solubilty of drugs in the perspective of medicinal and pharmaceutcal scientist

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1. Introduction 2. Medicinal chemist prospective3. Pharmaceutical scientist prospective 4. Conclusion

Solubility of drugs in the perspectives of Medicinal Chemist and Pharmaceutical Scientist

Sultan Ullah PhD ScholarSynthetic medicinal chemistry lab,College of pharmacy ,PNU.

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• Therapeutic effectiveness of a drug depends upon the bioavailability and ultimately upon the solubility of drug molecules.

• Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown.

• Currently only 8% of new drug candidates have both high solubility and permeability.

• Nearly 40% of the new chemical entities currently being discovered are poorly water soluble.

• More than one-third of the drugs listed in the U.S. Pharmacopoeia fall into the poorly water-soluble or water-insoluble categories.

• Low aqueous solubility is the major problem encountered with formulation development of new chemical entities.

• Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption.

Biopharmaceutical classification system

1. Introduction

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2. Medicinal chemist prospective

The 'rule of 5’ states that: poor absorption or permeation are more likely when:There are more than 5 H-bond donors (expressed as the sum of OHs and NHs);The MWT is over 500;The Log P is over 5 (or MLogP is over 4.15);There are more than 10 H-bond acceptors (expressed as the sum of Ns and Os);Compound classes that are substrates for biological transporters are exceptions to the rule. These orally active therapeutic classes outside the ‘rule of 5’ are: antibiotics, antifungals, vitamins and cardiac glycosides.

2.1 Lipinski Rule of Five

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• From the rule of five here are four parameters that should be globally associated with solubility and permeability;

• 1. molecular weight; • 2. Log P;• 3. The number of H-bond donors• 4. The number of H-bond acceptors.

• Large molecular weight ,lipid bilayer affect permeability.• Less orally active• An excessive number of hydrogen bond donor groups impairs permeability across a

membrane bi-layer• At the USAN library there is a sharp cutoff in the number of compounds containing more

than 5 OHs and NHs.• Many hydrogen bond acceptor groups also hinder permeability across a membrane bi-

layer


2.1. Lipinski Rule of Five

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2.2. Calculation of Absorption Parameters • For a good absorption of drugs, the four parameters mentioned in Lipinski rule of five are

calculated by the following methods.1. Over all approach • The four parameters used for the prediction of potential absorption problems can be easily

calculated with any computer and a programming language that supports or facilitates the analysis of molecular topology.

• MDL's sequence and MEDIT languages for MACCS have since successfully ported the algorithms to Tripos' SPL and MDL's ISIS PL languages in Pfizer.

• The parameters of molecular weight and sum of nitrogen and oxygen atoms are very simple to calculate and require no further discussion.

• Likewise, the calculation of the number of hydrogen-bond acceptors is simply the number of nitrogen and oxygen atoms attached to at least one hydrogen atom in their neutral state.


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2.2. Calculation of absorption parameters

2. MLog P. Log P by the method of MoriguchiThe method begins with a straightforward counting of• Lipophilic atoms (all carbons and halogens with a multiplier rule for normalizing their contributions) and• Hydrophilic atoms (all nitrogen and oxygen atoms). • Using a collection of 1230 compounds, Moriguchi et al. found that these two parameters alone account for 73% of the variance in the

experimental log Ps. When a ‘saturation correction’ is applied by raising the lipophilic parameter value to the 0.6 power and the hydrophilic parameter to the 0.9 power, the regression model accounted for 75% of the variance.

• The Moriguchi method then applies 11 correction factors, four that increase the hydrophobicity and seven that increase the lipophilicity, and the final equation accounts for 91% of the variance in the experimental log Ps of the 1230 compounds.

• The correction factors that increase hydrophobicity are:• 1. UB, the number of unsaturated bonds except for those in nitro groups. Aromatic compounds like benzene

are analyzed as having alternating single and double bonds so a benzene ring has 3 double bonds for the UB correction factor, naphthalene has a value of 5;

• 2. AMP, the correction factor for amphoteric compounds where each occurrence of an alpha amino acid structure adds 1.0 to the AMP parameter, while each amino benzoic acid and each pyridine carboxylic acid occurrence adds 0.5;

• 3. RNG, a dummy variable which has the value of 1.0 if the compound has any rings other than benzene or benzene condensed with other aromatic, hetero-aromatic, or hydrocarbon rings;

• 4. QN, the number of quaternary nitrogen atoms (if the nitrogen is part of an N-oxide, only 0.5 is added).


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2.2. Calculation of absorption parameters • The correction factors that increase lipophilicity1. PRX a proximity correction factor for nitrogen and oxygen atoms that are close to one another topologically. For each two atoms directly bonded to each other, add 2.0 and for each two atoms connected via a carbon, sulfur, or phosphorus atom, add 1.0 unless one of the two bonds connecting the two atoms is a double bond, in which case, according to some examples in the papers, you must add 2.0. In addition, for each carboxamide group, we add an extra 1.0 and for each sulfonamide group, we add 2.0;2. HB, a dummy variable which is set to 1.0 if there are any structural features that will create an internal hydrogen bond. We limited our programs to search for just the examples given in the Moriguchi paper as it is hard to determine how strong a hydrogen bond has to be to affect lipophilicity;3. POL, the number of heteroatoms connected to an aromatic ring by just one bond or the number of carbon atoms attached to two or more heteroatoms which are also attached to an aromatic ring by just one bond;4. ALK, a dummy parameter that is set to 1.0 if the molecule contains only carbon and hydrogen atoms and no more than one double bond;5. NO2, the number of nitro groups in the molecule;6. NCS, a variable that adds 1.0 for each isothiocyanate group and 0.5 for each thiocyanate group;7. BLM, a dummy parameter whose value is 1.0 if there is a beta lactam ring in the molecule.


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2.3. Prediction of aqueous thermodynamic solubility

• The prediction of the aqueous solubility of drug candidates is of paramount importance in assisting the discovery, as well as the development, of new drug entities. Low aqueous solubility even in the presence of a good permeation rate results in low absorption. Conversely, a compound with high aqueous solubility might be well absorbed, even if it possesses a moderate or low permeation rate

• Formulation efforts can help in addressing these problems, but there are severe limitations to the absorption enhancement that can be realistically achieved.

• Obviously, a method for predicting solubility of drug candidates at an early stage of discovery would have a great impact on the overall discovery and development process.


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• Aqueous solubility of a given molecule is the result of a complex interplay of several factors ranging from the hydrogen-bond donor and acceptor properties of the molecule and of water, to the energetic cost of disrupting the crystal lattice of the solid in order to bring it into solution (‘fluidization’).

• Thus, any method which would aim at predicting the aqueous solubility of a given molecule would have to take into account a more comprehensive ‘description’ of the molecule as the outcome of the complex interplay of factors.

• None of the presently available methods can truly be exploited for a relatively accurate prediction of solubility, if the target of the prediction is the solubility of complex pharmaceutical drug candidates.


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• The three basic quantities governing the solubility (S) of a given solid solute: S = f(Crystal Packing Energy + Cavitation Energy + Solvation Energy)• In this equation, the crystal packing energy is a (endoergic) term which accounts for energy

necessary to disrupt the crystal packing and to bring isolated molecules in gas phases, i.e. its enthalpy of sublimation.

• The cavitation energy is a (endoergic) term which accounts for the energy necessary to disrupt water (structured by its hydrogen bonds) and to create a cavity into which to host the solute molecule.

• The solvation energy might be defined as the sum (exoergic term) of favorable interactions between the solvent and the solute.

• Determination or estimation of melting point or, better, of their enthalpy of sublimation are major hurdles in the prediction of aqueous solubilities of crystalline solids products.

• At present no accurate and efficient method is available to predict these two quantities for the relatively complex molecules which are encountered in the pharmaceutical research.


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2.3.Prediction of aqueous thermodynamic solubility

• The following methods are designed by some scientist to predict the solubility of drugs. i. LSERs and TLSER methods ii. LogP and AQUAFAC methods iii. Other calculation methodsi. LSERs and TLSER methodsLinear Solvation Energy Relationships (LSERs), based upon solvatochromic parameters, have the advantage of a good theoretical background and offer a correlation between several molecular properties, and a solute property, SP. Most notably, the work of Abraham et al. has generated an equation of the general type:

LogSP = c + rR2 + aΣαH2 + bΣβH

2 + sπH2 + nVx

where c is a constant, R2 is an excess molar refractivity, Σα2H and Σβ2H are the (summation or ‘effective’) solute hydrogen-bond acidity and basicity, respectively, π2H is the solute dipolarity-polarizability and Vx is McGowan's characteristic volume.

Disadvantages of this method:Not suitable for complex multi-functional molecules such as drug candidates, especially if they are capable of intra-molecular hydrogen bonding, as is often the case


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Kamlet equations describing the solubility of aromatic solutes including polycyclic and chlorinated aromatic hydrocarbons. In these equations a term accounting for the crystal packing energy was introduced.

log Sw(aromatics) – (0.24−5.28V1/ 100) + 4.03βm +1.53αm−0.0099 (m.p.−25)

Disadvantage: not useful in close structural analogs where a large variation in melting points (>100 °C) is not expected (as might often be the case) and the ‘solution behavior’ could be estimated by solvatochromic parameters. The equations stemming from computed values have been termed TLSERs (Theoretical Linear Solvation Energy Relationships).


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ii. LogP and AQUAFAC methodsYalkowski, who using LogP (the logarithm of the octanol/water partition coefficient) and a term describing the energetic cost of the crystal and predicted the solubility of halogenated aromatic and polycyclic halogenated aromatic hydrocarbons. The general solubility equation, for organic non-electrolytes is reported below.

log Spred = −ΔSm(m.p.−25/ 1364) −log P + 0.80In this equation, ΔSm is the entropy of melting and m.p. is the melting point in °C. The signs of the two terms considered are physically reasonable, since an increase in either the first term (higher crystal packing energy) or in LogP (more lipophilic compound), would cause a decrease in the observed (molar) solubility Sm. The activity coefficient is best achieved by using the LogP method. Many computational methods are indeed available to address the prediction of LogP and the aqueous solubility of complex molecules. A well known and widely used program to predict LogP values is CLogP which uses a group-contribution approach to yield a LogP value.


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Yalkowski and colleagues discussed an improvement of the AQUAFAC (AQUeous Functional group Activity Coefficients) fragmental constant method. In this work, the authors describe a correlation between the sum of fragmental constants of a given molecule and the activity coefficient, defined as a measure of the non-ideality of the solution. log Spred = [−ΔSm(m.p.−25)/1364 ]−Σniqiwhere qi is the group contribution of the ith group and ni is the number of times the ith group appears in the molecule. The negative sign ofthe second term stems from the fact that the constant of polar groups (e.g. OH=−1.81) has a negative sign and a net negative sign of the summation of contributors would yield an overall positive contribution to solubility

Disadvantage: limited to molecule containing relatively simple functional groups

iii. Other calculation methodsBodor and Huang [49] and Nelson and Jurs [50] have reported methods based entirely on calculated geometric, electronic and topological descriptors, for a series of relatively simple liquid and solid solutes.


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3. Pharmaceutical scientist prospective

I. Physical Modifications A. Particle size reduction 1.Micronization 2.Nanosuspension 3.Sonocrystalisation 4.Supercritical fluid process

B. Modification of the crystal habit 1.Polymorphs 2.Pseudopolymorphs C. Drug dispersion in carriers 1. Eutectic mixtures 2. Solid dispersions 3. Solid solutions D. Complexation Use of complexing agents E. Solubilization by surfactants Microemulsions

II. Chemical Modifications 1. Change in the pH 2. Use of buffer 3. Derivatization

III. Other methods 1.co-crystallisation 2. co-solvency 3.Hydrotrophy 4.Solubilizing agents 5.Selective adsorption on insoluble carrier 6.Solvent deposition 7.Using soluble prodrug 8.Functional polymer technology 9.Precipitation Porous 10.microparticle technology 11.Nanotechnology approaches

Solubility enhancement techniques

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A. Particle size reduction: Particle size reduction can be achieved by a. Micronization b. nanosuspension c. Sonocrystalisation d.Supercritical fluid process

1. Micronization: • Micronization increases the dissolution rate of drugs through increased surface area. • Micronization of drugs is done by milling techniques using jet mill, rotor stator colloid mills etc. • Micronization is not suitable for drugs having a high dose number because it does not change the

saturation solubility of the drug . • The process involves reducing the size of the solid drug particles to 1 to 10 microns commonly by spray

drying or by use of attrition methods. The process is also called micro-milling.

2. Nanosuspension :

Nanosuspensions are sub-micron colloidal dispersion of pure particles of the drug, which are stabilized by surfactants.

Nanosuspension technology is used for efficient delivery of hydrophobic drugs . The particle size distribution of the solid particles in nanosuspensions is usually less than one micron with an average particle size ranging between 200 and 600 nm.

Increased dissolution rate due to larger surface area exposed. Eg., Nanosuspension approach has been employed drugs like paclitaxel, tarazepide, amphotericin B which are still on research stage.

Advantage :

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3.Sonocrystallisation :Particle size reduction on the basis of crystallisation by using ultrasound is Sonocrystallisation . Sonocrystallisation utilizes ultrasound power for inducing crystallisation . It not only enhances the nucleation rate but also an effective means of size reduction and controlling size distribution of the active pharmaceutical ingredients. Most applications use ultrasound in the range 20 kHz-5 MHz.

4. Supercritical fluid process : • A supercritical fluids are dense non-condensable fluid whose temperature and

pressure are greater than its critical temperature ( Tc ) and critical pressure ( Tp ) allowing it to assume the properties of both a liquid and a gas.

• Through manipulation of the pressure of SCFs, the favourable characteristics of gases – high diffusivity, low viscosity and low surface tension may be imparted upon the liquids to precisely control the solubilisation of a drug with a supercritical fluid.

• Once the drug particles are solubilised within SCFs, they may be recrystalised at greatly reduced particle sizes.

• A SCF process allows micronisation of drug particles within narrow range of particle size, often to sub-micron levels.

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B. Modification of the crystal habit:

One polymorphs form can No reversible transition change reversibly into another is possible. at a definite transition temperature below the melting point.

• Metastable forms are associated with higher energy and thus higher solubility. Similarly the amorphous form of drug is always more suited than crystalline form due to higher energy associated and increased surface area.

• The anhydrous form of a drug has greater solubility than the hydrates. This is because the hydrates are already in interaction

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Polymorphs

MonotropicEnantiotropic

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with water and therefore have less energy for crystal breakup in comparison to the anhydrates.

• They have greater aqueous solubility than the crystalline forms because they require less energy to transfer a molecule into solvent. Thus, the order for dissolution of different solid forms of drug is

• Melting followed by a rapid cooling or recrystallization from different solvents can produce metastable forms of a drug.

Amorphous > metastable polymorph > stable polymorph

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C. Drug dispersion in carriers:

The term “solid dispersions” refers to the dispersion of one or more active ingredients in an inert carrier in a solid state, frequently prepared by the

1.• Hot melt mehod

2.• Solvent evaporation method

3.• Hot melt extrusion method

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1. Hot melt method :

Drug + vehicle (m.p low, organic solvent – insoluble)

(heating)

Melting.

Freezing quickly

Dosage forms

Suitable to drugs and vehicles with promising heat stability.

A molecular dispersion can be achieved or not, depends on the

degree of supersaturation and rate of cooling used

in the process.

Important requisites :

1. Miscibility of the drug & carrier in the molten form,

2. Thermostability of the drug & carrier.

Suitable to drugs and vehicles with promising heat stability.

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2. Solvent evaporation method: Drug + vehicle ( both soluble in solvent) organic solvent solution

evaporate the solvent coprecipitates

dosage forms suitable to drugs with volatility or poor stability

Temperatures used for solvent evaporation generally lie in the range 23-65°C.

The solvent evaporation can be done by spray drying or freeze

drying.

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3.Hot-melt Extrusion: Hot melt extrusion of miscible components results in amorphous solid solution formation, whereas extrusion of an immiscible component leads to amorphous drug dispersed in crystalline excipient. The process has been useful in the preparation of solid dispersions in a single step.

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D. Complexation : Complexation is the reversible association between two or more molecules to form a nonbonded entity with a well defined stoichiometry . Complexation relies on relatively weak forces such as van-derwaal forces, hydrogen bonding and hydrophobic interactions.

Inclusion complexation : These are formed by the insertion of the nonpolar molecule or the nonpolar region of one molecule into the cavity of another molecule or group of molecules. The most commonly used host molecules are cyclodextrins . Cyclodextrins are non- reducing, crystalline , water soluble, cyclic, oligosaccharides. Cyclodextrins consist of glucose monomers arranged in a donut shape ring.

Inclusion complexation:

CYCLODEXTRIN

Hydrphobic

Hydrophillic

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The surface of the cyclodextrin molecules makes them water soluble, but the hydrophobic cavity provides a microenvironment for appropriately sized non-polar molecules. Based on the structure and properties of drug molecule it can form 1:1 or 1:2 drug cyclodextrin complex. Three naturally occurring CDs are α Cyclodextrin, β Cyclodextrin, and γ Cyclodextrin.

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Organic drug + water → Squeezed out by strong water-water interaction force.

Forms aggregates

Reduces the contact b/w nonpolar hydrocarbon moieties & the polar water molecule

Large nonpolar regions

Opposed by entropy

Random arrangement

Complexes stached can be homogeneous or mixed

Self association complexation

Staching complexation

Eg ., Nicotinamide,Anthracene,

Caffeine,Theobromine.

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E. Solubilization by surfactants: Surfactants are molecules withdistinct polar and nonpolar regions.Most surfactants consist of a hydrocarbon segment connected to a polar group. The polar group can be anionic, cationic, zwitter ionic or nonionic. The presence of surfactantsmay lower the surface tension and increase the solubility of the drug within an organic solvent .Microemulsion : A microemulsion is a four-component system composed of external phase, internal phase, surfactant and co surfactant . The addition of surfactant, which is predominately soluble in the internal phase unlike the co surfactant , results in the formation of an optically clear, isotropic, thermodynamically stable emulsion. It is termed as microemulsion because of the internal phase is <0.1 micron droplet diameter.

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The surfactant and the co surfactant alternate each other and form a mixed film at the interface, which contributes to the stability of the microemulsion . Non-ionic surfactants, such as Tweens ( polysorbates ) and Labrafil ( polyoxyethylated oleic glycerides ), with high hyrophile-lipophile balances are often used to ensure immediate formation of oil-in-water droplets during production. Advantages : Ease of preparation due to spontaneous formation. Thermodynamic stability, transparent and elegant appearance, enhanced penetration through the biological membranes, increased bioavailability and less inter- and intra-individual variability in drug pharmacokinetics.

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II. CHEMICAL MODIFICATIONS 1)By change of pH: For organic solutes that are ionizable, changing the pH of the system is the simplest and most effective means of increasing aqueous solubility .

LOWER pH UNIONISED FORM INSOLUBLE PPT

HIGHER pH IONISED FORM MORE SOLUBLE DRUG

Lower pH Ionized form More soluble drug

Higher pH UNIONISED FORM INSOLUBLE PPT

For weakly acidic drugs,

For weakly basic drugs,

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3) Derivatization : It is a technique used in chemistry which transforms a chemical compound into a product of similar chemical structure, called derivative. Derivatives have different solubility as that of adduct. It is used for quantification of adduct formation of esters and amides via acyl chlorides.

2) Use of buffer: Buffer maintains the pH of the solution overtime and it reduces or eliminate the potential for precipitation upon dilution. On dilution pH alteration occurs that decrease solubility . Change of pH by 1 fold increase solubility by 10 fold If it changes by one pH unit ,that decrease ionization of the drug and solubility decreases by 10 fold.

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1.Co-crystallization: A co-crystal may be defined as a crystalline material that consists of two or more molecular species held together by non-covalent forces. • Co-crystals are more stable, particularly as the co-crystallizing agents are solids at room temperature. • Co-crystals can be prepared by evaporation of a heteromeric solution or by grinding the components together. • Another technique for the preparation of co-crystals includes sublimation, growth from the melt, and slurry preparation.•Only three of the co-crystallizing agents are classified as generally recognised as safe (GRAS) it includes saccharin, nicotinamide and acetic acid limiting the pharmaceutical applications.

III. OTHER METHODS.

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2. Cosolvency : Cosolvents are prepared by mixing miscible or partially miscible solvents. Weak electrolytes and nonpolar molecules have poor water solubility and it can be improved by altering polarity of the solvent. It is well-known that the addition of an organic cosolvent to water can dramatically change the solubility of drugs. Cosolvent system works by reducing the interfacial tension between the aqueous solution and hydrophobic solute.

SOME PERANTRALPRODUCT THAT CONTAIN COSOLVENT 1.Diazepam - 10% ethanol + propylene glycol 2.Digoxin - 10% ethanol + propylene glycol

Aquous solvent - Etahnol, sorbitol, glycerin, propylene glycol.Non aquous solvent - glycerol dimethyl ketal, glycerol formal, glycofurol, dimethyl acetamide.

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3. Hydrotrophy : Hydrotrophy designate the increase in solubility in water due to the presence of large amount of additives. The mechanism by which it improves solubility is more closely related to complexation involving a weak interaction between the hydrotrophic agents (sodium benzoate, sodium acetate, sodium alginate, and urea).

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5. Selective adsorption on insoluble carriers: A highly active adsorbent such as inorganic clays like Bentonite can enhance the dissolution rate of poorly water-soluble drugs such as griseofulvin, indomethacin and prednisone by maintaining the concentration gradient at its maximum. 2 reasons suggested for rapid release of drugs from the surface of clays :- 1. weak physical bonding between adsorbate and adsorbent. 2. hydration and swelling of the clay in the aqueous media.

4. Solubilizing agents: The solubility of poorly soluble drug can also be improved by various solubilizing materials. PEG 400 is improving the solubility of hydrochlorthiazide85. Modified gum karaya (MGK), a recently developed excipient was evaluated as carrier for dissolution enhancement of poorly soluble drug, nimodipine .

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7. Use of soluble prodrug : Prodrug stratergy involves the incorporation of polar or ionizable moiety into the parent compound to improve aqueous solubility. Example : prodrug of established drugs has been successfully used to improve water solubility of corticosteroids benzodiazepines.

6. Solvent deposition: In this method, the poorly aqueous soluble drug such as Nifedipine is dissolved in an organic solvent like alcohol and deposited on an inert , hydrophilic, solid matrix such as starch or microcrystalline cellulose and evaporation of solvent is done.

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9. Precipitation: In this method, the poorly aqueous soluble drug such as cyclosporine is dissolved in a suitable organic solvent followed by its rapid mixing with a non-solvent to effect precipitation of drug in nano size particles. The product so prepared is also called as hydrosol. 10. Porous microparticle technology: The poorly water soluble drug is embedded in a microparticle having a porous, water soluble, sponge like matrix, dissolves wetting the drug and leaving a suspension of rapidly dissolving drug particles. These drug particles provide large surface area for increased dissolution rate . This is the core technology applied as HDDS.

8. Functional Polymer Technology : Functional polymer enhances the dissolution rate of poorly soluble drugs by avoiding the lattice energy of the drug crystal, which is the main barrier to rapid dissolution in aqueous media. The dissolution rate of poorly soluble , ionizable drug like cationic, anionic and amphoteric actives can be enhanced by this technology. Applied to heat sensitive materials and oils also.

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11. Nanotechnology approaches : For many new chemical entities of very low solubility ,oral bioavailability enhancement by micronization is not sufficient because micronized product has a tendency of agglomeration, which leads to decreased effective surface area for dissolution . Nanotechnology refers broadly to the study and use of materials and structures at the nanoscale level of approximately 100 nanometers (nm) or less .

NANOCRYSTAL: Size: 1-1000 nm Crystalline material with dimensions measured in nanometers. There are two distinct methods used for producing nanocrystals . 1 . bottom-up. 2. top-down . The top-down methods (i.e. Milling and High pressure homogenization ) start milling down from macroscopic level, e.g. from a powder that is micron sized. In bottom-up methods (i.e. Precipitation and Cryo -vacuum method), nanoscale materials are chemically composed from atomic and molecular components.

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NanoMorph : • The NanoMorph technology is to convert drug substances with low water-solubility from a coarse crystalline state into amorphous nanoparticles . •A suspension of drug substance in solvent is fed into a chamber, where it is rapidly mixed with another solvent. Immediately the drug substance suspension is converted into a true molecular solution. The admixture of an aqueous solution of a polymer induces precipitation of the drug substance. The polymer keeps the drug substance particles in their nanoparticulate state and prevents them from aggregation or growth. Using this technology the coarse crystalline drug substances are transformed into a nanodispersed amorphous state, without any physical milling or grinding procedures. It leads to the preparation of amorphous nanoparticles .

SOLUBILITY ANALYSIS

• Preformulation solubility studies focus on drug-solvent systems that could occur during the delivery of a drug candidate.

• Solubility is important for preparing solution which can be injected IV or IM OR drugs, which are unstable on contact with solvent.

• Analytical methods that are useful for solubility measurement include HPLC, GC, UV, and Fluoresence spectroscopy.

• Preformulation solubility studies usually include determinations of pka, temperature dependence, pH solubility profile, solubilization mechanisms, and rate of dissolution.

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pKa DeterminationsMany drugs are either weakly acidic or basic compounds. In

solution depending on the ph values, they exist as ionised or unionised species.

The unionised species are liquid soluble and hence more readily absorbed. The gastrointestinal absorption of weakly acidic or basic drugs depends on factors such as:

- fraction of drugs in unionised form, - pH at the site of absorption, - ionisation constant, - lipid solubility of the unionised species.The relative concentration of ionised and unionised form of weakly

acidic or basic drug in a solution can be calculated using Henderson Hesselbalch equation.

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• The stomach conditions are acidic in nature ranging in pH from 1-3, weakly acidic drugs are preferentially absorbed from the stomach. The ph of intestinal fluids ranges from 5-8, weakly basic compounds are absorbed from the intestine.

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Methods of determination of pKa :

1. Detection of spectral shifts by UV spectroscopy at various pH. Advantage: Dilute aqueous solutions can be analyzed by this

method.2. Potentiometric titration

Advantage: Maximum sensitivity for compounds with pKa in the range of 3

to 10.Disadvantage:

This method is unsuccessful for candidates where precipitation of the unionized forms occurs during titration. To prevent precipitation a co-solvent e.g. methanol or dimethylsulfoxide (DMSO) can be incorporated.

Effect of temperature

• The heat of solution, ΔHS, represents the heat released or absorbed when a mole of solute is dissolved in a large quantity of solvent. Most commonly, the solution process is endothermic, or ΔHs is positive, and thus increasing the solution temperature increases the drug solubility.

• Heat of solution can be determined from solubility values for saturated solutions equilibrated at controlled temperatures over the range of interest.

• Solvent systems involving cosolvents, micelles, and complexation have very different heats of solution in comparison to water.

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Partition coefficient

• The partition coefficient is defined as the ratio of un-ionised drug distributed between the organic and aqueous phases at equilibrium.

• Partition Coefficient (oil/ water) is a measure of a drug’s lipophilicity and an indication of its ability to cross cell membranes.

• Although partition coefficient data alone does not provide understanding of in vivo absorption, it does provide a means of characterizing the lipophilic/ hydrophilic nature of the drug.

• If P much greater than 1 are classified as lipophilic, whereas those with partition coefficient much less than 1 are indicative of a hydrophilic drug. 47

PO/W = (COIL/ CWATER)equilibrium

Dissolution • Dissolution of a drug particle is controlled by several

physicochemical properties, including chemical form, crystal habit, particle size, solubility, surface area, and wetting properties.

• The dissolution rate of a drug substance in which surface area is constant during dissolution is described by the modified Noyes-Whitney equation:

where D is the diffusion coefficient, h – diffusion layer at the solid-liquid interface, A – surface area of drug exposed to dissolution media, v – volume of media, CS – concentration of a saturated solution of the solute, C – concentration of drug in solution at time t dc/dt – dissolution rate.

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dc/dt = DA (CS – C) / hv

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4. Conclusion • Currently, only approximate estimates of the solubility of multifunctional and conformationally

flexible drug candidates are possible and these need to be supported by physical measurements which provide experimental ‘feedback’ on analogs in a particular class of compounds.

• A priori solubility estimation methods like Bodor's multi-parameter equation are the current best choice, but some of the required properties are not easily computed without a preliminary optimization of preferred conformations and good initial estimates. The accurate prediction of the solubility of complex multifunctional compounds at the moment still remains an elusive target.

• Oral activity prospects are improved through increased potency, but improvements in solubility or permeability can also achieve the same goal. Despite increasingly sophisticated formulation approaches, deficiencies in physico-chemical properties may represent the difference between failure and the development of a successful oral drug product.

REFERENCES

1. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 2012;64, Supplement:4-17.

2. Williams HD, Trevaskis NL, Charman SA, et al. Strategies to address low drug solubility in discovery and development. Pharmacological reviews 2013;65(1):315-499.

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solubilty of drugs in the perspective of medicinal and pharmaceutcal scientist