Solid State and Polymorphism of the Drug Substance in the Context of Quality by Design and ICH Guidelines Q8–Q12

Raumer, Markus von; Hilfiker, Rolf

doi:10.1002/9783527697847.ch1

Cited by 8 publications

(10 citation statements)

References 100 publications

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“…Regardless of numerous attempts, no anhydrous cocrystal with fumaric acid was observed, whereas a solvent-free cocrystal was obtained with its geometrical isomer, maleic acid. A PSZ−coformer stoichiometric ratio of 1 to 1 was suggested by 1 H NMR for both PSZ−MLE and PSZ−FUM cocrystals, while the cocrystals with the aliphatic dicarboxylic acids, such as adipic and succinic acid, show a PSZ−coformer stoichiometry of 2 to 1.…”

Section: ■ Resultsmentioning

confidence: 96%

“…Proton Nuclear Magnetic Resonance ( 1 H NMR). 1 H NMR analysis was carried out with a Bruker DPX300 spectrometer (Bruker AG, Fallanden, Switzerland) using a proton frequency of 300.13 MHz, a 30°excitation pulse, and a recycle delay of 1 s. Spectra were recorded by the accumulation of 16 scans in deuterated DMSO. The solvent peak was used for reference, and the chemical shifts were reported to the TMS scale.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…The molecular solid state strongly affects the physicochemical properties of organic compounds . To achieve solubility, dissolution rate, and absorption advantages, new solid forms of active pharmaceutical ingredients (APIs) are continuously developed, such as amorphous or coamorphous phases, polymorphs, and salts. , In this regard, cocrystals have received particular attention because they are potentially very useful in overcoming several drug limitations (e.g., solubility, dissolution, stability, and hygroscopicity).…”

Section: Introductionmentioning

confidence: 99%

“…1 H NMR spectra for the posaconazole starting material and the new cocrystals obtained; and COSMOquick, MC, and HBP calculation results (PDF) Solid-State Development Department, Solvias AG, CH-4303 Kaiseraugst, Switzerland; orcid.org/0000-0002-2879-9577; Email: fritz.blatter@solvias.com…”

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confidence: 99%

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Exploring the Cocrystal Landscape of Posaconazole by Combining High-Throughput Screening Experimentation with Computational Chemistry

Guidetti¹,

Hilfiker²,

Kuentz

et al. 2022

Crystal Growth & Design

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The development of multicomponent crystal forms, such as cocrystals, represents a means to enhance the dissolution and absorption properties of poorly water-soluble drug compounds. However, the successful discovery of new pharmaceutical cocrystals remains a time-and resource-consuming process. This study proposes the use of a combined computational-experimental high-throughput approach as a tool to accelerate and improve the efficiency of cocrystal screening exemplified by posaconazole. First, we employed the COSMOquick software to preselect and rank cocrystal candidates (coformers). Second, high-throughput crystallization experiments (HTCS) were conducted on the selected coformers. The HTCS results were successfully reproduced by liquid-assisted grinding and reaction crystallization, ultimately leading to the synthesis of thirteen new posaconazole cocrystals (7 anhydrous, 5 hydrates, and 1 solvate). The posaconazole cocrystals were characterized by PXRD, 1 H NMR, Fourier transform-Raman, thermogravimetry−Fourier transform infrared spectroscopy, and differential scanning calorimetry. In addition, the prediction performance of COSMOquick was compared to that of two alternative knowledge-based methods: molecular complementarity (MC) and hydrogen bond propensity (HBP). Although HBP does not perform better than random guessing for this case study, both MC and COSMOquick show good discriminatory ability, suggesting their use as a potential virtual tool to improve cocrystal screening.

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Section: ■ Resultsmentioning

confidence: 96%

Section: ■ Materials and Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Exploring the Cocrystal Landscape of Posaconazole by Combining High-Throughput Screening Experimentation with Computational Chemistry

Guidetti¹,

Hilfiker²,

Kuentz

et al. 2022

Crystal Growth & Design

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“…Usually, different polymorphic forms possess different physicochemical and, as a consequence, biological properties (bioavailability, dissolution rate, etc. ). − An undesired polymorphic transition can crucially influence the drug quality as occurred with ritonavir (the trademark is Norvir) . Therefore, an in-depth study of the polymorphism of an active pharmaceutical ingredient (API) aims not only at protecting the patent of a drug but also at choosing the most appropriate polymorphic form according to the combination of several factors such as manufacturability, stability, biological activity, reproducibility, etc. , …”

Section: Introductionmentioning

confidence: 99%

High-Pressure Influence on Piracetam Crystals: Studying by Quantum Chemical Methods

Vaksler

Idriss

Shishkina

2021

Crystal Growth & Design

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The method developed previously for studying mechanical properties using quantum chemical calculations was applied to predict the most probable direction of deformation of the piracetam polymorphic Form II under pressure. By the analysis of the pairwise interaction energies between molecules in Form II, this structure was classified as columnar-layered. The shear deformation modeling of the strongly bound fragments in crystal packing predicted the [100] crystallographic direction with a shift energy barrier of 5.2 kcal/mol to be the most probable within the (001) crystallographic plane for Form II deformation. Comparison of Form II before the polymorphic transition and Form V after the crystal structure change confirmed the results of quantum chemical modeling. The analysis of the shift energy profile indicated the characteristic features (a local minimum near the starting point, negative interaction energies between layers during the displacement, and a low shift energy barrier) that can be used to predict a polymorphic transition. The study of the pairwise interaction energies in the piracetam Forms II and V under pressure has revealed that the crystal structure can be changed under pressure in two stages. In the first stage, the polymorphic transition occurs due to the shift of weakly bound layers without changing the columnar-layered type of the crystal structure from the energetic viewpoint. In the second stage, a change in the ratio of the interaction energies between BSM1 and BSM2 results in the transition of the crystal structure type from columnar-layered to columnar without changing the polymorphic form.

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Phase Identification and Discovery of an Elusive Polymorph of Drug‐Polymer Inclusion Complex Using Automated 3D Electron Diffraction

Lightowler,

Li,

et al. 2024

Angewandte Chemie

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3D electron diffraction (3D ED) has shown great potential in crystal structure determination in materials, small organic molecules, and macromolecules. In this work, an automated, low‐dose and low‐bias 3D ED protocol has been implemented to identify six phases from a multiple‐phase melt‐crystallisation product of an active pharmaceutical ingredient, griseofulvin (GSF). Batch data collection under low‐dose conditions using a widely available commercial software was combined with automated data analysis to collect and process over 230 datasets in three days. Accurate unit cell paramters obtained from 3D ED data allowed direct phase identification of GSF Forms III, I and the known GSF inclusion complex (IC) with polyethylene glycol (PEG) (GSF‐PEG IC‐I), as well as three minor phases, namely GSF Forms II, V and an elusive new phase, GSF‐PEG IC‐II. Their structures were then directly determined by 3D ED. Furthermore, we reveal how the stabilities of the two GSF‐PEG IC polymorphs are closely related to their crystal structures. These results demonstrate the power of automated 3D ED for accurate phase identification and direct structure determination of complex, beam‐sensitive crystallisation products, which is significant for drug development where solid form screening is crucial for the overall efficacy of the drug product.

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Solid State and Polymorphism of the Drug Substance in the Context of Quality by Design and ICH Guidelines Q8–Q12

Cited by 8 publications

References 100 publications

Exploring the Cocrystal Landscape of Posaconazole by Combining High-Throughput Screening Experimentation with Computational Chemistry

Exploring the Cocrystal Landscape of Posaconazole by Combining High-Throughput Screening Experimentation with Computational Chemistry

High-Pressure Influence on Piracetam Crystals: Studying by Quantum Chemical Methods

Phase Identification and Discovery of an Elusive Polymorph of Drug‐Polymer Inclusion Complex Using Automated 3D Electron Diffraction

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