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Crystals
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Advances in Pharmaceutical Crystals: Numerical Simulations and Experimental Investigations
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Advances in Pharmaceutical Crystals: Numerical Simulations and Experimental Investigations

A special issue of Crystals (ISSN 2073-4352). This special issue belongs to the section "Industrial Crystallization".

Deadline for manuscript submissions: 20 September 2026 | Viewed by 1661

Editor

Prof. Dr. Jasna Prlić Kardum

E-Mail Website
Guest Editor
Department of Mechanical and Thermal Process Engineering, Faculty of Chemical Engineering and Technology, University of Zagreb, Trg Marka Marulića 19, 10000 Zagreb, Croatia
Interests: crystalisation; extraction; drying; transport phenomena; eutectic solvent; API solubility

Special Issue Information

Dear Colleagues,

The solid-state form of an active pharmaceutical ingredient, particularly its crystalline structure, is a critical determinant of drug product performance, influencing key properties such as solubility, stability, bioavailability and manufacturability. Understanding and controlling crystallization processes and final crystal forms are therefore paramount in pharmaceutical development. This field is being revolutionized by the powerful synergy between numerical simulations and advanced experimental investigations. Modern research leverages computational methods—including molecular dynamics, density functional theory and process modeling—to predict polymorphs, crystal habits and crystallization pathways. These simulations are intricately validated and guided by cutting-edge experimental techniques such as in situ spectroscopy, high-resolution X-ray diffraction and thermal analysis. This integrated approach accelerates the rational design of optimal pharmaceutical crystals with desired characteristics.

This Special Issue aims to compile high-quality original research and review articles that highlight recent progress at the intersection of computational and experimental studies of pharmaceutical crystals. Topics of interest include, but are not limited to:

  • Advanced control of granulometric characteristics (size, shape and distribution) to improve flowability and processability.
  • Strategies to improve solubility, stability and bioavailability through co-crystallization and the formation of multicomponent systems.
  • Innovative use of plant components in the crystallization process to adjust active pharmaceutical ingredient.
  • The role of numerical simulations in understanding and predicting crystal growth and phase transitions.
  • New crystallization techniques and characterization methods for complex pharmaceutical systems.
  • Prediction and stability assessment of polymorphs, hydrates and cocrystals.
  • Computational screening for crystal structure and co-former selection.
  • Process analytical technology and in situ monitoring of crystallization.
  • Design and control of crystal size, shape and morphology.
  • Interplay between crystal structure and bulk powder properties (flow and compaction).
  • Novel experimental characterization techniques for crystal forms.
  • Case studies on the integrated use of simulation and experiment in drug development.

Prof. Dr. Jasna Prlić Kardum
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Crystals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2100 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pharmaceutical crystals
  • polymorphism
  • cocrystals
  • crystallization process
  • molecular modeling
  • process simulation
  • in situ characterization
  • crystal engineering
  • solid-form screening
  • computational pharmaceutics

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  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
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Further information on MDPI's Special Issue policies can be found here.

Published Papers (2 papers)

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Research

18 pages, 3957 KB  
Article
Robustness-Aware Genetic Algorithm for Batch Crystallization with an LSTM Digital Twin
by Ivan Vrban, Nenad Bolf and Josip Budimir Sacher
Crystals 2026, 16(6), 367; https://doi.org/10.3390/cryst16060367 - 1 Jun 2026
Viewed by 616
Abstract
Batch crystallization processes are prone to batch-to-batch inconsistencies arising from operational uncertainties and equipment-induced noise. This study presents a Robustness-Aware Genetic Algorithm (RAGA) integrated with a Long Short-Term Memory (LSTM) digital twin for the design of robust crystallization procedures. The RAGA employs a [...] Read more.
Batch crystallization processes are prone to batch-to-batch inconsistencies arising from operational uncertainties and equipment-induced noise. This study presents a Robustness-Aware Genetic Algorithm (RAGA) integrated with a Long Short-Term Memory (LSTM) digital twin for the design of robust crystallization procedures. The RAGA employs a hierarchical fitness function that strictly enforces a target median crystal size D50 as the primary constraint while maximizing process yield as a secondary objective. Robustness is incorporated directly into the optimization by requiring candidate trajectories to satisfy the D50 specification across five independent stochastic realizations with perturbed operating conditions. A candidate is promoted in the evolutionary search only if all five evaluations produce a predicted D50 within ±2 µm of the target. The framework was applied to seeded cooling crystallization of creatine monohydrate across three target crystal sizes of 115, 125, and 135 µm. Robustness of optimal crystallization procedures was independently verified through 100-run Monte Carlo simulations under ±10% parameter perturbations with success defined as D50 within ±5 µm of target. Experimental validation at laboratory scale confirmed that optimized procedures translate to practice, with two of three target sizes achieved within the ±5 µm specification and the third deviating due to the combined effect of LSTM prediction uncertainty and thermal lag. Despite having no embedded mechanistic knowledge, the optimizer successfully converged on physically coherent crystallization strategies. Its variations in seed loading, batch time, and cooling trajectory parameters remained entirely consistent with established principles of supersaturation management. The results demonstrate that embedding robustness directly within the evolutionary optimization loop enables consistent crystal size control using data-driven models. Full article
(This article belongs to the Special Issue Advances in Pharmaceutical Crystals: Numerical Simulations and Experimental Investigations)
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18 pages, 835 KB  
Article
Entropy-Driven Isosymmetric Phase Transition in L-Serine Under Pressure: A Periodic DFT Study
by Anna Maria Mazurek, Monika Franczak-Rogowska and Łukasz Szeleszczuk
Crystals 2026, 16(4), 266; https://doi.org/10.3390/cryst16040266 - 16 Apr 2026
Viewed by 587
Abstract
Understanding pressure-induced isosymmetric phase transitions in molecular crystals requires consideration of both structural and thermodynamic factors, particularly in hydrogen-bonded systems. In this work, periodic density functional theory (DFT) calculations were employed to investigate the pressure-dependent behavior of L-serine and to elucidate the origin [...] Read more.
Understanding pressure-induced isosymmetric phase transitions in molecular crystals requires consideration of both structural and thermodynamic factors, particularly in hydrogen-bonded systems. In this work, periodic density functional theory (DFT) calculations were employed to investigate the pressure-dependent behavior of L-serine and to elucidate the origin of its experimentally observed phase transition between Phase I and Phase IV. Geometry optimizations performed at ambient pressure and 8.8 GPa reproduce the compression of the crystal lattice and the pressure-driven stabilization of Phase IV. However, no spontaneous reorientation of the hydroxyl groups is observed, indicating that the transition is not accessible within a purely static framework. To further explore the stability of the system, a series of modified crystal structures with different hydroxyl group orientations was generated and analyzed, revealing a complex energy landscape at ambient conditions that becomes significantly simplified under compression. Phonon calculations within the quasi-harmonic approximation demonstrate that the experimentally observed Phase I structure is not stabilized by enthalpy but by vibrational entropy, whose contribution increases with temperature. These results show that the phase transition in L-serine is governed by an interplay between lattice energy, hydrogen-bond rearrangement, and vibrational effects, and highlight that an accurate description of polymorphic stability in such systems requires inclusion of both static and dynamic contributions. Full article
(This article belongs to the Special Issue Advances in Pharmaceutical Crystals: Numerical Simulations and Experimental Investigations)
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