Characterising glass transition temperatures and glass dynamics in mesoporous silica-based amorphous drugs

Kissi, Eric Ofosu; Ruggiero, Michael T.; Hempel, Nele‐Johanna; Song, Zihui; Grohganz, Holger; Rades, Thomas

doi:10.1039/c9cp01764j

Cited by 19 publications

(8 citation statements)

References 43 publications

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“…On the other hand, when the amount of drug was lower than the maximum loading of the drug, the Tg of the drug was not observed. Other studies reported that the Tg of the drug in the mesoporous silica would be changed due to the different mobility of amorphous drugs [26,27]. The Tg event of the RTV amorphous state in the weight ratio of RTV/MPS1 of above 4:6 and CYP amorphous state in the CYP/MPS1 = 5:5 was almost similar with the RTV amorphous and CYP amorphous states, respectively.…”

Section: Discussionmentioning

confidence: 63%

“…However, other studies have reported that the molecular mobility of drugs loaded with small enough pores is significantly lower Pharmaceuticals 2022, 15, 93 3 of 16 than in bulk. This indicates the T g will be higher than the bulk amorphous [27,28]. On the other hand, the glass transition of the drug, which adsorbed monomolecularly on the silica surface, was not detected, as the monolayer of the drug on the silica surface does not contribute to the T g signal in the DSC.…”

Section: Introductionmentioning

confidence: 93%

“…Even though many studies have reported drug loading into various silica carriers under specific conditions [21,22,[26][27][28][29], the determination of the maximum drug loading amount into MPS is not clearly understood, particularly for the amorphous drugs categorized in class III, based on Taylor's classification, which has good glass formers that neither crystallize upon cooling nor reheating [15,29]. It is necessary to determine maximum drug loading experimentally to maximize its effect because drugs in MPS have shown incomplete release, although a supersaturated solution has been shown to be generated.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Drugs with Good Glass Formers in Loaded-Mesoporous Silica and Its Theoretical Value Relevance with Mesopores Surface and Pore-Filling Capacity

Budiman

Aulifa

2022

Pharmaceuticals

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The incorporation of a drug into mesoporous silica (MPS) is a promising strategy to stabilize its amorphous form. However, the drug within MPS has shown incomplete release, despite a supersaturated solution being generated. This indicates the determination of maximum drug loading in MPS below what is experimentally necessary to maximize the drug doses in the system. Therefore, this study aimed to characterize the drugs with good glass former loaded-mesoporous silica, determine the maximum drug loading, and compare its theoretical value relevance to monolayer covering the mesoporous (MCM) surface, as well as pore-filling capacity (PFC). Solvent evaporation and melt methods were used to load each drug into MPS. In addition, the glass transition of ritonavir (RTV) and cyclosporine A (CYP), as well as the melting peak of indomethacin (IDM) and saccharin (SAC) in mesoporous silica, were not discovered in the modulated differential scanning calorimetry (MDSC) curve, demonstrating that each drug was successfully incorporated into the mesopores. The amorphization of RTV-loaded MPS (RTV/MPS), CYP-loaded MPS (CYP/MPS), and IDM-loaded MPS (IDM/MPS) were confirmed as a halo pattern in powder X-ray diffraction measurements and a single glass transition event in the MDSC curve. Additionally, the good glass formers, nanoconfinement effect of MPS and silica surface interaction contributed to the amorphization of RTV, CYP and IDM within MPS. Meanwhile, the crystallization of SAC was observed in SAC-loaded MPS (SAC/MPS) due to its weak silica surface interaction and high recrystallization tendency. The maximum loading amount of RTV/MPS was experimentally close to the theoretical amount of MCM, showing monomolecular adsorption of RTV on the silica surface. On the other hand, the maximum loading amount of CYP/MPS and IDM/MPS was experimentally lower than the theoretical amount of MCM due to the lack of surface interaction. However, neither CYP or IDM occupied the entire silica surface, even though some drugs were adsorbed on the MPS surface. Moreover, the maximum loading amount of SAC/MPS was experimentally close to the theoretical amount of PFC, suggesting the multilayers of SAC within the MPS. Therefore, this study demonstrates that the characterization of drugs within MPS, such as molecular size and interaction of drug-silica surface, affects the loading efficiency of drugs within MPS that influence its relevance with the theoretical value of drugs.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Characterization of Drugs with Good Glass Formers in Loaded-Mesoporous Silica and Its Theoretical Value Relevance with Mesopores Surface and Pore-Filling Capacity

Budiman

Aulifa

2022

Pharmaceuticals

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“…The carbonyl group and phenyl rings of ritonavir also interact with the surface of MPS, as observed in the solid-state NMR experiment (Figure 3). The previous study also stated that the interaction of the drug with the MPS surface restricts their mobility and forms a monolayer [38][39][40]. The hydrogen bonding between the carbonyl group of RTV and the silanol group of MPS was also reported [34].…”

Section: Discussionmentioning

confidence: 94%

A Comparative Study of the Pharmaceutical Properties between Amorphous Drugs Loaded-Mesoporous Silica and Pure Amorphous Drugs Prepared by Solvent Evaporation

Budiman

Aulifa

2022

Pharmaceuticals

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The formulation of poorly water-soluble drugs is one of the main challenges in the pharmaceutical industry, especially in the development of oral dosage forms. Meanwhile, there is an increase in the number of poorly soluble drugs that have been discovered as new chemical entities. It was also reported that the physical transformation of a drug from a crystalline form into an amorphous state could be used to increase its solubility. Therefore, this study aims to evaluate the pharmaceutical properties of amorphous drug loaded-mesoporous silica (MPS) and pure amorphous drugs. Ritonavir (RTV) was used as a model of a poorly water-soluble drug due to its low recrystallization tendency. RTV loaded-MPS (RTV/MPS) and RTV amorphous were prepared using the solvent evaporation method. Based on observation, a halo pattern in the powder X-ray diffraction pattern and a single glass transition (Tg) in the modulated differential scanning calorimetry (MDSC) curve was discovered in RTV amorphous, indicating its amorphization. The Tg was not detected in RTV/MPS, which showed that the loading RTV was completed. The solid-state NMR and FT-IR spectroscopy also showed the interaction between RTV and the surface of MPS in the mesopores. The high supersaturation of RTV was not achieved for both RTV/MPS and the amorphous state due to its strong interaction with the surface of MPS and was not properly dispersed in the medium, respectively. In the dissolution test, the molecular dispersion of RTV within MPS caused rapid dissolution at the beginning, while the amorphous showed a low rate due to its agglomeration. The stability examination showed that the loading process significantly improved the physical and chemical stability of RTV amorphous. These results indicated that the pharmaceutical properties of amorphous drugs could be improved by loaded-MPS.

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“…These findings were underscored by the absence of melting endotherms in the DSC thermograms of the silica-based formulations after 90 days [39]. By contrast, melting peaks were observed in both samples of the extruded formulations after 90 days, indicating the presence of drug crystallinity (data not shown).…”

Section: Resultsmentioning

confidence: 96%

Opportunities for Successful Stabilization of Poor Glass-Forming Drugs: A Stability-Based Comparison of Mesoporous Silica Versus Hot Melt Extrusion Technologies

et al. 2019

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Amorphous formulation technologies to improve oral absorption of poorly soluble active pharmaceutical ingredients (APIs) have become increasingly prevalent. Currently, polymer-based amorphous formulations manufactured by spray drying, hot melt extrusion (HME), or co-precipitation are most common. However, these technologies have challenges in terms of the successful stabilization of poor glass former compounds in the amorphous form. An alternative approach is mesoporous silica, which stabilizes APIs in non-crystalline form via molecular adsorption inside nano-scale pores. In line with these considerations, two poor glass formers, haloperidol and carbamazepine, were formulated as polymer-based solid dispersion via HME and with mesoporous silica, and their stability was compared under accelerated conditions. Changes were monitored over three months with respect to solid-state form and dissolution. The results were supported by solid-state nuclear magnetic resonance spectroscopy (SS-NMR) and scanning electron microscopy (SEM). It was demonstrated that mesoporous silica was more successful than HME in the stabilization of the selected poor glass formers. While both drugs remained non-crystalline during the study using mesoporous silica, polymer-based HME formulations showed recrystallization after one week. Thus, mesoporous silica represents an attractive technology to extend the formulation toolbox to poorly soluble poor glass formers.

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Characterising glass transition temperatures and glass dynamics in mesoporous silica-based amorphous drugs

Abstract: Amorphous drug molecules bound to MPS surface are restricted in mobility, but they exhibit a primary glass transition temperature.

Cited by 19 publications

References 43 publications

Characterization of Drugs with Good Glass Formers in Loaded-Mesoporous Silica and Its Theoretical Value Relevance with Mesopores Surface and Pore-Filling Capacity

Characterization of Drugs with Good Glass Formers in Loaded-Mesoporous Silica and Its Theoretical Value Relevance with Mesopores Surface and Pore-Filling Capacity

A Comparative Study of the Pharmaceutical Properties between Amorphous Drugs Loaded-Mesoporous Silica and Pure Amorphous Drugs Prepared by Solvent Evaporation

Opportunities for Successful Stabilization of Poor Glass-Forming Drugs: A Stability-Based Comparison of Mesoporous Silica Versus Hot Melt Extrusion Technologies

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