Recent Advances in Pharmaceutical Cocrystals: From Bench to Market

Bandaru, Ravi Kumar; Rout, Smruti Rekha; Kenguva, Gowtham; Gorain, Bapi; Alhakamy, Nabil A.; Kesharwani, Prashant; Dandela, Rambabu

doi:10.3389/fphar.2021.780582

Cited by 39 publications

(47 citation statements)

References 109 publications

(176 reference statements)

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“…By controlling the crystal packing, cocrystals with the desired properties can be designed. The largest and most widely studied class of cocrystals are pharmaceutical cocrystals, that is, two drugs or one drug and a pharmaceutically acceptable coformer held together in the same crystal lattice by noncovalent interactions. − Cocrystallization allows for the manipulation and optimization of the physicochemical properties of an active pharmaceutical ingredient (API) such as chemical and physical stability, hygroscopicity, solubility, and dissolution behavior without the need for chemically modifying the API molecule. APIs often have more than one functional group that can interact with coformers.…”

Section: Introductionsupporting

confidence: 77%

Differences in Coformer Interactions of the 2,4-Diaminopyrimidines Pyrimethamine and Trimethoprim

Refat

O’Malley

Simmie

et al. 2022

Crystal Growth & Design

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The identification and study of supramolecular synthons is a fundamental task in the design of pharmaceutical cocrystals. The malaria drug pyrimethamine (pyr) and the antibiotic trimethoprim (tmp) are both 2,4diaminopyrimidine derivatives, providing the same C−NH 2 /NC/C−NH 2 and C−NH 2 /NC interaction sites. In this article, we analyze and compare the synthons observed in the crystal structures of tmp and pyr cocrystals and molecular salts with sulfamethazine (smz), α-ketoglutaric acid (keto), oxalic acid (ox), sebacic acid (seb), and azeliac acid (az). We show that the same coformer interacts with different binding sites of the 2,4-diaminopyrimidine ring in the respective tmp and pyr cocrystals or binds at the same site but gives H bonding patterns with different graph set notions. Pyr•smz•CH 3 OH is the first crystal structure in which the interaction of the sulfa drug at the C− NH 2 /NC/C−NH 2 site with three parallel NH 2 and R 1 2 (5) rings instead of the R 2 2 (8) motif typically observed in tmp + and pyr + carboxylates. Tmp/az is a rare example of cocrystal-salt polymorphism where the two solid-state forms have the same composition, stoichiometry, and main synthon. Theoretical calculations were performed to understand the order of stability, which is tmp•az cocrystal > (tmp + )(az − ) salt. Finally, two three-component tmp/sulfa drug/carboxylate cocrystals with a unique ternary synthon are described.

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Section: Introductionsupporting

confidence: 77%

Differences in Coformer Interactions of the 2,4-Diaminopyrimidines Pyrimethamine and Trimethoprim

Refat

O’Malley

Simmie

et al. 2022

Crystal Growth & Design

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“…Similarly, Entresto ® (Otsuka Pharmaceutical Co., Ltd., Japan), a medication used in the treatment of heart failure, is a combination of valsartan, an angiotensin II inhibitor, and sacubitril, a neprilysin inhibitor. The resultant co-crystal has led to an increased bioavailability of valsartan [56]. In the treatment of bacterial infections, the co-crystal formed by co-crystallizing amoxicillin and clavulanate exhibited increased antibacterial activity when compared to amoxicillin alone, due to β-lactamase inhibition attributed to clavulanate [22] Similarly, co-crystallization of isoniazid and pyrazinamide resulted in synergistic effect for tuberculosis treatment [57].…”

Section: Co-crystalsmentioning

confidence: 99%

Nano- and Crystal Engineering Approaches in the Development of Therapeutic Agents for Neoplastic Diseases

et al. 2022

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Cancer is a leading cause of death worldwide. It is a global quandary that requires the administration of many different active pharmaceutical ingredients (APIs) with different characteristics. As is the case with many APIs, cancer treatments exhibit poor aqueous solubility which can lead to low drug absorption, increased doses, and subsequently poor bioavailability and the occurrence of more adverse events. Several strategies have been envisaged to overcome this drawback, specifically for the treatment of neoplastic diseases. These include crystal engineering, in which new crystal structures are formed to improve drug physicochemical properties, and/or nanoengineering in which the reduction in particle size of the pristine crystal results in much improved physicochemical properties. Co-crystals, which are supramolecular complexes that comprise of an API and a co-crystal former (CCF) held together by non-covalent interactions in crystal lattice, have been developed to improve the performance of some anti-cancer drugs. Similarly, nanosizing through the formation of nanocrystals and, in some cases, the use of both crystal and nanoengineering to obtain nano co-crystals (NCC) have been used to increase the solubility as well as overall performance of many anticancer drugs. The formulation process of both micron and sub-micron crystalline formulations for the treatment of cancers makes use of relatively simple techniques and minimal amounts of excipients aside from stabilizers and co-formers. The flexibility of these crystalline formulations with regards to routes of administration and ability to target neoplastic tissue makes them ideal strategies for effectiveness of cancer treatments. In this review, we describe the use of crystalline formulations for the treatment of various neoplastic diseases. In addition, this review attempts to highlight the gaps in the current translation of these potential treatments into authorized medicines for use in clinical practice.

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“…A great number of techniques are known today for obtaining multicomponent crystals [ 23 ]. However, researchers rarely investigate the effect of different preparation methods of multicomponent crystals on the API’s physicochemical properties and pharmacokinetics [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, researchers rarely investigate the effect of different preparation methods of multicomponent crystals on the API’s physicochemical properties and pharmacokinetics [ 24 , 25 ]. Researchers typically use one of the most common methods for preparing multicomponent crystals, such as grinding, while the preparation method has a great influence on the characteristics of the solid state of a chemical (crystallinity, porosity, particle size, surface area) and its physicochemical properties, respectively [ 23 ]. In this work, the MCL multicomponent solid forms were obtained via multiple methods (liquid-assisted grinding (LAG), slurrying and lyophilization) and characterized comprehensively.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Improvement of Dissolution Behavior and Oral Bioavailability of Antifungal Miconazole via Cocrystal and Salt Formation

et al. 2022

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Miconazole shows low oral bioavailability in humans due to poor aqueous solubility, although it has demonstrated various pharmacological activities such as antifungal, anti-tubercular and anti-tumor effects. Cocrystal/salt formation is one of the effective methods for solving this problem. In this study, different methods (liquid-assisted grinding, slurrying and lyophilization) were used to investigate their impact on the formation of the miconazole multicomponent crystals with succinic, maleic and dl-tartaric acids. The solid state of the prepared powder was characterized by differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopy. It was found that lyophilization not only promotes partial amorphization of both salts but also allows obtaining a new polymorph of the miconazole salt with dl-tartaric acid. The lyophilized salts compared with the same samples prepared by two other methods showed better dissolution rates but low stability during the studies due to rapid recrystallization. Overall, it was determined that the preparation method of multicomponent crystals affects the solid-state characteristics and miconazole physicochemical properties significantly. The in vivo studies revealed that the miconazole multicomponent crystals indicated the higher peak blood concentration and area under the curve from 0 to 32 h values 2.4-, 2.9- and 4.6-fold higher than the pure drug. Therefore, this study demonstrated that multicomponent crystals are promising formulations for enhancing the oral bioavailability of poorly soluble compounds.

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Recent Advances in Pharmaceutical Cocrystals: From Bench to Market

Cited by 39 publications

References 109 publications

Differences in Coformer Interactions of the 2,4-Diaminopyrimidines Pyrimethamine and Trimethoprim

Differences in Coformer Interactions of the 2,4-Diaminopyrimidines Pyrimethamine and Trimethoprim

Nano- and Crystal Engineering Approaches in the Development of Therapeutic Agents for Neoplastic Diseases

Simultaneous Improvement of Dissolution Behavior and Oral Bioavailability of Antifungal Miconazole via Cocrystal and Salt Formation

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