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Pharmaceutics
Special Issues
Stability and Dissolution Behavior of Pharmaceutical Cocrystals
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Stability and Dissolution Behavior of Pharmaceutical Cocrystals

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (20 April 2022) | Viewed by 20126

Special Issue Editors

Prof. Dr. Naír Rodríguez-Hornedo

E-Mail Website
Guest Editor
University of Michigan, Ann Arbor, Ann Arbor, United States
Prof. Dr. Dea Herrera-Ruíz

E-Mail Website
Guest Editor
Universidad Autonoma del Estado de Morelos, Cuernavaca, Morelos, Mexico

Special Issue Information

Dear Colleagues,

We are delighted to present this Special Issue on “Stability and Dissolution Behavior of Pharmaceutical Cocrystals”.

Oral drug administration is not feasible for many life-saving medicines due to poor aqueous solubility. Cocrystals have emerged as a technology platform to enhance the aqueous solubility and bioavailability of orally administered drugs. Investigations concerning design and functional characterization of pharmaceutical cocrystals have rapidly increased in the last decade. Despite significant advances in cocrystal discovery, their translation into pharmaceutical products has been limited by their unpredictable dissolution behavior due to conversion to less soluble forms of the drug. Such conversions lead to erratic product behavior, nullify the cocrystal solubility advantage, and present difficulties in establishing in vitro–in vivo correlations that lead to optimal drug delivery. This problem has been addressed by empirical approaches on a case-by-case basis, and there is a need for conceptual designs of cocrystal delivery systems. Since the clinical benefits of cocrystals often depend on the kinetics of drug supersaturation and nucleation, there is a critical need to understand the dissolution, drug supersaturation and precipitation processes. As supersaturating drug delivery systems, cocrystals require formulation additives that generate kinetically sustainable supersaturations to dissolve the drug dose.

This issue aims to advance our current understanding of cocrystal stability and dissolution and provide meaningful cocrystal characterization methods to assess the influence of formulation additives on cocrystal thermodynamic stability and risk of phase conversion during dissolution process. We welcome contributions that deepen our knowledge of cocrystal dissolution mechanisms, approaches to control drug supersaturation, criteria for formulation additive selection, cocrystal to drug conversion pathways, methodologies for thermodynamic and kinetic characterization, and cocrystal property–function relationships including cocrystalline salts and polymorphs, among other relevant topics.

Prof. Dr. Naír Rodríguez-Hornedo
Prof. Dr. Dea Herrera-Ruíz
Guest Editors

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 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. Pharmaceutics 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.

Keywords

  • cocrystal dissolution
  • supersaturation
  • drug precipitation
  • precipitation inhibitors
  • phase transformation
  • pH
  • stability
  • surfactants
  • lipids
  • drug solubilizers
  • solubility

Published Papers (5 papers)

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Research

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30 pages, 14250 KiB  
Article
Tailoring Chlorthalidone Aqueous Solubility by Cocrystallization: Stability and Dissolution Behavior of a Novel Chlorthalidone-Caffeine Cocrystal
by Christian Rodríguez-Ruiz, Pedro Montes-Tolentino, Jorge Guillermo Domínguez-Chávez, Hugo Morales-Rojas, Herbert Höpfl and Dea Herrera-Ruiz
Pharmaceutics 2022, 14(2), 334; https://doi.org/10.3390/pharmaceutics14020334 - 30 Jan 2022
Cited by 8 | Viewed by 3739
Abstract
A cocrystal of the antihypertensive drug chlorthalidone (CTD) with caffeine (CAF) was obtained (CTD-CAF) by the slurry method, for which a 2:1 stoichiometric ratio was found by powder and single-crystal X-ray diffraction analysis. Cocrystal CTD-CAF showed a supramolecular organization in which CAF molecules [...] Read more.
A cocrystal of the antihypertensive drug chlorthalidone (CTD) with caffeine (CAF) was obtained (CTD-CAF) by the slurry method, for which a 2:1 stoichiometric ratio was found by powder and single-crystal X-ray diffraction analysis. Cocrystal CTD-CAF showed a supramolecular organization in which CAF molecules are embedded in channels of a 3D network of CTD molecules. The advantage of the cocrystal in comparison to CTD is reflected in a threefold solubility increase and in the dose/solubility ratios, which diminished from near-unit values for D0D to 0.29 for D0CC. Furthermore, dissolution experiments under non-sink conditions showed improved performance of CTD-CAF compared with pure CTD. Subsequent studies showed that CTD-CAF cocrystals transform to CTD form I where CTD precipitation inhibition could be achieved in the presence of pre-dissolved polymer HPMC 80–120 cPs, maintaining supersaturation drug concentrations for at least 180 min. Finally, dissolution experiments under sink conditions unveiled that the CTD-CAF cocrystal induced, in pH-independent manner, faster and more complete CTD dissolution when compared to commercial tablets of CTD. Due to the stability and dissolution behavior of the novel CTD-CAF cocrystal, it could be used to develop solid dosage forms using a lower CTD dose to obtain the same therapeutic response and fewer adverse effects. Full article
(This article belongs to the Special Issue Stability and Dissolution Behavior of Pharmaceutical Cocrystals)
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18 pages, 92200 KiB  
Article
Two Novel Palbociclib-Resorcinol and Palbociclib-Orcinol Cocrystals with Enhanced Solubility and Dissolution Rate
by Chenxin Duan, Wenwen Liu, Yunwen Tao, Feifei Liang, Yanming Chen, Xinyi Xiao, Guisen Zhang, Yin Chen and Chao Hao
Pharmaceutics 2022, 14(1), 23; https://doi.org/10.3390/pharmaceutics14010023 - 23 Dec 2021
Cited by 13 | Viewed by 4014
Abstract
Palbociclib (PAL) is an effective anti-breast cancer drug, but its use has been partly restricted due to poor bioavailability (resulting from extremely low water solubility) and serious adverse reactions. In this study, two cocrystals of PAL with resorcinol (RES) or orcinol (ORC) were [...] Read more.
Palbociclib (PAL) is an effective anti-breast cancer drug, but its use has been partly restricted due to poor bioavailability (resulting from extremely low water solubility) and serious adverse reactions. In this study, two cocrystals of PAL with resorcinol (RES) or orcinol (ORC) were prepared by evaporation crystallization to enhance their solubility. The cocrystals were characterized by single crystal X-ray diffraction, Hirshfeld surface analysis, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared and scanning electron microscopy. The intrinsic dissolution rates of the PAL cocrystals were determined in three different dissolution media (pH 1.0, pH 4.5 and pH 6.8), and both cocrystals showed improved dissolution rates at pH 1.0 and pH 6.8 in comparison to the parent drug. In addition, the cocrystals increased the solubility of PAL at pH 6.8 by 2–3 times and showed good stabilities in both the accelerated stability testing and stress testing. The PAL-RES cocrystal also exhibited an improved relative bioavailability (1.24 times) than PAL in vivo pharmacokinetics in rats. Moreover, the in vitro cytotoxicity assay of PAL-RES showed an increased IC50 value for normal cells, suggesting a better biosafety profile than PAL. Co-crystallization may represent a promising strategy for improving the physicochemical properties of PAL with better pharmacokinetics. Full article
(This article belongs to the Special Issue Stability and Dissolution Behavior of Pharmaceutical Cocrystals)
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23 pages, 6219 KiB  
Article
Stability of Pharmaceutical Co-Crystals at Humid Conditions Can Be Predicted
by Heiner Veith, Maximilian Zaeh, Christian Luebbert, Naír Rodríguez-Hornedo and Gabriele Sadowski
Pharmaceutics 2021, 13(3), 433; https://doi.org/10.3390/pharmaceutics13030433 - 23 Mar 2021
Cited by 11 | Viewed by 3509
Abstract
Knowledge of the stability of pharmaceutical formulations against relative humidity (RH) is essential if they are to become pharmaceutical products. The increasing interest in formulating active pharmaceutical ingredients as stable co-crystals (CCs) triggers the need for fast and reliable in-silico predictions of CC [...] Read more.
Knowledge of the stability of pharmaceutical formulations against relative humidity (RH) is essential if they are to become pharmaceutical products. The increasing interest in formulating active pharmaceutical ingredients as stable co-crystals (CCs) triggers the need for fast and reliable in-silico predictions of CC stability as a function of RH. CC storage at elevated RH can lead to deliquescence, which leads to CC dissolution and possible transformation to less soluble solid-state forms. In this work, the deliquescence RHs of the CCs succinic acid/nicotinamide, carbamazepine/nicotinamide, theophylline/citric acid, and urea/glutaric acid were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These deliquescence RH values together with predicted phase diagrams of CCs in water were used to determine critical storage conditions, that could lead to CC instability, that is, CC dissolution and precipitation of its components. The importance of CC phase purity on RH conditions for CC stability is demonstrated, where trace levels of a separate phase of active pharmaceutical ingredient or of coformer can significantly decrease the deliquescence RH. The use of additional excipients such as fructose or xylitol was predicted to decrease the deliquescence RH even further. All predictions were successfully validated by stability measurements at 58%, 76%, 86%, 93%, and 98% RH and 25 °C. Full article
(This article belongs to the Special Issue Stability and Dissolution Behavior of Pharmaceutical Cocrystals)
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20 pages, 3746 KiB  
Article
Effects of the Glass-Forming Ability and Annealing Conditions on Cocrystallization Behaviors via Rapid Solvent Removal: A Case Study of Voriconazole
by Si Nga Wong, Susan Wing Sze Chan, Xuexin Peng, Bianfei Xuan, Hok Wai Lee, Henry H. Y. Tong and Shing Fung Chow
Pharmaceutics 2020, 12(12), 1209; https://doi.org/10.3390/pharmaceutics12121209 - 14 Dec 2020
Cited by 10 | Viewed by 2518
Abstract
The kinetic entrapment of molecules in an amorphous phase is a common obstacle to cocrystal screening using rapid solvent removal, especially for drugs with a moderate or high glass-forming ability (GFA). The aim of this study was to elucidate the effects of the [...] Read more.
The kinetic entrapment of molecules in an amorphous phase is a common obstacle to cocrystal screening using rapid solvent removal, especially for drugs with a moderate or high glass-forming ability (GFA). The aim of this study was to elucidate the effects of the coformer’s GFA and annealing conditions on the nature of amorphous phase transformation to the cocrystal counterpart. Attempts were made to cocrystallize voriconazole (VRC) with four structural analogues, namely fumaric acid (FUM), tartaric acid (TAR), malic acid (MAL), and maleic acid (MAE). The overall GFA of VRC binary systems increased with decreasing glass transition temperatures (Tgs) of these diacids, which appeared as a critical parameter for predicting the cocrystallization propensity such that a high-Tg coformer is more desirable. A new 1:1 VRC-TAR cocrystal was successfully produced via a supercooled-mediated re-cocrystallization process, and characterized by PXRD, DSC, and FTIR. The cocrystal purity against the annealing temperature displayed a bell-shaped curve, with a threshold at 40 °C. The isothermal phase purity improved with annealing and adhered to the Kolmogorov–Johnson–Mehl–Avrami kinetics. The superior dissolution behavior of the VRC-TAR cocrystal could minimize VRC precipitation upon gastric emptying. This study offers a simple but useful guide for efficient cocrystal screening based on the Tg of structurally similar coformers, annealing temperature, and time. Full article
(This article belongs to the Special Issue Stability and Dissolution Behavior of Pharmaceutical Cocrystals)
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Review

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35 pages, 31711 KiB  
Review
Improving the Physicochemical and Biopharmaceutical Properties of Active Pharmaceutical Ingredients Derived from Traditional Chinese Medicine through Cocrystal Engineering
by Danyingzi Guan, Bianfei Xuan, Chengguang Wang, Ruitao Long, Yaqin Jiang, Lina Mao, Jinbing Kang, Ziwen Wang, Shing Fung Chow and Qun Zhou
Pharmaceutics 2021, 13(12), 2160; https://doi.org/10.3390/pharmaceutics13122160 - 15 Dec 2021
Cited by 17 | Viewed by 5101
Abstract
Active pharmaceutical ingredients (APIs) extracted and isolated from traditional Chinese medicines (TCMs) are of interest for drug development due to their wide range of biological activities. However, the overwhelming majority of APIs in TCMs (T-APIs), including flavonoids, terpenoids, alkaloids and phenolic acids, are [...] Read more.
Active pharmaceutical ingredients (APIs) extracted and isolated from traditional Chinese medicines (TCMs) are of interest for drug development due to their wide range of biological activities. However, the overwhelming majority of APIs in TCMs (T-APIs), including flavonoids, terpenoids, alkaloids and phenolic acids, are limited by their poor physicochemical and biopharmaceutical properties, such as solubility, dissolution performance, stability and tabletability for drug development. Cocrystallization of these T-APIs with coformers offers unique advantages to modulate physicochemical properties of these drugs without compromising the therapeutic benefits by non-covalent interactions. This review provides a comprehensive overview of current challenges, applications, and future directions of T-API cocrystals, including cocrystal designs, preparation methods, modifications and corresponding mechanisms of physicochemical and biopharmaceutical properties. Moreover, a variety of studies are presented to elucidate the relationship between the crystal structures of cocrystals and their resulting properties, along with the underlying mechanism for such changes. It is believed that a comprehensive understanding of cocrystal engineering could contribute to the development of more bioactive natural compounds into new drugs. Full article
(This article belongs to the Special Issue Stability and Dissolution Behavior of Pharmaceutical Cocrystals)
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