Descriptive Terms Of Solubility Biology Essay
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Published: Mon, 5 Dec 2016
The process of solubilization involves the breaking of inter-ionic or intermolecular bonds in the solute, the separation of the molecules of the solvent to provide space in the solvent for the solute, interaction between the solvent and the solute molecule or ion. (Shinde A. J., 2007)
Factors affecting solubility
The solubility depends on the physical form of the solid, the nature and composition of solvent medium as well as temperature and pressure of system. (James K., 1986)
Particle size of solid influences the solubility because smaller the particle size more is surface area to volume ratio and larger surface area allows a greater interaction with the solvent.
If the solution process absorbs energy then the solubility will be increased as the temperature is increased. If the solution process releases energy then the solubility will decrease with increasing temperature. Generally, an increase in the temperature of the solution increases the solubility of a solid solute. A few solid solutes are less soluble in warm solutions. For all gases, solubility decreases as the temperature of the solution increases.
For gaseous solutes, an increase in pressure increases solubility and a decrease in pressure decrease the solubility. For solids and liquid solutes, changes in pressure have practically no effect on solubility.
Nature of the solute solvent
Figure 1: Process of solubilization (Adopted from Reference Shinde A. J., 2007)
Therapeutic effectiveness of a drug depends upon ability of the dosage form to deliver the medicament to its site of action at a rate and amount sufficient to bring out the desired pharmacological response. Bioavailability is one of the principal pharmacokinetic properties of drugs, is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as oral), its bioavailability decreases (due to incomplete absorption or first-pass metabolism). The measurement of the amount of the drug in the plasma at periodic time intervals indirectly indicates the rate and extent at which the active pharmaceutical ingredient is absorbed from the drug product and becomes available at the site of action. Bioavailability is expressed as either absolute or relative bioavailability. (Brahmankar D. M., et al., 2009 and Thakkar H., et al., 2010)
Absolute bioavailability and Relative bioavailability
When the systemic availability of a drug administered orally is determined in comparison to its administration, it is called as absolute bioavailability. It is denoted by symbol F. Its determination is used to characterize a drug’s inherent absorption properties from the e.v. site. Intravenous dose is selected as a standard because the drug is administered directly into the systemic circulation (100% bioavailability) and avoids absorption step. Intramuscular dose can also be taken as a standard if the drug is poorly water soluble. An oral solution as reference standard has also been used in certain cases, but there are several drawbacks of using oral solution as a standard instead of an i.v. dose. (Brahmankar D. M., et al., 2009)
Relative or comparative bioavailability
When the systemic availability of a drug after oral administration is compared with that of an oral standard of the same drug (such as an aqueous or non aqueous solution or a suspension), it is referred to as relative or comparative bioavailability. It is denoted by symbol Fr. In contrast to absolute bioavailability; it is used to characterize absorption of a drug from its formulation. F and Fr are generally expressed in percentage. (Brahmankar D. M., et al., 2009)
Factors Influencing Bioavailability
Bioavailability of drug is influenced by the drug, dosage form and the interaction of these with the complex environment of the absorption site. For orally administered compound many factors including GI anatomy and physiology, bacterial, mucosal and hepatic metabolism may affect absorption. The possible contributing of all of these factors must be considered when examining drug absorption, when interpreting the results of bioavailability studies and when designing drugs and dosage forms to optimize absorption characteristics to achieve desired therapeutic goals. (Welling P. G., et al., 2006).
Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation, such factors may include:
Physicochemical properties of the drug (hydrophobicity, pKa, solubility)
he drug formulation (immediate release, excipients used, manufacturing methods, modified release – delayed release, extended release, sustained release, etc.)
Whether the drug is administered in a fed or fasted state
Gastric emptying rate
Enzyme induction/inhibition by other drugs/foods
Interactions with other drugs (e.g. antacids, alcohol, nicotine)
Interactions with other foods (e.g. grapefruit juice, pomello, cranberry juice)
Transporters: Substrate of an efflux transporter (e.g. P-glycoprotein)
Health of the gastrointestinal tract
Intestinal motility-alters the dissolution of the drug and degree of chemical degradation of drug by intestinal microflora.
Enzyme induction/inhibition by other drugs/foods
Individual Variation in Metabolic Differences
Age: In general, drugs are metabolized more slowly in fetal, neonatal, and geriatric populations
Phenotypic differences, enterohepatic circulation, diet, gender
Each of these factors may vary from patient to patient (inter-individual variation), and indeed in the same patient over time (intra-individual variation) (Thakkar H., et al., 2010).
Methods for enhancement of bioavailability
As per definition of bioavailability, drug with poor bioavailability is one with poor aqueous solubility and/or slow dissolution rate in biological fluids and poor permeability through the biomembrane owing to inadequate partition coefficient or lipophilicity or large molecular size such as that of protein or peptide drugs. Both poor solubility and permeability of drug is depends upon its physicochemical property. (Brahmankar D. M., et al., 2009)
Biopharmaceutical Classification System (BCS)
Based on intestinal permeability and solubility of drugs, Amidon et al., developed Biopharmaceutical Classification System (BCS) which classify drugs into one of the four groups. (Table 2).
Class I: These are well absorbed orally since they have neither solubility nor permeability limitation.
Class II: Shows variable absorption owing to solubility limitation.
Class III: also shows variable absorption owing to permeability limitation.
Class IV: are poorly absorbed orally owing to both solubility and permeability limitation.
Table 2: Biopharmaceutical Classification System
Abacavir, Acetaminophen, Acyclovir, Amitryptyline, Antipyrine, Atropine, Bucspirone, Caffeine, Captopril, Chloroquine, Chlorpheniramine, Cyclophosphmide, Desipramine, Diazepam, Dilitiazem, Diphenhydramine, Disopyramide, Doxepin, Doxycycline, Enlapril, Ephedrine, Ergonovine, Ethambutol, fluoxetine, Glucose, Imipramine, Ketorolac, Ketoprofen, Labetolol, Levodopa, Levofloxacin, Meperidine, Metoprolol, Metronidazole, Midazolam, Minocycline, Misoprostol, Nifedipine, Phenobarbital, Phenylalamine, Prednisolone, Primaquine, Promazine, Propranolol, Quinidine, Rosiglitazone, Salicylic acid, Theophylline, Zidovudine. Risperidone.
Amiodarone, Atorvastatin, Azithromycine, Carbamazepine, Carvedilol, Chlorpromazine, Ciprofloxancin, Cyclosporine, Danazol, Dapsone, Diclofenac, Digoxine, Erythromycin, Flurbiprofen, Glyburide, Griseofulvin, Ibuprofen, Indinavir, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Lovastatin, Mebendazole, Naproxen, Nelfinavir, Ofloxacin, Oxaprozin, Phenazopyridine, Phenytoin, Piroxicam, Raloxifene, Ritonavir, Saquinavir, Sirolimus, Spironolactone, Tacrolimus, Talmolol, Tamoxifen, Terfenadine, Telmisartan, Verapamil hydrochloride, Warfarin,
Acyclovir, Amiloride, Amoxicillin, Atenolol, Atropine, Bisphosphonates, Captopril, Cefazolin, Cetrizine, Cimetidine, Ciprofloxacin, Cloxacillin, Dicloxacillin, Erythromycin, Famotidine, Fexofenadine, Ganciclovir, Lisinopril, Metformin, Methotrexate, Nadolol, Pravastatin, Penicillins, Tetracyline, Trimethoprim, Valsartan, Zalcitabinne
Amphotericin B, Chlorthalidone, Chlorothiazide, Colistin, Ciprofloxacin, Furosemide, Hydrochlorothiazide, Mebandazole, Methotrexate, Neomycin.
BCS Class boundaries
Class boundary parameters (i.e., solubility, permeability, and dissolution) are for easy identification and determination of BCS class.
Solubility: A drug substance is considered highly soluble when the highest dose strength is soluble in 250 mL or less of water over a pH range of 1-7.5 at 37 °C.
Permeability: A drug substance is considered highly permeable when the extent of absorption in humans is greater than 90% of an administered dose, based on mass-balance or compared with an intravenous reference dose.
Dissolution: A drug product is considered rapidly dissolving when 85% or more of the labeled amount of drug substance dissolves within 30 min using USP Apparatus 1 or 2 in a volume of 900 mL or less of buffer solutions. (Reddy B. B. K., et al., 2011)
There are three approaches in overcoming bioavailability problems are:
It involves modification of formulation, manufacturing process or physicochemical properties of drug without changing chemical structure.
It involves alteration of pharmacokinetic of drug by altering its chemical structure by developing new chemical entity with desirable feature or prodrug design.
In which route of drug administration is changed such as changing from oral to parenteral route.
Pharmacokinetic approach has many drawbacks such as expensive, time consuming, repetition of clinical studies and long time of regulatory approval. Hence pharmaceutical approach is mainly aimed at altering the biopharmaceutical properties of drug by using one of the following ways:
By enhancing drug solubility or dissolution rate:
Supercritical fluid recrystallization
Spray freezing into liquid
Evaporative precipitation into aqueous solution
Use of surfactants
Use of salt forms
Use of precipitation inhibitors
Alteration of pH of drug microenvironment
Use of amorphous, anhydrates, solvates and metastable polymorphs
Selective adsorption on insoluble carriers
Molecular encapsulation with cyclodextrin
By enhancing drug permeability across biomembrane
By enhancing drug stability
Use of metabolism inhibitors
By Gastrointestinal retention
Methods of Assessing Bioavailability
The bioavailability of a drug substance formulated into a pharmaceutical product is fundamental to the goals of dosage form design and essential for the clinical efficacy of the medication. Thus, bioavailability testing, which measures the rate and extent of drug absorption, is a way to obtain evidence of the therapeutic utility of a drug product. Bioavailability determinations are performed by drug manufacturers to ensure that a given drug product will get the therapeutic agent to its site of action in an adequate concentration. Bioavailability studies are also carried out to compare the availability of a drug substance from different dosage forms or from the same dosage form produced by different manufacturers. There are two categories of method used for quantitative evaluation of bioavailability, pharmacokinetic method and pharmacodynamic method. (Chereson R. (1996) and Brahmankar D. M., et al., 2009)
This method is based on assumption that, pharmacokinetic profile reflects therapeutic effectiveness of drug. Hence these are indirect methods. The two major pharmacokinetic methods are:
Plasma level-time studies/ blood level studies
Blood level studies are the most common type of human bioavailability studies, and are based on the assumption that there is a direct relationship between the concentration of drug in blood or plasma and the concentration of drug at the site of action. By monitoring the concentration in the blood, it is thus possible to obtain an indirect measure of drug response. Following the administration of a single dose of a medication, blood samples are drawn at specific time intervals and analyzed for drug content. A profile is constructed showing the concentration of drug in blood at the specific times the samples were taken. The parameters such as AUC, Cmax, Tmax, etc are noted.
Urinary excretion studies
An alternative bioavailability study measures the cumulative amount of unchanged drug excreted in the urine. These studies involve collection of urine samples and the determination of the total quantity of drug excreted in the urine as a function of time. These studies are based on the premise that urinary excretion of the unchanged drug is directly proportional to the plasma concentration of total drug. Thus, the total quantity of drug excreted in the urine is a reflection of the quantity of drug absorbed from the gastrointestinal tract. (dXu/dt)max, (tu)max and Xuâˆž are three major parameters in urinary excretion data obtained with a single dose study.
This method is complementary to pharmacokinetic approaches and it involves direct measurement of drug effect on a physiological process as a function of time. The two pharmacodynamic methods involve determination of bioavailability from:
Acute pharmacological response:
When bioavailability measurement by pharmacokinetic methods is difficult, inaccurate and non reproducible, an acute pharmacological effect such as change in ECG or EEG readings, pupil diameter, etc is related to the time course of a given drug. Bioavailability then can be determined by construction of pharmacological effect-time curve as well as dose-response graph.
Therapeutic response method:
Theoretically this is most definite method. This method is based on observing the clinical response to a drug formulation given to patients suffering from disease for which it is intended to be used.
In-Vitro Dissolution and Bioavailability
The term commonly used to describe correlation between some physicochemical property of a dosage form and the biological availability of the drug from that dosage form is in-vitro in-vivo correlation (IVIVC). Specifically, it is felt that if such a correlation could be established, it would be possible to use in-vitro data to predict a drug’s in-vivo bioavailability. This would considerably reduce, or in some cases, completely eliminate the need for bioavailability tests. The desirability for this becomes clear when one considers the cost and time involved in bioavailability studies as well as the safety issues involved in administering drugs to healthy subjects or patients. It would certainly be preferable to be able to substitute a quick, inexpensive in-vitro test for in-vivo bioavailability studies. Hence best available tool today which can at least quantitatively assure about biological availability of a drug from its formulation is its in-vitro dissolution test.
Problems and Breakthroughs of Bioavailability Enhancement Techniques
There are many more methods used to enhance solubility, dissolution rate and hence bioavailability. But these methods have their own limitations. Salt formation of neutral compounds is not feasible and synthesis of weak acid and weak base salts may not always be practical. Moreover, the salts that are formed may convert back to their original acid or base forms and lead to aggregation in the gastrointestinal tract. Particle size reduction may not be desirable in situations where handling difficulties and poor wettability are experienced for very fine powders. To overcome these drawbacks, various other formulation strategies have been adopted including the use of cyclodextrins, nanoparticles, solid dispersions and permeation enhancers. Indeed, in some selected cases, these approaches have been successful. (Gursoy R. N., et al., 2004)
The major disadvantages of solid dispersion are related to their instability. Several systems have shown changes in crystallinity and a decrease in dissolution rate with aging. The crystallization of ritonavir from the supersaturated solution in a solid dispersion system was responsible for the withdrawal of the ritonavir capsule (Norvir, Abboft) from the market. Moisture and temperature have more of a deteriorating effect on solid dispersions than on physical mixtures. Some solid dispersion may not lend them to easy handling because of tackiness. (Dixit A. K., 2012)
In pH adjustment technique there is risk for precipitation upon dilution with aqueous media having a pH at which the compound is less soluble. Intravenously this may lead to emboli, orally it may cause variability. Also tolerability and toxicity (local and systemic) related with the use of a non physiological pH and extreme pHs. As with all solubilized and dissolved systems, a dissolved drug in an aqueous environment is frequently less stable chemically compared to formulations crystalline solid. The selected pH may accelerate hydrolysis or catalyze other degradation mechanisms. In particle size reduction technique; due to the high surface charge on discrete small particles, there is a strong tendency for particle agglomeration. Developing a solid dosage form with a high pay load without encouraging agglomeration may be technically challenging. Technically, development of sterile intravenous formulations is even more challenging. Complexation of drugs with cyclodextrins also have some drawbacks such as potential toxicity issue, regulatory and quality control issue related to presence of ligand may add complication and cost to the development process. (Vemula V. R., et al., 2010)
Lipid based drug delivery
In recent years, greatly interest has paying attention on lipid-based formulations to improve the oral bioavailability of poorly water soluble drug. Lipid formulations for oral administration of drugs generally consist of a drug dissolved in a blend of two or more excipients, which may be triglyceride oils, partial glycerides, surfactants or co-surfactants. Lipid formulations are a diverse group of formulations which have a wide range of properties. These result from blending of up to five classes of excipients, ranging from pure triglyceride oils, through mixed glycerides, lipophilic surfactants, hydrophilic surfactants and water-soluble co solvents. (Pouton C. W., 2000)
An ideal oral lipid-based dosage form must meet a number of demands: (Cannon J. B., 2011)
It should solubilize therapeutic amounts of the drug in the dosage form.
It should maintain adequate drug solubility over the entire shelf-life of the drug product (generally 2 years) under all anticipated storage conditions.
It should provide adequate chemical and physical stability for the drug and formulation components.
It must be composed of approved excipients in safe amounts.
Once ingested, it should facilitate dispersion of the dosage form in the intestinal milieu and maintain drug solubilization in the dispersed form.
It should adapt to the digestive processes of the GI tract such that digestion either enhances or maintains drug solubilization.
It should present the drug to the intestinal mucosal cells such that absorption into the cells and into the systemic circulation is optimized.
Lipid formulation classification system
The Lipid Formulation Classification System (LFCS) was introduced by Pouton C. W. as a working model in 2000 (Pouton C. W. 2000) and an extra ‘type’ of formulation (Type IV) was added in 2006 (Pouton C. W. 2006). In recent years the LFCS has been discussed more widely within the pharmaceutical industry to seek a consensus which can be adopted as a framework for comparing the performance of lipid-based formulations. (Pouton C. W., et al., 2008).
Table 3: Lipid Formulation Classification System
III A SEDDS
III B SMEDDS
Oils: triglycerides or mixed mono and diglycerides
Water-insoluble surfactants (HLB < 12)
Water-soluble surfactants (HLB > 12)
(e.g. PEG, proylene glycol, transcutol)
Particle size of dispersion (nm)
Significance of aqueous dilution
Solvent capacity unaffected
Some loss of solvent capacity
potential loss of solvent capacity
loss of solvent capacity
Significance of digestibility
Not crucial but likely to occur
Not crucial but may be inhibited
Not required and not likely to occur
May not be digestible
Self Micro Emulsifying Drug Delivery System
Self-emulsifying drug delivery systems (SEDDS) or selfemulsifying oil formulations (SEOF) are defined as isotropic mixtures of natural or synthetic oils, solid or liquid surfactants, or alternatively, one or more hydrophilic solvents and co-solvents/surfactants. Upon mild agitation followed by dilution in aqueous media, such as GI fluids, these systems can form fine oil-in-water (o/w) emulsions or microemulsions (SMEDDS). Self-emulsifying formulations spread readily in the GI tract, and the digestive motility of the stomach and the intestine provide the agitation necessary for self-emulsification. SEDDS typically produce emulsions with a droplet size between 100 and 300 nm while SMEDDS form transparent microemulsions with a droplet size of less than 50 nm. When compared with emulsions, which are sensitive and metastable dispersed forms, SEDDS are physically stable formulations that are easy to manufacture. Thus, for lipophilic drug compounds that exhibit dissolution rate-limited absorption, these systems may offer an improvement in the rate and extent of absorption and result in more reproducible blood-time profiles. (Gursoy R. N., et al., 2004 and Kohli K., et al., 2010)
Mechanism of Self Emulsification
According to Reiss, self-emulsification occurs when the entropy change that favors dispersion is greater than the energy required to increase the surface area of the dispersion. The free energy of the conventional emulsion is a direct function of the energy required to create a new surface between the oil and water phases and can be described by the equation: In emulsification process the free energy (âˆ†G) associated is given by the equation:
Where, âˆ†G is the free energy associated with the process (ignoring the free energy of mixing), N is the number of droplets of radius r and ó represents the interfacial energy. The two phases of emulsion tend to separate with time to reduce the interfacial area, and subsequently, the emulsion is stabilized by emulsifying agents, which form a monolayer of emulsion droplets, and hence reduces the interfacial energy, as well as providing a barrier to prevent coalescence. (Reiss H., 1975, Craig D. Q. M., et al., 1995 and Kohli K., et al., 2010 )
It was also suggested that, in case of SMEDDS, the free energy of formation is very low and positive or even negative which results in thermodynamic spontaneous emulsification. It has been suggested that self emulsification occurs due to penetration of water into the Liquid Crystalline (LC) phase that is formed at the oil/surfactant-water interface into which water can penetrate assisted by gentle agitation during self-emulsification. After water penetrates to a certain extent, there is disruption of the interface and a droplet formation. This LC phase is considered to be responsible for the high stability of the resulting nanoemulsion against coalescence. (Shah I., 2011)
Upon aqueous dilution the drug remains in the oil droplets or as a micellar solution since the surfactant concentration is very high in such formulations. (Pouton C. W., et al., 2008) The drug in the oil droplet may partition out in the intestinal fluid as shown in Figure 2. (Shah I. 2011)
Figure 2: Mechanism of drug partitioning in SMEDDS (Adopted from Reference Shah I. 2011)
Advantages and Disadvantages of SMEDDS (Shukla J. B., et. al., 2010)
Improvement in oral bioavailability
Dissolution rate dependant absorption is a major factor that limits the bioavailability of numerous poorly water soluble drugs. The ability of SMEDDS to present the drug to GIT in solubilised and micro emulsified form (globule size between 1-100 nm) and subsequent increase in specific surface area enable more efficient drug transport through the intestinal aqueous boundary layer and through the absorptive brush border membrane leading to improved bioavailability. Khoo S. M showed that the lipid-based formulations of halofantrine base afforded a six- to eight-fold improvement in absolute oral bioavailability relative to previous data of the solid halofantrine HCl tablet formulation. (Khoo S. M. et al., 1998)
Ease of manufacture and scale-up
Ease of manufacture and scale- up is one of the most important advantages that make SMEDDS unique when compared to other drug delivery systems like solid dispersions, liposomes, nanoparticles, etc., dealing with improvement of bio-availability. SMEDDS require very simple and economical manufacturing facilities like simple mixer with agitator and volumetric liquid filling equipment for large-scale manufacturing. This explains the interest of industry in the SMEDDS.
Reduction in inter-subject and intra-subject variability and food effects
There are several drugs which show large inter-subject and intra-subject variation in absorption leading to decreased performance of drug and patient non-compliance. Food is a major factor affecting the therapeutic performance of the drug in the body. SMEDDS are a boon for such drugs. Several research papers specifying that, the performance of SMEDDS is independent of food and, SMEDDS offer reproducibility of plasma profile are available. (Kohsaku K. et al., 2002)
Ability to deliver peptides that are prone to enzymatic hydrolysis in GIT
One unique property that makes SMEDDS superior as compared to the other drug delivery systems is their ability to deliver macromolecules like peptides, hormones, enzyme substrates and inhibitors and their ability to offer protection from enzymatic hydrolysis. The intestinal hydrolysis of prodrug by cholinesterase can be protected if Polysorbate 20 is emulsifier in micro emulsion formulation. (Cortesi R. et. al., 1997)
No influence of lipid digestion process
Unlike the other lipid-based drug delivery systems, the performance of SMEDDS is not influenced by the lipolysis, emulsification by the bile salts, action of pancreatic lipases and mixed micelle formation. SMEDDS are not necessarily digested before the drug is absorbed as they present the drug in micro-emulsified form which can easily penetrate the mucin and water unstirred layer.
Increased drug loading capacity
SMEDDS also provide the advantage of increased drug loading capacity when compared with conventional lipid solution as the solubility of poorly water soluble drugs with intermediate partition coefficient (2
Advantages of Smedds over Emulsion
SMEDDS not only offer the same advantages of emulsions of facilitating the solubility of hydrophobic drugs, but also overcomes the drawback of the layering of emulsions after sitting for a long time. SMEDDS can be easily stored since it belongs to a thermodynamics stable system.
Microemulsions formed by the SMEDDS exhibit good thermodynamics stability and optical transparency. The major difference between the above microemulsions and common emulsions lies in the particle size of droplets. The size of the droplets of common emulsion ranges between 0.2 and 10 Î¼m, and that of the droplets of microemulsion formed by the SMEDDS generally ranges between 2 and 100 nm (such droplets are called droplets of nano particles).Since the particle size is small, the total surface area for absorption and dispersion is significantly larger than that of solid dosage form and it can easily penetrate the gastrointestinal tract and be absorbed. The bioavailability of the drug is therefore improved.
SMEDDS offer numerous delivery options like filled hard gelatin capsules or soft gelatin capsules or can be formulated in to tablets whereas emulsions can only be given as an oral solutions.
One of the obstacles for the development of SMEDDS and other lipid-based formulations is the lack of good predicative in vitro models for assessment of the formulations.
Traditional dissolution methods do not work, because these formulations potentially are dependent on digestion prior to release of the drug.
This in vitro model needs further development and validation before its strength can be evaluated.
Further development will be based on in vitro – in vivo correlations and therefore different prototype lipid based formulations needs to be developed and tested in vivo in a suitable animal model.
The drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations in formulations (approximately 30-60%) which irritate GIT.
Moreover, volatile co solvents in the conventional self-microemulsifying formulations are known to migrate into the shells of soft or hard gelatin capsules, resulting in the precipitation of the lipophilic drugs.
The precipitation tendency of the drug on dilution may be higher due to
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