The aim of this book is to provide a brief but comprehensive overview on the issue of drug bioavailability improvement by preparation of a perspective dosage form – liquisolid systems. The introduction chapter about drug solubility and bioavailability is followed by a description of the general methods which could be used to improve drug bioavailability using approaches of chemistry, physical modification, and primarily pharmaceutical technology. Benefits and practical use of each method are documented by examples.
The main part of the book is aimed at characterization and description of liquisolid systems (LSS) – perspective dosage form for bioavailability improvement. Elementary principles of LSS formulation are described in detail, e.g. how to perform a preformulation study; how to choose the correct type and amount of excipients; how to evaluate the dosage forms, etc. All the above mentioned principles are documented with practical examples.
The book could be used as a textbook for students of natural, medical and pharmaceutical sciences as well as by researchers in this field or industrial area. Contemporary pharmacotherapy is characterized by the increasing amount of active substances that are only poorly soluble in water. This may lead to the limitation of their systemic absorption on oral administration which is closely related to the bioavailability. This category is estimated to include more than forty percent of active substances that are in general use.
So far, this poor aqueous solubility has been improved by physical or chemical modification of the active substance. In general, such changes are very expensive and troublesome, often leading to problems in stability, marketing authorization process, or administration comfort of the particular drug. This is one of the reasons why modern pharmaceutical technology has focused on those dosage forms that can increase the bioavailability of some active substances while maintaining suitable stability and administration comfort. Several processes that improve solubility, respectively bioavailability have been described and published. These include micronization, nanocrystals, and formulation of solid dispersions. Only recently, a novel trend has appeared – to take advantage of good solubility of active substances in chosen solvents, that is, to use the active substances in a liquid phase.
Content
1. BIOAVAILABILITY OF ACTIVE PHARMACEUTICAL INGREDIENTS
1.1 Bioavailability
1.2 Physical-chemical properties of active substances
1.2.1 Solubility
1.2.2 Acidobasic properties
1.2.3 Partition coefficient
1.2.4 Size and shape of the molecule
1.2.5 Binding to plasma proteins
1.3 Factors within the organism
1.3.1 Gastric emptying and intestinal motility
1.3.2 pH in stomach and intestine
1.3.3 Impact of enzymes
1.3.4 Drug metabolism and first-pass effect
1.3.5 Biorhythms
1.3.6 Intra- and interindividual variability
1.3.7 Dosage form
1.3.8 Food
2. METHODS TO IMPROVE BIOAVAILABILITY
2.1 Chemical modification of active substance
2.1.1 Salts
2.1.2 Hydrates
2.1.3 Cocrystals
2.1.4 Prodrugs
2.1.5 Chelation
2.2 Physical methods
2.2.1 Amorphism and crystal polymorphism
2.2.2 Controlled crystallization
2.2.2.1 Sono-crystallization
2.2.2.2 Crystallization from supracritical fluids
2.2.3 Freeze drying
2.2.4 Spray drying
2.2.5 Particle size reduction of active substances
2.2.5.1 Dry milling
2.2.5.2 Freeze milling
2.2.5.3 Wet milling
2.3 Technological means
2.3.1 Mediated dissolution
2.3.1.1 Increasing of wettability
2.3.1.2 Micellar solubilization
2.3.1.3 Cosolvents
2.3.1.4 Hydrotropes
2.3.2 Cyclodextrin complexes
2.3.3 pH adjustment
2.3.4 Solid dispersions
2.3.5 Interactive powder mixtures
2.3.6 Microgranulation
2.3.7 Self-emulsifying systems
2.3.8 Liquisolid systems
3. LIQUISOLID SYSTEMS
3.1 History
3.2 Advantages
3.3 Disadvantages
3.4 Technology
3.5 Preformulation testing
3.5.1 Flowable liquid retention potential
3.5.2 Liquisolid compressibility test
3.5.3 Optimal load factor
3.6 Excipients
3.6.1 Solvents
3.6.1.1 Propylene glycol
3.6.1.2 Liquid polyethylene glycols
3.6.1.3 Polysorbates
3.6.1.4 Glycerol
3.6.1.5 Poloxamers
3.6.1.6 Polyoxyethylated castor oil
3.6.1.7 Polyoxyethylated hydrogenated castor oil
3.6.1.8 Propylene glycol caprylate
3.6.1.9 Macrogol-15-hydroxystearate
3.6.1.10 Polyvinyl acetate
3.6.2 Conventional carriers
3.6.2.1 Modified starch
3.6.2.2 Lactose
3.6.2.3 Microcrystalline cellulose
3.6.2.4 Anhydrous dibasic calcium phosphate
3.6.2.5 Mesoporous silicates
3.6.2.6 Magnesium aluminometasilicates
3.6.2.6.1 Chemical structure
3.6.2.6.2 Properties
3.6.2.6.3 Improvement of flow properties of powders
3.6.2.6.4 Impact on the hardness of tablets
3.6.2.6.5 Liquisolid systems
3.6.2.6.6 Stabilisation of active substance
3.6.2.6.7 Medicinal and other uses
3.6.3 Carriers for controlled release liquisolid systems
3.6.3.1 Hydroxypropyl methylcellulose
3.6.3.2 Polymethylacrylates
3.6.4 Other carriers for liquisolid systems
3.6.4.1 F-Melt
3.6.4.2 Clays and clay minerals
3.6.4.2.1 Kaolinite
3.6.4.2.2 Imogolite
3.6.4.2.3 Halloysite
3.6.4.2.4 Bentonite
3.6.4.2.5 Montmorillonite
3.6.4.2.6 Talc
3.6.4.2.7 Sepiolite
3.6.4.2.8 Laponite
3.6.4.3 Zeolites
3.6.5 Coating material
3.6.5.1 Fumed silica
3.6.5.2 Silica gel
3.6.5.3 Calcium silicate
3.7 Evaluation of liquisolid systems
3.7.1 Evaluation of liquid phase
3.7.1.1 Viscosity
3.7.1.2 Solubility
3.7.2 Evaluation of solid raw materials
3.7.2.1 Size and shape of particles
3.7.2.1.1 Optical microscopy
3.7.2.1.2 Estimation of particle size by analytical sieving
3.7.2.1.3 Laser diffraction
3.7.2.1.4 Scanning electron microscopy
3.7.2.2 Density
3.7.2.2.1 Pycnometric density of solids
3.7.2.2.2 Bulk and tapped density
3.7.2.3 Porosity
3.7.2.4 Flow properties
3.7.2.4.1 Hausner ratio and compressibility index
3.7.2.4.2 Flow through an orifice
3.7.2.4.3 Angle of repose
3.7.2.4.4 Angle of slide
3.7.2.5 Specific surface area
3.7.2.5.1 BET isotherm
3.7.2.5.2 Transmission electron microscopy
3.7.2.5.3 Dye adsorption
3.7.2.6 Thermal analysis
3.7.2.7 X-ray diffraction
3.7.2.8 Fourier transformation of infra-red spectrum
3.7.2.9 Nuclear magnetic resonance
3.7.3 Evaluation of final LSS dosage forms
3.7.3.1 Uniformity of dosage units
3.7.3.2 Hardness
3.7.3.3 Friability
3.7.3.4 Disintegration
3.7.3.5 Dissolution
3.7.3.6 Contact angle
3.7.3.7 Water absorption ratio and wetting time
3.8 Use of liquisolid systems
3.8.1 Improvement of bioavailability
3.8.2 Controlled drug release
3.8.3 Oral dispersible tablets
3.8.4 Buccoadhesive tablets
3.8.5 Protection from light
Objectives and Topics
The primary objective of this book is to provide a comprehensive overview of techniques to improve the bioavailability of poorly soluble drugs, with a specific focus on the development, formulation, and evaluation of liquisolid systems. The work examines the chemical, physical, and technological strategies used to enhance drug solubility, followed by detailed insights into liquisolid system preparation and the necessary preformulation testing.
- Bioavailability improvement strategies
- Physical-chemical properties of active substances
- Technological methods (e.g., solid dispersions, micellar solubilization)
- Formulation principles of liquisolid systems
- Evaluation techniques for raw materials and final dosage forms
Excerpt from the Book
3.6.2.6 Magnesium aluminometasilicates
Magnesium aluminometasilicates occur naturally in clays. Amorphous magnesium aluminometasilicate in various grades is traded as Neusilin and is used as multifunctional excipient. In the beginning, it was marketed in Japan in 1954 as antacid. Later, its properties that enable the processing of drugs into solid dosage forms were discovered (Fuji Chemical Industries, 2014A).
3.6.2.6.1 Chemical structure
Magnesium aluminometasilicate consists of tetraedric or octaedric aluminum, octaedric magnesium, and tetraedric silicon units that are randomly connected in threedimensional structure (Figure 12) (Boswell, 2001).
Empiric formula: Al2O3 . MgO . 1.7SiO2 . xH2O
Summary of Chapters
BIOAVAILABILITY OF ACTIVE PHARMACEUTICAL INGREDIENTS: This chapter defines the fundamental concepts of bioavailability and describes how various physicochemical factors and physiological parameters influence drug absorption.
METHODS TO IMPROVE BIOAVAILABILITY: This section details diverse strategies—chemical, physical, and technological—for enhancing the solubility and dissolution rate of active ingredients from oral dosage forms.
LIQUISOLID SYSTEMS: This chapter serves as the core of the book, providing an in-depth analysis of liquisolid systems, covering their history, technological preparation, extensive preformulation testing, excipient roles, and specific applications in pharmaceutical product development.
Keywords
liquisolid systems, pharmaceutical technology, bioavailability, solubility, carrier, preformulation study, evaluation techniques, drug dissolution, solid dispersion, excipients, Neusilin, controlled release, orodispersible tablets, drug absorption, physicochemical properties
Frequently Asked Questions
What is the primary focus of this publication?
The book focuses on methods to improve the drug bioavailability of poorly soluble active substances, with a specific emphasis on the formulation and characterization of liquisolid systems.
What are the key thematic areas covered?
The main themes include biopharmaceutics, chemical and physical modification methods, various technological approaches to enhance dissolution, and the detailed pharmaceutical technology involved in creating liquisolid dosage forms.
What is the main objective of the research or work presented?
The aim is to provide a comprehensive textbook for students and researchers that documents the principles of liquisolid systems and the practical aspects of their formulation to enhance drug performance.
Which scientific methods are primarily utilized?
The work utilizes methods such as solubility testing, flow property evaluation (angle of repose, Hausner ratio), compressibility testing, and advanced analytical characterization like XRD, DSC, FT-IR, and SEM to evaluate raw materials and final dosage forms.
What content is addressed in the main body?
The main body covers the theoretical framework of bioavailability, specific methods for solubility enhancement, a thorough guide to preformulation and testing of liquisolid systems, and an analysis of excipients like silicates, clays, and zeolites.
How can this work be characterized?
This work is characterized by its systematic approach to pharmaceutical technology, specifically addressing the industrial feasibility and characterization of complex drug delivery systems.
What is the role of magnesium aluminometasilicate in the described systems?
Magnesium aluminometasilicate (Neusilin) is a crucial carrier in these systems due to its high sorption capacity, large specific surface area, inertness, and ability to stabilize amorphous forms of drugs.
Why are liquisolid systems considered perspective dosage forms?
They are considered perspective because they present active substances in a dissolved state within a solid matrix, which effectively bypasses the dissolution step during drug absorption in the gastrointestinal tract.
- Quote paper
- Dr. Jan Gajdziok (Author), Barbora Vraníková (Author), Klára Kostelanská (Author), David Vetchý (Author), Jan Muselík (Author), Roman Goněc (Author), 2018, Drug solubility and bioavailability improvement. Possible methods with emphasis on liquisolid systems formulation, Munich, GRIN Verlag, https://www.grin.com/document/442018
