Solubility Advantage of Amorphous Pharmaceuticals: II. Application of Quantitative Thermodynamic Relationships for Prediction of Solubility Enhancement in Structurally Diverse Insoluble Pharmaceuticals

Murdande, Sharad B.; Pikal, Michael J.; Shanker, Ravi; Bogner, Robin H.

doi:10.1007/s11095-010-0269-5

Cited by 184 publications

(173 citation statements)

References 31 publications

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“…Co-crystals are considering as a major class of pharmaceutical materials to promote the solubility and dissolution. Apart from co-crystals, other materials such as polymorphs, salts, and amorphous solids are also widely used to enhance dissolution and bioavailability of less soluble API [5], [6].…”

Section: Introductionmentioning

confidence: 99%

Carbamazepine-Fumaric Acid and Carbamazepine-Succinic Acid Co-crystal Screening Using Solution Based Method

Rahman¹,

Rahim²,

Chou³

et al. 2017

IJCEA

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Abstract-Co-crystal plays a critical role in the pharmaceutical industry and becoming as an alternative approach to improve the bioavailability of poor water soluble drugs especially for a weakly ionisable groups or neutral compounds. In this study the co-crystal screening was carried out for carbamazepine (CBZ) and co-crystal former (CCF) of fumaric acid (FUM) and succinic acid (SA) using non-stoichiometric method (addition of CBZ to CCF saturated solution) and stoichiometric method (evaporation of 1:1 molar ratio of CBZ to CCF) in acetonitrile, ethyl acetate, propanol, ethanol and formic acid solvent systems. The crystals produced from the screening were characterized using Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC) and Fourier Transform Infrared (FT-IR). The PXRD analysis had confirmed that the co-crystal was successfully formed in both methods for all of the solvent system studied with an exception to formic acid in the stoichiometric method for CBZ-FUM system and in all methods for CBZ-SA system. The findings from this analysis revealed that Form A and Form B of CBZ-FUM co-crystal had been successfully formed from different solvents systems. DSC analysis had shown that the melting point of CBZ-FUM and CBZ-SA co-crystals were in the range similar to the previous study. The characterization using FT-IR indicated that the functional groups which include amides and carboxylic acids were presented in the co-crystal produced. Further study on the co-crystal solubility and dissolution rate is needed in order to access the efficacy of the co-crystal since the screening methods have been successfully confirmed the formation of the co-crystal.

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Section: Introductionmentioning

confidence: 99%

Carbamazepine-Fumaric Acid and Carbamazepine-Succinic Acid Co-crystal Screening Using Solution Based Method

Rahman¹,

Rahim²,

Chou³

et al. 2017

IJCEA

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“…Amorphization of drugs is a major effective strategy to prepare solubilized formulations, because the crystal packing effect on a drug substance significantly decreases its solubility. [1][2][3] An amorphous compound is in a higher energy state and has a higher mobility than a crystalline compound, improving its solubility and dissolution properties. However, due to the higher energy state, the physical and chemical stability of amorphous compounds are relatively lower than those of a crystal.…”

mentioning

confidence: 99%

Physicochemical Evaluation and Developability Assessment of Co-amorphouses of Low Soluble Drugs and Comparison to the Co-crystals

Yamamoto

Kojima

Karashima

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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To judge the developability and analyze functional mechanism of co-amorphouses, we investigated the physicochemical properties of co-amorphouses and compare the properties with the co-crystals having the same drug and counters. Co-amorphous compounds are a novel approach to improve the physicochemical properties of drugs. A co-amorphous is in an amorphous solid state allowing non-ionic interactions between drug molecules and counter molecules. The co-amorphous compounds composed of itraconazole (ITZ) with the organic carboxyl acid, fumaric acid (FA) or L-tartaric acid (TA), were prepared by mechanical grinding. Potential interactions within ITZ-FA co-amorphous were assessed by Raman spectroscopy. ITZ-FA coamorphous was not crystallized as the co-crystal or as a single ITZ crystal, suggesting that the amorphous state, like the amorphous solid dispersion, was physically stable and that ITZ-FA co-amorphous was also chemically stable. In contrast, no clear interactions were observed within ITZ-TA co-amorphous, and the coamorphous was physically stable but chemically unstable. The solubility of the co-amorphous state was much higher than those of ITZ crystal and the co-crystals and was almost identical to that of amorphous ITZ. A co-amorphous compound like ITZ-FA co-amorphous might be feasible to implement in the development of solid drug products and bring some merits compared to the co-crystals, and the function is governed by the interaction between a drug and a counter. The co-amorphous approach may be an effective strategy for drug development and can contribute to the production of novel drugs with improved functions.Key words co-amorphous; co-crystal; stability; solubilization; interaction; itraconazole Solubility improvement is one of the most important challenges for drug development of poorly soluble drugs. Amorphization of drugs is a major effective strategy to prepare solubilized formulations, because the crystal packing effect on a drug substance significantly decreases its solubility. 1-3)An amorphous compound is in a higher energy state and has a higher mobility than a crystalline compound, improving its solubility and dissolution properties. However, due to the higher energy state, the physical and chemical stability of amorphous compounds are relatively lower than those of a crystal. 4,5) In many cases, an amorphous drug is formulated by solid dispersion with hydrophilic polymers to improve the amorphous drug stability. [6][7][8] The complex formed with polymers can prevent the drug's crystallization and maintain the physical stability of the amorphous state. Generally, weak interactions cannot sufficiently stabilize amorphous drugs. 9)The prediction and design leading to the interactions between the drug and the polymer are still difficult to accomplish. Therefore, solid dispersions combined with several kinds and amounts of polymers need to be tested.As another approach to enhance a drug's solubility, pharmaceutical co-crystals have been investigated and adapted to the drug development processes in...

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“…with X ray analysis, 26 the proof of the solubility enhancement is much more difficult due to the experimental difficulty of measuring the solubility of drug nanocrystals and amorphous drugs. [30][31][32][33] Some useful considerations can be drawn by making a comparison between our model and the well-known Ostwald-Freundlich model: Fig. 4A Fig.…”

Section: Resultsmentioning

confidence: 99%

Drug Nanocrystals: Theoretical Background of Solubility Increase and Dissolution Rate Enhancement

Hasa

Perissutti

Voinovich

et al. 2014

Chem.Biochem.Eng.Q.

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The peculiar higher solubility of drug nanocrystals compared to macrocrystals appeals to the pharmaceutical field. Indeed, until now, about 70 % of the potential drug candidates are discarded due to low bioavailability related with poor solubility in water. Since a modern and efficient design strategy for nanocrystal-based delivery systems requires the knowledge of the theoretical relation between nanocrystal size and solubility, the aim of this paper is to build up a physically-oriented thermodynamic model relating to nanocrystal dimensions with their melting temperature, enthalpy, solubility and dissolution rate. In particular, the developed model will be applied to vinpocetine, a poorly soluble drug used in the treatment of various types of cerebrovascular circulatory disorders.

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Solubility Advantage of Amorphous Pharmaceuticals: II. Application of Quantitative Thermodynamic Relationships for Prediction of Solubility Enhancement in Structurally Diverse Insoluble Pharmaceuticals

Abstract: It has been demonstrated that the theoretical approach does provide an accurate estimate of the maximum solubility enhancement by an amorphous drug relative to its crystalline form for structurally diverse insoluble drugs when recrystallization during dissolution is minimal.

Cited by 184 publications

References 31 publications

Carbamazepine-Fumaric Acid and Carbamazepine-Succinic Acid Co-crystal Screening Using Solution Based Method

Carbamazepine-Fumaric Acid and Carbamazepine-Succinic Acid Co-crystal Screening Using Solution Based Method

Physicochemical Evaluation and Developability Assessment of Co-amorphouses of Low Soluble Drugs and Comparison to the Co-crystals

Drug Nanocrystals: Theoretical Background of Solubility Increase and Dissolution Rate Enhancement

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