Benefits of cocrystallisation in pharmaceutical materials science: an update

Friščić, Tomislav; Jones, William

doi:10.1111/j.2042-7158.2010.01133.x

Cited by 205 publications

(83 citation statements)

References 95 publications

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“…The association of some technically problematic APIs such as paracetamol with certain coformers (e.g., trimethylglycine) assists their appropriate tableting by enhancing compressibility. 15,16) Other APIs exhibit better physical properties, such as improved flowability, that aid formulation processes. 17) Reducing the mobility of API molecules in the lattice of cocrystals improves storage stability of some oily and volatile APIs.…”

Section: Pharmaceutical Applications Of Cocrystalsmentioning

confidence: 99%

Characterization and Quality Control of Pharmaceutical Cocrystals

Izutsu¹,

Koide²,

Takata

et al. 2016

Chem. Pharm. Bull.

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Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality. Different cocrystal regulatory approaches between regions are also discussed. The physical characterization of cocrystals should include elucidating the structure of their objective crystal form as well as their possible variations (e.g., polymorphs, hydrates). Some solids may also contain crystals of individual components. Multiple processes to prepare pharmaceutical cocrystals (e.g., crystallization from solutions, grinding) vary in their applicable ingredients, scalability, and characteristics of resulting solids. The choice of the manufacturing method affects the quality control of particular cocrystals and their formulations. In vitro evaluation of the properties that govern clinical performance is attracting increasing attention in the development of pharmaceutical cocrystals. Understanding and mitigating possible factors perturbing the dissolution and/ or dissolved states, including solution-mediated phase transformation (SMPT) and precipitation from supersaturated solutions, are important to ensure the bioavailability of orally administrated lower-solubility APIs. The effect of polymer excipients on the performance of APIs emphasizes the relevance of formulation design for appropriate use.

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Section: Pharmaceutical Applications Of Cocrystalsmentioning

confidence: 99%

Characterization and Quality Control of Pharmaceutical Cocrystals

Izutsu¹,

Koide²,

Takata

et al. 2016

Chem. Pharm. Bull.

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“…[1][2][3][4][5][6][7][8][9][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.…”

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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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“…Pharmaceutical cocrystals offer a way to overcome the solubility issues 586 associated with BCS class II compounds while also retaining the thermodynamic 587 stability of the crystalline form of a drug 60,61 . Conventionally, the manufacture of 588 a pharmaceutical cocrystal product is divided into two major aspects: the 589 production/synthesis of the cocrystal itself and the subsequent formulation of 590 cocrystal into a pharmaceutical dosage form.…”

mentioning

confidence: 99%

Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Feasibility Studies and Physicochemical Characterization

Shu

Tian

et al. 2016

Mol. Pharmaceutics

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Abstract:16 Engineered Cocrystals offer an alternative solid drug form with tailored 17 physicochemical properties. Interestingly, although cocrystals provide many 18 new possibilities they also present new challenges, particularly in regard to their 19 design and large-scale manufacture. Current literature has primarily focused on 20 the preparation and characterization of novel cocrystals typically containing only 21 the drug and coformer, leaving the subsequent formulation less explored. In this 22paper we propose, for the first time, the use of hot melt extrusion for the 23 mechanochemical synthesis of pharmaceutical cocrystals in the presence of a 24 meltable binder. In this approach, we examine excipients that are amenable to 25 hot melt extrusion, forming a suspension of cocrystal particulates embedded in a 26 pharmaceutical matrix. Using ibuprofen and isonicotinamide as a model 27 cocrystal reagent pair, formulations extruded with a small molecular matrix 28 carrier (xylitol) were examined to be intimate mixtures wherein the newly 29 formed cocrystal particulates were physically suspended in a matrix. With 30 respect to formulations extruded using polymeric carriers (Soluplus ® and 31 Eudragit ® EPO, respectively), however, there was no evidence within PXRD 32 patterns of either crystalline ibuprofen or the cocrystal. Importantly, it was 33 established in this study that an appropriate carrier for a cocrystal reagent pair 34 during HME processing should satisfy certain criteria including limited 35 interaction with parent reagents and cocrystal product, processing temperature 36 sufficiently lower than the onset of cocrystal Tm, low melt viscosity and rapid 37 solidification upon cooling. 38 3

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Benefits of cocrystallisation in pharmaceutical materials science: an update

Cited by 205 publications

References 95 publications

Characterization and Quality Control of Pharmaceutical Cocrystals

Characterization and Quality Control of Pharmaceutical Cocrystals

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

Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Feasibility Studies and Physicochemical Characterization

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