Micronization and Agglomeration: Understanding the Impact of API Particle Properties on Dissolution and Permeability Using Solid State and Biopharmaceutical “Toolbox”

Saravanan, D.; Muthudoss, Prakash; Khullar, Praveen; Venis, A. Rose

doi:10.1007/s12247-019-09424-1

Cited by 11 publications

(5 citation statements)

References 41 publications

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“…This statement seems even more justified considering the fact that up to 40% of the used and most newly obtained active substances are poorly soluble (which is tantamount to their low bioavailability). Importantly, the improvement in this parameter is primarily achieved through chemical modification of APIs (e.g., formation of salts and prodrugs) that mainly improve their solubility. − However, also other processes, such as micronisation, granulation, cocrystallization, amorphization, , or formation of new polymorphic forms, have been used for the same purpose. In most cases, the improved solubility of APIs is associated with enhanced bioavailability, which is reflected in therapeutic benefits (the use of lower drug doses, reduced side effects, as well as lower production and therapy costs) .…”

Section: Introductionmentioning

confidence: 99%

Studying the Intermolecular Interactions, Structural Dynamics, and Non-Equilibrium Kinetics of Cilnidipine Infiltrated into Alumina and Silica Pores

et al. 2022

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In the present study, the behavior of the calcium channel blocker cilnidipine (CLN) infiltrated into silica (SiO 2 ) and anodic aluminum oxide (AAO) porous membranes characterized by a similar pore size (d = 8 nm and d = 10 nm, respectively) as well as the bulk sample has been investigated using differential scanning calorimetry, broadband dielectric spectroscopy (BDS), and Fourier-transform infrared spectroscopy (FTIR) techniques. The obtained data suggested the existence of two sets of CLN molecules in both confined systems (core and interfacial). They also revealed the lack of substantial differences in inter-and intramolecular dynamics of nanospatially restricted samples independently of the applied porous membranes. Moreover, the annealing experiments (isothermal time-dependent measurements) performed on the confined CLN clearly indicated that the whole equilibration process under confinement is governed by structural relaxation. It was also found that the β anneal parameters obtained from BDS and FTIR data upon equilibration of both confined samples are comparable (within 10%) to each other, while the equilibration constants are significantly different. This finding strongly emphasizes that there is a close connection between the inter-and intramolecular dynamics under nanospatial restriction.

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Section: Introductionmentioning

confidence: 99%

Studying the Intermolecular Interactions, Structural Dynamics, and Non-Equilibrium Kinetics of Cilnidipine Infiltrated into Alumina and Silica Pores

et al. 2022

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“…Therefore, a great effort has been put into increasing their solubility and bioavailability, allowing application of lower therapeutic doses and reducing toxic side effects . In fact, to date, different strategies have been considered and developed to enhance these pharmaceutically important parameters, including (i) the use of pro-drugs, (ii) salt formation (tartrate, succinate, mesylate, nitrate, hydrochloric), , (iii) micronization, − (iv) cocrystallization, , (v) formation of solid dispersions with soluble polymers (or saccharides), , and (vi) amorphization . In recent years, the last approach attracted increasing attention of the scientists and industry since the amorphous APIs are generally characterized by higher solubility (due to the lower energy barrier required to dissolve the molecule , ) and, consequently, bioavailability with respect to their crystalline counterparts.…”

Section: Introductionmentioning

confidence: 99%

Anormal Thermal History Effect on the Structural Dynamics of Probucol Infiltrated into Porous Alumina

et al. 2021

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Herein, broadband dielectric (BDS) and Fourier transform infrared spectroscopy (FTIR), together with differential scanning calorimetry (DSC) and X-ray diffraction (XRD), were applied to study the molecular dynamics, molecular interactions as well as physical stability of an amorphous Active Pharmaceutical Ingredient (API) probucol (PRO)infiltrated into anodic aluminum oxide (AAO) membranes of pore size, d ∼ 10−160 nm. Interestingly, the behavior of examined substance strongly depends on the applied thermal protocol. Remarkably, for the first time, we observed that the structural dynamics of the slowly cooled PRO under confinement is significantly enhanced when compared to that of the quenched material. This unusual behavior was interpreted as a result of surface-induced effects (including the formation of well-resolved interfacial H-bonded layer and adsorption− desorption processes near the interface) that are magnified by the extremely high sensitivity to density fluctuation of studied PRO, reflected in the enormous pressure coefficient of the glass transition temperature dT g /dp = 427 K/GPa. In fact, FTIR investigations revealed that PRO tends to self-associate under confinement and forms a strongly bonded interfacial layer, which controls the variation in the structural dynamics of core molecules. Finally, we observed that the tendency to crystallize of confined API is reduced with respect to the bulk, even though the critical size of PRO nuclei (r c ∼ 3 nm) is significantly lower than the smallest examined pore size. Nevertheless, after few weeks of storage, the investigated substance crystallized in larger pores, while it remained stable in the nanochannels of d = 10 nm. A combination of XRD and DSC measurements indicated that the infiltrated PRO forms two polymorphs, the stable form I (dominating in bulk) and unstable form II (prevailing under confinement). That means that porous matrices might be used to obtain and maintain prolonged stability of unstable polymorphic forms of API.

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“…Toltrazuril (Tol, Figure a), an acclaimed broad-spectrum and high-efficiency anticoccidial drug, is broadly applied in the prophylaxis and treatment of diseases in pets, livestock, poultry, and also in humans caused by Cryptosporidium , Eimeria, and Isospora . − Although Tol exhibits prominent pharmacological activities, its promising prospect is severely hampered by low aqueous solubility in the form of administration. , Some typical methods have been employed to improve the solubility and dissolution rate of Tol, such as solid dispersion, nanoemulsion, micronization, and cyclodextrin inclusion. ,, However, the stability and biocompatibility in these strategies have not yet met expectations. − In Tol molecule, the cyanurate scaffold (ring Cg1) possesses a coplanar π-conjugated configuration, and the Cg2 and Cg3 rings feature the high electron density based on the electrostatic potential (ESP), which will be conducive to constructing aromatic interactions with π···X interactions (Figure b). , Meanwhile, due to the attracting electron effect of the carbonyl groups, the H atom riding on the N atom in the Cg1 ring is obviously weakly acidic and the N(−H) atom becomes a stronger hydrogen bond donor. In addition, the rotatable σ bonds marked with red arrow in Figure a are prone to multiple configurations for packing.…”

Section: Introductionmentioning

confidence: 99%

Toltrazuril Polymorphs and the Effect on Hygroscopicity and Dissolution Rate

Zhang,

Chen,

Lin

et al. 2024

Crystal Growth & Design

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The different arrangement and/or conformation polymorphs frequently generate a pivotal difference in hygroscopicity, stability, and dissolvability. For the purpose of screening the preponderant polymorphs of toltrazuril (Tol) with the desired physicochemical property, two polymorphs (Forms I and II) are screened out, and structure−property relationships are meticulously explored. Interaction energy analyses show that Form II is not stronger than Form I in packing due to the lower intermolecular lattice energy. And the dissolution rate of Form II is higher than that of Form I because the loosened packing in Form II would facilitate diffusion and dissolution. The percentage of mass change of Forms I and II in hygroscopicity at 95% RH is less than 0.2%, and they are both nonhygroscopic crystalline forms. Interestingly, the weight increase of Form II at 95% RH is about twice that of Form I, which might be due to plentiful −CF 3 groups exposed on the facet (001) (about 72% area ratio) of Form II possessed a weakly negatively charged region to capture a few H 2 O molecules in surroundings. Overall, Form II not only exhibits higher solubility and dissolution rate relative to Form I, but also possesses good stability (high temperature, humidity, and light); hence, Form II might be an advantageous candidate crystalline form. This work may provide inspirational thinking for predicting the trends in hygroscopicity and dissolvability of polymorphic APIs and avoiding compromising upcoming pharmaceuticals.

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Micronization and Agglomeration: Understanding the Impact of API Particle Properties on Dissolution and Permeability Using Solid State and Biopharmaceutical “Toolbox”

Cited by 11 publications

References 41 publications

Studying the Intermolecular Interactions, Structural Dynamics, and Non-Equilibrium Kinetics of Cilnidipine Infiltrated into Alumina and Silica Pores

Studying the Intermolecular Interactions, Structural Dynamics, and Non-Equilibrium Kinetics of Cilnidipine Infiltrated into Alumina and Silica Pores

Anormal Thermal History Effect on the Structural Dynamics of Probucol Infiltrated into Porous Alumina

Toltrazuril Polymorphs and the Effect on Hygroscopicity and Dissolution Rate

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