Multicomponent ionic crystals of diltiazem with dicarboxylic acids toward understanding the structural aspects driving the drug-release

Diniz, Luan F.; Franco, Chris H. J.; Silva, Daniely F.; Martins, Larissa de Souza; Carvalho, Paulo S.; Souza, Mateus Araújo Castro e; Reis, Naialy Fernandes Araújo; Fernandes, Christian; Diniz, Renata

doi:10.1016/j.ijpharm.2021.120790

Cited by 8 publications

(7 citation statements)

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“…It is expected that in crystal structures efficiently packed, the solubilization process of the API tends to be lower. 47 When we compared the cumulative framework energies between adjacent molecules that appear within a radius of 3.8 Å from the ionic pairs MET + ⋯anion − and divide by the number of interactions (see Table 3), it is noted that the MET–SAC salt has the highest value (−14.22 kJ mol −1 ) followed by the salts MET–MAL (−11.97 kJ mol −1 ), MET–MLN (−10.20 kJ mol −1 ) and MET–HCl (−7.80 kJ mol −1 ). Notably, these energy values are inversely correlated with the salt's solubilities (see Section 3.7), indicating that for the lowest solubility salt (MET–SAC) the molecules have experienced a slightly more crowded crystalline environment than other MET salts.…”

Section: Resultsmentioning

confidence: 99%

Solid-state landscape and biopharmaceutical implications of novel metformin-based salts

et al. 2022

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Section: Resultsmentioning

confidence: 99%

Solid-state landscape and biopharmaceutical implications of novel metformin-based salts

et al. 2022

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“…From a structural point of view, molecules efficiently packed in the solid-state are subject to a higher contribution of stabilizing interaction forces, hampering the solubilization process. 79 For these evaluations, the simultaneous use of EF and HS tools allows to access the magnitude/topology of these interaction energies and the map of atom⋯atom contacts between molecules in the crystal environment. For the EPR solid forms considered herein, it is noted that the pure EPR ( E _ framework = −21.87 kJ mol −1 ) is more stable than the cocrystal EPR-CAF ( E _ framework = −17.41 kJ mol −1 ).…”

Section: Resultsmentioning

confidence: 99%

Energy framework and solubility: a new predictive model in the evaluation of the structure–property relationship of pharmaceutical solid forms

et al. 2022

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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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Multicomponent ionic crystals of diltiazem with dicarboxylic acids toward understanding the structural aspects driving the drug-release

Cited by 8 publications

References 50 publications

Solid-state landscape and biopharmaceutical implications of novel metformin-based salts

Solid-state landscape and biopharmaceutical implications of novel metformin-based salts

Energy framework and solubility: a new predictive model in the evaluation of the structure–property relationship of pharmaceutical solid forms

New Multicomponent Crystal Forms of Adiphenine with Low Hygroscopicity

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