Obtaining Cocrystals by Reaction Crystallization Method: Pharmaceutical Applications

Biscaia, Isabela Fanelli Barreto; Gomes, Samantha Nascimento; Bernardi, Luana; Oliveira, Paulo Renato de

doi:10.3390/pharmaceutics13060898

Cited by 15 publications

(10 citation statements)

References 78 publications

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“…Cocrystal preparation processes include solid-state grinding, solution-reaction crystallization, solvent evaporation, and slurry conversion, and have all been extensively reported to date. Numerous synthesis techniques have been utilized for the creation of pharmaceutical cocrystals [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. In addition, pharmaceutical cocrystals are easier to produce than ECCs.…”

Section: New Energetic Cocrystalsmentioning

confidence: 99%

Recent Progress on Synthesis, Characterization, and Performance of Energetic Cocrystals: A Review

Sultan

Haq

et al. 2022

Molecules

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In the niche area of energetic materials, a balance between energy and safety is extremely important. To address this “energy–safety contradiction”, energetic cocrystals have been introduced. The investigation of the synthesis methods, characteristics, and efficacy of energetic cocrystals is of the utmost importance for optimizing their design and development. This review covers (i) various synthesis methods for energetic cocrystals; (ii) discusses their characteristics such as structural properties, detonation performance, sensitivity analysis, thermal properties, and morphology mapping, along with other properties such as oxygen balance, solubility, and fluorescence; and (iii) performance with respect to energy contents (detonation velocity and pressure) and sensitivity. This is followed by concluding remarks together with future perspectives.

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Section: New Energetic Cocrystalsmentioning

confidence: 99%

Recent Progress on Synthesis, Characterization, and Performance of Energetic Cocrystals: A Review

Sultan

Haq

et al. 2022

Molecules

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“…In the case of dissociable compounds like cocrystals and salts, solid−liquid equilibrium is quantified by the solubility product constant (K sp ). 31,32 Thus, the relative supersaturation of multicomponent systems can be calculated using solubility products instead of solubility, with some examples of inorganic salts as follows. Hendricks et al used the K sp -based supersaturation to quantify the nucleation kinetics of BaSO 4 at a constant temperature, where K sp was known from the literature.…”

Section: Introductionmentioning

confidence: 99%

“…Several model-based and model-free methods are presented in the literature that require the measurement and calculation of this driving force. − However, most of them describe crystallization systems with indissociable products, where relative supersaturation can be defined as the ratio of the difference between actual concentration and solubility to the solubility. In the case of dissociable compounds like cocrystals and salts, solid–liquid equilibrium is quantified by the solubility product constant ( K sp ). , Thus, the relative supersaturation of multicomponent systems can be calculated using solubility products instead of solubility, with some examples of inorganic salts as follows. Hendricks et al used the K sp -based supersaturation to quantify the nucleation kinetics of BaSO 4 at a constant temperature, where K sp was known from the literature .…”

Section: Introductionmentioning

confidence: 99%

Population Balance Modeling of Diastereomeric Salt Resolution

Bosits

Orosz

Szalay

et al. 2023

Crystal Growth & Design

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Diastereomeric salt crystallization is a classical, widely applicable chiral resolution technique, which enables the separation of the enantiomers of both racemate and conglomerate-forming compounds. A resolution method for racemic pregabalin with l-tartaric acid was developed to obtain pure (S)-pregabalin l-tartrate monohydrate crystals with the yield ranging from 43 to 50%. A series of designed resolution experiments were executed at different cooling rates and temperature end points to estimate the crystallization kinetics using population balance modeling. Inline ATR-FTIR measurements of these experiments were used to calculate concentrations in the crystallization phase and to collect solid–liquid equilibrium data by the solubility trace method after product sampling. Since diastereomeric salts are dissociable ionic compounds, solubility product expressions were used in the model to express the relative supersaturation as the driving force of crystallization. As a result, a population balance model with secondary nucleation, growth, and agglomeration mechanisms was identified, and the simulated supersaturation profiles and product size distributions well reproduced the measured data.

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“…Many times, undesired technical properties can hinder the market of a drug with suitable pharmacokinetics and pharmacodynamics, and the correct choice of a solid form rises as the only alternative to overcome them. Flowability, compactability, compressibility, tablet ability, and hygroscopicity are some examples of technical properties defining certain crystal forms to be marketed. − Nowadays, the investigation of how drug technical characteristics can be modulated by the structure and presence of coformers in the solid state goes beyond the academy. Many patents of technically improved drug crystal forms have been deposited by great pharmaceutical companies, such as Pfizer, AstraZeneca, Novartis, Abbott, among others. − …”

Section: Introductionmentioning

confidence: 99%

New Multicomponent Crystal Forms of Adiphenine with Low Hygroscopicity

Ribeiro

Silva

Neto

et al. 2022

Crystal Growth & Design

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Adiphenine is an acetylcholine receptor inhibitor used as an antispasmodic drug due to its strong smooth muscle relaxant action. Adiphenine hydrochloride is largely marketed in drug associations to treat muscle spasms and relieve pain in colic and cramps. However, it presents serious problems with hygroscopicity and chemical stability under high humidity conditions, which have limited its use as an active pharmaceutical ingredient (API). Here, we have solved the adiphenine solid-state hygroscopicity problem through the preparation of stable, nonhygroscopic multicomponent crystal forms thereof. Two new salts of adiphenine were designed by recognition of intermolecular interaction patterns in the Cambridge Structural Database (CSD) and ΔpK a rules. Two generically recognized as safe (GRAS) coformers, namely, citric acid and oxalic acid, were chosen and formed monobasic salts with adiphenine. Crystal structure elucidation reveals that adiphenine adopts different conformations in our salts, while in the literature, hydrochloride adopts one, which is related to different intermolecular arrays. In the dynamic vapor sorption (DVS) analysis, it was verified that adiphenine citrate and adiphenine oxalate starts to incorporate water slowly from 50 to 70% of relative humidity (RH), increasing up to 3.2 and 2.6% of their initial masses in 90% of RH, respectively. At the end of the desorption cycle (RH = 0%), the samples retained only 0.12 and 0.08% of water relative to their initial masses. On the other hand, adiphenine hydrochloride exhibits a classical high hygroscopicity behavior, which retains water fast from 50% of relative humidity (RH), increasing up to 22% of its initial mass in 90% of RH and a net mass gain of 5% at the end of the desorption cycle (RH = 0%). Notably, both carboxylic acid salts had similar solubility as a function of medium pH, while the hydrochloride one was more soluble than them by factors ranging from 6.7 (relative to citrate in pH 1.2) to 28.2 (relative to oxalate in pH 4.5). Nevertheless, the pharmacokinetic parameters of adiphenine after oral administration of the capsules containing the salt forms did not reflect these solubility differences, since all adiphenine salt forms can be considered highly soluble drugs according to the Biopharmaceutics Classification System (dose/solubility ratio < 250 mL). It was observed that the rats treated with capsules containing adiphenine hydrochloride had an increase in AUC 0−∞ (1537 vs 914 vs 991 min μg mL −1 ) compared with rats treated with adiphenine citrate and oxalate capsules, respectively, even though the same t max (48 min) was observed. However, dosage tuning can bring the bioavailability of our salts into that of the hydrochloride salt, with the advantage of nonhygroscopicity and higher chemical stability.

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Obtaining Cocrystals by Reaction Crystallization Method: Pharmaceutical Applications

Cited by 15 publications

References 78 publications

Recent Progress on Synthesis, Characterization, and Performance of Energetic Cocrystals: A Review

Recent Progress on Synthesis, Characterization, and Performance of Energetic Cocrystals: A Review

Population Balance Modeling of Diastereomeric Salt Resolution

New Multicomponent Crystal Forms of Adiphenine with Low Hygroscopicity

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