INTRODUCTION:

Solubility is defined as a solute i.e. solid, liquid and gases dissolve into solvent to form ahomogeneous solution at specific temperature and pressure. Solubility of a substance mainly depends on the solvent used as well as on temperature and pressure condition. The oral route of drug administration is the most preferred route of administration of drug due to convenience and ease of administration.₁Orally administered drug is completely absorbs only when they show good solubility in gastric medium and such drugs show good bioavailability.There are various methodsare available which can be becoming to improve solubility of poorly water soluble drug and to improve its bioavailability.

Bioavailability is affected by several other factors like drug solubility in aqueous environment and drug permeability through lipophilic membranes being the important ones. Mostly physical modification approach is used to enhance water solubility but chemical modification is also the great importance in solubility. Recently medicinal chemistry approach is also involving to increase water solubility of drug which include Lipinski rule of five, veber rule and quantitative structure activity relationship.USP and BP classify the solubility regardless of the solvent used, just only in terms of analysis and have defined the criteria as given in table 1.₂

Table 1: Solubility criteriaas per Indian Pharmacopoeia:

Descriptive Term	Parts of solvent required for part of solute
Very soluble	Less than 1
Freely soluble	From 1 to 10
Soluble	From 10 to 30
Sparingly soluble	From 30 to 100
Slightly soluble	From 100 to 1000
Very slightly soluble	From 1000 to 10,000
Practically insoluble, or Insoluble	10,000 or more

One of the important guideline for predicting the intestinal drug absorption provided by the U.S. F.D.A. is the BCS classification. The two parameters are involved in this system are solubility and interstitial permeability. The Biopharmaceutics Classification System has divided all the drugs in to four classes. As for BCS class II & IV drugs has a rate limiting step, so increasing the solubility in turn increase the bioavailability for BCS class II & IV drugs.₃

BCS Classification of drugs:

Class I- high solubility and high permeability

Class II- Low solubility and high permeability

Class III- high solubility and high permeability

Class IV- Low solubility and Low permeability

Procedure of Solubilisation:

Solubilisation process takes place as follows:

1 Breaking of intermolecular bonds in solute.

2 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.

It basically occurs in three steps:

1. Holes open in a solvent

2. Molecules of the solid breaks away from the bulk

3. The freed solid molecule is integrated into the hole in the solvent.⁴

Figure 1: procedure of solubilization

Need for solubility enhancement:

For good Drug absorption from the GI tract there is need of solubility enhancement. There are a various factors involve in poor aqueous solubility and poor membrane permeability of the drug.

Molecule when administered an active drugs by oral route it must freely soluble in gastric and/or intestinal fluids before it can permeate the membranes of the GIT to reach systemic circulation. Hence, two areas of research that focus on improving the oral bioavailability of active agents include; enhancing of solubility and dissolution rate of poorly water soluble drugs.₅

Factors affecting solubilisation:

1. Particle size: Particle size is inversely proportional to solubility. As particle size decreases, surface area increases thus increasing the solubility of the solute in the solvent.

2. Temperature: Increase in temperature increases solubility.

3. Pressure: Solids and liquid solutes have no effect of pressure. But for gaseous solutes increase in pressure increases solubility and decrease in pressure decreases solubility.

4. Molecular size: Solubility of the substance isdecreased with increase in molecular size and molecular weight. In case of organic molecules, due to increase in branching the solubility increases.

5. Polarity: Polarity follows ‘like begets like’ phenomena. It is similar that polar solutes will dissolve in polar solvents only. Similarly, non-polar solutes will dissolve in non-polar solvents.

6. Polymorphs: Polymorphs can vary in melting point. Generally polymorphs are made as the changes in the structure results in the change in its solubility.⁶

Importance of solubility:

The most convenient and commonly employed route of drug delivery is oral route due to its advantages as ease of administration, high patient compliance, cost effectiveness, least sterility constraints, and flexibility in the design of dosage form. Thus, many generic drug companies are inclined more to produce bioequivalent oral drug products. The major challenge with the design of oral dosage forms lies with their poor solubility. The oral solubility and bioavailability depends on several factors includingdrug permeability, dissolution rate, first-pass metabolism, pre systemic metabolism, and susceptibility to efflux mechanisms. The main cause for low bioavailability is attributed to poor solubility and low permeability. Solubility is an important aspect for other dosage forms like parenterals as well^7.

Techniques of solubility and bioavailability enhancement

The techniques of solubility enhancement are categorized as follows

Chemical modifications:

Salt formation:

In general, aqueous solubility is a function of chemical structure and salts represent the class of drugs that are most likely to attain the desired extend of solubility in water. salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. Salt of weak acid and weak base generally have much higher aqueous solubility than the free acid and base.₈ Example if the drug can be given as a salt the solubility and dissolution can be improved as with penicillin V. Novobiocin and tolbutamide were observed lower absorption compared to their respective sodium salts. The alkaloidal base is slightly soluble in water but if the PH of medium is reduced by addition of acid, the solubility of base increase. The reason for this is increase in solubility: as the pH continue to reduce, the base converted into salt, which is relatively more soluble in water example: atropine, bupivacaine etc. The solubility of slightly soluble acid is increase as the PH is increase by addition of alkali, the reason being that a salt is formed. Example– Aspirin, Barbiturates. Salt formation have some limitations like it is not feasible for neutral compounds, the salt be hygroscopic and conversion of salt to free base or acid form of the drug on surface of solid dosage form that prevents or retards drug release⁹.

Co-crystallization:

This is one of the new approach available for the enhancement of drug solubility. It includes application of co-crystals also referred as molecular complexes. If the solvent is an integral part of the network structure and forms at least two component crystals, then it may be termed as co-crystal. If the solvent does not participate directly in the network itself, as in open frameworkstructures, then it is termed as clatharate (inclusion complex).₁₀ A co-crystal may be defined as a crystalline material that consists of two or more molecular (and electrically neutral) species held together by noncovalent forces. These co-crystals are more stable, particularly as the co-crystallizing agents are solids at room temperature. Three of the co-crystallizing agents are classified as generally regarded as safe (GRAS) includes saccharin, nicotinamide, and acetic acid limiting the pharmaceutical applications.

Figure 2: Preparation of co-crystals

Co-solvency:

The solubility of poorly soluble drugs in water can be increased by mixing it with some water miscible solvent in which the drug is readily soluble. This process is known as co-solvency and the solvent used in combination are known as cosolvent.₇Co-solvent system works by reducing the interfacial tension between the aqueous solution and hydrophobic solute. It is also commonly known as solvent blending. There is a dramatic change in the solubility of drugs by addition of organic co-solvent into the water. The cosolvents are having hydrogen acceptor or donor groups with a small hydrocarbon region. The hydrophobic hydrocarbon region usually interferes with the hydrogen bonding network of water which consequently reduces the intermolecular attraction of water while the hydrophilic hydrogen bonds ensures water solubility. Co-solvent formulations of poorly soluble drugs can be administered orally and parenterally. Poorly soluble compounds which are lipophillic or highly crystalline that have a high solubility in the solvent mixture may be suited to a co-solvent approach. Dimethyl sulfoxide (DMSO) and dimethyl acetoamide (DMA) have been widely used as co-solvents because of their large solubilization capacity for poorly soluble drugs and their relatively low toxicity. Advantages: Simple and rapid to formulate and produce. Disadvantages: As with all excipients, the toxicity and tolerability related with the level of solvent administered has to be considered. Uncontrolled precipitation occurs upon dilution with aqueous media.₁₁

Advantages of Co-solvency:

1. Compared to other solubilisation approaches very high drug concentrations of poorly soluble compounds can be dissolved.

2. Co- Solvents can enhance the solubility of poorly soluble compounds several thousand times compared to the aqueous solubility of the drug alone. Weak electrolytes and nonpolar molecules have poor water solubility and it can be improved by altering polarity of the solvent.

3. It is Simple and rapid method to formulate and produce.

BUFFERS:

Buffers are practically used to simply maintain the pH ofthe system over time. For pH solubilized drugs, anotherpractical use of a buffer is to reduce or eliminate thepotential for precipitation of the drug upon dilution.₁₂ Selection of Buffer:

· In desired pH range the buffer must have adequate capacity.

· It must be biologically safe for the use intended.

· There should be no deleterious effect on the stability of the final product.

· It should permit the use of other excipients like flavoring or coloring agents.

A very small change in pH results in more drug going into the solution. So, by observing the pH solubility profile, it helps in selection of buffer for optimum pH range.

Poor water soluble drug may potentially dissolve in water by applying a pH change. To access the solubility of this approach, the buffer capacity and tolerability of the selected pH are important to consider. Solubilized excipients that increase environmental pH within the dosage form to a range higher than pKa of weekly acidic drugs increase the solubility of that drug, those excipients that act as alkalizing agents may increase the solubility of weekly basic drugs. Advantages of pH adjustment include Simple to formulate and analyse, Simple to produce and fast track.

Hydrotropy method:

In this method by adding large amount of secondary solute increase the aqueous solubility of water insoluble drug. Hydrotropes are the compounds having both an anionic group and a hydrophobic aromatic ring or ring system. Hydrotropic agents are basically ionic organic salts, consists of alkali metal salts of various organic acids. Several salts with large anions or cations that are themselves very soluble in water result in “salting in” of non electrolytes called “hydrotropic salts”; a phenomenon known as “hydrotropism.”₆₃The hydrophilicity increase by anionic group and the ring system interacts with the solute to be dissolved. The mechanism involved in hydrotropy is related to complexation which involves interaction between lipophilic drugs and the hydrotropic agents such as urea, nicotinamide, sodium alginate, sodium benzoate etc.Concentrated aqueous hydrotropic solutions of sodium benzoate, sodium salicylate, urea, nicotinamide, sodium citrate and sodium acetate have been observed to enhance the aqueous solubilities of many poorly water soluble drugs.₁₃

Advantages of hydrotropy method:

1. In the hydrotropy method solvent character is independent of pH, has high selectivity and does not require emulsification.

2. In this method simply mix the drug with the hydrotropes in water.

3. It does not require chemical modification of hydrophobic drugs, use of organic solvents, or preparation of emulsion system.

Molecular encapsulation with cyclodextrins:

The beta- and gamma- cyclodextrins and several of their derivatives are unique in having the ability to form molecular inclusion complexes with hydrophobic drugs having poor aqueous solubility. These bucket shaped oligosaccharides produced from starch are versatile in having a hydrophobic cavity of size suitable enough to accommodate the lipophilic drug as guests; the outside of the host molecule is relatively hydrophilic. Thus the molecularly encapsulated drug has greatly improved aqueous solubility and dissolution rate.

Disruption of molecular planarity and symmetry:

The solubility of a solid solute in water is dependent on two factors: the crystallinity of the solute and the ability of the solute to interact with water Therefore, disruption of crystal packing would be an alternative method for improving aqueous solubility. However, few chemical modifications focused on crystal packing have been reported. General strategy to decrease melting point and crystal packing would be extremely attractive to medicinal chemists. Molecular planarity and symmetry are known to influence crystal packing, and disruption of molecular planarity would be expected to decrease the efficiency of crystal packing and the melting point. Very recently, Lowering analyzed the drug and clinical candidate database and reported that an increase in the fraction of sp3 - hybridized carbons is associated with a decrease in melting point.18 Thus, the relationship between molecular planarity and melting point could provide the basis for a strategy to increase solubility. An example of the relationship between solubility and molecular planarity is provided by the case of polychlorinated biphenyls (PCBs).

Examples of improvement of aqueous solubility by disruption of molecular planarity and symmetry are as follows:

1. Removal of Aromaticity.

2. Increase of Dihedral Angle/Disruption of Molecular Symmetry

3. Increase of Dihedral Angle/Disruption of Molecular Symmetry

4. Twisting of Fused Rings

Hydrogen bond formation and ionization:

The solubility of drug molecule in water greatly affects the routes of administration that are available as well as its absorption, distribution and elimination. The key concepts to keep in mind when considering the water solubility of a molecule are the potential for hydrogen bond formation and ionization of one or more functional groups within the molecule.

· Hydrogen bond formation: functional groups that cannot from hydrogen bonds do not enhance hydrophilicity and will contribute to the hydrophobic nature of the molecule. As a general rule, the more hydrogen bonds that are possible between a drug molecule and water, the greater the water solubility of the molecule.

· Ionization: in addition to the hydrogen bonding capacity of the molecule another type of interaction plays an important role in determining water solubility: the ion-dipole interaction. This type of interaction can occur with organic salts. Ion-dipole interactions occur between either a cation and the partially negatively charged atom found in a permanent dipole or an anion and the partially positive charged atom found in permanent dipole. Low molecular weight salts are water soluble and high molecular weight salts are water insoluble. The extent to which ionized molecule are soluble in water is also dependent on the presence of intramolecular ionic intractions.

The aqueous solubilities of organic compounds Sw are very important in many research areas, such as pharmaceutical or environmental science. A confident prediction of the aqueous solubility of a compound could greatly assist drug design by avoiding the synthesis of unsuitable compounds.

Enhanced water solubility via the addition of polar functionalities:

The majority of parenteral prodrugs involve prodrug modifications whereby a polar, most often an ionizable promoiety, is utilized to increase water solubility. Many recent examples have focused on the use of the phosphate group either directly linked to the parent drug, where possible, or through a linker group such as formaldehyde. Prednisolone (R=R1=H) and methylprednisolone (R=CH3, R1=H) are poorly water soluble corticosteroid drugs. To permit aqueous injection or ophthalmic delivery of these drugs, they must be converted into water soluble forms. Prednisolone phosphate (R=H, R1=PO3Na2) is prescribed as a water soluble prodrug for prednisolone that is activated in vivo byphosphatases.

LIPINSKI'S RULE OF FIVE:

Lipinski's rule of five also known as the Pfizer's rule of five or simply the Rule of five (RO5) is a rule of thumb to evaluate drug likeness or determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans. Lipinski’s rule of five shown in figure:

Figure: Lipinsky rule of five

Lipinski’s rule states that, in general, an orally active drug has no more than one violation of the above criteria. The rule describes molecular properties important for a drug’s pharmacokinetics in the human body, including their absorption, distribution, metabolism, and excretion (“ADME”). However, the rule does not predict if a compound is pharmacologically active. If the drugs is poorly absorb and have lower permeability meansit doesn’t follow the Lipinski’s rule of five. Poorly absorption of drug due to less solubility. Solubility and absorption are related to each other. Both this parameter are improve in drug when it follow the rule of five.

VEBER RULES:

The results of an experiment performed by Veber D F et al. examining the oral bioavailability of potential drug candidates in the rat let to the conclusion that other parameters existed for the description of drug likeness than the Lipinski rules. The main parameter taken into account during this experiment was the number of rotatable bonds as an indication of molecular flexibility. They therefore suggest the following filter for drug-likeness: Rotatable bonds < 12, Polar surface area < 140. This rule are important in determination of bioavailability and solubility of drug. Also, Veber et al. (2002) therefore raise the issue of molecular weight being a proper descriptor for absorption measurement as molecular weight might just be positively correlated with more precise properties like the rotatable bonds count, polar surface area and hydrogen bonds count.

Quantitative structure property relationship: A. Shayanfar et al describes a simple quantitative structure property relationship (QSPR) model for predicting the aqueous solubility of drugs which is validated by cross-validation methods. A data set of 220 drug or drug like molecules as a train set was employed and the accuracy of the proposed QSPR model was compared with those of the general solubility equation (GSE) and the linear solvation energy relationship (LSER). The developed model is: logSw=-1.120E - 0.599ClogP, in which Sw is the molar aqueous solubility of a drug, E is the excess molar refraction and ClogP is the computed logarithm of partition coefficient of drug. Average absolute error (AAE) and mean percentage deviation (MPD) were used as comparison criteria. The proposed QSPR provided better AAE and MPD for solubility prediction in comparison with GSE and LSER models. Process of QSPR are as follows: Preparation of input data, 3D geometry optimization, Calculation of descriptor Stastical analysis, QSPR report and prediction.

Aqueous solubility is a physical property that has been extensively studied. As a property involving water as the solvent, it is important in a diverse array of situations including pharmaceutical, environmental, and industrial applications. The biological activity of a drug compound is affected by the ability of the drug to be transported and absorbed. Drug design, therefore, must take into account physical property information such as aqueous solubility as well as biological activity.1,2 The rate and extent of biodegradation is also affected by the aqueous solubility of organic compounds in the environment.3,4 There is no question that the ability to predict the aqueous solubility of compounds is useful. Many different methods have been developed for the estimation of aqueous solubility with varying success and applicability.1,17 Some recent developments include a neural network model relating aqueous solubility to topological descriptors, 1 the use of the mobile order solubility model, 2, 5 a clustering approach, 11 group contribution approaches, 3,9,13,15 and linear and neural network models based on semi empirical quantum chemical descriptors.

REFERENCES:

1. Lachman L, Lieberman H, and Kanig JL. The Theory AndPractise of Industrial Pharmacy, Special Indian Edition 2009, 221.

2. Indian pharmacopoeia, Government of India ministry of health and family welfare, published by the government of publication, Delhi; 1996, 2:1-7.

3. Wu C.Y., Benet L.S., Predicting drug disposition via application of BCS: Transport /Absorption elimination interplay & development of a biopharmaceutical drug disposition classification system. Pharmaceutical research, 2005, 22(1): 23-27.

4. Chaudhary A, Nagaich U, Gulati N, Sharma V K, Khosa RL, Enhancement of solubilization and bioavailability of poorly soluble drugs by physical and chemical modifications: Arecent review, Journal of Advanced Pharmacy Education & Research 2012,2 (1), 32-67.

5. Pawar AR, Choudhari PD, Novel Techniques For Solubility, Dissolution Rate andBioavailability Enhancement of Class II & IV drugs, Asian Journal of Biomedical pharmaceutical science 2012, 13, 9-14

6. James K., Solubility and related properties. 28: Marcel Dekker Inc., Newyork, 986, 127 – 397

7. Edward KH and D. Li, Solubility in Drug Like Properties: Concept, Structure, Design and methods from ADME to toxicity optimization Elsevier 2008,56: 15-25.

8. Seshadri, N. Small Molecule Pharmaceutics - Amgen Inc. Strategies to Impact Solubilityand Dissolution Rate during Drug Lead Optimization: Salt Selection and Prodrug Design Approaches. APR, 2004; 7: 108-113

9. E. Nelson, E.L. Knoechel, W.E. Hamlin, J.G. Wagner, Influence of absorption rate of tolbutamide on rate of decline of blood sugar levels in normal humans, J. Pharm. Sci. 51(1962), 509–514.

10. Blagden N, Matas M, Gavan P. T, York P. Crystal engineering of active pharmaceuticalingredients to improve solubility anddissolution rates, Advanced Drug Delivery Reviews2007¡ 10 May.

11. Amin K, Dannenfelser R M, Zielinski J, Wang B. Lyophilization of polyethyleneglycol mixtures. J. Pharm. Sci. 2004, 93:22442249

12. Limbachiya M, Agrawal M, Sapariya A, Soni S. Internationajournal of pharmaceutical research and development,4(04), 2012, 071-086.

13. Rasool A.A. et al, Solubility enhancement ofsome water-insoluble drugs in the presence of Nicotinamide and related compounds. Journal of Pharmaceutical Sciences, 2006, 80: 4; 387-393.

Received on 26.04.2019 Accepted on 05.05.2019

Asian J. Pharm. Tech. 2019; 9(2):141-146.

DOI: 10.5958/2231-5713.2019.00024.2