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Pharmaceutics
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Cocrystal Applications in Drug Delivery (Volume II)
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Cocrystal Applications in Drug Delivery (Volume II)

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 November 2021) | Viewed by 27951

Special Issue Editor

Dr. Andrea Erxleben

E-Mail Website
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 (6 papers)

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Research

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14 pages, 2487 KiB  
Article
Synthesis and Characterization of a New Norfloxacin/Resorcinol Cocrystal with Enhanced Solubility and Dissolution Profile
by Hanan Fael, Rafael Barbas, Rafel Prohens, Clara Ràfols and Elisabet Fuguet
Pharmaceutics 2022, 14(1), 49; https://doi.org/10.3390/pharmaceutics14010049 - 27 Dec 2021
Cited by 18 | Viewed by 4304
Abstract
A new cocrystal of Norfloxacin, a poorly soluble fluoroquinolone antibiotic, has been synthetized by a solvent-mediated transformation experiment in toluene, using resorcinol as a coformer. The new cocrystal exists in both anhydrous and monohydrate forms with the same (1:1) Norfloxacin/resorcinol stoichiometry. The solubility [...] Read more.
A new cocrystal of Norfloxacin, a poorly soluble fluoroquinolone antibiotic, has been synthetized by a solvent-mediated transformation experiment in toluene, using resorcinol as a coformer. The new cocrystal exists in both anhydrous and monohydrate forms with the same (1:1) Norfloxacin/resorcinol stoichiometry. The solubility of Norfloxacin and the hydrated cocrystal were determined by the shake-flask method. While Norfloxacin has a solubility of 0.32 ± 0.02 mg/mL, the cocrystal has a solubility of 2.64 ± 0.39 mg/mL, approximately 10-fold higher. The dissolution rate was tested at four biorelevant pH levels of the gastrointestinal tract: 2.0, 4.0, 5.5, and 7.4. In a first set of comparative tests, the dissolution rate of Norfloxacin and the cocrystal was determined separately at each pH value. Both solid forms showed the highest dissolution rate at pH 2.0, where Norfloxacin is totally protonated. Then, the dissolution rate decreases as pH increases. In a second set of experiments, the dissolution of the cocrystal was evaluated by a unique dissolution test, in which the pH dynamically changed from 2.0 to 7.4, stepping 30 min at each of the four biorelevant pH values. Results were quite different in this case, since dissolution at pH 2 affects the behavior of Norfloxacin at the rest of the pH values. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery (Volume II))
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21 pages, 7702 KiB  
Article
Novel Polymorphic Cocrystals of the Non-Steroidal Anti-Inflammatory Drug Niflumic Acid: Expanding the Pharmaceutical Landscape
by Francisco Javier Acebedo-Martínez, Carolina Alarcón-Payer, Antonio Frontera, Rafael Barbas, Rafel Prohens, Milena Di Crisci, Alicia Domínguez-Martín, Jaime Gómez-Morales and Duane Choquesillo-Lazarte
Pharmaceutics 2021, 13(12), 2140; https://doi.org/10.3390/pharmaceutics13122140 - 13 Dec 2021
Cited by 12 | Viewed by 3819
Abstract
Any time the pharmaceutical industry develops a new drug, potential polymorphic events must be thoroughly described, because in a crystalline pharmaceutical solid, different arrangements of the same active pharmaceutical ingredient can yield to very different physicochemical properties that might be crucial for its [...] Read more.
Any time the pharmaceutical industry develops a new drug, potential polymorphic events must be thoroughly described, because in a crystalline pharmaceutical solid, different arrangements of the same active pharmaceutical ingredient can yield to very different physicochemical properties that might be crucial for its efficacy, such as dissolution, solubility, or stability. Polymorphism in cocrystal formulation cannot be neglected, either. In this work, two different cocrystal polymorphs of the non-steroidal anti-inflammatory drug niflumic acid and caffeine are reported. They have been synthesized by mechanochemical methods and thoroughly characterized in solid-state by powder and single crystal X-ray diffraction respectively, as well as other techniques such as thermal analyses, infrared spectroscopy and computational methods. Both theoretical and experimental results are in agreement, confirming a conformational polymorphism. The polymorph NIF–CAF Form I exhibits improved solubility and dissolution rate compared to NIF–CAF Form II, although Form II is significantly more stable than Form I. The conditions needed to obtain these polymorphs and their transition have been carefully characterized, revealing an intricate system. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery (Volume II))
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15 pages, 2799 KiB  
Article
Terahertz and Raman Spectroscopic Investigation of Monohydrate Cocrystal of Antitubercular Isoniazid with Protocatechuic Acid
by Yanhua Bo, Jiyuan Fang, Ziming Zhang, Jiadan Xue, Jianjun Liu, Zhi Hong and Yong Du
Pharmaceutics 2021, 13(8), 1303; https://doi.org/10.3390/pharmaceutics13081303 - 20 Aug 2021
Cited by 21 | Viewed by 2674
Abstract
Pharmaceutical cocrystal provides an alternative modification strategy for the formulation development of drugs owning to their potential ability to improve the physicochemical properties of active pharmaceutical ingredients (APIs) efficiently by changing inter-molecular interactions between raw materials. Isoniazid (INH) is an indispensable main drug [...] Read more.
Pharmaceutical cocrystal provides an alternative modification strategy for the formulation development of drugs owning to their potential ability to improve the physicochemical properties of active pharmaceutical ingredients (APIs) efficiently by changing inter-molecular interactions between raw materials. Isoniazid (INH) is an indispensable main drug for the treatment of tuberculosis, but its tablet formulation is unstable and prone to degradation. In the present study, the monohydrate cocrystal of INH and protocatechuic acid (PA) was prepared by solvent evaporation using PA as cocrystal former to optimize the properties of INH. The parent materials and corresponding 1:1 molar ratio INH-PA monohydrate cocrystal have been characterized by the terahertz time-domain (THz-TDS) and Raman spectroscopy. The THz absorption spectra displayed that there were obvious differences between the peaks of experimental cocrystal and the parent materials, and the same situation was found in Raman vibrational spectra. In addition, density functional theory (DFT) was applied to simulating and optimizing the structure of INH-PA monohydrate cocrystal and supplied corresponding vibrational modes. Our results provided a unique method to characterize the formation of INH-PA monohydrate cocrystal at the molecular-level and a lot of information about cocrystal structure and intra-molecular and/or inter-molecular hydrogen bond interactions in the emerging pharmaceutical cocrystal fields. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery (Volume II))
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17 pages, 1486 KiB  
Article
Improved Manufacturability and In Vivo Comparative Pharmacokinetics of Dapagliflozin Cocrystals in Beagle Dogs and Human Volunteers
by Sangho Cho, Jeongwook Lee, Yongwon Yoo, Minyong Cho, Seil Sohn and Beom-Jin Lee
Pharmaceutics 2021, 13(1), 70; https://doi.org/10.3390/pharmaceutics13010070 - 7 Jan 2021
Cited by 9 | Viewed by 5630
Abstract
Dapagliflozin (DAP), which improves glycemic control in patients with type 2 diabetes mellitus, has poor physical properties against heat and moisture, thus hindering its manufacturing potential. The superior physicochemical properties of a recently developed cocrystal of DAP and citric acid (DAP cocrystal) in [...] Read more.
Dapagliflozin (DAP), which improves glycemic control in patients with type 2 diabetes mellitus, has poor physical properties against heat and moisture, thus hindering its manufacturing potential. The superior physicochemical properties of a recently developed cocrystal of DAP and citric acid (DAP cocrystal) in comparison with those of DAP and Forxiga®, a patented solvate form with propandiol monohydrate, were identified via structural analysis and moisture sorption isotherm. For the first time, the formulation, manufacturability, and in vivo bioavailability of DAP cocrystals were successfully investigated to develop oral dosage forms that substitute Forxiga®. The intrinsic dissolution rate of DAP cocrystal was controlled by varying particle size distribution. Unlike the direct compression (DC), roller compaction (RC) was more preferable to obtain good flowability of dry granules for a continuous manufacturing system. The cocrystal structure was maintained throughout the stability assessment period. In Vitro dissolution pattern differences of the optimized DAP cocrystal tablet with RC and the reference tablet, Forxiga® 10 mg, were pharmaceutically equivalent within 5% in four different media. Furthermore, comparative pharmacokinetic analysis confirmed that a 10 mg DAP cocrystal tablet with RC was bioequivalent to a 10 mg Forxiga® tablet, as assessed in beagle dogs and human volunteers. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery (Volume II))
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13 pages, 4829 KiB  
Article
Complete Cocrystal Formation during Resonant Acoustic Wet Granulation: Effect of Granulation Liquids
by Ryoma Tanaka, Supisara Osotprasit, Jomjai Peerapattana, Kazuhide Ashizawa, Yusuke Hattori and Makoto Otsuka
Pharmaceutics 2021, 13(1), 56; https://doi.org/10.3390/pharmaceutics13010056 - 4 Jan 2021
Cited by 8 | Viewed by 4528
Abstract
The manufacturing of solid pharmaceutical dosage forms composed of cocrystals requires numerous processes during which there is risk of dissociation into parent molecules. Resonant acoustic wet granulation (RAG) was devised in an effort to complete theophylline–citric acid (THPCIT) cocrystal formation during the granulation [...] Read more.
The manufacturing of solid pharmaceutical dosage forms composed of cocrystals requires numerous processes during which there is risk of dissociation into parent molecules. Resonant acoustic wet granulation (RAG) was devised in an effort to complete theophylline–citric acid (THPCIT) cocrystal formation during the granulation process, thereby reducing the number of operations. In addition, the influence of granulation liquid was investigated. A mixture of anhydrous THP (drug), anhydrous CIT (coformer), and hydroxypropyl cellulose (granulating agent) was processed by RAG with water or ethanol as a granulation liquid. The purposes were to (i) form granules using RAG as a breakthrough method; (ii) accomplish the cocrystallization during the integrated unit operation; and (iii) characterize the final solid product (i.e., tablet). The RAG procedure achieved complete cocrystal formation (>99%) and adequately sized granules (d50: >250 μm). The granulation using water (GW) facilitated formation of cocrystal hydrate which were then transformed into anhydrous cocrystal after drying, while the granulation using ethanol (GE) resulted in the formation of anhydrous cocrystal before and after drying. The dissolution of the highly dense GW tablet, which was compressed from granules including fine powder due to the dehydration, was slower than that of the GE tablet. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery (Volume II))
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Review

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14 pages, 1460 KiB  
Review
Obtaining Cocrystals by Reaction Crystallization Method: Pharmaceutical Applications
by Isabela Fanelli Barreto Biscaia, Samantha Nascimento Gomes, Larissa Sakis Bernardi and Paulo Renato Oliveira
Pharmaceutics 2021, 13(6), 898; https://doi.org/10.3390/pharmaceutics13060898 - 17 Jun 2021
Cited by 19 | Viewed by 5358
Abstract
Cocrystals have gained attention in the pharmaceutical industry due to their ability to improve solubility, stability, in vitro dissolution rate, and bioavailability of poorly soluble drugs. Conceptually, cocrystals are multicomponent solids that contain two or more neutral molecules in stoichiometric amounts within the [...] Read more.
Cocrystals have gained attention in the pharmaceutical industry due to their ability to improve solubility, stability, in vitro dissolution rate, and bioavailability of poorly soluble drugs. Conceptually, cocrystals are multicomponent solids that contain two or more neutral molecules in stoichiometric amounts within the same crystal lattice. There are several techniques for obtaining cocrystals described in the literature; however, the focus of this article is the Reaction Crystallization Method (RCM). This method is based on the generation of a supersaturated solution with respect to the cocrystal, while this same solution is saturated or unsaturated with respect to the components of the cocrystal individually. The advantages of the RCM compared with other cocrystallization techniques include the ability to form cocrystals without crystallization of individual components, applicability to the development of in situ techniques for the screening of high quality cocrystals, possibility of large-scale production, and lower cost in both time and materials. An increasing number of scientific studies have demonstrated the use of RCM to synthesize cocrystals, mainly for drugs belonging to class II of the Biopharmaceutics Classification System. The promising results obtained by RCM have demonstrated the applicability of the method for obtaining pharmaceutical cocrystals that improve the biopharmaceutical characteristics of drugs. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery (Volume II))
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