Detection of Cocrystal Formation Based on Binary Phase Diagrams Using Thermal Analysis

Yamashita, Hiroyuki; Hirakura, Yutaka; Yuda, Masamichi; Teramura, Toshio; Terada, Katsuhide

doi:10.1007/s11095-012-0850-1

Cited by 145 publications

(143 citation statements)

References 37 publications

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“…Regardless of the above methods, recent years have witnessed the emergence of reports about the application of differential scanning calorimetry (DSC) as a simple and rapid approach towards co-crystal screening [18][19][20]. This approach is based on the heating, by a DSC device, of binary physical mixtures of drug and co-former.…”

Section: Introductionmentioning

confidence: 99%

“…This is based on the assumption that the melting point of co-crystal differs from that of output components, since in more than 50% of cases co-crystals showed a melting point lower than that of both drug and co-former [21]. Generally, when the physical mixture capable of co-crystal formation is heated, the following thermal effects should occur on the DSC scan: an exothermic peak associated with co-crystal formation directly after an endothermic peak, together with another endothermic effect recorded at a higher temperature than the first peaks and connected with co-crystal melting, or several endothermic peaks in temperatures different to the melting points of the pure components and associated with metastable eutectic melting, eutectic melting and co-crystal melting [18,19,22]. Furthermore, the possibility of co-crystal screening using the DSC method has also been described, where co-crystals could be prepared at different molar ratios [23].…”

Section: Introductionmentioning

confidence: 99%

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DSC as a screening tool for rapid co-crystal detection in binary mixtures of benzodiazepines with co-formers

Saganowska

Wesołowski

2017

J Therm Anal Calorim

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In recent years, co-crystals have been the subject of increasing interest within the pharmaceutical industry because these new solid forms of active pharmaceutical ingredients have the ability to enhance the bioavailability of poorly water-soluble drugs with a low dissolution rate. For this reason, it is crucial to prepare co-crystals of benzodiazepines, i.e. psychoactive drugs with a wide range of medical applications but classified as very slightly or practically insoluble in water. Thus, the objective of this research was to show to what extent the DSC method can be used as a screening tool for detection of cocrystal formation in binary physical mixtures of drugs and co-formers. To obtain potential co-crystals, eight benzodiazepines (diazepam, temazepam, oxazepam, lormetazepam, lorazepam, clonazepam, estazolam and chlordiazepoxide) were gently mixed in an agate mortar at 1:1 molar ratios with nine co-formers-succinic, glutaric, fumaric, citric and paminobenzoic acids, nicotinamide, saccharin, urea and caffeine, and heated under DSC conditions. A detailed comparison of the DSC scans of mixtures against scans of both ingredients in isolation indicates the occurrence of subtle physical changes in the samples. Thus, additional endothermic or exothermic peaks due to melting or crystallisation suggested the formation of potential co-crystals. To conclude, this study confirms that the DSC method can be used as a rapid screening tool for co-crystal detection. In this case, based on the DSC scans, 15 physical mixtures of benzodiazepines (clonazepam, diazepam, lorazepam, oxazepam and temazepam) with co-formers (citric, fumaric, glutaric, p-aminobenzoic and succinic acids, nicotinamide, saccharin and urea) have been selected as potential co-crystals for further detailed study.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DSC as a screening tool for rapid co-crystal detection in binary mixtures of benzodiazepines with co-formers

Saganowska

Wesołowski

2017

J Therm Anal Calorim

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“…High throughput screening (HTS) technologies have been employed for CCF screening. [10][11][12][13][14][15] However, CCF selection by HTS remains a time-and resource-consuming task. Therefore, an effective pre-screening method for CCF selection would be valuable for drug discovery and development.…”

mentioning

confidence: 99%

Stability Order of Caffeine Co-crystals Determined by Co-crystal Former Exchange Reaction and Its Application for the Validation of in Silico Models

2015

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The purpose of the present study was to determine the thermodynamic stability orders of co-crystals by co-crystal former (CCF) exchange reactions. Caffeine (CA) was employed as a model drug. The CCF exchange reaction was performed by liquid-assisted grinding using ethanol. When oxalic acid (OX) was added to CA-citric acid co-crystal (CA-CI), CA-CI converted to CA-OX, suggesting that CA-OX is more stable than CA-CI. The stability orders of other co-crystals were determined in the same manner. The stability order of CA co-crystals was determined as CA-OX≈CA-p-hydroxybenzoic acid (HY)>CA-CI>CA-malonic acid>CA-maleic acid. The stability order correlated with the difference in hydrogen bond energy estimated in silico, except for CA-HY. The π-π stacking in CA-HY was suggested as a reason for this discrepancy. The CCF exchange reaction was demonstrated as a useful method to determine the stability order of co-crystals, which can be used for the validation of in silico parameters to predict co-crystal formation.Key words co-crystal; co-crystal former; exchange reaction; caffeine; hydrogen bond energy Co-crystals have recently received much attention as a means of improving physicochemical properties of active pharmaceutical ingredients.1-10) The number of potential co-crystal formers (CCFs) can reach up to several hundred; therefore, an efficient strategy for CCF screening in drug discovery and development is required. High throughput screening (HTS) technologies have been employed for CCF screening.10-15) However, CCF selection by HTS remains a time-and resource-consuming task. Therefore, an effective pre-screening method for CCF selection would be valuable for drug discovery and development. In the case of salt selection, the difference in pK a values between a drug and a counterion (ΔpK a ) has been used as a criterion for the selection of potential counter-ion candidates.16) Similarly, some in silico physicochemical parameters for CCF selection were proposed by several research groups. [17][18][19][20] For example, the difference in hydrogen bond energy between a co-crystal and each of the sole components (ΔE) was proposed by Musumeci et al., based on the hypothesis that the formation of a co-crystal becomes more probable as ΔE becomes larger.21-23) However, ΔE has not been rigorously validated due to the lack of information about the stability order of co-crystals. The stability order of co-crystals can be determined by CCF exchange reactions. In the literature, there were a few studies on the CCF exchange reactions (a sulfonamide derivative 24) and carbamazepine 25) ). However, in these studies, only a few CCFs were employed so that the data is insufficient for validating in silico models.The purpose of the present study was to determine the stability orders of co-crystals by CCF exchange reaction. Caffeine (CA) was employed as a model drug. The stability order of five CA co-crystals was determined using the CCF exchange reaction. The stability order was then compared with the ΔE estimated in silico.

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“…The results show that when a physical mixture of molar ratio 1:1 is heated, all of component NCT and part of component ACV melt at the metastable eutectic temperature, forming cocrystal which then melts at 191.94-231.83°C [16]. The molar ratio of 5:5 showed the optimal melting point of forming a cocrystal as shown in Fig.…”

Section: Analysis Of Phase Diagram Of Binary Systemmentioning

confidence: 79%

Preparation of Acyclovir-Nicotinamide Cocrystal by Solvent Evaporation Technique With Variation of Solvent

Nawatila

W²,

Siswodihardjo³

et al. 2017

Asian J Pharm Clin Res

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Objective: This research aims to prepare cocrystal of acyclovir (ACV)-nicotinamide (NCT) by solvent evaporation with a variation of solvent (ethanol, glacial acetic acid, and HCl 0.1 N) to improve the bioavailability of ACV as an antiviral drug. Methods:Cocrystal were developed by solvent evaporation with 1:1 molar fraction, using variation of solvent such as ethanol, glacial acetic acid, and HCl 0.1 N. Further, the prepared ACV-NCT cocrystal were characterized for differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), and in vitro dissolution.Results: DSC thermogram showed that ACV-NCT cocrystal in ethanol and glacial acetic acid exhibited new endothermic peak at 221.16°C and 216.40°C, whereas no peaks were found for HCl 0.1 N. PXRD diffractogram showed that ACV-NCT cocrystal in ethanol exhibited new diffraction peaks at 2θ 5.9°; 9.2°; dan 13.3°, whereas no peaks were found for glacial acetic acid and HCl 0.1 N. FT-IR characterization of ACV-NCT cocrystal in ethanol showed disappearance of transmission peaks at 3373/cm indicating the loss of NH bands of NCT. Furthermore, C=O of ACV and NCT were observed at 1693/cm, and 1666/cm indicated a formation of hydrogen bonding between ACV and NCT. SEM micrographs showed that cocrystals have a different shape compared to ACV and NCT. DE 15 showed that there was a significant increase of ACV-NCT cocrystal dissolution rate in ethanol compared to the physical mixture and ACV. Conclusion:The study concludes that ACV-NCT cocrystal in ethanol were successfully formed and the dissolution rate of ACV can increase significantly (α=0.05).

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Detection of Cocrystal Formation Based on Binary Phase Diagrams Using Thermal Analysis

Abstract: These experimental observations demonstrated how the thermal events were attributed to phase transitions occurring in a binary mixture and clarified the relationship between exothermic peaks and cocrystal formation.

Cited by 145 publications

References 37 publications

DSC as a screening tool for rapid co-crystal detection in binary mixtures of benzodiazepines with co-formers

DSC as a screening tool for rapid co-crystal detection in binary mixtures of benzodiazepines with co-formers

Stability Order of Caffeine Co-crystals Determined by Co-crystal Former Exchange Reaction and Its Application for the Validation of in Silico Models

Preparation of Acyclovir-Nicotinamide Cocrystal by Solvent Evaporation Technique With Variation of Solvent

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