Dissolution Enhancement of Poorly Soluble Drugs

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (30 May 2018) | Viewed by 114749

Special Issue Editors


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Guest Editor
Otto H. York Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
Interests: particle engineering; pharmaceutical nanotechnology; drug nanosuspensions and nanocomposites; amorphous solid dispersions; multi-scale process modeling; pharmaceutical unit operations; milling; granulation; spray drying; extrusion
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Otto H. York Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
Interests: particle engineering; drug nano-particles and composites including thin films; amorphous solid dispersions; 3D printing; novel techniques for dry particle coating; film-coated particles; taste-masking and controlled release; nano-mixing; cohesive powder fluidization; discrete element modeling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

An increasing number of small molecules in the pipeline of pharmaceutical companies exhibit poor aqueous solubility, low dissolution rate, and, thus, poor bioavailability, which presents a major challenge in developing such molecules into medicines. To enhance the solubility and dissolution rate, several approaches have been developed, such as nano/micro-particle based formulations, amorphous solid dispersions, lipid-based drug delivery systems, pro-drugs, and co-crystals. Within the context of “Poorly Soluble Drugs,” this Special Issue aims to bring academicians and pharmaceutical scientists/engineers to disseminate knowledge and information about novel materials, formulations, processes, characterization–testing methods, and provide a fundamental understanding of existing formulations–processes and insight into the mechanisms by which solubility/dissolution rate of the drugs are enhanced. Papers providing insight into the formation, structure, physico-chemical properties, and physical stability of the dosages with poorly water-soluble drugs as well as those exploring glass-forming ability of drugs, recrystallization tendency, and nano/microparticle formation are especially welcome.

Prof. Ecevit  Bilgili
Prof. Rajesh N. Dave
Guest Editors

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Keywords

  • poorly water-soluble
  • dissolution rate
  • bioavailability enhancement
  • nanoparticles and nanocomposites
  • amorphous solid dispersions
  • lipid-based drug delivery systems
  • pro-drugs
  • co-crystals
  • physical stability
  • supersaturation
  • recrystallization

Published Papers (14 papers)

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Research

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13 pages, 3006 KiB  
Article
Processing Impact on Performance of Solid Dispersions
by Dan Zhang, Yung-Chi Lee, Zaher Shabani, Celeste Frankenfeld Lamm, Wei Zhu, Yongjun Li and Allen Templeton
Pharmaceutics 2018, 10(3), 142; https://doi.org/10.3390/pharmaceutics10030142 - 30 Aug 2018
Cited by 25 | Viewed by 4362
Abstract
The development of a weakly basic compound is often challenging due to changes in pH that the drug experiences throughout the gastrointestinal tract. As the drug transitions from the low pH of the stomach to the higher pH of the small intestine, drug [...] Read more.
The development of a weakly basic compound is often challenging due to changes in pH that the drug experiences throughout the gastrointestinal tract. As the drug transitions from the low pH of the stomach to the higher pH of the small intestine, drug solubility decreases. A stomach with a higher pH, caused by food or achlorhydric conditions brought about by certain medications, decreases even the initial solubility. This decreased drug solubility is reflected in lower in vivo exposures. In many cases, a solubility-enabling approach is needed to counteract the effect of gastrointestinal pH changes. Solid dispersions of amorphous drug in a polymer matrix have been demonstrated to be an effective tool to enhance bioavailability, with the potential to mitigate the food and achlorhydric effects frequently observed with conventional formulations. Because solid dispersions are in a metastable state, they are particularly sensitive to processing routes that may control particle attributes, stability, drug release profile, and bioperformance. A better understanding of the impacts of processing routes on the solid dispersion properties will not only enhance our ability to control the product properties, but also lower development risks. In this study, a weakly basic compound with greatly reduced solubility in higher pHs was incorporated into a solid dispersion via both spray drying and hot melt extrusion. The properties of the solid dispersion via these two processing routes were compared, and the impact on dissolution behavior and in vivo performance of the dispersions was investigated. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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14 pages, 2452 KiB  
Article
Development and Evaluation of a Reconstitutable Dry Suspension to Improve the Dissolution and Oral Absorption of Poorly Water-Soluble Celecoxib
by Hye-In Kim, Sang Yeob Park, Seok Ju Park, Jewon Lee, Kwan Hyung Cho, Jun-Pil Jee, Hee-Cheol Kim, Han-Joo Maeng and Dong-Jin Jang
Pharmaceutics 2018, 10(3), 140; https://doi.org/10.3390/pharmaceutics10030140 - 29 Aug 2018
Cited by 16 | Viewed by 5804
Abstract
This study aims at developing and evaluating reconstitutable dry suspension (RDS) improved for dissolution rate, oral absorption, and convenience of use of poorly water-soluble celecoxib (CXB). Micro-sized CXB particle was used to manufacture nanosuspension by using bead milling and then RDS was made [...] Read more.
This study aims at developing and evaluating reconstitutable dry suspension (RDS) improved for dissolution rate, oral absorption, and convenience of use of poorly water-soluble celecoxib (CXB). Micro-sized CXB particle was used to manufacture nanosuspension by using bead milling and then RDS was made by spray-drying the nanosuspension with effective resuspension agent, dextrin. The redispersibility, morphology, particle size, crystallinity, stability, dissolution, and pharmacokinetic profile of the RDS were evaluated. RDS was effectively reconstituted into nanoparticles in 775.8 ± 11.6 nm. It was confirmed that CXB particles are reduced into needle-shape ones in size after the bead-milling process, and the description of CXB was the same in the reconstituted suspension. Through the CXB crystallinity study using differential scanning calorimetry (DSC) and XRD analysis, it was identified that CXB has the CXB active pharmaceutical ingredient (API)’s original crystallinity after the bead milling and spray-drying process. In vitro dissolution of RDS was higher than that of CXB powder (93% versus 28% dissolution at 30 min). Furthermore, RDS formulation resulted in 5.7 and 6.3-fold higher area under the curve (AUC) and peak concentration (Cmax) of CXB compared to after oral administration of CXB powder in rats. Collectively, our results suggest that the RDS may be a potential oral dosage formulation for CXB to improve its bioavailability and patient compliance. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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20 pages, 3303 KiB  
Article
Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study
by Michael Brunsteiner, Johannes Khinast and Amrit Paudel
Pharmaceutics 2018, 10(3), 101; https://doi.org/10.3390/pharmaceutics10030101 - 21 Jul 2018
Cited by 20 | Viewed by 4568
Abstract
Amorphous solid dispersions are considered a promising formulation strategy for the oral delivery of poorly soluble drugs. The limiting factor for the applicability of this approach is the physical (in)stability of the amorphous phase in solid samples. Minimizing the risk of reduced shelf [...] Read more.
Amorphous solid dispersions are considered a promising formulation strategy for the oral delivery of poorly soluble drugs. The limiting factor for the applicability of this approach is the physical (in)stability of the amorphous phase in solid samples. Minimizing the risk of reduced shelf life for a new drug by establishing a suitable excipient/polymer-type from first principles would be desirable to accelerate formulation development. Here, we perform Molecular Dynamics simulations to determine properties of blends of eight different polymer–small molecule drug combinations for which stability data are available from a consistent set of literature data. We calculate thermodynamic factors (mixing energies) as well as mobilities (diffusion rates and roto-vibrational fluctuations). We find that either of the two factors, mobility and energetics, can determine the relative stability of the amorphous form for a given drug. Which factor is rate limiting depends on physico-chemical properties of the drug and the excipients/polymers. The methods outlined here can be readily employed for an in silico pre-screening of different excipients for a given drug to establish a qualitative ranking of the expected relative stabilities, thereby accelerating and streamlining formulation development. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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12 pages, 2880 KiB  
Article
Ginsenoside Drug Nanocomposites Prepared by the Aerosol Solvent Extraction System for Enhancing Drug Solubility and Stability
by Cheng Tao, Jianjun Zhang, Jiexin Wang and Yuan Le
Pharmaceutics 2018, 10(3), 95; https://doi.org/10.3390/pharmaceutics10030095 - 18 Jul 2018
Cited by 11 | Viewed by 3944
Abstract
Ginsenosides are the pharmacologically active constituents of ginseng. So far, more than 30 ginsenosides have been identified and widely used in pharmaceutical formulations. However, the therapeutic applications of ginsenosides are hampered by their poor solubility and low bioavailability. In this study, we selected [...] Read more.
Ginsenosides are the pharmacologically active constituents of ginseng. So far, more than 30 ginsenosides have been identified and widely used in pharmaceutical formulations. However, the therapeutic applications of ginsenosides are hampered by their poor solubility and low bioavailability. In this study, we selected two of the most important ginsenosides-Re and Rh2 as model drugs to prepare ginsenoside drug nanocomposites (NanoGS) using the simple aerosol solvent extraction system (ASES) technique to address the poor solubility and bioavailability of these compounds. Compared with raw ginsenosides, NanoGS exhibited significantly enhanced dissolution rate owing to their low crystallinity and high surface area. Furthermore, in vitro cellular investigations showed that NanoGS-Rh2 exhibited outstanding anticancer activity against MCF-7 cancer cells. Therefore, this study is expected to provide a promising strategy that could optimize and broaden the applications of ginsenosides, as well as other water-insoluble drugs in pharmaceutical formulations. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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12 pages, 3512 KiB  
Article
Solubility Improvement of Benexate through Salt Formation Using Artificial Sweetener
by Okky Dwichandra Putra, Daiki Umeda, Eriko Fujita, Tamami Haraguchi, Takahiro Uchida, Etsuo Yonemochi and Hidehiro Uekusa
Pharmaceutics 2018, 10(2), 64; https://doi.org/10.3390/pharmaceutics10020064 - 26 May 2018
Cited by 30 | Viewed by 6127
Abstract
Benexate, a drug used clinically as a defensive type anti-ulcer agent, has poor solubility and a bitter taste. To improve its solubility, a crystal engineering approach was proposed with the formation of novel salts using an artificial sweetener as a salt co-former. This [...] Read more.
Benexate, a drug used clinically as a defensive type anti-ulcer agent, has poor solubility and a bitter taste. To improve its solubility, a crystal engineering approach was proposed with the formation of novel salts using an artificial sweetener as a salt co-former. This was also expected to address the bitter taste of the drug. In this work, we report on the preparation and evaluation of the physicochemical properties of the novel salts benexate saccharinate monohydrate and benexate cyclamate whose crystal structures were determined by single-crystal X-ray structure analysis. These novel salts showed higher solubility and faster dissolution profiles that were associated with the occurrence of local layered-like structures. They also showed better moisture uptake profiles and were classified as non-hygroscopic materials. Therefore, benexate saccharinate monohydrate and benexate cyclamate expedited the development of sweet pharmaceutical salts of benexate with improved performances. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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13 pages, 5271 KiB  
Article
Influence of Solvent Composition on the Performance of Spray-Dried Co-Amorphous Formulations
by Jaya Mishra, Thomas Rades, Korbinian Löbmann and Holger Grohganz
Pharmaceutics 2018, 10(2), 47; https://doi.org/10.3390/pharmaceutics10020047 - 12 Apr 2018
Cited by 24 | Viewed by 5487
Abstract
Ball-milling is usually used to prepare co-amorphous drug–amino acid (AA) mixtures. In this study, co-amorphous drug–AA mixtures were produced using spray-drying, a scalable industrially preferred preparation method. The influence of the solvent type and solvent composition was investigated. Mixtures of indomethacin (IND) and [...] Read more.
Ball-milling is usually used to prepare co-amorphous drug–amino acid (AA) mixtures. In this study, co-amorphous drug–AA mixtures were produced using spray-drying, a scalable industrially preferred preparation method. The influence of the solvent type and solvent composition was investigated. Mixtures of indomethacin (IND) and each of the three AAs arginine, histidine, and lysine were ball-milled and spray-dried at a 1:1 molar ratio, respectively. Spray-drying was performed at different solvent ratios in (a) ethanol and water mixtures and (b) acetone and water mixtures. Different ratios of these solvents were chosen to study the effect of solvent mixtures on co-amorphous formulation. Residual crystallinity, thermal properties, salt/partial salt formation, and powder dissolution profiles of the IND–AA mixtures were investigated and compared to pure crystalline and amorphous IND. It was found that using spray-drying as a preparation method, all IND–AA mixtures could be successfully converted into the respective co-amorphous forms, irrespective of the type of solvent used, but depending on the solvent mixture ratios. Both ball-milled and spray-dried co-amorphous samples showed an enhanced dissolution rate and maintained supersaturation compared to the crystalline and amorphous IND itself. The spray-dried samples resulting in co-amorphous samples were stable for at least seven months of storage. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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15 pages, 4726 KiB  
Article
Orally Disintegrating Tablets Containing Melt Extruded Amorphous Solid Dispersion of Tacrolimus for Dissolution Enhancement
by Poovizhi Ponnammal, Parijat Kanaujia, Yin Yani, Wai Kiong Ng and Reginald B. H. Tan
Pharmaceutics 2018, 10(1), 35; https://doi.org/10.3390/pharmaceutics10010035 - 16 Mar 2018
Cited by 27 | Viewed by 7149
Abstract
In order to improve the aqueous solubility and dissolution of Tacrolimus (TAC), amorphous solid dispersions of TAC were prepared by hot melt extrusion with three hydrophilic polymers, Polyvinylpyrrolidone vinyl acetate (PVP VA64), Soluplus® and Hydroxypropyl Cellulose (HPC), at a drug loading of [...] Read more.
In order to improve the aqueous solubility and dissolution of Tacrolimus (TAC), amorphous solid dispersions of TAC were prepared by hot melt extrusion with three hydrophilic polymers, Polyvinylpyrrolidone vinyl acetate (PVP VA64), Soluplus® and Hydroxypropyl Cellulose (HPC), at a drug loading of 10% w/w. Molecular modeling was used to determine the miscibility of the drug with the carrier polymers by calculating the Hansen Solubility Parameters. Powder X-ray diffraction and differential scanning calorimetry (DSC) studies of powdered solid dispersions revealed the conversion of crystalline TAC to amorphous form. Fourier transform Infrared (FTIR) spectroscopy results indicated formation of hydrogen bond between TAC and polymers leading to stabilization of TAC in amorphous form. The extrudates were found to be stable under accelerated storage conditions for 3 months with no re-crystallization, indicating that hot melt extrusion is suitable for producing stable amorphous solid dispersions of TAC in PVP VA64, Soluplus® and HPC. Stable solid dispersions of amorphous TAC exhibited higher dissolution rate, with the solid dispersions releasing more than 80% drug in 15 min compared to the crystalline drug giving 5% drug release in two hours. These stable solid dispersions were incorporated into orally-disintegrating tablets in which the solid dispersion retained its solubility, dissolution and stability advantage. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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16 pages, 2621 KiB  
Article
Feasibility of Using Gluconolactone, Trehalose and Hydroxy-Propyl Gamma Cyclodextrin to Enhance Bendroflumethiazide Dissolution Using Lyophilisation and Physical Mixing Techniques
by Ashraf Saleh, Kenneth McGarry, Cheng Shu Chaw and Amal Ali Elkordy
Pharmaceutics 2018, 10(1), 22; https://doi.org/10.3390/pharmaceutics10010022 - 01 Feb 2018
Cited by 9 | Viewed by 6035
Abstract
Purpose: Hydrophobic drugs are facing a major challenge in dissolution rate enhancement and solubility in aqueous solutions; therefore, a variety of methods have been used to improve dissolution rate and/or solubility of bendroflumethiazide as a model hydrophobic drug. Methods: In this study, two [...] Read more.
Purpose: Hydrophobic drugs are facing a major challenge in dissolution rate enhancement and solubility in aqueous solutions; therefore, a variety of methods have been used to improve dissolution rate and/or solubility of bendroflumethiazide as a model hydrophobic drug. Methods: In this study, two main methods (physical mixing and lyophilisation) were used with gluconolactone, hydroxyl propyl γ-ccyclodextrin, and trehalose to explore this challenge. Bendroflumethiazide, practically insoluble in water, was mixed with one of the three excipients gluconolactone, hydroxyl propyl γ-cyclodextrin, and trehalose in three different ratios 1:1, 1:2, 1:5. To the best of our knowledge, the dissolution of the drug has not been previously enhanced by using either these methods or any of the used excipients. Samples containing drug and each of the excipients were characterized via dissolution testing, Fourier Transform infra-red spectroscopy, differential scanning calorimetry, and scanning electron microscopy. Results: The used methods showed a significant enhancement in dug dissolution rate; physical mixing significantly, p < 0.05, increased the percentage of the drug released with time; for example, bendroflumethiazide dissolution in distilled water was improved from less than 20% to 99.79% within 90 min for physically mixed drug-cyclodextrin 1:5. The lyophilisation process was enhanced and the drug dissolution rate and the highest drug dissolution was achieved for (drug-gluconolactone 1:1) with 98.98% drug release within 90 min. Conclusions: the physical mixing and freeze drying processes significantly increased the percentage of drug release with time. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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16 pages, 4180 KiB  
Article
Curcumin-Artemisinin Coamorphous Solid: Xenograft Model Preclinical Study
by M. K. Chaitanya Mannava, Kuthuru Suresh, Manish Kumar Bommaka, Durga Bhavani Konga and Ashwini Nangia
Pharmaceutics 2018, 10(1), 7; https://doi.org/10.3390/pharmaceutics10010007 - 09 Jan 2018
Cited by 32 | Viewed by 6373
Abstract
Curcumin is a natural compound present in Indian spice turmeric. It has diverse pharmacological action but low oral solubility and bioavailability continue to limit its use as a drug. With the aim of improving the bioavailability of Curcumin (CUR), we evaluated Curcumin-Pyrogallol (CUR-PYR) [...] Read more.
Curcumin is a natural compound present in Indian spice turmeric. It has diverse pharmacological action but low oral solubility and bioavailability continue to limit its use as a drug. With the aim of improving the bioavailability of Curcumin (CUR), we evaluated Curcumin-Pyrogallol (CUR-PYR) cocrystal and Curcumin-Artemisinin (CUR-ART) coamorphous solid. Both of these solid forms exhibited superior dissolution and pharmacokinetic behavior compared to pure CUR, which is practically insoluble in water. CUR-ART coamorphous solid showed two fold higher bioavailability than CUR-PYR cocrystal (at 200 mg/kg oral dose). Moreover, in simulated gastric and intestinal fluids (SGF and SIF), CUR-ART is stable up to 3 and 12 h, respectively. In addition, CUR-PYR and CUR-ART showed no adverse effects in toxicology studies (10 times higher dose at 2000 mg/kg). CUR-ART showed higher therapeutic effect and inhibited approximately 62% of tumor growth at 100 mg/kg oral dosage of CUR in xenograft models, which is equal to the positive control drug, doxorubicin (2 mg/kg) by i.v. administration. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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Review

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29 pages, 333 KiB  
Review
Nanocrystals of Poorly Soluble Drugs: Drug Bioavailability and Physicochemical Stability
by Maria Rosa Gigliobianco, Cristina Casadidio, Roberta Censi and Piera Di Martino
Pharmaceutics 2018, 10(3), 134; https://doi.org/10.3390/pharmaceutics10030134 - 21 Aug 2018
Cited by 184 | Viewed by 11676
Abstract
Many approaches have been developed over time to overcome the bioavailability limitations of poorly soluble drugs. With the advances in nanotechnology in recent decades, science and industry have been approaching this issue through the formulation of drugs as nanocrystals, which consist of “pure [...] Read more.
Many approaches have been developed over time to overcome the bioavailability limitations of poorly soluble drugs. With the advances in nanotechnology in recent decades, science and industry have been approaching this issue through the formulation of drugs as nanocrystals, which consist of “pure drugs and a minimum of surface active agents required for stabilization”. They are defined as “carrier-free submicron colloidal drug delivery systems with a mean particle size in the nanometer range, typically between 10–800 nm”. The primary importance of these nanoparticles was the reduction of particle size to nanoscale dimensions, with an increase in the particle surface area in contact with the dissolution medium, and thus in bioavailability. This approach has been proven successful, as demonstrated by the number of such drug products on the market. Nonetheless, despite the definition that indicates nanocrystals as a “carrier-free” system, surface active agents are necessary to prevent colloidal particles aggregation and thus improve stability. In addition, in more recent years, nanocrystal properties and technologies have attracted the interest of researchers as a means to obtain colloidal particles with modified biological properties, and thus their interest is now also addressed to modify the drug delivery and targeting. The present work provides an overview of the achievements in improving the bioavailability of poorly soluble drugs according to their administration route, describes the methods developed to overcome physicochemical and stability-related problems, and in particular reviews different stabilizers and surface agents that are able to modify the drug delivery and targeting. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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74 pages, 10488 KiB  
Review
Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium
by Indumathi Sathisaran and Sameer Vishvanath Dalvi
Pharmaceutics 2018, 10(3), 108; https://doi.org/10.3390/pharmaceutics10030108 - 31 Jul 2018
Cited by 141 | Viewed by 13526
Abstract
Biopharmaceutics Classification System (BCS) Class II and IV drugs suffer from poor aqueous solubility and hence low bioavailability. Most of these drugs are hydrophobic and cannot be developed into a pharmaceutical formulation due to their poor aqueous solubility. One of the ways to [...] Read more.
Biopharmaceutics Classification System (BCS) Class II and IV drugs suffer from poor aqueous solubility and hence low bioavailability. Most of these drugs are hydrophobic and cannot be developed into a pharmaceutical formulation due to their poor aqueous solubility. One of the ways to enhance the aqueous solubility of poorlywater-soluble drugs is to use the principles of crystal engineering to formulate cocrystals of these molecules with water-soluble molecules (which are generally called coformers). Many researchers have shown that the cocrystals significantly enhance the aqueous solubility of poorly water-soluble drugs. In this review, we present a consolidated account of reports available in the literature related to the cocrystallization of poorly water-soluble drugs. The current practice to formulate new drug cocrystals with enhanced solubility involves a lot of empiricism. Therefore, in this work, attempts have been made to understand a general framework involved in successful (and unsuccessful) cocrystallization events which can yield different solid forms such as cocrystals, cocrystal polymorphs, cocrystal hydrates/solvates, salts, coamorphous solids, eutectics and solid solutions. The rationale behind screening suitable coformers for cocrystallization has been explained based on the rules of five i.e., hydrogen bonding, halogen bonding (and in general non-covalent bonding), length of carbon chain, molecular recognition points and coformer aqueous solubility. Different techniques to screen coformers for effective cocrystallization and methods to synthesize cocrystals have been discussed. Recent advances in technologies for continuous and solvent-free production of cocrystals have also been discussed. Furthermore, mechanisms involved in solubilization of these solid forms and the parameters influencing dissolution and stability of specific solid forms have been discussed. Overall, this review provides a consolidated account of the rationale for design of cocrystals, past efforts, recent developments and future perspectives for cocrystallization research which will be extremely useful for researchers working in pharmaceutical formulation development. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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17 pages, 1294 KiB  
Review
Design Space and QbD Approach for Production of Drug Nanocrystals by Wet Media Milling Techniques
by Leena Peltonen
Pharmaceutics 2018, 10(3), 104; https://doi.org/10.3390/pharmaceutics10030104 - 25 Jul 2018
Cited by 50 | Viewed by 7329
Abstract
Drug nanocrystals are nanosized solid drug particles, the most important application of which is the improvement of solubility properties of poorly soluble drug materials. Drug nanocrystals can be produced by many different techniques, but the mostly used are different kinds of media milling [...] Read more.
Drug nanocrystals are nanosized solid drug particles, the most important application of which is the improvement of solubility properties of poorly soluble drug materials. Drug nanocrystals can be produced by many different techniques, but the mostly used are different kinds of media milling techniques; in milling, particle size of bulk sized drug material is decreased, with the aid of milling beads, to nanometer scale. Utilization of Quality by Design, QbD, approach in nanomilling improves the process-understanding of the system, and recently, the number of studies using the QbD approach in nanomilling has increased. In the QbD approach, the quality is built into the products and processes throughout the whole production chain. Definition of Critical Quality Attributes, CQAs, determines the targeted final product properties. CQAs are confirmed by setting Critical Process Parameters, CPPs, which include both process parameters but also input variables, like stabilizer amount or the solid state form of the drug. Finally, Design Space determines the limits in which CPPs should be in order to reach CQAs. This review discusses the milling process and process variables, CPPs, their impact on product properties, CQAs and challenges of the QbD approach in nanomilling studies. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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26 pages, 4258 KiB  
Review
Co-Amorphous Solid Dispersions for Solubility and Absorption Improvement of Drugs: Composition, Preparation, Characterization and Formulations for Oral Delivery
by Anna Karagianni, Kyriakos Kachrimanis and Ioannis Nikolakakis
Pharmaceutics 2018, 10(3), 98; https://doi.org/10.3390/pharmaceutics10030098 - 19 Jul 2018
Cited by 123 | Viewed by 17399
Abstract
The amorphous solid state offers an improved apparent solubility and dissolution rate. However, due to thermodynamic instability and recrystallization tendencies during processing, storage and dissolution, their potential application is limited. For this reason, the production of amorphous drugs with adequate stability remains a [...] Read more.
The amorphous solid state offers an improved apparent solubility and dissolution rate. However, due to thermodynamic instability and recrystallization tendencies during processing, storage and dissolution, their potential application is limited. For this reason, the production of amorphous drugs with adequate stability remains a major challenge and formulation strategies based on solid molecular dispersions are being exploited. Co-amorphous systems are a new formulation approach where the amorphous drug is stabilized through strong intermolecular interactions by a low molecular co-former. This review covers several topics applicable to co-amorphous drug delivery systems. In particular, it describes recent advances in the co-amorphous composition, preparation and solid-state characterization, as well as improvements of dissolution performance and absorption are detailed. Examples of drug-drug, drug-carboxylic acid and drug-amino acid co-amorphous dispersions interacting via hydrogen bonding, π−π interactions and ionic forces, are presented together with corresponding final dosage forms. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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62 pages, 3071 KiB  
Review
Bioavailability Enhancement of Poorly Water-Soluble Drugs via Nanocomposites: Formulation–Processing Aspects and Challenges
by Anagha Bhakay, Mahbubur Rahman, Rajesh N. Dave and Ecevit Bilgili
Pharmaceutics 2018, 10(3), 86; https://doi.org/10.3390/pharmaceutics10030086 - 08 Jul 2018
Cited by 136 | Viewed by 11965
Abstract
Drug nanoparticles embedded in a dispersant matrix as a secondary phase, i.e., drug-laden nanocomposites, offer a versatile delivery platform for enhancing the dissolution rate and bioavailability of poorly water-soluble drugs. Drug nanoparticles are prepared by top-down, bottom-up, or combinative approaches in the form [...] Read more.
Drug nanoparticles embedded in a dispersant matrix as a secondary phase, i.e., drug-laden nanocomposites, offer a versatile delivery platform for enhancing the dissolution rate and bioavailability of poorly water-soluble drugs. Drug nanoparticles are prepared by top-down, bottom-up, or combinative approaches in the form of nanosuspensions, which are subsequently dried to prepare drug-laden nanocomposites. In this comprehensive review paper, the term “nanocomposites” is used in a broad context to cover drug nanoparticle-laden intermediate products in the form of powders, cakes, and extrudates, which can be incorporated into final oral solid dosages via standard pharmaceutical unit operations, as well as drug nanoparticle-laden strip films. The objective of this paper is to review studies from 2012–2017 in the field of drug-laden nanocomposites. After a brief overview of the various approaches used for preparing drug nanoparticles, the review covers drying processes and dispersant formulations used for the production of drug-laden nanocomposites, as well as various characterization methods including quiescent and agitated redispersion tests. Traditional dispersants such as soluble polymers, surfactants, other water-soluble dispersants, and water-insoluble dispersants, as well as novel dispersants such as wet-milled superdisintegrants, are covered. They exhibit various functionalities such as drug nanoparticle stabilization, mitigation of aggregation, formation of nanocomposite matrix–film, wettability enhancement, and matrix erosion/disintegration. Major challenges such as nanoparticle aggregation and poor redispersibility that cause inferior dissolution performance of the drug-laden nanocomposites are highlighted. Literature data are analyzed in terms of usage frequency of various drying processes and dispersant classes. We provide some engineering considerations in comparing drying processes, which could account for some of the diverging trends in academia vs. industrial practice. Overall, this review provides rationale and guidance for drying process selection and robust nanocomposite formulation development, with insights into the roles of various classes of dispersants. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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