scholarly journals Drug-Rich Phases Induced by Amorphous Solid Dispersion: Arbitrary or Intentional Goal in Oral Drug Delivery?

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 889
Author(s):  
Kaijie Qian ◽  
Lorenzo Stella ◽  
David S. Jones ◽  
Gavin P. Andrews ◽  
Huachuan Du ◽  
...  
Keyword(s):  
Solid Dispersion ◽  
Oral Drug Delivery ◽  
Drug Product ◽  
Amorphous Solid ◽  
Water Soluble ◽  
Nucleation Theory ◽  
Product Development Process ◽  
Classical Nucleation Theory ◽  
Oral Drug ◽  
Amorphous Solid Dispersion

Among many methods to mitigate the solubility limitations of drug compounds, amorphous solid dispersion (ASD) is considered to be one of the most promising strategies to enhance the dissolution and bioavailability of poorly water-soluble drugs. The enhancement of ASD in the oral absorption of drugs has been mainly attributed to the high apparent drug solubility during the dissolution. In the last decade, with the implementations of new knowledge and advanced analytical techniques, a drug-rich transient metastable phase was frequently highlighted within the supersaturation stage of the ASD dissolution. The extended drug absorption and bioavailability enhancement may be attributed to the metastability of such drug-rich phases. In this paper, we have reviewed (i) the possible theory behind the formation and stabilization of such metastable drug-rich phases, with a focus on non-classical nucleation; (ii) the additional benefits of the ASD-induced drug-rich phases for bioavailability enhancements. It is envisaged that a greater understanding of the non-classical nucleation theory and its application on the ASD design might accelerate the drug product development process in the future.

scholarly journals The Development and Optimization of Hot-Melt Extruded Amorphous Solid Dispersions Containing Rivaroxaban in Combination with Polymers

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 344
Author(s):  
Jong-Hwa Lee ◽  
Hyeong Sik Jeong ◽  
Jong-Woo Jeong ◽  
Tae-Sung Koo ◽  
Do-Kyun Kim ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Dissolution Rate ◽  
Solid Dispersion ◽  
Oral Drug Delivery ◽  
Amorphous Solid ◽  
Drug Dissolution ◽  
Oral Drug ◽  
Amorphous Solid Dispersion ◽  
Screw Speed ◽  
Hot Melt

Rivaroxaban (RXB), a novel oral anticoagulant that directly inhibits factor Xa, is a poorly soluble drug belonging to Biopharmaceutics Classification System (BCS) class II. In this study, a hot-melt extruded amorphous solid dispersion (HME-ASD) containing RXB is prepared by changing the drug:polymer ratio (Polyvinylpyrrolidione-vinyl acetate 64, 1:1–1:4) and barrel temperature (200–240 °C), fixed at 20% of Cremophor® RH 40 and 15 rpm of the screw speed, using the hot-melt extruding technique. This study evaluates the solubility, dissolution behavior, and bioavailability for application to oral drug delivery and optimizes the formulation of rivaroxaban amorphous solid dispersion (RXB-ASD). Based on a central composite design, optimized RXB-ASD (PVP VA 64 ratio 1:4.1, barrel temperature 216.1 °C, Cremophor® RH 40 20%, screw speed 15 rpm) showed satisfactory results for dependent variables. An in vitro drug dissolution study exhibited relatively high dissolution in four media and achieved around an 80% cumulative drug release in 120 min. Optimized RXB-ASD was stable under the accelerated condition for three months without a change in crystallinity and the dissolution rate. A pharmacokinetic study of RXB-ASD in rats showed that the absorption was markedly increased in terms of rate and amount, i.e., the systemic exposure values, compared to raw RXB powder. These results showed the application of quality by design (QbD) in the formulation development of hot-melt extruded RXB-ASD, which can be used as an oral drug delivery system by increasing the dissolution rate and bioavailability.

Development of an in vivo -relevant drug product performance method for an amorphous solid dispersion

2017 ◽  
Vol 142 ◽  
pp. 307-314 ◽  
Author(s):  
Brian W. Pack ◽  
Yelizaveta Babayan ◽  
Mark A. Schrad ◽  
Paul A. Stroud ◽  
David C. Sperry ◽  
...  
Keyword(s):  
Solid Dispersion ◽  
Drug Product ◽  
Amorphous Solid ◽  
Product Performance ◽  
Amorphous Solid Dispersion

Recent Advances in Solid Dispersion Technology for Efficient Delivery of Poorly Water-Soluble Drugs

2019 ◽  
Vol 25 (13) ◽  
pp. 1524-1535 ◽  
Author(s):  
Gourav Paudwal ◽  
Neha Rawat ◽  
Rahul Gupta ◽  
Ashish Baldi ◽  
Gurdarshan Singh ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Solid Dispersion ◽  
Oral Drug Delivery ◽  
Water Soluble ◽  
Attrition Rate ◽  
Synthetic Methods ◽  
Oral Drug ◽  
Screening Methods ◽  
Formulation Development ◽  
Poorly Water Soluble

Drug discovery is generally considered as a costly affair and it takes approximately 15 years to reach a new chemical entity into the market. Among the recent potent drug molecules with most effective pharmacological properties, very few reached for Phase I clinical trial in humans. Unfortunately, the historical average reveals an almost 90% overall attrition rate in clinical trials. The solubility and permeability of a drug are the critical factors influencing the success of a drug. Oral drug delivery systems still continue to exist as the most favored, simplest and easiest administration route. A huge number of potential clinical candidates won’t make it to the market or accomplish their maximum capacity except if their solubility and oral bioavailability are enhanced by formulation. The solubility of drugs will continue to exist as important aspects of formulation development. With the emergence of synthetic methods for new molecule synthesis in chemistry and better screening methods, the number of poorly water soluble compounds has dramatically expanded in the last few years. Solid dispersion is one of the most important techniques as it can be prepared by several methods. It is mostly prepared with a drug having poor water solubility and it explores hydrophilic polymers either individually or in combination for the enhancement of solubility. In comparison to the conventional formulations such as tablets or capsules, there are different methods with which solid dispersions can be prepared and also have many benefits over conventional drug delivery approaches. Solid dispersion systems are potential for increasing the solubility, oral absorption and bioavailability of drugs and the significance of the solid dispersion technology is constantly increasing. The main focus of this review is to present recent advancements in the area of solid dispersion. This review also includes an account of recent patents on solid dispersion and clinical status of solid dispersion based formulations.

scholarly journals A Novel Rheological Method to Assess Drug-Polymer Interactions Regarding Miscibility and Crystallization of Drug in Amorphous Solid Dispersions for Oral Drug Delivery

Pharmaceutics ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 625 ◽  
Author(s):  
Georgia Tsakiridou ◽  
Christos Reppas ◽  
Martin Kuentz ◽  
Lida Kalantzi
Keyword(s):  
In Silico ◽  
Oral Drug Delivery ◽  
Solid Dispersions ◽  
Amorphous Solid ◽  
Water Soluble ◽  
Oral Drug ◽  
Main Task ◽  
Formulation Development ◽  
Scanning Calorimetry ◽  
Polymer Interactions

Solid dispersions provide a key technology to formulate poorly water-soluble drugs, and a main task of early development is appropriate selection of polymer. This study investigates the use of a novel rheology-based approach to evaluate miscibility and interactions of drugs with polymers regarding amorphous solid drug dispersions for oral administration. Tacrolimus was used as model drug and hydroxypropyl cellulose, ethylcellulose, Soluplus®, polyethyleneglycol 6000, Poloxamer-188 (Koliphor-188), and Eudragit® S100 were used as excipients. Solvent-based evaporation methods were used to prepare binary solid dispersions of drug and polymer. Data of the dilute solution viscosimetry were compared with in silico calculations of the Hansen solubility parameter (HSP), as well as phase separation/crystallization data obtained from X-ray diffraction and differential scanning calorimetry. HSP calculations in some cases led to false positive predictions of tacrolimus miscibility with the tested polymers. The novel rheology-based method provided valuable insights into drug-polymer interactions and likely miscibility with polymer. It is a rather fast, inexpensive, and robust analytical approach, which could be used complementary to in silico-based evaluation of polymers in early formulation development, especially in cases of rather large active pharmaceutical ingredients.

scholarly journals Applicability of an Experimental Grade of Hydroxypropyl Methylcellulose Acetate Succinate as a Carrier for Formation of Solid Dispersion with Indomethacin

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 353
Author(s):  
Hiroshi Ueda ◽  
Yuya Hirakawa ◽  
Hironori Tanaka ◽  
Tetsuya Miyano ◽  
Katsuji Sugita
Keyword(s):  
Solid Dispersion ◽  
Hydroxypropyl Methylcellulose ◽  
Principal Component ◽  
Amorphous Solid ◽  
Water Soluble ◽  
Amorphous Solid Dispersion ◽  
Scanning Calorimetry ◽  
Water Soluble Drugs ◽  
Poorly Water Soluble ◽  
Amorphous Drug

The transformation of a crystalline drug into an amorphous form is a promising way to enhance the oral bioavailability of poorly water-soluble drugs. Blending of a carrier, such as a hydrophilic polymer, with an amorphous drug is a widely used method to produce a solid dispersion and inhibit crystallization. This study investigates an experimental grade of hydroxypropyl methylcellulose acetate succinate, HPMCAS-MX (MX), as a solid dispersion carrier. Enhancement of thermal stability and reduction of the glass transition temperature (Tg) of MX compared with those of the conventional grade were evaluated through thermogravimetric analysis and differential scanning calorimetry (DSC). The formation of a homogeneous amorphous solid dispersion between MX and indomethacin was confirmed by X-ray powder diffraction analysis, DSC, and Raman mapping. It was observed that 10–30% MX did not act as an anti-plasticizer, but the utilization of >40% MX caused an increase in Tg and reduction of molecular mobility. This could be explained by a change in intermolecular interactions, inferred from infrared spectroscopy combined with principal component analysis. HPMCAS-MX exhibited similar performance to that of conventional-grade, HPMCAS-MG. Although HPMCAS-MX has thermal properties different from those of conventional-grade HPMCAS-MG, it retains its ability as a solid dispersion carrier.

scholarly journals In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1257
Author(s):  
Deanna M. Mudie ◽  
Aaron M. Stewart ◽  
Jesus A. Rosales ◽  
Molly S. Adam ◽  
Michael M. Morgen ◽  
...  
Keyword(s):  
Solid Dispersion ◽  
In Silico ◽  
Ph Effect ◽  
Hydroxypropyl Methylcellulose ◽  
Amorphous Solid ◽  
Dosage Forms ◽  
Water Soluble ◽  
Amorphous Solid Dispersion ◽  
In Silico Tools

Amorphous solid dispersion (ASD) dosage forms can improve the oral bioavailability of poorly water-soluble drugs, enabling the commercialization of new chemical entities and improving the efficacy and patient compliance of existing drugs. However, the development of robust, high-performing ASD dosage forms can be challenging, often requiring multiple formulation iterations, long timelines, and high cost. In a previous study, acalabrutinib/hydroxypropyl methylcellulose acetate succinate (HPMCAS)-H grade ASD tablets were shown to overcome the pH effect of commercially marketed Calquence in beagle dogs. This study describes the streamlined in vitro and in silico approach used to develop those ASD tablets. HPMCAS-H and -M grade polymers provided the longest acalabrutinib supersaturation sustainment in an initial screening study, and HPMCAS-H grade ASDs provided the highest in vitro area under the curve (AUC) in gastric to intestinal transfer dissolution tests at elevated gastric pH. In silico simulations of the HPMCAS-H ASD tablet and Calquence capsule provided good in vivo study prediction accuracy using a bottom–up approach (absolute average fold error of AUC0-inf < 2 except for Calquence + famotidine ≈ 3). This streamlined approach combined an understanding of key drug, polymer, and gastrointestinal properties with in vitro and in silico tools to overcome the acalabrutinib pH effect without the need for reformulation or multiple studies, showing promise for reducing time and costs to develop ASD drug products.

scholarly journals Thermal stability of amorphous sugar matrix, dried from methanol, as an amorphous solid dispersion carrier

2018 ◽  
Author(s):  
Koreyoshi Imamura ◽  
K. Takeda ◽  
K. Yamamoto ◽  
H. Imanaka ◽  
N. Ishida
Keyword(s):  
Thermal Stability ◽  
Solid Dispersion ◽  
Amorphous Solid ◽  
Water Soluble ◽  
Solid Matrix ◽  
Amorphous Solid Dispersion ◽  
Solid Mixture ◽  
Soluble Solid ◽  
Dispersion Technique ◽  
Thermal Stability Of

Developing a technique to disperse hydrophobic ingredients homogeneously in a water-soluble solid matrix (solid dispersion) is one of the topics that have been extensively investigated in the pharmaceutical and food industries. Recently, we have devised a novel solid dispersion technique (surfactant-free solid dispersion), in which a preliminarily amorphized sugar was dissolved in an organic media containing hydrophobic component, without using any surface active substances, and then vacuum dried into the amorphous solid mixture [Food Chem., 197 (2016) 1136; Mol. Pharm., 14 (2017) 791]. In this study, the physicochemical properties, especially thermal stability of the surfactant-free amorphous solid dispersion, were investigated. keywords: solid dispersion; amorphous sugar; surfactant-free; vacuum drying; glass transition temperature

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