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1.
Eur J Pharm Biopharm ; : 114423, 2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-39038523

RESUMO

Inflammatory skin diseases are typically managed with semi-solid formulations such as creams and ointments. These treatments often fail to remain on the skin for long, as they can be easily wiped off by clothing, necessitating frequent reapplication throughout the day and resulting in poor patient adherence. Therefore, this study sought to fabricate an electrospun dressing as an alternative dosage form that provides a sustained release of the anti-inflammatory agent tofacitinib over three days. In this study, three types of electrospun fiber dressings - uniaxial, coaxial, and layer-by-layer - were produced and examined for their morphological, mechanical, and release characteristics. In addition to a comprehensive characterization, another objective was to analyze the drug permeation behavior from these fiber dressings on porcine skin, comparing their performance to that of a tofacitinib cream. The layer-by-layer system notably exhibited a delayed drug release, while the uniaxial and coaxial systems demonstrated an initial burst release. However, the permeation studies revealed no significant differences between these systems, underscoring the necessity of conducting such studies - a crucial aspect often overlooked in research on electrospun fiber dressings. Overall, this study highlights the potential of electrospun, drug-loaded dressings for the treatment of inflammatory skin diseases.

2.
Phys Chem Chem Phys ; 26(19): 14149-14159, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38712380

RESUMO

It is generally accepted that water, as an effective plasticizer, decreases the glass transition temperatures (Tgs) of amorphous drugs, potentially resulting in physical instabilities. However, recent studies suggest that water can also increase the Tgs of the amorphous forms of the drugs prilocaine (PRL) and lidocaine (LID), thus acting as an anti-plasticizer. To further understand the nature of the anti-plasticizing effect of water, interactions with different solvents and the resulting structural features of PRL and LID were investigated by Fourier transform infrared spectroscopy (FTIR) and quantum chemical simulations. Heavy water (deuterium oxides) was chosen as a solvent, as the deuterium and hydrogen atoms are electronically identical. It was found that substituting hydrogen with deuterium showed a minimal impact on the anti-plasticization of water on PRL. Ethanol and ethylene glycol were chosen as solvents to compare the hydrogen bonding patterns occurring between the hydroxyl groups of the solvents and PRL and LID. Comparison of the various Tgs showed a weaker anti-plasticizing potential of these two solvents on PRL and LID. The frequency shifts of the amide CO groups of PRL and LID due to the interactions with water, heavy water, ethanol, and ethylene glycol as observed in the FTIR spectra showed a correlation with the binding energies calculated by quantum chemical simulations. Overall, this study showed that the combination of weak hydrogen bonding and strong electrostatic contributions in hydrated PRL and LID could play an important role in inducing the anti-plasticizing effect of water on those drugs.

3.
Int J Pharm ; 657: 124175, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38685442

RESUMO

Molecular interactions are crucial to stabilize amorphous drugs in amorphous solid dispersions (ASDs). Most polymers, however, have only a limited ability to form strong molecular interactions with drugs. Polymers tailored to fit the physicochemical properties of the drug molecule to be incorporated, for instance by allowing the incorporation of specific functional groups, would be highly sought-for in this regard. For this purpose, the novel allyl-terminated polymer methoxy(polyethylene glycol)-block-poly(jasmine lactone) (mPEG-b-PJL) has been synthesized and functionalized to potentially enhance specific drug-polymer interactions. This study investigated the use of mPEG-b-PJL in ASDs, using carvedilol (CAR), a weakly basic model drug. The findings revealed that the acidic functionalized form of the polymer (mPEG-b-PJL-COOH) indeed established stronger molecular interactions with CAR compared to its non-functionalized counterpart mPEG-b-PJL. Evaluations on polymer effectiveness in forming ASDs demonstrated that mPEG-b-PJL-COOH outperformed its non-functionalized counterpart in miscibility, drug loading ability, and stability, inferred from reduced molecular mobility. However, dissolution tests indicated that ASDs with mPEG-b-PJL-COOH did not significantly improve the dissolution behaviour compared to amorphous CAR alone, despite potential solubility enhancement through micelle formation. Overall, this study confirms the potential of functionalized polymers in ASD formulations, while the challenge of improving dissolution performance in these ASDs remains an area of further development.


Assuntos
Polietilenoglicóis , Polietilenoglicóis/química , Solubilidade , Carvedilol/química , Estabilidade de Medicamentos , Polímeros/química , Lactonas/química , Química Farmacêutica/métodos , Composição de Medicamentos/métodos
4.
Int J Pharm ; 651: 123807, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38220121

RESUMO

It is generally accepted that water as a plasticizer can decrease the glass transition temperatures (Tgs) of amorphous drugs and drug excipient systems. However, previous studies suggest that water, as an anti-plasticizer, can increase the Tgs of co-amorphous systems of prilocaine (PRL) and lidocaine (LID). In order to investigate the intermolecular interactions between water and co-amorphous PRL-LID systems, Fourier transform infrared spectroscopy (FTIR) and principal component analysis (PCA) were conducted. Water was found to bind with the carbonyl groups of PRL and LID molecularly evenly in the hydrated co-amorphous PRL-LID systems. Quantum chemical simulations visually confirmed the interactions between water and co-amorphous PRL-LID systems. Furthermore, the physical stability of hydrated co-amorphous PRL-LID systems was improved due to the anti-plasticizing effect of water, compared with the anhydrous samples. The preference of water to interact with the carbonyl groups of PRL and LID as binding sites could be associated with the anti-plasticizing effect of water on the co-amorphous PRL-LID systems.


Assuntos
Lidocaína , Prilocaína , Prilocaína/química , Temperatura de Transição , Temperatura , Água , Espectroscopia de Infravermelho com Transformada de Fourier , Estabilidade de Medicamentos , Varredura Diferencial de Calorimetria , Solubilidade
5.
Int J Pharm ; 652: 123798, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38190949

RESUMO

Successful oral delivery of liposomes requires formulations designed to withstand harsh gastrointestinal conditions, e.g., by converting to solid-state followed by loading into gastro-resistant delivery devices. The hypothesis was that the use of dextran-trehalose mixtures for spray drying would improve the rehydration kinetics of dried liposomes. The objectives were to determine the protective capacity of trehalose-dextran dehydration precursors and to increase the concentration of liposomes in the dry formulation volume. The study successfully demonstrated that 8.5% dextran combined with 76.5% trehalose protected CAF®04 liposomes during drying, with the liposome content maintained at 15% of the dry powder. Accordingly, the rehydration kinetics were slightly improved in formulations containing up to 8.5% dextran in the dry powder volume. Additionally, a 2.4-fold increase in lipid concentration (3 mM vs 7.245 mM) was achieved for spray dried CAF®04 liposomes. Ultimately, this study demonstrates the significance of trehalose as a primary carrier during spray drying of CAF®04 liposomes and highlights the advantage of incorporating small amounts of dextran to tune rehydration kinetics of spray-dried liposomes.


Assuntos
Lipossomos , Trealose , Dextranos , Secagem por Atomização , Pós , Tamanho da Partícula , Liofilização
6.
Eur J Pharm Biopharm ; 194: 1-8, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38029940

RESUMO

Molecular mobility in form of alpha and beta relaxations is considered crucial for characterization of amorphous lyophilizates and reflected in the transition temperatures Tgα and Tgß. Based on an overview of applied methods to study beta relaxations, Dynamic Mechanical analysis was used to measure Tgα and Tgß in amorphous freeze-dried samples. Lysozyme and trehalose as well as their mixtures in varying ratios were investigated. Three different residual moisture levels, ranging from roughly 0.5-7 % (w/w), were prepared via equilibration of the freeze-dried samples. Known plasticising effects of water on Tgα were confirmed, also via differential scanning calorimetry. In addition and contrary to expectations, an influence of water on the Tgß also was observed. On the other hand, an increasing amount of trehalose lowered Tgα but increased Tgß showing that Tgα and Tgß are not paired. The findings were interpreted with regard to their underlying molecular mechanisms and a correlation with the known influences of water and trehalose on stability. The results provide encouraging hints for future stability studies of freeze-dried protein formulations, which are urgently needed, not least for reasons of sustainability.


Assuntos
Muramidase , Trealose , Muramidase/química , Trealose/química , Água , Liofilização/métodos , Temperatura de Transição , Varredura Diferencial de Calorimetria
7.
Pharm Dev Technol ; 28(9): 907-914, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37869788

RESUMO

Co-amorphous systems are an evolving strategy to stabilize the amorphous form of a drug molecule with the aim of overcoming its poor water-solubility. With research focussing on the molecular level of co-amorphous systems, little is known about their downstream processing. In this study, tablets of co-amorphous carvedilol and aspartic acid (CAR-ASP) with calcium hydrogen phosphate and croscarmellose sodium as excipients were produced using a compaction simulator. The amorphous form of spray dried CAR-ASP and the subsequently produced tablets was confirmed with XRPD. Over the storage time of 12 weeks, no recrystallization of the amorphous material was observed. A central composite face-centred design with three factors was set up to investigate the interplay of formulation and processing variables with the tablet characteristics elastic work, tensile strength and disintegration time. As a result, increasing the amount of co-amorphous material led to a decrease in elastic work and an increased tensile strength. These effects were beneficial for tablet properties, namely harder tablets and reduced elasticity. Disintegration time was prolonged by amounts of up to 25-30% co-amorphous material, while larger amounts induced faster tablet disintegration. While showing the feasibility of compacting co-amorphous material with calcium hydrogen phosphate, this study also gives insight into how tablet characteristics are affected by co-amorphous material and relevant process parameters.


Assuntos
Química Farmacêutica , Comprimidos/química , Solubilidade
8.
Int J Pharm ; 644: 123318, 2023 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-37586574

RESUMO

The feasibility of co-amorphous systems to be wet granulated together with microcrystalline cellulose (MCC) was investigated. Solid state and molecular interactions were analysed for various co-amorphous drug-amino acid formulations of indomethacin with tryptophan and arginine, respectively, via XRPD, DSC and FTIR. The co-amorphous binary systems were produced by ball-milling for 90 min at different molar ratios followed by wet granulation with MCC and water in a miniaturised scale. Tryptophan containing systems showed crystalline reflections in their XRPD diffractograms and endothermal events in their DSC analyses, and were therefore excluded from upscaling attempts. The systems containing arginine were found to be remain amorphous for at least ten months and were upscaled for production in a high-shear blender under application of two different parameter settings. Under the harsher instrument settings, a composition with a low MCC ratio experienced recrystallisation during wet granulation, while all other compositions could be successfully processed via wet granulation and stayed stable for a storage period of at least twelve weeks, indicating that wet granulation of co-amorphous systems can be feasible.


Assuntos
Química Farmacêutica , Indometacina/química , Química Farmacêutica/métodos , Pós/química , Calorimetria , Espectroscopia de Infravermelho com Transformada de Fourier , Tamanho da Partícula , Estabilidade de Medicamentos
9.
Pharmaceutics ; 15(6)2023 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-37376022

RESUMO

Addressing antimicrobial resistance requires new approaches in various disciplines of pharmaceutical sciences. The fluoroquinolone levofloxacin (LEV) plays an important role in the therapy of lung infections. However, its effectiveness is limited by its severe side effects involving tendinopathy, muscle weakness and psychiatric disturbance. Therefore, there is a need for the development of an effective formulation of LEV with reduced systemic drug concentrations, thereby also reducing the consumption and excretion of antibiotics or metabolites. This study aimed for the development of a pulmonary-applicable LEV formulation. Co-amorphous LEV-L-arginine (ARG) particles were prepared by spray drying and characterised by scanning electron microscopy, modulated differential scanning calorimetry, X-ray powder diffraction, Fourier-transform infrared spectroscopy and next generation impactor analysis. Co-amorphous LEV-ARG salts were produced independently of varying process parameters. The use of 30% (v/v) ethanol as a solvent led to better aerodynamic properties compared to an aqueous solution. With a mass median aerodynamic diameter of just over 2 µm, a fine particle fraction of over 50% and an emitted dose of over 95%, the product was deemed suitable for a pulmonary application. The created process was robust towards the influence of temperature and feed rate, as changing these parameters did not have a significant influence on the critical quality attributes, indicating the feasibility of producing pulmonary-applicable co-amorphous particles for sustainable antibiotic therapy.

10.
Pharmaceutics ; 15(3)2023 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-36986718

RESUMO

Co-amorphous systems have been shown to be a promising strategy to address the poor water solubility of many drug candidates. However, little is known about the effect of downstream processing-induced stress on these systems. The aim of this study is to investigate the compaction properties of co-amorphous materials and their solid-state stability upon compaction. Model systems of co-amorphous materials consisting of carvedilol and the two co-formers aspartic acid and tryptophan were produced via spray drying. The solid state of matter was characterized using XRPD, DSC, and SEM. Co-amorphous tablets were produced with a compaction simulator, using varying amounts of MCC in the range of 24 to 95.5% (w/w) as a filler, and showed high compressibility. Higher contents of co-amorphous material led to an increase in the disintegration time; however, the tensile strength remained rather constant at around 3.8 MPa. No indication of recrystallization of the co-amorphous systems was observed. This study found that co-amorphous systems are able to deform plastically under pressure and form mechanically stable tablets.

11.
Eur J Pharm Biopharm ; 186: 1-6, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36878408

RESUMO

It is generally recognized that water, acting as a plasticizer, increases molecular mobility, leading to a decrease of the glass transition temperature (Tg) in amorphous systems. However, an anti-plasticizing effect of water was recently observed on prilocaine (PRL). This effect might be used in co-amorphous systems to moderate the plasticizing effect of water. Nicotinamide (NIC) can form co-amorphous systems with PRL. In order to investigate the effect of water on these co-amorphous systems, the Tgs and molecular mobility of hydrated co-amorphous NIC-PRL systems were compared with those of the respective anhydrous systems. Molecular mobility was estimated by considering the enthalpic recovery at the Tg using the Kohlrausch-Williams-Watts (KWW) equation. At molar ratios of NIC above 0.2, a plasticizing effect of water on co-amorphous NIC-PRL systems was observed with increasing the NIC concentration. In contrast, at molar ratios of NIC of 0.2 and below, water had an anti-plasticizing effect on the co-amorphous NIC-PRL systems, with increased Tgs and reduced mobility upon hydration.


Assuntos
Prilocaína , Água , Varredura Diferencial de Calorimetria , Temperatura de Transição , Fenômenos Químicos
12.
Eur J Pharm Sci ; 182: 106384, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36642346

RESUMO

For oral drug delivery the stability of liposomes against intestinal bile salts is of key importance. Here, asymmetric flow field-flow fractionation (AF4) coupled to multi-angle laser light scattering (MALLS) and a differential refractive index (dRI) detector was employed to monitor structural re-arrangement of liposomes upon exposure to the model bile salt taurocholate. For comparison, a conventional stability assay was employed using a hydrophilic marker and size exclusion chromatography (SEC) to separate released from liposome-entrapped dye. Calcein-containing liposomes with and without cholesterol were compared in terms of their in vitro stability upon exposure to bile salts by separating liposomes from co-existing colloidal species emerging after stress test using AF4/MALLS/dRI. Dynamic light scattering (DLS) was utilized in parallel. Our AF4/MALLS/dRI results suggested that exposure of egg-phospholipid liposomes to bile salts at physiological concentrations led to the formation of two new species of colloidal associates, likely (mixed) micelles. Subjecting cholesterol-containing liposomes to the same bile media did not lead to any new colloidal structures, indicating increased stability of these liposomes. Our SEC-based release assay largely confirmed these findings, indicating that AF4/MALLS/dRI is a suitable technique for prediction of in vitro oral stability of liposomal formulations. Moreover, the powerful AF4/MALLS/dRI technique appears promising to improve the understanding of the underlying mechanisms during bile salt-induced liposomal breakdown.


Assuntos
Portadores de Fármacos , Lipossomos , Lipossomos/química , Ácidos e Sais Biliares , Micelas , Sistemas de Liberação de Medicamentos , Tamanho da Partícula
13.
Pharmaceutics ; 15(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36678800

RESUMO

In non-strongly interacting co-amorphous systems, addition of a polymer, to further stabilize the co-amorphous systems, may influence the phase behavior between the components. In this study, the evolution of the composition of the amorphous phase in the ternary system carvedilol (CAR)-tryptophan (TRP)-hydroxypropylmethyl cellulose (HPMC) was investigated, based upon previously formed and characterized binary systems to which the third component was added (CAR - TRP + HPMC, CAR - HPMC + TRP and TRP - HPMC + CAR). Ball milling was used as the preparation method for all binary and ternary systems. The influence of the milling time on the co-amorphous systems was monitored by DSC and XRPD. Addition of HPMC reduced the miscibility of CAR with TRP due to hydrogen bond formation between CAR and polymer. These bonds became dominant for the interaction pattern. In addition, when CAR or TRP exceeded the miscibility limit in HPMC, phase separation and eventually crystallization of CAR and TRP was observed. All ternary co-amorphous systems eventually reached the same composition, albeit following different paths depending on the initially used binary system.

14.
Pharmaceutics ; 16(1)2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38258078

RESUMO

Using co-amorphous systems (CAMS) has shown promise in addressing the challenges associated with poorly water-soluble drugs. Quench-cooling is a commonly used CAMS preparation method, often followed by grinding or milling to achieve a fine powder that is suitable for subsequent characterization or further down-stream manufacturing. However, the impact of mechanical stress applied to CAMS has received little attention. In this study, the influence of mechanical stress on indomethacin-paracetamol CAMS was investigated. The investigation involved thermal analysis and solid-state characterization across various CAMS mixing ratios and levels of mechanical stress. The study revealed a negative effect of mechanical stress on stability, particularly on the excess components in CAMS. Higher levels of mechanical stress were observed to induce phase separation or recrystallization. Notably, samples at the optimal mixing ratio demonstrated greater resistance to the destabilization caused by mechanical stress. These results showed the significance of careful consideration of processing methods during formulation and the significance of optimizing mixing ratios in CAMS.

15.
Mol Pharm ; 19(9): 3199-3205, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-35876141

RESUMO

Water is generally regarded as a universal plasticizer of amorphous drugs or amorphous drug-containing systems. A decrease in glass-transition temperature (Tg) is considered the general result of this plasticizing effect. A recent study exhibits that water can increase the Tg of amorphous prilocaine (PRL) and thus shows an anti-plasticizing effect. The structurally similar drug lidocaine (LID) might show similar interactions with water, and thus an anti-plasticizing effect of water is hypothesized to also occur in amorphous LID. However, the influence of water on the Tg of LID cannot be determined directly due to the very low stability of LID in the amorphous form. It is possible to predict the Tg of LID from a co-amorphous system of PRL-LID using the Gordon-Taylor equation. Interactions were observed between PRL and LID based on the deviations between the experimental Tgs and the Tgs calculated by the conventional use of the Gordon-Taylor equation. A modified use of the Gordon-Taylor equation was applied using the optimal co-amorphous system as a separate component and the excess drug as the other component. The predicted Tg of fully hydrated LID could thus be determined and was found to be increased by 0.9 ± 0.7 K compared with the Tg of water-free amorphous LID. It could be shown that water exhibited a small anti-plasticizing effect on LID.


Assuntos
Vidro , Lidocaína , Varredura Diferencial de Calorimetria , Temperatura , Temperatura de Transição
16.
Mol Pharm ; 19(4): 1183-1190, 2022 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-35230110

RESUMO

In this study, surface diffusion of l-aspartic acid-carvedilol (ASP-CAR) co-amorphous systems at different ASP concentrations is measured and correlated with their physical stability. ASP-CAR films at ASP concentrations of 1-5% (w/w) were prepared by a newly developed method based on a vacuum compression molding process. Surface diffusion measurements were conducted on these systems based on the surface grating decay method using atomic force microscopy (AFM). The results demonstrate that a small amount of ASP (i.e., ≤ 5% w/w) in the co-amorphous systems could significantly slow down the grating decay process compared with that of pure amorphous CAR, indicating a reduced surface diffusion of CAR molecules. The decay time gradually increased in co-amorphous systems with increasing ASP concentration from 1 to 5% (w/w), with the longest observed decay time of around 800 h for the 5%ASP-CAR system, which was more than 200 times longer compared to the decay time of pure amorphous CAR (approximately 3 h). A good correlation between the decay constants of the pure amorphous CAR and co-amorphous films at ASP concentrations of 1-5% (w/w) and the physical stability of corresponding amorphous powder samples was found. Overall, this study provides a new method to prepare co-amorphous films for surface property measurements and reveals the impact of surface diffusion on the physical stability of co-amorphous systems.


Assuntos
Estabilidade de Medicamentos , Carvedilol , Difusão , Pós , Solubilidade , Propriedades de Superfície
17.
Int J Pharm ; 617: 121625, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35259442

RESUMO

Co-amorphous systems have been developed to address the solubility challenge of poorly water-soluble crystalline drugs. However, due to the thermodynamic instability of amorphous forms, amorphization may result in recrystallization during manufacturing, storage, or dissolution, which is one of the main challenges in the pharmaceutical development of amorphous systems. This could also be the case in some co-amorphous systems with only non-strong interactions between the drug and the co-former (such as hydrogen bond formation and π-π interactions). In this study, a small amount of polymer was added to the binary co-amorphous mixture carvedilol (CAR) - tryptophan (TRP) at a molar ratio of 1:1 and subjected to mechanical activation by ball milling to produce amorphous systems, in order to investigate the effect of co-formulated polymer on the physical properties (solubility, stability, etc.) of non-strongly interacting binary co-amorphous mixtures. After co-formulating polymer to the binary co-amorphous system, stronger interactions were found between CAR and polymer than between CAR and TRP in the ternary polymer containing co-amorphous systems. Compared to the corresponding binary co-amorphous systems, larger areas under the dissolution curves were achieved, indicating an improvement in dissolution behaviour due to a more gradual increase in dissolved drug concentration and a longer period of maintaining drug supersaturation. There was no negative effect of polymer addition on physical stability at room temperature under dry storage conditions for 6 months. Therefore, it is possible to design ternary co-amorphous drug delivery systems with optimized dissolution characteristics by adding a small amount of polymer into co-amorphous binary systems.


Assuntos
Polímeros , Triptofano , Carvedilol , Estabilidade de Medicamentos , Polímeros/química , Solubilidade , Triptofano/química
18.
Int J Pharm ; 605: 120802, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34144131

RESUMO

Co-amorphization has been utilized to improve the physical stability of the respective neat amorphous drugs. However, physical stability of co-amorphous systems is mostly investigated under dry conditions, leaving the potential influence of moisture on storage stability unclear. In this study, carvedilol-L-aspartic acid (CAR-ASP) co-amorphous systems at CAR to ASP molar ratios from 3:1 to 1:3 were investigated under non-dry conditions at two temperatures, i.e., 25 °C 55 %RH and 40 °C 55 %RH. Under these conditions, the highest physical stability of CAR-ASP systems was observed at the 1:1 M ratio. This finding differed from the optimal molar ratio previously obtained under dry conditions (CAR-ASP 1:1.5). Molecular interactions between CAR and ASP were affected by moisture, and salt disproportionation occurred during storage. Morphological differences of systems at different molar ratios could be observed already after one week of storage. Furthermore, variable temperature X-ray powder diffraction measurements showed that excess CAR or excess ASP, existing in the binary systems, resulted in a faster recrystallization compared to equimolar system. Overall, this study emphasizes the influence of moisture on co-amorphous systems during storage, and provides options to determine the optimal ratio of co-amorphous systems in presence of moisture at comparatively short storage times.


Assuntos
Estabilidade de Medicamentos , Varredura Diferencial de Calorimetria , Carvedilol , Pós , Temperatura , Difração de Raios X
19.
Pharmaceutics ; 13(3)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804159

RESUMO

Co-amorphous drug delivery systems (CAMS) are characterized by the combination of two or more (initially crystalline) low molecular weight components that form a homogeneous single-phase amorphous system. Over the past decades, CAMS have been widely investigated as a promising approach to address the challenge of low water solubility of many active pharmaceutical ingredients. Most of the studies on CAMS were performed on a case-by-case basis, and only a few systematic studies are available. A quantitative analysis of the literature on CAMS under certain aspects highlights not only which aspects have been of great interest, but also which future developments are necessary to expand this research field. This review provides a comprehensive updated overview on the current published work on CAMS using a quantitative approach, focusing on three critical quality attributes of CAMS, i.e., co-formability, physical stability, and dissolution performance. Specifically, co-formability, molar ratio of drug and co-former, preparation methods, physical stability, and in vitro and in vivo performance were covered. For each aspect, a quantitative assessment on the current status was performed, allowing both recent advances and remaining research gaps to be identified. Furthermore, novel research aspects such as the design of ternary CAMS are discussed.

20.
Molecules ; 26(4)2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33557164

RESUMO

Converting crystalline compounds into co-amorphous systems is an effective way to improve the solubility of poorly water-soluble drugs. It is, however, of critical importance for the physical stability of co-amorphous systems to find the optimal mixing ratio of the drug with the co-former. In this study, a novel approach for this challenge is presented, exemplified with the co-amorphous system carvedilol-tryptophan (CAR-TRP). Following X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) of the ball-milled samples to confirm their amorphous form, Fourier-transform infrared spectroscopy (FTIR) and principal component analysis (PCA) were applied to investigate intermolecular interactions. A clear deviation from a purely additive spectrum of CAR and TRP was visualized in the PCA score plot, with a maximum at around 30% drug (mol/mol). This deviation was attributed to hydrogen bonds of CAR with TRP ether groups. The sample containing 30% drug (mol/mol) was also the most stable sample during a stability test. Using the combination of FTIR with PCA is an effective approach to investigate the optimal mixing ratio of non-strong interacting co-amorphous systems.


Assuntos
Carvedilol/química , Triptofano/química , Composição de Medicamentos , Estabilidade de Medicamentos , Análise Multivariada , Solubilidade , Água/química
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