Is Failure of Cocrystallization Actually a Failure? Eutectic Formation in Cocrystal Screening of Hesperetin

Chadha, Kunal; Karan, Maninder; Chadha, Renu; Bhalla, Yashika; Vasisht, Karan

doi:10.1016/j.xphs.2017.04.038

Cited by 41 publications

(38 citation statements)

References 39 publications

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“…Although organic eutectics possess differences in critical properties related to product performance, like solubility, stability, and bioavailability, they have been relatively unexplored compared to salts and cocrystals [10,11]. In the past few years, the interest in eutectics has increased considerably for pharmaceutical applications, because the use of eutectics in pharmaceutical formulations is quite advantageous compared to other strategies for the following reasons: (1) eutectics are inexpensive, easier to produce and scale up [9,12]; (2) they are not considered new chemical entities [9] or a new crystal form [13] (e.g., cocrystal) and consequently do not require clinical trials; and (3) in eutectic systems, the drug and coformer exist as crystalline compounds, which are highly stable compared to amorphous materials [7,9,14].…”

Section: Introductionmentioning

confidence: 99%

Drug Solubility Enhancement through the Preparation of Multicomponent Organic Materials: Eutectics of Lovastatin with Carboxylic Acids

et al. 2019

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Lovastatin (LOV) is a drug used to treat hypercholesterolemia. Recent studies have identified its antioxidant effects and potential use in the treatment of some types of cancer. However, the low bioavailability related to its poor water solubility limits its use in solid oral dosage forms. Therefore, to improve the solubility of LOV three eutectic systems of LOV with the carboxylic acids benzoic (BEN), salicylic (SAL) and cinnamic (CIN) were obtained. Both binary phase and Tammann diagrams were constructed using differential scanning calorimetry (DSC) data of mixtures prepared from 0.1 to 1.0 molar ratios. Binary mixtures and eutectics were prepared by liquid-assisted grinding. The eutectics were further characterized by DSC and powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). The LOV-BEN, LOV-SAL and LOV-CIN system formed a eutectic at an LOV mole fraction of 0.19, 0.60 and 0.14, respectively. The systems exhibited improvements in LOV solubility, becoming more soluble by five-fold in the LOV-SAL system and approximately four-fold in the other two systems. Considering that the solubility enhancements and the carboxylic acids used are generally recognized as safe by the U.S. Food and Drug Administration (FDA), the LOV eutectic systems are promising materials to be used in a solubility enhancement strategy for pharmaceutical product formulation.

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Section: Introductionmentioning

confidence: 99%

Drug Solubility Enhancement through the Preparation of Multicomponent Organic Materials: Eutectics of Lovastatin with Carboxylic Acids

et al. 2019

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“… Schematic representation of Binary phase diagrams for ( A ) Eutectic formation [A and B—Binary components; T E —Eutectic temperature] [ 24 , 55 , 79 , 140 ], ( B ) Formation of solid solution [ 34 ], ( C ) Cocrystal formation [A and B—Binary components; C—Cocrystal phase; T E1 and T E2 —Eutectic temperatures] [ 24 , 73 , 140 , 145 ] and ( D ) Physical mixture [Dotted line-Onset of first component melting and dark line-Melting of the second component] [ 25 ]. …”

Section: Figurementioning

confidence: 99%

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

2018

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Biopharmaceutics Classification System (BCS) Class II and IV drugs suffer from poor aqueous solubility and hence low bioavailability. Most of these drugs are hydrophobic and cannot be developed into a pharmaceutical formulation due to their poor aqueous solubility. One of the ways to enhance the aqueous solubility of poorlywater-soluble drugs is to use the principles of crystal engineering to formulate cocrystals of these molecules with water-soluble molecules (which are generally called coformers). Many researchers have shown that the cocrystals significantly enhance the aqueous solubility of poorly water-soluble drugs. In this review, we present a consolidated account of reports available in the literature related to the cocrystallization of poorly water-soluble drugs. The current practice to formulate new drug cocrystals with enhanced solubility involves a lot of empiricism. Therefore, in this work, attempts have been made to understand a general framework involved in successful (and unsuccessful) cocrystallization events which can yield different solid forms such as cocrystals, cocrystal polymorphs, cocrystal hydrates/solvates, salts, coamorphous solids, eutectics and solid solutions. The rationale behind screening suitable coformers for cocrystallization has been explained based on the rules of five i.e., hydrogen bonding, halogen bonding (and in general non-covalent bonding), length of carbon chain, molecular recognition points and coformer aqueous solubility. Different techniques to screen coformers for effective cocrystallization and methods to synthesize cocrystals have been discussed. Recent advances in technologies for continuous and solvent-free production of cocrystals have also been discussed. Furthermore, mechanisms involved in solubilization of these solid forms and the parameters influencing dissolution and stability of specific solid forms have been discussed. Overall, this review provides a consolidated account of the rationale for design of cocrystals, past efforts, recent developments and future perspectives for cocrystallization research which will be extremely useful for researchers working in pharmaceutical formulation development.

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“…However, improvement in the dissolution rate is very well documented for many drug molecules such as antitubercular drug pyrazinamide, isoniazid, curcumin and hesperetin. [8][9][10][11] The plasma concentration at different time intervals of drug and eutectics was assessed by sophisticated RP-HPLC method. The results are elucidated by mean (± SD) plasma concentration-time profile after oral administration of various eutectics in Figure 4.…”

Section: Compounds/ Eutecticmentioning

confidence: 99%

“…Ample reports are available in the literature describing the enhancement in dissolution rate in eutectics as compared to pure drug molecules. [8][9][10][11][12] The faster dissolution rate gives adequate therapeutic retention to the drug molecules sufficient for its absorption and pharmacological action. Moreover, eutectics strengthen the legal aspects linked with cocrystals to considerably expand their intellectual property portfolios.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, eutectics strengthen the legal aspects linked with cocrystals to considerably expand their intellectual property portfolios. 11 Therefore eutectics form a viable alternative to modulate the drug molecule which suffers the low aqueous solubility across desired lines. 8 Consequently, the associated low transformation temperature, effortless purification, transparency, and availability of extensive choice of material, the organic eutectics have drawn considerable interest from various research groups.…”

Section: Introductionmentioning

confidence: 99%

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What if Cocrystallization Fails for Neutral Molecules? Screening Offered Eutectics as Alternate Pharmaceutical Materials: Leflunomide-a Case Study

2019

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Background: The manuscript is aimed to optimize the biopharmaceutical parameters of a poorly soluble, neutral anti-rheumatic drug ‘leflunomide’ by preparing its non-covalent derivatives (NCDs). For this various monocarboxylic acids- (adipic acid, picolinic acid) and dicarboxylic acids (maleic acid, malonic acid, sorbic acid), as well as pyridine carboxamide derivatives (nicotinamide, isonicotinamide), are used as coformers. Methods: The novel solid forms were rationally prepared and systematically characterized. Further, these solid forms were subjected to equilibrium solubility and intrinsic dissolution rate (IDR) analysis in three aqueous media (pH 1.2, pH 4.5 and pH 6.8). In vivo plasma studies in male Wistar rats were done to assess the effect on area under the curve (AUC) and the maximum concentration (Cmax) of leflunomide in prepared solid forms. Results: These NCD were primarily characterized to be eutectics rather than cocrystals as expected. The stoichiometry was established by phase diagrams. The negative value of heat of mixing indicated them to be of cluster type. In addition, leflunomide in eutectics showed approximately 9 folds increase in solubility up to 4 hours. Besides this, approximately 4 folds enhancement in the in IDR was also observed. Maximum increase in bioavailability indicated by enhanced values of AUC and Cmax (490.29 μg h-1 mL-1 and 31.42 μg mL-1, respectively) for leflunomide-maleic acid eutectic in comparison to pure LEF (AUC: 193.20 μg h-1 mL-1 and Cmax: 12.09 μg mL-1). Conclusion: The unsuccessful cocrystallization experiments were found be the latent eutectics. The evaluation of these novel eutectics of poorly soluble drug exhibited possibility to further amplify the scope of accessible material phase options other than pure active pharmaceutical ingredient (API) without disturbing the structural integrity.

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Is Failure of Cocrystallization Actually a Failure? Eutectic Formation in Cocrystal Screening of Hesperetin

Cited by 41 publications

References 39 publications

Drug Solubility Enhancement through the Preparation of Multicomponent Organic Materials: Eutectics of Lovastatin with Carboxylic Acids

Drug Solubility Enhancement through the Preparation of Multicomponent Organic Materials: Eutectics of Lovastatin with Carboxylic Acids

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

What if Cocrystallization Fails for Neutral Molecules? Screening Offered Eutectics as Alternate Pharmaceutical Materials: Leflunomide-a Case Study

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