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Polymorphs, Salts, and Cocrystals in Drug Delivery

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmaceutical Technology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 12901

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Prof. Dr. Stephen Byrn

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Department of Industrial and Physical Pharmacy, School of Pharmacy and Pharmaceutical Sciences, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47906, USA
Interests: solid state chemistry; pair distribution function; synchrotron x-ray diffraction; solid nanoparticles; drug quality; polymorphs; salts; cocrystals; amorphous forms
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Dear Colleagues,

Historically, the interest in polymorphs, salts, and cocrystals arose from a desire to control the solid form used in drug development and avoid costly delays such as the ritonavir disaster. Screening methods were developed by SSCI and other companies and marketed as potential solutions to these problems. Many large companies developed internal teams to address these issues. However, even in the early years, drug delivery scientists were interested in salts especially based on the early paper by Eino Nelson. Many years later, the application of polymorphs, cocrystals and salts, and other solid-state chemistry approaches to drug delivery has emerged as a powerful new method to control drug release and bioavailability.

This issue aims to compile and document some of the most powerful drug delivery methods using polymorphs, cocrystals, salts, and solid-state chemistry. The goal is to enable the reader to access important papers in this area in a single journal issue.

Prof. Dr. Stephen Byrn
Guest Editor

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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 100 words) can be sent to the Editorial Office for announcement on this website.

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-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals 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 2900 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.

Published Papers (7 papers)

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Research

16 pages, 2870 KiB

Open AccessArticle

Design and Evaluation of S-Protected Thiolated-Based Itopride Hydrochloride Polymeric Nanocrystals for Functional Dyspepsia: QbD-Driven Optimization, In Situ, In Vitro, and In Vivo Investigation

by Moutaz Y. Badr, Pratap Basim, Khaled M. Hosny, Waleed Y. Rizg, N. Raghavendra Naveen, Mallesh Kurakula, Fayez Alsulaimani, Awaji Y. Safhi, Fahad Y. Sabei, Mohammed Alissa and Abdulmohsin J. Alamoudi

Pharmaceuticals 2023, 16(7), 925; https://doi.org/10.3390/ph16070925 - 25 Jun 2023

Cited by 1 | Viewed by 1053

Abstract

Mucoadhesive nanosized crystalline aggregates (NCs) can be delivered by the gastrointestinal, nasal, or pulmonary route to improve retention at particular sites. Itopride hydrochloride (ITH) was selected as a drug candidate due to its absorption from the upper gastrointestinal tract. For drug localization and target-specific actions, mucoadhesive polymers are essential. The current work aimed to use second-generation mucoadhesive polymers (i.e., thiolated polymers) to enhance mucoadhesive characteristics. An ITH-NC formulation was enhanced using response surface methodology. Concentrations of Tween 80 and Polyvinyl pyrrolidone (PVP K-30) were selected as independent variables that could optimize the formulation to obtain the desired entrapment efficacy and particle size/diameter. It was found that a formulation prepared using Tween 80 at a concentration of 2.55% and PVP K-30 at 2% could accomplish the goals for which an optimized formulation was needed. Either xanthan gum (XG) or thiolated xanthan gum (TXG) was added to the optimized formulation to determine how they affected the mucoadhesive properties of the formulation. Studies demonstrated that there was an initial burst release of ITH from the ITH/NC/XG and ITH/NC/TXG in the early hours and then a steady release for 24 h. As anticipated, the TXG formulation had a better mucin interaction, and this was needed to ensure that the drug was distributed to tissues that produce mucus. Finally, at the measured concentrations, the ITH/NC showed minimal cytotoxicity against lung cells, indicating that it may have potential for additional in vivo research. The enhanced bioavailability and mean residence time of the designed mucoadhesive NC formulations were confirmed by pharmacokinetic studies. Full article

(This article belongs to the Special Issue Polymorphs, Salts, and Cocrystals in Drug Delivery)

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24 pages, 5069 KiB

Open AccessArticle

Diversity of Solid Forms Promoted by Ball Milling: Characterization and Intrinsic Dissolution Studies of Pioglitazone Hydrochloride and Fluvastatin Sodium Drug–Drug Systems

by Marco Villeda-Villegas, José C. Páez-Franco, Guadalupe Coyote-Dotor, Alejandra Núñez-Pineda, Alejandro Dorazco-González, Inés Fuentes-Noriega, Kenneth Rubio-Carrasco, Helen P. Toledo Jaldín, David Morales-Morales and Juan Manuel Germán-Acacio

Pharmaceuticals 2023, 16(6), 781; https://doi.org/10.3390/ph16060781 - 24 May 2023

Cited by 1 | Viewed by 1431

Abstract

Coamorphous salt in a 1:1 ratio prepared by ball milling from Fluvastatin sodium (FLV) and Pioglitazone hydrochloride (PGZ·HCl) can be selectively formed by neat grinding (NG). Furthermore, the salt–cocrystal continuum was preferably formed by employing liquid-assisted grinding (LAG) using ethanol (EtOH). Attempts to prepare the coamorphous salt starting from the salt–cocrystal continuum by NG were unsuccessful. Interestingly, through ball milling by NG or LAG, a great diversity of solid forms (PGZ·HCl-FLV 1:1) could be accessed: NG and hexane (coamorphous); ethyl acetate (physical mixture); EtOH (salt–cocrystal continuum); and water (which presents two T_g, indicating immiscibility of the components). An exploration was performed at different drug-to-drug ratios by NG. By differential scanning calorimetry (DSC), the presence of two endothermic events was observed in this screening: incongruous melting point (solidus) and excess of one of the components (liquidus), except in the 1:1 solid form. From these results, eutectic behavior was observed. Through the construction of a binary phase diagram, it was determined that the 1:1 molar ratio gives rise to the formation of the most stable coamorphous composition. Dissolution profile studies of these solid forms were carried out, specifically on pure FLV and the solid forms of PGZ⋅HCl-FLV (1:2; 1:4; and 1:6), together with the coamorphous 1:1 salt. By itself, pure FLV presented the highest K_int (13.6270 ± 0.8127 mg/cm²⋅min). On the other hand, the coamorphous 1:1 showed a very low K_int (0.0220 ± 0.0014 mg/cm²·min), indicating very fast recrystallization by the FLV, which avoids observing a sudden release of this drug in the solution. This same behavior was observed in the eutectic composition 1:2. In the other solid forms, the value of K_int increases along with the %w of FLV. From the mechanochemical point of view, ball milling by NG or LAG became an important synthetic tool since it allows obtaining a great variety of solid forms to explore the solid-state reactivity of the drug–drug solid-form PGZ HCl-FLV. Full article

(This article belongs to the Special Issue Polymorphs, Salts, and Cocrystals in Drug Delivery)

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22 pages, 7764 KiB

Open AccessArticle

Rational Coformer Selection in the Development of 6-Propyl-2-thiouracil Pharmaceutical Cocrystals

by Francisco Javier Acebedo-Martínez, Carolina Alarcón-Payer, Cristóbal Verdugo-Escamilla, Jesús Martín, Antonio Frontera, Alicia Domínguez-Martín, Jaime Gómez-Morales and Duane Choquesillo-Lazarte

Pharmaceuticals 2023, 16(3), 370; https://doi.org/10.3390/ph16030370 - 28 Feb 2023

Viewed by 1742

Abstract

Pharmaceutical multicomponent solids have proved to efficiently modulate the physicochemical properties of active pharmaceutical ingredients. In this context, polyphenols are interesting coformers for designing pharmaceutical cocrystals due to their wide safety profile and interesting antioxidant properties. The novel 6-propyl-2-thiouracil multicomponent solids have been obtained by mechanochemical synthesis and fully characterized by powder and single-crystal X-ray diffraction methods. The analysis of supramolecular synthons has been further performed with computational methods, with both results revealing a robust supramolecular organization influenced by the different positions of the hydroxyl groups within the polyphenolic coformers. All novel 6-propyl-2-thiouracil cocrystals show an enhanced solubility profile, but unfortunately, their thermodynamic stability in aqueous media is limited to 24 h. Full article

(This article belongs to the Special Issue Polymorphs, Salts, and Cocrystals in Drug Delivery)

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16 pages, 4912 KiB

Open AccessArticle

Developing In Situ Chemometric Models with Raman Spectroscopy for Monitoring an API Disproportionation with a Complex Polymorphic Landscape

by Shikhar Mohan, Yi Li, Kevin Chu, Bing Shi, Liliana De La Paz, Prarthana Bakre, Chris Foti, Victor Rucker and Chiajen Lai

Pharmaceuticals 2023, 16(2), 327; https://doi.org/10.3390/ph16020327 - 20 Feb 2023

Viewed by 1956

Abstract

An in situ Raman method was developed to characterize the disproportionation of two salts involving a complex polymorphic landscape comprising up to two metastable and one stable freebase forms. Few precedents exist for Raman calibration procedures for solid form quantitation involving more than two polymorphs, while no literature examples were found for cases with multiple metastable forms. Therefore, a new Raman calibration procedure was proposed by directly using disproportionation experiments to generate multiple calibration samples encompassing a range of polymorph ratios through in-line Raman measurements complemented by off-line reference X-ray diffraction measurements. The developed Raman methods were capable of accurately quantitating each solid form in situ when solid concentration variation was incorporated into the calibration dataset. The kinetic understanding of the thermodynamically driven polymorphic conversions gained from this Raman method guided the selection of the salt best suited for the delivery of the active ingredient in the drug product. This work provided a spectroscopic and mathematical approach for simultaneously quantitating multiple polymorphs from a complex mixture of solids with the objective of real-time monitoring. Full article

(This article belongs to the Special Issue Polymorphs, Salts, and Cocrystals in Drug Delivery)

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25 pages, 5425 KiB

Open AccessArticle

Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of Bedaquiline

by Mercy A. Okezue and Stephen R. Byrn

Pharmaceuticals 2023, 16(2), 257; https://doi.org/10.3390/ph16020257 - 08 Feb 2023

Cited by 1 | Viewed by 2074

Abstract

Bedaquiline has been approved as a combination therapy to treat multi-drug-resistant tuberculosis in adults ≥ 18 years old. The citrate, fumarate, phosphate, and tartrate salts have obtained patents, but the structures for these moieties have not been extensively described in the literature; only the powder X-ray patterns have been published. To expand the knowledge of the bedaquiline structure, this study provides detailed information for the synthesis, elucidation, characterization, and stability of four additional new potential molecular entities, namely, benzoate, hydrochloride (HCl), nicotinate, and malonate salts. The salts were formed using a 1:1 ratio of the counter ions (acids) to a 30 mg equivalent of the bedaquiline free base. The principles of the International Conference on Harmonization Q6 were used to characterize the new salts and their stability-indicating parameters were evaluated at 0, 3, and 6 months under accelerated conditions of 40 °C and 75% relative humidity. The benzoate salt exhibited the lowest tendency to lose its chemical potency. Aside from the HCl salt, the others retained their chemical structure, displaying long-term stability. All salts were non-hygroscopic and the hydrated benzoate and nicotinate salts were stable to dehydration. Regarding their chemical potencies, thermal analysis, chemical stability, and water sorption potential, the salts were ranked as follows: benzoate > malonate > nicotinate > HCl. Full article

(This article belongs to the Special Issue Polymorphs, Salts, and Cocrystals in Drug Delivery)

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20 pages, 5174 KiB

Open AccessArticle

Formation and Characterisation of Posaconazole Hydrate Form

by Michail Lykouras, Malvina Orkoula and Christos Kontoyannis

Pharmaceuticals 2023, 16(1), 65; https://doi.org/10.3390/ph16010065 - 31 Dec 2022

Cited by 1 | Viewed by 1634

Abstract

Posaconazole is an API added as Form I for the production of oral suspensions, but it is found as Form-S in the final formulation. In this study, it was found that this polymorphic conversion, which may affect the bioavailability, is due to an interaction with water. However, the relatively poor wettability of posaconazole Form I renders the complete wetting of its particles and production of pure Form-S challenging. Consequently, for its isolation, Form I should be dispersed in water followed by application of sonication for at least 10 min. Pure posaconazole Form-S was characterised using X-ray powder diffraction (XRPD), Raman spectroscopy, attenuated total reflection (ATR) spectroscopy, thermogravimetric analysis (TGA) and optical microscopy. From these techniques, posaconazole Form-S was characterised as a hydrate form, which includes three molecules of water per API molecule. Full article

(This article belongs to the Special Issue Polymorphs, Salts, and Cocrystals in Drug Delivery)

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14 pages, 4562 KiB

Open AccessArticle

Two Novel Co-Crystals of Naproxen: Comparison of Stability, Solubility and Intermolecular Interaction

by Cheng Xing, Ting Chen, Li Wang, Qi An, Yali Jin, Dezhi Yang, Li Zhang, Guanhua Du and Yang Lu

Pharmaceuticals 2022, 15(7), 807; https://doi.org/10.3390/ph15070807 - 29 Jun 2022

Cited by 5 | Viewed by 2241

Abstract

Two novel co-crystals of naproxen (NPX) were designed and prepared at a stoichiometric ratio of 1:1, namely, naproxen–caprolactam (NPX–CPL) and naproxen–oxymatrine (NPX–OMT). The characteristics of the co-crystals were evaluated in terms of stability and solubility studies. In terms of solubility, in four kinds of solvent systems with different pH, the solubility of NPX–OMT was significantly improved compared with that of NPX, whereas the NPX–CPL showed advantages in acidic solvent systems, indicating that the co-crystals can be applied to concoct preparations depending on therapeutic purposes. Furthermore, the experimental results of the thermal analysis showed that the co-crystal NPX–OMT had better thermal stability than the co-crystal NPX–CPL. Finally, as a complement to the single crystal X-ray diffraction (SC XRD) method, the theoretical calculation based on density functional theory (DFT) was also used to reveal the intermolecular interaction of the co-crystals at the molecular level and visually display the difference between them. Full article

(This article belongs to the Special Issue Polymorphs, Salts, and Cocrystals in Drug Delivery)

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