aoyama; Yutaro Ogaeri; Eiichi Yamamoto; Yosuke Demizu; Nahoko Uchiyama

This study characterized indomethacin–nicotinamide cocrystals using MicroED together with solid-state NMR, Raman spectroscopy, and powder X-ray diffraction. MicroED supplied the crystal structure, while NMR helped examine molecular interactions. The combined approach addressed properties that individual methods could not establish alone, offering a pharmaceutical cocrystal workflow relevant to API powders and formulations containing excipients.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1248/cpb.c25-00377

Original research
Molecular Pharmaceutics

Structural Analysis of Active Pharmaceutical Ingredients in Tablets Using 3D ED/MicroED

Keiyo Nakai; Takashi Kikuchi; Kuniyoshi Miki; Akito Sasaki; Mitsuhisa Yamano

The study examined API crystals directly in Allegra, Clarith, and Ibrance tablets using selected-area 3D ED/MicroED. Fexofenadine hydrochloride Form I and clarithromycin Form II retained their polymorphs, while palbociclib Form A showed slight lattice shrinkage. The results demonstrate formulation-level structural analysis and emphasize that a lattice change and a new polymorph are different findings.

MicroED structure determinationPharmaceutical solid stateFormulation Development & Manufacturing
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DOI: 10.1021/acs.molpharmaceut.5c00028

Original research
IUCrJ

SCXRD, CSP-NMRX and microED in the quest for three elusive polymorphs of meloxicam

Agata Jeziorna; Maura Malinska; Isaac Sugden; Piotr Paluch; Rafał Dolot; Marta K. Dudek

Three elusive meloxicam polymorphs required different structure-determination approaches. Single-crystal X-ray diffraction solved Form III, combined crystal structure prediction and NMR crystallography solved Form II, and electron diffraction resolved Form V, which contains four independent molecules in the asymmetric unit. The comparison highlights complementary strengths and limitations rather than establishing one universally superior crystallographic method.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1107/s2052252524011898

Original research
IUCrJ

From formulation to structure: 3D electron diffraction for the structure solution of a new indomethacin polymorph from an amorphous solid dispersion

Helen W. Leung; Royston C. B. Copley; Giulio I. Lampronti; Sarah J. Day; Lucy K. Saunders; Duncan N. Johnstone; Paul A. Midgley

3D electron diffraction resolved the structure of the ninth reported indomethacin polymorph, designated sigma, from crystals found within an amorphous solid dispersion. Subsequent experiments produced the same form by solvent evaporation. The work demonstrates structure determination directly from a formulation-related sample containing an excipient; it does not establish improved dissolution or clinical performance for the new form.

MicroED structure determinationPharmaceutical solid stateFormulation Development & Manufacturing
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DOI: 10.1107/s2052252524008121

Original research
Crystal Growth & Design

Polyethylene Glycol-Assisted Melt Crystallization of Two New Piroxicam Polymorphs Revealed by 3D Electron Diffraction

Jiaoyan Xu; Changlin Yao; Shufang Zhang; Xiaodong Zou; Yue Gui; Lei Wang; Hongyi Xu

Two previously unreported piroxicam polymorphs, Forms VIII and IX, emerged through polyethylene glycol-assisted melt crystallization. Their crystal structures were determined by 3D electron diffraction. Comparing the newly solved Form VIII with known Form IV allowed discussion of how differences in intermolecular hydrogen bonding contribute to melting behavior. The study concerns laboratory solid forms rather than validated drug-product performance.

MicroED structure determinationPharmaceutical solid state
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DOI: 10.1021/acs.cgd.4c00951

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