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Pharmaceutics
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Cocrystal Applications in Drug Delivery
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Cocrystal Applications in Drug Delivery

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

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 44237

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Andrea Erxleben

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Guest Editor
The SFI Research Centre for Pharmaceuticals, Bernal Institute, University of Limerick, Limerick, Ireland
Interests: pharmaceutical cocrystals; amorphous formulations; control of crystal size and habit
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pharmaceutical cocrystals are multicomponent crystals in which at least one component is an active pharmaceutical ingredient. Cocrystallisation has long been recognised as a promising approach to modify the physicochemical properties of a drug without making chemical modifications to the drug molecule itself. The literature on cocrystals is constantly growing, and the small number of FDA approved cocrystals is increasing. Cocrystal formation is an attractive strategy to improve the bioavailability of a poorly soluble drug, i.e., to enhance the effectiveness of the drug becoming available at the target site. So far, many studies have focussed on the application of crystal engineering principles to rationally design cocrystals, the identification of supramolecular synthons, and the relationship between coformer selection and dissolution enhancement. On the other hand, there are several aspects of cocrystals that are understudied or still present significant challenges, such as the prediction of cocrystal formation, their formulation, large-scale production and process design. This Special Issue aims to highlight the potential of cocrystals in drug delivery, and we invite contributions on all aspects of the topic, both from fundamental research and practical applications.

Dr. Andrea Erxleben
Guest Editor

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Keywords

  • crystal engineering
  • multicomponent crystals
  • prediction of cocrystal formation
  • crystal structure–property relationships
  • formulation
  • dissolution behaviour
  • in vitro properties
  • in vivo properties
  • large-scale preparation
  • cocrystal polymorphism

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Related Special Issue

Published Papers (9 papers)

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Editorial

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3 pages, 161 KiB  
Editorial
Cocrystal Applications in Drug Delivery
by Andrea Erxleben
Pharmaceutics 2020, 12(9), 834; https://doi.org/10.3390/pharmaceutics12090834 - 1 Sep 2020
Cited by 16 | Viewed by 3564
Abstract
Over the past two decades, considerable research efforts in academia and industry have gone into pharmaceutical cocrystals [...] Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery)

Research

Jump to: Editorial

18 pages, 3856 KiB  
Article
Identification and Pharmaceutical Characterization of a New Itraconazole Terephthalic Acid Cocrystal
by Ricardo Machado Cruz, Tereza Boleslavská, Josef Beránek, Eszter Tieger, Brendan Twamley, Maria Jose Santos-Martinez, Ondřej Dammer and Lidia Tajber
Pharmaceutics 2020, 12(8), 741; https://doi.org/10.3390/pharmaceutics12080741 - 6 Aug 2020
Cited by 19 | Viewed by 5644
Abstract
The crystallization of poorly soluble drug molecules with an excipient into new solid phases called cocrystals has gained a considerable popularity in the pharmaceutical field. In this work, the cocrystal approach was explored for a very poorly water soluble antifungal active, itraconazole (ITR), [...] Read more.
The crystallization of poorly soluble drug molecules with an excipient into new solid phases called cocrystals has gained a considerable popularity in the pharmaceutical field. In this work, the cocrystal approach was explored for a very poorly water soluble antifungal active, itraconazole (ITR), which was, for the first time, successfully converted into this multicomponent solid using an aromatic coformer, terephthalic acid (TER). The new cocrystal was characterized in terms of its solid-state and structural properties, and a panel of pharmaceutical tests including wettability and dissolution were performed. Evidence of the cocrystal formation was obtained from liquid-assisted grinding, but not neat grinding. An efficient method of the ITR–TER cocrystal formation was ball milling. The stoichiometry of the ITR–TER phase was 2:1 and the structure was stabilized by H-bonds. When comparing ITR–TER with other cocrystals, the intrinsic dissolution rates and powder dissolution profiles correlated with the aqueous solubility of the coformers. The rank order of the dissolution rates of the active pharmaceutical ingredient (API) from the cocrystals was ITR–oxalic acid > ITR–succinic acid > ITR–TER. Additionally, the ITR–TER cocrystal was stable in aqueous conditions and did not transform to the parent drug. In summary, this work presents another cocrystal of ITR that might be of use in pharmaceutical formulations. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery)
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28 pages, 8042 KiB  
Article
Salt Cocrystal of Diclofenac Sodium-L-Proline: Structural, Pseudopolymorphism, and Pharmaceutics Performance Study
by Ilma Nugrahani, Rizka A. Kumalasari, Winni N. Auli, Ayano Horikawa and Hidehiro Uekusa
Pharmaceutics 2020, 12(7), 690; https://doi.org/10.3390/pharmaceutics12070690 - 21 Jul 2020
Cited by 28 | Viewed by 6585
Abstract
Previously, we have reported on a zwitterionic cocrystal of diclofenac acid and L-proline. However, the solubility of this multicomponent crystal was still lower than that of diclofenac sodium salt. Therefore, this study aimed to observe whether a multicomponent crystal could be produced from [...] Read more.
Previously, we have reported on a zwitterionic cocrystal of diclofenac acid and L-proline. However, the solubility of this multicomponent crystal was still lower than that of diclofenac sodium salt. Therefore, this study aimed to observe whether a multicomponent crystal could be produced from diclofenac sodium hydrate with the same coformer, L-proline, which was expected to improve the pharmaceutics performance. Methods involved screening, solid phase characterization, structure determination, stability, and in vitro pharmaceutical performance tests. First, a phase diagram screen was carried out to identify the molar ratio of the multicomponent crystal formation. Next, the single crystals were prepared by slow evaporation under two conditions, which yielded two forms: one was a rod-shape and the second was a flat-square form. The characterization by infrared spectroscopy, thermal analysis, and diffractometry confirmed the formation of the new phases. Finally, structural determination using single crystal X-ray diffraction analysis solved the new salt cocrystals as a stable diclofenac–sodium–proline–water (1:1:1:4) named NDPT (natrium diclofenac proline tetrahydrate), and unstable diclofenac–sodium–proline–water (1:1:1:1), named NDPM (natrium diclofenac proline monohydrate). The solubility and dissolution rate of these multicomponent crystals were superior to those of diclofenac sodium alone. The experimental results that this salt cocrystal is suitable for further development. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery)
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16 pages, 4267 KiB  
Article
Improving Nefiracetam Dissolution and Solubility Behavior Using a Cocrystallization Approach
by Xavier Buol, Koen Robeyns, Camila Caro Garrido, Nikolay Tumanov, Laurent Collard, Johan Wouters and Tom Leyssens
Pharmaceutics 2020, 12(7), 653; https://doi.org/10.3390/pharmaceutics12070653 - 9 Jul 2020
Cited by 17 | Viewed by 3720
Abstract
In this work, we are the first to identify thirteen cocrystals of Nefiracetam, a poor water-soluble nootropic compound. Three of which were obtained with the biocompatible cocrystallization agents citric acid, oxalic acid, and zinc chloride. These latter have been fully structurally and physically [...] Read more.
In this work, we are the first to identify thirteen cocrystals of Nefiracetam, a poor water-soluble nootropic compound. Three of which were obtained with the biocompatible cocrystallization agents citric acid, oxalic acid, and zinc chloride. These latter have been fully structurally and physically characterized and the solubility, dissolution rate, and stability were compared to that of the initial Active Pharmaceutical Ingredient (API). Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery)
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22 pages, 4644 KiB  
Article
The Role of Cocrystallization-Mediated Altered Crystallographic Properties on the Tabletability of Rivaroxaban and Malonic Acid
by Dnyaneshwar P. Kale, Vibha Puri, Amit Kumar, Navin Kumar and Arvind K. Bansal
Pharmaceutics 2020, 12(6), 546; https://doi.org/10.3390/pharmaceutics12060546 - 12 Jun 2020
Cited by 19 | Viewed by 3192
Abstract
The present work aims to understand the crystallographic basis of the mechanical behavior of rivaroxaban-malonic acid cocrystal (RIV-MAL Co) in comparison to its parent constituents, i.e., rivaroxaban (RIV) and malonic acid (MAL). The mechanical behavior was evaluated at the bulk level by performing [...] Read more.
The present work aims to understand the crystallographic basis of the mechanical behavior of rivaroxaban-malonic acid cocrystal (RIV-MAL Co) in comparison to its parent constituents, i.e., rivaroxaban (RIV) and malonic acid (MAL). The mechanical behavior was evaluated at the bulk level by performing “out of die” bulk compaction and at the particle level by nanoindentation. The tabletability order for the three solids was MAL < RIV < RIV-MAL Co. MAL demonstrated “lower” tabletability because of its lower plasticity, despite it having reasonably good bonding strength (BS). The absence of a slip plane and “intermediate” BS contributed to this behavior. The “intermediate” tabletability of RIV was primarily attributed to the differential surface topologies of the slip planes. The presence of a primary slip plane (0 1 1) with flat-layered topology can favor the plastic deformation of RIV, whereas the corrugated topology of secondary slip planes (1 0 2) could adversely affect the plasticity. In addition, the higher elastic recovery of RIV crystal also contributed to its tabletability. The significantly “higher” tabletability of RIV-MAL Co among the three molecular solids was the result of its higher plasticity and BS. Flat-layered topology slip across the (0 0 1) plane, the higher degree of intermolecular interactions, and the larger separation between adjacent crystallographic layers contributed to improved mechanical behavior of RIV-MAL Co. Interestingly, a particle level deformation parameter H/E (i.e., ratio of mechanical hardness H to elastic modulus E) was found to inversely correlate with a bulk level deformation parameter σ0 (i.e., tensile strength at zero porosity). The present study highlighted the role of cocrystal crystallographic properties in improving the tabletability of materials. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery)
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17 pages, 3319 KiB  
Article
Quality by Design Optimization of Cold Sonochemical Synthesis of Zidovudine-Lamivudine Nanosuspensions
by Bwalya A. Witika, Vincent J. Smith and Roderick B. Walker
Pharmaceutics 2020, 12(4), 367; https://doi.org/10.3390/pharmaceutics12040367 - 17 Apr 2020
Cited by 18 | Viewed by 4429
Abstract
Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used to manage HIV/AIDS infection. The compounds require frequent dosing, exhibit unpredictable bioavailability and a side effect profile that includes hepato- and haema-toxicity. A novel pseudo one-solvent bottom-up approach and Design of Experiments using sodium [...] Read more.
Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used to manage HIV/AIDS infection. The compounds require frequent dosing, exhibit unpredictable bioavailability and a side effect profile that includes hepato- and haema-toxicity. A novel pseudo one-solvent bottom-up approach and Design of Experiments using sodium dodecyl sulphate (SDS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000) to electrosterically stablize the nano co-crystals was used to develop, produce and optimize 3TC and AZT nano co-crystals. Equimolar solutions of 3TC in surfactant dissolved in de-ionised water and AZT in methanol were rapidly injected into a vessel and sonicated at 4 °C. The resultant suspensions were characterized using a Zetasizer and the particle size, polydispersity index and Zeta potential determined. Optimization of the nanosuspensions was conducted using a Central Composite Design to produce nano co-crystals with specific identified and desirable Critical Quality Attributes including particle size (PS) < 1000 nm, polydispersity index (PDI) < 0.500 and Zeta potential (ZP) < −30mV. Further characterization was undertaken using Fourier Transform infrared spectroscopy, energy dispersive X-ray spectroscopy, differential scanning calorimetry, powder X-ray diffraction and transmission electron microscopy. In vitro cytotoxicity studies revealed that the optimized nano co-crystals reduced the toxicity of AZT and 3TC to HeLa cells. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery)
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22 pages, 5184 KiB  
Article
Application of 1-Hydroxy-4,5-Dimethyl-Imidazole 3-Oxide as Coformer in Formation of Pharmaceutical Cocrystals
by Aneta Wróblewska, Justyna Śniechowska, Sławomir Kaźmierski, Ewelina Wielgus, Grzegorz D. Bujacz, Grzegorz Mlostoń, Arkadiusz Chworos, Justyna Suwara and Marek J. Potrzebowski
Pharmaceutics 2020, 12(4), 359; https://doi.org/10.3390/pharmaceutics12040359 - 15 Apr 2020
Cited by 13 | Viewed by 3120
Abstract
Two, well defined binary crystals with 1-Hydroxy-4,5-Dimethyl-Imidazole 3-Oxide (HIMO) as coformer and thiobarbituric acid (TBA) as well barbituric acid (BA) as Active Pharmaceutical Ingredients (APIs) were obtained by cocrystallization (from methanol) or mechanochemically by grinding. The progress of cocrystal formation in a ball [...] Read more.
Two, well defined binary crystals with 1-Hydroxy-4,5-Dimethyl-Imidazole 3-Oxide (HIMO) as coformer and thiobarbituric acid (TBA) as well barbituric acid (BA) as Active Pharmaceutical Ingredients (APIs) were obtained by cocrystallization (from methanol) or mechanochemically by grinding. The progress of cocrystal formation in a ball mill was monitored by means of high-resolution, solid state NMR spectroscopy. The 13C CP/MAS, 15N CP/MAS and 1H Very Fast (VF) MAS NMR procedures were employed to inspect the tautomeric forms of the APIs, structure elucidation of the coformer and the obtained cocrystals. Single crystal X-ray studies allowed us to define the molecular structure and crystal packing for the coformer as well as the TBA/HIMO and BA/HIMO cocrystals. The intermolecular hydrogen bonding, π–π interactions and CH-π contacts responsible for higher order organization of supramolecular structures were determined. Biological studies of HIMO and the obtained cocrystals suggest that these complexes are not cytotoxic and can potentially be considered as therapeutic materials. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery)
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15 pages, 2195 KiB  
Article
A Comparative Study of the Effect of Different Stabilizers on the Critical Quality Attributes of Self-Assembling Nano Co-Crystals
by Bwalya A. Witika, Vincent J. Smith and Roderick B. Walker
Pharmaceutics 2020, 12(2), 182; https://doi.org/10.3390/pharmaceutics12020182 - 23 Feb 2020
Cited by 17 | Viewed by 5456
Abstract
Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used orally to manage HIV/AIDS infection. A pseudo one-solvent bottom-up approach was used to develop and produce nano co-crystals of 3TC and AZT. Equimolar amounts of 3TC dissolved in de-ionized water and AZT in methanol [...] Read more.
Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used orally to manage HIV/AIDS infection. A pseudo one-solvent bottom-up approach was used to develop and produce nano co-crystals of 3TC and AZT. Equimolar amounts of 3TC dissolved in de-ionized water and AZT in methanol were rapidly injected into a pre-cooled vessel and sonicated at 4 °C. The resultant suspensions were characterized using a Zetasizer. The particle size, polydispersity index and Zeta potential were elucidated. Further characterization was undertaken using powder X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and energy dispersive X-ray spectroscopy scanning electron microscopy. Different surfactants were assessed for their ability to stabilize the nano co-crystals and for their ability to produce nano co-crystals with specific and desirable critical quality attributes (CQA) including particle size (PS) < 1000 nm, polydispersity index (PDI) < 0.500 and Zeta potential (ZP) < −30 mV. All surfactants produced co-crystals in the nanometer range. The PDI and PS are concentration-dependent for all nano co-crystals manufactured while only ZP was within specification when sodium dodecyl sulfate was used in the process. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery)
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18 pages, 3874 KiB  
Article
Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers
by Reynaldo Salas-Zúñiga, Christian Rodríguez-Ruiz, Herbert Höpfl, Hugo Morales-Rojas, Obdulia Sánchez-Guadarrama, Patricia Rodríguez-Cuamatzi and Dea Herrera-Ruiz
Pharmaceutics 2020, 12(1), 23; https://doi.org/10.3390/pharmaceutics12010023 - 25 Dec 2019
Cited by 25 | Viewed by 7024
Abstract
The effect of hydroxypropyl methylcellulose (HPMC) and methylcellulose (Methocel® 60 HG) on the dissolution behavior of two cocrystals derived from nitazoxanide (NTZ), viz., nitazoxanide-glutaric acid (NTZ-GLU, 1:1) and nitazoxanide-succinic acid (NTZ-SUC, 2:1), was explored. Powder dissolution experiments under non-sink conditions showed similar [...] Read more.
The effect of hydroxypropyl methylcellulose (HPMC) and methylcellulose (Methocel® 60 HG) on the dissolution behavior of two cocrystals derived from nitazoxanide (NTZ), viz., nitazoxanide-glutaric acid (NTZ-GLU, 1:1) and nitazoxanide-succinic acid (NTZ-SUC, 2:1), was explored. Powder dissolution experiments under non-sink conditions showed similar dissolution profiles for the cocrystals and pure NTZ. However, pre-dissolved cellulosic polymer in the phosphate dissolution medium (pH 7.5) modified the dissolution profile of NTZ when starting from the cocrystals, achieving transient drug supersaturation. Subsequent dissolution studies under sink conditions of polymer-based pharmaceutical powder formulations with NTZ-SUC cocrystals gave a significant improvement of the apparent solubility of NTZ when compared with analogous formulations of pure NTZ and the physical mixture of NTZ and SUC. Scanning electron microscopy and powder X-ray diffraction analysis of samples recovered after the powder dissolution studies showed that the cocrystals undergo fast dissolution, drug supersaturation and precipitation both in the absence and presence of polymer, suggesting that the solubilization enhancement is due to polymer-induced delay of nucleation and crystal growth of the less soluble NTZ form. The study demonstrates that the incorporation of an appropriate excipient in adequate concentration can be a key factor for inducing and maintaining the solubilization of poorly soluble drugs starting from co-crystallized solid forms. In such a way, cocrystals can be suitable for the development of solid dosage forms with improved bioavailability and efficacy in the treatment of important parasitic and viral diseases, among others. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery)
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