A project paper submitted to the Department of Pharmacy, University of Asia Pacific in partial fulfilment of the requirements for the degree of Master of Science in Pharmaceutical Technology.
University Institute of Pharmaceutical Sciences is a flag bearer of excellence in Pharmaceutical education and research in the country. Here is another initiative to make study material available to everyone worldwide. Based on the new PCI guidelines and syllabus here we have a presentation dealing with the tablets and its excipients and Ideal properties of tablet and the methods and equipment for there for manufacturing.
Thank you for reading.
Hope it was of help to you.
UIPS,PU team
SOLID DISPERSION
Definition: The technology is the science of dispersing one or more active ingredients in an inert matrix in the solid stage.
Need of solid dispersion:
Increases Oral bioavailability of a drug
Increased dissolution rate.
Enhanced release of drugs from ointment.
Improved the solubility & stability.
The concept of solid dispersion was originally proposed by Sekiguchi & obi.
Increasing the dissolution, absorption & therapeutic efficacy of drugs in dosage forms.
Increasing solubility in water.
Improving the oral absorption and bioavailability of BCS Class II drugs.
The term solid dispersion refers to a group of solid products consisting of a hydrophilic matrix and a hydrophobic drug frequently prepared by fusion solvent method. The matrix can be amorphous or crystalline in nature .
University Institute of Pharmaceutical Sciences is a flag bearer of excellence in Pharmaceutical education and research in the country. Here is another initiative to make study material available to everyone worldwide. Based on the new PCI guidelines and syllabus here we have a presentation dealing with the tablets and its excipients and Ideal properties of tablet and the methods and equipment for there for manufacturing.
Thank you for reading.
Hope it was of help to you.
UIPS,PU team
SOLID DISPERSION
Definition: The technology is the science of dispersing one or more active ingredients in an inert matrix in the solid stage.
Need of solid dispersion:
Increases Oral bioavailability of a drug
Increased dissolution rate.
Enhanced release of drugs from ointment.
Improved the solubility & stability.
The concept of solid dispersion was originally proposed by Sekiguchi & obi.
Increasing the dissolution, absorption & therapeutic efficacy of drugs in dosage forms.
Increasing solubility in water.
Improving the oral absorption and bioavailability of BCS Class II drugs.
The term solid dispersion refers to a group of solid products consisting of a hydrophilic matrix and a hydrophobic drug frequently prepared by fusion solvent method. The matrix can be amorphous or crystalline in nature .
Formulation and evaluation of fast dissolving tabletsSURYAKANTVERMA2
The concept of mouth dissolving drug delivery systems (MDDDS) or fast dissolving tablets emerged with an objective to improve patient’s compliance.
These dosage forms rapidly disintegrate and/or dissolve to release the drug as soon as they come in contact with saliva, thus obviating the need for water during administration, an attribute that makes them highly attractive for pediatric and geriatric patients.
It includes Introductory part about what is Dissolution...then Mechanism of Dissolution is elaborated...Theories of Dissolution also given..It also includes Factors affecting Dissolution profile..Along with References given below for easily searching..
FORMULATION FACTORS EFFECTING BIOAVAILABILITY OF DRUGSN Anusha
Bioavailability means the rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action.
When the drug is given orally, only part of the administered dose appears in the plasma.
By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC).
This curve reflects the extent of absorption of the drug.
Pharmaceutical excipients are pharmacologically inert substances which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form to alter the functions.
DISSOLUTION
Dissolution is a process in which solid substance solubilizes in a given solvent
DISSOLUTION TESTING
A dissolution test uses an apparatus with specific test conditions in combination with acceptance criteria to evaluate the performance of the product. In-vitro test must predict the in-vivo behaviour
Factors in design of dissolution tests:
Factors relating to dissolution apparatus
Factors relation to dissolution fluid
Process parameters
Need of Dissolution Testing:
Development and optimisation of dosage forms
Batch to batch drug release uniformity
Quality, safety, efficacy and stability of the product
IVIV Correlation
Bioequivalence
Assessing pre and post approval changes
DISSOLUTION APPARATUS
Dissolution apparatus evolved to prepare a sample under controlled conditions thereby making the test repeatable.
Principle types of dissolution apparatus-
Close-compartment apparatus
Open-compartment apparatus
Dialysis systems
Ideal features of Dissolution Apparatus:
The fabrication, dimensions, and positioning of all components must be precisely specified and reproducible
Simple in design, easy to operate and useable
Sensitive
Nearly perfect sink conditions
Provide an easy means of introducing the dosage form into the dissolution medium
Provide minimum mechanical abrasion
Easy withdrawal of samples
Elimination of evaporation of solvent medium
DISSOLUTION METHODS
The Standard Dissolution Methods Database has been prepared by the Division of Bioequivalence, Office of Generic Drugs (OGD), Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA).
Official methods:
Rotating Basket
Rotating Paddle
Reciprocating Cylinder
Flow-Through Cell
Paddle Over Disc
Rotating Cylinder
Reciprocating Disc
Non-official methods:
Static Disc Method
Beaker Method
Flask Stirrer Method
Peristalsis Method
Rotating Bottle Method
Dialysis Method
Diffusion Cell Method
Dissolution Apparatus Types and their Applications
Problems associated with dissolution apparatus
USP Performance Verification Test (PVT):
The USP Performance Verification Test (PVT) assesses the suitable performance of apparatus used in dissolution testing.
Responsible for detecting problems associated with the dissolution apparatus that are found to be within mechanical tolerances.
REFERENCES
TRANSDERMAL THERAPEUTIC DRUG DELIVERY SYSTEMS N Anusha
Transdermal drug delivery systems (TDDS) can be defined as self-contained discrete dosage forms which, when applied to the intact skin, delivers the drug(s) through the skin at a controlled rate to the systemic circulation.
For transdermal drug delivery, it is considered ideal if the drug penetrates through the skin to the underlying blood supply without drug buildup in the dermal layers.
They provide extended therapy with a single application, thereby improving patient compliance over other dosage forms requiring more frequent dose administration.
Formulation and evaluation of fast dissolving tabletsSURYAKANTVERMA2
The concept of mouth dissolving drug delivery systems (MDDDS) or fast dissolving tablets emerged with an objective to improve patient’s compliance.
These dosage forms rapidly disintegrate and/or dissolve to release the drug as soon as they come in contact with saliva, thus obviating the need for water during administration, an attribute that makes them highly attractive for pediatric and geriatric patients.
It includes Introductory part about what is Dissolution...then Mechanism of Dissolution is elaborated...Theories of Dissolution also given..It also includes Factors affecting Dissolution profile..Along with References given below for easily searching..
FORMULATION FACTORS EFFECTING BIOAVAILABILITY OF DRUGSN Anusha
Bioavailability means the rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action.
When the drug is given orally, only part of the administered dose appears in the plasma.
By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC).
This curve reflects the extent of absorption of the drug.
Pharmaceutical excipients are pharmacologically inert substances which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form to alter the functions.
DISSOLUTION
Dissolution is a process in which solid substance solubilizes in a given solvent
DISSOLUTION TESTING
A dissolution test uses an apparatus with specific test conditions in combination with acceptance criteria to evaluate the performance of the product. In-vitro test must predict the in-vivo behaviour
Factors in design of dissolution tests:
Factors relating to dissolution apparatus
Factors relation to dissolution fluid
Process parameters
Need of Dissolution Testing:
Development and optimisation of dosage forms
Batch to batch drug release uniformity
Quality, safety, efficacy and stability of the product
IVIV Correlation
Bioequivalence
Assessing pre and post approval changes
DISSOLUTION APPARATUS
Dissolution apparatus evolved to prepare a sample under controlled conditions thereby making the test repeatable.
Principle types of dissolution apparatus-
Close-compartment apparatus
Open-compartment apparatus
Dialysis systems
Ideal features of Dissolution Apparatus:
The fabrication, dimensions, and positioning of all components must be precisely specified and reproducible
Simple in design, easy to operate and useable
Sensitive
Nearly perfect sink conditions
Provide an easy means of introducing the dosage form into the dissolution medium
Provide minimum mechanical abrasion
Easy withdrawal of samples
Elimination of evaporation of solvent medium
DISSOLUTION METHODS
The Standard Dissolution Methods Database has been prepared by the Division of Bioequivalence, Office of Generic Drugs (OGD), Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA).
Official methods:
Rotating Basket
Rotating Paddle
Reciprocating Cylinder
Flow-Through Cell
Paddle Over Disc
Rotating Cylinder
Reciprocating Disc
Non-official methods:
Static Disc Method
Beaker Method
Flask Stirrer Method
Peristalsis Method
Rotating Bottle Method
Dialysis Method
Diffusion Cell Method
Dissolution Apparatus Types and their Applications
Problems associated with dissolution apparatus
USP Performance Verification Test (PVT):
The USP Performance Verification Test (PVT) assesses the suitable performance of apparatus used in dissolution testing.
Responsible for detecting problems associated with the dissolution apparatus that are found to be within mechanical tolerances.
REFERENCES
TRANSDERMAL THERAPEUTIC DRUG DELIVERY SYSTEMS N Anusha
Transdermal drug delivery systems (TDDS) can be defined as self-contained discrete dosage forms which, when applied to the intact skin, delivers the drug(s) through the skin at a controlled rate to the systemic circulation.
For transdermal drug delivery, it is considered ideal if the drug penetrates through the skin to the underlying blood supply without drug buildup in the dermal layers.
They provide extended therapy with a single application, thereby improving patient compliance over other dosage forms requiring more frequent dose administration.
Formulation and Evaluation of Liquisolid Compacts of CarvedilolIOSR Journals
The purpose of this study is to develop a novel liquisolid technique to enhance the dissolution rate of
poorly water soluble drug Carvedilol, a BCS class II drug, which is a β-blocker, by using different excipients.
The main components of a liquisolid system are a non volatile solvent, carrier and coating materials and a
disintegrant. Liquisolid system refers to the formulations that are formed by conversion of liquid drugs, drug
suspensions or drug solution in non-volatile solvents into dry, non adherent, free flowing and compressible
powder mixture by blending with suitable carrier and coating materials. Hence the dissolution step, a prerequisite
for drug absorption, is by passed and better bioavailability of poorly soluble drug is achieved.
Liquisolid tablets of carvedilol are prepared by using PEG, PG, glycerine as non volatile liquid vehicles and
Avicel PH 101 and 102, Aerosil as carrier and coating materials respectively. Optimized formulation containing
20% drug in PEG 400, with Avicel 101 as carrier and Aerosil as coating material has shown 98.4% drug
release within 20 min which is better than marketed product (CARCA 12.5mg, Intas). The DSC and X-RD
studies are performed to investigate the physicochemical properties of formulation and drug excipient
interactions. The results are found to be satisfactory
Oral route of drug administration is the most preferred and convenient method of drug administration, but due to the poor solubility of drug is the major drawback for the dissolution and bioavailability of that drug. Absorption, distribution, metabolism and excretion of the drug depends on the solubility of the drug molecule. Solid dispersion is defined as dispersion of one or more active pharmaceutical ingredient in water soluble carriers at solid state to increase the dissolution of poorly water soluble drugs. Solid dispersion technique improves the dissolution rate of highly lipophilic drugs by enhancing bioavailability by means of decreasing particle size of drug, improving its wettability and forming amorphous particles of crystalline drugs. For preparation of solid dispersion carriers such as hydrophilic and hydrophobic are used. Nowadays the use of natural carriers is prepared over the synthetic carriers. Solid dispersion techniques are very effective and promising than conventional dosage forms. In this review we have mainly focused on historical background, introduction to solid dispersion, advantages and disadvantages, characterization of solid dispersion, method of preparation, applications, types of solid dispersion, carriers used in solid dispersion. Dhiresh Yennuwar | Snehal Jadhav | Mr. Sujit Kakade | Dr. Ravindra Patil | Dr. Ashok Bhosale "A Review on Solid Dispersion" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-6 | Issue-4 , June 2022, URL: https://www.ijtsrd.com/papers/ijtsrd50101.pdf Paper URL: https://www.ijtsrd.com/pharmacy/pharmaceutics/50101/a-review-on-solid-dispersion/dhiresh-yennuwar
Methods of enhancing Dissolution and bioavailability of poorly soluble drugsRam Kanth
Greetings!
Good Day to all...
Topic: Methods of Enhancing Bioavailability
Several approaches discussed are
1. Micrnoization
2. Use of Surrfactants
3. Use of Salt forms
4. Alteration of pH of microenvironment
5. Use of metastable polymorphs
6. Solute-Solvent Complexation
7. Solvent Deposition
8. Selective Adsorption on Insoluble Carriers
9. Solid Solutions
10. Eutectic Mixtures
11. Solid Dispersions
12. Molecular Encapsulation with Cyclodextrins
Please do clarify for doubts if any....
Thank you all for watching this presentation.
Liquisolid technique is a new
and promising method that can change the dissolution rate of drugs. It has been used to enhance
dissolution rate of poorly water-soluble drugs.
Orally Disintegrating Tablets (ODT) which disintegrates rapidly in saliva, usually within seconds,
without need for water. Drug dissolution, absorption, the onset of action and drug bioavailability
may be significantly increased better than those obtained from conventional dosage forms. combination of this two techniques is a promising approach for effective drug delivery
Direct Compression is the simplest form of oral dosage production as it contains the fewest process stages, leading to a shorter process cycle and faster production times.
Excipients have been defined in many ways, including as inert substances used as vehicles and diluents for drugs. The problem with this definition is that in recent years excipients have proved to be anything but inert, not only possessing the ability to react with other ingredients in the formulation, but also to cause adverse and hypersensitivity reactions in patients. These range from a mild rash to a potentially life-threatening reaction. Different brands of the same drug may contain different excipients, especially preservatives and colourants. The Consumer Medicines Information provides a list of excipients, and information on the safety of individual excipients can be found in drug reference guides.
“Gowning” is a set of garments worn while in a clean room or other controlled environment. The
level of gowning required is a function of the product or process, and its cleanliness
requirements.
Gowning can cover some or all of the following:
Head / hair
Beard / mustache
Face
Torso / Upper body
Legs / pants
Feet / shoes
Hands
Mucoadhesive polymers as drug delivery vehicles. The common principle underlying this drug administration route is the adhesion of the dosage form to the mucous layer until the polymer dissolves or the mucin replaces itself. Benefits for this route of drug administration are: prolonged drug delivery, targeted therapy and often improved bioavailability.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
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Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
1. Solid Dispersion
A project paper submitted to the Department of Pharmacy, University of Asia
Pacific in partial fulfillment of the requirements for the degree of
Master of Science in Pharmaceutical Technology
Submitted By:
H. M. Faruk
Registration No.: 17107113
Semester: Fall 2017
Department of Pharmacy
University of Asia Pacific
2. Page i of iv
Summary of Study
Solid dispersions have attracted considerable interest as an efficient means of improving the
dissolution rate and hence the bioavailability of a range of poorly water-soluble drugs. Solid
dispersions of poorly water-soluble drugs with water-soluble carriers have been reduced the
incidence of these problems and enhanced dissolution.They proposed the faster absorption of
poorly water-soluble drugs such as sulfathiazole by the formation of eutectic mixture with a
water-soluble and physiologically inert carries like urea. Upon exposure to aqueous fluids the
active drug released into fluids is fine, dispersed particles because of fine dispersion of the drug
in the solid eutectic mixture and the faster dissolution of the soluble matrix. These include
methods like spraying on sugar beads and direct capsule filling. Although there are some hurdles
like scale up and manufacturing cost to overcome, there lies a great promise that solid dispersion
technology will hasten the drug release profile of poorly water soluble drugs.The focus of this
review article on advantages, disadvantages and the method of preparation,and characterization
of the solid dispersion.
3. Page ii of iv
Table of Contents
SI. No. Topic Page
Summary of Study I
Table of Contents II
List of Tables IV
List of Figure IV
1 Introduction 01
2 Solid Dispersion 06
3 Classification of Solid Dispersion 07
3.1 Current trends in Solid Dispersions Techniques 10
3.2 First Generation Solid Dispersions 10
3.3 Second Generation Solid Dispersions 11
3.4 Third Generation Solid Dispersions 12
3.5 The Advantageous Properties of Solid Dispersions 13
4 Particle Size 13
4.1 Particle with Reduced Particle size and increased Dissolution rate 13
4.2 Particles with improved wettability 14
4.3 Particles with higher porosity 14
4.4 Drugs in amorphous state 15
4.5 Strategies to avoid drug recrystallization 15
4.5.1 Advantages of solid dispersions over other strategies to improve
bioavailability
16
4.5.2 Solid Dispersion Disadvantages 17
5 The Limitation Include 18
5.1 Detection of Crystallinity in Solid Dispersions 18
6 Methods of Preparation of Solid Dispersions 20
6.1 Melting Method 21
6.2 Solvent Method 21
6.3 Melting Solvent Method 22
6.4 Melt Extrusion Method 23
4. Page iii of iv
6.5 Lyophilization Technique 24
6.6 Melt Agglomeration Process 24
6.7 Electro Spinning 24
6.8 Super Critical Fluid Technology 25
7 Characterization of Solid Dispersion 25
7.1 The Techniques are available to detect crystallinity 26
7.2 Detection of Molecular Structure in Amorphous Solid Dispersion 27
7.3 Unmet needs and Challenges 28
7.3.1 Direct Capsule Filling 28
7.3.2 Electrostatic Spinning Method 29
7.3.3 Surface Active Carriers 29
8 Drug Solubility Properties 30
8.1 Drug Carrier Miscibility 30
8.2 Drug Carrier Interactions 30
8.3 Physical Structure 30
8.4 Amorphous Content 31
8.5 Stability 31
8.6 Dissolution Enhancement 31
8.7 Powder X- Ray Diffraction 31
8.8 Infrared Spectroscopy (IR) 31
8.9 Water Vapour Absorption 32
8.10 Isothermal Microcalorimetry 32
8.11 Dissolution Calorimetry 32
8.12 Macroscopic Techniques 32
8.13 Differential Scanning Calorimetry 32
8.14 Confocal Raman Spectroscopy 32
8.15 Temperature Modulated Differential Scanning Calorimetry 32
9 In Vitro Dissolution Studies 33
Conclusion 34
Reference 35
5. Page iv of iv
List of Tables
List of Figure
SI. No. Title Page
1 Poorly Water Soluble Drug 2
2 Various Formulation and chemical approaches for Dissolution 5
3 Classification of Solid Dispersion 10
4 Schematic Representation of the drug in solid Dispersion 17
5 Method of Preparation of Solid Dispersion 20
6 Overall Crystallization rate as a function of temperature 22
SI. No. Title Page
1 Classification of Solid Dispersions 08
2 Overview of Some Organic Solvents 23
6. Page 1 of 41
1 Introduction
The enhancements of oral bioavailability of such poorly water-soluble drugs often show poor
bioavailability because of low and erratic levels of absorption. Drugs that undergo dissolution
rate limited gastrointestinal absorption generally show improved dissolution and bio availability
as a result of reduction in particle size. However, micronizing of drugs often leads to aggregation
and agglomeration of particles, which results in poor wettability. Solid dispersions of poorly
water-soluble drugs with water-soluble carriers have been reduced the incidence of these
problems and enhanced dissolution. The development of solid dispersions as a practically viable
method to enhance bioavailability of poorly water-soluble drugs overcame the limitations of
previous approaches such as salt formation, solubilization by co-solvents, and particle size
reduction. Studies revealed that drugs in solid dispersion need not necessarily exist in the
micronized state. A fraction of the drug might molecularly disperse in the matrix, thereby
forming a solid dispersion. When the solid dispersion is exposed to aqueous media, the carrier
dissolves and the drug releases as fine colloidal particles.
The resulting enhanced surface area produces higher dissolution rate and bioavailability of
poorly water soluble drugs. In addition, in solid dispersions, a portion of drug dissolves
immediately to saturate the gastrointestinal tract fluid, and excess drug precipitates as fine
colloidal particles or oily globules of submicron size. Solid dispersion technique was firstly
demonstrated (Sekiguchi and Obi, 1996). They proposed the faster absorption of poorly water-
soluble drugs such as sulfathiazole by the formation of eutectic mixture with a water-soluble and
physiologically inert carries like urea. Upon exposure to aqueous fluids the active drug released
into fluids is fine, dispersed particles because of fine dispersion of the drug in the solid eutectic
mixture and the faster dissolution of the soluble matrix. The eutectic mixture contained 52 per
cent w/w of sulfathiazole and 48 per cent w/w of urea. The possibility of using solid solution
approach in which a drug is molecularly dispersed in soluble carrier was subsequently
introduced. A solid dispersion technique has been used by various researchers who have reported
encouraging results with different drugs. The first drug whose rate and extent of absorption was
significantly enhanced using the solid dispersion technique was sulfathiazole (Sekiguchi and
Obi, 1961). Technique for the preparation of solid dispersions, Lyophilization has also been
thought of as a molecular mixing technique where the drug and carrier were co-dissolved in
7. Page 2 of 41
cyclohexane, frozen and then sublimed under vacuum to obtain a lyophilized molecular
dispersion.
Numerous solid dispersion systems have been demonstrated in the pharmaceutical literature to
improve the dissolution properties of poorly water soluble drugs. Other methods, such as salt
formation, complexation with cyclodextrins, solubilization of drugs in solvent(s), and particle
size reduction have also been utilized to improve the dissolution properties of poorly water
soluble drugs; however, there are substantial limitations with each of these techniques. On the
other hand, formulation of drugs as solid dispersions offers a variety of processing and excipient
options that allow for flexibility when formulating oral delivery systems for poorly water soluble
drugs.
Fig. 1: A Schematic Representation of the Bioavailability Enhancement of a Poorly Water
Soluble Drug by Solid Dispersion Compared With Conventional Tablet or Capsule
8. Page 3 of 41
Oral bioavailability of a drug depends on its solubility and/or dissolution rate, and dissolution
may be the rate determining step for the onset of therapeutic activity. Therefore efforts to
increase drug dissolution of drug are often needed. Methods available to improve dissolution
include salt formation, micronization and addition of solvent or surface active agents. Solid
dispersion (SD) is one of such methods and it involves a dispersion of one or more active
ingredients in an inner carrier or matrix in solid state prepared by melting, dissolution in solvent
or melting-solvent method4. The technique has been used for a wide variety of poorly aqueous
soluble drug. Poorly soluble drugs represent a problem for their scarce availability related to
their low dissolution rate. The major drawback of low aqueous solubility is delays its absorption
from the gastrointestinal tract. Solubility behavior of a drug is one of the key determinants of its
oral bioavailability. Noyes-Whitney equation provides some hints as to how the dissolution rate
of even very poorly soluble compounds might be improved to minimize the limitations to oral
availability (Noyes and whitney, 1897; Van Drooge, 2006).
dC
dt
=
AD(Cs−C)
h
Where, dc/dt - is the rate of dissolution, A -is the surface area available for dissolution, D - is the
diffusion coefficient of the compound, Cs- is the solubility of the compound in the dissolution
medium, C -is the concentration of drug in the medium at time t and h - is the thickness of the
diffusion boundary layer adjacent to the surface of the dissolving compound. To increase the
dissolution rate from equation the following approaches are available. To increases the surface
area available for dissolution decreasing the particle size of drug.
Optimizing the wetting characteristics of compound surface.
To decrease the boundary layer thickness.
Ensure sink condition for dissolution.
Improve apparent solubility of drug under physiologically relevant conditions.
Drug administered in fed state is a way to improve the dissolution rate.
Of these possibilities, changes in the hydrodynamics are difficult to invoke in-vivo and the
maintenance of sink conditions will depend on how permeable the gastrointestinal mucosa is to
the compound as well as on the composition and volume of the luminal Fluids.
9. Page 4 of 41
Although some research effort has been directed towards permeability enhancement using
appropriate excipients, results to date have not been particularly encouraging. Administration of
the drug in the fed state may be an option to improve the dissolution rate and also to increase the
time available for dissolution; the likely magnitude of the food effect can be forecasted from
dissolution tests in bio relevant media (Galia et al., 1998).
The approaches that have commonly been used to overcome drawbacks associated with poorly
water-soluble drugs, in general includes micronization, salt formation, use of surfactant and use
of pro- drug, however all these techniques have certain limitations (Hancock and Zogra, 1997).
Techniques that have commonly been used to improve dissolution and bioavailability of poorly
water-soluble drugs, in general, include micronization, the use of surfactant, and the formation of
solid dispersions. Chiou and Riegelman outlined 6 types of drug carrier interactions in solid-state
dispersions: simple eutectic mixtures, solid solutions, glass solutions and glass suspensions,
amorphous precipitates, and compound or complex formation. Other factors such as increased
wettability, solubilization of the drug by the carrier at the diffusion layer, and the reduction or
absence of aggregation and agglomeration may also contribute to increased dissolution.
Micronization has several disadvantages, the main one being the limited opportunity to control
important characters of the final particle such as size, shape, morphology, surface properties and
electrostatic charges. In addition micronization is a high-energy process, which causes
disruptions in the drug s crystal lattice, resulting in the presence of disordered or amorphous
regions in the final product. The amorphous regions are thermodynamically unstable and are
therefore susceptible to re-crystallization upon storage, particularly in hot and humid conditions.
All poorly water-soluble drugs are not suitable for improving their solubility by salt formation.
The dissolution rate of a particular salt is usually different form that of parent compound.
However sodium and potassium salts of weak acids dissolve more rapidly than the free salts
(Hoerter and Dressman, 1997; Sekiguchi and Obi, 1961).
Potential disadvantages of salt forms include high reactivity with atmospheric carbon dioxide
and water resulting in precipitation of poorly water-soluble drug, epigastria distress due to high
alkalinity. Use of co-solvents or surfactants to improve dissolution rate pose problems, such as
patient compliance and commercialization. Even though particle size reduction increases the
dissolution rate, the formed fine powders showing poor wet ability and flow properties. Solid
10. Page 5 of 41
dispersion technique has come into existence to eliminate all these problems. However, the most
attractive option for increasing the release rate is improvement of the solubility through
formulation approaches (Taylor and Zogre, 1997; Goldbarg et al., 1966).
Fig. 2: Summarizes the Various Formulation and Chemical Approaches that can be taken to
improve the Solubility or to Increase the Available Surface Area for Dissolution
11. Page 6 of 41
2 Solid Dispersion
Chiou and Riegelman defined the term solid dispersion as “a dispersion involving the formation
of eutectic mixtures of drugs with water soluble carriers by melting of their physical mixtures”.
The term solid dispersion refers to the dispersion of one or more active ingredient in an inert
carrier or matrix at solid state prepared by melting (fusion), solvent, or the melting solvent
method (Sekiguchi and Obi, 1961; Chiou and Rielman, 1971). Suggested that the drug was
present in a eutectic mixture in a microcrystalline state (Sekiguchi et al., 1961), after few years
Goldberg et.al. Reported that all drug in solid dispersion might not necessarily be presents in a
microcrystalline state, a certain fraction of the drug might be molecular dispersion in the matrix,
thereby forming a solid solution. Once the solid dispersion was exposed to aqueous media & the
carrier dissolved, the drug was released as very fine, colloidal particles. Because of greatly
enhanced surface area obtained in this way, the dissolution rate and the bioavailability of poorly
water-soluble drugs were expected to be high. The commercial use of such systems has been
limited primarily because of manufacturing problems with solid dispersion systems may be
overcome by using surface active and self-emulsifying carriers. The carriers are melted at
elevated temperatures and the drugs are dissolved in molten carriers. The term solid dispersion
refers to a group of solid products consisting of at least two different components, generally a
hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous.
The drug can be dispersed molecularly, in amorphous particles (clusters) or in crystalline
particles. Solid dispersion refers to the dispersion of one or more active ingredients in an inert
carrier or matrix at solid state prepared by the melting (fusion), solvent or melting solvent
method. The dispersion of a drug or drugs in a solid diluents or diluents by traditional
mechanical mixing is not included in this category. The solid dispersion, a first stated by
Mayersohn and Gibaldi.
12. Page 7 of 41
3 Classification of Solid Dispersion
Based on their molecular arrangement, six different types of solid dispersions can be
distinguished. (In Table 1) Moreover, in various studies the designation of solid dispersions is
based on the method of preparation. However, since different preparation methods can result in
the same subtypes or similar preparation methods can result in different subtypes, it can be
argued that solid dispersions should preferably be designated according to their molecular
arrangement. Moreover, not the preparation method but the molecular arrangement governs the
properties of solid dispersions. Therefore, it is essential to use terms that indicate the molecular
arrangement in the solid dispersion. Knowledge about the molecular arrangement will enlarge
comprehension of the properties and behavior of solid dispersions.
Furthermore, it will facilitate optimization of their properties required for a specific application.
For example, the mechanism underpinning the dissolution of solid dispersions is poorly
understood. Many case studies showed accelerated dissolution of hydrophobic compounds using
solid dispersions but mechanisms are rarely discussed. The most important reason for that is the
lacking knowledge about the mode of incorporation of the hydrophobic drug in the matrix,
despite numerous efforts to clarify this. A question like, “is the drug present as a crystalline
phase or as amorphous Nano-particles or molecularly dispersed throughout the matrix” is rarely
discussed (Goldberg et al., 1965; Kreuter et al., 1999).
All three situations result in different drug concentrations at the dissolving interface. Still it has
not been fully elucidated how this affects dissolution behavior of solid dispersions. Secondly, the
physical and chemical stability of the matrix or the incorporated A: matrix in the amorphous
state, C: matrix in the crystalline state, A: drug dispersed as amorphous clusters in the matrix, C:
drug dispersed as crystalline particles in the matrix, M: drug molecularly dispersed throughout
the matrix The physical state of the matrix is also important for the chemical stability of the drug.
The crystallinity of the matrix influences the translational and rotational drug depends on the
mode of incorporation. If drug molecules, for example, are present in amorphous Nano-particles,
crystallization requires only rotational rearrangement. On the other hand, for a molecularly
dispersed drug, translational diffusion is necessary before crystallization can occur by rotational
rearrangements. Rearrangements of the drug necessary for degradation reactions. Finally, then
influence of drug load and method of preparation on dissolution behavior and stability of solid
13. Page 8 of 41
dispersions can only be understood and predicted when the relation between these characteristics
and the mode of incorporation is known (Chiou and Riegelman, 1971; Kreuter et al., 1999).
Table 1: Classification of Solid Dispersions in Six Subtypes
Solid Dispersion Type Matrix Drug Remarks Phase no.
I
Eutectics C C The first type of solid dispersions
prepared
2
II
Amorphous
precipitations in
crystalline matrix
C A Rarely encountered 2
III
Solid solutions C M Miscible at all compositions,
never prepared
1
Continuous solid
solution
C M Partially miscible,2 phase even
though drug is molecularly
dispersed
2
Discontinuous solid
solution
C M Molecular diameter of the drug
(solute) differs less than 15%
from matrix (solvent) diameter, In
last case the drug and matrix are
substitution. Can be continuous or
discontinuous, when
discontinuous: 2 phases even
through drug is molecularly
dispersed.
2
Intestinal solid
solutions
C M Drug (solute) molecular diameter
less than 59% of matrix (solvent)
diameter. Usually limited
miscibility, discontinuous,
Example: Drug in helical
intestinal space of PEG.
2
14. Page 9 of 41
IV
Glass Suspension A C Particle size of dispersed phase
dependent on cooling/evaporation
rate. Obtained after crystallization
of drug in amorphous matrix
2
V
Glass Suspension A A Particle size of dispersed phase
dependent on cooling/evaporation
rate many solid dispersions are of
this type
2
VI
Glass Suspension A M Required miscibility/solid
solubility, complex, formation or
upon fast cooling/evaporate
during preparation, many (recent)
examples especially with PVP
Related and other designations
I Complex formation C/A M Drug and matrix strongly interact
and form complexes in aqueous
environment. E.g. cyclodextrins
or solid surfactants
1
II C C Same as eutectics but eutectic
melting convergent with pure
material, for completely non-
interacting system.
2
III Prepare by addition of non-
solvent to solution of drug and
matrix
IV Prepare by vacuum drying, spray
drying, freeze drying and spray-
freeze drying, many examples
15. Page 10 of 41
3.1 Current Trends in Solid Dispersions Techniques
New manufacturing processes to obtain solid dispersions have also been developed to reduce the
drawbacks of the initial process. It is intended to discuss the recent advances related on the area
of solid dispersions. The classification of solid dispersions according to implementation and
recent advancement (Vasconcelos et al., 2007).
Fig. 3: The Classification of Solid Dispersions
3.2 First Generation Solid Dispersions
The first description of solid dispersions was from (Sekiguchi and Obi, 1961). They noted that
the formulation of eutectic mixtures improves the rate of drug release and consequently, the
bioavailability of poorly water soluble drugs. In the same decade, several solid dispersions were
described using poorly water soluble drugs, such as sulfathiazole and chloramphenicol
(Sekiguchi and Obi, 1996) using urea as high water soluble carrier. These solid dispersions
produced faster release and higher bioavailability than conventional formulations of the same
16. Page 11 of 41
drugs. The small particle size and the better wettability of the drug were the main reasons for the
observed improvements in bioavailability.
Later, (Levy, 1963; Kaning, 1964) developed solid dispersion systems, containing mannitol as
carrier, by preparing solid solutions through molecular dispersions instead of using eutectic
mixtures. The observed improvements were attributed to faster carrier dissolution, releasing
microcrystals or particles of drug (Simonelli, 1969).These solid dispersions, which could be
designed as first generation solid dispersions, were prepared using crystalline carriers.
Crystalline carriers include urea and sugars, which were the first carriers to be employed in solid
dispersions. They have the disadvantage of forming crystalline solid dispersions, which were
more thermodynamically stable and did not release the drug as quickly as amorphous ones.
3.3 Second Generation Solid Dispersions
In the late sixties it was observed that solid dispersions, where the drug was maintained in the
crystalline state, might not be as effective as the amorphous, because the former were more
thermodynamically stable.
Therefore, a second generation of solid dispersions appeared, containing amorphous carriers
instead of crystalline. Indeed, the most common solid dispersions do not use crystalline carriers
but amorphous. In the latter, the drugs are molecularly dispersed in an irregular form within an
amorphous carrier, which are usually polymers. Polymeric carriers have been the most successful
for solid dispersions, because they are able to originate amorphous solid dispersions. They are
divided into fully synthetic polymers and natural product-based polymers. Fully synthetic
polymers include povidone (PVP) (Vilhelmsen et al., 2005; Karavas, 2006; Yoshihashi, 2006)
polyethylene glycols (PEG) (Urbanetz, 2006; Guyot, 1995; Chiou and Riegelman, 1971) and
polymethacrylates. Natural product based polymers are mainly composed by cellulose
derivatives, such as hydroxypropyl methylcellulose (HPMC), ethyl cellulose or hydroxypropyl
cellulose (Tanaka, 2005) or starch derivate, like cyclodextrins (Won, 2005; Garcia-Zubiri, 2006).
Amorphous solid dispersions can be classified according to the molecular interaction of drug and
carriers in solid solutions, solid suspensions or a mixture of both (Drooge, 2006). In amorphous
solid solutions, drug and carrier are totally miscible and soluble, originating a homogeneous
molecular interaction between them. In these systems, the drug and carrier interaction energy is
extremely high, resulting in a really true solution. The use of polymers in the preparation of a
17. Page 12 of 41
true solid solution creates an amorphous product in which the crystalline drug is dissolved
(Vanden Mooter, 2006). This type of amorphous solid dispersion is homogeneous on a molecular
level. Therefore, only one phase is present. Amorphous solid suspensions occur when the drug
has limited carrier solubility or an extremely high melting point (Chiou and Riegelman, 1971).
Molecularly, the obtained dispersion does not have a homogeneous structure, but is composed of
two phases. Small drug particles, when dispersed in polymeric carriers, are able to provide an
amorphous final product. When a drug is both dissolved and suspended in the carrier, a
heterogeneous structure is obtained with mixed properties of amorphous solid solutions and
amorphous solid suspensions (Goldberg, 1966). In second generation solid dispersions, the drug
is in its supersaturated state because of forced solubilization in the carrier.
These systems are able to reduce the drug particle size to nearly a molecular level, to solubilize
or co-dissolve the drug by the water soluble carrier, to provide better wettability and
dispensability of the drug by the carrier material, and to produce amorphous forms of the drug
and carriers. In these solid dispersions, the carrier dissolution or mixtures of carriers dictates the
drug release profile (Damian, 2000).
3.4 Third Generation Solid Dispersions
These contain a surfactant carrier, or a mixture of amorphous polymers and surfactants as
carriers. These third generation solid dispersions are intended to achieve the highest degree of
bioavailability for poorly soluble drugs and to stabilize the solid dispersion, avoiding drug re-
crystallization. The use of surfactants such as inulin inutec SP1, compritol 888 ATO (Li FQ,
2006) gelucire 44/14 and poloxamer-407 as carriers was shown to be effective in originating
high polymorphic purity and enhanced in vivo bioavailability. The association of amorphous
polymers and surfactants has also been reported. For instance, the dissolution rate and
bioavailability of LAB, a poor water soluble drug, were improved after being dispersed in a
mixture of PEG and polysorbate80. The bioavailability of this solid dispersion was 10-fold
higher compared to the dry blend of micronized drug. In addition, the solid dispersion system
was physically and chemically stable for at least 16 months (Dannenfelser, 2004).HPMC was
also associated with poloxamer and polyoxyethylene hydrogenated castor oil to prepare an
amorphous felodipine solid dispersion. The inclusion of surfactants in the formulation containing
18. Page 13 of 41
a polymeric carrier may help to prevent precipitation and/or protect a fine crystalline precipitate
from agglomeration into much larger hydrophobic particles.
3.5 The Advantageous Properties of Solid Dispersions
Management of the drug release profile using solid dispersions is achieved by manipulation of
the carrier and solid dispersion particles properties. Parameters, such as carrier molecular weight
and composition, drug crystallinity and particle porosity and wettability, when successfully
controlled, can produce improvements in bioavailability (Ghaderi, 1999).
dC
dt
=
AD(Cs−C)
h
4 Particle Size
4.1 Particles with Reduced Particle Size and Increased Dissolution Rate
Molecular dispersions, as solid dispersions, represent the last state on particle size reduction, and
after carrier dissolution the drug is molecularly dispersed in the dissolution medium. Solid
dispersions apply this principle to drug release by creating a mixture of a poorly water soluble
drug and highly soluble carriers.
A high surface area is formed, resulting in an increased dissolution rate and, consequently,
improved bioavailability (Bikiris, 2005).
The fact that more than 40% of newly discovered drugs have little or negligible water solubility
presents a serious challenge to the successful development and commercialization of new drugs
in the pharmaceutical industry. Solubility and permeability are the main factors that control oral
bioavailability of a drug substance. Generally, when the drug solubility in water is less than 10
mg/ml, dissolution is the rate-limiting step in the process of drug absorption. Factors influencing
drug dissolution rate in aqueous solution are described in Noyes-Whitney equation: where dC/dT
is the rate of dissolution, A is the surface area available for dissolution, D is the diffusion
coefficient of the drug, Cs is the solubility of the drug in the dissolution medium, C is the
concentration of drug in the medium at time t and h is the thickness of the diffusion boundary
layer adjacent to the surface of the dissolving drug. According to this equation, dissolution rate
can be increased through increasing the surface area, and this can be achieved through reducing
the particle size.
19. Page 14 of 41
Different methods have been used to reduce the particle size, such as micronization, re-
crystallization, and freeze drying and spray drying. Micronization of poorly soluble drugs by
milling has been used for many years in the pharmaceutical industry in order to enhance the
dissolution rate of those drugs. For example the dissolution rate of micronized spironolactone
was higher than that of the standard form. However, fine particles may not always produce the
expected faster dissolution. This primarily results from the aggregation and agglomeration of
fine particles. In addition, poor wettability of fine powders may reduce the dissolution rate. Solid
dispersion techniques have been used to enhance the dissolution rate of many poorly water
soluble drugs.
Particle size reduction and reduced agglomeration would both increase the exposed surface area
of the drug. When solid solutions or amorphous precipitations are formed, particle size of the
active ingredient is reduced to the minimum level. In addition, the carrier material may
contribute to increasing the dissolution rate through its solubilizing and wettability-enhancing
properties. It was reported that urea increased the dissolution rate of chlorpropamide
incorporated into urea, through its solubilizing properties. The enhancement in dissolution rate as
a result of solid dispersion formation, relative to pure drug, varies from as high as 400-fold to
less than two-fold.
4.2 Particles with Improved Wettability
A strong contribution to the enhancement of drug solubility is related to the drug wettability
improvement verified in solid dispersions. It was observed that even carriers without any surface
activity, such as urea improved drug wettability.
Carriers with surface activity, such as cholic acid and bile salts, when used, can significantly
increase the wettability properties of drugs. Moreover, carriers can influence the drug dissolution
profile by direct dissolution or co-solvent effects. Recently, the inclusion of surfactants in the
third generation solid dispersions reinforced the importance of this property (Ghebremeskel,
2007).
4.3 Particles with Higher Porosity
Particles in solid dispersions have been found to have a higher degree of porosity. The increase
in porosity also depends on the carrier properties, for instance, solid dispersions containing linear
20. Page 15 of 41
polymers produce larger and more porous particles than those containing reticular polymers and,
therefore, result in a higher dissolution rate. The increased porosity of solid dispersion particles
also hastens the drug release profile (Vasconcelos and Costa, 2007).
4.4 Drugs in Amorphous State
Poorly water soluble crystalline drugs, when in the amorphous state tend to have higher
solubility. The enhancement of drug release can usually be achieved using the drug in its
amorphous state, because no energy is required to break up the crystal lattice during the
dissolution process. In solid dispersions, drugs are presented as supersaturated solutions after
system dissolution, and it is speculated that, if drugs precipitate, it is as a metastable polymorphic
form with higher solubility than the most stable crystal form. For drugs with low crystal energy
(low melting temperature or heat of fusion), the amorphous composition is primarily dictated by
the difference in melting temperature between drug and carrier. For drugs with high crystal
energy, higher amorphous compositions can be obtained by choosing carriers, which exhibit
specific interactions with them (Ghebremeskel and Vemavarapu, 2007).
4.5 Strategies to Avoid Drug Re-crystallization
Re-crystallization is the major disadvantage of solid dispersions. As amorphous systems, they are
thermodynamically unstable and have the tendency to change to a more stable state under re-
crystallization. Molecular mobility is a key factor governing the stability of amorphous phases,
because even at very high viscosity, below the glass transition temperature (Tg), there is enough
mobility for an amorphous system to crystallize over pharmaceutically relevant time scales.
Furthermore, it was postulated that crystallization above Tg would be governed by the
configurationally entropy, because this was a measure of the probability of molecules being in
the appropriate conformation, and by the mobility, because this was related to the number of
collisions per unit time.
Several experiments have been conducted to understand the stabilization of solid dispersions.
Recent studies observed very small reorientation motions in solid dispersions showing a detailed
heterogeneity of solid dispersions and detecting the sub-glass transition beta-relaxation as well as
alpha-relaxation, which may lead to nucleation and crystal growth.
21. Page 16 of 41
Molecular mobility of the amorphous system depends, not only on its composition, but also on
the manufacturing process as stated (Vasanthavada, 2005).
Solid dispersions exhibiting high conformational entropy and lower molecular mobility are more
physically stable. Polymers improve the physical stability of amorphous drugs in solid
dispersions by increasing the Tg of the miscible mixture, thereby reducing the molecular
mobility at regular storage temperatures, or by interacting specifically with functional groups of
the drugs. For a polymer to be effective in preventing crystallization, it has to be molecularly
miscible with the drug. For complete miscibility, interactions between the two components are
required. It is recognized that the majority of drugs contain hydrogen-bonding sites,
consequently, several studies have shown the formation of ion–dipole interactions and
intermolecular hydrogen bonding between drugs and polymers, and the disruption of the
hydrogen bonding pattern characteristic to the drug crystalline structure. These lead to a higher
miscibility and physical stability of the solid dispersions Specific drug polymer interactions were
observed. Showing that interaction energies, electron density, and vibrational data revealed a
stronger hydrogen bond of felodipine with PVP than with PEG, which was in agreement with the
dissolution rates of the corresponding solid dispersions (Schachter, 2004).
4.5.1 Advantages of solid dispersions
Improving drug bioavailability by changing their water solubility has been possible by chemical
or formulation approaches. Chemical approaches to improving bioavailability without changing
the active target can be achieved by salt formation or by incorporating polar or ionizable groups
in the main drug structure, resulting in the formation of a pro-drug. Solid dispersions appear to
be a better approach to improve drug solubility than these techniques, because they are easier to
produce and more applicable. For instance, salt formation can only be used for weakly acidic or
basic drugs and not for neutral. Furthermore, it is common that salt formation does not achieve
better bioavailability because of its in-vivo conversion into acidic or basic forms. Moreover,
these types of approaches have the major disadvantage that the sponsoring company is obliged to
perform clinical trials on these forms, since the product represents a NCE (Van Drooge, 2006).
Formulation approaches include solubilization and particle size reduction techniques, and solid
dispersions, among others. Solid dispersions are more acceptable to patients than solubilization
products, since they give rise to solid oral dosage forms instead of liquid as solubilization
22. Page 17 of 41
products usually do. Milling or micronization for particle size reduction is commonly performed
as approaches to improve solubility, on the basis of the increase in surface area. Solid dispersions
are more efficient than these particle size reduction techniques, since the latter have a particle
size reduction limit around 2–5 mm which frequently is not enough to improve considerably the
drug solubility or drug release in the small intestine and, consequently, to improve the
bioavailability. Moreover, solid powders with such a low particle size have poor mechanical
properties, such as low flow and high adhesion, and are extremely difficult to handle (Rasenack
and Muller, 2004).
4.5.2 Solid Dispersions Disadvantages
Despite extensive expertise with solid dispersions, they are not broadly used in commercial
products, mainly because there is the possibility that during processing (mechanical stress) or
storage (temperature and humidity stress) the amorphous state may undergo crystallization. The
effect of moisture on the storage stability of amorphous pharmaceuticals is also a significant
concern, because it may increase drug mobility and promote drug crystallization.
Moreover, most of the polymers used in solid dispersions can absorb moisture, which may result
in phase separation, crystal growth or conversion from the amorphous to the crystalline state or
from a metastable crystalline form to a more stable structure during storage. This may result in
decreased solubility and dissolution rate. Therefore, exploitation of the full potential of
amorphous solids requires their limitations of this technology have been a drawback for the
commercialization of solid (Johari, 2005; Wang, 2005).
Fig.4: Schematic Representation of Three Modes of Incorporation of the Drug in Solid
Dispersion Dispersions
23. Page 18 of 41
5 The Limitations Include
Laborious and expensive methods of preparation
Reproducibility of physic chemical characteristics
Difficulty in incorporating into formulation of dosage forms
Scale-up of manufacturing process and
Stability of the drug and vehicle
5.1 Detection of Crystallinity in Solid Dispersions
Several different molecular structures of the drug in the matrix can be encountered in solid
dispersions (Figure.3). Many attempts have been made to investigate the molecular arrangement
in solid dispersions. However, most effort has been put in discrimination between amorphous
and crystalline material. Consequently, for that purpose many techniques are available which
detect the amount of crystalline material in the dispersion. The amount of amorphous material is
never measured directly but is mostly derived from the amount of crystalline material in the
sample. It should be noted that through the assessment of crystallinity as method to determine the
amount of amorphous drug it will not be revealed whether the drug is present as amorphous drug
particles or as molecularly dispersed molecules, e.g. solid dispersions of type II or III and V or
VI (Corrigan and Healy, 2002).
Currently, the following techniques are available to detect (the degree of) crystallinity:
Powder X-ray diffraction can be used to qualitatively detect material with long rangeorder.
Sharper diffraction peaks indicate morecrystalline material. Recently developed X-ray
equipment is semi-quantitative.
Infrared spectroscopy (IR) can be used to detect the variation in the energy distribution of
interactions between drug and matrix. Sharp vibrational bands indicate crystallinity. Fourier
Transformed Infrared Spectroscopy (FTIR) was used to accurately detect crystallinity
ranging from 1 to 99% in pure material. However in solid dispersions only qualitative
detection was possible.
Water vapor sorption can be used to discriminate between amorphous and crystalline
material when the hygroscopicity is different. This method requires accurate data on the
hygroscopicity of both completely crystalline and completely amorphous samples. In some
24. Page 19 of 41
studies, amorphous materials were plasticized by water sorption and crystallized during the
experiment. However, crystallization can be accompanied by expel of water depending on
the degree of hydration of crystalline material. In this case, the loss of water is used to
calculate the amount of amorphous material. However, water vapor sorption in a binary
mixture, e.g. solid dispersions, can be much more complicated than in pure materials, firstly
because water vapoursorption is not always proportional to the composition of a binary
intimately mixed system. The second complication is that matrix or drug crystallization
during water vapoursorption is often not complete within the experimental time scale due to
sterical hindrance and proceeds to an unknown extent.
Isothermal Microcalorimetry measures the crystallization energy of amorphous material that
is heated above its Tg. However, this technique has some limitations. Firstly, this technique
can only be applied if the physical stability is such that only during the measurement
crystallization takes place. Secondly, it has to be assumed that all amorphous material
crystallizes. Thirdly, in a binary mixture of two amorphous compounds a distinction between
crystallization energies of drug and matrix is difficult.
Dissolution Calorimetry measures the energy of dissolution, which is dependent on the
crystallinity of the sample. Usually, dissolution of crystalline material is endothermic, where
as dissolution of amorphous material is exothermic.
The dissolution energies of the two components in both crystalline and amorphous state
should be determined in separate experiments in order to use this technique quantitatively.
However, also drug-matrix interactions will contribute to the dissolution energy of the solid
dispersion.
Macroscopic techniques that measure mechanical properties that are different for amorphous
and crystalline material can be indicative for the degree of crystallinity. Density
measurements and Dynamic Mechanical Analysis (DMA) determine the modulus of
elasticity and viscosity and thus affected by the degree of crystallinity. However, also the
techniques require knowledge about the additives of these properties in intimately mixed
binary solids.
The extent of super saturation during dissolution experiments of solid dispersions are
sometimes correlated to the mode of incorporation of the drug. It is unmistakable that the
mode of incorporation largely determines the dissolution behavior, but knowledge about
25. Page 20 of 41
dissolution behavior is too poor to draw any conclusions from dissolution experiments,
because it cannot be excluded that during dissolution crystallization of the drug occurs.
6 Methods of Preparation of Solid Dispersions
There are some methods used for preparation of solid dispersion system. These methods are
given bellow.
Melting method
Solvent method
Melting solvent method (melt evaporation)
Melt extrusion methods
Lyophilization techniques
Melt agglomeration Process
The use of surfactant
Electro spinning
Super Critical Fluid (SCF) technology
Fig. 5: Methods of Preparation of Solid Dispersion
26. Page 21 of 41
6.1 Melting Method
The melting or fusion method is the preparation of physical mixture of a drug and a water-
soluble carrier and heating it directly until it melted. The melted mixture is then solidified rapidly
in an ice-bath under vigorous stirring. The final solid mass is crushed, pulverized and sieved.
Appropriately this has undergone many modifications in pouring the homogenous melt in the
form of a thin layer onto a ferrite plate or a stainless steel plate and cooled by flowing air or
water on the opposite side of the plate. In addition, a super-saturation of a solute or drug in a
system can often be obtained by quenching the melt rapidly from a high temperature. Under such
conditions, the solute molecule is arrested in the solvent matrix by the instantaneous
solidification process. The quenching technique gives a much finer dispersion of crystallites
when used for simple eutectic mixtures.
However many substances, either drugs or carriers, may decompose during the fusion process
which employs high temperature. It may also cause evaporation of volatile drug or volatile
carrier during the fusion process at high temperature. Some of the means to overcome these
problems could be heating the physical mixture in a sealed container or melting it under vacuum
or in presence of inert gas like nitrogen to prevent oxidative degradation of drug or carrier
(Goldberg, 1996).
6.2 Solvent Method
In this method, the physical mixture of the drug and carrier is dissolved in a common solvent is
used, which is evaporated until a clear, solvent free film is left. The film is further dried to
constant weight. The main advantage of the solvent method is thermal decomposition of drugs or
carriers can be prevented because of the relatively low temperatures required for the evaporation
of organic solvents (Serajuddin, 1999).
27. Page 22 of 41
Fig. 6: Overall Crystallization Rate as a Function of Temperature Tg is the Glass Transition
Temperature and Tm is the Melting Temperature
However, some disadvantages are associated with this method such as
The higher cost of preparation
The difficulty in completely removing liquid solvent
The possible adverse effect of traces of the solvent on the chemical stability
The selection of a common volatile solvent
The difficulty of reproducing crystal form
In addition, a super saturation of the solute in the solid system cannot be attained except in a
System showing highly viscous properties
6.3 Melting Solvent Method (melt evaporation)
It involves preparation of solid dispersions by dissolving the drug in a suitable liquid solvent and
then incorporating the solution directly into the melt of polyethylene glycol, which is then
evaporated until a clear, solvent free film is left. The film is further dried to constant weight. The
5 –10% (w/w) of liquid compounds can be incorporated into polyethylene glycol 6000 without
significant loss of its solid property. It is possible that the selected solvent or dissolved drug may
not be miscible with the melt of the polyethylene glycol. Also the liquid solvent used may affect
the polymorphic form of the drug, which precipitates as the solid dispersion. This technique
possesses unique advantages of both the fusion and solvent evaporation methods. From a
practical standpoint, it is only limited to drugs with a low therapeutic dose e.g. below 50 mg.
28. Page 23 of 41
Table 2: Overview of Some Organic Solvents
Solvent Melting
point (oc)
Boiling
point (oc)
Vapor pressure at 25oc
(kpa)
Water 0 100 3.16
Ethanol -93.9 65 16.9
1-propanol -117 78.5 5.79
2-propanol -85.8 97.4 2.27
Chloroform -63 62 26.1
Dimethyl sulphoxide (DMSO) 19 189 0.08
Acidic acid 17 118 1.64
1,4-dioxane 12 102 4.92
2-methyl-2-propanol (TBA) 25 82 5.49
6.4 Melt Extrusion Method
The drug/carrier mix is typically processed with a twin-screw extruder. The drug/carrier mix is
simultaneously melted, homogenized and then extruded and shaped as tablets, granules, pellets,
sheets, sticks or powder. The intermediates can then be further processed into conventional
tablets. An important advantage of the hot melt extrusion method is that the drug/carrier mix is
only subjected to an elevated temperature for about 1min, which enables drugs that are
somewhat thermo labile to be processed. Solid dispersion by this method is composed of active
ingredient and carrier, and prepare by hot-stage extrusion using a co-rotating twin-screw
extruder. The concentration of drug in the dispersions is always 40% (w/w). The screw-
configuration consist of two mixing zones and three transport zones distribute over the entire
barrel length, the feeding rate is fix at 1 kg/h and the screw rate is set at 300 rpm. The five
temperature zones are set at 100, 130, 170, 180, and 185C from feeder to die. The extra diet are
collect after cooling at ambient temperature on a conveyer belt. Samples are milled for 1 min
with a laboratory cutting mill and sieve to exclude particles >355μm (Breitenbach, 2002).
29. Page 24 of 41
6.5 Lyophilization Technique
Lyophilization involves transfer of heat and mass to and from the product under preparation.
This technique was proposed as an alternative technique to solvent evaporation. Lyophilization
has been thought of a molecular mixing technique where the drug and carrier are co dissolved in
a common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion.
6.6 Melt Agglomeration Process
This technique has been used to prepare solid dispersion wherein the binder acts as a carrier. In
addition, solid dispersion are prepared either by heating binder, drug and excipient to a
temperature above the melting point of the binder (melt- in procedure) or by spraying a
dispersion of drug in molten binder on the heated excipient (spray-on procedure) by using a high
shear mixer. The rotary processor might be preferable to the high melt agglomeration because it
is easier to control the temperature and because a higher binder content can be incorporated in
the agglomerates. The effect of binder type, method of manufacturing and particle size are
critical parameters in preparation of solid dispersion by melt agglomeration. It has been found
that the melt in procedure gives a higher dissolution rates than the spray-on procedure with
PEG3000, poloxamer 188 and gelucire 50/13 attributed to immersion mechanism of agglomerate
formation and growth. In addition the melt in procedure also results in homogenous distribution
of drug in agglomerate. Larger particles results in densification of agglomerates while fine
particle cause complete adhesion to the mass to bowl shortly after melting attributed to
distribution and coalescence of the fine particles (Schaefer, 2001).
6.7 Electro Spinning
Electro spinning is a process in which solid fibers are produced from a polymeric fluid stream
solution or melt delivered through a millimeter-scale nozzle. This process involves the
application of a strong electrostatic field over a conductive capillary attaching to a reservoir
containing a polymer solution or melt and a conductive collection screen. Upon increasing the
electrostatic field strength up to but not exceeding a critical value, charge species accumulated
on the surface of a pendant drop destabilize the hemispherical shape into a conical shape
(commonly known as Taylor’s cone). Beyond the critical value, a charged polymer jet is ejected
from the apex of the cone (as a way of relieving the charge built-up on the surface of the pendant
30. Page 25 of 41
drop). The ejected charged jet is then carried to the collection screen via the electrostatic force.
The Columbic repulsion force is responsible for the thinning of the charged jet during its
trajectory to the collection screen. The thinning down of the charged jet is limited if the viscosity
increases, the charged jet is dried.
This technique has tremendous potential for the preparation of Nano fibers and controlling the
release of biomedicine, as it is simplest, the cheapest this technique can be utilized for the
preparation of solid dispersions in future.
6.8 Super Critical Fluid (SCF) Technology
The supercritical fluid and solvent techniques, carbon dioxide are usedan anti-solvent for the
solute but as absolvent with respect to the organic solvent. Different acronyms were used by
various authors to denote micronization processes: aerosol solvent extraction system,
precipitation with a compressed fluid anti-solvent, gas anti-solvent, and solution enhanced
dispersion by supercritical fluids, and supercritical anti-solvent.
The SAS process involves the spraying of the solution composed of the solute and of the organic
solvent into a continuous supercritical phase flowing concurrently. Use of supercritical carbon
dioxide is advantageous as it is much easier to remove from the polymeric materials when the
process is complete, even though a small amount of carbon dioxide remains trapped inside the
polymer; it poses no danger to the patient. In addition the ability of carbon dioxide to plasticize
and swell polymers can also be exploited and the process can be carried out near room
temperature. Moreover, supercritical fluids are used to lower the temperature of melt dispersion
process by reducing the melting temperature of dispersed active agent.
7 Characterization of Solid Dispersion
Several different molecular structures of the drug in the matrix can be encountered in solid
dispersions. Several techniques have been available to investigate the molecular arrangement in
solid dispersions. However, most effort has been put into differentiate between amorphous and
crystalline material. Many techniques are available which detect the amount of crystalline
material in the dispersion.
31. Page 26 of 41
7.1 The Techniques are Available to Detect Crystallinity
7.1.1 Powder X-Ray Diffraction can be used to Qualitatively Detect Material with Long
Range Order. Sharper Diffraction Peaks Indicate More Crystalline Material.
Recently developed X-ray equipment is semi quantitative. Infrared spectroscopy (IR) can be
used to detect the variation in the energy distribution of interactions between drug and matrix.
Sharp vibration alb and indicate crystallinity. Fourier Transformed Infrared Spectroscopy (FTIR)
was used to accurately detect crystallinity ranging from 1 to 99% in pure material. However in
solid dispersions only qualitative detection was possible. Water vapor sorption can be used to
discriminate between amorphous and crystalline material when the hygroscopicity is different.
This method requires accurate data on the hygroscopicity of both completely crystalline and
completely amorphous samples. Isothermal Microcalorimetry measures the crystallization
energy of amorphous material that is heated above its glass transition temperature (Tg). However,
this technique has some limitations. Firstly, this technique can only be applied if the physical
stability is such that only during the measurement crystallization takes place. Secondly, it has to
be assumed that all amorphous material crystallizes. Thirdly, in a binary mixture of two
amorphous compounds distinction between crystallization energies of drug and matrix is
difficult. Dissolution Calorimetry measures the energy of dissolution, which is dependent on the
crystallinity of the sample. Usually, dissolution of crystalline material is ending other mix;
whereas dissolution of amorphous material is exothermic. Macroscopic techniques that measure
mechanical properties that are different for amorphous and crystalline material can be indicative for the
degree of crystallinity. Density measurements and Dynamic Mechanical Analysis (DMA) determine the
modulus of elasticity and viscosity and thus affected by the degree of crystallinity. However, also the
techniques require knowledge about the additives of these properties in intimately mixed binary solids. A
frequently used technique to detect the amount of crystalline material is Differential Scanning
Calorimetry (DSC). In DSC, samples are heated with a constant heating rate and the amount of energy
necessary for that is detected. With DSC the temperatures at which thermal events occur can be detected.
Thermal events can be a glass to rubber transition, (re)crystallization, melting or degradation.
Furthermore, the melting- and re-crystallization energy can be quantified. The melting energy can be used
to detect the amount of crystalline material. Possibly, the re-crystallization energy can be used to calculate
the amount of amorphous material provided, that all amorphous material is transformed to the crystalline
state. If during DSC-measurements, amorphous material crystallizes, information is obtained on the
crystallization kinetics and on the physical stability of the amorphous sample.
32. Page 27 of 41
7.2 Detection of Molecular Structure in Amorphous solid Dispersions
The properties of a solid dispersion are highly affected by the uniformity of the distribution of
the drug in the matrix. The stability and dissolution behavior could be different for solid
dispersions that do not contain any crystalline drug particles, i.e. solid dispersions of type V and
VI or for type II and III. However, not only the Knowledge on the physical state (crystalline or
amorphous) is important; the distribution of the drug as amorphous or crystalline particles or as
separate drug molecules is relevant to the properties of the solid dispersion too. Nevertheless,
only very few studies focus particles versus molecular distribution or homogeneous mixtures.
Co focal Raman Spectroscopy was used to measure the homogeneity of the solid mixture of
ibuprofen in PVP. It was described that a standard deviation in drug content smaller than10%
was indicative of homogeneous distribution. Because of the pixel size of 2 μm3, uncertainty
remains about the presence of Nano-sized amorphous drug particles.
Using IR or FTIR, the extent of interactions between drug and matrix can be measured. The
interactions are indicative for the mode of incorporation of the drug, because separately
dispersed drug molecules will have more drug-matrix interactions than when the drug is present
in amorphous clusters or other multi-molecule arrangements.
Temperature Modulated Differential Scanning Calorimetry (TMDSC) can be used to assess the
degree of mixing of an incorporated drug. Due to the modulation, reversible and irreversible
events can be separated. For example, glass transitions (reversible) are separated from
crystallization or relaxation (irreversible) in amorphous materials. Furthermore the value of the
Tg is a function of the composition of the homogeneously mixed solid dispersion. It has been
shown that the sensitivity of TMDSC is higher than conventional DSC. Therefore this technique
can be used to assess the amount of molecularly dispersed drug and from that the fraction of drug
that is dispersed as separate molecules is calculated.
33. Page 28 of 41
7.3 Unmet Needs and Challenges
In spite of almost several years of research on solid dispersions, their commercial application is
limited. Only a few products have been marketed so far. Amongst these are:
1) Gris-PEG (Novartis), griseofulvin in PEG
2) Cesamet (Lily), nabilone in PVP
3) Sporanox (Janssen Pharmaceuticals/J&J), itraconazolein HPMC and PEG 20,000 sprayed on
sugar spheres.
The limitations of this technology have been a drawback for the commercialization of solid
dispersions. The limitations include:
1. Laborious and expensive methods of preparation,
2. Reproducibility of physicochemical characteristics,
3. Difficulty in incorporating into formulation of dosage forms,
4. Scale-up of manufacturing process, and
5. Stability of the drug and vehicle.
Various methods have been tried recently to overcome the limitation and make the preparation
practically feasible.
7.3.1 Direct Capsule Filling
Direct filling of hard gelatin capsules with the liquid melt of solid dispersions avoids grinding-
induced changes in the crystallinity of the drug. The filling of hard gelatin capsules has been
feasible in molten dispersions of Triamterene-PEG 500 using a Zanasi LZ 64 capsule filling
machine. However, PEG was not a suitable carrier for the direct capsule-filling method as the
water-soluble carrier dissolved more rapidly than the drug, resulting in drug-rich layers formed
over the surface of dissolving plugs, which prevented further dissolution of the drug. A
surfactant must be mixed with the carrier to avoid formation of a drug-rich surface layer (eg,
polysorbate80 with PEG, phosphatidyl choline with PEG). The temperature of the molten
solution should not exceed~70 0
C because it might compromise the hard-gelatin capsule shell.
34. Page 29 of 41
7.3.2 Electrostatic Spinning Method
This technology used in the polymer industry combines solid solution/dispersion technology
with nanotechnology Solid dispersions. This technology is now applied in the pharmaceutical
field. In this process, a liquid stream of a drug/polymer solution is subjected to a potential
between 5 and 30 kV. When electrical forces overcome the surface tension of the drug/polymer
solution at the air interface, fibers of submicron diameters are formed. As the solvent evaporates,
the formed fibers can be collected on a screen to give a nonwoven fabric, or they can be
collected on a spinning mandrill. The fiber diameters depend on surface tension, dielectric
constant, feeding rate, and electric field strength. Water-soluble polymers would be useful in the
formulation of immediate release dosage forms, and water-insoluble (both biodegradable and no
biodegradable) polymers are useful in controllable dissolution properties. Fabrics generated by
water-soluble carriers could be used in oral dosage formulations by direct incorporation of the
materials into a capsule. Itraconazole/HPMC Nano fibers have been prepared using this
technique.
7.3.3 Surface-active Carriers
A surface-active carrier may be preferable in almost all cases for the solid dispersion of poorly
water-soluble drugs. Two of the important surface-active carriers are Gelucire44/14 and Vitamin
E R-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Gelucire 44/14
(GattefosseCorp, Gennevilliers, France) has commonly been used in solid dispersion for the
bioavailability enhancement of drugs. Gelucire 44/14 is a mixture of glyceryl and PEG 1500
esters of long-chain fatty acids and is official in the European Pharmacopoeia as lauryl
macrogolglycerides; the suffixes 44 and 14 in its name refer, respectively, to its melting point
and hydrophilic lipophilic balance (HLB) value. Vitamin E TPGS National Formulary (NF)
(Eastman, Kingsport, TN) is prepared by the esertification of the acid group of d-Rtocopheryl
acid succinate by PEG 1000. The material has an HLB value of 13 and is miscible with water in
all parts. Its melting point, however, is relatively low (380
C), and it may require mixing with
other carriers to increase melting temperatures of formulations.
A commonly used surfactant, Polysorbate80, when mixed with solid PEG, has also been reported
to be an alternative surface-active carrier Polysorbate80 is liquid at room temperature; it forms a
solid matrix when it is mixed with a PEG because it incorporates within the amorphous regions
35. Page 30 of 41
of PEG solid structure. As much as 75% (wt/wt) Polysorbate80 was incorporated, PEG remained
semisolid, and the lowering of the melting temperature of the PEG used was<12o
C. The PEG-
polysorbate carriers have been found to enhance dissolution36 and bioavailability of drugs from
the solid dispersions. In corporation of 5% (wt/wt) phosphatidyl choline resulted in enhanced
dissolution rate of nifedipinefrom a PEG-based solid dispersion. Pulverized solid dispersions in
PEG containing varying amounts of ionic and nonionic surfactants, including sodium dodecyl
sulfate and Polysorbate80 gave increased dissolution rate of drug.
A solid dispersion of poorly soluble REV5901 in Gelucire44/14 under a fasting regimen had
much higher bioavailability in human volunteers than that of a tablet formulation even though
the micronized form of drug and a wetting agent were used in the tablet. The bioavailability of
unbidden are none in dosage from solid dispersion in Gelucire 44/14 and the Gelucire 44/14-
lecithin mixture were 2 and 3 times higher, respectively, than that of commercially available
tablet.
8 Drug Solubility Properties
8.1 Drug -carrier miscibility
Hot stage microscopy
Differential scanning calorimetry
Powder X-ray diffraction
NMR 1H Spin lattice relaxation time
8.2 Drug carrier interactions
FT-IR spectroscopy
Raman spectroscopy
Solid state NMR
8.3 Physical Structure
Scanning electron microscopy
Surface area analysis
Surface properties
Dynamic vapor sorption
36. Page 31 of 41
Inverse gas chromatography
Atomic force microscopy
Raman microscopy
8.4 Amorphous content
Polarized light optical microscopy
Hot stage microscopy
Humidity stage microscopy
DSC (MTDSC)
ITC
Powder X-ray diffraction
8.5 Stability
Humidity studies
Isothermal Calorimetry
DSC (Tg, Temperature re-crystallization)
Dynamic vapor sorption
Saturated solubility studies
8.6 Dissolution Enhancement
Dissolution
Intrinsic dissolution
Dynamic solubility
Dissolution in bio-relevant media
8.7 Powder X-ray Diffraction
Powder X-ray diffraction can be used to qualitatively detect material with long range order.
Sharper diffraction peaks indicate more crystalline material.
8.8 Infrared Spectroscopy (IR)
Infrared spectroscopy (IR) can be used to detect the variation in the energy distribution of
interactions between drug and matrix. Sharp vibrational bands indicate crystallinity. Fourier
37. Page 32 of 41
Transformed Infrared Spectroscopy (FTIR) was used to accurately detect crystallinity ranging
from 1 to 99% in pure material.
8.9 Water vapor Absorption
Water vapor sorption can be used to discriminate between amorphous and crystalline material
when the hygroscopicity is different. This method requires accurate data on the hygroscopicity of
both completely crystalline and completely amorphous samples.
8.10 Isothermal Microcalorimetry
Isothermal microcalorimetry measures the crystallization energy of amorphous material that is
heated above its glass transition temperature (Tg). This technique has some limitations. Firstly,
this technique can only be applied if the physical stability is such that only during the
measurement crystallization takes place. Secondly, it has to be assumed that all amorphous
material crystallizes. Thirdly, in a binary mixture of two amorphous compounds a distinction
between crystallization energies of drug and matrix is difficult (Sebhatu and Angberg, 1995).
8.11 Dissolution Calorimetry
Dissolution calorimetry measures the energy of dissolution, which is dependent on the
crystallinity of the sample. Usually, dissolution of crystalline material is endothermic, whereas
dissolution of amorphous material is exothermic.
8.12 Macroscopic Techniques
Macroscopic techniques that measure mechanical properties that are different amorphous and
crystalline material can be indicative for the degree of crystallinity. Density measurements and
Dynamic Mechanical Analysis (DMA) determine the modulus of elasticity for and viscosity and
thus affected by the degree of crystallinity. However, also these techniques require knowledge
about the additives of these properties in intimately mixed binary solids (Demeuter and Rahier,
1999).
8.13 Differential Scanning Calorimetry (DSC)
Frequently used technique to detect the amount of crystalline material is Differential Scanning
Calorimetry (DSC). In DSC, samples are heated with a constant heating rate and the amount of
energy necessary for that is detected. With DSC the temperatures at which thermal events occur
38. Page 33 of 41
can be detected. Thermal events can be a glass to rubber transition, (re) crystallization, melting
or degradation. Furthermore, the melting- and re-crystallization energy can be quantified. The
melting energy cans be used to detect the amount of crystalline material.
8.14 Confocal Raman Spectroscopy
Confocal Raman Spectroscopy is used to measure the homogeneity of the solid mixture. It is
described that a standard deviation in drug content smaller than10%was indicative of
homogeneous distribution. Because of the pixel size of 2 μm3, uncertainty remains about the
presence of Nano-sized amorphous drug particles.
8.15 Temperature Modulated Differential Scanning Calorimetry (TMDSC)
Temperature Modulated Differential Scanning Calorimetry (TMDSC) can be used to assess the
degree of mixing of an incorporated drug. Due to the modulation, reversible and irreversible
events can be separated. For example, glass transitions (reversible) are separated from
crystallization or relaxation (irreversible) in amorphous materials. Furthermore, the value of the
Tg is a function of the composition of the homogeneously mixed solid dispersion. It has been
shown that the sensitivity of TMDSC is higher than conventional DSC. Therefore this technique
can be used to assess the amount of molecularly dispersed drug. And from that the fraction of
drug that is dispersed as separate molecules is calculated (Vasanthavada, 2004; Cilurzo and
Minghetti, 2002).
9 In Vitro Dissolution Studies
In vitro dissolution studies are done for the find out dissolution behavior. The in-vitro dissolution
study can be used to demonstrate the bioavailability or bioequivalence of the drug product
through in vitro –in vivo correlation (IVIVC). On the other hand if absorption of the drug is
dissolution rate limited that means the drug in the gastrointestinal fluid passes freely through the
bio-membranes at a rate higher than it dissolves or is released from the dosage form.
39. Page 34 of 41
Conclusion
Solid dispersion systems have been realized as extremely useful tool in improving the dissolution
properties of poorly water-soluble drugs. In recent years, a great deal of knowledge has been
accumulated about solid dispersion technology, but their commercial application is limited.
Various methods have been tried recently to overcome the limitation and make the preparation
practically feasible. The problems involved in incorporating into formulation of dosage forms
have been gradually resolved with the advent of alternative strategies. These include methods
like spraying on sugar beads and direct capsule filling. Although there are some hurdles like
scale up and manufacturing cost to overcome, there lies a great promise that solid dispersion
technology will hasten the drug release profile of poorly water soluble drugs.
40. Page 35 of 41
References
Bikiaris. Solid dispersions of poorly water-soluble drugs. Journal of Pharmaceuticals
Science. 2005; 439: 58–67.
Breitenbach. Drug delivery technology. European Journal Pharmaceuticals and Bio
Pharmaceutics. 2002; 54: 107-117.
Ceballos A. In vitro release of theophylline from directly-compressed. Journal of
Pharmaceuticals Science. 2005; 60: 913–918.
Chauhan B. Preparation and evaluation of glibenclamidepoly glycolized glycerides solid
dispersions with silicon dioxide by spray drying technique. European Journal
Pharmaceuticals and Bio Pharmaceutics. 2005; 26:219–230.
Chiou WL, Riegelman S. Solid dispersion systems. Journal of Pharmaceuticals
Science.1971; 60: 1281–1302.
Chokshi R, Hossein Z. Hot Melt Extrusion Technique. International Journal of
Pharmaceuticals Research.2004; 3: 3-16.
Cilurzo F, Minghetti P, Casiraghi A, Montanari L. Solid dispersions. International
Journal of Pharmaceuticals Research.2002; 242(1-2): 313-317.
Corrigan OI, Healy AM. Surface-active carriers in pharmaceutical products. Journal of
Pharmaceutical Technology.2002; 2639-2653.
Craig DQM. Solid Dispersions in Water-Soluble Polymers. Journal of Pharmaceuticals
Science.2002; 231: 131–144.
Cutler L. Development of a functional effect at the blood-brain barrier. Journal of
Pharmaceuticals Science.2006; 95: 1944–1953.
Damian F. Characterization of Solid Dispersions. European Journal of Pharmaceuticals
Science.2000; 10: 311–322.
Dannenfelser RM. Development of clinical dosage forms for a poorly water soluble drug.
Journal of Pharmaceuticals Science.2004; 93: 1165–1175.
Demeuter P, Rahier H, Van Mele B. Characterization of Food Systems. Journal of
Pharmaceuticals Science.1999; 192(1): 77-85.
Dohrn R, Bertakis E, Behrend O, Voutsas E, Tassios D. Melting point depressions.
Journal of Molecular Liquid.2007; 131-132, 53-59.
41. Page 36 of 41
Drooge JV. Solid Dispersions at the Nano scale Using Fluorescence Resonance Energy
Transfer (FRET). Pharmaceuticals Research.2006; 27: 1149–1155.
Galia E, Nicola ides E, HoÈrter D, LoÈbenberg R, Reppas C, Dressman JB. Evaluation
of various dissolution of class I and II drugs. Pharmaceuticals Research.1998; 15: 698-
705.
Garcia-Zubiri. Thermal stability of solid dispersions. Pharmaceuticals Research.2006;
444: 57–64.
Ghaderi R. Preparation of biodegradable micro particles. Pharmaceutical Research.1999;
16: 676–681.
Ghebremeskel, Vemavarapu C, Lodaya M. Solid dispersions of poorly soluble API.
Journal of Pharmaceuticals Science.2007; 308: 119-129.
Ghebremeskel. Solid dispersions of poorly soluble API. Journal of Pharmaceuticals
Science.2007; 328: 119–120.
Goldberg A, Gibaldi M, Kanig L. Absorption of drugs via solid solutions and eutectic
mixtures II experimental. Journal of Pharmaceuticals Science.1996; 55: 482-487.
Goldberg AH, Gibaldi M, Kanig JL. Increasing dissolution rates and gastrointestinal
absorption of drugs. Journal of Pharmaceuticals Science.1965; 54: 1145-1148.
Goldberg AH, Gibaldi M, Kanig JL. Increasing dissolution rates and gastrointestinal
absorption of drugs. Journal of Pharmaceuticals Science.1966; 55: 482-487.
Goldberg AH. Increasing dissolution rates and gastrointestinal absorption of drugs.
Journal of Pharmaceuticals Science.1966; 55: 581–583.
Guyot M. Physicochemical characterization and dissolution of compounds and PEG solid
dispersions.Journal of Pharmaceuticals Science.1995; 123: 53–63.
Hancock BC, Zogra G. Characteristics and significance of the amorphous state in
pharmaceutical systems. Journal of Pharmaceuticals Science.1997; 86: 1-12.
Hasegawa S. Effects of water content in solid dispersions prepared by closed melting
method. Journal of Pharmaceuticals Science.2005; 302: 103–112.
Hoerter D, Dressman JB. Physicochemical properties on dissolution of drugs in the
gastrointestinal tract. Advance Drug Delivery Review. 1997; 25-14.
Hohman MM, Shin M, Rutledge G, Michael P. Brenner electro spinning and electrically
forced jets. Advance Drug Delivery Review.2001; 13(8):2221-2236.
42. Page 37 of 41
Huang J. solid dispersion in micro particles of controlled drug in delivery system.
International Journal of Pharmaceuticals Research.2006; 319: 44 54.
Johari GP. Dielectric studies of molecular motions in amorphous solid and ultra-viscous
acetaminophen. Journal of Pharmaceuticals Science.2005; 94:2207–2223.
Kang BK. Development of self-micro emulsifying drug delivery systems
(SMEDDS).International Journal of Pharmaceuticals Research.2004; 274: 65–73.
Kaning JL. Properties of Fused Mannitol in Compressed Tablets. Journal of
Pharmaceuticals Science.1964; 53: 188– 192.
Kaning JL. Properties of Fused Mannitol in Compressed Tablets. Journal of
Pharmaceuticals Science.1964; 53: 188–192.
Karata A. Improved solubility and dissolution rate of piroxicam using gelucire.
International Journal of Pharmaceuticals Research.2005; 60: 777–782. 19.
Karata A. Improved solubility and dissolution rate of piroxicam using gelucire.
International Journal of Pharmaceuticals Research.2005; 60: 777–782.
Karavas E. Effect of hydrogen bonding interactions on the release mechanism. European
Journal of Pharmaceuticals and Bio Pharmaceutics.2006; 63: 103–114.
Karavas E. Mucoadhesive properties for adjusting drug release. European Journal of
Pharmaceuticals and Bio Pharmaceutics.2006; 64: 115–126.
Kaushal AM, Guptam P, Bansal AK. Amorphous drug delivery systems. There Drug
Carrier System. 2004; 21(3): 133-193.
Konno H, Taylor LS. Influence of different polymers on the crystallization. Journal of
Pharmaceuticals Science.2006; 95: 2692–2705.
Kreuter J, Kreuter J, Herzfeldt CD. Classification of solid dispersion. Journal of
Pharmaceuticals Science.1999; 262-274.
Levy G. Effect of particle size on dissolution and gastrointestinal absorption rates of
pharmaceuticals. American journal of pharmacy.1963; 135: 78–92.
Li FQ. In Vitro controlled release of sodium ferulate from Compritol 888 ATO-based
matrix tablets. International Journal of Pharmaceuticals.2006; 324: 152–157.
Lloyd GR. Interaction between Paracetamol and polyethylene glycol 4000 in physical
mixes and solid dispersions. European Journal of Pharmaceuticals and Bio
Pharmaceutics.1999; 48: 59–65.
43. Page 38 of 41
Loftsson T, Brewster ME. Pharmaceutical application of cyclodextrins. Journal of
Pharmaceuticals Science.1996; 85: 1010-1025.
Muhrer G. To enhance the dissolution behavior of poorly water-soluble
drug.International Journal of Pharmaceuticals Science.2006; 308: 69–83.
Narang A, Shrivastava A. Solid dispersion technique. Drug Development and Industrial
Pharmacy. 2002; 26(8): 111-115.
Neamnark A, Rujiravanit R, Supaphol P. Electro spinning of hexanoyl Chitosan
Carbohydrate polymers. International Journal of Pharmaceuticals Science.2006; 66:298-
305.
Noyes, Whitney WR. The rate of solution of solid substances in their own solutions.
Journal of the American Chemical Society.1897; 19: 930-934.
Perissutti B, Newton JM, Podezeck F, Rubessa F. Preparation of extruded
Carbamazepine and PEG 4000 as a potential rapid release dosage form. European Journal
of Pharmaceutical and Biopharmaceutics.2002; 53: 125-132.
Pokharkar VB. Development characterization and stabilization of amorphous form of a
low Tg drug. Powder Technology.2006; 167: 20– 25.
Rasenack N, Muller BW. Micronize drug particles techniques. Pharmaceuticals
Development Technology.2004; 9:1–13.
Rodier E. Supercritical process to improve the dissolution rate of Eflucimibe. European
Journal Pharmaceuticals Science.2005; 26: 184–193.
Schachter DM. Solid state NMR perspective of drug-polymer solid solutions.
International Journal of Pharmaceuticals.2004; 281: 89–101.
Schaefer T. Melt Agglomeration Process. European Journal of Pharmaceuticals and Bio
pharmaceutics. 2001; 52(3):315-325.
Sebhatu T, Angberg M, Ahlneck C. Assessment of the degree of disorder in crystalline
solids particles. International Journal of Pharmaceutics.1995; 104: 135-144.
Sekiguchi K, Obi N. Studies on Absorption of Eutectic Mixture. Chemical and
Pharmaceuticals Bulletin.1996; 12: 134–144.
Sekiguchi K, Obi N. Studies on absorption of eutectic mixtures. European Journal of
Pharmaceutical and Bio pharmaceutics.1961; 9: 866–872.
44. Page 39 of 41
Sengodanguruswamy V, Mishra DN. Preparation and evaluation of solid dispersion. The
Pharmaceuticals Society of Japan. 2006; 126(2): 93-97.
Serajuddin A. Solid dispersion Technique. Journal of Pharmaceuticals Science. 1999; 88
(10): 891-900.
Serajuddin AT. Solid dispersion of poorly water-soluble drugs. Journal of
Pharmaceuticals Science.1999; 88: 1058–1066.
Shmeis RA. A mechanistic investigation of an amorphous pharmaceutical and its solid
dispersions part I. Pharmaceuticals Research. 2004; 21:2025–2030.
Simonelli AP. Dissolution rates of high energy polyvinyl pyrrolidone (PVP) -
sulfathiazole coprecipitates. Journal Pharmaceuticals Science.1969; 58: 538–549.
Taki S, Badens E, Charbit G. Controlled release system. Journal of Super critical
Fluids.2000; 21: 61-70.
Tanaka N. Development of novel sustained-release system, disintegration-controlled
matrix tablet (DCMT). Journal of Control Release.2005; 108:386–395.
Taylor LS, Zogra G. Spectroscopic characterization of interactions between PVP and
indomethacin in amorphous molecular dispersions. Pharmaceuticals Research.1997; 14:
1691-1698.
Taylor LS, Zografi G. Spectroscopic Characterization of between PVP and indomethacin
in amorphous molecular dispersions. Pharmaceuticals Research.1997; 14: 1691–1698.65.
Teberekidis VI, Sigalas MP. Theoretical study of hydrogen bond interactions. Journal of
Pharmaceuticals Science.2006; 803: 29–38.
Tsinontides SC, Rajniak P, Hunke WA, Placek J. Freeze drying-principles and practice
for successful scale-up to manufacturing. International Journal of Pharmaceuticals. 2004;
280 (1): 1-16.
Urbanetz NA. Stabilization of solid dispersions of nimodipine and polyethylene glycol
2000.European Journal of Pharmaceuticals Science.2006; 28: 67–76.
Van Drooge DJ. Characterization of the molecular distribution of drugs in glassy solid
dispersions. International Journal of Pharmaceuticals.2006; 310: 220–229.
VandenMooter G. Physical stabilization of amorphous ketoconazole in solid dispersions.
European Journal of Pharmaceuticals Science; Journal of Supercritical Fluids. 2001; 40:
153 162, 12, 261–269.
45. Page 40 of 41
VandenMooter G. The formulation of solid dispersions for poorly soluble drugs.
International Journal of Pharmaceuticals.2006; 316: 1–6.
Vasanthavada M, Tong WQ, Joshi Y, Kislalioglu MS. Phase behavior of amorphous
molecular dispersions I: Determination of the degree and mechanism of solid solubility.
Pharmaceuticals Research. 2004; 21(9): 1598-1606.
Vasanthavada M. Phase behavior of amorphous molecular dispersions II: Role of
hydrogen bonding. Pharmaceuticals Research.2005; 22: 440–448.
Vasanthavada M. Phase behavior of amorphous molecular dispersions I: Determination
of the degree and mechanism of solid solubility. Pharmaceuticals Research.2004; 21:
1598–1606.
Vasconcelos T, Costa P. Development of a rapid dissolving ibuprofen solid dispersion.
Pharmaceutical Sciences World Conference.2007; 23:11-130.
Vasconcelos TF, Sarmento B, Costa P. Solid dispersions as strategy to improve oral
bioavailability of poor water soluble drugs. Drug discovery today.2007; 12: 1069-1070.
Verreck G. Hot stage extrusion of paminosalicylic acid with EC using CO2 as a
temporary plasticizer. International Journal of Pharmaceuticals.2006; 327, 45–50.
Vilhelmsen T, Eliasenm H, Schaefer T. Effect of a melt agglomeration process on
agglomerates containing solid dispersions. International Journal of Pharmaceuticals.
2005; 303 (1- 2): 132-142.
Wang X. Solid state characteristics of ternary solid dispersions. International Journal of
Pharmaceuticals.2005; 303: 54–61.
Won DH. Improved physicochemical characteristics of solid dispersion
particles.International Journal of Pharmaceuticals.2005; 301: 199–208.
Yao WW. Thermodynamic properties for the system of ethylene glycol
6000.International Journal of Pharmaceuticals.2005; 437: 17–20.
Yoshihashi Y. Estimation of physical stability of amorphous solid dispersion.Journal of
Thermal Analysis of Calorimetric.2006; 85: 689–692.
Yoshioka M. Crystallization of indomethacin from the amorphous state below and above
its glass transition temperature.Journal of Pharmaceuticals Science.1994; 83: 1700–1705.
Yuksel N. Enhanced bioavailability of piroxicam using Gelucire 44/14.European Journal
Pharmaceuticals and Bio pharmaceutics.2003; 56: 453–459.
46. Page 41 of 41
Zhang R, Somasundaran P. Advances in adsorption of surfactants and their mixtures at
solid/solution interfaces. International Journal of Pharmaceutics.2006; 123: 213-229.
Zhang W, Yan E, Huang Z, Wang C, Xin Y, Zhao Q, Tong Y. Preparation and study of
PPV/ PVA Nano fibers via electro spinning PPV precursor alcohol solution. European
Polymer Journal.2007; 43: 802-897.
Zhou D. Physical stability of amorphous pharmaceuticals Importance of configurationally
thermodynamic quantities and molecular mobility. Journal of Pharmaceuticals
Science.2002; 91: 1863–1872.
Zhou D. Physical stability solid dispersion. Journal of Pharmaceuticals Science.2007; 96:
71–83.