scholarly journals Analytical and Computational Methods for the Estimation of Drug-Polymer Solubility and Miscibility in Solid Dispersions Development

Pharmaceutics ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 372 ◽  
Author(s):  
Djordje Medarević ◽  
Jelena Djuriš ◽  
Panagiotis Barmpalexis ◽  
Kyriakos Kachrimanis ◽  
Svetlana Ibrić
Keyword(s):  
Shelf Life ◽  
Drug Concentration ◽  
Single Phase ◽  
Drug Loading ◽  
Solid Dispersions ◽  
Physical Stability ◽  
Solubility Limit ◽  
Drug Dissolution ◽  
Phase System ◽  
Polymer Solubility

The development of stable solid dispersion formulations that maintain desired improvement of drug dissolution rate during the entire shelf life requires the analysis of drug-polymer solubility and miscibility. Only if the drug concentration is below the solubility limit in the polymer, the physical stability of solid dispersions is guaranteed without risk for drug (re)crystallization. If the drug concentration is above the solubility, but below the miscibility limit, the system is stabilized through intimate drug-polymer mixing, with additional kinetic stabilization if stored sufficiently below the mixture glass transition temperature. Therefore, it is of particular importance to assess the drug-polymer solubility and miscibility, to select suitable formulation (a type of polymer and drug loading), manufacturing process, and storage conditions, with the aim to ensure physical stability during the product shelf life. Drug-polymer solubility and miscibility can be assessed using analytical methods, which can detect whether the system is single-phase or not. Thermodynamic modeling enables a mechanistic understanding of drug-polymer solubility and miscibility and identification of formulation compositions with the expected formation of the stable single-phase system. Advance molecular modeling and simulation techniques enable getting insight into interactions between the drug and polymer at the molecular level, which determine whether the single-phase system formation will occur or not.

Fusion as an Approach to Enhance Dissolution Rate of a Poorly Water-Soluble Drug (Curcurmin)

2011 ◽  
Vol 393-395 ◽  
pp. 119-122
Author(s):  
Dong Hua Wan ◽  
Fen Lin ◽  
Qu Xiang Liao
Keyword(s):  
Dissolution Rate ◽  
Drug Loading ◽  
Solid Dispersions ◽  
Gastric Fluid ◽  
Molecular State ◽  
Water Soluble ◽  
Drug Dissolution ◽  
Simulated Gastric Fluid ◽  
Scanning Calorimetry ◽  
Rate Improvement

It’s well known that curcumin is practically insoluble in water. Therefore, to improve the drug dissolution rate, fusion approach was employed to prepare curcumin solid dispersions (SDs) in the carrier Pluronic F68 with three different drug loads. The dissolution rate of curcumin from the SDs was measured at simulated gastric fluid. The concentration of the dissolved drug in the medium was determined by HPLC. The dissolution rates of the formulations were dependent on the drug loading in SDs. 92.2% CUR was dissolved in 10 min from the SDs with 8.97% drug load, whereas the amounts of drug released were 65.8% and 84.2% within 120 min from the SDs with 18.9% and 29.0% drug loads, respectively. The Fourier transform infrared spectra indicated hydrogen bond between the drug and carrier. Furthermore, their physicochemical properties were well investigated using differential scanning calorimetry and X-ray diffraction. In the dispersions containing 8.97% CUR, the drug was in the molecular state. At a composition of approximately 18.9%, CUR was dispersed as micro-fine crystals. These interesting results indicate that the physical states of the drug in the carrier, which are governed by the drug loading, can affect the dissolution rate improvement.

scholarly journals Polyelectrolyte Matrices in the Modulation of Intermolecular Electrostatic Interactions for Amorphous Solid Dispersions: A Comprehensive Review

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1467
Author(s):  
Anastasia Tsiaxerli ◽  
Anna Karagianni ◽  
Andreas Ouranidis ◽  
Kyriakos Kachrimanis
Keyword(s):  
Electrostatic Interactions ◽  
Solid Dispersions ◽  
Physical Stability ◽  
Amorphous Solid ◽  
Drug Dissolution ◽  
Amorphous Solid Dispersions ◽  
Continuous Processes ◽  
Interpolyelectrolyte Complexes ◽  
Nonionic Polymers ◽  
Hot Melt

Polyelectrolyte polymers have been widely used in the pharmaceutical field as excipients to facilitate various drug delivery systems. Polyelectrolytes have been used to modulate the electrostatic environment and enhance favorable interactions between the drug and the polymer in amorphous solid dispersions (ASDs) prepared mainly by hot-melt extrusion. Polyelectrolytes have been used alone, or in combination with nonionic polymers as interpolyelectrolyte complexes, or after the addition of small molecular additives. They were found to enhance physical stability by favoring stabilizing intermolecular interactions, as well as to exert an antiplasticizing effect. Moreover, they not only enhance drug dissolution, but they have also been used for maintaining supersaturation, especially in the case of weakly basic drugs that tend to precipitate in the intestine. Additional uses include controlled and/or targeted drug release with enhanced physical stability and ease of preparation via novel continuous processes. Polyelectrolyte matrices, used along with scalable manufacturing methods in accordance with green chemistry principles, emerge as an attractive viable alternative for the preparation of ASDs with improved physical stability and biopharmaceutic performance.

scholarly journals A Novel Protocol Using Small-Scale Spray-Drying for the Efficient Screening of Solid Dispersions in Early Drug Development and Formulation, as a Straight Pathway from Screening to Manufacturing Stages

2018 ◽  
Vol 11 (3) ◽  
pp. 81
Author(s):  
Aymeric Ousset ◽  
Rosanna Chirico ◽  
Florent Robin ◽  
Martin Schubert ◽  
Pascal Somville ◽  
...  
Keyword(s):  
Spray Drying ◽  
Drug Loading ◽  
Solid Dispersions ◽  
Physical Stability ◽  
Amorphous State ◽  
Amorphous Solid ◽  
Screening Strategy ◽  
Water Soluble ◽  
Small Scale ◽  
Absorption Window

This work describes a novel screening strategy that implements small-scale spray-drying in early development of binary amorphous solid dispersions (ASDs). The proposed methodology consists of a three-stage decision protocol in which small batches (20–100 mg) of spray-dried solid dispersions (SDSDs) are evaluated in terms of drug–polymer miscibility, physical stability and dissolution performance in bio-predictive conditions. The objectives are to select the adequate carrier and drug-loading (DL) for the manufacturing of robust SDSD; and the appropriate stabilizer dissolved in the liquid vehicle of SDSD suspensions, which constitutes the common dosage form used during non-clinical studies. This methodology was verified with CDP146, a poorly water soluble (<2 µg/mL) API combined with four enteric polymers and four stabilizers. CDP146/HPMCAS-LF 40:60 (w/w) and 10% (w/v) PVPVA were identified as the lead SDSD and the best performing stabilizer, respectively. Lead SDSD suspensions (1–50 mg/mL) were found to preserve complete amorphous state during 8 h and maintain supersaturation in simulated rat intestinal fluids during the absorption window. Therefore, the implementation of spray-drying as a small-scale screening approach allowed maximizing screening effectiveness with respect to very limited API amounts (735 mg) and time resources (9 days), while removing transfer steps between screening and manufacturing phases.

scholarly journals Effect of Storage Humidity on Physical Stability of Spray-Dried Naproxen Amorphous Solid Dispersions with Polyvinylpyrrolidone: Two Fluid Nozzle vs. Three Fluid Nozzle

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1074
Author(s):  
Sonal V. Bhujbal ◽  
Yongchao Su ◽  
Vaibhav Pathak ◽  
Dmitry Y. Zemlyanov ◽  
Alex-Anthony Cavallaro ◽  
...  
Keyword(s):  
Spray Drying ◽  
Single Channel ◽  
Solid Dispersions ◽  
Physical Stability ◽  
Volume Ratio ◽  
Amorphous Solid ◽  
Drug Dissolution ◽  
Amorphous Solid Dispersions ◽  
Two Fluid ◽  
Spray Dried

In a spray drying operation, a two-fluid nozzle (2FN) with a single channel is commonly used for atomizing the feed solution. However, the less commonly used three-fluid nozzle (3FN) has two separate channels, which allow spray drying of materials in two incompatible solution systems. Although amorphous solid dispersions (ASDs) prepared using a 3FN have been reported to deliver comparable drug dissolution performance relative to those prepared using a 2FN, few studies have systematically examined the effect of 3FN on the physical stability. Therefore, the goal of this work is to systematically study the physical stability of ASDs that are spray-dried using a 3FN compared to those prepared using the traditional 2FN. For the 2FN, a single solution of naproxen and polyvinylpyrrolidone (PVP) was prepared in a mixture of acetone and water at a 1:1 volume ratio because 2FN allows for only one solution inlet. For the 3FN, naproxen and PVP were dissolved individually in acetone and water, respectively, because 3FN allows simultaneous entry of two solutions. Upon storage of the formulated ASDs at different humidity levels (25%, 55% and 75% RH), naproxen crystallized more quickly from the 3FN ASDs as compared with the 2FN ASDs. 3FN ASDs crystallized after 5 days of storage at all conditions, whereas 2FN ASDs did not crystallize even at 55% RH for two months. This relatively higher crystallization tendency of 3FN ASDs was attributed to the inhomogeneity of drug and polymers as identified by the solid-state Nuclear Magnetic Resonance findings, specifically due to poor mixing of water- and acetone-based solutions at the 3FN nozzle. When only acetone was used as a solvent to prepare drug-polymer solutions for 3FN, the formulated ASD was found to be stable for >3 months of storage (at 75% RH), which suggests that instability of the 3FN ASD was due to the insufficient mixing of water and acetone solutions. This study provides insights into the effects of solvent and nozzle choices on the physical stability of spray-dried ASDs.

Influence of β-Cyclodextrin and Hydroxypropyl-β-Cyclodextrin on Enhancement of Solubility and Dissolution of Isradipine

2017 ◽  
Vol 10 (3) ◽  
pp. 3752-3757
Author(s):  
Narendar D ◽  
Ettireddy S
Keyword(s):  
Inclusion Complex ◽  
Dissolution Rate ◽  
Solid Dispersions ◽  
Physical Stability ◽  
Molecular Complexes ◽  
In Vitro Dissolution ◽  
Molar Ratio ◽  
Phase Solubility ◽  
Cyclodextrin Complexation

The content of this investigation was to study the influence of β-cyclodextrin and hydroxy propyl-β-cyclodextrin complexation on enhancement of solubility and dissolution rate of isradipine. Based on preliminary phase solubility studies, solid complexes prepared by freeze drying method in 1:1 molar ratio were selected and characterized by DSC for confirmation of complex formation. Prepared solid dispersions were evaluated for drug content, solubility and in vitro dissolution. The physical stability of optimized formulation was studied at refrigerated and room temperature for 2 months. Solid state characterization of optimized complex performed by DSC and XRD studies.  Dissolution rate of isradipine was increased compared with pure drug and more with HP-β-CD inclusion complex than β-CD. DSC and XRD analyzes that drug was in amorphous form, when the drug was incorporated as isradipine β-CD and HP-β-CD inclusion complex. Stability studies resulted in low or no variations in the percentage of complexation efficiency suggesting good stability of molecular complexes. The results conclusively demonstrated that the enhancement of solubility and dissolution rate of isradipine by drug-cyclodextrin complexation was achieved.   

On the Problem of “Two-Phase” Activated Sludge

1991 ◽  
Vol 24 (7) ◽  
pp. 59-64 ◽  
Author(s):  
R. W. Szetela
Keyword(s):  
Activated Sludge ◽  
Single Phase ◽  
Phase System ◽  
Two Phase ◽  
Wastewater Treatment Process ◽  
Sludge Stabilization ◽  
Technological Advantage ◽  
In Series ◽  
State Models ◽  
Activated Sludge Systems

Steady-state models are presented to describe the wastewater treatment process in two activated sludge systems. One of these makes use of a single complete-mix reactor; the other one involves two complete-mix reactors arranged in series. The in-series system is equivalent to what is known as the “two-phase” activated sludge, a concept which is now being launched throughout Poland in conjunction with the PROMLECZ technology under implementation. Analysis of the mathematical models has revealed the following: (1) treatment efficiency, excess sludge production, energy consumption, and the degree of sludge stabilization are identical in the two systems; (2) there exists a technological equivalence of “two-phase” sludge with “single-phase” sludge; (3) the “two-phase” system has no technological advantage over the “single-phase” system.

Mesoporous Silica Molecular Sieve based Nanocarriers: Transpiring Drug Dissolution Research

2017 ◽  
Vol 23 (3) ◽  
pp. 467-480 ◽  
Author(s):  
Satyanarayan Pattnaik ◽  
Kamla Pathak
Keyword(s):  
Drug Release ◽  
Mesoporous Silica ◽  
Molecular Sieves ◽  
Release Kinetics ◽  
Drug Loading ◽  
Scale Up ◽  
Water Soluble ◽  
Drug Dissolution ◽  
Water Soluble Drugs ◽  
Loading Methods

Background: Improvement of oral bioavailability through enhancement of dissolution for poorly soluble drugs has been a very promising approach. Recently, mesoporous silica based molecular sieves have demonstrated excellent properties to enhance the dissolution velocity of poorly water-soluble drugs. Description: Current research in this area is focused on investigating the factors influencing the drug release from these carriers, the kinetics of drug release and manufacturing approaches to scale-up production for commercial manufacture. Conclusion: This comprehensive review provides an overview of different methods adopted for synthesis of mesoporous materials, influence of processing factors on properties of these materials and drug loading methods. The drug release kinetics from mesoporous silica systems, the manufacturability and stability of these formulations are reviewed. Finally, the safety and biocompatibility issues related to these silica based materials are discussed.

scholarly journals Preparation and Pharmacokinetic Study of Daidzein Long-Circulating Liposomes

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Qiao Wang ◽  
Wenjin Liu ◽  
Junjun Wang ◽  
Hong Liu ◽  
Yong Chen
Keyword(s):  
Single Dose ◽  
Drug Concentration ◽  
Drug Loading ◽  
Plasma Drug Concentration ◽  
The Body ◽  
Molar Ratio ◽  
Terminal Phase ◽  
Plasma Drug ◽  
Ultrasonic Time ◽  
Time Required

Abstract In this study, daidzein long-circulating liposomes (DLCL) were prepared using the ultrasonication and lipid film-hydration method. The optimized preparation conditions by the orthogonal design was as follows: 55 to 40 for the molar ratio of soybean phosphatidylcholine (SPC) to cholesterol, 1 to 10 for the mass ratio of daidzein to total lipid (SPC and cholesterol) (w:w), the indicated concentration of 5% DSPE-mPEG2000 (w:w), 50 °C for the hydration temperature, and 24 min for the ultrasonic time. Under these conditions, the encapsulation efficiency and drug loading of DLCL were 85.3 ± 3.6% and 8.2 ± 1.4%, respectively. The complete release times of DLCL in the medium of pH 1.2 and pH 6.9 increased by four- and twofold of that of free drugs, respectively. After rats were orally administered, a single dose of daidzein (30 mg/kg) and DLCL (containing equal dose of daidzein), respectively, and the MRT0−t (mean residence time, which is the time required for the elimination of 63.2% of drug in the body), t1/2 (the elimination half-life, which is the time required to halve the plasma drug concentration of the terminal phase), and AUC0−t (the area under the plasma drug concentration-time curve, which represents the total absorption after a single dose and reflects the drug absorption degree) of daidzein in DLCL group, increased by 1.6-, 1.8- and 2.5-fold as compared with those in the free group daidzein. Our results indicated that DLCL could not only reduce the first-pass effect of daidzein to promote its oral absorption, but also prolong its mean resident time to achieve the slow-release effect.

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